2024-03-28T14:30:12Z
https://eprints.whiterose.ac.uk/cgi/oai2
oai:eprints.whiterose.ac.uk:300
2014-06-04T20:21:01Z
7374617475733D707562
74797065733D61727469636C65
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/300/
Clinical features of a novel TIMP-3 mutation causing Sorsby's fundus dystrophy: implications for disease mechanism
Clarke, M.
Mitchell, K.W.
Goodship, J.
McDonnell, S.
Barker, M.D.
Griffiths, I.D.
McKie, N.
AIMS: To describe the phenotype in three family members affected by a novel mutation in the gene coding for the enzyme tissue inhibitor of metalloproteinase-3 (TIMP-3).
METHODS: Three members of the same family were seen with a history of nyctalopia and visual loss due to maculopathy. Clinical features were consistent with Sorsby's fundus dystrophy. Exon 5 of the gene coding for TIMP-3 was amplified by the polymerase chain reaction, single strand conformation polymorphism analysis undertaken and exon 5 amplicons were directly sequenced.
RESULTS: Onset of symptoms was in the third to fourth decade. Five of six eyes had geographic macular atrophy rather than neovascularisation as a cause for central visual loss. Peripheral retinal pigmentary disturbances were present. Scotopic ERGs were abnormal in all three. Mutation analysis showed a GT transversion in all three resulting in a premature termination codon, E139X, deleting most of the carboxy terminal domain of TIMP-3.
CONCLUSIONS: The patients described had a form of Sorsby's fundus dystrophy which fell at the severe end of the spectrum of this disease. Postulated disease mechanisms include deposition of dimerised TIMP-3 protein.
2001-12
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/300/1/barkermd1.pdf
Clarke, M., Mitchell, K.W., Goodship, J. et al. (4 more authors) (2001) Clinical features of a novel TIMP-3 mutation causing Sorsby's fundus dystrophy: implications for disease mechanism. British Journal of Ophthalmology, 85 (12). pp. 1429-1431. ISSN 1468-2079
http://bjo.bmjjournals.com/cgi/content/full/85/12/1429
doi:10.1136/bjo.85.12.1429
oai:eprints.whiterose.ac.uk:440
2014-06-05T07:59:03Z
7374617475733D707562
74797065733D61727469636C65
756E69743D536865666669656C64:536865666669656C642E5F5243:536865666669656C642E4B4252
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/440/
Localization of the Functional Domains of Human Tissue Inhibitor of Metalloproteinases-3 and the Effects of a Sorsby's Fundus Dystrophy Mutation
Langton, K.P.
Barker, M.D.
McKie, N.
A transient COS-7 cell expression system was used to
investigate the functional domain arrangement of tissue
inhibitor of metalloproteinases-3 (TIMP-3), specifically
to assess the contribution of the amino- and carboxylterminal
domains of the molecule to its matrix metalloproteinase
(MMP) inhibitory and extracellular matrix
(ECM) binding properties. Wild type TIMP-3 was entirely
localized to the ECM in both its glycosylated (27
kDa) and unglycosylated (24 kDa) forms. A COOH-terminally
truncated TIMP-3 molecule was found to be a non-
ECM bound MMP inhibitor, whereas a chimeric TIMP
molecule, consisting of the NH2-terminal domain of
TIMP-2 fused to the COOH-terminal domain of TIMP-3,
displayed ECM binding, albeit with a lower affinity than
the wild type TIMP-3 molecule. Thus the functional domain
arrangement of TIMP-3 is analogous to that seen in
TIMP-1 and -2, namely that the NH2-terminal domain is
responsible for MMP inhibition whereas the COOH-terminal
domain is most important in mediating the specific
functions of the molecule. A mutant TIMP-3 in
which serine 181 was changed to a cysteine, found in
Sorsby’s fundus dystrophy, a hereditary macular degenerative
disease, was also expressed in COS-7 cells. This
gave rise to an additional 48-kDa species (possibly a
TIMP-3 dimer) that retained its ability to inhibit MMPs
and localize to the ECM. These data favor the hypothesis
that the TIMP-3 mutations seen in Sorsby’s fundus dystrophy
contribute to disease progression by accumulation
of mutant protein rather than by the loss of functional
TIMP-3.
1998-07-03
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/440/1/barkermd3.pdf
Langton, K.P., Barker, M.D. and McKie, N. (1998) Localization of the Functional Domains of Human Tissue Inhibitor of Metalloproteinases-3 and the Effects of a Sorsby's Fundus Dystrophy Mutation. Journal of Biological Chemistry, 273 (27). pp. 16778-16781. ISSN 0021-9258
http://www.jbc.org/cgi/content/full/273/27/16778/
oai:eprints.whiterose.ac.uk:453
2014-06-05T18:41:30Z
7374617475733D707562
74797065733D61727469636C65
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/453/
A novel tissue inhibitor of metalloproteinases-3 mutation reveals a common molecular phenotype in sorsby's fundus dystrophy
Langton, K.P.
McKie, N.
Curtis, A.
Goodship, J.A.
Bond, P.M.
Barker, M.D.
Clarke, M.
Sorsby’s fundus dystrophy (SFD) is a dominantly inherited
degenerative disease of the retina that leads to
loss of vision in middle age. It has been shown to be
caused by mutations in the gene for tissue inhibitor of
metalloproteinases-3 (TIMP-3). Five different mutations
have previously been identified, all introducing an extra
cysteine residue into exon 5 (which forms part of the
C-terminal domain) of the TIMP-3 molecule; however,
the significance of these mutations to the disease phenotype
was unknown. In this report, we describe the
expression of several of these mutated genes, together
with a previously unreported novel TIMP-3 mutation
from a family with SFD that results in truncation of
most of the C-terminal domain of the molecule. Despite
these differences, all of these molecules are expressed
and exhibit characteristics of the normal protein, including
inhibition of metalloproteinases and binding to
the extracellular matrix. However, unlike wild-type
TIMP-3, they all form dimers. These observations, together
with the recent finding that expression of TIMP-3
is increased, rather than decreased, in eyes from patients
with SFD, provides compelling evidence that
dimerized TIMP-3 plays an active role in the disease
process by accumulating in the eye. Increased expression
of TIMP-3 is also observed in other degenerative
retinal diseases, including the more severe forms of agerelated
macular degeneration, the most common cause
of blindness in the elderly in developed countries. We
hypothesize that overexpression of TIMP-3 may prove to
be a critical step in the progression of a variety of degenerative
retinopathies.
2000-09-01
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/453/1/barkermd4.pdf
Langton, K.P., McKie, N., Curtis, A. et al. (4 more authors) (2000) A novel tissue inhibitor of metalloproteinases-3 mutation reveals a common molecular phenotype in sorsby's fundus dystrophy. Journal of Biological Chemistry, 275 (35). pp. 27027-27031. ISSN 0021-9258
http://www.jbc.org/cgi/content/full/275/35/27027
doi:10.1074/jbc.M909677199
oai:eprints.whiterose.ac.uk:461
2013-02-08T16:54:26Z
oai:eprints.whiterose.ac.uk:1077
2014-06-13T19:27:03Z
7374617475733D707562
74797065733D61727469636C65
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/1077/
Study protocol to investigate the effect of a lifestyle intervention on body weight, psychological health status and risk factors associated with disease recurrence in women recovering from breast cancer treatment
Saxton, J.M.
Daley, A.
Woodroofe, N.
Coleman, R.
Powers, H.
Mutrie, N.
Siddall, V.
Crank, H.
Background
Breast cancer survivors often encounter physiological and psychological problems related to their diagnosis and treatment that can influence long-term prognosis. The aim of this research is to investigate the effects of a lifestyle intervention on body weight and psychological well-being in women recovering from breast cancer treatment, and to determine the relationship between changes in these variables and biomarkers associated with disease recurrence and survival.
Methods/design
Following ethical approval, a total of 100 patients will be randomly assigned to a lifestyle intervention (incorporating dietary energy restriction in conjunction with aerobic exercise training) or normal care control group. Patients randomised to the dietary and exercise intervention will be given individualised healthy eating dietary advice and written information and attend moderate intensity aerobic exercise sessions on three to five days per week for a period of 24 weeks. The aim of this strategy is to induce a steady weight loss of up to 0.5 Kg each week. In addition, the overall quality of the diet will be examined with a view to (i) reducing the dietary intake of fat to ~25% of the total calories, (ii) eating at least 5 portions of fruit and vegetables a day, (iii) increasing the intake of fibre and reducing refined carbohydrates, and (iv) taking moderate amounts of alcohol. Outcome measures will include body weight and body composition, psychological health status (stress and depression), cardiorespiratory fitness and quality of life. In addition, biomarkers associated with disease recurrence, including stress hormones, estrogen status, inflammatory markers and indices of innate and adaptive immune function will be monitored.
Discussion
This research will provide valuable information on the effectiveness of a practical, easily implemented lifestyle intervention for evoking positive effects on body weight and psychological well-being, two important factors that can influence long-term prognosis in breast cancer survivors. However, the added value of the study is that it will also evaluate the effects of the lifestyle intervention on a range of biomarkers associated with disease recurrence and survival. Considered together, the results should improve our understanding of the potential role that lifestyle-modifiable factors could play in saving or prolonging lives.
2006-02-09
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/1077/1/bmc_1471-2407-6-35.pdf
Saxton, J.M., Daley, A., Woodroofe, N. et al. (5 more authors) (2006) Study protocol to investigate the effect of a lifestyle intervention on body weight, psychological health status and risk factors associated with disease recurrence in women recovering from breast cancer treatment. BMC Cancer, 6 (35). ISSN 1471-2407
http://www.biomedcentral.com/1471-2407/6/35
doi:10.1186/1471-2407-6-35
oai:eprints.whiterose.ac.uk:1099
2014-06-04T17:55:24Z
7374617475733D707562
74797065733D61727469636C65
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E435355
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E435355:536865666669656C642E534153
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/1099/
Role of tumour necrosis factor gene polymorphisms (-308 and -238) in breast cancer susceptibility and severity
Azmy, I.A.F.
Balasubramanian, S.P.
Wilson, A.G.
Stephenson, T.J.
Cox, A.
Brown, N.J.
Reed, M.W.R.
Introduction
Genetic polymorphisms in the promoter region of the tumour necrosis factor (TNF) gene can regulate gene expression and have been associated with inflammatory and malignant conditions. We have investigated two polymorphisms in the promoter of the TNF gene (-308 G>A and -238 G>A) for their role in breast cancer susceptibility and severity by means of an allelic association study.
Methods
Using a case–control study design, breast cancer patients (n = 709) and appropriate age-matched and sex-matched controls obtained from the Breast Screening Unit (n = 498) were genotyped for these TNF polymorphisms, using a high-throughput allelic discrimination method.
Results
Allele frequencies for both polymorphisms were similar in both breast cancer cases and controls. However, the -308 polymorphism was found to be associated with vascular invasion in breast tumours (P = 0.024). Comparison with other standard prognostic indices did not show any association for either genotype.
Conclusions
We demonstrated no association between the -308G>A polymorphism and the -238G>A polymorphism in the promoter region of TNF and susceptibility to breast cancer, in a large North European population. However, the -308 G>A polymorphism was found to be associated with the presence of vascular invasion in breast tumours.
2004-05-24
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/1099/1/bmc_bcr802.pdf
Azmy, I.A.F., Balasubramanian, S.P., Wilson, A.G. et al. (4 more authors) (2004) Role of tumour necrosis factor gene polymorphisms (-308 and -238) in breast cancer susceptibility and severity. Breast Cancer Research, 6 (4). R395 -R400. ISSN 1465-542X
http://breast-cancer-research.com/content/6/4/R395
doi:10.1186/bcr802
oai:eprints.whiterose.ac.uk:1563
2014-06-05T15:33:21Z
7374617475733D707562
74797065733D61727469636C65
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/1563/
Modelling the interactions between tumour cells and a blood vessel in a microenvironment within a vascular tumour
Breward, C.J.W.
Byrne, H.M.
Lewis, C.E.
In this paper, we develop a mathematical model to describe interactions between tumour cells and a compliant blood vessel that supplies oxygen to the region. We assume that, in addition to proliferating, the tumour cells die through apoptosis and necrosis. We also assume that pressure differences within the tumour mass, caused by spatial variations in proliferation and degradation, cause cell motion. We couple the behaviour of the blood vessel into the model for the oxygen tension. The model equations track the evolution of the densities of live and dead cells, the oxygen tension within the tumour, the live and dead cell speeds, the pressure and the width of the blood vessel. We present explicit solutions to the model for certain parameter regimes, and then solve the model numerically for more general parameter regimes. We show how the resulting steady-state behaviour varies as the key model parameters are changed. Finally, we discuss the biological implications of our work.
Cambridge University Press
2001-10
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/1563/1/lewisce1.pdf
Breward, C.J.W., Byrne, H.M. and Lewis, C.E. (2001) Modelling the interactions between tumour cells and a blood vessel in a microenvironment within a vascular tumour. European Journal of Applied Mathematics, 12 (5). pp. 529-556. ISSN 0956-7925
http://dx.doi.org/10.1017/S095679250100448X
doi:10.1017/S095679250100448X
oai:eprints.whiterose.ac.uk:1909
2014-06-05T08:51:46Z
oai:eprints.whiterose.ac.uk:2602
2014-06-06T05:17:47Z
7374617475733D707562
74797065733D61727469636C65
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/2602/
Anti-vascular agent Combretastatin A-4-P modulates Hypoxia Inducible Factor-1 and gene expression
Dachs, G.U.
Steele, A.J.
Coralli, C.
Kanthou, C.
Brooks, A.C.
Gunningham, S.P.
Currie, M.J.
Watson, A.I.
Robinson, B.A.
Tozer, G.M.
Background
A functional vascular network is essential for the survival, growth and spread of solid tumours, making blood vessels a key target for therapeutic strategies. Combretastatin A-4 phosphate (CA-4-P) is a tubulin-depolymerising agent in Phase II clinical trials as a vascular disrupting agent. Not much is known of the molecular effect of CA-4-P under tumour conditions. The tumour microenvironment differs markedly from that in normal tissue, specifically with respect to oxygenation (hypoxia). Gene regulation under tumour conditions is governed by hypoxia inducible factor 1 (HIF-1), controlling angiogenic and metastatic pathways.
Methods
We investigated the effect of CA-4-P on factors of the upstream and downstream signalling pathway of HIF-1 in vitro.
Results
CA-4-P treatment under hypoxia tended to reduce HIF-1 accumulation in a concentration-dependent manner, an effect which was more prominent in endothelial cells than in cancer cell lines. Conversely, CA-4-P increased HIF-1 accumulation under aerobic conditions in vitro. At these concentrations of CA-4-P under aerobic conditions, nuclear factor κB was activated via the small GTPase RhoA, and expression of the HIF-1 downstream angiogenic effector gene, vascular endothelial growth factor (VEGF-A), was increased.
Conclusion
Our findings advance the understanding of signal transduction pathways involved in the actions of the anti-vascular agent CA-4-P.
BioMed Central Ltd.
2006-12-07
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/2602/1/bmc-1471-2407-6-280.pdf
Dachs, G.U., Steele, A.J., Coralli, C. et al. (7 more authors) (2006) Anti-vascular agent Combretastatin A-4-P modulates Hypoxia Inducible Factor-1 and gene expression. BMC Cancer, 6 (Art. N). ISSN 1471-2407
http://dx.doi.org/10.1186/1471-2407-6-280
doi:10.1186/1471-2407-6-280
oai:eprints.whiterose.ac.uk:4819
2008-11-03T19:12:53Z
7374617475733D707562
74797065733D61727469636C65
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6E6F5F646F63756D656E74735F617661696C61626C65
https://eprints.whiterose.ac.uk/4819/
Pre-endoscopy serological testing for coeliac disease: evaluation of a
clinical decision tool
Hopper, A.D.
Cross, S.S.
Hurlstone, D.P.
McAlindon, M.E.
Lobo, A.J.
Hadjivassiliou, M.
Sloan, M.E.
Dixon, S.
Sanders, D.S.
Objective: To determine an effective diagnostic method of detecting all
cases of coeliac disease in patients referred for gastroscopy without
performing routine duodenal biopsy.
Design: An initial retrospective cohort of patients attending for
gastroscopy was analysed to derive a clinical decision toot that could
increase the detection of coeliac disease without performing routine
duodenal biopsy. The toot incorporated serology (measuring antibodies
to tissue transglutaminase) and stratifying patients according to their
referral symptoms (patients were classified as having a "high risk" or
"low risk" of coeliac disease). The decision tool was then tested on a
second cohort of patients attending for gastroscopy. In the second
cohort all patients had a routine duodenal biopsy and serology
performed.
Setting: Teaching hospital in Sheffield.
Participants: 2000 consecutive adult patients referred for gastroscopy
recruited prospectively.
Main outcome measure: Evaluation of a clinical decision toot using
patients' referral symptoms, tissue transglutaminase antibody results,
and duodenal biopsy results.
Results: No cases of coeliac disease were missed by the pre-endoscopy
testing algorithm. The prevalence of coeliac disease in patients
attending for endoscopy was 3.9% (77/2000, 95% confidence interval 3.1%
to 4.8%). The prevalence in the high risk and low risk groups was 9.6%
(71/739, 7.7% to 12.0%) and 0.5% (6/1261, 0.2% to 1.0%). The prevalence
of coeliac disease in patients who were negative for tissue
transglutaminase antibody was 0.4% (7/2000). The sensitivity,
specificity, positive predictive value, and negative predictive value
for a positive antibody result to diagnose coeliac disease was 90.9%,
90.9%, 28.6%, and 99.6%, respectively. Evaluation of the clinical
decision toot gave a sensitivity, specificity, positive predictive
value, and negative predictive value of 100%, 60.8%, 9.3%, and 100%,
respectively.
Conclusions: Pre-endoscopy serological testing in combination with
biopsy of high risk cases detected all cases of coeliac disease. The
use of this decision toot may enable the endoscopist to target patients
who need a duodenal biopsy.
BMJ Publishing
2007-04-07
Article
PeerReviewed
Hopper, A.D., Cross, S.S., Hurlstone, D.P. et al. (6 more authors) (2007) Pre-endoscopy serological testing for coeliac disease: evaluation of a clinical decision tool. BMJ, 334 (7596). p. 729. ISSN 0959-8146
http:dx.doi.org/10.1136/bmj.39133.668681.BE
doi:10.1136/bmj.39133.668681.BE
oai:eprints.whiterose.ac.uk:9014
2014-06-04T14:28:22Z
7374617475733D707562
74797065733D61727469636C65
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E444949
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/9014/
Optimizing the yield and utility of circulating cell-free DNA from plasma and serum
Xue, X.Y.
Teare, M.D.
Holen, I.
Zhu, Y.M.
Woll, P.J.
Background: Cell-free DNA (CFDNA) in the plasma/serum of patients with cancer demonstrates tumour-associated genetic alterations. offering possibilities for diagnosis, prognostication and disease monitoring. There is wide variation in the reported levels of CFDNA, associated with different methods used to collect, process and analyze blood samples. We therefore evaluated different aspects of laboratory protocols for the processing and purification of CFDNA in clinical studies.
Methods: We evaluated and compared the QlAamp kit and a Triton/Heat/Phenol protocol (THP) for CFDNA purification. Total CFDNA was quantified by PicoGreen assay and SYBR-Green real-time PCR assay was used to amplify specific genes to estimate the efficiency of different protocols.
Results: The efficiency of DNA extraction was 18.6% using the standard QlAamp protocol and 38.7% using the THP method (p<0.0001, unpaired t-test). A modified QlAamp protocol that included a proteinase incubation stage and elution volumes up to 300 mu l increased DNA yields, but was not as good as the THP method.
Conclusions: Blood samples should be kept at/or below room temperature (18 degrees C-22 degrees C) for no more than 2 h before plasma separation by double-spin. Because of its higher efficiency, low-cost and good-quality products, the THP protocol is preferred for extraction of CFDNA.
Elsevier
2009-06-27
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/9014/1/Woll_Optimizing.pdf
Xue, X.Y., Teare, M.D., Holen, I. et al. (2 more authors) (2009) Optimizing the yield and utility of circulating cell-free DNA from plasma and serum. Clinica Chimica Acta, 404 (2). pp. 100-104. ISSN 0009-8981
http://dx.doi.org/10.1016/j.cca.2009.02.018
10.1016/j.cca.2009.02.018
oai:eprints.whiterose.ac.uk:9604
2009-10-08T09:19:42Z
7374617475733D707562
74797065733D61727469636C65
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6E6F5F646F63756D656E74735F617661696C61626C65
https://eprints.whiterose.ac.uk/9604/
Endostatin gene variation and protein levels in breast cancer susceptibility and severity
Balasubramanian, S.
Cross, S.
Globe, J.
Cox, A.
Brown, N.
Reed, M.
BACKGROUND:
Endostatin is a potent endogenous anti-angiogenic agent which inhibits tumour growth. A non-synonymous coding polymorphism in the Endostatin gene is thought to affect Endostatin activity. We aimed to determine the role of this Endostatin polymorphism in breast cancer pathogenesis and any influence on serum Endostatin levels in healthy volunteers. Endostatin protein expression on a breast cancer micro array was also studied to determine any relationship to genotype and to breast cancer prognosis.
METHODS:
The 4349G > A (coding non-synonymous) polymorphism in exon 42 of the Endostatin gene was genotyped in approximately 846 breast cancer cases and 707 appropriate controls. In a separate healthy cohort of 57 individuals, in addition to genotyping, serum Endostatin levels were measured using enzyme linked immunosorbant assay (ELISA). A semi-quantitative assessment of Endostatin protein expression on immunostained tissue micro arrays (TMA) constructed from breast cancer samples of patients with genotype data was performed.
RESULTS:
The rare allele (A) was significantly associated with invasive breast cancers compared to non-invasive tumours (p = 0.03), but there was no association with tumour grade, nodal status, vascular invasion or overall survival. There was no association with breast cancer susceptibility. Serum Endostatin levels and Endostatin protein expression on the tissue micro array were not associated with genotype.
CONCLUSION:
The Endostatin 4349A allele is associated with invasive breast cancer. The Endostatin 4349G > A polymorphism however does not appear to be associated with breast cancer susceptibility or severity in invasive disease. By studying circulating levels and tumour Endostatin protein expression, we have shown that any influence of this polymorphism is unlikely to be through an effect on the levels of protein produced.
Biomed Central
2007-06
Article
NonPeerReviewed
Balasubramanian, S., Cross, S., Globe, J. et al. (3 more authors) (2007) Endostatin gene variation and protein levels in breast cancer susceptibility and severity. BMC Cancer, 7 (1). p. 107. ISSN 1471-2407
http://www.biomedcentral.com/1471-2407/7/107
doi:10.1186/1471-2407-7-107
oai:eprints.whiterose.ac.uk:9630
2009-10-01T13:03:17Z
7374617475733D707562
74797065733D61727469636C65
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6E6F5F646F63756D656E74735F617661696C61626C65
https://eprints.whiterose.ac.uk/9630/
Targeting the tumour microenvironment: denosumab, a new RANKL inhibitor
Coleman, R.E.
Bone is the most common site for metastasis and is of particular clinical importance in breast cancer, which is common and associated with a relatively long clinical course. Metastatic bone disease results from the interactions between cancer cells in the bone marrow microenvironment and normal bone cells rather than direct destruction by cancer cells. These growth factor and cytokine-mediated interactions typically lead to stimulation of both osteoclast and osteoblast function with uncoupling and imbalance in bone remodelling. This provides the rationale for bone-targeted therapies to reduce the risk of skeletal complications such as fracture, and to relieve bone pain. Additionally, bone-derived growth factors released from bone promote a fertile environment for the survival and proliferation of cancer cells, creating a vicious cycle of bone destruction. Receptor activator of NF-κB ligand (RANKL) is a key mediator in this process. Within the bone microenvironment, factors secreted by tumour cells stimulate stromal cells and osteoblasts to secrete RANKL, which binds to its cognate receptor RANK on the surface of precursor and mature osteoclasts. RANKL is a critical mediator of osteoclast differentiation, function, and survival.
Biomed Central
2009-06
Article
NonPeerReviewed
Coleman, R.E. (2009) Targeting the tumour microenvironment: denosumab, a new RANKL inhibitor. Breast Cancer Research, 11 (Suppl ). S16. ISSN 1465-5411
http://breast-cancer-research.com/content/11/S1/S16
doi:10.1186/bcr2277
oai:eprints.whiterose.ac.uk:9665
2009-10-08T09:48:12Z
7374617475733D707562
74797065733D61727469636C65
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6E6F5F646F63756D656E74735F617661696C61626C65
https://eprints.whiterose.ac.uk/9665/
Study Protocol: Randomised controlled trial to investigate the functional significance of marginal riboflavin status in young women in the UK (RIBOFEM)
Hill, M.H.E.
Mushtaq, S.
Williams, E.A.
Dainty, J.R.
Powers, H.J.
BACKGROUND:
The functional significance of moderate riboflavin deficiency as it is currently assessed is not well understood. Animal and human studies have suggested a role for riboflavin in the absorption and mobilisation of iron and as such may be important in maintaining haematological status. Recent National Diet and Nutrition Surveys in the United Kingdom have shown that young women in particular are at risk of moderate riboflavin deficiency and low iron status.
METHODS/DESIGN:
A randomised placebo controlled intervention trial was conducted to investigate the effect of riboflavin supplementation on various measures of haematological status in a group of moderately riboflavin deficient young women aged 19 to 25 years. Women who were low milk consumers were initially screened for riboflavin status as assessed by the erythrocyte glutathione reductase activation coefficient assay (EGRAC). One hundred and twenty three women with EGRAC values >1.40 were randomised to receive 2 mg, 4 mg riboflavin or placebo for 8 weeks. In addition 36 of these women were randomly allocated to an iron bioavailability study to investigate the effect of the intervention on the absorption or utilisation of iron using an established red cell incorporation technique.
DISCUSSION:
One hundred and nineteen women completed the intervention study, of whom 36 completed the bioavailability arm. Compliance was 96 ± 6% (mean ± SD). The most effective recruitment strategy for this gender and age group was e-communication (e-mail and website). The results of this study will clarify the functional significance of the current biochemical deficiency threshold for riboflavin status and will inform a re-evaluation of this biochemical threshold.
Biomed Central
2009-03
Article
NonPeerReviewed
Hill, M.H.E., Mushtaq, S., Williams, E.A. et al. (2 more authors) (2009) Study Protocol: Randomised controlled trial to investigate the functional significance of marginal riboflavin status in young women in the UK (RIBOFEM). BMC Public Health, 9 (1). p. 90. ISSN 1471-2458
http://www.biomedcentral.com/1471-2458/9/90
doi:10.1186/1471-2458-9-90
oai:eprints.whiterose.ac.uk:9747
2014-09-15T01:35:12Z
7374617475733D707562
74797065733D636F6E666572656E63655F6974656D
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6E6F5F646F63756D656E74735F617661696C61626C65
https://eprints.whiterose.ac.uk/9747/
Bevacizumab resistance in breast cancer: are neuropilins the key?
Staton, C.A.
Yang, Z.
Reed, M.W.R.
Brown, N.J.
During breast cancer growth and development, angiogenesis is triggered by the interaction between vascular endothelial growth factor (VEGF) and its receptors VEGF-R1 and VEGF-R2. In breast cancer, alternative VEGF receptors, the neuropilins (Np1 and Np2), are often upregulated and serve to augment the effects of VEGF-R1/VEGF-R2 binding and provide alternative signalling pathways. Recently, a humanized antibody, Bevacizumab (Bz), which prevents VEGF binding to VEGF-R1/VEGF-R2, in combination with chemotherapy demonstrated initial efficacy (increased progression-free survival) in breast cancer phase III clinical trials. Eventually, however, the tumours evade treatment control. This may be because neuropilins are not blocked by Bz and provide an alternative VEGF signalling pathway in breast cancer. Therefore the present study aims to evaluate the potential of enhancing efficacy of Bz treatment by simultaneously blocking VEGF–neuropilin binding.
2008-05
Conference or Workshop Item
NonPeerReviewed
Staton, C.A., Yang, Z., Reed, M.W.R. et al. (1 more author) (2008) Bevacizumab resistance in breast cancer: are neuropilins the key? In: Breast Cancer Research 2008, 13 May 2008, London, UK.
http://breast-cancer-research.com/content/10/S2/P75
oai:eprints.whiterose.ac.uk:9763
2016-11-18T17:09:47Z
oai:eprints.whiterose.ac.uk:10123
2013-02-08T16:59:32Z
7374617475733D707562
74797065733D61727469636C65
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/10123/
Functional image-based radiotherapy planning for non-small cell lung cancer: a simulation study
Bates, E.L.
Bragg, C.M.
Wild, J.M.
Hatton, M.Q.F.
Ireland, R.H.
Background and purpose: To investigate the incorporation of data from single-photon emission computed tomography (SPECT) or hyperpolarized helium-3 magnetic resonance imaging (He-3-MRI) into intensity-modulated radiotherapy (IMRT) planning for non-small cell lung cancer (NSCLC).
Material and methods: Seven scenarios were simulated that represent cases of NSCLC with significant functional lung defects. Two independent IMRT plans were produced for each scenario; one to minimise total lung volume receiving >= 20 Gy (V-20), and the other to minimise only the functional lung volume receiving >= 20 Gy (FV20). Dose-volume characteristics and a plan quality index related to planning target volume coverage by the 95% isodose (V-PTV95/FV20) were compared between anatomical and functional plans using the Wilcoxon signed ranks test.
Results: Compared to anatomical IMRT plans, functional planning reduced FV20 (median 2.7%, range 0.6-3.5%, p = 0.02), and total lung V-20 (median 1.5%, 0.5-2.7%, p = 0.02), with a small reduction in mean functional lung dose (median 0.4 Gy, 0-0.7 Gy, p = 0.03). There were no significant differences in target volume coverage or organ-at-risk doses. Plan quality index was improved for functional plans (median increase 1.4, range 0-11.8, p = 0.02).
Conclusions: Statistically significant reductions in FV20, V-20 and mean functional lung dose are possible when IMRT planning is supplemented by functional information derived from SPECT or He-3-MRI. (C) 2009 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 93 (2009) 32-36
Elsevier
2009-10
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/10123/1/Ireland1.pdf
Bates, E.L., Bragg, C.M., Wild, J.M. et al. (2 more authors) (2009) Functional image-based radiotherapy planning for non-small cell lung cancer: a simulation study. Radiotherapy and Oncology, 93 (1). pp. 32-36. ISSN 0167-8140
http://dx.doi.org/10.1016/j.radonc.2009.05.018
10.1016/j.radonc.2009.05.018
oai:eprints.whiterose.ac.uk:42710
2014-06-09T04:52:58Z
7374617475733D707562
74797065733D61727469636C65
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E444949
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/42710/
Sp1 acetylation is associated with loss of DNA binding at promoters associated with cell cycle arrest and cell death in a colon cell line
Waby, J.S.
Chirakkal, H.
Yu, C.W.
Griffiths, J.
Benson, R.S.P.
Bingle, C.D.
Corfe, B.M.
Butyrate, a known histone deacetylase inhibitor (HDACi) and product of fibre fermentation, is postulated to mediate the protective effect of dietary fibre against colon cancer. The transcription factor Sp1 is a target of acetylation and is known to be associated with class I HDACs, including HDAC1. Sp1 is a ubiquitous transcription factor and Sp1-regulated genes include those involved in cell cycle regulation, apoptosis and lipogenesis: all major pathways in cancer development. The only known acetylated residue of Sp1 is lysine703 which resides in the DNA binding domain. Here we show that acetylated Sp1 loses p21- and bak-promoter -binding function in vitro. Furthermore treatment with a panel of HDAC inhibitors showed clustering of activities for a subset of inhibitors, causing G2 cell cycle arrest, Sp1 acetylation, p21 and Bak over-expression, all with very similar EC50 concentrations. These HDACi activities were not distributed according to the molecular class of compound. In order to mimic loss of binding, an siRNA strategy was used to reduce Sp1 expression. This resulted in altered expression of multiple elements of the p53/p21 pathway. Taken together our data suggest a mechanistic model for the chemopreventive actions of butyrate in colon epithelial cells, and provide new insight into the differential activities some classes of HDAC inhibitors.
BioMed Central
2010-10-15
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/42710/1/Corfe_Sp1.pdf
Waby, J.S., Chirakkal, H., Yu, C.W. et al. (4 more authors) (2010) Sp1 acetylation is associated with loss of DNA binding at promoters associated with cell cycle arrest and cell death in a colon cell line. Molecular Cancer, 9. Art no.275. ISSN 1476-4598
http://dx.doi.org/10.1186/1476-4598-9-275
10.1186/1476-4598-9-275
oai:eprints.whiterose.ac.uk:42713
2014-06-09T06:44:04Z
7374617475733D707562
74797065733D61727469636C65
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/42713/
Butyrate suppresses expression of neuropilin I in colorectal cell lines through inhibition of Sp1 transactivation
Yu, D.C.W.
Waby, J.S.
Chirakkal, H.
Staton, C.A.
Corfe, B.M.
Background: Neuropilin is a transmembrane receptor for vascular endothelial growth factor (VEGF) and is expressed in normal endothelial cells and upregulated in cancer cells. Neuropilin-1 (NRP-1) has been shown to promote tumour cell migration and survival in colon cancer in response to VEGF binding. The expression profiles of neuropilins, associated co-receptors and known ligands have been mapped in three colorectal cell lines: Caco-2, HCT116 & HT29. We have previously shown that butyrate, a naturally occurring histone deacetylase inhibitor (HDACi) produced by fermentation of fibre in the colon, causes apoptosis of colon cancer cell lines.
Results: Here we demonstrate that butyrate down-regulates NRP-1 and VEGF at the mRNA and protein level in colorectal cancer cell lines. NRP-1 is a known transcriptional target of Sp1, whose activity is regulated by acetylation. NRP-1 down-regulation by butyrate was associated with decreased binding affinity of Sp1 for canonical Sp-binding sites in the NRP-1 promoter. siRNA-mediated knock-down of Sp1 implied that Sp1 may have strong DNA binding activity but weak transactivation potential.
Conclusion: The downregulation of the key apoptotic and angiogenesis regulator NRP-1 by butyrate suggests a novel contributory mechanism to the chemopreventive effect of dietary fibre.
BioMed Central
2010-10-15
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/42713/2/Corfe_Butyrate.pdf
Yu, D.C.W., Waby, J.S., Chirakkal, H. et al. (2 more authors) (2010) Butyrate suppresses expression of neuropilin I in colorectal cell lines through inhibition of Sp1 transactivation. Molecular Cancer, 9. Art no.276. ISSN 1476-4598
http://dx.doi.org/10.1186/1476-4598-9-276
10.1186/1476-4598-9-276
oai:eprints.whiterose.ac.uk:42899
2014-06-04T18:19:10Z
7374617475733D707562
74797065733D61727469636C65
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E444949
756E69743D536865666669656C64:536865666669656C642E464350:536865666669656C642E424953:536865666669656C642E424D53:536865666669656C642E47454E
756E69743D536865666669656C64:536865666669656C642E5F5243:536865666669656C642E47454E
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/42899/
Regulation of neutrophil senescence by microRNAs
Ward, J.R.
Heath, P.R.
Catto, J.W.
Whyte, M.K.B.
Milo, M.
Renshaw, S.A.
Neutrophils are rapidly recruited to sites of tissue injury or infection, where they protect against invading pathogens. Neutrophil functions are limited by a process of neutrophil senescence, which renders the cells unable to respond to chemoattractants, carry out respiratory burst, or degranulate. In parallel, aged neutrophils also undergo spontaneous apoptosis, which can be delayed by factors such as GMCSF. This is then followed by their subsequent removal by phagocytic cells such as macrophages, thereby preventing unwanted inflammation and tissue damage. Neutrophils translate mRNA to make new proteins that are important in maintaining functional longevity. We therefore hypothesised that neutrophil functions and lifespan might be regulated by microRNAs expressed within human neutrophils. Total RNA from highly purified neutrophils was prepared and subjected to microarray analysis using the Agilent human miRNA microarray V3. We found human neutrophils expressed a selected repertoire of 148 microRNAs and that 6 of these were significantly upregulated after a period of 4 hours in culture, at a time when the contribution of apoptosis is negligible. A list of predicted targets for these 6 microRNAs was generated from http://mirecords.biolead.org and compared to mRNA species downregulated over time, revealing 83 genes targeted by at least 2 out of the 6 regulated microRNAs. Pathway analysis of genes containing binding sites for these microRNAs identified the following pathways: chemokine and cytokine signalling, Ras pathway, and regulation of the actin cytoskeleton. Our data suggest that microRNAs may play a role in the regulation of neutrophil senescence and further suggest that manipulation of microRNAs might represent an area of future therapeutic interest for the treatment of inflammatory disease.
Public Library Science
2011-01
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/42899/1/Renshaw_Regulation.pdf
Ward, J.R., Heath, P.R., Catto, J.W. et al. (3 more authors) (2011) Regulation of neutrophil senescence by microRNAs. Plos One, 6 (1). Art no.e15810. ISSN 1932-6203
http://dx.doi.org/10.1371/journal.pone.0015810
10.1371/journal.pone.0015810
oai:eprints.whiterose.ac.uk:76229
2016-11-06T23:13:15Z
7374617475733D707562
74797065733D61727469636C65
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/76229/
Binocular visual acuity in intermittent exotropia: role of accommodative convergence.
Firth, A.Y.
Davis, H.
Horwood, A.M.
Elsevier Masson
2013-03-19
Article
PeerReviewed
text
en
cc_by_nc_nd_4
https://eprints.whiterose.ac.uk/76229/2/AJO%20letter%20Dec%2014%252C%202012.pdf
Firth, A.Y., Davis, H. and Horwood, A.M. (2013) Binocular visual acuity in intermittent exotropia: role of accommodative convergence. American Journal of Ophthalmology, 155 (4). pp. 776-777. ISSN 0002-9394
http://dx.doi.org/10.1016/j.ajo.2013.01.001
10.1016/j.ajo.2013.01.001
oai:eprints.whiterose.ac.uk:80404
2016-04-11T11:08:33Z
7374617475733D707562
74797065733D61727469636C65
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4E4555
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
756E69743D536865666669656C64:536865666669656C642E535448
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/80404/
Angiogenesis is associated with the onset of hyperplasia in human ductal breast disease
Bluff, J.E.
Menakuru, S.R.
Cross, S.S.
Higham, S.E.
Balasubramanian, S.P.
Brown, N.J.
Reed, M.W.
Staton, C.A.
BACKGROUND: The precise timing of the angiogenic switch and the role of angiogenesis in the development of breast malignancy is currently unknown. METHODS: Therefore, the expression of CD31 (pan endothelial cells (ECs)), endoglin (actively proliferating ECs), hypoxia-inducible factor-1 (HIF-1alpha), vascular endothelial growth factor-A (VEGF) and tissue factor (TF) were quantified in 140 surgical specimens comprising normal human breast, benign and pre-malignant hyperplastic tissue, in situ and invasive breast cancer specimens. RESULTS: Significant increases in angiogenesis (microvessel density) were observed between normal and benign hyperplastic breast tissue (P<0.005), and between in situ and invasive carcinomas (P<0.0005). In addition, significant increases in proliferating ECs were observed in benign hyperplastic breast compared with normal breast (P<0.05) cancers and in invasive compared with in situ cancers (P<0.005). Hypoxia-inducible factor-1alpha, VEGF and TF expression were significantly associated with increases in both angiogenesis and proliferating ECs (P<0.05). Moreover, HIF-1alpha was expressed by 60-75% of the hyperplastic lesions, and a significant association was observed between VEGF and TF in ECs (P<0.005) and invasive tumour cells (P<0.01). CONCLUSIONS: These findings are the first to suggest that the angiogenic switch, associated with increases in HIF-1alpha, VEGF and TF expression, occurs at the onset of hyperplasia in the mammary duct, although the greatest increase in angiogenesis occurs with the development of invasion.
Cancer Research UK
2009-08-18
Article
PeerReviewed
text
en
cc_by_nc_sa_3
https://eprints.whiterose.ac.uk/80404/1/Angiogenesis%20is%20associated%20with%20the%20onset%20of%20hyperplasia%20in%20human%20ductal%20breast%20disease..pdf
Bluff, J.E., Menakuru, S.R., Cross, S.S. orcid.org/0000-0003-2044-1754 <https://orcid.org/0000-0003-2044-1754> et al. (5 more authors) (2009) Angiogenesis is associated with the onset of hyperplasia in human ductal breast disease. British Journal of Cancer, 101 (4). pp. 666-672. ISSN 0007-0920
http://dx.doi.org/10.1038/sj.bjc.6605196
10.1038/sj.bjc.6605196
oai:eprints.whiterose.ac.uk:80632
2016-05-03T11:11:58Z
7374617475733D707562
74797065733D61727469636C65
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
756E69743D536865666669656C64:536865666669656C642E535448
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/80632/
Treatment related morbidity in differentiated thyroid cancer-a survey of clinicians.
Edafe, O.
Wadsley, J.
Harrison, B.J.
Balasubramanian, S.P.
Background: Differentiated thyroid cancer (DTC) has excellent long term survival in most patients. Long-term treatment related morbidity is therefore important, but may not be well characterised. The aim of this study was to conduct an electronic survey of clinicians involved in the care of patients with DTC to determine their views on treatment related morbidity. Methods: A nine item questionnaire was developed, piloted locally and sent by email to members of three United Kingdom (UK) medical organisations (Thyroid Cancer Forum, British Association of Endocrine and Thyroid Surgeons, British Thyroid Association). Results: 125 responses were received. Less than 5% of respondents had a formal protocol to detect morbidity associated with TSH suppression. Over 50% agreed that morbidity from TSH suppression is not well defined. The majority of responders also agreed that the long-term morbidity of hypocalcaemia, significant voice change and TSH suppression in DTC are not well characterised. Physicians perceived treatment related morbidity to be a bigger problem than surgeons (P = 0.019). Conclusion: Clinicians treating thyroid cancer agree that long-term treatment related morbidity from DTC is not well characterised. A study of the prevalence and severity of treatment related morbidity and its impact on health of patients with DTC is warranted.
BioMed Central
2014-03-11
Article
PeerReviewed
text
en
cc_by_4
https://eprints.whiterose.ac.uk/80632/1/Treatment%20related%20morbidity%20in%20differentiated%20thyroid%20cancer-a%20survey%20of%20clinicians..pdf
Edafe, O., Wadsley, J., Harrison, B.J. et al. (1 more author) (2014) Treatment related morbidity in differentiated thyroid cancer-a survey of clinicians. Thyroid Research, 7 (3). ISSN 1756-6614
http://dx.doi.org/10.1186/1756-6614-7-3
10.1186/1756-6614-7-3
oai:eprints.whiterose.ac.uk:80638
2023-06-23T21:41:49Z
7374617475733D707562
74797065733D61727469636C65
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
756E69743D536865666669656C64:536865666669656C642E535448
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/80638/
Systematic Review of the Use of Dried Blood Spots for Monitoring HIV Viral Load and for Early Infant Diagnosis
Smit, P.W.
Sollis, K.A.
Fiscus, S.
Ford, N.
Vitoria, M.
Essajee, S.
Barnett, D.
Cheng, B.
Crowe, S.M.
Denny, T.
Landay, A.
Stevens, W.
Habiyambere, V.
Perriens, J.H.
Peeling, R.W.
Background
Dried blood spots (DBS) have been used as alternative specimens to plasma to increase access to HIV viral load (VL) monitoring and early infant diagnosis (EID) in remote settings. We systematically reviewed evidence on the performance of DBS compared to plasma for VL monitoring and EID.
Methods and Findings
Thirteen peer reviewed HIV VL publications and five HIV EID papers were included. Depending on the technology and the viral load distribution in the study population, the percentage of DBS samples that are within 0.5 log of VL in plasma ranged from 52–100%. Because the input sample volume is much smaller in a blood spot, there is a risk of false negatives with DBS. Sensitivity of DBS VL was found to be 78–100% compared to plasma at VL below 1000 copies/ml, but this increased to 100% at a threshold of 5000 copies/ml. Unlike a plasma VL test which measures only cell free HIV RNA, a DBS VL also measures proviral DNA as well as cell-associated RNA, potentially leading to false positive results when using DBS. The systematic review showed that specificity was close to 100% at DBS VL above 5000 copies/ml, and this threshold would be the most reliable for predicting true virologic failure using DBS. For early infant diagnosis, DBS has a sensitivity of 100% compared to fresh whole blood or plasma in all studies.
Conclusions
Although limited data are available for EID, DBS offer a highly sensitive and specific sampling strategy to make viral load monitoring and early infant diagnosis more accessible in remote settings. A standardized approach for sampling, storing, and processing DBS samples would be essential to allow successful implementation.
Trial Registration
PROSPERO Registration #: CRD42013003621.
Public Library of Science
2014-03-06
Article
PeerReviewed
text
en
cc_by_4
https://eprints.whiterose.ac.uk/80638/1/Systematic%20review%20of%20the%20use%20of%20dried%20blood%20spots%20for%20monitoring%20HIV%20viral%20load%20and%20for%20early%20infant%20diagnosis..pdf
Smit, P.W., Sollis, K.A., Fiscus, S. et al. (12 more authors) (2014) Systematic Review of the Use of Dried Blood Spots for Monitoring HIV Viral Load and for Early Infant Diagnosis. PLoS ONE, 9 (3). ARTN e86461. ISSN 1932-6203
http://dx.doi.org/10.1371/journal.pone.0086461
10.1371/journal.pone.0086461
oai:eprints.whiterose.ac.uk:80639
2016-07-28T08:50:16Z
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https://eprints.whiterose.ac.uk/80639/
Systematic Review of the Performance of HIV Viral Load Technologies on Plasma Samples
Sollis, K.A.
Smit, P.W.
Fiscus, S.
Ford, N.
Vitoria, M.
Essajee, S.
Barnett, D.
Cheng, B.
Crowe, S.M.
Denny, T.
Landay, A.
Stevens, W.
Habiyambere, V.
Perrins, J.
Peeling, R.W.
Background
Viral load (VL) monitoring is the standard of care in developing country settings for detecting HIV treatment failure. Since 2010 the World Health Organization has recommended a phase-in approach to VL monitoring in resource-limited settings. We conducted a systematic review of the accuracy and precision of HIV VL technologies for treatment monitoring.
Methods and Findings
A search of Medline and Embase was conducted for studies evaluating the accuracy or reproducibility of commercially available HIV VL assays. 37 studies were included for review including evaluations of the Amplicor Monitor HIV-1 v1.5 (n = 25), Cobas TaqMan v2.0 (n = 11), Abbott RealTime HIV-1 (n = 23), Versant HIV-1 RNA bDNA 3.0 (n = 15), Versant HIV-1 RNA kPCR 1.0 (n = 2), ExaVir Load v3 (n = 2), and NucliSens EasyQ v2.0 (n = 1). All currently available HIV VL assays are of sufficient sensitivity to detect plasma virus levels at a lower detection limit of 1,000 copies/mL. Bias data comparing the Abbott RealTime HIV-1, TaqMan v2.0 to the Amplicor Monitor v1.5 showed a tendency of the Abbott RealTime HIV-1 to under-estimate results while the TaqMan v2.0 overestimated VL counts. Compared to the Amplicor Monitor v1.5, 2–26% and 9–70% of results from the Versant bDNA 3.0 and Abbott RealTime HIV-1 differed by greater than 0.5log10. The average intra and inter-assay variation of the Abbott RealTime HIV-1 were 2.95% (range 2.0–5.1%) and 5.44% (range 1.17–30.00%) across the range of VL counts (2log10–7log10).
Conclusions
This review found that all currently available HIV VL assays are of sufficient sensitivity to detect plasma VL of 1,000 copies/mL as a threshold to initiate investigations of treatment adherence or possible treatment failure. Sources of variability between VL assays include differences in technology platform, plasma input volume, and ability to detect HIV-1 subtypes. Monitoring of individual patients should be performed on the same technology platform to ensure appropriate interpretation of changes in VL.
Prospero registration # CD42013003603.
Public Library of Science
2014-02-18
Article
PeerReviewed
text
en
cc_by_4
https://eprints.whiterose.ac.uk/80639/1/Systematic%20review%20of%20the%20performance%20of%20HIV%20viral%20load%20technologies%20on%20plasma%20samples..pdf
Sollis, K.A., Smit, P.W., Fiscus, S. et al. (12 more authors) (2014) Systematic Review of the Performance of HIV Viral Load Technologies on Plasma Samples. PLoS ONE, 9 (2). ARTN e85869. ISSN 1932-6203
http://dx.doi.org/10.1371/journal.pone.0085869
10.1371/journal.pone.0085869
oai:eprints.whiterose.ac.uk:80773
2023-06-23T21:41:59Z
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https://eprints.whiterose.ac.uk/80773/
Acute In Vivo Response to an Alternative Implant for Urogynecology
Regueros, S.R.
Albersen, M.
Manodoro, S.
Zia, S.
Osman, N.I.
Bullock, A.J.
Chapple, C.R.
Deprest, J.
MacNeil, S.
Purpose. To investigate in vivo the acute host response to an alternative implant designed for the treatment of stress urinary incontinence (SUI) and pelvic organ prolapse (POP).
Methods. A biodegradable scaffold was produced from poly-L-lactic acid (PLA) using the electrospinning technique. Human and rat adipose-derived stem cells (ADSCs) were isolated and characterized by fluorescence-activated cell sorting and differentiation assays. PLA scaffolds were seeded and cultured for 2 weeks with human or rat ADSCs. Scaffolds with and without human or rat ADSCs were implanted subcutaneously on the abdominal wall of rats. After 3 and 7 days, 6 animals from each group were sacrificed. Sections from each sample were analyzed by Haematoxylin and Eosin staining, Sirius red staining, and immunohistochemistry for CD68, PECAM-1, and collagen I and III.
Results. Animals responded to the scaffolds with an acute macrophage response. After 7 days of implantation, there was extensive host cell penetration, new blood vessel formation, and new collagen deposition throughout the full thickness of the samples without obvious differences between cell-containing and cell-free scaffolds.
Conclusions. The acute in vivo response to an alternative implant (both with and without cells) for the treatment of SUI and POP showed good acute integration into the host tissues.
Hindawi Publishing Corporation
2014-07-17
Article
PeerReviewed
text
en
cc_by_3
https://eprints.whiterose.ac.uk/80773/7/Acute%20in%20vivo%20response%20to%20an%20alternative%20implant%20for%20urogynecology.pdf
Regueros, S.R., Albersen, M., Manodoro, S. et al. (6 more authors) (2014) Acute In Vivo Response to an Alternative Implant for Urogynecology. BioMed Research International, 2014. 853610. ISSN 2314-6133
http://dx.doi.org/10.1155/2014/853610
10.1155/2014/853610
oai:eprints.whiterose.ac.uk:81939
2023-06-23T21:43:19Z
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https://eprints.whiterose.ac.uk/81939/
Central Pain Processing in Chronic Chemotherapy-Induced Peripheral Neuropathy: A Functional Magnetic Resonance Imaging Study
Boland, E.G.
Selvarajah, D.
Hunter, M.
Ezaydi, Y.
Tesfaye, S.
Ahmedzai, S.H.
Snowden, J.A.
Wilkinson, I.D.
Life expectancy in multiple myeloma has significantly increased. However, a high incidence of chemotherapy induced
peripheral neuropathy (CIPN) can negatively influence quality of life during this period. This study applied functional
magnetic resonance imaging (fMRI) to compare areas associated with central pain processing in patients with multiple
myeloma who had chemotherapy induced peripheral neuropathy (MM-CIPN) with those from healthy volunteers (HV).
Twenty-four participants (n = 12 MM-CIPN, n = 12 HV) underwent Blood Oxygen Level-Dependent (BOLD) fMRI at 3T whilst
noxious heat-pain stimuli were applied to the foot and then thigh. Patients with MM-CIPN demonstrated greater activation
during painful stimulation in the precuneus compared to HV (p = 0.014, FWE-corrected). Patients with MM-CIPN exhibited
hypo-activation of the right superior frontal gyrus compared to HV (p = 0.031, FWE-corrected). Significant positive
correlation existed between the total neuropathy score (reduced version) and activation in the frontal operculum (close to
insular cortex) during foot stimulation in patients with MM-CIPN (p = 0.03, FWE-corrected; adjusted R2
= 0.87). Painful stimuli
delivered to MM-CIPN patients evoke differential activation of distinct cortical regions, reflecting a unique pattern of central
pain processing compared with healthy volunteers. This characteristic activation pattern associated with pain furthers the
understanding of the pathophysiology of painful chemotherapy induced peripheral neuropathy. Functional MRI provides a
tool for monitoring cerebral changes during anti-cancer and analgesic treatment.
Public Library of Science
2014-05-12
Article
PeerReviewed
text
en
cc_by_4
https://eprints.whiterose.ac.uk/81939/1/Central%20pain%20processing%20in%20chronic%20chemotherapy-induced%20peripheral%20neuropathy%3A%20a%20functional%20magnetic%20resonance%20imaging%20study..pdf
Boland, E.G., Selvarajah, D. orcid.org/0000-0001-7426-1105 <https://orcid.org/0000-0001-7426-1105>, Hunter, M. et al. (5 more authors) (2014) Central Pain Processing in Chronic Chemotherapy-Induced Peripheral Neuropathy: A Functional Magnetic Resonance Imaging Study. PLOS ONE, 9 (5). e96474. ISSN 1932-6203
http://dx.doi.org/10.1371/journal.pone.0096474
10.1371/journal.pone.0096474
oai:eprints.whiterose.ac.uk:81940
2017-02-08T12:35:48Z
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https://eprints.whiterose.ac.uk/81940/
Interleukin-7 deficiency in rheumatoid arthritis: consequences for therapy-induced lymphopenia
Ponchel, F.
Verburg, R.J.
Bingham, S.J.
Brown, A.K.
Moore, J.
Protheroe, A.
Short, K.
Lawson, C.A.
Morgan, A.W.
Quinn, M.
Buch, M.
Field, S.L.
Maltby, S.L.
Masurel, A.
Douglas, S.H.
Straszynski, L.
Fearon, U.
Veale, D.J.
Patel, P.
McGonagle, D.
Snowden, J.
Markham, A.F.
Ma, D.
van Laar, J.M.
Papadaki, H.A.
Emery, P.
Isaacs, J.D.
We previously demonstrated prolonged, profound CD4+ T-lymphopenia in rheumatoid arthritis (RA) patients following lymphocyte-depleting therapy. Poor reconstitution could result either from reduced de novo T-cell production through the thymus or from poor peripheral expansion of residual T-cells. Interleukin-7 (IL-7) is known to stimulate the thymus to produce new T-cells and to allow circulating mature T-cells to expand, thereby playing a critical role in T-cell homeostasis. In the present study we demonstrated reduced levels of circulating IL-7 in a cross-section of RA patients. IL-7 production by bone marrow stromal cell cultures was also compromised in RA. To investigate whether such an IL-7 deficiency could account for the prolonged lymphopenia observed in RA following therapeutic lymphodepletion, we compared RA patients and patients with solid cancers treated with high-dose chemotherapy and autologous progenitor cell rescue. Chemotherapy rendered all patients similarly lymphopenic, but this was sustained in RA patients at 12 months, as compared with the reconstitution that occurred in cancer patients by 3–4 months. Both cohorts produced naïve T-cells containing T-cell receptor excision circles. The main distinguishing feature between the groups was a failure to expand peripheral T-cells in RA, particularly memory cells during the first 3 months after treatment. Most importantly, there was no increase in serum IL-7 levels in RA, as compared with a fourfold rise in non-RA control individuals at the time of lymphopenia. Our data therefore suggest that RA patients are relatively IL-7 deficient and that this deficiency is likely to be an important contributing factor to poor early T-cell reconstitution in RA following therapeutic lymphodepletion. Furthermore, in RA patients with stable, well controlled disease, IL-7 levels were positively correlated with the T-cell receptor excision circle content of CD4+ T-cells, demonstrating a direct effect of IL-7 on thymic activity in this cohort.
BioMed Central
2004-11-16
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/81940/7/Interleukin-7%20deficiency%20in%20rheumatoid%20arthritis%3A%20consequences%20for%20therapy-induced%20lymphopenia.pdf
Ponchel, F., Verburg, R.J., Bingham, S.J. et al. (24 more authors) (2004) Interleukin-7 deficiency in rheumatoid arthritis: consequences for therapy-induced lymphopenia. Arthritis Research & Therapy, 7 (1). R80-R92. ISSN 1478-6354
https://dx.doi.org/10.1186/ar1452
10.1186/ar1452
oai:eprints.whiterose.ac.uk:81941
2017-02-08T12:36:24Z
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Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation
Snowden, J.A.
Saccardi, R.
Allez, M.
Ardizzone, S.
Arnold, R.
Cervera, R.
Denton, C.
Hawkey, C.
Labopin, M.
Mancardi, G.
Martin, R.
Moore, J.J.
Passweg, J.
Peters, C.
Rabusin, M.
Rovira, M.
van Laar, J.M.
Farge, D.
ADWP, E.
PDWP
In 1997, the first consensus guidelines for haematopoietic SCT (HSCT) in autoimmune diseases (ADs) were published, while an international coordinated clinical programme was launched. These guidelines provided broad principles for the field over the following decade and were accompanied by comprehensive data collection in the European Group for Blood and Marrow Transplantation (EBMT) AD Registry. Subsequently, retrospective analyses and prospective phase I/II studies generated evidence to support the feasibility, safety and efficacy of HSCT in several types of severe, treatment-resistant ADs, which became the basis for larger-scale phase II and III studies. In parallel, there has also been an era of immense progress in biological therapy in ADs. The aim of this document is to provide revised and updated guidelines for both the current application and future development of HSCT in ADs in relation to the benefits, risks and health economic considerations of other modern treatments. Patient safety considerations are central to guidance on patient selection and HSCT procedural aspects within appropriately experienced and Joint Accreditation Committee of International Society for Cellular Therapy and EBMT accredited centres. A need for prospective interventional and non-interventional studies, where feasible, along with systematic data reporting, in accordance with EBMT policies and procedures, is emphasized.
Nature Publishing Group
2012-06
Article
PeerReviewed
text
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cc_by_nc_nd_3
https://eprints.whiterose.ac.uk/81941/7/Haematopoietic%20SCT%20in%20severe%20autoimmune%20diseases%3A%20updated%20guidelines%20of%20the%20European%20Group%20for%20Blood%20and%20Marrow%20Transplantation.pdf
Snowden, J.A., Saccardi, R., Allez, M. et al. (17 more authors) (2012) Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplantation, 47 (6). pp. 770-790. ISSN 0268-3369
https://dx.doi.org/10.1038/bmt.2011.185
10.1038/bmt.2011.185
oai:eprints.whiterose.ac.uk:81942
2016-03-03T11:46:33Z
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https://eprints.whiterose.ac.uk/81942/
Follow-up care for cancer survivors: the views of clinicians
Greenfield, D.M.
Absolom, K.
Eiser, C.
Walters, S.J.
Michel, G.
Hancock, B.W.
Snowden, J.A.
Coleman, R.E.
Late Effects Grp
Nature Publishing Group
2009-08-11
Article
PeerReviewed
text
en
cc_by_nc_sa_3
https://eprints.whiterose.ac.uk/81942/1/Follow-up%20care%20for%20cancer%20survivors%3A%20the%20views%20of%20clinicians..pdf
Greenfield, D.M., Absolom, K., Eiser, C. et al. (6 more authors) (2009) Follow-up care for cancer survivors: the views of clinicians. British Journal of Cancer, 101 (4). pp. 568-574. ISSN 0007-0920
http://dx.doi.org/10.1038/sj.bjc.6605160
10.1038/sj.bjc.6605160
oai:eprints.whiterose.ac.uk:81943
2016-03-03T11:37:28Z
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https://eprints.whiterose.ac.uk/81943/
Follow-up care for cancer survivors: views of the younger adult
Absolom, K.
Eiser, C.
Michel, G.
Walters, S.J.
Hancock, B.W.
Coleman, R.E.
Snowden, J.A.
Greenfield, D.M.
Late Effects Grp
Nature Publishing Group
2009-08-11
Article
PeerReviewed
text
en
cc_by_nc_sa_3
https://eprints.whiterose.ac.uk/81943/1/Follow-up%20care%20for%20cancer%20survivors%3A%20views%20of%20the%20younger%20adult..pdf
Absolom, K., Eiser, C., Michel, G. et al. (6 more authors) (2009) Follow-up care for cancer survivors: views of the younger adult. British Journal of Cancer, 101 (4). pp. 561-567. ISSN 0007-0920
http://dx.doi.org/10.1038/sj.bjc.6605213
10.1038/sj.bjc.6605213
oai:eprints.whiterose.ac.uk:83544
2016-08-01T09:12:10Z
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https://eprints.whiterose.ac.uk/83544/
Validation of the NANA (Novel Assessment of Nutrition and Ageing) touch screen system for use at home by older adults
Astell, A.J.
Hwang, F.
Brown, L.J.E.
Timon, C.
Maclean, L.M.
Smith, T.
Adlam, T.
Khadra, H.
Williams, E.A.
Prospective measurement of nutrition, cognition, and physical activity in later life would facilitate early detection of detrimental change and early intervention but is hard to achieve in community settings. Technology can simplify the task and facilitate daily data collection. The Novel Assessment of Nutrition and Ageing (NANA) toolkit was developed to provide a holistic picture of an individual's function including diet, cognition and activity levels. This study aimed to validate the NANA toolkit for data collection in the community. Forty participants aged 65 years and over trialled the NANA toolkit in their homes for three 7-day periods at four-week intervals. Data collected using the NANA toolkit were compared with standard measures of diet (four-day food diary), cognitive ability (processing speed) and physical activity (self-report). Bland–Altman analysis of dietary intake (energy, carbohydrates, protein fat) found a good relationship with the food diary and cognitive processing speed and physical activity (hours) were significantly correlated with their standard counterparts. The NANA toolkit enables daily reporting of data that would otherwise be collected sporadically while reducing demands on participants; older adults can complete the daily reporting at home without a researcher being present; and it enables prospective investigation of several domains at once.
Elsevier
2014-12
Article
PeerReviewed
text
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cc_by_nc_nd_4
https://eprints.whiterose.ac.uk/83544/1/NANA%20validation%20Exp%20ger.pdf
Astell, A.J. orcid.org/0000-0002-6822-9472 <https://orcid.org/0000-0002-6822-9472>, Hwang, F., Brown, L.J.E. et al. (6 more authors) (2014) Validation of the NANA (Novel Assessment of Nutrition and Ageing) touch screen system for use at home by older adults. Experimental Gerontology, 60. pp. 100-107. ISSN 0531-5565
https://dx.doi.org/10.1016/j.exger.2014.10.008
10.1016/j.exger.2014.10.008
oai:eprints.whiterose.ac.uk:83893
2016-07-29T13:09:17Z
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https://eprints.whiterose.ac.uk/83893/
Histological evaluation of AMPK signalling in primary breast cancer.
Hadad, S.M.
Baker, L.
Quinlan, P.R.
Robertson, K.E.
Bray, S.E.
Thomson, G.
Kellock, D.
Jordan, L.B.
Purdie, C.A.
Hardie, D.G.
Fleming, S.
Thompson, A.M.
BACKGROUND: AMP-activated protein kinase (AMPK) acts as a cellular fuel gauge that responds to energy stress by suppressing cell growth and biosynthetic processes, thus ensuring that energy-consuming processes proceed only if there are sufficient metabolic resources. Malfunction of the AMPK pathway may allow cancer cells to undergo uncontrolled proliferation irrespective of their molecular energy levels. The aim of this study was to examine the state of AMPK phosphorylation histologically in primary breast cancer in relation to clinical and pathological parameters.
METHODS: Immunohistochemistry was performed using antibodies to phospho-AMPK (pAMPK), phospho-Acetyl Co-A Carboxylase (pACC) an established target for AMPK, HER2, ERalpha, and Ki67 on Tissue Micro-Array (TMA) slides of two cohorts of 117 and 237 primary breast cancers. The quick score method was used for scoring and patterns of protein expression were compared with clinical and pathological data, including a minimum 5 years follow up.
RESULTS: Reduced signal, compared with the strong expression in normal breast epithelium, using a pAMPK antibody was demonstrated in 101/113 (89.4%) and 217/236 (91.9%) of two cohorts of patients. pACC was significantly associated with pAMPK expression (p = 0.007 & p = 0.014 respectively). For both cohorts, reduced pAMPK signal was significantly associated with higher histological grade (p = 0.010 & p = 0.021 respectively) and axillary node metastasis (p = 0.061 & p = 0.039 respectively). No significant association was found between pAMPK and any of HER2, ERalpha, or Ki67 expression, disease-free survival or overall survival.
CONCLUSION: This study extends in vitro evidence through immunohistochemistry to confirm that AMPK is dysfunctional in primary breast cancer. Reduced signalling via the AMPK pathway, and the inverse relationship with histological grade and axillary node metastasis, suggests that AMPK re-activation could have therapeutic potential in breast cancer.
BioMed Central
2009-09-01
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/83893/1/Histological%20evaluation%20of%20AMPK%20signalling%20in%20primary%20breast%20cancer..pdf
Hadad, S.M., Baker, L., Quinlan, P.R. et al. (9 more authors) (2009) Histological evaluation of AMPK signalling in primary breast cancer. BMC Cancer, 9. 307.
http://dx.doi.org/10.1186/1471-2407-9-307
10.1186/1471-2407-9-307
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756E69743D536865666669656C64:536865666669656C642E535448
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/85490/
Treatment of bone metastases from breast cancer with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD)
COLEMAN, R.E.
WOLL, P.J.
MILES, M.
SCRIVENER, W.
RUBENS, R.D.
Twenty-eight patients with progressive symptomatic bone metastases from breast cancer received (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) 30 mg in 500 ml of 0.9% saline infused over 2 h every 14 days. No other systemic therapy for breast cancer was prescribed. All patients had progressed on at least one previous systemic treatment. APD was continued until the disease progressed. Patients were assessed for objective response by the UICC criteria. In addition, subjective response was determined by a pain questionnaire. Radiological evidence of bone healing with sclerosis of lytic disease (UICC partial response) was seen in 4 patients. The median duration of response was 10 months. Eleven patients had stable disease for at least 3 months (median 5 months) and 9 progressed. Symptomatic response occurred in 9 patients and 12 reported an improvement in quality of life. Treatment was tolerated well with no significant toxicity. In conclusion, long-term inhibition of bone destruction is possible with APD therapy alone and both subjective and objective responses are seen.
Cancer Research UK
1988-11
Article
PeerReviewed
text
en
cc_by_nc_nd_4
https://eprints.whiterose.ac.uk/85490/1/Treatment%20of%20bone%20metastases%20from%20breast%20cancer%20with%20%283-amino-1-hydroxypropylidene%29-1%2C1-bisphosphonate%20%28APD%29..pdf
COLEMAN, R.E., WOLL, P.J. orcid.org/0000-0002-1118-0831 <https://orcid.org/0000-0002-1118-0831>, MILES, M. et al. (2 more authors) (1988) Treatment of bone metastases from breast cancer with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD). British Journal of Cancer, 58 (5). pp. 621-625. ISSN 0007-0920
http://dx.doi.org/10.1038/bjc.1988.272
10.1038/bjc.1988.272
oai:eprints.whiterose.ac.uk:85492
2016-09-28T09:12:31Z
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756E69743D536865666669656C64:536865666669656C642E535448
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/85492/
Neuropeptide growth factors and cancer
WOLL, P.J.
Cancer Research UK
1991-03
Article
PeerReviewed
text
en
cc_by_nc_nd_4
https://eprints.whiterose.ac.uk/85492/1/Neuropeptide%20growth%20factors%20and%20cancer..pdf
WOLL, P.J. orcid.org/0000-0002-1118-0831 <https://orcid.org/0000-0002-1118-0831> (1991) Neuropeptide growth factors and cancer. British Journal of Cancer, 63 (3). pp. 469-475. ISSN 0007-0920
http://dx.doi.org/10.1038/bjc.1991.110
10.1038/bjc.1991.110
oai:eprints.whiterose.ac.uk:85494
2016-07-29T13:41:23Z
7374617475733D707562
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756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
756E69743D536865666669656C64:536865666669656C642E535448
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/85494/
Follow up after Primary Treatment of Soft Tissue Sarcoma: A Survey of Current Practice in the United Kingdom.
Gerrand, C.H.
Billingham, L.J.
Woll, P.J.
Grimer, R.J.
Despite the clinical and financial implications, there is little evidence about how patients who have been treated for soft tissue sarcoma should be followed up. The purpose of this study was to determine current practice in the United Kingdom. 192 clinicians treating patients with soft tissue sarcoma were surveyed with a postal questionnaire enquiring about frequency and method of follow up and how patients would be followed up in each of 3 clinical scenarios: a patient with a trunk or extremity tumour at low risk of relapse; a patient with a trunk or extremity tumour at high risk of relapse; and a patient with a retroperitoneal or abdominal tumour. 155 (81%) clinicians responded. Clinic visits and X-rays were the most frequently used methods of follow up. Chest CT scans, local site imaging, and blood tests were used infrequently. The intensity and methods of follow up varied with each of the clinical scenarios. There was a seven-to-twenty fold variation in cost between the least and the most expensive regimes. Respondents were generally supportive of the development of the clinical trial in this area.
Hindawi Publishing Corporation
2007
Article
PeerReviewed
text
en
cc_by_3
https://eprints.whiterose.ac.uk/85494/1/Follow%20up%20after%20Primary%20Treatment%20of%20Soft%20Tissue%20Sarcoma%3A%20A%20Survey%20of%20Current%20Practice%20in%20the%20United%20Kingdom..pdf
Gerrand, C.H., Billingham, L.J., Woll, P.J. orcid.org/0000-0002-1118-0831 <https://orcid.org/0000-0002-1118-0831> et al. (1 more author) (2007) Follow up after Primary Treatment of Soft Tissue Sarcoma: A Survey of Current Practice in the United Kingdom. Sarcoma, 2007. 34128. ISSN 1357-714X
http://dx.doi.org/10.1155/2007/34128
10.1155/2007/34128
oai:eprints.whiterose.ac.uk:85495
2016-07-29T13:54:18Z
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https://eprints.whiterose.ac.uk/85495/
A Phase II Nonrandomised Open-Label Study of Liposomal Daunorubicin (DaunoXome) in Advanced Soft Tissue Sarcoma.
McTiernan, A.
Whelan, J.
Leahy, M.
Woll, P.J.
Thirty four patients with advanced soft tissue sarcoma not previously treated with an anthracycline were treated with DaunoXome 100mg/m2 every 3 weeks. Thirty-three patients were evaluable for toxicity. Grade 3-4 neutropenia was seen in 20 patients (60.6%), complicated by febrile neutropenia in 2 (6.1%). Other grade 3 toxicities were rare. Among 32 patients assessable for response, one patient had a partial response, giving a response rate of 3.13% (95% confidence interval, 0.08-16.22%). Seven patients (21.9%) had stable disease, and 24 patients (75.0%) had disease progression. The median time to progression for all patients was 42 days (95% CI, 39-49) and the progression-free rate at 3 months was 12.5%. In conclusion, DaunoXome at this dose and schedule is well tolerated in patients with advanced soft tissue sarcoma, but is not associated with significant activity. Further studies at this dose and schedule cannot be recommended in this disease.
Hindawi Publishing Corporation
2006
Article
PeerReviewed
text
en
cc_by_3
https://eprints.whiterose.ac.uk/85495/1/A%20Phase%20II%20Nonrandomised%20Open-Label%20Study%20of%20Liposomal%20Daunorubicin%20%28DaunoXome%29%20in%20Advanced%20Soft%20Tissue%20Sarcoma..pdf
McTiernan, A., Whelan, J., Leahy, M. et al. (1 more author) (2006) A Phase II Nonrandomised Open-Label Study of Liposomal Daunorubicin (DaunoXome) in Advanced Soft Tissue Sarcoma. Sarcoma, 2006. 41080. ISSN 1357-714X
http://dx.doi.org/10.1155/SRCM/2006/41080
10.1155/SRCM/2006/41080
oai:eprints.whiterose.ac.uk:85496
2016-08-01T09:46:19Z
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756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
756E69743D536865666669656C64:536865666669656C642E535448
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/85496/
Relative hypocalcaemia and muscle cramps in patients receiving imatinib for gastrointestinal stromal tumour.
Zekri, J.M.
Robinson, M.H.
Woll, P.J.
Purpose. Imatinib treatment causes muscle cramps in up to 40% of patients, but their pathogenesis is unknown. We present a case series illustrating an association between imatinib, relative hypocalcaemia, and the development of cramps.
Patients. The index patient developed muscle spasms and cramps after receiving imatinib for gastrointestinal stromal tumour (GIST) for 5 months. The adjusted serum calcium had dropped to the lower limit of normal. The low serum calcium and muscle cramps improved on stopping imatinib and recurred on rechallenge. We reviewed the medical records of 16 further patients.
Results. Two patients reported muscle cramps (12%). There was a rapid and sustained reduction in adjusted serum calcium in the first 6 months from 2.45 +/- 0.11 mmol/L (mean +/- SD) to 2.30 +/- 0.08 mmol/L (p = 0.025).
Conclusion. Imatinib treatment of GIST is associated with reduction in serum calcium which may explain the development of neuromuscular symptoms. In patients receiving imatinib, serum electrolytes should be monitored and muscle cramps treated by correction of serum calcium, or an empirical trial of quinine sulphate.
Hindawi Publishing Corporation
2006
Article
PeerReviewed
text
en
cc_by_3
https://eprints.whiterose.ac.uk/85496/1/Relative%20hypocalcaemia%20and%20muscle%20cramps%20in%20patients%20receiving%20imatinib%20for%20gastrointestinal%20stromal%20tumour..pdf
Zekri, J.M., Robinson, M.H. and Woll, P.J. orcid.org/0000-0002-1118-0831 <https://orcid.org/0000-0002-1118-0831> (2006) Relative hypocalcaemia and muscle cramps in patients receiving imatinib for gastrointestinal stromal tumour. Sarcoma, 2006. 48948. ISSN 1357-714X
https://dx.doi.org/10.1155/SRCM/2006/48948
10.1155/SRCM/2006/48948
oai:eprints.whiterose.ac.uk:85497
2016-07-28T14:17:38Z
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756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
756E69743D536865666669656C64:536865666669656C642E535448
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/85497/
Production and upregulation of granulocyte chemotactic protein-2/CXCL6 by IL-1 beta and hypoxia in small cell lung cancer
Zhu, Y.M.
Bagstaff, S.M.
Woll, P.J.
Small cell lung cancer (SCLC) is characterised by early and widespread metastasis. However, SCLC cells have so far been found to produce low levels of known pro-angiogenic factors. We speculated that SCLC cells might produce alternative pro-angiogenic factors. Here, we report that a panel of SCLC cell lines constitutively secrete granulocyte chemotactic protein-2 (GCP-2)/CXCL6, a CXC ELR+ chemokine. In contrast, none of the three tested NSCLC cell lines secreted GCP-2. Production of GCP-2 in vivo was also confirmed in seven out of nine specimens with SCLC. We demonstrate that expression of GCP-2 is mediated by NF-κB as ALLN, an NF-κB pathway inhibitor, almost completely abolished GCP-2 production in SCLC cell lines. We also demonstrate that GCP-2 can be significantly upregulated by IL-1β and hypoxia in SCLC cell lines. This result suggests a role for GCP-2 in promoting tumour progression in vivo under unfavourable conditions such as oxygen deprivation. As SCLC cells express both GCP-2 and its receptors CXCR1 and CXCR2, their biological significance in SCLC progression was further studied. We demonstrate that GCP-2 is an autocrine growth factor. Cell proliferation was significantly inhibited by anti-GCP-2 neutralising antibody in two high-GCP-2-producing cell lines. In addition, expression of the proliferation marker PCNA was upregulated by exogenous GCP-2 in two low-GCP-2-producing cell lines. Taken together, these results suggest an important role for GCP-2 as an autocrine mitogen in the growth and metastasis of SCLC.
Cancer Research UK
2006-06-13
Article
PeerReviewed
text
en
cc_by_nc_sa_3
https://eprints.whiterose.ac.uk/85497/1/Production%20and%20upregulation%20of%20granulocyte%20chemotactic%20protein-2/CXCL6%20by%20IL-1beta%20and%20hypoxia%20in%20small%20cell%20lung%20cancer..pdf
Zhu, Y.M., Bagstaff, S.M. and Woll, P.J. orcid.org/0000-0002-1118-0831 <https://orcid.org/0000-0002-1118-0831> (2006) Production and upregulation of granulocyte chemotactic protein-2/CXCL6 by IL-1 beta and hypoxia in small cell lung cancer. British Journal of Cancer, 94 (12). pp. 1936-1941. ISSN 0007-0920
http://dx.doi.org/10.1038/sj.bjc.6603177
10.1038/sj.bjc.6603177
oai:eprints.whiterose.ac.uk:85498
2016-08-01T09:53:11Z
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756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
756E69743D536865666669656C64:536865666669656C642E535448
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/85498/
Interleukin-8/CXCL8 is a growth factor for human lung cancer cells
Zhu, Y.M.
Webster, S.J.
Flower, D.
Woll, P.J.
Interleukin-8/CXCL8 (IL-8) is a chemokine and angiogenic factor. Recently, IL-8 was identified as an autocrine growth factor in several human cancers. Here, we investigated the expression and function of IL-8 in lung cancer cells. The expressions of IL-8 and its receptors, CXCR1 and CXCR2, were examined in a panel of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cell lines. Using reverse transcription–polymerase chain reaction (RT–PCR) and enzyme-linked immunosorbent assay, we found that all NSCLC cell lines tested produced modest or high levels of IL-8 (up to 51 ng ml−1 106 cells−1). Expression of CXCR1 and CXCR2 was found by RT–PCR and flow cytometry in two out of three cell lines. In contrast, SCLC cell lines produced very low or undetectable levels of IL-8, but expressed CXCR1 and CXCR2. We next investigated whether IL-8 could act as an autocrine growth factor in two NSCLC cell lines (H460 and MOR/P) expressing both IL-8 and its receptors. We found that cell proliferation was attenuated by anti-IL-8 neutralising antibody to 71 and 76% in H460 and MOR/P, respectively (P<0.05). Exogenous IL-8 significantly stimulated cell proliferation in four SCLC cell lines tested in a dose-dependent fashion. Cell proliferation was increased by between 18% (P<0.05) and 37% (P<0.05). Stimulation of cell proliferation by IL-8 was also demonstrated by analysis of proliferating cell nuclear antigen expression and cell cycle in H69 cells. Furthermore, we investigated which receptor(s) mediated the mitogenic function of IL-8 in lung cancer cells. We found that cell proliferation was significantly reduced by anti-CXCR1 antibody but not by anti-CXCR2 antibody. In conclusion, IL-8 can act as an autocrine and/or paracrine growth factor for lung cancer cells, and the mitogenic function of IL-8 in lung cancer is mediated mainly by CXCR1 receptor.
Cancer Research UK
2004-11-23
Article
PeerReviewed
text
en
cc_by_nc_sa_3
https://eprints.whiterose.ac.uk/85498/1/Interleukin-8/CXCL8%20is%20a%20growth%20factor%20for%20human%20lung%20cancer%20cells..pdf
Zhu, Y.M., Webster, S.J., Flower, D. et al. (1 more author) (2004) Interleukin-8/CXCL8 is a growth factor for human lung cancer cells. British Journal of Cancer, 91 (11). pp. 1970-1976. ISSN 0007-0920
https://dx.doi.org/10.1038/sj.bjc.6602227
10.1038/sj.bjc.6602227
oai:eprints.whiterose.ac.uk:85499
2016-08-01T10:00:37Z
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756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
756E69743D536865666669656C64:536865666669656C642E535448
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https://eprints.whiterose.ac.uk/85499/
Tumour-specific arginine vasopressin promoter activation in small-cell lung cancer
Coulson, J.M.
Stanley, J.
Woll, P.J.
Small-cell lung cancer (SCLC) can produce numerous mitogenic neuropeptides, which are not found in normal respiratory epithelium. Arginine vasopressin is detected in up to two-thirds of SCLC tumours whereas normal physiological expression is essentially restricted to the hypothalamus. This presents the opportunity to identify elements of the gene promoter which could be exploited for SCLC-specific targeting. A series of human vasopressin 5′ promoter fragments (1048 bp, 468 bp and 199 bp) were isolated and cloned upstream of a reporter gene. These were transfected into a panel of ten cell lines, including SCLC with high or low endogenous vasopressin transcription, non-SCLC and bronchial epithelium. All these fragments directed reporter gene expression in the five SCLC cell lines, but had negligible activity in the control lines. The level of reporter gene expression reflected the level of endogenous vasopressin production, with up to 4.9-fold (s.d. 0.34) higher activity than an SV40 promoter. The elements required for this strong, restricted, SCLC-specific promoter activity are contained within the 199-bp fragment. Further analysis of this region indicated involvement of E-box transcription factor binding sites, although tumour-specificity was retained by a 65-bp minimal promoter fragment. These data show that a short region of the vasopressin promoter will drive strong expression in SCLC in vitro and raise the possibility of targeting gene therapy to these tumours.
Cancer Research UK
1999-07-30
Article
PeerReviewed
text
en
cc_by_nc_sa_3
https://eprints.whiterose.ac.uk/85499/1/Tumour-specific%20arginine%20vasopressin%20promoter%20activation%20in%20small-cell%20lung%20cancer..pdf
Coulson, J.M., Stanley, J. and Woll, P.J. orcid.org/0000-0002-1118-0831 <https://orcid.org/0000-0002-1118-0831> (1999) Tumour-specific arginine vasopressin promoter activation in small-cell lung cancer. British Journal of Cancer, 80 (12). pp. 1935-1944. ISSN 0007-0920
https://dx.doi.org/10.1038/sj.bjc.6690623
10.1038/sj.bjc.6690623
oai:eprints.whiterose.ac.uk:87248
2016-03-03T11:29:06Z
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756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E485252:536865666669656C642E484152
756E69743D536865666669656C64:536865666669656C642E535448
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https://eprints.whiterose.ac.uk/87248/
Case-mix fails to explain variation in mastectomy rates: management of screen-detected breast cancer in a UK region 1997-2003
Caldon, L.J.M.
Walters, S.J.
Reed, J.A.
Murphy, A.
Worley, A.
Reed, M.W.R.
Wide variation in the surgical management of breast cancer exists at hospital, regional, national and international level. To demonstrate whether variation in surgical practice observed at aggregate level between breast units persists following adjustment for case-mix, individual patient-level data from the Trent Breast Screening Programme Quality Assurance database (1997–2003) was analysed. Expected case-mix adjusted mastectomy rates were derived by logistic regression using the variables tumour size, site and grade, patient age and year of presentation, employing the region's overall case-mix adjusted practice as the reference population. The region's 11 breast screening units detected 5109 (3989 invasive) surgically managed primary breast cancers over the 6-year period. A total of 1828 mastectomies (Mx) were performed (Mx rate 35.8%, 95% confidence interval: 34.5–37.1%). Significant variation in mastectomy rates were observed between units (range 25–45%, P<0.0001), and persists following case-mix adjustment (P<0.0001). Two-fold variation in observed to expected unit mastectomy rate coefficient is demonstrated overall (range 0.66–1.36), increasing to almost four-fold variation in cancers less than 15 mm diameter (range 0.55–1.95). Significant variation in surgery for screen-detected primary breast cancer is not explained by case-mix. Further research is required to investigate potential patient and professional causative factors.
Nature Publishing Group
2005-01-17
Article
PeerReviewed
text
en
cc_by_nc_sa_3
https://eprints.whiterose.ac.uk/87248/1/Case-mix%20fails%20to%20explain%20variation%20in%20mastectomy%20rates%3A%20management%20of%20screen-detected%20breast%20cancer%20in%20a%20UK%20region%201997-2003..pdf
Caldon, L.J.M., Walters, S.J., Reed, J.A. et al. (3 more authors) (2005) Case-mix fails to explain variation in mastectomy rates: management of screen-detected breast cancer in a UK region 1997-2003. British Journal of Cancer, 92 (1). pp. 55-59. ISSN 0007-0920
http://dx.doi.org/10.1038/sj.bjc.6602264
10.1038/sj.bjc.6602264
oai:eprints.whiterose.ac.uk:87508
2016-07-29T14:04:28Z
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https://eprints.whiterose.ac.uk/87508/
Do Anti-Angiogenic VEGF (VEGFxxxb) Isoforms Exist? A Cautionary Tale
Harris, S.
Craze, M.
Newton, J.
Fisher, M.
Shima, D.T.
Tozer, G.M.
Kanthou, C.
Splicing of the human vascular endothelial growth factor-A (VEGF-A) gene has been reported to generate angiogenic (VEGFxxx) and anti-angiogenic (VEGFxxxb) isoforms. Corresponding VEGFxxxb isoforms have also been reported in rat and mouse. We examined VEGFxxxb expression in mouse fibrosarcoma cell lines expressing all or individual VEGF isoforms (VEGF120, 164 or 188), grown in vitro and in vivo, and compared results with those from normal mouse and human tissues. Importantly, genetic construction of VEGF164 and VEGF188 expressing fibrosarcomas, in which exon 7 is fused to the conventional exon 8, precludes VEGFxxxb splicing from occurring. Thus, these two fibrosarcoma cell lines provided endogenous negative controls. Using RT-PCR we show that primers designed to simultaneously amplify VEGFxxx and VEGFxxxb isoforms amplified only VEGFxxx variants in both species. Moreover, only VEGFxxx species were generated when mouse podocytes were treated with TGFβ-1, a reported activator of VEGFxxxb splice selection in human podocytes. A VEGF164/120 heteroduplex species was identified as a PCR artefact, specifically in mouse. VEGFxxxb isoform-specific PCR did amplify putative VEGFxxxb species in mouse and human tissues, but unexpectedly also in VEGF188 and VEGF164 fibrosarcoma cells and tumours, where splicing to produce true VEGFxxxb isoforms cannot occur. Moreover, these products were only consistently generated using reverse primers spanning more than 5 bases across the 8b/7 or 8b/5 splice junctions. Primer annealing to VEGFxxx transcripts and amplification of exon 8b primer ‘tails’ explained the artefactual generation of VEGFxxxb products, since the same products were generated when the PCR reactions were performed with cDNA from VEGF164/VEGF188 ‘knock-in’ vectors used in the generation of single VEGF isoform-expressing transgenic mice from which the fibrosarcoma lines were developed. Collectively, our results highlight important pitfalls in data interpretation associated with detecting VEGFxxxb isoforms using current methods, and demonstrate that anti-angiogenic isoforms are not commonly expressed in mouse or human tissues.
Public Library of Science
2012-05-02
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/87508/1/Do%20anti-angiogenic%20VEGF%20%28VEGFxxxb%29%20isoforms%20exist%3F%20A%20cautionary%20tale..pdf
Harris, S., Craze, M., Newton, J. et al. (4 more authors) (2012) Do Anti-Angiogenic VEGF (VEGFxxxb) Isoforms Exist? A Cautionary Tale. PLoS ONE, 7 (5). ARTN e35231. ISSN 1932-6203
http://dx.doi.org/10.1371/journal.pone.0035231
10.1371/journal.pone.0035231
oai:eprints.whiterose.ac.uk:88300
2016-09-28T09:34:53Z
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https://eprints.whiterose.ac.uk/88300/
Dual role for the latent transforming growth factor-beta binding protein in storage of latent TGF-beta in the extracellular matrix and as a structural matrix protein
Dallas, S.L.
Miyazono, K.
Skerry, T.M.
Mundy, G.R.
Bonewald, L.F.
The role of the latent TGF-beta binding protein (LTBP) is unclear. In cultures of fetal rat calvarial cells, which form mineralized bonelike nodules, both LTBP and the TGF-beta 1 precursor localized to large fibrillar structures in the extracellular matrix. The appearance of these fibrillar structures preceded the appearance of type I collagen fibers. Plasmin treatment abolished the fibrillar staining pattern for LTBP and released a complex containing both LTBP and TGF-beta. Antibodies and antisense oligonucleotides against LTBP inhibited the formation of mineralized bonelike nodules in long-term fetal rat calvarial cultures. Immunohistochemistry of fetal and adult rat bone confirmed a fibrillar staining pattern for LTBP in vivo. These findings, together with the known homology of LTBP to the fibrillin family of proteins, suggest a novel function for LTBP, in addition to its role in matrix storage of latent TGF-beta, as a structural matrix protein that may play a role in bone formation.
Rockefeller University Press
1995-10-15
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/88300/1/Dual%20role%20for%20the%20latent%20transforming%20growth%20factor-beta%20binding%20protein%20in%20storage%20of%20latent%20TGF-beta%20in%20the%20extracellular%20matrix%20and%20as%20a%20structural%20matrix%20protein..pdf
Dallas, S.L., Miyazono, K., Skerry, T.M. orcid.org/0000-0003-1319-5575 <https://orcid.org/0000-0003-1319-5575> et al. (2 more authors) (1995) Dual role for the latent transforming growth factor-beta binding protein in storage of latent TGF-beta in the extracellular matrix and as a structural matrix protein. The Journal of Cell Biology, 131 (2). pp. 539-549. ISSN 0021-9525
http://dx.doi.org/10.1083/jcb.131.2.539
10.1083/jcb.131.2.539
oai:eprints.whiterose.ac.uk:88607
2017-11-03T18:41:41Z
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https://eprints.whiterose.ac.uk/88607/
The Role of Tobacco Smoke in Bladder and Kidney Carcinogenesis: A Comparison of Exposures and Meta-analysis of Incidence and Mortality Risks.
Cumberbatch, M.G.
Rota, M.
Catto, J.W.
La Vecchia, C.
Context
Tobacco smoke includes a mix of carcinogens implicated in the etiology of bladder cancer (BC) and renal cell cancer (RCC).
Objective
We reviewed the impact of tobacco exposure on BCC and RCC incidence and mortality, and whether smoking cessation decreases the risk.
Evidence acquisition
A systematic review of original articles in English was performed in August 2013. Meta-analysis of risks was performed using adjusted risk ratios where available. Publication bias was assessed using Begg and Egger tests.
Evidence synthesis
We identified 2683 papers, of which 114 fulfilled our inclusion criteria, of which 90 studies investigated BC and 24 investigated RCC. The pooled relative risk (RR) of BC incidence was 2.57 (95% confidence interval [CI] 2.37–2.78) for all smokers, 3.37 (3.01–3.78) for current smokers, and 1.98 (1.76–2.22) for former smokers. The corresponding pooled RR of BC disease-specific mortality (DSM) was 1.79 (1.40–2.29), 1.89 (1.29–2.78) and 1.66 (1.10–2.52). The pooled RR of RCC incidence was 1.27 (1.18–135) for all smokers, 1.29 (1.14–1.46) for current smokers, and 1.14 (1.06–1.22) for former smokers. The corresponding RCC DSM risk was 1.20 (1.02–1.41), 1.32 (1.08–1.62), and 1.01 (0.85–1.18).
Conclusions
We present an up-to-date review of tobacco smoking and BC and RCC incidence and mortality. Tobacco smoking significantly increases the risk of BC and RCC incidence. BC incidence and DSM risk are greatest in current smokers and lowest in former smokers, indicating that smoking cessation confers benefit. We found that secondhand smoke exposure is associated with a significant increase in BC risk.
Patient summary
Tobacco smoking affects the development and progression of bladder cancer and renal cell cancer. Smoking cessation reduces the risks of developing and dying from these common cancers. We quantify these risks using the most up-to-date results published in the literature.
Elsevier
2016-09
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/88607/8/WRRO_88607.pdf
Cumberbatch, M.G., Rota, M., Catto, J.W. et al. (1 more author) (2016) The Role of Tobacco Smoke in Bladder and Kidney Carcinogenesis: A Comparison of Exposures and Meta-analysis of Incidence and Mortality Risks. European Urology, 70 (3). pp. 458-466. ISSN 0302-2838
http://dx.doi.org/10.1016/j.eururo.2015.06.042
10.1016/j.eururo.2015.06.042
oai:eprints.whiterose.ac.uk:88869
2016-03-09T02:27:44Z
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7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/88869/
Coping with melanoma-related worry: a qualitative study of the experiences and support needs of patients with malignant melanoma
Bird, J.
Coleman, P.
Danson, S.
Aims and objectives
To explore the patients' experience of having malignant melanoma, their related support needs and the processes that lead to these needs being met.
Background
The number of patients attending surveillance clinics after a diagnosis of malignant melanoma is increasing. In the UK specialist nurses provide support to patients, but little evidence exists about the nature of patients' support needs or their experience of having melanoma. Melanoma has often been researched within general cancer studies, yet the support needs of melanoma patients may be different from those of patients with other skin cancers or tumour types.
Design
A Grounded Theory Approach was used to guide sampling, data collection and analysis.
Methods
In-depth interviews were conducted with eleven patients who where purposively sampled. Transcripts were read several times, coded and categorised using the constant comparative method. Emergent categories were discussed with participants.
Results
Three emergent categories related to a core category of melanoma-related worry which formed a substantive theory about the strategies patients use to control this. Participants reported needing to have their concerns believed by others prior to and after diagnosis. They discussed discerning whom to share their concerns with depending upon who they felt would not perceive assisting them as being burdensome. They also sought ways to reassure themselves.
Conclusions
Patients need to have their fear and worries acknowledged by others. This includes nurses, healthcare professionals and family members. Patients will also use self-examination and the absence of symptoms to reassure themselves.
Relevance to clinical practice
Nurses play key roles throughout the patient's care; therefore they need to be sensitive to the fact that patients may consider them a primary source of support. When teaching self-examination it is important that nurses discuss that this may ease worry and aid coping.
Wiley
2015-04
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/88869/7/JCN%201114.pdf
Bird, J., Coleman, P. and Danson, S. (2015) Coping with melanoma-related worry: a qualitative study of the experiences and support needs of patients with malignant melanoma. Journal of Clinical Nursing, 24 (7-8). pp. 937-947. ISSN 0962-1067
http://dx.doi.org/10.1111/jocn.12758
10.1111/jocn.12758
oai:eprints.whiterose.ac.uk:90512
2018-03-22T01:15:04Z
7374617475733D707562
74797065733D61727469636C65
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
756E69743D536865666669656C64:536865666669656C642E535448
696E737469747574696F6E3D536865666669656C64
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https://eprints.whiterose.ac.uk/90512/
Molecular alterations that drive breast cancer metastasis to bone.
Ottewell, P.D.
O'Donnell, L.
Holen, I.
Epithelial cancers including breast and prostate commonly progress to form incurable bone metastases. For this to occur, cancer cells must adapt their phenotype and behaviour to enable detachment from the primary tumour, invasion into the vasculature, and homing to and subsequent colonisation of bone. It is widely accepted that the metastatic process is driven by the transformation of cancer cells from a sessile epithelial to a motile mesenchymal phenotype through epithelial-mesenchymal transition (EMT). Dissemination of these motile cells into the circulation provides the conduit for cells to metastasise to distant organs. However, accumulating evidence suggests that EMT is not sufficient for metastasis to occur and that specific tissue-homing factors are required for tumour cells to lodge and grow in bone. Once tumour cells are disseminated in the bone environment, they can revert into an epithelial phenotype through the reverse process of mesenchymal-epithelial transition (MET) and form secondary tumours. In this review, we describe the molecular alterations undertaken by breast cancer cells at each stage of the metastatic cascade and discuss how these changes facilitate bone metastasis.
Nature Publishing Group
2015-03-18
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/90512/1/BoneKEY%20review%202014.pdf
Ottewell, P.D., O'Donnell, L. and Holen, I. orcid.org/0000-0002-8759-6913 <https://orcid.org/0000-0002-8759-6913> (2015) Molecular alterations that drive breast cancer metastasis to bone. Bonekey Reports, 4. p. 643. ISSN 2047-6396
http://dx.doi.org/10.1038/bonekey.2015.10
10.1038/bonekey.2015.10
oai:eprints.whiterose.ac.uk:90919
2017-02-08T12:34:27Z
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756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
756E69743D536865666669656C64:536865666669656C642E535448
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https://eprints.whiterose.ac.uk/90919/
SCT for severe autoimmune diseases: consensus guidelines of the European Society for Blood and Marrow Transplantation for immune monitoring and biobanking
Alexander, T.
Bondanza, A.
Muraro, P.A.
Greco, R.
Saccardi, R.
Daikeler, T.
Kazmi, M.
Hawkey, C.
Simoes, B.P.
Leblanc, K.
Fibbe, W.E.
Moore, J.
Snarski, E.
Martin, T.
Hiepe, F.
Velardi, A.
Toubert, A.
Snowden, J.A.
Farge, D.
Party, EBMTADW
Party, IW
Over the past 15 years, SCT has emerged as a promising treatment option for patients with severe autoimmune diseases (ADs). Mechanistic studies recently provided the proof-of-concept that restoration of immunological tolerance can be achieved by haematopoietic SCT in chronic autoimmunity through eradication of the pathologic, immunologic memory and profound reconfiguration of the immune system, that is, immune ‘resetting’. Nevertheless, a number of areas remain unresolved and warrant further investigation to refine our understanding of the underlying mechanisms of action and to optimize clinical SCT protocols. Due to the low number of patients transplanted in each centre, it is essential to adequately collect and analyse biological samples in a larger cohort of patients under standardized conditions. The European society for blood and marrow transplantation Autoimmune Diseases and Immunobiology Working Parties have, therefore, undertaken a joint initiative to develop and implement guidelines for ‘good laboratory practice’ in relation to procurement, processing, storage and analysis of biological specimens for immune reconstitution studies in AD patients before, during and after SCT. The aim of this document is to provide practical recommendations for biobanking of samples and laboratory immune monitoring in patients with ADs undergoing SCT, both for routine supportive care purposes and investigational studies.
Nature Publishing Group
2015-02
Article
PeerReviewed
text
en
cc_by_nc_sa_4
https://eprints.whiterose.ac.uk/90919/14/SCT%20for%20severe%20autoimmune%20diseases%3A%20consensus%20guidelines%20of%20the%20European%20Society%20for%20Blood%20and%20Marrow%20Transplantation%20for%20immune%20monitoring%20and%20biobanking.pdf
Alexander, T., Bondanza, A., Muraro, P.A. et al. (18 more authors) (2015) SCT for severe autoimmune diseases: consensus guidelines of the European Society for Blood and Marrow Transplantation for immune monitoring and biobanking. Bone Marrow Transplantation, 50 (2). pp. 173-180. ISSN 0268-3369
http://www.doi.org/10.1038/bmt.2014.251
10.1038/bmt.2014.251
oai:eprints.whiterose.ac.uk:91237
2016-04-11T13:37:43Z
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756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
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https://eprints.whiterose.ac.uk/91237/
The frequency of osteolytic bone metastasis is determined by conditions of the soil, not the number of seeds; evidence from in vivo models of breast and prostate cancer
Wang, N.
Reeves, K.J.
Brown, H.K.
Fowles, A.C.M.
Docherty, F.E.
Ottewell, P.D.
Croucher, P.I.
Holen, I.
Eaton, C.L.
Background
While both preclinical and clinical studies suggest that the frequency of growing skeletal metastases is elevated in individuals with higher bone turnover, it is unclear whether this is a result of increased numbers of tumour cells arriving in active sites or of higher numbers of tumour cells being induced to divide by the bone micro-environment. Here we have investigated how the differences in bone turnover affect seeding of tumour cells and/or development of overt osteolytic bone metastasis using in vivo models of hormone-independent breast and prostate cancer.
Methods
Cohorts of 6 (young) and 16 (mature)-week old BALB/c nude mice were culled 1, 7 and 21 days after received intracardiac injection of luciferase expressing human prostate (PC3) or breast cancer (MDA-MB-231) cell lines labelled with a fluorescent cell membrane dye (Vybrant DiD). The presence of growing bone metastases was determined by bioluminescence using an in vivo imaging system (IVIS) and followed by anatomical confirmation of tumour metastatic sites post mortem, while the presence of individual fluorescently labelled tumour cells was evaluated using two-photon microscopy ex vivo. The bone remodelling activities were compared between young and mature naïve mice (both male and female) using micro-CT analysis, ELISA and bone histomorphometry.
Results
Both prostate and breast cancer cells generated higher numbers of overt skeletal lesions in young mice (~80%) than in mature mice (~20%). Although mature mice presented with fewer overt bone metastases, the number of tumour cells arriving/colonizing in the tibias was comparable between young and mature animals. Young naïve mice had lower bone volume but higher bone formation and resorption activities compared to mature animals.
Conclusions
Our studies suggest that higher frequencies of growing osteolytic skeletal metastases in these models are linked to increased bone turnover and not to the initial number of tumour cells entering the bone microenvironment.
BioMed Central
2015-10-20
Article
PeerReviewed
text
en
cc_by_4
https://eprints.whiterose.ac.uk/91237/1/The%20frequency%20of%20osteolytic%20bone%20metastasis%20is%20determined%20by%20conditions%20of%20the%20soil%2C%20not%20the%20number%20of%20seeds%3B%20evidence%20from%20in%20vivo%20models%20of%20breast%20and%20prostate%20cancer..pdf
Wang, N., Reeves, K.J., Brown, H.K. et al. (6 more authors) (2015) The frequency of osteolytic bone metastasis is determined by conditions of the soil, not the number of seeds; evidence from in vivo models of breast and prostate cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH, 34. 124. ISSN 1756-9966
http://dx.doi.org/10.1186/s13046-015-0240-8
10.1186/s13046-015-0240-8
oai:eprints.whiterose.ac.uk:91892
2023-06-23T21:55:08Z
7374617475733D707562
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https://eprints.whiterose.ac.uk/91892/
Gestational trophoblastic disease: does central nervous system chemoprophylaxis have a role?
Gillespie, A.M.
Siddiqui, N.
Coleman, R.E.
Hancock, B.W.
In the UK there are standardized surveillance procedures for gestational trophoblastic disease. However, there are differences in practice between the two treatment centres in terms of definition of persistent gestational trophoblastic disease, prognostic risk assessment and chemotherapeutic regimens. The role of prophylactic chemotherapy for cerebral micrometastatic disease in persistent gestational trophoblastic disease is unclear. We have analysed the outcome of 69 patients with lung metastases who elsewhere might have received prophylactic intrathecal chemotherapy. Of the 69 patients, 67 received intravenous chemotherapy only. The other two patients had cerebral metastases at presentation. One patient who received only intravenous chemotherapy subsequently developed a cerebral metastasis, but this patient's initial treatment was compromised by non-compliance. This experience supports our current policy of not treating patients with pulmonary metastases, without clinical evidence of central nervous system (CNS) involvement, with prophylactic intrathecal therapy.
Cancer Research UK
1999-03
Article
PeerReviewed
text
en
cc_by_nc_sa_3
https://eprints.whiterose.ac.uk/91892/6/Gestational%20trophoblastic%20disease%3A%20does%20central%20nervous%20system%20chemoprophylaxis%20have%20a%20role%3F.pdf
Gillespie, A.M., Siddiqui, N., Coleman, R.E. orcid.org/0000-0002-4275-1043 <https://orcid.org/0000-0002-4275-1043> et al. (1 more author) (1999) Gestational trophoblastic disease: does central nervous system chemoprophylaxis have a role? British Journal of Cancer, 79 (7-8). pp. 1270-1272. ISSN 0007-0920
http://www.doi.org/10.1038/sj.bjc.6690203
10.1038/sj.bjc.6690203
oai:eprints.whiterose.ac.uk:91968
2016-11-18T17:10:21Z
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https://eprints.whiterose.ac.uk/91968/
Inflammation decreases keratin level in ulcerative colitis; inadequate restoration associates with increased risk of colitis-associated cancer
Corfe, B.M.
Majumdar, D.
Assadsangabi, A.
Marsh, A.M.R.
Cross, S.S.
Connolly, J.B.
Evans, C.A.
Lobo, A.J.
Background Keratins are intermediate filament (IF) proteins, which form part of the epithelial cytoskeleton and which have been implicated pathology of inflammatory bowel diseases (IBD).
Methods In this study biopsies were obtained from IBD patients grouped by disease duration and subtype into eight categories based on cancer risk and inflammatory status: quiescent recent onset (<5 years) UC (ROUC); UC with primary sclerosing cholangitis; quiescent long-standing pancolitis (20–40 years) (LSPC); active colitis and non-inflamed proximal colonic mucosa; pancolitis with dysplasia-both dysplastic lesions (DT) and distal rectal mucosa (DR); control group without pathology. Alterations in IF protein composition across the groups were determined by quantitative proteomics. Key protein changes were validated by western immunoblotting and immunohistochemical analysis.
Result Acute inflammation resulted in reduced K8, K18, K19 and VIM (all p<0.05) compared to controls and non inflamed mucosa; reduced levels of if– associated proteins were also seen in DT and DR. Increased levels of keratins in LSPC was noted relative to controls or ROUC (K8, K18, K19 and VIM, p<0.05). Multiple K8 forms were noted on immunoblotting, with K8 phosphorylation reduced in progressive disease along with an increase in VIM:K8 ratio. K8 levels and phosphorylation are reduced in acute inflammation but appear restored or elevated in subjects with clinical and endoscopic remission (LSPC) but not apparent in subjects with elevated risk of cancer.
Conclusions These data suggest that keratin regulation in remission may influence subsequent cancer risk.
BMJ Publishing Group
2015-05-18
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/91968/1/Corfe%20et%20al%202015%20BMJ%20Gastro.pdf
Corfe, B.M., Majumdar, D., Assadsangabi, A. et al. (5 more authors) (2015) Inflammation decreases keratin level in ulcerative colitis; inadequate restoration associates with increased risk of colitis-associated cancer. BMJ Open Gastroenterology, 2. e000024 . ISSN 2054-4774
http://dx.doi.org/10.1136/bmjgast-2014-000024
10.1136/bmjgast-2014-000024
oai:eprints.whiterose.ac.uk:91969
2016-11-18T17:10:22Z
7374617475733D707562
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756E69743D536865666669656C64:536865666669656C642E464345:536865666669656C642E435045
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
756E69743D536865666669656C64:536865666669656C642E535448
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/91969/
Reduced keratin expression in colorectal neoplasia and associated fields is reversible by diet and resection
Evans, C.A.
Rosser, R.
Waby, J.S.
Noirel, J.
Wright, P.C.
Williams, E.A.
Riley, S.A.
Bury, J.P.
Corfe, B.M.
Background Patients with adenomatous colonic polyps are at increased risk of developing further polyps suggesting field-wide alterations in cancer predisposition. The current study aimed to identify molecular alterations in the normal mucosa in the proximity of adenomatous polyps and to assess the modulating effect of butyrate, a chemopreventive compound produced by fermentation of dietary residues.
Methods A cross-sectional study was undertaken in patients with adenomatous polyps: biopsy samples were taken from the adenoma, and from macroscopically normal mucosa on the contralateral wall to the adenoma and from the mid-sigmoid colon. In normal subjects biopsies were taken from the mid-sigmoid colon. Biopsies were frozen for proteomic analysis or formalin-fixed for immunohistochemistry. Proteomic analysis was undertaken using iTRAQ workflows followed by bioinformatics analyses. A second dietary fibre intervention study arm used the same endpoints and sampling strategy at the beginning and end of a high-fibre intervention.
Results Key findings were that keratins 8, 18 and 19 were reduced in expression level with progressive proximity to the lesion. Lesional tissue exhibited multiple K8 immunoreactive bands and overall reduced levels of keratin. Biopsies from normal subjects with low faecal butyrate also showed depressed keratin expression. Resection of the lesion and elevation of dietary fibre intake both appeared to restore keratin expression level.
Conclusion Changes in keratin expression associate with progression towards neoplasia, but remain modifiable risk factors. Dietary strategies may improve secondary chemoprevention.
BMJ Publishing Group
2015-04-15
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/91969/1/Evans%20et%20al%202015%20BMJ%20Gastro.pdf
Evans, C.A., Rosser, R., Waby, J.S. et al. (6 more authors) (2015) Reduced keratin expression in colorectal neoplasia and associated fields is reversible by diet and resection. BMJ Open Gastroenterology, 2. e000022 . ISSN 2054-4774
http://dx.doi.org/10.1136/bmjgast-2014-000022
10.1136/bmjgast-2014-000022
oai:eprints.whiterose.ac.uk:91970
2015-11-19T17:57:17Z
7374617475733D707562
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756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
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https://eprints.whiterose.ac.uk/91970/
Dysbiosis of the gut microbiota in disease.
Carding, S.
Verbeke, K.
Vipond, D.T.
Corfe, B.M.
Owen, L.J.
There is growing evidence that dysbiosis of the gut microbiota is associated with the pathogenesis of both intestinal and extra-intestinal disorders. Intestinal disorders include inflammatory bowel disease, irritable bowel syndrome (IBS), and coeliac disease, while extra-intestinal disorders include allergy, asthma, metabolic syndrome, cardiovascular disease, and obesity.
Co-Action Publishing
2015-02-02
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/91970/1/26191-149503-1-PB.pdf
Carding, S., Verbeke, K., Vipond, D.T. et al. (2 more authors) (2015) Dysbiosis of the gut microbiota in disease. Microbial Ecology in Health & Disease, 26. 26191 . ISSN 0891-060X
https://dx.doi.org/10.3402/mehd.v26.26191
10.3402/mehd.v26.26191
oai:eprints.whiterose.ac.uk:91971
2016-03-09T02:25:54Z
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756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
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https://eprints.whiterose.ac.uk/91971/
The multifactorial interplay of diet, the microbiome and appetite control: current knowledge and future challenges
Corfe, B.M.
Harden, C.J.
Bull, M.
Garaiova, I.
The recent availability of high-throughput nucleic acid sequencing technologies has rapidly advanced approaches to analysing the role of the gut microbiome in governance of human health, including gut health, and also metabolic, cardiovascular and mental health, inter alia. Recent scientific studies suggest that energy intake (EI) perturbations at the population level cannot account for the current obesity epidemic, and significant work is investigating the potential role of the microbiome, and in particular its metabolic products, notably SCFA, predominantly acetate, propionate and butyrate, the last of which is an energy source for the epithelium of the large intestine. The energy yield from dietary residues may be a significant factor influencing energy balance. This review posits that the contribution towards EI is governed by EI diet composition (not just fibre), the composition of the microbiome and by the levels of physical activity. Furthermore, we hypothesise that these factors do not exist in a steady state, but rather are dynamic, with both short- and medium-term effects on appetite regulation. We suggest that the existing modelling strategies for bacterial dynamics, specifically for growth in chemostat culture, are of utility in understanding the dynamic interplay of diet, activity and microbiomic organisation. Such approaches may be informative in optimising the application of dietary and microbial therapy to promote health.
Cambridge University Press
2015-08
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/91971/7/WRRO_91971.pdf
Corfe, B.M., Harden, C.J., Bull, M. et al. (1 more author) (2015) The multifactorial interplay of diet, the microbiome and appetite control: current knowledge and future challenges. Proceedings of the Nutrition Society, 74 (3). 235 - 244. ISSN 0029-6651
http://dx.doi.org/10.1017/S0029665114001670
10.1017/S0029665114001670
oai:eprints.whiterose.ac.uk:92217
2016-08-03T13:39:30Z
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https://eprints.whiterose.ac.uk/92217/
Oestrogen receptor positive breast cancer metastasis to bone: inhibition by targeting the bone microenvironment in vivo
Holen, I.
Walker, M.
Nutter, F.
Fowles, A.
Evans, C.A.
Eaton, C.L.
Ottewell, P.D.
Clinical trials have shown that adjuvant Zoledronic acid (ZOL) reduces the development of bone metastases irrespective of ER status. However, post-menopausal patients show anti-tumour benefit with ZOL whereas pre-menopausal patients do not. Here we have developed in vivo models of spontaneous ER+ve breast cancer metastasis to bone and investigated the effects of ZOL and oestrogen on tumour cell dissemination and growth. ER+ve (MCF7, T47D) or ER−ve (MDA-MB-231) cells were administered by inter-mammary or inter-cardiac injection into female nude mice ± estradiol. Mice were administered saline or 100 μg/kg ZOL weekly. Tumour growth, dissemination of tumour cells in blood, bone and bone turnover were monitored by luciferase imaging, histology, flow cytometry, two-photon microscopy, micro-CT and TRAP/P1NP ELISA. Estradiol induced metastasis of ER+ve cells to bone in 80–100 % of animals whereas bone metastases from ER−ve cells were unaffected. Administration of ZOL had no effect on tumour growth in the fat pad but significantly inhibited dissemination of ER+ve tumour cells to bone and frequency of bone metastasis. Estradiol and ZOL increased bone volume via different mechanisms: Estradiol increased activity of bone forming osteoblasts whereas administration of ZOL to estradiol supplemented mice decreased osteoclast activity and returned osteoblast activity to levels comparable to that of saline treated mice. ER−ve cells require increased osteoclast activity to grow in bone whereas ER+ve cells do not. Zol does not affect ER+ve tumour growth in soft tissue, however, inhibition of bone turnover by ZOL reduced dissemination and growth of ER+ve breast cancer cells in bone.
Springer Verlag
2016-03
Article
PeerReviewed
text
en
cc_by_4
https://eprints.whiterose.ac.uk/92217/1/art%253A10.1007%252Fs10585-015-9770-x.pdf
Holen, I. orcid.org/0000-0002-8759-6913 <https://orcid.org/0000-0002-8759-6913>, Walker, M., Nutter, F. et al. (4 more authors) (2016) Oestrogen receptor positive breast cancer metastasis to bone: inhibition by targeting the bone microenvironment in vivo. Clinical & Experimental Metastasis, 33 (3). pp. 211-224. ISSN 0262-0898
http://www.doi.org/10.1007/s10585-015-9770-x
10.1007/s10585-015-9770-x
oai:eprints.whiterose.ac.uk:92456
2016-11-16T08:30:08Z
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756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
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https://eprints.whiterose.ac.uk/92456/
A deterministic oscillatory model of microtubule growth and shrinkage for differential actions of short chain fatty acids.
Kilner, J.
Corfe, B.M.
McAuley, M.T.
Wilkinson, S.J.
Short chain fatty acids (SCFA), principally acetate, propionate, butyrate and valerate, are produced in pharmacologically relevant concentrations by the gut microbiome. Investigations indicate that they exert beneficial effects on colon epithelia. There is increasing interest in whether different SCFAs have distinct functions which may be exploited for prevention or treatment of colonic diseases including colorectal cancer (CRC), inflammatory bowel disease and obesity. Based on experimental evidence, we hypothesised that odd-chain SCFAs may possess anti-mitotic capabilities in colon cancer cells by disrupting microtubule (MT) structural integrity via dysregulation of β-tubulin isotypes. MT dynamic instability is an essential characteristic of MT cellular activity. We report a minimal deterministic model that takes a novel approach to explore the hypothesised pathway by triggering spontaneous oscillations to represent MT dynamic behaviour. The dynamicity parameters in silico were compared to those reported in vitro. Simulations of untreated and butyrate (even-chain length) treated cells reflected MT behaviour in interphase or untreated control cells. The propionate and valerate (odd-chain length) simulations displayed increased catastrophe frequencies and longer periods of MT-fibre shrinkage. Their enhanced dynamicity was dissimilar to that observed in mitotic cells, but parallel to that induced by MT-destabilisation treatments. Antimicrotubule drugs act through upward or downward modulation of MT dynamic instability. Our computational modelling suggests that metabolic engineering of the microbiome may facilitate managing CRC risk by predicting outcomes of SCFA treatments in combination with AMDs.
Royal Society of Chemistry
2016-01-01
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/92456/1/s1-ln218362572045830282-1939656818Hwf-634237564IdV58033612521836257PDF_HI0001.pdf
text
en
cc_by_3
https://eprints.whiterose.ac.uk/92456/8/c5mb00211g.pdf
Kilner, J., Corfe, B.M., McAuley, M.T. et al. (1 more author) (2016) A deterministic oscillatory model of microtubule growth and shrinkage for differential actions of short chain fatty acids. Molecular BioSystems , 12. pp. 93-101. ISSN 1742-206X
http://dx.doi.org/10.1039/c5mb00211g
10.1039/c5mb00211g
oai:eprints.whiterose.ac.uk:92675
2016-07-26T08:18:26Z
oai:eprints.whiterose.ac.uk:93031
2016-01-20T16:12:05Z
7374617475733D707562
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756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
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https://eprints.whiterose.ac.uk/93031/
Vitamin D associates with improved quality of life in participants with irritable bowel syndrome: outcomes from a pilot trial
Tazzyman, S.
Richards, N.
Trueman, A.R.
Evans, A.L.
Grant, V.A.
Garaiova, I.
Plummer, S.F.
Williams, E.A.
Corfe, B.M.
Background: Vitamin D deficiency has been associated or implicated with the pathophysiology of the gastrointestinal conditions inflammatory bowel disease and colorectal cancer, as well as with depression. No trials or epidemiology studies to date have investigated a link with irritable bowel syndrome (IBS). A single case report has suggested a benefit in IBS of vitamin D supplementation. We hypothesised that IBS participants with vitamin D insufficiency would benefit from repletion in terms of their IBS symptoms. We undertook a pilot trial to provide data to support a power calculation and to justify a full trial.
Methods: This was a randomised, double blinded, three-arm parallel design trial of vitamin D, placebo or a combination of vitamin D and probiotics. Participants were further stratified according to whether they were vitamin D replete or insufficient. Vitamin D status was determined by blood test at baseline and exit; IBS symptoms were assessed by validated questionnaire; dietary intakes were assessed by food frequency questionnaire.
Results: A significant proportion of the IBS population were vitamin D deficient, such that the replete stratum could not be adequately recruited. There was a significant association in the baseline data between circulating vitamin D level and quality of life (“How much has IBS affected your life?”). Supplementation significantly improved vitamin D level versus placebo. IBS symptoms were not significantly improved in this pilot, although a power calculation was enabled from the intervention data.
Conclusions: The IBS population exhibits significant levels of vitamin D insufficiency and would benefit from screening and possible supplementation. The impact of IBS on quality of life may be reduced by vitamin D level. Future trials should have a sample size of over 97
BMJ Publishing Group
2015-12-21
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/93031/1/Tazzyman%20et%20al%202015.pdf
Tazzyman, S., Richards, N., Trueman, A.R. et al. (6 more authors) (2015) Vitamin D associates with improved quality of life in participants with irritable bowel syndrome: outcomes from a pilot trial. BMJ Open Gastroenterology, 2. e000052. ISSN 2054-4774
http://dx.doi.org/10.1136/bmjgast-2015-000052
10.1136/bmjgast-2015-000052
oai:eprints.whiterose.ac.uk:93218
2023-06-23T21:57:04Z
7374617475733D707562
74797065733D61727469636C65
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544
756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
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https://eprints.whiterose.ac.uk/93218/
Side effects of analgesia may significantly reduce quality of life in symptomatic multiple myeloma: a cross-sectional prevalence study
Sloot, S.
Boland, J.
Snowden, J.A.
Ezaydi, Y.
Foster, A.
Gethin, A.
Green, T.
Chopra, L.
Verhagen, S.
Vissers, K.
Engels, Y.
Ahmedzai, S.H.
Background Pain is a common symptom in patients with
multiple myeloma (MM). Many patients are dependent on
analgesics and in particular opioids, but there is limited information
on the impact of these drugs and their side effects on
health-related quality of life (HRQoL).
Method In a cross-sectional study, semi-structured interviews
were performed in 21 patients attending the hospital with
symptomatic MM on pain medications. HRQoL was measured
using items 29 and 30 of the European Organisation for
Research and Treatment of Cancer (EORTC) QLQ-C30.
Results Patients were able to recall a median of two (range
0–4) analgesics. They spontaneously identified a median
of two (range 1–5) side effects attributable to their analgesic
medications. Patients’ assessment of HRQoL based on
the EORTC QLQ-C30 questions 29/30 was mean 48.3
(95 % CI; 38.7–57.9) out of 100. Patients’ assessment of
their HRQoL in the hypothetical situation, in which they
would not experience any side effects from analgesics, was
significantly higher: 62.6 (53.5–71.7) (t test, p=0.001).
Conclusion This study provides, for the first time, evidence
that side effects of analgesics are common in symptomatic
MM and may result in a statistically and clinically significant
reduction of self-reported HRQoL.
Springer Verlag
2014-08-28
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/93218/7/Side%20effects%20of%20analgesia%20may%20significantly%20reduce%20quality%20of%20life%20in%20symptomatic%20multiple%20myeloma%3A%20a%20cross-sectional%20prevalence%20study.pdf
Sloot, S., Boland, J., Snowden, J.A. et al. (9 more authors) (2014) Side effects of analgesia may significantly reduce quality of life in symptomatic multiple myeloma: a cross-sectional prevalence study. Supportive Care in Cancer, 23 (3). pp. 671-678. ISSN 0941-4355
http://dx.doi.org/10.1007/s00520-014-2358-1
10.1007/s00520-014-2358-1
oai:eprints.whiterose.ac.uk:93313
2016-12-17T01:38:06Z
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756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
756E69743D536865666669656C64:536865666669656C642E535448
696E737469747574696F6E3D536865666669656C64
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https://eprints.whiterose.ac.uk/93313/
Heterogeneity of luminal breast cancer characterised by immunohistochemical expression of basal markers
Sung, H.
Garcia-Closas, M.
Chang-Claude, J.
Blows, F.M.
Ali, H.R.
Figueroa, J.
Nevanlinna, H.
Fagerholm, R.
Heikkila, P.
Blomqvist, C.
Giles, G.G.
Milne, R.L.
Southey, M.C.
McLean, C.
Mannermaa, A.
Kosma, V.-M.
Kataja, V.
Sironen, R.
Couch, F.J.
Olson, J.E.
Hallberg, E.
Olswold, C.
Cox, A.
Cross, S.S.
Kraft, P.
Tamimi, R.M.
Eliassen, A.H.
Schmidt, M.K.
Bolla, M.K.
Wang, Q.
Easton, D.
Howat, W.J.
Coulson, P.
Pharoah, P.D.P.
Sherman, M.E.
Yang, X.R.
Background: Luminal A breast cancer defined as hormone receptor positive and human epidermal growth factor receptor 2 (HER2) negative is known to be heterogeneous. Previous study showed that luminal A tumours with the expression of basal markers ((cytokeratin (CK) 5 or CK5/6) or epidermal growth factor receptor (EGFR)) were associated with poorer prognosis compared with those that stained negative for basal markers. Prompted by this study, we assessed whether tumour characteristics and risk factors differed by basal marker status within luminal A tumours.
Methods: We pooled 5040 luminal A cases defined by immunohistochemistry (4490 basal-negative ((CK5 (or CK5/6))− and EGFR−) and 550 basal-positive ((CK5 (or CK5/6+)) or EGFR+)) from eight studies participating in the Breast Cancer Association Consortium. Case–case comparison was performed using unconditional logistic regression.
Results: Tumour characteristics and risk factors did not vary significantly by the expression of basal markers, although results suggested that basal-positive luminal tumours tended to be smaller and node negative, and were more common in women with a positive family history and lower body mass index.
Conclusions: Most established breast cancer risk factors were similar in basal-positive and basal-negative luminal A tumours. The non-significant but suggestive differences in tumour features and family history warrant further investigations.
Cancer Research UK
2016-02-02
Article
PeerReviewed
text
en
cc_by_nc_sa_4
https://eprints.whiterose.ac.uk/93313/1/bjc2015437a.pdf
Sung, H., Garcia-Closas, M., Chang-Claude, J. et al. (33 more authors) (2016) Heterogeneity of luminal breast cancer characterised by immunohistochemical expression of basal markers. British Journal of Cancer, 114 (3). pp. 298-304. ISSN 0007-0920
https://dx.doi.org/10.1038/bjc.2015.437
10.1038/bjc.2015.437
oai:eprints.whiterose.ac.uk:93340
2016-01-12T16:53:14Z
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756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
756E69743D536865666669656C64:536865666669656C642E464350:536865666669656C642E43484D
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696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/93340/
An Orally Bioavailable, Indole-3-glyoxylamide Based Series of Tubulin Polymerization Inhibitors Showing Tumor Growth Inhibition in a Mouse Xenograft Model of Head and Neck Cancer.
Colley, H.E.
Muthana, M.
Danson, S.J.
Jackson, L.V.
Brett, M.L.
Harrison, J.
Coole, S.F.
Mason, D.P.
Jennings, L.R.
Wong, M.
Tulasi, V.
Norman, D.
Lockey, P.M.
Williams, L.
Dossetter, A.G.
Griffen, E.J.
Thompson, M.J.
A number of indole-3-glyoxylamides have previously been reported as tubulin polymerization inhibitors, although none has yet been successfully developed clinically. We report here a new series of related compounds, modified according to a strategy of reducing aromatic ring count and introducing a greater degree of saturation, which retain potent tubulin polymerization activity but with a distinct SAR from previously documented libraries. A subset of active compounds from the reported series is shown to interact with tubulin at the colchicine binding site, disrupt the cellular microtubule network, and exert a cytotoxic effect against multiple cancer cell lines. Two compounds demonstrated significant tumor growth inhibition in a mouse xenograft model of head and neck cancer, a type of the disease which often proves resistant to chemotherapy, supporting further development of the current series as potential new therapeutics.
American Chemical Society
2015-12-10
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/93340/1/WRRO_93340.pdf
Colley, H.E., Muthana, M., Danson, S.J. et al. (14 more authors) (2015) An Orally Bioavailable, Indole-3-glyoxylamide Based Series of Tubulin Polymerization Inhibitors Showing Tumor Growth Inhibition in a Mouse Xenograft Model of Head and Neck Cancer. Journal of Medicinal Chemistry, 58 (23). 9309 - 9333. ISSN 0022-2623
http://dx.doi.org/10.1021/acs.jmedchem.5b01312
10.1021/acs.jmedchem.5b01312
oai:eprints.whiterose.ac.uk:93463
2016-01-26T13:26:40Z
7374617475733D707562
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756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
756E69743D536865666669656C64:536865666669656C642E535448
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https://eprints.whiterose.ac.uk/93463/
Crowdsourcing the General Public for Large Scale Molecular Pathology Studies in Cancer
Candido dos Reis, F.J.
Lynn, S.
Ali, H.R.
Eccles, D.
Hanby, A.
Provenzano, E.
Caldas, C.
Howat, W.J.
McDuffus, L.A.
Liu, B.
Daley, F.
Coulson, P.
Vyas, R.J.
Harris, L.M.
Owens, J.M.
Carton, A.F.M.
McQuillan, J.P.
Paterson, A.M.
Hirji, Z.
Christie, S.K.
Holmes, A.R.
Schmidt, M.K.
Garcia-Closas, M.
Easton, D.F.
Bolla, M.K.
Wang, Q.
Benitez, J.
Milne, R.L.
Mannermaa, A.
Couch, F.
Devilee, P.
Tollenaar, R.A.E.M.
Seynaeve, C.
Cox, A.
Cross, S.S.
Blows, F.M.
Sanders, J.
de Groot, R.
Figueroa, J.
Sherman, M.
Hooning, M.
Brenner, H.
Holleczek, B.
Stegmaier, C.
Lintott, C.
Pharoah, P.D.P.
Background: Citizen science, scientific research conducted by non-specialists, has the potential to facilitate biomedical research using available large-scale data, however validating the results is challenging. The Cell Slider is a citizen science project that intends to share images from tumors with the general public, enabling them to score tumor markers independently through an internet-based interface.
Methods: From October 2012 to June 2014, 98,293 Citizen Scientists accessed the Cell Slider web page and scored 180,172 sub-images derived from images of 12,326 tissue microarray cores labeled for estrogen receptor (ER). We evaluated the accuracy of Citizen Scientist's ER classification, and the association between ER status and prognosis by comparing their test performance against trained pathologists.
Findings: The area under ROC curve was 0.95 (95% CI 0.94 to 0.96) for cancer cell identification and 0.97 (95% CI 0.96 to 0.97) for ER status. ER positive tumors scored by Citizen Scientists were associated with survival in a similar way to that scored by trained pathologists. Survival probability at 15. years were 0.78 (95% CI 0.76 to 0.80) for ER-positive and 0.72 (95% CI 0.68 to 0.77) for ER-negative tumors based on Citizen Scientists classification. Based on pathologist classification, survival probability was 0.79 (95% CI 0.77 to 0.81) for ER-positive and 0.71 (95% CI 0.67 to 0.74) for ER-negative tumors. The hazard ratio for death was 0.26 (95% CI 0.18 to 0.37) at diagnosis and became greater than one after 6.5. years of follow-up for ER scored by Citizen Scientists, and 0.24 (95% CI 0.18 to 0.33) at diagnosis increasing thereafter to one after 6.7 (95% CI 4.1 to 10.9) years of follow-up for ER scored by pathologists.
Interpretation: Crowdsourcing of the general public to classify cancer pathology data for research is viable, engages the public and provides accurate ER data. Crowdsourced classification of research data may offer a valid solution to problems of throughput requiring human input.
Elsevier
2015-07-01
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/93463/1/1-s2.0-S2352396415300165-main.pdf
Candido dos Reis, F.J., Lynn, S., Ali, H.R. et al. (43 more authors) (2015) Crowdsourcing the General Public for Large Scale Molecular Pathology Studies in Cancer. EBioMedicine, 2 (7). 681 - 689. ISSN 2352-3964
http://dx.doi.org/10.1016/j.ebiom.2015.05.009
10.1016/j.ebiom.2015.05.009
oai:eprints.whiterose.ac.uk:93786
2016-11-15T18:00:34Z
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https://eprints.whiterose.ac.uk/93786/
Phase II/III weekly nab-paclitaxel plus gemcitabine or carboplatin versus gemcitabine/carboplatin as first-line treatment of patients with metastatic triple-negative breast cancer (the tnAcity study): study protocol for a randomized controlled trial
Yardley, D.A.
Brufsky, A.
Coleman, R.E.
Conte, P.F.
Cortes, J.
Glueck, S.
Nabholtz, J.-M.A.
O'Shaughnessy, J.
Beck, R.M.
Ko, A.
Renschler, M.F.
Barton, D.
Harbeck, N.
Background: Triple-negative breast cancer is an aggressive disease with unmet clinical needs. In a phase III study of patients with metastatic triple-negative breast cancer, first-line gemcitabine/carboplatin resulted in a median progression-free survival of 4.6 months. nab-Paclitaxel-based regimens (with gemcitabine or carboplatin ± bevacizumab) also demonstrated efficacy and safety in first-line phase II trials of human epidermal growth factor receptor 2-negative metastatic breast cancer.
Trial design: In this international, multicenter, open-label, randomized phase II/III trial, the efficacy and safety of first-line nab-paclitaxel with gemcitabine or with carboplatin will be compared with gemcitabine/carboplatin (control arm) for metastatic triple-negative breast cancer.
Methods: In the phase II portion, 240 patients with measurable metastatic triple-negative breast cancer and treatment naive for metastatic disease will be randomized 1:1:1 (stratified by disease-free interval: ≤ 1 versus > 1 year) to nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2, nab-paclitaxel 125 mg/m2 plus carboplatin area under the curve 2 mg × min/mL, or gemcitabine 1000 mg/m2 plus carboplatin area under the curve 2 mg × min/mL, all given on days 1 and 8 of a 21-day cycle. Investigator-assessed progression-free survival (primary endpoint), overall response rate, overall survival, and safety will be assessed. A ranking algorithm of five efficacy and safety parameters will be used to pick the “winner” of the nab-paclitaxel regimens. In the phase III portion, 550 patients will be randomized 1:1 (stratified by disease-free interval: ≤ 1 versus > 1 year, and prior adjuvant/neoadjuvant taxane use) to the nab-paclitaxel combination arm selected from the phase II portion or to the control arm. Patients in phase II will not be part of the phase III population. The phase III primary endpoint is blinded, independently-assessed progression-free survival; secondary endpoints include blinded, independently assessed overall response rate, overall survival, disease control rate, duration of response, and safety. Biomarker and circulating tumor-cell exploratory analyses and quality-of-life assessments will also be performed. A list of approving ethical bodies was provided in Additional file 1.
Discussion: The tnAcity trial aims to identify a new standard cytotoxic chemotherapy regimen for first-line treatment of metastatic triple-negative breast cancer.
BioMed Central
2015-12-16
Article
PeerReviewed
text
en
cc_by_4
https://eprints.whiterose.ac.uk/93786/13/art%253A10.1186%252Fs13063-015-1101-7%281%29.pdf
Yardley, D.A., Brufsky, A., Coleman, R.E. orcid.org/0000-0002-4275-1043 <https://orcid.org/0000-0002-4275-1043> et al. (10 more authors) (2015) Phase II/III weekly nab-paclitaxel plus gemcitabine or carboplatin versus gemcitabine/carboplatin as first-line treatment of patients with metastatic triple-negative breast cancer (the tnAcity study): study protocol for a randomized controlled trial. Trials, 16. 575. ISSN 1745-6215
http://www.doi.org/10.1186/s13063-015-1101-7
10.1186/s13063-015-1101-7
oai:eprints.whiterose.ac.uk:93787
2019-05-12T15:31:04Z
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https://eprints.whiterose.ac.uk/93787/
Enhanced MAF Oncogene Expression and Breast Cancer Bone Metastasis
Pavlovic, M.
Arnal-Estape, A.
Rojo, F.
Bellmunt, A.
Tarragona, M.
Guiu, M.
Planet, E.
Garcia-Albeniz, X.
Morales, M.
Urosevic, J.
Gawrzak, S.
Rovira, A.
Prat, A.
Nonell, L.
Lluch, A.
Jean-Mairet, J.
Coleman, R.
Albanell, J.
Gomis, R.R.
Background: There are currently no biomarkers for early breast cancer patient populations at risk of bone metastasis.
Identification of mediators of bone metastasis could be of clinical interest.
Methods: A de novo unbiased screening approach based on selection of highly bone metastatic breast cancer cells in vivo
was used to determine copy number aberrations (CNAs) associated with bone metastasis. The CNAs associated with bone
metastasis were examined in independent primary breast cancer datasets with annotated clinical follow-up. The MAF
gene encoded within the CNA associated with bone metastasis was subjected to gain and loss of function validation in
breast cancer cells (MCF7, T47D, ZR-75, and 4T1), its downstream mechanism validated, and tested in clinical samples.
A multivariable Cox cause-specific hazard model with competing events (death) was used to test the association between
16q23 or MAF and bone metastasis. All statistical tests were two-sided.
Results: 16q23 gain CNA encoding the transcription factor MAF mediates breast cancer bone metastasis through the control
of PTHrP. 16q23 gain (hazard ratio (HR) for bone metastasis = 14.5, 95% confidence interval (CI) = 6.4 to 32.9, P < .001) as well
as MAF overexpression (HR for bone metastasis = 2.5, 95% CI = 1.7 to 3.8, P < .001) in primary breast tumors were specifically
associated with risk of metastasis to bone but not to other organs.
Conclusions: These results suggest that MAF is a mediator of breast cancer bone metastasis. 16q23 gain or MAF protein
overexpression in tumors may help to select patients at risk of bone relapse.
Oxford University Press
2015-09-15
Article
PeerReviewed
text
en
cc_by_nc_nd_3
https://eprints.whiterose.ac.uk/93787/28/Enhanced%20MAF%20Oncogene%20Expression%20and%20Breast%20Cancer%20Bone%20Metastasis.pdf
Pavlovic, M., Arnal-Estape, A., Rojo, F. et al. (16 more authors) (2015) Enhanced MAF Oncogene Expression and Breast Cancer Bone Metastasis. JNCI: Journal of the National Cancer Institute, 107 (12). ARTN djv256. ISSN 0027-8874
http://dx.doi.org/10.1093/jnci/djv256
10.1093/jnci/djv256
oai:eprints.whiterose.ac.uk:94015
2016-01-21T11:18:52Z
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756E69743D536865666669656C64:536865666669656C642E535448
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7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/94015/
Multi-omic measurement of mutually exclusive loss-of-function enriches for candidate synthetic lethal gene pairs.
Wappett, M.
Dulak, A.
Yang, Z.R.
Al-Watban, A.
Bradford, J.R.
Dry, J.R.
BACKGROUND: Identification of synthetic lethal interactions in cancer cells could offer promising new therapeutic targets. Large-scale functional genomic screening presents an opportunity to test large numbers of cancer synthetic lethal hypotheses. Methods enriching for candidate synthetic lethal targets in molecularly defined cancer cell lines can steer effective design of screening efforts. Loss of one partner of a synthetic lethal gene pair creates a dependency on the other, thus synthetic lethal gene pairs should never show simultaneous loss-of-function. We have developed a computational approach to mine large multi-omic cancer data sets and identify gene pairs with mutually exclusive loss-of-function. Since loss-of-function may not always be genetic, we look for deleterious mutations, gene deletion and/or loss of mRNA expression by bimodality defined with a novel algorithm BiSEp.
RESULTS: Applying this toolkit to both tumour cell line and patient data, we achieve statistically significant enrichment for experimentally validated tumour suppressor genes and synthetic lethal gene pairings. Notably non-reliance on genetic loss reveals a number of known synthetic lethal relationships otherwise missed, resulting in marked improvement over genetic-only predictions. We go on to establish biological rationale surrounding a number of novel candidate synthetic lethal gene pairs with demonstrated dependencies in published cancer cell line shRNA screens.
CONCLUSIONS: This work introduces a multi-omic approach to define gene loss-of-function, and enrich for candidate synthetic lethal gene pairs in cell lines testable through functional screens. In doing so, we offer an additional resource to generate new cancer drug target and combination hypotheses. Algorithms discussed are freely available in the BiSEp CRAN package at http://cran.r-project.org/web/packages/BiSEp/index.html .
BioMed Central
2016-01-16
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/94015/1/art%253A10.1186%252Fs12864-016-2375-1.pdf
Wappett, M., Dulak, A., Yang, Z.R. et al. (3 more authors) (2016) Multi-omic measurement of mutually exclusive loss-of-function enriches for candidate synthetic lethal gene pairs. BMC Genomics, 17. 65. ISSN 1471-2164
http://dx.doi.org/10.1186/s12864-016-2375-1
10.1186/s12864-016-2375-1
oai:eprints.whiterose.ac.uk:94191
2016-04-12T09:45:46Z
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https://eprints.whiterose.ac.uk/94191/
Symptom burden, palliative care need and predictors of physical and psychological discomfort in two UK hospitals
Ryan, T.
Ingleton, C.
Gardiner, C.
Parker, C.
Gott, M.
Noble, B.
Background: The requirement to meet the palliative needs of acute hospital populations has grown in recent
years. With increasing numbers of frail older people needing hospital care as a result of both malignant and nonmalignant
conditions, emphasis is being placed upon understanding the physical, psychological and social burdens
experienced by patients. This study explores the extent of burden in two large UK hospitals, focusing upon those
patients who meet palliative care criteria. Furthermore, the paper explores the use of palliative services and
identifies the most significant clinical diagnostic and demographic factors which determine physical and
psychological burden.
Methods: Two hospital surveys were undertaken to identify burden using the Sheffield Profile for Assessment and
Referral to Care (SPARC). The Gold Standards Framework (GSF) is used to identify those patients meeting palliative
care criteria. Participants were identified as being in-patients during a two-week data collection phase for each site.
Data was gathered using face-to-face interviews or self-completion by patients or a proxy. Descriptive analyses
highlight prevalence and use of palliative care provision. Binary logistic regression assesses clinical diagnostic
predictor variables of physical and psychological burden.
Results: The sample consisted of 514 patients and elevated physical, psychological and social burden is identified
amongst those meeting palliative care criteria (n = 185). Tiredness (34.6%), pain (31.1%), weakness (28.8%) and
psychological discomfort (low mood 19.9%; anxiety 16.1%) are noted as being prevalent. A small number of these
participants accessed Specialist Palliative Care (8.2%). Dementia was identified as a predictor of physical (OR 3.94; p
< .05) and psychological burden (OR 2.88; p < .05), being female was a predictor of psychological burden (OR 2.00;
p < .05).
Conclusion: The paper highlights elevated levels of burden experienced by patients with palliative care
requirements. Moreover, the paper also indicates that a large proportion of such patients are not in receipt of
palliative approaches to their care. Furthermore, the paper identifies that those with non-malignant illnesses,
especially dementia, may experience high levels of physical and psychological burden.
BioMed Central
2013-02-26
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/94191/1/Symptom%20burden%2C%20palliative%20care%20need%20and%20predictors%20of%20physical%20and%20psychological%20discomfort%20in%20two%20UK%20hospitals..pdf
Ryan, T., Ingleton, C., Gardiner, C. orcid.org/0000-0003-1785-7054 <https://orcid.org/0000-0003-1785-7054> et al. (3 more authors) (2013) Symptom burden, palliative care need and predictors of physical and psychological discomfort in two UK hospitals. BMC PALLIATIVE CARE, 12. 11. ISSN 1472-684X
http://dx.doi.org/10.1186/1472-684X-12-11
10.1186/1472-684X-12-11
oai:eprints.whiterose.ac.uk:94192
2016-04-13T10:37:35Z
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756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
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https://eprints.whiterose.ac.uk/94192/
What is the extent of potentially avoidable admissions amongst hospital inpatients with palliative care needs?
Gott, M.
Gardiner, C.
Ingleton, C.
Cobb, M.
Noble, B.
Bennett, M.I.
Seymour, J.
Background: There is clear evidence that the full range of services required to support people dying at home are far from being implemented, either in England or elsewhere. No studies to date have attempted to identify the proportion of hospital admissions that could have been avoided amongst patients with palliative care needs, given existing and current local services. This study aimed to examine the extent of potentially avoidable admissions amongst hospital patients with palliative care needs.
Methods: A cross sectional survey of palliative care needs was undertaken in two acute hospitals in England. Appropriateness of admission was assessed by two Palliative Medicine Consultants using the following data collected from case notes: reasons for admission; diagnosis and co-morbidities; age and living arrangements; time and route of admission; medical and nursing plan on admission; specialist palliative care involvement; and evidence of cognitive impairment.
Results: A total of 1359 inpatients were present in the two hospitals at the time of the census. Of the 654
consenting patients/consultees, complete case note data were collected for 580 patients; the analysis in this paper relates to these 580 patients. Amongst 208 patients meeting diagnostic and prognostic criteria for palliative care need in two acute settings in England, only 6.7% were identified as ‘potentially avoidable’ hospitalisations. These patients had a median age of 84. Half of the patients lived in residential or nursing homes and it was concluded that most could have received care in this setting in place of hospital.
Conclusion: Our findings challenge assumptions that, within the existing configuration of palliative and end of life health and social care services, patients with palliative care needs experience a high level of potentially avoidable hospitalisations.
Keywords: Palliative care needs, End of life, Avoidable admissions, Inappropriate admissions, Survey, Acute hospital
BioMed Central
2013-02-18
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/94192/1/What%20is%20the%20extent%20of%20potentially%20avoidable%20admissions%20amongst%20hospital%20inpatients%20with%20palliative%20care%20needs%3F.pdf
Gott, M., Gardiner, C. orcid.org/0000-0003-1785-7054 <https://orcid.org/0000-0003-1785-7054>, Ingleton, C. et al. (4 more authors) (2013) What is the extent of potentially avoidable admissions amongst hospital inpatients with palliative care needs? BMC Palliative Care, 12 (9). ISSN 1472-684X
http://dx.doi.org/10.1186/1472-684X-12-9
10.1186/1472-684X-12-9
oai:eprints.whiterose.ac.uk:94772
2017-11-05T22:49:56Z
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https://eprints.whiterose.ac.uk/94772/
Discordant Haplotype Sequencing Identifies Functional Variants at the 2q33 Breast Cancer Risk Locus.
Camp, N.J.
Lin, W.Y.
Bigelow, A.
Burghel, G.J.
Mosbruger, T.
Parry, M.
Waller, R.G.
Rigas, S.H.
Tai, P.Y.
Berrett, K.
Rajamanickam, V.
Cosby, R.
Brock, I.W.
Jones, B.
Connley, D.
Sargent, R.
Wang, G.
Factor, R.E.
Bernard, P.S.
Cannon-Albright, L.
Knight, S.
Abo, R.
Werner, T.L.
Reed, M.W.
Gertz, J.
Cox, A.
The findings from genome-wide association studies hold enormous potential for novel insight into disease mechanisms. A major challenge in the field is to map these low risk association signals to their underlying functional sequence variants (FSVs). Simple sequence study designs are insufficient, as the vast numbers of statistically comparable variants and a limited knowledge of non-coding regulatory elements complicate prioritization. Furthermore, large sample sizes are typically required for adequate power to identify the initial association signals. One important question is whether similar sample sizes need to be sequenced to identify the FSVs. Here, we present a proof of principle example of an extreme discordant design to map FSVs within the 2q33 low-risk breast cancer locus. Our approach employed DNA sequencing of a small number of discordant haplotypes to efficiently identify candidate-FSVs. Our results were consistent with those from a 2000-fold larger, traditional imputation-based fine-mapping study. To prioritize further, we used expression-quantitative trait locus (eQTL) analysis of RNA sequencing from breast tissues, gene regulation annotations from the ENCODE consortium, and functional assays for differential enhancer activities. Notably, we implicate three regulatory variants at 2q33 that target CASP8 (rs3769823, rs3769821 in CASP8, and rs10197246 in ALS2CR12) as functionally relevant. We conclude that nested discordant haplotype sequencing is a promising approach to aid mapping of low-risk association loci. The ability to include more efficient sequencing designs into mapping efforts presents an opportunity for the field to capitalize on the potential of association loci and accelerate translation of association signals to their underlying FSVs.
American Association for Cancer Research
2016-04-01
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/94772/7/NIHMS67225.pdf
text
en
https://eprints.whiterose.ac.uk/94772/13/WRRO_94772.pdf
Camp, N.J., Lin, W.Y., Bigelow, A. et al. (23 more authors) (2016) Discordant Haplotype Sequencing Identifies Functional Variants at the 2q33 Breast Cancer Risk Locus. Cancer Research, 76 (7). pp. 1916-1925. ISSN 0008-5472
http://dx.doi.org/10.1158/0008-5472.CAN-15-1629
10.1158/0008-5472.CAN-15-1629
oai:eprints.whiterose.ac.uk:94773
2023-06-23T21:59:02Z
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https://eprints.whiterose.ac.uk/94773/
Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium
Lei, J.
Rudolph, A.
Moysich, K.B.
Behrens, S.
Goode, E.L.
Bolla, M.K.
Dennis, J.
Dunning, A.M.
Easton, D.F.
Wang, Q.
Benitez, J.
Hopper, J.L.
Southey, M.C.
Schmidt, M.K.
Broeks, A.
Fasching, P.A.
Haeberle, L.
Peto, J.
dos-Santos-Silva, I.
Sawyer, E.J.
Tomlinson, I.
Burwinkel, B.
Marmé, F.
Guénel, P.
Truong, T.
Bojesen, S.E.
Flyger, H.
Nielsen, S.F.
Nordestgaard, B.G.
González-Neira, A.
Menéndez, P.
Anton-Culver, H.
Neuhausen, S.L.
Brenner, H.
Arndt, V.
Meindl, A.
Schmutzler, R.K.
Brauch, H.
Hamann, U.
Nevanlinna, H.
Fagerholm, R.
Dörk, T.
Bogdanova, N.V.
Mannermaa, A.
Hartikainen, J.M.
Australian, O.S.G.
kConFab, I.
Van Dijck, L.
Smeets, A.
Flesch-Janys, D.
Eilber, U.
Radice, P.
Peterlongo, P.
Couch, F.J.
Hallberg, E.
Giles, G.G.
Milne, R.L.
Haiman, C.A.
Schumacher, F.
Simard, J.
Goldberg, M.S.
Kristensen, V.
Borresen-Dale, A.L.
Zheng, W.
Beeghly-Fadiel, A.
Winqvist, R.
Grip, M.
Andrulis, I.L.
Glendon, G.
García-Closas, M.
Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03–1.08; p value = 1.4 × 10−6). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10−3 and 7.0 × 10−3, respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10−3, 4.5 × 10−4 and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3,IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.
Springer Verlag
2016-01-01
Article
PeerReviewed
text
en
cc_by_4
https://eprints.whiterose.ac.uk/94773/3/art%253A10.1007%252Fs00439-015-1616-8.pdf
Lei, J., Rudolph, A., Moysich, K.B. et al. (67 more authors) (2016) Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium. Human Genetics, 135 (1). pp. 137-154. ISSN 0340-6717
http://dx.doi.org/10.1007/s00439-015-1616-8
10.1007/s00439-015-1616-8
oai:eprints.whiterose.ac.uk:95277
2016-03-07T14:23:27Z
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https://eprints.whiterose.ac.uk/95277/
The mortality of patients admitted with hip fracture and consolidation on chest radiograph
Paavana, T.
Lee, M.J.
Elphick, H.L.
Oxford University Press
2015-09
Article
NonPeerReviewed
Paavana, T., Lee, M.J. and Elphick, H.L. (2015) The mortality of patients admitted with hip fracture and consolidation on chest radiograph. Age and Ageing, 44. p. 4. ISSN 0002-0729
http://dx.doi.org/10.1093/ageing/afv106.15
10.1093/ageing/afv106.15
oai:eprints.whiterose.ac.uk:95304
2016-02-22T16:00:58Z
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https://eprints.whiterose.ac.uk/95304/
A TNF Variant that Associates with Susceptibility to Musculoskeletal Disease Modulates Thyroid Hormone Receptor Binding to Control Promoter Activation
Kiss-Toth, E.
Harlock, E.
Lath, D.
Quertermous, T.
Wilkinson, J.M.
Tumor necrosis factor (TNF) is a powerful pro-inflammatory cytokine and immuno-regulatory molecule, and
modulates susceptibility to musculoskeletal diseases. Several meta-analyses and replicated association studies have
implicated the minor ‘A’ variant within the TNF promoter single nucleotide polymorphism (SNP) rs361525 (-238A/G)
as a risk allele in joint related disorders, including psoriatic and juvenile idiopathic arthritis, and osteolysis after joint
arthroplasty. Here we characterized the effect of this variant on TNF promoter function. A transcriptional reporter,
encoding the -238A variant of the TNF promoter, resulted in 2.2 to 2.8 times greater transcriptional activation versus
the ‘G’ variant in murine macrophages when stimulated with pro-inflammatory stimuli. Bioinformatic analysis
predicted a putative binding site for thyroid hormone receptor (TR) for the -238A but not the -238G allele.
Overexpression of TR-α induced promoter expression 1.8-fold in the presence of the ‘A’ allele only. TR-α expression
both potentiated and sensitized the -238A response to LPS or a titanium particulate stimulus, whilst siRNA
knockdown of either THRA or THRB impaired transcriptional activation for the -238A variant only. This effect was
independent of receptor-ligand binding of triiodothyronine. Immunohistochemical analysis of osteolysis interface
membranes from patients undergoing revision surgery confirmed expression of TR-α within osteoclast nuclei at the
resorption surface. The ‘A’ allele at rs361525 confers increased transcriptional activation of the TNF promoter and
influences susceptibility to several arthritic conditions. This effect is modulated, at least in part, by binding of TR,
which both sensitizes and potentiates transcriptional activation of the ‘A’ variant independent of its endogenous
ligand.
Public Library of Science
2013-09-19
Article
PeerReviewed
text
en
cc_public_domain
https://eprints.whiterose.ac.uk/95304/1/A%20TNF%20variant%20that%20associates%20with%20susceptibility%20to%20musculoskeletal%20disease%20modulates%20thyroid%20hormone%20receptor%20binding%20to%20control%20promoter%20activation..pdf
Kiss-Toth, E., Harlock, E., Lath, D. et al. (2 more authors) (2013) A TNF Variant that Associates with Susceptibility to Musculoskeletal Disease Modulates Thyroid Hormone Receptor Binding to Control Promoter Activation. PLOS One, 8 (9). e76034. ISSN 1932-6203
http://dx.doi.org/10.1371/journal.pone.0076034
10.1371/journal.pone.0076034
oai:eprints.whiterose.ac.uk:95402
2016-11-03T08:02:10Z
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https://eprints.whiterose.ac.uk/95402/
The relationship between smoking and quality of life in advanced lung cancer patients: a prospective longitudinal study.
Danson, S.J.
Rowland, C.
Rowe, R.
Ellis, S.
Crabtree, C.
Horsman, J.M.
Wadsley, J.
Hatton, M.Q.
Woll, P.J.
Eiser, C.
PURPOSE: Smoking is a major cause of lung cancer, and continued smoking may compromise treatment efficacy and quality of life (health-related quality of life (HRQoL)) in patients with advanced lung cancer. Our aims were to determine (i) preference for treatments which promote quality over length of life depending on smoking status, (ii) the relationship between HRQoL and smoking status at diagnosis (T1), after controlling for demographic and clinical variables, and (iii) changes in HRQoL 6 months after diagnosis (T2) depending on smoking status. METHODS: Two hundred ninety-six patients with advanced lung cancer were given questionnaires to assess HRQoL (EORTC QLQ-C30), time-trade-off for life quality versus quantity (QQQ) and smoking history (current, former or never smoker) at diagnosis (T1) and 6 months later (T2). Medical data were extracted from case records. RESULTS: Questionnaires were returned by 202 (68.2 %) patients at T1 and 114 (53.3 %) at T2. Patients favoured treatments that would enhance quality of life over increased longevity. Those who continued smoking after diagnosis reported worse HRQoL than former smokers or those who never smoked. Smoking status was a significant independent predictor of coughing in T1 (worse in smokers) and cognitive functioning in T2 (better in never smokers). CONCLUSIONS: Smoking by patients with advanced lung cancer is associated with worse symptoms on diagnosis and poorer HRQoL for those who continue smoking. The results have implications to help staff explain the consequences of smoking to patients.
Springer Verlag
2015-09-12
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/95402/2/QOLAS%2520SCC%2520revision%2520210815.pdf
Danson, S.J., Rowland, C., Rowe, R. et al. (7 more authors) (2015) The relationship between smoking and quality of life in advanced lung cancer patients: a prospective longitudinal study. Supportive Care in Cancer. ISSN 0941-4355
https://dx.doi.org/10.1007/s00520-015-2928-x
10.1007/s00520-015-2928-x
oai:eprints.whiterose.ac.uk:95477
2016-02-23T09:47:35Z
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https://eprints.whiterose.ac.uk/95477/
Genetic predisposition to ductal carcinoma in situ of the breast
Petridis, C.
Brook, M.N.
Shah, V.
Kohut, K.
Gorman, P.
Caneppele, M.
Levi, D.
Papouli, E.
Orr, N.
Cox, A.
Cross, S.S.
Dos-Santos-Silva, I.
Peto, J.
Swerdlow, A.
Schoemaker, M.J.
Bolla, M.K.
Wang, Q.
Dennis, J.
Michailidou, K.
Benitez, J.
González-Neira, A.
Tessier, D.C.
Vincent, D.
Li, J.
Figueroa, J.
Kristensen, V.
Borresen-Dale, A.L.
Soucy, P.
Simard, J.
Milne, R.L.
Giles, G.G.
Margolin, S.
Lindblom, A.
Brüning, T.
Brauch, H.
Southey, M.C.
Hopper, J.L.
Dörk, T.
Bogdanova, N.V.
Kabisch, M.
Hamann, U.
Schmutzler, R.K.
Meindl, A.
Brenner, H.
Arndt, V.
Winqvist, R.
Pylkäs, K.
Fasching, P.A.
Beckmann, M.W.
Lubinski, J.
Jakubowska, A.
Mulligan, A.M.
Andrulis, I.L.
Tollenaar, R.A.
Devilee, P.
Le Marchand, L.
Haiman, C.A.
Mannermaa, A.
Kosma, V.M.
Radice, P.
Peterlongo, P.
Marme, F.
Burwinkel, B.
van Deurzen, C.H.
Hollestelle, A.
Miller, N.
Kerin, M.J.
Lambrechts, D.
Floris, G.
Wesseling, J.
Flyger, H.
Bojesen, S.E.
Yao, S.
Ambrosone, C.B.
Chenevix-Trench, G.
Truong, T.
Guénel, P.
Rudolph, A.
Chang-Claude, J.
Nevanlinna, H.
Blomqvist, C.
Czene, K.
Brand, J.S.
Olson, J.E.
Couch, F.J.
Dunning, A.M.
Hall, P.
Easton, D.F.
Pharoah, P.D.
Pinder, S.E.
Schmidt, M.K.
Tomlinson, I.
Roylance, R.
García-Closas, M.
Sawyer, E.J.
BACKGROUND: Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer. It is often associated with invasive ductal carcinoma (IDC), and is considered to be a non-obligate precursor of IDC. It is not clear to what extent these two forms of cancer share low-risk susceptibility loci, or whether there are differences in the strength of association for shared loci.
METHODS: To identify genetic polymorphisms that predispose to DCIS, we pooled data from 38 studies comprising 5,067 cases of DCIS, 24,584 cases of IDC and 37,467 controls, all genotyped using the iCOGS chip.
RESULTS: Most (67 %) of the 76 known breast cancer predisposition loci showed an association with DCIS in the same direction as previously reported for invasive breast cancer. Case-only analysis showed no evidence for differences between associations for IDC and DCIS after considering multiple testing. Analysis by estrogen receptor (ER) status confirmed that loci associated with ER positive IDC were also associated with ER positive DCIS. Analysis of DCIS by grade suggested that two independent SNPs at 11q13.3 near CCND1 were specific to low/intermediate grade DCIS (rs75915166, rs554219). These associations with grade remained after adjusting for ER status and were also found in IDC. We found no novel DCIS-specific loci at a genome wide significance level of P < 5.0x10(-8).
CONCLUSION: In conclusion, this study provides the strongest evidence to date of a shared genetic susceptibility for IDC and DCIS. Studies with larger numbers of DCIS are needed to determine if IDC or DCIS specific loci exist.
BioMed Central
2016-02-17
Article
PeerReviewed
text
en
cc_by_4
https://eprints.whiterose.ac.uk/95477/1/13058_2016_675_OnlinePDF.pdf
Petridis, C., Brook, M.N., Shah, V. et al. (92 more authors) (2016) Genetic predisposition to ductal carcinoma in situ of the breast. Breast Cancer Research, 18 (1). 22. ISSN 1465-542X
http://dx.doi.org/10.1186/s13058-016-0675-7
10.1186/s13058-016-0675-7
oai:eprints.whiterose.ac.uk:95523
2016-08-05T11:10:15Z
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https://eprints.whiterose.ac.uk/95523/
Directing cell therapy to anatomic target sites in vivo with magnetic resonance targeting
Muthana, M.
Kennerley, A.J.
Hughes, R.
Fagnano, E.
Richardson, J.
Paul, M.
Murdoch, C.
Wright, F.
Payne, C.
Lythgoe, M.F.
Farrow, N.
Dobson, J.
Conner, J.
Wild, J.M.
Lewis, C.
Cell-based therapy exploits modified human cells to treat diseases but its targeted application
in specific tissues, particularly those lying deep in the body where direct injection is not
possible, has been problematic. Here we use a magnetic resonance imaging (MRI) system to
direct macrophages carrying an oncolytic virus, Seprehvir, into primary and metastatic tumour
sites in mice. To achieve this, we magnetically label macrophages with super-paramagnetic
iron oxide nanoparticles and apply pulsed magnetic field gradients in the direction of the
tumour sites. Magnetic resonance targeting guides macrophages from the bloodstream into
tumours, resulting in increased tumour macrophage infiltration and reduction in tumour
burden and metastasis. Our study indicates that clinical MRI scanners can not only track the
location of magnetically labelled cells but also have the potential to steer them into one or
more target tissues.
Nature Publishing Group
2015-08-18
Article
PeerReviewed
text
en
cc_by_4
https://eprints.whiterose.ac.uk/95523/1/Muthana%20et%20al.%202015%20NC.pdf
Muthana, M., Kennerley, A.J., Hughes, R. et al. (12 more authors) (2015) Directing cell therapy to anatomic target sites in vivo with magnetic resonance targeting. Nature Communications, 6. 8009.
http://dx.doi.org/10.1038/ncomms9009
10.1038/ncomms9009
oai:eprints.whiterose.ac.uk:95625
2016-08-03T15:28:04Z
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https://eprints.whiterose.ac.uk/95625/
Identification of Candidate Driver Genes in Common Focal Chromosomal Aberrations of Microsatellite Stable Colorectal Cancer
Burghel, G.J.
Lin, W-Y.
Whitehouse, H.
Brock, I.
Hammond, D.
Bury, J.
Stephenson, Y.
George, R.
Cox, A.
Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. Chromosomal instability (CIN) is a major
driving force of microsatellite stable (MSS) sporadic CRC. CIN tumours are characterised by a large number of
somatic chromosomal copy number aberrations (SCNA) that frequently affect oncogenes and tumour suppressor
genes. The main aim of this work was to identify novel candidate CRC driver genes affected by recurrent and focal
SCNA. High resolution genome-wide comparative genome hybridisation (CGH) arrays were used to compare tumour
and normal DNA for 53 sporadic CRC cases. Context corrected common aberration (COCA) analysis and custom
algorithms identified 64 deletions and 32 gains of focal minimal common regions (FMCR) at high frequency (>10%).
Comparison of these FMCR with published genomic profiles from CRC revealed common overlap (42.2% of
deletions and 34.4% of copy gains). Pathway analysis showed that apoptosis and p53 signalling pathways were
commonly affected by deleted FMCR, and MAPK and potassium channel pathways by gains of FMCR. Candidate
tumour suppressor genes in deleted FMCR included RASSF3, IFNAR1, IFNAR2 and NFKBIA and candidate
oncogenes in gained FMCR included PRDM16, TNS1, RPA3 and KCNMA1. In conclusion, this study confirms some
previously identified aberrations in MSS CRC and provides in silico evidence for some novel candidate driver genes
Public Library of Science
2013-12-18
Article
PeerReviewed
text
en
cc_public_domain
https://eprints.whiterose.ac.uk/95625/1/Identification%20of%20candidate%20driver%20genes%20in%20common%20focal%20chromosomal%20aberrations%20of%20microsatellite%20stable%20colorectal%20cancer..pdf
Burghel, G.J., Lin, W-Y., Whitehouse, H. et al. (6 more authors) (2013) Identification of Candidate Driver Genes in Common Focal Chromosomal Aberrations of Microsatellite Stable Colorectal Cancer. PLOS ONE, 8 (12). UNSP e83859. ISSN 1932-6203
http://dx.doi.org/10.1371/journal.pone.0083859
10.1371/journal.pone.0083859
oai:eprints.whiterose.ac.uk:95897
2017-07-01T09:36:39Z
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https://eprints.whiterose.ac.uk/95897/
Eribulin in soft-tissue sarcoma.
Young, R.J.
Woll, P.J.
Elsevier
2016-04
Article
NonPeerReviewed
text
en
https://eprints.whiterose.ac.uk/95897/1/RY%20Eribulin%20commentary%20FINAL.pdf
Young, R.J. and Woll, P.J. (2016) Eribulin in soft-tissue sarcoma. Lancet, 387 (10028). pp. 1594-1596. ISSN 0140-6736
http://dx.doi.org/10.1016/S0140-6736(16)00162-8
10.1016/S0140-6736(16)00162-8
oai:eprints.whiterose.ac.uk:95898
2016-04-12T15:15:35Z
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https://eprints.whiterose.ac.uk/95898/
Molecular Alterations Associated with
Osteosarcoma Development
Ando, K.
Mori, K.
Verrecchia, F.
Marc, B.
Rédini, F.
Heymann, D.
Osteosarcoma is the most frequent malignant primary bone tumor characterized by a high potency to form lung metastases which
is the main cause of death. Unfortunately, the conventional chemotherapy is not fully effective on osteosarcoma metastases. The
progression of a primary tumor to metastasis requires multiple processes, which are neovascularization, proliferation, invasion,
survival in the bloodstream, apoptosis resistance, arrest at a distant organ, and outgrowth in secondary sites. Consequently,
recent studies have revealed new insights into the molecular mechanisms of metastasis development. The understanding of the
mechanism of molecular alterations can provide the identification of novel therapeutic targets and/or prognostic markers for
osteosarcoma treatment to improve the clinical outcome.
Hindawi Publishing Corporation
2012
Article
PeerReviewed
text
en
cc_by_3
https://eprints.whiterose.ac.uk/95898/1/Molecular%20alterations%20associated%20with%20osteosarcoma%20development..pdf
Ando, K., Mori, K., Verrecchia, F. et al. (3 more authors) (2012) Molecular Alterations Associated with Osteosarcoma Development. Sarcoma, 2012. 523432. ISSN 1357-714X
http://dx.doi.org/10.1155/2012/523432
10.1155/2012/523432
oai:eprints.whiterose.ac.uk:95899
2016-04-12T15:19:52Z
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https://eprints.whiterose.ac.uk/95899/
Pericyte-Like Progenitors Show High Immaturity and
Engraftment Potential as Compared with Mesenchymal
Stem Cells
Bouacida, A.
Rosset, P.
Trichet, V.
Guilloton, F.
Espagnolle, N.
Cordonier, T.
Heymann, D.
Layrolle, P.
Sensebe, L.
Deschaseaux, F.
Mesenchymal stem cells (MSCs) and pericyte progenitors (PPs) are both perivascular cells with similar multipotential
properties regardless of tissue of origin. We compared the phenotype and function of the 2 cell types derived from the
same bone-marrow samples but expanded in their respective media – pericyte conditions (endothelial cell growth medium
2 [EGM-2]) for PPs and standard medium (mesenchymal stem cell medium [MSM]) for MSCs. After 3 weeks of culture,
whatever the expansion medium, all cells showed similar characteristics (MSC markers and adipo-osteo-chondroblastic
differentiation potential), although neuronal potential was greater in EGM-2– than MSM-cultured cells. As compared with
MSM-cultured MSCs, EGM-2–cultured PPs showed higher expression of the pericyte-specific antigen 3G5 than a-smooth
muscle actin. In addition, EGM-2–cultured PPs showed an immature phenotype, with upregulation of stemness OCT4 and
SOX2 proteins and downregulation of markers of osteoblastic, chondroblastic, adipocytic and vascular smooth muscle
lineages. Despite having less effective in vitro immunosuppression capacities than standard MSCs, EGM-2–cultured PPs had
higher engraftment potentials when combined with biomaterials heterotopically-transplanted in Nude mice. Furthermore,
these engrafted cells generated more collagen matrix and were preferentially perivascular or lined trabeculae as compared
with MSM-cultured MSCs. In conclusion, EGM-2–cultured PPs are highly immature cells with increased plasticity and
engraftment potential.
Public Library of Science
2012-11-07
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/95899/1/Pericyte-like%20progenitors%20show%20high%20immaturity%20and%20engraftment%20potential%20as%20compared%20with%20mesenchymal%20stem%20cells..pdf
Bouacida, A., Rosset, P., Trichet, V. et al. (7 more authors) (2012) Pericyte-Like Progenitors Show High Immaturity and Engraftment Potential as Compared with Mesenchymal Stem Cells. PLoS ONE, 7 (11). e48648. ISSN 1932-6203
http://dx.doi.org/10.1371/journal.pone.0048648
10.1371/journal.pone.0048648
oai:eprints.whiterose.ac.uk:95900
2016-04-13T09:16:04Z
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https://eprints.whiterose.ac.uk/95900/
Constitutive Expression of TNF-Related Activation-Induced Cytokine (TRANCE)/Receptor Activating NF-kappa B Ligand (RANK)-L by Rat Plasmacytoid Dendritic Cells
Anjubault, T.
Martin, J.
Hubert, F-X.
Chauvin, C.
Heymann, D.
Josien, R.
Plasmacytoid dendritic cells (pDCs) are a subset of DCs whose major function relies on their capacity to produce large
amount of type I IFN upon stimulation via TLR 7 and 9. This function is evolutionary conserved and place pDC in critical
position in the innate immune response to virus. Here we show that rat pDC constitutively express TNF-related activationinduced
cytokine (TRANCE) also known as Receptor-activating NF-kB ligand (RANKL). TRANCE/RANKL is a member of the
TNF superfamily which plays a central role in osteoclastogenesis through its interaction with its receptor RANK. TRANCE/
RANK interaction are also involved in lymphoid organogenesis as well as T cell/DC cross talk. Unlike conventional DC, rat
CD4high pDC were shown to constitutively express TRANCE/RANKL both at the mRNA and the surface protein level. TRANCE/
RANKL was also induced on the CD4low subsets of pDC following activation by CpG. The secreted form of TRANCE/RANKL
was also produced by rat pDC. Of note, levels of mRNA, surface and secreted TRANCE/RANKL expression were similar to that
observed for activated T cells. TRANCE/RANKL expression was found on pDC in all lymphoid organs as well blood and BM
with a maximum expression in mesenteric lymph nodes. Despite this TRANCE/RANKL expression, we were unable to
demonstrate in vitro osteoclastogenesis activity for rat pDC. Taken together, these data identifies pDC as novel source of TRANCE/RANKL in the immune system.
Public Library of Science
2012-03-13
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/95900/1/Constitutive%20expression%20of%20TNF-related%20activation-induced%20cytokine%20%28TRANCE%29/receptor%20activating%20NF-%CE%BAB%20ligand%20%28RANK%29-L%20by%20rat%20plasmacytoid%20dendritic%20cells..pdf
Anjubault, T., Martin, J., Hubert, F-X. et al. (3 more authors) (2012) Constitutive Expression of TNF-Related Activation-Induced Cytokine (TRANCE)/Receptor Activating NF-kappa B Ligand (RANK)-L by Rat Plasmacytoid Dendritic Cells. PLoS ONE, 7 (3). e33713. ISSN 1932-6203
http://dx.doi.org/10.1371/journal.pone.0033713
10.1371/journal.pone.0033713
oai:eprints.whiterose.ac.uk:95901
2016-04-13T09:36:46Z
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756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
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https://eprints.whiterose.ac.uk/95901/
Osteoprotegerin, Pericytes and Bone-Like Vascular Calcification Are Associated with Carotid Plaque Stability
Davaine, J-M.
Quillard, T.
Brion, R.
Laperine, O.
Guyomarch, B.
Merlini, T.
Chatelais, M.
Guilbaud, F.
Brennan, M.A.
Charrier, C.
Heymann, D.
Goueffic, Y.
Heymann, M-F.
Background and Purpose: Vascular calcification, recapitulating bone formation, has a profound impact on plaque stability.
The aim of the present study was to determine the influence of bone-like vascular calcification (named osteoid
metaplasia = OM) and of osteoprotegerin on plaque stability.
Methods: Tissue from carotid endarterectomies were analysed for the presence of calcification and signs of vulnerability
according to AHA grading system. Osteoprotegerin (OPG), pericytes and endothelial cells were sought using immunohistochemistry.
Symptoms and preoperative imaging findings (CT-scan, MRI and Doppler-scan) were analyzed. Human
pericytes were cultured to evaluate their ability to secrete OPG and to influence mineralization in the plaque.
Results: Seventy-three carotid plaques (49 asymptomatic and 24 symptomatic) were harvested. A significantly higher
presence of OM (18.4% vs 0%, p,0.01), OPG (10.2% of ROI vs 3.4% of ROI, p,0.05) and pericytes (19% of ROI vs 3.8% of ROI,
p,0.05) were noted in asymptomatic compared to symptomatic plaques. Consistently, circulating OPG levels were higher
in the plasma of asymptomatic patients (3.2 ng/mL vs 2.5 ng/mL, p = 0.05). In vitro, human vascular pericytes secreted
considerable amounts of OPG and underwent osteoblastic differentiation. Pericytes also inhibited the osteoclastic
differentiation of CD14+ cells through their secretion of OPG.
Conclusions: OPG (intraplaque an plasmatic) and OM are associated with carotid plaque stability. Pericytes may be involved
in the secretion of intraplaque OPG and in the formation of OM.
Public Library of Science
2014-09-26
Article
PeerReviewed
text
en
cc_by_4
https://eprints.whiterose.ac.uk/95901/1/Osteoprotegerin%2C%20pericytes%20and%20bone-like%20vascular%20calcification%20are%20associated%20with%20carotid%20plaque%20stability..pdf
Davaine, J-M., Quillard, T., Brion, R. et al. (10 more authors) (2014) Osteoprotegerin, Pericytes and Bone-Like Vascular Calcification Are Associated with Carotid Plaque Stability. PLoS ONE, 9 (9). e107642. ISSN 1932-6203
http://dx.doi.org/10.1371/journal.pone.0107642
10.1371/journal.pone.0107642
oai:eprints.whiterose.ac.uk:95902
2019-08-30T13:23:09Z
oai:eprints.whiterose.ac.uk:95903
2016-04-13T10:13:18Z
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756E69743D536865666669656C64:536865666669656C642E46434D:536865666669656C642E4D4544:536865666669656C642E47454D:536865666669656C642E4F4350
696E737469747574696F6E3D536865666669656C64
7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/95903/
IL-1 beta and TNF alpha Promote Monocyte Viability through the Induction of GM-CSF Expression by Rheumatoid Arthritis Synovial Fibroblasts
Darrieutort-Laffite, C.
Boutet, M-A.
Chatelais, M.
Brion, R.
Blanchard, F.
Heymann, D.
Le Goff, B.
Background. Macrophages and synovial fibroblasts (SF) are two major cells implicated in the pathogenesis of rheumatoid arthritis (RA). SF could be a source of cytokines and growth factors driving macrophages survival and activation. Here, we studied the effect of SF on monocyte viability and phenotype. Methods. SF were isolated from synovial tissue of RA patients and CD14+ cells were isolated from peripheral blood of healthy donors. SF conditioned media were collected after 24 hours of culture with or without stimulation with TNFα or IL-1β. Macrophages polarisation was studied by flow cytometry. Results. Conditioned medium from SF significantly increased monocytes viability by 60% compared to CD14+ cells cultured in medium alone . This effect was enhanced using conditioned media from IL-1β and TNFα stimulated SF. GM-CSF but not M-CSF nor IL34 blocking antibodies was able to significantly decrease monocyte viability by 30% when added to the conditioned media from IL-1β and TNFα stimulated SF . Finally, monocyte cultured in presence of SF conditioned media did not exhibit a specific M1 or M2 phenotype. Conclusion. Overall, rheumatoid arthritis synovial fibroblasts stimulated with proinflammatory cytokines (IL-1β and TNFα) promote monocyte viability via GM-CSF but do not induce a specific macrophage polarization.
Hindawi Publishing Corporation
2014-11-17
Article
PeerReviewed
text
en
cc_by_3
https://eprints.whiterose.ac.uk/95903/1/IL-1%CE%B2%20and%20TNF%CE%B1%20promote%20monocyte%20viability%20through%20the%20induction%20of%20GM-CSF%20expression%20by%20rheumatoid%20arthritis%20synovial%20fibroblasts..pdf
Darrieutort-Laffite, C., Boutet, M-A., Chatelais, M. et al. (4 more authors) (2014) IL-1 beta and TNF alpha Promote Monocyte Viability through the Induction of GM-CSF Expression by Rheumatoid Arthritis Synovial Fibroblasts. Mediators of Inflammation, 2014. 241840. ISSN 0962-9351
http://dx.doi.org/10.1155/2014/241840
10.1155/2014/241840
oai:eprints.whiterose.ac.uk:95907
2016-04-12T14:54:12Z
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https://eprints.whiterose.ac.uk/95907/
Safety Concern between Autologous Fat Graft, Mesenchymal Stem Cell and Osteosarcoma Recurrence
Perrot, P.
Rousseau, J.
Bouffaut, A-L.
Redini, F.
Cassagnau, E.
Deschaseaux, F.
Heymann, M-F.
Heymann, D.
Duteille, F.
Trichet, V.
Gouin, F.
Background: Osteosarcoma is the most common malignant primary bone tumour in young adult treated by neo adjuvant
chemotherapy, surgical tumor removal and adjuvant multidrug chemotherapy. For correction of soft tissue defect
consecutive to surgery and/or tumor treatment, autologous fat graft has been proposed in plastic and reconstructive
surgery.
Principal Findings: We report here a case of a late local recurrence of osteosarcoma which occurred 13 years after the initial
pathology and 18 months after a lipofilling procedure. Because such recurrence was highly unexpected, we investigated the
possible relationship of tumor growth with fat injections and with mesenchymal stem/stromal cell like cells which are
largely found in fatty tissue. Results obtained in osteosarcoma pre-clinical models show that fat grafts or progenitor cells
promoted tumor growth.
Significance: These observations and results raise the question of whether autologous fat grafting is a safe reconstructive
procedure in a known post neoplasic context.
Public Library of Science
2010-06-08
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/95907/1/Safety%20concern%20between%20autologous%20fat%20graft%2C%20mesenchymal%20stem%20cell%20and%20osteosarcoma%20recurrence..pdf
Perrot, P., Rousseau, J., Bouffaut, A-L. et al. (8 more authors) (2010) Safety Concern between Autologous Fat Graft, Mesenchymal Stem Cell and Osteosarcoma Recurrence. PLOS ONE, 5 (6). e10999. ISSN 1932-6203
http://dx.doi.org/10.1371/journal.pone.0010999
10.1371/journal.pone.0010999
oai:eprints.whiterose.ac.uk:95908
2016-04-11T13:52:36Z
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https://eprints.whiterose.ac.uk/95908/
Receptor tyrosine kinases: Characterisation, mechanism of action and therapeutic interests for bone cancers
Segaliny, A.I.
Tellez-Gabriel, M.
Heymann, M-F.
Heymann, D.
Bone cancers are characterised by the development of tumour cells in bone sites, associated with a dysregulation of their environment. In the last two decades, numerous therapeutic strategies have been developed to target the cancer cells or tumour niche. As the crosstalk between these two entities is tightly controlled by the release of polypeptide mediators activating signalling pathways through several receptor tyrosine kinases (RTKs), RTK inhibitors have been designed. These inhibitors have shown exciting clinical impacts, such as imatinib mesylate, which has become a reference treatment for chronic myeloid leukaemia and gastrointestinal tumours. The present review gives an overview of the main molecular and functional characteristics of RTKs, and focuses on the clinical applications that are envisaged and already assessed for the treatment of bone sarcomas and bone metastases.
Elsevier
2015-03
Article
PeerReviewed
text
en
cc_by_4
https://eprints.whiterose.ac.uk/95908/1/Receptor%20tyrosine%20kinases%3A%20Characterisation%2C%20mechanism%20of%20action%20and%20therapeutic%20interests%20for%20bone%20cancers..pdf
Segaliny, A.I., Tellez-Gabriel, M., Heymann, M-F. et al. (1 more author) (2015) Receptor tyrosine kinases: Characterisation, mechanism of action and therapeutic interests for bone cancers. JOURNAL OF BONE ONCOLOGY, 4 (1). pp. 1-12. ISSN 2212-1374
http://dx.doi.org/10.1016/j.jbo.2015.01.001
10.1016/j.jbo.2015.01.001
oai:eprints.whiterose.ac.uk:95909
2023-06-23T22:00:23Z
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https://eprints.whiterose.ac.uk/95909/
Imatinib Mesylate Exerts Anti-Proliferative Effects on Osteosarcoma Cells and Inhibits the Tumour Growth in Immunocompetent Murine Models
Gobin, B.
Moriceau, G.
Ory, B.
Charrier, C.
Brion, R.
Blanchard, F.
Redini, F.
Heymann, D.
Osteosarcoma is the most common primary malignant bone tumour characterized by osteoid production and/or osteolytic lesions of bone. A lack of response to chemotherapeutic treatments shows the importance of exploring new therapeutic methods. Imatinib mesylate (Gleevec, Novartis Pharma), a tyrosine kinase inhibitor, was originally developed for the treatment of chronic myeloid leukemia. Several studies revealed that imatinib mesylate inhibits osteoclast differentiation through the M-CSFR pathway and activates osteoblast differentiation through PDGFR pathway, two key cells involved in the vicious cycle controlling the tumour development. The present study investigated the in vitro effects of imatinib mesylate on the proliferation, apoptosis, cell cycle, and migration ability of five osteosarcoma cell lines (human: MG-63, HOS; rat: OSRGA; mice: MOS-J, POS-1). Imatinib mesylate was also assessed as a curative and preventive treatment in two syngenic osteosarcoma models: MOS-J (mixed osteoblastic/osteolytic osteosarcoma) and POS-1 (undifferentiated osteosarcoma). Imatinib mesylate exhibited a dose-dependent anti-proliferative effect in all cell lines studied. The drug induced a G0/G1 cell cycle arrest in most cell lines, except for POS-1 and HOS cells that were blocked in the S phase. In addition, imatinib mesylate induced cell death and strongly inhibited osteosarcoma cell migration. In the MOS-J osteosarcoma model, oral administration of imatinib mesylate significantly inhibited the tumour development in both preventive and curative approaches. A phospho-receptor tyrosine kinase array kit revealed that PDGFRα, among 7 other receptors (PDFGFRβ, Axl, RYK, EGFR, EphA2 and 10, IGF1R), appears as one of the main molecular targets for imatinib mesylate. In the light of the present study and the literature, it would be particularly interesting to revisit therapeutic evaluation of imatinib mesylate in osteosarcoma according to the tyrosine-kinase receptor status of patients.
Public Library of Science
2014-03-05
Article
PeerReviewed
text
en
cc_by_4
https://eprints.whiterose.ac.uk/95909/7/Imatinib%20mesylate%20exerts%20anti-proliferative%20effects%20on%20osteosarcoma%20cells%20and%20inhibits%20the%20tumour%20growth%20in%20immunocompetent%20murine%20models.pdf
Gobin, B., Moriceau, G., Ory, B. et al. (5 more authors) (2014) Imatinib Mesylate Exerts Anti-Proliferative Effects on Osteosarcoma Cells and Inhibits the Tumour Growth in Immunocompetent Murine Models. PLoS ONE, 9 (3). e90795. ISSN 1932-6203
http://dx.doi.org/10.1371/journal.pone.0090795
10.1371/journal.pone.0090795
oai:eprints.whiterose.ac.uk:95910
2016-04-13T09:17:31Z
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Pre-clinical studies of bone regeneration with human bone marrow stromal cells and biphasic calcium phosphate
Brennan, M.A.
Renaud, A.
Amiaud, J.
Rojewski, M.T.
Schrezenmeier, H.
Heymann, D.
Trichet, V.
Layrolle, P.
Introduction
Repair of large bone defects remains a significant clinical challenge. Bone marrow stromal cells (BMSCs), a subset of which is known as bone marrow-derived mesenchymal stem cells, show therapeutic potential for bone regeneration. However, their isolation, expansion and implantation will need to be conducted under good manufacturing practices (GMP) at separate locations. An investigation which mimics this clinical scenario where large bone defects shall be regenerated is required before clinical trials can be initiated.
Methods
Seven batches of 100 million human ex-vivo expanded BMSCs from five donors were transported fresh in syringes from a GMP facility in Germany to France. BMSCs were mixed with biphasic calcium phosphate (BCP) biomaterial prior to subcutaneous implantation in nude mice. The capacity of BMSCs in unison with BCP to regenerate critical sized cranial bone defects was also evaluated. BMSCs expressing luciferase were used to assess the viability and bio-distribution of implanted cells. In situ hybridization, using the human-specific repetitive Alu sequence, was performed for the identification of human cells in explants.
Results
Eight weeks after implantation of BMSCs, mineralized bone containing mature bone marrow territories was formed in ectopic sites and in calvaria defects. Significant loss of cell viability was observed by bioluminescence imaging and only 1.5 percent of the initial number of transplanted cells remained after 37 days. After eight weeks, while explants were comprised primarily of host cells, there were also human cells attached along the periphery of BCP and embedded in osteocyte lacunae dispersed throughout the newly formed bone matrix.
Conclusions
This study demonstrates the safety and efficacy of BMSC/BCP combinations and provides crucial information for the implementation of BMSC therapy for bone regeneration.
BioMed Central
2014-10-13
Article
PeerReviewed
text
en
cc_by_4
https://eprints.whiterose.ac.uk/95910/1/Pre-clinical%20studies%20of%20bone%20regeneration%20with%20human%20bone%20marrow%20stromal%20cells%20and%20biphasic%20calcium%20phosphate..pdf
Brennan, M.A., Renaud, A., Amiaud, J. et al. (5 more authors) (2014) Pre-clinical studies of bone regeneration with human bone marrow stromal cells and biphasic calcium phosphate. Stem Cell Research & Therapy, 5. 114. ISSN 1757-6512
http://dx.doi.org/10.1186/scrt504
10.1186/scrt504
oai:eprints.whiterose.ac.uk:95911
2016-04-13T10:49:41Z
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https://eprints.whiterose.ac.uk/95911/
Oxytocin reverses osteoporosis in a sex-dependent manner.
Beranger, G.E.
Djedaini, M.
Battaglia, S.
Roux, C.H.
Scheideler, M.
Heymann, D.
Amri, E.Z.
Pisani, D.F.
The increase of life expectancy has led to the increase of age-related diseases such
as osteoporosis. Osteoporosis is characterized by bone weakening promoting the
occurrence of fractures with defective bone regeneration. Men aged over 50 have a
prevalence for osteoporosis of 20%, which is related to a decline in sex hormones
occurring during andropause or surgical orchidectomy. As we previously demonstrated
in a mouse model for menopause in women that treatment with the neurohypophyseal
peptide hormone oxytocin (OT) normalizes body weight and prevents the development
of osteoporosis, herein we addressed the effects of OT in male osteoporosis. Thus,
we treated orchidectomized mice, an animal model suitable for the study of male
osteoporosis, for 8 weeks with OT and then analyzed trabecular and cortical bone
parameters as well as fat mass using micro-computed tomography. Orchidectomized
mice displayed severe bone loss, muscle atrophy accompanied by fat mass gain as
expected in andropause. Interestingly, OT treatment in male mice normalized fat mass
as it did in female mice. However, although OT treatment led to a normalization of
bone parameters in ovariectomized mice, this did not happen in orchidectomized mice.
Moreover, loss of muscle mass was not reversed in orchidectomized mice upon OT
treatment. All of these observations indicate that OT acts on fat physiology in both sexes,
but in a sex specific manner with regard to bone physiology.
Frontiers Media
2015-05-19
Article
PeerReviewed
text
en
cc_by_4
https://eprints.whiterose.ac.uk/95911/1/Oxytocin%20reverses%20osteoporosis%20in%20a%20sex-dependent%20manner..pdf
Beranger, G.E., Djedaini, M., Battaglia, S. et al. (5 more authors) (2015) Oxytocin reverses osteoporosis in a sex-dependent manner. Frontiers in Endocrinology, 6. 81.
http://dx.doi.org/10.3389/fendo.2015.00081
10.3389/fendo.2015.00081
oai:eprints.whiterose.ac.uk:95912
2016-04-13T10:54:09Z
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Human breast cancer cells educate macrophages toward the M2 activation status
Sousa, S.
Brion, R.
Lintunen, M.
Kronqvist, P.
Sandholm, J.
Monkkonen, J.
Kellokumpu-Lehtinen, P-L.
Lauttia, S.
Tynninen, O.
Joensuu, H.
Heymann, D.
Maatta, J.A.
Introduction: The immune system plays a major role in cancer progression. In solid tumors, 5-40 % of the tumor
mass consists of tumor-associated macrophages (TAMs) and there is usually a correlation between the number of
TAMs and poor prognosis, depending on the tumor type. TAMs usually resemble M2 macrophages. Unlike
M1-macrophages which have pro-inflammatory and anti-cancer functions, M2-macrophages are immunosuppressive,
contribute to the matrix-remodeling, and hence favor tumor growth. The role of TAMs is not fully understood in
breast cancer progression.
Methods: Macrophage infiltration (CD68) and activation status (HLA-DRIIα, CD163) were evaluated in a large cohort
of human primary breast tumors (562 tissue microarray samples), by immunohistochemistry and scored by
automated image analysis algorithms. Survival between groups was compared using the Kaplan-Meier life-table
method and a Cox multivariate proportional hazards model. Macrophage education by breast cancer cells was
assessed by ex vivo differentiation of peripheral blood mononuclear cells (PBMCs) in the presence or absence of
breast cancer cell conditioned media (MDA-MB231, MCF-7 or T47D cell lines) and M1 or M2 inducing cytokines
(respectively IFN-γ, IL-4 and IL-10). Obtained macrophages were analyzed by flow cytometry (CD14, CD16, CD64,
CD86, CD200R and CD163), ELISA (IL-6, IL-8, IL-10, monocyte colony stimulating factor M-CSF) and zymography
(matrix metalloproteinase 9, MMP-9).
Results: Clinically, we found that high numbers of CD163+ M2-macrophages were strongly associated with fast
proliferation, poor differentiation, estrogen receptor negativity and histological ductal type (p<0.001) in the studied
cohort of human primary breast tumors. We demonstrated ex vivo that breast cancer cell-secreted factors modulate
macrophage differentiation toward the M2 phenotype. Furthermore, the more aggressive mesenchymal-like cell line
MDA-MB231, which secretes high levels of M-CSF, skews macrophages toward the more immunosuppressive M2c
subtype.
Conclusions: This study demonstrates that human breast cancer cells influence macrophage differentiation and that
TAM differentiation status correlates with recurrence free survival, thus further emphasizing that TAMs can similarly
affect therapy efficacy and patient outcome.
BioMed Central
2015-08-05
Article
PeerReviewed
text
en
cc_by_4
https://eprints.whiterose.ac.uk/95912/1/Human%20breast%20cancer%20cells%20educate%20macrophages%20toward%20the%20M2%20activation%20status..pdf
Sousa, S., Brion, R., Lintunen, M. et al. (9 more authors) (2015) Human breast cancer cells educate macrophages toward the M2 activation status. Breast Cancer Research, 17. 101. ISSN 1465-5411
http://dx.doi.org/10.1186/s13058-015-0621-0
10.1186/s13058-015-0621-0
oai:eprints.whiterose.ac.uk:95937
2016-03-03T11:32:55Z
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The views of older women towards mammographic screening: a qualitative and quantitative study
Collins, K.
Winslow, M.
Reed, M.W.
Walters, S.J.
Robinson, T.
Madan, J.
Green, T.
Cocker, H.
Wyld, L.
Nature Publishing Group
2010-05-11
Article
PeerReviewed
text
en
cc_by_nc_sa_3
https://eprints.whiterose.ac.uk/95937/1/The%20views%20of%20older%20women%20towards%20mammographic%20screening%3A%20a%20qualitative%20and%20quantitative%20study..pdf
Collins, K., Winslow, M., Reed, M.W. et al. (6 more authors) (2010) The views of older women towards mammographic screening: a qualitative and quantitative study. British Journal of Cancer, 102 (10). pp. 1461-1467. ISSN 0007-0920
http://dx.doi.org/10.1038/sj.bjc.6605662
10.1038/sj.bjc.6605662
oai:eprints.whiterose.ac.uk:96118
2017-01-16T13:16:32Z
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The use of surgery in the treatment of ER+ early stage breast cancer in England: Variation by time, age and patient characteristics
Richards, P.
Ward, S.
Morgan, J.
Lagord, C.
Reed, M.
Collins, K.
Wyld, L.
Aim - To assess whether the proportion of patients aged 70 and over with ER+ operable breast cancer in England who are treated with surgery has changed since 2002, and to determine whether age and individual level factors including tumour characteristics and co-morbidity influence treatment choice.
Methods - A retrospective cohort analysis of routinely collected cancer registration data from two English regions (West Midlands, Northern & Yorkshire) was carried out (n = 17,129). Trends in surgical use over time for different age groups were assessed graphically and with linear regression. Uni- and multivariable logistic regressions were used to assess the effects of age, comorbidity, deprivation and disease characteristics on treatment choice. Missing data was handled using multiple imputation.
Results - There is no evidence of a change in the proportion of patients treated surgically over time. The multivariable model shows that age remains an important predictor of whether or not a woman with ER+ operable breast cancer receives surgery after covariate adjustment (Odds ratio of surgery vs no surgery, 0.82 (per year over 70)). Co-morbidity, deprivation, symptomatic presentation, later stage at diagnosis and low grade are also associated with increased probability of non-surgical treatment.
Conclusion - Contrary to current NICE guidance in England, age appears to be an important factor in the decision to treat operable ER+ breast cancer non-surgically. Further research is needed to assess the role of other age-related factors on treatment choice, and the effect that current practice has on survival and mortality from breast cancer for older women.
Elsevier
2016-04
Article
PeerReviewed
text
en
cc_by_nc_nd_4
https://eprints.whiterose.ac.uk/96118/3/WRRO_96118.pdf
Richards, P., Ward, S., Morgan, J. et al. (4 more authors) (2016) The use of surgery in the treatment of ER+ early stage breast cancer in England: Variation by time, age and patient characteristics. European Journal of Surgical Oncology (EJSO), 42 (4). pp. 489-496. ISSN 0748-7983
http://dx.doi.org/10.1016/j.ejso.2015.12.012
10.1016/j.ejso.2015.12.012
oai:eprints.whiterose.ac.uk:96257
2016-08-08T08:31:08Z
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Visual Advantage in Deaf Adults Linked to Retinal Changes
Codina, C.
Pascalis, O.
Mody, C.
Toomey, P.
Rose, J.
Gummer, L.
Buckley, D.
The altered sensory experience of profound early onset deafness provokes sometimes large scale neural reorganisations. In particular, auditory-visual cross-modal plasticity occurs, wherein redundant auditory cortex becomes recruited to vision. However, the effect of human deafness on neural structures involved in visual processing prior to the visual cortex has never been investigated, either in humans or animals. We investigated neural changes at the retina and optic nerve head in profoundly deaf (N = 14) and hearing (N = 15) adults using Optical Coherence Tomography (OCT), an in-vivo light interference method of quantifying retinal micro-structure. We compared retinal changes with behavioural results from the same deaf and hearing adults, measuring sensitivity in the peripheral visual field using Goldmann perimetry. Deaf adults had significantly larger neural rim areas, within the optic nerve head in comparison to hearing controls suggesting greater retinal ganglion cell number. Deaf adults also demonstrated significantly larger visual field areas (indicating greater peripheral sensitivity) than controls. Furthermore, neural rim area was significantly correlated with visual field area in both deaf and hearing adults. Deaf adults also showed a significantly different pattern of retinal nerve fibre layer (RNFL) distribution compared to controls. Significant correlations between the depth of the RNFL at the inferior-nasal peripapillary retina and the corresponding far temporal and superior temporal visual field areas (sensitivity) were found. Our results show that cross-modal plasticity after early onset deafness may not be limited to the sensory cortices, noting specific retinal adaptations in early onset deaf adults which are significantly correlated with peripheral vision sensitivity.
Public Library of Science
2011-06-01
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/96257/1/Visual%20advantage%20in%20deaf%20adults%20linked%20to%20retinal%20changes..pdf
Codina, C., Pascalis, O., Mody, C. et al. (4 more authors) (2011) Visual Advantage in Deaf Adults Linked to Retinal Changes. PLoS ONE, 6 (6). e20417. ISSN 1932-6203
http://dx.doi.org/10.1371/journal.pone.0020417
10.1371/journal.pone.0020417
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2016-08-29T00:38:14Z
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Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.
Dunning, A.M.
Michailidou, K.
Kuchenbaecker, K.B.
Thompson, D.
French, J.D.
Beesley, J.
Healey, C.S.
Kar, S.
Pooley, K.A.
Lopez-Knowles, E.
Dicks, E.
Barrowdale, D.
Sinnott-Armstrong, N.A.
Sallari, R.C.
Hillman, K.M.
Kaufmann, S.
Sivakumaran, H.
Marjaneh, M.M.
Lee, J.S.
Hills, M.
Jarosz, M.
Drury, S.
Canisius, S.
Bolla, M.K.
Dennis, J.
Wang, Q.
Hopper, J.L.
Southey, M.C.
Broeks, A.
Schmidt, M.K.
Lophatananon, A.
Muir, K.
Beckmann, M.W.
Fasching, P.A.
Dos-Santos-Silva, I.
Peto, J.
Sawyer, E.J.
Tomlinson, I.
Burwinkel, B.
Marme, F.
Guénel, P.
Truong, T.
Bojesen, S.E.
Flyger, H.
González-Neira, A.
Perez, J.I.
Anton-Culver, H.
Eunjung, L.
Arndt, V.
Brenner, H.
Meindl, A.
Schmutzler, R.K.
Brauch, H.
Hamann, U.
Aittomäki, K.
Blomqvist, C.
Ito, H.
Matsuo, K.
Bogdanova, N.
Dörk, T.
Lindblom, A.
Margolin, S.
Kosma, V.M.
Mannermaa, A.
Tseng, C.C.
Wu, A.H.
Lambrechts, D.
Wildiers, H.
Chang-Claude, J.
Rudolph, A.
Peterlongo, P.
Radice, P.
Olson, J.E.
Giles, G.G.
Milne, R.L.
Haiman, C.A.
Henderson, B.E.
Goldberg, M.S.
Teo, S.H.
Yip, C.H.
Nord, S.
Borresen-Dale, A.L.
Kristensen, V.
Long, J.
Zheng, W.
Pylkäs, K.
Winqvist, R.
Andrulis, I.L.
Knight, J.A.
Devilee, P.
Seynaeve, C.
Figueroa, J.
Sherman, M.E.
Czene, K.
Darabi, H.
Hollestelle, A.
van den Ouweland, A.M.
Humphreys, K.
Gao, Y.T.
Shu, X.O.
Cox, A.
Cross, S.S.
Blot, W.
Cai, Q.
Ghoussaini, M.
Perkins, B.J.
Shah, M.
Choi, J.Y.
Kang, D.
Lee, S.C.
Hartman, M.
Kabisch, M.
Torres, D.
Jakubowska, A.
Lubinski, J.
Brennan, P.
Sangrajrang, S.
Ambrosone, C.B.
Toland, A.E.
Shen, C.Y.
Wu, P.E.
Orr, N.
Swerdlow, A.
McGuffog, L.
Healey, S.
Lee, A.
Kapuscinski, M.
John, E.M.
Terry, M.B.
Daly, M.B.
Goldgar, D.E.
Buys, S.S.
Janavicius, R.
Tihomirova, L.
Tung, N.
Dorfling, C.M.
van Rensburg, E.J.
Neuhausen, S.L.
Ejlertsen, B.
Hansen, T.V.
Osorio, A.
Benitez, J.
Rando, R.
Weitzel, J.N.
Bonanni, B.
Peissel, B.
Manoukian, S.
Papi, L.
Ottini, L.
Konstantopoulou, I.
Apostolou, P.
Garber, J.
Rashid, M.U.
Frost, D.
Izatt, L.
Ellis, S.
Godwin, A.K.
Arnold, N.
Niederacher, D.
Rhiem, K.
Bogdanova-Markov, N.
Sagne, C.
Stoppa-Lyonnet, D.
Damiola, F.
Sinilnikova, O.M.
Mazoyer, S.
Isaacs, C.
Claes, K.B.
De Leeneer, K.
de la Hoya, M.
Caldes, T.
Nevanlinna, H.
Khan, S.
Mensenkamp, A.R.
Hooning, M.J.
Rookus, M.A.
Kwong, A.
Olah, E.
Diez, O.
Brunet, J.
Pujana, M.A.
Gronwald, J.
Huzarski, T.
Barkardottir, R.B.
Laframboise, R.
Soucy, P.
Montagna, M.
Agata, S.
Teixeira, M.R.
Park, S.K.
Lindor, N.
Couch, F.J.
Tischkowitz, M.
Foretova, L.
Vijai, J.
Offit, K.
Singer, C.F.
Rappaport, C.
Phelan, C.M.
Greene, M.H.
Mai, P.L.
Rennert, G.
Imyanitov, E.N.
Hulick, P.J.
Phillips, K.A.
Piedmonte, M.
Mulligan, A.M.
Glendon, G.
Bojesen, A.
Thomassen, M.
Caligo, M.A.
Yoon, S.Y.
Friedman, E.
Laitman, Y.
Borg, A.
von Wachenfeldt, A.
Ehrencrona, H.
Rantala, J.
Olopade, O.I.
Ganz, P.A.
Nussbaum, R.L.
Gayther, S.A.
Nathanson, K.L.
Domchek, S.M.
Arun, B.K.
Mitchell, G.
Karlan, B.Y.
Lester, J.
Maskarinec, G.
Woolcott, C.
Scott, C.
Stone, J.
Apicella, C.
Tamimi, R.
Luben, R.
Khaw, K.T.
Helland, Å.
Haakensen, V.
Dowsett, M.
Pharoah, P.D.
Simard, J.
Hall, P.
García-Closas, M.
Vachon, C.
Chenevix-Trench, G.
Antoniou, A.C.
Easton, D.F.
Edwards, S.L.
We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
Nature Publishing Group
2016-02-29
Article
PeerReviewed
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https://eprints.whiterose.ac.uk/96288/1/NG-A39955R3_ESR1%20final%20manuscript.pdf
Dunning, A.M., Michailidou, K., Kuchenbaecker, K.B. et al. (245 more authors) (2016) Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170. Nature Genetics. ISSN 1061-4036
https://dx.doi.org/10.1038/ng.3521
10.1038/ng.3521
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No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing.
Easton, D.F.
Lesueur, F.
Decker, B.
Michailidou, K.
Li, J.
Allen, J.
Luccarini, C.
Pooley, K.A.
Shah, M.
Bolla, M.K.
Wang, Q.
Dennis, J.
Ahmad, J.
Thompson, E.R.
Damiola, F.
Pertesi, M.
Voegele, C.
Mebirouk, N.
Robinot, N.
Durand, G.
Forey, N.
Luben, R.N.
Ahmed, S.
Aittomäki, K.
Anton-Culver, H.
Arndt, V.
Baynes, C.
Beckman, M.W.
Benitez, J.
Van Den Berg, D.
Blot, W.J.
Bogdanova, N.V.
Bojesen, S.E.
Brenner, H.
Chang-Claude, J.
Chia, K.S.
Choi, J.Y.
Conroy, D.M.
Cox, A.
Cross, S.S.
Czene, K.
Darabi, H.
Devilee, P.
Eriksson, M.
Fasching, P.A.
Figueroa, J.
Flyger, H.
Fostira, F.
García-Closas, M.
Giles, G.G.
Glendon, G.
González-Neira, A.
Guénel, P.
Haiman, C.A
Hall, P.
Hart, S.N.
Hartman, M.
Hooning, M.J.
Hsiung, C.N.
Ito, H.
Jakubowska, A.
James, P.A
John, E.M.
Johnson, N.
Jones, M.
Kabisch, M.
Kang, D.
Kosma, V.M.
Kristensen, V.
Lambrechts, D.
Li, N.
Lindblom, A.
Long, J.
Lophatananon, A.
Lubinski, J.
Mannermaa, A.
Manoukian, S.
Margolin, S.
Matsuo, K.
Meindl, A.
Mitchell, G.
Muir, K.
Nevelsteen, I.
van den Ouweland, A.
Peterlongo, P.
Phuah, S.Y.
Pylkäs, K.
Rowley, S.M.
Sangrajrang, S.
Schmutzler, R.K.
Shen, C.Y.
Shu, X.O.
Southey, M.C
Surowy, H.
Swerdlow, A.
Teo, S.H.
Tollenaar, R.A.
Tomlinson, I.
Torres, D.
Truong, T.
Vachon, C.
Verhoef, S.
Wong-Brown, M.
Zheng, W.
Zheng, Y.
Nevanlinna, H.
Scott, R.J.
Andrulis, I.L.
Wu, A.H.
Hopper, J.L.
Couch, F.J.
Winqvist, R.
Burwinkel, B.
Sawyer, E.J.
Schmidt, M.K.
Rudolph, A.
Dörk, T.
Brauch, H
Hamann, U.
Neuhausen, S.L.
Milne, R.L.
Fletcher, O.
Pharoah, P.D.
Campbell, I.G.
Dunning, A.M.
Le Calvez-Kelm, F.
Goldgar, D.E.
Tavtigian, S.V.
Chenevix-Trench, G.
BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.
BMJ Publishing Group
2016-02-26
Article
PeerReviewed
text
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https://eprints.whiterose.ac.uk/96291/3/BRIP1_FINAL_JMG_REVISIONS.pdf
Easton, D.F., Lesueur, F., Decker, B. et al. (126 more authors) (2016) No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing. Journal of Medical Genetics . ISSN 0022-2593
http://jmg.bmj.com/content/early/2016/02/26/jmedgenet-2015-103529.abstract
10.1136/jmedgenet-2015-103529
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Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer
Shi, J.
Zhang, Y.
Zheng, W.
Michailidou, K.
Ghoussaini, M.
Bolla, M.K.
Wang, Q.
Dennis, J.
Lush, M.
Milne, R.L.
Shu, X-O.
Beesley, J.
Kar, S.
Andrulis, I.L.
Anton-Culver, H.
Arndt, V.
Beckmann, M.W.
Zhao, Z.
Guo, X.
Benitez, J.
Beeghly-Fadiel, A.
Blot, W.
Bogdanova, N.V.
Bojesen, S.E.
Brauch, H.
Brenner, H.
Brinton, L.
Broeks, A.
Brüning, T.
Burwinkel, B.
Cai, H.
Canisius, S.
Chang-Claude, J.
Choi, J-Y.
Couch, F.J.
Cox, A.
Cross, S.S.
Czene, K.
Darabi, H.
Devilee, P.
Droit, A.
Dork, T.
Fasching, P.A.
Fletcher, O.
Flyger, H.
Fostira, F.
Gaborieau, V.
García-Closas, M.
Giles, G.G.
Grip, M.
Guenel, P.
Haiman, C.A.
Hamann, U.
Hartman, M.
Miao, H.
Hollestelle, A.
Hopper, J.L.
Hsiung, C-N.
Ito, H.
Jakubowska, A.
Johnson, N.
Torres, D.
Kabisch, M.
Kang, D.
Khan, S.
Knight, J.A.
Kosma, V-M.
Lambrechts, D.
Li, J.
Lindblom, A.
Lophatananon, A.
Lubinski, J.
Mannermaa, A.
Manoukian, S.
Le Marchand, L.
Margolin, S.
Marme, F.
Matsuo, K.
McLean, C.
Meindl, A.
Muir, K.
Neuhausen, S.L.
Nevanlinna, H.
Nord, S.
Børresen-Dale, A-L.
Olson, J.E.
Orr, N.
van den Ouweland, A.M.W
Peterlongo, P.
Putti, T.C.
Rudolph, A.
Sangrajrang, S.
Sawyer, E.J.
Schmidt, M.K.
Schmutzler, R.K.
Shen, C-Y.
Hou, M-F.
Shrubsole, M.J.
Southey, M.C.
Swerdlow, A.
Teo, S.H.
Thienpont, B.
Toland, A.E.
Tollenaar, R.A.E.M.
Tomlinson, I.
Truong, T.
Tseng, C-C.
Wen, W.
Winqvist, R.
Wu, A.H.
Yip, C.H.
Zamora, P.M.
Zheng, Y.
Floris, G.
Cheng, C-Y.
Hooning, M.J.
Martens, J.W.M.
Seynaeve, C.
Kristensen, V.N.
Hall, P.
Pharoah, P.D.P.
Simard, J.
Chenevix-Trench, G.
Dunning, A.M.
Antoniou, A.C.
Easton, D.F.
Cai, Q.
Long, J.
Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. We conducted a fine-mapping study across 2.06 Mb (chr8:127,561,724 -129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium. We found three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional P = 5.8 × 10-6), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional P = 1.1 × 10-6), and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional P = 1.1 × 10-4). Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas, and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r2 = 0.77), were putatively functional variants for two of the five independent association signals. Our results highlight multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry
Wiley
2016-09-15
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/96295/3/Fine-mapping_8q24_IJC-15-1557_main_text.pdf
Shi, J., Zhang, Y., Zheng, W. et al. (125 more authors) (2016) Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer. International Journal of Cancer, 139 (6). pp. 1303-1317. ISSN 0020-7136
http://dx.doi.org/10.1002/ijc.30150
10.1002/ijc.30150
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Zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of Ewing's sarcoma via inhibition of cell migration
Odri, G.
Kim, P-P.
Lamoureux, F.
Charrier, C.
Battaglia, S.
Amiaud, J.
Heymann, D.
Gouin, F.
Redini, F.
Background: Ewing’s sarcoma (ES) is the second most frequent primitive malignant bone tumor in adolescents
with a very poor prognosis for high risk patients, mainly when lung metastases are detected (overall survival <15%
at 5 years). Zoledronic acid (ZA) is a potent inhibitor of bone resorption which induces osteoclast apoptosis. Our
previous studies showed a strong therapeutic potential of ZA as it inhibits ES cell growth in vitro and ES primary
tumor growth in vivo in a mouse model developed in bone site. However, no data are available on lung metastasis.
Therefore, the aim of this study was to determine the effect of ZA on ES cell invasion and metastatic properties.
Methods: Invasion assays were performed in vitro in Boyden’s chambers covered with Matrigel. Matrix
Metalloproteinase (MMP) activity was analyzed by zymography in ES cell culture supernatant. In vivo, a relevant
model of spontaneous lung metastases which disseminate from primary ES tumor was induced by the orthotopic
injection of 106 human ES cells in the tibia medullar cavity of nude mice. The effect of ZA (50 μg/kg, 3x/week)
was studied over a 4-week period. Lung metastases were observed macroscopically at autopsy and analysed
by histology.
Results: ZA induced a strong inhibition of ES cell invasion, probably due to down regulation of MMP-2
and −9 activities as analyzed by zymography. In vivo, ZA inhibits the dissemination of spontaneous lung
metastases from a primary ES tumor but had no effect on the growth of established lung metastases.
Conclusion: These results suggest that ZA could be used early in the treatment of ES to inhibit bone tumor
growth but also to prevent the early metastatic events to the lungs.
BioMed Central
2014-03-10
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/96313/1/Zoledronic%20acid%20inhibits%20pulmonary%20metastasis%20dissemination%20in%20a%20preclinical%20model%20of%20Ewing%27s%20sarcoma%20via%20inhibition%20of%20cell%20migration..pdf
Odri, G., Kim, P-P., Lamoureux, F. et al. (6 more authors) (2014) Zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of Ewing's sarcoma via inhibition of cell migration. BMC Cancer, 14. 169. ISSN 1471-2407
http://dx.doi.org/10.1186/1471-2407-14-169
10.1186/1471-2407-14-169
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The Bone Niche of Chondrosarcoma: A Sanctuary for
Drug Resistance, Tumour Growth and also a Source of
New Therapeutic Targets
David, E.
Blanchard, F.
Heymann, M.F.
De Pinieux, G.
Gouin, F.
Rédini, F.
Heymann, D.
Chondrosarcomas are malignant cartilage-forming tumours representing around 20% of malignant primary tumours of bone and
affect mainly adults in the third to sixth decade of life. Unfortunately, the molecular pathways controlling the genesis and the
growth of chondrosarcoma cells are still not fully defined. It is well admitted that the invasion of bone by tumour cells affects
the balance between early bone resorption and formation and induces an “inflammatory-like” environment which establishes a
dialogue between tumour cells and their environment. The bone tumour microenvironment is then described as a sanctuary that
contributes to the drug resistance patterns and may control at least in part the tumour growth. The concept of “niche” defined as a
specialized microenvironment that can promote the emergence of tumour stem cells and provide all the required factors for their
development recently emerges in the literature. The present paper aims to summarize the main evidence sustaining the existence
of a specific bone niche in the pathogenesis of chondrosarcomas.
Hindawi Publishing Corporation
2011-02-10
Article
PeerReviewed
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cc_by_3
https://eprints.whiterose.ac.uk/96314/1/The%20Bone%20Niche%20of%20Chondrosarcoma%3A%20A%20Sanctuary%20for%20Drug%20Resistance%2C%20Tumour%20Growth%20and%20also%20a%20Source%20of%20New%20Therapeutic%20Targets..pdf
David, E., Blanchard, F., Heymann, M.F. et al. (4 more authors) (2011) The Bone Niche of Chondrosarcoma: A Sanctuary for Drug Resistance, Tumour Growth and also a Source of New Therapeutic Targets. Sarcoma, 2011. 932451. ISSN 1357-714X
http://dx.doi.org/10.1155/2011/932451
10.1155/2011/932451
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A“Proteoglycan Targeting Strategy” for the
Scintigraphic Imaging and Monitoring of the Swarm Rat
Chondrosarcoma Orthotopic Model
Peyrode, C.
Gouin, F.
Vidal, A.
Auzeloux, P.
Besse, S.
Dauplat, M.M.
Askienazy, S.
Heymann, D.
Chezal, J.M.
Redini, F.
Miot-Noirault, E.
Our lab developed 99mTc-NTP 15-5 radiotracer as targeting proteoglycans (PGs) for the scintigraphic imaging of joint. This paper
reports preclinical results of 99mTc-NTP 15-5 imaging of an orthotopic model of Swarm rat chondrosarcoma (SRC). 99mTc-NTP
15-5 imaging of SRC-bearing and sham-operated animals was performed and quantified at regular intervals after surgery and
compared to bone scintigraphy and tumoural volume. Tumours were characterized by histology and PG assay. SRC exhibited
a significant 99mTc-NTP 15-5 uptake at very early stage after implant (with tumour/muscle ratio of 1.61 ± 0.14), whereas no
measurable tumour was evidenced. As tumour grew, mean tumour/muscle ratio was increased by 2.4, between the early and late
stage of pathology. Bone scintigraphy failed to image chondrosarcoma, even at the later stage of study. 99mTc-NTP 15-5 imaging
provided a suitable set of quantitative criteria for the in vivo characterization of chondrosarcoma behaviour in bone environment,
useful for achieving a greater understanding of the pathology.
Hindawi Publishing Corporation
2011
Article
PeerReviewed
text
en
cc_by_3
https://eprints.whiterose.ac.uk/96315/1/A%22Proteoglycan%20targeting%20strategy%22%20for%20the%20scintigraphic%20imaging%20and%20monitoring%20of%20the%20swarm%20rat%20chondrosarcoma%20orthotopic%20model..pdf
Peyrode, C., Gouin, F., Vidal, A. et al. (8 more authors) (2011) A“Proteoglycan Targeting Strategy” for the Scintigraphic Imaging and Monitoring of the Swarm Rat Chondrosarcoma Orthotopic Model. Sarcoma, 2011. 691608. ISSN 1357-714X
http://dx.doi.org/10.1155/2011/691608
10.1155/2011/691608
oai:eprints.whiterose.ac.uk:96316
2016-04-13T10:22:20Z
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7072696D6F3D6861735F7075626C6963
https://eprints.whiterose.ac.uk/96316/
Distinct Roles of Bcl-2 and Bcl-Xl in the Apoptosis of
Human Bone Marrow Mesenchymal Stem Cells during
Differentiation
Oliver, L.
Hue, E.
Rossignol, J.
Bougras, G.
Hulin, P.
Naveilhan, P.
Heymann, D.
Lescaudron, L.
Vallette, F.M.
Background: Adult mesenchymal stem cells (MSCs) can be maintained over extended periods of time before activation and differentiation. Little is known about the programs that sustain the survival of these cells.
Principal Findings: Undifferentiated adult human MSCs (hMSCs) did not undergo apoptosis in response to different cell death inducers. Conversely, the same inducers can readily induce apoptosis when hMSCs are engaged in the early stages of differentiation. The survival of undifferentiated cells is linked to the expression of Bcl-Xl and Bcl-2 in completely opposite ways. Bcl-Xl is expressed at similar levels in undifferentiated and differentiated hMSCs while Bcl-2 is expressed only in differentiated cells. In undifferentiated hMSCs, the down-regulation of Bcl-Xl is associated with an increased sensitivity to apoptosis while the ectopic expression of Bcl-2 induced apoptosis. This apoptosis is linked to the presence of cytoplasmic Nur 77 in undifferentiated hMSCs.
Significance: In hMSCs, the expression of Bcl-2 depends on cellular differentiation and can be either pro- or anti-apoptotic. Bcl-Xl, on the other hand, exhibits an anti-apoptotic activity under all conditions.
Public Library of Science
2011-05-12
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/96316/1/Distinct%20roles%20of%20Bcl-2%20and%20Bcl-Xl%20in%20the%20apoptosis%20of%20human%20bone%20marrow%20mesenchymal%20stem%20cells%20during%20differentiation..pdf
Oliver, L., Hue, E., Rossignol, J. et al. (6 more authors) (2011) Distinct Roles of Bcl-2 and Bcl-Xl in the Apoptosis of Human Bone Marrow Mesenchymal Stem Cells during Differentiation. PLoS ONE, 6 (5). e19820. ISSN 1932-6203
http://dx.doi.org/10.1371/journal.pone.0019820
10.1371/journal.pone.0019820
oai:eprints.whiterose.ac.uk:96317
2016-04-23T05:35:55Z
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https://eprints.whiterose.ac.uk/96317/
A combination of methotrexate and zoledronic acid prevents bone erosions and systemic bone mass loss in collagen induced arthritis
Le Goff, B.
Soltner, E.
Charrier, C.
Maugars, Y.
Redini, F.
Heymann, D.
Berthelot, J-M.
Introduction Osteoclasts play a key role in the pathogenesis of
bone erosion and systemic bone mass loss during rheumatoid
arthritis (RA). In this study, we aimed to determine the effect of
methotrexate (MTX) and zoledronic acid (ZA), used alone or in
combination, on osteoclast-mediated bone erosions and
systemic bone mass loss in a rat model of collagen induced
arthritis (CIA). We hypothesized that MTX and ZA could have an
additive effect to prevent both bone erosion and systemic bone
loss.
Methods Arthritis was induced in 64 female Sprague-Dawley
rats. After the clinical onset of CIA, rats were assigned to
treatment with MTX (1 mg/kg/week), ZA (100 μg/kg twice
weekly), both treatments at the same regimens, or vehicle.
Arthritis score and paw thickness were recorded twice weekly.
The rats were sacrificed on D28 and hind paws were removed
for radiographic, histological and immunohistochemical
analysis. The effects of treatments on osteoclastogenesis were
determined by Tartrate resistant acid phosphatase (TRAP)
staining. Micro-CT of the tibia was carried out for
histomorphometric analysis. Bone mass density was evaluated
by densitometry.
Results MTX significantly decreased the severity of CIA,
whereas ZA slightly exacerbated it. When these two drugs were
used in combination, MTX prevented the pro-inflammatory effect
of ZA. The combination of ZA with MTX was more effective than
MTX alone for reducing structural joint damage with a dramatic
decrease of osteoclasts' number in the eroded joints. However,
MTX alone also significantly reduced the number of osteoclasts
and the number of CD68+ mononuclear cells. ZA alone, or ZA
with MTX, significantly increased the systemic bone mass
density measured by densitometry and bone volume on
histomorphometric analysis.
Conclusions A combination of MTX and ZA prevented both
bone erosion and systemic bone loss in a rat model of arthritis.
Both treatments independently decreased the number of
osteoclasts in the eroded joint. However, while MTX probably
acts mainly through a decrease of inflammation, ZA has a direct
effect on osteoclasts, allowing a dramatic down-regulation of
these cells in inflamed joints. These two different mechanisms of
action provide support for the use of a combination of these two
drugs to improve the prevention of structural joint damage in RA.
BioMed Central
2009-12-10
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/96317/1/A%20combination%20of%20methotrexate%20and%20zoledronic%20acid%20prevents%20bone%20erosions%20and%20systemic%20bone%20mass%20loss%20in%20collagen%20induced%20arthritis..pdf
Le Goff, B., Soltner, E., Charrier, C. et al. (4 more authors) (2009) A combination of methotrexate and zoledronic acid prevents bone erosions and systemic bone mass loss in collagen induced arthritis. Arthritis Research & Therapy, 11 (6). R185. ISSN 1478-6354
http://dx.doi.org/10.1186/ar2877
10.1186/ar2877
oai:eprints.whiterose.ac.uk:96318
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https://eprints.whiterose.ac.uk/96318/
Tc-99m-NTP 15-5 assessment of the early therapeutic response of chondrosarcoma to zoledronic acid in the Swarm rat orthotopic model
Miot-Noirault, E.
David, E.
Vidal, A.
Peyrode, C.
Besse, S.
Dauplat, M-M.
Heymann, M-F.
Gouin, F.
Chezal, J-M.
Heymann, D.
Redini, F.
Background: Since proteoglycans (PGs) appear as key partners in chondrosarcoma biology, PG-targeted imaging using the radiotracer 99mTc-N-(triethylammonium)-3-propyl-[15]ane-N5 (99mTc-NTP 15-5) developed by our group was previously demonstrated to be a good single-photon emission computed tomography tracer for cartilage neoplasms. We therefore initiated this new preclinical study to evaluate the relevance of 99mTc-NTP 15-5 imaging for the in vivo monitoring and quantitative assessment of chondrosarcoma response to zoledronic acid (ZOL) in the Swarm rat orthotopic model.
Findings: Rats bearing chondrosarcoma in the orthotopic paratibial location were treated by ZOL (100 μg/kg, subcutaneously) or phosphate-buffered saline, twice a week, from day 4 to day 48 post-tumor implantation. 99mTc-NTP 15-5 imaging was performed at regular intervals with the target-to-background ratio (TBR) determined. Tumor volume was monitored using a calliper, and histology was performed at the end of the study. From day 11 to day 48, mean TBR values ranged from 1.7 ± 0.6 to 2.3 ± 0.6 in ZOL-treated rats and from 2.1 ± 1.0 to 4.9 ± 0.9 in controls. Tumor growth inhibition was evidenced using a calliper from day 24 and associated to a decrease in PG content in treated tumor tissues (confirmed by histology).
Conclusions: This work demonstrated two proofs of concept: (1) biphosphonate therapy could be a promising therapeutic approach for chondrosarcoma; (2) 99mTc-NTP 15-5 is expected to offer a novel imaging modality for the in vivo evaluation of the extracellular matrix features of chondrosarcoma, which could be useful for the follow-up and quantitative assessment of proteoglycan ‘downregulation’ associated to the response to therapeutic attempts.
BioMed Central
2013-05-20
Article
PeerReviewed
text
en
https://eprints.whiterose.ac.uk/96318/1/99mTc-NTP%2015-5%20assessment%20of%20the%20early%20therapeutic%20response%20of%20chondrosarcoma%20to%20zoledronic%20acid%20in%20the%20Swarm%20rat%20orthotopic%20model..pdf
Miot-Noirault, E., David, E., Vidal, A. et al. (8 more authors) (2013) Tc-99m-NTP 15-5 assessment of the early therapeutic response of chondrosarcoma to zoledronic acid in the Swarm rat orthotopic model. EJNMMI Research, 3. 40. ISSN 2191-219X
http://dx.doi.org/10.1186/2191-219X-3-40
10.1186/2191-219X-3-40
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