tbuckley/cabot-search huggingface dataset:
von Hippel-Lindau Gene Mutations in N-Nitrosodimethylamine-Induced Rat Renal Epithelial Tumors
Authors: Y.-H. Shiao, L. M. Anderson, B. A. Diwan, J. M. Rice, G. C. Hard
Journal: JNCI Journal of the National Cancer Institute (1998)

Background: Mutations in the von Hippel-Lindau (VHL) gene are common in human clear cell kidney cancers. Carcinogens in cigarette smoke, especially nitrosamines, are known to induce kidney tumors of a variety of histologic types in rodents—but with no evidence of VHL mutations; however, none of these tumors resembled human clear cell carcinomas. We examined Nnitrosodimethylamine- induced kidney tumors of the clear or mixed clear/ granular cell type in Wistar rats to assess the presence of VHL mutations. Methods: Sections of eight clear or mixed clear/granular cell kidney tumors that had been formalin fixed and paraffin embedded were microdissected. DNA was extracted from the microdissected tissue, and exons 1-3 of the rat VHL gene were examined by use of polymerase chain reaction and cycle sequencing techniques. Results: Four VHL gene mutations (three G:C to A:T and one A:T to G:C) were detected in three of the tumors in contrast to no mutations in 40 previously reported rat kidney tumors of other histologic types (three of eight tumors versus none of 40; two-sided Fisher's exact test; P = .003). Only tumors showing prominent swollen clear cell cytology with a signet-ring appearance had VHL mutations. Conclusions: To our knowledge, this is the first report of VHL mutations in kidney tumors after direct chemical exposure and provides a possible molecular pathway linking tobacco smoking to kidney cancer.
Celecoxib Promotes c-FLIP Degradation through Akt-Independent Inhibition of GSK3
Authors: Shuzhen Chen, Wei Cao, Ping Yue, Chunhai Hao, Fadlo R. Khuri, Shi-Yong Sun
Journal: Cancer Research (2011)

Abstract Celecoxib is a COX-2 inhibitor that reduces the risk of colon cancer. However, the basis for its cancer chemopreventive activity is not fully understood. In this study, we defined a mechanism of celecoxib action based on degradation of cellular FLICE-inhibitory protein (c-FLIP), a major regulator of the death receptor pathway of apoptosis. c-FLIP protein levels are regulated by ubiquitination and proteasome-mediated degradation. We found that celecoxib controlled c-FLIP ubiquitination through Akt-independent inhibition of glycogen synthase kinase-3 (GSK3), itself a candidate therapeutic target of interest in colon cancer. Celecoxib increased the levels of phosphorylated GSK3, including the α and β forms, even in cell lines, where phosphorylated Akt levels were not increased. Phosphoinositide 3-kinase inhibitors abrogated Akt phosphorylation as expected but had no effect on celecoxib-induced GSK3 phosphorylation. In contrast, protein kinase C (PKC) inhibitors abolished celecoxib-induced GSK3 phosphorylation, implying that celecoxib influenced GSK3 phosphorylation through a mechanism that relied upon PKC and not Akt. GSK3 blockade either by siRNA or kinase inhibitors was sufficient to attenuate c-FLIP levels. Combining celecoxib with GSK3 inhibition enhanced attenuation of c-FLIP and increased apoptosis. Proteasome inhibitor MG132 reversed the effects of GSK3 inhibition and increased c-FLIP ubiquitination, confirming that c-FLIP attenuation was mediated by proteasomal turnover as expected. Our findings reveal a novel mechanism through which the regulatory effects of c-FLIP on death receptor signaling are controlled by GSK3, which celecoxib acts at an upstream level to control independently of Akt. Cancer Res; 71(19); 6270–81. ©2011 AACR.
P141 Unwarranted variation in chronic obstructive pulmonary disease care: provision of pulmonary rehabilitation for Londoners
Authors: M. Buxton, S. Prigmore, K. Barnes, A. Coombes, S. Williams, L. Restrick
Journal: Thorax (2011)

<h3>Introduction and Objectives</h3> Pulmonary Rehabilitation (PR) is recognised as an essential component of care for patients with chronic obstructive pulmonary disease (COPD). However there is no national database of available or delivered PR services. The aim of this study was to identify and characterise PR services and service variation for a 7.75 million population in one Health Authority with 31 Primary Care Trusts (PCTs). <h3>Methods</h3> PR leads in each PCT were identified and a telephone interview conducted using 52 clinical and service related questions including estimated annual referrals, rolling/cohort model, sessions/week, PR duration, assessment (duration, exercise capacity (Incremental Shuttle Walk (ISW), 6 min Walk Test (6MWT)) and quality of life (QOL) measures), psychologist involvement, completion measures and availability of post PR-maintenance programmes. Provision of PR was compared to quality outcomes framework (QOF) prevalence of diagnosed COPD. <h3>Results</h3> 26/31 (84%) PCTs provide PR (74 programmes) from 32 service providers; 5 PCTs provide no PR. Provision was not related to COPD prevalence; the range of service referrals received was &lt;50 to &gt;700/year. 15/26 (58%) PCTS offered maintenance programmes. 52 programmes were rolling, 22 cohort, programme duration 6–8 weeks. 31/32 services provide 2 sessions/week (1 service 1 session/week); 15/32 (47%) services had psychology input. Assessments took 0.5–2 h/patient. 32/32 (100%) services used walking tests and 11/32 (34%) followed repeat walk guidance; 11/23 ISWT, 0/9 6MWT. Questionnaires used ranged between 1 and 5, 13/32 (41%) services used more than two questionnaires (See Abstract P141 table 1 below). (insert table as separate attachment) There was no standard definition of completion; range 50%–100% sessions attended. The range of estimates of completion rates (using own definitions) was &lt;30% to &gt;80%. <h3>Conclusions</h3> PR is not available in five PCTs, despite evidence for its value, and capacity does not match need. Half of PCTs offer post-PR programmes reflecting demand from patients who complete PR. Studies of the value of maintenance PR are now needed. Reducing unwarranted variation in assessment process (questionnaires and walking tests), and completion (definition and rates) using standardised approaches to delivery and measurement would potentially release capacity for unmet need.
Anchorage on fibronectin via VLA-5 ( 5 1 integrin) protects rheumatoid synovial cells from Fas-induced apoptosis
Authors: A Kitagawa
Journal: Annals of the Rheumatic Diseases (2005)

Rheumatoid synovial cells are resistant to apoptosis induction in vivo, whereas, fibroblast-like synovial cells in rheumatoid arthritis (RA-FLS) are vulnerable to Fas-induced apoptosis in vitro.To clarify this discrepancy by studying the contribution of the interaction between cellular integrin and matrix fibronectin (Fn), which is significantly increased in the rheumatoid joints, to the induction of apoptosis in RA-FLS.Integrin and Fas mRNAs were measured by reverse transcription-polymerase chain reaction in RA-FLS. Integrins expressed in rheumatoid synovial tissues were analysed by immunohistochemistry. RA-FLS plated either on Fn or on control poly-L-lysine were incubated with agonistic anti-Fas monoclonal antibodies (mAbs). Apoptosis induction was evaluated using terminal deoxynucleotidyl transferase mediated UTP nick end labelling (TUNEL) and immunoblotting for caspase-3 and poly (ADP-ribose) polymerase in the presence or absence of anti-VLA-5 mAb.VLA-5 (alpha5beta1 integrin), a major integrin expressed on RA-FLS, was required for the adhesion of RA-FLS on Fn. RA-FLS plated on Fn were more resistant to Fas-induced apoptosis than those plated on control poly-L-lysine. This protection by Fn was reversed by anti-VLA-5 mAb.Anchorage of RA-FLS on matrix Fn via VLA-5 protects RA-FLS from Fas-induced apoptosis, and Fn abundantly present in rheumatoid synovium appears to afford RA-FLS resistance against apoptosis induction in vivo.
Hypofractionated Stereotactic Radiation Therapy: An Effective Therapy for Recurrent High-Grade Gliomas
Authors: Shannon E. Fogh, David W. Andrews, Jon Glass, Walter Curran, Charles Glass, Colin Champ, James J. Evans, Terry Hyslop, Edward Pequignot, Beverly Downes, Eileen Comber, Mitchell Maltenfort, Adam P. Dicker, Maria Werner-Wasik
Journal: Journal of Clinical Oncology (2010)

Salvage options for recurrent high-grade gliomas (HGGs) are limited by cumulative toxicity and limited efficacy despite advances in chemotherapeutic and radiotherapeutic techniques. Previous studies have reported encouraging survival results and favorable toxicity with fractionated stereotactic radiotherapy, and small studies have shown similar benefit using a shortened course of hypofractionated stereotactic radiation therapy (H-SRT). We sought to determine the efficacy and toxicity profile of H-SRT alone or in addition to repeat craniotomy or concomitant chemotherapy.Between 1994 and 2008, 147 patients with recurrent HGG were treated with H-SRT (median dose, 35 Gy in 3.5-Gy fractions). Cox regression models were used to analyze survival outcomes. Variables included age, surgery before H-SRT, time to first recurrence, reirradiation dose, inclusion of chemotherapy with H-SRT, and gross tumor volume (GTV).Younger age (P = .001), smaller GTV (P = .025), and shorter time between diagnosis and recurrence (P = .034) were associated with improvement in survival from H-SRT. Doses of radiation > or = 35 Gy approached significance (P = .07). There was no significant benefit of surgical resection or chemotherapy in this population when analysis was controlled for other prognostic factors.H-SRT was well tolerated and resulted in a median survival time of 11 months after H-SRT, independent of re-operation or concomitant chemotherapy. Patients who experienced recurrence within 6 months after initial treatment had an excellent response and should not be disqualified from H-SRT. This is the largest series to examine the efficacy and tolerability of H-SRT in recurrent HGG.
Transplantation of Peripheral Blood Stem Cells as Compared With Bone Marrow From HLA-Identical Siblings in Adult Patients With Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia
Authors: O. Ringdén, M. Labopin, A. Bacigalupo, W. Arcese, U.W. Schaefer, R. Willemze, H. Koc, D. Bunjes, E. Gluckman, V. Rocha, A. Schattenberg, F. Frassoni
Journal: Journal of Clinical Oncology (2002)

PURPOSE: Several studies show that allogeneic peripheral blood stem cells (PBSCs) engraft more rapidly than bone marrow (BM). However, the data are inconsistent with regard to acute and chronic graft-versus-host disease (GVHD), relapse, transplant-related mortality (TRM), and leukemia-free survival (LFS). PATIENTS AND METHODS: Between January 1994 and December 2000, 3,465 adult patients (older than 15 years of age) were reported to the European Group for Blood and Marrow Transplantation Registry from 224 centers. Among acute myeloid leukemia (AML) patients, 1,537 patients received BM and 757 patients received PBSC. In acute lymphoblastic leukemia (ALL) patients, the corresponding figures were 826 versus 345 patients who were analyzed for engraftment, GVHD, TRM, relapse, LFS, and survival. RESULTS: In multivariate analysis, the recovery of neutrophils and platelets was faster with PBSC than with BM (P &lt; .0001). Chronic GVHD was associated with PBSC in patients with AML (relative risk [RR], 2.11; 95% confidence interval, 1.66 to 2.7; P &lt; .0001) and ALL (RR, 1.56; 95% confidence interval, 1.09 to 2.27; P = .02). PBSC versus BM in patients with AML or ALL was not significantly associated with acute GVHD, TRM, relapse, survival, or LFS. In multivariate analysis of patients with AML, factors significantly associated with improved LFS included first remission at transplant (P &lt; .0001), promyelocytic leukemia (M3) versus other French-American-British types (P &lt; .0001), and donor age below median 37 years (P = .02). In patients with ALL, first remission (P &lt; .0001) and methotrexate included in the immunosuppressive regimen (P = .001) were associated with improved LFS. CONCLUSION: Allogeneic PBSC results in faster neutrophil and platelet engraftment and a higher incidence of chronic GVHD than BM. However, acute GVHD, TRM, relapse, survival, and LFS were similar in patients receiving PBSCs versus BM.
Prevalence of occupational and environmental exposures in Australian patients with idiopathic pulmonary fibrosis (IPF)
Authors: E. Haydn Walters, Michael J. Abramson, Geza Benke, Shyamali Dharmage, Ian Glaspole, Ryan Hoy, Sacha Macansh, Tamera J. Corte
Journal: European Respiratory Journal (2014)

Background:  IPF is a fatal lung disease, with no current effective treatment. IPF is considered idiopathic by definition, but key environmental exposures may be important to its pathogenesis.  Methods: The Australian IPF Registry is a national cohort of IPF patients. Data collected include a questionnaire with detailed exposure history to tobacco, environment, and dust exposures. The prevalence of exposures and associations between rate of exposure and IPF were explored.  Results:  377 patients have consented to the Registry. 299 (79%) have completed exposure questionnaires (mean±SD: age 70.9±8.0yrs; 202 male; FVC 82.5±22.8%predicted). Smoking history: 204 ex-smokers, 9 current smokers, 85 non-smokers. Environmental exposures are reported in Table 1. Occupational exposures include asbestos 115 (40.8%; 95%CI: 35.2, 46.6),silica 37 (13.0%; 9.5, 17.4), chemicals 136 (47.1%; 41.4, 52.8) and dusty environments 153 (52.0%; 46.3, 57.7). The IPF rate in geographic areas correlated with exposure rate to chemicals (r=0.86, p=0.01) and dusty environments (r=1.0; pl0.001).  Conclusion:  IPF patients report a high prevalence of potentially adverse exposures, and exploratory analyses show a geographic relationship between some exposures and IPF. Further case control studies are needed to determine if these exposures are more prevalent in IPF patients than healthy controls.
Efficacy of rituximab in primary Sjögren's syndrome with peripheral nervous system involvement: results from the AIR registry
Authors: A Mekinian, P Ravaud, P Y Hatron, C Larroche, J Leone, B Gombert, M Hamidou, A Cantagrel, C Marcelli, S Rist, M Breban, D Launay, O Fain, J E Gottenberg, X Mariette
Journal: Annals of the Rheumatic Diseases (2011)

Objective To evaluate rituximab (RTX) in primary Sjögren's syndrome (pSS) with peripheral nervous system (PNS) involvement. Methods Patients with pSS and PNS involvement who were included in the French AIR registry were analysed. Results 17 patients (age 60 years (44–78 years); 14 were female) were analysed. Neurological improvement was noted in 11 patients (65%) at 3 months. Rankin scale decreased from 3 (1–5) to 2 (1–5), 2 (1–5) and 2 (1–6) after 3, 6 and 9 months (p=0.02). European Sjögren's Syndrome Disease Activity Index decreased from 18 (10–44) to 11 (5–20), 11 (5–29) and 12 (5–30) after 3, 6 and 9 months (p&lt;0.05). RTX was effective in neurological involvement in 9/10 patients with vasculitis or cryoglobulinaemia (90%) (group 1) at 3 months and in 2/7 cases (29%) without cryoglobulinaemia and vasculitis (p=0.03). Rankin and European Sjögren's Syndrome Disease Activity Index scales decreased significantly in group 1. Conclusion RTX seems effective in cryoglobulinaemia or vasculitis-related PNS involvement in pSS.
Cystic Fibrosis Is Associated with a Defect in Apical Receptor–Mediated Endocytosis in Mouse and Human Kidney
Authors: Franc[COMBINING CEDILLA]ois Jouret, Alfred Bernard, Cédric Hermans, Geneviève Dom, Sara Terryn, Teresinha Leal, Patrick Lebecque, Jean-Jacques Cassiman, Bob J. Scholte, Hugo R. de Jonge, Pierre J. Courtoy, Olivier Devuyst
Journal: Journal of the American Society of Nephrology (2007)

Inactivation of the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR) causes cystic fibrosis (CF). Although CFTR is expressed in the kidney, no overwhelming renal phenotype has been documented in patients with CF. This study investigated the expression, subcellular distribution, and processing of CFTR in the kidney; used various mouse models to assess the role of CFTR in proximal tubule (PT) endocytosis; and tested the relevance of these findings in patients with CF. The level of CFTR mRNA in mouse kidney approached that found in lung. CFTR was located in the apical area of PT cells, with a maximal intensity in the straight part (S3) of the PT. Fractionation showed that CFTR co-distributed with the chloride/proton exchanger ClC-5 in PT endosomes. <i>Cftr</i><sup>−/−</sup> mice showed impaired <sup>125</sup>I-β<sub>2</sub>-microglobulin uptake, together with a decreased amount of the multiligand receptor cubilin in the S3 segment and a significant loss of cubilin and its low molecular weight (LMW) ligands into the urine. Defective receptor-mediated endocytosis was found less consistently in <i>Cftr</i><sup>ΔF/ΔF</sup> mice, characterized by a large phenotypic heterogeneity and moderate <i>versus</i> mice that lacked ClC-5. A significant LMW proteinuria (and particularly transferrinuria) also was documented in a cohort of patients with CF but not in patients with asthma and chronic lung inflammation. In conclusion, CFTR inactivation leads to a moderate defect in receptor-mediated PT endocytosis, associated with a cubilin defect and a significant LMW proteinuria in mouse and human. The magnitude of the endocytosis defect that is caused by CFTR <i>versus</i> ClC-5 loss likely reflects functional heterogeneity along the PT.
Lipoprotein(a) Concentration and the Risk of Coronary Heart Disease, Stroke, and Nonvascular Mortality
Authors: S Erqou, S Kaptoge, PL Perry, E Di Angelantonio, A Thompson, IR White, SM Marcovina, R Collins, SG Thompson, J Danesh
Journal: JAMA (2009)

Circulating concentration of lipoprotein(a) (Lp[a]), a large glycoprotein attached to a low-density lipoprotein-like particle, may be associated with risk of coronary heart disease (CHD) and stroke.To assess the relationship of Lp(a) concentration with risk of major vascular and nonvascular outcomes.Long-term prospective studies that recorded Lp(a) concentration and subsequent major vascular morbidity and/or cause-specific mortality published between January 1970 and March 2009 were identified through electronic searches of MEDLINE and other databases, manual searches of reference lists, and discussion with collaborators.Individual records were provided for each of 126,634 participants in 36 prospective studies. During 1.3 million person-years of follow-up, 22,076 first-ever fatal or nonfatal vascular disease outcomes or nonvascular deaths were recorded, including 9336 CHD outcomes, 1903 ischemic strokes, 338 hemorrhagic strokes, 751 unclassified strokes, 1091 other vascular deaths, 8114 nonvascular deaths, and 242 deaths of unknown cause. Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. Analyses excluded participants with known preexisting CHD or stroke at baseline.Lipoprotein(a) concentration was weakly correlated with several conventional vascular risk factors and it was highly consistent within individuals over several years. Associations of Lp(a) with CHD risk were broadly continuous in shape. In the 24 cohort studies, the rates of CHD in the top and bottom thirds of baseline Lp(a) distributions, respectively, were 5.6 (95% confidence interval [CI], 5.4-5.9) per 1000 person-years and 4.4 (95% CI, 4.2-4.6) per 1000 person-years. The risk ratio for CHD, adjusted for age and sex only, was 1.16 (95% CI, 1.11-1.22) per 3.5-fold higher usual Lp(a) concentration (ie, per 1 SD), and it was 1.13 (95% CI, 1.09-1.18) following further adjustment for lipids and other conventional risk factors. The corresponding adjusted risk ratios were 1.10 (95% CI, 1.02-1.18) for ischemic stroke, 1.01 (95% CI, 0.98-1.05) for the aggregate of nonvascular mortality, 1.00 (95% CI, 0.97-1.04) for cancer deaths, and 1.00 (95% CI, 0.95-1.06) for nonvascular deaths other than cancer.Under a wide range of circumstances, there are continuous, independent, and modest associations of Lp(a) concentration with risk of CHD and stroke that appear exclusive to vascular outcomes.
Detection of TP53 dysfunction in chronic lymphocytic leukemia by an in vitro functional assay based on TP53 activation by the non-genotoxic drug Nutlin-3: a proposal for clinical application
Authors: Federico Pozzo, Michele Dal Bo, Nadia Peragine, Riccardo Bomben, Antonella Zucchetto, Francesca Maria Rossi, Massimo Degan, Davide Rossi, Annalisa Chiarenza, Alberto Grossi, Francesco Di Raimondo, Francesco Zaja, Gabriele Pozzato, Paola Secchiero, Gianluca Gaidano, Giovanni Del Poeta, Giorgio Zauli, Robin Foà, Anna Guarini, Valter Gattei
Journal: Journal of Hematology & Oncology (2013)

TP53 defects, i.e. 17p13 deletion and/or nucleotide mutations, associate with short survival and chemorefractoriness in chronic lymphocytic leukemia (CLL). In this context, since direct sequencing of the TP53 gene does not evaluate TP53 functionality, a functional assessment of TP53 pathway may be of interest to identify high risk CLL. By taking advantage of a training cohort of 100 CLL and a validation cohort of 40 CLL with different patterns of TP53 mutation/deletion by FISH and sequencing, we propose an in-vitro assay in which the modulation of TP53 protein and CDKN1A mRNA were investigated upon 24-hour exposure of CLL cells to Nutlin-3. The functional assay was set-up on cell lines recapitulating all TP53 genotypes (EHEB, TP53wt/wt; RAJI, TP53mut/wt; MEC-1 and MAVER1, TP53mut/del; HL-60, TP53del/del) and evaluated in two multi-institutional cohorts, purposely enriched in CLL bearing TP53 disruption: a training cohort of 100 cases and a validation cohort of 40 cases, both characterized by FISH and TP53 direct sequencing. Cells were exposed to 10 μM Nutlin-3 for 24 hours; TP53 accumulation was evaluated by Western blotting; TP53 transcriptional activity was determined by quantitative realtime PCR (qRT-PCR) of the TP53 target gene CDKN1A. According to TP53 protein modulation, in the training cohort we identified: i) 63 cases (51 TP53wt/wt, 12 TP53del/wt) with absence of basal TP53 and induction after treatment (normal pattern); ii) 18 cases (3 TP53mut/wt, 15 TP53mut/del) with high basal TP53 without increase after treatment (mutant pattern); iii) 19 cases (5 TP53mut/wt; 3 TP53mut/del; 11 TP53wt/wt) with basal TP53 that increases upon treatment (intermediate pattern). Evaluation of CDKN1A mRNA levels upon Nutlin-3 exposure showed that the 26 TP53 mutated (TP53mut/del or TP53mut/wt) cases had lower induction levels than the majority (57/63) of cases with normal pattern, and 10/12 cases with intermediate pattern without evidence of TP53 derangement by FISH and sequencing. These results were confirmed in the independent validation cohort of 40 cases (13 TP53wt/wt, 3 TP53del/wt, 12 TP53mut/del, 12 TP53mut/wt). The proposed functional assay may integrate the conventional analyses for the identification of TP53 dysregulated CLL.
Genetic and Hormonal Risk Factors in Breast Cancer
Authors: A.-M. Martin
Journal: JNCI Journal of the National Cancer Institute (2000)

Breast cancer poses a serious public health problem, and it is hoped that identification of genetic and environmental factors that contribute to the development of breast cancer will enhance prevention efforts. Two breast cancer susceptibility genes (BRCA1 and BRCA2) have been identified, and germline mutations in these genes are thought to account for between 5% and 10% of all breast cancer cases. Current findings suggest that mutations in other highly penetrant genes may play an important role in breast cancer susceptibility, and studies aimed at the isolation of these genes are under way. In addition, common variants in a number of gene classes are thought to act as low-penetrance susceptibility alleles, and efforts to identify and characterize these variants are under way. This review discusses the genetic components of susceptibility to breast cancer from the standpoint of both human genetics and rat models.