tbuckley/cabot-search huggingface dataset:
Local Recurrence after Breast-Conserving Therapy in Relation to Gene Expression Patterns in a Large Series of Patients
Authors: Bas Kreike, Hans Halfwerk, Nicola Armstrong, Peter Bult, John A. Foekens, Sanne C. Veltkamp, Dimitry S.A. Nuyten, Harry Bartelink, Marc J. van de Vijver
Journal: Clinical Cancer Research (2009)

The majority of patients with early-stage breast cancer are treated with breast-conserving therapy (BCT). Several clinical risk factors are associated with local recurrence (LR) after BCT but are unable to explain all instances of LR after BCT. Here, gene expression microarrays are used to identify novel risk factors for LR after BCT.Gene expression profiles of 56 primary invasive breast carcinomas from patients who developed a LR after BCT were compared with profiles of 109 tumors from patients who did not develop a LR after BCT. Both unsupervised and supervised methods of classification were used to separate patients into groups corresponding to disease outcome. In addition, for 15 patients, the gene expression profile in the recurrence was compared with that of the primary tumor.The two main clusters found by hierarchical cluster analysis of all 165 primary invasive breast carcinomas revealed no association with LR. Predefined gene sets (molecular subtypes and "chromosomal instability" signature) are associated with LR (P = 0.0002 and 0.003, respectively). Significant analysis of microarrays revealed an association between LR and cell proliferation, not captured by histologic grading. Class prediction analysis constructed a gene classifier, which was successfully validated, cross-platform, on an independent data set of 161 patients (log-rank P = 0.041). In multivariate analysis, young age was the only independent predictor of LR.We have constructed and cross-platform validated a gene expression profile predictive for LR after BCT, which is characterized by genes involved in cell proliferation but not a surrogate for high histologic grade.
MICA Variant Promotes Allosensitization after Kidney Transplantation
Authors: Pierre Tonnerre, Nathalie Gérard, Mathias Chatelais, Caroline Poli, Stéphanie Allard, Sylvie Cury, Céline Bressollette, Anne Cesbron-Gautier, Béatrice Charreau
Journal: Journal of the American Society of Nephrology (2013)

MHC class I-related chain A (MICA) antigens are surface glycoproteins strongly implicated in innate immunity, and the MICA gene is highly polymorphic. Clinical observations suggest a role for donor MICA antigens expressed on transplant endothelial cells in the alloimmune response, but the effect of MICA genotype is not well understood. Here, we investigated the immunologic effect of the A5.1 mutation, related to the common MICA*008 allele. Compared with wild-type endothelial cells (ECs), homozygosity for MICA A5.1 associated with an endothelial phenotype characterized by 7- to 10-fold higher levels of MICA mRNA and MICA proteins at the cell surface, as well as exclusive release in exosomes instead of enzymatic cleavage. Mechanistically, we did not detect quantitative changes in regulatory microRNAs. Functionally, A5.1 ECs enhanced NKG2D interaction and natural killer cell activation, promoting NKG2D-dependent lysis of ECs. In kidney transplant recipients, polyreactive anti-MICA sera bound preferentially to ECs from MICA A5.1 donors, suggesting that MICA*008(A5.1) molecules are the preferential antigenic determinants on ECs of grafts. Furthermore, the incidence of MICA A5.1 mismatch revealed a statistically significant association between donor MICA A5.1 and both anti-MICA sensitization and increased proteinuria in kidney recipients. Taken together, these results identify the A5.1 mutation as an immunodominant factor and a potential risk factor for transplant survival.
Genetic Variation and Effects on Human Eating Behavior
Authors: Mariken de Krom, Florianne Bauer, David Collier, R.A.H. Adan, Susanne E. la Fleur
Journal: Annual Review of Nutrition (2009)

Feeding is a physiological process, influenced by genetic factors and the environment. In recent years, many studies have been performed to unravel the involvement of genetics in both eating behavior and its pathological forms: eating disorders and obesity. In this review, we provide a condensed introduction on the neurological aspects of eating and we describe the current status of research into the genetics of eating behavior, primarily focused on specific traits such as taste, satiation, and hunger. This is followed by an overview on the genetic studies done to unravel the heritable background of obesity and eating disorders. We examine the discussion currently taking place in the field of genetics of complex disorders and phenotypes on how to perform good and powerful studies, with the use of large-scale whole-genome association studies as one of the possible solutions. In the final part of this review, we give our view on the latest developments, including endophenotype approaches and animal studies. Studies of endophenotypes of eating behavior may help to identify core traits that are genetically influenced. Such studies would yield important knowledge on the underlying biological scaffold on which diagnostic criteria for eating disorders could be based and would provide information to influence eating behavior toward healthier living.
Adolphe Abrahams memorial lecture, 1988. Exercise and lifestyle change.
Authors: R J Shephard
Journal: British Journal of Sports Medicine (1989)

While the evidence for a clustering of health habits is not particularly strong, there are both pedagogic and economic arguments in favour of a multifaceted approach to health education. The present review thus examines the impact of regular physical exercise upon other forms of health behaviour, testing the extent to which an activity programme can be a catalyst of improved lifestyle in both primary and secondary preventive therapy. The conceptual framework of health promotion is examined with particular reference to the models of Skinner, Becker, Fishbein, Triandis and Rokeach. Certain differences are noted between the decision to exercise and the marketing decisions for which Fishbein's model was originally designed. Nevertheless, in its later modifications, it provides a basic framework for understanding how human lifestyle is shaped. Theoretical mechanisms are suggested whereby exercise could influence such behaviours as cigarette smoking, alcohol consumption and drug usage, seat-belt usage, hypertension, body mass, lipid profile, promiscuous sexual behaviour, the carrying of lethal weapons, and acceptance of regular preventive medical examinations. The empirical evidence from both cross-sectional and longitudinal experiments shows a relatively weak association between exercise habits and other desirable forms of health behaviour. Moreover, it is arguable that other forms of health intervention such as smoking withdrawal or dieting might be equally effective as a primary change agent, and much of the observed association between exercise and other health habits could be attributable to a common dependence on demographic and socio-economic factors. On the other hand, the apparent weakness of associations may arise in part from difficulties in measuring both habitual physical activity and other forms of health behaviour, with a resultant attenuation of correlations. Possibly, a stronger association between exercise participation and other favourable health habits would be uncovered if attention were focused upon those forms of endurance exercise currently thought to enhance cardiac health. Given that moderate endurance exercise is also positive and pleasant advice, further examination of the potential of multifaceted but exercise-centered health promotion programmes appears warranted.
Abstract 1044: Pyruvate kinase M2 stimulates the epithelial-mesenchymal transition by genetically controlling E-cadherin expression in colon cancer
Authors: Masamitsu Konno, Atsushi Hamabe, Yuichiro Doki, Masaki Mori, Hideshi Ishii
Journal: Cancer Research (2014)

Abstract Pyruvate kinase M2 (PKM2) maintains aerobic glycolysis in cancer cells and stimulates cell proliferation by controlling cancer metabolism (Warburg effect)(Nature, 2008). In addition, PKM2 translocates to nucleus in response to EGFR signaling and up-regulates Cyclin D1 expression by controlling its transcription (Nature, 2011). PKM2 confers malignant potential by controlling both metabolism and nuclear function. In this study, we investigated the correlation between PKM2 and invasion and metastasis of colorectal cancer in terms of nuclear function, which has yet to be investigated. Tumor invasion is initiated with the change of epithelial-mesenchymal transition (EMT) in cancer cell, and we induced EMT by adding TGF-β1 and EGF to SW 480. After EGF induction, in parallel with E-cadherin down-regulation and Vimentin up-regulation, the expression of PKM2 was increased both in transcriptional and translational level and PKM2 translocated into nucleus. PKM2 knock-down by siRNA suppressed E-cadherin decrease and invasion capacity in invasion assay. We created sh pyruvate kinase SW 480 with mouse PKM1 or PKM2 was overexpressed both of which have DNA sequence resistant to sh pyruvate kinase. PKM2 overexpression stimulated EMT induction by enhancing E-cadherin decrease. The protein X was identified which interacted with PKM2 in nucleus in response to EMT induction, which was considered to have a key role in controlling EMT induction. We performed immunohistochemical staining with specific antibody to PKM2 using clinical samples of colorectal cancers. Clinicopathological analysis showed that PKM2 positivity significantly correlated with lymph node metastasis and distant organ metastasis. In conclusion, our data suggested that PKM2 nuclear function had a crucial role in controlling invasion and metastasis. Citation Format: Masamitsu Konno, Atsushi Hamabe, Yuichiro Doki, Masaki Mori, Hideshi Ishii. Pyruvate kinase M2 stimulates the epithelial-mesenchymal transition by genetically controlling E-cadherin expression in colon cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1044. doi:10.1158/1538-7445.AM2014-1044
Tobacco Smoking and Increased Risk of Death and Progression for Patients With p16-Positive and p16-Negative Oropharyngeal Cancer
Authors: Maura L. Gillison, Qiang Zhang, Richard Jordan, Weihong Xiao, William H. Westra, Andy Trotti, Sharon Spencer, Jonathan Harris, Christine H. Chung, K. Kian Ang
Journal: Journal of Clinical Oncology (2012)

Purpose Tobacco smoking is associated with oropharynx cancer survival, but to what extent cancer progression or death increases with increasing tobacco exposure is unknown. Patients and Methods Patients with oropharynx cancer enrolled onto a phase III trial of radiotherapy from 1991 to 1997 (Radiation Therapy Oncology Group [RTOG] 9003) or of chemoradiotherapy from 2002 to 2005 (RTOG 0129) were evaluated for tumor human papillomavirus status by a surrogate, p16 immunohistochemistry, and for tobacco exposure by a standardized questionnaire. Associations between tobacco exposure and overall survival (OS) and progression-free survival (PFS) were estimated by Cox proportional hazards models. Results Prevalence of p16-positive cancer was 39.5% among patients in RTOG 9003 and 68.0% in RTOG 0129. Median pack-years of tobacco smoking were lower among p16-positive than p16-negative patients in both trials (RTOG 9003: 29 v 45.9 pack-years; P = .02; RTOG 0129: 10 v 40 pack-years; P &lt; .001). After adjustment for p16 and other factors, risk of progression (PFS) or death (OS) increased by 1% per pack-year (for both, hazard ratio [HR], 1.01; 95% CI, 1.00 to 1.01; P = .002) or 2% per year of smoking (for both, HR, 1.02; 95% CI, 1.01 to 1.03; P &lt; .001) in both trials. In RTOG 9003, risk of death doubled (HR, 2.19; 95% CI, 1.46 to 3.28) among those who smoked during radiotherapy after accounting for pack-years and other factors, and risk of second primary tumors increased by 1.5% per pack-year (HR, 1.015; 95% CI, 1.005 to 1.026). Conclusion Risk of oropharyngeal cancer progression and death increases directly as a function of tobacco exposure at diagnosis and during therapy and is independent of tumor p16 status and treatment.
Elevated nitrite in breath condensates of children with respiratory disease
Authors: W. Formanek, D. Inci, R.P. Lauener, J.H. Wildhaber, U. Frey, G.L. Hall
Journal: European Respiratory Journal (2002)

The aim of the study was to determine the differences in nitrite, in the exhaled breath condensates of healthy children and those children with asthma, cystic fibrosis (CF) and nonasthmatic, episodic cough. Breath condensates were obtained from 66 children (43 males:23 females, 3.1–16 yrs) and included 29 asthmatics, 12 clinically stable CF patients, 12 children with cough but not asthma and 13 healthy volunteers. The collected condensate was assayed colourimetrically using the Griess reaction to determine nitrite concentrations. Patients with CF (median: 5–95% percentiles; 2.02: 0.43–6.37 µM) or asthma (2.10: 0.63–5.45 µM) had significantly higher levels of nitrite compared to healthy subjects (0.41: 0.13–1.83 µM; p&lt;0.05) or subjects with cough (0.75: 0.03–1.75 µM; p&lt;0.05). Airway inflammation, as assessed by the nitrite in breath condensates, is present in children with asthma and cystic fibrosis, but not those children with nonasthmatic, episodic cough. Nitrite can be conveniently, cheaply and rapidly measured in breath condensates of children as young as 3 yrs of age, and may prove useful for the assessment of airway inflammation in children with respiratory disease.
Characterisation of severe obliterative bronchiolitis in rheumatoid arthritis
Authors: G. Devouassoux, V. Cottin, H. Lioté, E. Marchand, I. Frachon, A. Schuller, F. Béjui-Thivolet, J-F. Cordier
Journal: European Respiratory Journal (2009)

The characteristics of patients with rheumatoid arthritis (RA) who develop obliterative bronchiolitis characterised by severe airflow obstruction have been hitherto poorly investigated. A retrospective study of 25 patients with RA and functional evidence of obliterative bronchiolitis (forced expiratory volume in one second (FEV 1 )/forced vital capacity (FVC) &lt;50% and/or residual volume (RV)/total lung capacity (TLC) &gt;140% predicted) was conducted. Patients (mean± sd age 64±11 yrs) included 17 never-smokers and eight ex-smokers (10.5±5.4 pack-yrs). The diagnosis of RA preceded respiratory symptoms in 88% of cases. Dyspnoea on exertion was present in all patients and bronchorrhea in 44%. High-resolution computed tomography findings included: bronchial wall thickening (96%), bronchiectasis (40%), mosaic pattern (40%), centrilobular emphysema (56%), and reticular and/or ground-glass opacities (32%). Pulmonary function tests showed: FEV 1 41±12% pred, FEV 1 /FVC 49±14%, FVC 70±20% pred, RV 148±68% pred and RV/TLC 142±34% pred. Lung biopsy, available in nine patients, demonstrated constrictive, follicular and mixed bronchiolitis. Patients were followed for 48.2±49 months. Treatment was poorly effective. Chronic respiratory failure occurred in 40% of patients, and four patients died. Obliterative bronchiolitis associated with rheumatoid arthritis is a severe and under-recognised condition leading to respiratory failure and death in a high proportion of patients.
Intratumoral Modeling of Gefitinib Pharmacokinetics and Pharmacodynamics in an Orthotopic Mouse Model of Glioblastoma
Authors: Jyoti Sharma, Hua Lv, James M. Gallo
Journal: Cancer Research (2013)

Like many solid tumors, glioblastomas are characterized by intratumoral biologic heterogeneity that may contribute to a variable distribution of drugs and their associated pharmacodynamic responses, such that the standard pharmacokinetic approaches based on analysis of whole-tumor homogenates may be inaccurate. To address this aspect of tumor pharmacology, we analyzed intratumoral pharmacokinetic/pharmacodynamic characteristics of the EGFR inhibitor gefitinib in mice with intracerebral tumors and developed corresponding mathematical models. Following a single oral dose of gefitinib (50 or 150 mg/kg), tumors were processed at selected times according to a novel brain tumor sectioning protocol that generated serial samples to measure gefitinib concentrations, phosphorylated extracellular signal-regulated kinase (pERK), and immunohistochemistry in 4 different regions of tumors. Notably, we observed up to 3-fold variations in intratumoral concentrations of gefitinib, but only up to half this variability in pERK levels. As we observed a similar degree of variation in the immunohistochemical index termed the microvessel pericyte index (MPI), a measure of permeability in the blood-brain barrier, we used MPI in a hybrid physiologically-based pharmacokinetic (PBPK) model to account for regional changes in drug distribution that were observed. Subsequently, the PBPK models were linked to a pharmacodynamic model that could account for the variability observed in pERK levels. Together, our tumor sectioning protocol enabled integration of the intratumoral pharmacokinetic/pharmacodynamic variability of gefitinib and immunohistochemical indices followed by the construction of a predictive PBPK/pharmacodynamic model. These types of models offer a mechanistic basis to understand tumor heterogeneity as it impacts the activity of anticancer drugs.
Endoscopic characterization of sessile serrated adenomas/polyps with and without dysplasia
Authors: Mariëlle Bouwens, Yasmijn van Herwaarden, Bjorn Winkens, Eveline Rondagh, Rogier de Ridder, Robert Riedl, Ann Driessen, Evelien Dekker, Ad Masclee, Silvia Sanduleanu
Journal: Endoscopy (2014)

<b>Background and study aims:</b> Sessile serrated adenomas/polyps (SSA/Ps) are precursors of colorectal cancer (CRC), but their endoscopic detection can be difficult. We therefore examined the endoscopic characteristics of SSA/Ps with and without dysplasia in a cross-sectional study. <b>Patients and methods:</b> We reviewed clinical, endoscopic, and histopathologic data from patients undergoing colonoscopy between February 2008 and February 2012. We categorized colorectal polyps according to anatomic site, size, and shape, and classified serrated polyps using the World Health Organization (WHO) classification. Multiple logistic regression analyses examined potential differences regarding site, size, and shape between SSA/Ps and colorectal adenomas (overall and advanced only). <b>Results:</b> We examined 7433 patients (mean age 59 years, 45.9 % men) with 5968 colorectal polyps. In total, we found 170 SSA/Ps (170/5968, 2.9 %), including 63 SSA/Ps with dysplasia (1.1 %) and 107 SSA/Ps without dysplasia (1.8 %). Compared with SSA/Ps with dysplasia, SSA/Ps without dysplasia were more often proximally located (odds ratio [OR] 3.3, 95 % confidence interval [95 %CI] 1.7 – 6.4), but less often < 6 mm in size (OR 0.6, 95 %CI 0.3 – 1.1). No significant differences were found regarding location between SSA/Ps with dysplasia and advanced adenomas (proximal colon, 47.6 % vs. 40.1 %). However, SSA/Ps with dysplasia were more often < 6 mm in size than advanced adenomas (OR 0.3, 95 %CI 0.2 – 0.5). Of the 63 dysplastic SSA/Ps, 6 (9.5 %) contained high grade dysplasia, but none invasive carcinoma. <b>Conclusions:</b> SSA/Ps with dysplasia are frequently < 6 mm in size, located throughout the colon and 9.5 % of them contain high grade dysplasia. These findings underscore the importance of high quality colonoscopic examination to maximize protection against CRC.
High Serum Testosterone Is Associated With Reduced Risk of Cardiovascular Events in Elderly Men
Authors: Claes Ohlsson, Elizabeth Barrett-Connor, Shalender Bhasin, Eric Orwoll, Fernand Labrie, Magnus K. Karlsson, Östen Ljunggren, Liesbeth Vandenput, Dan Mellström, Åsa Tivesten
Journal: Journal of the American College of Cardiology (2011)
TYK2 is a key regulator of the surveillance of B lymphoid tumors
Authors: Dagmar Stoiber, Boris Kovacic, Christian Schuster, Carola Schellack, Marina Karaghiosoff, Rita Kreibich, Eva Weisz, Michaela Artwohl, Olaf C. Kleine, Mathias Muller, Sabina Baumgartner-Parzer, Jacques Ghysdael, Michael Freissmuth, Veronika Sexl
Journal: Journal of Clinical Investigation (2004)

Aberrant activation of the JAK-STAT pathway has been implicated in tumor formation; for example, constitutive activation of JAK2 kinase or the enforced expression of STAT5 induces leukemia in mice. We show here that the Janus kinase TYK2 serves an opposite function. Mice deficient in TYK2 developed Abelson-induced B lymphoid leukemia/lymphoma as well as TEL-JAK2–induced T lymphoid leukemia with a higher incidence and shortened latency compared with WT controls. The cell-autonomous properties of Abelson murine leukemia virus–transformed (A-MuLV–transformed) TYK2–/– cells were unaltered, but the high susceptibility of TYK2–/– mice resulted from an impaired tumor surveillance, and accordingly, TYK2–/– A-MuLV–induced lymphomas were easily rejected after transplantation into WT hosts. The increased rate of leukemia/lymphoma formation was linked to a decreased in vitro cytotoxic capacity of TYK2–/– NK and NKT cells toward tumor-derived cells. RAG2/TYK2 double-knockout mice succumbed to A-MuLV–induced leukemia/lymphoma faster than RAG2–/–TYK2+/– mice. This defines NK cells as key players in tumor surveillance in Abelson-induced malignancies. Our observations provide compelling evidence that TYK2 is an important regulator of lymphoid tumor surveillance.
Pediatric Allergy: Principles and Practice
Authors: Jeffrey L. Kishiyama
Journal: JAMA (2011)

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