tbuckley/cabot-search huggingface dataset:
Cardiorespiratory fitness and risk of cancer incidence and cause-specific mortality following a cancer diagnosis in men: The Cooper Center longitudinal study.
Authors: Susan G. Lakoski, Carolyn Barlow, Ang Gao, Laura DeFina, Nina Radford, Steve Farrell, Benjamin Willis, Jeffrey M. Peppercorn, Pamela S. Douglas, Jarett Berry, Lee Jones
Journal: Journal of Clinical Oncology (2013)

1520 Background: Few studies have examined the prognostic importance of cardiorespiratory fitness (CRF) to predict cancer incidence or cause-specific mortality following a cancer diagnosis in men. Accordingly, we examined the relationships between baseline CRF and incidence of prostate, lung, or colorectal cancer in men at Medicare age and subsequent cause-specific mortality among men diagnosed with cancer. Methods: The Cooper Center Longitudinal Study (CCLS) is a prospective observational cohort study of participants undergoing a preventive health examination including CRF assessment at the Cooper Clinic in Dallas, Texas. We studied 17,049 men with a complete CCLS medical exam and cardiovascular risk factor assessment at a mean age of 50± 9 years. Cancer incidence was defined using Medicare claims data. Cox proportional models were used to estimate the risk of adjusted primary cancer incidence and cause-specific mortality after cancer according to baseline age-specific CRF quintiles (Q). Results: The mean times from CRF assessment to cancer incidence and death were 20.2 ± 8.2 years and 24.4 ± 8.5 years, respectively. During this period, 2885 men were diagnosed with prostate, lung, or colorectal cancer and 769 died. Compared with men in lowest CRF quintile, the adjusted hazard ratio (HR) for incident lung, colorectal, and prostate cancer incidence among men in the highest CRF quintile was 0.32 (95% CI: 0.20 to 0.51, p&lt;0.001), 0.62 (95% CI: 0.40 to 0.97, p=0.05), 1.13 (95% CI: 0.97 to 1.33, p=0.14), respectively. In men developing cancer, both cancer-specific mortality and cardiovascular-specific mortality declined across increasing CRF quintiles (p’s &lt;0.001). A 1-MET increase in CRF was associated with a 14% reduction in cancer-specific mortality (HR 0.86, 95% CI: 0.81-0.91, p&lt;0.001), and 23% reduction in cardiovascular-specific mortality (HR 0.77, 95% CI: 0.69-0.85, p&lt;0.001). Conclusions: Fitness is a strong independent predictor of incident lung and colorectal cancer and remained a robust predictor of cause-specific mortality in middle-aged and older men diagnosed with lung, prostate, or colorectal cancer.
Beta-Blockers Improved Survival Outcomes in Patients with Multiple Myeloma: A Retrospective Evaluation
Authors: Yi L. Hwa, Qian Shi, Shaji Kumar, Martha Q. Lacy, Morie A. Gertz, Prashant Kapoor, Francis K Buadi, Nelson Leung, David Dingli, Ronald S. Go, Suzanne R. Hayman, Wilson I Gonsalves, Stephen J. Russell, John A Lust, Yi Lin, S. Vincent Rajkumar, Angela Dispenzieri
Journal: Blood (2016)
Incorrect Scaling Factor and Errors in Figures and <i>P</i> Value Thresholds
Authors: Barbara B. Bendlin
Journal: JAMA Neurology (2017)

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Novel and Known Ribosomal Causes of Diamond-Blackfan Anemia Identified through Comprehensive Genomic Characterization
Authors: Payal Khincha, Lisa Mirabello, Steven R Ellis, Neelam Giri, Seth Brodie, Settara Chandrasekharappa, Frank Donovan, Weiyin Zhou, Belynda Hicks, Joseph Boland, Meredith Yeager, Kristine Jones, Bin Zhu, Mingyi Wang, Blanche P. Alter, Sharon A Savage
Journal: Blood (2016)
Abstract 187: Identification of Cardiac-specific Downstream Substrates of Protein Kinase G I as Potential Novel Anti Cardiac Remodeling Targets
Authors: Robert M Blanton, Angela Lane, Mark Aronovitz, Guang-rong Wang, Robrecht Thoonen, Roger Davis, Michael Mendelsohn, David Kass, Richard Karas
Journal: Circulation Research (2013)

We recently reported that mutation of the cGMP-dependent Protein Kinase G I alpha (PKGIα) N-terminal leucine zipper (LZ) domain (in the PKGIα LZ mutant, or LZM, mouse) accelerates LV remodeling and heart failure after TAC, and prevents the anti-remodeling effect of sildenafil. We therefore hypothesized that PKGIα attenuates remodeling by regulating cardiac signaling pathways that are dependent on substrate interactions mediated by its LZ domain. As a first step to identifying cardiac proteins downstream of PKGIα, we screened myocardial lysates for PKGIα LZ domain-interacting proteins. Our previous work revealed a requirement for the PKGIα LZ domain for the activation of anti-remodeling myocardial JNK activity after LV pressure overload. MLK3 is an MAPKKK that contains an LZ domain and activates JNK. We now demonstrate, by immunoprecipitation, that MLK 3 interacts with the PKGIα LZ domain in myocardial lysates. We show further that 8-Br-cGMP induces MLK3 phosphorylation on Threonine 277 and Serine 281 in WT, but not LZM myocardial lysates. And, in 293 cells transfected with FLAG-MLK3, 8Br-cGMP induced PKGIα-MLK3 co-precipitation, and increased phosphorylation of MLK3 on Thr277/Ser281. Co-transfection of MLK3 and PKGIα also induced MLK3 phosphorylation at the same sites. We next examined the cardiovascular effect of MLK3 deletion in vivo. Male 8 week old MLK3 -/- mice display basal bi-ventricular hypertrophy compared with littermate controls (LV/Tibia length 42.8 + 0.6 mg/cm in WT, 52.9 + 1.8 in MLK3 -/-; P &lt;0.01; RV/TL 10.8 + 0.1 mg/cm in WT, 13.3 + 0.3 in MLK3 -/-; P &lt;0.01; n= 7 WT, 5 MLK3 -/-). By 14-16 weeks of age, LVH progressed in the MLK3 -/- mice (LV/TL 47.7 + 1.3 mg/cm in WT, 59.8 + 7.5 in MLK3-/-; n= 6 WT, 9 MLK3-.-; P &lt;0.01). Arterial blood pressure was modestly increased, though still normal, in the MLK3 -/- mice (SBP 93 + 1 in WT, 113 + 1 in MLK3 -/-). And, 14-16 week MLK3 -/- mice have impaired LV diastolic function (tau 3.2 + 0.1 ms WT, 3.7 + 0.1 MLK3-/-; P 0.06). Our studies reveal a previously unknown function of MLK3 as a myocardial PKGIα effector and inhibitor of LVH. Together these results support the strategy of exploring LZ-dependent PKGIα substrates in the myocardium to identify novel therapeutic targets for cardiac remodeling.
Abstract 329: HSF-1 Knockout Enhances Dietary Cholesterol Metabolism by Inducing CYP7A1 Gene Expression and Attenuates Atherosclerosis
Authors: Govindasamy Ilangovan, Krishnamurthy Karthikeyan
Journal: Circulation Research (2013)

Objective: Coronary heart disease and diabetes are highly prevalent among obese populations due to aberrant dietary cholesterol metabolism. Here we investigated the effect of heat shock factor-1 (HSF-1) on atherosclerosis and dietary cholesterol metabolism. Methods and Results: Atherogenic western diet-induced weight gain was reduced in HSF-1 and LDLr double knock out mice (HSF-1 -/- /LDLr -/- ), compared to LDLr -/- mice. Atherosclerotic lesion growth in aortic arch and carotid regions was retarded. Also, repression of PPAR-γ2 and AMPKα expression in adipose tissue, low hepatic steatosis, and lessened plasma adiponectins and lipoproteins were observed. Furthermore, reduced heat shock proteins and their mRNA levels in atherosclerotic lesions correlated with reduction in lesion burden. In HSF-1 -/- /LDLr -/- liver, higher cholesterol 7α hydroxylase (CYP7A1, the rate limiting enzyme in the synthesis of bile acid from cholesterol) and MDR1/p-glycoprotein (bile salt transporter across the hepatocyte canalicular membrane) gene expressions were observed, consistent with higher bile acid sequestration and larger hepatic bile ducts. HSF-1 deletion, however, upregulated both CYP7A1 enzyme and MDR1/p-glycoportein expression and activities, due to removal of its repressive binding in the CYP7A1 and MDR1 gene promoters. This increased the conversion of cholesterol into 7-α-hydroxycholesterol and bile acid, and dietary cholesterol metabolism. Conclusions: HSF-1 ablation not only eliminates heat shock response to retard atherosclerosis, but it also transcriptionally upregulates CYP7A1 and MDR1/P-gp axis to increase cholesterol metabolism. Therefore, HSF-1 is a metabolic regulator of dietary cholesterol and a major contributor to heart disease among obese population.
Sex in basic research: concepts in the cardiovascular field
Authors: Renée Ventura-Clapier, Elke Dworatzek, Ute Seeland, Georgios Kararigas, Jean-Francois Arnal, Sandra Brunelleschi, Thomas C. Carpenter, Jeanette Erdmann, Flavia Franconi, Elisa Giannetta, Marek Glezerman, Susanna M. Hofmann, Claudine Junien, Miyuki Katai, Karolina Kublickiene, Inke R. König, Gregor Majdic, Walter Malorni, Christin Mieth, Virginia M. Miller, Rebecca M. Reynolds, Hiroaki Shimokawa, Cara Tannenbaum, Anna Maria D’Ursi, Vera Regitz-Zagrosek
Journal: Cardiovascular Research (2017)

Women and men, female and male animals and cells are biologically different, and acknowledgement of this fact is critical to advancing medicine. However, incorporating concepts of sex-specific analysis in basic research is largely neglected, introducing bias into translational findings, clinical concepts and drug development. Research funding agencies recently approached these issues but implementation of policy changes in the scientific community is still limited, probably due to deficits in concepts, knowledge and proper methodology. This expert review is based on the EUGenMed project (www.eugenmed.eu) developing a roadmap for implementing sex and gender in biomedical and health research. For sake of clarity and conciseness, examples are mainly taken from the cardiovascular field that may serve as a paradigm for others, since a significant amount of knowledge how sex and oestrogen determine the manifestation of many cardiovascular diseases (CVD) has been accumulated. As main concepts for implementation of sex in basic research, the study of primary cell and animals of both sexes, the study of the influence of genetic vs. hormonal factors and the analysis of sex chromosomes and sex specific statistics in genome wide association studies (GWAS) are discussed. The review also discusses methodological issues, and analyses strength, weaknesses, opportunities and threats in implementing sex-sensitive aspects into basic research.
Роль нарушений биоэлементного обмена при неалкогольной жировой болезни печени у больных сахарным диабетом 2-го типа
Authors: L.V. Zhuravlyova, O.V. Lakhno, O.I. Tsivenko, A.K. Zhuravlyova, Yu.A. Goryushko
Journal: GASTROENTEROLOGY (2014)

Были обследованы больные сахарным диабетом 2-го типа с жировой дистрофией печени. Кроме общепринятых методов, для дифференциальной диагностики использовали определение биоэлементного состава крови (калий, натрий, магний, медь, цинк, железо, кальций). Установлены изменения микро- и макроэлементного обмена у пациентов с сахарным диабетом 2-го типа и неалкогольной жировой болезнью печени в зависимости от активности патологического процесса в печени и стадии заболевания. Уместным при обследовании больных является определение уровней калия, натрия, кальция, магния, цинка, меди и железа как дополнительных критериев оценки степени тяжести заболевания и функционального состояния печени.
Activation of Skeletal Muscle AMPK Promotes Glucose Disposal and Glucose Lowering in Non-human Primates and Mice
Authors: Emily C. Cokorinos, Jake Delmore, Allan R. Reyes, Bina Albuquerque, Rasmus Kjøbsted, Nicolas O. Jørgensen, Jean-Luc Tran, Aditi Jatkar, Katherine Cialdea, Ryan M. Esquejo, John Meissen, Matthew F. Calabrese, Jason Cordes, Robert Moccia, David Tess, Christopher T. Salatto, Timothy M. Coskran, Alan C. Opsahl, Declan Flynn, Matthew Blatnik, Wenlin Li, Erick Kindt, Marc Foretz, Benoit Viollet, Jessica Ward, Ravi G. Kurumbail, Amit S. Kalgutkar, Jørgen F.P. Wojtaszewski, Kimberly O. Cameron, Russell A. Miller
Journal: Cell Metabolism (2017)
Role of the immunoglobulin constant region in the antitumor activity of antibodies to cytotoxic T-lymphocyte antigen-4 (CTLA-4).
Authors: Alan J. Korman, John Engelhardt, Vafa Shahabi, Roumyana Yordanova, Karla Henning, Timothy Chen, Mark Selby
Journal: Journal of Clinical Oncology (2013)

9055 Background: Anti-CTLA-4 therapy enhances antitumor T-cell responses by both cell-intrinsic and cell-extrinsic mechanisms. Effector T-cell (Teff) activation is increased directly by interfering with CTLA-4-B7 interactions that negatively regulate T cells and by interfering with CTLA-4 expressed on regulatory T cells (Tregs), which function to inhibit immune responses. To analyze in greater detail the mechanism of action of anti-CTLA-4 antibodies (Abs), we examined the role of the immunoglobulin constant region in the antitumor activity of anti-CTLA-4 Abs in mouse tumor models. Methods: The activity of anti-CTLA-4 Abs with different mouse IgG constant regions were compared in several mouse tumor models, and intratumoral and peripheral T cells were analyzed by FACS. DNA samples from 488 patients with metastatic melanoma who received ipilimumab in a phase III clinical trial, MDX010-20, were analyzed for polymorphisms in the IgG fragment c receptor (FcR) at FCGR3A (V158F) and FCGR2A (H131R) loci. Results: In subcutaneous MC38 and CT26 colon tumor models, an anti-CTLA-4 Ab containing the mouse IgG2a constant region exhibited enhanced antitumor activity compared to an anti-CTLA-4 Ab containing the IgG2b constant region, while anti-CTLA-4 Abs containing mouse IgG1 or a mutated mouse IgG1 D265A constant region showed no activity. Anti-CTLA-4-IgG2a caused a dramatic reduction of Tregs at the tumor site that resulted in a greater Teff/Treg ratio. In contrast, all isotypes resulted in expansion of Tregs in the periphery. These results point to an important role for FcR in the action of anti-CTLA-4 Abs. In patients from study MDX010-20, there was no association between the 2 FcR polymorphisms (FCGR3A and FCGR2A) and overall survival. Conclusions: These preclinical studies reveal a novel dual activity of anti-CTLA-4 Abs consisting of intratumoral reduction of Tregs together with activation of Teff cells. This effect is mediated by the constant region and is presumably due to antibody-dependent cellular cytotoxicity. The data suggest that FcR-bearing cells at the tumor site, as well as the presence of intratumoral Tregs, may be important factors in the antitumor activity of anti-CTLA-4 Abs.
Relationship between levels of HER-2 amplification and pathologic complete response to trastuzumab-based neoadjuvant treatment.
Authors: Cristina Masini, Alessandra Bisagni, Giuseppe Falco, Cristina Bassano, Licia Baldi, Giancarlo Bisagni, Gabriella Moretti, Adriana Albini, Guglielmo Ferrari, Corrado Boni, Giorgio Gardini
Journal: Journal of Clinical Oncology (2015)

e11605 Background: Fluorescence in situ hybridization (FISH) is used to determine human epidermal growth factor receptor-2 (HER-2) status and patients (pts) eligibility for trastuzumab therapy. Using FISH as primary test, we analyzed the relationship between pathologic complete response (pCR) to trastuzumab-based neoadjuvant therapy and levels of HER-2 amplification in stage II-IIIa breast cancer. Methods: We retrospectively reviewed the data of 68 HER-2 positive breast cancer pts treated from January 2009 to June 2014 with trastuzumab based neoadjuvant therapy. Biopsies or cytological samples were analyzed by dual-color FISH using a HER-2 gene–specific probe and a centromeric probe for chromosome 17 (PathVysion HER-2 DNA Probe kit, Vysis-Abbott) to determine HER-2 amplification. Tumors were classified by FISH as follow: low amplification (LA) [Gene Copy Number (GCN) < 6 and Ratio ≥ 2], intermediate amplification (IA)[6 ≤ GCN ≤ 10] and high amplification (HA) [(GCN > 10) or uncountable due to clusters of signals]. This cut-off was recommended by ASCO/CAP guidelines 2013. The repeated measure ANOVA and Student’s test were used to compare continuous variables. The χ2 test was used to compare discrete variables and multivariate logistic regression analysis to estimate odds ratios (OR) and two-sided 95% confidence interval (CI). All the analyses were performed using IBM-SPSS (v21.0). Results: HER-2 status of tumor samples as assessed by FISH was categorized as LA 12 pts (18%), IA 17 pts (25%) and HA 39 pts (57%). Trastuzumab-based neoadjuvant therapy achieved pCR in 20/68 (29%) tumors. Patient age, T or N stage, tumor grade, hormone receptor status, were not significantly related to pCR. The only variable related to pCR was the level of HER-2 amplification, with 17/39 (44%) in HA tumors, compared with 1/17 (6%) in IA and 2/12 (17%) in LA tumors (p = 0.01), confirmed in multivariate analysis for HA tumors with OR = 6.6 (CI 95%: 1.7-25, p < 0.006 ). Conclusions: Although the small number of cases in this study, our analysis shows that high levels of HER-2 amplification assessed by FISH are positive correlated to higher rate of pCR to trastuzumab-based neoadjuvant therapy.
High resolution mapping of the X chromosome pseudoautosomal region in two siblings with Hodgkin Lymphoma and Leri-Weill Dyschondrosteosis
Authors: Kimberley Spencer, Una Maye, Gareth Evans, John Radford, G Taylor, David Gokhale
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

3902 

The etiology of Hodgkin Lymphoma (HL) is thought to involve infectious and inherited factors. However, though HL occurs in families, the identity of the familial HL (FHL) gene(s) remains elusive. We previously reported the occurrence of HL in two sisters with the short stature syndrome Leri-Weill Dyschondrosteosis (LWD) (Gokhale et al . (1995), Leukemia , 9 :826-833). These individuals were previously shown to have a deletion of approximately 900 kb in the X chromosome pseudoautosomal region (XpPAR; Shears et al . (2003), B J Haematol ., 121 :375-380) encompassing the LWD gene, SHOX. We have now defined the deletion breakpoints in finer detail using a combination of microsatellite analysis, Multiplex Ligation dependent Probe Amplification (MLPA), analysis of 20 SNPs and microarray analysis. Although the CSF2RA, IL3RA and CD99 genes have previously been suggested as candidate FHL genes, our study shows that they lie a large distance (400 kb, 480 kb and 1680 kb respectively) from the deletion in the two siblings, and suggests that they are not involved in FHL. Although no other known genes are within the boundaries of the deletion, we have identified a gene nearby (between 10 and 85 kb from the centromeric end of the deletion), PPP2R3B, which encodes one of the subunits of the PP2A holoenzyme, a serine/threonine phosphatase involved in cell cycle regulation and a known tumor suppressor. We hypothesize that the regulation of PPP2R3B or other genes could have been disrupted by the deletion in these individuals. In addition, another subunit of the same complex lies on 4p16, near a marker that has been shown in a study by Goldin et al . (2006) ( J Med Genet , 42 :595-601) to be linked to the disease in a cohort of HL patients. Mutations in other genes encoding various PP2A subunits have been seen in other cancers, and PP2A has also been shown to be involved in viral transformation of cells.
Is There a Conflict of Interest?
Authors: Shiphra Ginsburg, Wendy Levinson
Journal: JAMA (2017)

Dr Patel is an internist who recently joined a large multidisciplinary clinic. She often refers her patients to 1 of the 6 cardiologists who work there. She has noticed that when her patients are seen by Dr Wells, they almost always undergo stenting procedures, whereas when her patients are seen by the other cardiologists, a larger variety of treatment approaches are used. At first she thought it was a coincidence or that perhaps she was somehow sending patients with more severe heart disease to Dr Wells. But then a colleague made an offhand comment that “If you want your patient to get stented, send them to Dr Wells.” She is concerned that her patients may have been overtreated and subjected to needless risk and that Dr Wells may not be acting in the best interests of his patients.
A 67-Year-Old Man With Irregular Pulse
Authors: Ashish Rai, Howard M. Waldman, Nureddin K. Almaddah
Journal: JAMA Cardiology (2017)

A 67-year-old white man with a history of hypertension presents to your hospital after noting irregular heartbeats on his home blood pressure monitor. He has no palpitations; the electrocardiogram shows several premature ventricular contractions. What would you do next?
Species of Metarhizium anisopliae complex implicated in human infections: retrospective sequencing study
Authors: C. Nourrisson, D. Dupont, R.-A. Lavergne, J. Dorin, F. Forouzanfar, J. Denis, K. Weeks, R. Joubert, F. Chiambaretta, T. Bourcier, S. Roux, A. Sénéchal, G. Benaïm, M. Wallon, E. Candolfi, V. Letscher-Bru, P. Poirier, M. Sabou
Journal: Clinical Microbiology and Infection (2017)
Comprehensive Genomic Analysis of Adult Burkitt Lymphoma Identifies the B-Cell Receptor Signaling Pathway As a Potential Therapeutic Target
Authors: Alyssa Bouska, Chengfeng Bi, Waseem Lone, Weiwei Zhang, Ambreen Kedwaii, Tayla B Heavican, Cynthia M Lachel, Jiayu Yu, Kai Fu, Roberto A. Ferro, Nanees Eldorghamy, Timothy C. Greiner, Julie M Vose, Dennis D Weisenburger, Randy D Gascoyne, Andreas Rosenwald, German Ott, Elias Campo, Lisa M Rimsza, Elaine S. Jaffe, Rita M Braziel, Reiner Siebert, Rodney R. Miles, Sandeep Dave, Anupama Reddy, Timothy W. McKeithan, Louis M. Staudt, Michael R Green, Wing Chung Chan, Javeed Iqbal
Journal: Blood (2016)
Curative Treatment for Muscle Invasive Bladder Cancer in Elderly Patients: A Systematic Review
Authors: Valérie Fonteyne, Piet Ost, Joaquim Bellmunt, Jean Pierre Droz, Pierre Mongiat-Artus, Brant Inman, Elena Paillaud, Fred Saad, Guillaume Ploussard
Journal: European Urology (2017)
Gait speed and pedestrian crossings in COPD
Authors: Claire M Nolan, Samantha S C Kon, Suhani Patel, Sarah E Jones, Ruth E Barker, Michael I Polkey, Matthew Maddocks, William D-C Man
Journal: Thorax (2017)

The assumed minimum walking speed at pedestrian crossings is 1.2 m/s. In this prospective cohort study, usual walking speed was measured over a 4 m course in 926 community-dwelling, ambulatory patients with stable COPD. Mean (SD) walking speed was 0.91 (0.24) m/s with only 10.7% walking at a speed equal or greater than 1.2 m/s. In order for 95% of this cohort to safely negotiate a pedestrian cross, traffic lights would have to assume a minimum walking speed of 0.50 m/s (2.4 times longer than current times). The current assumed normal walking speed for pedestrian crossings is inappropriate for patients with COPD. The studies were registered on clinicaltrials.gov and these data relate to the pre-results stage: NCT01649193 , NCT01515709 and NCT01507415 .