tbuckley/cabot-search huggingface dataset:
<i>TFAP2E</i> Methylation and Expression Status Does Not Predict Response to 5-FU-based Chemotherapy in Colorectal Cancer
Authors: Oscar Murcia, Rodrigo Jover, Cecilia Egoavil, Lucia Perez-Carbonell, Miriam Juárez, Eva Hernández-Illán, Estefania Rojas, Cristina Alenda, Francesc Balaguer, Montserrat Andreu, Xavier Llor, Antoni Castells, C. Richard Boland, Ajay Goel
Journal: Clinical Cancer Research (2018)

Purpose: A recent study reported that 5-fluorouracil (5-FU)-based chemotherapy is less effective in treating patients with advanced colorectal cancer demonstrating hypermethylation of the TFAP2E gene. The aim of our study was to confirm and validate these findings in large, uniformly treated, well-characterized patient cohorts.Experimental Design: Two cohorts of 783 patients with colorectal cancer: 532 from a population-based, multicenter cohort (EPICOLON I) and 251 patients from a clinic-based trial were used to study the effectiveness of TFAP2E methylation and expression as a predictor of response of colorectal cancer patients to 5-FU-based chemotherapy. DNA methylation status of the TFAP2E gene in patients with colorectal cancer was assessed by quantitative bisulfite pyrosequencing analysis. IHC analysis of the TFAP2E protein expression was also performed.Results: Correlation between TFAP2E methylation status and IHC staining was performed in 607 colorectal cancer samples. Among 357 hypermethylated tumors, only 141 (39.6%) exhibited loss of protein expression. Survival was not affected by TFAP2E hypermethylation in stage IV patients [HR, 1.21; 95% confidence interval (CI), 0.79-1.87; log-rank P = 0.6]. In stage II-III cases, disease-free survival was not influenced by TFAP2E hypermethylation status in 5-FU-treated (HR, 0.91; 95% CI, 0.52-1.59; log-rank P = 0.9) as well as in nontreated patients (HR, 0.88; 95% CI, 0.5-1.54; log-rank P = 0.7).Conclusions:TFAP2E hypermethylation does not correlate with loss of its protein expression. Our large, systematic, and comprehensive study indicates that TFAP2E methylation and expression may not play a major role in predicting response to 5-FU-based chemotherapy in patients with colorectal cancer. Clin Cancer Res; 24(12); 2820-7. ©2018 AACR.
Abstract 17121: Reduction in Total Cardiovascular Events With Long-term Use of Ticagrelor in Patients With Prior Myocardial Infarction in the PEGASUS-TIMI 54 Trial
Authors: Sabina A Murphy, Marc P Bonaca, Shinya Goto, Deepak L Bhatt, Philippe Gabriel Steg, Robert F Storey, Naveen Deenadayalu, Julia F Kuder, Giulia Magnani, Pierre Theroux, José C Nicolau, Jose López-Sendón, Anthony J Dalby, Assen Goudev, Diego Ardissino, Ramon Corbalan, Eva C Jensen, Peter Held, Eugene Braunwald, Marc S Sabatine
Journal: Circulation (2015)

Background: Long-term dual antiplatelet therapy with aspirin plus ticagrelor, a direct-acting reversibly-binding P2Y12 receptor antagonist, was recently shown in the PEGASUS-TIMI 54 trial (NCT01225562) to be superior to aspirin alone in preventing major adverse cardiovascular events in patients with a prior MI. Whereas prior analyses focused on time to first event, we hypothesized that total events including those beyond the first event would also be reduced with ticagrelor. Methods: We evaluated all primary endpoint (PEP) events (CV death, MI, stroke) during a median 33 month follow-up in patients randomized to ticagrelor (60 mg or 90 mg) vs placebo in the PEGASUS-TIMI 54 trial. Negative binomial regression &amp; other sensitivity models were used. Results: Among 21,162 patients, there were 1,830 PEP events (85% first events, n=1,558 and 15% subsequent events, n=272). Of the total PEP events, 1,041 were MIs (56.9%), 338 were strokes (18.5%), and 451 were CV deaths (24.6%). In patients with a PEP event, 86.3% had 1 event, 11.0% had 2 events, and 2.8% had 3 or more events (maximum 6). Total PEP events were reduced 17% with ticagrelor 60 mg vs placebo (incidence-rate ratio [IRR] 0.83, 95% CI 0.72-0.95, p=0.006) and 17% with ticagrelor 90 mg vs placebo (IRR 0.83, 95% CI 0.73-0.95, p=0.007). A Wei-Lin-Weissfeld time-to-event model showed similar reductions. In terms of irreversible harm events, for every 1000 patients treated for 3 years, ticagrelor would prevent 18 primary endpoint events, including (depending on the dose) 5 CV deaths, 8-11 MIs, and 3-4 strokes, and cause only 0 or 1 excess fatal bleeds or ICH (Figure). Conclusions: Patients with prior MI remain at high risk for recurrent vascular events. The addition of ticagrelor to aspirin significantly reduces the burden of total vascular events.
METABOLICALLY HEALTHY OBESITY IS ASSOCIATED WITH A FAVOURABLE VASCULAR PHENOTYPE AND LOW LEVELS PLASMA IL-6 IN PATIENTS WITH CORONARY ARTERY DISEASE: IMPLICATIONS FOR THE OBESITY PARADOX
Authors: Evangelos Oikonomou, Alexios Antonopoulos, Gerasimos Siasos, Sotirios Tsalamandris, Andreas Angelopoulos, Paraskevi Papanikolaou, Georgia Vogiatzi, Charalambos Antoniades, Vasiliki Tsigkou, Maria Paraskevi Panoilia, Dimitris Tousoulis
Journal: Journal of the American College of Cardiology (2018)
Whistleblowing training should be mandatory for medical students, BMA says
Authors: Matthew Limb
Journal: BMJ (2015)

Medical students should be given mandatory training and support in “whistleblowing” to raise concerns over patient care, the BMA has said.

Gursharan Johal, a foundation year one doctor from the Pennine Acute foundation trust, made the plea to the BMA’s conference of medical academic representatives (COMAR).

She said that the BMA had made “great progress” in educating and advising doctors about reporting unacceptable care or conditions. But she warned of “a cavernous gap in this vital work” regarding whistleblowing training in medical schools. …
Role of <i>Lgals9</i> Deficiency in Attenuating Nephritis and Arthritis in <scp>BALB</scp>/c Mice in a Pristane‐Induced Lupus Model
Authors: Sonia Zeggar, Katsue S. Watanabe, Sanae Teshigawara, Sumie Hiramatsu, Takayuki Katsuyama, Eri Katsuyama, Haruki Watanabe, Yoshinori Matsumoto, Tomoko Kawabata, Ken‐ei Sada, Toshiro Niki, Mitsuomi Hirashima, Jun Wada
Journal: Arthritis & Rheumatology (2018)

Objective In systemic lupus erythematosus ( SLE ), an autoimmune disease associated with multiple organ involvement, the development of lupus nephritis determines prognosis, and arthritis impairs quality of life. Galectin 9 (Gal‐9, Lgals9 ) is a β‐galactoside–binding lectin that has been used for clinical application in autoimmune diseases, since recombinant Gal‐9, as a ligand for T cell immunoglobulin and mucin domain–containing protein 3 ( TIM ‐3), induces apoptosis of activated CD 4+ TIM ‐3+ Th1 cells. This study was undertaken to investigate whether deficiency of Lgals9 has beneficial or deleterious effects on lupus in a murine model. Methods Gal‐9 +/+ and Gal‐9 −/− female BALB /c mice were injected with pristane, and the severity of arthritis, proteinuria, and levels of autoantibody production were assessed at several time points immediately following injection. At 7 months after pristane injection, renal pathologic features, the severity of joint inflammation, and formation of lipogranulomas were evaluated. Subsets of inflammatory cells in the spleen and peritoneal lavage were characterized, and expression levels of cytokines from peritoneal macrophages were analyzed. Results Lgals9 deficiency protected against the development of immune complex glomerulonephritis, arthritis, and peritoneal lipogranuloma formation in BALB/c mice in this murine model of pristane‐induced lupus. The populations of T cell subsets and B cells in the spleen and peritoneum were not altered by Lgals9 deficiency in pristane‐injected BALB /c mice. Furthermore, Lgals9 deficiency protected against pristane‐induced lupus without altering the Toll‐like receptor 7–type I interferon pathway. Conclusion Gal‐9 is required for the induction and development of lupus nephritis and arthritis in this murine model of SLE . The results of the current investigation provide a potential new strategy in which antagonism of Gal‐9 may be beneficial for the treatment of nephritis and arthritis in patients with SLE through targeting of activated macrophages.
Breast cancer brain metastasis: molecular mechanisms and directions for treatment
Authors: Rute M S M Pedrosa, Dana A Mustafa, Riccardo Soffietti, Johan M Kros
Journal: Neuro-Oncology (2018)

Abstract The development of brain metastasis (BM) of breast cancer is usually a late event with deleterious effect on the prognosis. Treatment options for intracerebral seeding of breast cancer are limited and, so far, nonspecific. Molecular detailing of subsequent events of penetration, seeding, and outgrowth in brain is highly relevant for developing therapeutic strategies to treat, or prevent, BM. We scrutinize recent literature for molecules and pathways that are operative in the formation of breast cancer BM. We also summarize current data on therapeutic efforts to specifically address BM of breast cancer. Data on molecular pathways underlying the formation of BM of breast cancer are sketchy and to some extent inconsistent. The molecular makeup of BM differs from that of the primary tumors, as well as from metastases at other sites. Current efforts to treat breast cancer BM are limited, and drugs used have proven effects on the primary tumors but lack specificity for the intracerebral tumors. More basic research is necessary to better characterize BM of breast cancer. Apart from the identification of drug targets defined by the intracerebral tumors, also targets in the molecular pathways involved in passing the blood–brain barrier and intracerebral tumor cell growth should be revealed.
Potent anti-viral vaccine adjuvant based on pH-degradable nanogels with covalently linked small molecule imidazoquinoline TLR7/8 agonist
Authors: Lutz Nuhn, Lien Van Hoecke, Kim Deswarte, Bert Schepens, Yupeng Li, Bart N. Lambrecht, Stefaan De Koker, Sunil A. David, Xavier Saelens, Bruno G. De Geest
Journal: Biomaterials (2018)
EFFICACY AND SAFETY OF DIRECT ORAL ANTICOAGULANTS IN INTERMEDIATE-HIGH RISK PULMONARY EMBOLISM: RESULTS FROM A MULTIDISCIPLINARY MULTICENTER PROSPECTIVE REGISTRY
Authors: Romain Chopard, Jean-Noel Andarelli, Lisbeth Cart, Marc Badoz, Fiona Ecarnot, Francois Schiele, Nicolas Meneveau
Journal: Journal of the American College of Cardiology (2018)
Obesity Progression Between Young Adulthood and Midlife and Incident Diabetes: A Retrospective Cohort Study of U.S. Adults
Authors: Andrew Stokes, Jason M. Collins, Bethany F. Grant, Robin F. Scamuffa, Chia-Wen Hsiao, Stephen S. Johnston, Eric M. Ammann, JoAnn E. Manson, Samuel H. Preston
Journal: Diabetes Care (2018)

OBJECTIVE Understanding how changes in weight over the life course shape risk for diabetes is critical for the prevention of diabetes. Using data from the National Health and Nutrition Examination Survey (NHANES), we investigated the association between self-reported weight change from young adulthood to midlife and incident diabetes. RESEARCH DESIGN AND METHODS We categorized individuals into four weight-change groups: those who remained nonobese (stable nonobese), those who moved from an obese BMI to a nonobese BMI (losing), those who moved from a nonobese BMI to an obese BMI (gaining), and those who remained obese (stable obese). Diabetes status was determined by self-report of a prior diagnosis, and age at diagnosis was used to establish time of diabetes onset. Hazard ratios (HRs) relating weight change to incident diabetes over 10 years of follow-up were calculated using Cox models adjusting for covariates. RESULTS Those who were obese and lost weight exhibited a significantly lower risk (HR 0.33; 95% CI 0.14, 0.76) of diabetes compared with those with stable obesity. We also observed lower risk among those who were stable nonobese (HR 0.22; 95% CI 0.18, 0.28) and those in the gaining category (HR 0.70; 95% CI 0.57, 0.87). Further, there was evidence of an increased incidence of diabetes among obese individuals who lost weight compared with individuals who were stable nonobese; however, weight loss was rare, and the association was not statistically significant. If those who were obese had become nonobese during the 10-year period, we estimate that 9.1% (95% CI 5.3, 12.8) of observed diabetes cases could have been averted, and if the population had maintained a normal BMI during the period, 64.2% (95% CI 59.4, 68.3) of cases could have been averted. CONCLUSIONS The findings from this study underscore the importance of population-level approaches to the prevention and treatment of obesity across the life course of individuals.
Otolaryngology on the net
Authors: Valerie Julie Brousseau
Journal: BMJ (2004)

O tolaryngology complaints represent more than half of all visits to general practitioners. Unfortunately, most medical programmes provide only superficial coverage of ear, nose, and throat (ENT) pathology. You can improve your understanding of the physiology and presentation of these diseases by visiting the following sites.

To learn about the physiology of special senses we recommend the London South Bank Medical School site (www.cf.ac.uk/biosi/staff/jacob/sensmnu.html), which gives units on olfaction, hearing, audio evoked potentials, taste, vision, and pheromones. You can check your …
CLINICAL OUTCOMES OF PERICARDIAL EFFUSIONS IN END-STAGE RENAL DISEASE: PERICARDITIS-ASSOCIATED VERSUS ASYMPTOMATIC
Authors: Karim Abdur Rehman, Jorge Betancor, Bo Xu, Arnav Kumar, Carlos Godoy Rivas, Leslie Wong, Paul Cremer, Craig Asher, Allan Klein
Journal: Journal of the American College of Cardiology (2018)
Impact of statins on outcomes in patients (pts) with metastatic castration resistant prostate cancer (mCRPC): Post-hoc analysis of data from COU-AA-301 and COU-AA-302 trials.
Authors: Guillermo de Velasco, David Lora, David Lorente, Toni K. Choueiri, Christopher Sweeney, Daniel E. Castellano
Journal: Journal of Clinical Oncology (2018)

230 Background: Retrospective database studies have suggested that statins may have a positive impact on some mCRPC pts treated with prednisone (P)/abiraterone (AA) Methods: We conducted a post-hoc analysis of individual pt data of mCRPC pts treated with AA and/or P on randomized phase III clinical trials COU -AA-301 and COU-AA-302 to analyze the impact of statins on overall survival (OS). Statistical analyses were performed using the Kaplan Meier method and Cox regression adjusted for known prognostic factors. This study, was carried out under YODA Project #2016-1136 Results: 458 (41%) prechemotherapy pts and 348 (29%) postchemotherapy pts were statins users (Table). Improved OS was observed for mCPRC pts who were statins users in the postdocetaxel setting [HR: 0.82 (95% CI: 0.71 to 0.94); p = 0.006], and there was a trend towards a prolonged OS in the predocetaxel setting [HR: 0.89 (95% CI: 0.77 to 1.03); p = 0.13] adjusted by interventional treatment (AA and/or P). In the predocetaxel setting there were no significant differences in OS between the groups AA/P/non-statin users and placebo/P/statin users (p=0.3). In the multivariate analysis, patients randomized to AA/P who were statins users and presenting ECOG &lt;2 had superior OS in the postdocetaxel setting. Similarly, age, ECOG and statin use were the strongest prognostic factors in the predocetaxel setting. Conclusions: In a post-hoc analysis of two prospective randomized clinical trials statin use was associated with superior OS in mCPRC pts treated with P or AA/P. Further studies are needed to confirm these results and guide use of statins as adjunct to P and A. [Table: see text]
Evaluation and Treatment of Male Hypogonadism
Authors: Robert M. Sargis, Andrew M. Davis
Journal: JAMA (2018)

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The Role of <i>Diabetes Care</i> and Its Contributions to the Field of Diabetes: A Profile in Progress
Authors: Lyn Reynolds, Saul M. Genuth
Journal: Diabetes Care (2018)

Progress in the field of diabetes comes from many sources, including novel ideas, research breakthroughs, expanding therapeutic options, technological advances, charismatic personalities, and enhanced communication between the scientific and clinical communities. It is in the latter realm that the American Diabetes Association’s (ADA’s) journal Diabetes Care has played an increasingly important role since its founding in 1978. Through the years, the journal has grown to become both a locus for and stimulus of all the other sources of progress in diabetes clinical research and care. From its inaugural year, during which there were concerns about how to fill six issues and an acceptance rate just under 50% (1), to its present 41st volume year, with monthly issues ∼3,000 submissions annually, and an acceptance rate for original articles of under 10%, Diabetes Care has emerged as the premier journal in its field.

The 1970s were a busy time in diabetes research that ushered in numerous transformative advances, supported by a marked increase in research funding from the National Institutes of Health (NIH) (2). The role and influence of the ADA were also broadening to include a greater focus on patient care, nursing practice, health care delivery, and professional education (3). Against this backdrop, ADA professional members began to wonder whether the association’s journal Diabetes (established in 1952) adequately addressed the needs of clinical investigators and clinicians treating patients with the disease. A committee appointed to study the question commissioned a physician survey that confirmed strong interest in a clinically oriented diabetes journal. Soon thereafter, Diabetes Care was launched. The second word of its title was an acronym for its focus on C linical and A pplied R esearch and E ducation (2).

In the 40 years since, annual submissions have increased more than 17-fold, the number of published articles has …
Evaluation of the MiCheck MIA test performance in differentiating aggressive from non-aggressive prostate cancer: The MiCheck-01 prospective trial.
Authors: Neal D. Shore, Christopher Michael Pieczonka, Ralph Jonathan Henderson, James L. Bailen, Jennifer Lynn Beebe-Dimmer, Julie J. Ruterbusch, Daniel R. Saltzstein, Raoul S. Concepcion, Robert Borotkanics, Rachel Levin, Sandra Wissmueller, Douglas Campbell, Brad Walsh
Journal: Journal of Clinical Oncology (2018)

TPS152 Background: A diagnostic test which can better inform both clinicians and patients regarding a decision to proceed with a prostate biopsy, while still utilizing traditional parameters of Prostate Specific Antigen (PSA) kinetics and/or the digital rectal examination (DRE) is still an unmet need. The MiCheck ® test is designed as a triage test to assist clinicians in the decision to proceed to prostate biopsy. The MiCheck ® test is a simple blood test that measures the levels of the Glypican-1 protein and related signalling molecules. The MiCheck ® -01 prospective trial builds on a previous pilot trial that examined the ability of the MiCheck ® test to distinguish between normal subjects, patients with benign disease or Gleason 7 and above prostate cancer. The MiCheck ® test showed sensitivity of 60% and specificity of 96% in distinguishing between subjects with Gleason ≥7 and normal or BPH patients. In a separate study, the MiCheck ® test could differentiate aggressive (GS ≥3+4) from non-aggressive (GS 3+3) prostate cancer with a sensitivity of 85% and specificity of 90%. Methods: The trial consists of two arms: Arm 1 (normal patients, n = 50) and Arm 2 (prostate biopsy patients, n = 300). Inclusion criteria: Arm 1: Age ≥50, Low PSA (performed at most 12 months prior, defined as PSA &lt; 1.5 ng/mL between ages 50 and 60 and PSA &lt; 3 ng/mL above age 60). Arm2: Age ≥40, all subjects who are referred for or have undergone either a de novo or a repeat prostate biopsy for high PSA (defined as PSA ≥ 1 ng/ml between ages 40 and 49, PSA ≥2 ng/mL between ages 50 and 60 and PSA ≥ 3 ng/mL for age 60 and above age 60). Key exclusion criteria: prior history of cancer, patients taking ADT, DRE or other prostate manipulation within 72 hrs, subjects taking 5 ARIs. Results: The trial has recruited 30 Arm 2 patients to date. Interim analyses will be performed following accrual of 100 and 200 Arm 2 patients. Full accrual is expected by mid Q4 2017. Conclusions: Interim analysis data will be presented showing test performance. COI and Funding: The trial is funded by Minomic International Ltd. Neal Shore is a member of Minomic’s Clinical Advisory Panel.
Impact of insurance status on survival in neuroendocrine tumors: A multi-institutional Study from the U.S. Neuroendocrine Study Group.
Authors: Paula Marincola Smith, Alexandra G Lopez-Aguiar, Mary Dillhoff, Eliza W Beal, George A. Poultsides, Eleftherios Makris, Flavio G. Rocha, Angelena Crown, Clifford Cho, Megan Beems, Emily Winslow, Victoria Rendell, Bradley A. Krasnick, Ryan Fields, Shishir Maithel, Kamran Idrees
Journal: Journal of Clinical Oncology (2018)

371 Background: Insurance status predicts access to medical care in the United States. Previous studies show uninsured and government insured patients have worse outcomes than those with private insurance. However, the impact of insurance status on survival in patients with Gastrointestinal Neuroendocrine Tumors (GI-NETs) is unclear. We evaluate the association between insurance status and survival in patients with GI-NETs. Methods: Our analysis includes 2022 patients who had surgical resection of GI-NETs at 8 institutions in the U.S. Neuroendocrine Study Group. Patients were categorized based on insurance as private (PI), government (GovI) or uninsured (UI). Factors associated with insurance status were assessed by uni- and multi-variate analysis. Primary endpoint was overall survival. Results: Patient demographics between the insurance categories were similar in ECOG performance status and tumor size at presentation. GovI patients had a higher median age than PI or UI (66 vs. 54 vs. 56 years respectively; p&lt;0.01). Uninsured patients were more likely African American (21.5%) or Latino (5%) compared to PI (11.5%, 2%) or GovI (15%, 2%) (p&lt;0.01). The UI group had a higher proportion of patients who underwent no surveillance imaging post-operatively (39%) compared to PI (26%) and GovI patients (26%) but this was not statistically significant (p=0.15). There was no difference in operative intent (curative vs. palliative) between groups (p=0.2). Five-year overall survival was 86% for PI, 82% for GovI, and 73% for UI patients (p&lt;0.01). On multivariate regression analysis, being uninsured was independently associated with reduced survival when controlling for ASA Class, ECOG, race, tumor location, neoadjuvant and adjuvant chemotherapy, Somatostatin analog, or radiation therapy (HR 1.39, p = 0.012). Conclusions: This is the first systematic analysis of insurance status’s association with overall survival in GI-NET patients. Our analysis shows uninsured or government insured patients have shortened survival compared to the privately insured. The disparity is likely underrepresented in this study, as we examined only patients who underwent surgical resection.