tbuckley/cabot-search huggingface dataset:
Chronic thromboembolic and pulmonary arterial hypertension share right ventricular and pulmonary artery CMR features
Authors: S. Hoette, N. Creuzé, C.E. Rochitte, G. Simonneau, M. Humbert, R. Souza, D. Chemla
Journal: Pulmonology (2019)

Cardiac magnetic resonance (CMR) imaging has gained importance in pulmonary hypertension (PH) and studies have demonstrated its use as a surrogate marker and in following treatment of these patients. The pathophysiology of PH differs between pulmonary arterial hypertension (PAH, group 1) and chronic thromboembolic PH (CTEPH, group 4).The present study tested the hypothesis that PAH and CTEPH display different characteristics on CMR imaging.46 patients were evaluated for pulmonary vascular disease in the French National Reference Center for PH (23 PAH and 23 CTEPH matched for age and gender). All patients had the right heart catheterization (RHC) and CMR imaging performed within 48h. CMR imaging was performed on a 1.5 T scanner.PAH and CTEPH had similar body surface area and similar invasive hemodynamics, including mean pulmonary arterial pressure, cardiac index, pulmonary vascular resistance and right atrial pressure. PAH and CTEPH had similar CMR data. Right ventricular (RV) morphology and function and pulmonary artery (PA) data were also similar.Age- and sex-matched PAH and CTEPH patients displayed similar values of the CMR indices of RV and PA morphology and function, suggesting that the RV-PA responses are similar in both groups, mostly related to the overall increase in after load.
Abstract P1-06-08: A p53-independent DNA damage response that regulates breast cancer phenotypes
Authors: KD Fagan-Solis, DA Simpson, M Kapustina, L Martelotto, JS Reis-Filho, JH Petrini, GP Gupta
Journal: Cancer Research (2019)

Abstract Defects in the DNA damage repair system result in increased genomic instability and have recently been implicated as being drivers of tumorigenesis in both familial and sporadic breast cancers. To maintain genomic integrity, cells have a DNA damage response (DDR) mechanism that functions to repair damaged DNA efficiently and commits cells to death if damage is irreparable. Failure of this mechanism results in genomic instability and cancer predisposition. Widespread chromosomal instability is a characteristic feature of Triple-Negative Breast Cancer (TNBC), making it difficult to decipher between genes that drive cancer development from those that play a bystander role. Little is known about what gives rise to the extensive genomic instability of TNBC, and presents a major deficit in our scientific and clinical knowledge. Oncogene induced hyper-proliferation results in replication-associated double strand breaks (DSBs) that engage an Mre11-Rad50-Nbs1 complex-dependent DDR. Classically, the oncogene induced DDR is believed to suppress tumorigenesis due to downstream activation of p53. Using genetically engineered primary mammary epithelial cell models, we demonstrate p53-independent effects of the Mre11-dependent DDR in suppressing proliferation and DNA damage induced by diverse oncogenic drivers. Single cell whole genome sequencing in Her2/Neu expressing primary mammary epithelial cells reveals a landscape of stochastic copy number aberrations induced by oncogenic stress that becomes enriched for a genomic scar pattern of larger-size deletions in cells with Mre11 hypomorphism. We identify Mre11 pathway hypomorphism in a subset of basal-like breast cancers (BLBC), which confers vulnerability to specific DNA damaging agents and DDR inhibitors in murine models of p53-deficient BLBC. Thus, assessing the functional status of the Mre11-dependent DDR pathway in p53-mutant breast cancers may provide an opportunity for therapeutic exploitation. Citation Format: Fagan-Solis KD, Simpson DA, Kapustina M, Martelotto L, Reis-Filho JS, Petrini JH, Gupta GP. A p53-independent DNA damage response that regulates breast cancer phenotypes [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-06-08.
Population-wide weight loss and regain in relation to diabetes burden and cardiovascular mortality in Cuba 1980-2010: repeated cross sectional surveys and ecological comparison of secular trends
Authors: F Javier Nieto
Journal: BMJ (2013)

The paper

Abstract

Objective To evaluate the associations between population-wide loss and gain in weight with diabetes prevalence, incidence, and mortality, as well as cardiovascular and cancer mortality trends, in Cuba over a 30 year interval.

Design Repeated cross sectional surveys and ecological comparison of secular trends.

Setting Cuba and the province of Cienfuegos, from 1980 to 2010.

Participants Measurements in Cienfuegos included a representative sample of 1657, 1351, 1667, and 1492 adults in 1991, 1995, 2001, and 2010, respectively. National surveys included a representative sample of 14 304, 22 851, and 8031 participants in 1995, 2001, and 2010, respectively.

Main outcome measures Changes in smoking, daily energy intake, physical activity, and body weight were tracked from 1980 to 2010 using national and regional surveys. Data for diabetes prevalence and incidence were obtained from national population based registries. Mortality trends were modelled using national vital statistics.

Results Rapid declines in diabetes and heart disease accompanied an average population-wide loss of 5.5 kg in weight, driven by an economic crisis in the mid-1990s. A rebound in population weight followed in 1995 (33.5% prevalence of overweight and obesity) and exceeded pre-crisis levels by 2010 (52.9% prevalence). The population-wide increase in weight was immediately followed by a 116% increase in diabetes prevalence and 140% increase in diabetes incidence. Six years into the weight rebound phase, diabetes mortality increased by 49% (from 9.3 deaths per 10 000 people in 2002 to 13.9 deaths per 10 000 people in 2010). A deceleration in the rate of decline in mortality from coronary heart disease was also observed.

Conclusions In relation to the Cuban experience …
Abstract P3-06-06: Lactate dehydrogenase B in breast cancer contributes to glycolytic phenotype and predicts response to neoadjuvant chemotherapy
Authors: JB Dennison, JR Molina, S Mitra, AM Gonzalez-Angulo, RE Brown, GB Mills
Journal: Cancer Research (2012)

Abstract Purpose: Although breast cancers are known to be molecularly heterogeneous, their metabolic heterogeneity is less well understood. This study aimed to identify and evaluate metabolic biomarkers in breast cancers and determine their ability to predict outcomes. Methods: mRNA microarray data from breast cancer cell lines were used to identify bimodal genes, those with the highest potential for robust high/low classification in a clinical setting. Using a panel of breast cancer cell lines, expression and activity of the highest scoring bimodal metabolism gene, lactate dehydrogenase B (LDHB), was quantified and associated with glycolytic phenotype. The contribution of LDHB to glycolysis was evaluated using MDA-MB-231 and HCC1937 cell lines with stable lentiviral knockdown of LDHB. mRNA expression of LDHB was evaluated for association with neoadjuvant chemotherapy response within clinical and PAM50-derived subtypes. Results: LDHB was highly expressed in cell lines with glycolytic, basal-like phenotypes. Knockdown of LDHB in cell lines reduced glycolytic dependence, linking LDHB expression directly to metabolic function. Using four independent patient datasets, LDHB mRNA expression was positively associated with basal subtype and negatively associated with luminal and HER2 subtypes. Furthermore, LDHB predicted basal phenotype independently of hormone-receptor (HR) clinical status (OR = 21.6 for HR-positive/HER2-negative and OR = 18.2 for triple-negative). While LDHB expression could predict basal phenotype, high LDHB expression identified aggressive breast cancer tumors that were primarily but not exclusively basal. Importantly, high LDHB expression predicted pathological complete response to neoadjuvant chemotherapy for both hormone receptor (HR) positive/HER2-negative (OR = 4.0, P = .0002) and triple-negative (OR = 3.0, P = .003) cancers. Consistent with increased response to chemotherapy, LDHB expression in basal cancers within the triple-negative group was associated with the proliferative marker CCNB1 (P &amp;lt; .0001). Conclusion: mRNA expression of LDHB as a single marker predicted glycolytic phenotype in cell lines and response to neoadjuvant chemotherapy in breast cancers independently of HR status. These observations support prospective clinical evaluation of LDHB as a predictive marker of response for breast cancer patients treated with neoadjuvant chemotherapy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-06.
Future research trends in understanding the mechanisms underlying allergic diseases for improved patient care
Authors: Heimo Breiteneder, Zuzana Diamant, Thomas Eiwegger, Wytske J. Fokkens, Claudia Traidl‐Hoffmann, Kari Nadeau, Robyn E. O’Hehir, Liam O’Mahony, Oliver Pfaar, Maria J. Torres, De Yun Wang, Luo Zhang, Cezmi A. Akdis
Journal: Allergy (2019)

Abstract The specialties of allergy and clinical immunology have entered the era of precision medicine with the stratification of diseases into distinct disease subsets, specific diagnoses, and targeted treatment options, including biologicals and small molecules. This article reviews recent developments in research and patient care and future trends in the discipline. The section on basic mechanisms of allergic diseases summarizes the current status and defines research needs in structural biology, type 2 inflammation, immune tolerance, neuroimmune mechanisms, role of the microbiome and diet, environmental factors, and respiratory viral infections. In the section on diagnostic challenges, clinical trials, precision medicine and immune monitoring of allergic diseases, asthma, allergic and nonallergic rhinitis, and new approaches to the diagnosis and treatment of drug hypersensitivity reactions are discussed in further detail. In the third section, unmet needs and future research areas for the treatment of allergic diseases are highlighted with topics on food allergy, biologics, small molecules, and novel therapeutic concepts in allergen‐specific immunotherapy for airway disease. Unknowns and future research needs are discussed at the end of each subsection.
Contact tracing following measles exposure on three international flights, Germany, 2017
Authors: Sebastian Thole, Daniela Kalhoefer, Maria an der Heiden, Doris Nordmann, Inka Daniels-Haardt, Annette Jurke
Journal: Eurosurveillance (2019)

When a person with contagious measles has travelled by aircraft, European guidelines recommend contact tracing of passengers and crew within 5 days of exposure for post-exposure prophylaxis (PEP), and within 12 days of exposure for informing passengers and crew, in order to prevent further transmissions. To be effective, contact tracing requires prompt diagnosis, immediate notification of public health authorities and rapid availability of passenger contact data. We report two events of contact tracing initiated in Germany after two individuals with measles travelled on three international flights. In one event, contact tracing was initiated late because laboratory confirmation of a clinically diagnosed measles case was awaited unnecessarily. Accessing passenger contact data was difficult in both events because of data protection issues with the airline which was not based in Germany. In both events, passengers were not reached in time to provide PEP, and one event resulted in at least two secondary measles cases. As all passengers were reached before the incubation period ended, tertiary cases were most probably prevented. Public health authorities and the transport sector must collaborate to resolve competing legal regulations for infection prevention and data protection, to simplify and accelerate identification of air travellers exposed to communicable diseases.
Implementing the European Renal Best Practice Guidelines suggests that prediction equations work well to differentiate risk of end-stage renal disease vs. death in older patients with low estimated glomerular filtration rate
Authors: Stein I. Hallan, Dena E. Rifkin, O. Alison Potok, Ronit Katz, Knut A. Langlo, Nisha Bansal, Joachim H. Ix
Journal: Kidney International (2019)

Recent European guidelines suggest using the kidney failure risk equation (KFRE) and mortality risk equation for kidney disease (MREK) to guide decisions on whether elderly patients with chronic kidney disease should be referred early for dialysis preparation. However, the concurrent use of the two risk equations has not been validated. To do so we evaluated 1,188 individuals over five years with estimated glomerular filtration rate (eGFR) under 45ml/min/1.73m2 and age over 65 years from the Norwegian population based HUNT study. Forty-two patients started renal replacement therapy and 462 died as their first clinical event. The KFRE was well calibrated (mean risk estimate 4.9% vs observed 3.5%) with high diagnostic accuracy (C-statistics 0.93). The MREK underestimated death risk in those with lower risk (mean risk estimate 30.1% vs observed 38.9%) and had moderate diagnostic accuracy (C-statistics 0.71). Only 31 individuals had estimated end stage kidney disease (ESRD) risk greater than death risk, and most experienced ESRD before death. Only two of 598 patients over 80 years old, and ten of 1,063 with eGFR 25-45ml/min/1.73m2 at baseline experienced ESRD. Decision curve analysis demonstrated that for risk adverse patients, deferring ESRD preparation may be appropriate until predicted ESRD risk exceeds predicted death risk. For those preferring a more aggressive approach, referral when eGFR is under 25 ml/min/1.73m2 may be beneficial if age remains under 80 years. Thus, the risk of ESRD is low compared to the risk of death in many older patients with chronic kidney disease stage 3b or worse, and combination of predicted ESRD and death risks, eGFR levels, age, and the patient`s valuations of harm and benefit can be helpful for deciding when to start dialysis preparations.
More than a headline
Authors: Katherine Bettany
Journal: BMJ (2013)

Abortion is more than a point of controversy and the subject of tired ethical case studies. Millions of women from around the world will have an abortion every year—you will be seeing them during the course of your future practice, yet clinical teaching tends to be scanty. No matter what your opinion and healthcare system you are part of, we have a duty of care to all of our patients, some of whom will have had or will be planning an abortion. Our clinical review will help you get …
A career in gastroenterology
Authors: Philip J Smith
Journal: BMJ (2016)

You should be interested in multiple organs and carrying out hands-on investigations Every day in gastroenterology is different. As a trainee, during a typical shift you will be expected to carry out investigations and execute management plans. These might include stopping a major gastrointestinal bleed; inserting a gastrostomy feeding tube to help someone receive enteral nutrition; draining ascites from a patient with decompensated chronic liver disease; counselling and supporting a patient with metastatic colorectal cancer and their family; or giving biological treatment to a patient with acute colitis. Gastroenterology is a diverse specialty, not just because of the many procedures you need to master but also because patients with gastroenterological disease often present in a different way to other medical patients. Unlike specialties such as cardiology and respiratory medicine, a gastroenterologist needs in-depth knowledge of multiple organs because signs and symptoms are often systemic and extraintestinal. Gastroenterologists are interested in the gastrointestinal tract—from mouth to anus. Although considered a single organ, it is conventionally divided anatomically into the upper gastrointestinal tract (mouth to ileum) and the lower gastrointestinal tract (caecum to anus). They also deal with disorders of the liver, biliary tree, and pancreas. Gastroenterologists are expected to manage patients with complex problems in many environments, including a general gastroenterology or hepatology ward, transplant centres, outpatient clinics, and intensive care units. These can be in district general hospitals or tertiary referral centres. Gastroenterologists also work in the endoscopy unit of a hospital, where they carry out intraluminal investigations using an endoscope. This is a flexible tube with a camera on the end, which transmits video or images to a television screen to show the inner workings of a patient’s gastrointestinal tract and biliary tree (box 1). #### Box 1: Common endoscopic procedures ##### Upper gastrointestinal tract ##### Lower gastrointestinal tract
Abstract P6-09-03: Association of Caspase 8 polymorphisms with TILs and disease-free survival in primary breast cancer patients
Authors: P Wimberger, HS Bachmann, JD Kuhlmann, T Link, E Kröber, C Thomssen, B Malle, M Vetter, EJ Kantelhardt
Journal: Cancer Research (2019)

Abstract BACKGROUND: The minor allele of two caspase-8 polymorphisms, namely CASP8 -652 6N InsDel and CASP8 Asp302His, were shown to promote survival of T-lymphocytes and were repeatedly associated with reduced breast cancer susceptibility. However, besides some preliminary findings, clinical relevance of these polymorphisms in patients with already existing primary breast cancer has not yet been established. Considering an immunomodulatory and potentially tumor-protective role of these caspase-8 variants, we genotyped 785 primary breast cancer patients and correlated caspase-8 variants with i) disease-free survival (DFS) and ii) the presence of tumor infiltrating lymphocytes (TILs). METHODS: Primary breast cancer samples were collected at the Martin-Luther University, Halle-Wittenberg between 2009 and 2011 as part of the multicenter prospective PiA trial (NCT 01592825). The majority of patients had luminal-like tumors (75.9%), followed by triple negative (10.1%), luminal-Her2-like (9.6%) and Her2-enriched tumors (4.5%). Genotyping was performed by pyrosequencing, TILs status was assessed by hematoxylin and eosin staining. RESULTS: The CASP8 -652 deletion was significantly associated with improved DFS in an allele-dose dependent manner (p=0.027). Homozygosity for the -652 6N Del variant was an independent predictor for improved DFS (p=0.005). In patients with a 302His/His genotype, there was no event of recurrence during the entire observation time. Combined analysis of diplotypes revealed that both polymorphisms had an influence on DFS (p=0.029). Interestingly, patients with the 302His/His variant among the unstratified patient cohort and among the luminal-like subtype alone had tumors with very low lymphocyte infiltration (0-10% TILs in 65% of cases compared to 31% of cases for other genotypes, p=0.025). CONCLUSION: In line with previous epidemiological findings, we propose a prognostically favorable role of the CASP8 -652 6N Del and the Asp302His variant in primary breast cancer patients. Moreover, we suggest for the first time a role of the Asp302His variant in immunosurveillance and lymphocyte infiltration of breast cancer. Our findings strongly encourage further analyze of these genetic variants as a biomarker for prognostic and immunotherapeutic considerations. Citation Format: Wimberger P, Bachmann HS, Kuhlmann JD, Link T, Kröber E, Thomssen C, Malle B, Vetter M, Kantelhardt EJ. Association of Caspase 8 polymorphisms with TILs and disease-free survival in primary breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-09-03.
Abstract P5-11-11: A preliminary assessment of knowledge, attitudes, and awareness surrounding ESR1 mutations and biomarker testing amongst medical oncologists
Authors: SB Goldfarb, MP Goetz, PP Plourde, E Attias, DJ Portman
Journal: Cancer Research (2019)

Abstract Background: Estrogen receptor gene (ESR1) mutations present in breast cancer patients are associated with resistance to endocrine therapy and worse patient outcomes. Recent findings suggest ESR1 mutations are present in up to 40% of metastatic breast cancer (mBC) patients' tumors. The objective of this study was to evaluate the perceptions of precision medicine and biomarker testing specific to ESR1 mutations among medical oncologists. Methods: Ten 60-minute web-assisted, telephone interviews were conducted with medical oncologists. Each physician was prescreened prior to being interviewed to ensure board certification and practice experience between 2 and 35 years. Each participant spent greater than 30% of their time on direct patient care and managed the treatment of more than 30 different cancer patients per month, with a minimum of 15 breast cancer patients, including at least five who had metastatic breast cancer and at least one patient with an ESR1 mutation. Results: A 10-20% prevalence of ESR1 mutation was estimated by the oncologists. However, the practitioners did accept the possibility of a 40% prevalence. Physician knowledge of ESR1 mutations included the relationship between ESR1 mutations and efficacy of endocrine therapies and its association with poorer outcomes. None of the medical oncologists interviewed were highly satisfied with the existing armamentarium of treatments for patients with an ESR1 mutation. In general, the interview participants were highly comfortable ordering ESR1 companion diagnostics to test for an ESR1 mutation, pending viable treatment options are available. Nonetheless, most physicians will wait until the patient has progression of disease before ordering a biomarker test. Several areas of unmet need in the mBC arena were offered by the survey participants, including more efficacious hormonal options for later-line therapies, better durability of remission, improved drug tolerability profiles, and lower treatment costs. Conclusion: Most oncologists acknowledged that personalized treatment is beneficial because it allows for better efficacy than a “one size fits all” approach. The study results also suggest that there are few barriers and drawbacks to the use of personalized medicine in the mBC arena, as most physicians expect precision medicine to account for the majority of advances in breast cancer treatments in the foreseeable future. Support: Sermonix Pharmaceuticals Citation Format: Goldfarb SB, Goetz MP, Plourde PP, Attias E, Portman DJ. A preliminary assessment of knowledge, attitudes, and awareness surrounding ESR1 mutations and biomarker testing amongst medical oncologists [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-11-11.