tbuckley/cabot-search huggingface dataset:
Adjuvant Ovarian Suppression in Premenopausal Breast Cancer
Authors: Prudence A Francis, Meredith M Regan, Gini F Fleming
Journal: New England Journal of Medicine (2015)

Suppression of ovarian estrogen production reduces the recurrence of hormonereceptor-positive early breast cancer in premenopausal women, but its value when added to tamoxifen is uncertain. METHODSWe randomly assigned 3066 premenopausal women, stratified according to prior receipt or nonreceipt of chemotherapy, to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression.The primary analysis tested the hypothesis that tamoxifen plus ovarian suppression would improve disease-free survival, as compared with tamoxifen alone.In the primary analysis, 46.7% of the patients had not received chemotherapy previously, and 53.3% had received chemotherapy and remained premenopausal. RESULTSAfter a median follow-up of 67 months, the estimated disease-free survival rate at 5 years was 86.6% in the tamoxifen-ovarian suppression group and 84.7% in the tamoxifen group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.83; 95% confidence interval [CI], 0.66 to 1.04; P = 0.10).Multivariable allowance for prognostic factors suggested a greater treatment effect with tamoxifen plus ovarian suppression than with tamoxifen alone (hazard ratio, 0.78; 95% CI, 0.62 to 0.98).Most recurrences occurred in patients who had received prior chemotherapy, among whom the rate of freedom from breast cancer at 5 years was 82.5% in the tamoxifen-ovarian suppression group and 78.0% in the tamoxifen group (hazard ratio for recurrence, 0.78; 95% CI, 0.60 to 1.02).At 5 years, the rate of freedom from breast cancer was 85.7% in the exemestane-ovarian suppression group (hazard ratio for recurrence vs. tamoxifen, 0.65; 95% CI, 0.49 to 0.87). CONCLUSIONSAdding ovarian suppression to tamoxifen did not provide a significant benefit in the overall study population.However, for women who were at sufficient risk for recurrence to warrant adjuvant chemotherapy and who remained premenopausal, the addition of ovarian suppression improved disease outcomes.Further improvement was seen with the use of exemestane plus ovarian suppression.(Funded by Pfizer and others; SOFT ClinicalTrials.govnumber, NCT00066690.)
AB0053 The effects of extracorporeal photochemotherapy on T cell activation and regulatory mechanisms in patients with systemic sclerosis
Authors: M. Zeher, G. Papp, S. Baráth, A. Szegedi, P. Szodoray
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> In systemic sclerosis (SSc), therapeutic options are limited mainly to the management of complications, halting fibrosis, therefore preventing disease progression is a great challenge. The aim of the present study was to evaluate the immunomodulatory effects of extracorporeal photochemotherapy (ECP) in SSc. <h3>Objectives</h3> In the study, we investigated the influence ofECP on lymphocyte activation and cell death by determining CD95, Annexin V, CD69 and HLA-DR expression on circulating T and B cells in SSc patients, and assessing their changing after ECP therapies. Moreover, we evaluated the relationship between lymphocyte activation and changes in certain immune parameters following ECP treatments. <h3>Methods</h3> We enrolled 16 SSc patients, who received 12 ECP treatments in total. Blood samples were taken prior to the first therapy and 6 weeks after each cycle. Samples were also obtained from 16 healthy controls. Lymphocyte subgroups were quantified by flow cytometry. <h3>Results</h3> Initially, patients had higher numbers and percentages of peripheral CD95+ T cells, but not CD95+ B cells, compared to control values. After ECP treatments, values of CD95+ T cells decreased and became similar to controls. Annexin V expression on T and B cells did not changed during the therapy. We observed significant negative correlation between the changes in percentages of peripheral CD95+ T cells and CD4+ CD25+ Treg cells. Although neither early-activated (CD69+) nor late-activated (HLA-DR+) T lymphocytes showed any changes after ECP, clear negative correlations developed between them and the functional ability of CD4+CD25+ Treg cells after the last treatment. <h3>Conclusions</h3> Our results indicate that the initial increase of CD95+ expression in SSc presumably reflects a physiological response to the pronounced autoimmune processes, which can be effectively attenuated by the restoration of regulative T cell numbers and functions as the result of ECP therapy. <h3>Disclosure of Interest</h3> None Declared
Offline: A global health crisis? No, something far worse
Authors: Richard Horton
Journal: The Lancet (2020)

Every evening we scour those graphs looking for signs that the epidemic is in retreat. New cases of coronavirus disease 2019 (COVID-19). People in hospital with COVID-19. Critical care beds with COVID-19 patients. Daily COVID-19 deaths in hospital. And then the final and bluntly worded "global death comparison". Those with responsibility for leading us through this emergency have called it "a once in a century global health crisis". This statement is incorrect on two grounds. First, because we cannot know what the rest of the century will bring.
Putative contributions of circadian clock and sleep in the context of SARS-CoV-2 infection
Authors: Miguel Meira e Cruz, Masaaki Miyazawa, David Gozal
Journal: European Respiratory Journal (2020)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the aetiological agent of the pandemic coronavirus disease 2019 (COVID-19), is a newly found member of the Coronaviridae family, and is closely related to, albeit with important differences from, SARS-CoV [1]. It enters human cells through the binding of surface spike (S) glycoprotein with angiotensin-converting enzyme 2 (ACE2) [2–4]. The distal S1 subunit of the S protein is responsible for receptor binding, while the transmembrane S2 subunit mediates fusion between the viral envelope and the target cell membrane following proteolytic cleavage by specific cellular enzymes such as transmembrane serine protease 2 for S protein priming [5]. As it is likely that expression levels of ACE2 affect the efficiency of virus attachment and entry, as well as disease severity [6], and the interactions between viral S protein and ACE2 may directly cause lung injury [7], ACE2 may be a potential target of therapeutic and preventative interventions [8]. Circadian deregulation and poor or insufficient sleep may facilitate COVID-19 infection and severity <https://bit.ly/2VUlIIJ>
Нарушение микробиоценоза толстого кишечника и частота синдрома избыточного бактериального роста у больных хроническими воспалительными заболеваниями кишечника
Authors: Yu.M. Stepanov, M.V. Titova, O.M. Tatarchuk
Journal: GASTROENTEROLOGY (2020)

Актуальность. В настоящее время хронические воспалительные заболевания кишечника (ХВЗК), яркими представителями которых являются болезнь Крона (БК) и неспецифический язвенный колит (НЯК), в связи с высокой распространенностью и заболеваемостью, тяжестью течения заболевания и трудностями диагностики остаются одной из наиболее сложных и нерешенных проблем современной гастроэнтерологии. К сожалению, и сегодня этиология ХВЗК точно неизвестна, однако наиболее вероятной считают гипотезу иммунного «гиперответа», вызванного факторами окружающей среды к измененной микробиоте кишечника или патогенным микроорганизмам у генетически склонного хозяина. Изменения микробиоты при ХВЗК общепризнанны, а их исследование имеет большое значение для более глубокого понимания этиологии и патогенеза этих заболеваний и поиска новых альтернативных методов лечения. Именно поэтому исследования дисбиоза кишечника при ХВЗК привлекают все большее внимание ученых всего мира. Цель исследования: исследовать особенности дисбиоза кишечника и частоту синдрома избыточного бактериального роста (СИБР) у пациентов с ХВЗК в зависимости от нозологии и пола. Материалы и методы. Проведено обследование 46 больных ХВЗК в возрасте от 20 до 79 лет, в среднем (47,4 ± 2,4) года. В зависимости от нозологии все пациенты были разделены на 2 группы. Первую составляли 15 пациентов с БK, вторую — 31 больной НЯК. Среди пациентов было 19 женщин и 27 мужчин. Всем больным был проведен водородный дыхательный тест (ВДТ) для выявления СИБР и бактериологическое исследование кала. Результаты. Микробиологические исследования выявили наличие глубоких изменений качественного и количественного состава микрофлоры толстой кишки у 97,8 % больных ХВЗК, с преобладанием дисбиоза II степени у 48,4 % больных НЯК и дисбиоза II и III степени у 33,3 % больных БК. Эти изменения были обусловлены уменьшением количества бифидо- и лактофлоры, повышением концентрации условно-патогенных микроорганизмов и дрожжеподобных грибов. Результаты, полученные при проведении ВДТ, свидетельствуют о высокой частоте СИБР у пациентов с ХВЗК (50 %). При анализе данных выявлено, что СИБР преимущественно определялся у больных НЯК (51,6 %). По гендерному признаку в обеих нозологических группах больных с выявленным СИБР преобладали мужчины. Выводы. Полученные результаты свидетельствуют о том, что практически всем больным с ХВЗК присущи изменения микробиоты кишечника, главным образом за счет резкого снижения численности основных симбионтов толстокишечного микробиоценоза и роста концентрации условно-патогенной микрофлоры. Микробиологическое исследование кала и ВДТ являются самыми доступными неинвазивными методами, позволяющими быстро выявить нарушения микрофлоры кишечника.
Abstract 17808: Comparison Between Different Strategies of Rheumatic Heart Disease Echocardiographic Screening in Brazil: Data From the PROVAR Study
Authors: Bruno R Nascimento, Andrea Z Beaton, Adriana C Diamantino, Maria do Carmo P Nunes, Alison T Reese, Kaciane K Oliveira, Gabriel A Carmo, Tainá V Lourenço, Gabriela Z Ruiz, Letícia Maria M Rabelo, Antonio Luiz P Ribeiro, Craig Sable
Journal: Circulation (2017)

Introduction: The accuracy of clinical examination is limited for the early diagnosis of rheumatic heart disease (RHD), and echocardiographic screening has emerged as an important epidemiological t...
Abstract 14469: Diastolic Dysfunction and High Susceptibility to Arrhythmias in a Mouse Model of Restrictive Cardiomyopathy
Authors: Emmanuel M Camors, Alyson H Roth, Enkhsaikhan Purevjav, Evangelia L Kranias, Jeffrey A Towbin
Journal: Circulation (2019)

Introduction: Restrictive cardiomyopathy (RCM) is an inherited cardiac muscle disorder characterized by abnormal relaxation of the ventricles, conduction abnormalities, and life-threatening ventric...
Abstract 13320: Diagnostic Utility of Cardiac Magnetic Resonance/18F-fluorodeoxyglcose Positron Emission Tomography Fusion Imaging in Cardiac Sarcoidosis
Authors: Masakazu Yasuda, Yoshinori Kagioka, Mana Okune, Kakehi Kazuyoshi, Takayuki Kawamura, Hayato Kaida, Kazunari Ishii, Yoshitaka Iwanaga
Journal: Circulation (2019)

Introduction: Although cardiac magnetic resonance (CMR) and 18F-fluorodeoxyglcose (FDG)-positron emission tomography (PET) have been utilized for diagnosis of cardiac sarcoidosis (CS), active CS is...
Endoscopic treatment of gastroesophageal variceal bleeding after oxaliplatin-based chemotherapy in patients with colorectal cancer
Authors: Xiaoquan Huang, Feng Li, Lifen Wang, Mei Xiao, Liyuan Ni, Siyu Jiang, Yuan Ji, Chunqing Zhang, Wei Zhang, Jian Wang, Shiyao Chen
Journal: Endoscopy (2020)

Abstract Background Oxaliplatin, used as first-choice treatment for colorectal cancer (CRC), induces sinusoidal endothelial injury and portal hypertension. This study investigated the characteristics of oxaliplatin-induced portal hypertension and evaluated the efficacy of endoscopic management of gastroesophageal variceal bleeding. Methods We performed a retrospective, multicenter, case-control study between January 2010 and December 2018. Patients who received oxaliplatin-based chemotherapy after CRC surgery and presented with portal hypertension and gastroesophageal varices were compared with consecutive patients with hepatitis B-related cirrhotic portal hypertension receiving endoscopic treatment for variceal bleeding. Results 39 patients with oxaliplatin-induced portal hypertension were identified, 35 of whom had a history of variceal bleeding. The median period between start of oxaliplatin-based chemotherapy and the occurrence of varices was 50.4 months (n = 39). A total of 26 patients with oxaliplatin-related portal hypertension and 230 patients with hepatitis B-related portal hypertension underwent endoscopic treatment. Kaplan-Meier analysis revealed that the 1-year rebleeding rate was significantly higher in the oxaliplatin group than in the hepatitis B group (43.3 % vs. 19.0 %, P = 0.001). Multivariable Cox regression analysis showed that oxaliplatin-based chemotherapy was an independent factor for 3-year rebleeding (hazard ratio [HR] 2.46, 95 % confidence interval [CI] 1.24–4.87; P = 0.01) and 3-year overall mortality (HR 9.43, 95 %CI 2.32–38.31; P = 0.002). Conclusions Oxaliplatin-related portal hypertension was characterized by massive ascites, splenomegaly, gastric varices, concomitant arterioportal fistula, and relatively normal liver function. Endoscopic treatment to prevent variceal rebleeding in these patients was unsatisfactory compared with endoscopic treatment for hepatitis B-related portal hypertension.
Circulating tumor cells in locally advanced breast cancer
Authors: J. A. García-Sáenz, M. Martín, M. Maestro, M. Vidaurreta, S. Veganzones, S. Rafael, A. Casado, J. Bobokova, J. Sastre, M. Arroyo, E. Diaz-Rubio
Journal: Journal of Clinical Oncology (2009)

e22159 Background: A prospective study was conducted to determine the value of changes in circulating tumor cell (CTC) levels prior to and after the first cycle of neoadjuvant treatment in early prediction of pathologic response in locally advanced breast cancer (LABC). Methods: Two blood samples were obtained from 72 eligible LABC patients to isolate and enumerate CTCs before neoadjuvant chemotherapy started on day 1, and on day 21, immediately before second cycle administration. Results: Sixty patients (83.3%) had ≤1 CTC in the first sample and response rates in this cohort were: pathologic complete response (PCR) in 2 patients (5%); partial response (PR) in 35 (87.5%); stable disease (SD) in 2 (5%); progressive disease (PR) in 1 (2.5%). Twelve patients (16.7%) had ≥2 CTCs in the first sample; these patients were more likely to have triple negative tumors. All 12 had fewer CTCs in the second sample. Response rates in this second cohort of 12 patients were: PCR in 4 (34%); PR, 6 (50%); SD, 1 (8%); and PD, 1 (8%). pCR rate was markedly better in this second cohort (p&lt;0.0042; OR 14.5, 95% CI 2.3–92). Conclusions: This study suggests that the presence of CTCs prior to neoadjuvant therapy might be a predictor of response to this therapy. No significant financial relationships to disclose.
A Phase II Intergroup Trial of PET-Directed Therapy for Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): SWOG Study S1001 (NCT01359592)
Authors: Daniel Persky, Hongli Li, Deborah M. Stephens, Steven I. Park, Nancy L. Bartlett, Lode J. Swinnen, Paul M. Barr, Jerome D. Winegarden, Louis S. Constine, Thomas J. Fitzgerald, John P. Leonard, Brad S Kahl, Michael L. Leblanc, Joo Y. Song, Richard I. Fisher, Lisa M. Rimsza, Sonali M. Smith, Jonathan W. Friedberg
Journal: Blood (2017)
Mavacamten Treatment for Obstructive Hypertrophic Cardiomyopathy
Authors: Stephen B. Heitner, Daniel Jacoby, Steven J. Lester, Anjali Owens, Andrew Wang, David Zhang, Joseph Lambing, June Lee, Marc Semigran, Amy J. Sehnert
Journal: Annals of Internal Medicine (2019)

Obstructive hypertrophic cardiomyopathy is a debilitating and potentially life-threatening condition for which available therapies are few and frequently of limited benefit. This clinical trial ass...
Abstract PR02: A mutational signature in human colorectal cancer induced by genotoxic <i>pks+</i> E. coli
Authors: Jens Puschhof, Cayetano Pleguezuelos-Manzano, Axel Rosendahl Huber, Ruben van Bostel, Hans Clevers
Journal: Cancer Research (2020)

Abstract Various species of intestinal microbiota have been associated with the development of colorectal cancer (CRC), yet a direct role of bacteria in the occurrence of oncogenic mutations has not been established. Escherichia coli can carry the pathogenicity island pks within their genomes, which encodes a set of enzymes that synthesize colibactin. This compound can alkylate nascent DNA on adenine residues, and it has been shown to induce double-strand breaks in cultured cells. We hypothesized that pks+ E. coli are carcinogenic through the mutagenic action of colibactin. To test this, we exposed human intestinal organoids for 5 months to genotoxic pks+ Escherichia coli by repeated luminal injection. Whole-genome sequencing (WGS) of clonal organoids before and after exposure revealed a distinct and reproducible mutational signature, which was completely absent in organoids that were injected with isogenic pks-deficient bacteria. This signature encompasses a single base substitution trinucleotide signature (SBS-pks) with a marked transcriptional strand bias in line with damage on adenine residues, which was accompanied by a specific indel signature (ID-pks). Moreover, a distinct preference for the wider sequence context was detected, fitting a structural model of colibactin bound to DNA. This mutational signature was detected in three cohorts containing more than 6,000 human cancer genomes, and contribution of this signature could be detected in a subset of CRC genomes and more rarely in other cancer types. Finally, we identified driver genes harboring the colibactin target motif and could attribute driver mutations from CRC genomes to the signature. Our study describes a highly specific mutational cancer signature that reflects mutagenic activity of pks+ bacteria in the intestinal lumen, which can induce oncogenic mutations and could contribute to cancer initiation. This abstract is also being presented as Poster A02. Citation Format: Jens Puschhof, Cayetano Pleguezuelos-Manzano, Axel Rosendahl Huber, Ruben van Bostel, Hans Clevers. A mutational signature in human colorectal cancer induced by genotoxic pks+ E. coli [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr PR02.
CDK12 inhibition reduces abnormalities in cells from patients with myotonic dystrophy and in a mouse model
Authors: Ami Ketley, Marzena Wojciechowska, Sonja Ghidelli-Disse, Paul Bamborough, Tushar K. Ghosh, Marta Lopez Morato, Saam Sedehizadeh, Naveed Altaf Malik, Zhenzhi Tang, Paulina Powalowska, Matthew Tanner, Rudolf Billeter-Clark, Rebecca C. Trueman, Philippine C. Geiszler, Alessandra Agostini, Othman Othman, Markus Bösche, Marcus Bantscheff, Martin Rüdiger, Danuta E. Mossakowska, David H. Drewry, William J. Zuercher, Charles A. Thornton, Gerard Drewes, Iain Uings, Christopher J. Hayes, J. David Brook
Journal: Science Translational Medicine (2020)

CDK12 inhibition reduces mutant transcripts and nuclear foci in DM1 cells and produces splicing correction and phenotypic benefit in a mouse model.
A Premalignant Cell-Based Model for Functionalization and Classification of <i>PTEN</i> Variants
Authors: Jesse T. Chao, Rocio Hollman, Warren M. Meyers, Fabian Meili, Kenneth A. Matreyek, Pamela Dean, Douglas M. Fowler, Kurt Haas, Calvin D. Roskelley, Christopher J.R. Loewen
Journal: Cancer Research (2020)

As sequencing becomes more economical, we are identifying sequence variations in the population faster than ever. For disease-associated genes, it is imperative that we differentiate a sequence variant as either benign or pathogenic, such that the appropriate therapeutic interventions or surveillance can be implemented. PTEN is a frequently mutated tumor suppressor that has been linked to the PTEN hamartoma tumor syndrome. Although the domain structure of PTEN and the functional impact of a number of its most common tumor-linked mutations have been characterized, there is a lack of information about many recently identified clinical variants. To address this challenge, we developed a cell-based assay that utilizes a premalignant phenotype of normal mammary epithelial cells lacking PTEN. We measured the ability of PTEN variants to rescue the spheroid formation phenotype of PTEN-/- MCF10A cells maintained in suspension. As proof of concept, we functionalized 47 missense variants using this assay, only 19 of which have clear classifications in ClinVar. We utilized a machine learning model trained with annotated genotypic data to classify variants as benign or pathogenic based on our functional scores. Our model predicted with high accuracy that loss of PTEN function was indicative of pathogenicity. We also determined that the pathogenicity of certain variants may have arisen from reduced stability of the protein product. Overall, this assay outperformed computational predictions, was scalable, and had a short run time, serving as an ideal alternative for annotating the clinical significance of cancer-associated PTEN variants. SIGNIFICANCE: Combined three-dimensional tumor spheroid modeling and machine learning classifies PTEN missense variants, over 70% of which are currently listed as variants of uncertain significance. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/13/2775/F1.large.jpg.
Doctor with mesothelioma wins settlement for asbestos exposure in late 1990s
Authors: Clare Dyer
Journal: BMJ (2020)

A doctor has won a substantial settlement from the NHS after the High Court ruled that she contracted mesothelioma from exposure to asbestos while training in an NHS hospital two decades ago.

Kate Richmond, 44, developed stomach pains in 2018 and was given only two to three years to live after peritoneal mesothelioma was diagnosed.

Now living near Melbourne, Australia, where she worked as a GP, she was a junior doctor at Walsgrave Hospital in Coventry in the late 1990s and early 2000s. The hospital was demolished in 2006 to make way for the University Hospital.

Richmond is married with two children aged …
Mediastinal 99mTc-Methylene Diphosphonate Accumulation in a Patient With Primary Mediastinal Soft Tissue Giant Cell Tumor
Authors: Haotian Chen, Qiuping Fan, Minggang Su
Journal: Clinical Nuclear Medicine (2020)

Abstract Soft tissue giant cell tumor (GCT) is rare. It usually involves the extremities. We report the case of a 37-year-old woman who was suspected of having mediastinal tumor on radiograph. Thoracic CT revealed the tumor had extensive calcification and invaded the adjacent vertebrae and spinal canal. It intensively accumulated 99m Tc-methylene diphosphonate on bone scan. The tumor showed hypointensity on T1-weighted and mixed intensity on T2-weighted fat-saturated sagittal images. Finally, a soft tissue GCT was confirmed by pathology. The case cautions us soft tissue GCT should be in the differential diagnosis spectrum in a calcified posterior mediastinal mass with 99m Tc-methylene diphosphonate accumulation.
Treatment of Rheumatoid Arthritis
Authors: L. Schmidt
Journal: BMJ (1949)

At present, there are no firm guidelines for the treatment of COVID-19–related emotional distress. The current approach is based on our knowledge of how to manage anxiety in medically ill patients, taking into consideration all associated medical comorbidities, drug-drug interactions, and the patient’s specific needs and preexisting mental illness. Interventions should be implemented at the bedside to augment the patient’s own resiliency in coping with these stressful events. A targeted combination of psychopharmacology (targeting acute anxiety and panic symptoms) and psychotherapy (relaxation techniques, breathing exercises, and encouragement) is recommended.