tbuckley/cabot-search huggingface dataset:
A nationwide genomic screening project for small cell lung cancer in Japan (LC-SCRUM-Japan).
Authors: Haruyasu Murakami, Shigeki Umemura, Masahiro Shinoda, Masato Shingyoji, Yukari Ogawa, Koji Takeda, Kaname Nosaki, Norio Okamoto, Hiromi Aono, Satoshi Hara, Shoichi Kuyama, Akiko Sato, Nobuhiro Kanaji, Tamio Okimoto, Yuki Kataoka, Shingo Matsumoto, Hibiki Udagawa, Kiyotaka Yoh, Katsuya Tsuchihara, Koichi Goto
Journal: Journal of Clinical Oncology (2017)

8518 Background: Recent genomic studies of small-cell lung cancer (SCLC) have identified promising therapeutic strategies for this highly lethal form of cancer. Thus, we established a nationwide lung cancer genomic screening project in Japan (LC-SCRUM-Japan) to identify SCLC patients harboring targetable genomic alterations for the development of novel targeted therapies. Methods: The samples were subjected to a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay, enabling the simultaneous analysis of 143 cancer-related genes. Results: As of December 2016, 133 institutions were participating and 295 patients had been enrolled. The median age was 69 years (range, 14-90 years). Two hundred seventeen (74%) were male and most patients (93%) were smokers. Among 268 samples completed analysis, we identified high prevalence of inactivating TP53/RB1 mutations in 198 (74%) /82 (31) of cases, respectively. MYC/MYCL1/MYCN amplifications were detected in 10 (4%) /13 (5) /4 (1) of cases, respectively. The NGS analysis also showed that 62 (23%) of cases had at least one targetable genomic alterations, including 7 EGFR activating mutations (3%), 6 KRAS activating mutations (2%), and 8 FGFR1 copy number gains (3%). No case was positive for ALK or ROS1 fusions. Never-smokers (71% vs. 5%, p&lt;0.001) were significantly frequent in the EGFR type compared to the others. The KRAS type showed significantly poor progression free survival (PFS) of the first-line chemotherapy compared to the others (median PFS 1.2 vs. 6.1 months, respectively; p&lt;0.001). Mutations in the PI3K/AKT/mTOR pathway were detected in 22 (8%) of the tumors: 10 PIK3CA mutations (4%), 9 PTEN inactivating mutations (3%) and 3 TSC2 inactivating mutations (1%). Among them, a case with PTEN mutation was enrolled in the investigator initiated phase II study of gedatolisib named “EAGLE-PAT” (UMIN 000020585). Conclusions: We identified a series of targetable genomic alterations in SCLC. This nationwide screening system is helpful for identifying targetable genomic alterations and their clinical features, contributing to the development of novel targeted therapies for this disease. Updated screening results will be presented at the 2017 ASCO Annual Meeting.
TCT-100 Feasibility of Early Mechanical Circulatory Support in Acute Myocardial Infarction Complicated by Cardiogenic Shock: The Detroit Cardiogenic Shock Initiative
Authors: Mir Basir, Theodore Schreiber, Simon Dixon, Khaldoon Alaswad, Kiritkumar Patel, Steven Almany, Akshay Khandelwal, Augustine George, Michael Ashbrook, Nimrod Blank, Nishtha Sareen, William O'Neill
Journal: Journal of the American College of Cardiology (2017)
Insulin secretion and decreased glucose clearance are associated with enhanced fibrogenesis and a high risk of disease progression in non-diabetic patients with Non Alcoholic Fatty Liver Disease
Authors: Younes Ramy, Rosso Chiara, Gaggini Melania, Mezzabotta Lavinia, Marietti Milena, Carli Fabrizia, Salomone Federico, Buzzigoli Emma, Gian Paolo Caviglia, Barbieri Chiara, Maria Lorena Abate, Smedile Antonina, Giorgio Maria Saracco, Quentin M. Anstee, Diana J. Leeming, Gastaldelli Amalia, Schuppan Detlef, Bugianesi Elisabetta
Journal: Hepatology (2017)
Discontinuing Inappropriate Medication Use in Nursing Home Residents
Authors: Hans Wouters, Jessica Scheper, Hedi Koning, Chris Brouwer, Jos W. Twisk, Helene van der Meer, Froukje Boersma, Sytse U. Zuidema, Katja Taxis
Journal: Annals of Internal Medicine (2017)

Background: Inappropriate prescribing is a well-known clinical problem in nursing home residents, but few interventions have focused on reducing inappropriate medication use. Objective: To examine successful discontinuation of inappropriate medication use and to improve prescribing in nursing home residents. Design: Pragmatic cluster randomized controlled trial, with clustering by elder care physicians and their wards. (ClinicalTrials.gov: NCT01876095) Setting: 59 Dutch nursing home wards for long-term care. Patients: Residents with a life expectancy greater than 4 weeks who consented to treatment with medication. Intervention: Multidisciplinary Multistep Medication Review (3MR) consisting of an assessment of the patient perspective, medical history, critical appraisal of medications, a meeting between the treating elder care physician and the pharmacist, and implementation of medication changes. Measurements: Successful discontinuation of use of at least 1 inappropriate drug (that is, without relapse or severe withdrawal symptoms) and clinical outcomes (neuropsychiatric symptoms, cognitive function, and quality of life) after 4 months of follow-up. Results: Nineteen elder care physicians (33 wards) performed the 3MR, and 16 elder care physicians (26 wards) followed standard procedures. A total of 426 nursing home residents (233 in the intervention group and 193 in the control group) were followed for an average of 144 days (SD, 21). In an analysis of all participants, use of at least 1 inappropriate medication was successfully discontinued for 91 (39.1%) residents in the intervention group versus 57 (29.5%) in the control group (adjusted relative risk, 1.37 [95% CI, 1.02 to 1.75]). Clinical outcomes did not deteriorate between baseline and follow-up. Limitations: The 3MR was done only once. Some withdrawal symptoms or relapses may have been missed. Conclusion: The 3MR is effective in discontinuing inappropriate medication use in frail nursing home residents without a decline in their well-being. Primary Funding Source: Netherlands Organisation for Health Research and Development.
Surto de Salmonella enteritidis fagotipo 1 em turistas britânicos em Maiorca, Junho de 1996
Authors: P Wall, L Ward, S Crespi, C Furtado
Journal: Eurosurveillance (1997)

Entre 11 e 25 de Junho de 1996, tres turistas britânicos adoeceram durante as suas ferias no mesmo hotel de Alcudia em Maiorca tendo sido diagnosticada uma infeccao a Salmonella enteritidis apos o seu regresso a Inglaterra. A 10 de Julho de 1996, um inspector de saude ambiental informou a Divisao de Doencas Gastrointestinais do PHLS Centro de Vigilância de Doencas Transmissiveis-CVDT (PHLS Communicable Disease Surveillance Centre). O CVDT contactou um microbiologista de Alcudia, que declarou ter efectuado um inquerito sobre um surto de gastroenterite no hotel, na altura em que os tres turistas britânicos se encontravam hospedados. Trata-se de um grande hotel destinado unicamente a veraneantes britânicos e em que as estadias incluem, geralmente, o pequeno almoco e o jantar. Os veraneantes que tem gastroenterite durante a estadia podem consultar um medico generalista local que se desloca ao hotel. A maior parte dos casos sao tratados sintomaticamente e a analise das fezes nao sao pedidas por rotina. Apenas os casos mais graves sao referenciados para o hospital.
Abstract 20097: Burden of Arrhythmias in Patients Hospitalized With Cardiac Amyloidosis
Authors: Yogita M Rochlani, Shah N Nishi, Abdul Hakeem, Sabha Bhatti
Journal: Circulation (2015)

Introduction: Cardiac Amyloidosis (CA) predisposes patients to atrial and ventricular arrhythmias. Data on distribution of arrhythmias in this patient population is scarce. We sought to study the prevalence of various types of arrhythmias in this vulnerable patient population. Methods: Patients hospitalized with a diagnosis of CA were identified using appropriate ICD 9 codes from the Nationwide Inpatient Sample for the period between 2007-2011. Cardiac arrhythmias listed in the discharge diagnosis were recorded based on ICD 9 codes. Statistical analysis was done using SAS v9.3 (Cary Institute Inc., Cary, NC). Results: A total of 13,602 patients hospitalized for CA between 2007-2011 were identified of which 52.6% (n=7157) had an arrhythmia listed during the hospitalization (table). The most common arrhythmia was atrial fibrillation (AF) (32.3%, n= 4390), followed by ventricular tachycardia (9.9%, n=1352), atrial flutter (6.5%, n=878) and atrioventricular blocks (3.5%, n=470). There was no gender difference in prevalence of arrhythmias. All-cause mortality during hospitalization was 10%. In hospitalized patients, ventricular tachycardia was the most common life threatening arrhythmia followed by ventricular fibrillation. Conclusions: CA patients have a high arrhythmia burden with a high incidence of AF and life threatening arrhythmias such as ventricular tachycardia and fibrillation. Whether this patient population will benefit from ICD implantation for primary prevention is not clearly known. Further research is required to identify specific arrhythmic risk factors and develop guidelines for primary prevention of sudden cardiac death in this patient population.
TCT-771 30-Day Outcomes in Patients with a Society of Thoracic Surgeons Predicted Risk of Mortality &lt;3% from the Evolut R FORWARD Study
Authors: Eberhard Grube, Nicolas Van Mieghem, Thomas Modine, Sabine Bleiziffer, Nikos Werner, Stephan Windecker
Journal: Journal of the American College of Cardiology (2017)
Rationale for the treatment of Wilms tumour in the UMBRELLA SIOP–RTSG 2016 protocol
Authors: Marry M. van den Heuvel-Eibrink, Janna A. Hol, Kathy Pritchard-Jones, Harm van Tinteren, Rhoikos Furtwängler, Arnauld C. Verschuur, Gordan M. Vujanic, Ivo Leuschner, Jesper Brok, Christian Rübe, Anne M. Smets, Geert O. Janssens, Jan Godzinski, Gema L. Ramírez-Villar, Beatriz de Camargo, Heidi Segers, Paola Collini, Manfred Gessler, Christophe Bergeron, Filippo Spreafico, Norbert Graf
Journal: Nature Reviews Urology (2017)

The Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP-RTSG) has developed a new protocol for the diagnosis and treatment of childhood renal tumours, the UMBRELLA SIOP-RTSG 2016 (the UMBRELLA protocol), to continue international collaboration in the treatment of childhood renal tumours. This protocol will support integrated biomarker and imaging research, focussing on assessing the independent prognostic value of genomic changes within the tumour and the volume of the blastemal component that survives preoperative chemotherapy. Treatment guidelines for Wilms tumours in the UMBRELLA protocol include recommendations for localized, metastatic, and bilateral disease, for all age groups, and for relapsed disease. These recommendations have been established by a multidisciplinary panel of leading experts on renal tumours within the SIOP-RTSG. The UMBRELLA protocol should promote international collaboration and research and serve as the SIOP-RTSG best available treatment standard.
Cardiovascular and All-Cause Mortality Risk Associated With Urinary Excretion of 8-oxoGuo, a Biomarker for RNA Oxidation, in Patients With Type 2 Diabetes: A Prospective Cohort Study
Authors: Laura K. Kjær, Vanja Cejvanovic, Trine Henriksen, Kasper M. Petersen, Torben Hansen, Oluf Pedersen, Cramer K. Christensen, Christian Torp-Pedersen, Thomas A. Gerds, Ivan Brandslund, Thomas Mandrup-Poulsen, Henrik E. Poulsen
Journal: Diabetes Care (2017)

Cardiovascular mortality risk remains high among patients with type 2 diabetes. Oxidative stress indicated by high urinary excretion of the biomarker for RNA oxidation, 8-oxo-7,8-dihydroguanosine (8-oxoGuo), is associated with an increased risk of death in newly diagnosed and treated patients. We assessed whether 8-oxoGuo is associated with specific cardiovascular and all-cause mortality risk.Urinary biomarkers for nucleic acid oxidation were measured in a cohort of patients with type 2 diabetes aged ≥60 years (n = 1,863), along with biochemical measurements, questionnaire findings, and Central Person Registry information to estimate the hazard ratios (HRs) for log2-transformed RNA oxidation using Cox regression.During the 5-year follow-up, 173 of 1,863 patients had died (9.3%), including 73 patients who died of cardiovascular disease (42.2%). Doubling of RNA oxidation was associated with an HR of all-cause mortality of 2.10 (95% CI 1.63-2.71; P < 0.001) and an HR of cardiovascular death of 1.82 (95% CI 1.20-2.77; P = 0.005) after multiple adjustments. The 5-year absolute risks (ARs) of all-cause mortality (AR 13.9 [95% CI 10.8-17.0] vs. AR 6.10 [95% CI 4.00-8.30]) and cardiovascular mortality (AR 5.49 [95% CI 3.44-7.55] vs. AR 3.16 [95% CI 1.59-4.73]) were approximately two times higher in the highest quartile of RNA oxidation than in the lowest quartile.We conclude that high RNA oxidation is associated with all-cause and cardiovascular mortality risk in patients with type 2 diabetes. Targeting oxidative stress via interventions with long-term follow-up may reveal the predictive potential of the biomarker 8-oxoGuo.
TCT-470 Worldwide Everyday Practice Registry Assessing the Xposition S Self-apposing Stent in Challenging Lesions with Vessel Diameter Variance (SIZING Registry)
Authors: Marcus Siry, Adam Sukiennik, Daniel Weilenmann, Samer Somi, Steffen Schnupp, Gillian A. Jessurun, Alexander Ijsselmuiden, Robert-Jan van Geuns, Anais Balland, Floris Kauer
Journal: Journal of the American College of Cardiology (2018)
B lymphocytes limit senescence‐driven fibrosis resolution and favor hepatocarcinogenesis in mouse liver injury
Authors: Francesca Faggioli, Eleonora Palagano, Luca Di Tommaso, Matteo Donadon, Veronica Marrella, Camilla Recordati, Stefano Mantero, Anna Villa, Paolo Vezzoni, Barbara Cassani
Journal: Hepatology (2017)

Hepatocellular carcinoma (HCC) is a frequent neoplasia and a leading cause of inflammation-related cancer mortality. Despite that most HCCs arise from persistent inflammatory conditions, pathways linking chronic inflammation to cancer development are still incompletely elucidated. We dissected the role of adaptive immunity in the Mdr2 knockout (Mdr2-/- ) mouse, a model of inflammation-associated cancer, in which ablation of adaptive immunity has been induced genetically (Rag2-/- Mdr2-/- and μMt-Mdr2-/- mice) or with in vivo treatments using lymphocyte-specific depleting antibodies (anti-CD20 or anti-CD4/CD8). We found that activated B and T lymphocytes, secreting fibrogenic tumor necrosis factor alpha (TNFα) and other proinflammatory cytokines, infiltrated liver of the Mdr2-/- mice during chronic fibrosing cholangitis. Lymphocyte ablation, in the Rag2-/- Mdr2-/- and μMt-Mdr2-/- mice, strongly suppressed hepatic stellate cell (HSC) activation and extracellular matrix deposition, enhancing HSC transition to cellular senescence. Moreover, lack of lymphocytes changed the intrahepatic metabolic/oxidative state, resulting in skewed macrophage polarization toward an anti-inflammatory M2 phenotype. Remarkably, hepatocarcinogenesis was significantly suppressed in the Rag2-/- Mdr2-/- mice, correlating with reduced TNFα/NF-κB (nuclear factor kappa B) pathway activation. Ablation of CD20+ B cells, but not of CD4+ /CD8+ T cells, in Mdr2-/- mice, promoted senescence-mediated fibrosis resolution and inhibited the protumorigenic TNFα/NF-κB pathway. Interestingly, presence of infiltrating B cells correlated with increased tumor aggressiveness and reduced disease-free survival in human HCC.Adaptive immunity sustains liver fibrosis (LF) and favors HCC growth in chronic injury, by modulating innate components of inflammation and limiting the extent of HSC senescence. Therapies designed for B-cell targeting may be an effective strategy in LF. (Hepatology 2018;67:1970-1985).
Do adjuvants add to the efficacy and tolerance of bowel preparations? A meta-analysis of randomized trials
Authors: Sophie Restellini, Omar Kherad, Charles Menard, Myriam Martel, Alan Barkun
Journal: Endoscopy (2017)

Abstract Background and study aims Recommendations on adjuvant use with bowel preparations remain disparate. We performed a meta-analysis determining the clinical impact of adding an adjuvant to polyethylene glycol (PEG), sodium phosphate, picosulfate (PICO), or oral sulfate solutions (OSS)-based regimens. Methods Systematic searches were made of MEDLINE, EMBASE, Scopus, CENTRAL and ISI Web of knowledge for randomized trials from January 1980 to April 2016 that assessed preparations with or without adjuvants, given in split and non-split dosing, and PEG high- (&gt; 3 L) or low-dose (≤ 2 L) regimens. Bowel cleansing efficacy was the primary outcome. Secondary outcomes included patient willingness to repeat the procedure, and polyp and adenoma detection rates. Results Of 3093 citations, 77 trials fulfilled the inclusion criteria. Overall, addition of an adjuvant compared with no adjuvant, irrespective of the type of preparation and mode of administration, yielded improvements in bowel cleanliness (odds ratio [OR] 1.23 [1.01 – 1.51]) without greater willingness to repeat (OR 1.40 [0.91 – 2.15]). Adjuvants combined with high-dose PEG significantly improved colon cleansing (OR 1.96 [1.32 – 2.94]). The odds for achieving adequate preparation with low-dose PEG with an adjuvant were not different to high-dose PEG alone (OR 0.95 [0.73 – 1.22]), but yielded improved tolerance (OR 3.22 [1.85 – 5.55]). However, split high-dose PEG yielded superior cleanliness to low-dose PEG with adjuvants (OR 2.53 [1.25 – 5.13]). No differences were noted for OSS and PICO comparisons, or for any products regarding polyp or adenoma detection rates. Conclusions Critical heterogeneity precludes firm conclusion on the impact of adjuvants with existing bowel preparations. Additional research is required to better characterize the methods of administration and resulting roles of adjuvants in an era of split-dosing.
Abstract 12464: Exosomes Loaded With Microrna-126 Prevents Sepsis-induced Cardiac Dysfunction in Endothelial Cell Hspa12b Deficient Mice
Authors: Xia Zhang, Xiaohui Wang, Tuanzhu Ha, Li Liu, He Ma, John Kalbfleisch, Race Kao, David Williams, Chuanfu Li
Journal: Circulation (2015)

We have previously shown that increased expression of endothelial heat shock protein A12B (HSPA12B) attenuates LPS-induced cardiac dysfunction. MicroRNA-126 (miR-126) specifically targets adhesion molecules in endothelial cells. This study examined the role of miR-126 in HSPA12B-induced cardioprotection in sepsis. Endothelial HSPA12B-/- (n=6) and wild type (WT, n=6) mice were subjected to cecal ligation and puncture (CLP)-induced sepsis. Sham surgery served as sham control (n=6). Cardiac function was examined by echocardiography before and 6 h after CLP. CLP sepsis significantly decreased ejection fraction (EF%) by 34.8% and fractional shortening (%FS) by 43.1% in WT mice. EF% and FS% values in HSPA12B-/- septic mice showed further decreases of 19.9% and 22.5% compared with WT septic mice. The levels of ICAM1 and VCAM1 and the infiltration of immune cells (macrophages and neutrophils) into the myocardium of HSPA12B-/- septic mice were markedly greater than WT septic mice. The vascular permeability in HSPA12B-/- septic mice was much more severe than in WT septic mice. Importantly, the levels of circulating miR-126 in HSPA12B-/- septic mice were much lower than in WT septic mice. To examine whether decreased miR-126 is responsible for cardiac dysfunction in HSPA12B-/- septic mice, we loaded exosomes with miR-126 by transfection of bone marrow stromal cells with miR-126 mimics followed by isolation of exosomes 24 hours after transfection. Scrambled miR served as the miR control (miR-control). Exosomes loaded with miR-126 or miR-control were delivered into the myocardium through the right carotid artery immediately after induction of CLP (n=5-6/group). Cardiac function was significantly improved by delivery of miR-126 into the myocardium as evidenced by increased the values of EF% (51%) and FS% (59%), when compared with HSPA12B-/- septic mice. MiR-126 delivery significantly suppressed the expression of adhesion molecules, reduced immune cell infiltration in the myocardium, and improved vascular permeability in HSPA12B-/- septic mice. Delivery of miR-control did not alter cardiac dysfunction in HSPA12B-/- septic mice. We conclude that miR-126 plays a critical protective role in endothelial HSAP12B in preservation of cardiac function in sepsis.
RNA virus interference via CRISPR/Cas13a system in plants
Authors: Rashid Aman, Zahir Ali, Haroon Butt, Ahmed Mahas, Fatimah Aljedaani, Muhammad Zuhaib Khan, Shouwei Ding, Magdy Mahfouz
Journal: Genome biology (2018)

CRISPR/Cas systems confer immunity against invading nucleic acids and phages in bacteria and archaea. CRISPR/Cas13a (known previously as C2c2) is a class 2 type VI-A ribonuclease capable of targeting and cleaving single-stranded RNA (ssRNA) molecules of the phage genome. Here, we employ CRISPR/Cas13a to engineer interference with an RNA virus, Turnip Mosaic Virus (TuMV), in plants. CRISPR/Cas13a produces interference against green fluorescent protein (GFP)-expressing TuMV in transient assays and stable overexpression lines of Nicotiana benthamiana. CRISPR RNA (crRNAs) targeting the HC-Pro and GFP sequences exhibit better interference than those targeting other regions such as coat protein (CP) sequence. Cas13a can also process pre-crRNAs into functional crRNAs. Our data indicate that CRISPR/Cas13a can be used for engineering interference against RNA viruses, providing a potential novel mechanism for RNA-guided immunity against RNA viruses and for other RNA manipulations in plants.
The ISB Cancer Genomics Cloud: A Flexible Cloud-Based Platform for Cancer Genomics Research
Authors: Sheila M. Reynolds, Michael Miller, Phyliss Lee, Kalle Leinonen, Suzanne M. Paquette, Zack Rodebaugh, Abigail Hahn, David L. Gibbs, Joseph Slagel, William J. Longabaugh, Varsha Dhankani, Madelyn Reyes, Todd Pihl, Mark Backus, Matthew Bookman, Nicole Deflaux, Jonathan Bingham, David Pot, Ilya Shmulevich
Journal: Cancer Research (2017)

Abstract The ISB Cancer Genomics Cloud (ISB-CGC) is one of three pilot projects funded by the National Cancer Institute to explore new approaches to computing on large cancer datasets in a cloud environment. With a focus on Data as a Service, the ISB-CGC offers multiple avenues for accessing and analyzing The Cancer Genome Atlas, TARGET, and other important references such as GENCODE and COSMIC using the Google Cloud Platform. The open approach allows researchers to choose approaches best suited to the task at hand: from analyzing terabytes of data using complex workflows to developing new analysis methods in common languages such as Python, R, and SQL; to using an interactive web application to create synthetic patient cohorts and to explore the wealth of available genomic data. Links to resources and documentation can be found at www.isb-cgc.org. Cancer Res; 77(21); e7–10. ©2017 AACR.
Tolvaptan and Autosomal Dominant Polycystic Kidney Disease
Authors: Julie R. Ingelfinger
Journal: New England Journal of Medicine (2017)

Approximately half the patients with autosomal dominant polycystic kidney disease (ADPKD), a condition due to deficiency in polycystin 1 or 2, have end-stage kidney disease by 60 years of age.1,2 Once progression begins, the mean decline in the estimated glomerular filtration rate (GFR) is approximately 4 to 6 ml per minute per 1.73 m2 of body-surface area per year. Therapy to prevent deterioration of GFR in patients with ADPKD has been elusive, despite mechanistic studies targeting pathogenesis. In addition, the burden of therapy in patients who have other symptoms from their ADPKD — hypertension, abdominal fullness and pain from cysts, . . .
Soluble St2 is Regulated By P75NTR and Predicts Mortality in Diabetic Patients With Critical Limb Ischemia
Authors: Andrea Caporalil, Marco Meloni, Ashely M. Miller, Klemens Vierlinger, Christa Noehammer Noehammer, Gaia Spinetti, Orazio Fortunato, Paolo Madeddu, Costanza Emanueli
Journal: Circulation (2012)