tbuckley/cabot-search huggingface dataset:
Abstract 23071: Hydroquinidine Abolishes Life-threatening Arrhythmic Events in Patients With Short QT Syndrome
Authors: Andrea Mazzanti, Riccardo Maragna, Gaetano Vacanti, Anna Kostopoulou, Maira Marino, Nicola Monteforte, Raffaella Bloise, Eleonora Pagan, Carlo Napolitano, Vincenzo Bagnardi, Silvia G. Priori
Journal: Circulation (2017)

Background: Short QT Syndrome (SQTS) is one of the rarest and most lethal inherited arrhythmogenic syndromes. Preliminary data have shown that hydroquinidine (HQ) is effective in prolonging the duration of QT interval and in preventing the induction of ventricular arrhythmias during programmed electrical stimulation in SQTS patients. No data exist regarding the efficacy of HQ in reducing cardiac events in SQTS patients. Objective: To determine whether HQ reduces the occurrence of Life-threatening Arrhythmic Events (LAE), defined as aborted cardiac arrest and sudden cardiac death, in SQTS patients. Methods: Cohort study on consecutive SQTS patients referred to our center and treated with HQ. The endpoint was to evaluate the antiarrhythmic efficacy of HQ, by comparing the percentage of patients with LAE, the number of LAE per patient and the annual rate of LAE before and after the beginning of therapy with HQ (mean duration of therapy 6±1 years). Results: The study population was comprised of 17 SQTS patients with the following characteristics: 13 (76%) males, age at beginning of therapy with HQ 29±3 years, QTc interval before treatment 331±3 ms. Therapy with HQ was ceased in 2 cases (12%) after 1 week due to gastrointestinal intolerance, while in the remaining 15 patients HQ was administered continuously for 6±1 years, at an average dose of 528±42 mg per day (7±0.6 mg/kg/day). HQ significantly prolonged the QTc interval in all patients, by a mean of 60±6 ms (p&lt;0.001). HQ reduced to zero the percentage of patients with LAE (from 40% to 0%, p=0.03), the mean number of LAE per patient (from 0.73±0.3 to 0, p=0.026) and the annual rate of LAE (from 12.2% to 0%, p=0.028). Conclusions: We showed for the first time that HQ, besides normalizing the duration of the QT interval, is associated with a major reduction of life-threatening arrhythmic events in SQTS patients, thus representing an efficacious therapeutic approach in this group of individuals. Early discontinuation due to gastrointestinal intolerance occurred in 12% of patients.
Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study
Authors: Caroline Robert, Antoni Ribas, Jacob Schachter, Ana Arance, Jean-Jacques Grob, Laurent Mortier, Adil Daud, Matteo S Carlino, Catriona M McNeil, Michal Lotem, James M G Larkin, Paul Lorigan, Bart Neyns, Christian U Blank, Teresa M Petrella, Omid Hamid, Shu-Chih Su, Clemens Krepler, Nageatte Ibrahim, Georgina V Long
Journal: The Lancet Oncology (2019)
Reply to Bronswijk
Authors: Flávio A. O. B. Silva, Rogério Colaiacovo, Osvaldo Araki, Anna F. Domene, Lucio Rossini
Journal: Endoscopy (2019)

See also:Endoscopic ultrasound-guided ablation of pancreatic neuroendocrine tumors: with or without alcohol?Endoscopy 2019; 51(08): 798-798DOI: 10.1055/a-0889-8106
Being socially uninterested versus not having social prediction skills: The impact of multisensory integration deficits on social skills in autism
Authors: Giuseppe Riva, Daniele Di Lernia, Antonios Dakanalis
Journal: Behavioral and Brain Sciences (2019)

Abstract Jaswal &amp; Akhtar in their target article convincingly argue that subjects with autism do not have diminished social motivation. However, they still recognize that autistic people behave socially in an unusual way. Why? Here we suggest that these behaviours are the results of a multisensory integration deficit. Viewed from this perspective, the assumption that autistic people's unusual behaviours indicate diminished social motivation has to be replaced by the one that they have diminished social prediction skills.
Spatial and Temporal Heterogeneity of Panel-Based Tumor Mutational Burden in Pulmonary Adenocarcinoma: Separating Biology From Technical Artifacts
Authors: Daniel Kazdal, Volker Endris, Michael Allgäuer, Mark Kriegsmann, Jonas Leichsenring, Anna-Lena Volckmar, Alexander Harms, Martina Kirchner, Katharina Kriegsmann, Olaf Neumann, Regine Brandt, Suranand B. Talla, Eugen Rempel, Carolin Ploeger, Moritz von Winterfeld, Petros Christopoulos, Diana M. Merino, Mark Stewart, Jeff Allen, Helge Bischoff, Michael Meister, Thomas Muley, Felix Herth, Roland Penzel, Arne Warth, Hauke Winter, Stefan Fröhling, Solange Peters, Charles Swanton, Michael Thomas, Peter Schirmacher, Jan Budczies, Albrecht Stenzinger
Journal: Journal of Thoracic Oncology (2019)

BackgroundTumor mutational burden (TMB) is an emerging biomarker used to identify patients who are more likely to benefit from immuno-oncology therapy. Aside from various unsettled technical aspects, biological variables such as tumor cell content and intratumor heterogeneity may play an important role in determining TMB.MethodsTMB estimates were determined applying the TruSight Oncology 500 targeted sequencing panel. Spatial and temporal heterogeneity was analyzed by multiregion sequencing (two to six samples) of 24 pulmonary adenocarcinomas and by sequencing a set of matched primary tumors, locoregional lymph node metastases, and distant metastases in five patients.ResultsOn average, a coding region of 1.28 Mbp was covered with a mean read depth of 609x. Manual validation of the mutation-calls confirmed a good performance, but revealed noticeable misclassification during germline filtering. Different regions within a tumor showed considerable spatial TMB variance in 30% (7 of 24) of the cases (maximum difference, 14.13 mut/Mbp). Lymph node–derived TMB was significantly lower (p = 0.016). In 13 cases, distinct mutational profiles were exclusive to different regions of a tumor, leading to higher values for simulated aggregated TMB. Combined, intratumor heterogeneity and the aggregated TMB could result in divergent TMB designation in 17% of the analyzed patients. TMB variation between primary tumor and distant metastases existed but was not profound.ConclusionsOur data show that, in addition to technical aspects such as germline filtering, the tumor content and spatially divergent mutational profiles within a tumor are relevant factors influencing TMB estimation, revealing limitations of single-sample–based TMB estimations in a clinical context.
Outcome of Applying the ESC 0/1-hour Algorithm in Patients With Suspected Myocardial Infarction
Authors: Raphael Twerenbold, Juan Pablo Costabel, Thomas Nestelberger, Roberto Campos, Desiree Wussler, Rosina Arbucci, Marcia Cortes, Jasper Boeddinghaus, Benjamin Baumgartner, Christian H. Nickel, Roland Bingisser, Patrick Badertscher, Christian Puelacher, Jeanne du Fay de Lavallaz, Karin Wildi, Maria Rubini Giménez, Joan Walter, Mario Meier, Benjamin Hafner, Pedro Lopez Ayala, Jens Lohrmann, Valentina Troester, Luca Koechlin, Tobias Zimmermann, Danielle M. Gualandro, Tobias Reichlin, Florencia Lambardi, Silvana Resi, Alberto Alves de Lima, Marcelo Trivi, Christian Mueller
Journal: Journal of the American College of Cardiology (2019)
A physical biomarker of the quality of cultured corneal endothelial cells and of the long-term prognosis of corneal restoration in patients
Authors: Akihisa Yamamoto, Hiroshi Tanaka, Munetoyo Toda, Chie Sotozono, Junji Hamuro, Shigeru Kinoshita, Morio Ueno, Motomu Tanaka
Journal: Nature Biomedical Engineering (2019)
Adverse changes in body composition of cancer surivors with BRCA mutations.
Authors: Aileen Caceres
Journal: Journal of Clinical Oncology (2013)

e12514 Background: Post-diagnosis weight gain is a risk factor for cancer recurrence and many individuals diagnosed with breast and ovarian cancer gain weight during and after treatment. In the present study, we have measured the anthropometrics of cancer survivors with BRCA mutations and have studied the association between anthropometrics and post-diagnosis weight gain. Methods: The study population included 37 breast and ovarian cancer survivors with BRCA mutations, 45 BRCA previvors, and 26 controls. Anthropometric measurements included body mass index (BMI; kg weight/ m 2 height) and body composition (% fat and lean tissue, assessed by using 4-lead bioelectric impedance). Post-diagnosis weight gain was determined via questionnaire. Potential effectors of anthropometrics included: diet (3-day food records), physical activity (General Practice Physical Activity Questionnaire), physical health (co-morbidities, Rand-36 Physical Health Quality of Life (QoL)), and psychological status (Beck Anxiety Inventory, Rand-36 Emotional Health QoL). Results: We found no significant differences in BMI between the survivors, previvors or controls (26+2 (SEM), 25+1, 25+1, respectively). However, the % lean body mass of the cancer survivors was significantly lower and their % body fat significantly higher than the previvors or controls (p=0.0005). Measures of body composition (% fat and lean mass) were independent predictors of post-diagnosis weight gain (r=0.86, p&lt;0.001). No significant association was found between body composition measures and psychological status, energy intake or food composition. However, the adverse body composition measures of the survivors were associated significantly with physical inactivity (p&lt;0.01), number of co-morbidities (p&lt;0.0001), and physical health QoL (p&lt;0.01). Conclusions: BRCA cancer survivors have adverse changes in body composition that increase their risk for weight gain and disease relapse. Based upon these findings, it is important for the survivorship care plan to include: 1) education regarding post-diagnosis weight gain, 2) a physical activity regimen, 3) health management, and 4) interval assessment of anthropometrics, including body composition, during and after treatment.
Incidence and risk factors of dysphagia after variceal band ligation
Authors: Saraswathi Arasu, Hammad Liaquat, Jaspreet Suri, Adam C. Ehrlich, Frank K. Friedenberg
Journal: Clinical and Molecular Hepatology (2019)

There is a lack of data on long-term morbidity, particularly dysphagia, following endoscopic variceal band ligation (EVL). The aim of this study are to assess the incidence of dysphagia and variables associated with this complication after EVL.We identified individuals who completed at least one session of EVL as their sole treatment for varices from August 2012 to December 2017. Included patients achieved "complete eradication" of varices not requiring further therapy. Patients ≥90 days from their last EVL session completed a modified version of the Mayo Clinic Dysphagia Questionnaire. Individuals with dysphagia were invited to undergo a barium esophagram. Patients with pre-EVL dysphagia were excluded.Of the patients, 68 possessed inclusion criteria, nine (13.2%) died and 20 (29.4%) were lost to follow up. For the remaining 39 (57.4%) patients, 23 were males, mean age of 61.7±8.6 years. The most common etiology of liver disease was hepatitis C virus (n=18; 46.2%). The median number of banding sessions was 2.0 (interquartile range [IQR], 1.0-4.0) with a median of 9.0 bands placed (IQR, 3.0-14.0). Twelve patients (30.8%) developed new-onset dysphagia post-EVL. In univariate analysis, pre-EVL MELD score and non-emergent initial banding were associated with long-term dysphagia. In a regression model adjusted for age, sex, number of bands, and use of acid suppression after EVL, no factor was independently associated with dysphagia (all P>0.05). No strictures were identified on subsequent esophageal evaluation.Approximately 30% of patients developed new-onset, chronic dysphagia post-EVL. Incident dysphagia was associated with a non-emergent initial banding session. The mechanism for dysphagia remains unknown.
Peroral endoscopic myotomy regains anatomical structure and improves emptying for achalasia with multiple esophageal diverticula
Authors: Xin-Yang Liu, Quan-Lin Li, Tai-Wei Jiao, Ming-Jun Sun, Ping-Hong Zhou
Journal: Endoscopy (2019)

See also:Reply to Jacobs et al.Endoscopy 2020; 52(02): 154-154DOI: 10.1055/a-1026-6084See also:Two birds, one scope: peroral endoscopic myotomy as a treatment for achalasia and esophageal diverticulaEndoscopy 2020; 52(02): 153-153DOI: 10.1055/a-1024-4062
Endoscopic ultrasound-guided pancreatic duct drainage using a novel fine-gauge electrocautery dilator
Authors: Koichiro Mandai, Koji Uno, Kenjiro Yasuda
Journal: Endoscopy (2019)

Endoscopic ultrasound-guided pancreatic duct drainage (EUS-PD) is an alternative technique that can be performed after endoscopic transpapillary pancreatic duct drainage fails [1]. During EUS-PD procedures, needle tract dilation remains a challenge. Recently, a novel fine-gauge electrocautery dilator (Fine025; Medico’s Hirata Inc., Osaka, Japan) has become available in Japan ([Fig. 1]). The distal end of the outer dilator contains a metal tip. The top of this tip is only 3 Fr, allowing a smaller burning effect [2]. We describe EUS-PD using this dilator in a patient with hard pancreatic parenchyma.
Lifetime Risk and Heritability of Amyotrophic Lateral Sclerosis
Authors: Marie Ryan, Mark Heverin, Russell L. McLaughlin, Orla Hardiman
Journal: JAMA Neurology (2019)

Heritability describes the proportion of variance in the risk of developing a condition that is explained by genetic factors. Although amyotrophic lateral sclerosis (ALS) is known to have a complex genetic origin, disease heritability remains unclear.To determine the extent of ALS heritability and assess the association of sex with disease transmission.A prospective population-based parent-offspring heritability study was conducted from January 1, 2008, to December 31, 2017 to assess ALS heritability, and was the first study to assess heritability in the context of known gene mutations of large effect. A total of 1123 incident cases of ALS, diagnosed according to the El Escorial criteria and recorded on the Irish ALS register, were identified. Ninety-two individuals were excluded (non-Irish parental origin [n = 86] and familial ALS [n = 6]), and 1117 patients were included in the final analysis.Annual age-specific and sex-specific standardized ALS incidence and mortality-adjusted lifetime risk were determined. Sex-specific heritability estimates were calculated for the overall study cohort, for those known to carry the C9orf72 (OMIM 614260) variant, and for those with no known genetic risk.A total of 32 parent-child ALS dyads were identified during the study period. Affected offspring were younger at the onset of disease (mean age, 52.0 years; 95% CI, 48.8-55.3 years) compared with their parents (mean age, 69.6 years; 95% CI, 62.4-76.9 years; P = .008). Lifetime risk of developing ALS in first-degree relatives of individuals with ALS was increased compared with the general population (1.4% [32 of 2234] vs 0.3% [2.6 of 1000]; P < .001). Mean lifetime heritability of ALS for the overall study cohort was 52.3% (95% CI, 42.9%-61.7%) and 36.9% (95% CI, 19.8%-53.9%) for those with no known genetic risk. Heritability estimates were highest in mother-daughter pairings (66.2%; 95% CI, 58.5%-73.9%).This population-based study confirms that up to 50% of variance in ALS has a genetic basis, and that the presence of the C9orf72 variant is an important determinant of heritability. First-degree relatives of individuals with ALS without a known genetic basis remain at increased risk of developing ALS compared with the general population. A higher heritability estimate in mother-daughter pairings points to a sex-mediated effect that has been previously unrecognized.
Novel epigenetic, quantitative, and qualitative insights on the socialness of autism
Authors: William Michael Brown, Ewan Foxley-Webb
Journal: Behavioral and Brain Sciences (2019)

Abstract Three complementary points to Jaswal &amp; Akhtar are raised: (1) As a person with autism, I desire sociality despite vulnerability to others’ antisocial behaviour; (2) Asperger's conflation of autism with psychopathy (Czech 2018) likely caused clinicians to disregard social motivation among those with autism; and (3) adverse experiences cause social-engagement diversity to develop in all people, not just those on the spectrum.
HIV: dolutegravir should be preferred treatment option in all populations, says WHO
Authors: Gareth Iacobucci
Journal: BMJ (2019)

The World Health Organization has recommended that the HIV drug dolutegravir (DTG) be the preferred first line and second line treatment for all populations, after new evidence showed that potential risks to pregnant women and those of childbearing potential is lower than previously thought.

Concerns about a possible link between DTG and neural tube defects in infants born to women using the drug at the …
Spread of α-synuclein pathology through the brain connectome is modulated by selective vulnerability and predicted by network analysis
Authors: Michael X. Henderson, Eli J. Cornblath, Adam Darwich, Bin Zhang, Hannah Brown, Ronald J. Gathagan, Raizel M. Sandler, Danielle S. Bassett, John Q. Trojanowski, Virginia M. Y. Lee
Journal: Nature Neuroscience (2019)
Expansion of the Concept of Micropapillary Adenocarcinoma to Include a Newly Recognized Filigree Pattern as Well as the Classical Pattern Based on 1468 Stage I Lung Adenocarcinomas
Authors: Katsura Emoto, Takashi Eguchi, Kay See Tan, Yusuke Takahashi, Rania G. Aly, Natasha Rekhtman, William D. Travis, Prasad S. Adusumilli
Journal: Journal of Thoracic Oncology (2019)
A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of SCH 727965, a novel cyclin-dependent kinase inhibitor, administered weekly in subjects with advanced malignancies
Authors: J. Nemunaitis, M. Saltzman, M. A. Rosenberg, D. Khaira, K. Small, P. Kirschmeier, P. Statkevich, M. Abutarif, S. Yao, R. Bannerji
Journal: Journal of Clinical Oncology (2009)

3535 Background: SCH 727965 is a potent and selective inhibitor of the cyclin-dependent kinases CDK1,2,5 and 9 with IC 50 's of &lt; 5nM. SCH 727965 induces apoptosis in a broad array of tumor cell lines, causes tumor growth inhibition or regression in various xenograft models, and has a greater therapeutic index than flavopiridol in an in vivo screening model. SCH 727965 was advanced into clinical trials. Methods: SCH 727965 was administered by 2-hour IV infusion on days 1, 8 and 15 of a 28-day cycle. Doses were escalated with an accelerated titration algorithm to define the maximally administered dose (MAD) and the recommended phase 2 dose (RPTD). PD assessments included an ex vivo PHA lymphocyte stimulation assay, skin biopsies for IHC measurement of retinoblastoma protein phosphorylation, and functional imaging using FDG-PET/CT scans. PK and PD data were obtained during Cycle 1. Results: 43 subjects have been treated at doses ranging from 0.33 to 14 mg/m 2 . The most common treatment-emergent adverse events were nausea, anemia, and fatigue. The MAD was 14 mg/m 2 defined by a DLT of grade 3 hypotension in one subject and transient grade 4 hyperuricemia in another subject. The RPTD was 12 mg/m 2 . Grade 3 or 4 treatment related adverse events were uncommon. Grade 3 or 4 neutropenia was seen in only 3 subjects. SCH 727965 inhibition of lymphocyte proliferation was dose-dependent, indicating a PD effect, and was sustained up to 8 hours post-dose at the RPTD. Drug exposure was dose-proportional. SCH 727965 was rapidly eliminated with a terminal half-life of 1.5 to 3 hours. No objective responses by RECIST criteria have yet been observed although PET SUV signal decreases as large as &gt;30% have been observed in some subjects. Conclusions: SCH 727965 is safe and well tolerated at the recommended phase 2 dose of 12 mg/m 2 . The AE profile of weekly dosing differed from that seen in an every -21 day dosing schedule, and plasma concentrations at the RPTD or lower doses were above those required for in vivo efficacy in xenograft tumor models. PD activity was verified in an ex vivo lymphocyte proliferation assay, and preliminary changes on PET/CT suggest drug related modulation of tumor metabolic activity. [Table: see text]
Rare Germline Variant in NFATC4 Associated with Familial Chronic Lymphocytic Leukemia
Authors: Gilad Itchaki, Grace Tiao, Ma Reina D. Improgo, Siddha Kasar, Bethany Tesar, Stacey Marie Fernandes, Nathalie Pochet, Emily M McWilliams, Harrison Bai, Arnold S. Freedman, Gad Getz, Jennifer R. Brown
Journal: Blood (2017)
Structure-guided drug design identifies a BRD4-selective small molecule that suppresses HIV
Authors: Qingli Niu, Zhiqing Liu, Edrous Alamer, Xiuzhen Fan, Haiying Chen, Janice Endsley, Benjamin B. Gelman, Bing Tian, Jerome H. Kim, Nelson L. Michael, Merlin L. Robb, Jintanat Ananworanich, Jia Zhou, Haitao Hu
Journal: Journal of Clinical Investigation (2019)

HIV integrates its provirus into the host genome and establishes latent infection. Antiretroviral therapy (ART) can control HIV viremia, but cannot eradicate or cure the virus. Approaches targeting host epigenetic machinery to repress HIV, leading to an aviremic state free of ART, are needed. Bromodomain and extraterminal (BET) family protein BRD4 is an epigenetic reader involved in HIV transcriptional regulation. Using structure-guided drug design, we identified a small molecule (ZL0580) that induced epigenetic suppression of HIV via BRD4. We showed that ZL0580 induced HIV suppression in multiple in vitro and ex vivo cell models. Combination treatment of cells of aviremic HIV-infected individuals with ART and ZL0580 revealed that ZL0580 accelerated HIV suppression during ART and delayed viral rebound after ART cessation. Mechanistically different from the BET/BRD4 pan-inhibitor JQ1, which nonselectively binds to BD1 and BD2 domains of all BET proteins, ZL0580 selectively bound to BD1 domain of BRD4. We further demonstrate that ZL0580 induced HIV suppression by inhibiting Tat transactivation and transcription elongation as well as by inducing repressive chromatin structure at the HIV promoter. Our findings establish a proof of concept for modulation of BRD4 to epigenetically suppress HIV and provide a promising chemical scaffold for the development of probes and/or therapeutic agents for HIV epigenetic silencing.