tbuckley/cabot-search huggingface dataset:
Pancreas Volume Declines During the First Year After Diagnosis of Type 1 Diabetes and Exhibits Altered Diffusion at Disease Onset
Authors: John Virostko, Jon Williams, Melissa Hilmes, Chris Bowman, Jordan J. Wright, Liping Du, Hakmook Kang, William E. Russell, Alvin C. Powers, Daniel J. Moore
Journal: Diabetes Care (2018)

OBJECTIVE This study investigated the temporal dynamics of pancreas volume and microstructure in children and adolescents with recent-onset type 1 diabetes (T1D) and individuals without diabetes, including a subset expressing autoantibodies associated with the early stages of T1D. RESEARCH DESIGN AND METHODS MRI was performed in individuals with recent-onset stage 3 T1D (n = 51; median age 13 years) within 100 days after diagnosis (mean 67 days), 6 months, and 1 year postdiagnosis. Longitudinal MRI measurements were also made in similarly aged control participants (n = 57) and in autoantibody-positive individuals without diabetes (n = 20). The MRI protocol consisted of anatomical imaging to determine pancreas volume and quantitative MRI protocols interrogating tissue microstructure and composition. RESULTS Within 100 days of diabetes onset, individuals with T1D had a smaller pancreas (median volume 28.6 mL) than control participants (median volume 48.4 mL; P &amp;lt; 0.001), including when normalized by individual weight (P &amp;lt; 0.001). Longitudinal measurements of pancreas volume increased in control participants over the year, consistent with adolescent growth, but pancreas volume declined over the first year after T1D diagnosis (P &amp;lt; 0.001). In multiple autoantibody–positive individuals, the pancreas volume was significantly larger than that of the T1D cohort (P = 0.017) but smaller than that of the control cohort (P = 0.04). Diffusion-weighted MRI showed that individuals with recent-onset T1D had a higher apparent diffusion coefficient (P = 0.012), suggesting a loss of cellular structural integrity, with heterogeneous pancreatic distribution. CONCLUSIONS These results indicate that pancreas volume is decreased in stages 1, 2, and 3 of T1D and decreases during the first year after diabetes onset and that this loss of pancreatic volume is accompanied by microstructural changes.
Virtual reality simulator versus box-trainer to teach minimally invasive procedures: A meta-analysis
Authors: Hugo Gonçalo Guedes, Zêmia Maria Câmara Costa Ferreira, Layra Ribeiro de Sousa Leão, Edna Frasson Souza Montero, José Pinhata Otoch, Everson Luiz de Almeida Artifon
Journal: International Journal of Surgery (2018)
Advances in developing novel therapeutic strategies for Alzheimer’s disease
Authors: Jiqing Cao, Jianwei Hou, Jing Ping, Dongming Cai
Journal: Molecular Neurodegeneration (2018)

Alzheimer’s Disease (AD), the most prevalent neurodegenerative disease of aging, affects one in eight older Americans. Nearly all drug treatments tested for AD today have failed to show any efficacy. There is a great need for therapies to prevent and/or slow the progression of AD. The major challenge in AD drug development is lack of clarity about the mechanisms underlying AD pathogenesis and pathophysiology. Several studies support the notion that AD is a multifactorial disease. While there is abundant evidence that amyloid plays a role in AD pathogenesis, other mechanisms have been implicated in AD such as tangle formation and spread, dysregulated protein degradation pathways, neuroinflammation, and loss of support by neurotrophic factors. Therefore, current paradigms of AD drug design have been shifted from single target approach (primarily amyloid-centric) to developing drugs targeted at multiple disease aspects, and from treating AD at later stages of disease progression to focusing on preventive strategies at early stages of disease development. Here, we summarize current strategies and new trends of AD drug development, including pre-clinical and clinical trials that target different aspects of disease (mechanism-based versus non-mechanism based, e.g. symptomatic treatments, lifestyle modifications and risk factor management).
Widespread RNA editing dysregulation in brains from autistic individuals
Authors: Stephen S. Tran, Hyun-Ik Jun, Jae Hoon Bahn, Adel Azghadi, Gokul Ramaswami, Eric L. Van Nostrand, Thai B. Nguyen, Yun-Hua E. Hsiao, Changhoon Lee, Gabriel A. Pratt, Verónica Martínez-Cerdeño, Randi J. Hagerman, Gene W. Yeo, Daniel H. Geschwind, Xinshu Xiao
Journal: Nature Neuroscience (2018)
Third Molar Extraction and Persistent Use of Opioids—Reply
Authors: Chad M. Brummett, Calista Harbaugh, Romesh P. Nalliah
Journal: JAMA (2018)

In Reply Dr Ferguson and colleagues raised concerns about our study demonstrating an association between perioperative opioid prescribing and new persistent opioid use in opioid-naive adolescents and young adults undergoing third molar (wisdom tooth) extraction.1
Abstract 19004: Contact Force Recovery Predicts Absence of Cardiac Perforation During Steam Pop Formation
Authors: Anand V Ganapathy, Alireza Nazeri, Krithika S Ganapathy, Mehdi Razavi
Journal: Circulation (2015)

Introduction: Cardiac perforations (CP) are an uncommon complication of radiofrequency ablation (RFA) that has profound clinical importance. We previously published results showing that the presence of contact force recovery after a steam pop occurs can be used to predict the absence of perforation in the absence of pericardium. Now, we aimed to determine if this relationship exists with the pericardium present, validate our results from the previous study, and determine the effects pericardium has on RFA. Methods: A 7.5F Thermocool Smarttouch force-sensing catheter (Biosense Webster Inc., Diamond Bar, CA) was used to perform left atrial RFA under direct observation in five open-chest sheep. The catheter’s contact force was measured every 50 ms during RFA. After each steam pop, the presence (+) or absence (-) of CP was noted as well as if pericardium was present or not over the ablation site. The contact force signals were then analyzed to determine if contact force recovery was present. In addition, the rate of perforation in the presence or absence of pericardium was also compared. Results: A total of 86 steam pops occurred (Table 1); 62 with pericardium and 24 without pericardium. For the pericardial data, contact force recovery was seen in 16 of the 49 CP- cases (33%) and 0 of the 13 CP+ cases (0%), p = 0.03. For the nonpericardial data, contact force recovery was seen in 6 of the 14 CP- cases (43%) and 0 of the 10 CP+ cases (0%), p = 0.02. The rate of cardiac perforation was 21% with pericardium and 42% without, p = 0.05. Pericardial tissue showed extensive charring during steam pops, even in the absence of CP. Conclusions: Contact-force recovery predicts the absence of CP during RFA independent of the presence or absence of the pericardium, confirming prior work. Our results suggest the pericardium decreases the likelihood of perforation, perhaps by acting as a thermal sink. Further studies are needed to correlate these results with clinical experiences.
Evaluation of Sustained Minimal Residual Disease (MRD) Negativity in Relapsed/Refractory Multiple Myeloma (RRMM) Patients (Pts) Treated with Daratumumab in Combination with Lenalidomide Plus Dexamethasone (D-Rd) or Bortezomib Plus Dexamethasone (D-Vd): Analysis of Pollux and Castor
Authors: Hervé Avet-Loiseau, Jesus F San-Miguel, Tineke Casneuf, Shinsuke Iida, Sagar Lonial, Saad Z. Usmani, Andrew Spencer, Philippe Moreau, Torben Plesner, Katja Weisel, Jon Ukropec, Linda Okonkwo, Sonali Trivedi, Christopher Joseph Velas, Xiang Qin, Ming Qi, Christopher Chiu, Nizar Bahlis
Journal: Blood (2018)
Abstract 19331: Quantification of Tethering Patterns in Secondary Mitral Regurgitation by 3D Echocardiography Mitral Valve Mapping
Authors: Romain Capoulade, Christos G Mihos, Mark D Handschumacher, Jonathan G Teoh, Xin Zeng, Yong H Park, Philipp E Bartko, David A D’Alessandro, Serguei Melnitchouk, Robert A Levine, Judy W Hung
Journal: Circulation (2016)

Background: Secondary mitral regurgitation (SMR) results from mitral valve (MV) tethering, typically quantified globally as total area or volume. However, MV tethering pattern is often heterogeneous. We aimed to develop and quantify regional MV tethering “maps” in patients with SMR using 3D transesophageal echocardiography (TEE). Methods: Thirty three patients with ≥moderate SMR and 19 controls underwent 3D TEE and analyses (Omni4D). MV annulus, leaflet area, coaptation line and tenting height (TH: distance between the annular plane and leaflets) were measured at mid-systole (fig A). Anterior (AL) and posterior (PL) mitral leaflets were divided into three equal segments (A1, A2, A3 and P1, P2, P3) to assess regional MV tethering patterns and leaflet area, and to identify the location of maximal TH (maxTH) (fig A). Results: Patients with SMR had significantly larger 3D leaflet area and tenting height for both leaflets, as well as for all individual segments of both leaflets (fig B). The leaflet area was 32...
Muscle Expression of Type I and Type <scp>II</scp> Interferons Is Increased in Juvenile Dermatomyositis and Related to Clinical and Histologic Features
Authors: Gian Marco Moneta, Denise Pires Marafon, Emiliano Marasco, Silvia Rosina, Margherita Verardo, Chiara Fiorillo, Carlo Minetti, Luisa Bracci‐Laudiero, Angelo Ravelli, Fabrizio De Benedetti, Rebecca Nicolai
Journal: Arthritis & Rheumatology (2018)

Objective To evaluate the expression of type I interferon ( IFN α/β)– and type II IFN ( IFN γ)–inducible genes in muscle biopsy specimens from patients with juvenile dermatomyositis ( DM ) and to correlate their expression levels with histologic and clinical features. Methods Expression levels of IFN ‐inducible genes and proinflammatory cytokines were assessed by quantitative polymerase chain reaction in muscle biopsy specimens from patients with juvenile DM (n = 39), patients with Duchenne's muscular dystrophy ( DMD ), and healthy controls. Muscle biopsy sections were stained and scored for severity of histopathologic features. The charts of patients with juvenile DM were reviewed for clinical features at the time of sampling and long‐term outcomes. Results Muscle expression levels of IFN α/β‐inducible genes (type I IFN score), IFN γ, IFN γ‐inducible genes (type II IFN score), and tumor necrosis factor ( TNF ) were significantly higher in juvenile DM patients not receiving glucocorticoid therapy before muscle biopsy (n = 27) compared to DMD patients (n = 24) (type I IFN score, P &lt; 0.0001; type II IFN score, P &lt; 0.001; TNF, P &lt; 0.05) and healthy controls (n = 4) (type I IFN score, P &lt; 0.01; type II IFN score, P &lt; 0.01; TNF, P &lt; 0.05). Immunofluorescence staining of muscle biopsy sections from untreated juvenile DM patients showed increased immunoreactivity for IFN γ and HLA class II molecules compared to controls. Type I and type II IFN scores were correlated with typical histopathologic features of juvenile DM muscle biopsy samples, such as infiltration of endomysial CD3+ cells (type I IFN score, r = 0.68; type II IFN score, r = 0.63), perimysial CD3+ cells (type I IFN score, r = 0.59; type II IFN score, r = 0.66), CD68+ cells (type II IFN score, r = 0.46), and perifascicular atrophy (type I IFN score, r = 0.61; type II IFN score, r = 0.77). Juvenile DM patients with a high type I IFN score, a high type II IFN score, and high TNF expression levels showed more severe disease activity at biopsy ( P &lt; 0.05). In addition, juvenile DM patients with a high type II IFN score at biopsy reached clinically inactive disease significantly later than patients with low type II IFN score (log rank chi‐square value 13.53, P &lt; 0.001). Conclusion The increased expression of IFN ‐inducible genes in the muscle in juvenile DM patients and their association with histologic and clinical features further support a pathogenic role for both type I and type II IFN s in juvenile DM .
Molecules targeting the androgen receptor (AR) signaling axis beyond the AR‐Ligand binding domain
Authors: N. G. R. Dayan Elshan, Matthew B. Rettig, Michael E. Jung
Journal: Medicinal Research Reviews (2018)

Prostate cancer (PCa) is the second most common cause of cancer-related mortality in men in the United States. The androgen receptor (AR) and the physiological pathways it regulates are central to the initiation and progression of PCa. As a member of the nuclear steroid receptor family, it is a transcription factor with three distinct functional domains (ligand-binding domain [LBD], DNA-binding domain [DBD], and transactivation domain [TAD]) in its structure. All clinically approved drugs for PCa ultimately target the AR-LBD. Clinically active drugs that target the DBD and TAD have not yet been developed due to multiple factors. Despite these limitations, the last several years have seen a rise in the discovery of molecules that could successfully target these domains. This review aims to present and comprehensively discuss such molecules that affect AR signaling through direct or indirect interactions with the AR-TAD or the DBD. The compounds discussed here include hairpin polyamides, niclosamide, marine sponge-derived small molecules (eg, EPI compounds), mahanine, VPC compounds, JN compounds, and bromodomain and extraterminal domain inhibitors. We highlight the significant in vitro and in vivo data found for each compound and the apparent limitations and/or potential for further development of these agents as PCa therapies.
Abstract P013: Prevalence, Correlates and Prognosis of Healthy Vascular Aging in a Western Community-dwelling Population
Authors: Teemu Niiranen, Asya Lyass, Martin Larson, Naomi Hamburg, Emelia Benjamin, Gary Mitchell, Ramachandran Vasan
Journal: Circulation (2017)

Introduction: Although hypertension in the elderly is no longer considered harmless, increasing arterial stiffness and blood pressure (BP) are still widely seen as inevitable parts of the aging process. However, these phenomena may not be unavoidable as they are nearly absent in populations leading traditional hunter-gatherer lifestyles. Our study had 3 aims: 1) to define a new concept - healthy vascular aging (HVA); 2) to assess prevalence and correlates of HVA in a sample acculturated to a western life-style; and 3) to estimate the magnitude of cardiovascular (CVD) risk associated with HVA vs. absence of HVA. Methods: We studied 3197 Framingham Heart Study participants aged ≥50 years (62±9 years, 56% women) who underwent physical examination, interviews, and measurement of carotid-femoral pulse wave velocity (PWV) in 1999-2008. We defined HVA as no hypertension (BP &lt;140/90 mmHg without antihypertensive treatment) and PWV &lt;7.6 m/s (equivalent to +2 SD above mean of non-hypertensive reference sample aged &lt;30 years with no CVD risk factors). We used logistic regression models that included physical activity, caloric intake, and classical CVD factors as covariates to assess the correlates of HVA. For each participant, we constructed a cardiovascular health score based on presence vs. absence of 6 modifiable risk factors (cholesterol, plasma glucose, healthy diet score, physical activity, body mass index (BMI), and smoking) defined as dichotomous variables according to the American Heart Association’s Life’s Simple 7 score (modified to exclude hypertension). We estimated odds ratios (OR) per 1-unit increase in cardiovascular health score for HVA. We used Cox regression models adjusted for classical CVD risk factors, including systolic BP, to assess the relationship between HVA and incident CVD events (CVD death, myocardial infarction, heart failure, stroke, and unstable angina). Results: In our sample, only 566 (17.7%) had HVA. Lower age (OR per 1-SD increase 0.18, 95% confidence interval [CI] 0.14-0.23), female sex (OR 2.03; 95% CI 1.54-2.68), lower BMI (OR per 1-SD increase 0.54; 95% CI 0.47-0.63) and no diabetes (OR 0.09; 95% CI 0.02-0.36) were significantly associated with HVA. A 1-unit increase in the cardiovascular health score conferred 1.55-fold (95% CI 1.38-1.74) odds of HVA. During follow-up (median 9.6 years), 391 participants had CVD events. HVA was associated with an age- and sex-adjusted hazard ratio (HR) of 0.36 (95% CI, 0.22-0.60) and a multivariable-adjusted HR of 0.45 (95% CI, 0.26-0.77) for CVD relative to absence of HVA. Conclusions: One in 6 individuals experiences HVA in our sample. Individuals with HVA are at a considerably low risk of CVD. Prevention strategies targeting modifiable factors and behaviors included in Life’s Simple 7 are important for preventing or delaying vascular aging and the associated risk of CVD.
Chronic Myeloid Leukemia Diagnosed during Pregnancy: Therapy, Outcomes and Follow-up
Authors: Ekaterina Chelysheva, Elisabetta Abruzzese, Delphine Rea, Dong-Wook Kim, Khamida Kazakbaeva, Sukhrob Saliev, Konstantin Kotlyarchuk, Evgenia Polushkina, Roman Shmakov, Julia Chabaeva, Sergei M. Kulikov, Anna G Turkina
Journal: Blood (2018)
Abstract 12457: Carotid Intima-Media Thickness and Aortic Stiffness are Elevated in Chronic Obstructive Pulmonary Disease (COPD) Subjects Compared to Controls and Not Associated With Systemic Inflammation
Authors: Marie Fisk, Kaisa Mäki Petäjä, Nichola Gale, Divya Mohan, Joseph Cheriyan, John R Cockcroft, Julia Forman, Ruth Tal-Singer, Michael I Polkey, Carmel M McEniery, Ian B Wilkinson
Journal: Circulation (2015)

Introduction: COPD is associated with increased cardiovascular risk, independent of established risk factors. Carotid intima thickness (CIMT) and carotid-femoral aortic pulse wave velocity (aPWV) are surrogate measures of cardiovascular risk and small studies have suggested elevated CIMT and aPWV in COPD are associated with systemic inflammation. We investigated this further as part of the ERICA (Evaluation of Role of Inflammation in Chronic Airways disease) multi-centre UK study: the largest cohort study focussing on cardiovascular manifestations in COPD. Hypothesis: COPD subjects have increased CIMT and aPWV compared to controls and CIMT and aPWV are associated with systemic inflammation in COPD. Methods: Spirometry, cardiovascular history and assessment, CIMT and haemodynamic measures including aPWV were performed in 432 COPD patients recruited from Cambridge and Cardiff study centres only. Age and gender matched healthy controls (n=324) were evaluated for comparison. Possible determinants for CIMT and aPWV in COPD subjects were assessed by linear regression analysis. Results: Mean age of COPD and control subjects was 67 years (SEM±0.41), 61% were male. COPD subjects, when compared to controls had increased CIMT (0.85±0.01mm vs 0.70 ±0.08mm, p=0.0001) and aPWV (10.35±0.12m/s vs 8.22 ±0.1m/s, p=0.0001), which were maintained after adjustment for mean arterial pressure (MAP) and heart rate (HR). COPD subjects also had higher brachial systolic BP (Δ 12±0.2mmHg, p=0.0001), and central systolic BP (Δ 12±0.2mmHg, p=0.0001). COPD was an independent determinant of CIMT and aPWV in pooled analysis of COPD and controls (p=0.0001 respectively). In COPD, age and systolic BP were independently associated with CIMT; and age, MAP and HR were determinants of aPWV. Inflammatory markers (fibrinogen, CRP, WCC), smoking status and pack years smoked were not associated with CIMT or aPWV. Conclusions: These data support the theory of accelerated ageing in COPD subjects compared to matched controls, which may partly explain the excess cardiovascular risk seen. As systemic inflammatory biomarkers did not relate to CIMT or aPWV, consideration of novel therapeutic targets to ameliorate premature arterial stiffening in COPD, merits further investigation.
Allele-Specific Methylation of <i>SPDEF</i>: A Novel Moderator of Psychosocial Stress and Substance Abuse
Authors: Nicole Tay, Christine Macare, Yun Liu, Barbara Ruggeri, Tianye Jia, Congying Chu, Francesca Biondo, Alex Ing, Qiang Luo, Daniil Sarkysian, Tobias Banaschewski, Gareth J. Barker, Arun L.W. Bokde, Uli Bromberg, Christian Büchel, Erin Burke Quinlan, Sylvane Desrivières, Herta Flor, Vincent Frouin, Hugh Garavan, Penny Gowland, Andreas Heinz, Bernd Ittermann, Jean-Luc Martinot, Eric Artiges, Frauke Nees, Dimitri Papadopoulos Orfanos, Tomáš Paus, Luise Poustka, Sarah Hohmann, Juliane H. Fröhner, Michael N. Smolka, Henrik Walter, Robert Whelan, Helge Frieling, Stefan Bleich, Edward D. Barker, Ann-Christine Syvänen, Joëlle Rüegg, Tomas J. Ekström, Georgy Bakalkin, Gunter Schumann
Journal: American Journal of Psychiatry (2018)

Psychosocial stress is a key risk factor for substance abuse among adolescents. Recently, epigenetic processes such as DNA methylation have emerged as potential mechanisms that could mediate this relationship. The authors conducted a genome-wide methylation analysis to investigate whether differentially methylated regions are associated with psychosocial stress in an adolescent population.A methylome-wide analysis of differentially methylated regions was used to examine a sample of 1,287 14-year-old adolescents (50.7% of them female) from the European IMAGEN study. The Illumina 450k array was used to assess DNA methylation, pyrosequencing was used for technical replication, and linear regression analyses were used to identify associations with psychosocial stress and substance use (alcohol and tobacco). Findings were replicated by pyrosequencing a test sample of 413 participants from the IMAGEN study.Hypermethylation in the sterile alpha motif/pointed domain containing the ETS transcription factor (SPDEF) gene locus was associated with a greater number of stressful life events in an allele-dependent way. Among individuals with the minor G-allele, SPDEF methylation moderated the association between psychosocial stress and substance abuse. SPDEF methylation interacted with lifetime stress in gray matter volume in the right cuneus, which in turn was associated with the frequency of alcohol and tobacco use. SPDEF was involved in the regulation of trans-genes linked to substance use.Taken together, the study findings describe a novel epigenetic mechanism that helps explain how psychosocial stress exposure influences adolescent substance abuse.
Loss of ABAT-Mediated GABAergic System Promotes Basal-Like Breast Cancer Progression by Activating Ca<sup>2+</sup>-NFAT1 Axis
Authors: Xingyu Chen, Qianhua Cao, Ruocen Liao, Xuebiao Wu, Shining Xun, Jian Huang, Chenfang Dong
Journal: Theranostics (2018)

Basal-like breast cancer (BLBC) is the most aggressive subtype with a poor clinical outcome; however, the molecular mechanisms underlying aggressiveness in BLBC remain poorly understood. Methods: The effects of gamma-aminobutyrate aminotransferase (ABAT) on GABA receptors, Ca2+-NFAT1 axis, and cancer cell behavior were assessed by Ca2+ imaging, Western blotting, immunostaining, colony formation, and migration and invasion assays. We elucidated the relationship between ABAT and Snail by luciferase reporter and ChIP assays. The effect of ABAT expression on BLBC cells was determined by in vitro and in vivo tumorigenesis and a lung metastasis mouse model. Results: We showed that, compared to other subtypes, ABAT was considerably decreased in BLBC. Mechanistically, ABAT expression was downregulated due to Snail-mediated repression leading to increased GABA production. GABA then elevated intracellular Ca2+ concentration by activating GABA-A receptor (GABAA), which contributed to the efficient activation of NFAT1 in BLBC cells. ABAT expression resulted in inhibition of tumorigenicity, both in vitro and in vivo, and metastasis of BLBC cells. Thus, loss of ABAT contributed to BLBC aggressiveness by activating the Ca2+-NFAT1 axis. In breast cancer patients, loss of ABAT expression was strongly correlated with large tumor size, high grade and metastatic tendency, poor survival, and chemotherapy resistance. Conclusions: Our findings have provided underlying molecular details for the aggressive behavior of BLBC. The Snail-mediated downregulation of ABAT expression in BLBC provides tumorigenic and metastatic advantages by activating GABA-mediated Ca2+-NFAT1 axis. Thus, our results have identified potential prognostic indicators and therapeutic targets for this challenging disease.