tbuckley/cabot-search huggingface dataset:
Pancreatic Islet Transplantation in Humans: Recent Progress and Future Directions
Authors: Michael R Rickels, R Paul Robertson
Journal: Endocrine Reviews (2018)

Pancreatic islet transplantation has become an established approach to β-cell replacement therapy for the treatment of insulin-deficient diabetes. Recent progress in techniques for islet isolation, islet culture, and peritransplant management of the islet transplant recipient has resulted in substantial improvements in metabolic and safety outcomes for patients. For patients requiring total or subtotal pancreatectomy for benign disease of the pancreas, isolation of islets from the diseased pancreas with intrahepatic transplantation of autologous islets can prevent or ameliorate postsurgical diabetes, and for patients previously experiencing painful recurrent acute or chronic pancreatitis, quality of life is substantially improved. For patients with type 1 diabetes or insulin-deficient forms of pancreatogenic (type 3c) diabetes, isolation of islets from a deceased donor pancreas with intrahepatic transplantation of allogeneic islets can ameliorate problematic hypoglycemia, stabilize glycemic lability, and maintain on-target glycemic control, consequently with improved quality of life, and often without the requirement for insulin therapy. Because the metabolic benefits are dependent on the numbers of islets transplanted that survive engraftment, recipients of autoislets are limited to receive the number of islets isolated from their own pancreas, whereas recipients of alloislets may receive islets isolated from more than one donor pancreas. The development of alternative sources of islet cells for transplantation, whether from autologous, allogeneic, or xenogeneic tissues, is an active area of investigation that promises to expand access and indications for islet transplantation in the future treatment of diabetes.
Inhibitor of Differentiation-1 Sustains Mutant <i>KRAS</i>-Driven Progression, Maintenance, and Metastasis of Lung Adenocarcinoma via Regulation of a FOSL1 Network
Authors: Marta Román, Inés López, Elisabeth Guruceaga, Iosune Baraibar, Margarita Ecay, María Collantes, Ernest Nadal, Adrián Vallejo, Silvia Cadenas, Marta Echavarri-de Miguel, Jae Hwi Jang, Patxi San Martin-Uriz, Laura Castro-Labrador, Amaia Vilas-Zornoza, David Lara-Astiaso, Mariano Ponz-Sarvise, Christian Rolfo, Edgardo S. Santos, Luis E. Raez, Simona Taverna, Carmen Behrens, Walter Weder, Ignacio I. Wistuba, Silvestre Vicent, Ignacio Gil-Bazo
Journal: Cancer Research (2018)

Abstract Because of the refractory nature of mutant KRAS lung adenocarcinoma (LUAD) to current therapies, identification of new molecular targets is essential. Genes with a prognostic role in mutant KRAS LUAD have proven to be potential molecular targets for therapeutic development. Here we determine the clinical, functional, and mechanistic role of inhibitor of differentiation-1 (Id1) in mutant KRAS LUAD. Analysis of LUAD cohorts from TCGA and SPORE showed that high expression of Id1 was a marker of poor survival in patients harboring mutant, but not wild-type KRAS. Abrogation of Id1 induced G2–M arrest and apoptosis in mutant KRAS LUAD cells. In vivo, loss of Id1 strongly impaired tumor growth and maintenance as well as liver metastasis, resulting in improved survival. Mechanistically, Id1 was regulated by the KRAS oncogene through JNK, and loss of Id1 resulted in downregulation of elements of the mitotic machinery via inhibition of the transcription factor FOSL1 and of several kinases within the KRAS signaling network. Our study provides clinical, functional, and mechanistic evidence underscoring Id1 as a critical gene in mutant KRAS LUAD and warrants further studies of Id1 as a therapeutic target in patients with LUAD. Significance: These findings highlight the prognostic significance of the transcriptional regulator Id1 in KRAS-mutant lung adenocarcinoma and provide mechanistic insight into how it controls tumor growth and metastasis.
Winter pressures: moving trainees to wards in crisis must not become “normalised,” says HEE
Authors: Abi Rimmer
Journal: BMJ (2018)

Reassigning trainees to work in hospital departments under stress is acceptable “in exceptional circumstances” but should “never be seen as the preferred solution to the problem of winter pressures,” Health Education England has said in new guidance.1

However, moving trainees from a training environment to deliver services elsewhere “risks crucial training being missed or delayed, and widening gaps in the future senior workforce,” warned the trainee doctors’ group of the Academy of Medical Royal Colleges and the BMA’s Junior Doctors Committee in a joint statement.2 They said that moving trainees to deal with pressure also puts patients at risk because they were being treated by doctors working in unfamiliar settings and specialties.

HEE said that there was now “a predictable state of increased urgent and emergency care demand between December and March each year.” To maintain care of patients over this …
Abstract P060: A Point-based Prediction Model for Predicting 10-year Risk of Developing Type 2 Diabetes Mellitus in Japanese Men: Aichi Workers’ Cohort Study
Authors: Yuanying Li, Hiroshi Yatsuya, Yoshihisa Hirakawa, Atsuhiko Ota, Masaaki Matsunaga, Hilawe Esayas Haregot, Chifa Chiang, Yan Zhang, Koji Tamakoshi, Hideaki Toyoshima, Atsuko Aoyama
Journal: Circulation (2017)

Objective: Preventive services including screening for diabetes and its potential risk factorsare available to more Americans under Obamacare Preventive Care. Stratifying individuals by the predicted risk of developing type 2 diabetes mellitus (T2DM) would be useful for improving public health with efficient interventions. Although a number of T2DM prediction models have been reported, there is little evidence in East Asians, especially that from long-term follow-up studies. They are reported to have lower ability of innate insulin secretion and develop diabetes at much lower body mass index (BMI) than Caucasians and African Americans. Thus, this study aims to develop a point-based prediction model for 10-year risk of developing T2DM incidence in middle-aged Japanese men. Method: We followed 3,540 males in a worksite in Japan who were aged 35-64 years and free of diabetes in 2002 until March 31, 2015. Relationships of baseline age (continuous), BMI (&lt;23, 23- &lt;25 [reference category (Ref)], 25- &lt;27.5, ≥27.5 kg/m 2 ), current smoking status (yes, no [Ref]), alcohol consumption(0 [Ref], &lt;23, 23- &lt;46, ≥46 g/day), regular exercise of a moderate or higher intensity, an interval of ≥3 days per week, and a duration of ≥30 minutes per time (yes [Ref], no), medication use for dyslipidemia (yes, no [Ref]), family history of diabetes (having the first degree’s relatives with diabetes, not having [Ref]), serum triglycerides (&lt;150 [Ref], ≥150 mg/dl), high density lipoprotein cholesterol(≥40 [Ref], &lt;40 mg/dl), and fasting blood glucose (&lt;100 [Ref], 100- &lt;110, 110- &lt;126 mg/dl) with incidence of T2DM were examined by Cox proportional hazard model. Variables significantly associated with T2DM (p&lt;0.10) in the univariate models were simultaneously entered into a multivariate model, and backward variable selection procedure was done to determine the final multivariate model. Points were assigned for each predictor according to the method used in the Framingham Study. Result: During the median follow-up of 12.2 years, 342 males developed T2DM. The point-based model employing BMI, current smoking status, family history of diabetes, and blood levels of triglycerides and fasting blood glucose showed reasonable discrimination (c-statistics: 0.73) and goodness of fit (Hosmer-Lemeshow p=0.22). Conclusion: Our point-based prediction model showed applicability in terms of identifying middle-aged Japanese men at high risk of developing T2DM. The present findings warrants further investigations to determine whether using the point-based prediction models is effective to reduce T2DM incidence.
Cholestatic Drug‐Induced Liver Injury Caused by Mifepristone
Authors: Katalina Funke, Don C. Rockey
Journal: Hepatology (2018)

1Department of Internal MedicineMedical University of South CarolinaCharlestonSC * Address Correspondence and Reprint Requests to: Don C. Rockey, M.D. Department of Internal Medicine, Medical University of South Carolina 96 Jonathan Lucas Street, Suite 803 Charleston, SC 29425 E‐mail: [email protected] Tel.: +1‐843‐792‐2914 Fax: +1‐843‐792‐5265
The European research collaboration for Children's Interstitial Lung Disease (ChILDEU) ERS Clinical Research Collaboration
Authors: Steve Cunningham, Carlee Gilbert, Nico Schwerk
Journal: European Respiratory Journal (2018)

<b>Enhanced</b><b>clinical, parent, academic and industry engagement in the field of children9s interstitial lung diseases will help improve case ascertainment, mechanisms and therapeutic developments for these ultra-rare conditions</b>http://ow.ly/SM0I30mC3Jk
Secreted Gal-3BP is a novel promising target for non-internalizing Antibody–Drug Conjugates
Authors: Francesco Giansanti, Emily Capone, Sara Ponziani, Enza Piccolo, Roberta Gentile, Alessia Lamolinara, Antonella Di Campli, Michele Sallese, Valentina Iacobelli, Annamaria Cimini, Vincenzo De Laurenzi, Rossano Lattanzio, Mauro Piantelli, Rodolfo Ippoliti, Gianluca Sala, Stefano Iacobelli
Journal: Journal of Controlled Release (2018)

Galectin-3-binding protein (Gal-3BP) has been identified as a cancer and metastasis-associated, secreted protein that is expressed by the large majority of cancers. The present study describes a special type of non-internalizing antibody-drug-conjugates that specifically target Gal-3BP. Here, we show that the humanized 1959 antibody, which specifically recognizes secreted Gal-3BP, selectively localized around tumor but not normal cells. A site specific disulfide linkage with thiol-maytansinoids to unpaired cysteine residues of 1959, resulting in a drug-antibody ratio of 2, yielded an ADC product, which cured A375m melanoma bearing mice. ADC products based on the non-internalizing 1959 antibody may be useful for the treatment of several human malignancies, as the cognate antigen is abundantly expressed and secreted by several cancers, while being present at low levels in most normal adult tissues.
OP0072 Sleep problems and fatigue as a predictor for the onset of chronic widespread painover a 5- and 18-year perspective. a 20-year prospective study
Authors: K Aili, M. Andersson, A. Bremander, E. Haglund, I. Larsson, S. Bergman
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> If localised pain represent one end of a pain spectra, with overall better general health, chronic widespread pain (CWP) and fibromyalgia represent the other end of the spectra with worse general health and more comorbidities with other somatic diseases and mental illness. Sleep problems and fatigue are common among individuals reporting CWP and previous research indicate that sleep problems may be an important predictor for pain prognosis. <h3>Objectives</h3> The aim of this population-based study was to investigate if sleep problems and fatigue predict the onset of CWP 5 and 18 years later. <h3>Methods</h3> In order to get more stable baseline classifications of CWP, a wash-out period was used, including only individuals who had not reported CWP (according to <sup><sup>ACR 1990</sup></sup> criteria for fibromyalgia) at baseline (−98) and three years prior baseline (−95). In all, data from 1249 individuals entered the analyses for the 5 year follow-up (−03) and 791 entered for the 18 year follow-up (−16). Four parameters related to sleep (difficulties initiating sleep, maintaining sleep, early morning awakening and non-restorative sleep), and one parameter related to fatigue (SF-36 vitality scale) were investigated as predictors for CWP. Binary logistic regression analysis were used for analyses. <h3>Results</h3> All investigated parameters predicted the onset of CWP five years later (problems with initiating sleep (OR 1.91; 1.16–3.14), maintaining sleep (OR 1.85; 1.14–3.01), early awakening (OR 2.0; 1.37–3.75), non-restorative sleep (OR 2.27; 1.37–3.75) and fatigue (OR 3.70; 1.76–7.84)) in a model adjusted for age, gender, socio-economy and mental health. All parameters except problems with early awakening predicted the onset of CWP also 18 years later. In all, 785 individuals did not report any of the sleeping problems at baseline (fatigue not included), 268 reported one of the problems, 167 two, 128 three and 117 subjects reported to have all four sleep problems. Reporting all four sleep problems was significantly associated with CWP at follow-up at both time points when adjusting for age, gender, socio economy and mental health (OR 4.00; 2.03–7.91 and OR 3.95; 1.90–8.20); adjusting for age, gender, socio economy and number of pain regions (OR 2.94; 1.48–5.82 and OR 2.65; 1.24–5.64) and in a model adjusting for age, gender, socio economy and pain severity (OR 2.97;1.53–5.76; and OR 3.02;1.47–6.21) for the 5 year and 18 year follow-up respectively, compared to not reporting any of the sleep problems at baseline. <h3>Conclusions</h3> Both sleeping problems and fatigue predicts the onset of CWP 5- and 18 years later. The results highlight the importance of the assessment of sleep quality in the clinic. <h3>Disclosure of Interest</h3> None declared
Correction to our Letter to the Editor about “CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer”
Authors: Robert R J Coebergh van den Braak, John W M Martens, Jan N M Ijzermans
Journal: New England Journal of Medicine (2018)

To the Editor: In our letter to the Editor1 regarding the article by Dalerba et al.2 on the role of CDX2 expression in stage II and stage III colon cancer, we asserted that we could not confirm tha...
A comparative study elucidating the substantial functional defects of electroporated T cells relative to a mechanical SQZ-based approach
Authors: J. Hanson, J. Cole, L. Cassereau, J. Bugge, T. Ditommaso, J. Gilbert, H. Bernstein, A. Sharei
Journal: Annals of Oncology (2018)

Background: Ex vivo manipulation of primary cells is critical to the success of cell-based therapies, however, limitations of existing ex vivo delivery approaches may dramatically restrict the use of cell engineering to treat disease. Methods: We used a genome-wide approach to study optimized electroporation treatment and microfluidic cell squeezing to identify the impact of delivery technique on gene expression profiles in human T cells. To validate the microarray results, we used a multiplex cytokine analysis comprised of 42 key T cell cytokines to assess perturbation of cytokine secretion. Finally, in a direct comparison of therapeutic functionality, the efficacy of T cells edited for PD-1 via electroporation and cell squeezing was assessed using therapeutic treatment of the Eg.7 OVA tumor model. Results: We identified striking disruptions in transcript expression after treatment with electroporation (17% of genes mis-regulated, FDR q < 0.1), whereas cells treated with microfluidic squeezing had similar expression profiles to untreated control cells (0% of genes mis-regulated, FDR q < 0.1). These genetic disruptions result in concomitant perturbation of cytokine secretion including a 648-fold increase in IL-2 secretion (p < 0.01) and a 30-fold increase in IFNγ secretion (p < 0.05) in electroporated cells. Squeezing cells did not result in the non-specific secretion of any of the 42 cytokines tested. Ultimately, the effects at the transcript and protein level resulted in functional deficiencies in vivo with electroporated T cells failing to demonstrate sustained antigen-specific effector responses and tumor control. Conclusions: This work demonstrates that the delivery mechanism used to insert biomolecules affects functionality and warrants further study. The significant differences in outcomes from the two techniques underscores the importance of understanding the impact of intracellular delivery methods on cell function for research and clinical applications. Hence, for both research and therapeutic applications, the functional and safety consequences of the selected intracellular delivery technique and its impact on cell phenotype should be carefully evaluated. Legal entity responsible for the study: SQZ Biotechnologies. Funding: SQZ Biotechnologies. Disclosure: J. Hanson, J. Cole, L. Cassereau, J. Bugge, T. Ditommaso, J. Gilbert, H. Bernstein, A. Sharei: Employed by SQZ Biotech.
Abstract 17576: Platelet Activity and Effector Cell Properties: A Randomized Trial of Aspirin versus Clopidogrel in Patients With HIV on Antiretroviral Therapy
Authors: Emanuela Marcantoni, Nicole Allen, Matthew Cambria, Rebecca Dann, Meghan O’Brien, Adriana Heguy, Jeffrey S Berger
Journal: Circulation (2017)

Introduction and hypothesis: Human Immunodeficiency Virus (HIV)-infected subjects are at significant risk for cardiovascular disease (CVD), even after controlling for traditional risk factors. Func...
Abstract 19259: Dynamic Metabolomic Profiling Reveals Evidence for Metabolic Inflexibility in the Failing Heart
Authors: Jean-Paul Kovalik, Poh Ling Koh, Jianhong Ching, Carolyn S Lam, Mark Richards, Raymond Wong, Siong Sung Wong, Wan Xian Chan, Louis L Teo, Seet Yoong Loh, Dinna Soon, Hean-Yee Ong, Gerard Leong, Fazlur Rehman Jaufeerally, Nur Faezah, John Totman, Teresa Kwan, Ru San Tan, David Townsend, Angela S Koh
Journal: Circulation (2017)

Introduction: Metabolic signatures of heart failure (HF) phenotypes generally portray static, single time point differences between disease and control groups. Dynamic changes in metabolite in response to cues such as glucose loading are rarely determined in human HF studies. Methods: This was a multi-centre study that involved HF patients with reduced ejection fraction (EF) and controls. All patients underwent a protocol that involved fasting overnight, followed by an early morning oral glucose drink (75 gram). Blood sampling at (Time 1) baseline (prior to glucose drink), (ii) (Time 2) 2 hours after glucose drink, (iii) (Time 3) 3 hours after baseline were performed. Targeted high mass spectrometry measured 65 circulating acyl-carnitines in serum (nanomolar). Results: This analysis consisted of 19 subjects (mean age 53±10 years; 8 females (42%) (HF n=9 (all EF <50%); controls n=10). All subjects were non-diabetic, as confirmed by fasting glucose and glycated haemoglobin levels. At Time 1, there were sign...
Abstract 19805: Development of a Novel Human Anti-OPG Antibody That Attenuates Experimental Pulmonary Arterial Hypertension
Authors: Nadine D Arnold, Josephine A Pickworth, Joana A Carvalho, Adam T Braithwaite, James Iremonger, Laura West, Helen L Casbolt, Lewis J Renshall, Volker Germaschewski, Matthew McCourt, Holly R Evans, Philip Bland-Ward, David G Kiely, Sheila E Francis, Allan Lawrie
Journal: Circulation (2017)

Introduction: Pulmonary arterial hypertension (PAH) is a fatal disease driven by a sustained pulmonary vasoconstriction and progressive vasculopathy leading to right heart failure. Current therapie...
Assessing the Association Between GLP-1 Receptor Agonist Use and Diabetic Retinopathy Through the FDA Adverse Event Reporting System
Authors: Tiansheng Wang, Wenchao Lu, Huilin Tang, John B. Buse, Til Stürmer, Emily W. Gower
Journal: Diabetes Care (2018)

Recently, the Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6) suggested that semaglutide may increase the risk for diabetic retinopathy (DR) adverse events (AEs) compared with placebo. Other trials of glucagon-like peptide 1 receptor agonists (GLP-1RA) showed a numerically higher incidence of DR AEs for liraglutide but not exenatide. However, these trials did not systematically assess DR. Our population-based cohort study of older U.S. adults suggested that GLP-1RA use for approximately 1 year does not increase DR risk (1). As current evidence on GLP-1RA–associated DR risk is still limited, we conducted a disproportionality analysis of the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database to examine the association between GLP-1RA and DR events.

We used generic and brand names to identify GLP-1RA (exenatide, liraglutide, albiglutide, and dulaglutide) and comparator drugs in the FAERS database and Medical Dictionary for Regulatory Activities (MedDRA v21.0) preferred terms to identify DR cases (diabetic retinopathy, retinopathy, macular edema, retinopathy proliferative, retinopathy hemorrhagic, blindness, vitreous hemorrhage) from 28 April 2005 (approval date for the first GLP-1RA, exenatide) to 30 September 2017. We performed a disproportionality analysis using the reporting odds ratio (ROR) to assess whether there is a signal for a potentially increased risk of DR among GLP-1RA users. The ROR is calculated by …
PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia
Authors: Tonya M. Gilbert, Nicole R. Zürcher, Christine J. Wu, Anisha Bhanot, Baileigh G. Hightower, Minhae Kim, Daniel S. Albrecht, Hsiao-Ying Wey, Frederick A. Schroeder, Anais Rodriguez-Thompson, Thomas M. Morin, Kamber L. Hart, Amelia M. Pellegrini, Misha M. Riley, Changning Wang, Steven M. Stufflebeam, Stephen J. Haggarty, Daphne J. Holt, Marco L. Loggia, Roy H. Perlis, Hannah E. Brown, Joshua L. Roffman, Jacob M. Hooker
Journal: Journal of Clinical Investigation (2018)

Patients with schizophrenia (SCZ) experience chronic cognitive deficits. Histone deacetylases (HDACs) are enzymes that regulate cognitive circuitry; however, the role of HDACs in cognitive disorders, including SCZ, remains unknown in humans. We previously determined that HDAC2 mRNA levels were lower in dorsolateral prefrontal cortex (DLPFC) tissue from donors with SCZ compared with controls. Here we investigated the relationship between in vivo HDAC expression and cognitive impairment in patients with SCZ and matched healthy controls using [11C]Martinostat positron emission tomography (PET).In a case-control study, relative [11C]Martinostat uptake was compared between 14 patients with SCZ or schizoaffective disorder (SCZ/SAD) and 17 controls using hypothesis-driven region-of-interest analysis and unbiased whole brain voxel-wise approaches. Clinical measures, including the MATRICS consensus cognitive battery, were administered.Relative HDAC expression was lower in the DLPFC of patients with SCZ/SAD compared with controls, and HDAC expression positively correlated with cognitive performance scores across groups. Patients with SCZ/SAD also showed lower relative HDAC expression in the dorsomedial prefrontal cortex and orbitofrontal gyrus, and higher relative HDAC expression in the cerebral white matter, pons, and cerebellum compared with controls.These findings provide in vivo evidence of HDAC dysregulation in patients with SCZ and suggest that altered HDAC expression may impact cognitive function in humans.National Institute of Mental Health (NIMH), Brain and Behavior Foundation, Massachusetts General Hospital (MGH), Athinoula A. Martinos Center for Biomedical Imaging, National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH Shared Instrumentation Grant Program.