tbuckley/cabot-search huggingface dataset:
Abstract 16619: Bone Marrow Cell Therapy Improves Left Ventricular Function And Survival in Patients With Chronic Ischemic Heart Disease and Cardiomyopathy
Authors: Anweshan Samanta, Muhammad R Afzal, Briha Ansari, Vinodh Jeevanantham, Buddhadeb Dawn
Journal: Circulation (2015)

Introduction: Results from randomized controlled trials (RCTs) of bone marrow cell (BMC) therapy for cardiac repair have been discordant. The true impact of BMC therapy in patients with chronic ischemic heart disease (CIHD) and ischemic heart failure remain unclear. Hypothesis: We hypothesized that BMC injection would improve clinical outcomes and left ventricular (LV) parameters in patients with CIHD. Methods: We performed a systematic review and meta-analysis of data from RCTs of BMC therapy on LV ejection fraction (LVEF), LV end-systolic volume (LVESV), LV end-diastolic volume (LVEDV), infarct scar size, and clinical outcomes in patients with CIHD. Database searches based on specified criteria identified 15 eligible RCTs (enrolling 648 CIHD patients). Changes in predefined parameters were analyzed with random-effects meta-analysis. Peto odds ratio (OR) was calculated for clinical outcomes. Results: Compared with standard therapy, BMC transplantation improved LVEF (3.84%; 95% confidence interval [CI], 2.30 to 5.38; P&lt;0.00001), reduced scar size (-5.90%; 95% CI, -8.03 to -3.78; P&lt;0.00001) and LVESV (-10.37 ml; 95% CI, (-18.56 to -2.18; P=0.01). Reduction in LVEDV (-1.84 ml; 95% CI, -9.13 to 5.46; P=0.62) was not significant. The improvement in LVEF in BMC-treated patients was also significant (1.78%; 95% CI: 0.63 to 2.93; P=0.002) in a separate analysis of RCTs that used MRI. Importantly, BMC therapy reduced all-cause mortality (OR: 0.35; 95% CI 0.16 to 0.73; P=0.005) and incidence of cerebrovascular accident (CVA) (OR: 0.07; 95% CI, 0.01 to 0.55; P=0.01) and tended to reduce the incidence of heart failure (OR: 0.36; 95% CI 0.11 to 1.14; P=0.08) in patients with CIHD (Table). Conclusions: BMC therapy improves LVEF, LVESV, and infarct scar size in patients with CIHD. The improvement in LVEF was also confirmed in meta-analysis of RCTs using MRI. Importantly, these numerically small benefits translated into improved clinical outcomes in BMC-treated CIHD patients.
IBD BioResource: an open-access platform of 25 000 patients to accelerate research in Crohn’s and Colitis
Authors: Miles Parkes
Journal: Gut (2019)

Give us the tools and we will finish the job

-Winston Churchill

An alliance of clinicians, academics, research nurses, funders, coordinators, programmers and, most importantly, patients has come together in the UK to deliver a powerful new platform to accelerate Crohn’s and Colitis research—the inflammatory bowel disease (IBD) BioResource. As part of the National Institute for Health Research (NIHR) BioResource for translational research, 25 000 patients in over 90 hospitals UK-wide have signed up since we launched in January 2016 (figure 1). All have detailed phenotypes databased including Montreal classification,1 treatment response history (updated annually), surgical history and comorbidities (see IBD BioResource panel descriptive, Clinical data collection sheet and Health and Lifestyle questionnaire). Serum, plasma and DNA samples are banked; and genome-wide genetic profiling undertaken. Participants’ data and samples can be studied, and they themselves surveyed or recalled for resampling or downstream studies (see figure 2). Critically, such studies can be led by any UK or overseas investigator whether from the worlds of clinical research, pharmacovigilance, science or industry.



Figure 1 
IBD BioResource recruitment in over 90 hospitals in the UK. IBD, inflammatory bowel disease.





Figure 2 
How the IBD BioResource works. HES, Hospital Episode Statistics; HSCN, Health Social Care Network; IBD, inflammatory bowel disease; NHS, National Health Service.



A key motivation is to leverage recent genetics advances, and by understanding the functional impact of IBD-associated gene variants accelerate translation of the new knowledge for clinical benefit. Beyond this, it is increasingly evident that the IBD BioResource can facilitate a wide spectrum of research. This might include anything from mining existing data or samples or surveying the cohort regarding outcomes of newly licensed treatments, to pharmacogenetic research. It could also be used to expedite recruitment to intervention studies, including experimental medicine and conventional drug trials.

Gene discovery in Crohn’s disease and ulcerative colitis has placed …
PF413 CARDIAC, VASCULAR, AND HYPERTENSION SAFETY OF BOSUTINIB VS IMATINIB FOR NEWLY DIAGNOSED CHRONIC MYELOID LEUKEMIA IN THE BFORE TRIAL
Authors: T.H. Brümmendorf, C. Gambacorti‐Passerini, R. Clark, E. Leip, A. Viqueira, V. Kota, M. Deininger, J.E. Cortes
Journal: HemaSphere (2019)

Background: Tyrosine kinase inhibitor therapy has been linked to cardiac and vascular events. Aims: Cardiac, vascular, and hypertension treatment‐emergent adverse events (TEAEs) with bosutinib or imatinib for newly diagnosed chronic phase chronic myeloid leukemia were analyzed. Methods: Patients who received ≥1 dose of bosutinib (n = 268) or imatinib (n = 265) 400 mg/day in the phase 3 BFORE trial (NCT02130557) were included. Prespecified MedDRA terms comprised the clusters of investigator assessed TEAEs. Exposure‐adjusted TEAE rate was defined as the number of patients with TEAEs / total patient‐year, where patient‐year = the sum of total time to first TEAE for patients with TEAEs and treatment duration for patients without TEAEs. Results: After ≥36 months of follow‐up, 65% vs 62% of patients in the bosutinib vs imatinib arm were still on treatment. Rates of TEAEs, treatment withdrawals, and drug‐related TEAEs in the clusters of interest were low in both arms (Table). The most common cardiac, vascular, and hypertension TEAEs, respectively, were sinus bradycardia (2%), angina pectoris (3%), and hypertension (7%) vs prolonged QT (3%), peripheral coldness (1%), and hypertension (9%) with bosutinib vs imatinib; corresponding grade 3/4/5 TEAE rates in the respective clusters were 3%, 3%, and 4% vs 1%, 0.4%, and 4%. Hypertension was the only grade 3/4 TEAE occurring in ≥1% of patients in either arm (4% each); 1 grade 5 TEAE each was noted for bosutinib (cardiac failure) and imatinib (cerebrovascular accident). Exposure‐adjusted rates of cardiac, vascular, and hypertension TEAEs, respectively, were 0.04, 0.03, and 0.04 vs 0.03, 0.01, and 0.04 (grade 3/4/5 only: 0.01, 0.01, and 0.02 vs 0.01, 0.002, and 0.02) for bosutinib vs imatinib. Summary/Conclusion: Cardiac, vascular, and hypertension TEAE rates were similarly low with bosutinib and imatinib. A majority of TEAEs were low grade and few led to treatment withdrawal. image
Abstract 12866: Association Between Critical Care Unit Utilization and Long-Term Outcomes Among Initially Stable Patients With Non-ST Segment Elevation Myocardial Infarction
Authors: Alexander C Fanaroff, Anita Y Chen, Sean van Diepen, Eric D Peterson, Tracy Y Wang
Journal: Circulation (2018)

Background: There is substantial variation in hospital utilization of ICUs for hemodynamically stable patients with non-ST segment elevation myocardial infarction (NSTEMI). While ICU utilization ra...
Preliminary Results of a Phase 1 Dose Escalation Study of the First-in-Class Anti-CD74 Antibody Drug Conjugate (ADC), STRO-001, in Patients with Advanced B-Cell Malignancies
Authors: Nirav N. Shah, Amrita Y. Krishnan, Nina D. Shah, John M Burke, Jason M. Melear, Alexander I. Spira, Leslie L. Popplewell, Charalambos B. Andreadis, Saurabh Chhabra, Jeff P. Sharman, Jonathan L. Kaufman, Jonathon B. Cohen, Ruben Niesvizky, Thomas G. Martin, Clifford DiLea, Jason Kuriakose, Shannon L. Matheny, John P. Leonard, Arturo Molina
Journal: Blood (2019)
Abstract 19221: Developing a Clinical Predication Model for 1-Year Health Status Outcomes in Peripheral Arterial Disease: Insights From the PORTRAIT Registry
Authors: Kim G Smolderen, Jinyang Wang, Phil Jones, Clementine Labrosciano, John Spertus
Journal: Circulation (2017)

Introduction: Patients with peripheral arterial disease (PAD) have different therapeutic options, but it is unknown how their personal characteristics and different treatments might impact their he...
Intestinal Fungal Dysbiosis and Systemic Immune Response to Fungi in Patients With Alcoholic Hepatitis
Authors: Sonja Lang, Yi Duan, Jinyuan Liu, Manolito G. Torralba, Claire Kuelbs, Meritxell Ventura‐Cots, Juan G. Abraldes, Francisco Bosques‐Padilla, Elizabeth C. Verna, Robert S. Brown, Victor Vargas, Jose Altamirano, Juan Caballería, Debbie Shawcross, Michael R. Lucey, Alexandre Louvet, Philippe Mathurin, Guadalupe Garcia‐Tsao, Samuel B. Ho, Xin M. Tu, Ramon Bataller, Peter Stärkel, Derrick E. Fouts, Bernd Schnabl
Journal: Hepatology (2019)

Chronic alcohol consumption causes increased intestinal permeability and changes in the intestinal microbiota composition, which contribute to the development and progression of alcohol-related liver disease. In this setting, little is known about commensal fungi in the gut. We studied the intestinal mycobiota in a cohort of patients with alcoholic hepatitis, patients with alcohol use disorder, and nonalcoholic controls using fungal-specific internal transcribed spacer amplicon sequencing of fecal samples. We further measured serum anti-Saccharomyces cerevisiae antibodies (ASCA) as a systemic immune response to fungal products or fungi. Candida was the most abundant genus in the fecal mycobiota of the two alcohol groups, whereas genus Penicillium dominated the mycobiome of nonalcoholic controls. We observed a lower diversity in the alcohol groups compared with controls. Antibiotic or steroid treatment was not associated with a lower diversity. Patients with alcoholic hepatitis had significantly higher ASCA levels compared to patients with alcohol use disorder and to nonalcoholic controls. Within the alcoholic hepatitis cohort, patients with levels of at least 34 IU/mL had a significantly lower 90-day survival (59%) compared with those with ASCA levels less than 34 IU/mL (80%) with an adjusted hazard ratio of 3.13 (95% CI, 1.11-8.82; P = 0.031). Conclusion: Patients with alcohol-associated liver disease have a lower fungal diversity with an overgrowth of Candida compared with controls. Higher serum ASCA was associated with increased mortality in patients with alcoholic hepatitis. Intestinal fungi may serve as a therapeutic target to improve survival, and ASCA may be useful to predict the outcome in patients with alcoholic hepatitis.
PB2406 THE INFLUENCE OF XMNI AND BCL11A GENE MODIFIERS ON HEMOGLOBIN F LEVELS IN EGYPTIAN β‐THALASSEMIA MAJOR PATIENTS
Authors: E. Nasreldin, S. galal, M. atwa, H. abdellatif, N. idris, G. ezzat, M. gaber, M. dahpy, D. raffat
Journal: HemaSphere (2019)

Background: β‐thalassemia major (β‐TM) is an autosomal recessive disorder in which β‐globin chain synthesis is severely decreased or absent which lead to blood transfusion dependency with its catastrophic complications. Polymorphisms at position ‐158 of XmnI‐HBG2 on chromosome 11 and BCL11A site on chromosome 2p16 might be associated with elevated hemoglobin F (HbF) expression which may,in turn,improve β‐thalassemia severity Aims: This study aims to explore the modifying effects of XmnI and BCL11A loci on HbF levels in Egyptian β‐thalassemia patients Methods: A prospective case‐control study of 70 multi‐transfused β‐thalassemia major patients and 22 controls was conducted in Paediatric hematology unit of Assiut university hospital from January 2016 till April 2017. PCR‐RFLP was used for detection of single nucleotide polymorphisms at XmnI and BCL11A site loci. Results: XmnI Polymorphism detected in 9 of 70 patients and associated with higher mean HbF levels (53.48%) than patients without polymorphism (meanHbF level was 42.23%)(P‐Value = 0.035).The frequency of CT heterozygousgenotype was 8(11.4%), TT homozygous genotype was (1.4%) while the wild genotype CC detected in 61 (87.1%) of the cases. While BCL11A Polymorphism detected in 21 of 70 patients had no effect on either Hb or HbF levels (P‐Value = 0.26). The TT genotype frequency was 49 (70%) and TC heterozygous genotype was detected in 21 (30 %) of patients. The CC genotype was absent. Summary/Conclusion: The presence of XmnI polymorphism rather than BCL11A polymorphism has a modifying effect on HbF production and increased Hb levels between β‐TM patients and so, it helps in identifying patients’ benefits from HU therapy. image
SP0127 PATIENT ENGAGEMENT WITHIN THE EUROPEAN MEDICINES AGENCY
Authors: Nathalie Bere
Journal: Annals of the Rheumatic Diseases (2019)

<h3></h3> The European Medicines Agency (EMA) is the European regulatory body whose role is to evaluate and supervise medicines across the European Union. EMA has been engaging with patients and consumers for many years and today, patient involvement is an integral part of the work at EMA, with a diverse range of opportunities in place to include the patient's voice at various stages along the medicines regulatory life-cycle. Key to successful engagement has been the need for flexibility, a range of well-tested methodologies and a robust system of support and training. Patients and caregivers' real-life perspectives and unique insights complement the scientific data within EMA reviews; they provide input on proposed protocol designs and participate in expert meetings and written consultations on medicines evaluation. They are voting members of EMA committees and they review medical information written for the public. Evidence has shown their contributions make a difference and ultimately help ensure that the Agency"s outcomes are as meaningful and relevant as possible for all concerned. Some of the key challenges and conclusions of our journey will be highlighted to serve as a guide to those considering a similar, rewarding path. <h3>Disclosure of Interests:</h3> None declared
Analysis of Host Responses to Hepatitis B and Delta Viral Infections in a Micro‐scalable Hepatic Co‐culture System
Authors: Benjamin Y. Winer, Jenna M. Gaska, Gabriel Lipkowitz, Yaron Bram, Amit Parekh, Lance Parsons, Robert Leach, Rohit Jindal, Cheul H. Cho, Anil Shrirao, Eric Novik, Robert E. Schwartz, Alexander Ploss
Journal: Hepatology (2019)

Hepatitis B virus (HBV) remains a major global health problem with 257 million chronically infected individuals worldwide, of whom approximately 20 million are co‐infected with hepatitis delta virus (HDV). Progress toward a better understanding of the complex interplay between these two viruses and the development of novel therapies have been hampered by the scarcity of suitable cell culture models that mimic the natural environment of the liver. Here, we established HBV and HBV/HDV co‐infections and super‐infections in self‐assembling co‐cultured primary human hepatocytes (SACC‐PHHs) for up to 28 days in a 384‐well format and highlight the suitability of this platform for high‐throughput drug testing. We performed RNA sequencing at days 8 and 28 on SACC‐PHHs, either HBV mono‐infected or HBV/HDV co‐infected. Our transcriptomic analysis demonstrates that hepatocytes in SACC‐PHHs maintain a mature hepatic phenotype over time, regardless of infection condition. We confirm that HBV is a stealth virus, as it does not induce a strong innate immune response; rather, oxidative phosphorylation and extracellular matrix–receptor interactions are dysregulated to create an environment that promotes persistence. Notably, HDV co‐infection also did not lead to statistically significant transcriptional changes across multiple donors and replicates. The lack of innate immune activation is not due to SACC‐PHHs being impaired in their ability to induce interferon stimulated genes (ISGs). Rather, polyinosinic:polycytidylic acid exposure activates ISGs, and this stimulation significantly inhibits HBV infection, yet only minimally affects the ability of HDV to infect and persist. Conclusion: These data demonstrate that the SACC‐PHH system is a versatile platform for studying HBV/HDV co‐infections and holds promise for performing chemical library screens and improving our understanding of the host response to such infections.
Correspondence between Resting-State Activity and Brain Gene Expression
Authors: Guang-Zhong Wang, T. Grant Belgard, Deng Mao, Leslie Chen, Stefano Berto, Todd M. Preuss, Hanzhang Lu, Daniel H. Geschwind, Genevieve Konopka
Journal: Neuron (2015)

The relationship between functional brain activity and gene expression has not been fully explored in the human brain. Here, we identify significant correlations between gene expression in the brain and functional activity by comparing fractional amplitude of low-frequency fluctuations (fALFF) from two independent human fMRI resting-state datasets to regional cortical gene expression from a newly generated RNA-seq dataset and two additional gene expression datasets to obtain robust and reproducible correlations. We find significantly more genes correlated with fALFF than expected by chance and identify specific genes correlated with the imaging signals in multiple expression datasets in the default mode network. Together, these data support a population-level relationship between regional steady-state brain gene expression and resting-state brain activity.
PB2360 EARLY VS DELAYED G-CSF IN MULTIPLE MYELOMA AUTOLOGOUS STEM CELL TRANSPLANT
Authors: A. Iqbal, A. Nag, M. Bhattacharyya
Journal: HemaSphere (2019)

Background: Prophylactic use of G-CSF on Day + 6 of PBSC infusion has been the standard of care for Autologous Stem Cell Transplantation. In Multiple Myeloma patients however, this practice has been challenged lately to have doubtful clinical benefits. In latest prospective trials, scheduled use of G-CSF and delayed G-CSF were not different in terms of neutrophil engraftment, febrile neutropenia and infection rates with only modest benefit in hospitalization days. In Indian scenario however, the benefit of reduced cost may not outweigh risks of morbidity and mortality associated with delayed G-CSF Aims: 1. To prospectively analyze patients of Multiple Myeloma undergoing Autologous SCT for neutrophil engarftment with or without prophylactic G-CSF 2. To analyze the risk vs benefit vis a vis prophylactic vs delayed G-CSF in terms of Neutrophil engraftment, incidence and duration of febrile neutropenia, use of empirical antifungal use, hospitalization days and mortality Methods: We conducted a single centre prospective study to find out the kinetics of neutrophil recovery and associated complications of severe neutropenia in 25 patients of Multiple myeloma who underwent Auto SCT with high dose melphalan between Jan,2015 and June,2017. 15 patients received scheduled G-CSF on day + 6 and 10 patients received delayed G-CSF upon first signs of neutrophil recovery or in febrile neutropenia Results: We found out that our patients had faster neutrophil recovery and engraftment (median 11 days) than previous reports with or without scheduled G-CSF. Prophylactic group received a median of 6 doses as compared to a median of 3 doses in the delayed group. However the incidence of febrile neutropenia (6 vs 2; p < 0.01), cumulative duration of febrile neutropenia (18 vs 4 days; p < 0.01), and duration of empirical antifungal use (28 vs 2 days; p < 0.01) were higher in patients with delayed G-CSF. Hospitalization days were also higher in delayed G-CSF (35 vs 24 days; p > 0.05). No deaths were reported. Summary/Conclusion: The results vary from western literature on transplants in myeloma patients. In India where infective complications following high dose therapies are higher, current findings suggest that use of scheduled early G-CSF at D + 6 to hasten neutrophil recovery may be continued for routine practice.
Abstract 14586: Anxiety but Not Depression Influences Risk of Stroke in Adults With Atrial Fibrillation: CVRN WAVE Study
Authors: Christine Baumgartner, Dongjie Fan, Margaret C Fang, Daniel E Singer, Daniel M Witt, Marc S Williams, Jerry Gurwitz, Sue-Hee Sung, Alan S Go
Journal: Circulation (2017)

Introduction: Anxiety and depression are associated with worse outcomes in several cardiovascular conditions, but little is known about whether they impact outcomes in adults with atrial fibrillati...
PB2088 SAFETY OF GENERIC AZACITIDINE IN MYELOID NEOPLASMS–A SINGLE CENTRE EXPERIENCE
Authors: N. A. Abdul Halim, K. Y. Loh, A. Ho, G. C. Wong, Z. Lao, H. J. Ng
Journal: HemaSphere (2019)

Background: Azacitidine is one of the two hypomethylating agents that are used commonly in myeloid neoplasms. Generic formulations in haematological conditions are increasingly being used due to their lower cost. Our institution, Singapore General Hospital, switched all azacitidine to the generic version, Azadine, from 1st September 2018. Currently, there has been no reported comparison of safety and efficacy between the branded Vidaza and generic azacitidine. Aims: To evaluate the safety of generic azacitidine (Azadine) in patients who are treated for myeloid neoplasms in Singapore General Hospital. Methods This is a prospective analysis of patients who received Azadine from September 2018 to February 2019. Patients who received azacitidine following allogeneic stem cell transplant were excluded. Results: A total of 41 patients and 97 cycles of generic azacitidine were analysed. The median age was 71 years old (28-81) and 61% of the patients were male. The indications of treatment were acute myeloid leukemia in 54%, myelodysplastic syndrome in 39%, and myeloproliferative/myelodysplastic syndrome in 7%. 21 patients (51%) had received Vidaza before and 8 (20%) had concomitant venetoclax. The most common grade 3/4 adverse events were cytopenias–anaemia 66%, neutropenia 66%, thrombocytopenia 63%. Other grade 3/4 adverse events were infection 41%, hypokalaemia 17%, bleeding 7%, and vomiting 5%. 20 patients (49%) had treatment discontinuation for the following reasons: death 22%, transplant 7%, a change to more intensive therapy 5%, complications 7% and patients’ wishes 7%. None of the deaths was attributed to Azadine. Dose was reduced in 2 patients, both due to physicians’ preference. 4 patients (10%) had grade 2 toxic erythema of chemotherapy, which was higher than our usual experience with Vidaza. In all patients the onset of the rash was less than 5 days after starting Azadine with no recurrence in the subsequent cycles. Summary/Conclusion: The safety profile of Azadine is comparable to known rates of adverse events of Vidaza. There is a possibility of higher risk of toxic erythema of chemotherapy with Azadine but numbers are too small currently to make any meaningful conclusions. A longer follow up is also needed to evaluate the efficacy of Azadine.
The intracellular domain of CX3CL1 regulates adult neurogenesis and Alzheimer’s amyloid pathology
Authors: Qingyuan Fan, Manoshi Gayen, Neeraj Singh, Fan Gao, Wanxia He, Xiangyou Hu, Li-Huei Tsai, Riqiang Yan
Journal: The Journal of Experimental Medicine (2019)

The membrane-anchored CX3CL1 is best known to exert its signaling function through binding its receptor CX3CR1. This study demonstrates a novel function that CX3CL1 exerts. CX3CL1 is sequentially cleaved by α-, β-, and γ-secretase, and the released CX3CL1 intracellular domain (CX3CL1-ICD) would translocate into the cell nucleus to alter gene expression due to this back-signaling function. Amyloid deposition and neuronal loss were significantly reduced when membrane-anchored CX3CL1 C-terminal fragment (CX3CL1-ct) was overexpressed in Alzheimer’s 5xFAD mouse model. The reversal of neuronal loss in 5xFAD can be attributed to increased neurogenesis by CX3CL1-ICD, as revealed by morphological and unbiased RNA-sequencing analyses. Mechanistically, this CX3CL1 back-signal likely enhances developmental and adult neurogenesis through the TGFβ2/3-Smad2/3 pathway and other genes important for neurogenesis. Induction of CX3CL1 back-signaling may not only be a promising novel mechanism to replenish neuronal loss but also for reducing amyloid deposition for Alzheimer’s treatment.