tbuckley/cabot-search huggingface dataset:
Comparison of Risk of Osteoporotic Fracture in Denosumab vs Alendronate Treatment Within 3 Years of Initiation
Authors: Alma B. Pedersen, Uffe Heide-Jørgensen, Henrik T. Sørensen, Daniel Prieto-Alhambra, Vera Ehrenstein
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Head-to-head randomized clinical trials showed greater efficacy of denosumab vs alendronate in improving bone mineral density. Although there is an association of changes in bone mineral density with reductions in fracture risk, the magnitude of the association is not well established. <h3>Objective</h3> To compare the risk of hip and any fracture in patients treated with denosumab and alendronate in routine practice settings. <h3>Design, Setting, and Participants</h3> This Danish nationwide, population-based, historical cohort study of a population with universal access to health care used prospectively collected, individually linked data from Danish health registries with complete follow-up. Cohorts consisted of 92 355 individuals 50 years or older who were new users of denosumab (n = 4624) or alendronate (n = 87 731) from May 2010 to December 2017 after at least 1 year without an antiosteoporosis medication dispensing. <h3>Exposures</h3> Initiation of denosumab or alendronate. <h3>Main Outcomes and Measures</h3> The primary outcome was hospitalization for hip fracture, and the secondary outcome was hospitalization for any fracture. Inverse probability of treatment weights and the intention-to-treat approach were used to calculate cumulative incidences and adjusted hazard ratios (aHRs) with 95% CIs. <h3>Results</h3> Of the 92 355 included patients, 75 046 (81.3%) were women, and the mean (SD) age was 71 (10) years. The denosumab cohort had a lower proportion of men than the alendronate cohort (12.7% [589] vs 19.0% [16 700]), while age distributions were similar in the 2 cohorts. Within 3 years of follow-up, initiation of denosumab or alendronate was associated with cumulative incidences of 3.7% and 3.1%, respectively, for hip fracture and 9.0% and 9.0%, respectively, for any fracture. Overall, the aHRs for denosumab vs alendronate were 1.08 (95% CI, 0.92-1.28) for hip fracture and 0.92 (95% CI, 0.83-1.02) for any fracture. The aHR of denosumab vs alendronate for hip fracture was 1.07 (95% CI, 0.85-1.34) among patients with a history of any fracture and 1.05 (95% CI, 0.83-1.32) among patients without history of fracture. The aHR for any fracture for denosumab vs alendronate was 0.84 (95% CI, 0.71-0.98) among patients with a history of any fracture and 0.77 (95% CI, 0.64-0.93) among patients with no history of fracture. <h3>Conclusions and Relevance</h3> Treatment with denosumab and alendronate was associated with similar risks of hip or any fracture over a 3-year period, regardless of fracture history.
Assessing telephone-delivered cognitive–behavioural therapy (CBT) and web-delivered CBT versus treatment as usual in irritable bowel syndrome (ACTIB): a multicentre randomised trial
Authors: Hazel Anne Everitt, Sabine Landau, Gilly O’Reilly, Alice Sibelli, Stephanie Hughes, Sula Windgassen, Rachel Holland, Paul Little, Paul McCrone, Felicity Bishop, Kimberley Goldsmith, Nicholas Coleman, Robert Logan, Trudie Chalder, Rona Moss-Morris
Journal: Gut (2019)

Objective To evaluate the clinical effectiveness of two modes of cognitive–behavioural therapy (CBT) for IBS compared with treatment as usual (TAU) in refractory IBS. Design A three-arm randomised controlled trial assessing telephone-delivered CBT (TCBT), web-based CBT (WCBT) with minimal therapist support, and TAU. Blinding participants and therapists was not possible. Chief investigator, assessors and statisticians were blinded. Participants were adults with refractory IBS (clinically significant symptoms for ≥12 months despite first-line therapies), recruited by letter and opportunistically from 74 general practices and three gastroenterology centres in London and South of England between May 2014 to March 2016. Co-primary outcomes were IBS Symptom Severity Score (IBS-SSS) and Work and Social Adjustment Scale (WSAS) at 12 months. Results 558/1452 (38.4%) patients screened for eligibility were randomised: 76% female: 91% white: mean age 43 years. (391/558) 70.1% completed 12 months of follow-up. Primary outcomes: Compared with TAU (IBS-SSS 205.6 at 12 months), IBS-SSS was 61.6 (95% CI 33.8 to 89.5) points lower (p&lt;0.001) in TCBT and 35.2 (95% CI 12.6 to 57.8) points lower (p=0.002) in WCBT at 12 months. Compared with TAU (WSAS score 10.8 at 12 months) WSAS was 3.5 (95% CI 1.9 to 5.1) points lower (p&lt;0.001) in TCBT and 3.0 (95% CI 1.3 to 4.6) points lower (p=0.001) in WCBT. All secondary outcomes showed significantly greater improvement (p≤0.002) in CBT arms compared with TAU. There were no serious adverse reactions to treatment. Conclusion Both CBT interventions were superior to TAU up to 12 months of follow-up. Trial registration number ISRCTN44427879 .
SAT-127-The clinical course of recurrent versus refractory ascites in outpatients with cirrhosis
Authors: Marta Tonon, Salvatore Piano, Carmine Gambino, Eleonora Bertoli, Andrea Martini, Alessandra Brocca, Marco Di Pascoli, Silvano Fasolato, Patrizia Pontisso, Paolo Angeli
Journal: Journal of Hepatology (2019)
Photopharmacology and opto-chemogenetics of TRPC channels-some therapeutic visions
Authors: Sanja Curcic, Oleksandra Tiapko, Klaus Groschner
Journal: Pharmacology & Therapeutics (2019)

Non-selective cation conductances formed by transient receptor potential canonical (TRPC) proteins govern the function and fate of a wide range of human cell types. In the past decade, evidence has accumulated for a pivotal role of these channels in human diseases, raising substantial interest in their therapeutic targeting. As yet, an appreciable number of small molecules for block and modulation of recombinant TRPC conductances have been identified. However, groundbreaking progress in TRPC pharmacology towards therapeutic applications is lagging behind due to incomplete understanding of their molecular pharmacology and their exact role in disease. A major breakthrough that is expected to overcome these hurdles is the recent success in obtaining high-resolution structure information on TRPC channel complexes and the advent of TRP photopharmacology and optogenetics. Here, we summarize current concepts of enhancing the precision of therapeutic interference with TRPC signaling and TRPC-mediated pathological processes.
First-line versus second or further-line crizotinib for trial patients with advanced non-small-cell lung cancer harboring <i>ALK</i> rearrangements.
Authors: Jinji Yang, Yuanyuan Lei, Xuchao Zhang, Qing Zhou, Hong hong Yan, Hua-Jun Chen, Haiyan Tu, Zheng Wang, Chongrui Xu, Jian Su, Yi-sheng Huang, Bin-Chao Wang, Ben-Yuan Jiang, Xiao-Yan Bai, Wenzhao Zhong, Xue-Ning Yang, Yi-Long Wu
Journal: Journal of Clinical Oncology (2015)

e19139 Background: No randomized controlled trials compared first-line to second-line crizotinib in advanced non-small-cell lung cancer (NSCLC) harboring ALK rearrangements. We aim to investigate progression-free survival (PFS), objective response rate (ORR) and overall survival (OS) of first-line versus second or further-line crizotinib for trial patients with advanced NSCLC harboring ALK rearrangements. Methods: From December 2010 to August 2014, 68 trial patients with advanced NSCLC harboring ALK rearrangements detected by fluorescence in situ hybridization (FISH) received crizotinib (250mg bid) treatment at Guangdong Lung Cancer Institute. Tumor response was assessed according to RECIST 1.1 criteria every six weeks. Retrospectively, PFS, ORR and OS were compared respectively between first-line and second or further-line crizotinib. Results: The last follow-up was on January 29, 2015. Median follow-up time was 33.8 months (95%CI, 21.4-46.1). There were 22, 29, 13, 2, and 2 patients in first, second, third, fourth and fifth-line crizotinib respectively. Median PFS (mPFS) was 13.8 months (95% CI, 7.6-19.9) in first-line, 6.8 months (95% CI, 0.6-13.0) in second-line, P= 0.007, and 7.0 months (95% CI, 3.8-10.2) in second and further-line crizotinib, P= 0.049. ORR was 81.8% (18/22), 72.4% (21/29), P= 0.429, and 69.6% (32/46), P= 0.273, respectively. OS data were not mature. Two-year survival rate was 65% (95% CI, 0.434~0.866),47% (95% CI, 0.274~0.666) and 50% (95% CI, 0.343~0.657) respectively. Conclusions: First-line was significantly superior to second or further-line crizotinib with respect to PFS in advanced NSCLC harboring ALK rearrangements. ORR was similar. However, randomized controlled trials are warranted in this setting.
Clinical experience and correlates of ipilimumab 3 mg/kg with GM-CSF in advanced melanoma.
Authors: Jason John Luke, Hilary Donahue, Mizuki Nishino, Anita Giobbie-Hurder, Meredith Davis, Nancy Bailey, Patrick Alexander Ott, F. Stephen Hodi
Journal: Journal of Clinical Oncology (2015)

e20025 Background: The combination of ipilimumab (IPI) 10 mg/kg with GM-CSF (GM) demonstrated an improvement in overall survival and safety profile over IPI alone in a randomized phase II trial. No experience of IPI 3 mg/kg with GM (IPI-GM) has been described. We treated a cohort of patients with IPI 3 mg/kg plus GM in standard practice at a single institution. Methods: Patients (pts) not eligible for clinical trials were offered IPI-GM. Patients were taught to manually draw up GM (sargramostim) via syringe from drug vials. IPI was given as per standard practice every 3 weeks x 4. GM was given as a subcutaneous injection of 250 mcg flat dose by the pt at home on days 1-14 of each ipi cycle. Response was assessed for pts receiving ≥ 2 doses. Toxicity was assessed using CTCAEv4. PBMC were collected pretreatment and at week 12 of ipilimumab treatment. Results: 32 pts (M:17) received ≥ 1 dose of IPI-GM (27 ≥ 2 doses). Characteristics included (median) age: 63 yrs; ECOG: 1; %BRAF: NRAS: Other (19:34:47); Prior therapies: 0; LDH: 169 (23% elevated) and ALC: 1.1, prior RT: 56%; sites of disease: ≥ 3; brain: 41%. 88.6% of maximal number of GM doses were administered. Total irAE included 37% G1-4, 11% G3-4. The 3 pts that experienced G3-4 irAEs were complex. 1 pt had previously discontinued IPI alone due to G3 rash 1 year earlier and upon reinduction with the combination developed G3 rash again with dermatomyositis. 2 pts developed G3 colitis including 1 with a history of collagenous colitis and another of advanced age (90). Investigator review of efficacy is described in the table. Blinded radiologist RECIST and irRC review, correlation of baseline and week 7 parameters and immune correlates will be reported. Conclusions: Ipi-GM treatment is feasible in standard practice. In this poor-risk population efficacy appeared to be increased and toxicity decreased relative to historical ipi alone reports. 12 wks 16 wks 24 wks PD 44% 46% 60% SD 41% 35% 20% PR 15% 15% 16% CR 0% 4% 4%
PS-212-Liver transplantation in patients with grade 3 acute-on-chronic liver failure: Pre-transplant risk factors of post-transplant mortality
Authors: Thierry Artzner, Baptiste Michard, Emmanuel Weiss, Louise Barbier, Zaid Noorah, Jean-Claude Merle, Tasneem Pirani, Catherine Paugam-Burtz, Claire Francoz, francois durand, Eleni Theocharidou, John O’Grady, William Bernal, Nigel HEATON, Ephrem Salamé, Petru Bucur, Helene Barrault, François Lefebvre, Lawrence Serfaty, Camille Besch, Francis Schneider, Eric Levesque, François Faitot
Journal: Journal of Hepatology (2019)
Abstract 12998: Decade-Long Trends in Patient Characteristics, Management, and In-Hospital Outcomes of Diabetic Patients with Acute Myocardial Infarction
Authors: Samuel W Joffe, Mayra Tisminetzky, Ibrahim Kassas, Darleen Lessard, Jorge Yarzebski, Joel Gore, Robert J Goldberg
Journal: Circulation (2013)

Background: Diabetic patients have historically had more complications and higher mortality rates after acute myocardial infarction (AMI) than non-diabetics. The objectives of this community-based study were to describe recent trends in patient characteristics, treatment practices, and in-hospital outcomes in diabetic compared to non-diabetic patients hospitalized with STEMI or NSTEMI. Methods: We reviewed the medical records of 6,903 patients with a past medical history of diabetes (n =2,329) or no diabetes (n=4,574) hospitalized for STEMI (n=2,537) or NSTEMI (n=4,366) between 1997 and 2009 at 11 Massachusetts hospitals. Results: Diabetic patients presenting with either STEMI or NSTEMI were more likely to be older, female, and to have a higher prevalence of comorbidities than non-diabetics. Compared to non-diabetics, diabetic patients were more likely to develop important in-hospital complications including heart failure (STEMI 39% vs 27%, NSTEMI 50% vs 35%) and cardiogenic shock (STEMI 10% vs 8%, NSTEMI...
Immune contexture defined by single cell technology for prognosis prediction and immunotherapy guidance in cancer
Authors: Tong Wu, Xuan Wu, Hong‐Yang Wang, Lei Chen
Journal: Cancer Communications (2019)

Abstract Tumor immune microenvironment is closely related to tumor initiation, prognosis, and response to immunotherapy. The immune landscapes, number of infiltrating immune cells, and the localization of lymphocytes in the tumor vary in across different types of tumors. The immune contexture in cancer, which is determined by the density, composition, functional state and organization of the leukocyte infiltrate of the tumor, can yield information relevant to the prediction of treatment response and patients’ prognosis. Better understanding of the immune atlas in human tumors have been achieved with the development and application of single‐cell analysis technology, which has provided a reference for prognosis, and insights on new targets for immunotherapy. In this review, we summarized the different characteristics of immune contexture in cancer defined by a variety of single‐cell techniques, which have enhanced our understanding on the pathophysiology of the tumor microenvironment. We believe that there are much more to be uncovered in this rapidly developing field of medicine, and they will predict the prognosis of cancer patients and guide the rational design of immunotherapies for success in cancer eradication.
Incidental Primary Breast Lymphoma on 99mTc-Sestamibi Myocardial Perfusion Imaging With SPECT/CT
Authors: Zilong Deng, Aisheng Dong, Min Zhao, Youhong Tang, Yutao Liu
Journal: Clinical Nuclear Medicine (2019)

Abstract We present a 53-year-old woman who had shortness of breath and atypical chest pain and underwent 99m Tc-sestamibi myocardial perfusion imaging to detect coronary artery disease. The raw data in cine format showed an incidental focus close to the heart, and SPECT/CT fused images revealed a focus of intense uptake in the left breast. The subsequent histopathologic findings and 18 F-FDG PET/CT imaging confirmed the diagnosis as primary breast lymphoma. After 3 cycles of chemotherapy, previously visualized abnormal uptake in the left breast disappeared on the follow-up PET/CT.
The Epidemiology of Antiphospholipid Syndrome: A Population‐Based Study
Authors: Ali Duarte‐García, Michael M. Pham, Cynthia S. Crowson, Shreyasee Amin, Kevin G. Moder, Rajiv K. Pruthi, Kenneth J. Warrington, Eric. L. Matteson
Journal: Arthritis & Rheumatology (2019)

To estimate the annual incidence and prevalence of and frequency of mortality associated with antiphospholipid syndrome (APS).An inception cohort of patients with incident APS in 2000-2015 from a geographically well-defined population was identified based on comprehensive individual medical records review. All cases met the 2006 Sydney criteria for APS (primary definition) or had a diagnosis of APS confirmed by physician consensus (secondary definition). Levels of lupus anticoagulant, IgM and IgG anticardiolipin antibodies, and anti-β2-glycoprotein I antibodies were tested in a centralized laboratory. Incidence rates were age- and sex-adjusted to the 2010 US white population. Prevalence estimates were obtained from the incidence rates, assuming that there was no increased mortality associated with APS and that migration in or out of the area was independent of disease status.Among this cohort in 2000-2015, 33 cases of incident APS, as defined by the Sydney criteria, were identified (mean age of patients 54.2 years; 55% female, 97% white). The annual incidence of APS in adults ages ≥18 years was 2.1 (95% confidence interval [95% CI] 1.4-2.8) per 100,000 population. Incidence rates were similar in both sexes. The estimated prevalence of APS was 50 (95% CI 42-58) per 100,000 population, and was similar in both sexes. Six patients (18%) had a concurrent diagnosis of systemic lupus erythematosus. The most frequent clinical manifestation was deep vein thrombosis. The overall frequency of mortality among patients with APS was not significantly different from that in the general population (standardized mortality ratio 1.61, 95% CI 0.74-3.05).APS occurred in ~2 persons per 100,000 population per year. The estimated prevalence was 50 per 100,000 population. Overall mortality was not notably different from that observed in the general population.
Abstract 20947: Dnmt and Hdac Inhibitors Together Inhibits Lps Induced Cell Death by Modulating Stat3 Jmjd3 Signaling Axis
Authors: Saheli Ganguly Samanta, Zhigang Zhou, Sheeja Rajasingh, Bahar Barani, Nicholas Drosos, Buddhadeb Dawn, Johnson Rajasingh
Journal: Circulation (2017)

Introduction: Inflammation associated with acute lung injury (ALI) is caused by direct insult to the lungs or by sepsis, which is responsible for tissue damage and cell death. Although the therapeutic effectiveness of epigenetic modifiers can potentially limit lung inflammation, few studies have examined the combinatorial (Aza+TSA) use of a DNA methyl transferase (DNMT) inhibitor, Aza (5-Aza 2-deoxycytidine), and histone deacetylase (HDAC) inhibitor, TSA (Trichostatin A), on the recovery of cell death mechanisms in macrophages. Hypothesis: Therapy with Aza+TSA will reduce cell death by interfering with phosphorylation of JNK and ERK and thereby inhibit JMJD3 expression. Methods and Results: In an LPS-induced ALI mouse model, a single dose of Aza+TSA prevented lung inflammation and injury with significant reduction in mortality as compared with mice treated with either Aza or TSA alone (Thangavel J 2014). DNA ladder analysis shows a decrease in the DNA breaks in LPS-induced bone marrow derived macrophages (BMDMs) treated with Aza+TSA when compared to untreated LPS control (Fig. A) . There is also a reduction in phosphorylation of JNK and ERK in LPS-induced BMDMs when treated together compared to untreated or treated with either Aza or TSA alone. This reduction is caused by the decrease in JMJD3 expression when STAT3 was pulled down after the combined treatment of Aza+TSA, emphasizing the involvement of STAT3-JMJD3 signaling in inflammation associated cell death mechanism (Fig. B) . Conclusions: LPS acts on macrophages through activation of the MAPK pathway followed by the modulation of STAT3-JMJD3 associated with cell death. Administration of DNMT and HDAC inhibitor together interrupts STAT3-mediated decrease in the JMJD3 signaling pathway and cell death in BMDM. !--[endif]--&gt;
High OGT activity is essential for MYC-driven proliferation of prostate cancer cells
Authors: Harri M Itkonen, Alfonso Urbanucci, Sara ES Martin, Aziz Khan, Anthony Mathelier, Bernd Thiede, Suzanne Walker, Ian G Mills
Journal: Theranostics (2019)

O-GlcNAc transferase (OGT) is overexpressed in aggressive prostate cancer.OGT modifies intra-cellular proteins via single sugar conjugation (O-GlcNAcylation) to alter their activity.We recently discovered the first fast-acting OGT inhibitor OSMI-2.Here, we probe the stability and function of the chromatin O-GlcNAc and identify transcription factors that coordinate with OGT to promote proliferation of prostate cancer cells.Methods: Chromatin immunoprecipitation (ChIP) coupled to sequencing (seq), formaldehyde-assisted isolation of regulatory elements, RNA-seq and reverse-phase protein arrays (RPPA) were used to study the importance of OGT for chromatin structure and transcription.Mass spectrometry, western blot, RT-qPCR, cell cycle analysis and viability assays were used to establish the role of OGT for MYC-related processes.Prostate cancer patient data profiled for both mRNA and protein levels were used to validate findings.Results: We show for the first time that OGT inhibition leads to a rapid loss of O-GlcNAc chromatin mark.O-GlcNAc ChIP-seq regions overlap with super-enhancers (SE) and MYC binding sites.OGT inhibition leads to down-regulation of SE-dependent genes.We establish the first O-GlcNAc chromatin consensus motif, which we use as a bait for mass spectrometry.By combining the proteomic data from oligonucleotide enrichment with O-GlcNAc and MYC ChIP-mass spectrometry, we identify host cell factor 1 (HCF-1) as an interaction partner of MYC.Inhibition of OGT disrupts this interaction and compromises MYC's ability to confer androgen-independent proliferation to prostate cancer cells.We show that OGT is required for MYC-mediated stabilization of mitotic proteins, including Cyclin B1, and/or the increased translation of their coding transcripts.This implies that increased expression of mRNA is not always required to achieve increased protein expression and confer aggressive phenotype.Indeed, high expression of Cyclin B1 protein has strong predictive value in prostate cancer patients (p=0.000014) while mRNA does not.Conclusions: OGT promotes SE-dependent gene expression.OGT activity is required for the interaction between MYC and HCF-1 and expression of MYC-regulated mitotic proteins.These features render OGT essential for the androgen-independent, MYC-driven proliferation of prostate cancer cells.Androgen-independency is the major mechanism of prostate cancer progression, and our study identifies OGT as an essential mediator in this process.