tbuckley/cabot-search huggingface dataset:
Inflammation in the Pathophysiology and Therapy of Cardiometabolic Disease
Authors: Marc Y Donath, Daniel T Meier, Marianne Böni-Schnetzler
Journal: Endocrine Reviews (2019)

The role of chronic inflammation in the pathogenesis of type 2 diabetes mellitus and associated complications is now well established. Therapeutic interventions counteracting metabolic inflammation improve insulin secretion and action and glucose control and may prevent long-term complications. Thus, a number of anti-inflammatory drugs approved for the treatment of other inflammatory conditions are evaluated in patients with metabolic syndrome. Most advanced are clinical studies with IL-1 antagonists showing improved β-cell function and glycemia and prevention of cardiovascular diseases and heart failure. However, alternative anti-inflammatory treatments, alone or in combinations, may turn out to be more effective, depending on genetic predispositions, duration, and manifestation of the disease. Thus, there is a great need for comprehensive and well-designed clinical studies to implement anti-inflammatory drugs in the treatment of patients with metabolic syndrome and its associated conditions.
THER-14. SMALL MOLECULE INHIBITOR TARGETING SELF-RENEWAL AS A THERAPEUTIC OPTION FOR RECURRENT MEDULLOBLASTOMA
Authors: Ashley Adile, David Bakhshinyan, Chitra Venugopal, Minomi Subapanditha, Marla Weetall, Thomas Davis, Sheila Singh
Journal: Neuro-Oncology (2019)

Medulloblastoma (MB) is the most common pediatric brain tumor malignancy, and one of the leading causes of childhood cancer mortality. Often associated with tumor recurrence, relapsed MB patients are limited to palliation outwith the paucity of clinical trials available, carrying a mortality rate approaching 100%. Selectively targeting the MB stem cell population that evade conventional chemoradiotherapy and drive recurrence, can reduce the self-renewal and proliferative properties characteristic of aggressive cancer stem cells. Previous work identified BMI1, a master stem cell regulatory protein and epigenetic modifier, as a novel therapeutic target of developmental pathways active during tumorigenesis. Given that small molecule inhibitors targeting BMI1 correlated with diminished tumorigenic potential in other cancers, through industry partnership, we employ PTC596, a BMI1 inhibitor, providing extensive evidence of an efficacious therapy for treatment-refractory and recurrent MB through translational inhibition of BMI1. PTC596 effectively decreases the endogenous levels of BMI1 in our primary patient-derived MB cells, while abrogating the self-renewal capacity of MB stem cells. Novel to this work is the combinatorial MB patient-derived xenograft (PDX) mouse model, where tumor-bearing immune deficient mice were treated with standard chemoradiotherapy along with PTC596. Remarkably, an even greater survival benefit and reduction in tumor burden was seen in both concurrently and sequentially treated PDX cohorts. Such promising preclinical results have rapidly translated to the clinic with impending implementation of a North American clinical trial for children with recurrent MB. As BMI1 is implicated in the maintenance of aggressive childhood and adult brain tumors, BMI1-targeted therapies offer great clinical interest, with the potential of providing avenues for de-escalating therapies that otherwise cause severe neurological and psychosocial sequelae.
Bleomycin hydrolase protects mice from bleomycin induced death and is involved in bleomycin induced lung fibrosis
Authors: Elizabeth L. Travis, Min Wang, John D. Allard, Gary Peltz
Journal: Cancer Research (2004)

5127  Bleomycin hydrolase (BH) is a cysteine protease that inactivates the antitumor glycopeptide bleomycin (BLM), which is used in the treatment of human cancers. A dose limiting side effect of BLM treatment is pulmonary fibrosis. Using our mouse genetic model, we previously demonstrated a significant quantitative trait loci (Blmpf2) to BLM induced lung fibrosis on chromosome 11 (LOD = 5.6) in males only. One candidate gene in this linkage region is BH gene. Our previous studies of BH activity showed that this enzyme modulates bleomycin-induced pulmonary fibrosis. In this study, to further demonstrate that the BH gene is a susceptibility gene for BLM-induced pulmonary fibrosis, we investigated nucleotide polymorphisms between fibrosis resistant C3Hf/Kam (C3H) and fibrosis prone C57BL/6 (B6) strain, the correlation of the polymorphisms with phenotype in C3H and B6 derived F2 mice, and the effect of BH on BLM-induced pulmonary fibrosis by using BH KO mice. We analyzed single nucleotide polymorphism (SNP) of BH gene by sequencing BH cDNA from the lungs of C3H and B6 mice, by SNP discovery, and genotyped the F2 mice with restriction fragment length polymorphism. We phenotyped BLM-induced pulmonary fibrosis in BH KO mice and F2 mice after treatment with 100mg/kg bleomycin given subcutaneously via a 7 day Alzet osmotic mini-pump. Mice were sacrificed when moribund or 56 days after pump implantation, the end of the experiment. The lungs were taken for histological staining and pulmonary fibrosis was quantified as percent fibrosis (%PF) by dividing the fibrotic area by the area of the whole lung. Sequence analysis and SNP discovery revealed a SNP (C in C3H and T in B6) in the third base pair of codon 364 in exon 9. This polymorphism significantly correlated with BLM induced-pulmonary fibrosis in male F2 mice (%PF = 12.5 for T/T alleles and 1.2 for C/C alleles, P=0.0008). There was no association of this polymorphism with BLM-induced pulmonary fibrosis in female mice (%PF= 2.7 for T/T alleles and 4.1 for C/C alleles P=0.45), consistent with our previous linkage study. Finally, we examined the effect of BLM in a BH KO model. Two thirds(6/9)of the BH-/- mice given 50mg/kg, half of our standard dose, died during of systemic toxicity . In contrast, all BH+/+, BH+/− and B6 mice survived until the end of the experiment after the same dose. The fibrosis score in BH+/− mice (n=4) was 5.6 fold higher than that in the BH+/+ mice (n=3) (%PF= 3.8 for BH+/− and 0.68 for BH+/+). These data suggest that BH gene protects mice from BLM-induced death. This work is supported by NCI grant RO1 CA64193 and LSA
Abstract 19519: Healthy-Heart Behaviors, Risk Factor Knowledge, and Health-Literacy Among Ecuador's Rural Poor
Authors: Cheryl A Westlake, Mauricio Espinel, Fernando Ortega
Journal: Circulation (2017)

Introduction: Cardiovascular disease (CVD) is the most common (23%) cause of death in Ecuador. Of the major CVD risk factors, high BP, total/HDL cholesterol, and glucose, plus risk factor (RF) know...
Abstract OT2-06-01: Highly innovative personalized RNA-immunotherapy for patients with triple negative breast cancer
Authors: M Schmidt, S Bolte, K Frenzel, L Heesen, E Derhovanessian, V Bukur, M Diken, J Gruetzner, S Kreiter, A Klein, A Kuhn, D Langer, M Loewer, H Lindman, A Schneeweiss, O Tuereci, U Sahin
Journal: Cancer Research (2019)

Abstract Background: The treatment of triple negative breast cancer (TNBC) is hampered by the lack of established therapeutic targets such as hormone receptors or HER-2. Chemotherapy and radiotherapy is the standard of care, yet survival rates in TNBC remain poor. Approaches tailored to the patient's individual tumor signature may lead to improved therapeutic outcome. We have set up a clinical workflow covering drug development (from target discovery to manufacturing) and drug release providing a custom-made investigational medicinal product (IMP) for each individual patient. Trial Design: A phase I/II trial assesses the feasibility, safety and biological efficacy of this personalized immunotherapy in three clinical sites in Germany and Sweden. TNBC patients (pT1cN0M0 – TxNxM0) after completion of initial standard of care therapy will be allocated to one of two study arms. Patients in ARM1 receive 8 vaccination cycles with a personalized combination of shared tumor-associated antigens, selected based on each patient tumor's antigen-expression profile out of a WAREHOUSE of pre-manufactured mRNA vaccine. Patients in ARM2 receive the personalized mRNA WAREHOUSE vaccine followed by 8 vaccination cycles of an on-demand manufactured mRNA MUTANOME vaccine encoding up to twenty unique neo-epitopes of the individual patient identified by next generation sequencing. The mRNAs are administered intravenously as a nanoparticulate lipoplex formulation, which protects RNA from degradation, activates innate immunity, transfects APCs and consequently induces highly potent antigen-specific T-cell responses. The treatment of 12 patients in ARM1 is completed and enrolment of patients for ARM2 has started. Preliminary data show that the RNA-WAREHOUSE approach is feasible and can be applied safely. Biomarker analysis is ongoing. This approach is promising as it addresses the heterogeneity of TNBC. The TNBC-MERIT trial was initially funded by the EU Commission's FP7 and led by BioNTech AG. Citation Format: Schmidt M, Bolte S, Frenzel K, Heesen L, Derhovanessian E, Bukur V, Diken M, Gruetzner J, Kreiter S, Klein A, Kuhn A, Langer D, Loewer M, Lindman H, Schneeweiss A, Tuereci O, Sahin U. Highly innovative personalized RNA-immunotherapy for patients with triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-06-01.
THER-23. RESULTS OF THE ZERO CHILDHOOD CANCER INTEGRATED PRECISION MEDICINE PLATFORM FOR PAEDIATRIC HIGH-RISK BRAIN TUMOURS
Authors: Maria Tsoli, Loretta Lau, Paulette Barahona, Chelsea Mayoh, Tim Failes, Marie Wong, Alexandra Sherstyuk, Andrew J Gifford, Amit Kumar, Emily Mould, Caitlin Ung, Ornella Tolhurst, Anjana Gopalakrishnan, Dylan Grebert-Wade, Patrick Strong, Peter Trebilcock, Richard Lock, Vanessa Tyrrell, Toby Trahair, Katherine Tucker, Meera Warby, Greg Arndt, Murray Norris, Michelle Haber, Glenn Marshall, Tracey O’Brien, Dong Anh Khuong Quang, Marc Cowley, Paul Ekert, David S Ziegler
Journal: Neuro-Oncology (2019)

Brain tumours represent the most common solid tumour of childhood and result in significant morbidity and mortality. The Zero Childhood Cancer national child precision medicine program aims to identify targeted therapeutic agents for high-risk paediatric malignancies (expected survival <30%) including brain tumours. Here we will report on the Pilot Feasibility Study (TARGET) and the initial experience of the National Clinical Trial (PRISM), which opened in September of 2017. A total of 200 patients have been enrolled, 59 in the pilot phase (TARGET) and 141 in the National study (PRISM) out of which 77 patients (38.5%) had CNS malignancies, of which 64 cases have completed curation. Molecular analysis of these cases identified actionable molecular aberrations in 47 patients (73.4%). Ten cases (15.6%) had a reportable germline cancer predisposition variant. Overall, the most common aberrant genetic changes observed include TP53 mutations, CDKN2A/B biallelic loss, PDGFRA over-expression mainly in the presence of amplification, and fusions containing either NTRK or BRAF. In 2 cases, the somatic genomic findings changed the primary diagnosis. Fresh tissue collection permitted in vitro high throughput screening (HTS) (120 single agents) in 32/69 (46.3%) of cases with additional cultures currently under development. Hits were identified in 2 cultures and recommendations were made. Four PDX models from successful primary cultures were established where single and combination drug efficacy studies have been performed based on recommendations made from molecular profiling or HTS analysis. Currently multiple PDX models are under evaluation either from successful primary cultures or direct intracranial injection of biopsies. In this study we will present an overview of the molecular and preclinical platforms and their impact on the management of paediatric patients with aggressive brain tumours.
Patient-Physician Relationship in the Age of Expanded Access to Information
Authors: Eric Weinlander
Journal: JAMA (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Paracoccidioidomycosis-Induced Pulmonary Hypertension
Authors: P. Leao, S. Setembre Batah, A. L. dos Santos, M. F. Hrycyk, J. Veronez Franco, D. de Souza Veronez, E. Nascimento, R. Martinez, E. Bagagli, A. I. de Padua, J. Baddini-Martinez, V. L. Capelozzi, A. T. Fabro
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
Diagnosis and classification of amyopathic dermatomyositis
Authors: J.S.S. Concha, M. Tarazi, C.J. Kushner, R.G. Gaffney, V.P. Werth
Journal: British Journal of Dermatology (2019)

Dermatomyositis is an inflammatory disorder in which characteristic skin lesions (affected patches) are associated with inflammation and weakness of the muscles. Some individuals have muscle changes but no skin signs (inflammatory myopathy), whereas some others have only skin lesions and may never develop muscle inflammation (amyopathic dermatomyositis). Existing criteria for classifying muscle inflammation do not recognise amyopathic dermatomyositis. The authors, based at the University of Pennsylvania, USA, used the PubMed database to search medical literature (i.e. research) from June to August 2018 on the diagnosis and classification of amyopathic dermatomyositis. They found 226 articles on diagnosis and 32 specifically on classification. The current validated criteria for recognising skin features fail to include 25% of patients. Amyopathic dermatomyositis can be misdiagnosed clinically (by the doctor) and histologically (after a tissue sample is looked at under a microscope) as another inflammatory skin disease such as cutaneous lupus erythematosus. It is important to make a diagnosis of dermatomyositis since these people are at greater risk of inflammatory lung disease and internal cancers and should be screened for these conditions. The authors conclude that more specific description of skin lesions is needed to clarify the diagnosis, together with additional information such as the presence of autoantibodies in the blood (which are produced by the immune system to fight off illness), some of which are uniquely found in specific patterns of dermatomyositis. More accurate diagnosis will enable more specific treatment in the future.
DIPG-26. ACVR1 R206H COOPERATES WITH H3.1K27M IN PROMOTING DIFFUSE INTRINSIC PONTINE GLIOMA PATHOGENESIS
Authors: Christine Hoeman, Francisco Cordero, Guo Hu, Katie Misuraca, Megan Romero, Herminio Cardona, Javad Nazarian, Rintaro Hashizume, Roger McLendon, Paul Yu, Daniele Procissi, Samantha Gadd, Oren Becher
Journal: Neuro-Oncology (2019)

Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, resulting in the death of 200–300 children each year in the United States. Recently it was discovered that approximately 25% of all DIPG cases harbor activating ACVR1mutations, a gene that encodes Activin A receptor (ALK2), a receptor in the bone morphogenetic protein (BMP) pathway, and that DIPGs with ALK2 mutations commonly harbor an H3.1K27M mutation. Herein, we used the RCAS/TVA retroviral system to study the effects of ACVR1 mutations and H3.1K27M on DIPG pathogenesis. In vitro expression of ACVR1 R206H with and without H3.1K27M in nestin-expressing brainstem progenitors resulted in upregulation of mesenchymal markers and revealed Stat3 activation by gene set enrichment analysis (GSEA) analysis. Neonatal expression of ACVR1 R206H or G328V in combination with H3.1K27M and p53 deletion in nestin-expressing brainstem progenitors induced glioma-like lesions expressing mesenchymal markers along with Stat3 activation but were not sufficient for full gliomagenesis in vivo. In combination with platelet-derived growth factor A (PDGFA) signaling, ACVR1 R206H and H3.1K27M significantly decreased survival and increased tumor incidence. We demonstrate that targeting the BMP signaling may be an effective therapeutic strategy to treat ACVR1 R206H mutant DIPGs as exogenous Noggin expression at tumor initiation significantly increased tumor latency and treatment of ACVR1 R206H mutant murine DIPGs with LDN212854, an ACVR1 inhibitor, significantly prolonged their survival. We confirm relevance of our model to the human disease as human DIPG models with ACVR1 mutations were also sensitive to treatment with LDN212854 in vitro. Altogether, our studies demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile in part due to Stat3 activation, and identify LDN212854 as a promising compound to treat children with DIPG.
What, If, and When to Move: Basal Ganglia Circuits and Self-Paced Action Initiation
Authors: Andreas Klaus, Joaquim Alves da Silva, Rui M. Costa
Journal: Annual Review of Neuroscience (2019)

Deciding what to do and when to move is vital to our survival. Clinical and fundamental studies have identified basal ganglia circuits as critical for this process. The main input nucleus of the basal ganglia, the striatum, receives inputs from frontal, sensory, and motor cortices and interconnected thalamic areas that provide information about potential goals, context, and actions and directly or indirectly modulates basal ganglia outputs. The striatum also receives dopaminergic inputs that can signal reward prediction errors and also behavioral transitions and movement initiation. Here we review studies and models of how direct and indirect pathways can modulate basal ganglia outputs to facilitate movement initiation, and we discuss the role of cortical and dopaminergic inputs to the striatum in determining what to do and if and when to do it. Complex but exciting scenarios emerge that shed new light on how basal ganglia circuits modulate self-paced movement initiation.
Response to: ‘Assessment of responsiveness of the musculoskeletal component of SLE-DAS in an independent cohort’, by Hassan et al
Authors: Diogo Jesus, Margherita Zen, Andrea Doria, Luís Sousa Inês
Journal: Annals of the Rheumatic Diseases (2019)

Response to: 'Assessment of responsiveness of the musculoskeletal component of SLE-DAS in an independent cohort', by Hassan et al It was with great interest that we read the letter 'Assessment of responsiveness of the musculoskeletal component of SLE-DAS in an independent cohort' by Hassan et al. 1 We recently published the derivation and validation of the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS), a new continuous measure of SLE disease activity with high sensitivity and specificity to change. 2 Hassan et al report in their letter that in an analysis of 20 SLE patients, the responsiveness of the arthritis component of SLE-DAS(largeeffectsizeof-0.548)issuperiortothatofthe arthritis component of SLE Disease Activity Index (DAI)-2K (mediumeffectsizeof-0.418). 1 3 These results corroborate our data. 24 Moreover, Hassan et al report that the arthritis component of SLE-DAS presents a similarly large effect size comparing with the arthritis component of the British Isles Lupus Assess-mentGroup(BILAG)(-0.576).AshighlightedbyHassanet al, the SLE-DAS is expected to present a more robust inter-reader reliability than physician visual analogue scale and BILAG, and to be less dependent on the training and expertise of the assessors than BILAG.We further emphasise that SLE-DAS is a global disease activity index (non-organ specific), which presents a major advantage over BILAG for use in daily clinical practice, as it is much less time-consuming and requires a collection time similar to SLEDAI.Hassan et al report that joint ultrasonography (US) is able to detect subclinical synovitis in SLE patients.We agree that in selected patients joint US can be useful to complement clinical assessment.However, the requirement for US joint assessment is not advisable to integrate a disease activity instrument, such as SLE-DAS, as it would constitute a major barrier for its practicality.Importantly, previous studies did not find any added value of systematic joint US assessment for treatment decision in chronic arthritis.
Inconsistency Between Contrast-Enhanced CT and Bone Scintigraphy in Revealing Radiation Nephritis
Authors: Wenjia Zhu, Hongnan Zhen, Ning Ding, Hongli Jing, Li Huo
Journal: Clinical Nuclear Medicine (2019)

Abstract A 34-year-old woman with pancreatic acinar cell carcinoma underwent a 99m Tc-MDP bone scan to rule out potential bone metastasis because of back pain 18 months after radiation therapy. The bone scintigraphy revealed increased uptake over the upper pole of both kidneys corresponding to the portions of the kidneys included within the radiation field, consisting with radiation nephritis.
ATRT-12. BINIMETINIB SUPPRESSES THE GROWTH OF ATYPICAL TERATOID/RHABDOID TUMOR CELLS AND INDUCES APOPOTOSIS
Authors: Shubin Shahab, Jeffrey Rubens, Charles Eberhart, Eric Raabe
Journal: Neuro-Oncology (2019)

Atypical teratoid/rhabdoid (AT/RT) tumors are a class of malignant CNS tumors disproportionately affecting children with limited therapeutic options. Our group has previously demonstrated that the MAP kinase pathway is altered in a large proportion of these tumors and the MEK inhibitor selumetinib decreases cell growth and promotes apoptosis of AT/RT cells. One of the major drawbacks of selumetinib is its poor blood-brain barrier penetration. Binimetinib is a novel MEK inhibitor currently in pediatric phase II clinical trials for low grade glioma that has improved brain penetration. Binimetinib inhibits AT/RT growth at nanomolar concentrations, with IC25 values of 66.9 nM, 36.68 nM, 69.75 nM, 622.7 nM.and IC50 values of 101.06 nM, 107.69 nM, 691.485 nM and 1429.9 nM for CHLA266, CHLA06, BT37 and BT12 respectively. Binimetinib successfully decreases cell proliferation[ER1] and induces apoptosis (2–3 fold induction of cleaved PARP; p<0.005 for CHLA06 at 250 nM of MEK162 and at for BT37 at 1000 nM of MEK162 by cleaved caspase 3 positive cells on immunofluorescence) in AT/RT cell lines, suggesting binimetinib could offer a potential avenue for treating these deadly tumors.