tbuckley/cabot-search huggingface dataset:
Abstract 16678: A Novel p38-Alpha MAPK Inhibitor Reverses Sugen/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats
Authors: Allan Kardec N Alencar, Grazielle F Silva, Marina M Silva, Jaqueline S da Silva, Josenildo S Araujo, Tadeu L Montagnoli, Rosana C Freitas, Carlos A Fraga, Roberto T Sudo, Gisele Zapata-Sudo
Journal: Circulation (2018)

Introduction: Pulmonary arterial hypertension (PAH) is a disease characterized by pulmonary vascular remodeling with subsequent right ventricular (RV) failure. Hypothesis: The p38-alpha mitogen-activated protein kinase (p38-α MAPK) plays a pathogenic role in PAH. This work investigated the effects of a selective p38-alpha MAPK inhibitor, named LASSBio-1824, on hypoxia + SU5416 -induced PAH. Methods: Male Wistar rats (180-220 g) were exposed to 3 weeks of hypoxia and i.p. injection of VEGFR antagonist (SU5416; 20 mg/kg/week). Experimental groups were: Control + vehicle (DMSO), SuHx + vehicle (PAH group) and SuHx + LASSBio-1824 (20 mg/kg/day for 2 weeks). Results: Pulmonary acceleration time (ms) was reduced from 44.7 ± 1.1 (control) to 20.6 ± 1.7 in SuHx + vehicle group (P &lt; 0.05) and restored to 38.9 ± 2.9 in SuHx + LASSBio-1824 group (P&lt; 0.05). RV systolic pressures (mmHg) were increased from 30.1 ± 3.2 (control) to 109.5 ± 7.5 in SuHx group and reduced to 47.5 ± 5.3 after treatment with LASSBio-1824 (P &lt; 0.05). The medial wall thickness of distal pulmonary arterioles (&lt; 50 μm) was measured by immunohistochemistry for alpha-SMA expression which was increased from 40.7 ± 3.5 % (control) to 64.1 ± 3.1 % in PAH animals (P &lt; 0.05) and was reduced in the treated group (52.2 ± 2.9). Acetylcholine-induced maximal relaxation (% ) in pulmonary arteries was reduced from 77.9 ± 5.2 to 17.2 ± 3.5 in PAH group. LASSBio-1824 increased that response to 67.8 ± 5.6 % (P &lt; 0.05), indicating the ame- lioration of endothelial function. RV hypertrophy was detected because its wall thickness (mm) increased from 0.56 ± 0.02 (control) to 1.3 ± 0.03 in SuHx + vehicle group (P &lt; 0.05) and the ratio between RV and left ventricle + septum increased from 1.50 ± 0.03 to 2.0 ± 0.2. Treatment with LASSBio-1824 significantly reduced the RV hypertrophy (ratio of 1.7 ± 0.07). Conclusion: The inhibition of p38-alpha MAPK isoform by LASSBio-1824 represents an impor- tant approach for the treatment of PAH in the future, which improves the underlying remodeling and inflammation processes.
Diagnostic Accuracy of Immunoglobulin Heavy Chain Rearrangement, FDG-PET/CT and Unilateral Bone Marrow Trephination for Detecting Bone Marrow Involvement in Diffuse Large B Cell Lymphoma
Authors: Seung-Yeon Jung, Sung-Hoon Jung, Seo-Yeon Ahn, Je-Jung Lee, Hyeoung-Joon Kim, Jun Hyung Lee, Myung Geun Shin, Su Woong Yoo, Deok-Hwan Yang
Journal: Blood (2018)
Defending optimistic rationalism: A reply to commentators
Authors: Joshua May
Journal: Behavioral and Brain Sciences (2019)

In response, I elaborate on my conception of moral reasoning, as well as clarify the structure of debunking arguments and how my cautious optimism is only of the "glass half full" sort. I also explain how rationalism can capture insights purportedly only explained by sentimentalist and Humean views. The reply concludes by clarifying and admitting some limits of the book's scope.
Pharmacokinetic and pharmacodynamic analysis of topotecan administered in combination with PS 341 in patients with advanced malignancy
Authors: M. Tomita, L. Xin, B. Freeman, S. Twomey, G. Pizzorno, J. R. Murren
Journal: Journal of Clinical Oncology (2006)

2033 Background: In vitro exposure to camptothecin results in down-regulation of the target enzyme, topoisomerase I (topo) via multi-ubiquitination and proteasomal degradation of the protein-linked DNA breaks. To prevent loss of topo, and thus circumvent a possible mechanism of resistance to the topo inhibitors, we conducted a dose escalating phase I study of topotecan in combination with the proteosome inhibitor PS 341. We now report the pharmacokinetic and pharmacodynamic analysis of the trial. Methods: Patients with advanced cancer were treated with topotecan alone at the following dose escalating levels: 0.75, 1.0,1,25 and 1.5 mg/m 2 as a 60 min infusion d x 5 during cycle 1. In subsequent cycles (21 days), cohorts of 3–6 patients received PS 341 as a 30 min infusion on days 1, 4, 8 and 11 at the following dose levels: 0.6, 0.8, 1.0 and 1.3 mg/m 2 . Topo expression was determined by western blot on peripheral blood mononuclear cells (PBMCs) sampled throughout the first 5-day treatment period of cycles #1 and 2. Total topotecan plasma pharmacokinetics were studied with the first doses of topotecan on cycle #1 (topotecan alone) and cycle #2 (topotecan after PS 341). Results: Samples were collected from 22 patients and 38 patient-cycles. In the first week of cycle #1, 9 of 22 (41 %) patients demonstrated a significant decrease in topo expression (range 0.2 - 1 fold) compared with the baseline level. Topo levels did not change (7/22, 32%) or increased (6/22, 27%) in the remaining patients. After administration of PS 341 during cycle #2, PBMC from 10 of 17 patients (59 %) analyzed showed a greater than 0.3 fold increase (range: 0.32 to 63) in topo concentration, and topo levels in 4 patients (23 %) were unchanged. Preliminary pharmacokinetic analysis indicates that PS 341 may interact with topotecan. Conclusions: There is a heterogeneous response in PBMC topo levels following administration of topotecan. However, addition of PS 341 to topotecan stabilized or increased PBMC topo I levels in the majority of patients, suggesting a possible role for PS341 in inhibiting camptothecin-induced topo protein degradation. Further studies combining proteasome inhibitors with topotecan to overcome drug resistance based on topo degradation are warranted. No significant financial relationships to disclose.
Scotland strikes deal to offer cystic fibrosis drugs
Authors: Bryan Christie
Journal: BMJ (2019)

Expensive drugs to treat cystic fibrosis will be made available in the UK for the first time, after the Scottish government struck a deal with the manufacturer that will benefit around 400 patients.

The agreement in Scotland increases pressure for the drugs to be made available in other parts of the UK, and the Department of Health in England has urged the US manufacturer, Vertex Pharmaceuticals, to accept an offer that the …
Redefining Heart Failure With a Reduced Ejection Fraction
Authors: Javed Butler, Stefan D. Anker, Milton Packer
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
Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface
Authors: Jessica Koach, Jessica K. Holien, Hassina Massudi, Daniel R. Carter, Olivia C. Ciampa, Mika Herath, Taylor Lim, Janith A. Seneviratne, Giorgio Milazzo, Jayne E. Murray, Joshua A. McCarroll, Bing Liu, Chelsea Mayoh, Bryce Keenan, Brendan W. Stevenson, Michael A. Gorman, Jessica L. Bell, Larissa Doughty, Stefan Hüttelmaier, Andre Oberthuer, Matthias Fischer, Andrew J. Gifford, Tao Liu, Xiaoling Zhang, Shizhen Zhu, W. Clay Gustafson, Michelle Haber, Murray D. Norris, Jamie I. Fletcher, Giovanni Perini, Michael W. Parker, Belamy B. Cheung, Glenn M. Marshall
Journal: Cancer Research (2019)

MYCN is a major driver for the childhood cancer, neuroblastoma, however, there are no inhibitors of this target. Enhanced MYCN protein stability is a key component of MYCN oncogenesis and is maintained by multiple feedforward expression loops involving MYCN transactivation target genes. Here, we reveal the oncogenic role of a novel MYCN target and binding protein, proliferation-associated 2AG4 (PA2G4). Chromatin immunoprecipitation studies demonstrated that MYCN occupies the PA2G4 gene promoter, stimulating transcription. Direct binding of PA2G4 to MYCN protein blocked proteolysis of MYCN and enhanced colony formation in a MYCN-dependent manner. Using molecular modeling, surface plasmon resonance, and mutagenesis studies, we mapped the MYCN-PA2G4 interaction site to a 14 amino acid MYCN sequence and a surface crevice of PA2G4. Competitive chemical inhibition of the MYCN-PA2G4 protein-protein interface had potent inhibitory effects on neuroblastoma tumorigenesis in vivo. Treated tumors showed reduced levels of both MYCN and PA2G4. Our findings demonstrate a critical role for PA2G4 as a cofactor in MYCN-driven neuroblastoma and highlight competitive inhibition of the PA2G4-MYCN protein binding as a novel therapeutic strategy in the disease. SIGNIFICANCE: Competitive chemical inhibition of the PA2G4-MYCN protein interface provides a basis for drug design of small molecules targeting MYC and MYCN-binding partners in malignancies driven by MYC family oncoproteins.
Beyond duty hours: leveraging large-scale paging data to monitor resident workload
Authors: Amit Kaushal, Laurence Katznelson, Robert A. Harrington
Journal: npj Digital Medicine (2019)

Abstract Monitoring and managing resident workload is a cornerstone of policy in graduate medical education, and the duty hours metric is the backbone of current regulations. While the duty hours metric measures hours worked, it does not capture differences in intensity of work completed during those hours, which may independently contribute to fatigue and burnout. Few such metrics exist. Digital data streams generated during the usual course of hospital operations can serve as a novel source of insight into workload intensity by providing high-resolution, minute-by-minute data at the individual level; however, study and use of these data streams for workload monitoring has been limited to date. Paging data is one such data stream. In this work, we analyze over 500,000 pages—two full years of pages in an academic internal medicine residency program—to characterize paging patterns among housestaff. We demonstrate technical feasibility, validity, and utility of paging burden as a metric to provide insight into resident workload beyond duty hours alone, and illustrate a general framework for evaluation and incorporation of novel digital data streams into resident workload monitoring.
Toxicity and efficacy of busulfan-melphalan (BuMel) compared to treosulfan-melphalan (TreoMel) high dose chemotherapy (HDCT) consolidation in high-risk Ewing sarcoma (ES): A 12-year monoinstitutional experience.
Authors: Massimo Eraldo Abate, Anna Paioli, Marilena Cesari, Alessandra Longhi, Emanuela Palmerini, Elisabetta Setola, Elisa Carretta, Silvia Cammelli, Letizia Ronchi, Michele Rocca, Marco Manfrini, Katia Scotlandi, Davide Maria Donati
Journal: Journal of Clinical Oncology (2019)

e22507 Background: We compared toxicity and outcomes of BuMel and TreoMel HDCT consolidation with stem cell rescue in high-risk ES pts prospectively treated in 5 consecutive trials at the Istituto Ortopedico Rizzoli, Bologna, Italy. Methods: Eligible pts had histologically proven diagnosis of ES, high-risk disease defined as localized disease with poor histological/radiological response to standard chemotherapy or lung/pleural metastases or extra-pulmonary metastases or relapsed disease, were aged &lt; 40. All pts received previous standard chemotherapy (vincristine, ifosfamide, doxorubicin, etoposide, cyclophosphamide actinomycin-D) and surgery and/or radiation therapy (RT) as local treatment. From June 1, 2011, TreoMel was used instead of BuMel to avoid potential severe complications related to busulfan, as in case of previous RT on axial skeleton/pelvis. Pts with lung metastases received lung irradiation 12-15 Gy at least 2 months after HDCT. Results: Between January 1, 2007, and September 30, 2018, 98 pts received BuMel or TreoMel: 52 pts with localized disease (7 TreoMel), 26 pts with lung/pleural metastases (5 TreoMel), 10 pts with extra-pulmonary metastases (4 TreoMel) and 10 pts with relapsed disease (1 TreoMel). Median age was 18 yrs (range 3-39 yrs). 14 out of 17 TreoMel pts received previous RT on axial skeleton/pelvis. Median follow up is 4.2 yrs (range 10 mo. - 12 yrs). Pts treated with TreoMel showed a significant lower incidence of grade 3-4 stomatitis (p = &lt; 0.001) and of all grade ≥ 3 non-hematological toxicities (p = &lt; 0.001). One pt died of BuMel-related toxicity (sinusoidal obstruction syndrome/veno-occlusive disease) and none after TreoMel. For localized ES, the 5yr-EFS was 66.7% (95%CI, 47.9-78) for BuMel pts and 66.7% (95CI%, 19.5-90.4) for TreoMel pts. Conclusions: In high-risk ES, TreoMel is significantly less toxic then BuMel. Combining RT on central/axial sites and TreoMel is feasible. In localized ES, results show similar 5yr-EFS between BuMel and TreoMel. TreoMel could be used instead of BuMel when busulfan is contraindicated.
No statistical impact of intra-tumoral overexpression of EGFR, VEGF and p53 on the overall survival in head and neck squamous cell cancer (HNSCC): Preliminary results of the GORTEC 99–02 randomized trial
Authors: J. Metges, A. Volant, A. Auperin, V. Gregoire, P. Maingon, J. Lesaunier, G. Calais, J. Bourhis
Journal: Journal of Clinical Oncology (2007)

6010 Background: Predictive and prognostic factors are warranted to improve the management of HNSCC patients. We designed a prospective study to analyze the p53 status, vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) tumoral overexpression of the patients included in the GORTEC 99–02 prospective phase III trial which compared conventional radiotherapy (RT) plus 5FU and carboplatin (FUP) vs RT with concomitant boost and FUP vs very accelerated RT Methods: This propective study has been designed to include 820 patients. We present here the results in a sub group of 219 patients for whom the immunohistochemical overexpression of EGFR, P53 and VEGF was analyzed. Association beetween these markers and TNM staging, age, sex,disease progression and survival was evaluated. Tumor overexpression was assessed by immunohistochemistry for EGFR (Dako EGFR pharmDx™ kit), VEGF (Santa Cruz Biotech), P53 (Dako). EGFR status was defined as positive or negative.If positive, we evaluated the percentage of cells presenting the same intensity of staining. Staining pattern was qualified as “diffuse” if more than 95% of cancer nests were stained with the same intensity, and as “mosaic” if the staining was heterogeneous Statistical analysis were performed using Spearman correlation coefficient, Kruskal-Wallis test for quantitative variables, chi2 and Fisher exact test for qualitative variables and Logrank test and cox model for survival analysis. Multivariate analysis of survival took into account T and N status, tumor localisation and the type of treatment. Results: Positive expression for P53, VEGF and EGFR were respectively found in 56.4%, 61.1% and 94%.Diffuse EGFR status was associated with higher T status (p=0.0141). VEGF(+) status was associated with increased EGFR staining (p=0.0017). Patients with p53+ status were younger than p53(-) (p=0.0362). P53,VEGF and EGFR expressions were not significatively related to survival Conclusions: These preliminary results don’t found any relationship between intra-tumoral markors and survival in HNSCC.Work supported by a french PHRC from the national Institute of Health No significant financial relationships to disclose.
Abstract 11125: Soluble Urokinase Plasminogen Activator Receptor is a Strong Prognostic Indicator of Mortality in Acutely Breathless Patients
Authors: Janice Chew-Harris, Sarah Appleby, Richard Troughton, Mark Richards, Christopher Pemberton
Journal: Circulation (2018)

Introduction: Soluble urokinase plasminogen activator receptor (suPAR) is a circulating protein believed to be responsible for immune dysfunction leading to plague vulnerability. Its use in heart f...
CDK12 inhibition mediates DNA damage and is synergistic with sorafenib treatment in hepatocellular carcinoma
Authors: Cun Wang, Hui Wang, Cor Lieftink, Aimee du Chatinier, Dongmei Gao, Guangzhi Jin, Haojie Jin, Roderick L Beijersbergen, Wenxin Qin, René Bernards
Journal: Gut (2019)

Hepatocellular carcinoma (HCC) is one of the most frequent malignancies and a major leading cause of cancer-related deaths worldwide. Several therapeutic options like sorafenib and regorafenib provide only modest survival benefit to patients with HCC. This study aims to identify novel druggable candidate genes for patients with HCC.A non-biased CRISPR (clustered regularly interspaced short palindromic repeats) loss-of-function genetic screen targeting all known human kinases was performed to identify vulnerabilities of HCC cells. Whole-transcriptome sequencing (RNA-Seq) and bioinformatics analyses were performed to explore the mechanisms of the action of a cyclin-dependent kinase 12 (CDK12) inhibitor in HCC cells. Multiple in vitro and in vivo assays were used to study the synergistic effects of the combination of CDK12 inhibition and sorafenib.We identify CDK12 as critically required for most HCC cell lines. Suppression of CDK12 using short hairpin RNAs (shRNAs) or its inhibition by the covalent small molecule inhibitor THZ531 leads to robust proliferation inhibition. THZ531 preferentially suppresses the expression of DNA repair-related genes and induces strong DNA damage response in HCC cell lines. The combination of THZ531 and sorafenib shows striking synergy by inducing apoptosis or senescence in HCC cells. The synergy between THZ531 and sorafenib may derive from the notion that THZ531 impairs the adaptive responses of HCC cells induced by sorafenib treatment.Our data highlight the potential of CDK12 as a drug target for patients with HCC. The striking synergy of THZ531 and sorafenib suggests a potential combination therapy for this difficult to treat cancer.
A Multicenter Retrospective Experience of Hematologic Neoplasms in Pregnancy
Authors: Álvaro Cabrera-García, Samuel Vargas-Trujillo, Alonso Hernández-Company, Carolina Balderas-Delgado, Guillermo Días-Vargas, Espinoza Ramiro, Efreen Montaño Figueroa, Everardo Antonio Barragan-Romero, Tito Ramirez-Lozada, Leopoldo Gatica-Galina, Etzel Camargo Romero, Christian Ramos-Peñafiel, Humberto Baldemar Baldemar Castellanos Sinco, Edith Elizalde-Silva, Flor Cruz-Antonio, Andrea Ambriz-Reyes, Victor Manuel Vidal-González
Journal: Blood (2017)
Lifestyle Interventions for Weight Management in People with Serious Mental Illness: A Systematic Review with Meta-Analysis, Trial Sequential Analysis, and Meta-Regression Analysis Exploring the Mediators and Moderators of Treatment Effects
Authors: Helene Speyer, Ane Storch Jakobsen, Casper Westergaard, Hans Christian Brix Nørgaard, Charlotta Pisinger, Jesper Krogh, Carsten Hjorthøj, Merete Nordentoft, Christian Gluud, Christoph U. Correll, Kirstine Bro Jørgensen
Journal: Psychotherapy and Psychosomatics (2019)

Background: Serious mental illness (SMI) reduces life expectancy, primarily due to somatic comorbidity linked to obesity. Meta-analyses have found beneficial effects of lifestyle interventions in people with SMI and recommended their implementation to manage obesity. Objective: The objective of this systematic review was to assess the benefits and harms of individualized lifestyle interventions for weight in people diagnosed with SMI and to explore potential mediators and moderators of the effect. Methods: The protocol was registered at PROSPERO (CRD42016049093). Randomized clinical trials (RCTs) assessing the effect of individualized lifestyle interventions on weight management in people with SMI were included. Primary outcomes were differences in endpoint body mass index (BMI) and the proportion achieving clinically relevant weight loss (≥5%). Secondary outcomes included quality of life, cardiometabolic risk factors, and adverse effects. Results: We included 41 RCTs (n = 4,267). All trials were at high risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions. The experimental interventions reduced the mean difference in BMI by –0.63 kg/m2 (95% confidence interval [CI] = –1.02 to –0.23; p = 0.002; I2 = 70.7%) compared to the control groups. At postintervention follow-up (17 RCTs), the effect size remained similar but was no longer significant (BMI = –0.63 kg/m2; 95% CI = –1.30 to 0.04; p = 0.07; I2 = 48.8%). The risk ratio for losing ≥5% of baseline weight was 1.51 (95% CI = 1.07–2.13; p = 0.02) compared to the control groups. GRADE showed very low or low quality of evidence. Conclusion: There is a statistically significant, but clinically insignificant, mean effect of individualized lifestyle interventions for weight reduction in people with SMI.