tbuckley/cabot-search huggingface dataset:
First-in-human, first-in-class phase 1 study of a novel oral multi-AGC kinase inhibitor AT13148 in patients (pts) with advanced solid tumors.
Authors: Rajiv Kumar, Joaquin Mateo, Alan D. Smith, Khurum Hayat Khan, Ruth Ruddle, Karen E Swales, Shaun Decordova, Zoe Backholer, Paul Jones, Christine Tran, Satyanarayana Seeramreddi, Robert McLeod, Timothy Anthony Yap, Florence I. Raynaud, Michelle D Garrett, Udai Banerji
Journal: Journal of Clinical Oncology (2014)

2554 Background: Aberrant signaling through the AGC kinases is implicated as a critical driver of multiple cancers. AT13148 is a novel multi-AGC kinase inhibitor, which potently inhibits AKT, P70S6K, PKA and ROCKI/II. Following promising in vivoantitumor activity through mechanisms distinct from specific AKT inhibitors, a phase I trial was initiated. Methods: Pts with advanced solid tumors were enrolled onto study using a standard 3+3 dose escalation strategy. AT13148 was given orally on days (D) 1, 3 and 5 of every week, in 28-day cycles. The starting dose was 5mg, with a 4-week dose limiting toxicity (DLT) period. Pharmacokinetic (PK) parameters were assessed after a run-in dose (D1-7) and at cycle (C)2 D1. Pharmacodynamic (PD) biomarkers for AKT signaling were analyzed in tumor, platelet rich plasma (PRP) and hair follicles at multiple timepoints. Results: 14 pts were treated with AT13148 (7M: 7F; 4 ECOG 0, 10 ECOG 1). Median age 57y. Median duration of treatment was 40 days (range 25-76). AT13148 was well tolerated with no drug-related toxicities observed. No DLTs have been observed in 9 evaluable pts in 3 completed dose levels (5, 10 and 20mg). PK analysis in 3 pts at 20mg AT13148 demonstrated Cmax between 18-50nmol/L , with Tmax of 4h. The average T1/2was 24h resulting in a 2 fold increase in exposure on cycle 2. Preliminary PD data in PRP showed no modulation of pAKT, pGSK3β or pP70S6K at the first 2 dose levels i.e. 5 and 10mg cohorts. 2 pts currently remain on study in the 20mg cohort. Conclusions: AT13148 was well tolerated and showed no drug-related toxicities at 5, 10 and 20mg doses. Preliminary PK and PD data are in keeping with early phases of dose escalation. Dose escalation will continue until a MTD is established. Clinical trial information: NCT01585701.
Abstract 19434: The Novel PPARalpha-Selective Agonist K-877 Improves Dyslipidemia, Enhances Reverse Cholesterol Transport and Decreases Inflammation and Atherosclerosis
Authors: Nathalie Hennuyer, Isabelle Duplan, Charlotte Paquet, Jonathan Vanhoutte, Véronique Touche, Giulia Chinetti, Sophie Lestavel, Toshiaki Takizawa, Yukiyoshi Yamazaki, Sohei Tanabe, Bart Staels
Journal: Circulation (2013)

Background: Atherosclerosis is characterized by lipid accumulation and chronic inflammation in the arterial wall. Elevated levels of apolipoprotein (apo) B-containing lipoproteins are a risk factor for cardiovascular disease (CVD). By contrast, plasma levels of high-density lipoprotein (HDL) and apoA-I are protective against CVD by enhancing HDL functionality and reverse cholesterol transport (RCT). Activation of peroxisome proliferator-activated receptor-alpha (PPARalpha), a ligand-activated transcription factor, controls plasma lipid metabolism, macrophage cholesterol handling as well as the inflammatory response. Objective: To study whether pharmacological activation of PPARalpha with the highly potent PPARalpha ligand, K-877, improves lipid metabolism, macrophage cholesterol efflux, inflammation and consequently atherosclerosis development in human apoA-I transgenic mice and in the human apolipoprotein E2 knock-in mouse (apo E2KI) model of mixed dyslipidemia and atherosclerosis. Methods and results: In polarized Caco-2/TC7 human intestinal epithelium cells, K-877 treatment decreased apoB secretion and increased the expression of PPARalpha target genes involved in fatty acid oxidation and intestinal HDL production. Moreover, K-877 induced secretion of apoA-I in HDL particles. In primary human macrophages, K-877 promoted macrophage cholesterol efflux to HDL. K-877 treatment of human apoA-I transgenic mice induced plasma HDL cholesterol and apoA-I levels. Moreover, K-877 stimulated in vivo RCT in these mice. In addition, K-877 treatment exerted anti-inflammatory properties in murine and human macrophages. K-877 treatment not only improved the lipid profile, but also reduced inflammatory and macrophage marker gene expression in the aortic crosses as well as aortic atherosclerotic lesion burden in western diet-fed apo E2KI mice. Conclusion: These results demonstrate that the novel PPARalpha agonist K-877 exerts beneficial effects on lipid metabolism, RCT and inflammation resulting in anti-atherogenic properties.
Abstract 8915: Utility of Transmural Myocardial Strain Profile to Predict Early Left Ventricular Dysfunction in Patients with Duchenne Muscular Dystrophy
Authors: Tetsushi Yamamoto, Hidekazu Tanaka, Takamitsu Imanishi, Nobuhide Hayashi, Yasuhiro Takeshima, Hiroya Kawai, Seiji Kawano, Ken-ichi Hirata
Journal: Circulation (2011)

Background: Myocardial damage in Duchenne muscular dystrophy (DMD) leads to lethal outcome. Therefore, early detection of myocardial changes in DMD is important because earlier treatment might help to prevent the development of myocardial fibrosis. Transmural myocardial strain distribution can be obtained as a form of transmural strain profile using myocardial tissue Doppler strain imaging. Accordingly, the aim of this study was to test the hypothesis that transmural strain profile (TMSP) analysis can predict future left ventricular (LV) dysfunction in DMD patients with preserved ejection fraction (EF). Methods: We studied 57 consecutive DMD patients who did not have LV wall motion abnormality; EF 60±7% (all ≥ 55%), aged 11±3 years. Echocardiography was performed at baseline and 1-year follow-up. TMSP was evaluated in the posterior wall from mid-LV short-axis view (Aplio-XG Toshiba Corp.). Results: Thirty-seven patients (65%) had normal TMSP pattern (Group 1), and the remaining 20 patients (35%) were classified as TMSP with a notch (Group 2). The peak strain value in the posterior wall and EF were similar between two groups. Of 20 patients in Group 2, 8 patients (40%) had wall motion abnormality in the posterior wall at 1-year follow-up. On the other hand, no patient in Group 1 had wall motion abnormality at 1-year follow-up (p&lt;0.001 vs. Group 2). Conclusions: Subclinical LV dysfunction can be detected with TMSP in DMD patients who do not have wall motion abnormalities by conventional echocardiography. TMSP with notch was useful at evaluating early subtle changes in DMD patients, and may be useful for predicting future LV dysfunction.
Further Limitations of a Model-Based Study of People Living With HIV and Lung Cancer Mortality
Authors: Zhuangming Marc Lai, Srishti Chhabra
Journal: JAMA Internal Medicine (2018)

To the Editor In an Original Investigation published in a recent issue of JAMA Internal Medicine, Reddy and colleagues1 used a microsimulation model to calculate cumulative lung cancer mortality in people living with HIV (PLWH) on antiretroviral therapy stratified by age, sex, and smoking exposure.
Chemosensitivity of triple-negative breast cancer cell lines to cisplatin and gemcitabine
Authors: Elizabeth Alli, Kedar Hastak, James Ford
Journal: Cancer Research (2008)

643   The basal-like subtype of breast cancer is characterized by a “triple negative” phenotype (i.e. negative for expression of the estrogen, progesterone, and HER2 receptors), and shares a similar expression profile to breast cancers with  BRCA1  mutations. These cancers are often associated with a poor outcome and are resistant to current treatment options. Previous work from our and other laboratories has shown sensitivity of BRCA1-deficient cells to cisplatin. Recently, we have also found that BRCA1-deficient cells were more sensitive to gemcitabine compared to wild-type BRCA1 cells. We thus hypothesized that the triple-negative phenotype would also render cellular sensitivity to cisplatin and gemcitabine. Therefore, we first identified a panel of breast cancer cell lines with triple negative status (HCC38, HCC1143, HCC1806, MDAMB468, and hs578t) and confirmed the lack of ER, PR, and HER2 expression by Western blot. We then compared these triple negative cell lines to other breast cancer cell lines (MCF7 and BT474) for sensitivity to cisplatin and gemcitabine by methylene blue staining and MTT assay. We found that the triple negative cell lines were more sensitive to cisplatin and gemcitabine compared to the other cancer cell lines. Moreover, the triple negative cell lines were more sensitive to gemcitabine (IC 50 =2-8 nm) than cisplatin (IC 50 =50-100 μM). This effect was not observed for doxorubicin or paclitaxel. To determine the mechanism of cellular sensitivity to cisplatin and gemcitabine, we probed for similarities between the triple negative and BRCA1-deficient cell lines. First, we analyzed the triple negative cell lines for functional BRCA1 by examining expression of the protein in the nucleus by Western blot, and found that the triple negative cell lines expressed nuclear BRCA1. We then analyzed published microarray data for expression changes common to the triple negative and BRCA1-mutated cell lines, and identified p63 to be significantly overexpressed (p
Patients with adult- and late childhood-onset atopic dermatitis report a higher burden of disease severity than patients with early childhood-onset atopic dermatitis.
Authors: Peck Y. Ong, Zelma Chiesa Fuxench, Luz S. Fonacier, Lawrence B. Schwartz, Mitchell H. Grayson, Julie Block, Lynda Mitchell, Joel M. Gelfand, Jonathan I. Silverberg, David J. Margolis, Mark Boguniewicz, Eric L. Simpson
Journal: Journal of Allergy and Clinical Immunology (2018)
Future of Neurologic Examination in Clinical Practice
Authors: Laurence Bindoff
Journal: JAMA Neurology (2018)

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 Neurology HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Neurology journal
Evolutionary Perspectives on Genetic and Environmental Risk Factors for Psychiatric Disorders
Authors: Matthew C. Keller
Journal: Annual Review of Clinical Psychology (2018)

Evolutionary medicine uses evolutionary theory to help elucidate why humans are vulnerable to disease and disorders. I discuss two different types of evolutionary explanations that have been used to help understand human psychiatric disorders. First, a consistent finding is that psychiatric disorders are moderately to highly heritable, and many, such as schizophrenia, are also highly disabling and appear to decrease Darwinian fitness. Models used in evolutionary genetics to understand why genetic variation exists in fitness-related traits can be used to understand why risk alleles for psychiatric disorders persist in the population. The usual explanation for species-typical adaptations—natural selection—is less useful for understanding individual differences in genetic risk to disorders. Rather, two other types of models, mutation-selection-drift and balancing selection, offer frameworks for understanding why genetic variation in risk to psychiatric (and other) disorders exists, and each makes predictions that are now testable using whole-genome data. Second, species-typical capacities to mount reactions to negative events are likely to have been crafted by natural selection to minimize fitness loss. The pain reaction to tissue damage is almost certainly such an example, but it has been argued that the capacity to experience depressive symptoms such as sadness, anhedonia, crying, and fatigue in the face of adverse life situations may have been crafted by natural selection as well. I review the rationale and strength of evidence for this hypothesis. Evolutionary hypotheses of psychiatric disorders are important not only for offering explanations for why psychiatric disorders exist, but also for generating new, testable hypotheses and understanding how best to design studies and analyze data.
Melanoma risk prediction using a multilocus genetic risk score in the Women's Health Initiative cohort
Authors: Hyunje G. Cho, Katherine J. Ransohoff, Lingyao Yang, Haley Hedlin, Themistocles Assimes, Jiali Han, Marcia Stefanick, Jean Y. Tang, Kavita Y. Sarin
Journal: Journal of the American Academy of Dermatology (2018)
Abstract 9398: Cornell Product Criteria for Left Ventricular Hypertrophy Strongly Predicts the Presence of Diastolic Dysfunction
Authors: Joseph M Krepp, Fay Lin, James K Min, Richard B Devereux, Peter M Okin
Journal: Circulation (2012)

Background: Abnormal left ventricular (LV) diastolic function is a known predictor of poor cardiovascular outcomes. Although ECG LV hypertrophy (LVH) has been related to LV systolic dysfunction and both prevalent and incident heart failure, whether ECG LVH is associated with LV diastolic dysfunction (DD) is unknown. Methods: From a cohort of patients who underwent both cardiac computed tomographic angiography and transthoracic echocardiography (TTE) with complete evaluation of diastolic function, 185 that underwent ECG within one year of TTE were identified as the study group. The presence of DD was determined according to standard guidelines via evaluation of mitral inflow velocities, tissue Doppler imaging, deceleration time, isovolumic relaxation time, pulmonary venous systolic: diastolic ratio, and left atrial enlargement. ECG LVH by Cornell product (CP) criteria was categorized into the highest quartile (≥1595 mm[[Unable to Display Character: ⋅]]ms) vs the lower three quartiles or evaluated as a continuous variable with odds ratios (OR) calculated for each SD of the mean (664 mm[[Unable to Display Character: ⋅]]ms) higher CP. Results: Among the 185 patients (56.2% female, mean age 54.6 ± 15.6), mean CP was 1240 ± 664 mm[[Unable to Display Character: ⋅]]ms and 105 (57%) had DD. In univariate logistic regression analysis, being in the upper quartile of CP was associated with over fivefold greater odds of DD (OR 5.1 95% CI 2.2-11.7, p&lt;0.001). In alternative analyses treating CP as a continuous variable, each 1 SD increase in CP was associated with an OR of 1.9 for DD (95% CI 1.3-2.7 p&lt;0.001). In multivariate logistic regression analyses adjusting for statistically significant univariate predictors of DD including age, history of hypertension, hypercholesterolemia, indexed LV mass, R wave axis, degree of coronary artery disease, PR interval and ST segment deviation as covariates, the highest quartile of CP remained associated with a significantly increased odds of having DD (OR 5.7 95% CI 2.2-14.7 p=0.001); alternatively, each 1 SD of CP was associated with a 1.8-fold increased odds of DD (95% CI 1.2-2.5 p=0.003). Conclusions: Cornell product ECG LVH is a powerful predictor of the presence of diastolic dysfunction, even after adjustment for potential confounding risk factors and ECG variables.
Lipid profile and effect of statin treatment in pooled phase II and phase III baricitinib studies
Authors: Peter C Taylor, Joel M Kremer, Paul Emery, Steven H Zuckerman, Giacomo Ruotolo, Jinglin Zhong, Lei Chen, Sarah Witt, Chadi Saifan, Monika Kurzawa, James D Otvos, Margery A Connelly, William L Macias, Douglas E Schlichting, Terence P Rooney, Stephanie de Bono, Iain B McInnes
Journal: Annals of the Rheumatic Diseases (2018)

Objectives Lipid profiles are altered by active disease in patients with rheumatoid arthritis (RA) and may be further modified by treatment with Janus kinase inhibitors and other disease-modifying antirheumatic drugs. Methods Lipid data were analysed from phase II and III studies of 4 mg (n=997) and 2 mg (n=479) oral baricitinib administered once daily in patients with moderate-to-severe active RA. Lipoprotein particle size and number and GlycA were evaluated with nuclear magnetic resonance in one phase III study. The effect of statin therapy on lipid levels was evaluated in patients on statins at baseline and in patients who initiated statins during the study. Results Treatment with baricitinib was associated with increased levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides, but no significant change in LDL-C:HDL-C ratio. Lipid levels plateaued after 12 weeks of treatment. Baricitinib treatment increased large LDL and decreased small, dense LDL particle numbers and GlycA. Lipid changes from baseline were not significantly different between baseline statin users and non-users. In patients who initiated statin therapy during the study, LDL-C, triglycerides (baricitinib 4 mg only) and apolipoprotein B decreased to pre-baricitinib levels; HDL-C and apolipoprotein A-I levels remained elevated. Conclusions Baricitinib was associated with increased LDL-C, HDL-C and triglyceride levels, but did not alter the LDL-C:HDL-C ratio. Evaluation of cardiovascular event rates during long-term treatment is warranted to further characterise these findings and their possible clinical implications. Trial registration number NCT00902486, NCT01469013 , NCT01185353 , NCT01721044 , NCT01721057 , NCT01711359 , NCT01710358 , NCT01885078 .
Intravenous magnesium sulfate for acute wheezing in young children: a randomised double-blind trial
Authors: Hannele Pruikkonen, Terhi Tapiainen, Merja Kallio, Teija Dunder, Tytti Pokka, Matti Uhari, Marjo Renko
Journal: European Respiratory Journal (2018)

Magnesium sulfate has been shown to be an effective treatment in older children with asthma exacerbations, but it has not been investigated in acute severe virus-induced wheezing in young children. The study enrolled 61 children aged 6 months to 4 years. Inclusion criteria were severe wheezing, classified as a score of ≥6 points as assessed by the Respiratory Distress Assessment Instrument (RDAI) after initial treatment with salbutamol, and the symptoms of acute viral infection. The children were randomly allocated to receive either an infusion of magnesium sulfate (40 mg·kg −1 ) or 0.9% sodium chloride as a placebo infusion for 20 min. Primary outcome measure was mean change in RDAI scores from baseline to 6 h after the treatment. Change in the severity of wheezing from baseline to 6 h after the treatment, as measured by mean± sd RDAI scores, was 4.7±2.6 in the magnesium sulfate group and 4.2±4.2 in the placebo group (difference 0.5, 95% CI −1.3 to 2.3, p=0.594). Intravenous magnesium sulfate was ineffective in treating acute severe virus-induced wheezing in young children, in contrast to the previous efficacy demonstrated in older children.
Laboratory Eligibility Criteria as Potential Barriers to Participation by Black Men in Prostate Cancer Clinical Trials
Authors: Marie E. Vastola, David D. Yang, Vinayak Muralidhar, Brandon A. Mahal, Christopher S. Lathan, Bradley A. McGregor, Paul L. Nguyen
Journal: JAMA Oncology (2018)

Association of African American Race and Outcomes in Low-Risk Prostate Cancer With Active Surveillance
L'ablation intracanalaire utilisant un cystotome pendant la papillectomie endoscopique peut réduire le taux de récidive tumorale à long terme
Authors: E Perez-Cuadrado-Robles, H Piessevaux, TG Moreels, A Jouret-Mourin, P Deprez
Journal: Endoscopy (2018)

La faisabilité et les résultats de la résection endoscopique dans les tumeurs ampullaires à croissance intracanalaire restent peu claires.
Generation of Neutrophil Mediators During an Experimental Infection with Rhinovirus-16 in Asthmatic Patients
Authors: Robert A. Sullivan, Evan Rajadhyaksha, Patricia Jorge, Holliday T. Carper, Deborah D. Murphy, Thomas A.E. Platts-Mills, Peter W. Heymann
Journal: Journal of Allergy and Clinical Immunology (2018)
<i>Notes from the Field</i>: Public Health Response to a Human Immunodeficiency Virus Outbreak Associated with Unsafe Injection Practices — Roka Commune, Cambodia, 2016
Authors: Ugonna C. Ijeoma, Sin Sansam, Sok Srun, Hoy Vannara, Sou Sanith, Tek Sopheap, Robert D. Newman, Renuka Gadde, Selenic Dejana, Ahmed Saadani Hassani, Vanthy Ly, Bakary Drammeh, Anindya De, Johnita Byrd, Naomi Bock
Journal: MMWR Morbidity and Mortality Weekly Report (2018)
Regulation of the Cell Biology of Antigen Cross-Presentation
Authors: J. Magarian Blander
Journal: Annual Review of Immunology (2018)

Antigen cross-presentation is an adaptation of the cellular process of loading MHC-I molecules with endogenous peptides during their biosynthesis within the endoplasmic reticulum. Cross-presented peptides derive from internalized proteins, microbial pathogens, and transformed or dying cells. The physical separation of internalized cargo from the endoplasmic reticulum, where the machinery for assembling peptide–MHC-I complexes resides, poses a challenge. To solve this problem, deliberate rewiring of organelle communication within cells is necessary to prepare for cross-presentation, and different endocytic receptors and vesicular traffic patterns customize the emergent cross-presentation compartment to the nature of the peptide source. Three distinct pathways of vesicular traffic converge to form the ideal cross-presentation compartment, each regulated differently to supply a unique component that enables cross-presentation of a diverse repertoire of peptides. Delivery of centerpiece MHC-I molecules is the critical step regulated by microbe-sensitive Toll-like receptors. Defining the subcellular sources of MHC-I and identifying sites of peptide loading during cross-presentation remain key challenges.
Stability of ARDS subphenotypes over time in two randomised controlled trials
Authors: Kevin Delucchi, Katie R Famous, Lorraine B Ware, Polly E Parsons, B Taylor Thompson, Carolyn S Calfee
Journal: Thorax (2018)

Rationale Two distinct acute respiratory distress syndrome (ARDS) subphenotypes have been identified using data obtained at time of enrolment in clinical trials; it remains unknown if these subphenotypes are durable over time. Objective To determine the stability of ARDS subphenotypes over time. Methods Secondary analysis of data from two randomised controlled trials in ARDS, the ARMA trial of lung protective ventilation (n=473; patients randomised to low tidal volumes only) and the ALVEOLI trial of low versus high positive end-expiratory pressure (n=549). Latent class analysis (LCA) and latent transition analysis (LTA) were applied to data from day 0 and day 3, independent of clinical outcomes. Measurements and main results In ALVEOLI, LCA indicated strong evidence of two ARDS latent classes at days 0 and 3; in ARMA, evidence of two classes was stronger at day 0 than at day 3. The clinical and biological features of these two classes were similar to those in our prior work and were largely stable over time, though class 2 demonstrated evidence of progressive organ failures by day 3, compared with class 1. In both LCA and LTA models, the majority of patients (&gt;94%) stayed in the same class from day 0 to day 3. Clinical outcomes were statistically significantly worse in class 2 than class 1 and were more strongly associated with day 3 class assignment. Conclusions ARDS subphenotypes are largely stable over the first 3 days of enrolment in two ARDS Network trials, suggesting that subphenotype identification may be feasible in the context of clinical trials.