tbuckley/cabot-search huggingface dataset:
Multivariate analysis of pharmacokinetics (PK) and pharmacogenetics (PG) factors following irinotecan (CPT) treatment and the risk of developing neutropenia or diarrhea.
Authors: B. Valenzuela, J. Rebollo, V. Escudero, E. Martinez-Navarro, R. Gonzalez
Journal: Journal of Clinical Oncology (2011)

e13052 Background: The principal dose-limiting toxicities of CPT are diarrhea and neutropenia related to CPT exposure (AUC of SN-38 and SN-38G). Genetic polymorphisms in UDP-glucuronosyltransferase (UGT) 1A1, involved in SN-38 glucuronidation has been linked to interindividual PK variability and CPT toxicity. Variants in other UGTs enzymes like 1A7 and 1A9 can play a crucial role in the PK and pharmacodynamic (PD) profile of SN-38. The objective was to explore PK, PG and PD relationships of CPT in cancer patients. Methods: Blood samples were taken at 60 min, 2, 4, 6, 24 and 48 hours after the start of CPT infusion. Total CPT and its metabolites plasma concentrations were measured by HPLC. Clearance (Cl) of SN38, Cl of SN38-G, AUC of SN-38, AUC of SN38G and the ratio between these AUCs (AUC SN-38G /AUC SN-38) were calculated. UGT1A1, A7 and A9 genotypes were obtained from blood genomic DNA by direct sequencing. Toxicity was evaluated using standard NCI grading criteria, within two months after initiation of treatment. Association between toxicity, exposure and genotype was investigated by uni- and multivariate analysis. Odds ratios for severe (grade III/IV) neutropenia or diarrhea were estimated by logistic regression. Results: A total of 71 patients (22 female and 49 male) were included in the analysis. Median age was 59 (range 25-91). Histologies were: lung 29 pts, colorectal 23, glioma 4, gastric 6, ovary 4 and others 5. Mean dose of CPT administered was 150 mg/m2 (range 70-450) every 2-3 weeks. The frequency of neutropenia and diarrhea were 18.8% and 19.7%, respectively. Clearance of SN38 was (OR= 0.996, 95% CI = 0.992-1.001) and UGT1A9 were predictive of neutropenia. Relative risk of neutropenia in patients with UGT1A9 -118(dT)9/10 or -118(dT)9/9 genotypes vs wild-type patients (UGT1A9 -118(dT)10/10) were 1.9 and 2.6-fold, respectively. The ratio AUC SN-38G/AUC SN-38 was the only predictor for diarrhea (OR= 0.742, 95% CI = 0.551-0.998). Conclusions: This analysis suggests the clearance of SN38, UGT1A9 genotype and the ratio AUC SN-38G/AUC SN-38 are predictors of the main toxicities derived from CPT treatment.
Abstract 12455: Evaluation of N-Terminal Pro-B-type Natriuretic Peptide as a Therapeutic Response Biomarker in Group I Pulmonary Arterial Hypertension
Authors: Aaron M Wolfson, Micheal L Maitland, Vasiliki Thomeas, Cherylanne Glassner, Mardi Gomberg-Maitland
Journal: Circulation (2014)

Purpose: Goal directed management of left heart failure with an NT-proBNP target-based approach has some evidence of providing a survival benefit. To evaluate the potential utility of serial NT-proBNP measurements for goal-directed therapy in right heart failure we retrospectively assessed NT-proBNP as a predictor for survival in Group I pulmonary arterial hypertension (PAH) patients. Methods: We identified 103 Group I PAH patients from a pulmonary hypertension registry who had baseline elevated NT-proBNP prior to either the initiation or escalation of therapy and at least two serial NT-proBNP measurements. In a two-step process, we (1) estimated baseline NT-proBNP and slope (rate of change of NT-proBNP) with a linear mixed-effects model using all patient data and then (2) compared the power of serial versus single measurements in predicting survival with measured and model-derived values of baseline NT-proBNP with a Receiver Operative Characteristic (ROC) curve analysis . Survival was determined using the Kaplan-Meier methodology. Results: ROC curve analysis revealed significantly higher AUC for model-derived NT-proBNP values compared to the measured values (AUC: for baseline 0.74 vs 0.66, p= 0.009; for slope 0.78 vs 0.66, p= 0.02). Optimal cutpoints for prediction of survival on baseline NT-proBNP were 2012 (measured) vs. 1810 (model-derived) pg/mL. The optimal cutpoint for model-derived change in NT-proBNP was -0.004 log10pg/mL/month. Sensitivity, specificity, and negative predictive values for the three predictor variables were: 64%, 67%, 80% (measured baseline NT-proBNP), 61%, 80%, 81% (model-derived baseline NT-proBNP) and 73%, 57%, 85% (model-derived slope). Conclusions: In PAH patients, serial NT-proBNP measurements better predict survival than single measurements. This retrospective finding reveals that changes in NT-proBNP are associated with overall survival in PAH patients, and set initial target values for a pilot prospective study of NT-proBNP goal-directed therapy.
Significant Improvement In Quality Of Life (QoL) In Patients With Chronic Myeloproliferative Neoplasms and Myelofibrosis Treated With JAK-1 and JAK-2 Inhibitor Ruxolitinib. A Single Institution Experience In Mexico
Authors: Pablo Vargas-Viveros, Rafael Hurtado Monroy, Myrna Candelaria-Hernandez
Journal: Blood (2013)
The contribution of neuropsychology to psychiatry
Authors: R S Keefe
Journal: American Journal of Psychiatry (1995)

Neuropsychological test data are applied with increasing frequency in research studies and clinical practice in psychiatry. This article addresses three popular assumptions about neuropsychological test data and describes the limitations and contributions of neuropsychological assessment of patients with psychiatric disorders.All research articles from major journals in psychiatry and clinical psychology since 1991 that focused on neuropsychological assessment of psychiatric patients were reviewed. Other journals and earlier studies were reviewed selectively.Neuropsychological test data have made significant contributions to the development of hypotheses about abnormal brain structure and function in patients with psychiatric disorders, yet many findings from neuropsychological assessments of psychiatric patients are misinterpreted. The extent to which neuropsychological test data in psychiatric populations can be interpreted to reflect abnormalities in brain structure and function is frequently exaggerated, as is the ability of neuropsychological measures to serve as specific cognitive probes in imaging studies of physiological activation. On the other hand, the utility of neuropsychological test batteries as measures of the patterns of cognitive strength and deficit in individuals with specific psychiatric disorders is frequently underestimated.In addition to testing models of regional brain dysfunction in psychiatric disorders, neuropsychological tests can provide researchers in psychiatry with an improved understanding of the relation between central cognitive impairments and symptoms and serve to identify cognitive predictors of course of illness, and they may provide a method for discriminating among heterogeneous forms of some psychiatric disorders. Clinically, neuropsychological test data can be used to develop treatment strategies tailored for an individual's specific cognitive strengths and deficits.
Mortality and air pollution: associations persist with continued advances in research methodology.
Authors: C A Pope
Journal: Environmental Health Perspectives (1999)

In this issue of Environmental Health Perspectives there are papers by Fairley, Neas et al., and Lee and Schwartz.Although these papers present different approaches, they provide a reasonable representation of state- of-the-art epidemiologic research that evaluates daily changes in mortality and air pollution.The authors of these papers include investigators who have been primary con- tributors to the development of this research.The earliest and most methodologically simple studies that evaluated day-to-day changes in mortality associated with air pol- lution were studies that focused on severe air pollution episodes.These studies simply compared death counts for several days or weeks before, during, and after pollution episodes.Substantially elevated cardiopulmonary mortality associated with severe air pollution episodes in Meuse Valley, Belgium, in 1930 (1); Donora, Pennsylvania, in 1948 -5FAJ? 1 4q1,11
Research on the psychosocial treatment of schizophrenia: a summary report
Authors: L R Mosher, S J Keith
Journal: American Journal of Psychiatry (1979)

The authors present an overview of research on psychosocial treatments for schizophrenia. Findings from studies of five therapeutic approaches--individual psychotherapy, group psychotherapy, family therapy, milieu therapy, and community support systems--are discussed in detail. The usefulness of each type of therapy is critically assessed on the basis of available data from controlled outcome studies. The authors make recommendations regarding high-priority areas to be addressed in future studies of psychosocial treatment.
Rivaroxaban Versus Enoxaparin For Prevention Of Venous Thromboembolism In Elective Total Hip Replacement: A Retrospective Cohort Study
Authors: Stephanie W Young, Jason Kielly, Maria Mathews, Andrew Furey, Kuljit Grewal, Lisa D Bishop, Carla Dillon, Tiffany Lee, John Hawboldt, Laurie Twells
Journal: Blood (2013)
HCP-05COMBINED MANAGEMENT AND THE ROLE OF COMORBIDITIES IN ELDERLY GLIOBLASTOMA
Authors: Carmine Carapella, Veronica Villani, Chiara Zucchella, Stefano Telera, Isabella Sperduti, Antonello Vidiri, Alessandra Fabi, Laura Marucci, Andrea Pace
Journal: Neuro-Oncology (2015)

The management of elderly glioblastoma (GBM) remains controversial for under-representation in controlled trials, for modest tolerance of treatments, and higher rate of side effects. Age was identified as an important prognostic factor for survival, mainly in patients with poor performance status. The presence of co-morbidities (CM) represents an important issue in elderly because the correlation with frailty, and the role as predictor of disability and mortality. The aim of this study was to evaluate the impact of CM on outcome of elderly GBM. METHODS: Patients affected by GBM with age ≥ 65 years have been enrolled in a prospective study. For each patient, CM were identified with the Cumulative Illness Rating Scale (CIRS). RESULTS: Sixty-six elderly patients affected by GBM were enrolled into the study. The average age at diagnosis was 73 years (range 65-87). The median PFS at 12 months has been 8 months, with a rate of 29.1% patients free of progression at 1 year. The median OS has been 18 months (95% CI 13-23), with a survival rate of 35% at 2 years. The univariate analysis showed that the severity of CM is a strong predictor of disease progression (HR = 1.24, 95% CIs from 1.11 to 1.38, p = 0.000). Multivariate analysis confirmed that the severity of CM (HR = 1.24 for each increase of CIRS score, 95% CIs from 1.11 to 1.38, p = 0.000) is an independent predictor of disease progression. In addition, higher score of CM and age higher than 75 years are associated with short survival. DISCUSSION: We observed that high CM score is an independent predictor of disease progression and shorter survival. The evaluation of CM should drive therapeutic decisions in elderly GBM. In subgroups of elderly GBM without high score of CM, standard treatments should be considered. Further studies on elderly GBM are warranted to confirm these data.
Conformation of ryanodine receptor-2 gates store-operated calcium entry in rat pulmonary arterial myocytes
Authors: Amanda H.Y. Lin, Hui Sun, Omkar Paudel, Mo-Jun Lin, James S.K. Sham
Journal: Cardiovascular Research (2016)

Store-operated Ca2+ entry (SOCE) contributes to a multitude of physiological and pathophysiological functions in pulmonary vasculatures. SOCE attributable to inositol 1,4,5-trisphosphate receptor (InsP3R)-gated Ca2+ store has been studied extensively, but the role of ryanodine receptor (RyR)-gated store in SOCE remains unclear. The present study aims to delineate the relationship between RyR-gated Ca2+ stores and SOCE, and characterize the properties of RyR-gated Ca2+ entry in pulmonary artery smooth muscle cells (PASMCs). PASMCs were isolated from intralobar pulmonary arteries of male Wister rats. Application of the RyR1/2 agonist 4-chloro-m-cresol (4-CmC) activated robust Ca2+ entry in PASMCs. It was blocked by Gd3+ and the RyR2 modulator K201 but was unaffected by the RyR1/3 antagonist dantrolene and the InsP3R inhibitor xestospongin C, suggesting RyR2 is mainly involved in the process. siRNA knockdown of STIM1, TRPC1, and Orai1, or interruption of STIM1 translocation with ML-9 significantly attenuated the 4-CmC-induced SOCE, similar to SOCE induced by thapsigargin. However, depletion of RyR-gated store with caffeine failed to activate Ca2+ entry. Inclusion of ryanodine, which itself did not cause Ca2+ entry, uncovered caffeine-induced SOCE in a concentration-dependent manner, suggesting binding of ryanodine to RyR is permissive for the process. This Ca2+ entry had the same molecular and pharmacological properties of 4-CmC-induced SOCE, and it persisted once activated even after caffeine washout. Measurement of Ca2+ in sarcoplasmic reticulum (SR) showed that 4-CmC and caffeine application with or without ryanodine reduced SR Ca2+ to similar extent, suggesting store-depletion was not the cause of the discrepancy. Moreover, caffeine/ryanodine and 4-CmC failed to initiate SOCE in cells transfected with the ryanodine-binding deficient mutant RyR2-I4827T. RyR2-gated Ca2+ store contributes to SOCE in PASMCs; however, store-depletion alone is insufficient but requires a specific RyR conformation modifiable by ryanodine binding to activate Ca2+ entry.
Socioeconomic burden of subsyndromal depressive symptoms and major depression in a sample of the general population
Authors: L L Judd, M P Paulus, K B Wells, M H Rapaport
Journal: American Journal of Psychiatry (1996)

The authors' goal was to evaluate the association between impairment in daily function and subsyndromal depressive symptoms as well as major depression to determine the economic and societal significance of these conditions.Using 12-month prevalence data gathered by the National Institute of Mental Health (NIMH) Epidemiologic Catchment Area Program (ECA), based on responses to the NIMH Diagnostic Interview Schedule, the authors divided the 2,393 subjects from the Los Angeles ECA site into three groups: subjects with subsyndromal depressive symptoms (N = 270), major depression (N = 102), and no depressive disorder or symptoms (N = 2,021). The groups were compared on 10 domains of functional outcome and well-being.Significantly more subjects with depressive symptoms than subjects who had no disorder reported high levels of household strain, social irritability, and financial strain as well as limitations in physical or job functioning, restricted activity days, bed days, and poor health status. Significantly more subjects with major depression than subjects with no disorder reported major financial losses, bed days, high levels of financial strain, limitations in physical or job functioning, and poor health status. Except for lower self-ratings of health status, no significant differences were found between subjects with subsyndromal symptoms and those with major depression.Significantly more people with subsyndromal depressive symptoms or major depression reported impairment in eight of 10 functional domains than did subjects with no disorder. The high 1-year prevalence of subsyndromal depressive symptoms, combined with the associated functional impairment, emphasizes the clinical and public health importance and need for additional investigations into these symptoms.
Multi-Arm, Nonrandomized, Open-Label Phase Ib Study to Evaluate Fp1039/Gsk3052230 with Chemotherapy in Nsclc and Mpm with Deregulated Fgf Pathway Signaling
Authors: P. Garrido, E. Felip, J.P. Delord, L. Paz-Ares, F. Barlesi, H. Arkenau, P. Lara, P.K. Paik, D. Morgensztern, S. Gadgeel, K. Reckamp, E. Bertino, S. Orlov, E. Levchenko, I. Delgado, J.M. Trigo, S. Viteri, J.F. Vansteenkiste, H. Kindler, U.N. Lassen
Journal: Annals of Oncology (2014)
Abstract 18516: Common Atrial Fibrillation Susceptibility Alleles Enhance Clinical Risk Prediction Model for Postoperative Atrial fibrillation
Authors: Babar Parvez, Raafia Muhammad, M. Benjamin Shoemaker, Marcia Blair, Kaylen C Kor, Nancy Brown, Dan Roden, Willian S Bush, Dawood Darbar
Journal: Circulation (2012)

Introduction: Atrial fibrillation (AF) is a common adverse event following coronary artery bypass graft (CABG) surgery. The aim of this study was to evaluate whether single nucleotide polymorphisms (SNPs) conferring AF susceptibility identified by genome wide association (GWA) studies improve the traditional clinical risk prediction model for postoperative AF. Methods: Our study population consisted of 829 prospectively enrolled patients in the Vanderbilt Cardiac Surgery Registry (VCSR) undergoing CABG without concurrent valve surgery. Postoperative AF (12 months post surgery) was evaluated by review of medical records, ECGs and Holter monitors. Clinical variables in the model included age at the time of CABG, race, gender, history of AF, diabetes, hypertension, heart failure, CAD, LVEF, PR interval and use of beta-blockers, ACE inhibitors, statins, aspirin, and COX inhibitors. Thirteen AF-associated SNPs (rs13376333 and rs6666258 at 1q21; rs3903239 at 1q24; rs2200733, rs10033464 and rs6817105 at 4q25; rs3807989 at 7q31; rs10821415 at 9q22; rs10824026 at 10q22; rs1152591 at 14q23; rs7164883 at 15q24; rs2106261 and rs7193343 at 16q22) were genotyped using the Sequenom platform. Results: Subjects with two or more missing variables were excluded from the analysis (final cohort 444 subjects). SNP rs10033464 was not in Hardy-Weinberg equilibrium and hence removed from the analysis. Using multiple logistic regression, a model containing 12 SNPs, and all clinical covariates was fitted and found to be highly significant (P&lt;0.001). A likelihood ratio test comparing the complete model (clinical and genetic covariates) to a reduced model containing only clinical variables was also highly significant (P&lt;0.001), indicating an improvement in model fit with the inclusion of AF susceptibility alleles. The area under the receiver operator characteristic curve significantly improved from 0.759 (clinical variables only) to 0.816 (combined), (P&lt;0.001). Conclusion: Our data show that AF susceptibility alleles enhance the clinical risk prediction model for the development of AF after cardiac surgery. Pre-procedural genotyping of AF susceptibility alleles may improve risk stratification in patients undergoing CABG surgery.
Neurotensin signaling stimulates glioblastoma cell proliferation by upregulating c-Myc and inhibiting miR-29b-1 and miR-129-3p
Authors: Qing Ouyang, Gang Chen, Ji Zhou, Lei Li, Zhen Dong, Rui Yang, Lunshan Xu, Hongjuan Cui, Minhui Xu, Liang Yi
Journal: Neuro-Oncology (2015)

Neurotensin (NTS) and its primary receptor NTSR1 are implicated in cancer progression. Aberrant expression of NTS/NTSR1 contributes to the proliferation of glioblastoma cells; however, the mechanism is not fully understood.Microarray and real-time PCR were performed to identify the NTS-regulated micro (mi)RNAs. The targets of the miRNAs were identified by luciferase assays and immunoblot analysis. The c-Myc binding sites in the miR-29b-1 and cyclin-dependent kinase (CDK)4 promoters were identified through chromatin immunoprecipitation assay. Cell proliferation was evaluated by Cell Counting Kit-8 assay and flow cytometry analysis. An orthotopic xenograft model demonstrated the role of NTS/NTSR1 and miRNAs in glioblastoma growth in vivo.Pharmacological inhibition or small interfering NTSR1 treatment blocked glioblastoma cell cycle progression in the G1 phase with a concomitantly decreased expression of CDK6, CDK4, and c-Myc. Knockdown of NTSR1 increased the expression of miR-29b-1 and miR-129-3p, which were responsible for the decreased CDK6 expression. NTS/NTSR1 signaling activated the transcription factor c-Myc in U87 cells, leading to increased CDK4 expression and repressed miR-29b-1 expression. Knockdown of NTSR1 decreased the glioblastoma growth in vivo and significantly prolonged the survival time of the tumor-bearing mice, an effect that can be largely reversed by antagomir.Our study showed a novel regulatory mechanism of NTS/NTSR1, an upstream signaling of miRNAs and c-Myc, in glioblastoma progression. The inhibition of the NTSR1 function or the upregulation of miR-29b-1 and miR-129-3p expression impaired glioma cell proliferation. These results suggested that the NTS/NTSR1/c-Myc/miRNA axis may be a potential therapeutic target for glioblastoma therapy.
DIET AND TISSUE GROWTH
Authors: Arthur H. Smith, Theodore S. Moise
Journal: The Journal of Experimental Medicine (1924)

THE RELATIVE TOXICITY OF CHLOROFORM GIVEN SUBCUTANEOUSLY TO RATS FED ON TWO DIETS DEFICIENT IN RESPECT TO THEIR NITROGENOUS COMPONENTS, THE SOLE SOURCES OF PROTEIN IN WHICH WERE, RESPECTIVELY, GLIADIN AND GELATIN AND TO RATS WITHOUT FOOD, IS AS FOLLOWS: gelatin diet > fasting > gliadin diet. The rate of regeneration of liver cells after chloroform poisoning in rats fed a diet in which gliadin is the only protein is about as rapid as that in animals fed a diet containing casein as the source of nitrogen. The rate of regeneration on a food containing its nitrogen as gelatin and also during fasting is definitely slower than that in animals fed the gliadin food. The results of these experiments indicate that the requirement for the essential amino acids for growth of individual organs of the body is less than that for correlated growth of the whole body.
Focal adhesions control stretch-induced rho signaling and vascular permeability via paxillin – GEF-H1 functional complex
Authors: Konstantin Birukov, Grzegorz Gawlak, Yufeng Tian
Journal: European Respiratory Journal (2014)

Suboptimal ventilator support or regional ventilation heterogeneity in inflamed lungs causes excessive tissue distension which triggers stretch-induced pathologic signaling and may lead to vascular leak and lung dysfunction. Focal adhesions (FA) are cell-substrate adhesive complexes participating in cellular mechanotransduction and regulation of the Rho GTPase pathway. Stretch-induced Rho regulation remains poorly understood. We used human lung endothelial cells (EC) exposed to pathologic cyclic stretch (CS) at 18% distension to test the hypothesis that FA protein paxillin participates in CS-induced Rho activation by recruiting the Rho-specific guanine nucleotide exchange factor GEF-H1. CS induced phosphorylation of paxillin, activated p42/44-MAP kinase, Rho GTPase, paxillin/GEF-H1/p42/44-MAPK association. CS caused nearly 2-fold increase in EC permeability, which was attenuated by paxillin knockdown. Expression of paxillin-Y31/118F phosphorylation mutant decreased the CS-induced paxillin/GEF-H1 association (16.3+/-4.1%), GEF-H1 activation (28.9+/-9.2%), and EC permeability (28.7+/-8.1%), but not CS-induced p42/44-MAPK activation. Inhibition of p42/44-MAPK suppressed CS-induced paxillin/GEF-H1 interactions (15.9+/-7.9%), GEF-H1 activation (11.7+/-4.3%) and disruption of EC monolayer. Expression of GEF-H1T678A lacking p42/44-MAPK phosphorylation site attenuated Rho activation (31.2+/-11.6%). We conclude that MAPK-dependent targeting of GEF-H1 to paxillin is involved in the regulation of CS-induced Rho signaling and EC permeability. This study proposes a novel concept of paxillin-GEF-H1-p42/44-MAPK module as a regulator of pathologic mechanotransduction.