Phase IB Study of GITR Agonist Antibody TRX518 Singly and in Combination with Gemcitabine, Pembrolizumab, or Nivolumab in Patients with Advanced Solid Tumors.

Purpose: TRX518 is a mAb engaging the glucocorticoid-induced TNF receptor-related protein (GITR). This open-label, phase I study (TRX518-003) evaluated the safety and efficacy of repeated dose TRX518 monotherapy and in combination with gemcitabine, pembrolizumab, or nivolumab in advanced solid tumors.

Patients And Methods: TRX518 monotherapy was dose escalated (Part A) and expanded (Part B) up to 4 mg/kg loading, 1 mg/kg every 3 weeks.

Safety, Efficacy, and Biomarker Results from a Phase Ib Study of the Anti-DKK1 Antibody DKN-01 in Combination with Pembrolizumab in Advanced Esophagogastric Cancers.

Therapeutic combinations targeting innate and adaptive immunity and predictive biomarkers of response in esophagogastric cancer (EGC) are needed. We assessed safety and clinical utility of DKN-01 (a novel DKK1-neutralizing IgG4 antibody) combined with pembrolizumab and retrospectively determined DKK1 tumoral expression as a biomarker. Patients with advanced EGC received intravenous DKN-01 (150 or 300 mg) on days 1 and 15 with pembrolizumab 200 mg on day 1 in 21-day cycles.

Long-term Overall Survival and Predictors in Anti-PD-1-naive Melanoma Patients With Brain Metastases Treated With Immune Checkpoint Inhibitors in the Real-world Setting: A Multicohort Study.

Long-term survival outcomes among melanoma patients with brain metastases treated with immune checkpoint inhibitors are limited. In this retrospective study at 2 centers, metastatic melanoma patients with radiographic evidence of brain metastases who received anti-programmed death-1 (PD-1) monotherapy or nivolumab in combination with ipilimumab between 2014 and 2017 were included. Overall survival (OS) was assessed in diagnosis-specific graded prognostic assessment (ds-GPA) and melanoma-molecular graded prognostic assessment (molGPA) prognostic risk groups.

Author Correction: Subsets of exhausted CD8 T cells differentially mediate tumor control and respond to checkpoint blockade.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Complex inter-relationship of body mass index, gender and serum creatinine on survival: exploring the obesity paradox in melanoma patients treated with checkpoint inhibition.

Background: A male gender driven obesity paradox (improved survival for overweight/obese patients compared to normal weight) was recently shown in melanoma in the context of checkpoint inhibition (anti-PD-1/anti-CTLA4 monotherapy) in a pooled meta-analysis. We characterized the relationship of Body Mass Index (BMI) with survival and explored gender-based interactions with surrogates of body composition/malnutrition in the context of PD-1 blockade as monotherapy or in combination with ipilimumab in a real-world setting.

Methods: Advanced melanoma patients who received at least one dose of pembrolizumab, nivolumab, or nivolumab plus ipilimumab (combination) from June 2014 to September 2016 were included in this retrospective cohort study (N = 139).

Subsets of exhausted CD8 T cells differentially mediate tumor control and respond to checkpoint blockade.

T cell dysfunction is a hallmark of many cancers, but the basis for T cell dysfunction and the mechanisms by which antibody blockade of the inhibitory receptor PD-1 (anti-PD-1) reinvigorates T cells are not fully understood. Here we show that such therapy acts on a specific subpopulation of exhausted CD8 tumor-infiltrating lymphocytes (TILs). Dysfunctional CD8 TILs possess canonical epigenetic and transcriptional features of exhaustion that mirror those seen in chronic viral infection.

Association mapping of quantitative resistance to charcoal root rot in mulberry germplasm.

Outbreaks of root rot disease in the productive South Indian sericulture belt have threatened the sustainability of the industry. Macrophomina phaseolina (Tassi) Goid. causing charcoal rot is the predominant pathogen to which all productive mulberry cultivars are susceptible.

Inhibition of Spontaneous Contractility of Isolated Caprine Ureter by Flupirtine.

Context: Kv7 potassium channels are expressed in several types of smooth muscles and could mediate physiological responses in the tissues expressed. Flupirtine is an analgesic that acts by opening Kv7 potassium channels. It has been shown to inhibit the contractility of several types of isolated smooth muscle.

Th17 Inhibitors in Active Psoriatic Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials.

Background: Several biologics targeting the Th17 pathway have been developed for the treatment of psoriatic arthritis (PsA), a disabling disease with moderate response and an increased incidence of serious infections to first-line biologics (TNF-α antagonists). Th17 inhibitors could replace TNF-α antagonists as first-line biologic agents. We determined the overall treatment effect of Th17 pathway inhibitors compared to placebo or active control on American College of Rheumatology (ACR) 20 response at week 12 (primary objective), risk of infections, discontinuation of treatment due to adverse events, and serious adverse events during the placebo-controlled period (12-24 weeks) in adults with active PsA in published randomized controlled trials.

Inhibition by Benidipine of Contractility of Isolated Proximal and Distal Caprine Ureter.

Context: Benidipine is a calcium channel blocker that blocks all the major types (L, N, and T) of calcium channels. It has been shown to inhibit the contractility of many isolated smooth muscles but not isolated ureter.

Aims: This study evaluated the ability of benidipine to inhibit the spontaneous contractility of isolated proximal and distal caprine (goat) ureter.

A Nonparametric Pharmacokinetic Approach to Determine the Optimal Dosing Regimen for 30-Minute and 3-Hour Meropenem Infusions in Critically Ill Patients.

Background: Pharmacokinetics of meropenem differ widely in the critically ill population. It is imperative to maintain meropenem concentrations above the inhibitory concentrations for most of the interdose interval. A population pharmacokinetic/pharmacodynamic model was developed to determine the probability of target attainment for 3-hour and 30-minute infusion regimens in this population.

Therapeutic Drug Monitoring of Levetiracetam and Lamotrigine: Is There a Need?

Background: This study was a retrospective assessment of the therapeutic drug monitoring data collected for levetiracetam and lamotrigine from a clinical setting. The proportion of patients in relation to the therapeutic ranges for serum concentrations of lamotrigine and levetiracetam was estimated, and the influence of age and anticonvulsant comedications on their clearances were studied.

Methods: Information on levetiracetam (2011-2013) and lamotrigine (2008-2013) dose, trough concentration, age, sex, body weight, and anticonvulsant comedications prescribed was obtained from the therapeutic drug monitoring register and archived medical records.

High cost burden and health consequences of antibiotic resistance: the price to pay.

Introduction: Rising antibiotic resistance may negatively affect the health and cost of care for patients. This study aimed to determine the impact of antibiotic resistance on costs and health consequences for patients.

Methodology: A one-year observational study was conducted at Christian Medical College, Vellore, a tertiary care hospital, on patients admitted into medical wards with a preliminary diagnosis of suspected sepsis.

STRUCTURE PLOT: a program for drawing elegant STRUCTURE bar plots in user friendly interface.

Background: Understanding structure of the population is one of the major objective of many genetic studies. The program STRUCTURE is commonly used to infer population structure using multi-locus genotype data. However, a tool with graphical-user interface is currently not available to visualize STRUCTURE bar plots.

The impact of policy guidelines on hospital antibiotic use over a decade: a segmented time series analysis.

Introduction: Antibiotic pressure contributes to rising antibiotic resistance. Policy guidelines encourage rational prescribing behavior, but effectiveness in containing antibiotic use needs further assessment. This study therefore assessed the patterns of antibiotic use over a decade and analyzed the impact of different modes of guideline development and dissemination on inpatient antibiotic use.

A pharmacological profile of ribavirin and monitoring of its plasma concentration in chronic hepatitis C infection.

Chronic hepatitis C (CHC) infection, usually an asymptomatic infection, has long-term serious complications such as cirrhosis, hepatocellular carcinoma, and end-stage liver disease requiring liver transplantation (LT). Several novel drugs against hepatitis C which form part of 'specifically targeted antiviral therapy for hepatitis C' (STAT-C) have been developed. These include NS3/4A protease inhibitors telaprevir, boceprevir, and nucleoside/non-nucleoside polymerase inhibitors (NS5A) which hold promise for future therapy.

Role of cancer antigen-125 from pleural & ascitic fluid samples in non malignant conditions.

Background & Objective: CA-125, an ovarian tumor marker is known to increase in non malignant conditions such as tubercular and non tubercular pleuritis and ascites. We undertook this study to evaluate non-specific rise in CA-125 levels in conditions associated with pleural effusion and ascites and also to understand the mechanism of its secretion.

Methods: CA-125 levels in 38 pleural and 46 ascitic fluid samples from non malignant cases and 10 blood samples from pulmonary tuberculosis cases were estimated by ELISA.