Phase II Trial of Pembrolizumab in Combination With Bevacizumab for Untreated Melanoma Brain Metastases.

Purpose: Anti-vascular endothelial growth factor therapy enhances PD-1 inhibitor activity in preclinical models and has been used to treat perilesional cerebral edema and radiation necrosis.

Methods: We conducted a two-institution phase II trial of bevacizumab and pembrolizumab in patients with untreated melanoma brain metastasis (MBM) (ClinicalTrials.gov identifier: NCT02681549).

Incorporating Circulating Tumor DNA Testing Into Clinical Trials: A Position Paper by the National Cancer Institute GI Oncology Circulating Tumor DNA Working Group.

Purpose: Circulating tumor DNA (ctDNA) is an emerging tool in the evaluation of GI cancers. Challenges remain in defining its utility and role as a primary end point in therapeutic trials. The National Cancer Institute (NCI) ctDNA GI working group was created to evaluate current data and provide guidance on the inclusion of ctDNA in GI cancer trials.

Perceived impact on patient routines/responsibilities for surgery and a non-surgical primary treatment option in recurrent LG-IR-NMIBC: findings from the ENVISION phase 3 trial.

Purpose: Adults with low-grade intermediate risk non-muscle-invasive bladder cancer (LG-IR-NMIBC) commonly ask urologists how their routine/responsibilities will be affected by treatments, including the standard of care, transurethral resection of bladder tumor (TURBT). We asked patients in the ENVISION trial (NCT05243550) to compare TURBT to a non-surgical primary treatment (UGN-102 containing mitomycin) for acceptability and impact on their routine/responsibilities.

Materials And Methods: ENVISION (NCT05243550) is a phase 3, single arm trial where UGN-102 was administered as six weekly intravesical instillations.

Rapid butterfly declines across the United States during the 21st century.

Numerous declines have been documented across insect groups, and the potential consequences of insect losses are dire. Butterflies are the most surveyed insect taxa, yet analyses have been limited in geographic scale or rely on data from a single monitoring program. Using records of 12.

Macroevolutionary divergence of gene expression driven by selection on protein abundance.

The regulation of messenger RNA (mRNA) and protein abundances is well-studied, but less is known about the evolutionary processes shaping their relationship. To address this, we derived a new phylogenetic model and applied it to multispecies mammalian data. Our analyses reveal (i) strong stabilizing selection on protein abundances over macroevolutionary time, (ii) mutations affecting mRNA abundances minimally impact protein abundances, (iii) mRNA abundances evolve under selection to align with protein abundances, and (iv) mRNA abundances adapt faster than protein abundances owing to greater mutational opportunity.

Dynamic Response and Energy Conversion of Coupled Cantilevers with Dual Piezoelectric-Triboelectric Harvesting Mechanisms.

This study presents a Hybrid Piezoelectric-Triboelectric Energy Harvester (HPTEH) composed of two coupled cantilever beams, designed to enhance energy generation and broaden bandwidth by combining piezoelectric and triboelectric mechanisms. A theoretical 2-DOF lumped model was developed and validated with experimental results, demonstrating good agreement. Experimental findings reveal that Beam I exhibits a softening effect, with resonance frequencies shifting to lower values and increased displacement amplitudes under higher excitation levels due to material nonlinearities and strain-induced voltage generation.

Racemic mimics. Part 1. Nickel coordination compounds.

To date there are very few examples of crystallographically well-documented racemic mimics. The original discovery of this class of crystals occurred at a time when crystallography was in its infancy, data collection and processing were tedious and limited by X-ray equipment, and computing power was indeed limited. Therefore, this interesting class of crystalline molecules, potentially having useful biological uses, is today one of those scientific orphans largely ignored in the crystallographic realm.

Burden of illness for patients with primary biliary cholangitis: an observational study of clinical characteristics and healthcare resource utilization.

To evaluate the clinical characteristics and healthcare resource utilization for acute care and its costs for patients with primary biliary cholangitis (PBC) with or without cirrhosis. This retrospective observational cohort study was conducted using two datasets (Komodo's Healthcare Map™ [Komodo Health] and Optum Clinformatics Data Mart [CDM] database) between 2015 and 2023. Patients (≥18 years) with PBC were identified based on ≥1 inpatient or ≥2 outpatient claims.

Out-of-hospital assessment and triage of paracetamol (acetaminophen) exposure in the United States and Canada: a consensus guideline.

Introduction: Consensus guidelines for out-of-hospital assessment and triage of paracetamol (acetaminophen) exposure were published in 2006. Changes in the healthcare system, paracetamol ingestion trends, and availability of paracetamol-containing products necessitate an update to these guidelines. Updated guidelines were created for out-of-hospital management of paracetamol exposure in the United States and Canada.

Leveraging efficiency metrics for the optimization of CELMoDs™ as cereblon-based molecular glue degraders.

Efficiency metrics are useful in medicinal chemistry to track small molecule progress in lead optimization (LO). Molecular glue degraders are small molecules that mediate targeted protein degradation by chemically inducing proximity between an E3 ligase and a protein target. The potency and depth of protein degradation are important factors in identifying molecular glue drug candidates.

Species delimitation and DNA barcoding for Chinese Mantodea (Insecta, Dictyoptera).

DNA barcoding has been proposed as a rapid and reliable tool for animal identification and species delineation. The 5' end of the mitochondrial cytochrome oxidase I gene (COI-5P) was sequenced for 318 specimens of 55 mantis species. Of these, 44 species had not been sequenced before, thus being new COI-5P barcode sequences to science.

Drug Repurposing in Pancreatic Cancer: A Multi-Stakeholder Perspective to Improve Treatment Options for Pancreatic Cancer Patients.

Pancreatic cancer (PC) remains one of the most challenging malignancies to treat. Current therapeutic options are unsatisfactory, and there is an urgent need for more effective and less toxic drugs to improve the dismal prognosis of PC. In recent years, drug repurposing (DR) has emerged as an attractive strategy to identify novel treatments for PC by leveraging existing drugs approved for other indications.

Assessment of non-tumor liver parenchyma damage in advanced gastric cancer treatment with transarterial infusion chemotherapy: a study using imaging and hepatic injury indicators.

Introduction: This study aimed to evaluate non-tumor liver parenchymal injury in advanced gastric cancer patients undergoing transarterial infusion chemotherapy (TAI) using imaging parameters and liver injury biomarkers, providing objective evidence for early detection of drug-induced liver injury.

Methods: A retrospective analysis was conducted on 52 advanced gastric cancer patients who received TAI at our center from July 2015 to July 2023. Abdominal CT images and laboratory data were collected before and after treatment.

Patient Preferences for HR+/HER2- Early Breast Cancer Adjuvant Treatment: A Multicountry Discrete Choice Experiment.

Introduction: More adjuvant treatment options are becoming available for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer (EBC) based on results of clinical trials. This study quantified the importance of different attributes of EBC adjuvant therapies to patients and the benefit-risk tradeoffs patients were willing to make.

Methods: Women with HR+/HER2- EBC completed an online discrete choice experiment (DCE) survey; the design was informed by clinical data, qualitative interviews ( = 40), and pre-testing interviews ( = 40).

Gender categorization and memory in transgender and cisgender people.

Gender categorization is central to everyday life. Discussions about gender have traditionally focused on , or gender categories to which a person might have an internal sense of belonging (e.g.

AWT020: a novel fusion protein harnessing PD-1 blockade and selective IL-2 Cis-activation for enhanced anti-tumor immunity and diminished toxicity.

Background: The clinical success of the immune checkpoint inhibitor (ICI) targeting programmed cell death protein 1 (PD-1) has revolutionized cancer treatment. However, the full potential of PD-1 blockade therapy remains unrealized, as response rates are still low across many cancer types. Interleukin-2 (IL-2)-based immunotherapies hold promise, as they can stimulate robust T cell expansion and enhance effector function - activities that could synergize potently with PD-1 blockade.

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Milvexian in Healthy Chinese Adults.

Background: Milvexian is a small molecule, selective factor XIa (FXIa) inhibitor being developed as an oral anticoagulant. This study assessed the pharmacokinetics, pharmacodynamics (activated partial thromboplastin time [aPTT]), and safety of milvexian in healthy Chinese subjects.

Methods: Part 1: Thirty subjects were randomly assigned 1:1:1 to receive milvexian 25 mg on Day 1 followed by 25 mg once daily (QD) on Days 5-12; milvexian 25 mg twice daily at 12-hour intervals (BID) on Days 1-8; or milvexian 100 mg BID on Days 1-8.

Ribosomal protein S25 promotes cell cycle entry for a productive BK polyomavirus infection.

Many viruses use alternate mechanisms to initiate protein translation owing to their limited coding capacity. The ribosomal protein S25 (RPS25/eS25) is required for efficient non-canonical mechanisms of translation initiation, such as internal ribosomal entry site (IRES) initiation or ribosomal shunting, but eS25 is not required for efficient cap-dependent initiation. Thus, eS25 knockdown can be used to evaluate whether a virus relies on alternative mechanisms of initiation.

Pembrolizumab plus chemotherapy in advanced or recurrent endometrial cancer: overall survival and exploratory analyses of the NRG GY018 phase 3 randomized trial.

Historically, the treatment of patients with advanced stage or recurrent endometrial cancer included paclitaxel plus carboplatin. Immunotherapy in combination with chemotherapy resulted in improved clinical outcomes in several solid tumors. In the phase 3 NRG GY018 study, pembrolizumab plus chemotherapy significantly improved investigator-assessed progression-free survival (PFS; primary endpoint) versus placebo plus chemotherapy in patients with advanced/metastatic/recurrent endometrial cancer regardless of mismatch repair status.

Regulatory considerations for successful implementation of digital endpoints in clinical trials for drug development.

Regulatory acceptance of Digital Health Technology (DHT) -derived endpoints can be a long, multifaceted and costly process. Success relies on establishing a global strategy as part of the development program including health authority consultations to ensure alignment with regulatory requirements. In this manuscript, the authors provide stepwise guidance for successful implementation of DHT-derived endpoints in clinical trials for drug development.

Emerging supersolidity in photonic-crystal polariton condensates.

A supersolid is a counter-intuitive phase of matter in which its constituent particles are arranged into a crystalline structure, yet they are free to flow without friction. This requires the particles to share a global macroscopic phase while being able to reduce their total energy by spontaneous, spatial self-organization. The existence of the supersolid phase of matter was speculated more than 50 years ago.

A positron emission tomography tracer for the imaging of oxidative stress in the central nervous system.

Reactive oxygen and nitrogen species (RONS) contribute to the pathogenesis of neurodegeneration, but the inability to detect RONS in vivo in the central nervous system has confounded the interpretation of results of clinical trials of antioxidants. Here we report the synthesis and characterization of a positron emission tomography (PET) probe, [F]fluoroedaravone ([F]FEDV), for the in vivo quantification of oxidative stress. Derived from the antioxidant edaravone, the probe can diffuse through the blood-brain barrier and is stable in human plasma.