Nitroreductase-Activated Probes for Monitoring Hypoxia.

Hypoxia, a hallmark of solid tumors, complicates cancer treatment by reducing the efficacy of radiotherapy and chemotherapy. To optimize strategies for hypoxia detection and targeted cancer therapy, this work explores the development of hypoxia-responsive fluorescent probes. In this study, we compared various nitroaromatic groups and both elimination-based and cyclization-based self-immolative designs to study nitroreductase (NTR) activation.

Randomization procedures in parallel-arm cluster randomized trials in low- and middle-income countries: a review of 300 trials published between 2017-2022.

Objectives: Cluster randomized trials (CRTs) are frequently used to evaluate interventions in low- and middle-income countries (LMICs). Robust execution and transparent reporting of randomization procedures are essential for successful implementation and accurate interpretation of CRTs. Our objectives were to review the quality of reporting and implementation of randomization procedures in a sample of parallel-arm CRTs conducted in LMICs.

The Lethal Combination of Pregabalin With Other Recreational Drugs.

This case presents a 33-year-old male with a four-day history of worsening altered mental status and rhabdomyolysis. He experienced delusions, restlessness, and visual hallucinations, exacerbated by prolonged multidrug abuse, including over-the-counter pregabalin (Lyrica) for pain relief and recreational ketamine. Despite an initially incomplete history and unclear etiology, the patient was admitted for toxic-metabolic encephalopathy with acute kidney injury (AKI) and required significant medical management for confusion, acidosis, and electrolyte disturbances.

Radiation vs. trans-oral surgery for treatment de-escalation in HPV-related oropharyngeal cancers: Primary analysis of the ORATOR2 randomized trial.

Background: The optimal treatment de-escalation approach for HPV-related oropharyngeal squamous cell carcinomas (OPSCC) is unknown. The objective was to assess two de-escalation approaches: primary radiotherapy (RT) vs. transoral surgical (TOS).

Massive Pulmonary Embolism Masked as Asthma Exacerbation.

This case report presents the case of a 41-year-old Caucasian male with no significant past medical history who presented to the emergency department (ED) due to altered mental status. The patient used his brother's inhaler due to shortness of breath (SOB) and wheezing without any improvement. Later the patient was brought to the ED via Emergency Medical Services (EMS) and was intubated due to severe respiratory acidosis.

Diffuse large B-cell lymphoma: examining evolving patterns in mortality, incidence, and demographics.

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, characterized by its aggressive nature and heterogeneity. This study analyzes recent trends in DLBCL including trends in hospitalization, inpatient mortality, and costs.

Methods: Using the Nationwide Inpatient Sample (NIS) database from 2016 until 2020, a retrospective cohort study was performed to identify DLBCL hospitalization, discharges, and investigate outcomes.

Identification and validation of a T cell receptor targeting KRAS G12V in HLA-A*11:01 pancreatic cancer patients.

T cells targeting a KRAS mutation can induce durable tumor regression in some patients with metastatic epithelial cancer. It is unknown whether T cells targeting mutant KRAS that are capable of killing tumor cells can be identified from peripheral blood of patients with pancreatic cancer. We developed an in vitro stimulation approach and identified HLA-A*11:01-restricted KRAS G12V-reactive CD8+ T cells and HLA-DRB1*15:01-restricted KRAS G12V-reactive CD4+ T cells from peripheral blood of 2 out of 6 HLA-A*11:01-positive patients with pancreatic cancer whose tumors expressed KRAS G12V.

More T cell receptors to the RAScue in cancer?

Treatment with T cells genetically engineered to express tumor-reactive T cell receptors (TCRs), known as TCR-gene therapy (TCR-T), is a promising immunotherapeutic approach for patients with cancer. The identification of optimal TCRs to use and tumor antigens to target are key considerations for TCR-T. In this issue of the JCI, Bear and colleagues report on their use of in vitro assays to characterize four HLA-A*03:01- or HLA-A*11:01-restricted TCRs targeting the oncogenic KRAS G12V mutation.

Radiotherapy Versus Transoral Robotic Surgery for Oropharyngeal Squamous Cell Carcinoma: Final Results of the ORATOR Randomized Trial.

Radiotherapy (RT) and transoral robotic surgery (TORS) are both curative-intent treatment options for oropharyngeal squamous cell carcinoma (OPSCC). Herein, we report the final outcomes of the ORATOR trial comparing these modalities, 5 years after enrollment completion. We randomly assigned 68 patients with T1-2N0-2 OPSCC to RT (with chemotherapy if node-positive) versus TORS plus neck dissection (± adjuvant RT/chemoradiation).

Unpacking and Utilizing Neuroscience Core Concepts.

Core concepts, or overarching principles that identify patterns in processes and phenomena, provide a framework for organizing facts and understanding. Core concepts have existed for many years in some life science disciplines, including biology, microbiology, and physiology, yet have only recently been published for neuroscience through a multi-year community-derived project which identified the following neuroscience core concepts: Communication Modalities, Emergence, Evolution, Gene-Environment Interactions, Information Processing, Nervous System Functions, Plasticity, and Structure-Function Relationship. The current phase of the core concepts work involves two arms: utilizing and "unpacking.

Phenotypic-Based Discovery and Exploration of a Resorufin Scaffold with Activity against Mycobacterium tuberculosis.

Tuberculosis remains a leading cause of death by infectious disease. The long treatment regimen and the spread of drug-resistant strains of the causative agent Mycobacterium tuberculosis (Mtb) necessitates the development of new treatment options. In a phenotypic screen, nitrofuran-resorufin conjugate 1 was identified as a potent sub-micromolar inhibitor of whole cell Mtb.

The formyl peptide receptors FPR1 and FPR2 as targets for inflammatory disorders: recent advances in the development of small-molecule agonists.

Formyl peptide receptors (FPRs) comprise a class of chemoattractant pattern recognition receptors, for which several physiological functions like host-defences, as well as the regulation of inflammatory responses, have been ascribed. With accumulating evidence that agonism of FPR1/FPR2 can confer pro-resolution of inflammation, increased attention from academia and industry has led to the discovery of new and interesting small-molecule FPR1/FPR2 agonists. Focused attention on the development of appropriate physicochemical and pharmacokinetic profiles is yielding synthesis of new compounds with promising in vivo readouts.

Multidisciplinary care improves outcomes for patients with carotid body paragangliomas-The UCLA experience.

Objective: To evaluate the effects and outcomes of multidisciplinary surgical approaches in the management of carotid body tumors (CBT).

Methods: A single-center retrospective study at the University of California-Los Angeles Medical Center was conducted on patients who presented with CBTs and underwent surgical resections from 1998 to 2020. Statistical analysis was performed using IBM SPSS v27 and Excel.

A small molecule inhibitor of PTP1B and PTPN2 enhances T cell anti-tumor immunity.

The inhibition of protein tyrosine phosphatases 1B (PTP1B) and N2 (PTPN2) has emerged as an exciting approach for bolstering T cell anti-tumor immunity. ABBV-CLS-484 is a PTP1B/PTPN2 inhibitor in clinical trials for solid tumors. Here we have explored the therapeutic potential of a related small-molecule-inhibitor, Compound-182.

A small molecule inhibitor of PTP1B and PTPN2 enhances T cell anti-tumor immunity.

The inhibition of protein tyrosine phosphatases (PTPs), such as PTP1B and PTPN2 that function as intracellular checkpoints, has emerged as an exciting new approach for bolstering T cell anti-tumor immunity to combat cancer. ABBV-CLS-484 is a dual PTP1B and PTPN2 inhibitor currently in clinical trials for solid tumors. Here we have explored the therapeutic potential of targeting PTP1B and PTPN2 with a related small molecule inhibitor, Compound 182.

Population-based Long-term Outcomes for Squamous Cell Carcinoma of the Nasal Cavity.

Background: This study evaluates population-based outcomes of patients with squamous cell carcinoma (SCC) of the nasal cavity treated in British Columbia.

Methods: A retrospective review of nasal cavity SCC treated from 1984 to 2014 was performed (n = 159). Locoregional recurrence (LRR) and overall survival (OS) were evaluated.

Novel Diarylthioether Compounds as Agents for the Treatment of Chagas Disease.

Herein, we describe the hit optimization of a novel diarylthioether chemical class found to be active against ; the parasite responsible for Chagas disease. The hit compound was discovered through a whole-cell phenotypic screen and as such, the mechanism of action for this chemical class is unknown. Our investigations led to clear structure-activity relationships and the discovery of several analogues with high potency.

Expressing antigen binding fragments with high titers in a targeted integration CHO host by optimizing expression vector gene copy numbers and position: A case study.

Antigen binding fragments (Fab) are a promising class of therapeutics as they maintain high potency while having significantly smaller size relative to full-length antibodies. Because Fab molecules are aglycosylated, many expression platforms, including prokaryotic, yeast, and mammalian cells, have been developed for their expression, with Escherichia coli being the most commonly used Fab expression system. In this study, we have examined production of a difficult to express Fab molecule in a targeted integration (TI) Chinese Hamster Ovary (CHO) host.

A xenograft study of human adipose stromal cell-based vocal fold mucosal replacement in rabbits.

Objectives: Vocal fold (VF) scarring, manifested by increased collagen, decreased glycosaminoglycans (GAGs), and disrupted elastic fibers, remains a negative consequence of VF injury or resection. The objective of this study is to compare four reconstructive options after Vf mucosal resection in rabbits. A Cell-Based Outer Vocal fold Replacement (COVR) using human adipose-derived mesenchymal stromal cells (hASCs) in fibrin scaffold is directly compared with a decellularized scaffold implant, hASC injection, and resection alone without reconstruction.

A rapid and universal liquid chromatograph-mass spectrometry-based platform, refmAb-Q nSMOL, for monitoring monoclonal antibody therapeutics.

Accurate quantitation of antibodies is critical for development of monoclonal antibody therapeutics (mAbs). Therapeutic drug monitoring has been applied to measure levels of mAbs in clinics for dose adjustment for autoimmune disease. Trough levels of mAbs can be a biomarker for cancer immunotherapy.

Neoantigen-Specific T Cells in Adoptive Cell Therapy.

The holy grail of cancer therapeutics is the destruction of cancer cells while avoiding harm to normal cells. Cancer is unique from normal tissues because of the presence of somatic mutations that accumulate during tumorigenesis. Some nonsynonymous mutations can give rise to mutated peptide antigens (hereafter referred to as neoantigens) that can be specifically recognized by T cells.