Gasdermin D is activated but does not drive neurodegeneration in SOD1 model of ALS: Implications for targeting pyroptosis.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, microgliosis, and neuroinflammation. While pyroptosis, an inflammatory form of programmed cell death, has been implicated in ALS, the specific role of Gasdermin D (GSDMD) - the primary executioner of pyroptosis - remains unexplored. In this study, we examined the function of GSDMD in the well-established SOD1 mouse model of ALS.

An Advanced Cardiac Life Support Application Improves Performance during Simulated Cardiac Arrest.

Objectives:  Variability in cardiopulmonary arrest training and management leads to inconsistent outcomes during in-hospital cardiac arrest. Existing clinical decision aids, such as American Heart Association (AHA) advanced cardiovascular life support (ACLS) pocket cards and third-party mobile apps, often lack comprehensive management guidance. We developed a novel, guided ACLS mobile app and evaluated user performance during simulated cardiac arrest according to the 2020 AHA ACLS guidelines via randomized controlled trial.

Multicenter expanded access program for access to investigational products for amyotrophic lateral sclerosis.

Introduction/aims: Expanded access (EA) is a Food and Drug Administration-regulated pathway to provide access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. The aim of this report is to share the design and operations of a multicenter, multidrug EA program for amyotrophic lateral sclerosis (ALS) across nine US centers.

Methods: A central coordination center was established to design and conduct the program.

Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration.

Mitochondrial dysfunction and axon loss are hallmarks of neurologic diseases. Gasdermin (GSDM) proteins are executioner pore-forming molecules that mediate cell death, yet their roles in the central nervous system (CNS) are not well understood. Here, we find that one GSDM family member, GSDME, is expressed by both mouse and human neurons.

Bacteria hijack a meningeal neuroimmune axis to facilitate brain invasion.

The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache. Bacterial meningitis causes life-threatening infections of the meninges and central nervous system, affecting more than 2.5 million people a year.

Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection.

Neuroepithelial crosstalk is critical for gut physiology. However, the mechanisms by which sensory neurons communicate with epithelial cells to mediate gut barrier protection at homeostasis and during inflammation are not well understood. Here, we find that Nav1.

Pharmacotherapy for Amyotrophic Lateral Sclerosis: A Review of Approved and Upcoming Agents.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder involving loss of upper and lower motor neurons, with most cases ending in death within 3-5 years of onset. Several molecular and cellular pathways have been identified to cause ALS; however, treatments to stop or reverse disease progression are yet to be found. Riluzole, a neuroprotective agent offering only a modest survival benefit, has long been the sole disease-modifying therapy for ALS.

Derivation and validation of a risk classification tree for patients with synovial sarcoma.

Background: Synovial sarcoma (SS) accounts for 8%-10% of all soft-tissue sarcomas. Clinical presentation and outcomes vary, yet discrete risk groups based on validated prognostic indices are not defined for the full spectrum of patients with SS.

Methods: We performed a retrospective cohort study using data from the SEER (surveillance, epidemiology, and end results program) database of SS patients who were <70 years of age at diagnosis.

Catching a killer: Mechanisms of programmed cell death and immune activation in Amyotrophic Lateral Sclerosis.

In the central nervous system (CNS), execution of programmed cell death (PCD) is crucial for proper neurodevelopment. However, aberrant activation of these pathways in adult CNS leads to neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). How a cell dies is critical, as it can drive local immune activation and tissue damage.

Anthrax toxins regulate pain signaling and can deliver molecular cargoes into ANTXR2 DRG sensory neurons.

Bacterial products can act on neurons to alter signaling and function. In the present study, we found that dorsal root ganglion (DRG) sensory neurons are enriched for ANTXR2, the high-affinity receptor for anthrax toxins. Anthrax toxins are composed of protective antigen (PA), which binds to ANTXR2, and the protein cargoes edema factor (EF) and lethal factor (LF).

VLDLR and ApoER2 are receptors for multiple alphaviruses.

Alphaviruses, like many other arthropod-borne viruses, infect vertebrate species and insect vectors separated by hundreds of millions of years of evolutionary history. Entry into evolutionarily divergent host cells can be accomplished by recognition of different cellular receptors in different species, or by binding to receptors that are highly conserved across species. Although multiple alphavirus receptors have been described, most are not shared among vertebrate and invertebrate hosts.

Nociceptive Sensory Neurons Mediate Inflammation Induced by Edema Toxin.

Bacterial products are able to act on nociceptive neurons during pathogenic infection. Neurogenic inflammation is an active part of pain signaling and has recently been shown to impact host-pathogen defense. Edema Toxin (ET) produces striking edema in peripheral tissues, but the cellular mechanisms involved in tissue swelling are not completely understood.

Landscape of phase 1 clinical trials for minors with cancer in the United States.

Objectives: Understanding trends in characteristics of early phase trials that allow minors with cancer to participate may inform additional efforts to improve cancer drug development for young people.

Methods: We accessed data for oncology phase 1 or phase 1/2 trials in the United States from ClinicalTrials.gov with lower age bound for eligibility <18 years.

Sponsorship of oncology clinical trials in the United States according to age of eligibility.

Background: The sponsorship mix of trials relevant to young people with cancer has not been reported. Understanding this sponsorship mix may have implications for policies and regulations related to pediatric cancer drug development.

Methods: We analyzed sponsorship of interventional trials first opened in the United States from 2007 to 2018 using the ClinicalTrials.

Timing of first-in-child trials of FDA-approved oncology drugs.

Aim: The lag time between initial human studies of oncology agents and the first-in-child clinical trials of these agents has not been defined.

Methods: We conducted a systematic analysis of time from first-in-human trials to first-in-child trials (age of eligibility <18 years) of agents first approved by the US Food and Drug Administration (FDA) for any oncology indication from 1997 to 2017. We used clinical trial registry data, published literature and oncology abstracts to identify relevant trials and start dates.

Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription.

The transcription factor Max is a basic-helix-loop-helix leucine zipper (bHLHLZ) protein that forms homodimers or interacts with other bHLHLZ proteins, including Myc and Mxd proteins. Among this dynamic network of interactions, the Myc/Max heterodimer has crucial roles in regulating normal cellular processes, but its transcriptional activity is deregulated in a majority of human cancers. Despite this significance, the arsenal of high-quality chemical probes to interrogate these proteins remains limited.

Recent discoveries and applications involving small-molecule microarrays.

High-throughput and unbiased binding assays have proven useful in probe discovery for a myriad of biomolecules, including targets of unknown structure or function and historically challenging target classes. Over the past decade, a number of novel formats for executing large-scale binding assays have been developed and used successfully in probe discovery campaigns. Here we review the use of one such format, the small-molecule microarray (SMM), as a tool for discovering protein-small molecule interactions.