Targeting strategies for modulating pre-mRNA splicing with small molecules: Recent advances.

The concept of using small molecules to therapeutically modulate pre-mRNA splicing was validated with the US Food and Drug Administration (FDA) approval of Evrysdi® (risdiplam) in 2020. Since then, efforts have continued unabated toward the discovery of new splicing-modulating drugs. However, the drug development world has evolved in the 10 years since risdiplam precursors were first identified in high-throughput screening (HTS).

Small molecule splicing modifiers with systemic HTT-lowering activity.

Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin (HTT) gene. Consequently, the mutant protein is ubiquitously expressed and drives pathogenesis of HD through a toxic gain-of-function mechanism. Animal models of HD have demonstrated that reducing huntingtin (HTT) protein levels alleviates motor and neuropathological abnormalities.

Long-term and pathological outcomes of low- and intermediate-risk prostate cancer after radical prostatectomy: implications for active surveillance.

Purpose: The safety of active surveillance (AS) in favorable intermediate-risk (FIR) prostate cancer (PCa) remains uncertain. To provide guidance on clinical decision-making, we examined long-term and pathological outcomes of low-risk and intermediate-risk PCa patients after radical prostatectomy (RP).

Methods: The study involved 5693 patients diagnosed between 1994 and 2019 with low-risk, FIR, and unfavorable intermediate-risk (UIR) PCa (stratification according to the AUA guidelines) who underwent RP.

Discovery and Optimization of Indolyl-Containing 4-Hydroxy-2-Pyridone Type II DNA Topoisomerase Inhibitors Active against Multidrug Resistant Gram-negative Bacteria.

There exists an urgent medical need to identify new chemical entities (NCEs) targeting multidrug resistant (MDR) bacterial infections, particularly those caused by Gram-negative pathogens. 4-Hydroxy-2-pyridones represent a novel class of nonfluoroquinolone inhibitors of bacterial type II topoisomerases active against MDR Gram-negative bacteria. Herein, we report on the discovery and structure-activity relationships of a series of fused indolyl-containing 4-hydroxy-2-pyridones with improved in vitro antibacterial activity against fluoroquinolone resistant strains.

Surgical Critical Care for the Trauma Patient with Cardiac Disease.

The elderly population is rapidly increasing in number. Therefore, geriatric trauma is becoming more prevalent. All practitioners caring for geriatric trauma patients should be familiar with the structural and functional changes naturally occurring in the aging heart, as well as common preexisting cardiac diseases in the geriatric population.

Discovery and Optimization of Small Molecule Splicing Modifiers of Survival Motor Neuron 2 as a Treatment for Spinal Muscular Atrophy.

The underlying cause of spinal muscular atrophy (SMA) is a deficiency of the survival motor neuron (SMN) protein. Starting from hits identified in a high-throughput screening campaign and through structure-activity relationship investigations, we have developed small molecules that potently shift the alternative splicing of the SMN2 exon 7, resulting in increased production of the full-length SMN mRNA and protein. Three novel chemical series, represented by compounds 9, 14, and 20, have been optimized to increase the level of SMN protein by >50% in SMA patient-derived fibroblasts at concentrations of <160 nM.

Specific Correction of Alternative Survival Motor Neuron 2 Splicing by Small Molecules: Discovery of a Potential Novel Medicine To Treat Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is the leading genetic cause of infant and toddler mortality, and there is currently no approved therapy available. SMA is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. These mutations or deletions result in low levels of functional SMN protein.

Effect of C-Terminal S-Palmitoylation on D2 Dopamine Receptor Trafficking and Stability.

We have used bioorthogonal click chemistry (BCC), a sensitive non-isotopic labeling method, to analyze the palmitoylation status of the D2 dopamine receptor (D2R), a G protein-coupled receptor (GPCR) crucial for regulation of processes such as mood, reward, and motor control. By analyzing a series of D2R constructs containing mutations in cysteine residues, we found that palmitoylation of the D2R most likely occurs on the C-terminal cysteine residue (C443) of the polypeptide. D2Rs in which C443 was deleted showed significantly reduced palmitoylation levels, plasma membrane expression, and protein stability compared to wild-type D2Rs.

Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces low, insufficient levels of functional SMN protein due to alternative splicing that truncates the transcript. The decreased levels of SMN protein lead to progressive neuromuscular degeneration and high rates of mortality.

Assessing patient-caregiver communication in cancer--a psychometric validation of the Cancer Communication Assessment Tool (CCAT-PF) in a German sample.

Purpose: The recently introduced Cancer Communication Assessment Tool (CCAT-PF) measures congruence in patient-caregiver communication and was initially validated in lung cancer patients. Contributing to a greater proportion of the variance in the conflict scores, primary caregivers were hypothesized to experience greater stress. For a detailed understanding of conflicting communication patterns of cancer-affected families, our study aimed for psychometric validation of the CCAT-PF in a sample covering heterogeneous tumor entities.

Humanitarian care by a forward surgical team in afghanistan.

Background: The mission of a Forward Surgical Team (FST) is to provide immediate lifesaving surgery to wounded U.S. and coalition forces.

Improving compliance with malaria chemoprophylaxis in Afghanistan.

Objective: Historically, compliance with malaria chemoprophylaxis by military service members (MSM) has been notoriously low, ranging from 30 to 56%. Since 2002, 28 to 85 cases per year of malaria have occurred in MSM deployed to Afghanistan. During their deployment to Afghanistan, the authors identified a low compliance rate with malaria chemoprophylaxis.

Bladder stones in Afghan children.

Objectives: Military surgeons have been providing humanitarian care in Afghanistan since 2002. There are scant published reports on the details of that care. We report here the experience of deployed U.

Breast radiation correlates with side of parathyroid adenoma.

Background: Prior head and neck irradiation is a known risk factor for hyperparathyroidism. It is not clear whether irradiation for breast cancer, which may expose the neck to radiation, is also a risk factor for hyperparathyroidism. The present study analyzes the association between the side of radiation to the chest following breast surgery and the side of subsequent parathyroid adenoma development.

Management of the mangled face by a forward surgical team.

A mangled face is an uncommon injury that can occur in a combat zone as a result of blunt trauma, penetrating trauma or explosion injury. Despite the patient?s dramatic disfigurement, attention needs to focus on the basic ABC?s of initial trauma management. We present an injured Afghan civilian with a severe facial injury.

Interaction between the D2 dopamine receptor and neuronal calcium sensor-1 analyzed by fluorescence anisotropy.

Neuronal calcium sensor-1 (NCS-1) is a small calcium binding protein that plays a key role in the internalization and desensitization of activated D2 dopamine receptors (D2Rs). Here, we have used fluorescence anisotropy (FA) and a panel of NCS-1 EF-hand variants to interrogate the interaction between the D2R and NCS-1. Our data are consistent with the following conclusions.

Dopamine receptor interacting proteins: targeting neuronal calcium sensor-1/D2 dopamine receptor interaction for antipsychotic drug development.

D2 dopamine receptors (D2Rs) represent an important class of receptors in the pharmacological development of novel therapeutic drugs for the treatment of schizophrenia. Recent research into D2R signaling suggests that receptor properties are dependent on interaction with a cohort of dopamine receptor interacting proteins (DRIPs) within a macromolecular structure termed the signalplex. One component of this signalplex is neuronal calcium sensor 1 (NCS-1) a protein found to regulate the phosphorylation, trafficking, and signaling profile of the D2R in neurons.

Neurotensin receptor-1 inducible palmitoylation is required for efficient receptor-mediated mitogenic-signaling within structured membrane microdomains.

Neurotensin receptor-1 (NTSR-1) is a G-protein coupled receptor (GPCR) that has been recently identified as a mediator of cancer progression. NTSR-1 and its endogenous ligand, neurotensin (NTS), are co-expressed in several breast cancer cell lines and breast cancer tumor samples. Based on our previously published study demonstrating that intact structured membrane microdomains (SMDs) are required for NTSR-1 mitogenic signaling, we hypothesized that regulated receptor palmitoylation is responsible for NTSR-1 localization and signaling within SMDs upon NTS stimulation.

Does previous head and neck irradiation increase the chance of multigland disease in patients with hyperparathyroidism?

Background: Exposure to therapeutic radiation, whether used to treat lymphoma, breast cancer, or benign conditions, such as acne, is thought to cause an increased risk for thyroid and/or parathyroid neoplasia. We therefore investigated whether patients with a history of head/neck irradiation and hyperparathyroidism (HPT) had a higher incidence of multigland disease.

Methods: Between November 2000 and May 2010, 1,428 patients with HPT underwent parathyroidectomy at our institution.

Asymmetric cooperative catalysis of strong Brønsted acid-promoted reactions using chiral ureas.

Cationic organic intermediates participate in a wide variety of useful synthetic transformations, but their high reactivity can render selectivity in competing pathways difficult to control. Here, we describe a strategy for inducing enantioselectivity in reactions of protio-iminium ions, wherein a chiral catalyst interacts with the highly reactive intermediate through a network of noncovalent interactions. This interaction leads to an attenuation of the reactivity of the iminium ion and allows high enantioselectivity in cycloadditions with electron-rich alkenes (the Povarov reaction).

Proteomic and functional analysis of NCS-1 binding proteins reveals novel signaling pathways required for inner ear development in zebrafish.

Background: The semicircular canals, a subdivision of the vestibular system of the vertebrate inner ear, function as sensors of angular acceleration. Little is currently known, however, regarding the underlying molecular mechanisms that govern the development of this intricate structure. Zebrafish represent a particularly tractable model system for the study of inner ear development.

Longterm followup assessment of a HER2/neu peptide (E75) vaccine for prevention of recurrence in high-risk prostate cancer patients.

Background: E75 is an immunogenic peptide from the HER2/neu protein that is expressed in prostate cancer. High-risk prostate cancer (HRPC) patients demonstrating varying levels of HER2/neu expression were vaccinated with E75 peptide plus granulocyte-macrophage colony-stimulating factor to prevent postprostatectomy PSA and clinical recurrences.

Study Design: Forty evaluable HRPC patients were prospectively identified using the validated Center for Prostate Disease Research/CaPSURE high-risk equation and enrolled.