Discovery of MK-1084: An Orally Bioavailable and Low-Dose KRAS Inhibitor.

Oncogenic mutations in the gene account for 30% of all human tumors; more than 60% of which present as KRAS mutations at the hotspot codon 12. After decades of intense pursuit, a covalent inhibition strategy has enabled selective targeting of this previously "undruggable" target. Herein, we disclose our journey toward the discovery of MK-1084, an orally bioavailable and low-dose KRAS covalent inhibitor currently in phase I clinical trials (NCT05067283).

Broad Survey of Selectivity in the Heterogeneous Hydrogenation of Heterocycles.

A broad survey of heterogeneous hydrogenation catalysts has been conducted for the reduction of heterocycles commonly found in pharmaceuticals. The comparative reactivity of these substrates is reported as a function of catalyst, temperature, and hydrogen pressure. This analysis provided several catalysts with complementary reactivity between substrates.

Acoustically Driven Magnon-Phonon Coupling in a Layered Antiferromagnet.

Harnessing the causal relationships between mechanical and magnetic properties of Van der Waals materials presents a wealth of untapped opportunity for scientific and technological advancement, from precision sensing to novel memories. This can, however, only be exploited if the means exist to efficiently interface with the magnetoelastic interaction. Here, we demonstrate acoustically driven spin-wave resonance in a crystalline antiferromagnet, chromium trichloride, via surface acoustic wave irradiation.

Interspecies exciton interactions lead to enhanced nonlinearity of dipolar excitons and polaritons in MoS homobilayers.

Nonlinear interactions between excitons strongly coupled to light are key for accessing quantum many-body phenomena in polariton systems. Atomically-thin two-dimensional semiconductors provide an attractive platform for strong light-matter coupling owing to many controllable excitonic degrees of freedom. Among these, the recently emerged exciton hybridization opens access to unexplored excitonic species, with a promise of enhanced interactions.

Early Use of Iloprost in Nonfreezing Cold Injury.

Nonfreezing cold injury (NFCI) is caused by prolonged exposure to cold, usually wet conditions and represents a separate pathological entity from frostbite. The pathophysiology of NFCI is characterized by vasoconstriction and microcirculatory disturbance. Iloprost, a synthetic prostaglandin analogue with vasodilatory properties is a recognized adjuvant treatment in frostbite; however, its role in NFCI is unclear.

Does Bail Reform Decarcerate Mental Illness? Public Health Challenges for a Large County Jail System.

Although bail reform reduces jail census, whether or not its effects extend to incarcerated individuals with mental illness is unknown. Using a novel high-sensitivity measure of serious mental illness (SMI) from jail-based electronic health records, we conducted an interrupted time series analysis assessing the impact of Illinois bail reform on total jail registrations and the nested subset with SMI ± co-occurring substance use disorder (SUD). Compared with a decline in total jail registrations, admission of individuals with SMI ± SUD showed no decline.

Prevalence and risk factors for opioid related mortality among probation clients in an American city.

Introduction: Substance use disorder researchers and treatment professionals have long recognized that risk of opioid-related mortality (ORM) is elevated after release from jail and prison. However, there are gaps in knowledge around ORM among people on probation and the relationship of ORM to drug testing and treatment referral while under supervision. Understanding this relationship is critical for probation officers who are often tasked with referring clients to treatment and monitoring compliance with treatment, without having a clinical background.

Comprehensive Strategies to Bicyclic Prolines: Applications in the Synthesis of Potent Arginase Inhibitors.

Comprehensive synthetic strategies afforded a diverse set of structurally unique bicyclic proline-containing arginase inhibitors with a high degree of three-dimensionality. The analogs that favored the Cγ-exo conformation of the proline improved the arginase potency over the initial lead. The novel synthetic strategies reported here not only enable access to previously unknown stereochemically complex proline derivatives but also provide a foundation for the future synthesis of bicyclic proline analogs, which incorporate inherent three-dimensional character into building blocks, medicine, and catalysts and could have a profound impact on the conformation of proline-containing peptides and macrocycles.

Structure-Based Discovery of Proline-Derived Arginase Inhibitors with Improved Oral Bioavailability for Immuno-Oncology.

Recent data suggest that the inhibition of arginase (ARG) has therapeutic potential for the treatment of a number of indications ranging from pulmonary and vascular disease to cancer. Thus, high demand exists for selective small molecule ARG inhibitors with favorable druglike properties and good oral bioavailability. In light of the significant challenges associated with the unique physicochemical properties of previously disclosed ARG inhibitors, we use structure-based drug design combined with a focused optimization strategy to discover a class of boronic acids featuring a privileged proline scaffold with superior potency and oral bioavailability.

Association Between Treatment Progression, Disease Refractoriness, and Burden of Illness Among Hospitalized Patients With Status Epilepticus.

Importance: Status epilepticus (SE) is associated with poor clinical outcomes and high cost. Increased levels of refractory SE require treatment with additional medications and carry increased morbidity and mortality, but the associations between SE refractoriness, clinical outcomes, and cost remain poorly characterized.

Objective: To examine differences in clinical outcomes and costs associated with hospitalization for SE of varying refractoriness.

Discovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy.

The action of arginase, a metalloenzyme responsible for the hydrolysis of arginine to urea and ornithine, is hypothesized to suppress immune-cell activity within the tumor microenvironment, and thus its inhibition may constitute a means by which to potentiate the efficacy of immunotherapeutics such as anti-PD-1 checkpoint inhibitors. Taking inspiration from reported enzyme-inhibitor cocrystal structures, we designed and synthesized novel inhibitors of human arginase possessing a fused 5,5-bicyclic ring system. The prototypical member of this class, , when dosed orally, successfully demonstrated serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model, despite modest oral bioavailability.

Manipulating molecules with strong coupling: harvesting triplet excitons in organic exciton microcavities.

Exciton-polaritons are quasiparticles with mixed photon and exciton character that demonstrate rich quantum phenomena, novel optoelectronic devices and the potential to modify chemical properties of materials. Organic materials are of current interest as active materials for their ability to sustain exciton-polaritons even at room temperature. However, within organic optoelectronic devices, it is often the 'dark' spin-1 triplet excitons that dominate operation.

Chemotherapy versus surgery for initial treatment in advanced ovarian epithelial cancer.

Background: Epithelial ovarian cancer presents at an advanced stage in the majority of women. These women require surgery and chemotherapy for optimal treatment. Conventional treatment has been to perform surgery first and then give chemotherapy.

Mindfulness-Based Relapse Prevention in a Jail Drug Treatment Program.

Background: More than half of prisoners in the United States are estimated to suffer from a substance use disorder. Mindfulness involves attention to the present moment, and nonjudgmental acceptance of sensations, thoughts, and emotional states. Mindfulness-based relapse prevention (MBRP) following substance use disorder treatment has been shown to reduce substance use.

Epidermal growth factor receptor blockers for the treatment of ovarian cancer.

Background: This is an update of a previously published version of the review (Issue 10, 2011).Epithelial ovarian cancer (EOC) is the seventh most common cause of cancer death among women worldwide. Treatment consists of a combination of surgical debulking and platinum-based chemotherapy.

A Next Generation Synthesis of BACE1 Inhibitor Verubecestat (MK-8931).

The development of a commercial manufacturing route to verubecestat (MK-8931) is described, highlights of which include the application of a continuous processing step to outcompete fast proton transfer in a Mannich-type ketimine addition, a copper-catalyzed amidation reaction, and an optimized guanidinylation procedure to form the key iminothiadiazine dioxide core.

Untargeted Metabotyping Reveals Population-Level Variation in Plant Flavonoids and Alkaloids.

Metabolomics provides a powerful platform to characterize plants at the biochemical level, allowing a search for underlying genes and associations with higher level complex traits such as yield and nutritional value. Efficient and reliable methods to characterize metabolic variation in economically important species are considered of high value to the evaluation and prioritization of germplasm and breeding lines. In this investigation, a large-scale metabolomic survey was performed on a collection of diverse perennial ryegrass ( L.

Assessing Implicit Cognition Among Patients Lost to Follow-up for HIV Care: A Preliminary Study.

Objective: While a growing body of research indicates that implicit cognitive processes play an important role in a range of health behaviors, the assessment of these impulsive, associative mental processes among patients living with HIV has received little attention. This preliminary study explored how multidimensional scaling (MDS) could be used to assess implicit cognitive processes among patients lost to follow-up for HIV care and develop interventions to improve their engagement.

Method: The sample consisted of 33 patients who were identified as lost to follow up for HIV care at two urban hospitals.

Intramolecular Hydrogen Transfer Reactions Catalyzed by Pentamethylcyclopentadienyl Rhodium and Cobalt Olefin Complexes: Mechanistic Studies.

The mechanism of intramolecular transfer dehydrogenation catalyzed by [CpM(VTMS)] (, M=Rh, , M=Co, Cp* = CMe, VTMS = vinyltrimethylsilane) complexes has been studied using vinyl silane protected alcohols as substrates. Deuterium-labeled substrates have been synthesized and the regioselectivity of H/D transfers investigated using H and H NMR spectroscopy. The labeling studies establish a regioselective pathway consisting of alkene directed α C-H activation, 2,1 alkene insertion, and finally β-hydride elimination to give silyl enol ether products.

Prison Meditation Movements and Mass Incarceration.

By some estimates, more than half of inmates held in jails and prisons in the United States have a substance use disorder. Treatments involving the teaching of meditation and other contemplative practices have been developed for a variety of physical and mental disorders, including drug and alcohol addiction. At the same time, an expanding volunteer movement across the country has been bringing meditation and yoga into jails and prisons.

HIV prevention and education in state prison systems: an update.

The prevalence rate of HIV infection in jails and prisons is approximately 5 times the rate in the U.S. general population.

Role of endothelial progenitor cells and inflammatory cytokines in healing of diabetic foot ulcers.

Background: To evaluate changes in endothelial progenitor cells (EPCs) and cytokines in patients with diabetic foot ulceration (DFU) in association with wound healing.

Methods: We studied healthy subjects, diabetic patients not at risk of DFU, at risk of DFU and with active DFU. We prospectively followed the DFU patients over a 12-week period.

"What Could Have Been Different": A Qualitative Study of Syndemic Theory and HIV Prevention among Young Men Who Have Sex with Men.

Young men who have sex with men (MSM) experience multiple health disparities, including alcohol and drug use, partner violence, victimization due to sexual orientation, and HIV infection. Syndemic theorists explain the clustering of these disparities among adult MSM as a result of cultural marginalization. To date, research on a similar emerging syndemic among young MSM has been limited to quantitative studies.