Targeting c-MYC and gain-of-function p53 through inhibition or degradation of the kinase LZK suppresses the growth of HNSCC tumors.

The worldwide annual frequency and lethality of head and neck squamous cell carcinoma (HNSCC) is not improving, and thus, new therapeutic approaches are needed. Approximately 70% of HNSCC cases have either amplification or overexpression of , which encodes the kinase LZK. Here, we found that LZK is a therapeutic target in HNSCC and that small-molecule inhibition of its catalytic function decreased the viability of HNSCC cells with amplified .

Targeting GOF p53 and c-MYC through LZK Inhibition or Degradation Suppresses Head and Neck Tumor Growth.

The worldwide frequency of head and neck squamous cell carcinoma (HNSCC) is approximately 800,000 new cases, with 430,000 deaths annually. We determined that LZK (encoded by ) is a therapeutic target in HNSCC and showed that inhibition with small molecule inhibitors decreases the viability of HNSCC cells with amplified . A drug-resistant mutant of LZK blocks decreases in cell viability due to LZK inhibition, indicating on-target activity by two separate small molecules.

Targeting NAD+ Metabolism Vulnerability in FH-Deficient Hereditary Leiomyomatosis and Renal Cell Carcinoma with the Novel NAMPT Inhibitor OT-82.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an inherited cancer syndrome caused by germline pathogenic variants in the fumarate hydratase (FH) gene. Affected individuals are at risk for developing cutaneous and uterine leiomyomas and aggressive FH-deficient renal cell carcinoma (RCC) with a papillary histology. Due to a disrupted tricarboxylic acid cycle, FH-deficient kidney cancers rely on aerobic glycolysis for energy production, potentially creating compensatory metabolic vulnerabilities.

Toward a CRISPR-based mouse model of -deficient clear cell kidney cancer: Initial experience and lessons learned.

CRISPR is revolutionizing the ability to do somatic gene editing in mice for the purpose of creating new cancer models. Inactivation of the tumor suppressor gene is the signature initiating event in the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC). Such tumors are usually driven by the excessive HIF2 activity that arises when the gene product, pVHL, is defective.

Preclinical Therapeutic Efficacy of RAF/MEK/ERK and IGF1R/AKT/mTOR Inhibition in Neuroblastoma.

Activating mutations in the RAS/MAPK pathway are observed in relapsed neuroblastoma. Preclinical studies indicate that these tumors have an increased sensitivity to inhibitors of the RAS/MAPK pathway, such as MEK inhibitors. MEK inhibitors do not induce durable responses as single agents, indicating a need to identify synergistic combinations of targeted agents to provide therapeutic benefit.

The Combination of Trametinib and Ganitumab is Effective in RAS-Mutated PAX-Fusion Negative Rhabdomyosarcoma Models.

Purpose: PAX-fusion negative rhabdomyosarcoma (FN RMS) is driven by alterations in the RAS/MAP kinase pathway and is partially responsive to MEK inhibition. Overexpression of IGF1R and its ligands is also observed in FN RMS. Preclinical and clinical studies have suggested that IGF1R is itself an important target in FN RMS.

Assessing the Effectiveness of a Primary Care Provider Office-Based Intervention for Increasing Organ Donor Registration Rates in Two New York State Counties.

Despite strong public support, organ donor registration rates (RR) continue to lag while need only grows. In the United States, the traditional registration site is the Department of Motor Vehicles (DMV), however Primary care provider (PCP) offices have been considered as alternate locations for increasing RR. Twelve PCP offices across 2 New York Counties were subjected to a control week where participants received only a registration opportunity and an intervention week with the addition of a motivational poster and informational brochure.

The Impact of a Diabetes Transitions of Care Clinic on Hospital Utilization and Patient Care.

Background: There is currently limited guidance from the American Diabetes Association regarding transitions of care for patients with diabetes.

Objective: This study's aim was to determine the impact of a diabetes-specific transitions of care clinic (TOCC) on hospital utilization and patient outcomes in recently discharged patients with diabetes.

Methods: This retrospective study evaluated patients seen by TOCC as compared with similar patients discharged from the study institution the year prior.

Predictive modeling in neurocritical care using causal artificial intelligence.

Artificial intelligence (AI) and digital twin models of various systems have long been used in industry to test products quickly and efficiently. Use of digital twins in clinical medicine caught attention with the development of Archimedes, an AI model of diabetes, in 2003. More recently, AI models have been applied to the fields of cardiology, endocrinology, and undergraduate medical education.

Viral inosine triphosphatase: A mysterious enzyme with typical activity, but an atypical function.

Plant viruses typically have highly condensed genomes, yet the plant-pathogenic viruses Cassava brown streak virus, Ugandan cassava brown streak virus, and Euphorbia ringspot virus are unusual in encoding an enzyme not yet found in any other virus, the "house-cleaning" enzyme inosine triphosphatase. Inosine triphosphatases (ITPases) are highly conserved enzymes that occur in all kingdoms of life and perform a house-cleaning function by hydrolysing the noncanonical nucleotide inosine triphosphate to inosine monophosphate. The ITPases encoded by cassava brown streak virus and Ugandan cassava brown streak virus have been characterized biochemically and are shown to have typical ITPase activity.

The Indenoisoquinoline LMP517: A Novel Antitumor Agent Targeting both TOP1 and TOP2.

The camptothecin derivatives topoisomerase I (TOP1) inhibitors, irinotecan and topotecan, are FDA approved for the treatment of colorectal, ovarian, lung and breast cancers. Because of the chemical instability of camptothecins, short plasma half-life, drug efflux by the multidrug-resistance ABC transporters, and the severe diarrhea produced by irinotecan, indenoisoquinoline TOP1 inhibitors (LMP400, LMP776, and LMP744), which overcome these limitations, have been developed and are in clinical development. Further modifications of the indenoisoquinolines led to the fluoroindenoisoquinolines, one of which, LMP517, is the focus of this study.

Improvement in the medication reconciliation postdischarge quality measure after implementation of a pharmacist-run service.

Objective: This study aimed to evaluate the impact of a pharmacist-led postsurgical discharge medication reconciliation program in an accountable care organization-like setting.

Setting: Multidisciplinary primary care network in Central Ohio.

Practice Description: Ambulatory care pharmacists are integrated in a primary care network, which includes a centralized focus on assistance with population health metrics, along with an interdisciplinary team.

The macrocyclizing protease butelase 1 remains autocatalytic and reveals the structural basis for ligase activity.

Plant asparaginyl endopeptidases (AEPs) are expressed as inactive zymogens that perform maturation of seed storage protein upon cleavage-dependent autoactivation in the low-pH environment of storage vacuoles. The AEPs have attracted attention for their macrocyclization reactions, and have been classified as cleavage or ligation specialists. However, we have recently shown that the ability of AEPs to produce either cyclic or acyclic products can be altered by mutations to the active site region, and that several AEPs are capable of macrocyclization given favorable pH conditions.

Novel Fluoroindenoisoquinoline Non-Camptothecin Topoisomerase I Inhibitors.

Contrary to other anticancer targets, topoisomerase I (TOP1) is targeted by only one chemical class of FDA-approved drugs: topotecan and irinotecan, the derivatives of the plant alkaloid, camptothecin. The indenoisoquinolines LMP400, LMP744, and LMP776 are novel noncamptothecin TOP1 inhibitors in clinical trial, which overcome the limitations of camptothecins. To further improve metabolic stability, their methoxy groups have been replaced by fluorine, as in the fluoroindenoisoquinolines NSC 781517 (LMP517), NSC 779135 (LMP135), and NSC 779134 (LMP134).

Structural basis of ribosomal peptide macrocyclization in plants.

Constrained, cyclic peptides encoded by plant genes represent a new generation of drug leads. Evolution has repeatedly recruited the Cys-protease asparaginyl endopeptidase (AEP) to perform their head-to-tail ligation. These macrocyclization reactions use the substrates amino terminus instead of water to deacylate, so a peptide bond is formed.

Training therapists to work with people with intellectual disability in Improving Access to Psychological Therapies (IAPT) services.

Background: Current policy in the England suggests that people with intellectual disabilities should, where possible, access mainstream mental health services; this should include access to mainstream therapy services. It is likely that mainstream therapists will need training and support to work with people with intellectual disabilities.

Method: Sixty-eight therapists working in an English Improving Access to Psychological Therapies (IAPT) service received one- or 2-day training on working with people with intellectual disabilities.

Two proteins for the price of one: Structural studies of the dual-destiny protein preproalbumin with sunflower trypsin inhibitor-1.

Seed storage proteins are both an important source of nutrition for humans and essential for seedling establishment. Interestingly, unusual napin-type 2S seed storage albumin precursors in sunflowers contain a sequence that is released as a macrocyclic peptide during post-translational processing. The mechanism by which such peptides emerge from linear precursor proteins has received increased attention; however, the structural characterization of intact precursor proteins has been limited.

Poplar MYB115 and MYB134 Transcription Factors Regulate Proanthocyanidin Synthesis and Structure.

The accumulation of proanthocyanidins is regulated by a complex of transcription factors composed of R2R3 MYB, basic helix-loop-helix, and WD40 proteins that activate the promoters of biosynthetic genes. In poplar (genus ), MYB134 is known to regulate proanthocyanidin biosynthesis by activating key flavonoid genes. Here, we characterize a second MYB regulator of proanthocyanidins, MYB115.

Macrocyclization by asparaginyl endopeptidases.

Contents Summary 923 I. Introduction 923 II. Plant AEPs with macrocyclizing ability 924 III.

Evidence for Ancient Origins of Bowman-Birk Inhibitors from .

Bowman-Birk Inhibitors (BBIs) are a well-known family of plant protease inhibitors first described 70 years ago. BBIs are known only in the legume (Fabaceae) and cereal (Poaceae) families, but peptides that mimic their trypsin-inhibitory loops exist in sunflowers () and frogs. The disparate biosynthetic origins and distant phylogenetic distribution implies these loops evolved independently, but their structural similarity suggests a common ancestor.

Community correctional agents' views of medication-assisted treatment: Examining their influence on treatment referrals and community supervision practices.

Background: Alcohol and opioid use disorders are common among adults under community supervision. Although several medications (medication-assisted treatment or MAT) are Food and Drug Administration (FDA)-approved to treat such disorders, they are underutilized with this population despite established effectiveness at decreasing substance use. This paper examines how community correctional agents' understanding of addiction and views of MAT influence their professional actions regarding addiction medications.