Overcoming resistance to arginine deprivation therapy using GC7 in pleural mesothelioma.

Pleural mesothelioma is a highly chemotherapy-resistant cancer. Approximately 50% of mesotheliomas do not express argininosuccinate synthetase 1 (ASS1), the rate-limiting enzyme in arginine biosynthesis, making arginine depletion with pegylated arginine deiminase (ADI-PEG20) an attractive therapeutic strategy. We investigated whether combinatory treatment composed of ADI-PEG20 and polyamine inhibitors constitutes a promising novel therapeutic strategy to overcome ADI-PEG20 resistance in mesothelioma patients.

Patient Satisfaction With Long-term Sacral Neuromodulation for Fecal Incontinence: Experience From a Single Tertiary Center.

Background: Sacral neuromodulation is an effective treatment for fecal incontinence in the long term. Efficacy is typically assessed using bowel diary, symptom severity, and quality-of-life questionnaires, and "success" is defined as more than 50% improvement in these measures. However, patient satisfaction may be a more meaningful and individualized measure of treatment efficacy.

Pediatric Firearm Violence in America.

We have a firearm public health crisis in the United States, with firearm injuries being the leading cause of death in children. The state of pediatric firearm violence will be summarized through a synopsis of an expert panel of pediatric-focused advanced practice registered nurses. A review of related statistics, policy initiatives, programs, screening tools, and resources to support providers to intervene with patients, parents, and caregivers is summarized.

Molecular annotation of G protein variants in a neurological disorder.

Heterotrimeric G proteins transduce extracellular chemical messages to generate appropriate intracellular responses. Point mutations in GNAO1, encoding the G protein α subunit, have been implicated in a pathogenic condition characterized by seizures, movement disorders, intellectual disability, and developmental delay (GNAO1 disorder). However, the effects of these mutations on G protein structure and function are unclear.

DNA mismatch repair deficient cancer - Emerging biomarkers of resistance to immune checkpoint inhibition.

The DNA mismatch repair pathway is involved in the identification, excision, and repair of base-base mismatches and indel loops in the genome. Mismatch repair deficiency occurs in approximately 20% of all cancers and results in a type of DNA damage called microsatellite instability. In 2017, the immune checkpoint inhibitor, Pembrolizumab, an anti-PD-1 therapy, was approved for use in all unresectable or metastatic tumours that were mismatch repair deficient or had high microsatellite instability regardless of tissue origin.

Microtubule-associated proteins MAP7 and MAP7D1 promote DNA double-strand break repair in the G1 cell cycle phase.

The DNA-damage response is a complex signaling network that guards genomic integrity. The microtubule cytoskeleton is involved in the repair of DNA double-strand breaks; however, little is known about which cytoskeleton-related proteins are involved in DNA repair and how. Using quantitative proteomics, we discovered that microtubule associated proteins MAP7 and MAP7D1 interact with several DNA repair proteins including DNA double-strand break repair proteins RAD50, BRCA1 and 53BP1.

Catalytic site mutations confer multiple states of G protein activation.

Heterotrimeric guanine nucleotide-binding proteins (G proteins) that function as molecular switches for cellular growth and metabolism are activated by GTP and inactivated by GTP hydrolysis. In uveal melanoma, a conserved glutamine residue critical for GTP hydrolysis in the G protein α subunit is often mutated in Gα or Gα to either leucine or proline. In contrast, other glutamine mutations or mutations in other Gα subtypes are rare.

Statin Treatment as a Targeted Therapy for APC-Mutated Colorectal Cancer.

Background: Mutations in the tumor suppressor gene Adenomatous Polyposis Coli () are found in 80% of sporadic colorectal cancer (CRC) tumors and are also responsible for the inherited form of CRC, Familial adenomatous polyposis (FAP).

Methods: To identify novel therapeutic strategies for the treatment of mutated CRC, we generated a drug screening platform that incorporates a human cellular model of mutant CRC using CRISPR-cas9 gene editing and performed an FDA-approved drug screen targeting over 1000 compounds.

Results: We have identified the group of HMG-CoA Reductase (HMGCR) inhibitors known as statins, which cause a significantly greater loss in cell viability in the mutated cell lines and in mutated patient derived xenograft (PDX) models, compared to wild-type cells.

A Drug Screening Revealed Novel Potential Agents against Malignant Pleural Mesothelioma.

The lack of effective therapies remains one of the main challenges for malignant pleural mesothelioma (MPM). In this perspective, drug repositioning could accelerate the identification of novel treatments. We screened 1170 FDA-approved drugs on a SV40-immortalized mesothelial (MeT-5A) and five MPM (Mero-14, Mero-25, IST-Mes2, NCI-H28 and MSTO-211H) cell lines.

Carvedilol targets β-arrestins to rewire innate immunity and improve oncolytic adenoviral therapy.

Oncolytic viruses are being tested in clinical trials, including in women with ovarian cancer. We use a drug-repurposing approach to identify existing drugs that enhance the activity of oncolytic adenoviruses. This reveals that carvedilol, a β-arrestin-biased β-blocker, synergises with both wild-type adenovirus and the E1A-CR2-deleted oncolytic adenovirus, dl922-947.

Hepatic TM6SF2 Is Required for Lipidation of VLDL in a Pre-Golgi Compartment in Mice and Rats.

Background & Aims: Substitution of lysine for glutamic acid at residu 167 in Transmembrane 6 superfamily member 2 (TM6SF2) is associated with fatty liver disease and reduced plasma lipid levels. Tm6sf2 mice replicate the human phenotype but were not suitable for detailed mechanistic studies. As an alternative model, we generated Tm6sf2 rats to determine the subcellular location and function of TM6SF2.

Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes.

An early event in lung oncogenesis is loss of the tumour suppressor gene LIMD1 (LIM domains containing 1); this encodes a scaffold protein, which suppresses tumorigenesis via a number of different mechanisms. Approximately 45% of non-small cell lung cancers (NSCLC) are deficient in LIMD1, yet this subtype of NSCLC has been overlooked in preclinical and clinical investigations. Defining therapeutic targets in these LIMD1 loss-of-function patients is difficult due to a lack of 'druggable' targets, thus alternative approaches are required.

Implementing PDSA Methodology for Pediatric Appendicitis Increases Care Value for a Tertiary Children's Hospital.

Introduction: We used the plan-do-study-act (PDSA) framework to develop and implement an evidence-based clinical practice guideline (CPG) within an urban, tertiary children's referral center.

Methods: We developed an evidence-based CPG for appendicitis using iterative PDSA cycles. Similar CPGs from other centers were reviewed and modified for local implementation.

The emerging relationship between metabolism and DNA repair.

The DNA damage response (DDR) consists of multiple specialized pathways that recognize different insults sustained by DNA and repairs them where possible to avoid the accumulation of mutations. While loss of activity of genes in the DDR has been extensively associated with cancer predisposition and progression, in recent years it has become evident that there is a relationship between the DDR and cellular metabolism. The activity of the metabolic pathways can influence the DDR by regulating the availability of substrates required for the repair process and the function of its players.

Chloroxine overrides DNA damage tolerance to restore platinum sensitivity in high-grade serous ovarian cancer.

High-grade serous cancer (HGSC) accounts for ~67% of all ovarian cancer deaths. Although initially sensitive to platinum chemotherapy, resistance is inevitable and there is an unmet clinical need for novel therapies that can circumvent this event. We performed a drug screen with 1177 FDA-approved drugs and identified the hydroxyquinoline drug, chloroxine.

Endocannabinoids Inhibit the Induction of Virulence in Enteric Pathogens.

Endocannabinoids are host-derived lipid hormones that fundamentally impact gastrointestinal (GI) biology. The use of cannabis and other exocannabinoids as anecdotal treatments for various GI disorders inspired the search for mechanisms by which these compounds mediate their effects, which led to the discovery of the mammalian endocannabinoid system. Dysregulated endocannabinoid signaling was linked to inflammation and the gut microbiota.

MLH1 deficiency leads to deregulated mitochondrial metabolism.

The DNA mismatch repair (MMR) pathway is responsible for the repair of base-base mismatches and insertion/deletion loops that arise during DNA replication. MMR deficiency is currently estimated to be present in 15-17% of colorectal cancer cases and 30% of endometrial cancers. MLH1 is one of the key proteins involved in the MMR pathway.

Defective fatty acid oxidation in mice with muscle-specific acyl-CoA synthetase 1 deficiency increases amino acid use and impairs muscle function.

Loss of long-chain acyl-CoA synthetase isoform-1 (ACSL1) in mouse skeletal muscle () severely reduces acyl-CoA synthetase activity and fatty acid oxidation. However, the effects of decreased fatty acid oxidation on skeletal muscle function, histology, use of alternative fuels, and mitochondrial function and morphology are unclear. We observed that mice have impaired voluntary running capacity and muscle grip strength and that their gastrocnemius muscle contains myocytes with central nuclei, indicating muscle regeneration.

Three-phase liquid extraction: a simple and fast method for lipidomic workflows.

An unbiased sample preparation free of interferents (i.e., competing analytes, detergents, plastics) is critical to any lipid MS workflow.

Glucagon Receptor Antagonism Improves Glucose Metabolism and Cardiac Function by Promoting AMP-Mediated Protein Kinase in Diabetic Mice.

The antidiabetic potential of glucagon receptor antagonism presents an opportunity for use in an insulin-centric clinical environment. To investigate the metabolic effects of glucagon receptor antagonism in type 2 diabetes, we treated Lepr and Lep mice with REMD 2.59, a human monoclonal antibody and competitive antagonist of the glucagon receptor.