Epidemiological and clinical burden of EGFR Exon 20 insertion in advanced non-small cell lung cancer: A systematic literature review.

Objectives: The burden of epidermal growth factor receptor (EGFR) exon 20 insertion mutation (Exon 20ins) in non-small cell lung cancer is not well understood. A systematic review was conducted to identify evidence on mutation frequency, prognostic impact, clinical, patient-reported, and economic outcomes associated with Exon 20ins.

Materials And Methods: Searches were conducted in Embase and Medline and supplemented with recent conference proceedings.

Convergent observations of MK-801-induced impairment in rat 5C-CPT performance across laboratories: reversal with a D but not nicotinic agonist.

Introduction: Cognitive function is closely linked to functional outcomes in psychiatric disorders such as schizophrenia, however developing effective treatments for cognitive dysfunction have proven elusive. Potential reasons for this may include the complexity of diseases, the absence of appropriate and translatable animal tests of cognitive dysfunction, and the reproducibility of findings. Attention is a key component of cognitive function traditionally assessed in the clinic using a variant of the continuous performance test (CPT).

Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties.

Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused on optimizing physicochemical and pharmacokinetic properties, and have developed a new selective inhibitor, compound (IPN60090), which is currently in phase 1 clinical trials.

Mechanical Strain of the Trilobed Transposition Flap in Artificial Skin Models: Pivotal Restraint Decreases With Decreasing Rotational Angles.

Background: In transposition flaps, thicker tissue and higher degrees of rotation are associated with increased pivotal restraint; however, limited experimental data exist quantifying the degree to which these affect flap biomechanics. The use of artificial skin models in conjunction with digital image correlation technology allows for investigation into biomechanical properties of skin flaps.

Objective: To quantify the effects of tissue thickness and rotational angles on pivotal restraint within transposition flaps using artificial skin models.

Comparison of Two Handheld Digital Dual Inclinometry Techniques in the Measurement of Lumbar Flexion Active Range of Motion.

Context: An accurate assessment of lumbar spine active range of motion (AROM) is clinically important. Dual inclinometry is recommended as the optimal technique for measuring lumbar flexion AROM; however, the procedures differ in the literature.

Objective: To compare 2 different handheld digital dual inclinometry (HDDI) techniques for evaluating lumbar flexion AROM.

Medical cannabis and mental health: A guided systematic review.

This review considers the potential influences of the use of cannabis for therapeutic purposes (CTP) on areas of interest to mental health professionals, with foci on adult psychopathology and assessment. We identified 31 articles relating to the use of CTP and mental health, and 29 review articles on cannabis use and mental health that did not focus on use for therapeutic purposes. Results reflect the prominence of mental health conditions among the reasons for CTP use, and the relative dearth of high-quality evidence related to CTP in this context, thereby highlighting the need for further research into the harms and benefits of medical cannabis relative to other therapeutic options.

Discovery of a novel trans-1,4-dioxycyclohexane GPR119 agonist series.

The design and optimization of a novel trans-1,4-dioxycyclohexane GPR119 agonist series is described. A lead compound 21 was found to be a potent and efficacious GPR119 agonist across species, and possessed overall favorable pharmaceutical properties. Compound 21 demonstrated robust acute and chronic regulatory effects on glycemic parameters in the diabetic or non-diabetic rodent models.

A Paddock to reef monitoring and modelling framework for the Great Barrier Reef: Paddock and catchment component.

Targets for improvements in water quality entering the Great Barrier Reef (GBR) have been set through the Reef Water Quality Protection Plan (Reef Plan). To measure and report on progress towards the targets set a program has been established that combines monitoring and modelling at paddock through to catchment and reef scales; the Paddock to Reef Integrated Monitoring, Modelling and Reporting Program (Paddock to Reef Program). This program aims to provide evidence of links between land management activities, water quality and reef health.

N-oleoyldopamine enhances glucose homeostasis through the activation of GPR119.

G protein-coupled receptor 119 (GPR119) is largely restricted to pancreatic insulin-producing beta-cells and intestinal glucagon-like peptide-1-producing L-cells. Synthetic agonists of this receptor elicit glucose-dependent release of these endocrine factors, thereby enhancing glycemic control. Oleoylethanolamide also activates GPR119, but it remains unclear whether endogenous production of this lipid modulates GPR119 activity under normal or dysglycemic conditions.

Discovery of the first potent and orally efficacious agonist of the orphan G-protein coupled receptor 119.

GPR119 is a rhodopsin-like GPCR expressed in pancreatic beta-cells and incretin releasing cells in the GI tract. As with incretins, GPR119 increases cAMP levels in these cell types, thus making it a highly attractive potential target for the treatment of diabetes. The discovery of the first reported potent agonist of GPR119, 2-fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine (8g, AR231453), is described starting from an initial inverse agonist screening hit.

A role for intestinal endocrine cell-expressed g protein-coupled receptor 119 in glycemic control by enhancing glucagon-like Peptide-1 and glucose-dependent insulinotropic Peptide release.

We recently showed that activation of G protein-coupled receptor 119 (GPR119) (also termed glucose dependent insulinotropic receptor) improves glucose homeostasis via direct cAMP-mediated enhancement of glucose-dependent insulin release in pancreatic beta-cells. Here we show that GPR119 also stimulates incretin hormone release and thus may regulate glucose homeostasis by this additional mechanism. GPR119 mRNA was found to be expressed at significant levels in intestinal subregions that produce glucose-dependent insulinotropic peptide and glucagon-like peptide (GLP)-1.

A role for beta-cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucose-dependent insulin release.

Pancreatic beta-cell dysfunction is a hallmark event in the pathogenesis of type 2 diabetes. Injectable peptide agonists of the glucagon-like peptide 1 (GLP-1) receptor have shown significant promise as antidiabetic agents by virtue of their ability to amplify glucose-dependent insulin release and preserve pancreatic beta-cell mass. These effects are mediated via stimulation of cAMP through beta-cell GLP-1 receptors.

Synthesis of Sansalvamide A derivatives and their cytotoxicity in the MSS colon cancer cell line HT-29.

We report the synthesis of thirty-six Sansalvamide A derivatives, and their biological activity against colon cancer HT-29 cell line, a microsatellite stable (MSS) colon cancer cell-line. The thirty-six compounds can be divided into three subsets, where the first subset of compounds contains L-amino acids, the second subset contains D-amino acids, and the third subset contains both D- and L-amino acids. Five compounds exhibited excellent inhibitory activity (>75% inhibition).

Novel antibiotics: C-2 symmetrical macrocycles inhibiting Holliday junction DNA binding by E. coli RuvC.

Holliday junctions (HJs) are formed as transient DNA intermediates during site-specific and homologous recombination. Both of these genetic exchange pathways are critical for normal DNA metabolism and repair. Trapping HJs leads to bacterial cell death by preventing proper segregation of the resulting interlinked chromosomes.

Synthesis and cytotoxicity of novel sansalvamide A derivatives.

Described are the syntheses of 14 derivatives of the natural product Sansalvamide A, where two are more active against HCT 116 colon cancer cell lines than the natural product. These derivatives were synthesized using a combinatorial-type strategy that permits elucidation of the amino acid role in the cytotoxicity, and they lay the groundwork for development of new anticancer agents. [structure: see text]

The transcriptional coactivator p300 plays a critical role in the hypertrophic and protective pathways induced by phenylephrine in cardiac cells but is specific to the hypertrophic effect of urocortin.

Anacardic acid is an alkylsalicylic acid obtained from cashew-nut-shell liquid, and is a potent inhibitor of p300 histone acetyl-transferase (HAT) activity. We have used anacardic acid to prevent the induction of hypertrophy in isolated neonatal rat cardiomyocytes. Hypertrophy was detected as an increase in cell size, the rearrangement of sarcomeres into a striated pattern, and the induction of embryonic genes beta-MHC and ANF.

Organ donation in Hawaii: impact of the final rule.

Background: In an effort to increase organ donation, the Department of Health and Human Services issued the Final Rule in 1998. The Health Care Financing Administration (HCFA) later required hospitals to notify organ procurement organizations (OPO) of all deaths and imminent deaths in order to remain eligible for Medicare and Medicaid reimbursement. We set out to determine the impact of the Final Rule on organ donation in Hawaii.