Activating Inducible T-cell Costimulator Yields Antitumor Activity Alone and in Combination with Anti-PD-1 Checkpoint Blockade.

Unlabelled: In recent years, there has been considerable interest in mAb-based induction of costimulatory receptor signaling as an approach to combat cancer. However, promising nonclinical data have yet to translate to a meaningful clinical benefit. Inducible T-cell costimulator (ICOS) is a costimulatory receptor important for immune responses.

Preparing for the Behavioral Health Impact of COVID-19 in Michigan.

Purpose Of Review: As a global pandemic, COVID-19 has profoundly disrupted the lives of individuals, families, communities, and nations. This report summarizes the expected impact of COVID-19 on behavioral health, as well as strategies to address mental health needs during the COVID-19 pandemic and its aftermath. The state of Michigan in the USA is used to illustrate the complexity of the mental health issues and the critical gaps in the behavioral health infrastructure as they pertain to COVID-19.

Sumatriptan Induced Takotsubo Cardiomyopathy; the Headache of the Heart: A Case Report.

Takotsubo Cardiomyopathy (TCM) is an increasing recognized form of acute reversible left ventricular systolic dysfunction not related to obstructive coronary disease. The exact physiology of this disorder is not yet known, however multiple agents have been hypothesized to have a link to this condition. Most commonly, TCM has been hypothesized as being triggered by a catecholamine surge after an inciting event.

An open-label phase IB study to evaluate GSK3052230 in combination with paclitaxel and carboplatin, or docetaxel, in FGFR1-amplified non-small cell lung cancer.

Objectives: GSK3052230 (FP-1039) is a soluble fusion protein that acts as ligand trap sequestering fibroblast growth factors (FGFs) involved in tumor growth and angiogenesis, while sparing the hormonal FGFs. Because of this selectivity, the molecule is predicted to avoid toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. Herein we report the results of a phase 1b study where GSK3052330 was administered with standard of care chemotherapy in FGFR1-amplified squamous non-small cell lung cancer (sqNSCLC) patients.

A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma.

Background Fibroblast growth factors (FGFs) have a fundamental role in cancer. Sequestering FGFs with GSK3052230 (FP-1039) blocks their ability to activate FGFRs while avoiding toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. Methods A multicenter, open-label, phase Ib study evaluated weekly GSK3052230 added to pemetrexed/cisplatin in patients with treatment-naive, unresectable malignant pleural mesothelioma.

A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors.

The PI3K/protein kinase B (AKT) pathway is commonly activated in several tumor types. Selective targeting of p110β could result in successful pathway inhibition while avoiding the on- and off-target effects of pan-PI3K inhibitors. GSK2636771 is a potent, orally bioavailable, adenosine triphosphate-competitive, selective inhibitor of PI3Kβ.

Inhibition of FGF/FGFR autocrine signaling in mesothelioma with the FGF ligand trap, FP-1039/GSK3052230.

Fibroblast growth factor (FGF) ligand-dependent signaling has a fundamental role in cancer development and tumor maintenance. GSK3052230 (also known as FP-1039) is a soluble decoy receptor that sequesters FGFs and inhibits FGFR signaling. Herein, the efficacy of this molecule was tested in models of mesothelioma, a tumor type shown to express high levels of FGF2 and FGFR1.

Long-Range Inhibitor-Induced Conformational Regulation of Human IRE1α Endoribonuclease Activity.

Activation of the inositol-requiring enzyme-1 alpha (IRE1α) protein caused by endoplasmic reticulum stress results in the homodimerization of the N-terminal endoplasmic reticulum luminal domains, autophosphorylation of the cytoplasmic kinase domains, and conformational changes to the cytoplasmic endoribonuclease (RNase) domains, which render them functional and can lead to the splicing of X-box binding protein 1 (XBP 1) mRNA. Herein, we report the first crystal structures of the cytoplasmic portion of a human phosphorylated IRE1α dimer in complex with (R)-2-(3,4-dichlorobenzyl)-N-(4-methylbenzyl)-2,7-diazaspiro(4.5)decane-7-carboxamide, a novel, IRE1α-selective kinase inhibitor, and staurosporine, a broad spectrum kinase inhibitor.

Structural insights into the architecture of the hyperthermophilic Fusellovirus SSV1.

The structure and assembly of many icosahedral and helical viruses are well-characterized. However, the molecular basis for the unique spindle-shaped morphology of many viruses that infect Archaea remains unknown. To understand the architecture and assembly of these viruses, the spindle-shaped virus SSV1 was examined using cryo-EM, providing the first 3D-structure of a spindle-shaped virus as well as insight into SSV1 biology, assembly and evolution.

Treatment of patients with type 2 diabetes with exenatide once weekly versus oral glucose-lowering medications or insulin glargine: achievement of glycemic and cardiovascular goals.

Background: Diabetes is associated with a higher risk for adverse cardiovascular outcomes. To improve the health outcomes of patients with type 2 diabetes (T2DM), the American Diabetes Association (ADA) recommended target goals for the improvement of glycemic control and the reduction of cardiovascular risk factors associated with the disease. This retrospective analysis calculated the absolute benefit increase (ABI) of using exenatide once weekly (QW), a glucagon-like peptide-1 (GLP-1) receptor agonist, vs an oral glucose-lowering medication or insulin glargine to achieve ADA-recommended goals.

GLP-1 receptor activated insulin secretion from pancreatic β-cells: mechanism and glucose dependence.

The major goal in the treatment of type 2 diabetes mellitus is to control the hyperglycaemia characteristic of the disease. However, treatment with common therapies such as insulin or insulinotrophic sulphonylureas (SU), while effective in reducing hyperglycaemia, may impose a greater risk of hypoglycaemia, as neither therapy is self-regulated by ambient blood glucose concentrations. Hypoglycaemia has been associated with adverse physical and psychological outcomes and may contribute to negative cardiovascular events; hence minimization of hypoglycaemia risk is clinically advantageous.

Efficacy of GLP-1 receptor agonists and DPP-4 inhibitors: meta-analysis and systematic review.

Background: Considerable clinical data on the treatment of type 2 diabetes with incretin-based therapies (glucagon-like peptide 1 receptor agonists [GLP-1RAs] and dipeptidyl-peptidase IV [DPP-4] inhibitors) are available.

Objective: This meta-analysis was performed to support the understanding of the overall evidence by summarizing the findings from studies of the incretin-based therapies.

Methods: The MEDLINE, EMBASE, BIOSIS, and BIOSIS trial databases were searched for relevant literature published between January 1, 1990, and June 30, 2011.

Long-term cost-consequence analysis of exenatide once weekly vs sitagliptin or pioglitazone for the treatment of type 2 diabetes patients in the United States.

Objective: Exenatide once-weekly (ExQW) is a GLP-1 receptor agonist shown to lower glucose and cardiovascular risk factors in patients with type 2 diabetes mellitus (T2DM). The objective of this study was to estimate the clinical benefits and associated economic benefits of treatment with ExQW compared with sitagliptin or pioglitazone in the US.

Methods: The IMS CORE Diabetes Model, a validated computer simulation model, was used to project lifetime clinical outcomes and complication costs.

The effects of exenatide bid on metabolic control, medication use and hospitalization in patients with type 2 diabetes mellitus in clinical practice: a systematic review.

The objective of this systematic review was to assess the published literature on the effectiveness of exenatide twice daily (exenatide) in clinical practice, specifically its effects on haemoglobin A1c (A1C), fasting glucose (FG), weight, systolic blood pressure (SBP), medication use, hospitalization and cardiovascular disease (CVD) outcomes. A systematic literature search using the MEDLINE database of English language literature published between January 2005 and May 2011 was performed. The review included retrospective or prospective observational studies that included 100 or more patients per treatment group.

Clinical implications of exenatide as a twice-daily or once-weekly therapy for type 2 diabetes.

Exenatide (exendin-4) is a 39-amino acid peptide belonging to the glucagon-like peptide-1 (GLP-1) receptor agonist class that has been demonstrated to improve glycemic control in patients with type 2 diabetes mellitus. Exenatide can be injected twice daily (ExBID) before meals or once weekly (ExQW) when encompassed within dissolvable poly-(D,L-lactide-co-glycolide) microspheres. The primary difference between these formulations is the plasma concentration of exenatide over time, with the long-acting form providing continuous delivery.

Encapsulation of exenatide in poly-(D,L-lactide-co-glycolide) microspheres produced an investigational long-acting once-weekly formulation for type 2 diabetes.

Exenatide once-weekly (EQW [2 mg s.c.]) is under development as monotherapy as an adjunct to diet and exercise or as a combination therapy with an oral antidiabetes drug(s) in adults with type 2 diabetes.

Growth phase-dependent gene regulation in vivo in Sulfolobus solfataricus.

Ribosomal genes are strongly regulated dependent on growth phase in all organisms, but this regulation is poorly understood in Archaea. Moreover, very little is known about growth phase-dependent gene regulation in Archaea. SSV1-based lacS reporter gene constructs containing the Sulfolobus 16S/23S rRNA gene core promoter, the TF55α core promoter, or the native lacS promoter were tested in Sulfolobus solfataricus cells lacking the lacS gene.

Dose accuracy and injection force of disposable pens delivering pramlintide for the treatment of diabetes.

Background: The pen injection format, typically used for insulin administration, has been adapted for the injectable, noninsulin diabetes therapy pramlintide. Administered before major meals, pramlintide therapy requires two to four injections/day in addition to the patients' usual insulin injections. The dose accuracy and injection force was determined for the 60 and 120 µg pramlintide pens.

Noise exposure in convertible automobiles.

Objective: To quantify the noise exposure received while driving a convertible automobile with the top open, compared with the top closed.

Methods: Five different convertible automobiles were driven, with the top both closed and open, and noise levels measured. The cars were tested at speeds of 88.

Characterization of GSK2334470, a novel and highly specific inhibitor of PDK1.

PDK1 (3-phosphoinositide-dependent protein kinase 1) activates a group of protein kinases belonging to the AGC [PKA (protein kinase A)/PKG (protein kinase G)/PKC (protein kinase C)]-kinase family that play important roles in mediating diverse biological processes. Many cancer-driving mutations induce activation of PDK1 targets including Akt, S6K (p70 ribosomal S6 kinase) and SGK (serum- and glucocorticoid-induced protein kinase). In the present paper, we describe the small molecule GSK2334470, which inhibits PDK1 with an IC₅₀ of ~10 nM, but does not suppress the activity of 93 other protein kinases including 13 AGC-kinases most related to PDK1 at 500-fold higher concentrations.

Prophylactic use of anti-emetic medications reduced nausea and vomiting associated with exenatide treatment: a retrospective analysis of an open-label, parallel-group, single-dose study in healthy subjects.

Aims: Transient nausea and, to a lesser extent, vomiting are common adverse effects of exenatide that can be mitigated by dose titration and usually do not result in treatment discontinuation. This retrospective analysis of data from a phase 1, open-label, parallel-group, single-dose study in healthy subjects evaluated the effect of oral anti-emetics on exenatide-associated nausea and vomiting and on the pharmacokinetics of exenatide.

Methods: A single subcutaneous dose (10 μg) of exenatide was administered to 120 healthy subjects (19-65 years, BMI 23-35 kg/m(2) ).

Negative feedback control of HIF-1 through REDD1-regulated ROS suppresses tumorigenesis.

The HIF family of hypoxia-inducible transcription factors are key mediators of the physiologic response to hypoxia, whose dysregulation promotes tumorigenesis. One important HIF-1 effector is the REDD1 protein, which is induced by HIF-1 and which functions as an essential regulator of TOR complex 1 (TORC1) activity in Drosophila and mammalian cells. Here we demonstrate a negative feedback loop for regulation of HIF-1 by REDD1, which plays a key role in tumor suppression.

Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling.

Hypoxia induces rapid and dramatic changes in cellular metabolism, in part through inhibition of target of rapamycin (TOR) kinase complex 1 (TORC1) activity. Genetic studies have shown the tuberous sclerosis tumor suppressors TSC1/2 and the REDD1 protein to be essential for hypoxia regulation of TORC1 activity in Drosophila and in mammalian cells. The molecular mechanism and physiologic significance of this effect of hypoxia remain unknown.

The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers.

Breast cancers lacking estrogen and progesterone receptor expression and Her2 amplification exhibit distinct gene expression profiles and clinical features, and they comprise the majority of BRCA1-associated tumors. Here we demonstrated that the p53 family member p63 controls a pathway for p73-dependent cisplatin sensitivity specific to these "triple-negative" tumors. In vivo, DeltaNp63 and TAp73 isoforms were coexpressed exclusively within a subset of triple-negative primary breast cancers that commonly exhibited mutational inactivation of p53.