The Development of INT131 as a Selective PPARγ Modulator: Approach to a Safer Insulin Sensitizer

INT131 (formerly T0903131, T131, AMG131) is a potent non-thiazolidinedione (TZD) selective peroxisome proliferator-activated receptor γ modulator (SPPARM) currently in Phase 2 clinical trials for treatment of type-2 diabetes mellitus (T2DM). This new chemical entity represents a second generation SPPARM approach developed after the first generation PPARγ full agonists to address their inherent limitations. INT131 was specifically and carefully designed using preclinical models to exhibit a biological profile of strong efficacy with de minimis side effects compared to PPARγ full agonists. As a potent PPARγ modulator, INT131 binds to PPARγ with high affinity. In pharmacology models of diabetes and in early clinical studies, it achieved a high level of efficacy in terms of antidiabetic actions such as insulin sensitization and glucose and insulin lowering, but had little activity in terms of other, undesired, effects associated with TZD PPARγ full agonists such as edema and adipogenesis. Ongoing clinical development is directed at translating these findings into establishing a novel and effective treatment for T2DM patients with an improved safety profile in relation to that currently available

A p38 Mitogen‐Activated Protein Kinase Inhibitor Arrests Active Alveolar Bone Loss in a Rat Periodontitis Model

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141943/1/jper1992.pd

Smoking prevalence and smoking cessation services for pregnant women in Scotland

Over 20% of women smoke throughout pregnancy despite the known risks to mother and child. Engagement in face-to-face support is a good measure of service reach. The Scottish Government has set a target that by 2010 8% of smokers will quit. At present less than 4% stop during pregnancy. We aimed to establish a denominator for pregnant smokers in Scotland and describe the proportion who are referred to specialist services, engage in one-to-one counselling, set a quit date and quit 4 weeks later. In Scotland, a small proportion of pregnant smokers are supported to stop. Poor outcomes are a product of current limitations to each step of service provision - identification, referral, engagement and treatment. Many smokers are not asked about smoking at maternity booking or provide false information. Carbon monoxide breath testing can bypass this difficulty. Identified smokers may not be referred but an opt-out referral policy can remove this barrier. Engagement at home allowed a greater proportion to set a quit date and quit, but costs were higher

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Inhibition of Transforming Growth Factor ␤ Signaling Reduces Pancreatic Adenocarcinoma Growth and Invasiveness □ S

ABSTRACT Transforming growth factor ␤ (TGF␤) is a pleiotropic factor that regulates cell proliferation, angiogenesis, metastasis, and immune suppression. Dysregulation of the TGF␤ pathway in tumor cells often leads to resistance to the antiproliferative effects of TGF␤ while supporting other cellular processes that promote tumor invasiveness and growth. In the present study, SD-208, a 2,4-disubstituted pteridine, ATP-competitive inhibitor of the TGF␤ receptor I kinase (TGF␤RI), was used to inhibit cellular activities and tumor progression of PANC-1, a human pancreatic tumor line. SD-208 blocked TGF␤-dependent Smad2 phosphorylation and expression of TGF␤-inducible proteins in cell culture. cDNA microarray analysis and functional gene clustering identified groups of TGF␤-regulated genes involved in metastasis, angiogenesis, cell proliferation, survival, and apoptosis. These gene responses were inhibited by SD-208. Using a Boyden chamber motility assay, we demonstrated that SD-208 inhibited TGF␤-stimulated invasion in vitro. An orthotopic xenograft mouse model revealed that SD-208 reduced primary tumor growth and decreased the incidence of metastasis in vivo. Our findings suggest mechanisms through which TGF␤ signaling may promote tumor progression in pancreatic adenocarcinoma. Moreover, they suggest that inhibition of TGF␤RI with a small-molecule inhibitor may be effective as a therapeutic approach to treat human pancreatic cancer

A Novel Statistical Algorithm for Gene Expression Analysis Helps Differentiate Pregnane X Receptor-Dependent and Independent Mechanisms of Toxicity

Genome-wide gene expression profiling has become standard for assessing potential liabilities as well as for elucidating mechanisms of toxicity of drug candidates under development. Analysis of microarray data is often challenging due to the lack of a statistical model that is amenable to biological variation in a small number of samples. Here we present a novel non-parametric algorithm that requires minimal assumptions about the data distribution. Our method for determining differential expression consists of two steps: 1) We apply a nominal threshold on fold change and platform p-value to designate whether a gene is differentially expressed in each treated and control sample relative to the averaged control pool, and 2) We compared the number of samples satisfying criteria in step 1 between the treated and control groups to estimate the statistical significance based on a null distribution established by sample permutations. The method captures group effect without being too sensitive to anomalies as it allows tolerance for potential non-responders in the treatment group and outliers in the control group. Performance and results of this method were compared with the Significant Analysis of Microarrays (SAM) method. These two methods were applied to investigate hepatic transcriptional responses of wild-type (PXR+/+) and pregnane X receptor-knockout (PXR−/−) mice after 96 h exposure to CMP013, an inhibitor of β-secretase (β-site of amyloid precursor protein cleaving enzyme 1 or BACE1). Our results showed that CMP013 led to transcriptional changes in hallmark PXR-regulated genes and induced a cascade of gene expression changes that explained the hepatomegaly observed only in PXR+/+ animals. Comparison of concordant expression changes between PXR+/+ and PXR−/− mice also suggested a PXR-independent association between CMP013 and perturbations to cellular stress, lipid metabolism, and biliary transport

Expert consensus and recommendations on safety criteria for active mobilization of mechanically ventilated critically ill adults

Introduction: The aim of this study was to develop consensus recommendations on safety parameters for mobilizing adult, mechanically ventilated, intensive care unit (ICU) patients. Methods: A systematic literature review was followed by a meeting of 23 multidisciplinary ICU experts to seek consensus regarding the safe mobilization of mechanically ventilated patients. Results: Safety considerations were summarized in four categories: respiratory, cardiovascular, neurological and other. Consensus was achieved on all criteria for safe mobilization, with the exception being levels of vasoactive agents. Intubation via an endotracheal tube was not a contraindication to early mobilization and a fraction of inspired oxygen less than 0.6 with a percutaneous oxygen saturation more than 90% and a respiratory rate less than 30 breaths/minute were considered safe criteria for in- and out-of-bed mobilization if there were no other contraindications. At an international meeting, 94 multidisciplinary ICU clinicians concurred with the proposed recommendations. Conclusion: Consensus recommendations regarding safety criteria for mobilization of adult, mechanically ventilated patients in the ICU have the potential to guide ICU rehabilitation whilst minimizing the risk of adverse events