Nanomolar-potency small molecule inhibitor of STAT5 protein

© 2014 American Chemical Society. We herein report the design and synthesis of the first nanomolar binding inhibitor of STAT5 protein. Lead compound 13a, possessing a phosphotyrosyl-mimicking salicylic acid group, potently and selectively binds to STAT5 over STAT3, inhibits STAT5-SH2 domain complexation events in vitro, silences activated STAT5 in leukemic cells, as well as STAT5's downstream transcriptional targets, including MYC and MCL1, and, as a result, leads to apoptosis. We believe 13a represents a useful probe for interrogating STAT5 function in cells as well as being a potential candidate for advanced preclinical trials

Non-destructive experimental testing and modeling of electrical impedance behavior of untreated and treated ultra-soft clayey soils

The characterization of ultra-soft clayey soil exhibits extreme challenges due to low shear strength of such material. Hence, inspecting the non-destructive electrical impedance behavior of untreated and treated ultra-soft clayey soils gains more attention. Both shear strength and electrical impedance were measured experimentally for both untreated and treated ultra-soft clayey soils. The shear strength of untreated ultra-soft clayey soil reached 0.17 kPa for 10% bentonite content, while the shear strengths increased to 0.27 kPa and 6.7 kPa for 10% bentonite content treated with 2% lime and 10% polymer, respectively. The electrical impedance of the ultra-soft clayey soil has shown a significant decrease from 1.6 kΩ to 0.607 kΩ when the bentonite content increased from 2% to 10% at a frequency of 300 kHz. The 10% lime and 10% polymer treatments have decreased the electrical impedances of ultra-soft clayey soil with 10% bentonite from 0.607 kΩ to 0.12 kΩ and 0.176 kΩ, respectively, at a frequency of 300 kHz. A new mathematical model has been accordingly proposed to model the non-destructive electrical impedance-frequency relationship for both untreated and treated ultra-soft clayey soils. The new model has shown a good agreement with experimental data with coefficient of determination (R2) up to 0.99 and root mean square error (RMSE) of 0.007 kΩ

Recompression Index (Cr) for Overconsolidated Soft Clay Soils

Overestimation of settlement on overconsolidated soft clays may require ground improvement before construction with added delay and cost to a project. Since the soft soil shear strength is low, the structures on the soft soils are generally designed so that the increase in stress is relatively small and the total stress in the ground will be close to the preconsolidation pressure. Hence the recompression index, determined from a consolidation test is very important parameter in estimating the settlement. Although recompression index has been quantified in the literature, its determination may not be applicable to all soft soils in its current form. The influence of stress level on the recompression index is not clearly quantified. This study focused on developing methods for determining the recompression index of overconsolidated soft clay soils. Based on the methods used to determine the recompression index, over 750% difference in the minimum and maximum Cr values was observed for the Houston area soft clay. Effect of applied stresses on the recompression index was also investigated

Successful clearance of human parainfluenza virus type 2 viraemia with intravenous ribavirin and immunoglobulin in a patient with acute myocarditis

10.1016/j.jcv.2012.10.005Journal of Clinical Virology56137-40JCVI

Isolation and characterization of the cDNA encoding human DNA methyltransferase.

We have cloned a series of overlapping cDNA clones encoding a 5194 bp transcript for human DNA methyltransferase (DNA MTase). This sequence potentially codes for a protein of 1495 amino acids with a predicted molecular weight of 169 kDa. The human DNA MTase cDNA has eighty percent homology at the nucleotide level, and the predicted protein has seventy-four percent identity at the amino acid level, to the DNA MTase cDNA cloned from mouse cells. Like the murine DNA MTase, the amino terminal two-thirds of the human protein contains a cysteine-rich region suggestive of a metal-binding domain. The carboxy terminal one-third of the protein shows considerable similarity to prokaryotic (cytosine-5)-methyltransferases. The arrangement of multiple motifs conserved in the prokaryotic genes is preserved in the human DNA MTase, including the relative position of a proline-cysteine dipeptide thought to be an essential catalytic site in all (cytosine-5)-methyltransferases. A single 5.2 kb transcript was detected in all human tissues tested, with the highest levels of expression observed in RNA from placenta, brain, heart and lung. DNA MTase cDNA clones were used to screen a chromosome 19 genomic cosmid library. The DNA MTase-positive cosmids which are estimated to span a genomic distance of 93 kb have been localized to 19p13.2-p13.3 by fluorescence in situ hybridization. Isolation of the cDNA for human DNA MTase will allow further study of the regulation of DNA MTase expression, and of the role of this enzyme in establishing DNA methylation patterns in both normal and neoplastic cells

Sofosbuvir/Velpatasvir Is Effective and Safe in Patients with Concomitant Proton PUMP Inhibitor Use in Clinical Studies

BACKGROUND: Prior to the availability of Phase 1 drug interaction data, concomitant proton pump inhibitor (PPI) use was prohibited in clinical trials of Sofosbuvir/Velpatasvir (SOF/VEL). Later, clinical studies allowed use of up to 20 mg omeprazole or equivalent dosing. PURPOSE: This analysis evaluated the efficacy and safety of patients with and without compensated cirrhosis who received SOF/VEL for 12 weeks and reported concomitant use of a PPI. METHODS: This was a retrospective analysis of efficacy and safety data from 12 Phase 2 and Phase 3 clinical studies where patients of all genotypes with and without compensated cirrhosis received 12 weeks of SOF/VEL and reported concomitant use of a PPI. Efficacy was assessed by sustained virologic response 12 weeks after treatment (SVR12) and relapse rates and safety was assessed by treatment- emergent adverse events (AEs). RESULT(S): 87 patients reported concomitant use of a PPI. The mean age (range) was 57 years (26- 78), 79% were male and 75% white; 56% of patients were infected with HCV genotype 3 and 29% with genotype 1; 37% of patients had compensated cirrhosis and 39% were treatment experienced. The most common PPI was omeprazole (68% of patients). SVR12 was 97% (84 of 87 patients). Of the 3 patients who did not achieve SVR12, 2 patients relapsed (relapse rate 2%) and one patient with history of diabetes discontinued SOF/VEL after 7 days of dosing due to hyperglycemia. No other patient had an AE leading to discontinuation or interruption of SOF/VEL. 78% of patients had an AE, most of which were mild, and 11% had a serious AE. These efficacy and safety values are comparable to patients enrolled in the same studies who received SOF/VEL for 12 weeks without concomitant use of a PPI (SVR12 97% [2,445 of 2,517 patients]; relapse rate 2% [40 of 2488 patients]). CONCLUSION(S): In Phase 2 and Phase 3 clinical studies, SOF/VEL for 12 weeks was effective and safe in patients with concomitant PPI use. These data support the use of SOF/VEL according to labeled recommendations with respect to co-administration of PPIs and other acid reducing agents