Notes

Neonatal supervision of an subanaesthetic dose of JM-1232(*) within rodents ends in absolutely no behavioural failures inside their adult years.
These included (a) awareness and discourse on gender related issues, (b) framing domestic violence as a social issue, (c) supporting the empowerment of women, (d) supporting disclosure of violence, and (e) supporting intervening in cases of violence. Implications of our findings for social change work in the response to domestic violence are discussed. HIGHLIGHTS Community narratives can provide an important means of detecting changes in norms. Social movements can target and change community narratives to redefine problems. Community engagement that empowers communities can create empowering narratives. This study highlights various counter narratives in the response to domestic violence. Implications for social change work are discussed.Background & aims Despite surgical and chemotherapeutic advances, the five-year survival rate for Stage IV Hepatoblastoma (HB), the predominant pediatric liver tumor, remains at 27%. YAP1 and β-Catenin co-activation occurs in 80% of children's HB; however, a lack of conditional genetic models precludes tumor maintenance exploration. Thus, the need for a targeted therapy remains unmet. Given the predominance of YAP1 and β-Catenin activation in HB, we sought to evaluate YAP1 as a therapeutic target in HB. Approach & results We engineered the first conditional HB murine model using hydrodynamic injection to deliver transposon plasmids encoding inducible YAP1S127A , constitutive β-CateninDelN90 , and a luciferase reporter to murine liver. Tumor regression was evaluated using bioluminescent imaging, and tumor landscape characterized using RNA and ATAC sequencing, and DNA foot-printing. Here we show that YAP1S127A withdrawal mediates >90% tumor regression with survival for 230+ days in mice. YAP1 S127A withdrawal promotes apoptosis in a subset of tumor cells and in remaining cells induces a cell fate switch driving therapeutic differentiation of HB tumors into Ki-67 negative "hbHep cells" with hepatocyte-like morphology and mature hepatocyte gene expression. YAP1 S127A withdrawal drives formation of hbHeps by modulating liver differentiation transcription factor (TF) occupancy. Indeed, tumor-derived hbHeps, consistent with their reprogrammed transcriptional landscape, regain partial hepatocyte function and rescue liver damage in mice. Conclusions YAP1S127A withdrawal, without silencing oncogenic β-Catenin, significantly regresses hepatoblastoma, providing the first in vivo data to support YAP1 as a therapeutic target for HB. YAP1S127A withdrawal alone sufficiently drives long-term regression in hepatoblastoma because it promotes cell death in a subset of tumor cells and modulates transcription factor occupancy to reverse the fate of residual tumor cells to mimic functional hepatocytes.Background Lanadelumab demonstrated efficacy in preventing HAE attacks in the phase 3 HELP Study. Objective To assess time to onset of effect and long-term efficacy of lanadelumab, based on exploratory findings from the HELP Study. Methods Eligible patients with HAE type I/II received lanadelumab 150 mg every 4 weeks (q4wks), 300 mg q4wks, 300 mg q2wks, or placebo. Ad hoc analyses evaluated day 0-69 findings using a Poisson regression model accounting for overdispersion. Least-squares mean monthly HAE attack rate for lanadelumab was compared with placebo. Intrapatient comparisons for days 0-69 versus steady state (days 70-182) used a paired t-test for continuous endpoints or Kappa statistics for categorical endpoints. Results 125 patients were randomized and treated. During days 0-69, mean monthly attack rate was significantly lower with lanadelumab (0.41-0.76) versus placebo (2.04), including attacks requiring acute treatment (0.33-0.61 vs. SP 600125 negative control nmr 1.66) and moderate/severe attacks (0.31-0.48 vs. 1.33, all P ≤ 0.001). More patients receiving lanadelumab versus placebo were attack free (37.9-48.1% vs 7.3%) and responders (85.7-100% vs. 26.8%). During steady state, the efficacy of lanadelumab versus placebo was similar or improved versus days 0-69. Intrapatient differences were significant with lanadelumab 300 mg q4wks for select outcomes. Lanadelumab efficacy was durable-HAE attack rate was consistently lower versus placebo, from the first 2 weeks of treatment through study end. TEAEs were comparable during days 0-69 and 70-182. Conclusion Protection with lanadelumab started from the first dose and continued throughout the entire study period.We previously reported bidirectional gene expression regulation of the Bone Morphogenetic Proteins (BMP2, 4, & 7) in chick retinal pigment epithelium (RPE) in response to imposed optical defocus and form-deprivation (FD). This study investigated whether there are local (regional) differences in these effects. 19-day old White-Leghorn chicks wore monocular +10 or - 10 D lenses, or diffusers (FD) for 2 or 48 h, after which RPE samples were collected from both eyes, from a central circular zone (3 mm radius), and 3 mm wide annular mid-peripheral and peripheral zones in all cases. BMP2, 4, and 7 gene expression levels in RPE from treated and fellow control eyes were compared as well as differences across zones. With the +10 D lens, increased expression of both BMP2 and BMP4 genes was observed in central and mid-peripheral zones but not the peripheral zone after 2 and 48 h. In contrast, with the -10 D lens BMP2 gene expression was significantly decreased in all three zones after 2 and 48 h. Similar patterns of BMP2 gene expression were observed in all three zones after 48 h of FD. Smaller changes were recorded for BMP4 and BMP7 gene expression for both myopia-inducing treatments. That optical defocus- and FD-induced changes in BMP gene expression in chick RPE show treatment-dependent local (regional) differences suggest important differences in the nature and contributions of local retinal and underlying RPE regions to eye growth regulation. This article is protected by copyright. All rights reserved.Background Serum feline pancreatic lipase immunoreactivity (fPL) commonly is used in the assessment of sick cats suspected to have pancreatitis but its diagnostic utility is debated. Objectives To evaluate the diagnostic utility of the Spec fPL test and selected serum biochemistry tests in the diagnosis of pancreatitis in cats. Animals Two hundred seventy-four client-owned cats presented to a university teaching hospital in the United Kingdom, from April 2013 to May 2017, in which Spec fPL was measured. Methods Cats were classified into 1 of 4 groups based on clinical signs (all cats), ultrasonographic findings (all cats) and histopathological or cytological assessment of the pancreas where available (9 cats) regardless of Spec fPL concentration. The groups were (a) definite pancreatitis (n = 9), (b) probable pancreatitis (n = 49), (c) possible pancreatitis (n = 139), and (d) unlikely pancreatitis (n = 77). Spec fPL and selected serum biochemistry test results were compared among groups. Results Serum fPL concentrations >5.
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