Denckerspivey5958

NF1, PTEN, CDKN2A, SPRED1, ATM, CHEK2, and ARID1B were commonly affected by chromosomal copy loss, while TERT, KIT, BRAF, YAP1, CDK4, CCND1, GAB2, MDM2, SKP2, and MITF were commonly amplified. Further notable genomic alterations occurring at lower frequencies indicated commonality of signaling networks in tumorigenesis, including MAPK, PI3K, Notch, Wnt/β-catenin, cell cycle, DNA repair, and telomere maintenance pathways. This analysis identified genomic aberrations that provide some insight to the way in which specific pathways may be disrupted. IMPLICATIONS Our analysis has shown that mucosal melanomas have a diverse range of genomic alterations in several biological pathways. VISUAL OVERVIEW http//mcr.aacrjournals.org/content/molcanres/19/6/991/F1.large.jpg.Ferroptosis is a new form of regulated cell death resulting from the accumulation of lipid-reactive oxygen species. A growing number of studies indicate ferroptosis as an important tumor suppressor mechanism having therapeutic potential in cancers. Previously, we identified TAZ, a Hippo pathway effector, regulates ferroptosis in renal and ovarian cancer cells. Pitavastatin Because YAP (Yes-associated protein 1) is the one and only paralog of TAZ, sharing high sequence similarity and functional redundancy with TAZ, we tested the potential roles of YAP in regulating ferroptosis. Here, we provide experimental evidence that YAP removal confers ferroptosis resistance, whereas overexpression of YAP sensitizes cancer cells to ferroptosis. Furthermore, integrative analysis of transcriptome reveals S-phase kinase-associated protein 2 (SKP2), an E3 ubiquitin ligase, as a YAP direct target gene that regulates ferroptosis. We found that the YAP knockdown represses the expression of SKP2. Importantly, the genetic and chemical inhibitions of SKP2 robustly protect cells from ferroptosis. In addition, knockdown of YAP or SKP2 abolishes the lipid peroxidation during erastin-induced ferroptosis. Collectively, our results indicate that YAP, similar to TAZ, is a determinant of ferroptosis through regulating the expression of SKP2. Therefore, our results support the connection between Hippo pathway effectors and ferroptosis with significant therapeutic implications. IMPLICATIONS This study reveals that YAP promotes ferroptosis by regulating SKP2, suggesting novel therapeutic options for YAP-driven tumors.

Results of cardiovascular outcome trials (CVOTs) suggest Asians may derive greater benefit than Whites from newer classes of antihyperglycemic medications.

To provide summary hazard ratio (HR) estimates for cardiovascular efficacy of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) stratified by race (Asian vs. White).

A systematic review performed in PubMed from 1 January 2015 to 8 December 2020.

Randomized placebo-controlled CVOTs of SGLT2is and GLP-1RAs that reported HRs (95% CIs) for

) major adverse cardiovascular event (MACE) in patients with diabetes and

) cardiovascular (CV) death/hospitalization for heart failure (HHF) in patients with HF and reduced ejection fraction (HFrEF).

HRs (95% CIs) for selected outcomes in Asians and Whites were extracted from each trial, adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Random-effects meta-analyses were performed to examine differences and MACE benefit from GLP-1RAs in patients with type 2 diabetes.

We reevaluated the Action for Health in Diabetes (Look AHEAD) intervention, incorporating diabetes subgroups, to identify whether intensive lifestyle intervention (ILI) is associated with differential risk for cardiovascular disease (CVD) by diabetes subgroup.

In the Look AHEAD trial, 5,145 participants, aged 45-76 years, with type 2 diabetes (T2D) and overweight or obesity were randomly assigned to 10 years of ILI or a control condition of diabetes support and education. The ILI focused on weight loss through decreased caloric intake and increased physical activity. To characterize diabetes subgroups, we applied k-means clustering to data on age of diabetes diagnosis, BMI, waist circumference, and glycated hemoglobin. We examined whether relative intervention effects on the trial's prespecified CVD outcomes varied among diabetes subgroups.

We characterized four subgroups related to older age at diabetes onset (42% of sample), poor glucose control (14%), severe obesity (24%), and younger age at diabetes onset (20%). We observed interactions (all

< 0.05) between intervention and diabetes subgroups for three separate composite cardiovascular outcomes. Randomization to ILI was associated with increased risk for each cardiovascular outcome only among the poor-glucose-control subgroup (hazard ratio >1.32). Among the three other diabetes subgroups, ILI was not associated with increased risk for CVD.

Among overweight and obese adults with T2D, a lifestyle intervention was associated with differential risk for CVD that was dependent on diabetes subgroup. Diabetes subgroups may be important to identify the patients who would achieve benefit and avoid harm from an ILI.

Among overweight and obese adults with T2D, a lifestyle intervention was associated with differential risk for CVD that was dependent on diabetes subgroup. Diabetes subgroups may be important to identify the patients who would achieve benefit and avoid harm from an ILI.Care of the critically ill newborn includes support for the birth mother/parents with regular updates around the clinical condition of the baby, and involvement in discussions around complex decision-making issues . Discussions around continuation or discontinuation of life-sustaining are challenging even in the most straightforward of cases, but what happens when the birth mother is critically unwell? Such cases can lead to uncertainty around who should assume the parental role for these difficult discussions . In this round table discussion, we explore the ethical, moral and legal uncertainties raised by coincident severe maternal and neonatal illness in the context of surrogacy.In a recent article, 'Why lockdown of the elderly is not ageist and why levelling down equality is wrong', Savulescu and Cameron argue that a selective lockdown of older people is not ageist because it would treat people unequally based on morally relevant differences. This response argues that a selective lockdown of older people living in long-term care homes would be unjust because it would allow the expansive liberties of the general public to undermine the basic liberties of older people, and because it would discriminate on the basis of extrinsic disadvantages.