Conditional disruption of rictor demonstrates a direct requirement for mTORC2 in skin tumor development and continued growth of established tumors

These studies show for the first time that mTORC2 is essential for skin tumor development and maintenance of established tumors, but is dispensable for normal keratinocyte proliferation. They further suggest that mTORC2 controls pro-survival pathways in vitro and in tumor

Driving performance in older adults: Current measures, findings, and implications for roadway safety

BACKGROUND AND OBJECTIVES: Over 10,000 people a day turn 65 in the United States. For many older adults, driving represents an essential component of independence and is one of the most important factors in overall mobility. Recent survey studies in older adults suggest that up to 60% of older adult drivers with mild cognitive impairment, and up to 30% with dementia, continue to drive. The purpose of this review is to provide a comprehensive and detailed resource on the topics of cognition and driving for clinicians, researchers, and policymakers working on efforts related to older adult drivers. RESEARCH DESIGN AND METHODS: Publications on PubMed and Medline and discussions with experts working in geriatrics, technology, driving policy, psychology, and diverse aspects of driving performance were utilized to inform the current review. RESULTS: Research indicates that there is a complex and inverse correlation between multiple cognitive measures, driving performance, and risky driving behaviors. The fragmented nature of available peer-reviewed literature, and a reliance on correlative data, do not currently allow for the identification of the temporal and reciprocal nature of the interplay between cognition and driving endpoints. DISCUSSION AND IMPLICATIONS: There are currently no widely accepted definitions, conceptual models, or uniform set of analyses for conducting geriatric research that is focused on driving. Establishing conventions for conducting research that harmonizes the fields of geriatrics, cognition, and driving research is critical for the development of the evidence base that will inform clinical practice and road safety policy

Ornithine Decarboxylase mRNA is Stabilized in an mTORC1-dependent Manner in Ras-transformed Cells

Upon Ras activation, ODC (ornithine decarboxylase) is markedly induced, and numerous studies suggest that ODC expression is controlled by Ras effector pathways. ODC is therefore a potential target in the treatment and prevention of Ras-driven tumours. In the present study we compared ODC mRNA translation profiles and stability in normal and Ras12V-transformed RIE-1 (rat intestinal epithelial) cells. While translation initiation of ODC increased modestly in Ras12V cells, ODC mRNA was stabilized 8-fold. Treatment with the specific mTORC1 [mTOR (mammalian target of rapamycin) complex 1] inhibitor rapamycin or siRNA (small interfering RNA) knockdown of mTOR destabilized the ODC mRNA, but rapamycin had only a minor effect on ODC translation initiation. Inhibition of mTORC1 also reduced the association of the mRNA-binding protein HuR with the ODC transcript. We have shown previously that HuR binding to the ODC 3′UTR (untranslated region) results in significant stabilization of the ODC mRNA, which contains several AU-rich regions within its 3′UTR that may act as regulatory sequences. Analysis of ODC 3′UTR deletion constructs suggests that cis-acting elements between base 1969 and base 2141 of the ODC mRNA act to stabilize the ODC transcript. These experiments thus define a novel mechanism of ODC synthesis control. Regulation of ODC mRNA decay could be an important means of limiting polyamine accumulation and subsequent tumour development

Psychological and Social Suffering of Another Generation of Palestinian Children Living Under Occupation: An Urgent Call to Advocate [Viewpoint]

Alastair Ager - ORCID: 0000-0002-9474-3563 https://orcid.org/0000-0002-9474-3563https://www.hhrjournal.org/2024/05/psychological-and-social-suffering-of-another-generation-of-palestinian-children-living-under-occupation-an-urgent-call-to-advocate/26pubpub

Percutaneous Revascularization for Ischemic Ventricular Dysfunction : Rationale and Design of the REVIVED-BCIS2 Trial: Percutaneous Coronary Intervention for Ischemic Cardiomyopathy

OBJECTIVES: Evaluate whether PCI in combination with optimal medical therapy (OMT) will reduce all-cause death and hospitalization for HF compared to a strategy of OMT alone. BACKGROUND: Ischemic cardiomyopathy (ICM) is the most common cause of heart failure (HF) and is associated with significant mortality and morbidity. Surgical revascularization has been shown to improve long-term outcomes in some patients, but surgery itself carries a major early hazard. Percutaneous coronary intervention (PCI) may allow a better balance between risk and benefit. METHODS: REVIVED-BCIS2 is a prospective, multi-center, open-label, randomized controlled trial, funded by the National Institute for Health Research in the United Kingdom. Follow-up will be for at least 2 years from randomization. Secondary outcomes include left ventricular ejection fraction (LVEF), quality of life scores, appropriate implantable cardioverter defibrillator therapy and acute myocardial infarction. Patients with LVEF ≤35%, extensive coronary disease and demonstrable myocardial viability are eligible for inclusion and those with a myocardial infarction within 4 weeks, decompensated HF or sustained ventricular arrhythmias within 72 h are excluded. A trial of 700 patients has more than 85% power to detect a 30% relative reduction in hazard. RESULTS: A total of 400 patients have been enrolled to date. CONCLUSIONS: International guidelines do not provide firm recommendations on the role of PCI in managing severe ICM, because of a lack of robust evidence. REVIVED-BCIS2 will provide the first randomized data on the efficacy and safety of PCI in ICM and has the potential to inform guidelines pertaining to both revascularization and HF. (Study of Efficacy and Safety of Percutaneous Coronary Intervention to Improve Survival in Heart Failure [REVIVED-BCIS2]; NCT01920048) (REVascularisation for Ischaemic VEntricular Dysfunction; ISRCTN45979711)

Clinically Actionable Hypercholesterolemia and Hypertriglyceridemia in Children with Nonalcoholic Fatty Liver Disease

OBJECTIVE: To determine the percentage of children with nonalcoholic fatty liver disease (NAFLD) in whom intervention for low-density lipoprotein cholesterol or triglycerides was indicated based on National Heart, Lung, and Blood Institute guidelines. STUDY DESIGN: This multicenter, longitudinal cohort study included children with NAFLD enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Nonalcoholic Steatohepatitis Clinical Research Network. Fasting lipid profiles were obtained at diagnosis. Standardized dietary recommendations were provided. After 1 year, lipid profiles were repeated and interpreted according to National Heart, Lung, and Blood Institute Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction. Main outcomes were meeting criteria for clinically actionable dyslipidemia at baseline, and either achieving lipid goal at follow-up or meeting criteria for ongoing intervention. RESULTS: There were 585 participants, with a mean age of 12.8 years. The prevalence of children warranting intervention for low-density lipoprotein cholesterol at baseline was 14%. After 1 year of recommended dietary changes, 51% achieved goal low-density lipoprotein cholesterol, 27% qualified for enhanced dietary and lifestyle modifications, and 22% met criteria for pharmacologic intervention. Elevated triglycerides were more prevalent, with 51% meeting criteria for intervention. At 1 year, 25% achieved goal triglycerides with diet and lifestyle changes, 38% met criteria for advanced dietary modifications, and 37% qualified for antihyperlipidemic medications. CONCLUSIONS: More than one-half of children with NAFLD met intervention thresholds for dyslipidemia. Based on the burden of clinically relevant dyslipidemia, lipid screening in children with NAFLD is warranted. Clinicians caring for children with NAFLD should be familiar with lipid management

Building a Quantum Engineering Undergraduate Program

Contribution: A roadmap is provided for building a quantum engineering education program to satisfy U.S. national and international workforce needs. Background: The rapidly growing quantum information science and engineering (QISE) industry will require both quantum-aware and quantum-proficient engineers at the bachelor\u27s level. Research Question: What is the best way to provide a flexible framework that can be tailored for the full academic ecosystem? Methodology: A workshop of 480 QISE researchers from across academia, government, industry, and national laboratories was convened to draw on best practices; representative authors developed this roadmap. Findings: 1) For quantum-aware engineers, design of a first quantum engineering course, accessible to all STEM students, is described; 2) for the education and training of quantum-proficient engineers, both a quantum engineering minor accessible to all STEM majors, and a quantum track directly integrated into individual engineering majors are detailed, requiring only three to four newly developed courses complementing existing STEM classes; 3) a conceptual QISE course for implementation at any postsecondary institution, including community colleges and military schools, is delineated; 4) QISE presents extraordinary opportunities to work toward rectifying issues of inclusivity and equity that continue to be pervasive within engineering. A plan to do so is presented, as well as how quantum engineering education offers an excellent set of education research opportunities; and 5) a hands-on training plan on quantum hardware is outlined, a key component of any quantum engineering program, with a variety of technologies, including optics, atoms and ions, cryogenic and solid-state technologies, nanofabrication, and control and readout electronics

Building a Quantum Engineering Undergraduate Program

The rapidly growing quantum information science and engineering (QISE) industry will require both quantum-aware and quantum-proficient engineers at the bachelor's level. We provide a roadmap for building a quantum engineering education program to satisfy this need. For quantum-aware engineers, we describe how to design a first quantum engineering course accessible to all STEM students. For the education and training of quantum-proficient engineers, we detail both a quantum engineering minor accessible to all STEM majors, and a quantum track directly integrated into individual engineering majors. We propose that such programs typically require only three or four newly developed courses that complement existing engineering and science classes available on most larger campuses. We describe a conceptual quantum information science course for implementation at any post-secondary institution, including community colleges and military schools. QISE presents extraordinary opportunities to work towards rectifying issues of inclusivity and equity that continue to be pervasive within engineering. We present a plan to do so and describe how quantum engineering education presents an excellent set of education research opportunities. Finally, we outline a hands-on training plan on quantum hardware, a key component of any quantum engineering program, with a variety of technologies including optics, atoms and ions, cryogenic and solid-state technologies, nanofabrication, and control and readout electronics. Our recommendations provide a flexible framework that can be tailored for academic institutions ranging from teaching and undergraduate-focused two- and four-year colleges to research-intensive universities.Comment: 25 pages, 2 figure

The Human Serum Metabolome

Continuing improvements in analytical technology along with an increased interest in performing comprehensive, quantitative metabolic profiling, is leading to increased interest pressures within the metabolomics community to develop centralized metabolite reference resources for certain clinically important biofluids, such as cerebrospinal fluid, urine and blood. As part of an ongoing effort to systematically characterize the human metabolome through the Human Metabolome Project, we have undertaken the task of characterizing the human serum metabolome. In doing so, we have combined targeted and non-targeted NMR, GC-MS and LC-MS methods with computer-aided literature mining to identify and quantify a comprehensive, if not absolutely complete, set of metabolites commonly detected and quantified (with today's technology) in the human serum metabolome. Our use of multiple metabolomics platforms and technologies allowed us to substantially enhance the level of metabolome coverage while critically assessing the relative strengths and weaknesses of these platforms or technologies. Tables containing the complete set of 4229 confirmed and highly probable human serum compounds, their concentrations, related literature references and links to their known disease associations are freely available at http://www.serummetabolome.ca

In Children with Nonalcoholic Fatty Liver Disease, Zone 1 Steatosis is Associated with Advanced Fibrosis

Background & Aims Focal zone 1 steatosis, although rare in adults with nonalcoholic fatty liver disease (NAFLD), does occur in children with NAFLD. We investigated whether focal zone 1 steatosis and focal zone 3 steatosis are distinct subphenotypes of pediatric NAFLD. We aimed to determine associations between the zonality of steatosis and demographic, clinical, and histologic features in children with NAFLD. Methods We performed a cross-sectional study of baseline data from 813 children (age <18 years; mean age, 12.8 ± 2.7 years). The subjects had biopsy-proven NAFLD and were enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network. Liver histology was reviewed using the Nonalcoholic Steatohepatitis Clinical Research Network scoring system. Results Zone 1 steatosis was present in 18% of children with NAFLD (n = 146) and zone 3 steatosis was present in 32% (n = 244). Children with zone 1 steatosis were significantly younger (10 vs 14 years; P < .001) and a significantly higher proportion had any fibrosis (81% vs 51%; P < .001) or advanced fibrosis (13% vs 5%; P < .001) compared with children with zone 3 steatosis. In contrast, children with zone 3 steatosis were significantly more likely to have steatohepatitis (30% vs 6% in children with zone 1 steatosis; P < .001). Conclusions Children with zone 1 or zone 3 distribution of steatosis have an important subphenotype of pediatric NAFLD. Children with zone 1 steatosis are more likely to have advanced fibrosis and children with zone 3 steatosis are more likely to have steatohepatitis. To achieve a comprehensive understanding of pediatric NAFLD, studies of pathophysiology, natural history, and response to treatment should account for the zonality of steatosis