Sorafenib Alters Interstitial Proton and Sodium Levels in the Tumor Microenvironment: A H/Na Spectroscopic Imaging Study.

Cellular metabolism is inextricably linked to transmembrane levels of proton (H), sodium (Na), and potassium (K) ions. Although reduced sodium-potassium pump (Na-K ATPase) activity in tumors directly disturbs transmembrane Na and K levels, this dysfunction is a result of upregulated aerobic glycolysis generating excessive cytosolic H (and lactate) which are extruded to acidify the interstitial space. These oncogene-directed metabolic changes, affecting intracellular Na and H, can be further exacerbated by upregulation of ion exchangers/transporters.

Aberrant splicing in Huntington's disease accompanies disrupted TDP-43 activity and altered m6A RNA modification.

Huntington's disease (HD) is caused by a CAG repeat expansion in the HTT gene, leading to altered gene expression. However, the mechanisms leading to disrupted RNA processing in HD remain unclear. Here we identify TDP-43 and the N6-methyladenosine (m6A) writer protein METTL3 to be upstream regulators of exon skipping in multiple HD systems.

Trends in use of tobacco and cannabis across different alcohol consumption levels in the United States, 2010-19.

Aims: People often drink alcohol and use other substances concurrently, increasing the risk of adverse health outcomes. Our aims were to: (i) assess temporal trends in tobacco and/or cannabis use by varying alcohol consumption levels and (ii) identify associated factors of polysubstance use in high-risk alcohol users.

Methods: We conducted a repeated cross-sectional study combining 2010-19 U.

Polygenic risk for epigenetic aging and adverse life experiences interact to predict growth in adolescent depression in a racially/ethnically diverse sample.

Introduction: Research has yet to examine the interplay between indices of environmental risk and resilience processes and genetic predisposition for epigenetic aging in predicting early adolescent depressive symptoms. In the current study we examine whether adverse life events and parental acceptance moderate polygenic predisposition for GrimAge epigenetic aging in predicting trajectories of depressive symptoms across early adolescence.

Method: Using data from the Adolescent Brain Development Study (ABCD, N = 11,875), we created polygenic scores for GrimAge, and examined whether exposure to adverse life events and parental acceptance moderated the relation between genetic risk and depressive symptom trajectories from age 10/11 to 12/13 using growth mixture modelling.

Impact of chronic ethanol consumption and SARS-COV-2 on the liver and intestine: A pilot dose-response study in mice.

Background: During the coronavirus disease 2019 (COVID-19) pandemic, there was a marked increase in alcohol consumption. COVID-19 superimposed on underlying liver disease notably worsens the outcome of many forms of liver injury. The goal of a current pilot study was to test the dual exposure of alcohol and COVID-19 infection in an experimental animal model of alcohol-associated liver disease (ALD).

Deeper response predicts better outcomes in high-risk-smoldering-myeloma: results of the I-PRISM phase II clinical trial.

Early therapeutic intervention in high-risk smoldering multiple myeloma (HR-SMM) has shown benefits, however, no studies have assessed whether biochemical progression or response depth predicts long-term outcomes. The single-arm I-PRISM phase II trial (NCT02916771) evaluated ixazomib, lenalidomide, and dexamethasone in 55 patients with HR-SMM. The primary endpoint, median progression-free survival (PFS), was not reached (NR) (95% CI: 57.

High prevalence of alcohol use disorders in 454 young adult offspring from the San Diego prospective study.

Background: Preliminary evaluations of 212 drinking offspring from the San Diego Prospective Study (SDPD) indicated that over 50% developed alcohol use disorder (AUD) by their mid-20s. The present analysis evaluated if those findings remained robust when the group increased to 454 individuals, a sample size that facilitated a search for potential contributors to the high AUD prevalence.

Methods: Semistructured interviews were used to evaluate lifetime AUD diagnoses in 224 daughters and 230 sons from the SDPS (N = 454) by mean age 26.

Optimal population screening strategies for liver fibrosis associated with metabolic dysfunction-associated steatotic liver disease.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is an important public health threat, potentially leading to chronic liver disease and liver cancer. Current guidelines recommend using the FIB-4 score for initial identification of subjects at risk of future complications. We formulate a novel population screening strategy based on the Steatosis-Associated Fibrosis Estimator (SAFE) score, recently developed for MASLD risk stratification in primary care.

Developing Benchmarking Metrics for Appropriate Ordering of Vitamin D, Thyroid Testing, and Iron Workups.

Background: Laboratory stewardship programs are increasingly adopted to enhance test utilization and improve patient care. Despite their potential, implementation within complex healthcare systems remains challenging. Benchmarking metrics helps institutions compare their performance against peers or best practices.

Cerebrospinal fluid β2-microglobulin promotes the tau pathology through microglia-astrocyte communication in Alzheimer's disease.

Background: Cerebrospinal fluid (CSF) β2-microglobulin (β2M) has been demonstrated as an important factor in β-amyloid (Aβ) neurotoxicity and a potential target for Alzheimer's disease (AD). However, more investigation is required to ascertain the relationship between β2M and glial activities in AD pathogenesis.

Methods: In this study, 211 participants from the Alzheimer's disease Neuroimaging Initiative (ADNI) with CSF and Plasma β2M, CSF glial fibrillary acidic protein (GFAP), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), Aβ, phosphorylated-tau (P-tau) and total tau (T-tau) were divided into four groups, stage 0, 1, 2, and suspected non-AD pathology (SNAP) based on the National Institute on Aging- Alzheimer's Association (NIA-AA) criteria.

The Future Hospital in Global Health Systems: The Future Hospital as an Entity.

Health care is changing rapidly. Hospitals are, and will remain, an essential setting to deliver it. We discuss how to maximise the benefits of hospitals in the future in different geographic and health system settings, highlighting a series of cross-cutting issues.

Dengue virus IgG and neutralizing antibody titers measured with standard and mature viruses are protective.

The standard dengue virus (DENV) neutralization assay inconsistently predicts dengue protection. We compare how IgG ELISA, envelope domain III (EDIII), or non-structural protein 1 (NS1) binding antibodies, and titers from plaque reduction neutralization tests (PRNTs) using standard and mature viruses are associated with dengue. The ELISA measures IgG antibodies that bind to inactivated DENV1-4.

Regional patterns and climatic predictors of viruses in honey bee (Apis mellifera) colonies over time.

Honey bee viruses are serious pathogens that can cause poor colony health and productivity. We analyzed a multi-year longitudinal dataset of abundances of nine honey bee viruses (deformed wing virus A, deformed wing virus B, black queen cell virus, sacbrood virus, Lake Sinai virus, Kashmir bee virus, acute bee paralysis virus, chronic bee paralysis virus, and Israeli acute paralysis virus) in colonies located across Canada to describe broad trends in virus intensity and occurrence among regions and years. We also tested climatic variables (temperature, wind speed, and precipitation) as predictors in an effort to understand possible drivers underlying seasonal patterns in viral prevalence.

Structural basis for catalysis and selectivity of phospholipid synthesis by eukaryotic choline-phosphotransferase.

Phospholipids are the most abundant component in lipid membranes and are essential for the structural and functional integrity of the cell. In eukaryotic cells, phospholipids are primarily synthesized de novo through the Kennedy pathway that involves multiple enzymatic processes. The terminal reaction is mediated by a group of cytidine-5'-diphosphate (CDP)-choline /CDP-ethanolamine-phosphotransferases (CPT/EPT) that use 1,2-diacylglycerol (DAG) and CDP-choline or CDP-ethanolamine to produce phosphatidylcholine (PC) or phosphatidylethanolamine (PE) that are the main phospholipids in eukaryotic cells.

Targeting chromosomally unstable tumors with a selective KIF18A inhibitor.

Chromosome instability is a prevalent vulnerability of cancer cells that has yet to be fully exploited therapeutically. To identify genes uniquely essential to chromosomally unstable cells, we mined the Cancer Dependency Map for genes essential in tumor cells with high levels of copy number aberrations. We identify and validate KIF18A, a mitotic kinesin, as a vulnerability of chromosomally unstable cancer cells.

Pituitary adenylate cyclase-activating polypeptide (PACAP)overexpression in the paraventricular nucleus of the thalamus alters motivated and affective behavior in female rats.

Background: Pituitary adenylate cyclase-activating polypeptide (PACAP) has been found to be involved in a wide range of motivated and affective behaviors. While the PACAP-38 isoform is more densely expressed than PACAP-27 in most of the brain, PACAP-27 is more highly expressed in the rodent paraventricular nucleus of the thalamus (PVT), where females also have greater expression than males. Notably, the role of PACAP-27 expression in cells of the PVT has not been explored.

T helper 2 cell-directed immunotherapy eliminates precancerous skin lesions.

The continuous rise in skin cancer incidence highlights an imperative for improved skin cancer prevention. Topical calcipotriol-plus-5-fluorouracil (calcipotriol-plus-5-FU) immunotherapy effectively eliminates precancerous skin lesions and prevents squamous cell carcinoma (SCC) in patients. However, its mechanism of action remains unclear.

Identification of Transdiagnostic Childhood Externalizing Pathology Within an Electronic Medical Records Database and Application to the Analysis of Rare Copy Number Variation.

Externalizing traits and behaviors are broadly defined by impairments in self-regulation and impulse control that typically begin in childhood and adolescence. Externalizing behaviors, traits, and symptoms span a range of traditional psychiatric diagnostic categories. In this study, we sought to generate an algorithm that could reliably identify transdiagnostic childhood-onset externalizing cases and controls within a university hospital electronic health record (EHR) database.

Parental Problem Drinking, Parent Emotion Socialization and Child Emotion Regulation.

The current study examines mother and father PPD as a risk factor for child emotion regulation difficulties. A model was tested in which parent depression and parent emotion socialization of children were serial intervening variables. Parent emotion socialization was assessed via parent self-reported supportive and nonsupportive reactions to child negative emotions.

Whole genome methylation sequencing in blood from persons with mild cognitive impairment and dementia due to Alzheimer's disease identifies cognitive status.

Introduction: Whole genome methylation sequencing (WGMS) in blood identifies differential DNA methylation in persons with late-onset dementia due to Alzheimer's disease (AD) but has not been tested in persons with mild cognitive impairment (MCI).

Methods: We used WGMS to compare DNA methylation levels at 25,244,219 CpG loci in 382 blood samples from 99 persons with MCI, 109 with AD, and 174 who are cognitively unimpaired (CU).

Results: WGMS identified 9756 differentially methylated positions (DMPs) in persons with MCI, including 1743 differentially methylated genes encoding proteins in biological pathways related to synapse organization, dendrite development, and ion transport.

Oral fentanyl consumption and withdrawal impairs fear extinction learning and enhances basolateral amygdala principal neuron excitatory-inhibitory balance in male and female mice.

The number of opioid overdose deaths has increased over the past several years, mainly driven by an increase in the availability of highly potent synthetic opioids, like fentanyl, in the un-regulated drug supply. Over the last few years, changes in the drug supply, and in particular the availability of counterfeit pills containing fentanyl, have made oral use of opioids a more common route of administration. Here, we used a drinking in the dark (DiD) paradigm to model oral fentanyl self-administration using increasing fentanyl concentrations in male and female mice over 5 weeks.

Novel Application of Skills for Psychological Recovery as an Early Intervention for Posttraumatic Stress Disorder, Depression, and Alcohol Misuse in Survivors of Recent Sexual Assault: A Case Series.

Skills for Psychological Recovery (SPR) is an evidence-informed, early intervention for teaching survivors coping skills in the aftermath of recent disasters. Although SPR has not been tested following recent sexual assault, there is theoretical support for applying SPR to the needs of recent sexual assault survivors. The current study is the first to describe the application of SPR among survivors of recent sexual assault.