Rapid activation of ARF6 after RAF inhibition augments BRAFV600E and promotes therapy resistance.

The intrinsic ability of cancer cells to evade death underpins tumorigenesis, progression, metastasis and the survival of drug-tolerant persister (DTP) cells. Herein, we discovered that when activated, the small GTPase ARF6 plays a central role in tumor survival by facilitating expression of the BRAF oncoprotein. Tumor-specific deletion caused a significant reduction in BRAF protein and MAPK signaling and prevented rapid tumor progression.

Impact of myotomy length on per-oral endoscopic myotomy (POEM) outcomes for achalasia: a meta-analysis of randomized trials.

Introduction: Peroral endoscopic myotomy (POEM) has been established as a safe and effective intervention for Type I and II achalasia. Studies have shown that short POEM is non-inferior to long POEM, with some evidence of decreased incidence of gastroesophageal reflux disease (GERD). This meta-analysis aims to systematically review and analyze randomized controlled trials (RCTs) data comparing clinical and safety outcomes for long and short POEM procedures while further investigating differences in GERD and other long-term clinical outcomes.

SATURN MRI: study protocol for the statin use in intracerebral hemorrhage patients MRI ancillary study.

Background: The benefit-risk of statins in patients with lobar intracerebral hemorrhage (ICH) is under investigation in the StATins Use in intRacerebral hemorrhage patieNts (SATURN) trial. The relationship between statin use in ICH survivors, MRI markers of cerebral small vessel disease (CSVD), and outcomes such as recurrent ICH or major adverse cardiovascular or cerebrovascular events (MACCE) is unclear. The ancillary study, SATURN-MRI, intends to evaluate the interrelationship between statin use, the progression of MRI markers of CSVD, and cognitive and functional outcomes.

Atrial fibrillation and atherosclerosis cause different vascular brain lesions on magnetic resonance imaging.

Background And Aims: Atrial fibrillation (AF) and atherosclerosis pre-dispose to the occurrence of vascular brain lesions compared with the general population, yet direct comparisons of brain lesion patterns between these two cardiovascular patient groups are lacking. This study sought to compare the prevalence and distribution of vascular brain lesions on cerebral magnetic resonance imaging (MRI) between patients with AF and those with atherosclerosis.

Methods: Baseline clinical data and standardized brain MRI scans from the Swiss Atrial Fibrillation cohort study (Swiss-AF; representing patients with AF) and the COMPASS MRI sub-study (COMPASS MIND; representing patients with atherosclerosis without AF) were used to compare the prevalence of lacunar and non-lacunar infarcts, periventricular and deep white matter hyperintensities (WMH), and cerebral micro-bleeds (CMB) between groups.

Respiratory Event-related Physiological Biomarkers and Cognitive Performance in Obstructive Sleep Apnea.

Rationale: Individuals with obstructive sleep apnea (OSA) are at increased risk of cognitive impairment. However, the physiologic mechanisms that link OSA to this impairment are unclear. We assessed the association between novel physiologic biomarkers (, respiratory event-related electroencephalographic (EEG) activity and autonomic responses) and the risk of cognitive impairment.

Integrative genomic identification of therapeutic targets for pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, and new therapeutic strategies are urgently needed. Here, we conduct an integrative, genome-scale examination of genetic dependencies and cell surface targets using CRISPR-Cas screening and multi-omic data, including single-nucleus and spatial transcriptomic data from patient tumors. We systematically identify clinically tractable and biomarker-linked PDAC dependencies, including CDS2 as a synthetic lethal target in cancer cells expressing signatures of epithelial-to-mesenchymal transition.

Prognostic Role of Myocarditis-Like Episodes and Their Treatment in Patients With Pathogenic Desmoplakin Variants.

Background: Inflammatory, myocarditis-like episodes precede and are associated with higher risk of sustained ventricular arrhythmias and heart failure in patients with pathogenic or likely pathogenic desmoplakin (DSP) variants. Whether the recurrence and treatment of myocarditis-like episodes influence the outcomes in this population is unknown. This study aimed to assess the prognostic impact of the recurrence and treatment of myocarditis-like episodes in patients with pathogenic or likely pathogenic DSP variants.

National Versus State-Level Racial Disparities in Acute Stroke Interventions Using Get With The Guidelines-Stroke Data.

Background: Racial disparities have been reported in stroke care, but understanding if there is regional variability is critical to focusing policies and resources. Here, we sought to study racial and ethnic inequity in the administration of thrombolysis and thrombectomy at the national and state levels.

Methods: We conducted a retrospective cohort study using Get With The Guidelines-Stroke Program registry data from 2003 to 2022 to evaluate racial disparities in the administration of acute stroke treatments in US patients.

FICD (FIC Domain Protein Adenylyl Transferase) Deficiency Protects Mice From Hypertrophy-Induced Heart Failure and Promotes BiP (Binding Immunoglobulin Protein) -Mediated Activation of the Unfolded Protein Response and Endoplasmic Reticulum-Selective Autophagy in Cardiomyocytes.

Background: Cardiomyocytes require the HSP70 (heat shock protein 70) chaperone BiP (binding immunoglobulin protein) to maintain proteostasis in the endoplasmic reticulum (ER) following cardiac stress. The adenylyl transferase FICD (FIC domain protein adenylyl transferase) is increasingly recognized to regulate BiP activity through the posttranslational addition of an adenosine monophosphate moiety to BiP surface residues. However, the physiological impact of FICD-mediated BiP regulation in the context of cardiovascular health is unknown.

Vascular Contributions to Cognitive Impairment and Dementia in the United States: Prevalence and Incidence: A Scientific Statement From the American Heart Association.

Vascular contributions to cognitive impairment and dementia (VCID) are common and may be the most preventable cause of clinically significant cognitive decline. However, an estimate of the prevalence and incidence of VCID in the United States is lacking. In this scientific statement, we reviewed studies on the incidence and prevalence of VCID, defined as patients diagnosed with vascular dementia, evidence of vascular dementia in epidemiological studies, neuropathological evidence of cerebrovascular contributions to dementia, and neuroimaging evidence of covert (clinically silent) cerebrovascular disease.

Enhancing Alzheimer Disease Detection Using Neuropsychiatric Symptoms: The Role of Mild Behavioural Impairment in the Revised NIA-AA Research Framework.

BackgroundAs the prevalence of Alzheimer disease (AD) rises, early identification of at-risk individuals is essential for effective intervention. Mild behavioral impairment (MBI), which captures emergent and persistent neuropsychiatric symptoms (NPS) in later life, may enhance early detection of AD; however, its associations with 2024 NIA-AA Core 1 biomarkers remain unexplored. We investigated associations between MBI and cerebrospinal fluid (CSF) amyloid β-42 (Aβ42) and phosphorylated tau-181 (p-tau181).

Transtympanic Injection of Antioxidant-Eluting Microparticles for Otoprotection From Cisplatin Toxicity in a Mouse Model.

Objective: Cisplatin is a chemotherapeutic agent with the undesirable side effect of ototoxicity. Transtympanic injections of antioxidant formulations may provide local otoprotection. We tested a novel antioxidant-eluting microparticle for its otoprotective capability from systemic cisplatin as measured by cochlear electrophysiology.

Creating a Clinical Care Pathway for Depressive Symptoms and Disorders in Long-Term Care: A Modified Delphi Process.

Objectives: To create an evidence- and expert-informed clinical care pathway focused on identifying and treating depressive symptoms and disorders in long-term care (LTC) residents.

Design: Modified Delphi survey.

Setting And Participants: Delphi participants were LTC health care providers, LTC administrators, friend/family caregivers of residents living in LTC, and residents of LTC.

Toward compassionate communication: a rapid review on facilitating the dementia disclosure process.

Individuals with dementia and their care partners often report dissatisfaction with the disclosure process due to insufficient information and support. Healthcare providers face challenges in effective communication and connecting patients to post-diagnostic resources. To address these issues and emphasize person-centered communication, especially in diverse communities, we conducted a rapid systematic review consolidating preferences for dementia diagnosis disclosure from patients, care partners, and healthcare providers.

The contribution of truncating variants to human cardiomyopathy.

Background: Genetic diagnosis has become increasingly important to guide clinical decision making for patients with dilated cardiomyopathy (DCM). Disease-causing (P/LP) missense variants in the gene cause a highly penetrant arrhythmogenic dilated cardiomyopathy (DCM), but the role of truncating variants ( ) is unclear.

Objective: Assess the contribution of to DCM.

MRI findings intracranial hemorrhages in ARCADIA-MRI: an ancillary study to the ARCADIA trial.

Background And Purpose: The ARCADIA-MRI study, an ancillary study to the randomized Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke (ARCADIA) trial, reported that the risk of incident non-lacunar covert infarcts was lower in the apixaban group than the aspirin group. This paper presents the additional, prespecified, exploratory outcomes beyond the primary paper, specifically examining the effect of apixaban on hemorrhagic lesions on MRI.

Materials And Methods: The ARCADIA-MRI study was conducted in conjunction with ARCADIA trial visits, with follow-up durations ranging from 4 months to 5.

Eradicating Drug Tolerant Persister Cells in EGFR-Mutated Non-Small Cell Lung Cancer by Targeting TROP2 with CAR-T cellular therapy.

EGFR tyrosine kinase inhibitors (TKIs) have dramatically improved outcomes for EGFR-mutated non-small cell lung cancer (NSCLC) patients, but relapse frequently occurs due to drug tolerant persister (DTP) cells that can evolve and develop diverse mechanisms of drug resistance. In samples from patients with EGFR-mutated NSCLC treated with EGFR-TKIs in the neoadjuvant setting, we observed enriched expression of the cell surface protein TROP2, a target of clinically active antibody drug conjugates (ADCs). We confirmed these findings across multiple EGFR-mutated NSCLC cell line and patient-derived xenograft models treated with osimertinib in vivo.

Diagnosis and management of cerebral amyloid angiopathy: a scientific statement from the International CAA Association and the World Stroke Organization.

Cerebral amyloid angiopathy (CAA) is a well-recognized and challenging disease for neurologists and other clinicians caring for the rapidly aging worldwide population. CAA is a major cause of spontaneous lobar intracerebral hemorrhage (ICH), and can also cause transient focal neurological episodes, and convexity subarachnoid hemorrhage, CAA-associated ICH has a high mortality, morbidity, and recurrence rate. CAA can affect a wide range of clinical decisions including use of antithrombotic medications, safety for anti-β-amyloid peptide (Aβ) immunotherapy, and need for anti-inflammatory or immunosuppressive treatment.

Association of dietary macronutrients with MRI-detected vascular brain injury and cognition in 9886 middle-aged participants from four countries: for the Canadian Alliance of Healthy Hearts and Minds (CAHHM) and the Prospective Urban Rural Epidemiolog (PURE) Study Investigators.

Background: Epidemiologic evidence relating macronutrient intake and changes in the brain and cognition are limited. We assessed the associations of macronutrient consumption, including carbohydrate, protein, total fat, saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids, with vascular brain injury and cognitive scores.

Methods: We analyzed cross-sectional data from 9886 middle-aged adults in four countries free of clinically apparent cardiovascular disease from the Canadian Alliance for Healthy Hearts and Minds (CAHHM) and the Prospective Urban Rural Epidemiological MIND (PURE-MIND) studies.

Advancing clinical trial readiness in white matter disease and related dementias: key steps for future research progress.

White matter disease, a broad-spectrum term that covers various types of white matter lesions and degeneration, is strongly related to age-related neurodegenerative disorders including Alzheimer's disease (AD), and vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's related dementias (ADRD). There is no specific treatment for white matter disease. Therefore, basic research and clinical studies are essential for future outcomes.

Diagnostic Criteria and Disease Staging for Desmoplakin Cardiomyopathy.

Background: Desmoplakin (DSP) cardiomyopathy, caused by variants in the gene , is a unique subtype of cardiomyopathy distinct from typical dilated or arrhythmogenic right ventricular cardiomyopathies. Specific diagnostic and disease staging criteria have yet to be developed for DSP cardiomyopathy.

Objective: Utilizing a large cohort of DSP cardiomyopathy patients and their genotype-positive family members, this study aims to develop diagnostic and disease staging criteria for DSP cardiomyopathy.

Cytopenias and infections following ciltacabtagene autoleucel in heavily-pretreated relapsed or refractory multiple myeloma.

Ciltacabtagene autoleucel (cilta-cel) was FDA-approved in February 2022 for the treatment of relapsed/refractory multiple myeloma after 4 lines of therapy. On CARTITUDE-1 trial, grade ≥3 cytopenias and infections were common. Herein, we sought to characterize cytopenias and infections after cilta-cel infusion in the standard-of-care setting.

Management of Patients With Mild Cognitive Impairment in the Era of Anti-Amyloid Therapy: A Worldwide Neurology Survey.

Background And Objectives: The aim of this study was to explore practice patterns in managing mild cognitive impairment (MCI). The investigation and management of MCI is considered important because it offers the opportunity to potentially stave off conversion to dementia. However, there are few data on current practices/approaches in this area, especially worldwide; such data can help identify potential disparities and anticipate adoption of new therapies.

Immune impacts of fire smoke exposure.

Exposure to fire smoke has become a global health concern and is associated with increased morbidity and mortality. There is a lack of understanding of the specific immune mechanisms involved in smoke exposure, with preventive and targeted interventions needed. After exposure to fire smoke, which includes PM, toxic metals and perfluoroalkyl and polyfluoroalkyl substances, epidemiology-based studies have demonstrated increases in respiratory (for example, asthma exacerbation), cardiac (for example, myocardial infarction, arrhythmias), neurological (for example, stroke) and pregnancy-related (for example, low birthweight, premature birth) outcomes.