Context-dependent effects of CDKN2A and other 9p21 gene losses during the evolution of esophageal cancer.

CDKN2A is a tumor suppressor located in chromosome 9p21 and frequently lost in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). How CDKN2A and other 9p21 gene co-deletions affect EAC evolution remains understudied. We explored the effects of 9p21 loss in EACs and cancer progressor and non-progressor BEs with matched genomic, transcriptomic and clinical data.

Genetically Engineered, Multichromophore Virus-Like Nanoparticles with Ultranarrow Distribution of Emission Intensity.

Variance in the properties of optical mesoscopic probes is often a limiting factor in applications. In the thermodynamic limit, the smaller the probe, the larger the relative variance. However, specific viral protein cages can assemble efficiently outside the bounds of statistical fluctuations at equilibrium through a process that is characterized by intrinsic quality-control and self-limiting capabilities.

Basic Science and Pathogenesis.

Background: White matter hyperintensities (WMH) are commonly observed on MRI in Alzheimer's disease (AD), but the molecular pathways underlying their relationships with the ATN biomarkers remain unclear. The aim of this study was to identify genetic variants that may modify the relationship between WMH and the ATN biomarkers.

Method: This genome-wide interaction study (GWIS) included individuals with AD, MCI, and normal cognition from ADNI (n = 1012).

Basic Science and Pathogenesis.

Background: Annotation of target genes of non-coding GWAS loci remains a challenge since 1) regulatory elements identified by GWAS can be metabases away from its actual target, 2) one regulatory element can target multiple genes, and 3) multiple regulatory elements can target one gene. AD GWAS in populations with different ancestries have identified different loci, suggesting ancestry-specific genetic risks. To understand the connection between associated loci (potential regulatory elements) and their target genes, we conducted Hi-C analysis in frontal cortex of African American (AA) and Non-Hispanic Whites (NHW) AD patients to map chromatin loops, which often represent enhancer-promoter (EP) interactions.

Basic Science and Pathogenesis.

Background: Polygenic Risk Scores (PRS) are important in predicting disease risk and are usually rely on markers selected by thresholding p-values from genome-wide association studies (GWAS). In traditional approaches, one single model is built to calculate risk scores, employing effect size to determine additive risk. However, this traditional method overlooks potential interactions between genetic loci resulting in reduced prediction power.

Basic Science and Pathogenesis.

Background: The effect size of APOE4 varies across genetic ancestries with African (AFR) local ancestry conferring a lower risk when compared to other ancestries. Recently, we identified a strong effect of the A allele of rs10423769 (with a minor allele frequency of 0.12 in AFR and 0.

Basic Science and Pathogenesis.

Background: Alzheimer's Disease (AD) and Age-Related Macular Degeneration (AMD) are two age related neurodegenerative diseases that share multiple characteristics, including deposition of amyloid beta. In AD, amyloid plaque accumulation contributes to neurological dysfunction, while in AMD amyloid is a component of the hallmark retinal drusen complexes that lead to degeneration of central vision. Both diseases have significant and opposite risk due to the APOE e4 and e2 alleles.

Basic Science and Pathogenesis.

Background: Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is a pathological process diagnosed at autopsy, involving deposition of TDP-43 in the medial temporal lobes. The name LATE-NC was recently proposed to represent the pathological process, while "LATE" has been suggested to represent the clinical syndrome. However, there are currently no available criteria to diagnose this syndrome during life, and the clinical phenotype is not well understood.

Basic Science and Pathogenesis.

Background: Hispanic/Latino populations are underrepresented in Alzheimer Disease (AD) genetic studies. The Puerto Rican (PR) population, a three-way admixed (European, African, and Amerindian) population is the second-largest Hispanic group in the continental US. We performed a genome-wide association study (GWAS) in the PR population to identify novel AD susceptibility loci and characterize known AD genetic risk loci.

Basic Science and Pathogenesis.

Background: Apolipoprotein (Apo) E4, a main susceptibility gene for Alzheimer's disease (AD) is associated with increased vascular dysfunction, amyloid pathology, and neurodegeneration. The effector pathways leading to increased vascular risk in ApoE4 carriers needs to be established. Platelet aggregation is a key marker of vascular dysfunction and studies need to examine whether a relationship of ApoE4 allele status and platelet biology exists METHOD: We examined cross-sectional associations of platelet aggregation with ApoE genotypes (E2 or E4 against E3, the most common) in middle-aged cognitively normal participants at the Framingham Heart Study (FHS) Gen3, New Offspring Spouse (NOS), and Omni2 Cohorts.

Basic Science and Pathogenesis.

Background: While Alzheimer's disease and dementia prevalence increase with age, some older adults retain cognitive performance equal to those in mid-life. One group, referred to as SuperAgers (SA), are ≥ 80 years old and demonstrate episodic memory function at or above the level expected for a middle-aged adult. Genetic studies of SA may reveal heritable factors that promote superior cognition in older adults.

Basic Science and Pathogenesis.

Background: Non-Hispanic White APOE4 carriers have a higher risk of developing AD compared to African American APOE4 carriers. The local ancestry (LA) surrounding the APOE region was previously shown to be the primary factor in this risk difference. APOE4 carriers of European LA (ELA) have been found to have higher APOE4 expression and chromatin accessibility compared to African LA (ALA).

Basic Science and Pathogenesis.

Background: Mosaic loss of chromosome Y (mLOY) refers to acquired aneuploidy in a fraction of somatic cells. In aging men, this has been suggested as a possible biomarker for increased risk of numerous diseases, including Alzheimer's disease (AD). We investigated mLOY estimated from whole genome sequencing (WGS) as a risk factor for AD in the Midwestern Amish, a founder population with homogeneous lifestyle, reducing the effect of confounding environmental factors.

Basic Science and Pathogenesis.

Background: The "Recruitment and Retention for Alzheimer's Disease Diversity Genetic Cohorts in the ADSP (READD-ADSP)" is developing a resource to expand ancestral diversity in Alzheimer disease (AD) studies to dissect the genetic architecture of AD across different populations. In addition to US sites, READD-ADSP includes four US sites and nine countries in sub-Saharan Africa through the Africa Dementia Consortium (AfDC). The overall goal of READD-ADSP is to identify genetically driven targets in diverse groups including African Americans and Hispanic/Latinos in US, and Africans.

Clinical Manifestations.

Background: Frontotemporal dementia (FTD) presents with heterogeneous neuropsychiatric symptoms (NPS). These symptoms often begin prior to the onset of FTD, and progress throughout the prodromal stages of FTD. Particularly, familial FTD due to autosomal dominant genetic mutations might display mutation-specific NPS profiles.

Clinical Manifestations.

Background: Due to the shortage of healthcare professionals with expertise in diagnosis and treatment of Alzheimer disease and related dementias, there are long wait times to be evaluated in dementia specialty clinics and no clear guidance about how to allocate limited resources. The purpose of this study was to examine utility of cognitive screening measures administered by clinic staff to determine level of cognitive impairment to aid in decisions about which patients may benefit from full diagnostic services.

Methods: Participants were 169 older adults who completed an intake interview, including a brief cognitive screening test, conducted by a neuropsychologist at a dementia specialty clinic.

Clinical Manifestations.

Background: Motivational disturbances are a major harbinger for dementia, being associated with a two- to seven-fold higher conversion rate from mild cognitive impairment. However, there are currently no objective assessment methods for identifying motivational disturbances in older adults (OA). Here, we present preliminary findings from a larger study which aims to validate an objective behavioral measure of effort in OAs by investigating the effects of age, risk, and reward (gain vs.

Clinical Manifestations.

Background: Mild Behavioral Impairment (MBI) is a condition characterized by neuropsychiatric symptoms (NPS) in older adults without dementia, serving as a precursor to various forms of dementia. This study explores the association between NPS and functional connectivity (FC) within the default mode network (DMN), executive control network (ECN), and salience network (SN) across three high-risk cohorts: mild cognitive impairment (due to Alzheimer's) (MCI, n = 79), cerebrovascular disease (CVD, n = 144), and Parkinson's disease (PD, n = 132).

Method: A total of 367 participants were recruited from the Ontario Neurodegenerative Disease Research Initiative (ONDRI).

Bringing Pandemic Science to the Classroom: Building Public Health Capacity at a Rural Kentucky High School.

In response to the COVID-19 pandemic, a multidisciplinary team at the University of Kentucky developed an interdisciplinary science, technology, engineering, and mathematics and environmental health unit-the Wastewater Assessment for Coronavirus in Kentucky: Implementing Enhanced Surveillance Technology (WACKIEST) Unit-for high school students in summer 2022. This case study outlines the WACKIEST Unit, which focused on wastewater surveillance and COVID-19, the obstacles faced during development and recruitment, and implementation of the WACKIEST Unit in conjunction with a rural wastewater surveillance initiative. The unit was implemented in spring 2023 at a rural high school in Kentucky, spanning 12 days and engaging 190 students.

Integrating Pharmacogenomics into the Broader Construct of Genomic Medicine: Efforts by the ClinGen Pharmacogenomics Working Group (PGxWG).

Pharmacogenomics (PGx) is focused on the relationship between an individual's genetic makeup and their response to medications, with the overarching aim of guiding prescribing decisions to improve drug efficacy and reduce adverse events. The PGx and genomic medicine communities have worked independently for over 2 decades, developing separate standards and terminology, making implementation of PGx across all areas of genomic medicine difficult. To address this issue, the Clinical Genome Resource (ClinGen) Pharmacogenomics Working Group (PGxWG) was established by the National Institutes of Health (NIH)-funded ClinGen to initially create frameworks for evaluating gene-drug response clinical validity and actionability aligned with the ClinGen frameworks for evaluating monogenic gene-disease relationships, and a framework for classifying germline PGx variants similar to the American College of Medical Genetics (ACMG) and Association of Molecular Pathology (AMP) system for interpretation of disease-causing variants.

Pneumatosis Intestinalis and Concurrent Focal Diaphragmatic Pneumatosis Cystoides Presenting With Pneumoperitoneum in a 20 Year-Old Male: A Case Report.

Pneumatosis cystoides intestinalis can present with concurrent diaphragmatic cysts, a previously undocumented phenomenon. Surgical management may be required, but further investigation is needed to understand the pathogenesis and optimize management in atypical and chronic cases, such as this case with a history of corrected intestinal malrotation.

Filsuvez (Birch Triterpenes) Topical Gel.

Filsuvez (birch triterpenes) topical gel received approval in 2023 for the treatment of epidermolysis bullosa (EB) in pediatric patients (aged ≥6 months) and adults. It promotes wound healing by modulating inflammation, encouraging new tissue formation, and maintaining the skin barrier. In a randomized, double-blind, controlled, parallel-group, phase III trial (EASE, NCT03068780), 223 patients were randomly assigned to two groups: the first group received treatment with birch triterpenes topical gel (study gel, n = 109), and the second group received treatment with vehicle gel (n = 114).

Zelsuvmi (Berdazimer) Topical Gel.

Zelsuvmi (berdazimer) topical gel has been approved recently for the treatment of molluscum contagiosum (MC) in patients aged ≥1 year. In three phase 3, randomized, double-blind, vehicle-controlled trials of similar design, berdazimer was investigated for the treatment of MC. Berdazimer or vehicle was applied once daily on MC lesions until complete lesion clearance was observed or for up to 12 weeks.

Frequency of Spondyloarthritis Symptoms Among U.S. Patients with Inflammatory Bowel Disease: A Cross-sectional Multi-Center Study.

Objective: Spondyloarthritis (SpA) is the most common extraintestinal manifestation of inflammatory bowel disease (IBD). The application of screening tools to detect SpA in patients with IBD may lead to earlier recognition of SpA and affect treatment decisions.

Methods: A combination of two previously described SpA screening questionnaires, DETAIL and IBIS-Q, was administered to consecutive patients with IBD attending IBD specialty clinics in six U.