Explainable Machine Learning to Predict Treatment Response in Advanced Non-Small Cell Lung Cancer.

Purpose: Immune checkpoint inhibitors (ICIs) have demonstrated promise in the treatment of various cancers. Single-drug ICI therapy (immuno-oncology [IO] monotherapy) that targets PD-L1 is the standard of care in patients with advanced non-small cell lung cancer (NSCLC) with PD-L1 expression ≥50%. We sought to find out if a machine learning (ML) algorithm can perform better as a predictive biomarker than PD-L1 alone.

Incidence and Risk Factors of Diagnosed Young-Adult-Onset Type 2 Diabetes in the U.S.: The National Health Interview Survey 2016-2022.

Objective: To estimate the incidence and identify risk factors for diagnosed type 2 diabetes (T2D) among young U.S. adults.

Successful Treatment of Primary Acanthamoeba Cutis in a Patient With Chronic Lymphocytic Leukemia on Acalabrutinib.

Primary cutaneous amoebiasis is rare, and typically affects immunocompromised patients and presents with unique clinical and histopathologic changes. Untreated, the infection could progress to involve the central nervous system, which is almost universally fatal. We present a case of primary cutaneous acanthamoebiasis in a patient with chronic lymphocytic leukemia on acalabrutinib.

Beyond the Nest: The Role of Financial Independence in Young Adult Health.

Background: This study aimed to examine the impact of neighborhood conditions and household material hardship experiences on young adult health outcomes, while also considering financial autonomy as a critical determinant of health.

Method: We employed a cross-sectional observational design with a diverse sample of young adults from a large urban university. Structural equation modeling was used to analyze the relationships between neighborhood conditions and material hardship with health outcomes by financial autonomy.

Spatially dependent tissue distribution of thyroid hormones by plasma thyroid hormone binding proteins.

Plasma thyroid hormone (TH) binding proteins (THBPs), including thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin (ALB), carry THs to extrathyroidal sites, where THs are unloaded locally and then taken up via membrane transporters into the tissue proper. The respective roles of THBPs in supplying THs for tissue uptake are not completely understood. To investigate this, we developed a spatial human physiologically based kinetic (PBK) model of THs, which produces several novel findings.

Hormonal Therapies for Acne: A Comprehensive Update for Dermatologists.

Introduction: Acne impairs quality of life, often leads to permanent scars, and causes psychological distress. This review aims to update dermatologists on the Federal Drug Administration (FDA)-approved and off-label use of combined oral contraceptives (COC), clascoterone, spironolactone, and emerging hormonal therapies for acne treatment.

Methods: We reviewed current literature on hormonal acne treatments and discussed common patient concerns, barriers to care, and individualized care needs.

Basic Science and Pathogenesis.

Background: MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression, but we have limited insight into their role in age-related cerebral pathologies. Here, we investigated the association between miRNAs and nine age-related cerebral pathologies in participants of the ROS/MAP cohorts.

Method: MiRNA sequencing was performed on samples from the dorsolateral prefrontal cortex of 617 brain donors from participants of the ROS/MAP cohorts.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is a devastating neurodegenerative disorder with few therapies to treat, mitigate or prevent its onset. Understanding of this disease is predominantly based on research in non-Hispanic Whites (NHW) although AD disproportionately affects African Americans (AA) and Latin Americans (LA), underrepresented in AD research. To address this knowledge gap, the Accelerating Medicine Partnership for Alzheimer's Disease (AMP-AD) Diversity Working Group was launched to generate multi-omics data from post-mortem brain tissue from donors of predominantly AA and LA descent.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) has a complex etiology where insults in multiple pathways conspire to disrupt neuronal function, yet molecular changes underlying AD remain poorly understood. Previously, we performed mass-spectrometry on post-mortem human brain tissue to identify >40 protein co-expression modules correlated to AD pathological and clinical traits. Module 42 has the strongest correlation to AD pathology and consists of 32 proteins including SMOC1, a predicted driver of network behavior and potential biomarker for AD.

Basic Science and Pathogenesis.

Background: The extracellular amyloid plaques, one of the pathological hallmarks of Alzheimers Disease (AD), are frequently also observed in the cortex of cognitively unimpaired subjects or as co-pathology in other neurodegenerative diseases. Progressive deposition of fibrillar amyloid-β (Aβ) as amyloid plaques for two decades prior disease onset leads to extensive isomerization of Aβ N-terminus. Quantifying the extent of isomerized Aβ can be provide insight into the different stages of amyloidosis in the brain.

Basic Science and Pathogenesis.

Background: A better understanding of the molecular process that drive Alzheimer's disease(AD) are required to develop effective biomarkers and therapies. This includes determining how essential elements like Fe, Cu and Zn are involved in the disease. In the literature there is debate over the role of iron in AD and there are reports of increased, decreased and unchanged levels of Fe in AD brain.

Basic Science and Pathogenesis.

Background: The locus coeruleus (LC), is the first brain region to develop hyperphosphorylated tau (ptau) inclusions in Alzheimer's disease (AD) and undergoes catastrophic degeneration in later stages of the disease. Importantly, the LC is the main noradrenergic nucleus in the brain and source of NE in the forebrain, and dysregulation of the neurotransmitter norepinephrine (NE) is associated with AD symptoms, as its release in the forebrain regulates attention, arousal, stress response, and learning and memory. Moreover, the LC may transmit pathogenic tau to the forebrain via its extensive projections.

Basic Science and Pathogenesis.

Background: In neurodegenerative disease such as Alzheimer's disease and stroke, the brain transitions to pro-inflammatory profile, where microglia and T-cells in the brain have increase inflammatory profiles, along with increased Kv1.3 potassium channel abundance. Pharmacological blockade of Kv1.

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: Alzheimer's Disease (AD) is a pressing global health concern, particularly among the elderly population. Early detection and intervention are vital for effective management. Recent research has identified the Locus Corelulus (LC) as one of the initial sites of pathology in AD, characterized by the degeneration of norepinephrine (NE) producing cells, resulting in cognitive and mood disturbances.

Basic Science and Pathogenesis.

Background: Mediterranean diets may reduce Alzheimer's disease (AD) risk and preserve cognitive function relative to Western diets by protecting against inflammation. In a long term controlled randomized trial of Mediterranean vs. Western diet consumption in cynomolgus macaques (Macaca fascicularis), difficult to conduct in humans, we found significant anti-inflammatory effects of Mediterranean diet on circulating monocyte and brain temporal cortex transcriptional profiles.

Basic Science and Pathogenesis.

Background: Circular RNA represents a distinctive form of noncoding RNA resulting from back-splicing of exons and introns in mRNA. CircRNA has been shown play important roles in neurological diseases, such as Alzheimer's disease (AD). Some recent studies also have demonstrated circRNA is enriched in the mammal brain and differentially altered during AD.

Basic Science and Pathogenesis.

Background: Systemic inflammation plays a pivotal role in many chronic diseases including Alzheimer's disease (AD). Assessing the composition of immune pathways in neurodegenerative diseases can contribute to precision medicine. Using publicly available transcriptomic data, we sought to elucidate transcriptional networks pertinent to inflammatory pathways across brain regions and peripheral blood in AD/mild cognitive impairment (MCI) and peripheral blood in Parkinson's disease (PD).

Basic Science and Pathogenesis.

Background: The microtubule-associated Tau gene (MAPT) undergoes alternative splicing to produce isoforms with varying combinations of microtubule-binding region (MTBR) repeats (3R, 4R). The MTBR is the predominant region that forms paired helical filaments and neurofibrillary tangles fibrils in disease. Alzheimer's disease (AD) is a mixed Tauopathy containing both 3R and 4R isoforms.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is one of the leading causes of death among seniors in the United States and costs the nation over $300 billion each year. Neuropathologically, AD is characterized by neuronal loss, Aβ deposits in the form of plaques, and intracellular aggregates of tau protein in the form of neurofibrillary tangles (NFT). The amyloid cascade hypothesis, one of the leading hypotheses of AD pathogenesis, suggests that Aβ aggregates are directly neurotoxic, triggering downstream neurodegeneration.

Basic Science and Pathogenesis.

Background: Recently, a highly significant brain proteome divergent modules change between Alzheimer's disease (AD) and CRND8 APP transgenic mice has been found. The M42 module is the module in human AD most highly correlated with amyloid and tau pathologies and cognitive decline. Among all proteins in this module, the (SPARC-related modular calcium-binding protein 1) SMOC1 is emerging as a robust biomarker of amyloid deposition in CSF.

Basic Science and Pathogenesis.

Background: Large-scale unbiased proteomic profiling studies have identified a cluster of 31 proteins co-expressed with APP, which is termed the matrisome module 42 (M42). M42 is enriched in AD risk genes, including APOE, with mostly secreted proteins that bind heparin, collectively strongly correlate with the burden of brain pathology and cognitive trajectory, and localize to amyloid plaques in AD brain. For these reasons, M42 has been nominated as a novel therapeutic target for enabling drug discovery by our TREAT-AD Center.

Basic Science and Pathogenesis.

Background: The Apolipoprotein-E (APOE) ε4 gene variant is the strongest genetic risk factor for late-onset Alzheimer's Disease, but is not entirely predictive. Emerging evidence suggests environmental factors contribute to disease etiology, with epidemiological studies associating pesticide exposure with lower cognitive scores. Dichlorodiphenyltrichloroethane (DDT), a pesticide used extensively in the US until 1972, persists in trace amounts due to its long half-life, bioaccumulation, and existing dumpsites.

Basic Science and Pathogenesis.

Background: In Alzheimer's disease (AD), changes in the brain transcriptome are hypothesized to mediate the impact of neuropathology on cognition. Gene expression profiling from postmortem brain tissue is a promising approach to identify causal pathways; however, there are challenges to definitively resolve the upstream pathologic triggers along with the downstream consequences for AD clinical manifestations.

Method: We have functionally dissected 30 AD-associated gene coexpression modules using a cross-species strategy in Drosophila melanogaster models.