Exosomal ALPPL2 and THBS2 as biomarkers for early detection and disease monitoring of pancreatic ductal adenocarcinoma.

Background: Lack of reliable biomarkers for early detection and monitoring contributes to the poor prognosis of pancreatic ductal adenocarcinoma (PDAC), as the current clinical marker, CA19-9, lacks adequate specificity and sensitivity.

Methods: Serum concentrations of ALPPL2-positive and THBS2-positive exosomes were measured using an ExoView assay in two cohorts: a cohort of 219 subjects, including non-disease controls and patients with early- or late-stage PDAC, and a longitudinal cohort of 26 patients with advanced PDAC undergoing treatment.

Results: Exosomal ALPPL2 and THBS2 distinguished non-cancer cases from PDAC with high accuracy; area under the curve (AUC) values = 0.

Upcycling human excrement: the gut microbiome to soil microbiome axis.

Human excrement composting (HEC) is a sustainable strategy for human excrement (HE) management that recycles nutrients and mitigates health risks while reducing reliance on freshwater, fossil fuels, and fertilizers. A mixture of HE and bulking material was collected from 15 composting toilets and composted as 15 biological replicates in modified 19-liter buckets under mesophilic conditions with weekly sampling for one year. We hypothesized that (i) the microbiome of 1 year old compost would resemble that of a soil and/or food and landscape waste compost microbiome more closely than the original HE; and (ii) the human fecal indicators, and , would be undetectable after 52 weeks using qPCR and culturing.

Integration of Genome and Epigenetic Testing in the Diagnostic Evaluation of Developmental Delay: Differentiating Börjeson-Forssman-Lehmann (BFLS) and White-Kernohan (WHIKERS) Syndromes.

: More than 1500 genes are associated with developmental delay and intellectual disability, with variants in many of these genes contributing to a shared phenotype. The discovery of variants of uncertain significance (VUS) found in these genes during genetic testing can lead to ambiguity and further delay in diagnosis and medical management. Phenotyping, additional genetic testing, and functional studies can all add valuable information to help reclassify these variants.

V600E Mutation Has Variable Tumor-Specific Effects on Expression of MAPK Pathway Genes That Could Affect Patient Outcome.

BRAF inhibitors have a 50-70% response rate in melanoma but are less effective for thyroid cancer. Differential response may be from activation or expression of downstream mitogen-activated protein kinase (MAPK) pathway genes. Retrospective analysis compared whole exome and transcriptome sequencing in melanoma and thyroid cancers from April 2019 to October 2023.

Spousal correlations for nine psychiatric disorders are consistent across cultures and persistent over generations.

Trait similarities between spouses are a key factor that shapes the landscape of complex human traits. The driving force behind the spousal correlations can increase the overall prevalence of disorders, influence occurrences of comorbidities and bias estimations of genetic architectures. However, there is a lack of large-scale studies examining cultural differences and generational trends in spousal correlations for psychiatric disorders.

Whole-genome duplications revealed by macronuclear genomes of five rare species of the model ciliates Paramecium.

Paramecium, a group of ciliates with a long evolutionary history, plays essential roles in freshwater ecosystems and has been model for genetic, cellular, and evolutionary studies for over a century. Despite the valuable contributions of genomic resources such as ParameciumDB, genomic data are still mostly limited to species in and near the P. aurelia group.

NK cell-derived extracellular vesicles enhance cytotoxicity and immune cell recruitment in non-small cell lung cancer.

Introduction: Immune-based agents, especially Immune Checkpoint Inhibitors (ICI), are standard of care therapy in non-small cell lung cancers (NSCLC); however, a significant number of patient tumors fail to respond, or develop resistance. While target expression, mutation burden and oncogenic pathways impact responses, an established mechanism contributing to ICI therapy failure is evasion of T-cell responses via downregulation of human leukocyte antigen (HLA). Conversely, natural killer (NK) cells eQector function is enhanced in the absence of HLA, making NK cellular therapies an attractive option for ICI resistant tumors.

Comprehensive tumor-immune profiling reveals mediators of paradoxical immune sensitivity in sarcomatoid renal cell carcinoma.

Renal cell carcinoma with sarcomatoid features (sRCC) is a highly aggressive tumor type yet preferentially responds to immune checkpoint blockade (ICB). To better understand microenvironmental mediators of this paradoxical immune sensitivity, we performed single-cell analyses of human sRCC tumors compared against clear cell RCC (ccRCC), with validation spatially and in bulk transcriptomic datasets totaling over 3,000 RCC tumors. We describe a robust immune network in sRCC using these orthogonal approaches: tumor-infiltrating T cells in sRCC are more activated, and subsequently exhausted, while being enriched for CXCL13 expression.

A spatial transcriptomic atlas of acute neonatal lung injury across development and disease severity.

A molecular understanding of lung organogenesis requires delineation of the timing and regulation of the cellular transitions that ultimately form and support a surface capable of gas exchange. Although the advent of single-cell transcriptomics has allowed for the discovery and identification of transcriptionally distinct cell populations present during lung development, the spatiotemporal dynamics of these transcriptional shifts remain undefined. With imaging-based spatial transcriptomics, we analyzed the gene expression patterns in 17 human infant lungs at varying stages of development and injury, creating a spatial transcriptomic atlas of approximately 1.

ALKBH1 drives tumorigenesis and drug resistance via tRNA decoding reprogramming and codon-biased translation.

Cancer cells utilize codon-biased translation to fuel tumorigenesis and drug resistance, but underlying mechanisms remain poorly understood. Here, we show ALKBH1 is overexpressed in acute myeloid leukemia (AML) and essential for leukemia stem/initiating cell (LSC/LIC) self-renewal and AML development/maintenance, whereas dispensable for normal hematopoiesis. ALKBH1 enhances mitochondrial assembly/function and oxidative phosphorylation (OXPHOS), crucial for AML survival/proliferation and resistance to venetoclax, a potent BCL2 inhibitor and widely-used first-line targeted therapy for AML in clinic.

RNA mA modification: a key regulator in normal and malignant processes.

The dedicated control of gene abundance is essential for both biological and pathological processes in mammals. Multiple layers of gene expression regulation, including transcriptional, post-transcriptional, translational, and post-translational regulation, collectively determine the highly dynamic equilibrium of functional protein abundance. Epigenetic modifications play indispensable roles in fine-tuning gene expression at either DNA, RNA, or protein level.

Therapeutic Plasma Exchange: Current and Emerging Applications to Mitigate Cellular Signaling in Disease.

Therapeutic plasma exchange (TPE) is a blood purification technique which functions to remove pathological plasma constituents such as autoantibodies, inflammatory cytokines, immune complexes, and extracellular vesicles (EVs) that contribute to a range of disease states. In this review, we examine current and emerging indications for TPE across cardiovascular, metabolic, neurological, inflammatory, and oncological diseases. We cover emerging preclinical animal models and new applications, emphasizing the roles of cellular signaling and EV biology in mediating plasma functions, and discuss unique therapeutic "windows of opportunity" offered by TPE.

Comparative genomics of the parasite Trichomonas vaginalis reveals genes involved in spillover from birds to humans.

Trichomonas vaginalis, the causative agent of the venereal disease trichomoniasis, infects men and women globally and is associated with serious outcomes during pregnancy, increased risk of HIV-1 infection, and cancers of the human reproductive tract. Species of trichomonad parasitize a range of hosts in addition to humans, including birds, livestock, and pets. Genetic analysis of trichomonads recovered from columbid birds has provided evidence that they undergo frequent host-switching, and that a spillover event from columbids likely gave rise to T.

A mRNA vaccine encoding for a 60-mer Nipah virus G glycoprotein nanoparticle elicits a robust neutralizing antibodies response against the Nipah virus.

The Nipah virus is a zoonotic pathogen causing encephalitis and acute respiratory illness in humans with very high fatality rates. Here we report a novel messenger RNA vaccine that directly encodes for a nanoparticle displaying 60 head domains of the Nipah virus G (NiV G) glycoprotein that acts as a highly effective antigen. A vaccine encoding for the NiV G nanoparticle elicits high antibody titers against NiV G and a robust neutralizing antibody response with a pseudotyped Nipah virus system.

Unpacking bedaquiline heteroresistance: the importance of intermediate profiles for phenotypic drug susceptibility testing.

Phenotypic drug susceptibility testing (pDST) remains a widely used standard for determination of resistance for several drugs for the complex. Next-generation sequencing technologies can identify heteroresistant populations at low frequencies, but little is known about the impact of heteroresistance on bedaquiline (BDQ) pDST results. We simulated heteroresistance using -generated mutants mixed with the progenitor strain at various percentages (1%-20%) and performed pDST using the BACTEC MGIT 960 platform (1 and 2 µg/mL BDQ concentrations) coupled with EpiCenter TB-eXtended individual drug Susceptibility Testing software.

PepSeq as a highly multiplexed platform for melioidosis antigen discovery and vaccine development.

Introduction: Vaccination aims to prevent or mitigate disease by priming the immune system prior to infection. While historical vaccine development relied mostly on trial-and-error, modern approaches have become more directed. By leveraging our growing understanding of pathogen biology and immune correlates of protection, we can design vaccines in ways that promote protective responses.

Genetic variants influencing liver fat in normal-weight individuals of European ancestry.

Background & Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) occurs across a wide spectrum of body weights, yet the genetic determinants underlying hepatic steatosis in individuals with normal BMI remain underexplored. This study aimed to identify genetic variants associated with liver fat fraction in normal-weight individuals.

Methods: We performed a genome-wide association study (GWAS) using magnetic resonance imaging-proton density fat fraction (MRI-PDFF) data from 10,918 normal-weight participants (BMI <25 kg/m) of European ancestry in the UK Biobank.

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease.

Background: Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis.

Results: We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.

A hypoxia-responsive tRNA-derived small RNA confers renal protection through RNA autophagy.

Transfer RNA-derived small RNAs (tsRNAs or tDRs) perform a range of cellular functions. Here, we showed that tRNA-Asp-GTC-3'tDR, a hypoxia-induced tDR derived from the 3' end of tRNA-Asp-GTC, activated autophagic flux in kidney cells and its silencing blocked autophagic flux. Functional gain-/loss-of-function studies in murine kidney disease models demonstrated a substantial renoprotective function of tRNA-Asp-GTC-3'tDR.

Current and future role of carfilzomib-based quadruplet combinations as therapy for newly diagnosed multiple myeloma.

The treatment of newly diagnosed multiple myeloma (NDMM) has advanced rapidly in recent years, with the standard of care (SOC) now including not only triplet combinations of proteasome inhibitors (PIs), immunomodulatory agents, and steroids but also quadruplet combinations that add the anti-CD38 monoclonal antibodies isatuximab (Isa) or daratumumab (D) to a triplet backbone. In addition to the widely used bortezomib-lenalidomide-dexamethasone (VRd) combination, an alternative triplet option that can be considered is the combination of the second-generation PI carfilzomib (K) with lenalidomide-dexamethasone (KRd). In patients with transplant-eligible NDMM, US treatment guidelines have included the KRd triplet as a recommended regimen and the quadruplet combinations of either Isa-KRd or D-KRd as additional options.

MEDICATION EXPOSURE AND NEURODEGENERATIVE DISEASE RISK ACROSS NATIONAL BIOBANKS.

Unlabelled: Advanced age, genetics, and environmental exposures are leading contributors to the development of neurodegenerative disorders (NDD). In this study, we used data from the UK Biobank (UKB) and the All of Us (AoU) initiative to determine if exposure to specific medications are associated with an increased or decreased risk of NDD, including Alzheimer's (AD), Parkinson's disease (PD), and all-cause dementia (DEM). We investigated the associations between these diseases and prescription drug exposures through an unbiased analysis, assessing both lifetime risk and risk from exposures occurring more than ten years before diagnosis, while also accounting for comorbid conditions.

Autophagy activators normalize aberrant Tau proteostasis and rescue synapses in human familial Alzheimer's disease iPSC-derived cortical organoids.

Alzheimer's disease (AD) is the most common form of dementia worldwide. Despite extensive progress, the cellular and molecular mechanisms of AD remain incompletely understood, partially due to inadequate disease models. To illuminate the earliest changes in hereditary (familial) Alzheimer's disease, we developed an isogenic AD cerebrocortical organoid (CO) model.

The extracellular vesicle transcriptome provides tissue-specific functional genomic annotation relevant to disease susceptibility in obesity.

We characterized circulating extracellular vesicles (EVs) in obese and lean humans, identifying transcriptional cargo differentially expressed in obesity (277 unique genes; false discovery rate < 10%). Since circulating EVs may have broad origin, we compared this obesity EV transcriptome with expression from human visceral-adipose-tissue-derived EVs from freshly collected and cultured biopsies from the same obese individuals, observing high concordance. Using a comprehensive set of adipose-specific epigenomic and chromatin conformation assays, we found that the differentially expressed transcripts from the EVs were those regulated in adipose by body mass index-associated SNPs (p < 5 × 108) from a large-scale genome-wide association study (GWAS).