👤 W Gary Anderson

We investigated the relationship between cerebrospinal fluid (CSF) and plasma biomarkers of inflammation, neurodegeneration, and neurocognitive performance in people with HIV (PWH), using longitudinal samples from two previously published cohorts: ACTG A5090 (virally suppressed on antiretroviral therapy, ART) and A736 (ART-naïve or failing). We analyzed paired CSF and plasma samples, as well as 7-domain standardized neurocognitive test scores, at baseline and 24 weeks. Biomarkers included markers of inflammation (e.g., TNF-α, IL-6, IP-10) and neurodegeneration (e.g., NFL, p-Tau217, Aβ42), which were quantified via high-sensitivity immunoassays. Associations with cognition were tested using regression, mediation, and interaction models. Cross-sectional analyses revealed nominal associations between inflammatory markers and cognitive performance, with plasma IL-6 and IP-10 at baseline, and CSF TNFα at week 24 showing the strongest correlations (p < 0.05, uncorrected); however, none survived correction for multiple comparisons. Conversely, higher CSF Aβ42 and plasma BDNF were positively associated with memory and executive function. Longitudinally, biomarker changes did not significantly predict change in global cognition (ΔNPZ-8); the strongest trend (p-Tau217, ρ = -0.12, p = 0.38) was not statistically significant, and multivariate models failed to identify robust predictors (R These results suggest a potential role of CSF TNFα in mediating the neurocognitive effects of HIV and highlight compartment-specific inflammatory dynamics. Plasma TNFα, GFAP, and NFL may serve as peripheral indicators of CNS pathology, though with only moderate concordance. Astrocyte-tau interactions require cautious interpretation pending replication in larger cohorts. Show less

Unimolecular triagonists drive substantial weight loss in patients with obesity by engaging the glucagon-like peptide 1 receptor (GLP-1R) and glucose dependent insulinotropic polypeptide receptor (GIPR) to reduce food intake (FI) and the hepatic glucagon receptor (GcgR) to enhance energy expenditure (EE). However, their development has been challenged by deleterious cardiovascular (CV) effects, including increased heart rate (HR), elongated QTc, and arrhythmia mediated by GcgR agonism. GLP-1R mono-agonists on the other hand improve both obesity and CV outcomes with negligible effects on EE. We sought to imbue peptide GLP-1R agonists with an EE enhancing effect by combining them with ectopic GLP-1R expression and agonism in hepatocytes. We used an adeno-associated virus (AAV) to induce the expression of a functional, liver-specific GLP-1R combined with traditional peptide agonist treatment to drive greater body weight loss via reduced energy intake and increased energy expenditure. Agonism of the ectopic GLP-1R with either semaglutide, a cAMP biased GLP-1R analogue (NNC5840), or a dual GLP-1R/GIPR agonist in wild-type (WT) diet induced obese (DIO) mice led to enhanced EE and improved weight loss compared to peptide agonist treatment alone. This represents a novel mechanism for achieving poly-pharmacology to treat obesity. Show less

Lithium deficiency may contribute to Alzheimer disease pathogenesis. No randomized clinical trial has examined lithium's effects on cognition, neuroimaging, and plasma biomarkers in mild cognitive impairment (MCI). To examine the feasibility, safety, and preliminary efficacy of lithium carbonate for delaying cognitive decline in older adults with MCI. This single-site, randomized, double-blind, placebo-controlled pilot feasibility clinical trial was conducted at the University of Pittsburgh School of Medicine from February 2018 to August 2024, with 2-year follow-up. Analyses used linear mixed-effects models in the intention-to-treat population. Adults aged 60 years or older with MCI who were free of major psychiatric or neurologic illness and contraindications to lithium were included. Of 170 individuals assessed, 83 were randomized (41 lithium vs 42 placebo), with 80 starting treatment (41 lithium vs 39 placebo). Data were analyzed from August 2024 to December 2025. Daily low-dose lithium carbonate or placebo for 2 years. Six prespecified coprimary outcomes included cognitive performance (California Verbal Learning Test-II [CVLT-II] delayed recall, Brief Visuospatial Memory Test-Revised, preclinical Alzheimer cognitive composite), hippocampal volume, cortical gray matter volume, and brain-derived neurotrophic factor. Among 80 participants (mean [SD] age, lithium: 72.93 [8.77] years; placebo: 71.22 [6.47] years; 56% female), none of the 6 coprimary outcomes met the prespecified significance threshold. Mean (SD) CVLT-II baseline scores were 7.95 (3.4) for lithium and 7.90 (3.9) for placebo; scores declined 1.42 points annually in the placebo group vs 0.73 points in the lithium group (difference, 0.69 points per year; 95% CI, 0.01-1.37; P = .05). Hippocampal and cortical volumes showed a decline over time in both groups, but no significant treatment × time interactions. Serious adverse events occurred in 12 of 41 (29%) receiving lithium vs 9 of 39 (23%) receiving placebo; none were definitely treatment related. One death occurred in the placebo group. Common adverse events included increased creatinine levels (12 of 41 [29%] with lithium vs 12 of 39 [31%] with placebo), diarrhea (12 of 41 [29%] vs 6 of 39 [15%]), tiredness (12 of 41 [29%] vs 6 of 39 [15%]), and tremor occurrence (10 of 41 [24%] vs 6 of 39 [15%]). This pilot randomized clinical trial established feasibility, confirmed safety and tolerability, and generated effect size estimates for future trials of low-dose lithium in MCI. None of the coprimary outcomes met the prespecified significance threshold. ClinicalTrials.gov Identifier: NCT03185208. Show less

Lecanemab binds "protofibrils," which are poorly characterized in human brain. It is unknown why lecanemab caused fewer amyloid-related imaging abnormalities (ARIAs) than other antibodies in trials. The apolipoprotein E (APOE) ε4 allele increases ARIA risk through unknown mechanisms. Equilibrium binding constants (K Lecanemab and aducanumab had indistinguishable preference for "protofibrils." Antibody preference for plaque-enriched versus CAA-enriched Aβ did not differ in soluble extracts or by IF staining but differed slightly in insoluble extracts. The APOE ε4 allele was associated with more soluble antibody-accessible Aβ. Lecanemab's binding target is similar to other antibodies'. Differences in antibody preference for plaque versus CAA Aβ may not explain differences in ARIA with edema rates. Show less

Evidence linking modifiable risk factors to age-related brain diseases, such as dementia, stroke, and depression (DSD), is robust, yet limited regarding long-term change in modifiable risk factors in association with these conditions, particularly in real-world settings. This study aimed to assess whether longitudinal changes in modifiable brain health risk factors were associated with reduced risk of DSD. We analyzed UK Biobank data (2006-2019) from 155,469 participants with general practitioner-linked data. The Brain Care Score (BCS) assesses 12 modifiable risk factors across lifestyle, physical, and social-emotional domains. Longitudinal BCS measurements were derived from repeated general practitioner (GP)-recorded measurements. Changes in the BCS were modeled using linear mixed-effects models, and associations with DSD were evaluated using multivariable Cox models, adjusting for baseline BCS and genetic risk (polygenic risk scores for stroke and depression, and APOE genotype for dementia). Among 155,469 participants (median age = 51 years, 54.3% women), the median annual BCS change was 0.14 (Q1-Q3 = 0.008-0.30) points over a median follow-up of 12.3 years (Q1-Q3 = 11.5-13.1 years). Over time, 82.1% improved their BCS, 12.9% remained stable, and 5.0% worsened over time. Each 1-point annual increase in the BCS was associated with 4% lower risk of incident age-related brain diseases (hazard ratio [HR] = 0.96, 95% confidence interval [CI] = 0.95-0.97). In this large real-world cohort, improvements in modifiable risk factor profiles were associated with lower incidence of DSD, regardless of genetic risk or baseline BCS. Our results provide important information for communicating with patients about the brain health benefits of improving risk factor profiles. ANN NEUROL 2026;99:1113-1123. Show less

The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; however, the mechanism of action of these loci remains to be elucidated. To molecularly characterize these childhood obesity loci, we sought to determine the underlying causal variants and the corresponding effector genes within diverse cellular contexts. Integrating childhood obesity GWAS summary statistics with our existing 3D genomic datasets for 57 human cell types, consisting of high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq, and RNA-seq, we applied stratified LD score regression and calculated the proportion of genome-wide SNP heritability attributable to cell type-specific features, revealing pancreatic alpha cell enrichment as the most statistically significant. Subsequent chromatin contact-based fine-mapping was carried out for genome-wide significant childhood obesity loci and their linkage disequilibrium proxies to implicate effector genes, yielded the most abundant number of candidate variants and target genes at the Show less

We tested whether genetically proxied non-high-density lipoprotein cholesterol (non-HDL-C)-lowering drug targets reduce risk of all-cause dementia. We included 1,091,775 individuals from three prospective general population cohorts with individual-level data and two consortia with summary-level data. We selected genetic variants within HMGCR, NPC1L1, PCSK9, ANGPTL4, LPL, and CETP associated with non-HDL-C. These variants were used as exposures in Cox regression and one- and two-sample Mendelian randomization. Results were meta-analyzed. Meta-analysis of one-sample Mendelian randomization odds ratios per 1 mmol/L (39 mg/dL) lower non-HDL-C was 0.24 (0.18-0.31) for HMGCR, 0.18 (0.12-0.25) for NPC1L1, 0.97 (0.70-1.35) for PCSK9, 1.66 (0.52-5.36) for ANGPTL4, 1.41 (0.63-3.16) for LPL, and 0.30 (0.26-0.34) for CETP. Cox regression and two-sample Mendelian randomization results were mostly directionally consistent. Genetic lowering of non-HDL cholesterol via HMGCR, NPC1L1, and CETP reduces the risk of dementia. This reflects the effect of lifelong differences in non-HDL cholesterol on risk of dementia. Variants in HMGCR, NPC1L1, and CETP reduce the risk of dementia via non-high-density lipoprotein cholesterol (non-HDL-C). An effect of PCSK9, ANGPTL4, and LPL variants on dementia risk cannot be excluded. This reflects the effect of lifelong lower non-HDL-C on risk of dementia. Show less

The interplay between intracellular and intravascular lipolysis is crucial for maintaining circulating lipid levels and systemic energy homeostasis. Adipose triglyceride lipase (ATGL) and lipoprotein lipase (LPL), the primary triglyceride (TG) lipases responsible for these two spatially separate processes, are highly expressed in adipose tissue. Yet the mechanisms underlying their coordinated regulation remain undetermined. Here, we demonstrate that genetic ablation of G0S2, a specific inhibitory protein of ATGL, completely abolished diet-induced hypertriglyceridemia and significantly attenuated atherogenesis in mice. These effects were attributable to enhanced whole-body TG clearance, not altered hepatic TG secretion. Specifically, G0S2 deletion increased circulating LPL concentration and activity, predominantly through LPL production from white adipose tissue (WAT). Strikingly, transplantation of G0S2-deficient WAT normalized plasma TG levels in mice with hypertriglyceridemia. In conjunction with improved insulin sensitivity and decreased ANGPTL4 expression, the absence of G0S2 enhanced the stability of LPL protein in adipocytes, a phenomenon that could be reversed upon ATGL inhibition. Collectively, these findings highlight the pivotal role of adipocyte G0S2 in regulating both intracellular and intravascular lipolysis, and the possibility of targeting G0S2 as a viable pharmacological approach to reducing levels of circulating TGs. Show less

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder that increases risk for premature coronary artery disease and has accessible and effective interventions. The Dutch lipid clinic network is currently the most used diagnostic criterion; however, genetic sequencing provides a definitive diagnosis of FH. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify individuals who were genotype positive for FH. Participants were recruited from 3 geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; and Jacksonville, FL). Participants underwent Exome+ sequencing (dba Helix, San Mateo, CA) and return of results for specific genetic findings in At the time of the study, 84 413 participants were enrolled in the Tapestry study. Annotation and interpretation of all variants in genes for FH resulted in the identification of 419 likely pathogenic and pathogenic variants (prevalence, 0.50%), which included 116 Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have familial hypercholesterolemia. URL: https://www.clinicaltrials.gov; Unique identifier: NCT05212428. Show less

Forward genetic screening is a powerful approach to assign functions to genes and can be used to elucidate the many genes whose functions remain unknown. A key step in forward genetic screening is mapping: identification of the gene causing the phenotype. Existing mapping methods use a bioinformatic mapping-by-sequencing approach based on allelic frequency calculations that often identify large genomic regions which contain an intractable number of candidate genes for testing. Here, we describe WheresWalker, a modern mapping-by-sequencing algorithm that identifies a mutation-containing interval and then supports positional cloning to shrink the interval, which drastically reduces the number of potential candidates, allowing for extremely rapid mutation identification. We validated this method using mutants from a forward genetic mutagenesis screen in zebrafish for modifiers of ApoB-lipoprotein metabolism. WheresWalker correctly mapped and identified novel zebrafish mutations in mttp, apobb.1, and mia2 genes, as well as a previously published mutation in maize. Further, we used WheresWalker to identify a previously unappreciated ApoB-lipoprotein metabolism-modifying locus, slc3a2a. Show less

APC, the core scaffold of the Wnt destruction complex, targets the transcriptional co-activator β-catenin for proteolysis. There is no convincing evidence that APC directs degradation of other substrates. Using a reconstituted cytosolic extract-based system and complementary in vivo and cellular assays, we show that SREBP2, the master regulator of cholesterol biosynthesis, is a direct APC-AXIN1 substrate. APC-dependent SREBP2 degradation is conserved in Show less

Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia. Show less

L-asparaginase is essential in treating pediatric acute lymphoblastic leukemia (ALL) but is limited by hypersensitivity reactions in up to 70% of patients, leading to severe, dose-limiting complications and compromised event-free survival. This study conducted a genome-wide association study (GWAS) in a discovery cohort of 221 pediatric cancer patients who experienced l-asparaginase-induced hypersensitivity reactions (≥CTCAE grade 2) and 705 controls without hypersensitivity despite equivalent exposure. Results were replicated in an independent cohort of 41 cases and 139 controls. Significant associations were identified between hypersensitivity and four genes crucial for amino acid stress response: CYP1B1 (rs59569490; odds ratio [OR]  =  8.5; 95% confidence interval [CI], 3.9-18.5; p  =  1.5 × 10 The cumulative incidence of these large effect variants highlights their significance for the identification of patients at high risk of l-asparaginase-induced hypersensitivity. Successfully identifying patients at increased risk of hypersensitivity reactions can inform personalized treatment strategies and limit these harmful dose-limiting reactions in pediatric ALL. Show less

The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; however, the mechanism of action of these loci remains to be elucidated. To molecularly characterize these childhood obesity loci we sought to determine the underlying causal variants and the corresponding effector genes within diverse cellular contexts. Integrating childhood obesity GWAS summary statistics with our existing 3D genomic datasets for 57 human cell types, consisting of high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq, and RNA-seq, we applied stratified LD score regression and calculated the proportion of genome-wide SNP heritability attributable to cell type-specific features, revealing pancreatic alpha cell enrichment as the most statistically significant. Subsequent chromatin contact-based fine-mapping was carried out for genome-wide significant childhood obesity loci and their linkage disequilibrium proxies to implicate effector genes, yielded the most abundant number of candidate variants and target genes at the Show less

Non-Alcoholic Fatty Liver Disease (NAFLD) prevalence is rising and can lead to detrimental health outcomes such as Non-Alcoholic Steatohepatitis (NASH), cirrhosis, and cancer. Recent studies have indicated that Cytochrome P450 2B6 (CYP2B6) is an anti-obesity CYP in humans and mice. Cyp2b-null mice are diet-induced obese, and human CYP2B6-transgenic (hCYP2B6-Tg) mice reverse the obesity or diabetes progression, but with increased liver triglyceride accumulation in association with an increase of several oxylipins. Notably, 9-hydroxyoctadecadienoic acid (9-HODE) produced from linoleic acid (LA, 18:2, ω-6) is the most prominent of these and 9-hydroxyoctadecatrienoic acid (9-HOTrE) from alpha-linolenic acid (ALA, 18:3, ω-3) is the most preferentially produced when controlling for substrate concentrations in vitro. Transactivation assays indicate that 9-HODE and 9-HOTrE activate PPARα and PPARγ. In Seahorse assays performed in HepG2 cells, 9-HOTrE increased spare respiratory capacity, slightly decreased palmitate metabolism, and increased non-glycolytic acidification in a manner consistent with slightly increased glutamine utilization; however, 9-HODE exhibited no effect on metabolism. Both compounds increased triglyceride and pyruvate concentrations, most strongly by 9-HOTrE, consistent with increased spare respiratory capacity. qPCR analysis revealed several perturbations in fatty acid uptake and metabolism gene expression. 9-HODE increased expression of CD36, FASN, PPARγ, and FoxA2 that are involved in lipid uptake and production. 9-HOTrE decreased ANGPTL4 expression and increased FASN expression consistent with increased fatty acid uptake, fatty acid production, and AMPK activation. Our findings support the hypothesis that 9-HODE and 9-HOTrE promote steatosis, but through different mechanisms as 9-HODE is directly involved in fatty acid uptake and synthesis; 9-HOTrE weakly inhibits mitochondrial fatty acid metabolism while increasing glutamine use. Show less

To execute a large-scale, decentralized, clinical-grade whole exome sequencing study, coined Tapestry, for clinical practice, research discovery, and genomic education. Between July 1, 2020, and May 31, 2024, we invited 1,287,608 adult Mayo Clinic patients to participate in Tapestry. Of those contacted, 114,673 patients were consented and 98,222 (65.2% women) are currently enrolled: 62,495 (63.6%) were recruited from Minnesota-, 18,353 (18.7%) from Florida- and 17,374 (17.7%) from Arizona-based practices. Saliva from participants was used to extract DNA, and whole exome sequencing plus ∼300,000 single nucleotide polymorphisms (ie, Exome+ assay) were sequenced by a clinical lab. Results for the Centers for Disease Control and Prevention Tier 1 genes (eg, hereditary breast, ovarian cancer syndrome: BRCA1/2; Lynch syndrome: MLH1, MSH2, MSH6, PMS2, and EPCAM; and familial hypercholesterolemia: APOB, LDLR, PCSK9, and LDLRAP1) were interpreted and entered into the electronic health record. The median age of participants was 59.1 years and ∼11% were from racial/ethnic groups under-represented in research. One thousand eight hundred nineteen (1.9%) participants had actionable pathogenic or likely pathogenic variants (50.0% BRCA1/2, 28.4% familial hypercholesterolemia, and 22.2% Lynch syndrome). Positive results were communicated by genetic counselors who educated patients and providers. Thus far, 62,758 patients' Exome+ assays are stored for research, and the Tapestry Data Access Committee has received 118 requests from investigators, of which 82 have been approved, resulting in the delivery of 1,117,410 Exome+ assays to researchers. A large, decentralized, clinical Exome+ assay study in a tertiary medical center detects actionable germline variants, educates patients as well as providers, and offers access to big data for discovery that advances human health. clinicaltrials.gov Identifier: NCT05212428. Show less

Zebrafish are an ideal model organism to study lipid metabolism and to elucidate the molecular underpinnings of human lipid-associated disorders. Unlike murine models, to which various standardized high lipid diets such as a high-cholesterol diet (HCD) are available, there has yet to be a uniformly adopted zebrafish HCD protocol. In this study, we have developed an improved HCD protocol and thoroughly tested its impact on zebrafish lipid deposition and lipoprotein regulation in a dose- and time-dependent manner. The diet stability, reproducibility, and fish palatability were also validated. Fish fed HCD developed hypercholesterolemia as indicated by significantly elevated ApoB-containing lipoproteins (ApoB-LPs) and increased plasma levels of cholesterol and cholesterol esters. Feeding of the HCD to larvae for 8 days produced hepatic steatosis that became more stable and sever after 1 day of fasting and was associated with an opaque liver phenotype (dark under transmitted light). Unlike larvae, adult fish fed HCD for 14 days followed by a 3-day fast did not develop a stable fatty liver phenotype, though the fish had higher ApoB-LP levels in plasma and an upregulated lipogenesis gene fasn in adipose tissue. In conclusion, our HCD zebrafish protocol represents an effective and reliable approach for studying the temporal characteristics of the physiological and biochemical responses to high levels of dietary cholesterol and provides insights into the mechanisms that may underlie fatty liver disease. Show less

Interleukin (IL)-22 is a potential therapeutic protein for the treatment of metabolic diseases such as obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease due to its involvement in multiple cellular pathways and observed hepatoprotective effects. The short serum half-life of IL-22 has previously limited its use in clinical applications; however, the development of mRNA-lipid nanoparticle (LNP) technology offers a novel therapeutic approach that uses a host-generated IL-22 fusion protein. In the present study, the effects of administration of an mRNA-LNP encoding IL-22 on metabolic disease parameters was investigated in various mouse models. C57BL/6NCrl mice were used to confirm mouse serum albumin (MSA)-IL-22 protein expression prior to assessments in C57BL/6NTac and CETP/ApoB transgenic mouse models of metabolic disease. Mice were fed either regular chow or a modified amylin liver nonalcoholic steatohepatitis-inducing diet prior to receiving either LNP-encapsulated MSA-IL-22 or MSA mRNA via intravenous or intramuscular injection. Metabolic markers were monitored for the duration of the experiments, and postmortem histology assessment and analysis of metabolic gene expression pathways were performed. MSA-IL-22 was detectable for ≥8 days following administration. Improvements in body weight, lipid metabolism, glucose metabolism, and lipogenic and fibrotic marker gene expression in the liver were observed in the MSA-IL-22-treated mice, and these effects were shown to be durable. These results support the application of mRNA-encoded IL-22 as a promising treatment strategy for metabolic syndrome and associated comorbidities in human populations. Show less

How distinct mesodermal lineages - extraembryonic, lateral, intermediate, paraxial and axial - are specified from pluripotent epiblast during gastrulation is a longstanding open question. By investigating AXIN, a negative regulator of the WNT/β-catenin pathway, we have uncovered new roles for WNT signaling in the determination of mesodermal fates. We undertook complementary approaches to dissect the role of WNT signaling that augmented a detailed analysis of Show less

A recent paper concluded that cholesteryl ester transfer protein (CETP) inhibition may be a viable target to treat dementia, based on human genetic evidence of a protective effect of target inhibition on risk of Lewy body and Parkinson's dementia. Alzheimer's disease, which is by far the most prevalent cause of dementia (around 80% of all dementia cases) was not included as an outcome. Evidence shows CETP inhibition is unlikely to affect Alzheimer's risk and may even potentially modestly increase risk. There is also little evidence to support an effect of CETP inhibition on all-cause or vascular dementia. Thus, CETP inhibition is unlikely to be a viable target to treat the most prevalent causes of dementia. Show less

G-quadruplexes (G4s) are secondary DNA and RNA structures stabilized by positive cations in a central channel formed by stacked tetrads of Hoogsteen base-paired guanines. G4s form from G-rich sequences across the genome, whose biased distribution in regulatory regions points towards a gene-regulatory role. G4s can themselves be regulated by helicases, such as DHX36 (aliases: G4R1 and RHAU), which possess the necessary activity to resolve these stable structures. G4s have been shown to both positively and negatively regulate gene expression when stabilized by ligands, or through the loss of helicase activity. Using Show less

Futibatinib, a covalently-binding inhibitor of fibroblast growth factor receptor (FGFR)1-4 gained approval for the treatment of refractory, advanced intrahepatic cholangiocarcinoma (iCCA) harboring an FGFR2 fusion/other rearrangement. An integrated analysis was performed to evaluate safety and provide guidance on the management of futibatinib-associated adverse events (AEs) in patients with unresectable/metastatic tumors, including iCCA. Data from three global phase I or II studies of futibatinib (NCT02052778; JapicCTI-142552) were pooled. AEs were graded per NCI CTCAE v4.03, where applicable. Safety was analyzed for patients receiving any futibatinib starting dose (overall population) and in those receiving the approved starting dose of 20 mg once every day. In total, 469 patients with one of 33 known tumor types were analyzed, including 318 patients who received futibatinib 20 mg every day. AEs of clinical interest (AECI; any grade/grade ≥3) in the overall population included hyperphosphatemia (82%/19%), nail disorders (27%/1%), hepatic AEs (27%/11%), stomatitis (19%/3%), palmar-plantar erythrodysesthesia syndrome (PPES; 13%/3%), rash (9%/0%), retinal disorders (8%/0%), and cataract (4%/1%). Median time to onset of grade ≥3 AECIs ranged from 9 days (hyperphosphatemia) to 125 days (cataract). Grade ≥3 hyperphosphatemia, hepatic AEs, PPES, and nail disorders resolved to grade ≤2 within a median of 7, 7, 8, and 28 days, respectively. Discontinuations due to treatment-related AEs were rare (2%), and no treatment-related deaths occurred. AE management included phosphate-lowering medication and dose adjustments. Futibatinib showed a consistent and manageable safety profile across patients with various tumor types. AECIs were mostly reversible with appropriate clinical management. Show less

Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade lymphoma with no standard therapy. Nine asymptomatic patients treated with a first-in-human, neoantigen DNA vaccine experienced no dose limiting toxicities (primary endpoint, NCT01209871). All patients achieve stable disease or better, with one minor response, and median time to progression of 72+ months. Post-vaccine single-cell transcriptomics reveal dichotomous antitumor responses, with reduced tumor B-cells (tracked by unique B cell receptor) and their survival pathways, but no change in clonal plasma cells. Downregulation of human leukocyte antigen (HLA) class II molecules and paradoxical upregulation of insulin-like growth factor (IGF) by the latter suggest resistance mechanisms. Vaccine therapy activates and expands bone marrow T-cell clonotypes, and functional neoantigen-specific responses (secondary endpoint), but not co-inhibitory pathways or Treg, and reduces protumoral signaling by myeloid cells, suggesting favorable perturbation of the tumor immune microenvironment. Future strategies may require combinations of vaccines with agents targeting plasma cell subpopulations, or blockade of IGF-1 signaling or myeloid cell checkpoints. Show less

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL. Show less

The correct labeling of a genetic variant as pathogenic is important as breeding decisions based on incorrect DNA tests can lead to the unwarranted exclusion of animals, potentially compromising the long-term health of a population. In human medicine, the American college of Medical Genetics (ACMG) guidelines provide a framework for variant classification. This study aims to apply these guidelines to six genetic variants associated with hypertrophic cardiomyopathy (HCM) in certain cat breeds and to propose a modified criterion for variant classification. Genetic samples were sourced from five cat breeds: Maine Coon, Sphynx, Ragdoll, Devon Rex, and British Short- and Longhair. Allele frequencies were determined, and in the subset with phenotypes available, odds ratios to determine the association with HCM were calculated. Two variants, MYBPC3:c.91G > C [A31P] and MYBPC3:c.2453C > T [R818W], were designated as pathogenic. One variant, MYH7:c.5647G > A [E1883K], was found likely pathogenic, while the remaining three were labeled as variants of unknown significance. Routine genetic testing is advised solely for the MYBPC3:c.91G > C [A31P] in the Maine Coon and MYBPC3:c.2453C > T [R818W] in the Ragdoll breed. The human ACMG guidelines serve as a suitable foundational tool to ascertain which variants to include; however, refining them for application in veterinary medicine might be beneficial. Show less

Lysosomal storage disorders (LSDs) are a genetically and clinically diverse group of diseases characterized by lysosomal dysfunction. Batten disease is a family of severe LSDs primarily impacting the central nervous system. Here we show that AF38469, a small molecule inhibitor of sortilin, improves lysosomal and glial pathology across multiple LSD models. Live-cell imaging and comparative transcriptomics demonstrates that the transcription factor EB (TFEB), an upstream regulator of lysosomal biogenesis, is activated upon treatment with AF38469. Utilizing CLN2 and CLN3 Batten disease mouse models, we performed a short-term efficacy study and show that treatment with AF38469 prevents the accumulation of lysosomal storage material and the development of neuroinflammation, key disease associated pathologies. Tremor phenotypes, an early behavioral phenotype in the CLN2 disease model, were also completely rescued. These findings reveal sortilin inhibition as a novel and highly efficacious therapeutic modality for the treatment of multiple forms of Batten disease. Show less

Artificial intelligence (AI) models applied to 12-lead ECG waveforms can predict atrial fibrillation (AF), a heritable and morbid arrhythmia. However, the factors forming the basis of risk predictions from AI models are usually not well understood. We hypothesized that there might be a genetic basis for an AI algorithm for predicting the 5-year risk of new-onset AF using 12-lead ECGs (ECG-AI)-based risk estimates. We applied a validated ECG-AI model for predicting incident AF to ECGs from 39 986 UK Biobank participants without AF. We then performed a genome-wide association study (GWAS) of the predicted AF risk and compared it with an AF GWAS and a GWAS of risk estimates from a clinical variable model. In the ECG-AI GWAS, we identified 3 signals ( Predicted AF risk from an ECG-AI model is influenced by genetic variation implicating sarcomeric, ion channel and body height pathways. ECG-AI models may identify individuals at risk for disease via specific biological pathways. Show less

Fibroblast growth factors (FGFs) are key regulators of the remarkable regenerative capacity of the liver. Mice lacking FGF receptors 1 and 2 (Fgfr1 and Fgfr2) in hepatocytes are hypersensitive to cytotoxic injury during liver regeneration. Using these mice as a model for impaired liver regeneration, we identified a critical role for the ubiquitin ligase Uhrf2 in protecting hepatocytes from bile acid accumulation during liver regeneration. During regeneration after partial hepatectomy, Show less

Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade B-cell lymphoma of the bone marrow. Despite a cumulative risk of progression, there is no approved therapy for patients in the asymptomatic phase. We conducted a first-in-human clinical trial of a novel therapeutic DNA idiotype neoantigen vaccine in nine patients with asymptomatic LPL. Treatment was well tolerated with no dose limiting toxicities. One patient achieved a minor response, and all remaining patients experienced stable disease, with median time to disease progression of 61+ months. Direct interrogation of the tumor microenvironment by single-cell transcriptome analysis revealed an unexpected dichotomous antitumor response, with significantly reduced numbers of clonal tumor mature B-cells, tracked by their unique BCR, and downregulation of genes involved in signaling pathways critical for B-cell survival post-vaccine, but no change in clonal plasma cell subpopulations. Downregulation of HLA class II molecule expression suggested intrinsic resistance by tumor plasma cell subpopulations and cell-cell interaction analyses predicted paradoxical upregulation of IGF signaling post vaccine by plasma cell, but not mature B-cell subpopulations, suggesting a potential mechanism of acquired resistance. Vaccine therapy induced dynamic changes in bone marrow T-cells, including upregulation of signaling pathways involved in T-cell activation, expansion of T-cell clonotypes, increased T-cell clonal diversity, and functional tumor antigen-specific cytokine production, with little change in co-inhibitory pathways or Treg. Vaccine therapy also globally altered cell-cell communication networks across various bone marrow cell types and was associated with reduction of protumoral signaling by myeloid cells, principally non-classical monocytes. These results suggest that this prototype neoantigen vaccine favorably perturbed the tumor immune microenvironment, resulting in reduction of clonal tumor mature B-cell, but not plasma cell subpopulations. Future strategies to improve clinical efficacy may require combinations of neoantigen vaccines with agents which specifically target LPL plasma cell subpopulations, or enable blockade of IGF-1 signaling or myeloid cell checkpoints. Show less