👤 BonDurant Lucas

The number of people living with Alzheimer's disease (AD) is increasing worldwide as populations age. A hallmark of AD is the accumulation of amyloid-β (Aβ) in the brain, and pathways regulating amyloid-β precursor protein (AβPP) processing are of major interest for disease-modifying and preventive strategies such as exercise. Regular exercise is associated with a reduced risk of AD, potentially through limiting Aβ accumulation, yet the underlying cellular mechanisms remain unclear. Acute bouts of exercise induce the release of circulating signalling molecules that may influence AβPP metabolism. To investigate the effects of exercise on AβPP processing, human induced pluripotent stem cell (iPSC)-derived neurons and astrocytes were treated with serum collected before and immediately after high-intensity exercise. Both healthy control and familial AD (PSEN1 A246E) neurons and astrocytes were independently exposed to 10 % pre- or post-exercise serum for 30 min, after which markers of AβPP processing were quantified. Post-exercise serum contained increased amounts of Lacate, BDNF, IL-6, sAβPPα, and Aβ₁-₄₂, and reduced neprilysin activity (p < 0.05). Treatment with post-exercise serum acutely elevated ADAM10 activity in neurons, which was replicated by spiking lactate in pre-exercise serum. sAβPPα was also increased in PSEN1 neurons following post exercise serum treatment with increased Aβ₁-₄₂ secretion in both PSEN1 neurons and astrocytes (p < 0.05). These findings demonstrate that human post-exercise serum can modulate AβPP processing in iPSC-derived neural cells. This supports the concept that circulating exercise-induced factors can influence neuronal pathways relevant to AD pathology. Show less

Mild traumatic brain injury can disrupt brain function and is associated with high morbidity and healthcare utilization. While many individuals recover from mild traumatic brain injury, a significant proportion experience long-term sequelae, collectively known as post-concussion syndrome. Symptoms of post-concussion syndrome include headache, dizziness, insomnia, cognitive processing difficulties and mental health disturbances. The disease burden is augmented by the current lack of objective measures to accurately predict long-term symptoms and deficits, providing an opportunity to utilize biomarkers in biofluids. A large proportion of available diagnostic clinical tools are subjective symptom scores. This review aims to explore current fluid biomarkers, grouped by clinical symptoms. With the available literature, we have discovered a wide range of fluid biomarkers that have been investigated for predicting post-traumatic headache, including neuropeptides; sleep disturbances, such as cortisol and melatonin; vestibular disturbances, including interleukin-6 and neurone-specific enolase; and vomiting, such as S100B. Along with physical symptoms, biomarkers investigated for predicting cognitive disturbances include inflammatory markers, S100B, neurofilament light chain, tau, microRNA and hormones. Biomarkers to predict mental health disturbances may include brain-derived neurotrophic factor, tau and cortisol. By utilizing such biomarkers, there is capacity to adopt a personalized medicine approach to facilitate early interventions for those most in need while also identifying individuals with a favourable prognosis who can safely return to their normal activities. Show less

Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy that lacks reliable biomarkers to guide treatment decisions. Effective prognostic tools are needed to improve its clinical management. We conducted a comprehensive proteomic analysis on 115 PDA patient samples with matched adjacent normal tissue. A 20-protein diagnostic panel was identified (LGALS1, ANXA2, LGALS3BP, CTSD, S100P, COL12A1, SFN, THBS2, CTHRC1, THBS1, SERPINB5, LAMC2, POSTN, CEACAM6, CTSE, PLEC, PKM, S100A11, TAGLN2, ALDOA). Consensus clustering analysis identified four prognostic proteomic subtypes. Subtypes with poorer prognoses exhibited upregulation of neutrophil degranulation, extracellular matrix remodeling, focal adhesion, Mesenchymal Epithelial Transition, collagen formation, and PI3K-Akt-mTOR-related pathways, indicating a predominance of basal-like and activated stromal features. In tumors with homologous recombination deficiency or Catalogue of Somatic Mutations in Cancer Signature-3, several immune-related proteins were enriched. An 18-protein (PURB, SDCBP2, CD2BP2, GALM, SERPINA3, OAS3, FAN1, ZPR1, KRT2, NUDT2, SMNDC1, SERPINA4, CUTA, WDR36, POSTN, CLEC11A, PEX14, and PI4KA) risk score was developed and validated using multicox regression analyses with LASSO regularization. The risk score demonstrated independent prognostic significance for overall survival and recurrence, and was validated in an independent proteomic dataset generated using a different proteomic technology. This study thus introduces four novel prognostic PDA subtypes, and an 18-protein risk score validated in an independent dataset, which shows promise for improving survival prediction and could serve as a valuable tool for personalized treatment guidance. The findings from this study have significant implications for the future of pancreatic cancer management. By identifying a 20-protein panel with diagnostic and screening potential, this research provides a foundation for developing early detection tools for PDA, an aggressive cancer with limited treatment options. The classification of PDA into four proteomic subtypes with distinct prognostic outcomes paves the way for subtype-specific therapeutic approaches, allowing clinicians to better stratify patients based on their risk profiles. Additionally, the validated 18-protein risk score, which enhances survival prediction and operates independently of existing clinical variables, represents a promising tool for personalized prognostic assessments. Incorporating these proteomic-based biomarkers into clinical practice could improve diagnostic accuracy, guide individualized treatment decisions, and ultimately enhance patient outcomes in PDA. This study underscores the potential of proteomic profiling to improve cancer treatment by providing targeted, actionable insights into tumor biology. Show less

Approximately half of hypertrophic cardiomyopathy (HCM) patients lack a precise genetic diagnosis. The likelihood of identifying clinically relevant variants increased over time. In this study, we conducted a gene-centric reanalysis of exome data of 200 HCM cases 5 years after the initial analysis. This reanalysis prioritized genes with a matched HCM entry in the OMIM database and recently emerging HCM-associated genes gathered using a text mining-based literature review. Further classification of the identified genes and variants was performed using the Clinical Genome Resource (ClinGen) resource and American College of Medical Genetics and Genomics (ACMG) guidelines to assess the robustness of gene-disease association and the clinical actionability of the prioritized variants. As expected, the majority of patients carried variants in Our study revealed that no variants were found in the Show less

Adipogenesis is a complex process controlled by intrinsic and extrinsic factors that regulate preadipocyte proliferation, adipogenic capacity and maturation of metabolic function. Here we show that insulin and IGF-1 receptors are essential for mature adipocyte survival and that deletion of both IR and IGF1R specifically in fat using a tamoxifen inducible-AdipoQ-Cre (Ai-DKO) leads to rapid and severe loss of adipocytes in all depots, associated with a metabolic syndrome characterized by hypertriglyceridemia, hyperglycemia, hyperinsulinemia, fatty liver, and pancreatic beta cell proliferation. In this model, this pathological phenotype reverses over a few weeks, in large part, due to preadipocyte proliferation and adipose tissue regeneration. Incubation of preadipocytes with serum from the Ai-DKO mice in vitro stimulates cell proliferation, and this effect can be mimicked by conditioned media from liver slices of Ai-DKO mice, but not by media of cultured Ai-DKO adipocytes, indicating a hepatic origin of the growth factor. Proteomic analysis of serum reveals apolipoprotein C3 (APOC3), a protein secreted by liver, as one of the most upregulated proteins in the Ai-DKO mice. In vitro, purified and delipidated APOC3 stimulates preadipocyte proliferation, however, knockdown of hepatic APOC3 in vivo in Ai-DKO mice is not sufficient to block adipose regeneration. Thus, lipodystrophy is associated with presence of increased preadipocyte-stimulating growth factors in serum. Our study indicates that APOC3 is one contributing factor to preadipocyte proliferation, however, other still-unidentified circulating growth factors are also likely present in Ai-DKO mice. Identification of these factors may provide a new approach to regulation of adipose mass in health and disease. Show less

Successful vaccination strategies offer the potential for lifelong immunity against infectious diseases and cancer. There has been increased attention regarding the limited translation of some preclinical findings generated using specific pathogen-free (SPF) laboratory mice to humans. One potential reason for the difference between preclinical and clinical findings lies in maturation status of the immune system at the time of challenge. In this study, we used a "dirty" mouse model, where SPF laboratory mice were cohoused (CoH) with pet store mice to permit microbe transfer and immune system maturation, to investigate the priming of a naive T cell response after vaccination with a peptide subunit mixed with polyinosinic-polycytidylic acid and agonistic anti-CD40 mAb. Although this vaccination platform induced robust antitumor immunity in SPF mice, it failed to do so in microbially experienced CoH mice. Subsequent investigation revealed that despite similar numbers of Ag-specific naive CD4 and CD8 T cell precursors, the expansion, differentiation, and recall responses of these CD4 and CD8 T cell populations in CoH mice were significantly reduced compared with SPF mice after vaccination. Evaluation of the dendritic cell compartment revealed reduced IL-27p28 expression by XCR1+ dendritic cells from CoH mice after vaccination, correlating with reduced T cell expansion. Importantly, administration of recombinant IL-27:EBI3 complex to CoH mice shortly after vaccination significantly boosted Ag-specific CD8 and CD4 T cell expansion, further implicating the defect to be T cell extrinsic. Collectively, our data show the potential limitation of exclusive use of SPF mice when testing vaccine efficacy. Show less

The role of omega-3 fatty acid in multiple sclerosis (MS) susceptibility is unclear. To determine whether fish/seafood intake or genetic factors that regulate omega-3 fatty acids levels are associated with MS risk. We examined the association of fish and shrimp consumption and 13 tag single nucleotide polymorphisms (SNPs) in Consuming fish/seafood at least once a week or at least once a month with regular fish oil use was associated with 44% reduced odds of MS/CIS (adjusted OR = 0.56; 95% CI = 0.41-0.76; These findings suggest that omega-3 fatty acid intake may be an important modifiable risk factor for MS. This is consistent with the other known health benefits of fish consumption and complementary genetic studies supporting a key role for omega-3 regulation. Show less

The cholesterol-sensing nuclear receptor liver X receptor (LXR) and the glucose-sensing transcription factor carbohydrate responsive element-binding protein (ChREBP) are central players in regulating glucose and lipid metabolism in the liver. More knowledge of their mechanistic interplay is needed to understand their role in pathological conditions like fatty liver disease and insulin resistance. In the current study, LXR and ChREBP co-occupancy was examined by analyzing ChIP-seq datasets from mice livers. LXR and ChREBP interaction was determined by Co-immunoprecipitation (CoIP) and their transactivity was assessed by real-time quantitative polymerase chain reaction (qPCR) of target genes and gene reporter assays. Chromatin binding capacity was determined by ChIP-qPCR assays. Our data show that LXRα and ChREBPα interact physically and show a high co-occupancy at regulatory regions in the mouse genome. LXRα co-activates ChREBPα and regulates ChREBP-specific target genes in vitro and in vivo. This co-activation is dependent on functional recognition elements for ChREBP but not for LXR, indicating that ChREBPα recruits LXRα to chromatin in Show less

Melanocortin 4 receptor (MC4R) plays a key role in regulation of appetite activated by its main ligand α-melanocyte-stimulating hormone (α-MSH) in both central and peripheral targets. α-MSH also binds to circulating immunoglobulins (Igs) but the functional significance of such immune complexes (ICs) in MC4R signaling in normal and pathological conditions of altered appetite has remained unknown. To address this question, we analyzed plasma levels, affinity kinetics, and binding epitopes of α-MSH-reactive IgG extracted from plasma samples of female patients with hyperphagic obesity, anorexia nervosa, bulimia nervosa, binge-eating disorder, and healthy controls. Ability of α-MSH/IgG IC to bind and activate human MC4R were studied in vitro and to influence feeding behavior in vivo in rodents. We found that α-MSH-reactive IgG were low in obese but increased in anorectic and bulimic patients and displayed different epitope and kinetics of IC formation. Importantly, while α-MSH/IgG IC from all subjects were binding and activating MC4R, the receptor binding affinity was decreased in obesity. Additionally, α-MSH/IgG IC had lower MC4R-mediated cAMP activation threshold as compared with α-MSH alone in all but not obese subjects. Furthermore, the cellular internalization rate of α-MSH/IgG IC by MC4R-expressing cells was decreased in obese but increased in patients with anorexia nervosa. Moreover, IgG from obese patients prevented central anorexigenic effect of α-MSH. These findings reveal that MC4R is physiologically activated by IC formed by α-MSH/IgG and that different levels and molecular properties of α-MSH-reactive IgG underlie biological activity of such IC relevant to altered appetite in obesity and eating disorders. Show less

Transcriptome-wide association studies (TWAS) have recently gained great attention due to their ability to prioritize complex trait-associated genes and promote potential therapeutics development for complex human diseases. TWAS integrates genotypic data with expression quantitative trait loci (eQTLs) to predict genetically regulated gene expression components and associates predictions with a trait of interest. As such, TWAS can prioritize genes whose differential expressions contribute to the trait of interest and provide mechanistic explanation of complex trait(s). Tissue-specific eQTL information grants TWAS the ability to perform association analysis on tissues whose gene expression profiles are otherwise hard to obtain, such as liver and heart. However, as eQTLs are tissue context-dependent, whether and how the tissue-specificity of eQTLs influences TWAS gene prioritization has not been fully investigated. In this study, we addressed this question by adopting two distinct TWAS methods, PrediXcan and UTMOST, which assume single tissue and integrative tissue effects of eQTLs, respectively. Thirty-eight baseline laboratory traits in 4,360 antiretroviral treatment-naïve individuals from the AIDS Clinical Trials Group (ACTG) studies comprised the input dataset for TWAS. We performed TWAS in a tissue-specific manner and obtained a total of 430 significant gene-trait associations (q-value < 0.05) across multiple tissues. Single tissue-based analysis by PrediXcan contributed 116 of the 430 associations including 64 unique gene-trait pairs in 28 tissues. Integrative tissue-based analysis by UTMOST found the other 314 significant associations that include 50 unique gene-trait pairs across all 44 tissues. Both analyses were able to replicate some associations identified in past variant-based genome-wide association studies (GWAS), such as high-density lipoprotein (HDL) and CETP (PrediXcan, q-value = 3.2e-16). Both analyses also identified novel associations. Moreover, single tissue-based and integrative tissuebased analysis shared 11 of 103 unique gene-trait pairs, for example, PSRC1-low-density lipoprotein (PrediXcan's lowest q-value = 8.5e-06; UTMOST's lowest q-value = 1.8e-05). This study suggests that single tissue-based analysis may have performed better at discovering gene-trait associations when combining results from all tissues. Integrative tissue-based analysis was better at prioritizing genes in multiple tissues and in trait-related tissue. Additional exploration is needed to confirm this conclusion. Finally, although single tissue-based and integrative tissue-based analysis shared significant novel discoveries, tissue context-dependency of eQTLs impacted TWAS gene prioritization. This study provides preliminary data to support continued work on tissue contextdependency of eQTL studies and TWAS. Show less

The high resistance against current therapies found in non-small-cell lung cancer (NSCLC) has been associated to cancer stem-like cells (CSCs), a population for which the identification of targets and biomarkers is still under development. In this study, primary cultures from early-stage NSCLC patients were established, using sphere-forming assays for CSC enrichment and adherent conditions for the control counterparts. Patient-derived tumorspheres showed self-renewal and unlimited exponential growth potentials, resistance against chemotherapeutic agents, invasion and differentiation capacities in vitro, and superior tumorigenic potential in vivo. Using quantitative PCR, gene expression profiles were analyzed and NANOG, NOTCH3, CD44, CDKN1A, SNAI1, and ITGA6 were selected to distinguish tumorspheres from adherent cells. Immunoblot and immunofluorescence analyses confirmed that proteins encoded by these genes were consistently increased in tumorspheres from adenocarcinoma patients and showed differential localization and expression patterns. The prognostic role of genes significantly overexpressed in tumorspheres was evaluated in a NSCLC cohort (N = 661) from The Cancer Genome Atlas. Based on a Cox regression analysis, CDKN1A, SNAI1, and ITGA6 were found to be associated with prognosis and used to calculate a gene expression score, named CSC score. Kaplan-Meier survival analysis showed that patients with high CSC score have shorter overall survival (OS) in the entire cohort [37.7 vs. 60.4 months (mo), p = 0.001] and the adenocarcinoma subcohort [36.6 vs. 53.5 mo, p = 0.003], but not in the squamous cell carcinoma one. Multivariate analysis indicated that this gene expression score is an independent biomarker of prognosis for OS in both the entire cohort [hazard ratio (HR): 1.498; 95% confidence interval (CI), 1.167-1.922; p = 0.001] and the adenocarcinoma subcohort [HR: 1.869; 95% CI, 1.275-2.738; p = 0.001]. This score was also analyzed in an independent cohort of 114 adenocarcinoma patients, confirming its prognostic value [42.90 vs. not reached (NR) mo, p = 0.020]. In conclusion, our findings provide relevant prognostic information for lung adenocarcinoma patients and the basis for developing novel therapies. Further studies are required to identify suitable markers and targets for lung squamous cell carcinoma patients. Show less

Cell surface glycans, such as heparan sulfate (HS), are increasingly identified as co-regulators of growth factor signaling in early embryonic development; therefore, chemical tailoring of HS activity within the cellular glycocalyx of stem cells offers an opportunity to control their differentiation. The growth factors FGF2 and BMP4 are involved in mediating the exit of murine embryonic stem cells (mESCs) from their pluripotent state and their differentiation toward mesodermal cell types, respectively. Here, we report a method for remodeling the glycocalyx of mutant Ext1 Show less