👤 Shubhroz Gill

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

Metabolic-dysfunction associated steatohepatitis (MASH) arises from sustained triglyceride overload of the intestine-liver axis, yet current therapies rarely coordinate intestinal lipid entry with hepatic triglyceride disposal. Here we identify a phenolic-acid fraction as a dual-compartment metabolic modulator that couples intestinal lipase inhibition to CPT1α-PPARα-dependent hepatic β-oxidation across species. Across species, we investigated the kinetics and metabolic actions of a phenolic fraction (PhAM) using recombinant lipase systems, epithelial transport assays, hepatocyte models, pharmacokinetics, diet-induced metabolic disease paradigms, quantitative histopathology, and a 24-week randomized placebo-controlled clinical trial. PhAM selectively suppresses pancreatic and intestinal lipases non-competitively, lowering V_max with minimal K_m change, resembling some features of orlistat, but via a distinct, non-covalent mechanism. In Caco-2 monolayers and ex vivo loops, it reduces apical-to-basolateral fatty-acid flux, depletes intracellular triglycerides, and limits luminal-to-plasma lipid transfer. PhAM is orally bioavailable, with measurable plasma exposure and prolonged intestinal residence. Under high-fat feeding, it increases fecal fat loss, attenuates post-lipid-load triglyceride excursions, and lowers hepatic triglycerides without altering ApoB secretion. Its triglyceride-lowering effect requires CPT1α-dependent mitochondrial import and PPARα activation, elevates β-hydroxybutyrate, and induces oxidative genes while sparing lipogenesis. In chronic MASH, PhAM reduces steatosis, ballooning, inflammation, and metabolic-dysfunction associated steatotic liver disease (MASLD) Activity Score. A 24-week clinical subgroup, defined by ultrasound and transaminase enrichment, showed dose-responsive improvements in ultrasonographic steatosis and metabolic biomarkers. Collectively, these findings define PhAM as a phenolic-acid-based agent that aligns intestinal lipid restriction with hepatic oxidative unloading, offering a mechanistically coherent framework for potentially addressing steatotic liver disease-associated metabolic features. Show less

Periventricular nodular heterotopia (PVNH) is a common malformation of cortical development. We describe a distinctive imaging phenotype characterized by bilateral small heterotopic nodules of grey matter in the frontal periventricular regions, with an overview of the clinical, imaging, and genetic features. Investigators reviewed available brain MRI studies, clinical records and genetic findings of 32 individuals with bilateral frontal PVNH, ascertained from multiple centres between 1996 and 2021. The imaging phenotype consists of multiple, small, bilateral nodules of PVNH maximal along the frontal horns of the lateral ventricles. Frontal PVNH was associated with heterogeneous, often subtle, additional brain malformations in 72 % (23/32) individuals. The clinical phenotype was variable and included mild focal epilepsy in 7/32 and mild-moderate cognitive impairment or developmental delay in 13/32. Microarray was normal in 13/16 and exome or genome sequencing normal in 8/13 where testing was performed. A genetic diagnosis was achieved in seven patients; pathogenic chromosome deletions of 7q11.23 and 7p22.1, pathogenic intragenic variants in KANSL1, STXBP1 and MAP1B (mother-daughter pair), and a combined 13q12.12 deletion (containing SACS) and an intragenic SACS variant. Bilateral frontal PVNH has a variable clinical phenotype, but generally milder sequelae than other forms of bilateral PVNH. A genetic diagnosis was made by chromosome microarray alone in 13 % or by exome or genome sequencing in 38 % where access to testing was available, with no recurrent genetic cause being found. Our PVNH cohort data suggest that PVNH could be classified in three main groups: FLNA-associated "classic" bilateral frontocentral PVNH, posterior/infrasylvian PVNH and this third pattern of bilateral frontal PVNH, accounting for ∼10 % of all cases of PVNH. Show less

Clinical trials have shown that interleukin-6 (IL-6) signaling inhibitors reduce lipoprotein(a) [Lp(a)] levels, though the relevance of this reduction to atherosclerotic cardiovascular disease (ASCVD) risk is uncertain. We leveraged Mendelian randomization (MR) to investigate the extent to which Lp(a) reduction mediates the effects of IL-6 signaling inhibition on ASCVD. IL-6 signaling inhibition was proxied by the IL6R variant p.Asp358Ala and scaled to C-reactive protein (CRP) levels. Genetic associations with Lp(a) were obtained from UK Biobank (n = 343,681). Outcomes included large-artery atherosclerotic stroke (LAAS: 6399 cases), carotid plaque (29,760 cases), and coronary artery disease (CAD: 181,522 cases). MR analyses estimated the association of IL-6 signaling inhibition with Lp(a) and ASCVD, and we quantified the proportion of the IL-6-ASCVD association mediated by Lp(a). Individual-level analyses tested whether effects of IL-6 signaling inhibition on Lp(a) and CAD were amplified in carriers of Lp(a)-raising variants. Genetically proxied IL-6 signaling inhibition modestly reduced Lp(a) (-3.01 mg/dL per 1-ln(CRP) reduction, 95% CI -4.79, -1.23) and protected against all ASCVD outcomes (ORs: 0.34-0.69). Lp(a) mediated only a small proportion of the IL-6-ASCVD association (range: 1.3%-4.8%). In carriers of Lp(a)-raising variants, the IL-6-Lp(a) association was stronger (-9.8 mg/dL, 95% CI -14.6, -5.1; p These findings suggest that Lp(a) minimally mediates and does not modify the cardiovascular benefits of IL-6 signaling inhibition, supporting these targets as independent and complementary for ASCVD. The amplified IL-6-Lp(a) association in carriers of Lp(a)-raising variants warrants replication. Show less

Lipoprotein(a) (Lp(a)) is a highly atherogenic lipoprotein and the target of investigational therapies. Using a Mendelian randomization study design, we aimed to clarify associations between genetically predicted Lp(a) levels and cerebrovascular disease outcomes and related phenotypes. We obtained genetic associations with Lp(a) levels ( Genetically predicted Lp(a) levels associated with significantly increased risk of all-cause ischemic stroke (odds ratio [OR], 1.04 [95% CI, 1.02-1.07], Elevated Lp(a) is primarily associated with ischemic stroke due to large artery atherosclerosis, while showing no link to cerebral small vessel disease. These findings support prioritization of patients with atherosclerotic cerebrovascular disease in Lp(a)-lowering stroke prevention trials. Show less

Neuroplasticity, the brain's capacity to adapt structurally and functionally in response to experiences, is a key factor in recovery from neurological conditions. Growing interest has focused on physical and emotional interventions as potential modulators of neuroplastic processes. A narrative review was conducted using a structured PubMed search of articles published between January 2018 and March 2023. Studies were included if they examined physical activity, emotional well-being, or cognitive training, with outcomes relevant to neuroplasticity. Publications outside these parameters, non-English studies, and case reports were excluded. Twenty-seven articles met the inclusion criteria. The literature described a range of possible influences. Exercise was frequently linked with markers such as brain-derived neurotrophic factor (BDNF) and synaptic plasticity. Emotional interventions, including stress reduction and mindfulness, were reported to have variable effects on neural adaptation. Cognitive training was discussed in relation to functional recovery in conditions such as stroke and traumatic brain injury (TBI). Findings across studies were heterogeneous, and conclusions were limited by differences in study designs and outcome measures. Current evidence suggests that both physical and emotional interventions may influence neuroplasticity, though results are not uniform. The diversity of methodologies and measured outcomes indicates that more rigorous and standardized research is needed. While the reviewed literature points to potential benefits of physical and emotional interventions in modulating neuroplasticity, evidence remains preliminary. Further high-quality longitudinal studies are required to clarify their role in neurological rehabilitation and clinical care. Show less

Therapies targeting the LPL (lipoprotein lipase) pathway are under development for cardiometabolic disease. Insights into their efficacy-both alone and in combination with existing lipid-lowering therapies-modes of action, and safety of these agents are essential to inform clinical development. Using Mendelian randomization, we aimed to (1) evaluate efficacy, (2) explore shared mechanisms, (3) assess additive effects with approved lipid-lowering drugs, and (4) identify secondary indications and potential adverse effects. We selected triglyceride-lowering genetic variants located in the genes encoding ANGPTL3 (angiopoietin-like 3), ANGPTL4 (angiopoietin-like 4), APOC3 (apolipoprotein C3), and LPL and conducted drug target Mendelian randomization on primary outcomes including coronary artery disease and type 2 diabetes, and secondary outcomes, including apolipoprotein B, waist-to-hip ratio, body mass index, and 233 metabolic biomarkers. We conducted interaction Mendelian randomization analyses in 488 139 UK Biobank participants to test the effect of combination therapy targeting the LPL and LDLR (low-density lipoprotein receptor) pathways. Finally, we investigated potential secondary indications and adverse effects by leveraging genetic association data on 1204 disease end points. Genetically predicted triglyceride lowering through the perturbation of LPL pathway activation targets ANGPTL4, APOC3, and LPL was associated with a lower risk of coronary artery disease and type 2 diabetes and lower apolipoprotein B. Genetically predicted triglyceride lowering through ANGPTL4 was associated with a lower waist-to-hip ratio, suggestive of a favorable body fat distribution. There was no evidence of a multiplicative interaction between genetically proxied perturbation of ANGPTL4, APOC3, and LPL and that of HMGCR (HMG-CoA reductase) and PCSK9 (proprotein convertase subtilisin/kexin type 9) on coronary artery disease and type 2 diabetes, consistent with additive effects. Finally, associations of genetically predicted LPL pathway targeting were supportive of the broad safety of these targets. Our findings provide genetic evidence supporting the efficacy and safety of LPL pathway activation therapies for the prevention of coronary artery disease and type 2 diabetes, alone or in combination with statins or PCSK9 inhibitors. Show less

Cirrhosis and hepatocellular carcinoma (HCC) are long-term complications of chronic liver disease (CLD). In this large multi-ancestry genome-wide association study of all-cause cirrhosis (35,481 cases, 2.36M controls) and HCC (6,680 cases, 1.76M controls), we identified 27 loci associated with cirrhosis (10 novel) and 11 with HCC (three novel). Three novel cirrhosis loci were replicated in independent cohorts (e.g. Show less

RNA interference therapies targeting liver expression of the gene proprotein convertase subtilisin/kexin type 9 (PCSK9) lower LDL-cholesterol (LDL-C) and apolipoprotein B (apoB) levels. As opposed to monoclonal antibodies, which neutralise PCSK9 circulating protein, their effect on atherosclerotic cardiovascular disease (ASCVD) outcomes is unknown. We used genetic variants in the PCSK9 locus influencing PCSK9 function or gene expression in the liver to determine whether antibodies against PCSK9 and RNA interference therapies could have comparable effects on ASCVD. We performed genome-wide genotyping and RNA sequencing of 504 human liver sample and identified a genetic variant (rs472495) explaining 5.6% of liver PCSK9 gene expression to mimic lifelong RNA interference of PCSK9. We used the PCSK9 R46L variant, known to alter PCSK9 function, to model antibody-based PCSK9 inhibition. For each standard deviation decrease in apoB levels, both variants were similarly associated with coronary artery disease risk: (odds ratio [OR] = 0.40, 95% confidence interval [CI]: 0.31-0.51, P = 3.7e-13 for rs472495 which affects liver PCSK9 expression) and (OR = 0.48, 95% CI: 0.43-0.55, P = 1.3e-28 for R46L which affects protein levels). Comparable effects of these two genetic inhibition approaches were observed for aortic stenosis, heart failure, ischemic stroke, Type 2 diabetes and glycemic traits as well as non-alcoholic fatty liver disease and liver enzymes. For a given reduction in apoB levels, genetically predicted reductions in PCSK9 function (mimicking PCSK9 neutralizing antibodies) and liver PCSK9 gene expression levels (mimicking PCSK9 RNA interference) were comparably associated with a lower risk of coronary artery disease. These genetic data suggest that LDL-C/apoB reductions may provide cardiovascular benefits, regardless of how PCSK9 function is inhibited. Show less

Apolipoprotein C-III (APOC3) inhibitors are approved for hypertriglyceridaemia. Genetic evidence suggests that APOC3 inhibition may also prevent coronary artery disease (CAD), but mechanisms remain unclear. To clarify how APOC3 inhibition could prevent CAD, we performed two-step cis-Mendelian randomization using genetic variants in the Remnant cholesterol best explains the mechanism through which APOC3 inhibition could prevent CAD. APOC3 inhibition may influence fasting remnant cholesterol to a greater extent than non-fasting remnant cholesterol. People with high levels of remnant cholesterol could benefit from APOC3 inhibition. Show less

Large observational and Mendelian randomization (MR) studies have demonstrated a strong association between both elevated LDL cholesterol (LDL-c) and triglycerides (TG) with risk of aortic stenosis (AS), although randomized trials showed no benefit of statins for AS. It consequently remains uncertain whether lipid-lowering therapies have a role to prevent or treat AS. We used a drug-target MR approach to investigate the genetically predicted effect of lipid-lowering therapies on risk of AS. We collected summary statistics for LDL-c, TG, and AS from genome-wide association studies (GWAS) including 1 320 016, 1 253 277, and 412 181 European participants from the Global Lipids Genetics Consortium and FinnGen study, respectively. We identified genetic proxies for PCSK9 inhibitors, statins, bempedoic acid, and ezetimibe as single nucleotide polymorphisms in or within 200 kb of the target genes (PCSK9, HMGCR, ACLY, and NPC1L1, respectively), which were also significantly associated with LDL-c at P < 5 × 10-8. We used a similar approach to identify genetic proxies for the TG-lowering agents fenofibrates, APOC3 inhibitors, and ANGPTL3 inhibitors using the target genes PPARA, APOC3, and ANGPTL3, respectively. Inverse variance-weighted was the primary analysis method. Sensitivity analyses included weighted median, weighted mode, and MR-Egger, followed by the outlier-exclusion approaches MR-PRESSO and Cook's distance. We also performed multivariable analyses to evaluate whether the predicted effect of PCSK9 inhibition may be mediated by lipoprotein(a). We performed replication and negative control analyses using GWAS of AS and height including 653 867 and 408 112 participants, respectively. Genetically proxied PCSK9 inhibition was significantly associated with reduced AS risk (odds ratio [OR] 0.61, 95% confidence interval [CI] 0.52-0.72, P < 0.0001) on main, replication, and all sensitivity analyses. Genetically proxied ezetimibe (OR 0.49, 95% CI 0.31-0.78, P = 0.003), bempedoic acid (OR 0.0054, 95% CI 0.0002-0.12, P = 0.0009), and statins (OR 0.61, 95% CI 0.46-0.81, P = 0.0006) were similarly associated with reduced AS risk, although the latter were not significant on replication analyses. Amongst the TG-lowering agents, genetically proxied APOC3 inhibition was associated with reduced AS risk (OR 0.78, 95% CI 0.70-0.88, P < 0.0001), but fenofibrate (OR 0.64, 95% CI 0.09-4.53, P = 0.65) and ANGPTL3 inhibitors (OR 1.05, 95% CI 0.77-1.43, P = 0.74) were not. Genetically proxied lipid-lowering therapies are significantly associated with reduced risk of AS. Early initiation and sustained administration of lipid-lowering therapies may prevent AS progression and warrants further research in the clinical trial setting. Show less

Identification of drug-repurposing targets with genetic and biological support is an economically and temporally efficient strategy for improving the treatment of diseases. We employed a cross-disciplinary approach to identify potential therapeutics for the prevention of metabolic-dysfunction-associated steatotic liver disease (MASLD) in at-risk individuals by using humans as a model organism. We identified 212 putative candidate genes associated with MASLD by using data from a large multi-ancestry genetic association study, of which 158 (74.5%) were previously unreported. From this set, we identified 57 genes that encode for druggable protein targets and for which the effects of increasing genetically predicted gene expression on MASLD risk align with the function of that drug on the protein target. We then used We then evaluated these potential targets for evidence of efficacy by using Mendelian randomization, pathway analysis, and protein structural modeling. Through these approaches, we present compelling evidence to suggest that the activation of FADS1 by icosapent ethyl, as well as S1PR2 by fingolimod, could be a promising therapeutic strategy for MASLD prevention. Show less

Identification of drug-repurposing targets with genetic and biological support is an economically and temporally efficient strategy for improving treatment of diseases. We employed a cross-disciplinary approach to identify potential treatments for metabolic dysfunction associated steatotic liver disease (MASLD) using humans as a model organism. We identified 212 putative causal genes associated with MASLD using data from a large multi-ancestry genetic association study, of which 158 (74.5%) are novel. From this set we identified 57 genes that encode for druggable protein targets, and where the effects of increasing genetically predicted gene expression on MASLD risk align with the function of that drug on the protein target. These potential targets were then evaluated for evidence of efficacy using Mendelian randomization, pathway analysis, and protein structural modeling. Using these approaches, we present compelling evidence to suggest activation of Show less

Osteoglophonic dysplasia (OGD) is a rare skeletal disorder caused by certain variants in FGFR1. The FGFR1 gene encodes a receptor vital for osteogenesis in the axial and craniofacial skeleton. Key OGD features include craniosynostosis, craniofacial dysmorphism, impacted teeth, rhizomelic shortening, and nonossifying fibromas. Patients may have hypophosphatemia due to high FGF23 levels. We report two OGD patients with the c.1141T > C FGFR1 variant [p.(Cys381Arg)], initially diagnosed with Pfeiffer syndrome. Both showed classic symptoms as well as signs not previously reported, including elevated frontal temperature and overlapping toes. This report emphasizes distinguishing OGD from similar disorders and expanding the clinical phenotype. Show less

We report eight children with de novo pathogenic DNA variants in chromatin-related genes: MORC2, CHD7, KANSL1, KMT2D, ZMYND11, HIST1HIE, EP300, and KMT2B. All children experienced infection or vaccine-provoked neuroregression or abrupt-onset neuropsychiatric syndromes. Most had delayed development (n = 6) before the first regression, and four had immune deficiency or autoimmunity (n = 4). At a mean age of 4 years 2 months (range 1-8 years), symptoms included infection-provoked autistic/language regression (n = 6), cognitive decline (n = 3), gait deterioration (n = 3), or abrupt-onset anxiety, obsessive-compulsive disorder, and/or tics (n = 5). Three children had ongoing infection-provoked deteriorations. Six children benefited from intravenous immunoglobulin (n = 3) or antibiotics (n = 4). Ribonucleic acid expression of the eight chromatin genes was similar in neuronal, glial, and peripheral leukocytes, unlike non-chromatin neurodevelopmental genes, which have predominantly neuronal expression. These cases demonstrate the role of chromatin dysregulation in autistic regression and abrupt-onset neuropsychiatric syndromes, potentially related to brain and immune gene dysregulation. 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

The presence of epithelial-mesenchymal transition (EMT) in breast cancer (BC) cells has been linked to worse prognosis and may influence response to systemic treatment. We explored the effect of EMT in tumor samples of patients with metastatic BC on disease-free interval and overall survival in those patients receiving eribulin or cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). Key inclusion criteria included available archived primary BC tissue and, where available, matched metastatic biopsy. Patients received eribulin and/or a CDK4/6i in the metastatic setting. Specimens were assessed for biomarkers by immunohistochemistry (CDH1, AE1/3, VIM, CDH2, ZEB1, pSMAD2, and SMAD4) and gene expression by droplet digital polymerase chain reaction ( Between 2002 and 2020, 127 patients were included (95 early-stage disease at diagnosis with metastatic relapse, 32 de novo metastatic disease). In metastatic samples, presence of ZEB1 overexpression was associated with shorter time to recurrence (48.1 months shorter; We demonstrate in our exploratory study that biomarkers involved in the process of EMT could have a prognostic impact in a cohort of patients with BC uniformly treated and with long-term follow-up. Genes known to be involved in EMT were associated with improved eribulin efficacy, while suggesting a poorer outcome with CDK4/6i. Show less

Preclinical and genetic studies suggest that impaired glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling worsens glycemic control. The relationship between GIPR signaling and the risk of cancers influenced by impaired glucose homeostasis is unclear. We examined the association of a variant in Show less

The study aimed to discover novel genetic loci for atrial fibrillation (AF), explore the shared genetic etiologies between AF and other cardiovascular and cardiometabolic traits, and uncover AF pathogenesis using Mendelian randomization analysis. We conducted a genome-wide association study meta-analysis including 109,787 AF cases and 1,165,920 controls of European ancestry and identified 215 loci, among which 91 were novel. We performed Genomic Structural Equation Modeling analysis between AF and four cardiovascular comorbidities (coronary artery disease, ischemic stroke, heart failure, and vneous thromboembolism) and found 189 loci shared across these diseases as well as a universal genetic locus shared by atherosclerotic outcomes (i.e., rs1537373 near This genome-wide association study and trans-omic Mendelian randomization analysis provides insights into disease risk prediction, pathophysiology and downstream sequelae. Show less

Though immune checkpoint inhibition has recently shown encouraging clinical efficacy in mesothelioma, most patients do not respond. Combining immune checkpoint inhibition with radiotherapy presents an attractive option for improving treatment responses owing to the various immunomodulatory effects of radiation on tumors. However, the ideal dosing and scheduling of combined treatment remains elusive, as it is poorly studied in mesothelioma. The present study characterizes the dose- and time-dependent changes to expression of various immune markers and cytokines important to antitumor responses following irradiation of mesothelioma cell lines. Two murine (AB1, AE17) and two human (BYE, JU77) mesothelioma cell lines were treated with titrated gamma-radiation doses (1-8 Gy) and the expression of MHC class-I, MHC class-II and PD-L1 was measured over a series of post-irradiation timepoints (1-72 hours) by flow cytometry. Levels of cytokines IL-1α, IL-1β, IL-6, IL-10, IL-12p70, IL-17A, IL-23, IL-27, MCP-1, IFN-β, IFN-γ, TNF-α, and GM-CSF were measured by multiplex immunoassay in murine cell lines following 8 Gy radiation. Following irradiation, a dose-dependent upregulation of MHC-I and PD-L1 was observed on three of the four cell lines studied to varying extents. For all cell lines, the increase in marker expression was most pronounced 72 hours after radiation. At this timepoint, increases in levels of cytokines IFN-β, MCP-1 and IL-6 were observed following irradiation with 8 Gy in AB1 but not AE17, reflecting patterns in marker expression. Overall, this study establishes the dose- and time-dependent changes in immune marker expression of commonly studied mesothelioma cell lines following radiation and will inform future study into optimal dosing and scheduling of combined radiotherapy and immune checkpoint inhibition for mesothelioma. Show less

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder, with mutations in hundreds of genes contributing to its risk. Herein, we studied lymphoblastoid cell lines (LCLs) from children diagnosed with autistic disorder ( Show less

Koolen-de Vries syndrome (KdVS) is a genetic condition caused by 17q21.31 microdeletions or pathogenic variants in KANSL1. Affected patients most commonly exhibit some or all of the following: neonatal hypotonia, developmental impairment, facial dysmorphic features, and congenital malformations. Epilepsy occurs in approximately half, often with phenotypes on the epilepsyaphasia spectrum. We describe six children with KdVS found to have continuous spike-wave in sleep (CSWS) on EEG, four of whom were diagnosed with epileptic encephalopathy with CSWS and two with Landau-Kleffner syndrome. When compared with other children with CSWS on EEG, patients with KdVS may present at slightly later ages and with a longer interval between seizure diagnosis and identification of CSWS. There is no clear best treatment for children with CSWS, but two patients in our cohort were trialed on a variation of the ketogenic diet, and both reported clinical improvement. In one of the patients, the response was dramatic, and CSWS recurred when weaning of the ketogenic diet was attempted. Based on our findings, an EEG capturing a prolonged period of sleep should be arranged in any child with KdVS presenting with developmental regression or plateau, particularly if they have a preceding history of seizures. Show less

Repetitive low-level blast exposure is one of the major occupational health concerns among US military service members and law enforcement. This study seeks to identify gene expression using microRNA and RNA sequencing in whole-blood samples from experienced breachers and unexposed controls. We performed experimental RNA sequencing using Illumina’s HiSeq 2500 Sequencing System, and microRNA analysis using NanoString Technology nCounter miRNA expression panel in whole-blood total RNA samples from 15 experienced breachers and 14 age-, sex-, and race-matched unexposed controls. We identified 10 significantly dysregulated genes between experienced breachers and unexposed controls, with FDR corrected <0.05: One upregulated gene, LINC00996 (long intergenic non-protein coding RNA 996); and nine downregulated genes, IGLV3-16 (immunoglobulin lambda variable 3-16), CD200 (CD200 molecule), LILRB5 (leukocyte immunoglobulin-like receptor B5), ZNF667-AS1 (ZNF667 antisense RNA 1), LMOD1 (leiomodin 1), CNTNAP2 (contactin-associated protein 2), EVPL (envoplakin), DPF3 (double PHD fingers 3), and IGHV4-34 (immunoglobulin heavy variable 4-34). The dysregulated gene expressions reported here have been associated with chronic inflammation and immune response, suggesting that these pathways may relate to the risk of lasting neurological symptoms following high exposures to blast over a career. Show less

The aim of this study was to leverage human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide (GIP) signalling. Data were obtained from summary statistics of large-scale genome-wide association studies. We examined whether genetic associations for type 2 diabetes liability in the GIP and GIPR genes co-localised with genetic associations for 11 cardiometabolic outcomes. For those outcomes that showed evidence of co-localisation (posterior probability >0.8), we performed Mendelian randomisation analyses to estimate the association of genetically proxied GIP signalling with risk of cardiometabolic outcomes, and to test whether this exceeded the estimate observed when considering type 2 diabetes liability variants from other regions of the genome. Evidence of co-localisation with genetic associations of type 2 diabetes liability at both the GIP and GIPR genes was observed for five outcomes. Mendelian randomisation analyses provided evidence for associations of lower genetically proxied type 2 diabetes liability at the GIP and GIPR genes with lower BMI (estimate in SD units -0.16, 95% CI -0.30, -0.02), C-reactive protein (-0.13, 95% CI -0.19, -0.08) and triacylglycerol levels (-0.17, 95% CI -0.22, -0.12), and higher HDL-cholesterol levels (0.19, 95% CI 0.14, 0.25). For all of these outcomes, the estimates were greater in magnitude than those observed when considering type 2 diabetes liability variants from other regions of the genome. This study provides genetic evidence to support a beneficial role of sustained GIP signalling on cardiometabolic health greater than that expected from improved glycaemic control alone. Further clinical investigation is warranted. All data used in this study are publicly available. The scripts for the analysis are available at: https://github.com/vkarhune/GeneticallyProxiedGIP . Show less

Obesity is a global epidemic that causes morbidity and impaired quality of life. The melanocortin receptor 4 (MC4R) is at the crux of appetite, energy homeostasis, and body-weight control in the central nervous system and is a prime target for anti-obesity drugs. Here, we present the cryo-electron microscopy (cryo-EM) structure of the human MC4R-G Show less

Susceptibility to severe hypertriglyceridemia (HTG), defined as plasma triglyceride (TG) levels ≥10 mmol/L (880 mg/dL), is conferred by both heterozygous rare variants in five genes involved in TG metabolism and numerous common single-nucleotide polymorphisms (SNPs) associated with TG levels. To date, these genetic susceptibility factors have been comprehensively assessed primarily in severe HTG patients of European ancestry. Here, we expand our analysis to HTG patients of East Asian and Hispanic ancestry. The genomic DNA of 336, 63 and 199 severe HTG patients of European, East Asian and Hispanic ancestry, respectively, was evaluated using a targeted next-generation sequencing panel to screen for: 1) rare variants in LPL, APOA5, APOC2, GPIHBP1 and LMF1; 2) common, small-to-moderate effect SNPs, quantified using a polygenic score; and 3) common, large-effect polymorphisms, APOA5 p.G185C and p.S19W. While the proportion of individuals with high polygenic scores was similar, frequency of rare variant carriers varied across ancestries. Compared with ancestry-matched controls, Hispanic patients were the most likely to have a rare variant (OR = 5.02; 95% CI 3.07-8.21; p < 0.001), while European patients were the least likely (OR = 2.56; 95% CI 1.58-4.13; p < 0.001). The APOA5 p.G185C polymorphism, exclusive to East Asians, was significantly enriched in patients compared with controls (OR = 10.1; 95% CI 5.6-18.3; p < 0.001), showing the highest enrichment among the measured genetic factors. While TG-associated rare variants and common SNPs are both found in statistical excess in severe HTG patients of different ancestral backgrounds, the overall genetic profiles of each ancestry group were distinct. Show less

Histological risk factors for lymph node metastasis (LNM) in early-stage colorectal cancers (CRC) have been described, although the predictive utility of these factors varies. Improved LNM risk assessment based on findings in endoscopic colon and rectal excisions is necessary for optimal surgical management of CRC patients with pathologic T1- /T2-staged invasive depth (i.e., tumor not invading beyond the muscularis propria layer); as the current system is overly conservative, and results in many unnecessary radical surgeries. To identify molecular features in early CRC with elevated LNM potential, we carried out proteomic and gene expression profiling to compare T1 lymph node (LN) negative with T1/2 LN positive CRC tumors from formalin-fixed paraffin-embedded (FFPE) specimens. Using a data-independent acquisition mass spectrometry workflow, we detected over 7400 proteins and quantified over 4400 in all 21 specimens. Proteins from tumors with LN metastasis were enriched with effectors of epithelial-mesenchymal transition (EMT) and gene expression profiling confirmed activation of key transcription factors, SNAI1 and ZEB1, as well as a reduction in E-cadherin expression. Toward an implementation pathway, we investigated immunohistochemistry assays targeting four EMT-related proteins. While MS could reliably discern twofold protein abundance changes, we found the semiquantitative nature of IHC scoring limited confirmation of this degree of protein expression difference. This study demonstrated that EMT effectors are associated with locoregional metastasis in T1/T2 CRC and could be used to augment metastatic risk assessment, although further developments are required to enable routine implementation. Show less

Obesity has become a worldwide health concern. Pharmacotherapies are now being introduced because lifestyle modifications alone are insufficient for weight management. The treatment outcomes of current approved anti-obesity agents are not satisfying due to drug-related intolerances. And so natural therapies including herbal medicines are popular alternatives for weight reduction; however, there are limited studies about their mechanism of actions. Five databases (PubMed, Scopus, Google Scholar, Science Direct, Proquest) were searched to investigate the targets and safety profiles of the current and past anti-obesity drugs that have been approved by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA) as well as the commonly used off-label agents. The targets for weight-loss natural products and their principle bioactive components have also been searched. Only articles in English were included. The targets for current anti-obesity single agents include pancreatic lipase, Glucagon Like Peptide-1(GLP-1) receptor, and serotonin 2C (5-HT2C) receptor. Potential targets such as amylin, pancreatic alpha amylase, leptin receptor, melanocortin receptor 4 receptor (MC4R), Peroxisome Proliferator- Activated Receptors gamma (PPAR γ), endocannabinoid 1 (CB1) receptor and Adenosine Monophosphate (AMP)-Activated Protein Kinase (AMPK) were discussed in various studies. Natural compounds have been found to interact with targets like pancreatic lipase, pancreatic alpha amylase, AMPK and PPAR γ to achieve weight reduction. Current pharmacotherapies and natural chemical compounds do act on same targets. Further investigations on the interactions between herbal compounds and the above targets are essential for the development of novel weight-loss therapies. Show less