👤 Roger S McIntyre

Treatment failures in rheumatoid arthritis (RA) leads to undesirable morbidity associated with immunosuppression. Recent studies of synovial tissue from refractory RA patients highlight the role of synovial fibroblasts and vascular endothelium in driving treatment failure. Utilizing high-dimensional spatial transcriptomics, we uncovered a crucial role for neurotrophin signaling in driving abnormal vascular maturation in RA synovia. Neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT3), induce differentiation of synovial fibroblasts into mural cells - pericytes and vascular smooth muscle cells. Mechanistically, NOTCH3 signaling activates a cascade of neurotrophin signaling through transcriptional induction of NGFR, a co-receptor for NGF. In RA synovial tissue explants, stimulation with NGF, BDNF, or NT3 leads to a dramatic increase in maturation of synovial tissue vasculature. Conversely, pharmacologic inhibition with neurotrophin inhibitors drastically abolished maturation of vascularization in RA synovial explants. Notably, the FDA-approved tropomyosin receptor kinase (TRK) inhibitors larotrectinib and entrectinib effectively reverse synovial vascular maturation in human RA tissue explants.Our findings suggest that fibroblast-derived neurotrophin signaling is a critical pathway in sustaining mature blood vessels in RA synovia, and that neurotrophin inhibitors reverse abnormal vascular maturation in RA. In rheumatoid arthritis, fibroblast neurotrophin signaling drives abnormal vascular maturation by inducing differentiation of fibroblasts into vascular mural cells. Show less

A converging mechanistic theme across mental disorders involves impaired neuroplasticity and reduced brain-derived neurotrophic factor (BDNF). Glucagon-like peptide-1 receptor agonists (GLP-1RAs), used for type 2 diabetes and obesity, have shown neuroprotective potential, but whether these effects are mediated by BDNF is unclear. This systematic review synthesised molecular evidence linking GLP-1RA administration to BDNF changes and evaluated their contribution to illness progression in neurodegenerative and psychiatric disorders. A systematic search of PubMed, Ovid and Google Scholar from inception to September 6, 2025, identified studies reporting BDNF-related outcomes following GLP-1RA treatment. Eligible studies included primary in vivo or in vitro research on GLP-1RAs in models of neurodegenerative or psychiatric disorders. Risk of bias was assessed using SYRCLE and QUIN tools. The initial search yielded 300 records, of which 18 met the inclusion criteria. Across these studies, GLP-1RAs consistently enhanced BDNF expression and signalling in models of diabetes, neurodegeneration and neurotoxicity, with diabetic models included for their relevance to GLP-1RA pharmacology and shared neuroinflammatory pathway. Reported increases in BDNF expression ranged from 76 % to 377 %, correlating with improved synaptic plasticity, cognition and neuronal survival. In vitro, GLP-1 and exendin-4 increased BDNF expression and axonal transport even under Aβ oligomer exposure. While most neuroprotection aligned with BDNF upregulation, some effects occurred independently through alternative pathways. GLP-1RAs upregulate BDNF in preclinical models, supporting its role as a key mediator of neuroprotection. Despite some BDNF-independent actions, the consistent restoration of neurotrophic support positions BDNF as a central pathway for disease modification. Show less

BackgroundStress is a major trigger for migraine attacks. Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, releasing glucocorticoids (GCs) to maintain homeostasis, and migraine attacks may occur as an adverse effect of this response. We previously demonstrated in a mouse model that inhibiting corticosterone (CORT) synthesis by administering metyrapone before stress prevented stress-induced migraine-like behaviors. Given the unpredictable nature of stressors and their onset or termination, it is critical to better understand the adaptive and maladaptive effects of the HPA stress response. Here, we aimed to evaluate the effects of HPA axis modulation following the end of stress exposure.MethodsRepeated stress induces migraine-like behaviors and priming to sodium nitroprusside (SNP) in mice. Metyrapone (to inhibit CORT synthesis), CORT (to evaluate its effects after exogenous administration), and adrenocorticotropic hormone (ACTH) (to test the effects of a hormone upstream to CORT) were administered post-stress. Additionally, α-melanocyte-stimulating hormone (α-MSH, an ACTH cleavage product) and tetrahydroisoquinoline (THIQ), a melanocortin 4 receptor (MC4R) agonist, were administered to examine melanocortin receptor involvement. Facial hypersensitivity was assessed via von Frey testing and grimace scoring was used to evaluate non-evoked pain. Serum CORT levels were measured in both control and stressed mice following ACTH administration.ResultsWe examined post-stress HPA axis modulation on stress-induced facial hypersensitivity. Metyrapone reduced acute-phase hypersensitivity and reduced priming to SNP, suggesting sustained synthesis of CORT after stress plays a role in development of migraine-like behavior. Surprisingly, both CORT and ACTH treatments at 1- and 24-h post-stress alleviated stress-induced behaviors and priming. To determine if ACTH effects were mediated by an elevation in circulating CORT, metyrapone was administered before the ACTH injection. Metyrapone increased the ACTH reversal of stress effects on facial hypersensitivity. Furthermore, post-stress ACTH injections significantly increased serum CORT levels within 30 min. In addition to ACTH effects on CORT levels, ACTH effects could be mediated by the melanocortin system. Post-stress administration of α-MSH or the MC4R agonist THIQ, reduced migraine-like behaviors.ConclusionsThere is a complex relationship between stress, the HPA axis, and melanocortin signaling, in the effects of repeated stress exposure on migraine-like behaviors. In the early post-stress response phase, there are contributions from both CORT and MC4R signaling in the maintenance of behavioral effects. These findings suggest that targeting the HPA axis and MC4R after stress may be a potential therapeutic approach for stress-induced migraine attacks. Show less

Heterozygous familial hypercholesterolemia (HeFH) is the most prevalent inherited dyslipidemia, and it predisposes individuals to premature atherosclerotic cardiovascular disease. Genetic testing can provide a definitive diagnosis. The spectrum of causal DNA variants in Ontario patients with hypercholesterolemia is not fully defined. In Southwestern Ontario patients with a clinical diagnosis of HeFH, we performed targeted next-generation DNA sequencing and bioinformatic analysis to determine the qualitative and quantitative spectrum of pathogenic and likely pathogenic (P/LP) variants. We observed 101 unique P/LP variants in 254 patients, of which 6 were novel This study provides a comprehensive overview of the clinical and genetic spectrum of HeFH in Southwestern Ontario. The P/LP variant diversity reflects historical colonization and later migration patterns both from across the world and interprovincially from Quebec. Show less

Neovascular age-related macular degeneration (nvAMD) is the leading cause of severe vision loss in the elderly in the developed world. While the introduction of therapies targeting vascular endothelial growth factor (VEGF) has provided the first opportunity to significantly improve vision in patients with nvAMD, many patients respond inadequately to current anti-VEGF therapies. It was recently demonstrated that expression of a second angiogenic mediator, angiopoietin-like 4 (ANGPTL4), synergizes with VEGF to promote choroidal neovascularization (CNV) in mice and correlates with reduced response to anti-VEGF therapy in patients with nvAMD. Here, we report that expression of ANGPTL4 in patients with nvAMD increases following treatment with anti-VEGF therapy and that this increase is dependent on accumulation of hypoxia-inducible factor (HIF)-1α in response to inhibition of VEGF/KDR signaling in the retinal pigment epithelium (RPE). We therefore explored HIF-1 inhibition with 32-134D, a recently developed pharmacologic HIF-inhibitor, for the treatment of nvAMD. 32-134D prevented the expression of both VEGF and ANGPTL4 and was at least as effective as aflibercept in treating CNV in mice. Moreover, by preventing the increase in HIF-1α accumulation in the RPE in response to anti-VEGF therapy, combining 32-134D with aflibercept was more effective than either drug alone for the treatment of CNV. Collectively, these results help explain why many patients with nvAMD respond inadequately to anti-VEGF therapy and suggest that the HIF inhibitor 32-134D will be an effective drug-alone or in combination with current anti-VEGF therapies-for the treatment of patients with this blinding disease. Show less

To investigate the relationship between plasma lipoprotein (a) (Lp[a]) and lipid profiles in patients with severe hypertriglyceridaemia (HTG). This case-control study undertook a retrospective chart review of patients from the Lipid Genetics Clinic at London Health Sciences Centre in Ontario, Canada. Plasma Lp(a) was compared between patients with severe HTG and healthy normolipidaemic control subjects. Severe HTG was defined by plasma triglycerides (TG) ≥ 10 mmol/l. Pairwise correlations between Lp(a), TG, apolipoprotein B (apo B) and non-high-density lipoprotein cholesterol (non-HDL-C) were evaluated. This study reviewed 4400 patients and identified 154 patients with severe HTG, which were compared with 272 control subjects. The median Lp(a) was significantly lower in patients with severe HTG compared with control subjects (5.0 versus 10.2 mg/dl, respectively). No correlation was observed between Lp(a) and TG or non-HDL-C. Lp(a) and apo B were modestly correlated in patients with severe HTG ( Patients with severe HTG have lower plasma Lp(a) than normolipidaemic control subjects. The basis for this relationship is not immediately apparent but is hypothesis-generating and warrants further investigation. Show less

Treatment options for the Triple-Negative Breast Cancer (TNBC) subtype remain limited and the outcome for patients with advanced TNBC is very poor. The standard of care is chemotherapy, but approximately 50% of tumors develop resistance. We performed gene expression profiling of 58 TNBC tumor samples by microarray, comparing chemosensitive with chemoresistant tumors, which revealed that one of the top upregulated genes was TGFβ2. A connectivity mapping bioinformatics analysis predicted that the SRC inhibitor Dasatinib was a potential pharmacological inhibitor of chemoresistant TNBCs. Claudin-low TNBC cell lines were selected to represent poor-outcome, chemoresistant TNBC, for in vitro experiments and in vivo models. In vitro, we identified a signaling axis linking SRC, AKT and ERK2, which in turn upregulated the stability of the transcription factors, Slug and Snail. Slug was shown to repress TGFβ2-antisense 1 to promote TGFβ2 signaling, upregulating cell survival via apoptosis and DNA-damage responses. Additionally, an orthotopic allograft in vivo model demonstrated that the SRC inhibitor Dasatinib reduced tumor growth as a single agent, and enhanced responses to the TNBC mainstay drug, Epirubicin. Targeting the SRC-Slug-TGFβ2 axis may therefore lead to better treatment options and improve patient outcomes in this highly aggressive subpopulation of TNBCs. Show less

Biallelic pathogenic variants in APOA5 are an infrequent cause of familial chylomicronemia syndrome characterized by severe, refractory hypertriglyceridemia (HTG), and fasting plasma triglyceride (TG) >10 mmol/L (>875 mg/dL). The TG phenotype of heterozygous individuals with one copy of a pathogenic APOA5 variant is less familiar. We evaluated the longitudinal TG phenotype of individuals with a single pathogenic APOA5 variant allele. Medically stable outpatients from Ontario, Canada were selected for study based on having: 1) a rare pathogenic APOA5 variant in a single allele; and 2) at least three serial fasting TG measurements obtained over >1.5 years of follow-up. Seven patients were followed for a mean of 5.3 ± 3.7 years. Fasting TG levels varied widely both within and between patients. Three patients displayed at least one normal TG measurement (<2.0 mmol/L or <175 mg/dL). All patients displayed mild-to-moderate HTG (2 to 9.9 mmol/L or 175 to 875 mg/dL) at multiple time points. Five patients displayed at least one severe HTG measurement. 10%, 54%, and 36% of all TG measurements were in normal, mild-to-moderate, and severe HTG ranges, respectively. Heterozygosity for pathogenic variants in APOA5 is associated with highly variable TG phenotypes both within and between patients. Heterozygosity confers susceptibility to elevated TG levels, with secondary factors likely modulating the phenotypic severity. Show less

High triglyceride (TG) levels are associated with an increased risk for atherosclerotic cardiovascular disease (ASCVD) and pancreatitis. The objectives for this study were to evaluate for the coexistence of severe HTG and pancreatitis in two different geographic regions of Turkey and to identify rare variants that cause monogenic HTG in our country. In our study from 2014 to 2019, patients with severe HTG who presented to the endocrinology outpatient clinics with TG levels >500 mg/dL (5.7 mmol/L) were evaluated. The LPL, APOC2, APOA5, GPIHBP1, LMF1, and APOE genes were sequenced using next generation sequencing to screen for potentially pathogenic variants. Potentially pathogenic variants were identified in 64 (47.1%) of 136 patients. Variants in LPL were seen in 42 (30.9%) cases, APOA5 variants in 10 (7.4%) cases, APOC2 variants in 5 (3.7%) cases, LMF1 variants in 5 (3.7%) cases, and APOE mutations in 2 (1.5%) cases. In the subgroup that experienced pancreatitis (n = 76, 56.3%), LPL variants were seen at higher frequency (P <0.001) than in the subgroup with no history of pancreatitis (n = 60, 43.7%). Patients who developed pancreatitis (56.3%) demonstrated a median TG of 2083 mg/dL (23.5 mmol/L), and patients without pancreatitis (43.7%) demonstrated a median TG of 1244.5 mg/dL (14.1 mmol/L) (P <0.001). Accurate approach to HTG diagnosis is important for the prevention of pancreatitis and ASCVD. Evaluation of variants in primary HTG after excluding secondary causes may help provide a patient-centric precision treatment plan. 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

Genetic determinants of severe hypertriglyceridemia include both common variants with small effects (assessed using polygenic risk scores) plus heterozygous and homozygous rare variants in canonical genes directly affecting triglyceride metabolism. Here, we broadened our scope to detect associations with rare loss-of-function variants in genes affecting noncanonical pathways, including those known to affect triglyceride metabolism indirectly. Approach and Results: From targeted next-generation sequencing of 69 metabolism-related genes in 265 patients of European descent with severe hypertriglyceridemia (≥10 mmol/L or ≥885 mg/dL) and 477 normolipidemic controls, we focused on the association of rare heterozygous loss-of-function variants in individual genes. We observed that compared with controls, severe hypertriglyceridemia patients were 20.2× (95% CI, 1.11-366.1; Our findings indicate that rare variants in a noncanonical gene for triglyceride metabolism, namely Show less

Hypertriglyceridemia (HTG) is a complex trait defined by elevated plasma triglyceride levels. Genetic determinants of HTG have so far been examined in a piecemeal manner; understanding of its molecular basis, both monogenic and polygenic, is thus incomplete. The objective of this study was to characterize genetic profiles of patients with severe HTG, and quantify the genetic determinants and molecular contributors. We concurrently assessed rare and common variants in two independent cohorts of 251 and 312 Caucasian patients with severe HTG. DNA was subjected to targeted next-generation sequencing of 73 genes and 185 SNPs associated with dyslipidemia. LPL, APOC2, GPIHBP1, APOA5, and LMF1 genes were screened for rare variants, and a polygenic risk score was used to assess the accumulation of common variants. As there were no significant differences in the prevalence of genetic determinants between cohorts, data were combined for all 563 patients: 1.1% had biallelic (homozygous or compound heterozygous) rare variants, 14.4% had heterozygous rare variants, 32.0% had an extreme accumulation of common variants (ie, high polygenic risk), and 52.6% remained genetically undefined. Patients with HTG were 5.77 times (95% CI [4.26-7.82]; P < .0001) more likely to carry one of these types of genetic susceptibility compared with controls. We report the most in-depth, systematic evaluation of genetic determinants of severe HTG to date. The predominant feature was an extreme accumulation of common variants (high polygenic risk score), whereas a substantial proportion of patients also carried heterozygous rare variants. Overall, 46.3% of patients had polygenic HTG, whereas only 1.1% had biallelic or homozygous monogenic HTG. Show less

We describe a case of a 36-year-old woman with severe hypertriglyceridemia likely caused by double heterozygosity of a known pathogenic APOA5 nonsense variant (p.Q275X) and a novel CREB3L3 nonsense variant (p.C296X) on a background of very strong polygenic susceptibility. Her clinical course worsened with development of eruptive xanthomata after oral administration of 2 mg estradiol twice daily for 2 weeks as part of a medical protocol for intrauterine embryo transfer following in vitro fertilization. Her triglyceride levels decreased to baseline and xanthomata resolved without treatment after discontinuation of hormonal therapy, which also resulted in termination of pregnancy. Before undergoing a second embryo transfer using her natural cycle and no exogenous hormones, the patient started combination therapy with eicosapentaenoic acid ethyl ester and gemfibrozil, leading to an ∼80% decrease in triglyceride levels. She continued treatment throughout pregnancy, which progressed to term with the delivery of healthy twins. Show less

Cilia are evolutionarily conserved organelles found on many mammalian cell types, including neuronal populations. Although neuronal cilia, including those on olfactory sensory neurons (OSNs), are often delineated by localization of adenylyl cyclase 3 (AC3, also known as ADCY3), the mechanisms responsible for targeting integral membrane proteins are largely unknown. Post-translational modification by small ubiquitin-like modifier (SUMO) proteins plays an important role in protein localization processes such as nuclear-cytosolic transport. Here, we identified through bioinformatic analysis that adenylyl cyclases harbor conserved SUMOylation motifs, and show that AC3 is a substrate for SUMO modification. Functionally, overexpression of the SUMO protease SENP2 prevented ciliary localization of AC3, without affecting ciliation or cilia maintenance. Furthermore, AC3-SUMO mutants did not localize to cilia. To test whether SUMOylation is sufficient for cilia entry, we compared localization of ANO2, which possesses a SUMO motif, and ANO1, which lacks SUMOylation sites and does not localize to cilia. Introduction of SUMOylation sites into ANO1 was not sufficient for ciliary entry. These data suggest that SUMOylation is necessary but not sufficient for ciliary trafficking of select constituents, further establishing the link between ciliary and nuclear import. Show less

Cilia dysfunction underlies a class of human diseases with variable penetrance in different organ systems. Across eukaryotes, intraflagellar transport (IFT) facilitates cilia biogenesis and cargo trafficking, but our understanding of mammalian IFT is insufficient. Here we perform live analysis of cilia ultrastructure, composition and cargo transport in native mammalian tissue using olfactory sensory neurons. Proximal and distal axonemes of these neurons show no bias towards IFT kinesin-2 choice, and Kif17 homodimer is dispensable for distal segment IFT. We identify Bardet-Biedl syndrome proteins (BBSome) as bona fide constituents of IFT in olfactory sensory neurons, and show that they exist in 1:1 stoichiometry with IFT particles. Conversely, subpopulations of peripheral membrane proteins, as well as transmembrane olfactory signalling pathway components, are capable of IFT but with significantly less frequency and/or duration. Our results yield a model for IFT and cargo trafficking in native mammalian cilia and may explain the penetrance of specific ciliopathy phenotypes in olfactory neurons. Show less

Genome-wide association studies (GWAS) have identified multiple loci associated with plasma lipid concentrations. Common variants at these loci together explain <10% of variation in each lipid trait. Rare variants with large individual effects may also contribute to the heritability of lipid traits; however, the extent to which rare variants affect lipid phenotypes remains to be determined. Here we show an accumulation of rare variants, or a mutation skew, in GWAS-identified genes in individuals with hypertriglyceridemia (HTG). Through GWAS, we identified common variants in APOA5, GCKR, LPL and APOB associated with HTG. Resequencing of these genes revealed a significant burden of 154 rare missense or nonsense variants in 438 individuals with HTG, compared to 53 variants in 327 controls (P = 6.2 x 10(-8)), corresponding to a carrier frequency of 28.1% of affected individuals and 15.3% of controls (P = 2.6 x 10(-5)). Considering rare variants in these genes incrementally increased the proportion of genetic variation contributing to HTG. Show less