A5052270672- Bladder and Urothelial Cancer Treatments
- Gut microbiota and health
- Esophageal Cancer Research and Treatment
- Pulmonary Hypertension Research and Treatments
- Cancer Immunotherapy and Biomarkers
- Mitochondrial Function and Pathology
- Immune cells in cancer
- MicroRNA in disease regulation
- Biomarkers in Disease Mechanisms
- Hormonal Regulation and Hypertension
- Hemoglobinopathies and Related Disorders
- Congenital Heart Disease Studies
- Eosinophilic Disorders and Syndromes
- ATP Synthase and ATPases Research
- Cardiovascular Disease and Adiposity
- Cardiomyopathy and Myosin Studies
- Liver physiology and pathology
- Cancer-related molecular mechanisms research
- Epigenetics and DNA Methylation
Queen's University
2022-2024
Queens University
2022
Abstract Poor response to Bacillus Calmette-Guérin (BCG) immunotherapy remains a major barrier in the management of patients with non–muscle invasive bladder cancer (NMIBC). Multiple factors are associated poor outcomes, including biological aging and female sex. More recently, it has emerged that B-cell–infiltrated pretreatment immune microenvironment NMIBC tumors can influence intravesically administered BCG. The mechanisms underlying roles B cells poorly understood. Here, we show...
Drp1 (dynamin-related protein 1), a large GTPase, mediates the increased mitochondrial fission, which contributes to hyperproliferation of pulmonary artery smooth muscle cells in arterial hypertension (PAH). We developed potent GTPase inhibitor, Drpitor1a, but its specificity, pharmacokinetics, and efficacy PAH are unknown.
<div>Abstract<p>Poor response to Bacillus Calmette-Guérin (BCG) immunotherapy remains a major barrier in the management of patients with non–muscle invasive bladder cancer (NMIBC). Multiple factors are associated poor outcomes, including biological aging and female sex. More recently, it has emerged that B‐cell–infiltrated pretreatment immune microenvironment NMIBC tumors can influence intravesically administered BCG. The mechanisms underlying roles B cells poorly understood....
Abstract Poor response to Bacillus Calmette-Guérin (BCG) immunotherapy remains a major barrier in the management of patients with non-muscle-invasive bladder cancer (NMIBC). Among multiple factors contributing poor outcomes, B cell infiltrated pre-treatment immune microenvironment NMIBC tumors has emerged as key determinant BCG. The mechanisms underlying paradoxical roles cells are poorly understood. Here, we show that dominant tertiary lymphoid structures (TLSs), hallmark feature chronic...
Introduction: The ductus arteriosus (DA) is a fetal vessel connecting the pulmonary artery (PA) and aorta, diverting oxygenated blood away from developing lungs to systemic circulation. Following first breath, DA rapidly constricts in response increased arterial oxygen (O 2 ) which simultaneously induces relaxation of small resistance arteries (rPA). These changes, vital for adaptation neonatal life, separate circulations (DA vasoconstriction) enable adequate perfusion newly ventilated (PA...
Introduction: Mitochondrial fission is mediated by dynamin related protein-1 (Drp1) activation; however, to complete fission, we have evidence that Drp1 requires assistance from the GTPase 2 (DNM2). Hypothesis: DNM2 interacts with regulate mitotic and cell cycle progression, permitting hyperproliferative phenotype of pulmonary artery smooth muscle cells (PASMC) in arterial hypertension (PAH). Methods: Colocalization was assessed using STED super resolution confocal microscopy. Interaction...
Introduction: Dynamin-related protein 1 (Drp1) activation increases mitochondrial fission and cell cycle progression in hyperproliferative cells, termed mitotic fission. However, the diameter of a apparatus comprised solely Drp1 its binding partners appears insufficient to complete Moreover, mechanism linking is unknown, suggesting an additional mediator terminal steps Hypothesis: The large GTPase, dynamin 2 (DNM2), interacts with regulate progression. Corollary: DNM2 epigenetically...
<p>Gating strategy for identifying different subsets of T cells.</p>
<p>B‐cell depletion alters expression profiles of immune regulatory genes in the bladder microenvironment.</p>
<p>Contour plots showing myeloid and T cell populations.</p>
<p>Tumor-adjacent TLS characterized using multiplex IF and NanoString GeoMx DSP.</p>
<p>Effect of transient B‐cell depletion and BBN exposure on urothelium exposed female male mice.</p>
<p>BBN exposure and BCG treatment alters plasma immunoglobulin profiles in a sex differential manner.</p>
<p>Gating strategy for identifying atypical B cells (ABCs) and myeloid cell population.</p>
<p>Immune infiltration in the bladder microenvironment after repeated BCG treatment and B‐cell depletion BBN exposed mice.</p>
<p>Splenic ABC expansion is enhanced by a combination of BBN exposure and BCG treatment.</p>
<p>Expansion of ABCs in the systemic and local bladder microenvironment.</p>
<p>B‐cell differentiation to ABCs following in vitro treatment with IFN-<i>γ</i>, IL-21 and BCG is sex-dependent.</p>
Background: Pulmonary Arterial Hypertension (PAH) is a fatal cardiopulmonary disorder characterized by adverse vascular remodelling of small pulmonary arteries, which increases resistance and demand on the right ventricle (RV), ultimately leading to RV fibrosis failure. Emerging evidence suggests that inflammation plays crucial role in PAH pathogenesis. Here, we study Clonal Hematopoiesis Indeterminate Potential (CHIP), somatic mutations genes such as DNMT3A TET2 , promotes an inflammatory...
Background: Mutations are found in 10-20% of idiopathic PAH (IPAH) patients, but none identified connective tissue disease-associated (APAH), which accounts for ~45% cases. TET2 mutations, a cause clonal hematopoiesis indeterminant potential (CHIP), predispose to an inflammatory type PAH. We now examine mutations another CHIP gene, DNMT3A, Methods: assessed DNMT3A mutation prevalence Biobank subjects as compared with controls, first using whole exome sequencing (WES)-derived calls 1832...
Background: Pulmonary Arterial Hypertension (PAH) is characterized by pulmonary vascular remodeling of the precapillary arteries. Increasing evidence suggests that inflammation plays an essential role in PAH development. Understanding involvement immunity this context can provide valuable insights into pathogenesis PAH. DNA Methyltransferase 3A ( DNMT3A ) mutations lead to altered methylation patterns immune cells, potentially affecting expression immune-regulatory genes. Here, we...
Background: The right ventricle (RV) fails in pulmonary arterial hypertension (PAH) part due to inflammation. In male PAH, RV CCR2 + macrophages induce inflammation via NLRP3 inflammasome. Since PAH males have worse outcomes, a cardioprotective role of the female sex hormones is suggested. Hypothesis: Ovariectomy (OVX) females recapitulates males’ disease severity by increasing inhibition ameliorates function and OVX rats with monocrotaline (MCT)-induced PAH. Methods: was induced MCT...
Abstract Rationale Dynamin-related protein 1 (Drp1), a large GTPase, mediates mitochondrial fission. Increased Drp1-mediated fission permits accelerated mitosis, contributing to hyperproliferation of pulmonary artery smooth muscle cells (PASMC), which characterizes arterial hypertension (PAH). We developed Drp1 inhibitor, Drpitor1a, and tested its ability regress PAH. Objectives Assess Drpitor1a’s efficacy toxicity in: a)normal PAH human PASMC (hPASMC); b)normal rats versus with established...