Biomedical subjects

Gregory D Jenkins

Publications and source records attributed to Gregory D Jenkins.

5 recordsLinked to original sources

PubMed2026

Novel association of NAV3 with dilated cardiomyopathy and its role in cardiac fibrosis.

A genome-wide association study (GWAS) identified neuron navigator 3 (NAV3) as a potential genetic determinant of myocardial recovery in dilated cardiomyopathy (DCM). This study aimed to understand its functional role in cardiac pathophysiology by leveraging omics approaches. Single-cell RNA-seq transcriptomic data from previously published adult human hearts indicate that NAV3 expression is highest in cardiac fibroblasts, suggesting its functional role in these cells. In vitro, stimulation of primary human ventricular cardiac fibroblasts with transforming growth factor β1 (TGF-β1) induced NAV3 expression in a dose and time-dependent manner. Small-interfering-RNA-mediated knockdown of NAV3 significantly attenuated TGF-β1-induced fibroblast activation, reducing the expression of α-smooth muscle actin (α-SMA), collagens, and fibronectin. RNA sequencing of NAV3-silenced fibroblasts, confirmed by Western blot, revealed upregulation of cell cycle regulators and downregulation of profibrotic markers, suggesting that NAV3 facilitates TGF-β1-induced cell cycle arrest and fibroblast-to-myofibroblast transition. Notably, NAV3 silencing did not alter canonical SMAD2/3 phosphorylation, implying a role for NAV3 in modulating fibrotic signaling through other pathways. Our findings provide functional and mechanistic insights into NAV3's novel role in cardiac fibrosis, showing that reduced NAV3 expression attenuates TGF-β1-mediated fibroblast activation by regulating cell cycle signaling. These results support further investigation of NAV3 as a potential modulator of cardiac fibrosis and myocardial recovery in DCM.NEW & NOTEWORTHY This study uncovers a previously unrecognized role for NAV3 in TGF-β1-driven cardiac fibroblast activation. We show that NAV3 facilitates profibrotic remodeling through noncanonical signaling and cell cycle arrest, independently of SMAD2/3. These findings position NAV3 as a novel regulator of fibroblast phenotype and a potential modulator of cardiac fibrosis.

Humans↗

PubMed2006

Human SULT1A1 gene: copy number differences and functional implications.

SULT1A1, which catalyzes the sulfate conjugation of a wide variety of natural and synthetic compounds, is genetically polymorphic. Biochemical and pharmacogenetic studies have demonstrated that individual variation in the level of enzyme activity is inherited. Common single-nucleotide polymorphisms (SNPs) located in the open reading frame and in the 5'-flanking region (5'-FR) may account for a portion of this individual variation. In this study, we demonstrate the presence of SULT1A1 gene deletions and duplications, representing an additional source of variability in the metabolic activity of this enzyme. A quantitative multiplex PCR assay was used to measure the extent of copy number differences and the frequency of these events in different populations. An analysis of DNA from 362 Caucasian-American and 99 African-American showed the presence of 1 to approximately 5 copies of SULT1A1 in individual samples: 5% of Caucasian subjects contained a single copy of the gene and 26% had three or more copies, while 63% of African-American subjects had three or more copies. Analysis of the genomic region surrounding the SULT1A1 gene in three separate cases with a deletion demonstrated that the entire SULT1A1 gene was affected. Reporter assays, constructed for each of the various 5'-FR SNP haplotypes, suggest that these may also play a role in SULT1A1 activity. However, the variability in the level of enzyme activity among 23 human platelet and 267 human liver samples was best explained by gene copy number differences when all sources of genetic variability were considered (P < 0.0001). Overall, these observations have obvious implications for the effectiveness of SULT1A1 as a drug and hormone metabolizing enzyme and its potential role as a risk factor for disease.

Adult↗

PubMed2006

Exact tests of Hardy-Weinberg equilibrium and homogeneity of disequilibrium across strata.

Detecting departures from Hardy-Weinberg equilibrium (HWE) of marker-genotype frequencies is a crucial first step in almost all human genetic analyses. When a sample is stratified by multiple ethnic groups, it is important to allow the marker-allele frequencies to differ over the strata. In this situation, it is common to test for HWE by using an exact test within each stratum and then using the minimum P value as a global test. This approach does not account for multiple testing, and, because it does not combine information over strata, it does not have optimal power. Several approximate methods to combine information over strata have been proposed, but most of them sum over strata a measure of departure from HWE; if the departures are in different directions, then summing can diminish the overall evidence of departure from HWE. An exact stratified test is more appealing because it uses the probability of genotype configurations across the strata as evidence for global departures from HWE. We developed an exact stratified test for HWE for diallelic markers, such as single-nucleotide polymorphisms (SNPs), and an exact test for homogeneity of Hardy-Weinberg disequilibrium. By applying our methods to data from Perlegen and HapMap--a combined total of more than five million SNP genotypes, with three to four strata and strata sizes ranging from 23 to 60 subjects--we illustrate that the exact stratified test provides more-robust and more-powerful results than those obtained by either the minimum of exact test P values over strata or approximate stratified tests that sum measures of departure from HWE. Hence, our new methods should be useful for samples composed of multiple ethnic groups.

Computer Simulation↗

PubMed2005

Randomized controlled clinical trial of glargine versus ultralente insulin in the treatment of type 1 diabetes.

OBJECTIVE: Multiple daily insulin injection programs are commonly accompanied by considerable glycemic variation and hypoglycemia. We conducted a randomized crossover design clinical trial to compare glargine with ultralente insulin as a basal insulin in type 1 diabetes. RESEARCH DESIGN AND METHODS: To determine whether the use of glargine insulin as a basal insulin would result in a comparable HbA1c and less glycemic variation and hypoglycemia than ultralente insulin, 22 individuals (aged 44 +/- 14 years [+/-SD], 55% men) with type 1 diabetes who were experienced with multiple daily insulin injections and had an HbA1c of <7.8% were randomized in a crossover design to receive either glargine or ultralente as the basal insulin for 4 months. Aspart insulin was used as the prandial insulin. Physicians providing insulin dose adjustment advice were masked to the type of basal insulin. RESULTS: Treatment with glargine resulted in lower mean HbA1c (6.82 +/- 0.13 vs. 7.02 +/- 0.13, difference: 0.2 +/- 0.08, P = 0.026), less nocturnal variability (plasma glucose 49.06 +/- 4.74 vs. 62.36 +/- 5.21 mg/dl, P = 0.04), and less hypoglycemia (24.5 +/- 2.99 vs. 31.3 +/- 4.04 events, P = 0.05), primarily due to less daytime hypoglycemia (P = 0.002). On the other hand, serious hypoglycemia and average glucose concentration measured with continuous subcutaneous glucose monitoring did not differ. CONCLUSIONS: We conclude that while use of either ultralente or glargine as a basal insulin can result in excellent glycemic control, treatment with glargine is associated with slightly but significantly lower HbA1c and less nocturnal glycemic variability and hypoglycemia.

Adult↗

PubMed2002

Completion pneumonectomy: factors affecting operative mortality and cardiopulmonary morbidity.

BACKGROUND: The purpose of this report is to analyze preoperative and perioperative factors affecting operative mortality and cardiopulmonary morbidity after a completion pneumonectomy. METHODS: We retrospectively reviewed all patients who underwent completion pneumonectomy from January 1985 through September 1998 at the Mayo Clinic in Rochester, MN. Factors affecting operative mortality and postoperative morbidity and were analyzed using univariate and multivariate analysis. RESULTS: There were 115 patients (73 men and 42 women), with a median age of 64 years (range, 12 to 83 years). Indication for pneumonectomy was benign disease in 57 patients (49.6%), lung cancer in 51 (44.3%) and metastatic disease in 7 (6.1%). There were 24 deaths (mortality 20.9%, 95% CI 13.9% to 29.4%). Mortality for patients undergoing completion pneumonectomy for benign disease, lung cancer, and metastatic cancer was 26.3%, 17.6%, and 0%, respectively (p = 0.24). Factors adversely affecting mortality with univariate analysis included advanced age (p = 0.004), preoperative corticosteriod use (p = 0.01), decreased preoperative diffusion capacity of lung to carbon monoxide (p = 0.01), intraoperative blood transfusion (p = 0.04), and excessive crystalloid infusion within the first 12 hours (p = 0.01) and 24 hours (0.03) postoperatively, respectively. Factors adversely affecting mortality with multivariate analysis included advanced age (p = 0.001), preoperative corticosteriod use (p = 0.002), and low preoperative hemoglobin (p = 0.02). Cardiopulmonary complications occurred in 72 patients (63.7%). Factors adversely affecting morbidity with univariate analysis included benign disease (p = 0.002), decreased preoperative diffusion capacity of lung to carbon monoxide (p = 0.04), bronchial stump reinforcement (p = 0.0001), and excessive crystalloid infusion within the first 12 hours (p = 0.006) and 24 hours (p = 0.02) postoperatively, respectively. Factors adversely affecting morbidity with multivariate analysis included advanced age (p = 0.005) and bronchial stump reinforcement (p = 0.001). CONCLUSIONS: Multiple factors adversely affect operative mortality and cardiopulmonary morbidity after completion pneumonectomy. Although completion pneumonectomy remains a high-risk procedure, especially for benign disease, it still should be considered a treatment option in selected patients.

Adolescent↗