Browsing by Subject "PAH"

Now showing 1 - 4 of 4
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    Polycyclic Aromatic Hydrocarbons and Pancreatic Cancer: An Analysis of the Blood Biomarker, r-1,t-2,3,c-4-Tetrahydroxy-1,2,3,4-tetrahydrophenanthrene and Selected Metabolism Gene SNPs
    (MDPI, 2024-02-28) Nguyen, Sierra; Carlson, Heather; Yoder, Andrea; Bamlet, William R.; Oberg, Ann L.; Petersen, Gloria M.; Carmella, Steven G.; Hecht, Stephen S.; Jansen, Rick J.; Richard M. Fairbanks School of Public Health
    Exposure to polycyclic aromatic hydrocarbons (PAHs), byproducts of incomplete combustion, and their effects on the development of cancer are still being evaluated. Recent studies have analyzed the relationship between PAHs and tobacco or dietary intake in the form of processed foods and smoked/well-done meats. This study aims to assess the association of a blood biomarker and metabolite of PAHs, r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), dietary intake, selected metabolism SNPs, and pancreatic cancer. Demographics, food-frequency data, SNPs, treatment history, and levels of PheT in plasma were determined from 400 participants (202 cases and 198 controls) and evaluated based on pancreatic adenocarcinoma diagnosis. Demographic and dietary variables were selected based on previously published literature indicating association with pancreatic cancer. A multiple regression model combined the significant demographic and food items with SNPs. Final multivariate logistic regression significant factors (p-value < 0.05) associated with pancreatic cancer included: Type 2 Diabetes [OR = 6.26 (95% CI = 2.83, 14.46)], PheT [1.03 (1.02, 1.05)], very well-done red meat [0.90 (0.83, 0.96)], fruit/vegetable servings [1.35 (1.06, 1.73)], recessive (rs12203582) [4.11 (1.77, 9.91)], recessive (rs56679) [0.2 (0.06, 0.85)], overdominant (rs3784605) [3.14 (1.69, 6.01)], and overdominant (rs721430) [0.39 (0.19, 0.76)]. Of note, by design, the level of smoking did not differ between our cases and controls. This study does not provide strong evidence that PheT is a biomarker of pancreatic cancer susceptibility independent of dietary intake and select metabolism SNPs among a nonsmoking population.
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    A prescribed walking regimen plus arginine supplementation improves function and quality of life for patients with pulmonary arterial hypertension: a pilot study
    (SAGE, 2017-12-04) Brown, Mary Beth; Kempf, Attie; Collins, Catherine M.; Long, Gary M.; Owens, Matthew; Gupta, Shikha; Hellman, Yaron; Wong, Vincent; Farber, Mark; Lahm, Tim; Physical Therapy, School of Health and Rehabilitation Sciences
    Current evidence suggests that exercise training is beneficial in pulmonary arterial hypertension (PAH). Unfortunately, the standard supervised, hospital-based programs limit patient accessibility to this important intervention. Our proof-of-concept study aimed to provide insight into the usefulness of a prescribed walking regimen along with arginine supplementation to improve outcomes for patients with PAH. Twelve PAH patients (all women) in New York Heart Association (NYHA) functional class (FC) II (n = 7) or III (n = 5) and in stable condition for ≥ 3 months were enrolled. Patients performed home- and fitness-center- based walking at 65–75% heart rate (HR) reserve for 45 min, six sessions/week for 12 weeks. Concomitant L-arginine supplementation (6000 mg/day) was provided to maximize beneficial endothelial training adaptations. Cardiopulmonary exercise testing, 6-min walk testing (6MWT), echocardiography, laboratory studies, and quality of life (QoL) survey (SF-36) were performed at baseline and 12 weeks. Eleven patients completed the study (72 session adherence rate = 96 ± 3%). Objective improvement was demonstrated by the 6MWT distance (increased by 40 ± 13 m, P = 0.01), VO2max (increased by 2 ± 0.7 mL/kg/min, P = 0.02), time-to-VO2max (increased by 2.5 ± 0.6 min, P = 0.001), VO2 at anaerobic threshold (increased by 1.3 ± 0.5 mL/kg/min, P = 0.04), HR recovery (reduced by 68 ± 23% in slope, P = 0.01), and SF-36 subscales of Physical Functioning and Energy/Fatigue (increased by 70 ± 34% and 74 ± 34%, respectively, P < 0.05). No adverse events occurred, and right ventricular function and brain natriuretic peptide levels remained stable, suggesting safety of the intervention. This proof-of-concept study indicates that a simple walking regimen with arginine supplementation is a safe and efficacious intervention for clinically stable PAH patients, with gains in objective function and QoL measures. Further investigation in a randomized controlled trial is warranted.
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    Skeletal muscle blood flow during exercise is reduced in a rat model of pulmonary hypertension
    (American Physiological Society, 2022-10-18) Long, Gary Marshall; Troutman, Ashley D.; Gray , Derrick A.; Fisher, Amanda J.; Lahm, Tim; Coggan, Andrew R.; Brown, Mary Beth; Kinesiology, School of Health and Human Sciences
    Pulmonary arterial hypertension (PAH) is characterized by exercise intolerance. Muscle blood flow may be reduced during exercise in PAH; however, this has not been directly measured. Therefore, we investigated blood flow during exercise in a rat model of monocrotaline (MCT)-induced pulmonary hypertension (PH). Male Sprague-Dawley rats (∼200 g) were injected with 60 mg/kg MCT (MCT, n = 23) and vehicle control (saline; CON, n = 16). Maximal rate of oxygen consumption (V̇o2max) and voluntary running were measured before PH induction. Right ventricle (RV) morphology and function were assessed via echocardiography and invasive hemodynamic measures. Treadmill running at 50% V̇o2max was performed by a subgroup of rats (MCT, n = 8; CON, n = 7). Injection of fluorescent microspheres determined muscle blood flow via photo spectroscopy. MCT demonstrated a severe phenotype via RV hypertrophy (Fulton index, 0.61 vs. 0.31; P < 0.001), high RV systolic pressure (51.5 vs. 22.4 mmHg; P < 0.001), and lower V̇o2max (53.2 vs. 71.8 mL·min−1·kg−1; P < 0.0001) compared with CON. Two-way ANOVA revealed exercising skeletal muscle blood flow relative to power output was reduced in MCT compared with CON (P < 0.001), and plasma lactate was increased in MCT (10.8 vs. 4.5 mmol/L; P = 0.002). Significant relationships between skeletal blood flow and blood lactate during exercise were observed for individual muscles (r = −0.58 to −0.74; P < 0.05). No differences in capillarization were identified. Skeletal muscle blood flow is significantly reduced in experimental PH. Reduced blood flow during exercise may be, at least in part, consequent to reduced exercise intensity in PH. This adds further evidence of peripheral muscle dysfunction and exercise intolerance in PAH.
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    Studying the Effect of TBX4 Loss-of-Function on Postnatal Lung Development and How it Predisposes to Pulmonary Hypertension
    (2024-07) Maldonado Velez, Gabriel; Aldred, Micheala A.; Machado, Roberto F.; Tepper, Robert S.; Wek, Ronald C.; White, Kenneth E.
    The term pulmonary hypertension (PH) describes a heterogeneous group of pulmonary and cardiovascular disorders and is estimated to affect 1% of the global population. The World Symposium on Pulmonary Hypertension divides patients into a five-tier classification system based on etiology and clinical findings with the aim of improving the clinical approach to patients. Group 1 PH, also known as pulmonary arterial hypertension, is a rare form of the disease with a prevalence of 15-50 cases per one million individuals. Deleterious variants within the bone morphogenetic protein receptor type 2 (BMPR2) gene are found in approximately 70-80% of the cases. However, at least twelve additional genes are known to have a definitive gene-disease relationship with PAH, including T-box 4 (TBX4). Genetic predisposition may also contribute to group 3 PH, also known as PH due to chronic lung disease or hypoxia. Heterozygous pathogenic variants within TBX4 have been reported in cases from both PH groups. Therefore, the diagnosis and classification of PH in patients with TBX4 mutations may be more challenging due to its contributions to the pathogenesis of both groups. For a decade, deleterious variants or large mutations involving TBX4 have been reported throughout the literature, but more progress has yet to be made toward understanding the mechanisms underlying the pathogenesis of PH in those patients. Therefore, in this project, using mouse genetics, we sought to disrupt Tbx4 expression and investigate if there is consistency with the diseases observed in humans. We found that Tbx4 mutant lungs have increasing alveolar simplification as confirmed by mean linear intercept (MLI) at P14 (25%), P36 (31.7%), and P180 (49.5%). The lungs also have reduced vascularization as indicated by a 39.4% reduction in the number of vWF-positive vessels. Consistent with PH, mutant mice have higher RVSP (19.4%), vascular remodeling, and mild right ventricular hypertrophy (RVH). RNA sequence analyses revealed enrichment of pathways (canonical WNT, VEGF, and BMP signaling) and genes (Lgr5, Tnc, Wnt3a, Areg, Gdf2, and Bmper) relevant to lung alveologenesis, angiogenesis, and PH. This study contributes significant knowledge that clinicians can use to diagnose, classify, and treat patients with TBX4 mutations.