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Clinical and molecular implications of RGS2 promoter genetic variation in severe asthma
(Elsevier, 2022) Cardet, Juan Carlos; Kim, Donghwa; Bleecker, Eugene R.; Casale, Thomas B.; Israel, Elliot; Mauger, David; Meyers, Deborah A.; Ampleford, Elizabeth; Hawkins, Gregory A.; Tu, Yaping; Liggett, Stephen B.; Ortega, Victor E.; SARP-3 investigators; Pediatrics, School of Medicine
Background: Regulator of G protein signaling (RGS) 2 terminates bronchoconstrictive Gαq signaling; murine RGS2 knockout demonstrate airway hyperresponsiveness. While RGS2 promoter variants rs2746071 and rs2746072 associate with a clinical mild asthma phenotype, their impact on human airway smooth muscle (HASM) contractility and asthma severity outcomes is unknown.
Objective: We sought to determine whether reductions in RGS2 expression seen with these 2 RGS2 promoter variants augment HASM contractility and associate with an asthma severity phenotype.
Methods: We transfected HASM with a range of RGS2-specific small interfering RNA (siRNA) concentrations and determined RGS2 protein expression by Western blot analysis and intracellular calcium flux induced by histamine (a Gαq-coupled H1 receptor bronchoconstrictive agonist). We conducted regression-based genotype association analyses of RGS2 variants from 611 patients from the National Heart, Lung, and Blood Institute Severe Asthma Research Program 3.
Results: RGS2-specific siRNA caused dose-dependent increases in histamine-stimulated bronchoconstrictive intracellular calcium signaling (2-way ANOVA, P < .0001) with a concomitant decrease in RGS2 protein expression. RGS2-specific siRNA did not affect Gαq-independent ionomycin-induced intracellular calcium signaling (P = .42). The minor allele frequency of rs2746071 and rs2746072 was 0.46 and 0.28 among African American/non-Hispanic Black patients and was 0.28 and 0.27 among non-Hispanic White patients, among whom these single nucleotide polymorphisms were in stronger linkage disequilibrium (r2 = 0.97). Among non-Hispanic White patients, risk allele homozygotes for rs2746072 and rs2746071 each had nearly 2-fold greater asthma exacerbation rates relative to alternative genotypes with wild-type alleles (Padditive = 2.86 × 10-5/Precessive = 5.22 × 10-6 and Padditive = 3.46 × 10-6/Precessive = 6.74 × 10-7, respectively) at baseline, which was confirmed by prospective longitudinal exacerbation data.
Conclusion: RGS2 promoter variation associates with a molecular and clinical phenotype characterized by enhanced bronchoconstrictive stimulation in vitro and higher asthma exacerbations rates in non-Hispanic White patients.
The Antibacterial Effect of Electromagnetic Stimulation On In Vitro Endodontic Biofilms
(2024-06) Whitfield, Tyler; Spolnik, Kenneth; Ehrlich, Ygal; Movila, Alexandru
Non-surgical root canal treatment (NSRCT) is indicated for endodontic infection. However, it is generally indicated under conditions that have caused inflammation, infection, and/or necrosis of the pulpal tissue. In recent years, an electromagnetic stimulation (EMS) device has been created by the International Society for Electromagnetic Dentistry (Tominaga Dental Clinic, Naruto, Japan). This device transmits electromagnetic waves and is used to augment the disinfection of the RCT. This novel method may accomplish the RCT disinfection by creating a synergistic reaction via thermal and electrical energy, allowing the potential to enhance root canal disinfection [2, 3]. Japanese researchers have also found promising results with its synergistic use clinically [4, 5]. Previous results have shown an increased anti-microbial effect with synergistic use of sodium hypochlorite, but this study will explore the direct anti-microbial effect of electromagnetic stimulation.
Maternal COVID-19, vaccination safety in pregnancy, and evidence of protective immunity
(Elsevier, 2021) Pham, Amelie; Aronoff, David M.; Thompson, Jennifer L.; Medicine, School of Medicine
Region-specific associations among tissue-level mechanical properties, porosity, and composition in human male femora
(Elsevier, 2022) Mandair, Gurjit S.; Bigelow, Erin M. R.; Viswanathan, Gowri; Ward, Ferrous S.; Patton, Daniella M.; Schlecht, Stephen H.; Jepsen, Karl J.; Kohn, David H.; Orthopaedic Surgery, School of Medicine
Region-specific differences in age-related bone remodeling are known to exist. We therefore hypothesized that the decline in tissue-level strength and post-yield strain (PYS) with age is not uniform within the femur, but is driven by region-specific differences in porosity and composition. Four-point bending was conducted on anterior, posterior, medial, and lateral beams from male cadaveric femora (n = 33, 18-89 yrs of age). Mid-cortical porosity, composition, and mineralization were assessed using nano-computed tomography (nanoCT), Raman spectroscopy, and ashing assays. Traits between bones from young and elderly groups were compared, while multivariate analyses were used to identify traits that predicted strength and PYS at the regional level. We show that age-related decline in porosity and mechanical properties varied regionally, with highest positive slope of age vs. Log(porosity) found in posterior and anterior bone, and steepest negative slopes of age vs. strength and age vs. PYS found in anterior bone. Multivariate analyses show that Log(porosity) and/or Raman 1246/1269 ratio explained 46-51% of the variance in strength in anterior and posterior bone. Three out of five traits related to Log(porosity), mineral crystallinity, 1246/1269, mineral/matrix ratio, and/or hydroxyproline/proline (Hyp/Pro) ratio, explained 35-50% of the variance in PYS in anterior, posterior and lateral bones. Log(porosity) and Hyp/Pro ratio alone explained 13% and 19% of the variance in strength and PYS in medial bone, respectively. The predictive performance of multivariate analyses was negatively impacted by pooling data across all bone regions, underscoring the complexity of the femur and that the use of pooled analyses may obscure underlying region-specific differences.
Effects of the WRITE Symptoms Interventions on Symptoms and Quality of Life Among Patients With Recurrent Ovarian Cancers: An NRG Oncology/GOG Study (GOG-0259)
(American Society of Clinical Oncology, 2022) Donovan, Heidi S.; Sereika, Susan M.; Wenzel, Lari B.; Edwards, Robert P.; Knapp, Judith E.; Hughes, Susan H.; Roberge, Mary C.; Thomas, Teresa H.; Klein, Sara Jo; Spring, Michael B.; Nolte, Susan; Landrum, Lisa M.; Casey, A. Catherine; Mutch, David G.; DeBernardo, Robert L.; Muller, Carolyn Y.; Sullivan, Stephanie A.; Ward, Sandra E.; Obstetrics and Gynecology, School of Medicine
Purpose: GOG-259 was a 3-arm randomized controlled trial of two web-based symptom management interventions for patients with recurrent ovarian cancer. Primary aims were to compare the efficacy of the nurse-guided (Nurse-WRITE) and self-directed (SD-WRITE) interventions to Enhanced Usual Care (EUC) in improving symptoms (burden and controllability) and quality of life (QOL).
Methods: Patients with recurrent or persistent ovarian, fallopian, or primary peritoneal cancer with 3+ symptoms were eligible for the study. Participants completed baseline (BL) surveys (symptom burden and controllability and QOL) before random assignment. WRITE interventions lasted 8 weeks to develop symptom management plans for three target symptoms. All women received EUC: monthly online symptom assessment with provider reports; online resources; and every 2-week e-mails. Outcomes were evaluated at 8 and 12 weeks after BL. Repeated-measures modeling with linear contrasts evaluated group by time effects on symptom burden, controllability, and QOL, controlling for key covariates.
Results: Participants (N = 497) reported mean age of 59.3 ± 9.2 years. At BL, 84% were receiving chemotherapy and reported a mean of 14.2 ± 4.9 concurrent symptoms, most commonly fatigue, constipation, and peripheral neuropathy. Symptom burden and QOL improved significantly over time (P < .001) for all three groups. A group by time interaction (P < .001) for symptom controllability was noted whereby both WRITE intervention groups had similar improvements from BL to 8 and 12 weeks, whereas EUC did not improve over time.
Conclusion: Both WRITE Intervention groups showed significantly greater improvements in symptom controllability from BL to 8 and BL to 12 weeks compared with EUC. There were no significant differences between Nurse-WRITE and SD-WRITE. SD-WRITE has potential as a scalable intervention for a future implementation study.