July 2021 Member Publications
- Jin L, Lorkiewicz P, Xie Z, Bhatnagar A, Srivastava S, Conklin DJ. Acrolein but not its metabolite, 3-Hydroxypropylmercapturic acid (3HPMA), activates vascular transient receptor potential Ankyrin-1 (TRPA1): Physiological to toxicological implications. Toxicol Appl Pharmacol. 2021 Jul 13:115647. doi: 10.1016/j.taap.2021.115647. Epub ahead of print. PMID: 34271065.
Impact Statement: Exposure to acrolein is linked with cardiopulmonary toxicity and cardiovascular disease (CVD) risk in humans, yet the mechanisms by which acrolein exposure confers CVD risk is unclear. This study showed that acrolein in isolated blood vessels is vasorelaxant at low levels (physiological) yet vasotoxic at high levels (toxicological), while the major metabolite of acrolein, 3-hydroxypropyl mercapturic acid (3HPMA), was weakly vasoactive and non-toxic indicating it likely does not directly account for vascular injury. These findings support the continued use of 3HPMA as a biomarker of acrolein exposure and warrant further research on mechanisms of acrolein-induced vascular injury to develop interventions that can protect human health.
Cai L. Prevention or therapy of the cardiomyopathy by fine O-GlcNAcylation balance: hopes and concerns. Cardiovasc Res. 2021 Jul 12:cvab226. doi: 10.1093/cvr/cvab226. Epub ahead of print. PMID: 34254135.
Impact Statement: This is a commentary for a recent study that has brought us many hopes for the potential gene therapy for diabetic cardiomyopathy (DCM). The authors first noticed the significant increase in O-GlcNAc modified proteins in the heart tissues of patients with diabetes, which was positively and inversely correlated with their HbA1c or blood glucose levels and with cardiac ejection fraction, respectively. Then the authors transferred O-GlcNAcase gene with adeno-associated viral vector to diabetic mice with diastolic dysfunction, a typical early feature of DCM. The gene therapy significantly reduced diabetes-increased expression of O-GlcNAc proteins and expressions of pro-fibrotic genes coding the proteins involved in fibrosis, and interstitial and perivascular type I and type III collagen deposition and improved diastolic dysfunction. Therefore, this is a milestone study to confirm the potential therapeutic reversion of DCM by correcting the balance of O-GlcNacylation in the diabetic heart, even though there remain some unanswered issues.
- Tian Y, Wang Z, Zheng X, Song W, Cai L, Rane M, Zhao Y. KLF15 negatively regulates cardiac fibrosis by which SDF-1β attenuates cardiac fibrosis in type 2 diabetic mice. Toxicol Appl Pharmacol. 2021 Jul 23;427:115654. doi: 10.1016/j.taap.2021.115654. Epub ahead of print. PMID: 34310909.
Impact statement: Tian et. al. demonstrated that T2D decreased cardiac function and KLF15 expression, while increasing cardiac fibrosis. SDF-1 increased KLF-15 expression, decreased cardiac fibrosis, and increased cardiac function in T2D mice, providing a novel therapeutic option for treatment of cardiac fibrosis in T2D patients.
- Karimi SM, Salunkhe SS, White KB, Little BB, McKinney WP, Mitra R, Chen Y, Adkins ER, Barclay JA, Ezekekwu E, He CX, Hurst DM, Popescu MM, Swinney DN, Johnson DA, Hollenbach R, Moyer SS, DuPré NC. Prevalence of unmasked and improperly masked behavior in indoor public areas during the COVID-19 pandemic: Analysis of a stratified random sample from Louisville, Kentucky. PLoS One. 2021 Jul 28;16(7):e0248324. doi: 10.1371/journal.pone.0248324. PMID: 34319978; PMCID: PMC8318281.
Impact Statement: During the height of the COVID-19 pandemic in 2020 when vaccines were not largely available, we observed mask usage in Louisville's public areas. Differences in mask usage were observed by geographic areas, size and type of public area, and by perceived age and sex, which can aid public health practitioners in their efforts to promote COVID-19 prevention practices.
- Stover AM, Kurtzman R, Walker Bissram J, Jansen J, Carr P, Atkinson T, Ellis CT, Freeman AT, Turner K, Basch EM. Stakeholder Perceptions of Key Aspects of High-Quality Cancer Care to Assess with Patient Reported Outcome Measures: A Systematic Review. Cancers (Basel). 2021 Jul 20;13(14):3628. doi: 10.3390/cancers13143628. PMID: 34298841; PMCID: PMC8306432.
Impact Statement: This systematic review showed that patients and other stakeholders perceive high-quality cancer care to be adequate control of physical and psychosocial symptoms. Results were used to inform feasibility testing of patient reported outcome measures (PROMs) as performance measures in six U.S. cancer centers.
- Li X, Haberzettl P, Conklin DJ, Bhatnagar A, Rouchka EC, Zhang M, O'Toole TE. Exposure to Fine Particulate Matter Air Pollution Alters mRNA and miRNA Expression in Bone Marrow-Derived Endothelial Progenitor Cells from Mice. Genes (Basel). 2021 Jul 10;12(7):1058. doi: 10.3390/genes12071058. PMID: 34356074; PMCID: PMC8307414.
Impact Statement: Exposure to fine air borne particulate matter is associated with cardiovascular, immunological, and cognitive disorders, but the mechanism for this is unclear. This study provides evidence that such exposures alters the expression of protein at the genetic level and that this can occur in a group of bone marrow stem cells. This mechanism may underlie adverse outcomes associated with other inhalation exposures, such as that to cigarette smoke.
- Muluhngwi P, Klinge CM. Identification and Roles of miR-29b-1-3p and miR29a-3p-Regulated and Non-Regulated lncRNAs in Endocrine-Sensitive and Resistant Breast Cancer Cells. Cancers (Basel). 2021 Jul 14;13(14):3530. doi: 10.3390/cancers13143530. PMID: 34298743; PMCID: PMC8307416.
Impact Statement: Although breast cancer patients whose initial breast tumor expressed estrogen receptor alpha (ERα) are successfully treated with drugs targeting ERα, many patients develop resistance to these endocrine therapies and disease progression to metastasis remains a major clinical problem. This paper summarizes the role of long non-coding RNAs (lncRNA) regulated by miR-29 in endocrine-resistant breast cancer cells and clinical samples.
- Perpich JD, Yakoumatos L, Johns P, Stocke KS, Fitzsimonds ZR, Wilkey DW, Merchant ML, Miller DP, Lamont RJ. Identification and characterization of a UbK family kinase in Porphyromonas gingivalis that phosphorylates the RprY response regulator. Mol Oral Microbiol. 2021 Jul 9. doi: 10.1111/omi.12347. Epub ahead of print. PMID: 34241965.
Impact Statement: Porphyromonas gingivalis is a major pathogen in periodontal diseases and possesses an array of colonization and virulence factors contributing to retention, survival, and proliferation in the dynamic and diverse ecosystems of the oral cavity. The P. gingivalis genome contains one system, the orphan response regulator (RR) RprY, that controls heterotypic community development. This study employed multiple approaches including in vitro kinase assays and phosphoproteomics to delineate the system by which RprY is activated.
- Paré G, Vitry J, Merchant ML, Vaillancourt M, Murru A, Shen Y, Elowe S, Lahoud MH, Naccache PH, McLeish KR, Fernandes MJ. The Inhibitory Receptor CLEC12A Regulates PI3K-Akt Signaling to Inhibit Neutrophil Activation and Cytokine Release. Front Immunol. 2021 Jun 21;12:650808. doi: 10.3389/fimmu.2021.650808. PMID: 34234773; PMCID: PMC8256872.
Impact Statement: The myeloid inhibitory C-type lectin receptor CLEC12A limits neutrophil activation and pro-inflammatory pathways in experimental models of inflammatory arthritis. Phosphoproteomic analysis identified candidate signaling molecules regulated by CLEC12A. Further studies defined early molecular events underpinning CLEC12A signaling in human neutrophils modulating cytokine synthesis. Targeting this pathway could be useful therapeutically to dampen inflammation.
- Srivastava DK, George EO, Lu Z, Rai SN. Impact of unequal censoring and insufficient follow-up on comparing survival outcomes: Applications to clinical studies. Stat Methods Med Res. 2021 Jul 7:9622802211017592. doi: 10.1177/09622802211017592. Epub ahead of print. PMID: 34232837.
Impact statement: Clinical trials with survival endpoints are typically designed to enroll patients for a specified number of years, (usually 2-3 years) with another specified duration of follow-up (usually 2-3 years). With random accrual time and follow-up time lead to complex censoring patterns. Conflicting findings were observed for comparing cardiovascular events in patients who took Rofecoxib (Vioxx). Here, using extensive simulation studies, we assess the impact of such censorings on statistical procedures for comparing two treatment groups. Clinical studies with survival outcome should be properly designed to maintain power by considering the censoring patterns.
- Zhang CH, Sears L, Myers JV, Brock GN, Sears CG, Zierold KM. Proximity to coal-fired power plants and neurobehavioral symptoms in children. J Expo Sci Environ Epidemiol. 2021 Jul 13:1–11. doi: 10.1038/s41370-021-00369-7. Epub ahead of print. PMID: 34257388; PMCID: PMC8275639.
Impact statement: This study used geospatial mapping to determine if child behavior problems were associated with proximity to coal-burning power plants with coal ash storage sites containing known neurotoxins. Results indicated that children living closer to these coal-burning plants had increased risk of anxiety, ADHD and social problems suggesting a need for further consideration of environmental exposures in improving child neurobehavioral health.
- Maharaj AR, Wu H, Zimmerman KO, Muller WJ, Sullivan JE, Sherwin CMT, Autmizguine J, Rathore MH, Hornik CD, Al-Uzri A, Payne EH, Benjamin DK Jr, Hornik CP; Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering Committee. Pharmacokinetics of Ceftazidime in Children and Adolescents with Obesity. Paediatr Drugs. 2021 Jul 23. doi: 10.1007/s40272-021-00460-4. Epub ahead of print. PMID: 34302290.
Impact Statement: The aim of this study was to develop a pharmacokinetic model to evaluate ceftazidime pharmacokinetics in a cohort that included a predominate number of children and adolescents with obesity and assess the efficacy of two different dosing strategies. The results show that dosing 40 mg/kg every six hours intravenously (maximum dose 8 grams/day) met the target minimum inhibitory concentration for efficacy. This research is critical because obese patients tend to have poorer outcomes with infections therefore dosing antibiotics appropriately may improve their outcome.
- Coleman CJ, Yeager RA, Riggs DW, Coleman NC, Garcia GR, Bhatnagar A, Pope CA. Greenness, air pollution, and mortality risk: A U.S. cohort study of cancer patients and survivors. Environ Int. 2021 Jul 29;157:106797. doi: 10.1016/j.envint.2021.106797. Epub ahead of print. PMID: 34332301.
Impact statement: This paper enables samples sites to be selected to ensure objective and equitable estimates for COVID-19 infection prevalence throughout Louisville, Kentucky. With such sampling, wastewater testing data is utilized to inform public health response and variant tracking.
Yeager R, Holm RH, Saurabh K, Fuqua JL, Talley D, Bhatnagar A, Smith T. Wastewater Sample Site Selection to Estimate Geographically Resolved Community Prevalence of COVID-19: A Sampling Protocol Perspective. Geohealth. 2021 Jul 1;5(7):e2021GH000420. doi: 10.1029/2021GH000420. PMID: 34222738; PMCID: PMC8240399.
Impact Statement: We found that cancer patients living in areas with high levels of vegetation had a higher likelihood of cancer survival. We also found that this association was not impacted by air pollution, as some have suspected