Low-Level ionizing radiation induces selective killing of HIV-1-infected cells with reversal of cytokine induction using mtor inhibitors
Creator:
Batrakova, E.V., Pinto, D.O., Kashanchi, F., Noren Hooten, N., Evans, M.K., Heredia, A., Vo, T.T., Cowen, M., DeMarino, C., Kim, Y., Barclay, R.A., Pleet, M.L., and Iordanskiy, S.
Date of publication:
2020
Abstract Tesim:
HIV-1 infects 39.5 million people worldwide, and cART is effective in preventing viral spread by reducing HIV-1 plasma viral loads to undetectable levels. However, viral reservoirs persist by mechanisms, including the inhibition of autophagy by HIV-1 proteins (i.e., Nef and Tat). HIV-1 reservoirs can be targeted by the “shock and kill” strategy, which utilizes latency-reversing agents (LRAs) to activate latent proviruses and immunotarget the virus-producing cells. Yet, limitations include reduced LRA permeability across anatomical barriers and immune hyper-activation. Ionizing radiation (IR) induces effective viral activation across anatomical barriers. Like other LRAs, IR may cause inflammation and modulate the secretion of extracellular vesicles (EVs). We and others have shown that cells may secrete cytokines and viral proteins in EVs and, therefore, LRAs may contribute to inflammatory EVs. In the present study, we mitigated the effects of IR-induced inflammatory EVs (i.e., TNF-α), through the use of mTOR inhibitors (mTORi; Rapamycin and INK128). Further, mTORi were found to enhance the selective killing of HIV-1-infected myeloid and T-cell reservoirs at the exclusion of uninfected cells, potentially via inhibition of viral transcription/translation and induction of autophagy. Collectively, the proposed regimen using cART, IR, and mTORi presents a novel approach allowing for the targeting of viral reservoirs, prevention of immune hyper-activation, and selectively killing latently infected HIV-1 cells.
Resource type:
Article
Affiliation Label Tesim:
Department of Medicine
DOI:
https://doi.org/10.17615/kwcv-g557
Edition:
Publisher
Identifier:
https://dx.doi.org/10.3390/v12080885 and PMID 32823598
ISSN:
1999-4915
Journal Issue:
8
Journal Title:
Viruses
Journal Volume:
12
Keyword:
Ionizing radiation, MTOR inhibition, HIV-1, Shock and kill, Inflammation, Cell death, Latency reversal, Extracellular vesicles, HIV-1 therapy, and Autophagy
Language Label:
English
License Label:
Attribution 3.0 United States
Other Affiliation:
George Mason University, National Institutes of Health, University of Maryland, Baltimore, and Uniformed Services University of the Health Sciences
Person:
Batrakova, E.V., Pinto, D.O., Kashanchi, F., Noren Hooten, N., Evans, M.K., Heredia, A., Vo, T.T., Cowen, M., DeMarino, C., Kim, Y., Barclay, R.A., Pleet, M.L., and Iordanskiy, S.
Drug nanoformulations hold remarkable promise for the efficient delivery of therapeutics to a disease site. Unfortunately, artificial nanocarriers, mostly liposomes and polymeric nanoparticles, show limited applications due to the unfavorable pharmacokinetics and rapid clearance from the blood circulation by the reticuloendothelial system (RES). Besides, many of them have high cytotoxicity, low biodegradability, and the inability to cross biological barriers, including the blood brain barrier. Extracellular vesicles (EVs) are novel candidates for drug delivery systems with high bioavailability, exceptional biocompatibility, and low immunogenicity. They provide a means for intercellular communication and the transmission of bioactive compounds to targeted tissues, cells, and organs. These features have made them increasingly attractive as a therapeutic platform in recent years. However, there are many obstacles to designing EV-based therapeutics. In this review, we will outline the main hurdles and limitations for therapeutic and clinical applications of drug loaded EV formulations and describe various attempts to solve these problems.
Resource type:
Article
Affiliation Label Tesim:
Eshelman School of Pharmacy and Center for Nanotechnology in Drug Delivery
DOI:
https://doi.org/10.17615/gkde-7912
Edition:
Publisher
Identifier:
https://dx.doi.org/10.3390/pharmaceutics12121171
ISSN:
1999-4923
Journal Issue:
12
Journal Title:
Pharmaceutics
Journal Volume:
12
Keyword:
Drug delivery, Clinical applications, and Extracellular vesicles
Targeting beclin1 as an adjunctive therapy against hiv using mannosylated polyethylenimine nanoparticles
Creator:
Rodriguez, M., Zhao, Y., El-Hage, N., Batrakova, E.V., Karuppan, M.K.M., and Soler, Y.
Date of publication:
2021
Abstract Tesim:
Using nanoparticle-based RNA interference (RNAi), we have previously shown that silenc-ing the host autophagic protein, Beclin1, in HIV-infected human microglia and astrocytes restricts HIV replication and its viral-associated inflammatory responses. Here, we confirmed the efficacy of Beclin1 small interfering RNA (siBeclin1) as an adjunctive antiviral and anti-inflammatory therapy in myeloid human microglia and primary human astrocytes infected with HIV, both with and without exposure to combined antiretroviral (cART) drugs. To specifically target human microglia and human astrocytes, we used a nanoparticle (NP) comprised of linear cationic polyethylenimine (PEI) conjugated with mannose (Man) and encapsulated with siBeclin1. The target specificity of the PEI-Man NP was confirmed in vitro using human neuronal and glial cells transfected with the NP encapsulated with fluorescein isothiocyanate (FITC). PEI-Man-siBeclin1 NPs were intranasally deliv-ered to healthy C57BL/6 mice in order to report the biodistribution of siBeclin1 in different areas of the brain, measured using stem-loop RT-PCR. Postmortem brains recovered at 1–48 h post-treatment with the PEI-Man-siRNA NP showed no significant changes in the secretion of the chemokines regulated on activation, normal T cell expressed and secreted (RANTES) and monocyte chemotactic protein-1 (MCP-1) and showed significant decreases in the secretion of the cytokines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) when compared to phosphate-buffered saline (PBS)-treated brains. Nissl staining showed minimal differences between the neuronal structures when compared to PBS-treated brains, which correlated with no adverse behavioral affects. To confirm the brain and peripheral organ distribution of PEI-siBeclin1 in living mice, we used the In vivo Imaging System (IVIS) and demonstrated a significant brain accumulation of siBeclin1 through intranasal administration.
Resource type:
Article
Affiliation Label Tesim:
Eshelman School of Pharmacy
DOI:
https://doi.org/10.17615/wz7c-5p21
Edition:
Publisher
Identifier:
https://dx.doi.org/10.3390/pharmaceutics13020223
ISSN:
1999-4923
Journal Issue:
2
Journal Title:
Pharmaceutics
Journal Volume:
13
Keyword:
HIV, In vivo imaging system, Polyethylenimine nanoparticle, Beclin1, and Intranasal delivery
Language Label:
English
License Label:
Attribution 3.0 United States
Other Affiliation:
Florida International University
Page End:
17
Page Start:
1
Person:
Rodriguez, M., Zhao, Y., El-Hage, N., Batrakova, E.V., Karuppan, M.K.M., and Soler, Y.
Transcriptome-wide association study of blood cell traits in african ancestry and hispanic/latino populations
Creator:
Jorgenson, E., Li, Y., Liu, Y., Qian, H., Hodonsky, C.J., Fornage, M., Wang, T., Sun, Q., Chen, J., Buyske, S., Yin, J., Xie, M., North, K.E., Raffield, L.M., Smith, J.A., Kowalski, M.H., Bien, S.A., Rowland, B., Reiner, A.P., Rich, S.S., Rotter, J.I., Tapia, A.L., Argos, M., Young, K.L., Choquet, H., Zhao, W., Avery, C.L., Zhou, X., Kooperberg, C., Wen, J., Loos, R.J.F., Rosen, J.D., Graff, M., Moon, J.-Y., Shang, L., and Shan, Y.
Date of publication:
2021
Abstract Tesim:
Background: Thousands of genetic variants have been associated with hematological traits, though target genes remain unknown at most loci. Moreover, limited analyses have been conducted in African ancestry and Hispanic/Latino populations; hematological trait associated variants more common in these populations have likely been missed. Methods: To derive gene expression prediction models, we used ancestry-stratified datasets from the Multi-Ethnic Study of Atherosclerosis (MESA, including n = 229 African American and n = 381 Hispanic/Latino participants, monocytes) and the Depression Genes and Networks study (DGN, n = 922 European ancestry participants, whole blood). We then performed a transcriptome-wide association study (TWAS) for platelet count, hemoglobin, hematocrit, and white blood cell count in African (n = 27,955) and Hispanic/Latino (n = 28,324) ancestry participants. Results: Our results revealed 24 suggestive signals (p < 1 × 10−4 ) that were conditionally distinct from known GWAS identified variants and successfully replicated these signals in European ancestry subjects from UK Biobank. We found modestly improved correlation of predicted and measured gene expression in an independent African American cohort (the Genetic Epidemiology Network of Arteriopathy (GENOA) study (n = 802), lymphoblastoid cell lines) using the larger DGN reference panel; however, some genes were well predicted using MESA but not DGN. Conclusions: These analyses demonstrate the importance of performing TWAS and other genetic analyses across diverse populations and of balancing sample size and ancestry background matching when selecting a TWAS reference panel.
Resource type:
Article
Affiliation Label Tesim:
Department of Genetics, Department of Statistics and Operations Research, Department of Biostatistics, and Department of Epidemiology
DOI:
https://doi.org/10.17615/x9y4-pk77
Edition:
Publisher
Identifier:
https://dx.doi.org/10.3390/genes12071049
ISSN:
2073-4425
Journal Issue:
7
Journal Title:
Genes
Journal Volume:
12
Keyword:
Expression analysis, Non-European populations, Ancestry, and TWAS (transcriptome-wide association study)
Language Label:
English
License Label:
Attribution 3.0 United States
ORCID:
Other Affiliation:
Regeneron Genetics Center, , Duke University, University of Virginia, The University of Texas Health Science Center, Albert Einstein College of Medicine, Rutgers University, Kaiser Permanente Northern California, University of Michigan, Fred Hutchinson Cancer Research Center, University of Washington, Harbor-UCLA Medical Center, University of Illinois at Chicago, and Icahn School of Medicine at Mount Sinai
Person:
Jorgenson, E., Li, Y., Liu, Y., Qian, H., Hodonsky, C.J., Fornage, M., Wang, T., Sun, Q., Chen, J., Buyske, S., Yin, J., Xie, M., North, K.E., Raffield, L.M., Smith, J.A., Kowalski, M.H., Bien, S.A., Rowland, B., Reiner, A.P., Rich, S.S., Rotter, J.I., Tapia, A.L., Argos, M., Young, K.L., Choquet, H., Zhao, W., Avery, C.L., Zhou, X., Kooperberg, C., Wen, J., Loos, R.J.F., Rosen, J.D., Graff, M., Moon, J.-Y., Shang, L., and Shan, Y.
Expressheart: Web portal to visualize transcriptome profiles of non-cardiomyocyte cells
Creator:
Qian, L., Dong, Y., Zentz, S.C., Roach, J., Luan, C., Yang, Y., Zelt, R., Li, G., Xie, Y., Liu, J., and Li, Y.
Date of publication:
2021
Abstract Tesim:
Unveiling the molecular features in the heart is essential for the study of heart diseases. Non-cardiomyocytes (nonCMs) play critical roles in providing structural and mechanical support to the working myocardium. There is an increasing amount of single-cell RNA-sequencing (scRNA-seq) data characterizing the transcriptomic profiles of nonCM cells. However, no tool allows researchers to easily access the information. Thus, in this study, we develop an open-access web portal, Express-Heart, to visualize scRNA-seq data of nonCMs from five laboratories encompassing three species. ExpressHeart enables comprehensive visualization of major cell types and subtypes in each study; visualizes gene expression in each cell type/subtype in various ways; and facilitates identifying cell-type-specific and species-specific marker genes. ExpressHeart also provides an interface to directly combine information across datasets, for example, generating lists of high confidence DEGs by taking the intersection across different datasets. Moreover, ExpressHeart performs comparisons across datasets. We show that some homolog genes (e.g., Mmp14 in mice and mmp14b in zebrafish) are expressed in different cell types between mice and zebrafish, suggesting different functions across species. We expect ExpressHeart to serve as a valuable portal for investigators, shedding light on the roles of genes on heart development in nonCM cells.
Resource type:
Article
Affiliation Label Tesim:
Department of Pathology and Laboratory Medicine, Department of Biostatistics, Department of Research Computing, and Department of Statistics and Operations Research
DOI:
https://doi.org/10.17615/wgg2-9c06
Edition:
Publisher
Identifier:
https://dx.doi.org/10.3390/ijms22168943
ISSN:
1661-6596
Journal Issue:
16
Journal Title:
International Journal of Molecular Sciences
Journal Volume:
22
Keyword:
Cross-species comparison, R Shiny, Non-cardiomyocytes, Single-cell RNA-sequencing, Expressheart, Visualization, and Differentially expressed genes
Language Label:
English
License Label:
Attribution 3.0 United States
ORCID:
Other Affiliation:
Person:
Qian, L., Dong, Y., Zentz, S.C., Roach, J., Luan, C., Yang, Y., Zelt, R., Li, G., Xie, Y., Liu, J., and Li, Y.
One-year follow-up examination of the impact of the North Carolina healthy food small retailer program on healthy food availability, purchases, and consumption
Creator:
Laska, M.N., Ammerman, A., Truesdale, K.P., Pitts, S.B.J., McGuirt, J.T., Bell, R., Haynes-Maslow, L., and Wu, Q.
Date of publication:
2018
Abstract Tesim:
We examined the short-term impact of the North Carolina Healthy Food Small Retailer Program (HFSRP), a legislatively appropriated bill providing funding up to $25,000 to small food retailers for equipment to stock and promote healthier foods, on store-level availability and purchase of healthy foods and beverages, as well as customer dietary patterns, one year post-policy implementation. We evaluated healthy food availability using a validated audit tool, purchases using customer bag-checks, and diet using self-reported questionnaires and skin carotenoid levels, assessed via Veggie Meter™, a non-invasive tool to objectively measure fruit and vegetable consumption. Difference-in-difference analyses were used to examine changes in HFSRP stores versus control stores after 1 year. There were statistically significant improvements in healthy food supply scores (availability), with the Healthy Food Supply HFS score being −0.44 points lower in control stores and 3.13 points higher in HFSRP stores pre/post HFSRP (p = 0.04). However, there were no statistically significant changes in purchases or self-reported consumption or skin carotenoids among customers in HFSRP versus control stores. Additional time or other supports for retailers (e.g., marketing and promotional materials) may be needed for HFSRP implementation to influence purchase and consumption.
Resource type:
Article
Affiliation Label Tesim:
Department of Nutrition
DOI:
https://doi.org/10.17615/ak7v-4r20
Edition:
Publisher
ISSN:
1661-7827
Journal Issue:
12
Journal Title:
International Journal of Environmental Research and Public Health
Journal Volume:
15
Keyword:
Nutrition policy, Rural populations, Health disparities, and Food deserts
Language Label:
English
License Label:
Attribution 3.0 United States
Other Affiliation:
University of Minnesota, Minneapolis, East Carolina University, University of North Carolina at Greensboro, and North Carolina State University
Person:
Laska, M.N., Ammerman, A., Truesdale, K.P., Pitts, S.B.J., McGuirt, J.T., Bell, R., Haynes-Maslow, L., and Wu, Q.
Dnmts and impact of cpg content, transcription factors, consensus motifs, lncrnas, and histone marks on dna methylation
Creator:
Hernández-Sotelo, D., Loaeza-Loaeza, J., and Beltran, A.S.
Date of publication:
2020
Abstract Tesim:
DNA methyltransferases (DNMTs) play an essential role in DNA methylation and transcriptional regulation in the genome. DNMTs, along with other poorly studied elements, modulate the dynamic DNA methylation patterns of embryonic and adult cells. We summarize the current knowledge on the molecular mechanism of DNMTs’ functional targeting to maintain genome-wide DNA methylation patterns. We focus on DNMTs’ intrinsic characteristics, transcriptional regulation, and post-transcriptional modifications. Furthermore, we focus special attention on the DNMTs’ specificity for target sites, including key cis-regulatory factors such as CpG content, common motifs, transcription factors (TF) binding sites, lncRNAs, and histone marks to regulate DNA methylation. We also review how complexes of DNMTs/TFs or DNMTs/lncRNAs are involved in DNA methylation in specific genome regions. Understanding these processes is essential because the spatiotemporal regulation of DNA methylation modulates gene expression in health and disease.
Resource type:
Article
Affiliation Label Tesim:
Department of Pharmacology
DOI:
https://doi.org/10.17615/apc7-ma42
Edition:
Publisher
Identifier:
PMID 33198240 and https://dx.doi.org/10.3390/genes11111336
ISSN:
2073-4425
Journal Issue:
11
Journal Title:
Genes
Journal Volume:
11
Keyword:
CpG content, Methylation, Consensus motifs, DNMT, and Histone marks and transcription factors
Language Label:
English
License Label:
Attribution 3.0 United States
Other Affiliation:
Universidad Autónoma de Guerrero
Page End:
19
Page Start:
1
Person:
Hernández-Sotelo, D., Loaeza-Loaeza, J., and Beltran, A.S.
Associations between blood metabolic profile at 7 years old and eating disorders in adolescence: Findings from the avon longitudinal study of parents and children
Creator:
Loos, R.J.F., Micali, N., Abdulkadir, M., De Stavola, B.L., Bulik, C.M., Herle, M., Lawlor, D.A., Ferreira, D.L.S., Hübel, C., and Bryant-Waugh, R.
Date of publication:
2019
Abstract Tesim:
Eating disorders are severe illnesses characterized by both psychiatric and metabolic factors. We explored the prospective role of metabolic risk in eating disorders in a UK cohort (n = 2929 participants), measuring 158 metabolic traits in non-fasting EDTA-plasma by nuclear magnetic resonance. We associated metabolic markers at 7 years (exposure) with risk for anorexia nervosa and binge-eating disorder (outcomes) at 14, 16, and 18 years using logistic regression adjusted for maternal education, child's sex, age, body mass index, and calorie intake at 7 years. Elevated very low-density lipoproteins, triglycerides, apolipoprotein-B/A, and monounsaturated fatty acids ratio were associated with lower odds of anorexia nervosa at age 18, while elevated high-density lipoproteins, docosahexaenoic acid and polyunsaturated fatty acids ratio, and fatty acid unsaturation were associated with higher risk for anorexia nervosa at 18 years. Elevated linoleic acid and n-6 fatty acid ratios were associated with lower odds of binge-eating disorder at 16 years, while elevated saturated fatty acid ratio was associated with higher odds of binge-eating disorder. Most associations had large confidence intervals and showed, for anorexia nervosa, different directions across time points. Overall, our results show some evidence for a role of metabolic factors in eating disorders development in adolescence.
Resource type:
Article
Affiliation Label Tesim:
Department of Psychiatry
DOI:
https://doi.org/10.17615/zgn0-mr11
Identifier:
https://dx.doi.org/10.3390/metabo9090191
ISSN:
2218-1989
Journal Issue:
9
Journal Title:
Metabolites
Journal Volume:
9
Keyword:
Binge-eating disorder, EDTA-plasma, Nuclear magnetic resonance, ALSPAC, Anorexia nervosa, Metabolomics, and Eating disorders
Language Label:
English
License Label:
Attribution 3.0 United States
Other Affiliation:
Icahn Mount Sinai School of Medicine, Geneva University Hospital, University of Geneva, University College London, University of Bristol, and Karolinska Institutet
Person:
Loos, R.J.F., Micali, N., Abdulkadir, M., De Stavola, B.L., Bulik, C.M., Herle, M., Lawlor, D.A., Ferreira, D.L.S., Hübel, C., and Bryant-Waugh, R.
A lean quality improvement initiative to enhance tobacco use treatment in a cancer hospital
Creator:
Goldstein, A.O., Wang, K., Ruebush, E., Meyer, C., Sisler, L., and Mitra, S.
Date of publication:
2020
Abstract Tesim:
Sustained tobacco use after cancer diagnosis decreases treatment effectiveness while increasing treatment side effects, primary cancer recurrence, and the occurrence of secondary cancers. Delivering tobacco use treatment to fewer patients due to inefficient workflow represents missed opportunities to deliver life-saving care. In 2017, the National Cancer Institute initiated the Cancer Cessation Initiative (C3I) to push new tobacco cessation resources into cancer centers across the United States. This grant allowed the University of North Carolina Tobacco Treatment Program (UNC TTP) to dramatically expand tobacco use treatment (TUT) services to patients at the North Carolina Cancer Hospital (NCCH). With this push, the team saw an opportunity to utilize Lean Six Sigma, a set of quality improvement (QI) tools, to streamline their processes and uncover the root causes of program inefficiencies. A 12-month QI project using the Lean A3 problem-solving tool was implemented to examine the team’s workflow. The study team mapped out the processes and, as a result, developed multiple “experiments” to test within the NCCH to address workflow efficiency and clinical reach. Outcome measures from the baseline to follow-up included: (1) the number of new patient referrals per month, and (2) the number of counseling sessions delivered per month. From the baseline to final state, the team’s referrals increased from a mean of 10 to 24 per month, and counseling sessions increased from a mean of 74 to 84 per month. This project provided a deeper understanding of how workflow inefficiencies can be eliminated in the clinical setting, how technology can be harnessed to increase reach, and finally, that soliciting and using feedback from NCCH leadership can remove barriers and improve patient care.
Resource type:
Article
Affiliation Label Tesim:
Department of Family Medicine and UNC Lineberger Comprehensive Cancer Center
DOI:
https://doi.org/10.17615/jb3g-1w17
Identifier:
PMID 32213994 and https://dx.doi.org/10.3390/ijerph17062165
ISSN:
1661-7827
Journal Issue:
6
Journal Title:
International Journal of Environmental Research and Public Health
Journal Volume:
17
Keyword:
Process improvement, Cancer patients, Tobacco use, and Smoking cessation
Language Label:
English
License Label:
Attribution 3.0 United States
Person:
Goldstein, A.O., Wang, K., Ruebush, E., Meyer, C., Sisler, L., and Mitra, S.
Using a family systems approach to treat tobacco use among cancer patients
Creator:
Goldstein, A.O., Sisler, L., Meyer, C., Mitra, S., and Ruebush, E.
Date of publication:
2020
Abstract Tesim:
Tobacco use treatment is an essential component of cancer care. Family members play a significant role in smoking behavior, but more research is needed regarding the development, implementation, and impact of family-based interventions in cancer care. The UNC Tobacco Treatment Program conducted an 18-month pilot study to examine the feasibility of implementing a family systems approach to treat tobacco use among patients at the North Carolina Cancer Hospital and to measure the impact of such an approach on patient abstinence. Implementation included four phases: (1) modifying the electronic health record and monthly report generated from the electronic health record; (2) training Tobacco Treatment Specialists to provide family counseling; (3) integrating family members into patients’ treatment; and (4) conducting six-month follow-up calls. During the course of the study, 42% (N = 221/532) of patients had family members integrated into their tobacco use treatment. Only 21 patients (4%) had family members present but not integrated into the treatment plan. At the six-month follow up time point, the seven-day point-prevalence quit rate for patients with family integration was 28% (N = 56/200), compared to 23% (N = 67/291) (p = 0.105) for patients without family integration. Integration of family members is clearly possible in an academic medical center’s oncology tobacco treatment program. Although pilot results were not statistically significant at 6 months, a potentially higher quit rate suggests a need for expanded research on methods to integrate family members in oncology settings for patients with tobacco-related cancers.
Resource type:
Article
Affiliation Label Tesim:
UNC Lineberger Comprehensive Cancer Center and Department of Family Medicine
DOI:
https://doi.org/10.17615/1yta-wm92
Identifier:
PMID 32204529 and https://dx.doi.org/10.3390/ijerph17062050
ISSN:
1661-7827
Journal Issue:
6
Journal Title:
International Journal of Environmental Research and Public Health
Journal Volume:
17
Keyword:
Family systems, Tobacco treatment, Cessation, Family interventions, and Smoking cessation
Language Label:
English
License Label:
Attribution 3.0 United States
ORCID:
Other Affiliation:
Person:
Goldstein, A.O., Sisler, L., Meyer, C., Mitra, S., and Ruebush, E.