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Alcohol Consumption Is Associated with Poor Prognosis in Obese Patients with COVID-19: A Mendelian Randomization Study Using UK Biobank.
Fan, X, Liu, Z, Poulsen, KL, Wu, X, Miyata, T, Dasarathy, S, Rotroff, DM, Nagy, LE
Nutrients. 2021;(5)
Abstract
BACKGROUND Acute and chronic alcohol abuse has adverse impacts on both the innate and adaptive immune response, which may result in reduced resistance to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and promote the progression of coronavirus disease 2019 (COVID-19). However, there are no large population-based data evaluating potential causal associations between alcohol consumption and COVID-19. METHODS We conducted a Mendelian randomization study using data from UK Biobank to explore the association between alcohol consumption and risk of SARS-CoV-2 infection and serious clinical outcomes in patients with COVID-19. A total of 12,937 participants aged 50-83 who tested for SARS-CoV-2 between 16 March to 27 July 2020 (12.1% tested positive) were included in the analysis. The exposure factor was alcohol consumption. Main outcomes were SARS-CoV-2 positivity and death in COVID-19 patients. We generated allele scores using three genetic variants (rs1229984 (Alcohol Dehydrogenase 1B, ADH1B), rs1260326 (Glucokinase Regulator, GCKR), and rs13107325 (Solute Carrier Family 39 Member 8, SLC39A8)) and applied the allele scores as the instrumental variables to assess the effect of alcohol consumption on outcomes. Analyses were conducted separately for white participants with and without obesity. RESULTS Of the 12,937 participants, 4496 were never or infrequent drinkers and 8441 were frequent drinkers. Both logistic regression and Mendelian randomization analyses found no evidence that alcohol consumption was associated with risk of SARS-CoV-2 infection in participants either with or without obesity (All q > 0.10). However, frequent drinking, especially heavy drinking (HR = 2.07, 95%CI 1.24-3.47; q = 0.054), was associated with higher risk of death in patients with obesity and COVID-19, but not in patients without obesity. Notably, the risk of death in frequent drinkers with obesity increased slightly with the average amount of alcohol consumed weekly (All q < 0.10). CONCLUSIONS Our findings suggest that alcohol consumption has adverse effects on the progression of COVID-19 in white participants with obesity, but was not associated with susceptibility to SARS-CoV-2 infection.
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Decreased expression of CTR2 predicts poor prognosis of patients with clear cell renal cell carcinoma.
Xia, Y, Liu, L, Long, Q, Bai, Q, Wang, J, Xu, J, Guo, J
Urologic oncology. 2016;(1):5.e1-9
Abstract
PURPOSE Clear cell renal cell carcinoma (ccRCC) is well known for its hypervascularity due to the Von Hippel-Lindau/hypoxia-inducible factor dysregulation. Recent findings suggested that copper transporter 2 (CTR2) is also associated with angiogenesis through copper׳s modulation of the hypoxia-inducible factor pathway. Our group thus explored the prognostic role of CTR2 in patients with ccRCC. MATERIALS AND METHODS A total of 331 patients with ccRCC who underwent nephrectomy were enrolled between February 2005 and June 2007 at a single institution. The median follow-up was 98.97 months (2.63-120.47mo). Patients׳ samples were collected and stained for CTR2 by immunohistochemistry. The staining intensity was analyzed quantitatively and defined as high/low expression using X-tile software. Stage, Size, Grade, and Necrosis score and University of California Los Angeles Integrated Staging System score were applied to stratify patients׳ risks. Survival analyses were performed through the Kaplan-Meier method and Cox proportional hazard model. After integrating tumoral CTR2 expression with other clinical parameters, 2 nomograms were generated for overall survival (OS) and disease-free survival (DFS) prediction. RESULTS CTR2 expression in ccRCC was decreased compared with that in the peritumoral tissue (P<0.001) and negatively correlated with many other clinical parameters. In survival analyses using the Kaplan-Meier method, low tumoral CTR2 expression displayed a dismal prognostic effect both in OS and DFS prediction (P<0.001). Multivariate analyses also revealed the same result after adjusted with other clinical parameters (P<0.001). Stratifying patients into 3 risk levels using the Stage, Size, Grade, and Necrosis score and University of California Los Angeles Integrated Staging System score, decreased CTR2 expression associated with shorter OS and DFS in the low- and intermediate-risk groups. Moreover, the generated nomogram integrating tumoral CTR2 expression performed better in predicting patients׳ OS than using TNM stages alone (c-index = 0.799; 95% CI: 0.752-0.846 vs. 0.691; 95% CI: 0.637-0.745). CONCLUSIONS CTR2 is a novel prognostic marker for patients with ccRCC both in OS and DFS prediction, and could be incorporated with other clinical parameters for better patient risk stratification.
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Duodenal ferroportin is up-regulated in patients with chronic hepatitis C.
Ma, L, Zou, T, Yuan, Y, Lv, J, Dong, X, Yang, G, Zhu, Y, Luo, J, Zhang, Z, Yang, J
PloS one. 2014;(10):e110658
Abstract
Hepatitis C virus (HCV) infection is a leading cause of liver-related mortality. Chronic hepatitis C (CHC) is frequently associated with disturbances in iron homeostasis, with serum iron and hepatic iron stores being elevated. Accumulating evidence indicates that chronic HCV infection suppresses expression of hepatic hepcidin, a key mediator of iron homeostasis, leading to iron overload conditions. Since hepcidin mediates degradation of ferroportin, a basolateral transporter involved in the release of iron from cells, diminished hepcidin expression probably leads to up-regulation of ferroportin-1 (Fpn1) in patients with CHC. In this study, we determined the protein levels of duodenal Fpn1, and found that its expression was significantly up-regulated in patients with CHC. The expression of duodenal Fpn1 is negatively correlated with mRNA levels of hepcidin, and positively correlated with serum iron parameters. Although iron is a critical factor for growth of a variety of pathogenic bacteria, our results suggest that iron overload in blood does not increase the infection rate of bacteria in patients with CHC.
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Phase IIa study of the immunogenicity and safety of the novel Staphylococcus aureus vaccine V710 in adults with end-stage renal disease receiving hemodialysis.
Moustafa, M, Aronoff, GR, Chandran, C, Hartzel, JS, Smugar, SS, Galphin, CM, Mailloux, LU, Brown, E, Dinubile, MJ, Kartsonis, NA, et al
Clinical and vaccine immunology : CVI. 2012;(9):1509-16
Abstract
Bacteremia is the second leading cause of death in patients with end-stage renal disease who are on hemodialysis. A vaccine eliciting long-term immune responses against Staphylococcus aureus in patients on chronic hemodialysis may reduce the incidence of bacteremia and its complications in these patients. V710 is a vaccine containing iron surface determinant B (IsdB), a highly conserved S. aureus surface protein, which has been shown to be immunogenic in healthy subjects. In this blinded phase II immunogenicity study, 206 chronic hemodialysis patients between the ages of 18 and 80 years old were randomized to receive 60 μg V710 (with or without adjuvant), 90 μg V710 (with adjuvant), or a placebo in various combinations on days 1, 28, and 180. All 201 vaccinated patients were to be followed through day 360. The primary hypothesis was that at least 1 of the 3 groups receiving 2 V710 doses on days 1 and 28 would have a ≥2.5 geometric mean fold rise (GMFR) in anti-IsdB IgG titers over the baseline 28 days after the second vaccination (day 56). At day 56, all three groups receiving 2 doses of V710 achieved a ≥2.5 GMFR in anti-IsdB antibodies compared to the baseline (P values of <0.001 for all 3 groups), satisfying the primary immunogenicity hypothesis. None of the 33 reported serious adverse experiences were considered vaccine related by the investigators. V710 induced sustained antibody responses for at least 1 year postvaccination in patients on chronic hemodialysis.
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The immunogenicity and safety of different formulations of a novel Staphylococcus aureus vaccine (V710): results of two Phase I studies.
Harro, CD, Betts, RF, Hartzel, JS, Onorato, MT, Lipka, J, Smugar, SS, Kartsonis, NA
Vaccine. 2012;(9):1729-36
Abstract
Merck V710 is a novel vaccine that contains the highly conserved Staphylococcus aureus iron surface determinant B (IsdB) protein. V710 has induced positive immune responses in healthy subjects. The purpose of the two studies described herein was to evaluate the immunogenicity and safety of two different formulations of V710. Both studies were randomized, controlled, double-blind, parallel-group trials. Study 1 compared liquid, aluminum-adjuvanted V710 (30 μg) with liquid, non-adjuvanted V710 (30 μg) in a 1:1 ratio in 64 healthy adults (18-70 years). Study 2 compared non-adjuvanted lyophilized V710 (60 μg) with saline placebo in a 4:1 ratio in 51 healthy adults (18-80 years). Blood was collected at screening and up to Day 360 postvaccination in Study 1, and at screening and up to Day 84 postvaccination in Study 2. Sera were analyzed for IsdB-specific antibodies using a total IgG assay. The primary endpoints in Study 1 were the proportion of patients with a positive immune response (≥2-fold rise in IsdB-specific IgG antibody level) the geometric mean concentration (GMC), and the geometric mean-fold rise (GMFR), all from baseline at Day 14. The primary endpoint in Study 2 was the GMFR in IsdB-specific IgG antibody concentration from baseline at Day 14. In Study 1, 84.4% responded in the adjuvanted V710 group, and 71.9% in the non-adjuvanted V710 group. The GMC was 115.4 μg/mL in the adjuvanted group and 99.1 μg/mL in the nonadjuvanted group. The GMFR in antibody concentration in the group receiving aluminum-adjuvanted V710 was 4.5 and the GMFR in the group receiving non-adjuvanted V710 was 4.0. In Study 2, the GMFR in antibody concentration in the V710 group was 5.3, and 80.5% had a positive immune response. None responded in the placebo group. Positive immune response was seen in the active treatment groups over the full duration of each study. There were no serious adverse experiences (AE) in either study, and no patients discontinued due to an AE. There were no clinically meaningful differences in AEs between groups in either study. In conclusion, V710, both with and without aluminum adjuvant, and in both liquid and lyophilized formulations, was immunogenic within 14 days of vaccination. All treatments showed similar safety profiles.
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Zinc supplementation of young men alters metallothionein, zinc transporter, and cytokine gene expression in leukocyte populations.
Aydemir, TB, Blanchard, RK, Cousins, RJ
Proceedings of the National Academy of Sciences of the United States of America. 2006;(6):1699-704
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Abstract
An effective measure to assess zinc status of humans has remained elusive, in contrast to iron, where a number of indicators of metabolism/function are available. Using monocytes, T lymphocytes, and granulocytes isolated by magnetic sorting and dried blood spots (DBS) derived from 50 mul of peripheral blood, we evaluated the response of metallothionein (MT), zinc transporter, and cytokine genes to a modest (15 mg of Zn per day) dietary zinc supplement in human subjects. Transcript abundance was measured by quantitative real-time RT-PCR (QRT-PCR). Zinc supplementation increased MT mRNA abundance by up to 2-fold in RNA from leukocyte subsets, and 4-fold in RNA from DBS. Transcript levels for the zinc transporter genes ZnT1 and Zip3 were increased and decreased, respectively, by zinc supplementation. Expression of the ZnT and Zip genes among leukocyte subsets differ by up to 270-fold. Monocytes and granulocytes from supplemented subjects were activated by LPS, whereas T lymphocytes were activated by mimicking antigen presentation. With zinc consumption, TNF-alpha and IL-1beta expression was greater in activated monocytes and granulocytes, and IFN-gamma mRNA levels were higher in activated T lymphocytes. These studies show that QRT-PCR is a tool to reliably measure transcript abundance for nutritionally responsive genes in human subjects, and that a small sample of whole dried blood, when appropriately collected, can be used as the source of total RNA for QRT-PCR analysis. The results obtained also show that zinc supplementation of human subjects programs specific leukocytic subsets to show enhanced cytokine expression upon activation by stimulators of immunity.