Mitochondria support critical cellular functions, such as energy production through oxidative phosphorylation, regulation of reactive oxygen species, apoptosis, and calcium homeostasis. Given the ...heightened level of cellular activity in patients with asthma, we sought to determine whether mitochondrial DNA (mtDNA) copy number measured in peripheral blood differed between individuals with and without asthma. Whole genome sequence data was generated as part of the Trans-Omics for Precision Medicine (TOPMed) Program on participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) and the Study of African Americans, Asthma, Genes, & Environment II (SAGE II). We restricted our analysis to individuals who self-identified as African American (3,651 asthma cases and 1,344 controls). Mitochondrial copy number was estimated using the sequencing read depth ratio for the mitochondrial and nuclear genomes. Respiratory complex expression was assessed using RNA-sequencing. Average mitochondrial copy number was significantly higher among individuals with asthma when compared with controls (SAPPHIRE: 218.60 vs. 200.47, P<0.001; SAGE II: 235.99 vs. 223.07, P<0.001). Asthma status was significantly associated with mitochondrial copy number after accounting for potential explanatory variables, such as participant age, sex, leukocyte counts, and mitochondrial haplogroup. Despite the consistent relationship between asthma status and mitochondrial copy number, the latter was not associated with time-to-exacerbation or patient-reported asthma control. Mitochondrial respiratory complex gene expression was disproportionately lower in individuals with asthma when compared with individuals without asthma and other protein-encoding genes. We observed a robust association between asthma and higher mitochondrial copy number. Asthma having an effect on mitochondria function was also supported by lower respiratory complex gene expression in this group.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background: Inflammatory cells such as tumor infiltrating lymphocytes (comprising T and B cells) are often present in prostate tissue undergoing tumorigenesis but their role in disease ...progression is unclear. The current study aims to characterize the expression dynamics of CD3, CD4 and CD20 lymphocytes from the pre- to post-malignant prostate environment and the association of these dynamics with aggressive prostate cancer.
Methods: The study sample included 72 prostate cancer cases (44 whites and 28 African American) that underwent surgery as their primary treatment and had a benign prostate biopsy at least one year before diagnosis and were followed for biochemical recurrence (BCR). Counts of CD3-, CD4- and CD20-positive lymphocytes were quantified by immunohistochemistry using an automated multi-image processing procedure in pre-malignant benign biopsy (BB), tumor-adjacent benign (TAB) and malignant tumor glandular (MTG) regions of prostatectomy. A cox proportional hazards model was used to estimate the hazard ratio (HR) of time to BCR associated with inflammatory marker count in different regions of the prostate. Clustering was performed to identify similar trends of expression changes of CD3, CD4 and CD20 between the regions - BB, TAG and MTG using Time-series Anytime Density Peaks Clustering (TADPole).
Results: The risk of BCR was significantly reduced in men who had an elevated CD20 count in the TAG (HR=0.80, p=0.01) after adjusting for race, age at diagnosis, PSA at the time of benign biopsy and the Gleason grade group. CD3 and CD4 counts in the prostate regions did not show any significant association to BCR. TADPole identified four main different patterns of CD20 expression changes across the BB-TAB-MTG regions namely 1) minimal to no change in expression between the regions (n=45 pairs); 2) high expression in BB/no expression in TAG/higher expression in MTG (n=3 pairs); 3) high expression in BB/higher expression in TAG/no expression in MTG (n=8 pairs); 4) no expression in BB/higher expression in TAG compared to MTG (n=16 pairs). In comparison to the reference group (Cluster 1), Cluster 4 was at 3.5 times higher risk of BCR with an adjusted HR of 3.5 (p=0.0184).
Conclusion: Elevated CD20 expression in TAG was associated with less aggressive disease. Furthermore, cases that had CD20 expression highest in their benign prostate adjacent to tumor preceded by absence of CD20 expression in their pre-malignant benign prostate had the most aggressive disease course. Further studies are warranted to understand how CD20 lymphocyte dynamic changes influence prostate tumorigenesis.
Citation Format: Sudha M. Sadasivan, Yalei Chen, Nilesh S. Gupta, Ryan Sanii, Kevin R. Bobbitt, Dhananjay A. Chitale, Sean R. Williamson, Andrew G. Rundle, Deliang Tang, Benjamin A. Rybicki. Change in B cell lymphocyte expression from the pre- to post-malignant prostate predicts disease aggressiveness abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 80.
Keywords: African Americans; cytokine; immunohistochemistry; inflammation; odds ratio ABSTRACT Growth and differentiation factor 15 (GDF-15), also known as macrophage inhibitory cytokine 1 (MIC-1), ...may act as both a tumor suppressor and promotor and, by regulating NF-PHIB and macrophage signaling, promote early prostate carcinogenesis. To determine whether expression of these two inflammation-related proteins affect prostate cancer susceptibility, dual immunostaining of benign prostate biopsies for GDF-15 and NF-PHIB was done in a study of 503 case-control pairs matched on date, age, and race, nested within a historical cohort of 10,478 men. GDF-15 and NF-PHIB expression levels were positively correlated (r = 0.39; p < 0.0001), and both were significantly lower in African American (AA) compared with White men. In adjusted models that included both markers, the odds ratio (OR) for NF-PHIB expression was statistically significant, OR =0.87; p = 0.03; 95% confidence interval (CI) =0.77-0.99, while GDF-15 expression was associated with a nominally increased risk, OR =1.06; p = 0.27; 95% CI =0.96-1.17. When modeling expression levels by quartiles, the highest quartile of NF-PHIB expression was associated with almost a fifty percent reduction in prostate cancer risk (OR =0.51; p = 0.03; 95% CI =0.29-0.92). In stratified models, NF-PHIB had the strongest negative association with prostate cancer in non-aggressive cases (p = 0.03), older men (p = 0.03), and in case-control pairs with longer follow-up (p = 0.02). Risk associated with GDF-15 expression was best fit using nonlinear regression modeling where both first (p = 0.02) and second (p = 0.03) order GDF-15 risk terms were associated with significantly increased risk. This modeling approach also revealed significantly increased risk associated with GDF-15 expression for subsamples defined by AA race, aggressive disease, younger age, and in case-control pairs with longer follow-up. Therefore, although positively correlated in benign prostatic biopsies, NF-PHIB and GDF-15 expression appear to exert opposite effects on risk of prostate tumor development. CAPTION(S): Fig S1 Fig S2 Fig S3 Fig S4 Supplementary Material Table S1-S4 Byline: Benjamin A. Rybicki, Sudha M. Sadasivan, Yalei Chen, Oleksandr Kravtsov, Watchareepohn Palangmonthip, Kanika Arora, Nilesh S. Gupta, Sean Williamson, Kevin Bobbitt, Dhananjay A. Chitale, Deliang Tang, Andrew G. Rundle, Kenneth A. Iczkowski
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
The infant gut's ability to suppress immunologic reactions to food proteins could be influenced by levels of TGFβ in breast milk. We hypothesized that lower levels of TGFβ1 in the breast ...milk (BM) of mothers in the WHEALS birth cohort are associated with atopy at infant age 2–3 yrs.
Methods
We used data collected during infancy in addition to the results of skin prick tests (SPT+) and measures of specific IgE >0.35 IU/ml (spIgE) to milk, egg, and peanut at infant age 2–3 years. Infants were classified as food allergic (FA) based on parental report of infant symptoms/diagnoses and information from clinical assessments.
Results
Data for 304 cohort members were analyzed. Among non‐black infants, BM‐TGFβ1 was lower for those classified as FA (vs. no FA) and those SPT+ (vs., SPT‐), geometric mean = 1100 pg/ml vs. 1417pg/ml, p = 0.081; and 1100 pg/ml vs. 1415pg/ml, p = 0.064, respectively. Among infants of non‐atopic mothers, BM‐TGFβ1 was lower for those with elevated (vs. not elevated) sIgE, geometric mean = 1347 pg/ml vs. 1651 pg/ml, p = 0.047. Using logistic regression, adjusted odds ratios describing the association of BM‐TGFβ1 to the presence of atopic indicators in the infant were in the hypothesized direction only for non‐black infants of non‐atopic mothers: aORs for FA, sIgE and SPT+ were 0.08, 0.34, and 0.26 respectively; p = 0.091, 0.13, and 0.23.
Conclusion
Immune benefit of BM‐TGFβ1 could inform prevention strategies. Evidence of an association appears greatly influenced by infant race and maternal atopy. More research can determine if these relationships represent a modifiable risk factor for the development of food allergy in certain subgroups.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Photochemical generation of dimethylsilylene, methyl(phenyl)silylene and diphenylsilylene in the presence of high concentrations of 1,3-butadiene leads to the formation of ...1-sila-3,4-divinylcyclopentanes as major products in addition to the anticipated 1-silacyclopent-3-enes. Also obtained are the ene-reaction products from the silenes, formed by formal 1,3-silyl shifts in the bis(trimethylsilyl)arylsilanes that are employed as the photochemical precursors of MePhSi: and Ph
2Si:. Evidence is presented that both the divinylsilacyclopentanes and the silacyclopent-3-enes arise from vinylsilirane intermediates that can be trapped by acetone, yielding stable 3,3-dimethyl-4-vinyl-1-sila-2-oxolanes.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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