Background: Crown-like structures in breast adipose tissue (CLS-B), composed of necrotic adipocytes encircled by macrophages, are associated with obesity and hypothesized to worsen breast cancer prognosis; however, data are sparse, particularly in multi-racial populations. Methods:We assessed specimens for CLS-B from 174 African-American and 168 White women with stage I-III breast cancer treated by mastectomy. Benign breast tissue from an uninvolved quadrant was immunohistochemically stained for CD68 to determine CLS-B presence and density (per cm 2 of adipose tissue). Demographic and lifestyle factors, collected via medical record review, were analyzed for associations with CLS-B using logistic regression. Multivariable Cox proportional hazards models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between CLS-B and overall (OS) or progression-free (PFS) survival.Results: Detection of any CLS-B was similar between African-American (32%) and White (29%) patients with no evidence of an association between race and CLS-B in multivariable models (OR = 0.82, 95% CI = 0.49-1.36). Detection of CLS-B was associated with obesity (OR = 4.73, 95% CI = 2.48-9.01) and age ≥ 60 years at diagnosis (OR = 1.78, 95% CI = 0.99-3.21). There was some evidence of associations with parity and current smoking status. Detection of CLS-B was not associated with OS (HR = 1.02, 95% CI = 0.55-1.87) or PFS (HR = 0.99, 95% CI = 0.59-1.67). Conclusions: Our results show a strong, positive association between BMI and CLS-B in non-tumor tissue similar to previous findings. Detection of CLS-B did not vary by race and was not associated with worse OS or PFS.
Zn2+ deficiency (ZnD) is a common comorbidity of many chronic diseases. In these settings, ZnD exacerbates hypertension. Whether ZnD alone is sufficient to alter blood pressure (BP) is unknown. To explore the role of Zn2+ in BP regulation, adult mice were fed a Zn2+-adequate (ZnA) or a Zn2+-deficient (ZnD) diet. A subset of ZnD mice were either returned to the ZnA diet or treated with hydrochlorothiazide (HCTZ), a Na+-Cl− cotransporter (NCC) inhibitor. To reduce intracellular Zn2+ in vitro, mouse distal convoluted tubule cells were cultured in N,N,N′,N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN, a Zn2+ chelator)- or vehicle (DMSO)-containing medium. To replete intracellular Zn2+, TPEN-exposed cells were then cultured in Zn2+-supplemented medium. ZnD promoted a biphasic BP response, characterized by episodes of high BP. BP increases were accompanied by reduced renal Na+ excretion and NCC upregulation. These effects were reversed in Zn2+-replete mice. Likewise, HCTZ stimulated natriuresis and reversed BP increases. In vitro, Zn2+ depletion increased NCC expression. Furthermore, TPEN promoted NCC surface localization and Na+ uptake activity. Zn2+ repletion reversed TPEN effects on NCC. These data indicate that 1) Zn2+ contributes to BP regulation via modulation of renal Na+ transport, 2) renal NCC mediates ZnD-induced hypertension, and 3) NCC is a Zn2+-regulated transporter that is upregulated with ZnD. This study links dysregulated renal Na+ handling to ZnD-induced hypertension. Furthermore, NCC is identified as a novel mechanism by which Zn2+ regulates BP. Understanding the mechanisms of ZnD-induced BP dysregulation may have an important therapeutic impact on hypertension.
Background: Calcineurin inhibitors (CNIs) are vital immunosuppressive therapies in the management of inflammatory conditions. A long-term consequence is nephrotoxicity. In the kidneys, the primary, catalytic calcineurin (CnA) isoforms are CnAα and CnAβ. While the renal phenotype of CnAα-/- mice substantially mirrors CNI-induced nephrotoxicity, the mechanisms downstream of CnAa are poorly understood. Hypothesis: Since NADPH oxidase-2 (Nox2)-derived oxidative damage is implicated in CNI-induced nephrotoxicity, we hypothesized that CnAα inhibition drives Nox2 upregulation and promotes oxidative stress. Experimental Design: To test the hypothesis, Nox2 regulation was investigated in kidneys from CnAα-/-, CnAβ-/- and WT littermate mice. To identify the downstream mediator of CnAα, NFAT and NFκB regulation was examined. To test if Nox2 is transcriptionally regulated via a NFκB pathway, CnAα-/- and WT renal fibroblasts were treated with the NFκB inhibitor, caffeic acid phenethyl ester. Results: Our findings showed that CsA treatment induced Nox2 upregulation and oxidative stress. Further, Nox2 upregulation and elevated ROS generation occurred only in CnAα-/- mice. In these mice, NFκB but not NFAT activity was increased. In CnAα-/- renal fibroblasts, NFκB inhibition prevented Nox2 upregulation and ROS generation. Conclusions: These findings indicate that 1) CnAα loss stimulates Nox2 upregulation, 2) NFκB is a novel CnAα-regulated transcription factor and 3) NFκB mediates CnAα-induced Nox2 and ROS upregulation. Significance: Our results demonstrate that CnAα plays a key role in Nox2 and ROS generation. Further, these novel findings provide evidence of divergent CnA isoform signaling pathways. Finally, this study advocates for CnAα-sparing CNIs, ultimately circumventing the CNI nephrotoxicity.
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