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Immune mechanisms have been recognized to have a role in the pathogenesis of hypertension, vascular disease and kidney damage in humans and animals for many decades. Contemporary advances in experimentation have permitted a deeper understanding of the mechanisms by which inflammation and immunity participate in cardiovascular disease, and multiple observations have demonstrated strong correlations between the discoveries made in animals and those made in patients with hypertension. Of note, striking phenotypic similarities have been observed in the infiltration of immune cells in the kidney and the development of end-organ damage in patients and animal models with sodium-sensitive hypertension. The available data suggest that an initial salt-induced increase in renal perfusion pressure, which is likely independent of immune mechanisms, induces the infiltration of immune cells into the kidney. The mechanisms mediating immune cell infiltration in the kidney are not well understood but likely involve tissue damage, the direct influence of salt to stimulate immune cell activation, sympathetic nerve stimulation or other factors. The infiltrating cells then release cytokines, free radicals and other factors that contribute to renal damage as well as increased retention of sodium and water and vascular resistance, which lead to the further development of hypertension.Immune mechanisms have important roles in the development of hypertension and end-organ damage. In this Review, David Mattson discusses these mechanisms with a focus on salt-sensitive hypertension and adaptive immunity.

Background Some patients with rectal cancer who receive neoadjuvant chemoradiotherapy (nCRT) achieve a pathologic complete response (pCR) and may be eligible for less radical surgery or non-operative management. The aim of this study was to identify variables that predict pCR after nCRT for rectal cancer and to examine the impact of pCR on postoperative complications. Methods A retrospective review was performed of the NCDB from 2006 to 2011. Patients with rectal cancer who received nCRT followed by radical resection were included in this study. Multivariable analysis of the association between clinicopathologic characteristics and pCR was performed, and propensity-adjusted analysis was used to identify differences in postoperative morbidity between pCR and non-pCR patients. Results A total of 23,747 patients were included in the study. Factors associated with pCR included lower tumor grade, lower clinical T and N stage, higher radiation dose, and delaying surgery by more than 6–8 weeks after the end of radiation, while lack of health insurance was linked with a lower likelihood of pCR. Complete response was not associated with an increased risk of major postoperative complications. Conclusions Several clinical, pathologic, and treatment variables can help to predict which patients are most likely to have pCR after nCRT for rectal cancer. Awareness of these variables can be valuable in counseling patients regarding prognosis and treatment options.

Research studying the role of inflammation in hypertension and cardiovascular disease has flourished in recent years; however, the exact mechanisms by which the activated immune cells lead to the development and maintenance of hypertension remain to be elucidated. The objectives of this brief review are to summarize and discuss the most recent findings in the field, with special emphasis on potential therapeutics to treat or prevent hypertension. This review will cover novel immune cell subtypes recently associated to the disease including the novel role of cytokines, toll-like receptors, and inflammasomes in hypertension.

Purpose Acute skin toxicity is one of the most common side effects of breast cancer radiotherapy. To date, no one has estimated the nonmedical out-of-pocket expenses associated with this side effect. The primary aim of the present descriptive, exploratory study was to assess the feasibility of a newly developed skin toxicity costs questionnaire. The secondary aims were to: (1) estimate nonmedical out-of-pocket costs, (2) examine the nature of the costs, (3) explore potential background predictors of costs, and (4) explore the relationship between patient-reported dermatologic quality of life and expenditures. Methods A total of 50 patients (mean age = 54.88, Stage 0–III) undergoing external beam radiotherapy completed a demographics/medical history questionnaire as well as a seven-item Skin Toxicity Costs (STC) questionnaire and the Skindex-16 in week 5 of treatment. Results Mean skin toxicity costs were $131.64 (standard error [SE] = $23.68). Most frequently incurred expenditures were new undergarments and products to manage toxicity. Education was a significant unique predictor of spending, with more educated women spending more money. Greater functioning impairment was associated with greater costs. The STC proved to be a practical, brief measure which successfully indicated specific areas of patient expenditures and need. Conclusions Results reveal the nonmedical, out-of-pocket costs associated with acute skin toxicity in the context of breast cancer radiotherapy. To our knowledge, this study is the first to quantify individual costs associated with this treatment side effect, as well as the first to present a scale specifically designed to assess such costs. Relevance In future research, the STC could be used as an outcome variable in skin toxicity prevention and control research, as a behavioral indicator of symptom burden, or as part of a needs assessment.

Background Esophageal cancer (ESC) is an aggressive disease which often presents at an advanced stage. Despite trimodal therapy, 40–50% patients can develop metastatic disease by 18 months. Identification of patients at risk for metastatic spread is challenging with need for improved prognostication. We investigated whether the immune landscape of pretreatment tissue was associated with relapse in ESC patients. Methods Between April 2010 and October 2018, we identified 25 patients who had undergone trimodal therapy for ESC and had pretreatment biopsies suitable for analyses. We performed high-throughput multispectral immunofluorescence (mIF) analysis on formalin-fixed paraffin embedded biopsy samples. Analysis of 27 unique populations via immune and exhaustion mIF panels was performed and expression was normalized to total cell counts. Results Of the 25 patients analyzed, the median follow-up time was 23.9 months, during which 12 (48%) patients suffered a relapse with a median time to progression of 13.1 months. mIF revealed higher expression of HLA-DR ( p  = 0.019), CD8/LAG3 ( p  = 0.046), and CD8/CTLA4 ( p  = 0.027) among patients without relapse. Time to progression (TTP) and disease-specific survival (DSS) were stratified by median expression of each significant subpopulation and formally tested by the log-rank test. Higher than median expression of HLA-DR ( p  = 0.027), CD8/LAG3 ( p  = 0.039), and CD8/CTLA4 ( p  = 0.039) were significantly associated with TTP. Similarly, HLA-DR ( p  = 0.0069) and CD8/CTLA4 ( p  = 0.036) were significantly associated with improved DSS, whereas no significant observations were found with CD8/LAG3 ( p  = 0.11) expression. Stromal, but not tumoral expression of CD163 and CD163/PDL1 were significantly associated with improved TTP and DSS. Conclusions High expression of HLA-DR, CD8/CTLA4, and stromal expression of CD163 and CD163/PDL1 within pretreatment biopsy ESC samples was associated with significantly reduced rates of relapse. Increased presence of these markers suggests that an improved immune landscape is associated with less aggressive disease and may provide an opportunity for risk-based treatment strategies.

Purpose of ReviewIn this article, we summarize the current literature supporting metabolic and redox signaling pathways as important mechanisms underlying T cell activation in the context of hypertension.Recent FindingsT cell immunometabolism undergoes dramatic remodeling in order to meet the demands of T cell activation, differentiation, and proliferation. Recent evidence demonstrates that the T cell oxidation–reduction (redox) system also undergoes significant changes upon activation, which can itself modulate metabolic processes and T cell function. Dysregulation of these signaling pathways can lead to aberrant T cell activation and inappropriate ROS production, both of which are linked to pathological conditions like hypertension.SummaryWhile the contribution of T cells to the progression of hypertension has been thoroughly investigated, how T cell metabolism and redox signaling changes, both separately and together, is an area of study that remains largely untouched. This review presents evidence from our own laboratory as well as others to highlight the importance of these two mechanisms in the study of hypertension.

Tumor necrosis factor α (TNFα) is a major proinflammatory cytokine and its level is elevated in hypertensive states. Inflammation occurs in the kidneys during the development of hypertension. We hypothesized that TNFα specifically in the kidney contributes to the development of hypertension and renal injury in Dahl salt-sensitive (SS) rats, a widely used model of human salt-sensitive hypertension and renal injury. SS rats were chronically instrumented for renal interstitial infusion and blood pressure measurement in conscious, freely moving state. Gene expression was measured using real-time PCR and renal injury assessed with histological analysis. The abundance of TNFα in the renal medulla of SS rats, but not the salt-insensitive congenic SS.13 BN26 rats, was significantly increased when rats had been fed a high-salt diet for 7 days (n = 6 or 9, p < 0.01). The abundance of TNFα receptors in the renal medulla was significantly higher in SS rats than SS.13 BN26 rats. Renal interstitial administration of Etanercept, an inhibitor of TNFα, significantly attenuated the development of hypertension in SS rats on a high-salt diet (n = 7–8, p < 0.05). Glomerulosclerosis and interstitial fibrosis were also significantly ameliorated. These findings indicate intrarenal TNFα contributes to the development of hypertension and renal injury in SS rats.

Atherosclerosis remains a major cause of death in the developed world despite the success of therapies that lower cholesterol and BP. The intermediate-conductance calcium-activated potassium channel KCa3.1 is expressed in multiple cell types implicated in atherogenesis, and pharmacological blockade of this channel inhibits VSMC and lymphocyte activation in rats and mice. We found that coronary vessels from patients with coronary artery disease expressed elevated levels of KCa3.1. In Apoe(-/-) mice, a genetic model of atherosclerosis, KCa3.1 expression was elevated in the VSMCs, macrophages, and T lymphocytes that infiltrated atherosclerotic lesions. Selective pharmacological blockade and gene silencing of KCa3.1 suppressed proliferation, migration, and oxidative stress of human VSMCs. Furthermore, VSMC proliferation and macrophage activation were reduced in KCa3.1(-/-) mice. In vivo therapy with 2 KCa3.1 blockers, TRAM-34 and clotrimazole, significantly reduced the development of atherosclerosis in aortas of Apoe(-/-) mice by suppressing VSMC proliferation and migration into plaques, decreasing infiltration of plaques by macrophages and T lymphocytes, and reducing oxidative stress. Therapeutic concentrations of TRAM-34 in mice caused no discernible toxicity after repeated dosing and did not compromise the immune response to influenza virus. These data suggest that KCa3.1 blockers represent a promising therapeutic strategy for atherosclerosis.