The Role of Obesity in Breast Cancer Pathogenesis.

Research has shown that obesity increases the risk for type 2 diabetes mellitus (Type 2 DM) by promoting insulin resistance, increases serum estrogen levels by the upregulation of aromatase, and promotes the release of reactive oxygen species (ROS) by macrophages. Increased circulating glucose has been shown to activate mammalian target of rapamycin (mTOR), a significant signaling pathway in breast cancer pathogenesis. Estrogen plays an instrumental role in estrogen-receptor-positive breast cancers. The role of ROS in breast cancer warrants continued investigation, in relation to both pathogenesis and treatment of breast cancer. We aim to review the role of obesity in breast cancer pathogenesis and novel therapies mediating obesity-associated breast cancer development. We explore the association between body mass index (BMI) and breast cancer incidence and the mechanisms by which oxidative stress modulates breast cancer pathogenesis. We discuss the role of glutathione, a ubiquitous antioxidant, in breast cancer therapy. Lastly, we review breast cancer therapies targeting mTOR signaling, leptin signaling, blood sugar reduction, and novel immunotherapy targets.

A Rare Case of Cutaneous Metastasis of Renal Cell Carcinoma to the Lateral Thigh.

Renal cell carcinoma (RCC) is a common cancer type in the United States, and at the time of diagnosis, many patients already have metastatic disease. RCC typically metastasizes to the lungs, liver, and bones, with few cases manifesting cutaneous metastasis. Most incidences of RCC metastases reported in the literature have been on the face and scalp. We discuss a case of a 64-year-old male patient who presented with a history of RCC and a purpuric nodule on his lateral thigh. Histopathological examination revealed vacuolated cytoplasm with areas of cytoplasmic clearing; the cells stained positively for cytokeratin AE1/AE3, CAM5.2, and PAX8. Cutaneous metastatic RCC was subsequently diagnosed. Cutaneous manifestations of RCC, particularly to the thigh, remain a rare presentation of metastatic RCC.

The Role of Glutathione in Prevention of COVID-19 Immunothrombosis: A Review.

Immunothrombosis has emerged as a dominant pathological process exacerbating morbidity and mortality in acute- and long-COVID-19 infections. The hypercoagulable state is due in part to immune system dysregulation, inflammation and endothelial cell damage, as well as a reduction in defense systems. One defense mechanism in particular is glutathione (GSH), a ubiquitously found antioxidant. Evidence suggests that reduction in GSH increases viral replication, pro-inflammatory cytokine release, and thrombosis, as well as decreases macrophage-mediated fibrin removal. The collection of adverse effects as a result of GSH depletion in states like COVID-19 suggest that GSH depletion is a dominant mechanism of immunothrombosis cascade. We aim to review the current literature on the influence of GSH on COVID-19 immunothrombosis pathogenesis, as well as the beneficial effects of GSH as a novel therapeutic for acute- and long-COVID-19.

Negative Influence of Insufficient Sleep on Endothelial Vasodilator and Fibrinolytic Function in Hypertensive Adults.

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A Novel Regimen for Treating Melanoma: MCL1 Inhibitors and Azacitidine.

Although treatment options for melanoma patients have expanded in recent years with the approval of immunotherapy and targeted therapy, there is still an unmet need for new treatment options for patients that are ineligible for, or resistant to these therapies. BH3 mimetics, drugs that mimic the activity of pro-apoptotic BCL2 family proteins, have recently achieved remarkable success in the clinical setting. The combination of BH3 mimetic ABT-199 (venetoclax) plus azacitidine has shown substantial benefit in treating acute myelogenous leukemia. We evaluated the efficacy of various combinations of BH3 mimetic + azacitidine in fourteen human melanoma cell lines from cutaneous, mucosal, acral and uveal subtypes. Using a combination of cell viability assay, BCL2 family knockdown cell lines, live cell imaging, and sphere formation assay, we found that combining inhibition of MCL1, an anti-apoptotic BCL2 protein, with azacitidine had substantial pro-apoptotic effects in multiple melanoma cell lines. Specifically, this combination reduced cell viability, proliferation, sphere formation, and induced apoptosis. In addition, this combination is highly effective at reducing cell viability in rare mucosal and uveal subtypes. Overall, our data suggest this combination as a promising therapeutic option for some patients with melanoma and should be further explored in clinical trials.

Outcomes After Accelerated Partial Breast Irradiation in Women With Triple Negative Subtype and Other "High Risk" Variables Categorized as Cautionary in The ASTRO Guidelines.

PURPOSE: To report a primary objective clinical outcome of ipsilateral breast recurrence following accelerated partial breast irradiation (APBI) in women with triple negative and other high risk breast cancer (as described in 2017 ASTRO guidelines) (i.e., age 40-49, size 2.1-3.0 cm, estrogen receptor negative and invasive lobular breast cancer). Secondary objectives of axillary and regional failure as well as overall survival are also reported. METHODS AND MATERIAL: Patients from two clinical trials (NCT01185145, NCT01185132) were treated with 38.5 Gy IMRT or 3D-CRT APBI w/3.85 Gy fraction/BID fractionation for 10 fractions. Triple negative and other high risk patients (n=269) were compared to a total of 478 low risk patients which ASTRO defined as "suitable" for APBI. High risk patients, for the purpose of this study, were defined as those who possess one or more high risk criteria: triple negative (n=30), tumor size >2 cm <3 cm (n=50), HER 2+ (n=54), age range 40-50 years (n=120), ER- (n=43), and ILC histology (n=52). RESULTS: Median follow up was 4.0 years for all patients. No significant difference was found for this high-risk cohort at 5 years for ipsilateral breast, or regional recurrences. Axillary recurrence was significantly adversely impacted by triple negative and ER- statuses (p=0.01, p=0.04). There were significant correlations between triple negative type and axillary recurrence on multivariate analysis (p=0.03). Overall survival for all patients was unaffected by any of the high-risk categories. CONCLUSION: The data from this study suggests that women possessing high risk features are at no more meaningful risk for recurrence than other patients considered to be acceptable for APBI treatment. However, the finding of axillary recurrence in patients with triple negative breast cancer does warrant a degree of caution in proceeding with accelerated partial breast irradiation technique in this patient group.

Endothelin-1-induced endothelial microvesicles impair endothelial cell function.

The aim of this study was to determine the effects of endothelin-1 (ET-1)-generated endothelial microvesicles (EMVs) on endothelial cell inflammation, apoptosis, and endothelial nitric oxide synthase (eNOS). Human umbilical vein endothelial cells (HUVECs) were treated with ET-1 for 24 h. EMVs released into the supernatant from cells treated with ET-1 or vehicle were isolated and quantified. EMV release was higher (P < 0.05) in cells treated with ET-1 compared with control (95 ± 15 vs. 54 ± 5 EMV/µL). Fresh HUVECs were then treated with either ET-1, ET-1-induced EMVs, or control EMVs for 24 h. ET-1-generated EMVs induced significantly higher release of IL-6 (181.0 ± 16.0 vs. 132.1 ± 8.1 pg/mL) and IL-8 (303.4 ± 37.4 vs. 211.8 ± 10.0 pg/mL), as well as greater total NF-κB p65 (76.0 ± 7.6 vs. 57.1 ± 2.1 AU) and active NF-κB p65 (Ser-536) (11.6 ± 0.9 vs. 6.8 ± 1.0 AU) expression than control EMVs. There were no significant differences in expression of caspase-9 (230.1 ± 24.3 vs. 243.6 ± 22.3 AU), caspase-3 (271.9 ± 22.7 vs. 265.1 ± 30.5 AU), and active caspase-3 (4.4 ± 0.4 vs. 4.3 ± 0.1 AU) in cells treated with ET-1-EMVs versus control EMVs. Total eNOS (108.4 ± 11.4 vs. 158.8 ± 1.6 AU) and activated eNOS (4.7 ± 0.5 vs. 9.6 ± 1.4 AU) were significantly lower in endothelial cells treated with ET-1-generated EMVs compared with control EMVs. The effects of ET-1-generated EMVs on cellular markers and mediators of endothelial inflammation, as well as eNOS function, was comparable to the effects of ET-1. In summary, ET-1 induces an EMV phenotype that adversely affects endothelial cell function. ET-1-generated EMVs may contribute to the atherogenic effect of ET-1.NEW & NOTEWORTHY Endothelin-1 (ET-1) is a potent vasoconstrictor peptide released by the endothelium that contributes to the regulation of vascular tone. Overexpression of ET-1 has been implicated in the etiology of atherosclerotic vascular disease. Endothelial cell-derived microvesicles (EMVs) play a pivotal role in vascular health and disease. Their functional phenotype is largely dictated by the stimulus for release. EMVs released in response to various pathological conditions have been shown to elicit deleterious vascular effects. In the present study, we determined, in vitro, the effect of ET-1 on EMV release from endothelial cells and the effects of ET-1-generated EMVs on endothelial cell inflammation, apoptosis, and endothelial nitric oxide synthase (eNOS). ET-1 induced a marked increase in EMV release. ET-1-generated EMVs significantly increased endothelial cell inflammation and reduced eNOS protein expression and activation. Moreover, the endothelial effects of ET-1-derived EMVs were similar to the direct effects of ET-1. ET-1-generated EMVs may contribute to the proatherogenic profile of ET-1.