Melanoma Screening—Reply

In Reply I thank Elwood et al for highlighting their previous efforts to develop more robust evidence to guide melanoma screening efforts. However, their work found similar findings as Matsumoto et al, with increased thin melanoma ascertainment in patients who had undergone screening skin examinations. While they modeled possible associations with mortality based on thickness data, their work did not look at actual mortality, either all cause or melanoma related.

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Novembre 2022

Melanoma Screening

To the Editor We agree with the title of the Editorial by Swerlick, but it omits the considerable efforts to mount a randomized clinical trial in Australia. We assessed melanoma screening in 1992, recommending a randomized clinical trial at ages 45 to 69 years to assess mortality. Subsequently, a similar trial based on whole-body examinations by primary care practitioners (PCPs) was proposed. A pilot phase showing that screening increased enough to allow detection of a 20% reduction in mortality over 15 years was reported in 2002. The trial cost approximately $8.4 million; after national and international peer review, the research costs were approved, which were approximately half the total. However, the other costs, including payments to PCPs for the screening examinations, were not funded. Thus, the full trial was not conducted.

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Novembre 2022

Abstract 11801: Glycoprotein Nonmetastatic Melanoma Proteinbbregulates Lysosomal Integrity and Lifespan of Senescent Endothelial Cells

Circulation, Volume 146, Issue Suppl_1, Page A11801-A11801, November 8, 2022. Introduction:The accumulation of senescent cells during aging relates to the development of various age-related pathologies including atherosclerosis and heart failure, which can be improved by specific elimination of senescent cells, so called “senolysis”. We have identified glycoprotein nonmetastatic melanoma protein B (GPNMB) as an antigen specifically expressed by senescent endothelial cells, so called “seno-antigen”. Also, we previously developed the vaccine against Gpnmb, eliminated senescent cells in mice, leading to an improvement of age-related pathologies. However, detailed function of GPNMB in senescent cells is still uncertain.Purpose:To elucidate the role of GPNMB in senescent cells and cardiovascular-related pathologies.Methods:Overexpression or depletion of GPNMB in endothelial cells (ECs) were generated. Cellular senescence was induced in ECs by doxorubicin. Gpnmb-knockout or overexpressed (Gp-KO or Gp-OE) mice were generated and imposed to hind-limb ischemia treatment or high-fat-diet feeding to evaluate vascular functions. Double transgenic mice (ApoE-KO and Gp-KO or Gp-OE) were also generated and imposed to high-fat diet to develop atherosclerosis.Results:The depletion of GPNMB in ECs was proved to shorten their replicative lifespan, and increase the expression of negative cell cycle regulators including p53, p21 and p16. Conversely, overexpressed GPNMB protected ECs from senescence stress.In vivostudies showed the impairment of vascular function, atherogenesis, and endothelium-dependent vasodilatation were enhanced in Gp-KO mice, but attenuated in Gp-OE mice. Furthermore, GPNMB was found to localize on lysosomal membrane. Cells with depleted GPNMB demonstrated the accumulation of dysfunctional lysosomes, indicated the contribution of GPNMB in maintaining lysosome integrity. Under senescence-associated lysosomal stress, elevated GPNMB expression was detected, contributing to senescent cells survival.Conclusions:GPNMB acts as a protective factor to senescent cells. Seno-antigen targeting GPNMB is possibly considered as an efficient strategy against cardiovascular diseases and other age-associated disorders with higher selectivity and fewer off-target effects.

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Ottobre 2022

Abstract 15638: Proinflammatory and Proangiogenic State Promotes Malignant Melanoma Progression in Mouse Model of HFpEF

Circulation, Volume 146, Issue Suppl_1, Page A15638-A15638, November 8, 2022. Epidemiological studies have shown that the incidence of various cancers, such as malignant melanoma is higher in patients with heart failure (both HFrEF and HFpEF) than in age-matched population, but the underlying mechanisms remain unknown. We hypothesized that in HFpEF a chronic systemic inflammation promotes malignant melanoma progression. To test this hypothesis orthotopic melanoma xenograft model was employed in a mouse model of HFpEF. Mice with uninephrectomy, aldosterone infusion (UNX-Aldo) with osmotic minipump (Alzet, 0.30 μg/h), and high salt ingestion (1% in drinking water) develop left ventricle diastolic dysfunction as indicated by a significantly (p

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Ottobre 2022