Penas, C. | bioRxiv Science

bioRxiv2024

Temporary cerebral ischaemia impairs thromboxane A2 constriction and induces hypertrophic remodelling in peripheral mesenteric arteries of hypertensive rats: limited reversal despite long-term suberoylanilide hydroxamic acid cerebroprotection

Stroke induces brain injury, especially severe in hypertensive patients, and elevates mortality rates through non-neurological complications. However, the potential effects of a transient ischaemic episode on the peripheral vasculature of hypertensive individuals remain unclear. Here, we investigated whether transient cerebral ischaemia (90 min)/reperfusion (1 or 8 days) induces alterations in mesenteric resistance artery (MRA) properties in adult male spontaneously hypertensive rats (SHR). In addition, we assessed whether the reported cerebroprotective effects of suberoylanilide hydroxamic acid (SAHA; 50 mg/kg; administered intraperitoneally at 1, 4, or 6 h after reperfusion onset) extend long-term and include beneficial effects on MRAs. Functional and structural properties of MRAs were examined at 1- and 8-days post-stroke. Nuclei distribution, collagen content, and oxidative stress were assessed. Ischaemic brain damage was evaluated longitudinally using magnetic resonance imaging. Following stroke, MRAs from SHR exhibited non-reversible impaired contractile responses to the thromboxane A2 receptor agonist U46619. Stroke increased the MRA cross-sectional area, wall thickness, and wall/lumen ratio due to augmented collagen deposition. These changes were partially sustained 8 days later. SAHA did not improve U46619-induced contractions but mitigated stroke-induced oxidative stress and collagen deposition, preventing MRA remodelling at 24 h of reperfusion. Furthermore, SAHA induced sustained cerebroprotective effects over 8 days, including reduced brain infarct and oedema, and improved neurological scores. However, SAHA had minimal impact on chronic MRA contractile impairments and remodelling. These findings suggest that stroke causes MRA changes in hypertensive subjects. While SAHA treatment offers long-term protection against brain damage, it cannot fully restore MRA alterations.

neuroscience↗

bioRxiv2019

A new clinical tool to predict outcome in early-stage melanoma patients

Around 25% of early-stage melanoma patients eventually develop metastasis. Thus, we set out to define serological biomarkers that could be used along with clinical and histopathological features of the disease to predict these events. We previously demonstrated that in stage II melanoma patients, serum levels of dermcidin (DCD) were associated with metastatic progression. Based on the relevance of the immune response on the cancer progression and the recent association of DCD with local and systemic immune response against cancer cells, serum DCD was analyzed in a new cohort of patients along with IL-4, IL-6, IL-10, IL-17A, IFN{gamma} TGF{beta} and GM-CSF. We included 448 melanoma patients, 323 of whom were diagnosed as stages I-II according to AJCC. Levels of selected cytokines were determined by ELISA and Luminex and obtained data were analyzed employing Machine Learning and Kaplan-Meier techniques to define an algorithm capable of accurately classifying early-stage melanoma patients with a high and low risk of developing metastasis. The results show that in early-stage melanoma patients, serum levels of the cytokines IL-4, GM-CSF and DCD together with the Breslow thickness are those that best predict melanoma metastasis. Moreover, resulting algorithm represents a new tool to discriminate subjects with good prognosis from those with high risk for a future metastasis. Novelty and ImpactWe have developed a prognostic equation that considers the serum IL-4, GM-CSF and DCD levels, along with the Breslow thickness to accurately classify melanoma outcome in patients. In this sense, a rigorous follow-up is recommended for early-stage melanoma patients with a high Breslow thickness, high serum IL-4 levels and low GM-CSF and DCD levels at the time of diagnosis, given the elevated risk for these patients to develop metastasis during follow-up.

pathology↗