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- The renin-angiotensin system in healthy human platelets: expressed but inactivePublication . Panosetti, François; Cuenot, François M.; Auguste, Damian S. Saint; Martins Cavaco, Ana Cláudia; Nunes, Allancer D. C.; Lu, Philip H. J.; Magrini, Céline; Molot, Max; Sanglard, Gabriel; Günçü, Rodi; Zouaghi, Yassine; Béguelin, Charles; Lima, Augusto Martins; Stergiopulos, NikolaosPlatelets play a crucial role in arterial thrombus formation, offering potential for new antiplatelet therapies with reduced bleeding risk. Here, we investigated the role of the renin-angiotensin system (RAS) in human platelets and explored its potential link to COVID-19 coagulopathy. Experiments were performed ex vivo on healthy human platelets. The expression of RAS receptors (Mas, MrgD, ACE, ACE2, AT1 and AT2) was evaluated using western blot and immunofluorescence. Platelets were incubated in vitro with either Captopril or different RAS peptides including Alamandine, Angiotensin-I, Angiotensin-II, Angiotensin-(1-7), and Angiotensin-(1-9). Platelet adhesion was measured by spectrophotometry using BCECF fluorescence. Platelet activation and aggregation were analyzed using aggregometry after stimulation with extracellular matrix proteins. ACE and ACE2 activity were assessed using Fluorescent Peptides (FPS). We demonstrated that healthy human platelets express all the tested RAS receptors. However, RAS peptides did not modulate platelet adhesion or aggregation despite a wide range of concentrations tested. ACE activity was detected in platelet lysates, but it was not inhibited by Captopril, while ACE2 activity was undetectable. Our findings suggest that while RAS receptors are expressed in platelets, RAS peptides do not impact platelet function, at least in our experimental setting. COVID-19 coagulopathy may occur independently of the RAS.
- A randomized controlled trial assessing the release of circulating tumor and mesenchymal cells in no-touch radical nephrectomyPublication . Leitão, Tito Palmela; Corredeira, Patrícia; Rodrigues, Carolina; Piairo, Paulina; Miranda, Miguel; Martins Cavaco, Ana Cláudia; Kucharczak, Sandra; Antunes, Marília; Peixoto, Sara; Reis, José Palma dos; Lopes, Tomé; Diéguez, Lorena; Costa, LuísAbstract: Background: Circulating tumor cells (CTCs) may be the missing renal cell carcinoma (RCC) biomarker. No-touch (NT) resection has shown benefit in several tumors. Methods: A randomized controlled trial comparing CTC and circulating mesenchymal cell (CMC) release in no-touch (NT) vs. conventional (C) laparoscopic RN. Blood samples were collected at operation room arrival (S0), specimen extraction (S1), postoperative D1, and D30. CTCs were isolated and analyzed using RUBYchip™. Results: Thirty-four patients were included. No significant differences were found between groups in CTC and CMC counts, count variations between time points, complications, and survival. The total circulating cell detection rates in the NT, C, and overall RCC groups were 58.3%, 80.0%, and 70.4% at S0; 41.6%, 86.7%, and 66.7% at S1; 50.0%, 64.3%, and 60.0% at D1; and 54.5%, 42.9%, and 44.0% at D30, respectively. A progressive decrease in CMCs was observed in the C group after surgery, especially at D1 (4.78 to 1.64 CMCs/7.5 mL blood, p = 0.035). Healthy controls had no circulating cells; however, high CMC counts were found in chronic inflammation controls and oncocytoma patients, with no significant difference from RCC patients (p = 0.460). Conclusions: NT RN did not reduce circulating cell release nor improve survival compared to C RN.
- Exploring the clinical benefits of genomic profiling for advanced solid tumors in Portugal.Publication . Tavares, Nuno; Damaso, Sara; Brás, Raquel Lopes; Guedes, Helena; Simões, Pedro; Rodrigues, Tania; Costa, Diogo Alpuim; Bonito, Nuno Antunes; Pratas, Edgar; Macedo, Daniela; Filipe, Frederico Ferreira; Martins Cavaco, Ana Cláudia; Pavanello, Marina; Costa, LuisBackground: Comprehensive genomic profiling (CGP) plays a significant role in precision oncology by pairing genomic alterations from different tumor types with molecularly targeted therapies. However, the evaluation of its real-world impact, clinical utility, and effects on quality of life remain unexplored. The FRONTAL study (Foundation medicine Real wOrld evideNce in porTugAL) is an ongoing multicentric academic study that aims to establish a national registry of portuguese patients with solid tumors that underwent CGP through Foundation Medicine tests (FoundationOne CDx, Liquid CDx, and Heme). Methods: The study enrolled portuguese patients diagnosed with advanced solid tumors who were not eligible for curative treatment at the time of recruitment. Patients who had previously done CGP evaluation could be included if the test was conducted within one year before the start of the study. CGP data was retrieved from the Foundation Medicine reports and clinical data from the medical records. Actionable genomic findings were reported if associated to therapies for the patient’s tumor type or with proven clinical benefit in other tumor types based on the NCCN Categories of Evidence and Consensus. In addition, quality of life questionnaires (QLQ-C30) were collected for a subset of patients. The primary outcome was a binary endpoint of disease control at 16 weeks of treatment, defined by the absence of progression at that timepoint. Results: Genomic and real-world clinical data were collected and analyzed for 146 patients ( . 70% of the cohort), from 10 different sites in Portugal. Several cancer types were included, with colorectal tumors being the most common (19%), followed by sarcomas (18%) and pancreatic tumors (12%). According to the Foundation Medicine reports, actionable molecular alterations were described in 52% of the cohort. Twenty-three percent of the patients had their therapeutic decision changed due to the CGP result. The most frequent alterations among these patients included high tumor mutational burden (TMB) and/or microsatellite instability (MSI) (35%), as well as pathogenic mutations in PIK3CA (15%) and ATM (12%). Forty-three percent of patients with changed therapy were reported to have achieved disease control at 16 weeks of treatment. Half of the patients with disease control had either high TMB, MSI, or BRAF mutations, reinforcing that evaluating actionable alterations with tissue-agnostic FDA approvals benefit oncology patients. Conclusions: The FRONTAL study highlights the clinical utility of CGP in advanced solid tumors. We identified actionable alterations in 52% of patients, leading to changes in treatment for 23% of the cohort. These findings support the value of CGP in guiding personalized therapies and emphasize the need for further research into its impact on patient outcomes and quality of life. Research Sponsor: None.