Venetoclax is a potent hepsin inhibitor that reduces the metastatic and prothrombotic phenotypes of hepsin-expressing colorectal cancer cells.

Introduction: Hepsin is a type II transmembrane serine protease and its expression has been linked to greater tumorigenicity and worse prognosis in different tumors. Recently, our group demonstrated that high hepsin levels from primary tumor were associated with a higher risk of metastasis and thrombosis in localized colorectal cancer patients. This study aims to explore the molecular role of hepsin in colorectal cancer. Methods: Hepsin levels in plasma from resected and metastatic colorectal cancer patients were analyzed by ELISA. The effect of hepsin levels on cell migration, invasion, and proliferation, as well as on the activation of crucial cancer signaling pathways, was performed in vitro using colorectal cancer cells. A thrombin generation assay determined the procoagulant function of hepsin from these cells. A virtual screening of a database containing more than 2000 FDA-approved compounds was performed to screen hepsin inhibitors, and selected compounds were tested in vitro for their ability to suppress hepsin effects in colorectal cancer cells. Xenotransplantation assays were done in zebrafish larvae to study the impact of venetoclax on invasion promoted by hepsin. Results: Our results showed higher plasma hepsin levels in metastatic patients, among which, hepsin was higher in those suffering thrombosis. Hepsin overexpression increased colorectal cancer cell invasion, Erk1/2 and STAT3 phosphorylation, and thrombin generation in plasma. In addition, we identified venetoclax as a potent hepsin inhibitor that reduced the metastatic and prothrombotic phenotypes of hepsin-expressing colorectal cancer cells. Interestingly, pretreatment with Venetoclax of cells overexpressing hepsin reduced their invasiveness in vivo. Discussion: Our results demonstrate that hepsin overexpression correlates with a more aggressive and prothrombotic tumor phenotype. Likewise, they demonstrate the antitumor role of venetoclax as a hepsin inhibitor, laying the groundwork for molecular-targeted therapy for colorectal cancer.

Implication of Hepsin from Primary Tumor in the Prognosis of Colorectal Cancer Patients.

Hepsin is a type II transmembrane serine protease whose deregulation promotes tumor invasion by proteolysis of the pericellular components. In colorectal cancer, the implication of hepsin is unknown. Consequently, we aimed to study the correlations between hepsin expression and different clinical-histopathological variables in 169 patients with localized colorectal cancer and 118 with metastases. Tissue microarrays were produced from samples at diagnosis of primary tumors and stained with an anti-hepsin antibody. Hepsin expression was correlated with clinical-histopathological variables by using the chi-square and Kruskal−Wallis tests, Kaplan−Meier and Aalen−Johansen estimators, and Cox and Fine and Gray multivariate models. In localized cancer patients, high-intensity hepsin staining was associated with reduced 5-year disease-free survival (p-value = 0.16). Medium and high intensity of hepsin expression versus low expression was associated with an increased risk of metastatic relapse (hazard ratio 2.83, p-value = 0.035 and hazard ratio 3.30, p-value = 0.012, respectively), being a better prognostic factor than classic histological variables. Additionally, in patients with localized tumor, 5-year thrombosis cumulative incidence increased with the increment of hepsin expression (p-value = 0.038). Medium and high intensities of hepsin with respect to low intensity were associated with an increase in thrombotic risk (hazard ratio 7.71, p-value = 0.043 and hazard ratio 9.02, p-value = 0.028, respectively). This relationship was independent of previous tumor relapse (p-value = 0.036). Among metastatic patients, low hepsin expression was associated with a low degree of tumor differentiation (p-value < 0.001) and with major metastatic dissemination (p-value = 0.023). Hepsin is a potential thrombotic and metastatic biomarker in patients with localized colorectal cancer. In metastatic patients, hepsin behaves in a paradoxical way with respect to differentiation and invasion processes.

Perfil clínico y epidemiológico de los pacientes con diagnóstico de neumonía viral incluidos en la vigilancia centinela del Hospital Nacional de Niños Benjamín Bloom, de enero 2014 a diciembre 2015 / Clinical and epidemiological profile of patients with a diagnosis of viral pneumonia included in the sentinel surveillance of the Benjamin Bloom National Children's Hospital, from January 2014 to December 2015

Las neumonías virales son una de las principales causas de morbimortalidad en el mundo y principalmente en países en vías de desarrollo, de esto se deriva la importancia de conocer el comportamiento estacional y evolución clínica de los diferentes virus respiratorios presentes en nuestro medio, para poder mejorar la atención y disminuir la mortalidad por estos. El presente trabajo pretende determinar factores clínicos y epidemiológicos encontrados en pacientes diagnosticados con neumonía viral notificados por la vigilancia centinela del Hospital Nacional de niños Benjamín Bloom en el periodo de Enero 2015 a Diciembre 2016, además identificar aquellos virus respiratorios que producen enfermedad grave en la población infantil. El estudio se realizó de forma descriptiva, retrospectiva y de corte transversal. Entre los resultados más importantes se encontró que durante el año 2015 hubo un aumento del 44% en los casos positivos de neumonías virales, además se identificaron 5 virus circulantes durante ambos años los cuales fueron: Virus Sincitial Respiratorio, Adenovirus, Parainfluenza e influenza A y B. El agente etiológico predominante durante ambos años fue el VSR que fue causante del 72% de casos positivos de virus respiratorio. También se encontró una mortalidad por virus respiratorios del 12%