ABSTRACT
Influenza A viruses (IAV) pose substantial burden on human and animal health. Avian, swine and human IAV bind sialic acid on host glycans as receptor, whereas some bat IAV require MHC class II complexes for cell entry. It is unknown how this difference evolved and whether dual receptor specificity is possible. Here we show that human H2N2 IAV and related avian H2N2 possess dual receptor specificity in cell lines and primary human airway cultures. Using sialylation-deficient cells, we reveal that entry via MHC class II is independent of sialic acid. We find that MHC class II from humans, pigs, ducks, swans and chickens but not bats can mediate H2 IAV entry and that this is conserved in Eurasian avian H2. Our results demonstrate that IAV can possess dual receptor specificity for sialic acid and MHC class II, and suggest a role for MHC class II-dependent entry in zoonotic IAV infections.
ABSTRACT
Cancer patients often undergo rounds of trial-and-error to find the most effective treatment because there is no test in the clinical practice for predicting therapy response. Here, we conduct a clinical study to validate the zebrafish patient-derived xenograft model (zAvatar) as a fast predictive platform for personalized treatment in colorectal cancer. zAvatars are generated with patient tumor cells, treated exactly with the same therapy as their corresponding patient and analyzed at single-cell resolution. By individually comparing the clinical responses of 55 patients with their zAvatar-test, we develop a decision tree model integrating tumor stage, zAvatar-apoptosis, and zAvatar-metastatic potential. This model accurately forecasts patient progression with 91% accuracy. Importantly, patients with a sensitive zAvatar-test exhibit longer progression-free survival compared to those with a resistant test. We propose the zAvatar-test as a rapid approach to guide clinical decisions, optimizing treatment options and improving the survival of cancer patients.
Subject(s)
Colorectal Neoplasms , Zebrafish , Animals , Female , Humans , Male , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Disease Models, Animal , Precision Medicine/methods , Progression-Free Survival , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: A proportion of rectal cancer patients who achieve a clinical complete response may develop local regrowth. Although salvage appears to provide appropriate local control, the risk of distant metastases is less known. OBJECTIVE: To compare the risk of distant metastases between patients who achieve a clinical complete response (watch-and-wait strategy) and subsequent local regrowth and patients managed by surgery after chemoradiation. DESIGN: Retrospective multicenter cohort study. SETTINGS: This study used data of patients from 3 institutions who were treated between 1993 and 2019. PATIENTS: Patients with initial clinical complete response (after neoadjuvant therapy) followed by local regrowth and patients with near-complete pathological response (≤10%) after straightforward surgery after chemoradiation were included. MAIN OUTCOME MEASURES: Univariate and multivariate analyses were performed to identify risk factors for distant metastases. Kaplan-Meier curves were created (log-rank test) to compare survival outcomes. Analyses were performed using time zero as last day of radiation therapy or as date of salvage resection in the local regrowth group. RESULTS: Twenty-one of 79 patients with local regrowth developed distant metastases, whereas only 10 of 74 after upfront total mesorectal excision following neoadjuvant chemoradiation therapy ( p = 0.04). Local regrowth and final pathology (ypT3-4) were the only independent risk factors associated with distant metastases. When using date of salvage resection as time zero, distant metastases-free survival rates were significantly inferior for patients with local regrowth (70% vs 86%; p = 0.01). LIMITATIONS: Small number of patients, many neoadjuvant therapies, and selection bias. CONCLUSIONS: Patients undergoing watch-and-wait strategy who develop local regrowth are at higher risk for development of distant metastases compared to patients with near-complete pathological response managed by upfront surgery after chemoradiation. See Video Abstract. NUEVO CRECIMIENTO LOCAL Y EL RIESGO DE METSTASIS A DISTANCIA ENTRE PACIENTES SOMETIDOS A OBSERVACIN Y ESPERA POR CNCER DE RECTO CUL ES EL MEJOR GRUPO DE CONTROL ESTUDIO RETROSPECTIVO MUTICNTRICO: ANTECEDENTES:Una proporción de pacientes que logran una respuesta clínica completa pueden desarrollar un nuevo crecimiento local. Si bien el rescate parece proporcionar un control local apropiado, el riesgo de metástasis a distancia es menos conocido.OBJETIVO:Comparar el riesgo de metástasis a distancia entre los pacientes que logran una respuesta clínica completa (estrategia de observación y espera) y el nuevo crecimiento local posterior con los pacientes tratados con cirugía después de la quimiorradiación.DISEÑO:Estudio de cohorte multicéntrico retrospectivo.CONFIGURACIÓN:Este estudio utilizó datos de pacientes de 3 instituciones que fueron tratados entre 1993 y 2019.PACIENTES:Pacientes con respuesta clínica completa inicial (después de la terapia neoadyuvante) seguida de crecimiento local nuevo y pacientes con respuesta patológica casi completa (≤10 %) después de cirugía directa después de quimiorradiación.PRINCIPALES MEDIDAS DE RESULTADO:Se realizó un análisis univariante/multivariante para identificar los factores de riesgo de metástasis a distancia. Se crearon curvas de Kaplan-Meier (prueba de rango logarítmico) para comparar los resultados de supervivencia. El análisis se realizó utilizando el tiempo cero como último día de radioterapia (1) o como fecha de resección de rescate (2) en el grupo de recrecimiento local.RESULTADOS:Veintiuno de 79 pacientes con recrecimiento local desarrollaron metástasis a distancia, mientras que solo 10 de 74 después de una cirugía sencilla (p = 0,04). El recrecimiento local y la patología final (ypT3-4) fueron los únicos factores de riesgo independientes asociados con las metástasis a distancia. Cuando se utilizó la fecha de la resección de rescate como tiempo cero, las tasas de supervivencia sin metástasis a distancia fueron significativamente inferiores para los pacientes con recrecimiento local (70 frente a 86 %; p = 0,01).LIMITACIONES:Pequeño número de pacientes, muchas terapias neoadyuvantes, sesgo de selección.CONCLUSIONES:Los pacientes sometidos a observación y espera que desarrollan un nuevo crecimiento local tienen un mayor riesgo de desarrollar metástasis a distancia en comparación con los pacientes con una respuesta patológica casi completa manejados con cirugía por adelantado después de la quimiorradiación. (Traducción-Dr. Xavier Delgadillo ).