RESUMO
Autophagy is an evolutionarily conserved pathway responsible for delivery of cytoplasmic material into the lysosomal degradation pathway to enable vesicular exocytosis. Interleukin (IL)-2 is produced by T-cells and its activity is important for immunoregulation. Fibroblasts are an immune competent cell type, playing a critical role in wound healing, chronic inflammation, and tumor development. Although autophagy plays an important role in each of these processes, whether it regulates IL-2 activity in fibroblasts is unknown. Here, we show that autophagy is required for IL-2-induced cell growth in fibroblasts. IL-2 significantly induced autophagy in mouse embryonic fibroblasts (MEFs) and primary lung fibroblasts. Autophagy inhibitors (e.g., 3-methylamphetamine and bafilomycin A1) or knockdown of ATG5 and beclin 1 blocked clinical grade IL-2-induced autophagy. Moreover, IL-2 induced HMGB1 cytoplasmic translocation in MEFs and promoted interaction between HMGB1 and beclin1, which is required for autophagy induction. Pharmacological and genetic inhibition of autophagy inhibited IL-2-induced cell proliferation and enhanced IL-2-induced apoptosis. These findings suggest that autophagy is an important pro-survival regulator for IL-2-induced cell growth in fibroblasts.
Assuntos
Autofagia/fisiologia , Proliferação de Células/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Interleucina-2/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/fisiologia , Autofagia/genética , Proteína 5 Relacionada à Autofagia , Proteína Beclina-1 , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Células Cultivadas , Embrião de Mamíferos , Fibroblastos/metabolismo , Fibroblastos/fisiologia , Técnicas de Silenciamento de Genes , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Proteína HMGB1/fisiologia , Camundongos , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/fisiologia , Ligação Proteica/fisiologia , Transporte Proteico/fisiologia , RNA Interferente Pequeno/farmacologiaRESUMO
Minimally invasive distal pancreatectomy has become increasingly used in practice. While laparoscopic approach is the most commonly used technique, robotic distal pancreatectomy (RDP) has emerged as a safe, feasible and effective approach for distal pancreatectomy. Most studies have shown that RDP improved perioperative surgical outcomes and has equivalent oncologic outcomes to open technique. Widespread adoption is limited by a steep learning curve, higher costs and the need for institutional training protocols in place for safe integration of the platform into practice.
Assuntos
Laparoscopia , Neoplasias Pancreáticas , Procedimentos Cirúrgicos Robóticos , Robótica , Humanos , Pancreatectomia , Neoplasias Pancreáticas/cirurgiaRESUMO
Over the last two decades, there have been significant changes in the management of patients with localized pancreatic cancer. The rationale for an evolution toward a neoadjuvant approach and summary of relevant clinical trials is reviewed. Controversies in identifying optimal neoadjuvant therapeutic approaches are discussed.
Assuntos
Terapia Neoadjuvante , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológicoRESUMO
BACKGROUND: Cancer treatments can cause a variety of symptoms that impair quality of life and functioning but are frequently missed by clinicians. Smartphone and wearable sensors may capture behavioral and physiological changes indicative of symptom burden, enabling passive and remote real-time monitoring of fluctuating symptoms. OBJECTIVE: The aim of this study was to examine whether smartphone and Fitbit data could be used to estimate daily symptom burden before and after pancreatic surgery. METHODS: A total of 44 patients scheduled for pancreatic surgery participated in this prospective longitudinal study and provided sufficient sensor and self-reported symptom data for analyses. Participants collected smartphone sensor and Fitbit data and completed daily symptom ratings starting at least two weeks before surgery, throughout their inpatient recovery, and for up to 60 days after postoperative discharge. Day-level behavioral features reflecting mobility and activity patterns, sleep, screen time, heart rate, and communication were extracted from raw smartphone and Fitbit data and used to classify the next day as high or low symptom burden, adjusted for each individual's typical level of reported symptoms. In addition to the overall symptom burden, we examined pain, fatigue, and diarrhea specifically. RESULTS: Models using light gradient boosting machine (LightGBM) were able to correctly predict whether the next day would be a high symptom day with 73.5% accuracy, surpassing baseline models. The most important sensor features for discriminating high symptom days were related to physical activity bouts, sleep, heart rate, and location. LightGBM models predicting next-day diarrhea (79.0% accuracy), fatigue (75.8% accuracy), and pain (79.6% accuracy) performed similarly. CONCLUSIONS: Results suggest that digital biomarkers may be useful in predicting patient-reported symptom burden before and after cancer surgery. Although model performance in this small sample may not be adequate for clinical implementation, findings support the feasibility of collecting mobile sensor data from older patients who are acutely ill as well as the potential clinical value of mobile sensing for passive monitoring of patients with cancer and suggest that data from devices that many patients already own and use may be useful in detecting worsening perioperative symptoms and triggering just-in-time symptom management interventions.
RESUMO
Background: Neutrophil extracellular traps (NETs) are generated when activated neutrophils, driven by PAD4, release their DNA, histones, HMGB1, and other intracellular granule components. NETs play a role in acute pancreatitis, worsening pancreatic inflammation, and promoting pancreatic duct obstruction. The autophagy inhibitor chloroquine (CQ) inhibits NET formation; therefore, we investigated the impact of CQ mediated NET inhibition in murine models of pancreatitis and human correlative studies. Methods: L-arginine and choline deficient ethionine supplemented (CDE) diet models of acute pancreatitis were studied in wild type and PAD4-/- mice, incapable of forming NETs. Isolated neutrophils were stimulated to induce NET formation and visualized with fluorescence microscopy. CQ treatment (0.5 mg/ml PO) was initiated after induction of pancreatitis. Biomarkers of NET formation, including cell-free DNA, citrullinated histone H3 (CitH3), and MPO-DNA conjugates were measured in murine serum and correlative human patient serum samples. Results: We first confirmed the role of NETs in the pathophysiology of acute pancreatitis by demonstrating that PAD4-/- mice had decreased pancreatitis severity and improved survival compared to wild-type controls. Furthermore, patients with severe acute pancreatitis had elevated levels of cell-free DNA and MPO-DNA conjugates, consistent with NET formation. Neutrophils from mice with pancreatitis were more prone to NET formation and CQ decreased this propensity to form NETs. CQ significantly reduced serum cell-free DNA and citrullinated histone H3 in murine models of pancreatitis, increasing survival in both models. Conclusions: Inhibition of NETs with CQ decreases the severity of acute pancreatitis and improves survival. Translating these findings into clinical trials of acute pancreatitis is warranted.
Assuntos
Armadilhas Extracelulares/imunologia , Infiltração de Neutrófilos , Neutrófilos/imunologia , Pancreatite/diagnóstico , Pancreatite/etiologia , Doença Aguda , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Biomarcadores , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Modelos Animais de Doenças , Armadilhas Extracelulares/metabolismo , Feminino , Humanos , Mediadores da Inflamação , Camundongos , Camundongos Knockout , Infiltração de Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Pancreatite/tratamento farmacológico , Pancreatite/mortalidade , Índice de Gravidade de DoençaRESUMO
We identified a critical role for receptor for advanced glycation end products (RAGE) in the intratumoral accumulation of myeloid-derived suppressor cells (MDSCs) during pancreatic carcinogenesis. The absence of RAGE markedly delayed neoplasia and limited MDSC accumulation in mice expressing an oncogenic variant of Kras. In spite of MDSCs, these mice accumulated non-immunosuppressive macrophages. Thus, RAGE regulates carcinogenesis and consequent myeloid responses.