RESUMEN
Renal ischemia/reperfusion (I/R) injury is a local sterile inflammatory response driven by innate immunity. Emerging data have revealed that complement and neutrophils contribute to hyperinflammation and oxidative stress in I/R induced acute kidney injury (AKI). However, the interplay between the C3a/C3aR axis and neutrophil extracellular traps (NETs) is imcompletelyunderstood. Here, we utilize genetically engineered mouse models and pharmacological inhibitors to investigate this association. The C3a/C3aR axis is found to promote neutrophil recruitment and NETs formation, thereby accelerating renal damage and dysfunction. Knockout of C3aR restores NETs release and improves renal function after I/R injury. Antibody-mediated blockade of NETs can also significantly ameliorate renal tubular injury and inflammation. Consistently, under stimulation by C3a, neutrophils are activated to promote NETs formation and subsequent renal tubular epithelial cell damage, and blocking C3aR rescued the injury. Interfering with reactive oxygen species (ROS) accumulation in neutrophils by antioxidant treatment significantly attenuates NETs formation. Our findings demonstrate that the C3a/C3aR-ROS-NETs axis constitutes a promising target for prevention or treatment of renal I/R injury.
Asunto(s)
Trampas Extracelulares , Daño por Reperfusión , Ratones , Animales , Especies Reactivas de Oxígeno , Ratones Noqueados , Riñón/fisiología , Neutrófilos , Daño por Reperfusión/prevención & controlRESUMEN
Long-term placement of non-degradable silicone rubber pancreatic duct stents in the body is likely to cause inflammation and injury. Therefore, it is necessary to develop degradable and biocompatible stents to replace silicone rubber tubes as pancreatic duct stents. The purpose of our research was to verify the feasibility and biological safety of extrusion-based 3D printed radiopaque chitosan (CS) ducts for pancreaticojejunostomy. Chitosan-barium sulfate (CS-Ba) ducts with different molecular weights (low-, medium-, and high-molecular weight CS-Ba: LCS-Ba, MCS-Ba, and HCS-Ba, respectively) were soaked in vitro in simulated pancreatic juice (SPJ) (pH 8.0) with or without pancreatin for 16 weeks. Changes in their weight, water absorption rate and mechanical properties were tested regularly. The biocompatibility, degradation and radiopaque performance were verified by in vivo and in vitro experiments. The results showed that CS-Ba ducts prepared by this method had regular compact structures and good molding effects. In addition, the lower the molecular weight of the CS-Ba ducts was, the faster the degradation rate was. Extrusion-based 3D-printed CS-Ba ducts have mechanical properties that match those of soft tissue, good biocompatibility and radioopacity. In vitro studies have also shown that CS-Ba ducts can promote the growth of fibroblasts. These stents have great potential for use in pancreatic duct stent applications in the future.
RESUMEN
BACKGROUND: Liver metastasis is an important prognostic factor for pancreatic neuroendocrine neoplasms (pNENs), but the relationship between the clinical features of patients with pNEN and liver metastasis remains undetermined. The aim of this study was to establish and validate an easy-to-use nomogram to predict liver-metastasis in patients with pNEN. METHODS: We obtained the clinicopathologic data of 2960 patients with pancreatic neuroendocrine neoplasms from the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2016. Univariate and multivariate logistic regression were done to screen out independent influencing factors to establish the nomogram. The calibration plots and the area under the receiver operating characteristic curve (AUC) were used to evaluate the performance of nomogram. Decision curve analysis (DCA) was applied to compare the novel model with the conventional predictive methods. RESULTS: A total of 2960 patients with pancreatic neuroendocrine neoplasms were included in the study. Among these, 1974 patients were assigned to the training group and 986 patients to the validation group. Multivariate logistic regression identified, tumor size, grade, other site metastasis, T stage and N stage as independent risk factors. The calibration plot showed good discriminative ability in the training and validation groups, with C-indexes of 0.850 for the training cohort and 0.846 for the validation cohort. The AUC values were 0.850 (95% CI 0.830-0.869) and 0.839 (95% CI 0.812-0.866), respectively. The nomogram total points (NTP) had the potential to stratify patients into low risk, medium risk and high risk (P < 0.001). Finally, comparing the nomogram with traditional prediction methods, the DCA curve showed that the nomogram had better net benefit. CONCLUSIONS: Our nomogram has a good ability to predict liver metastasis of pancreatic neuroendocrine neoplasms, and it can guide clinicians to provide suitable prevention and treatment measures for patients with medium- and high-risk liver metastasis.
Asunto(s)
Neoplasias Hepáticas , Nomogramas , Estudios de Cohortes , Humanos , Estadificación de Neoplasias , PronósticoRESUMEN
BACKGROUND: Robotic pancreaticoduodenectomy (RPD) has been increasingly performed for patients with periampullary tumours and tumours in the pancreatic head. This method offers several technical advantages compared to open and laparoscopic surgeries. However, the surgical results often vary depending on the experience of different pancreatic centres. METHODS: A retrospective study of our first 55 cases of RPD from August 2016 to April 2020 was conducted to evaluate the perioperative outcomes of RPD and to summarize the operative experiences in a single intuition. Benign and malignant tumours in the pancreatic head or periampullary tumours without obvious vascular and adjacent organ invasion were included in this study. Perioperative characteristics and postoperative complications of the enrolled patients were retrospectively collected. RESULTS: The first 17 cases were robot-assisted laparoscopic pancreaticoduodenectomy (RA-LPD) and the remaining 38 patients underwent total RPD. The RA-LPD group had a remarkably longer operative time than the total RPD group (415.3±89.2 vs. 362.4±75.6 min, P=0.047). The incidences of biliary leakage, chyle leakage, DGE, intra-abdominal infection and intra-abdominal haemorrhage were 3.6%, 0.0%, 5.5%, 9.1% and 5.5%, respectively. Two patients underwent relaparotomy due to severe intra-abdominal haemorrhage. The median length of hospital stay was 14 (11 to 19) days. There were no deaths during the perioperative period. CONCLUSIONS: RPD is a technically feasible procedure for selected patients with periampullary tumours and tumours in the pancreatic head in experienced hands.
RESUMEN
Cancer-associated fibroblasts (CAFs) are crucial for forming the desmoplastic stroma that is associated with chemoresistance in pancreatic ductal adenocarcinoma (PDAC). In the clinic, depleting dense stroma in PDAC tumor tissue is a promising chemotherapeutic strategy. In this study, we report that the local hyperthermia can reduce the number of CAFs in the PDAC PDX mouse mode, which further augments chemotherapeutic efficiency in the PDAC therapy. To achieve this goal, a photothermal-chemotherapeutic agent termed as Abraxane@MoSe2 as a vehicle-saving theranostic probe is prepared by simply mixing an FDA-approved Abraxane and hydrophobic MoSe2 nanosheets via electrostatic and hydrophobic interactions. After labeling with indocyanine green (ICG) dye on the Abraxane@MoSe2, a relatively high fluorescence signal (near infrared second (NIR II)) in PDX tumors can be obtained, which can be precisely imaging-guide local photothermal-chemotherapy upon the 808 nm laser irradiation in vivo. Importantly, the synergy therapeutic efficiency in PDAC is enhanced by the photothermal effect reduction of the number of CAFs, which is confirmed viaα-SMA and vimentin immunofluorescence analysis. This combined therapeutic strategy may provide a new sight for PDAC therapy.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Paclitaxel Unido a Albúmina/administración & dosificación , Antineoplásicos/administración & dosificación , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Molibdeno/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Selenio/administración & dosificación , Paclitaxel Unido a Albúmina/química , Paclitaxel Unido a Albúmina/efectos de la radiación , Animales , Antineoplásicos/química , Antineoplásicos/efectos de la radiación , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Eritrocitos/efectos de los fármacos , Hemólisis/efectos de los fármacos , Humanos , Rayos Láser , Ratones Desnudos , Molibdeno/química , Molibdeno/efectos de la radiación , Fotoquimioterapia , Selenio/química , Selenio/efectos de la radiaciónRESUMEN
BACKGROUND: Aberrant expression of Wiskott-Aldrich syndrome protein interacting protein family member 1 (WIPF1) contributes to the invasion and metastasis of several malignancies. However, the role of WIPF1 in human pancreatic ductal adenocarcinoma (PDAC) remains poorly understood. METHODS: Human pancreatic cancer samples from PDAC patients were collected for methylation analysis. Bioinformatic prediction program and luciferase reporter assay were used to identify microRNAs regulating WIPF1 expression. The association between WIPF1 expression and the overall survival (OS) of patients with PDAC was evaluated by using The Cancer Genome Atlas (TCGA) database. The roles of miR-141/200c and WIPF1 on the invasion and metastasis of PDAC cells were investigated both in vitro and in vivo. RESULTS: We found that compared to the surrounding non-cancerous tissues, there was significantly increased methylation of miR-200c and miR-141 in human PDAC tissues that resulted in their silencing, whereas the members of the other cluster of miR-200 family including miR-200a, miR-200b and miR-429 were hypomethylated. Our data show that forced expression of miR-141 or miR-200c suppressed invasion and metastasis of PDAC cells both in vitro and in xenograft and identified WIPF1 as a direct target of miR-141 and miR-200c. Both miR-141 and miR-200c inhibit WIPF1 by directly interacting with its 3'-untranslated region. Remarkably, silencing of WIPF1 blocked PDAC growth and metastasis both in vitro and in vivo, whereas forced WIPF1 overexpression antagonized the tumor suppressive effect of miR-141/200c. Additionally, by using TCGA database we showed that high expression of WIPF1 correlated with poor survival in patients with PDAC. Moreover, we show that miR-141 and miR-200c blocked YAP/TAZ expression by suppressing WIPF1. CONCLUSIONS: We have identified WIPF1 as an oncoprotein in PDAC and a direct target of miR-141/miR-200c. We have also defined the miR-141/200c-WIPF1-YAP/TAZ as a novel signaling pathway that is involved in the regulation of the invasion and metastasis of human PDAC cells.