The effects of NLRP3 inflammasome inhibition by MCC950 on LPS-induced pancreatic adenocarcinoma inflammation.
- 作者列表："Yaw ACK","Chan EWL","Yap JKY","Mai CW
PURPOSE:Pancreatic cancer is a lethal form of cancer that can be triggered by prolonged or acute inflammation of the pancreas. Inflammation have been shown to be regulated by a group of key protein molecules known as the inflammasomes. The NLRP3 inflammasome is the most studied inflammasome and have been strongly implicated to regulate cancer cell proliferation. Therefore, this study aimed to examine the regulation of NLRP3 inflammasome under LPS-induced inflammation and its role in modulating cell proliferation in a panel of pancreatic cancer cells. METHODS:The effects of LPS-induced NLRP3 activation in the presence or absence of MCC950, NLRP3-specific inhibitor, was tested on a panel of three pancreatic cancer cell lines (SW1990, PANC1 and Panc10.05). Western blotting, cell viability kits and ELISA kits were used to examine the effects of LPS-induced NLRP3 activation and inhibition by MCC950 on NLRP3 expression, cell viability, caspase-1 activity and cytokine IL-1β, respectively. RESULTS:LPS-induced inflammation in the presence of ATP activates NLRP3 that subsequently increases pancreatic cancer cell proliferation by increasing caspase-1 activity leading to overall production of IL-1β. The inhibition of the NLRP3 inflammasome activation via the specific NLRP3 antagonist MCC950 was able to reduce the cell viability of pancreatic cancer cells. However, the efficacy of MCC950 varies between cell types which is most probably due to the difference in ASC expressions which have a different role in inflammasome activation. CONCLUSION:There is a dynamic interaction between inflammasome that regulates inflammasome-mediated inflammation in pancreatic adenocarcinoma cells.
目的: 胰腺癌是一种致命的癌症，可由胰腺的长期或急性炎症引发。炎症已被证明是由一组被称为炎症小体的关键蛋白分子调节的。NLRP3炎症小体是研究最多的炎症小体，并且已经强烈涉及调节癌细胞增殖。因此，本研究旨在检测LPS诱导的炎症下NLRP3炎症小体的调节及其在一组胰腺癌细胞中调节细胞增殖的作用。 方法: 在三种胰腺癌细胞系 (SW1990、PANC1和Panc10.05) 的组中测试LPS诱导的NLRP3活化在存在或不存在MCC950 (NLRP3-specific抑制剂) 的情况下的作用。Western blotting、细胞活力试剂盒和ELISA试剂盒分别检测LPS诱导NLRP3活化和MCC950抑制对NLRP3表达、细胞活力、caspase-1活性和细胞因子IL-1β 的影响。 结果: LPS诱导的炎症在ATP存在下激活NLRP3，其随后通过增加caspase-1活性增加胰腺癌细胞增殖，导致IL-1β 的总体产生。通过特异性NLRP3拮抗剂MCC950抑制NLRP3炎症小体活化能够降低胰腺癌细胞的细胞活力。然而，MCC950的功效在细胞类型之间变化，这最可能是由于在炎症小体激活中具有不同作用的ASC表达的差异。 结论: 炎症小体之间存在动态相互作用，调控炎症小体介导的胰腺癌细胞炎症反应。
METHODS:OBJECTIVE:The aim of this study was to investigate the key molecular alterations in small primary pancreatic neuroendocrine tumors (PanNETs) associated with the development of liver metastases. BACKGROUND:Well-differentiated PanNETs with small size are typically indolent; however, a limited subset metastasize to the liver. METHODS:A total of 87 small primary PanNETs (<3 cm), including 32 metastatic cases and 55 nonmetastatic cases after a 5-year follow-up, were immunolabeled for DAXX/ATRX and analyzed for alternative lengthening of telomeres (ALT) by Fluorescence In Situ Hybridization. A subset of these cases, 24 that metastasized and 24 that did not metastasize, were assessed by targeted next-generation sequencing and whole-genome copy number variation. RESULTS:In the entire cohort, high Ki-67 (OR 1.369; 95% CI 1.121-1.673; P = 0.002), N-stage (OR 4.568; 95% CI 1.458-14.312; P = 0.009), and ALT-positivity (OR 3.486; 95% CI 1.093-11.115; P = 0.035) were independently associated with liver metastases. In the subset assessed by next-generation sequencing and copy number variation analysis, 3 molecular subtypes with differing risks of liver metastases were identified. Group 1 (n = 15; 73% metastasized) was characterized by recurrent chromosomal gains, CN-LOH, DAXX mutations, and ALT-positivity. Group 2 (n = 19; 42% metastasized, including 5 G1 tumors) was characterized by limited copy number alterations and mutations. Group 3 (n = 14; 35% metastasized) were defined by chromosome 11 loss. CONCLUSIONS:We identified genomic patterns of small PanNETs associated with a different risk for liver metastases. Molecular alterations, such as DAXX mutations, chromosomal gains, and ALT, are associated with an increased risk of metastasis in small PanNETs. Therefore, targeted sequencing and/or ALT analysis may help in the clinical decisions for these small PanNETs.
METHODS::Background: This retrospective comparative case series study aims to analyze the pancreatic fistula rates of internal and external stenting of the pancreatojejunostomy (PJ) anastomosis in patients who underwent pancreatoduodenectomy (PD) for periampullary tumors.Methods: Ninety-eight patients with periampullary tumors who were operated between 2010 and 2017 were enrolled in this study. A classic open PD with Roux-en-Y PJ reconstruction was performed in all cases.Results: The PJ anastomosis of 53 patients (54%) were stented internally whereas in 45 patients (46%) external stenting was preferred. Pancreatic fistula was observed in 29 patients (29.6%). Internal stenting and soft pancreatic tissue were found to be related to higher pancreatic fistula rates with odds ratios of 3.27 (p = .024) and 3.4 (p = .017), respectively. When only grade B and grade C fistulas were taken into account, the type of stenting has lost its significance but the texture of the remnant pancreas was still associated with 'clinically important' pancreatic fistula.Conclusions: We concluded that the external stenting of the PJ anastomosis may be considered as an effective approach for reducing postoperative pancreatic leaks in PD-planned patients for periampullary tumors. Although our study was retrospectively designed, we used standard charts to gather patient data and compared two stenting methods among homogeneous patient groups.
METHODS:BACKGROUND:Heavily pretreated pancreatic cancer patients have a grave prognosis. In this case series study, we evaluated the safety and efficacy of nab-paclitaxel-based chemotherapy for such patients. METHODS:The data of pancreatic adenocarcinoma patients (n = 40) treated with nab-paclitaxel after the failure of gemcitabine or fluoropyrimidines at our institution in 2013-2015 were reviewed. RESULTS:The median number of prior chemotherapy regimens was two (range, 1-6). Eighteen patients had an Eastern Cooperative Oncology Group performance status of ≥2. The regimens comprised nab-paclitaxel combined with the following drugs: gemcitabine (n = 28), gemcitabine and fluoropyrimidine (n = 3), platinum and fluoropyrimidine (n = 4), fluoropyrimidine (n = 4), and irinotecan and fluoropyrimidine (n = 1). The median dose of nab-paclitaxel was 63 (range, 51-72) mg/m2/dose, with the schedule of D1/15, D1/8, and D1/8/15 followed in 23, 14, and 3 patients, respectively. The median overall survival was 5.1 (95% CI, 4.6-5.7) months. Among 32 evaluable patients, two partial responses and six stable diseases were observed. The median progression-free survival was 2.6 (95% CI, 1.9-3.2) months. Grade 3/4 leucopenia or neutropenia was observed in three and two patients, respectively. Grade 3/4 anemia was observed in four patients. Other significant (grade 3 or more) nonhematological toxicities were not frequent, except for sepsis/infection (n = 7). However, more severe anemia or sepsis/infection was significantly associated with disease control. CONCLUSION:In heavily pretreated pancreatic adenocarcinoma patients, low-dose nab-paclitaxel-based chemotherapy was fairly tolerable with modest efficacy.