Relationship of EGFR-TKI Targeted Therapy and Pyroptosis in Non-small Cell Lung Cancer / 肿瘤防治研究

Objective To explore the relationship between pyroptosis and treatment in non-small cell lung cancer patients treated with tyrosine kinase inhibitors targeted therapy. Methods Stable transfection strains with common EGFR mutations found in clinical practice were constructed through lentiviral transfection. LDH and Western blot experiments were conducted to determine the degree and mechanism of pyroptosis after osimertinib treatment. Animal experiments verified the effect of pyroptosis on treatment efficacy. ELISA was used to explore the potential connection between pyroptosis and tumor immunotherapy. Results After osimertinib treatment on stable lines, the EGFR-L858R mutation had obvious pyroptosis at the morphology and protein levels. Western blot experiment confirmed that pyroptosis was mediated by GSDME (P < 0.0001). Experiments through the overexpression of GSDME and corresponding animal studies discovered that the degree of pyroptosis affected the treatment outcome. Blood analysis revealed that the level of IL-1β secreted by EGFR-L858R and EGFR-L858R-GSDME-OE mice after treatment was higher than that of the control group (P < 0.0001), and it may regulate tumor immunity to a certain extent. Conclusion Osimertinib can induce pyroptosis in EGFR-L858R mutant strains mediated by GSDME, and the level of pyroptosis in cell lines is positively correlated with therapeutic effect to a certain extent.

NDFIP1 limits cellular TAZ accumulation via exosomal sorting to inhibit NSCLC proliferation

NDFIP1 has been previously reported as a tumor suppressor in multiple solid tumors, but the function of NDFIP1 in NSCLC and the underlying mechanism are still unknown. Besides, the WW domain containing proteins can be recognized by NDFIP1, resulted in the loading of the target proteins into exosomes. However, whether WW domain-containing transcription regulator 1 (WWTR1, also known as TAZ) can be packaged into exosomes by NDFIP1 and if so, whether the release of this oncogenic protein via exosomes has an effect on tumor development has not been investigated to any extent. Here, we first found that NDFIP1 was low expressed in NSCLC samples and cell lines, which is associated with shorter OS. Then, we confirmed the interaction between TAZ and NDFIP1, and the existence of TAZ in exosomes, which requires NDFIP1. Critically, knockout of NDFIP1 led to TAZ accumulation with no change in its mRNA level and degradation rate. And the cellular TAZ level could be altered by exosome secretion. Furthermore, NDFIP1 inhibited proliferation in vitro and in vivo, and silencing TAZ eliminated the increase of proliferation caused by NDFIP1 knockout. Moreover, TAZ was negatively correlated with NDFIP1 in subcutaneous xenograft model and clinical samples, and the serum exosomal TAZ level was lower in NSCLC patients. In summary, our data uncover a new tumor suppressor, NDFIP1 in NSCLC, and a new exosome-related regulatory mechanism of TAZ.

Autophagy induction by SIRT6 is involved in oxidative stress-induced neuronal damage

SIRT6 is a NAD(+)-dependent histone deacetylase and has been implicated in the regulation of genomic stability, DNA repair, metabolic homeostasis and several diseases. The effect of SIRT6 in cerebral ischemia and oxygen/glucose deprivation (OGD) has been reported, however the role of SIRT6 in oxidative stress damage remains unclear. Here we used SH-SY5Y neuronal cells and found that overexpression of SIRT6 led to decreased cell viability and increased necrotic cell death and reactive oxygen species (ROS) production under oxidative stress. Mechanistic study revealed that SIRT6 induced autophagy via attenuation of AKT signaling and treatment with autophagy inhibitor 3-MA or knockdown of autophagy-related protein Atg5 rescued H2O2-induced neuronal injury. Conversely, SIRT6 inhibition suppressed autophagy and reduced oxidative stress-induced neuronal damage. These results suggest that SIRT6 might be a potential therapeutic target for neuroprotection.

Delayed massive haemorrhage after pancreatic resection / 中华普通外科杂志

Objective To explore the cause,treatment and prognosis of delayed massive haemorrhage (DMH) after pancreatic resection.Method Clinical data of 1554 patients undergoing pancreatectomy in our hospital from Aug 2003 to Aug 2013 were retrospectively analyzed.Results 16 patients suffered from DMH,including 13 patients who had undergone pancreaticoduodenectomy,and 3 patients who had had resection of pancreatic body and tail.Gastrointestinal haemorrhage occurred in 6 patients,intra-abdominal haemorrhage occurred in 10 patients,respectively.Reoperations were performed in 11 patients,transcatheter arterial embolization (TAE) undertaken in 2 patients,and endoscopic treatment in 3 patients.10 patients recovered after treatment,6 patients (6/16) died.Conclusions The mortality of DMH after pancreatic surgery is high.Postoperative pancreatic leak and gastrointestinal stress ulcer are the most possible risk factors,intra-abdominal arterial haemorrhage is the main cause of death.

Inhibition of SIRT6 in prostate cancer reduces cell viability and increases sensitivity to chemotherapeutics

SIRT6 is an important histone modifying protein that regulates DNA repair, telomere maintenance, energy metabolism, and target gene expression. Recently SIRT6 has been identified as a tumor suppressor and is down-regulated in certain cancer types, but not in other cancers. From deposited gene profiling studies we found that SIRT6 was overexpressed in prostate tumors, compared with normal or paratumor prostate tissues. Tissue micro-array studies confirmed the higher levels of SIRT6 in both prostate tumor tissues and prostate cancer cells than in their normal counterparts. Knockdown of SIRT6 in human prostate cancer cells led to sub-G1 phase arrest of cell cycle, increased apoptosis, elevated DNA damage level and decrease in BCL2 gene expression. Moreover, SIRT6-deficiency reduced cell viability and enhanced chemotherapeutics sensitivity. Taken together, this study provides the first evidence of SIRT6 overexpression in human prostate cancer, and SIRT6 regulation could be exploited for prostate cancer therapy.

Management of biliary complications following orthotopic liver transplantation / 中国普通外科杂志

Objective To evaluate the management of biliary complications (BC) following orthotopic liver transplantation (OLT). Methods From Feb 1999 to Feb 2004, 236 cases underwent OLT with end-to-end choledocho-choledochostomy. Biliary anastomosis was performed by intermittent suture with T tube placement in 96 cases, without T tube in 39 cases, by continuous suture in posterior wall and intermittent suture in anterior wall and without T tube in 101 cases. Results Thirty-two (13.3%) patients developed BC, with incidences in group 1, 2 and 3 of 17.7%, 15.4% and 7.9%, respectively. The incidence of hepatic hilar and/or intrahepatic bile duct strictures was 8.3%, 2.6% and 1.0%, respectively. BC incidence in group 3 significantly decreased. Twenty patients with biliary stricture underwent endoscopic and/or radiological interventions, and stricture resolution was achieved in 90% of patients with anastomotic strictures and 60% of patients with hepatic hilar and/or intrahepatic strictures. Conclusions Modified biliary tract reconstruction technique contributes to the decrease of BC. Endoscopic and/or radiological interventions should be used for non-ischemic anastomotic biliary strictures or simple hepatic hilar strictures.

Pretreatment of hypertonic saline attenuates the hepatic ischemia reperfusion injury induced by neutrophils / 中国病理生理杂志

AIM:To explore the effect of the pretreatment of hypertonic saline(HTS) in hepatic ischemia reperfusion(I/R) injury.METHODS:The rats were divided into sham group(sham group),ischemia reperfusion group(IR group) and pretreatment of hypertonic saline group(HTS group).Partial hepatic ischemia reperfusion model was used.The rats were sacrificed at the time of 1 h,3 h,6 h,12 h and 24 h after reperfusion in each group,respectively.Blood samples were obtained to examine ALT.The expression of the CD11b/CD18(Mac-1) on the neutrophils was analyzed by flow cytometry.RT-PCR and Western blotting were used to examine the expression of intercellular adhesion molecule-1(ICAM-1) in livers and chromatometry was performed to detect the activity of myeloperoxidase(MPO) in livers.The morphology of hepatocytes and the structure of sinusoid were observed by histological examinations.RESULTS:① HTS pretreatment decreased the level of ALT at the time points of 3 h,6 h and 12 h after reperfusion(P