EDNRB isoform 3 confers Temozolomide resistance in A375 melanoma cells by modulating membrane potential, reactive oxygen species and mitochondrial Ca2.

BACKGROUND: The role of endothelin receptor type B (EDNRB) isoform 3 involved in Temozolomide (TMZ)-induced melanoma cell death has not yet been elucidated. METHODS: The subcellular localization of EDNRB isoform 3 was determined by confocal and immunoblotting assays. Silencing EDNRB isoform 3 was performed by CRISPR/Cas9. Apoptosis was assessed by annexin V/propium iodide staining and caspases 3/7/9 activity. Mitochondrial membrane potential, reactive oxygen species and mitochondrial Ca2+ were measured by flow cytometry. Apoptosis protein array was applied. RESULTS: Confocal and immunoblot analyses indicate mitochondrial localization of EDNRB isoform 3 and the first N-terminal (1-22) amino acids are sufficient for its mitochondrial targeting. EDNRB isoform 3 depleted A375 cells significantly confers chemoresistance with mitochondrial depolarization, reduced reactive oxygen species, enhanced mitochondrial Ca2+ uptake and decreased caspase 9 activation. Additionally, apoptosis array shows that lack of EDNRB isoform 3 has relatively lower expression of phosphorylation of p53 at S392 and a slightly higher expression of Paraoxonase 2. CONCLUSION: Our findings raise the possibility of targeting EDNRB isoform 3 as a new therapeutic strategy in combination with TMZ for melanoma treatment.

[Effect of intermittent pneumatic compression on coagulation function and deep venous hemodynamics of lower limbs after rectal cancer resection].

OBJECTIVE: To investigate the effects of intermittent pneumatic compression (IPC) on coagulation function, deep venous hemodynamics and prevention of deep venous thrombosis (DVT) of lower limbs in patients after rectal cancer resection. METHODS: A total of 120 patients undergoing rectal cancer resection were randomly divided into non-IPC group (control group, n=60) and IPC group (n=60). The control group received routine treatment after resection and the IPC group received IPC based on the routine treatments. Prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), international normalized ratio (INR) and volume of D-dimer (D-D) were detected before operation and 1-, 3-, 5- and 7-day after operation. Meanwhile, blood flow velocity and caliber of external iliac vein, femoral vein and popliteal vein were examined by color Doppler ultrasound, then the average blood flow velocity and blood flow volume were calculated. RESULTS: Incidence of lower limb DVT was 13.3% (8/60) and 1.7% (1/60) in control group and IPC group respectively with significant difference (P<0.05). The differences in PT, APTT and INR were not significant (P>0.05) at 1-day after operation as compared to the preoperative level, while FIB and D-D both increased (P<0.05), all presented no significant difference among the two groups (P>0.05). PT shortened gradually (P<0.05), APTT and INR did not change significantly (P>0.05), FIB and D-D increased gradually (P<0.05), and no significant differences were found between the two groups at the same time point (all P>0.05). All the above parameters in the control group were significantly lower than those in IPC group (all P<0.05). CONCLUSIONS: IPC can improve hemodynamics indexes of deep veins of lower limb in patients after rectal cancer operation, and prevent the lower limb DVT. IPC is a safe, simple and convenient physical therapy.

[Meta-analysis of efficacy and safety of liver transplantation in treating cholangiocarcinoma].

OBJECTIVE: To evaluate the therapeutic efficacy and safety of liver transplantation for patients with cholangiocarcinoma. METHODS: According to the requirements of Cochrane systematic review, a thorough literature search was performed in Pubmed/Medline, Embase and Cochrane Central Register electronic databases ranged between 1995 and 2009 in terms of the key words "liver transplantation", and "cholangiocarcinoma" or "cholangiocellular carcinoma" or "bile duct cancer". And restricted the articles published in the English language. Two reviewers independently screened the studies for eligibility, evaluated the quality and extracted the data from the eligible studies with confirmation by cross-checking. Data were processed for a meta-analysis by Stata 10 software with 1-, 3-, 5-year survival rates and incidence of complications. RESULTS: A total of 14 clinical trials containing 605 patients were finally enrolled in this study. The overall 1-, 3-, 5-year pooled survival rates were 73% (95%CI: 0.65 - 0.80), 42% (95%CI: 0.33 - 0.51) and 39% (95%CI: 0.28 - 0.51), respectively. Of note, preoperative adjuvant therapies (OLT-PAT group) rendered the transplanted individuals comparably favorable outcomes with 1-, 3-, 5-year pooled survival rates of 83% (95%CI: 0.57 - 0.98), 57% (95%CI: 0.18 - 0.92) and 65% (95%CI: 0.40 - 0.87), respectively. In addition, the overall pooled incidence of complications was 62% (95%CI: 0.44 - 0.78), among which that of OLT-PAT group (58%, 95%CI: 0.20 - 0.92) was relatively acceptable compared to those of liver transplantation alone (61%, 95%CI: 0.33 - 0.85) and liver transplantation with extended bile duct resection (78%, 95%CI: 0.55 - 0.94). CONCLUSIONS: In comparison to curative resection of cholangiocarcinoma with the 5-year survival rate reported from 20% to 40%, the role of liver transplantation alone is so limited, but neoadjuvant radiochemotherapy combined with liver transplantation can bring better short- and long-term prognosis.

Effect of preoperative biliary drainage on malignant obstructive jaundice: a meta-analysis.

AIM: To evaluate the effect of preoperative biliary drainage (PBD) on obstructive jaundice resulting from malignant tumors. METHODS: According to the requirements of Cochrane systematic review, studies in the English language were retrieved from MEDLINE and Embase databases from 1995 to 2009 with the key word "preoperative biliary drainage". Two reviewers independently screened the eligible studies, evaluated their academic level and extracted the data from the eligible studies confirmed by cross-checking. Data about patients with and without PBD after resection of malignant tumors were processed for meta-analysis using the Stata 9.2 software, including postoperative mortality, incidence of postoperative pancreatic and bile leakage, abdominal abscess, delayed gastric emptying and incision infection. RESULTS: Fourteen retrospective cohort studies involving 1826 patients with malignant obstructive jaundice accorded with our inclusion criteria, and were included in meta-analysis. Their baseline characteristics were comparable in all the studies. No significant difference was found in combined risk ratio (RR) of postoperative mortality and incidence of pancreatic and bile leakage, abdominal abscess, delayed gastric emptying between patients with and without PBD. However, the combined RR for the incidence of postoperative incision infection was improved better in patients with PBD than in those without PBD (P < 0.05). CONCLUSION: PBD cannot significantly reduce the postoperative mortality and complications of malignant obstructive jaundice, and therefore should not be used as a preoperative routine procedure for malignant obstructive jaundice.