Comparison of the clinical effectiveness of hepaticojejunostomy and self-expanding metal stents for bypassing the bile ducts in patients with unresectable pancreatic head cancer complicated by obstructive jaundice.

OBJECTIVE: Aim: To improve treatment outcomes of patients with unresectable pancreatic head cancer complicated by obstructive jaundice by improving the tactics and techniques of surgical interventions. PATIENTS AND METHODS: Materials and Methods: Depending on the treatment tactics, patients were randomised to the main group (53 people) or the comparison group (54 people). The results of correction of obstructive jaundice by Roux-en-Y end to side hepaticojejunostomy (main group) and common bile duct prosthetics with self-expanding metal stents (comparison group) were compared. RESULTS: Results: The use of self-expanding metal stents for internal drainage of the biliary system compared to hepaticojejunostomy operations reduced the incidence of postoperative complications by 29.9% (χ2=13.7, 95% CI 14.38-44.08, p=0.0002) and mortality by 7.5% (χ2=4.16, 95% CI -0.05-17.79, p=0.04). Within 8-10 months after biliary stenting, 11.1% (6/54) of patients developed recurrent jaundice and cholangitis, and another 7.4% (4/54) of patients developed duodenal stenosis with a tumour. These complications led to repeated hospitalisation and biliary restentation in 4 (7.4%) cases, and duodenal stenting by self-expanding metal stents in 4 (7.4%) patients. CONCLUSION: Conclusions: The choice of biliodigestive shunting method should be selected depending on the expected survival time of patients. If the prognosis of survival is up to 8 months, it is advisable to perform prosthetics of the common bile duct with self-expanding metal stents, if more than 8 months, it is advisable to perform hepaticojejunal anastomosis with prophylactic gastrojejunal anastomosis.

PALLIATIVE SURGICAL TREATMENT OF PATIENTS WITH UNRESECTABLE CANCER OF THE HEAD OF THE PANCREAS COMPLICATED BY MECHANICAL JAUNDICE.

OBJECTIVE: The aim: To improve the results of palliative surgical treatment of patients with unresectable cancer of the head of the pancreas, complicated by obstructive jaundice, disturbances of evacuation from the stomach, cancerous pancreatitis by improving surgical tactics and techniques of surgical interventions.. PATIENTS AND METHODS: Materials and methods: There were 277 patients with unresectable cancer of the head of the pancreas participated in the study, who were divided into control (n=159) and main (n=118) groups depending on treatment tactics. RESULTS: . Results: The operation of choice in the surgical treatment of patients with unresectable cancer of the head of the pancreas, complicated by obturation of the biliary system and duodenum with a high surgical risk is endoscopic stenting of the bile ducts and duodenum with nitinol stents, which is accompanied by a decrease in the frequency of postoperative complications from 72.7 to 29.6% (χ2=5.8, 95% CI 8.26-65.39, p=0.01), mortality from 36.4% to 0.0% (χ2=10.69, 95% CI 11.8- 64.65, p=0.001). The patient's formation of biliodigestive and prophylactic gastrodigestive anastomosis is an effective and safe procedure, which, in comparison with only biliodigestive shunting, reduces the frequency of postoperative complications by 16.2% (χ2=6.61, 95% CI 3.69-30.89, p=0.01), improves quality of life and prevents repeated surgical operations to restore evacuation from the stomach. CONCLUSION: Conclusions: The use of the proposed surgical tactics and technique of surgical interventions in patients with unresectable cancer of the head of the pancreas, complicated by obstructive jaundice, disturbances of evacuation from the stomach, cancerous pancreatitis made it possible to reduce the frequency of complications by 9.3% (χ2=3.94, 95% CI 0.09-17.86, p=0.04) and fatal cases by 5.8% (χ2=4.5, 95% CI 0.42-12.72, p=0.03).

Cortisol controls endoplasmic reticulum stress and hypoxia dependent regulation of insulin receptor and related genes expression in HEK293 cells.

Objective. Glucocorticoids are important stress-responsive regulators of insulin-dependent metabolic processes realized through specific changes in genome function. The aim of this study was to investigate the impact of cortisol on insulin receptor and related genes expression in HEK293 cells upon induction the endoplasmic reticulum (ER) stress by tunicamycin and hypoxia. Methods. The human embryonic kidney cell line HEK293 was used. Cells were exposed to cortisol (10 µM) as well as inducers of hypoxia (dimethyloxalylglycine, DMOG; 0.5 mM) and ER stress (tunicamycin; 0.2 µg/ml) for 4 h. The RNA from these cells was extracted and reverse transcribed. The expression level of INSR, IRS2, and INSIG2 and some ER stress responsive genes encoding XBP1n, non-spliced variant, XBP1s, alternatively spliced variant of XBP1, and DNAJB9 proteins, was measured by quantitative polymerase chain reaction and normalized to ACTB. Results. We showed that exposure of HEK293 cells to cortisol elicited up-regulation in the expression of INSR and DNAJB9 genes and down-regulation of XBP1s, XBP1n, IRS2, and INSIG2 mRNA levels. At the same time, induction of hypoxia by DMOG led to an up-regulation of the expression level of most studied mRNAs: XBP1s and XBP1n, IRS2 and INSIG2, but did not change significantly INSR and DNAJB9 gene expression. We also showed that combined impact of cortisol and hypoxia introduced the up-regulation of INSR and suppressed XBP1n mRNA expression levels. Furthermore, the exposure of HEK293 cells to tunicamycin affected the expression of IRS2 gene and increased the level of XBP1n mRNA. At the same time, the combined treatment of these cells with cortisol and inductor of ER stress had much stronger impact on the expression of all the tested genes: strongly increased the mRNA level of ER stress dependent factors XBP1s and DNAJB9 as well as INSR and INSIG2, but down-regulated IRS2 and XBP1n. Conclusion. Taken together, the present study indicates that cortisol may interact with ER stress and hypoxia in the regulation of ER stress dependent XBP1 and DNAJB9 mRNA expression as well as INSR and its signaling and that this corticosteroid hormone modified the impact of hypoxia and especially tunicamycin on the expression of most studied genes in HEK293 cells. These data demonstrate molecular mechanisms of glucocorticoids interaction with ER stress and insulin signaling at the cellular level.

Expression of IDE and PITRM1 genes in ERN1 knockdown U87 glioma cells: effect of hypoxia and glucose deprivation.

OBJECTIVE: The aim of the present investigation was to study the expression of genes encoding polyfunctional proteins insulinase (insulin degrading enzyme, IDE) and pitrilysin metallopeptidase 1 (PITRM1) in U87 glioma cells in response to inhibition of endoplasmic reticulum stress signaling mediated by ERN1/IRE1 (endoplasmic reticulum to nucleus signaling 1) for evaluation of their possible significance in the control of metabolism through ERN1 signaling as well as hypoxia, glucose and glutamine deprivations. METHODS: The expression level of IDE and PITRM1 genes was studied in control and ERN1 knockdown U87 glioma cells under glucose and glutamine deprivations as well as hypoxia by quantitative polymerase chain reaction. RESULTS: It was found that the expression level of IDE and PITRM1 genes was down-regulated in ERN1 knockdown (without ERN1 protein kinase and endoribonuclease activity) glioma cells in comparison with the control glioma cells, being more significant for PITRM1 gene. We also found up-regulation of microRNA MIR7-2 and MIRLET7A2, which have specific binding sites in 3'-untranslated region of IDE and PITRM1 mRNAs, correspondingly, and can participate in posttranscriptional regulation of these mRNA expressions. Only inhibition of ERN1 endoribonuclease did not change significantly the expression of IDE and PITRM1 genes in glioma cells. The expression of IDE and PITRM1 genes is preferentially regulated by ERN1 protein kinase. We also showed that hypoxia down-regulated the expression of IDE and PITRM1 genes and that knockdown of ERN1 signaling enzyme function modified the response of these gene expressions to hypoxia. Glucose deprivation increased the expression level of IDE and PITRM1 genes, but ERN1 knockdown enhanced only the effect of glucose deprivation on PITRM1 gene expression. Glutamine deprivation did not affect the expression of IDE gene in both types of glioma cells, but up-regulated PITRM1 gene and this up-regulation was stronger in ERN1 knockdown cells. CONCLUSIONS: Results of this investigation demonstrate that ERN1 knockdown significantly decreases the expression of IDE and PITRM1 genes by ERN1 protein kinase mediated mechanism. The expression of both studied genes was sensitive to hypoxia as well as glucose deprivation and dependent on ERN1 signaling in gene-specific manner. It is possible that the level of these genes expression under hypoxia and glucose deprivation is a result of complex interaction of variable endoplasmic reticulum stress related and unrelated regulatory factors and contributed to the control of the cell metabolism.

Hypoxic regulation of EDN1, EDNRA, EDNRB, and ECE1 gene expressions in ERN1 knockdown U87 glioma cells.

OBJECTIVE: The aim of the present investigation was to study the effect of hypoxia on the expression of genes encoding endothelin-1 (EDN1) and its cognate receptors (EDNRA and EDNRB) as well as endothelin converting enzyme 1 (ECE1) in U87 glioma cells in response to inhibition of endoplasmic reticulum stress signaling mediated by ERN1/IRE1 (endoplasmic reticulum to nucleus signaling 1) for evaluation of their possible significance in the control of glioma growth through ERN1 and hypoxia. METHODS: The expression level of EDN1, EDNRA, EDNRB, and ECE1 genes as well as micro-RNA miR-19, miR-96, and miR-206 was studied in control and ERN1 knockdown U87 glioma cells under hypoxia by quantitative polymerase chain reaction. RESULTS: It was shown that the expression level of EDN1, EDNRA, EDNRB, and ECE1 genes was up-regulated in ERN1 knockdown glioma cells in comparison with the control glioma cells, being more significant for endothelin-1. We also observed down-regulation of microRNA miR-206, miR-96, and miR-19a, which have specific binding sites in mRNA EDN1, EDNRA, and EDNRB, correspondingly, and can participate in posttranscriptional regulation of these mRNA expressions. Furthermore, inhibition of ERN1 endoribonuclease lead to up-regulation of EDNRA and ECE1 gene expressions and down-regulation of the expression level of EDN1 and EDNRB genes in glioma cells. Thus, the expression of EDNRA and ECE1 genes is regulated by ERN1 endoribonuclease, but EDN1 and EDNRB genes preferentially by ERN1 protein kinase. We have also shown that hypoxia enhanced the expression of EDN1, EDNRA, and ECE1 genes and that knockdown of ERN1 signaling enzyme function significantly modified the response of all studied gene expressions to hypoxia. Thus, effect of hypoxia on the expression level of EDN1 and ECE1 genes was significantly or completely reduced in ERN1 knockdown glioma cells since the expression of EDNRA gene was down-regulated under hypoxia. Moreover, hypoxia is induced the expression of EDNRB gene in ERN1 knockdown glioma cells. CONCLUSIONS: Results of this investigation demonstrate that ERN1 knockdown significantly increased the expression of endothelin-1 and its receptors as well as ECE1 genes by different mechanisms and that all studied gene expressions were sensitive to hypoxia. It is possible that hypoxic regulation of the expression of these genes is a result of complex interaction of variable ERN1 related transcription and regulatory factors with HIF1A and possibly contributed to the control of glioma growth.