Drug resistance mediated by ABC transporters such as P-glycoprotein (P-gp) continues to be a major impediment to effective cancer chemotherapy. We have developed a panel of highly specific peptide inhibitors of P-gp based on the structure of the transmembrane domains of the transporter. These peptides are thought to exert their inhibitory action by disrupting the proper assembly of P-gp. A novel 96-well-plate assay based on the efflux of fluorescent P-gp substrate DiOC2 (3-ethyl-2-[3-(3-ethyl-2(3H)-benzoxazolylidene)-1-propenyl]benzoxazolium iodide) was developed and used for structure-functional characterization of transporter inhibitors. The studies strongly suggest that potent and selective inhibitors of ABC transporters can now be developed solely on the basis of the primary structures of the target proteins. The inhibition of P-gp with transmembrane peptides was shown to be chirality-independent. A 25-residue long retroinverso D-analogue of transmembrane domain 5 inhibited the efflux of the fluorescent P-gp substrate with an IC50 of 500 nM. Transmembrane peptides effectively sensitized resistant cancer cells to doxorubicin in vitro without demonstrating any cell toxicity of their own. The newly synthesized P-gp antagonists appear to be promising nontoxic drug resistance inhibitors that merit further development.
BackgroundAcute gallstone disease is a high‐volume emergency general surgery presentation with wide variations in the quality of care provided across the UK. This controlled cohort evaluation assessed whether participation in a quality improvement collaborative approach reduced time to surgery for patients with acute gallstone disease to fewer than 8 days from presentation, in line with national guidance.MethodsPatients admitted to hospital with acute biliary conditions in England and Wales between 1 April 2014 and 31 December 2017 were identified from Hospital Episode Statistics data. Time series of quarterly activity were produced for the Cholecystectomy Quality Improvement Collaborative (Chole‐QuIC) and all other acute National Health Service hospitals (control group). A negative binomial regression model was used to compare the proportion of patients having surgery within 8 days in the baseline and intervention periods.ResultsOf 13 sites invited to join Chole‐QuIC, 12 participated throughout the collaborative, which ran from October 2016 to January 2018. Of 7944 admissions, 1160 patients had a cholecystectomy within 8 days of admission, a significant improvement (P < 0·050) from baseline performance. This represented a relative change of 1·56 (95 per cent c.i. 1·38 to 1·75), compared with 1·08 for the control group. At the individual site level, eight of the 12 Chole‐QuIC sites showed a significant improvement (P < 0·050), with four sites increasing their 8‐day surgery rate to over 20 per cent of all emergency admissions, well above the mean of 15·3 per cent for control hospitals.ConclusionA surgeon‐led quality improvement collaborative approach improved care for patients requiring emergency cholecystectomy.
Oxidative stress is defined as the imbalance between the generation of reactive oxygen species and antioxidant defense mechanisms. The cardiovascular system is a major target for reactive oxygen species. Cardiomyocytes and the vasculature of the heart can be severely damaged as a result of oxidative stress. In this paper, we discuss recent findings with respect to the role of oxidative stress in heart disease. The efficacies of treatments with vitamins and wine-derived compounds, as well as innovative gene therapeutic experiments that may potentially alleviate oxidative stress-induced disease, are also discussed.
A 50-year-old female presented with acute epigastric abdominal pain, diarrhea, nausea, and vomiting for two days. Laboratory data showed hyperbilirubinemia and leukocytosis. Abdominal imagining was concerning for a pancreatic head/uncinate process lesion concerning a pancreatic neoplasm. Subsequent esophagogastroduodenoscopy with endoscopic ultrasound and endoscopic retrograde cholangiopancreatography found the major papilla adjacent to an inflamed and infected duodenal diverticulum, which was extrinsically compressing the distal common bile duct, causing biliary obstruction and common bile duct dilation. These findings are consistent with a diagnosis of Lemmel’s syndrome. A biliary sphincterotomy was performed to relieve the obstruction and one temporary plastic biliary stent was placed into the common bile duct. The duodenal diverticulitis was treated with antibiotics for 10 days and the patient made a good recovery.
A diverse group of patients presenting to an urgent care center following the destruction of an ED by natural disaster can be cared for in an EDOS, regardless of association with a physical ED. An urgent care center with an associated EDOS can be implemented to provide patient care in a disaster situation. This may be useful when existing ED or hospital resources are compromised. (Disaster Med Public Health Preparedness. 2016;10:405-410).
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