Chimeric antigen receptor-modified human regulatory T cells that constitutively express IL-10 maintain their phenotype and are potently suppressive

Clinical trials of Treg therapy in transplantation are currently entering phases IIa and IIb, with the majority of these employing polyclonal Treg populations that harbor a broad specificity. Enhancing Treg specificity is possible with the use of chimeric antigen receptors (CARs), which can be customized to respond to a specific human leukocyte antigen (HLA). In this study, we build on our previous work in the development of HLA-A2 CAR-Tregs by further equipping cells with the constitutive expression of interleukin 10 (IL-10) and an imaging reporter as additional payloads. Cells were engineered to express combinations of these domains and assessed for phenotype and function. Cells expressing the full construct maintained a stable phenotype after transduction, were specifically activated by HLA-A2, and suppressed alloresponses potently. The addition of IL-10 provided an additional advantage to suppressive capacity. This study therefore provides an important proof-of-principle for this cell engineering approach for next-generation Treg therapy in transplantation.     

Epigenetic dysregulation in Epstein-Barr virus-associated gastric carcinoma: Disease and treatments

Epstein-Barr virus(EBV)-associated gastric carcinoma(EBVaGC)comprises nearly 10%of gastric carcinoma cases worldwide.Recently,it was recognised to have unique clinicopathologic characteristics,including male predominance,lower rates of lymph node involvement,and better prognosis.EBVaGC is further characterised by abnormal hypermethylation of tumour suppressor gene promoter regions,causing down-regulation of their expression.In the present review,we critically discuss the role of EBV in gastric carcinogenesis,summarising the role of viral proteins and microRNAs with respect to aberrant methylation in EBVaGC.Given the role of epigenetic dysregulation in tumourigenesis,epigenetic modifiers may represent a novel therapeutic strategy.     

Percutaneous nephrolithotripsy under assisted local anaesthesia for high risk patients: Is it effective?

ObjectivesThe aim of the present study is to evaluate the feasibility and safety of performing PNL under local anesthesia in a selected group of patients who are at high risk for general anesthesia.Patients and methodsForty seven patients underwent PNL under local anesthesia. There were 38 males and 9 females with a mean age of 62 years. All patients were at medical high-risk for general anesthesia, with an American Society of Anesthesiologists (ASA) score of 3. The indications for local anesthesia in this study were obstructed single functioning kidney with azotemia in 29 patients, hepatic insufficiency in 8 patients, cardiac problems in 7 patients and 3 patients had hepatocellular carcinoma. The mean stone size was 2.7 cm (range 2–3.1 cm). Local infiltration with 10–20 cc of 2% lidocaine at the site of puncture was used in all cases. Narcotics were given 30 min prior to the procedure and medazolam was given intraoperatively upon demand. Utrasound guided puncture was performed in all cases and tract dilatation was then done under fluoroscopy using high pressure balloon catheter in 35 and Alken's metal dilators in 12 cases. Stones were then retrieved after disintegration in the same cession in 33 patients, while the other 14 patients underwent staged PNL, where a 12 Fr. nephrostomy tube was placed in the first stage, followed by tract dilatation and stone retrieval one week later.ResultsOut of 47 patients included, 44 had successful PNL either one stage (30 patients) or two stages (14 patients). Only 3 patients could not tolerate pain and the procedure was terminated after placement of nephrostomy tube and stone retrieval was completed later under general anesthesia.ConclusionOur results demonstrated that PNL under local anesthesia with narcotics and sedatives seems to be a satisfying solution for the treatment of a selected group of patients with renal pelvic stones and who have high anesthetic risk. However, additional studies with different groups of patients are required to validate our results.