Testicular germ cell tumours (GCTs) of adolescents and adults can be subdivided into seminomas (referred to as dysgerminomas of the ovary) and non-seminomas, all referred to as type II GCTs. They originate from carcinoma in situ (CIS), being the malignant counterparts of primordial germ cells (PGCs)/gonocytes. The invasive components mimic embryogenesis, including the stem cell component embryonal carcinoma (EC), the somatic lineage teratoma (TE), and the extra-embryonic tissues yolk sac tumour (YST) and choriocarcinoma (CH). The other type is the so-called spermatocytic seminomas (SS, type III GCT), composed of neoplastic primary spermatocytes. We reported previously that the miRNAs hsa-miR 371-373 cluster is involved in overruling cellular senescence induced by oncogenic stress, allowing cells to become malignant. Here we report the first high-throughput screen of 156 microRNAs in a series of type II and III GCTs (n = 69, in duplicate) using a quantitative PCR-based approach. After normalization to allow inter-sample analysis, the technical replicates clustered together, and the previous hsa-miRNA 371-373 cluster finding was confirmed. Unsupervised cluster analysis demonstrated that the cell lines are different from the in vivo samples. The in vivo samples, both normal and malignant, clustered predominantly based on their maturation status. This parallels normal embryogenesis, rather than chromosomal anomalies in the tumours. miRNAs within a single cluster showed a similar expression pattern, implying common regulatory mechanisms. Normal testicular tissue expressed most discriminating miRNAs at a higher level than SE and SS. Moreover, differentiated non-seminomas showed overexpression of discriminating miRNAs. These results support the model that miRNAs are involved in regulating differentiation of stem cells, retained in GCTs.

Obesity has been recognized as a major risk factor for chronic kidney disease, but the underlying mechanism remains elusive. Here, we investigated the mechanism whereby long-term high-fat diet (HFD) feeding induces renal injury in mice. The C57BL/6 mice fed HFD for 16 weeks developed obesity, diabetes, and kidney dysfunction manifested by albuminuria and blood accumulation of BUN and creatinine. The HFD-fed kidney showed marked glomerular and tubular injuries, including prominent defects in the glomerular filtration barrier and increased tubular cell apoptosis. Mechanistically, HFD feeding markedly increased triglyceride and cholesterol contents in the kidney and activated lipogenic pathways for cholesterol and triglyceride synthesis. HFD feeding also increased oxidative stress and induced mitochondrial fission in tubular cells, thereby activating the pro-apoptotic pathway. In HK-2 and mesangial cell cultures, high glucose, fatty acid, and TNF-α combination was able to activate the lipogenic pathways, increase oxidative stress, promote mitochondrial fission, and activate the pro-apoptotic pathway, all of which could be attenuated by an inhibitor that depleted reactive oxygen species. Taken together, these observations suggest that long-term HFD feeding causes kidney injury at least in part as a result of tissue lipid accumulation, increased oxidative stress, and mitochondrial dysfunction, which promote excess programmed cell death.

PurposePostoperative delirium is a serious and common complication, it occurs in 13–50% of elderly patients after major surgery, and presages adverse outcomes. Emerging literature suggests that dexmedetomidine sedation in critical care units (intensive care unit) is associated with reduced incidence of delirium. However, few studies have investigated whether postoperative continuous infusion of dexmedetomidine could safely decrease the incidence of delirium in elderly patients admitted to general surgical wards after noncardiac surgery.Patients and methodsThis double-blind, randomized, placebo-controlled trial was conducted in patients aged 65 years or older undergoing major elective noncardiac surgery without a planned ICU stay. Eligible patients were randomly assigned to receive either dexmedetomidine (0.1 μg/kg/h) or placebo (0.9% normal saline) immediately after surgery though patient-controlled intravenous analgesia device. The primary outcome was the incidence of delirium during the first 5 postoperative days. Secondary outcomes included postoperative subjective pain scores and subjective sleep quality. The study dates were from January 2018 to January 2019.ResultsA total of 557 patients were randomly assigned to receive either dexmedetomidine (n=281) or placebo (n=276). The incidence of postoperative delirium had no difference between the dexmedetomidine and placebo groups (11.7% [33 of 281] vs 13.8% [38 of 276], P=0.47). Compared with placebo group, patients in dexmedetomidine group reported significant lower numerical rating score pain scores at 3, 12, 24, and 48 hrs after surgery (all P<0.05) and significant improved Richards Campbell Sleep Questionnaire results during the first 3 postoperative days (all P<0.0001). Dexmedetomidine-related adverse events were similar between the two groups.ConclusionPostoperative continuous infusion of dexmedetomidine did not decrease the incidence of postoperative delirium in elderly patients admitted to general surgical wards after elective noncardiac surgery.

T follicular helper (Tfh) cells provide help for antigen-specific B cells. We have previously shown that Tfh cell frequency was increased and associated with auto-antibodies in patients with rheumatoid arthritis (RA), suggesting a possible involvement of Tfh cells in its pathogenesis. Mesenchymal stem cells (MSCs) represent a promising alternative cell therapy for RA by modulating T and B cell activation and proliferation. However, it remains unknown whether MSCs have immunoregulation on Tfh cells. In this paper, we have demonstrated that allogeneic MSCs could suppress Tfh cell differentiation in RA patients partly via the production of indoleamine 2,3-dioxygenase (IDO). IFNγ generated from Tfh cell differentiation system induced IDO expression on MSCs. MSCs transplantation (MSCT) into collagen-induced arthritis (CIA) mice prevented arthritis progression by inhibiting both the number and function of Tfh cells in vivo. These findings reveal a novel suppressive function of MSCs in Tfh cells, which has implication in understanding the underlying mechanisms of the immunotherapeutic effects of MSCs on RA patients.

Diets high in animal fats are associated with increased risks of inflammatory bowel disease, but the mechanism remains unclear. In this study, we investigated the effect of high-fat diet (HFD) on the development of experimental colitis in mice. Relative to mice fed low-fat diet (LFD), HFD feeding for 4 wk increased the levels of triglyceride, cholesterol, and free fatty acids in the plasma as well as within the colonic mucosa. In an experimental colitis model induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS), mice on 4-wk HFD exhibited more severe colonic inflammation and developed more severe colitis compared with the LFD counterparts. HFD feeding resulted in higher production of mucosal pro-inflammatory cytokines, greater activation of the myosin light chain kinase (MLCK) tight junction regulatory pathway, and greater increases in mucosal barrier permeability in mice following TNBS induction. HFD feeding also induced gp91, an NADPH oxidase subunit, and promoted reactive oxygen species (ROS) production in both colonic epithelial cells and lamina propria cells. In HCT116 cell culture, palmitic acid or palmitic acid and TNF-α combination markedly increased ROS production and induced the MLCK pathway, and these effects were markedly diminished in the presence of a ROS scavenger. Taken together, these data suggest that HFD promotes colitis by aggravating mucosal oxidative stress, which rapidly drives mucosal inflammation and increases intestinal mucosal barrier permeability. NEW & NOTEWORTHY This study demonstrates high-fat diet feeding promotes colitis in a 2,4,6-trinitrobenzenesulfonic acid-induced experimental colitis model in mice. The underlying mechanism is that high-fat diet induces oxidative stress in the colonic mucosa, which increases colonic epithelial barrier permeability and drives colonic mucosal inflammation. These observations provide molecular evidence that diets high in saturated fats are detrimental to patients with inflammatory bowel diseases.