Despite the skepticism that once prevailed among immunologists, it is now widely accepted that the normal immune system harbors a T-cell population, called regulatory T cells (Treg cells), specialized for immune suppression. It was first shown that depletion of a T-cell subpopulation from normal rodents produced autoimmune disease. Search for a molecular marker specific for such autoimmune-preventive Treg cells has revealed that the majority, if not all, of them constitutively express the CD25 molecule as depletion of CD25+CD4+ T cells spontaneously evokes autoimmune disease in otherwise normal rodents. The expression of CD25 by Treg cells has made it possible to delineate their developmental pathways, in particular their thymic development, and establish simple in vitro assay for assessing their suppressive activity. The marker and the in vitro assay have helped to identify human Treg cells with similar functional and phenotypic characteristics. Recent efforts have shown that natural Treg cells specifically express the transcription factor Foxp3 and that mutations of the Foxp3 gene produce a variety of immunological diseases in humans and rodents. Specific expression of Foxp3 in natural Treg cells has enabled their functional and developmental characterization by genetic approach. These studies altogether have provided firm evidence for Foxp3+CD25+CD4+ Treg cells as an indispensable cellular constituent of the normal immune system for establishing and maintaining immunologic self-tolerance and immune homeostasis. Treg cells are now within the scope of clinical use to treat immunological diseases and control physiological and pathological immune responses.

Regulatory T Cells

[Von Hippel-Lindau disease].

The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses

Oncogenic activation of the phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB/AKT), and mammalian target of rapamycin (mTOR) pathway is a frequent event in prostate cancer that facilitates tumor formation, disease progression and therapeutic resistance Recent discoveries indicate that the complex crosstalk between the PI3K-AKT-mTOR pathway and multiple interacting cell signaling cascades can further promote prostate cancer progression and influence the sensitivity of prostate cancer cells to PI3K-AKT-mTOR-targeted therapies being explored in the clinic, as well as standard treatment approaches such as androgen-deprivation therapy (ADT) However, the full extent of the PI3K-AKT-mTOR signaling network during prostate tumorigenesis, invasive progression and disease recurrence remains to be determined In this review, we outline the emerging diversity of the genetic alterations that lead to activated PI3K-AKT-mTOR signaling in prostate cancer, and discuss new mechanistic insights into the interplay between the PI3K-AKT-mTOR pathway and several key interacting oncogenic signaling cascades that can cooperate to facilitate prostate cancer growth and drug-resistance, specifically the androgen receptor (AR), mitogen-activated protein kinase (MAPK), and WNT signaling cascades Ultimately, deepening our understanding of the broader PI3K-AKT-mTOR signaling network is crucial to aid patient stratification for PI3K-AKT-mTOR pathway-directed therapies, and to discover new therapeutic approaches for prostate cancer that improve patient outcome

The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling.

Chitosan and gelatin-based electrospun fibers for bone tissue engineering.

Aims The aims of the present study were to characterize the pharmacokinetics of voriconazole in renal transplant recipients and to identify factors significantly affecting pharmacokinetic parameters. We also aimed to explore the optimal dosing regimens for patients who developed invasive fungal infections. Methods A total of 105 patients (342 concentrations) were included prospectively in a population pharmacokinetic analysis. Nonlinear mixed-effects models were developed using Phoenix NLME software. Dosing simulations were performed based on the final model. Results A one-compartment model with first-order absorption and elimination was used to characterize voriconazole pharmacokinetics. Population estimates of clearance, volume of distribution and oral bioavailability were 2.88 l·h-1 , 169.3 l and 58%, respectively. The allele frequencies of cytochrome P450 gene (CYP) 2C19*2, *3 and *17 variants were 29.2%, 5.2% and 0.5%, respectively. CYP2C19 genotype had a significant effect on the clearance. Voriconazole trough concentrations in poor metabolizers were significantly higher than in intermediate metabolizers and extensive metabolizers alike. The volume of distribution increased with increased body weight. The oral bioavailability was substantially lower within 1 month after transplantation but increased with postoperative time. Dosing simulations indicated that during the early postoperative period, poor metabolizers could be treated with 150 mg intravenously or 250 mg orally twice daily; intermediate metabolizers with 200 mg intravenously or 350 mg orally twice daily; and extensive metabolizers with 300 mg intravenously twice daily. Conclusions Using a combination of CYP2C19 genotype and postoperative time to determine the initial voriconazole dosing regimens followed by therapeutic drug monitoring could help to advance individualized treatment in renal transplantation patients with invasive fungal infections.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bcp.13595

Population pharmacokinetics of voriconazole and CYP2C19 polymorphisms for optimizing dosing regimens in renal transplant recipients.

Mitochondrial transcription factor A (TFAM) is required for mitochondrial DNA (mtDNA) replication and transcription. microRNAs (miRNAs) act as key factors in the regulation of gene expression. However, the roles of TFAM and certain miRNAs and their association in cancer development remain unclear. The present study reported that the expression of TFAM was significantly increased in bladder cancer, while the expression of miRNA-590-3p was downregulated. The luciferase assay showed that TFAM was the direct target of miRNA-590-3p. Furthermore, the forced overexpression of miRNA-590-3p significantly inhibited the proliferation, migration and colony-forming ability of 5637 cells, which was in contrast with the results from the forced overexpression of TFAM in the 5637 cells. Furthermore, cell proliferation- and migration-related genes, including phosphoinositide-3-kinase (PI3K), Akt, matrix metalloproteinase (MMP)-2 and MMP9, were significantly downregulated in the miRNA-590-3p-overex-pressing 5637 cells, but upregulated in the TFAM-overexpressing cells. In conclusion, the present study suggested that TFAM, a direct target of miRNA-590-3p, may play a significant role in the tumorigenesis of bladder cancer and thus may be a promising target for cancer therapeutics.

/pdf/roles-of-mitochondrial-transcription-factor-a-and-microrna-1oquxb82t3.pdf

Roles of mitochondrial transcription factor A and microRNA-590-3p in the development of bladder cancer

Osteoporosis (OP) has emerged as a frequent and devastating complication of organ solid transplantation process. Bone loss after organ transplant is related to adverse effects of immunosuppressants on bone remodeling and bone quality. Many factors contribute to the pathogenesis of OP in transplanted patients. Many mechanisms of OP have been deeply approached. Drugs for OP can be generally divided into “bone resorption inhibitors” and “bone formation accelerators,” the former hindering bone resorption by osteoclasts and the latter increasing bone formation by osteoblasts. Currently, bisphosphonates, which are bone resorption inhibitors drugs, are more commonly used clinically than others. Using the signaling pathway or implantation bone marrow stem cell provides a novel direction for the treatment of OP, especially OP after transplantation. This review addresses the mechanism of OP and its correlation with organ transplantation, lists prevention and management of bone loss in the transplant recipient, and discusses the recipients of different age and gender.

https://downloads.hindawi.com/journals/ije/2015/280164.pdf

Mechanism and Treatment Strategy of Osteoporosis after Transplantation

The dysregulation of miR‑126 has been reported to correlate with the progression of several cancer types. The present study demonstrated that miR‑126 was significantly downregulated in prostate cancer (PCa) tissues compared with normal prostate tissues. In vitro and in vivo studies indicated that forced overexpression of miR‑126 significantly suppressed the proliferation of PCa cell lines. Additionally, a Transwell assay showed that enhanced expression of miR‑126 inhibited metastasis in PCa in vitro. Furthermore, pik3r2 was confirmed to be a direct target of miR‑126 in PCa. It was also shown that pik3r2 was upregulated in PCa tissues and this inversely correlated with miR‑126 in PCa tissues. In conclusion, these results revealed that aberrant expression of miR‑126 promoted the progression of PCa and may serve as a novel therapeutic biomarker for PCa.

/pdf/microrna-126-inhibits-proliferation-and-metastasis-by-13qh947lxf.pdf

Shaojie Yu

Papers

Population pharmacokinetics of voriconazole and CYP2C19 polymorphisms for optimizing dosing regimens in renal transplant recipients.

Roles of mitochondrial transcription factor A and microRNA-590-3p in the development of bladder cancer

Mechanism and Treatment Strategy of Osteoporosis after Transplantation

MicroRNA‑126 inhibits proliferation and metastasis by targeting pik3r2 in prostate cancer.

Anti-OX40L monoclonal antibody prolongs secondary heart allograft survival based on CD40/CD40L and LFA-1/ICAM-1 blockade.