Background: Tacrolimus (Tac, or FK506), a calcineurin inhibitor (CNI), is the first-line immu-nosuppressant which consists of the footstone as immunosuppressive regimens in kidney transplantation. However, the drug toxicity and the significant differences of pharmacokinetics (PK) and pharmacodynam-ics (PD) among individuals are hidden troubles for clinical application. Recently, emerging evidences of Tac pharmacogenetics (PG) regarding drug absorption, metabolism, disposition, excretion and response are discovered for better understanding of this drug.Method: We reviewed the published articles regarding the Tac PG and its effects on PK and PD in kidney transplantation. In addition, we summarized information on polygenic algorithms.Results: The polymorphism of genes encoding metabolic enzymes and transporters related to Tac were largely investigated, but the results were inconsistent. In addition to CYP3A4, CYP3A5 and P-gp (also known as ABCB1), single nucleotide polymorphisms (SNPs) might also affect the PK and PD parameters of Tac.Conclusion: The correlation between Tac PK, PD and PG is very complex. Although many factors need to be verified, it is envisaged that thorough understanding of PG may assist clinicians to predict the optimal starting dosage, help adjust the maintenance regimen, as well as identify high risk patients for adverse ef-fects or drug inefficacy

Background Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for patients with advanced non-small-cell lung cancer (aNSCLC), but immune-related adverse events (irAEs) have been evidenced curtailed the clinical use of them. Purpose The aim of this study was to research the influences of inflammation-related peripheral blood markers, including neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) levels, on anti-PD-1 inhibitor-induced irAEs. Patients and Methods A retrospective analysis was conducted of patients treated with PD-1 inhibitors for stage III–IV NSCLC at a single center from 2017 to 2020 were included. Clinical characteristics, peripheral blood markers at the baseline and before subsequent treatment cycles were collected. NLR and PLR were calculated by division of neutrophil and platelet by lymphocyte measured in peripheral blood. The development of irAEs was evaluated and monitored from the therapy start based on CTCAE V4.03. Results A total of 150 patients were included. Fifty-seven patients had occurred at least one irAEs during follow-up, and mainly grade 1–2 (73.68%). Pruritus, rash and thyroiditis were the most commonly irAEs. Low NLR, PLR and neutrophil at baseline were significantly associated with the development of severe irAEs ( P -values were 0.023, 0.0016 and 0.009). The levels of neutrophil, NLR and PLR also significantly decreased when occurred irAEs compared with baseline (P-values were 0.0069, 0.017 and 1.18E-5, respectively). Conclusion The levels of NLR, PLR and neutrophil were associated with the increased risk of severe irAEs when baseline levels were low. NLR, PLR, and neutrophil are simple and available biomarkers that can be used to help predict severe adverse effects in NSCLC patients treated with anti-PD-1 inhibitors.

The highly variable pharmacokinetics and narrow therapeutic window of tacrolimus (TAC) has hampered its clinical use. Genetic polymorphisms may contribute to the variable response, but the evidence is not compelling, and the explanation is unclear. In this study we attempted to find previously unknown genetic factors that may influence the TAC dose requirements. The association of 105 pathway-related single nucleotide polymorphisms (SNPs) with TAC dose-adjusted concentrations (C0/D) was examined at 7, 30 and 90 d post-operation in 382 Chinese kidney transplant recipients. In CYP3A5 non-expressers, the patients carrying the IL-3 rs181781 AA genotype showed a significantly higher TAC logC0/D than those with the AG genotype at 30 and 90 d post-operation (AA vs AG, 2.21±0.06 vs 2.01±0.03, P=0.004; and 2.17±0.06 vs 2.03±0.03, P=0.033, respectively), and than those with the GG genotype at 30 d (AA vs GG, 2.21±0.06 vs 2.04±0.03, P=0.011). At 30 d, the TAC logC0/D in the grouped AG+GG genotypes of CTLA4 rs4553808 was significantly lower than that in the AA genotype (P=0.041) in CYP3A5 expressers, but it was higher (P=0.008) in the non-expressers. We further validated the influence of CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437 on the TAC C0/D; other candidate SNPs were not associated with the differences in TAC C0/D. In conclusion, genetic polymorphisms in the immune genes IL-3 rs181781 and CTLA4 rs4553808 may influence the TAC C0/D. They may, together with CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437, contribute to the variation in TAC dose requirements. When conducting individualized therapy with tacrolimus, these genetic factors should be taken into account.

Cancer is an important threat to public health because of its high morbidity and mortality. In recent decades, immune checkpoint inhibitors (ICIs) have ushered a new therapeutic era in clinical oncology. The rapid development of immune checkpoint therapy is due to its inspiring clinical efficacy in a group of cancer types. Metformin, an effective agent for the management of type 2 diabetes mellitus (T2DM), has shown beneficial effects on cancer prevention and cancer treatment. Emerging studies have suggested that metformin in combination with ICI treatment could improve the anticancer effects of ICIs. Hence, we conducted a review to summarize the effects of metformin on ICI therapy. We also review the pleiotropic mechanisms of metformin combined with ICIs in cancer therapy, including its direct and indirect effects on the host immune system.