Immune checkpoint signaling plays an important role in immunosuppression in multiple myeloma (MM). Blood levels of soluble programmed death-ligand 1 (sPD-L1), a checkpoint-relevant protein, might predict treatment response and survival outcomes in MM patients. We used an enzyme-linked immunosorbent assay to measure serum sPD-L1 levels in 81 newly diagnosed MM patients. We found that myeloma patients had higher sPD-L1 concentrations than healthy controls. The best sPD-L1 cutoff value for predicting disease progression risk was 2.783 ng/mL. The overall response rate to treatment was higher in low sPD-L1 patients than in high sPD-L1 patients. The 3-year progression free survival (PFS) and overall survival (OS) rates for all patients were 16% and 64%, respectively. Multivariate survival analysis including Eastern Cooperative Oncology Group performance status score, treatment response, and sPD-L1 level showed that a less than partial treatment response (PR) and higher sPD-L1 levels (>2.783 ng/ml) were independent prognostic factors for shorter PFS; neither factor was predictive of OS. The serum sPD-L1 level is a valuable biomarker for predicting treatment response and an independent prognostic factor for PFS. PD-1/PD-L1 blockade may be a promising novel immune-based therapeutic strategy in MM.

The purpose of this study was to clarify the outcome of the ratio between metastatic and examined lymph nodes (N ratio) in gastric cancer patients with < or =15 examined lymph nodes after D2 lymphadenectomy. A retrospective study was performed in 906 patients with gastric cancer who had undergone D2 resection. Patients with < or =15 examined lymph nodes (group 1, n = 729) and those with >15 lymph nodes (group 2, n = 177) were analyzed separately. N ratio categories were identified as follows: N ratio 0, 0%; N ratio 1, 1% to 9%; N ratio 2, 10% to 25%; N ratio 3, >25%. Univariate analysis found that both the tumor, node, metastasis system (N staging system) and N ratio system well classified patients with significantly different prognosis. By multivariate analysis, only the N ratio classification was retained as an independent prognostic factor in both group 1 and 2 compared with the N stage system. Furthermore, when patients were divided into four groups according to the number of lymph nodes examined (1 to 3, 4 to 7, 8 to 11, and 12 to 15), the 5-year survival rates remained similar between groups according to the same N ratio (p > .05). Positive N ratio classification is a better prognostic tool compared with N staging system after D2 resection in patients with gastric cancer. It can prevent stage migration and can be used regardless of the examined number of lymph nodes.

Background:Interleukin-10 (IL-10) is a inhibiting inflammatory cytokine that plays an important role in immune suppressive microenvironment in multiple myeloma (MM). Whether the level of serum IL-10 could predict treatment response and survival outcomes or not needs to be investigated in MM patients.Methods:The level of IL-10 in serum was measured using enzyme-linked immunosorbent assay in 188 patients with newly diagnosed MM.Results:The best cutoff value for IL-10 in predicting survival is 169.69 pg ml−1 with an area under the curve (AUC) value of 0.747 (P<0.001). In all, 92 patients (48.9%) were classified as high-IL-10 group (>169.96 pg ml−1) and 96 patients (51.1%) as low-IL-10 group (⩽169.96 pg ml−1). The overall response rate (ORR) was 79.2% in low-IL-10 group, significantly higher than that in high-IL-10 group (53.3%, P<0.001). Patients in low-IL-10 group had significantly better survival compared with those in high-IL-10 group (3-year PFS rate: 69.3% vs 13.3%, P<0.001; 3-year OS rate: 93.6% vs 51.9%, P<0.001). Multivariate analysis revealed that serum IL-10 level >169.96 pg ml−1 at diagnosis and certain cytogenetic abnormalities were two adverse factors for PFS and OS.Conclusions:Our data suggest that serum IL-10 at diagnosis is a novel, powerful predictor of prognosis for MM.

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Mammalian two-pore-channels (TPC1, 2; TPCN1, TPCN2) are ubiquitously- expressed, PI(3,5)P2-activated, Na+-selective channels in the endosomes and lysosomes that regulate luminal pH homeostasis, membrane trafficking, and Ebola viral infection. Whereas the channel activity of TPC1 is strongly dependent on membrane voltage, TPC2 lacks such voltage dependence despite the presence of the presumed ‘S4 voltage-sensing’ domains. By performing high-throughput screening followed by lysosomal electrophysiology, here we identified a class of tricyclic anti-depressants (TCAs) as small-molecule agonists of TPC channels. TCAs activate both TPC1 and TPC2 in a voltage-dependent manner, referred to as Lysosomal Na+ channel Voltage-dependent Activators (LyNa-VAs). We also identified another compound which, like PI(3,5)P2, activates TPC2 independent of voltage, suggesting the existence of agonist-specific gating mechanisms. Our identification of small-molecule TPC agonists should facilitate the studies of the cell biological roles of TPCs and can also readily explain the reported effects of TCAs in the modulation of autophagy and lysosomal functions.

ObjectiveEffects of the diet-induced gut microbiota dysbiosis reach far beyond the gut. We aim to uncover the direct evidence involving the gut–testis axis in the aetiology of impaired spermatogenesis.DesignAn excessive-energy diet-induced metabolic syndrome (MetS) sheep model was established. The testicular samples, host metabolomes and gut microbiome were analysed. Faecal microbiota transplantation (FMT) confirmed the linkage between gut microbiota and spermatogenesis.ResultsWe demonstrated that the number of arrested spermatogonia was markedly elevated by using 10× single-cell RNA-seq in the MetS model. Furthermore, through using metabolomics profiling and 16S rDNA-seq, we discovered that the absorption of vitamin A in the gut was abolished due to a notable reduction of bile acid levels, which was significantly associated with reduced abundance of Ruminococcaceae_NK4A214_group. Notably, the abnormal metabolic effects of vitamin A were transferable to the testicular cells through the circulating blood, which contributed to abnormal spermatogenesis, as confirmed by FMT.ConclusionThese findings define a starting point for linking the testicular function and regulation of gut microbiota via host metabolomes and will be of potential value for the treatment of male infertility in MetS.

For developing gene therapy for chronic myelogenous leukemia (CML), we evaluated the feasibility of using autologous bone marrow stromal cells (BMSCs) of one CML patient as a target cell population and studied the efficiency of recombinant adenovirus-mediated human Gamma Interferon (hIFN-gamma) gene transfer into BMSCs. BMSCs can be readily obtained, expanded, and successfully transduced with adenoviral vectors in vitro. We studied the in vitro expression of hIFN-gamma in human BMSCs following transduction with Ad/hIFN-gamma. On transduction of BMSCs at a MOI of 50, the expression and secretion of hIFN-gamma were achieved as high as 5492 +/- 660 approximately 50647 +/- 4049 ng/10(6) cells per 24 h over the course of 3 weeks. We further studied the effects of hIFN-gamma produced by transduced BMSCs on the proliferation of the human leukemia cell line K562 cells in vitro, proliferation of K562 cells was markedly inhibited in the experimental groups as compared with the other two control groups after 5 days of coculture. We also found that the percentage of K562 cells in the G(1) phase of cell cycle can be increased by treatment of hIFN-gamma produced by Ad/hIFN-gamma transduced BMSCs, but the percentage of K562 cells in the S phase of cell cycle can be decreased in the same time. Apoptosis rate of K562 cells in the experimental groups was 30.8 +/- 8.5%, as compared with the other two control groups (5.6 +/- 1.3% and 5.5 +/- 0.8%, respectively) (p < 0.01). Our results indicate that hIFN-gamma gene engineered BMSCs of CML donors could be successfully established and that local production of hIFN-gamma is sufficiently to inhibit the proliferation of K562 cells and induce apoptosis of K562 cells in vitro, suggesting an important potential use in the clinical gene therapy of CML.

Alzheimer's disease (AD) is the most common cause to dementia and predicted to influence about 35 million people by the end of 2050. In this study, we discover alterations of myelin morphology in hippocampus tissues of 2-month-old APP/PS1 mouse. Myelin sheath is thicker and internodal distance is shorter in APP/PS1 mouse. Oligodendrocytes, differentiated from oligodendrocytes progenitor cells (OPCs), are responsible for formation and maintenance of myelin sheath in central nervous system (CNS). Our current results demonstrate that the oligodendrocytes development is disordered in 2-month-old APP/PS1 mouse. Neuregulin-1 type III, which is critical for both oligodendrocytes development and CNS myelination, is found up-regulated in hippocampus tissues of APP/PS1 mouse by western blots. Furthermore, we find active-caspase-6 can cleave neuregulin-1 type III at the cytoplasmic region. Given together, this study indicates the alterations of myelin morphology and oligodendrocytes development in 2-month-old APP/PS1 mouse, and the alterations might be highly associated with neuregulin-1 type III and active-caspase-6.