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Soft markers are nonspecific findings detected by ultrasonography during the second trimester that are often transient and nonpathologic but may imply an increased risk of underlying fetal aneuploidy. However, large-scale prospectively stratified studies focusing on the prevalence of chromosomal aberrations, including copy number variants, in fetuses with different types of isolated soft markers have rarely been published in the literature.This study aimed to investigate clinical outcomes in fetuses with isolated soft markers by single nucleotide polymorphism array with long-term follow-up and to propose a diagnostic algorithm based on specific types of soft markers.The prevalence of fetal isolated soft markers was 13.2% (7869 of 59,503). A total of 2466 fetuses with ultrasonographic soft markers during the second trimester, which were subjected to single nucleotide polymorphism array with long-term follow-up, were selected in this prospective study over a 5-year period. Soft markers were categorized into 12 groups. The demographic profile and chromosomal microarray analysis detection results were analyzed and compared among different groups.The overall prevalence of chromosomal aberrations in fetuses with soft markers was 4.3% (107 of 2466), which comprised 40.2% with numeric chromosomal abnormalities, 48.6% with pathogenic copy number variants, and 11.2% with likely pathogenic copy number variants. The incidence of numeric chromosomal abnormalities was significantly higher in multiple soft markers (5.5% vs 1.5%; P=.001) and the thickened nuchal fold group (8.3% vs 1.7%; P=.024). Meanwhile, the incidence of pathogenic copy number variants was significantly higher in multiple soft markers (5.5% vs 2.4%; P=.046) and the short femur length group (6.6% vs 2.2%; P.0001). The incidences of pathogenic copy number variants in fetuses with isolated echogenic intracardiac focus, enlarged cisterna magna, choroid plexus cysts, echogenic bowel, or single umbilical artery were lower than 1.5%. The normal infant rate in fetuses without chromosomal aberrations was 91.7%; however, it was significantly lower in the mild ventriculomegaly (86.2% vs 93.0%; P.0001) and short femur length groups (71.4% vs 93.6%; P.0001).The potential chromosomal aberrations and clinical prognoses varied widely among different types of isolated soft markers. Pathogenic copy number variants are more often present in specific soft markers, especially when multiple soft markers are found. Thus, a specific soft marker type-based prenatal genetic testing algorithm was proposed.

The prevalence of type 2 diabetes mellitus (DM) is increasing in the children population. It is well known that inflammation contributes to the type 2 DM pathogenesis. Interleukin 38 (IL-38) is one newly identified anti-inflammatory factor. Therefore, we investigated whether the expression level of IL-38 is associated with type 2 DM in the children and the underlying mechanism. Children with recently diagnosed type 2 diabetes mellitus were recruited and studied. The healthy subjects without glucose metabolism abnormalities were used as controls. The IL-38 expression level was determined by quantitative PCR and ELISA (Enzyme-linked immunoassay). Statistic analysis showed that the IL-38 level was significantly associated with type 2 DM and insulin resistance in the children. The patients were then divided into two groups, one group sensitive to insulin therapy while the other resistant to insulin therapy. Data showed that the IL-38 was highly expressed in the group sensitive to insulin therapy. In the mice model, overexpressing the IL-38 could suppress the expression of IL-36, a pro-inflammatory factor, and also the diabetes development. Thus our results showed that higher IL-38 was associated with the increased insulin sensitive in children with type 2 DM and inhibited T2DM development in the mouse model through suppressing the function of IL-36.

Due to subtle symptoms and the absence of effective early screening methods, most of epithelial ovarian cancer patients are diagnosed in the late stage, when current treatment strategies are not so satisfactory. To date, ovarian cancer is still the leading cause of gynecological malignancy deaths in women. The formation of massive ascites is one of the important characteristics of epithelial ovarian carcinoma in the late stage. Cancer cells, existing in ascites in the form of spheroids, play an important role in metastasis and recurrence of the malignancy. Alpha5/beta1 integrin has been found to participate in the formation of epithelial ovarian cancer multicellular spheroids in vitro. But if we want to choose alpha5- and beta1-integrin subunits as treatment targets, we must specifically block the two subunits in cancer cells, because these two subunits are very important for the physiological activities in normal cells. Based on the knowledge mentioned above, we present hypotheses that we can inhibit specifically the expression of alpha5/beta1 integrin in cancer cells with the help of complementary replication defective adenovirus. As a result, the formation of cancer cells spheroids in ascites might be interfered with and the treatment effects and prognosis of epithelial ovarian cancer might be improved.

Objectives The underlying mechanisms of protective immunity of placental trophoblast cells against bacterial infection remain largely unknown. NOD1 are intracellular pattern recognition receptors that are activated by bacterial peptides and mediate innate immunity. This study aimed to investigate the expression and function of NOD1 in first trimester trophoblast cells, and evaluate the potential role of trophoblast cells in infection-associated inflammation. Study design Human extravillous trophoblast cell line HTR8 cells were stimulated with various concentrations of iE-DAP for various periods of time. NOD1 expression was detected by immunofluorescence, and the changes in NOD1 and RICK mRNA and protein in H8 cells were determined by real-time polymerase chain reaction and Western blot analysis. The concentrations of interleukin (IL)-8 and IL-6 secreted by H8 cells were examined by enzyme-linked immunosorbent assay. NF-κB transcription activity and P65 expression were detected by electrophoretic mobility shift assay and Western blot analysis. Results H8 cells expressed NOD1, and the effects of iE-DAP on NOD1 were dose- and time-dependent. The concentration of IL-8 increased gradually with increasing concentration of iE-DAP, and the levels of IL-8 and IL-6 were associated with the duration of exposure to iE-DAP. The dose of iE-DAP was significantly associated with expression of RICK and P65, and stimulation of H8 cells by iE-DAP altered NF-κB transcription activity. Conclusions NOD1 may have a role in mediating infection-associated inflammation. Once iE-DAP is recognized by NOD1, the inflammatory response may be induced via NOD1–RICK–NF-κB-mediated pathways.

Hypoxia-inducible factor 1 (HIF-1) is a master transcriptional factor. Under normal oxygen tension, HIF-1 activity is usually suppressed due to the rapid, oxygen-dependent degradation of one of its two subunits, HIF-1 alpha. Here we report that normoxic HIF-1 activity can be upregulated through NO-mediated S-nitrosylation and stabilization of HIF-1 alpha. In murine tumors, exposure to ionizing radiation stimulated the generation of NO in tumor-associated macrophages. As a result, the HIF-1 alpha protein is S-nitrosylated at Cys533 (through "biotin switch" assay) in the oxygen-dependent degradation domain, which prevents its destruction. Importantly, this mechanism appears to be independent of the prolylhydroxylase-based pathway that is involved in oxygen-dependent regulation of HIF-1 alpha. Selective disruption of this S-nitrosylation significantly attenuated both radiation-induced and macrophage-induced activation of HIF-1 alpha. This interaction between NO and HIF-1 sheds new light on their involvement in tumor response to treatment as well as mammalian inflammation process in general.

Top of pageAbstract Neuroblastoma is one of the most common solid tumors of childhood. Response to conventional therapy in patients with advanced stage disease is low and mortality is high. Novel therapeutic approaches that improve patient survival are clearly needed. Tumor- derived glucose-regulated protein 94 (GRP94/gp96), a HSP90 family member, has shown great promise as a tumor vaccine. In this study, we explored the therapeutic efficacy of a combined GRP94/gp96- based genetic immunotherapy and radiation therapy strategy in a mouse neuroblastoma model: Neuro 2a. An adenovirus encoding a secretable form of GRP94 gene (AdsGRP94) was evaluated in various anti-tumor experiments. Lethally irradiated, virus-infected cells were used as vaccines. Adenoviral vectors were also injected directly into tumors in conjunction with tumor irradiation. The results showed that inoculation of AdsGRP94 infected Neuro 2a cells in syngeneic A/J mouse could result in significant tumor growth delay. Vaccination with lethally irradiated, AdsGRP94-infected Neuro 2a cells completely prevented subsequent tumor growth from challenge inoculations of as many as 107cells/mouse. Splenocytes from mice immunized with AdsGRP94-infected tumor cells showed significant increase in specific tumor cell lytic ability as compared to splenocytes from mice immunized with control-virus infected cells. In addition, intracellular cytokine staining results showed AdsGRP94-infected tumor cells immunization could increase T cell IFN-g generation, especially in CD8+ T cell group. In established tumor models, when vaccination was combined with radiation therapy and intratumoral AdsGRP94 injections, tumor growth was markedly inhibited. Our results indicate that combined AdsGRP94-based immunotherapy and radiation therapy may be a potentially effective strategy for neuroblastoma treatment.