Background: The antigen HCA587 (also known as MAGE-C2), which is considered a cancer-testis antigen, exhibits upregulated expression in a wide range of malignant tumors with unique immunological properties, and may thus serve as a promising target for tumor immunotherapy. Objective: To explore the antitumor effect of the HCA587 protein vaccine and the response of humoral and cell-mediated immunity. Methods: The HCA587 protein vaccine was formulated with adjuvants CpG and and ISCOM. B16 melanoma cells were subcutaneously inoculated to C57BL/6 mice, followed by treatment with HCA587 protein vaccine subcutaneously. Mouse survival was monitored daily, and tumor volume was measured every 2 to 3 days. The tumor sizes, survival time and immune cells in tumor tissues were detected. And the vital immune cell subset and effector molecules were explored. Results: After treatment with HCA587 protein vaccine, the vaccination generated elicited significant immune responses, which delayed tumor growth and improved animal survival. The vaccination increased the proportion of CD4+ T cells expressing IFN-γ and granzyme B in tumor tissues. Depletion of CD4+T cells resulted in an almost complete abrogation of the antitumor effect of the vaccination, suggesting that the antitumor efficacy was mediated by CD4+ T cells. In addition, knockout of IFN-γ resulted in a decrease in granzyme B levels which were secreted by CD4+ T cells, and the antitumor effect was also significantly attenuated. Conclusion: The HCA587 protein vaccine may increase the levels of granzyme B expressed by CD4+ T cells, and this increase is dependent on IFN-γ, and the vaccine resulted in a specific tumor immune response and subsequent eradication of the tumor.
The pathogenesis of bipolar disorder (BD), a chronic mood disorder, is largely unknown. Noncoding RNAs play important roles in the pathogenesis of BD. However, little is known about the correlations of long noncoding RNAs (lncRNAs) with BD. Illumina high-throughput sequencing in BD patients and normal controls was used to identify differentially expressed (DE) genes. Two-step real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to validate DE-RNAs in the first cohort (50 BD and 50 control subjects). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and lncRNA-mRNA coexpression and lncRNA-microRNA (miRNA)-messenger RNA (mRNA) competing endogenous RNA (ceRNA) network analyses were used to predict the functions of DE-RNAs. Receiver operating characteristic (ROC) curve analysis and logistic regression were applied to evaluate diagnostic performance in an additional testing group (80 BD and 66 control subjects). A total of 576 significantly DE-lncRNAs and 262 DE-mRNAs were identified in BD patients, and 95 lncRNA-miRNA-mRNA interactions were used to construct a ceRNA regulatory network. Analysis of the first cohort showed that six RNAs (NR_028138.1, TCONS_00018621, TCONS_00002186, TNF, PID1, and SDK1) were differentially expressed in the BD group (P < 0.01). NR_028138.1 was used to establish a BD diagnostic model (area under the ROC curve 0.923, P < 0.004, 95% CI: 0.830–0.999). Verification in the second cohort revealed uniformly significant differences in NR_028138.1 (P < 0.0001). This study constructed a ceRNA regulatory network and provided a hypothesis for the pathogenesis of BD. NR_028138.1 was identified as a central element involved in the transcriptional regulation in BD and a potential biomarker.
Asthenozoospermia (AZS) is characterized by reduced sperm motility and its pathogenesis remains poorly understood. Piwi-interacting RNAs (piRNAs) have been indicated to serve important roles in spermatogenesis. However, little is known about the correlation of piRNA expression with AZS. In the present study, small RNA sequencing (small RNA-seq) was performed on sperm samples from AZS patients and fertile controls. Reverse transcription-quantitative (RT-q) PCR was used to validate the small RNA-seq results. Bioinformatics analyses were performed to predict the functions of differentially expressed piRNAs (DEpiRNAs). Logistic regression models were constructed and receiver operating characteristic curve (ROC) analysis was used to evaluate their diagnostic performance. A total of 114 upregulated and 169 downregulated piRNAs were detected in AZS patients. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that the DEpiRNAs were mainly associated with transcription, signal transduction, cell differentiation, metal ion binding and focal adhesion. These results were verified by RT-qPCR analysis of eight selected piRNAs. The PCR results were consistent with the sequencing results in patients with AZS compared with controls in the first cohort. The expression of piR-hsa-32694, piR-hsa-26591, piR-hsa-18725 and piR-hsa-18586 was significantly upregulated in patients with AZS. The diagnostic power of the four piRNAs was further analyzed using ROC analysis; piR-hsa-26591 exhibited an area under the ROC curve (AUC) of 0.913 (95% CI: 0.795-0.994). Logistic regression modelling and subsequent ROC analysis indicated that the combination of the 4 piRNAs achieved good diagnostic efficacy (AUC: 0.935).
Atrial fibrillation (AF) is commonly prevalent in patients with hypertrophic cardiomyopathy (HCM). However, whether the prevalence and incidence of AF are different between genotype-positive vs. genotype-negative patients with HCM remains controversial. Recent evidence has indicated that AF is often the first presentation of genetic HCM patients in the absence of a cardiomyopathy phenotype, implying the importance of genetic testing in this population with early-onset AF. However, the association of the identified sarcomere gene variants with HCM occurrence in the future remains unclear. How the identification of these cardiomyopathy gene variants should influence the use of anticoagulation therapy for a patient with early-onset AF is still undefined. In this review, we sought to assess the genetic variants, pathophysiological pathways, and oral anticoagulation in patients with HCM and AF.
Although tumor cells are easily to growth in the bodies of immunodeficicent animals such as nude mice and NOD-SCID mice, it's hard for acute leukemia cells to grow in the bone marrow of nude mice or NOD-SCID mice even when mice receive extra immunosuppressive treatment such as splenectomy, cyclophosphamide and irradiation. This study aimed to establish a mice model with systemic leukemia using another highly immunodeficicent NPG mice without immunosuppressive treatment before inoculation. 5-week NPG mice were inoculated with 1x107(Group A) or 5x107 (Group B) SHI-1 cells (a cell line derived from a refractory acute monocytic leukemia patient) via tail vein. One NPG mice in each group was killed by ether randomly at the day 14, 21, 28 after inoculation, other NPG mice were observed the survival time. The leukemic cells engrafted in the NPG mice were detected by the following methods: the blast cells were detected by the blood smear and flow cytometer, the MLL-AF6 fuse gene of SHI-1 cells were detected by PCR amplification, the human CD45 positive cells infiltrated in the organs of NPG mice were detected by histopathological examination and immunohistochemistry. At the day 14 after inoculation with SHI-1 cells, fewer blasts cells were found in the smear of peripheral blood of group B; MLL-AF6 fuse gene could be amplified in the spleen of NPG mice in group A and in spleen and bone marrow in group B (Fig A); histopathological examination had shown that CD45 positive leukemia cell just infiltrated in spleen. At the day 21 after inoculation, more blasts were found in the smear of peripheral blood both in group A and B; MLL-AF6 fuse gene were amplified in the organs of NPG mice such as Spleen, liver, kidney, stomach, lung, heart and bone marrow(Fig A); 5.16% and 0.82% of CD45 and CD33 positive cells were detected in the peripheral blood of NPG mice in group A and B respectively; a green solid neoplasm were found in the kidney of NPG mice in group B, leukemia cells were found in the organ of heart, liver, spleen, stomach, kidney and lung in the NPG mice of both groups by histopathological examination. From the third week, the NPG mice presented anorexia, hunched posture, lethargy and weight loss. For the mice sacrificed in the day 28 after inoculation, the proportion of CD45 and CD33 positive cells in peripheral blood, bone marrow and spleen were 9.60%, 11.4% and 23.20% in group A and were 11.0%,37.80% and 60.5% in group B (Fig B). Green solid tumors were grown in many organs such as kidney, liver, spleen, stomach, heart, lymph node and the soft tissues in the NPG mice killed in day 28 after inoculation and the mice which were dead spontaneous (Fig C); When NPG mice were dead, the weight of spleen in group B is significantly higher than the weight of spleen in group A(P<0.05) (Fig D). The median survival time of NPG in group A and group B is 33 and 30 days respectively. Pathological examination and immunohistochemical staining had shown that leukemic cells could infiltrated to many of the organs of NPG mice and the grade of leukemia infiltration was positively correlated with cells numbers of inoculation and the survival time of NPG mice (Fig E). Altogether, SHI-1 cell could growth in the NPG mice without any pre-immunosuppressive treatment and formed a systemic leukemia in NPG mice as like in acute leukemia patients. This efficient and reproducible model may be a useful tool for the studies of the pathogenesis in acute monocytic leukemia. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
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