Naringenin Alleviates Radiation-Induced Intestinal Injury by Inhibiting TRPV6 in Mice.

SCOPE: Naringenin (NAR) possesses unique anti-inflammatory, antiapoptosis effects and various bioactivities; however, its role against radiation-induced intestinal injury (RIII) remains unclear. This study aims to investigate whether NAR has protective effects against radiation-induced intestinal injury and the underlying mechanisms. METHODS AND RESULTS: C57BL/6J mice are exposed to a single dose of 13 Gy X-ray total abdominal irradiation (TAI), then gavaged with NAR for 7 days. NAR treatment prolongs the survival rate, protects crypts and villi from damage, alleviates the level of radiation-induced inflammation, and mitigates intestinal barrier damage in the irradiated mice. Additionally, NAR reduces immune cell infiltration and intestinal epithelial cell apoptosis. NAR also shows radioprotective effects in human colon cancer cells (HCT116) and human intestinal epithelial cells (NCM460). It reduces cell damage by reducing intracellular calcium ion levels and reactive oxygen species (ROS) levels. NAR-mediated radioprotection is associated with the downregulation of transient receptor potential vanilloid 6 (TRPV6), and inhibition of apoptosis pathway. Notably, treatment with NAR fails to further increase the protective effects of the TRPV6 inhibitor 2-APB, indicating that TRPV6 inhibition is essential for NAR activity. CONCLUSION: NAR inhibits the apoptosis pathway by downregulating TRPV6 and reducing calcium ion level, thereby alleviating RIII. Therefore, NAR is a promising therapeutic drug for RIII.

Pregnane steroid glycosides with multidrug resistance reversal activity from the stems of Marsdenia tenacissima.

Eighteen previously unreported pregnane glycosides, namely marsdenosides S1-S18, along with 15 known analogues, have been isolated from the stems of Marsdenia tenacissima. The structures of the undescribed compounds were elucidated by spectroscopic means, and their absolute configurations were established on the basis of time-dependent density functional theory (TD-DFT) based electronic circular dichroism (ECD) calculation, X-ray crystallography and acid hydrolysis. All the isolates were evaluated for their chemo-reversal ability against P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in MCF-7/ADR cell line, and nine ones displayed moderate MDR reversal activity with reversal folds in the range of 2.45-9.01. The most active 12-O-acetyl-20-O-benzoyl-(14,17,18-orthoacetate)-dihydrosarcostin-3-O-ß-d-thevetopyranosyl-(1 â†’ 4)-O-ß-d-oleandropyranosyl-(1 â†’ 4)-O-ß-d-cymaropyranoside increased the sensitivity of MCF-7/ADR cell to adriamycin comparably to the reference drug verapamil (RF = 8.93).

Pregnane steroids and steroid glycosides with multidrug resistance reversal activity from Marsdenia tenacissima.

Twenty compounds comprising four pregnane steroids (2-4 & 20) and 16 pregnane glycosides (1 & 5-19) have been obtained from the ethanol extract of the roots of a Dai ethnological herb, Marsdenia tenacissima. Their structures were characterized on the basis of comprehensive spectroscopic analyses with 17 ones (1-17) being reported for the first time, including the rare cases (2 & 3) of free C21 steroids with 17α-acetyl substitution, compounds 4-7 bearing an unusual 14α-OH, and the first examples with simultaneous 14α-OH/17α-acetyl substitution (7) and glycosylation at C-12 position (10 & 11). An empirical rule for the identification of C-17 configuration, in C21 steroids incorporating the marsdenin constitution structure, was also proposed. All the isolates, along with an array of previously reported analogues in our compound library, were screened for their chemo-reversal ability against P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in MCF-7/ADR cell line, and six compounds exhibited moderate MDR reversal activity with reversal folds ranging from 1.92 to 4.44.

Anti-tumor effect of infant-derived Enterococcus via the inhibition of proliferation and inflammation as well as the promotion of apoptosis.

Probiotic Enterococcus hirae WEHI01 and Enterococcus faecium WEFA23 from infants were previously found to effectively inhibit the development of melanoma. In this study, their immunomodulatory and antitumor mechanisms were systemically studied. In vitro assay showed that E. hirae WEHI01 and E. faecium WEFA23 achieved biphasic immune regulation, which was revealed by the activation of resting spleen lymphocytes and RAW264.7 macrophages, as well as the anti-inflammation effect when immune cells were treated with LPS. The antitumor effects of E. hirae WEHI01 and E. faecium WEFA23 in vitro and vivo were then investigated. CCK8 and the cell scratch assay showed that the conditioned media, which were co-incubated with Enterococcus and spleen lymphocytes, significantly inhibited the proliferation and migration of B16F10, HepG-2 and HT-29 cells. The results of the tumor-bearing mice model experiment showed that E. faecium WEFA23 inhibition of the growth of tumors in mice, and the anti-tumor mechanism involved three aspects, namely tumor proliferation (decreasing expressions of LDHA, VEGF, MMP2, MMP9 and HIF-1α), inhibition of the pro-inflammation state (decreasing expressions of IL-6, TGF-ß and IL-17) and the promotion of apoptosis (increasing expression of Bax/Bcl-2, caspase-3 and p53). The results suggest that the two strains of Enterococcus could be promising candidates for treating melanoma with a highly inhibitory effect.

Retraction Notice to: Long Noncoding RNA OIP5-AS1 Promotes the Progression of Liver Hepatocellular Carcinoma via Regulating the hsa-miR-26a-3p/EPHA2 Axis.

[This retracts the article DOI: 10.1016/j.omtn.2020.05.032.].

Aberrant Gene Expression Profiling in Men With Sertoli Cell-Only Syndrome.

Sertoli cell-only syndrome (SCOS) is the most severe and common pathological type of non-obstructive azoospermia. The etiology of SCOS remains largely unknown to date despite a handful of studies reported in this area. According to the gene expression of testicular tissue samples in six datasets from the Gene Expression Omnibus, we detected 1441 differentially expressed genes (DEGs) between SCOS and obstructive azoospermia (OA) testicular tissue samples. Enriched GO terms and KEGG pathways for the downregulated genes included various terms and pathways related to cell cycle and reproduction, while the enrichment for the upregulated genes yielded many inflammation-related terms and pathways. In accordance with the protein-protein interaction (PPI) network, all genes in the most critical module belonged to the downregulated DEGs, and we obtained nine hub genes, including CCNB1, AURKA, CCNA2, BIRC5, TYMS, UBE2C, CDC20, TOP2A, and OIP5. Among these hub genes, six were also found in the most significant SCOS-specific module obtained from consensus module analysis. In addition, most of SCOS-specific modules did not have a consensus counterpart. Based on the downregulated genes, transcription factors (TFs) and kinases within the upstream regulatory network were predicted. Then, we compared the difference in infiltrating levels of immune cells between OA and SCOS samples and found a significantly higher degree of infiltration for most immune cells in SCOS than OA samples. Moreover, CD56bright natural killer cell was significantly associated with six hub genes. Enriched hallmark pathways in SCOS had remarkably more upregulated pathways than the downregulated ones. Collectively, we detected DEGs, significant modules, hub genes, upstream TFs and kinases, enriched downstream pathways, and infiltrated immune cells that might be specifically implicated in the pathogenesis of SCOS. These findings provide new insights into the pathogenesis of SCOS and fuel future advances in its theranostics.

A Comprehensive Genomic Analysis Constructs miRNA-mRNA Interaction Network in Hepatoblastoma.

Hepatoblastoma (HB) is a rare disease but nevertheless the most common hepatic tumor in the pediatric population. For patients with advanced HB, the prognosis is dismal and there are limited therapeutic options. Multiple microRNAs (miRNAs) were reported to be involved in HB development, but the miRNA-mRNA interaction network in HB remains elusive. Through a comparison between HB and normal liver samples in the GSE131329 dataset, we detected 580 upregulated differentially expressed mRNAs (DE-mRNAs) and 790 downregulated DE-mRNAs. As for the GSE153089 dataset, the first cluster of differentially expressed miRNAs (DE-miRNAs) were detected between fetal-type tumor and normal liver groups, while the second cluster of DE-miRNAs were detected between embryonal-type tumor and normal liver groups. Through the intersection of these two clusters of DE-miRNAs, 33 upregulated hub miRNAs, and 12 downregulated hub miRNAs were obtained. Based on the respective hub miRNAs, the upstream transcription factors (TFs) were detected via TransmiR v2.0, while the downstream target genes were predicted via miRNet database. The intersection of target genes of respective hub miRNAs and corresponding DE-mRNAs contributed to 250 downregulated candidate genes and 202 upregulated candidate genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses demonstrated the upregulated candidate genes mainly enriched in the terms and pathways relating to the cell cycle. We constructed protein-protein interaction (PPI) network, and obtained 211 node pairs for the downregulated candidate genes and 157 node pairs for the upregulated candidate genes. Cytoscape software was applied for visualizing the PPI network and respective top 10 hub genes were identified using CytoHubba. The expression values of hub genes in the PPI network were subsequently validated through Oncopression database followed by quantitative real-time polymerase chain reaction (qRT-PCR) in HB and matched normal liver tissues, resulting in six significant downregulated genes and seven significant upregulated genes. The miRNA-mRNA interaction network was finally constructed. In conclusion, we uncover various miRNAs, TFs, and hub genes as potential regulators in HB pathogenesis. Additionally, the miRNA-mRNA interaction network, PPI modules, and pathways may provide potential biomarkers for future HB theranostics.

Exosomal microRNA-15a from mesenchymal stem cells impedes hepatocellular carcinoma progression via downregulation of SALL4.

Hepatocellular carcinoma (HCC) is a heterogeneous tumor with an increased incidence worldwide accompanied by high mortality and dismal prognosis. Emerging evidence indicates that mesenchymal stem cells (MSCs)-derived exosomes possess protective effects against various human diseases by transporting microRNAs (miRNAs or miRs). We aimed to explore the role of exosomal miR-15a derived from MSCs and its related mechanisms in HCC. Exosomes were isolated from transduced MSCs and co-incubated with Hep3B and Huh7 cells. miR-15a expression was examined by RT-qPCR in HCC cells, MSCs, and secreted exosomes. CCK-8, transwell, and flow cytometry were used to detect the effects of miR-15a or spalt-like transcription factor 4 (SALL4) on cell proliferative, migrating, invasive, and apoptotic properties. A dual-luciferase reporter gene assay was performed to validate the predicted targeting relationship of miR-15a with SALL4. Finally, in vivo experiments in nude mice were implemented to assess the impact of exosome-delivered miR-15a on HCC. The exosomes from MSCs restrained HCC cell proliferative, migrating, and invasive potentials, and accelerated their apoptosis. miR-15a was expressed at low levels in HCC cells and could bind to SALL4, thus curtailing the proliferative, migrating, and invasive abilities of HCC cells. Exosomes successfully delivered miR-15a to HCC cells. Exosomal miR-15a depressed tumorigenicity and metastasis of HCC tumors in vivo. Overall, exosomal miR-15a from MSCs can downregulate SALL4 expression and thereby retard HCC development.

The role of mediator complex subunit 19 in human diseases.

Mediator is an evolutionarily conserved multi-protein complex that mediates the interaction between different proteins as a basic linker in the transcription mechanism of eukaryotes. It interacts with RNA polymerase II and participates in the process of gene expression. Mediator complex subunit 19 or regulation by oxygen 3, or lung cancer metastasis-related protein 1 is located at the head of the mediator complex; it is a multi-protein co-activator that induces the transcription of RNA polymerase II by DNA transcription factors. It is a tumor-related gene that plays an important role in transcriptional regulation, cell proliferation, and apoptosis and is closely related to the occurrence and development of the cancers of the lung, bladder, skin, etc. Here, we used the structure of mediator complex subunit 19 to review its role in tumor progression, fat metabolism, drug therapy, as well as the novel coronavirus, which has attracted much attention at present, suggesting that mediator complex subunit 19 has broad application in the occurrence and development of clinical diseases. As a tumor-related gene, the role and mechanism of mediator complex subunit 19 in the regulation of tumor growth could be of great significance for the diagnosis, prognosis, and treatment of mediator complex subunit 19 -related tumors.

MicroRNA-497-5p Is Downregulated in Hepatocellular Carcinoma and Associated with Tumorigenesis and Poor Prognosis in Patients.

BACKGROUND: MicroRNAs (miRNAs) have been demonstrated to exhibit important regulatory roles in multiple malignancies, including hepatocellular carcinoma (HCC). hsa-miR-497-5p was reported to involve in cancer progression and poor prognosis in many kinds of tumors. However, the expression and its clinical significance of hsa-miR-497-5p in HCC remain unclear. METHODS: In the present study, we investigated the expression of hsa-miR-497-5p in HCC and analyzed the correction of clinical features with prognosis. The expression levels of hsa-miR-497-5p and potential target genes were analyzed in HCC and adjacent noncancerous tissues using The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) datasets. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to analyze hsa-miR-497-5p levels in 328 HCC tissues and 30 paired adjacent noncancer tissues. Overall survival (OS) and progression-free survival (PFS) of patients with HCC were assessed using the Kaplan-Meier method and the log-rank test. RESULTS: The hsa-miR-497-5p expression levels were decreased, and its target genes ACTG1, CSNK1D, PPP1CC, and BIRC5 were upregulated in HCC tissues compared with normal tissues. Lower levels of hsa-miR-497-5p expression and higher levels of the four target genes were significantly associated with higher tumor diameter. Moreover, patients with lower hsa-miR-497-5p expression and higher target genes levels had shorter OS. CONCLUSION: The expression levels of hsa-miR-497-5p may play an important regulatory role in HCC and are closely correlated with HCC progression and poor prognosis in patients. The hsa-miR-497-5p may be a specific therapeutic target for the treatment of HCC.

microRNA-320b suppresses HNF4G and IGF2BP2 expression to inhibit angiogenesis and tumor growth of lung cancer.

We examined the effect of microRNA-320b (miR-320b) on tumor growth and angiogenesis in lung cancer and also determined its downstream molecular mechanisms. Lung cancer tissues and adjacent non-cancerous tissues were collected from 66 patients with lung cancer. miR-320b expression was experimentally determined to be expressed at low level in cancer tissues. The results of gain-of-function experiments suggested that miR-320b overexpression suppressed cancer cell invasion, tube formation, tumor volume and angiogenesis in xenografted nude mice. Hepatocyte nuclear factor 4 gamma (HNF4G) was identified as a target of miR-320b based on in silico analysis. Dual-luciferase reporter gene assays further identified the binding relationship between HNF4G and miR-320b. Lung cancer tissues exhibited increased expression of HNF4G and insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). Meanwhile, HNF4G knockdown suppressed IGF2BP2 expression, thereby repressing cancer cell invasion and tube formation. Furthermore, IGF2BP2 modified m6A to increase the expression of thymidine kinase 1 (TK1), thus promoting angiogenesis. In nude mice, restoration of TK1 reversed the suppressive effect of miR-320b overexpression on tumor growth rate and CD31 expression. In conclusion, miR-320b suppresses lung cancer growth and angiogenesis by inhibiting HNF4G, IGF2BP2 and TK1.

Integrated Protein-Protein Interaction and Weighted Gene Co-expression Network Analysis Uncover Three Key Genes in Hepatoblastoma.

Hepatoblastoma (HB) is the most common liver tumor in the pediatric population, with typically poor outcomes for advanced-stage or chemotherapy-refractory HB patients. The objective of this study was to identify genes involved in HB pathogenesis via microarray analysis and subsequent experimental validation. We identified 856 differentially expressed genes (DEGs) between HB and normal liver tissue based on two publicly available microarray datasets (GSE131329 and GSE75271) after data merging and batch effect correction. Protein-protein interaction (PPI) analysis and weighted gene co-expression network analysis (WGCNA) were conducted to explore HB-related critical modules and hub genes. Subsequently, Gene Ontology (GO) analysis was used to reveal critical biological functions in the initiation and progression of HB. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that genes involved in cell cycle phase transition and the PI3K/AKT signaling were associated with HB. The intersection of hub genes identified by both PPI and WGCNA analyses revealed five potential candidate genes. Based on receiver operating characteristic (ROC) curve analysis and reports in the literature, we selected CCNA2, CDK1, and CDC20 as key genes of interest to validate experimentally. CCNA2, CDK1, or CDC20 small interfering RNA (siRNA) knockdown inhibited aggressive biological properties of both HepG2 and HuH-6 cell lines in vitro. In conclusion, we identified CCNA2, CDK1, and CDC20 as new potential therapeutic biomarkers for HB, providing novel insights into important and viable targets in future HB treatment.

Systematic analysis using a bioinformatics strategy identifies SFTA1P and LINC00519 as potential prognostic biomarkers for lung squamous cell carcinoma.

Lung cancer has high incidence and mortality rates, in which lung squamous cell carcinoma (LUSC) is a primary type of non-small cell lung carcinoma (NSCLC). The aim of our study was to discover long non-coding RNAs (lncRNAs) associated with diagnose and prognosis for LUSC. RNA sequencing data obtained from LUSC samples were extracted from The Cancer Genome Atlas database (TCGA). Two prognosis-associated lncRNAs (including SFTA1P and LINC00519) were selected from LUSC samples, and the expression levels were also verified to be associated abnormal in LUSC clinical samples. Our findings demonstrate that lncRNAs SFTA1P and LINC00519 exert important functions in human LUSC and may serve as new targets for LUSC diagnosis and therapy.

microRNA-125a targets MAVS and TRAF6 to modulate interferon signaling and promote HCV infection.

Hepatitis C virus (HCV) can cause chronic lifelong infections in humans, resulting in sustained hepatic inflammation, liver cirrhosis, and hepatocellular carcinoma. The clearance of HCV infections is dependent upon effective and coordinated innate and adaptive antiviral immune responses. However, HCV has evolved a range of strategies that enable it to evade or overcome the host immune response, enabling the virus to persist in susceptible hosts through mechanisms that remain to be fully clarified. Herein, we describe a novel mechanism whereby HCV can evade immune surveillance by activating microRNA (miR)-125a. Hepatocytes upregulate miR-125a following HCV infection, and serum from HCV-infected patients similarly exhibits the upregulation of this miRNA. We found that miR-125a is able to target and suppress the expression of two key genes associated with the interferon (IFN) signaling pathway - mitochondrial antiviral signaling (MAVS) and TNF receptor-associated factor 6 (TRAF6). Disrupting the expression of these genes can in turn compromise type I IFN responses to HCV. Together, our data reveal that HCV infection results in the upregulation of miR-125a, which negatively regulates IFN signaling via inhibiting the expression of MAVS and TRAF6, thereby enabling the virus to evade innate antiviral immunity. Targeting this pathway may thus represent an efficient approach to treating HCV and bolstering antiviral immune responses in infected patients.

Comprehensive analysis to identify DLEU2L/TAOK1 axis as a prognostic biomarker in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the deadliest malignant tumors that are harmful to human health. Increasing evidence has underscored the critical role of the competitive endogenous RNA (ceRNA) regulatory networks among various human cancers. However, the complexity and behavior characteristics of the ceRNA network in HCC were still unclear. In this study, we aimed to clarify a phosphatase and tensin homolog (PTEN)-related ceRNA regulatory network and identify potential prognostic markers associated with HCC. The expression profiles of three RNAs (long non-coding RNAs [lncRNAs], microRNAs [miRNAs], and mRNAs) were extracted from The Cancer Genome Atlas (TCGA) database. The DLEU2L-hsa-miR-100-5p/ hsa-miR-99a-5p-TAOK1 ceRNA network related to the prognosis of HCC was obtained by performing bioinformatics analysis. Importantly, we identified the DLEU2L/TAOK1 axis in the ceRNA by using correlation analysis, and it appeared to become a clinical prognostic model by Cox regression analysis. Furthermore, methylation analyses suggested that the abnormal upregulation of the DLEU2L/TAOK1 axis likely resulted from hypomethylation, and immune infiltration analysis showed that the DLEU2L/TAOK1 axis may have an impact on the changes in the tumor immune microenvironment and the development of HCC. In summary, the current study constructing a ceRNA-based DLEU2L/TAOK1 axis might be a novel important prognostic factor associated with the diagnosis and prognosis of HCC.

KDM5A silencing transcriptionally suppresses the FXYD3-PI3K/AKT axis to inhibit angiogenesis in hepatocellular cancer via miR-433 up-regulation.

Hepatocellular cancer (HCC) has been reported to belong to one of the highly vascularized solid tumours accompanied with angiogenesis of human umbilical vein endothelial cells (HUVECs). KDM5A, an attractive drug target, plays a critical role in diverse physiological processes. Thus, this study aims to investigate its role in angiogenesis and underlying mechanisms in HCC. ChIP-qPCR was utilized to validate enrichment of H3K4me3 and KDM5A on the promotor region of miR-433, while dual luciferase assay was carried out to confirm the targeting relationship between miR-433 and FXYD3. Scratch assay, transwell assay, Edu assay, pseudo-tube formation assay and mice with xenografted tumours were conducted to investigate the physiological function of KDM5A-miR-433-FXYD3-PI3K-AKT axis in the progression of HCC after loss- and gain-function assays. KDM5A p-p85 and p-AKT were highly expressed but miR-433 was down-regulated in HCC tissues and cell lines. Depletion of KDM5A led to reduced migrative, invasive and proliferative capacities in HCC cells, including growth and a lowered HUVEC angiogenic capacity in vitro. Furthermore, KDM5A suppressed the expression of miR-433 by demethylating H3K4me3 on its promoterregion. miR-433 negatively targeted FXYD3. Depleting miR-433 or re-expressing FXYD3 restores the reduced migrative, invasive and proliferative capacities, and lowers the HUVEC angiogenic capacity caused by silencing KDM5A. Therefore, KDM5A silencing significantly suppresses HCC tumorigenesis in vivo, accompanied with down-regulated miR-433 and up-regulated FXYD3-PI3K-AKT axis in tumour tissues. Lastly, KDM5A activates the FXYD3-PI3K-AKT axis to enhance angiogenesis in HCC by suppressing miR-433.

Characterization and antitumor activity of novel exopolysaccharide APS of Lactobacillus plantarum WLPL09 from human breast milk.

Two exopolysaccharides, NPS and APS, were isolated from L. plantarum WLPL09 and purified by ion-exchange chromatography. The structural analyses showed that molecular weight of NPS and APS were 72.60 kDa and 33.22 kDa, respectively. NPS was mainly composed of mannose and glucose, in molar ratio of 85.35:14.65, while APS was composed of mannose, glucose and galactose, in molar ratio of 89.69:8.65:1.66. In in vitro antitumor assays, APS displayed strong anti-proliferative effect against HepG2 hepatocellular carcinoma cells and HCT-8 colon adenocarcinoma cells in a dose-dependent manner. Morphological and flow cytometry analyses revealed that APS strongly induced apoptosis of HepG2 and HCT-8, especially for HCT-8. Furthermore, APS significantly up-regulated the mRNA level of apoptosis-related genes in cancer cells, and remarkably improved the activities of caspase-3, -8 and -9 in HepG2, caspase-3 and -8 in HCT-8. These results suggest APS might be explored as a potential, natural antitumor agent for functional food.

Long Noncoding RNA OIP5-AS1 Promotes the Progression of Liver Hepatocellular Carcinoma via Regulating the hsa-miR-26a-3p/EPHA2 Axis.

Numerous studies have suggested that dysregulated long noncoding RNAs (lncRNAs) contributed to the development and progression of many cancers. lncRNA OIP5 antisense RNA 1 (OIP5-AS1) has been reported to be increased in several cancers. However, the roles of OIP5-AS1 in liver hepatocellular carcinoma (LIHC) remain to be investigated. In this study, we demonstrated that OIP5-AS1 was upregulated in LIHC tissue specimens and its overexpression was associated with the poor survival of patients with LIHC. Furthermore, loss-of function experiments indicated that OIP5-AS1 promoted cell proliferation and inhibited cell apoptosis both in vitro and in vivo. Moreover, binding sites between OIP5-AS1 and hsa-miR-26a-3p as well as between hsa-miR-26a-3p and EPHA2 were confirmed by luciferase assays. Finally, a rescue assay was performed to prove the effect of the OIP5-AS1/hsa-miR-26a-3p/EPHA2 axis on LIHC cell biological behaviors. Based on all of the above findings, our results suggested that OIP5-AS1 promoted LIHC cell proliferation and invasion via regulating the hsa-miR-26a-3p/EPHA2 axis.

Possible misdiagnosis of 46,XX testicular disorders of sex development in infertile males.

Objectives: The 46,XX disorders of sex development (DSD) is a rare genetic cause of male infertility and possible misdiagnosis of this condition has never been reported. We aim to investigate clinical characteristics and laboratory results of infertile males with possibly misdiagnosed 46,XX DSD. Methods: Between January 2008 and December 2017, a retrospective case series study was performed involving sixteen 46,XX DSD males without azoospermia factor (AZF) deletion. Demographics, clinical features, laboratory results and assisted reproductive technology (ART) outcomes of these patients were depicted, and the underlying accurate diagnosis was also discussed. Results: The mean age was 30.06 ± 5.40 years old. Thirteen patients (81.25%) merely obtained secondary school education. Gynaecomastia occurred in one case, and cryptorchidism appeared in two cases. Testicular volumes were equal to 15 mL on two sides in one patient who had severe asthenozoospermia. Thirteen patients (81.25%) had bilateral atrophic testes which were below 5 mL. The majority of patients were observed with elevated levels of gonadotropic hormones and decreased testosterone values. Neither AZF region nor sex-determining region Y gene was absent among all patients. Twelve patients had normal ejaculatory function, whereas four were diagnosed with ejaculatory dysfunction. Eleven patients (68.75%) were diagnosed with azoospermia. Testicular sperm aspiration was performed in six subjects (37.50%). The pathological results showed that Leydig cell hyperplasia with spermatic failure was found in each case, and no sperm was found in testicular tissue. ART with donor sperm was conducted in 15 patients. Live birth was achieved in three cases through artificial insemination by donor and in one case using in-vitro fertilization by donor. Conclusions: Chromosomal analysis rarely yields 46,XX karyotype combined with no deletion of AZF in infertile males. Under this condition, molecular analysis should be conducted to avoid potential misdiagnosis and false interpretation of other findings.

Dual Regulatory Mechanisms of Expression and Mutation Involving Metabolism-Related Genes FDFT1 and UQCR5 during CLM.

Colorectal cancer (CRC) is the third most common cancer worldwide, and liver metastasis presents a major cause of CRC-associated death. Extensive genomic analysis has provided valuable insight into the pathogenesis and progression of CRC; however, a comprehensive proteogenomic characterization of CRC liver metastasis (CLM) has yet to be reported. Here, we analyzed the proteomes of 44 paired normal colorectal tissues and CRC tissues with or without liver metastasis, as well as analyzed genomics of CRC characterized previously by The Cancer Genome Atlas (TCGA) to conduct integrated proteogenomic analyses. We identified a total of 2,170 significantly deregulated proteins associated with CLM, 14.88% of which were involved in metabolic pathways. The mutated peptide number was found to have potential prognosis value, and somatic variants revealed two metabolism-related genes UQCR5 and FDFT1 that frequently mutated only in the liver metastatic cohort and displayed dysregulated protein abundance with biological function and clinical significance in CLM. Proteogenomic characterization and integrative and comparative genomic analysis provides functional context and prognostic value to annotate genomic abnormalities and affords a new paradigm for understanding human colon and rectal cancer liver metastasis.