Serum ADAM metallopeptidase domain 12 as a promising diagnostic biomarker for breast and liver cancer

Background ADAM metallopeptidase domain 12 (ADAM12) is generally upregulated in tissues of various tumors, emerging as a prognostic biomarker. However, the clinical significance of serum ADAM12 in tumors still remains to be fully elucidated. The present study aimed to investigate the expression and prognostic value of serum ADAM12 in tumor patients. Materials and methods Serum samples were collected from healthy doners (HDs; n = 87) and patients (n = 238) with a clinical diagnosis of breast, liver, lung, stomach and esophageal (STES) and thyroid cancer. Serum ADAM12 protein and mRNA expression was detected by enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR), respectively. Receiver–operator characteristic (ROC) analysis was performed to explored the prognostic value of serum ADAM12 expression. Results The expression of serum ADAM12 in breast and liver cancer patients was significantly upregulated compared with HDs. In patients with breast cancer, the levels of serum ADAM12 protein and mRNA were significantly higher in tumor stages than that in HDs (p < 0.05), with AUC value of 0.82. In liver cancer, elevated levels of serum ADAM12 protein were significantly correlated with clinical stage (r = 0.74; p = 6.9e−4) and T stage (r = 0.74, p = 7.6e−4), and attained AUC value of 1. However, the clinical significance of serum ADAM12 expression in lung, STES and thyroid cancer had not been found. Conclusions Serum ADAM12 expression showed high degree of tumor heterogeneity, and may be a valuable noninvasive diagnostic and prognostic biomarker for breast and liver cancer (AU)

Pan-cancer analysis of tumor mutation burden sensitive tumors reveals tumor-specific subtypes and hub genes related to immune infiltration.

BACKGROUND: High tumor mutation burden (TMB) failed to serve as a favorable prognostic biomarker for immunotherapy across all tumors. This study aimed to explore TMB-sensitive tumors on a pan-cancer level and construct their immune infiltration phenotypes in TMB-high groups. METHODS: Pan-cancer patients were separated into TMB-high and TMB-low groups based on the median TMB values per tumor. TMB-related genes were identified using differently expressed genes (DEGs) and differently mutated genes (DMGs) between the above two TMB groups. CIBERSORT algorithm was used to estimate the abundance of 22 tumor immune infiltrating cells (TIICs). Consensus clustering analysis was applied to predict molecular subtypes. Cox regression analysis was performed to evaluate the correlations between hub genes and TIICs and immunomodulator genes. RESULTS: Nine TMB-sensitive tumors were identified by high-frequency of TMB-related genes. A total of 126 tumor-specific hub genes (1 in BLCA, 19 in BRCA, 4 in COAD, 4 in HNSC, 25 in LUAD, 2 in LUSC, 27 in SKCM, 37 in STAD, and 7 UCEC) were identified. In five out of nine TMB-sensitive tumors, the molecular subtypes based on hub gene expression were characterized by TMB values, prognostic values and tumor-specific TIICs levels. In TMB-high groups, hub genes associated immune infiltration phenotypes were constructed with key TIICs and immunomodulators spanning TMB-sensitive tumors. CONCLUSIONS: Our tumor-specific analysis revealed hub genes associated immune infiltration features may serve as potential therapeutic targets and prognostic markers of immunotherapy, providing the potential underlying mechanism of immune infiltration in TMB-high groups across TMB-sensitive tumors.

Serum ADAM metallopeptidase domain 12 as a promising diagnostic biomarker for breast and liver cancer.

BACKGROUND: ADAM metallopeptidase domain 12 (ADAM12) is generally upregulated in tissues of various tumors, emerging as a prognostic biomarker. However, the clinical significance of serum ADAM12 in tumors still remains to be fully elucidated. The present study aimed to investigate the expression and prognostic value of serum ADAM12 in tumor patients. MATERIALS AND METHODS: Serum samples were collected from healthy doners (HDs; n = 87) and patients (n = 238) with a clinical diagnosis of breast, liver, lung, stomach and esophageal (STES) and thyroid cancer. Serum ADAM12 protein and mRNA expression was detected by enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR), respectively. Receiver-operator characteristic (ROC) analysis was performed to explored the prognostic value of serum ADAM12 expression. RESULTS: The expression of serum ADAM12 in breast and liver cancer patients was significantly upregulated compared with HDs. In patients with breast cancer, the levels of serum ADAM12 protein and mRNA were significantly higher in tumor stages than that in HDs (p < 0.05), with AUC value of 0.82. In liver cancer, elevated levels of serum ADAM12 protein were significantly correlated with clinical stage (r = 0.74; p = 6.9e-4) and T stage (r = 0.74, p = 7.6e-4), and attained AUC value of 1. However, the clinical significance of serum ADAM12 expression in lung, STES and thyroid cancer had not been found. CONCLUSIONS: Serum ADAM12 expression showed high degree of tumor heterogeneity, and may be a valuable noninvasive diagnostic and prognostic biomarker for breast and liver cancer.

Identification of Three Core Secretome Genes Associated with Immune Infiltration in High Tumor Mutation Burden Across 14 Major Solid Tumors.

BACKGROUND: Secretome genes, encoding proteins secreted from the cell, are involved in the tumor immune response and correlated with levels of tumor mutation burden (TMB) in multiple tumors. This study aimed to identify core secretome genes and their potential association with immunomodulators and immune infiltration in high TMB groups across 14 major solid tumors through bioinformatics analysis. METHODS: Multi-omics data for 14 major solid tumors were downloaded from The Cancer Genome Atlas (TCGA) database. Patients were divided into high TMB (TMB-high) and low TMB (TMB-low) groups using the median TMB values for each of the solid tumors. The CIBERSORT algorithm was conducted to estimate the proportion of 22 tumor-infiltrating immune cells (TIICs). Kaplan-Meier analysis and the log-rank test were utilized to screened prognosis-related genes. The correlations between core secretome genes and TIICs were analyzed using Spearman correlation coefficients. RESULTS: In TMB-high groups, multi-omics data analysis revealed that secretome genes were strongly associated with clinical characteristics, and 65 prognosis-related secretome genes were screened. Among the prognosis-related genes, 21 core secretome genes were identified, and strongly associated with five types of TIICs, namely activated NK cells, follicular helper T cells, CD8 T cells, and macrophages M0 and M2. Notably, three secretome genes (ADAMTS12, COL12A1, and COL5A2) were significantly related to immunomodulators and TIICs in multiple solid tumors. In addition, 12 core secretome genes were significantly differentially expressed between responding and non-responding patients receiving immunotherapy. Furthermore, core secretome genes may be involved in the PI3K/AKT signaling pathway. CONCLUSION: We examined the prognostic significance of secretome genes and their potential association with immunomodulators and immune infiltration across 14 major solid tumors. In summary, three secretome genes (ADAMTS12, COL12A1, and COL5A2) may be pivotal mediators of immune infiltration in TMB-high patients, which may help to identify patients who could benefit from immunotherapy.

Multilayer tubes that constrict, dilate, and curl in response to stimuli.

Tubular structures in nature have the ability to respond to their environment-for example, blood vessels can constrict or dilate, thereby regulating flow velocity and blood pressure. These tubes have multiple concentric layers, with each layer having a distinct composition and properties. Inspired by such natural structures, we have synthesized responsive multilayer tubes in the laboratory without resorting to complex equipment such as a 3-D printer. Each layer of our tubes is a polymer gel formed by free-radical polymerization of water-soluble monomers. We can precisely control the inner diameter of the tube, the number of layers in the tube wall, and the thickness and chemistry of each layer. Tubes synthesized in this manner are robust, flexible, and stretchable. Moreover, our technique allows us to incorporate stimuli-responsive polymers into distinct regions of these tubes, and the resulting tubes can change their shape in response to external stimuli such as pH or temperature. In the case of laterally patterned tubes, the tube can be made to constrict or dilate over a particular segment-a behavior that is reminiscent of blood vessels. In the case of longitudinally patterned tubes, a straight tube can be induced to systematically curl into a coil. The versatility of our technique is further shown by constructing complex tubular architectures, including branched networks. On the whole, the polymeric tubes shown in this paper exhibit remarkable properties that cannot be realized by other techniques. Such tubes could find utility in biomedical engineering to construct anatomically realistic mimics of various tissues.

Circulating Adipokine Levels in Nonobese Women With Polycystic Ovary Syndrome and in Nonobese Control Women: A Systematic Review and Meta-Analysis.

Levels of circulating adipokines in nonobese polycystic ovary syndrome (PCOS) patients have been reported in many studies. However, the results are inconsistent. The aim of this meta-analysis is to assess whether the levels of circulating adipokines are changed in nonobese PCOS relative to nonobese healthy controls. To identify eligible studies, a literature research was performed in the PubMed, Embase, and Web of Science databases without restricting by region, journal, or language. A total of 81 studies met the eligibility criteria. The meta-analysis showed that the circulating level of adiponectin (standardized mean difference [SMD]: -0.95; 95% CI: -1.36 to -0.53) was significantly decreased in nonobese PCOS patients. In contrast, the circulating levels of chemerin (SMD: 1.13; 95% CI: 0.08 to 2.18), leptin (SMD: 0.47; 95% CI: 0.13 to 0.81), resistin (SMD: 0.45; 95% CI: 0.03 to 0.88), and visfatin (SMD: 1.38; 95% CI: 0.68 to 2.09) were significantly increased in nonobese PCOS patients. There were no significant changes in the circulating levels of apelin (SMD: 0.32; 95% CI: -1.34 to 1.99), irisin (SMD: 1.01; 95% CI: -0.68 to 2.70), omentin (SMD: -0.37; 95% CI: -1.05 to 0.31), or vaspin (SMD: 0.09; 95% CI: -0.14 to 0.32). Thus, scientific evidence suggests that the circulating adipokine levels are altered in nonobese PCOS patients compared to nonobese healthy controls. Therefore, independent of the degree of obesity, dysregulated circulating adipokine levels might play important roles in the occurrence and development of PCOS.

LINC00261 functions as a competing endogenous RNA to regulate BCL2L11 expression by sponging miR-132-3p in endometriosis.

Endometriosis is a benign disease but manifests with malignant features and limited treatment options. Women with endometriosis should not be ignored or patronized by the medical profession and society. In this regard, a major cultural change and searching for the optimum therapeutic regimen from multiple perspectives is needed in China even in the whole world. Long non-coding RNAs are crucial for various human diseases while its potential functions and mechanisms are largely unknown in endometriosis. LINC00261 was significantly downregulated in endometriosis tissues and our study indicated that it suppresses proliferation and invasion of endometriosis cells functionally in vitro. Insights of the mechanism of competitive endogenous RNAs were obtained from bioinformatic analysis, RIP, RNA pull-down and luciferase assays, which further confirmed that LINC00261 functions as a molecular sponge to regulate BCL2L11 expression by binding to miR-132-3p directly. These data defined LINC00261/miR-132-3p/BCL2L11 regulatory networks may be a novel therapeutic target for endometriosis.

Upregulation of long noncoding RNA TUG1 by EGR1 promotes adenomyotic epithelial cell migration and invasion through recruiting EZH2 and suppressing TIMP2.

Emerging studies showed that lncRNA taurine upregulated 1 (TUG1) plays important roles in diverse biological processes. However, there is no previously published research reporting the regulatory role of lncRNAs in the progression of adenomyosis. In the present study, we found that TUG1 is upregulated in human adenomyosis, and the overexpression of TUG1 is associated with the transcription factor early growth response 1 (EGR1). Functionally, the knockdown of TUG1 inhibited adenomyotic epithelial cell migration and invasion but not growth. The mechanistic experiments demonstrated that the function of TUG1 in adenomyotic epithelial cell invasion is, at least in part, through recruiting the enhancer of zeste homolog 2 (EZH2) to the promoter of tissue inhibitor of metalloproteinases 2 (TIMP2) and negatively regulating its expression. Our study demonstrated that TUG1 promotes the migration and invasion of human adenomyotic epithelial cells, and EGR1/TUG1/EZH2/TIMP2 may be a potential therapeutic target for adenomyosis.

Long non-coding RNA LINC00261 inhibits cell growth and migration in endometriosis.

AIM: A previous study reported that LINC00261 is significantly downregulated in human ectopic endometrial tissues. The present study aimed to explore whether LINC00261 is functional in endometriosis cell proliferation, apoptosis and migration. METHODS: By transfecting human endometriosis cell line CRL-7566 with plasmids containing LINC00261, we successfully established the cell CRL-7566/LINC00261 with a high LINC00261 expression level. Cell-counting kit-8 and colony formation assays were conducted to evaluate the effect of LINC00261 on cell proliferation, and flow cytometry analysis and transwell migration assay were conducted to evaluate its effect on cell apoptosis and cell migration, respectively. RESULTS: Cell-counting kit-8 and colony formation assays both indicated that LINC00261 could inhibit cell proliferation in CRL-7566. Flow cytometry analysis confirmed that LINC00261 mediated inhibition of cell proliferation, which might be a consequence of inducting apoptosis. Furthermore, transwell migration assay indicated that LINC00261 could inhibit cell migration in endometriosis. CONCLUSION: LncRNA LINC00261 is capable of inhibiting cell growth and migration in endometriosis.

Effect of Momordica charantia protein on proliferation, apoptosis and the AKT signal transduction pathway in the human endometrial carcinoma Ishikawa H cell line in vitro.

Endometrial carcinoma (EC) is one of the most common female malignancies, and there is an urgent requirement to explore new therapeutic strategies. In the present study, Ishikawa H cells were treated with Momordica charantia protein (MCP30). The cell morphology, growth inhibition rate, cell cycle distribution, and expression of phosphate and tensin homolog, P-AKT and AKT were measured. DNA fragmentation analysis and Annexin V-fluorescein isothiocyanate/propidium iodide double staining assay were used to analyze cell apoptosis. MCP30 decreased the viability of Ishikawa H cells in a dose- and time-dependent manner. The early apoptotic rates of Ishikawa H cells treated with MCP30 at 666.67 pM reached to 16.07±0.15%, following 72 h of treatment. DNA ladder was observed in cells treated with 333.33 and 666.67 pM MCP30 following 72 h of treatment. MCP30 blocks Ishikawa H cells from progressing between the S-phase and the G2/M-phase in a time- and concentration-dependent manner. Western blotting revealed that MCP30 treatment decreased the levels of P-AKT in a dose-dependent manner. It was revealed that MCP30 decreases cell proliferation, and induces apoptosis and S-phase cell cycle arrest through the AKT signaling pathway in Ishikawa H cells.

Overexpression of salusin-ß is associated with poor prognosis in ovarian cancer.

Ovarian cancer is recognized as one of the worst gynecologic malignancies associated with rapid metastasis and poor overall survival rate. The identified valuable molecular biomarkers criticize importance of timely diagnosis for ovarian cancer. Salusin-ß levels are dramatically increased in women with polycystic ovarian syndrome. However, the roles of salusin-ß in ovarian cancer have yet to be fully elucidated. A total of 57 paired ovarian cancer specimens and matched adjacent normal tissues were used to measure the salusin-ß levels. The prognostic value of salusin-ß for tumor progression and survival rate was investigated. The effects of salusin-ß on ovarian cancer cell proliferation and epithelial-mesenchymal transition were also explored. The expression of salusin-ß was significantly increased in ovarian cancer tissue specimens compared with matched normal adjacent tissue (P<0.05). The high salusin-ß level was closely related with FIGO stage and lymph node metastases. The ovarian cancer patients with high salusin-ß had a shorter overall survival (P<0.05). Salusin-ß obviously enhanced the proliferation and epithelial mesenchymal-transition of SKOV3 cells. Furthermore, salusin-ß substantially decreased the expression of p-GSK-3ß and GSK-3ß, but stimulated the ß-catenin expression and downstream genes of wnt/ß-catenin including cyclin D1 and C-myc. Our data demonstrated for the first time that upregulated salusin-ß may be a novel independent prognostic biomarker for overall survival of ovarian cancer. Salusin-ß accelerated the proliferation and epithelial mesenchymal transition of ovarian cancer cells at least partly via activation of Wnt/ß-catenin signaling pathway. Salusin-ß may be an important target for therapeutic intervention in ovarian cancer.

Transcriptional network in ovarian cancer cell line SKOV3 treated with Pinellia pedatisecta Schott extract.

Ovarian cancer is the most lethal disease among the malignant tumors of female reproductive organs. Few successful therapeutic options exist for patients with ovarian cancer. The common therapeutic methods are surgical operation, chemotherapy, radiotherapy, and combination of these treatments. In recent years, studies have indicated that Pinellia pedatisecta Schott (PPS), a traditional Chinese medicine, could inhibit tumor growth. In this study, we demonstrated that PPS extract could induce apoptosis in SKOV3 cells in a dose- and time-dependent manner. We further conducted transcriptome sequencing on PPS extract-treated SKOV3 cells along with controls, and identified 1,754 transcripts whose expression differs at least 3-fold over the controls. These differentially expressed transcripts include the apoptosis-related genes such as the caspase family members, and were significantly enriched in steroid biosynthesis in the KEGG pathway database compared with the transcriptome background. Most of the differentially expressed transcripts from this pathway were upregulated in PPS extract-treated cell line, indicating that PPS extract-induced apoptosis was accompanied by increased steroid biosynthesis (e.g. zymosterol). These results suggest that PPS extract could be a new cytostatic therapeutic agent for ovarian cancer.

Cervical cancer systemic inflammation score: a novel predictor of prognosis.

Inflammation contributes to development and progression in a variety of cancers, including cervical cancer. We developed a novel cervical cancer systemic inflammation score (CCSIS) based on the preoperative platelet-to-lymphocyte ratio (PLR) and serum albumin levels. A retrospective analysis of clinical data from 795 patients with operable cervical cancer was then conducted to investigate the prognostic value of CCSIS and its association with the patients' clinicopathological features, overall survival (OS), and disease-free survival (DFS). CCSIS was predictive of OS and DFS. High CCSIS was correlated with more advanced FIGO stages, poor tumor differentiation, and the presence of PLN and LVSI. Both albumin levels and the PLR were independent prognostic indicators for operable cervical cancer. The use of the CCSIS could improve risk stratification and traditional clinicopathological analysis in cervical cancer.

(Z)-Ethyl 2-(2,4-dimethyl-benzyl-idene)-7-methyl-3-oxo-5-phenyl-3,5-dihydro-2H-thia-zolo[3,2-a]pyrimidine-6-carboxyl-ate.

In the title compound, C(25)H(24)N(2)O(3)S, the dihedral angles between the thia-zole ring and the phenyl and substituted benzene rings are 84.91 (11) and 11.58 (10)°, respectively. The dihydro-pyrimidine ring adopts a flattened boat conformation. The olefinic double bond is in a Z configuration.

Protective effect of calcium folinate against methotrexate-induced endosalpinx damage in rats.

The aim of this study was to evaluate the protective effect of calcium folinate (CF) applied in 10% of the methotrexate (MTX) dosage against morphologic and steroid-receptor damage induced by MTX in rat endosalpinx. The result indicated that endosalpingitis, the ultrastructural damage of endosalpinx, and a change in estrogen and P receptor expression induced by low- and high-dose MTX in endosalpinx can be reversed completely and partly (B1, B2) by combined treatment with CF, suggesting that CF combined with MTX protects against the side effects induced by MTX.

Examination of the effects of methotrexate on histological and steroid receptor changes in the endosalpinx of the rat.

OBJECTIVES: Methotrexate (MTX) has been a prevalent drug in conservative treatment of unruptured tubal pregnancy for many years. However, few researchers have performed morphological and protein analysis simultaneously to evaluate the specific toxic effects of MTX on the fallopian tubes. The aim of this study was to investigate acute and long-term toxic effects of increasing doses of MTX on the fallopian tubes and a possible dose-effect relationship. We also discuss the potential implications for subsequent pregnancies. STUDY DESIGN: At the 10th day and the 2nd and 3rd months after MTX treatment, a total of 108 females SD rats in estrus stage (27 rats in each group) were collected according to the dose of MTX i.p.: 1, 2, 5mg/kg body weight in groups I, II and III respectively and physiological saline i.p. in group IV for control. Nine rats in each group were killed at each time point and tissues close to the ampulla of the fallopian tubes were dissected for HE staining and routine histological observation. Estrogen receptor (ER) and progesterone receptor (PR) expression was detected by immunohistochemistry and Western blot. RESULTS: Morphological observation showed acute endosalpingitis in group I, becoming more intense with increasing doses of MTX in groups II and III in a reversible mode. Expression of ER in the endosalpinx significantly decreased in parallel with increasing doses of MTX in a dose-effect manner, which was reversible in groups I and II and irreversible in group III. Furthermore, ER and PR could recover close to normal levels in groups I and II after the 3rd month, while they could not restore to normal in group III. CONCLUSIONS: These results provide the first evidence that MTX (>or=5mg/kg) can induce long-term, irreversible damage to steroid hormone receptors in the fallopian tubes in a dose-dependent manner. We tentatively suggest that MTX should be used in a relatively small and safe range of dosage in order to avoid impairment and potential risk of subsequent tubal pregnancy or infertility.