Depression and myocardial injury in ST-segment elevation myocardial infarction: A cardiac magnetic resonance imaging study.

BACKGROUND: Depression is common in patients with myocardial infarction and has been independently associated with adverse outcomes. However, the association between depression and myocardial injury on cardiac magnetic resonance (CMR) in patients with ST-segment elevation myocardial infarction (STEMI) has still not been assessed. AIM: To assess the association between depression and myocardial injury on CMR in patients with STEMI. METHODS: A total of 107 STEMI patients undergoing primary percutaneous coronary intervention (P-PCI) were analyzed in this prospectivecohort study. Each subject completed the Patient Health Questionnaire-9 (PHQ-9) to assess the presence and severity of depressive symptoms. CMR was performed at a median of 3 d after P-PCI for quantifying post-MI myocardial injury. Correlations between depression identified by the PHQ-9 and myocardial injury measured on CMR were assessed. RESULTS: In this study, 19 patients (17.8%) were diagnosed with major depression identified by the PHQ-9 ≥ 10. PHQ-9 was analyzed both as a continuous variable and dichotomous variable. After multivariable adjustment, the proportion of patients with large infarction size was significantly higher in the major depression group (PHQ-9 ≥ 10) (OR: 4.840, 95%CI: 1.122-20.868, P =0.034). When the PHQ-9 was evaluated as a continuous variable, after multivariable adjustment, an increased PHQ-9 score was associated with an increased risk of large infarction size (OR: 1.226, 95%CI: 1.073-1.401, P =0.003). CONCLUSION: In patients with STEMI undergoing PCI, depression was independently associated with a large infarction size.

Interplay between regulation by methylation and noncoding RNAs in cancers.

Cancer is one of the most important health problems today; therefore, many researchers are focusing on exploring the mechanisms underlying its development and treatment. The field of cancer epigenetics has flourished in recent decades, and studies have shown that different epigenetic events, such as DNA methylation, histone modification, and noncoding RNA regulation, work together to influence cancer development and progression. In this short review, we summarize the interactions between methylation and noncoding RNAs that affect cancer development.

Genome-wide analysis of the three-way interplay among gene expression, estrogen receptor expression and chemotherapeutic sensitivity in breast cancer.

The expression of estrogen receptor α (ER) in breast cancers may be indicative of a favorable prognosis and most of these cancers respond to anti-estrogens or aromatase inhibitors. However, ER-positive (ER+) breast cancers receiving anti-hormone and/or chemotherapy sometimes lose their ER expression, which leads to the evolution of the disease to higher aggressiveness and drug resistance. In the present study, an ER-modified signature (EMS) was developed from the expression profile of a chemoresistant MCF-7 breast cancer cell line that lost ER expression during long-term treatment with a chemotherapeutic agent. The EMS could discriminate the ER-negative (ER-) breast cancer cells from the ER+ ones, which included seven pathways essential for the ER- cell development. Furthermore, the EMS indicated a more malignant subgroup of the ER- cells by discriminating the chemoresistant ER- cells from the chemosensitive ones. In addition, the classified chemoresistant ER- patients demonstrated worse prognosis. In conclusion, we developed a new method to discriminate subgroups of ER- breast cancer cells.

Genome-wide profiling of long non-coding RNA expression patterns in anthracycline-resistant breast cancer cells.

Long non-coding RNAs (lncRNAs) are involved in cancer progression. In the present study, we analyzed the lncRNA profiles in adriamycin-resistant and -sensitive breast cancer cells and found a group of dysregulated lncRNAs in the adriamycin-resistant cells. Expression of the dysregulated lncRNAs was correlated with dysregulated mRNAs, and these were enriched in GO and KEGG pathways associated with cancer progression and chemoresistance development. Among these lncRNA-mRNA interactions, some lncRNAs may cis­regulate neighboring protein-coding genes and be involved in chemoresistance. We then validated that the lncRNA NONHSAT028712 regulated nearby CDK2 and interfered with the cell cycle and chemoresistance. Furthermore, we identified another group of lncRNAs that trans-regulated genes by interacting with different transcription factors. For example, NONHSAT057282 and NONHSAG023333 modulated chemoresistance and most likely interacted with the transcription factors ELF1 and E2F1, respectively. In conclusion, in the present study, we report for the first time the lncRNA expression patterns in adriamycin-resistant breast cancer cells, and provide a group of novel lncRNA targets that mediate chemoresistance development in both cis- and trans-action modes.

Targeting PSG1 to enhance chemotherapeutic efficacy: new application for anti-coagulant the dicumarol.

Chemotherapeutic response is critical for the successful treatment and good prognosis in cancer patients. In this study, we analysed the gene expression profiles of preoperative samples from oestrogen receptor (ER)-negative breast cancer patients with different responses to taxane-anthracycline-based (TA-based) chemotherapy, and identified a group of genes that was predictive. Pregnancy specific beta-1-glycoprotein 1 (PSG1) played a central role within signalling pathways of these genes. Inhibiting PSG1 can effectively reduce chemoresistance via a transforming growth factor-ß (TGF-ß)-related pathway in ER-negative breast cancer cells. Drug screening then identified dicumarol (DCM) to target the PSG1 and inhibit chemoresistance to TA-based chemotherapy in vitro, in vivo, and in clinical samples. Taken together, this study highlights PSG1 as an important mediator of chemoresistance, whose effect could be diminished by DCM.

Clinical utility of letrozole in the treatment of breast cancer: a Chinese perspective.

The incidence rate of breast cancers in People's Republic of China has increased in the last decade, and many cases are responsive to hormone therapies. The third-generation aromatase inhibitor letrozole inhibits estrogen production, and is more efficacious than the estrogen receptor inhibitor tamoxifen. In recent years, letrozole has been widely used to treat postmenopausal breast cancers in People's Republic of China. Also, metastatic, premenopausal, and male breast cancers have been effectively treated by a combination of letrozole with cytotoxic, radiation, or other therapies. In this review, we provide a perspective and summary of recent advances in the use of letrozole for breast cancer in Chinese patients.

Genome-wide profiles of methylation, microRNAs, and gene expression in chemoresistant breast cancer.

Cancer chemoresistance is regulated by complex genetic and epigenetic networks. In this study, the features of gene expression, methylation, and microRNA (miRNA) expression were investigated with high-throughput sequencing in human breast cancer MCF-7 cells resistant to adriamycin (MCF-7/ADM) and paclitaxel (MCF-7/PTX). We found that: ① both of the chemoresistant cell lines had similar, massive changes in gene expression, methylation, and miRNA expression versus chemosensitive controls. ② Pairwise integration of the data highlighted sets of genes that were regulated by either methylation or miRNAs, and sets of miRNAs whose expression was controlled by DNA methylation in chemoresistant cells. ③ By combining the three sets of high-throughput data, we obtained a list of genes whose expression was regulated by both methylation and miRNAs in chemoresistant cells; ④ Expression of these genes was then validated in clinical breast cancer samples to generate a 17-gene signature that showed good predictive and prognostic power in triple-negative breast cancer patients receiving anthracycline-taxane-based neoadjuvant chemotherapy. In conclusion, our results have generated a new workflow for the integrated analysis of the effects of miRNAs and methylation on gene expression during the development of chemoresistance.

A new agent developed by biotransformation of polyphyllin VII inhibits chemoresistance in breast cancer.

Biotransformation by the endophytes of certain plants changes various compounds, and this 'green' chemistry becomes increasingly important for finding new products with pharmacological activity. In this study, polyphyllin VII (PPL7) was biotransformed by endophytes from the medicinal plant Paris polyphylla Smith, var. yunnanensis. This produced a new compound, ZH-2, with pharmacological activity in vitro and in vivo. ZH-2 was more potent than PPL7 in selectively killing more chemoresistant than chemosensitive breast cancer cells. ZH-2 also re-sensitized chemoresistant breast cancer cells, as evidenced by the improved anti-cancer activity of commonly-used chemotherapeutic agent in vitro, in vivo, and in clinical samples. This anti-chemoresistance effect of ZH-2 was associated with inhibiting the epithelial-mesenchymal transition (EMT) pathway. Taken together, our findings are the first one to link biotransformation with a biomedicine. The results provide insights into developing new pharmacologically-active agents via biotransformation by endophytes.

Transient receptor potential channel C5 in cancer chemoresistance.

The transient receptor potential (TRP) superfamily contains at least 28 homologs in mammalian. These proteins form TRP channels are permeable to monovalent and divalent cations and participate in a variety of physiological functions. Dysregulation of TRP channels is responsible for numerous diseases. This review provides a brief short overview of mammalian TRP channels with a focus on TRPC5 and its role in cancers. Dysregulation of TRPC5 interrupts Ca(2+) homeostasis in cancer cells, which activates signaling pathways that are highly associated with cancer progression, especially cancer chemoresistance. Based on the important role of TRPC5, we also discuss the potential of TRPC5 as a target for therapeutic intervention. Either direct targeting of TRPC5 or indirect interruption of TRPC5-related signaling pathways may effectively overcome cancer chemoresistance.

A transcription/translation-based gene signature predicts resistance to chemotherapy in breast cancer.

Although chemotherapy is widely used to treat human cancers, most chemotherapeutic agents only benefit a small fraction of patients because of the heterogeneity of cancers. Therefore, identifying of the sensitivity of cancers toward various chemotherapies would be important for choosing of chemotherapeutic regime. In this study, a 23-gene chemoresistance signature was developed from chemoresistant breast cancers. Functions of the genes in the signature were related with transcription and translation. The signature was indicative of chemoresistance and associated with poor prognosis in multiple chemotherapeutic agents and cancer types. Furthermore, by applying computational approaches, we identified several compounds that might specifically affect the chemoresistant signature. Decitabine (DAC) was the compound most likely to target the signature. In vitro and clinical analysis confirmed effect of DAC toward both breast cancer cell lines and ovarian cancers respectively. In conclusion, our study identified a chemoresistant signature that is both predictive and prognostic, and the signature-related chemoresistance could be suppressed by DAC treatment.

A 20-gene signature in predicting the chemoresistance of breast cancer to taxane-based chemotherapy.

To date, there is no effective marker to predict chemoresistance in cancers. In this study, we aimed to find a signature that can detect chemoresistance to taxane-based therapies in breast cancer. By studying the gene-expression profiling in discovery cohorts with 92 taxane-resistant and 68 taxane-sensitive patients, a 20-gene taxane-based chemotherapy signature (TAXSig) and a TAXSig equation were developed. The TAXSig and its equation were later validated in five further independent datasets with a total of 659 patients. In general, the TAXSig equation easily and effectively discriminated between chemoresistant and chemosensitive individuals. The TAXSig-identified groups showed significant differences in clinical outcomes both in estrogen-receptor-positive and -negative (ER(-)) breast cancer patients, while the TAXSig was especially powerful in identifying ER(-) patients who had a good prognosis and were chemosensitive. In conclusion, the TAXSig is a reliable, effective, and reproducible means of classifying chemoresistance to taxane-based therapies in breast cancer.

Methylation-regulated miR-149 modulates chemoresistance by targeting GlcNAc N-deacetylase/N-sulfotransferase-1 in human breast cancer.

Dysregulation of microRNA is strongly implicated in the chemoresistance of cancer. In this study, we found that miR-149 was downregulated and involved in chemoresistance in adriamycin (ADM)-resistant human breast cancer cells (MCF-7/ADM). Downregulation of miR-149 was related to hypermethylation of its 5'-UTR; this methylation also affected the expression of the glypican 1 gene, which is both the host and the target gene of miR-149. Furthermore, we found that miR-149 modulated chemoresistance through targeting the expression of GlcNAc N-deacetylase/N-sulfotransferase-1 (NDST1). With downregulated miR-149, NDST1 expression was increased in chemoresistant MCF-7/ADM cells versus control MCF-7 wild-type cells. The increased NDST1 then activated a heparan sulfate-related pathway involving activation of heparanase. Finally, expression of miR-149 and NDST1 was confirmed in clinical chemoresistant samples of breast cancers receiving anthracycline/taxane-based chemotherapies. The high expression of NDST1 was also an unfavorable predictor for distant relapse-free survival in Her2 and basal breast cancers. Taken together, our findings demonstrate that miR-149 is regulated by methylation, and is a modulator of cancer chemoresistance by targeting NDST1.

A methylation-based regulatory network for microRNA 320a in chemoresistant breast cancer.

We previously demonstrated that the overexpression of transient receptor potential channel C5 (TRPC5) and nuclear factor of activated T-cells isoform c3 (NFATC3) are essential for cancer chemoresistance, but how TRPC5 and NFATC3 are regulated was still unclear. In this study, microRNA 320a (miR-320a) was found to be down-regulated in chemoresistant cancer cells. MiR-320a directly targeted TRPC5 and NFATC3, and down-regulation of miR-320a triggered TRPC5 and NFATC3 overexpression. In chemoresistant cells, down-regulation of miR-320a was associated with regulation by methylation, which implicated promoter methylation of the miR-320a coding sequence. Furthermore, the transcription factor v-ets erythroblastosis virus E26 oncogene homolog 1 (ETS-1), which inhibited miR-320a expression, was activated in chemoresistant cancer cells; such activation was associated with hypomethylation of the ETS-1 promoter. Lastly, the down-regulation of miR-320a and high expression of TRPC5, NFATC3, and ETS-1 were verified in clinically chemoresistant samples. Low expression of MiR-320a was also found to be a significant unfavorable predictor for clinic outcome. In conclusion, miR-320a is a mediator of chemoresistance by targeting TRPC5 and NFATC3. Expression of miR-320a is regulated by methylation of its promoter and that of ETS-1.

Trichosanthin affects HSV-1 replication in Hep-2 cells.

Trichosanthin (TCS) is a type I ribosome-inactivating protein that inhibits the replication of both human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 1 (HSV-1). The mechanism of inhibition is not clear. This investigation explored the effects of TCS on the stages of HSV-1 infection in Hep-2 cells, from attachment to release. We demonstrated that TCS reduced HSV-1 antigen and DNA content and interfered with viral replication as early as 3-15 h after infection. TCS had no effect on HSV-1 attachment, penetration or immediate-early gene expression. However, the expression of early and late genes and virion release were diminished. In summary, this study demonstrates that TCS primarily affects HSV-1 replication in Hep-2 cells during the early to late infection period.