piR-1919609 Is an Ideal Potential Target for Reversing Platinum Resistance in Ovarian Cancer.

PURPOSE: PIWI-interacting RNAs (piRNAs) are a type of noncoding small RNA that can interact with PIWI-like RNA-mediated gene silencing (PIWIL) proteins to affect biological processes such as transposon silencing through epigenetic effects. Recent studies have found that piRNAs are widely dysregulated in tumors and associated with tumor progression and a poor prognosis. Therefore, this study aimed to investigate the effect of piR-1919609 on the proliferation, apoptosis, and drug resistance of ovarian cancer cells. METHODS: In this study, we used small RNA sequencing to screen and identify differentially expressed piRNAs in primary ovarian cancer, recurrent ovarian cancer, and normal ovaries. A large-scale verification study was performed to verify the expression of piR-1919609 in different types of ovarian tissue, including ovarian cancer tissue and normal ovaries, by RT-PCR and to analyze its association with the clinical prognosis of ovarian cancer. The expression of PIWILs in ovarian cancer was verified by RT-PCR, Western blotting and immunofluorescence. The effects of piR-1919609 on ovarian cancer cell proliferation, apoptosis and drug resistance were studied through in vitro and in vivo models. RESULTS: (1) piR-1919609 was highly expressed in platinum-resistant ovarian cancer tissues (p < 0.05), and this upregulation was significantly associated with a poor prognosis and a shorter recurrence time in ovarian cancer patients (p < 0.05). (2) PIWIL2 was strongly expressed in ovarian cancer tissues (p < 0.05). It was expressed both in the cytoplasm and nucleus of ovarian cancer cells. (3) Overexpression of piR-1919609 promoted ovarian cancer cell proliferation, inhibited apoptosis, and promoted tumor growth in nude mice. (4) Inhibition of piR-1919609 effectively reversed ovarian cancer drug resistance. CONCLUSION: In summary, we showed that piR-1919609 is involved in the regulation of drug resistance in ovarian cancer cells and might be an ideal potential target for reversing platinum resistance in ovarian cancer.

Identification of PDZD11 as a Potential Biomarker Associated with Immune Infiltration for Diagnosis and Prognosis in Epithelial Ovarian Cancer.

Purpose: Evidence has indicated that PDZD11 is involved in regulating adherens junction. However, the distinct effect of its aberrant expression on epithelial ovarian cancer (EOC) awaits clarification. Methods: In this study, public databases (Gene Expression Omnibus, The Cancer Genome Atlas, and The Genotype-Tissue Expression), online analysis tools (Kaplan-Meier plotter and TIMER), and data analysis methods (Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and the CIBERSORT algorithm) were fully utilized to analyze the differential expression, diagnostic efficiency, prognostic significance, potential function, and correlation with immune infiltration of PDZD11. The differential expression of PDZD11 was tested by immunohistochemistry in EOC tissues (78 cases) and control tissues (37 cases). Results: Our results indicate that PDZD11 was remarkably overexpressed in EOC, which was associated with advanced cancer stages, no lymphatic metastasis status, and poor prognosis. Moreover, PDZD11 played a role in cell adhesion, cell proliferation, and immune responses. Also, PDZD11 was significantly related to the abundances of infiltrating immune cells in EOC, including neutrophils, macrophages, dendritic cells, CD8+ T cells, and CD4+ T cells, and its expression was positively co-expressed with well-known immune checkpoints, including TIGIT, TIM3, LAG3, CTLA4, and PD-1. Conclusion: These results suggest that PDZD11 could be a potential diagnostic and prognostic biomarker associated with immune infiltration in EOC, and our findings might help elucidate the function of PDZD11 in carcinogenesis.

New peptides with immunomodulatory activity identified from rice proteins through peptidomic and in silico analysis.

The new food-derived bio-functional peptides are urgently needed globally, but the separation and purification process for obtaining the immunopeptides from food is low efficiency and highly time-consuming. In the present study, rice proteins were extracted and identified by using liquid chromatography/tandem mass spectrometry (LC-MS/MS). Furthermore, a strategy combining immuno-prediction and in silico simulation was used to screen for peptides showing immunomodulatory activity, including inhibition of the release of nitric oxide, tumor necrosis factor-α, and the interleukins IL-6 and IL-1ß in lipopolysaccharide-induced RAW264.7 mouse macrophages. This LC-MS/MS identification and immuno-prediction method may provide insights for the potential identification of more food-derived immunopeptides.

ARRDC3 as a Diagnostic and Prognostic Biomarker for Epithelial Ovarian Cancer Based on Data Mining.

PURPOSE: The dysregulation of arrestin domain containing 3 (ARRDC3) has an important effect on oncogenesis and tumor progression in many cancers, including renal cell carcinoma and breast cancer. However, the role of ARRDC3 in ovarian cancer (OC) has not been reported. METHODS: The present study explored the diagnostic and prognostic roles of ARRDC3 in ovarian cancer using GEPIA, ONCOMINE, GEO, and Kaplan-Meier Plotter databases for training and validation. Then, we conducted a stratified analysis for clinicopathological factors using Kaplan-Meier Plotter and GEPIA databases. To further explore the mechanisms, we also used the MIST database to visualize the protein-protein interaction network of ARRDC3 associated with OC. The gene-gene interaction network was visualized by GeneMANIA plugin in Cytoscape 3.8.0 software, and the associated co-expression genes of ARRDC3 were analyzed by the cBioPortal database. The 100 top co-expression genes chosen for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used by the DAVID website. RESULTS: A significant difference in ARRDC3 mRNA expression was found between OC and normal ovary tissues. ARRDC3 could potentially be implicated in the diagnosis of OC. A high ARRDC3 mRNA expression level was associated with poor overall survival and progression-free survival. However, no significance was reported in respect to post progression survival. Except for histology, which had no prognostic value for PPS in stratified analysis, stratified analysis of other factors had prognostic value for OS, PFS, and PPS. Interestingly, we found a positive correlation between ARRDC3 expression and CD8+ T cells, macrophages, neutrophils, and dendritic cells, indicating that ARRDC3 might be associated with immune infiltration of these immune cells. Co-expression genes enrichment analysis found that they were involved in the Renin-angiotensin system pathway. CONCLUSION: Differentially expressed ARRDC3 might be a potential prognostic and diagnostic marker in Ovarian Cancer.

Deceleration capacity of heart rate predicts trastuzumab-related cardiotoxicity in patients with HER2-positive breast cancer: A prospective observational study.

WHAT IS KNOWN AND OBJECTIVES: Trastuzumab is the standard choice for anti-human epidermal growth factor receptor 2 (HER2) therapy. Cardiotoxicity is one of the main adverse effects of trastuzumab. How to early predict trastuzumab-related cardiotoxicity remains a significant problem in clinical practice. The deceleration capacity of the heart rate (DC) has been shown to be a powerful predictor of adverse outcomes in various heart diseases. In the study, the role of DC in early predicting trastuzumab-related cardiotoxicity was investigated. METHODS: A total of 150 patients were prospectively investigated the clinical value of the DC in predicting trastuzumab-related cardiotoxicity in patients with HER2-positive breast cancer treated with trastuzumab at Guangxi Medical University Cancer Hospital from June 2015 to June 2017. DC, mean heart rate and heart rate variability (HRV) indices, including the standard deviation of all normal RR intervals (SDNN) and the square root of the mean of the squared differences between adjacent normal RR intervals (RMSSD), were assessed before treatment, and the left ventricular ejection fraction (LVEF) was regularly monitored for 2 years (before, during and after treatment) to evaluate cardiotoxicity. RESULTS: Among 150 eligible patients, 28 (18.7%) developed cardiotoxicity. Patients with cardiotoxicity were older (P < .05), higher anthracycline dose (P < .001) and had lower RMSSD (P < .05), SDNN, DC and baseline LVEF (P < .001), than patients without cardiotoxicity. Logistic regression analysis revealed lower DC, lower baseline LVEF and higher anthracycline dose were independent risk factors of trastuzumab-related cardiotoxicity. Receiver operating characteristic (ROC) curve analysis revealed a greater area under the curve for DC than for the baseline LVEF in predicting cardiotoxicity (0.88 vs 0.77, P = .032). Additionally, DC had higher sensitivity (78.6% vs 67.9%) and specificity (83.6% vs 77.9%) in predicting cardiotoxicity than the baseline LVEF. Linear regression analysis showed among patients who developed cardiotoxicity, lower DC was associated with an earlier onset (P < .01). WHAT IS NEW AND CONCLUSION: The present study found that DC was a stronger predictor of trastuzumab-related cardiotoxicity development than the baseline LVEF and HRV. Linear regression analysis showed among patients who developed cardiotoxicity, lower DC was associated with an earlier onset. DC should be a potential clinical indicator for the early prediction of trastuzumab-related cardiotoxicity.

TM4SF1 is a potential target for anti-invasion and metastasis in ovarian cancer.

BACKGROUND: Patients with ovarian cancer commonly have a poor prognosis, owing to its invasiveness and distant metastasis. Studies have found TM4SF1 participates in regulating tumor cell invasion and migration. Therefore, it is expected to become a target for anti-invasion and metastasis in ovarian cancer. METHODS: The expression of TM4SF1 in normal ovarian epithelial tissues, benign ovarian tumor tissues, primary foci of epithelial ovarian cancer and the matched lymph mode metastatic foci was detected using immunohistochemistry to analyze its association with prognosis. The expression of TM4SF1 in HO8910PM, SKOV3 was inhibited using RNAi, and the growth, proliferation, migration, invasion abilities of HO8910PM and SKOV3 cells and the growth of xenograft tumors in nude mice were examined. RESULTS: (1) The positive expression rate of TM4SF1 protein in epithelial ovarian cancer tissues (90.90%) was higher than that in benign ovarian tumor tissues (65.22%) and normal ovarian epithelial tissues (31.25%), and both differences were significant (P < 0.05). The expression of TM4SF1 protein was positive in all metastatic lymph node foci and matched primary foci (100%). (2) The level of TM4SF1 protein expression was positively correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage and histological grade. However, The positive TM4SF1 protein expression was not an independent factor of prognosis (P > 0.05). (3) Silencing TM4SF1 expression did not affect growth, proliferation, or cell cycle distribution but inhibited the migration and invasion abilities of HO8910PM and SKOV3 cells. Silencing TM4SF1 expression inhibited the growth of xenograft tumors in nude mice. CONCLUSION: TM4SF1 is a potential target for anti-invasion and metastasis in ovarian cancer.

Clinical Application of the Heart Rate Deceleration Capacity Test to Predict Epirubicin-induced Cardiotoxicity.

OBJECTIVE: To investigate the clinical value of heart rate deceleration capacity (DC) in predicting the risk of epirubicin-induced cardiotoxicity. METHODS: The CK-MB and cTnI levels and DC values of 86 patients were examined before chemotherapy and again after 2 and 4 cycles of chemotherapy. Patients were divided into low-risk group (LRG) (40 cases), medium-risk group (26 cases), and high-risk group (HRG) (20 cases) based on the calculated DC values. RESULTS: After 4 cycles of chemotherapy, HRG showed a significantly greater increase in serum CK-MB (17.1 ± 4.9 vs. 14.6 ± 3.7) and cTnI (1.28 ± 0.38 vs. 1.0 ± 0.29) concentrations over the prechemotherapy levels when compared with LRG. After 2 and 4 cycles of chemotherapy, HRG exhibited a significantly greater increase in mean heart rate (2 cycles: 79.6 ± 6.0 vs. 77.6 ± 6.7; 4 cycles: 88.2 ± 10.2 vs. 82.4 ± 6.2) and the supraventricular (2 cycles: 68.9 ± 19.3 vs. 57.2 ± 17.6; 4 cycles: 131.1 ± 29.5 vs. 91.7 ± 16.5) and ventricular arrhythmia counts (2 cycles: 179.0 ± 20.5 vs. 162.3 ± 16.3; 4 cycles: 228.6 ± 44.8 vs. 187.4 ± 22.6) over the prechemotherapy values compared with LRG. When the supraventricular and ventricular arrhythmia counts measured after 4 cycles of chemotherapy were compared with those obtained before chemotherapy, HRG (131.1 ± 29.5 and 228.6 ± 44.8, respectively) showed the largest differences, followed by medium-risk group (107.4 ± 31.9 and 202.0 ± 29.8, respectively) and then LRG (91.7 ± 16.5 and 187.4 ± 22.6, respectively) (P < 0.01). After 4 cycles of chemotherapy, the incidence rates of ventricular arrhythmia greater than Lown's grade 3 (30% vs. 2.5%), QTc (20% vs. 0) elongation, and ST-T (40% vs. 5%) changes in HRG were significantly higher than those observed in LRG (P < 0.05). CONCLUSIONS: DC test was shown to be an effective predictor of the risk of epirubicin-induced cardiotoxicity.