Artificial Intelligence Techniques for Prostate Cancer Detection through Dual-Channel Tissue Feature Engineering

The optimal diagnostic and treatment strategies for prostate cancer (PCa) are constantly changing. Given the importance of accurate diagnosis, texture analysis of stained prostate tissues is important for automatic PCa detection. We used artificial intelligence (AI) techniques to classify dual-channel tissue features extracted from Hematoxylin and Eosin (H&E) tissue images, respectively. Tissue feature engineering was performed to extract first-order statistic (FOS)-based textural features from each stained channel, and cancer classification between benign and malignant was carried out based on important features. Recursive feature elimination (RFE) and one-way analysis of variance (ANOVA) methods were used to identify significant features, which provided the best five features out of the extracted six features. The AI techniques used in this study for binary classification (benign vs. malignant and low-grade vs. high-grade) were support vector machine (SVM), logistic regression (LR), bagging tree, boosting tree, and dual-channel bidirectional long short-term memory (DC-BiLSTM) network. Further, a comparative analysis was carried out between the AI algorithms. Two different datasets were used for PCa classification. Out of these, the first dataset (private) was used for training and testing the AI models and the second dataset (public) was used only for testing to evaluate model performance. The automatic AI classification system performed well and showed satisfactory results according to the hypothesis of this study.ope

Role of p53 in antioxidant defense of HPV-positive cervical carcinoma cells following H2O2 exposure

In HPV-positive cervical carcinoma cells, p53 protein is functionally antagonized by the E6 oncoprotein. We investigated a possible role of p53 in antioxidant defense of HPV-positive cervical cancer cell lines. We found that SiHa cells containing integrated HPV 16 had higher expression of p53 and exhibited the greatest resistant to H2O2-induced oxidative damage, compared with HeLa, CaSki and ME180 cell lines. Downregulation of p53 resulted in the inhibition of p53-regulated antioxidant enzymes and elevated intracellular ROS in SiHa cells. By contrast, the ROS level was not affected in HeLa, CaSki and ME180 cell lines after inhibition of the p53 protein. Under mild or severe H2O2-induced stress, p53-deficient SiHa cells exhibited much higher ROS levels than control SiHa cells. Furthermore, we analyzed cell viability and apoptosis after H2O2 treatment and found that p53 deficiency sensitized SiHa cells to H2O2 damage. Inhibition of p53 resulted in excessive oxidation of DNA; control SiHa cells exhibited a more rapid removal of 8-oxo-7,8-dihydro-2′-deoxyguanosine from DNA compared with p53-deficient SiHa cells exposed to the same level of H2O2 challenge. These data collectively show that endogenous p53 in SiHa cells has an antioxidant function and involves in the reinforcement of the antioxidant defense.ope

NM23 as a prognostic biomarker in ovarian serous carcinoma

The nm23 gene is a reported metastasis suppressor gene. Recent studies have shown that its expression has tissue specificity. The role of nm23 in human ovarian cancer is still controversial. This study examines the prognostic significance of nm23 expression in patients with serous ovarian carcinoma. Following comparative proteomics in 13 fresh frozen ovarian serous cancer tissues with other histological types of ovarian cancers, validation was performed using immunohistochemistry on clinically well-designed 73 ovarian serous carcinoma microarray samples that were retrieved from ovarian cancer patients from 1990 to 2003. Statistical analysis of the results was performed using chi(2) test, Cox proportional regression, the Kaplan-Meier method and log-rank test. We found that the expression of nm23 inversely correlated with peritoneal seeding (P=0.009). However, strong nm23 expression was associated with mortality in patients with ovarian carcinoma in univariate analysis (P=0.04). Poor prognostic factors of disease-free survival included tumor residue more than 2 cm (P=0.02), bilaterality (P=0.01) and peritoneal seeding (P<0.01), whereas poor prognostic factors affecting overall survival included peritoneal seeding (P=0.05). In Kaplan-Meier analysis, strong nm23 immunoreactivity correlates with poor overall survival (P=0.04) but not with poor disease-free survival. In conclusion, overexpression of nm23 is independently associated with decreased overall survival in patients with ovarian carcinoma and also significantly correlates with mortality. Nm23 may have a biological function that leads to poor clinical outcomes in ovarian carcinoma.ope

Compression-induced Expression of Glycolysis Genes in CAFs Correlates With EMT and Angiogenesis Gene Expression in Breast Cancer

Tumor growth increases compressive stress within a tissue, which is associated with solid tumor progression. However, very little is known about how compressive stress contributes to tumor progression. Here, we show that compressive stress induces glycolysis in human breast cancer associated fibroblast (CAF) cells and thereby contributes to the expression of epithelial to mesenchymal (EMT)- and angiogenesis-related genes in breast cancer cells. Lactate production was increased in compressed CAF cells, in a manner dependent on the expression of metabolic genes ENO2, HK2, and PFKFB3. Conditioned medium from compressed CAFs promoted the proliferation of breast cancer cells and the expression of EMT and/or angiogenesis-related genes. In patient tissues with high compressive stress, the expression of compression-induced metabolic genes was significantly and positively correlated with EMT and/or angiogenesis-related gene expression and metastasis size. These findings illustrate a mechanotransduction pathway involving stromal glycolysis that may be relevant also for other solid tumours.ope

Mechanical compression induces VEGFA overexpression in breast cancer via DNMT3A-dependent miR-9 downregulation

Tumor growth generates mechanical compression, which may trigger mechanotransduction in cancer and stromal cells and promote tumor progression. However, very little is known about how compression stimulates signal transduction and contributes to tumor progression. In the present study, we demonstrated that compression enhances a tumor progression phenotype using an in vitro compression model, and validated the results from the in vitro model with high- and low-compressed breast cancer tissues. Mechanical compression induced miR-9 downregulation by DNMT3A-dependent promoter methylation in the MDA-MB-231 and BT-474 breast cancer cell lines and in cancer-associated fibroblasts. The overexpression of miR-9 target genes (LAMC2, ITGA6, and EIF4E) was induced by miR-9 downregulation, which eventually enhanced vascular endothelial growth factors production. Demethylation and decompression could reverse compression-induced miR-9 downregulation and following overexpression of miR-9 target genes and VEGFA.ope

Analysis of Matrix Metalloproteinase Expression in the Recurrence of Superficial Low Grade Urothelial Bladder Cancer

Purpose: Superficial bladder transitional cell carcinomas (TCCa) have high recurrence rates following endoscopic resection. Most of the parameters used for the prediction of a recurrence are associated with high grade TCCa. However, there are few valid parameters for prediction of the recurrence of low grade TCCa. We aimed to elucidate the prime factor of a recurrence of superficial low grade bladder TCCa. Materials and Methods: Thirty cases of superficial low grade bladder TCCa were analyzed, 15 of which were recurred cases. Fresh frozen tumor and normal tissues were used for the analysis. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) and Western blots analyses were subsequently performed to evaluate the validity of the molecules identified by a 0.12K cDNA array, including matrix metalloproteinase (MMP), oncogenes and cell-cycle-related genes. Results: On cDNA microarray analysis, MMP-1, 2, 9, 12 and 15, and transforming growth factor beta1 (TGFbeta1), vascular endothelial growth factor (VEGF) and fos were found to be significantly upregulated in the recurred cases. From the real-time RT-PCR for the validation of those molecules, MMP-1 and 12, and TGFbeta1, VEGF and fos were significantly overexpressed in the recurred cases. Western blot showed significant overexpression of MMP-1 and 12, and TGFbeta1, VEGF and fos in the recurred cases. Conclusions: The overexpressions of MMP-1 and 12, and TGFbeta1, VEGF and fos may be associated with the recurrence of superficial low grade bladder TCCa.ope

Transcriptome-wide analysis of compression-induced microRNA expression alteration in breast cancer for mining therapeutic targets

Tumor growth-generated mechanical compression may increase or decrease expression of microRNAs, leading to tumor progression. However, little is known about whether mechanical compression induces aberrant expression of microRNAs in cancer and stromal cells. To investigate the relationship between compression and microRNA expression, microRNA array analysis was performed with breast cancer cell lines and cancer-associated fibroblasts (CAFs) exposed to different compressive conditions. In our study, mechanical compression induced alteration of microRNA expression level in breast cancer cells and CAFs. The alteration was greater in the breast cancer cells than CAFs. Mechanical compression mainly induced upregulation of microRNAs rather than downregulation. In a parallel mRNA array analysis, more than 25% of downregulated target genes were functionally involved in tumor suppression (apoptosis, cell adhesion, and cell cycle arrest), whereas generally less than 15% were associated with tumor progression (epithelial-mesenchymal transition, migration, invasion, and angiogenesis). Of all cells examined, MDA-MB-231 cells showed the largest number of compression-upregulated microRNAs. miR-4769-5p and miR-4446-3p were upregulated by compression in both MDA-MB-231 cells and CAFs. Our results suggest that mechanical compression induces changes in microRNA expression level, which contribute to tumor progression. In addition, miR-4769-5p and miR-4446-3p may be potential therapeutic targets for incurable cancers, such as triple negative breast cancer, in that this would reduce or prevent downregulation of tumor-suppressing genes in both the tumor and its microenvironment simultaneously.ope

Composite Three-Marker Assay for Early Detection of Kidney Cancer

BACKGROUND: Early detection of renal cell carcinoma using serum/plasma biomarkers remains challenging. To validate clinical performance of potential candidate markers for kidney tumors, three-marker assay composed of nicotinamide N-methyltransferase (NNMT), L-plastin (LCP1), and nonmetastatic cells 1 protein (NM23A) was evaluated. METHODS: Patients with kidney cancer and control group were included in the clinical evaluation. Participants were divided into cohorts representing the training group of control group including healthy and benign tumors (n = 102) and patients with kidney cancer (n = 87) that were used to identify criteria for scoring. Then, we developed a three-marker assay that was validated with a cohort of test group samples (n = 100). A scoring method based on the cut-point of each of the three markers was used to evaluate the diagnostic performance of the marker combination. RESULTS: Plasma levels of NNMT, LCP1, and NM23A were highly elevated in patients with kidney cancer (P < 0.0001). In 289 blind sample tests with control subjects (n = 175) and patients with kidney cancer (n = 114), the diagnostic accuracy of NNMT alone and the three-marker assay was 0.913 and 0.932, respectively. When 90% specificity was defined, the sensitivity of NNMT and the three-marker assay was 71.9% and 95.7%, respectively. The predictive value of the three-marker assay was 87.2% (+PPV) and 97% (-PPV). CONCLUSIONS: The composite assay with NNMT, LCP1, and NM23A was a promising novel serum marker assay for the early detection of malignant kidney tumors covering subtypes of RCC with high diagnostic characteristics. Impact: NNMT/LCP1/NM23A triple markers could be a helpful screening assay to detect early RCC.ope

Angiopoietin-2 promotes ER+ breast cancer cell survival in bone marrow niche

In estrogen receptor-positive (ER+) breast cancer, it is recognized that metastases may develop after a long period of dormancy. Bone marrow (BM) vascular niche is where the dormant tumor cells are most likely to reside. So far, it is not fully understood why the dormant tumor cells become proliferative and eventually generate tumor. We hypothesized that therapeutic or menopause-related estrogen depletion may be the switch behind dormant ER+ tumor cell awakening in BM. We utilized an existing experimental model of BM endothelial niche that can simulate ER+ tumor cell dormancy to test our hypothesis. In results, estrogen depletion paradoxically promoted ER+ tumor cell proliferation in the BM endothelial niche, and their molecular phenotype shifted from dormant to awaken. Following estrogen depletion, the BM niche cells produced angiopoietin-2 (ANGPT2), which destabilized niche endothelium by interfering ANGPT1/Tie2 signaling, and promoted ER+ tumor cell survival under estrogen deficiency via cell surface integrin &1. Knockdown of ANGPT2 completely negated ER+ tumor cell awakening in the niche. Furthermore, ANGPT2 expression in ER+ tumor human samples was associated with increased risk of distant metastasis only in those who underwent adjuvant estrogen depletion therapy, not in those who did not undergo adjuvant therapy. In conclusion, we demonstrate that ANGPT2 signaling activated after estrogen depletion paradoxically triggers ER+ tumor cell awakening from dormancy in their BM niche, partly indirectly via endothelial Tie2 receptor and partly directly via tumor cell surface integrin &1.ope

Ovarian Clear Cell Carcinoma Sub-Typing by ARID1A Expression

PURPOSE: Loss of AT-rich DNA-interacting domain 1A (ARID1A) has been identified as a driving mutation of ovarian clear cell carcinoma (O-CCC), a triple-negative ovarian cancer that is intermediary between serous and endometrioid subtypes, in regards to molecular and clinical behaviors. However, about half of O-CCCs still express BAF250a, the protein encoded by ARID1A. Herein, we aimed to identify signatures of ARID1A-positive O-CCC in comparison with its ARID1A-negative counterpart. MATERIALS AND METHODS: Seventy cases of O-CCC were included in this study. Histologic grades and patterns of primary tumor, molecular marker immunohistochemistry profiles, and clinical outcomes were analyzed. RESULTS: Forty-eight (69%) O-CCCs did not express BAF250a, which were designated as "ARID1A-negative." The other 22 (31%) O-CCCs were designated as "ARID1A-positive." ARID1A-positive tumors were more likely to be histologically of high grades (41% vs. 10%, p=0.003), ERβ-positive (45% vs. 17%, p=0.011), and less likely to be HNF1β-positive (77% vs. 96%, p=0.016) and E-cadherin-positive (59% vs. 83%, p=0.028) than ARID1A-negative tumors. Patient age, parity, tumor stage were not significantly different in between the two groups. Cancer-specific survival was not significantly different either. CONCLUSION: We classified O-CCCs according to ARID1A expression status. ARID1A-positive O-CCCs exhibited distinct immunohistochemical features from ARID1A-negative tumors, suggesting a different underlying molecular event during carcinogenesis.ope