Development of machine learning prognostic models for overall survival of prostate cancer patients with lymph node-positive.

Prostate cancer (PCa) patients with lymph node involvement (LNI) constitute a single-risk group with varied prognoses. Existing studies on this group have focused solely on those who underwent prostatectomy (RP), using statistical models to predict prognosis. This study aimed to develop an easily accessible individual survival prediction tool based on multiple machine learning (ML) algorithms to predict survival probability for PCa patients with LNI. A total of 3280 PCa patients with LNI were identified from the Surveillance, Epidemiology, and End Results (SEER) database, covering the years 2000-2019. The primary endpoint was overall survival (OS). Gradient Boosting Survival Analysis (GBSA), Random Survival Forest (RSF), and Extra Survival Trees (EST) were used to develop prognosis models, which were compared to Cox regression. Discrimination was evaluated using the time-dependent areas under the receiver operating characteristic curve (time-dependent AUC) and the concordance index (c-index). Calibration was assessed using the time-dependent Brier score (time-dependent BS) and the integrated Brier score (IBS). Moreover, the beeswarm summary plot in SHAP (SHapley Additive exPlanations) was used to display the contribution of variables to the results. The 3280 patients were randomly split into a training cohort (n = 2624) and a validation cohort (n = 656). Nine variables including age at diagnosis, race, marital status, clinical T stage, prostate-specific antigen (PSA) level at diagnosis, Gleason Score (GS), number of positive lymph nodes, radical prostatectomy (RP), and radiotherapy (RT) were used to develop models. The mean time-dependent AUC for GBSA, RSF, and EST was 0.782 (95% confidence interval [CI] 0.779-0.783), 0.779 (95% CI 0.776-0.780), and 0.781 (95% CI 0.778-0.782), respectively, which were higher than the Cox regression model of 0.770 (95% CI 0.769-0.773). Additionally, all models demonstrated almost similar calibration, with low IBS. A web-based prediction tool was developed using the best-performing GBSA, which is accessible at https://pengzihexjtu-pca-n1.streamlit.app/ . ML algorithms showed better performance compared with Cox regression and we developed a web-based tool, which may help to guide patient treatment and follow-up.

ZNF746 promotes M2 macrophage polarisation and favours tumour progression in breast cancer via the Jagged1/Notch pathway.

Breast cancer (BC) is a major threat to women's health. BC is a heterogeneous disease and treatment strategies and outcomes differ between subtypes. Investigating the molecular mechanisms of BC will help to identify potential therapeutic targets and develop new therapies. Here we report that zinc finger protein 746 (ZNF746), a Krüppel-associated box and zinc finger protein, exhibits tumour-promoting properties in BC. Functional experiments (cell growth, colony formation, cell cycle analysis, and transwell analysis) were used to evaluate the proliferation, migration, and invasion capacity of BC cells. Immunohistochemistry was performed to detect the expression of ZNF746, CD163 (M2 macrophage marker), and HES1 (Notch target) in BC tissues. ZNF746 was highly expressed in BC tissues compared to adjacent paired non-tumour tissues. Patients with M1 BC had higher expression of ZNF746 compared to patients with non-metastatic (M0) BC, and higher expression of ZNF746 was associated with poorer overall survival. The immunohistochemical results showed a positive correlation between the expression of ZNF746 and the expression of CD163 or HES1. ZNF746 promoted BC cell proliferation, migration, and invasion and increased the expression of molecules essential for monocyte recruitment and differentiation (CCL2 and CSF1). Furthermore, THP-1 monocytes cultured in the conditioned medium derived from BC cells overexpressing ZNF746 exhibited enhanced M2 polarisation. In contrast, ZNF746 knockdown reduced BC cell proliferation, migration, and invasion and suppressed M2 polarisation. Mechanistically, ZNF746 promoted the activation of the Jagged1/Notch pathway, and the Jagged1 siRNA-mediated blockade of this pathway prevented the tumour-promoting functions of ZNF746. In conclusion, this study uncovers the role of ZNF746 in promoting M2 macrophage polarisation and suggests that ZNF746 may be a promising therapeutic target for limiting BC progression.

[Effects of Pseudomonas aeruginosa on root activity and leaf physiological characteristics in rice (Oryza sativa L.) seedling under cadmium stress]. / é“œç»¿å‡å•èƒžèŒå¯¹é•‰èƒè¿«è‹—æœŸæ°´ç¨»æ ¹ç³»æ´»åŠ›åŠå¶ç‰‡ç”Ÿç†ç‰¹æ€§çš„å½±å“.

To reveal the physiological effects of rice alleviated by cadmium-tolerant Pseudomonas aeruginosa under cadmium stress condition, the influences of bacterial strian on the root vigor and leaf physiological characteristics were analyzed under a set of hydroponic experiments involving adding bacteria suspension, empty carrier, microbial inoculum with 20 µmol·L-1 Cd. Cadmium-free treatment as control. The results showed that the root vigor was significantly inhibited, leaf photosynthetic rate decreased, and the contents of soluble protein, flavonoid and total phenols in rice leaves were reduced, while the contents of malondialdehyde (MDA) and superoxide anion(O2-·) increased significantly under cadmium stress condition. Compared with cadmium treatment, root vigors of rice were increased by 36.1%-42.5% and 49.4%-53.0% respectively in bacteria suspension and microbial inoculum additions, net photosynthetic rates in leaves were increased by 118.5%-147.1% and 137.6%-156.9%, and the contents of soluble protein were increased by 37.0%-49.3% and 37.7%-72.6%, respectively. For the bacteria suspension treatment, the activities of SOD, POD and CAT in leaves were increased by 25.8%-36.6%, 40.9%-55.9%, 24.0%-29.2%, and the activities of SOD, POD and CAT in leaves under microbial inoculum treatment were increased by 36.9%-42.6%, 82.7%-92.6% and 43.3%-52.2%, respectively, with the stimulative effects on antioxidation enzymes in rice leaves being higher than those of bacteria suspension. Compared with cadmium treatment, the contents of MDA and O2-· in rice leaves were reduced by 44.8%-54.7%, 29.4%-41.9% and 9.9%-10.2%, 3.0%-7.1% in microbial inoculum and bacteria suspension treatments, respectively. In contrast, the contents of flavonoids and total phenols were increased by 125.4%-135.7%, 100.8%-119.4% and 139.4%-146.7%, 115.0%-134.7%, respectively. In summary, P. aeruginosa and the microbial inoculum could promote rice seedling growth by improving root vigor and photosynthetic rate, as well as the contents of flavonoids and total phenols, which led to the fact that P. aeruginosa could significantly alleviate the stress of cadmium on rice.

MicroRNA-490 inhibits tumorigenesis and progression in breast cancer.

MicroRNAs are consistently reported to regulate gene expression in all cancer cell types by modulating a wide range of biological processes, including cell proliferation, differentiation, and apoptosis, which are associated with tumor development and progression. Previous studies have revealed that miR-490-3p regulates cell proliferation and apoptosis in cancers, such as hepatocellular carcinoma, lung cancer, bladder cancer, and ovarian carcinoma. In this study, we explored the hitherto unrevealed role of miR-490-3p in breast cancer. We tested miR-490-3p expression in breast cancer tissue and paracarcinoma tissue using reverse transcription-polymerase chain reaction. We also transfected the human breast cancer cell lines MCF-7 and T47D with miR-490-3p; subsequently, we determined the cell phenotype and the expression of Ras homolog gene family member A (RhoA), Bcl-xL, matrix metalloproteinase-9, and P70S6K (P70S6 kinase). Dual-luciferase reporter assay and a xenograft mouse model were used to reveal the roles of miR-490-3p and its target gene RHOA. We found that the levels of miR-490-3p were lower in the breast cancer tissue than in the paracarcinoma tissues. The overexpression of miR-490-3p suppressed breast cancer cell proliferation and promoted early stage apoptosis. Western blotting results revealed that the miR-490-3p overexpression reduced RhoA, Bcl-XL, matrix metalloproteinase-9, and P70S6K protein expression. The dual-luciferase reporter assay confirmed that RhoA is a target of miR-490-3p. The xenograft mouse model confirmed that miR-490-3p overexpression suppressed tumor growth and reduced RhoA expression. Our results indicate that miR-490-3p acts as oncosuppressive microRNA to inhibit breast cancer tumorigenesis and progression by targeting RhoA directly. It may contribute to breast cancer diagnosis and treatment.

Potent anticancer effects of lentivirus encoding a Drosophila melanogaster deoxyribonucleoside kinase mutant combined with brivudine.

OBJECTIVE: Deoxyribonucleoside kinase of Drosophila melanogaster (Dm-dNK) mutants have been reported to exert suicide gene effects in combined gene/chemotherapy of cancer. Here, we aimed to further evaluate the capacity of the mutanted enzyme and its potential for inhibiting cancer cell growth. METHODS: We altered the sequence of the last 10 amino acids of Dm-dNK to perform site-directed mutagenesis and constructed active site mutanted Dm-dNK (Dm-dNKmut), RT-PCR and western bloting studies were used to reveal the expression of lentivirus mediated Dm-dNKmut in a breast cancer cell line (Bcap37), a gastric cancer cell line (SGC7901) and a colorectal cancer cell line (CCL187). [3H]-labeled substrates were used for enzyme activity assays, cell cytotoxicity was assessed by MTT assays, cell proliferation using a hemocytometer and apoptosis induction by thenannexin-V-FITC labeled FACS method. In vivo, an animal study was set out in which BALB/C nude mice bearing tumors were treated with lentivirus mediated expression of Dm-dNKmut with the pyrimidine nucleoside analog brivudine (BVDU, (E)-5-(2-bromovinyl)-(2-deoxyuridine). RESULTS: The Dm-dNKmut could be stably expressed in the cancer cell lines and retained its enzymatic activity. Moreover, the cells expressing Dm-dNKmut exhibited increased sensitivity in combination with BVDU, with induction of apoptosis in vitro and in vivo. CONCLUSION: These findings underlined the importance of BVDU phosphorylated by Dm-dNKmut in transduced cancer cells and the potential role of Dm-dNKmut as a suicide gene, thus providing the basis for future intensive research for cancer therapy.

Study on the skip metastasis of axillary lymph nodes in breast cancer and their relation with Gli1 expression.

The skip metastasis (SM) of axillary lymph nodes (ALN) in breast cancer is an important phenomenon which is crucial to determine the correct choice of surgical resection. The mechanism of SM of ALN is unclear. Gli1 protein is a core epithelial-to-mesenchymal transition (EMT) regulatory factor that plays essential roles in both development and disease processes and has been associated with metastasis in carcinomas. The aim of this study was to investigate the clinicopathological characteristics of SM and evaluate the significance of Gli1 expression in breast cancer patients with metastasis of ALN. Clinicopathological data from 1,037 female breast cancer patients who underwent radical mastectomy were retrospectively reviewed. In this study, an SM was defined as level I absence but level II and/or level III involvement. The expression of Gli1 was evaluated by immunohistochemistry in 102 non-SM cases with positive nodes and 33 SM cases. In univariate analysis, we found that pN category, TNM stage, intrinsic subtypes and Gli1 expression was significant risk factor of SM. Further logistic regression analysis revealed that luminal A cases had a lower risk of SM relative to luminal B 1 (HER2 negative) cases. Further multivariate analysis revealed that Gli1 expression and numbers of positive lymph nodes were the independent factors which associated with SM. Collectively, Breast cancer with SM of ALN associated with the intrinsic subtype of the luminal B1. Gli1 expression related with the procession of breast cancer with SM, which can be used as a predictor of SM of ALN in breast cancer.

Expression of CD133, PAX2, ESA, and GPR30 in invasive ductal breast carcinomas.

BACKGROUND: Biomarkers in breast neoplasms provide invaluable information regarding prognosis and help determining the optimal treatment. We have examined the possible correlation between cancer stem cell (CSC)-like markers (CD133, paired box gene 2 protein (PAX2), epithelial specific antigen (ESA)), and a new membrane estrogen receptor (G-protein coupled receptor 30 (GPR30)) in invasive ductal breast carcinomas with known clinicopathological parameters, tumor recurrence, and expression of some known biomarkers. METHODS: In 74 invasive ductal breast carcinomas, we investigated the protein expression of these molecular markers by immunohistochemistry, and their associations with known clinicopathological parameters, tumor recurrence, and expression of some known biomarkers. We studied the interrelationship between the expressions of these proteins. RESULTS: CD133, a putative CSC marker, was positively related to tumor size, tumor stage, and lymph node metastasis. PAX2 was negatively correlated with tumor recurrence. ESA, one of the breast CSC markers, was an indicator of tumor recurrence. GPR30 was associated with hormone receptors. Despite the correlation between GPR30 and the nuclear estrogen receptor, the expression was dependent. Positive staining of GPR30 in tumors displayed a significant association with high C-erbB2 expression and a tendency for tumor recurrence. A positive relationship between GPR30 and CD133 existed. CONCLUSION: Detecting the expression of CD133, PAX2, ESA, and GPR30 in invasive ductal breast carcinomas may be of help in more accurately predicting the aggressive properties of breast cancer and determining the optimal treatment.

[Study on lymph node metastasis in 292 patients with early gastric cancer].

OBJECTIVE: To evaluate the status of lymph node metastasis (LNM) and reasonable procedure in early gastric cancer (EGC). METHODS: Two hundred and ninety-two patients with histologically proven mucosal or submucosal gastric cancer who underwent gastrectomy/lymphadenectomy were included in this study. The numbers of total dissected lymph node were all above 15 in all patients. The clinical characteristics, pathologic features, and LNM were assessed by univariate and multivariate analysis. RESULTS: LNM were observed in 43 of 292 cases (14.7%), and 6.4% in mucosal lesions and 22.4% in submucosal lesions. The LNM was identified in 12.7% at the first level, 7.2% at the second level and 0.34% at the third level. The LNM frequency was found in the 6, 3, 4, 1, 5 lymph node (from high to low) consequently at the first level and the 7, 8a lymph node at the second level. The EGC with nodal involvement and the tumors < 2.0 cm in diameter were all depressed type. The diameter of elevated type with LNM was no less than 3.0 cm in this series. The depth of invasion and lymphatic vessel involvement were independent influencing factors in LNM on multivariate analysis (P<0.05). CONCLUSIONS: Less extensive surgery might be considered for the elevated type EGC, and tumors 3.0 cm in diameter. With respect to the depressed type EGC/tumors > 3.0 cm in diameter, gastrectomy with D2 lymphadenectomy is proper.

[Expression of programmed cell death 4 and its clinicopathological significance in human pancreatic cancer].

OBJECTIVE: To investigate the expression of programmed cell death 4 (PDCD4) protein and its clinicopathological significance in human pancreatic cancer. METHODS: Immunohistochemistry was used to examine the expression of PDCD4 protein in 69 specimens of pancreatic cancer and Western blot in 8 fresh specimens. RESULTS: The expression of PDCD4 protein was significantly lower in all 8 fresh pancreatic cancer tissues than that in non-cancerous tissues detected by Western blot. Compared with non-cancerous pancreatic tissue (> 80% of positive cells), low PDCD4 expression was shown in 69 pancreatic cancer tissues (< 30% of positive cells in 36 cases and 30%-80% of positive expression cells in 33 cases). In the 33 cases with 30% and 80% of positive expression cells, the expression rates of PDCD4 protein were 57.6%, 24.2%, and 18.2% in well, moderately, and poorly differentiated cancers, respectively. In the 36 cases less than 30% of positive expression cells, however, the expression rate of PDCD4 protein in well, moderately, and poorly differentiated cases were 19.4%, 41.7%, and 38.9%, respectively. 67.4% (15/23) of the moderately differentiated cases and 70% (14/20) of the poorly differentiated cases showed < 30% of positive expression cells. Only 26.9% (7/26) of the well differentiated cases, however, showed < 30% of positive expression cells, indicating that low PDCD4 expression was associated with histological grade (P < 0.01). There was no relationship between PDCD4 expression and other clinicopathological parameters including patients' sex, age, and TNM stage. CONCLUSIONS: Expression of PDCD4 protein is low in human pancreatic cancer and is correlated with the differentiation levels of human pancreatic cancer. PDCD4 may play an important role in the occurrence and development of pancreatic carcinomas.

[Comparison of pBcl-2 and pBax expression in primary invasive ductal pancreatic cancer between Chinese and Japanese patients].

OBJECTIVE: To clarify the clinicopathologic significance of the expression of the Bcl-2 protein (pBcl-2) and the Bax protein (pBax), and their clinical implications in Chinese and Japanese patients with human invasive ductal carcinomas (IDCs) of the pancreas. METHODS: The study included 59 Chinese and 65 Japanese patients with IDCs of the pancreas. pBcl-2 and pBax expression were immuno-stained with streptavidin-biotin (SAB) method. RESULTS: pBcl-2 (+) was seen in 35.6% of Chinese and in 23.1% of Japanese patients. pBax (+) was seen in 49.2% of Chinese and 64.7% of Japanese patients. A comparison between them showed that there were significant differences in the male patients, in the patients with the moderately differentiated cancer, and in the elderly patients (chi squared = 4.447, P = 0.035; chi squared = 4.114, P = 0.043; chi squared = 6.657, P = 0.010 respective). In both Chinese and Japanese patients, those with pBcl-2 positive expression had a significantly higher survival rate than those with negative one (chi squared = 9.99, P = 0.0016; chi squared = 7.63, P = 0.0058). The group with pBax positive expression had a significantly higher survival rate in Japanese patients (chi squared = 9.37, P = 0.0022). Japanese patients whose tumors exhibited pBcl-2 and pBax positive immunostaining survived significantly longer than Chinese patients did (chi squared = 4.48, P = 0.0342; chi squared = 5.23, P = 0.023). CONCLUSIONS: The expressions of both pBcl-2 and pBax are high found in Chinese and Japanese patients. The pBcl-2 positive expression implies a better prognosis in both Chinese and Japanese patients with IDCs of the pancreas. The effect of pBax expression on prognosis is different between Chinese and Japanese patients.