Machine learning for identifying tumor stemness genes and developing prognostic model in gastric cancer.

Gastric cancer presents a formidable challenge, marked by its debilitating nature and often dire prognosis. Emerging evidence underscores the pivotal role of tumor stem cells in exacerbating treatment resistance and fueling disease recurrence in gastric cancer. Thus, the identification of genes contributing to tumor stemness assumes paramount importance. Employing a comprehensive approach encompassing ssGSEA, WGCNA, and various machine learning algorithms, this study endeavors to delineate tumor stemness key genes (TSKGs). Subsequently, these genes were harnessed to construct a prognostic model, termed the Tumor Stemness Risk Genes Prognostic Model (TSRGPM). Through PCA, Cox regression analysis and ROC curve analysis, the efficacy of Tumor Stemness Risk Scores (TSRS) in stratifying patient risk profiles was underscored, affirming its ability as an independent prognostic indicator. Notably, the TSRS exhibited a significant correlation with lymph node metastasis in gastric cancer. Furthermore, leveraging algorithms such as CIBERSORT to dissect immune infiltration patterns revealed a notable association between TSRS and monocytes and other cell. Subsequent scrutiny of tumor stemness risk genes (TSRGs) culminated in the identification of CDC25A for detailed investigation. Bioinformatics analyses unveil CDC25A's implication in driving the malignant phenotype of tumors, with a discernible impact on cell proliferation and DNA replication in gastric cancer. Noteworthy validation through in vitro experiments corroborated the bioinformatics findings, elucidating the pivotal role of CDC25A expression in modulating tumor stemness in gastric cancer. In summation, the established and validated TSRGPM holds promise in prognostication and delineation of potential therapeutic targets, thus heralding a pivotal stride towards personalized management of this malignancy.

Spatiotemporal trends of cardiovascular disease burden attributable to low physical activity during 1990-2019: an analysis of the Global Burden of Disease Study 2019.

OBJECTIVES: The epidemiological trends of cardiovascular disease (CVD) burden attributed to low physical activity (LPA) across various regions and countries are poorly understood. Hence, we assessed the global, regional, and national spatiotemporal trends of LPA-related CVD from 1990 to 2019. STUDY DESIGN: We conducted a secondary analysis of the Global Burden of Disease Study 2019. The data on LPA-related CVD were examined with regard to sex, age, year, and Socio-Demographic Index (SDI). METHODS: We assessed the temporal changes in age-standardized mortality rate (ASMR) and age-standardized death rate (ASDR) using the estimated annual percentage change (EAPC) over a 30-year period. RESULTS: There were a staggering 0.64 million deaths and 9.99 million disability-adjusted life-years globally attributed to LPA-related CVD in 2019. The majority of the LPA-related CVD burden was observed in the population aged ≥80 years. It also indicated a high disease burden of LPA-related CVD in Central Asia, Arabian Peninsula, and North Africa. Although there has been a decline in ASMR and ASDR associated with LPA-related CVD on a global scale, the countries experiencing the most substantial increase in LPA-related CVD burden are Uzbekistan, Tajikistan, and Azerbaijan. The ASMR and ASDR remained stable in regions with low, low-middle, and middle SDI levels. The EAPCs of ASMR and ASDR were negatively linked with SDI in 2019. CONCLUSIONS: From 1990 to 2019, LPA led to a significant and escalating burden of CVD in certain regions, namely, Uzbekistan, Tajikistan, and Azerbaijan. It is imperative for governments and policymakers to implement regulatory measures and strategic interventions aimed at mitigating this burden.

The global, regional, and national disease burden of breast cancer attributable to tobacco from 1990 to 2019: a global burden of disease study.

OBJECTIVE: Tobacco has been identified as a significant contributory element to the development of breast cancer. Our objective was to evaluate the spatiotemporal trends of tobacco-related breast cancer at the global, regional, and national scales during 1990-2019. METHODS: We extracted data on mortality, disability adjusted of life years (DALYs), age-standardized mortality rate (ASMR), and age-standardized DALYs rate (ASDR) from the Global Burden of Disease (GBD) study 2019. Estimated annual percentage change (EAPC) was computed to assess the temporal change in ASDR and ASMR. RESULTS: In 2019, the deaths and DALYs attributed to tobacco-related breast cancer were estimated to be 35,439 (95% UI: 22,179-48,119) and 1,060,590 (95% UI: 622,550-1,462,580), respectively. These figures accounted for 5.1% and 5.2% of the total burden of breast cancer. ASMR and ASDR increased in low SDI regions, remained stable in low-middle and middle SDI regions and declined in high and high-middle SDI regions. The burden of breast cancer attributable to tobacco varied notably among regions and nations. Oceania, Southern Latin America, and Central Europe were the GBD regions with the highest number of ASMR and DALYs. There was a positive relationship between age-standardized rate and SDI value in 2019 across 204 nations or territories. A negative association was observed between the EAPC in ASMR or ASDR and the human development index (HDI) in 2019 (R = -0.55, p < 0.01 for ASMR; R = -0.56, p < 0.01 for ASDR). CONCLUSION: Tobacco is one important and modifiable risk factor for breast cancer. The heterogeneity in both the spatial and temporal distribution can be attributed to factors such as aging, population growth, and SDI. These findings substantiate the necessity of expediting the enforcement of tobacco-free legislation in order to safeguard populations from the detrimental effects of tobacco.

Effectiveness of adjuvant chemotherapy for elderly patients with triple-negative breast cancer.

There is little evidence determining whether elderly patients (from 70 to 90 years old) with triple-negative breast cancer could benefit from adjuvant chemotherapy (AC).  This study explores the effect of AC in these population following surgery. A total of 4610 patients were identified in the Surveillance, Epidemiology, and End Results database (2010-2018). Multiple imputation by chained equations was performed to impute missing data. Inverse probability of treatment weighting (IPTW) was applied to reduce the selection bias. IPTW-adjusted Kaplan-Meiers survival analysis and Cox proportional hazards models were performed to compare breast cancer specific survival (BCSS) and overall survival (OS) in the two treatment groups. The patients were classified into the chemotherapy (n=1989) and the observation (n=2621) groups. The percentage of patients receiving AC versus observation increased significantly from 2010 to 2018 (estimated annual percentage change, 1.49%; 95%CI, 0.75-2.16%, p=0.002). The 5-year IPTW-adjusted rates of BCSS and OS in AC group were better than that in observation group (BCSS: 82.32% vs. 78.42%, p=0.010; OS: 75.54% vs. 64.65%, p<0.001). The patients could benefit from AC based on the results of IPTW-adjusted Cox proportional hazards regression analysis (BCSS: HR, 0.77, 95%CI, 0.62-0.94, p=0.012; OS: HR, 0.66, 95%CI, 0.57-0.78, p<0.001). AC was associated with a significant outcome benefit across the year at diagnosis, marital status, stage, lymph node, surgery, and radiation subgroups (all p<0.050). Patients with T1ab could not benefit from AC (p>0.050). In conclusion, we presented a BCSS and OS benefit from AC in elderly patients with triple-negative breast cancer (TNBC). AC remained a reasonable treatment approach in these specific patients. For the patients with T1ab, de-escalated treatment would be administrated with caution.

Global, regional, and national burden of hypertensive heart disease during 1990-2019: an analysis of the global burden of disease study 2019.

BACKGROUND: Hypertensive heart disease (HHD) is a major public health issue worldwide. We analyzed the global, regional, and national burden of HHD between the years 1990 and 2019 in relation to age, gender, and socioeconomic factors. METHODS: The prevalence and death rates, the disability adjusted life-years (DALY), and the corresponding age-standardized rates of HHD were extracted from the Global Burden of Disease study 2019. The epidemiological trends were evaluated by calculating the estimated annual percentage changes (EAPC) of the above variates. RESULTS: A total of 19.60 million HHD cases were documented in 2019 compared to 7.82 million in 1990, corresponding to an EAPC of 0.17. Contrarily, the global age-standardized death rate (ASDR) and age-standardized DALYs decreased with respective EAPCs of - 0.74 and - 1.02. HHD mostly occurred in people aged over 65. The disease burden of HHD varied considerably between countries, and univariate linear regression indicated that many socioeconomic variables had significantly negative correlations with age-standardized DALY rate. CONCLUSION: HHD cases have increased over the last three decades; however the mortality rate has declined. Multi-faceted improvements in health, education and income could help to alleviate the disease burden of HHD, specially in some regions with lower socio-demographic index and higher ASDR.

The Role of Adjuvant Chemotherapy in Metaplastic Breast Carcinoma: A Competing Risk Analysis of the SEER Database.

Purpose: Chemotherapy is the clinically recommended treatment for patients with operable metaplastic breast carcinoma (MBC); however, its impact remains controversial. This study investigated the possible role of chemotherapy in the treatment of MBC. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify the operable MBC patients. The competing risk analysis along with the propensity score matching (PSM) method was performed to evaluate the effect of chemotherapy. Moreover, a competing risk nomogram was built to identify prognosis in patients with MBC. Results: Of the 1137 patients with MBC, 775 received chemotherapy and 362 did not receive chemotherapy. The 5-year cumulative incidence of breast cancer-specific death (BCSD) showed similar outcomes in both the Chemo and No-Chemo groups (21.1 vs. 24.3%, p = 0.57). Chemotherapy showed no apparent association with BCSD (HR, 1.07; 95% CI, 0.72-1.60; p = 0.72), even after subgroup analysis or PSM. Race, tumor size, lymph node status, and radiation were identified as the significant factors for MBC after a penalized variable selection process. In addition, a competing risk nomogram showed relatively good accuracy of prediction with a C-index of 0.766 (95% CI, 0.700-0.824). Conclusion: Our findings demonstrated that chemotherapy did not improve BCSD for operable MBC patients. Thus, it may indicate the need to reduce exposure to the current chemotherapy strategies for patients with resectable MBC. Additionally, some novel treatment strategies are required urgently to identify and target the potential biomarkers.

A five-gene signature for predicting overall survival of esophagus adenocarcinoma.

ABSTRACT: Esophageal adenocarcinoma (EAC) is common and aggressive with increasing trend of incidence. Urgent need for an effective signature to assess EAC prognosis and facilitate tailored treatment is required.Differentially expressed mRNAs (DEMs) were identified by analyzing EAC tissues and adjacent normal samples from The Cancer Genome Atlas (TCGA). Then univariate regression analyses were performed to confirm prognostic DEMs. We used least absolute shrinkage and selection operator (LASSO) to build a prognostic mRNA signature whose performance was assessed by Kaplan-Meier curve, receiver operating characteristic (ROC). GSE72874 were used as an external test set. The performances of the signature were also validated in internal TCGA and external test sets. Gene set enrichment analysis (GSEA) and tumor immunity analysis were performed to decipher the biological mechanisms of the signature.A 5-mRNA signature consisted of SLC26A9, SINHCAF, MICB, KRT19, and MT1X was developed to predict prognosis of EAC. The 5-mRNA signature was promising as a biomarker for predicting 3-year survival rate of EAC in the internal test set, the entire TCGA set, and the external test set with areas under the curve (AUC) = 0.849, 0.924, and 0.747, respectively. Patients were divided into low- and high-risk groups based on risk scores of the signature. The high-risk group was mainly associated with cancer-related pathways and low levels of B cell infiltration.The 5-mRNA prognostic signature we identified can reliably predict prognosis and facilitate individualized treatment decisions for EAC patients.

The role of chemotherapy in patients with T1bN0M0 triple-negative breast cancer: a real-world competing risk analysis.

The objective of the present study was to implement Kaplan-Meier analysis, competing risk analysis, and propensity score matching to evaluate whether the patients with T1bN0M0 triple-negative breast (TNBC) could benefit from adjuvant chemotherapy. A total of 1849 patients were identified in the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015. All eligible patients were divided into two cohorts, the chemotherapy (1155 patients) and the no-chemotherapy (694 patients) cohorts. Similar 5-year breast cancer-specific survival (BCSS) was observed in the chemotherapy and no-chemotherapy cohorts (96.1% vs. 96.0%, p=0.820). The results of the competing risk analysis showed a comparable 5-year breast cancer-specific death (BCSD) in both groups (chemotherapy 3.6% vs. no-chemotherapy 3.4%, p=0.778). Also, a higher 5-year other causes death (OCD) was observed in the no-chemotherapy cohort (0.7% vs. 5.4%, p<0.001). Multivariable competing risks regression models showed no association between chemotherapy and BCSS (HR, 1.21; 95%CI, 0.64-2.31; p=0.560). After 1:1 PSM, no significant difference was also observed for BCSD and OCD between two cohorts. The value of adjuvant chemotherapy in patients with T1bN0M0 TNBC is less than the present guidelines recommend, suggesting that de-escalated treatment could be a potentially beneficial strategy in appropriately selected patients.

Role of marital status on the prognosis in esophagus adenocarcinoma: a real-world competing risk analysis.

Aim: The purpose of this study was to assess the role of marital status in esophageal adenocarcinoma (EAC). Methods: We identified 8341 EAC patients based on the Surveillance, Epidemiology and End Results database during 2007-2015, of whom 7275 were male and 1066 were female. Temporal trends, competing risk analysis and propensity score matching were performed. Results: There was an upward trend for the rate of unmarried patients in both male and female populations (p < 0.05). Unmarried status represented an independent risk factor for higher cancer-specific death (CSD) in males (hazard ratio: 1.11; 95% CI: 1.04-1.18; p = 0.001) but not in females (hazard ratio: 0.96; 95% CI: 0.81-1.13; p = 0.610). Married EAC patients experienced lower CSD compared with their unmarried counterparts in the male cohort.

Effects of Marital Status on Prognosis in Women with Infiltrating Ductal Carcinoma of the Breast: A Real-World 1: 1 Propensity-Matched Study.

BACKGROUND The effects of marital status on infiltrating ductal carcinoma of breast cancer (IDC) have not been studied in detail. This study investigated the impact of marital status on IDC patients. MATERIAL AND METHODS SEER databases were searched from 2010 to 2015 for subjects who were married, divorced, single, and widowed. The influence of marital status on breast cancer-specific survival (BCSS) and overall survival (OS) of IDC patients was investigated through multivariate Cox regression analysis and Kaplan-Meier analysis. To prevent bias, propensity score matching (PSM) analysis was performed. RESULTS The 5-year OS was 89.6%in married patients, 84.9% in divorced patients, 83.5% in single patients, and 71.3% in widowed patients (p<0.001). The 5-year BCSS were 92.9%, 90.2%, 87.6%, and 86.4%, respectively (p<0.001). Multivariate Cox regression analysis revealed that marriage was a protective factor for patients with IDC in terms of OS (divorced: HR, 1.27; 95% CI, 1.21-1.32; p<0.001; single: HR, 1.36; 95% CI, 1.31-1.42; p<0.001; widowed: HR, 1.42; 95% CI, 1.36-1.48; p<0.001) and BCSS (divorced: HR, 1.15; 95% CI, 1.09-1.21; p<0.001; single: HR, 1.27; 95% CI, 1.21-1.33; p<0.001; widowed: HR, 1.32; 95% CI, 1.25-1.40; p<0.001). Following subgroup and PSM analysis, married patients were shown to have better OS and BCSS as opposed to divorced, single, or widowed patients. CONCLUSIONS We identify marital status as a predictor of survival in those with IDC. Widowed patients showed the highest mortality risk.

Bioinformatics analysis of esophageal cancer unveils an integrated mRNA-lncRNA signature for predicting prognosis.

Esophageal cancer (ESCA) carries a poor prognosis among gastrointestinal malignancies. The present study developed a signature based on mRNAs and long non-coding RNAs (lncRNAs) to predict prognosis in ESCA by using The Cancer Genome Atlas database. By using least absolute shrinkage and selection operator penalized regression, a set of RNAs (three mRNAs and two lncRNAs) was identified and used to build a risk score system of ESCA prognosis, which was used to stratify patients having considerable diverse survival in the training set [hazard ratio (HR), 3.932; 95% CI, 1.555-9.944; P<0.002] into high- and low-risk groups. The authentication of the results was achieved through the test set (HR, 3.150; 95% CI, 1.113-8.918; P<0.02) and the entire set (HR, 3.181; 95% CI, 1.686-6.006; P<0.0002). The results from multivariate Cox proportional hazard regression analysis in the entire set suggested that the prognostic significance of this signature may be independent of patients' clinicopathological characteristics. Furthermore, this signature was associated with several molecular signaling pathways of cancer according to Gene Set Enrichment Analysis. In addition, a nomogram was built and the risk score and TNM stage were integrated to estimate the 1- and 3-year overall survival rates. The results from the present study demonstrated that the integrated mRNA-lncRNA signature may be considered as a novel biomarker for the prognosis of ESCA.

Detection and analysis of multiple biomarkers in ovarian cancer: clinical significance in diagnosis, treatment, and prognosis evaluation.

BACKGROUND: The purpose of this study was to explore the clinical significance of CA125, CK7, CK20, ER, PR, C-erbb2, and P-gp in ovarian cancer. METHODS: Ovarian cancer patients were recruited from Nantong Cancer Hospital between March 2006 and July 2011. The expressions of CA125, CK7, CK20, ER, PR, C-erbb2, and P-gp were determined by immunohistochemistry (IHC).The chi-square test (χ2) was used to analyze the correlation between each index and the clinical characteristics of the patients. The patients were followed up to record the cancer recurrence time. The Kaplan-Meier method was used to map the cumulative recurrence-free survival (RFS) rate, and COX regression analysis was established for multivariate analysis. RESULTS: The results of IHC showed that the positive expression rates of CA125, CK7, ER, C-erbb2, and P-gp in malignant ovarian cancer tissues were significantly higher than those in benign ovarian cancer tissues. CA125 expression in malignant ovarian cancer was significantly correlated with the age of patients and the Federation of International Gynecology and Obstetrics (FIGO) stage. CK7 expression in malignant ovarian cancer was significantly correlated with the age, tissue differentiation, and number of residual lesions. CK20 expression in malignant ovarian cancer was significantly correlated with the age and tissue differentiation of the patients. ER expression in malignant ovarian cancer was significantly correlated with the age of patients and FIGO stage. PR expression in malignant ovarian cancer was significantly correlated with the age of the patients. C-erbb2 expression in malignant ovarian cancer was significantly correlated with the age of the patients. P-gp expression in malignant ovarian cancer was significantly correlated with the patient age, pathological type, and tissue differentiation. The expression of CA125, CK7, CK20, C-erbb2, and P-gp had significant effects on the prognosis of patients with ovarian cancer. The COX regression analysis showed that P-gp was an independent risk factor for ovarian cancer. CONCLUSIONS: In malignant ovarian cancer tissues, CA125, CK7, CK20, ER, PR, C-erbb2, and P-gp are over-expressed. The expression of P-gp is an independent risk factor for ovarian cancer, and it can be an important target for the treatment of malignant ovarian cancer.

A six-microRNA signature can better predict overall survival of patients with esophagus adenocarcinoma.

BACKGROUND: The microRNAs (miRNAs) have been validated as prognostic markers in many cancers. Here, we aimed at developing a miRNA-based signature for predicting the prognosis of esophagus adenocarcinoma (EAC). METHODS: The RNA-sequencing data set of EAC was downloaded from The Cancer Genome Atlas (TCGA). Eighty-four patients with EAC were classified into a training set and a test set randomly. Using univariate Cox regression analysis and the least absolute shrinkage and selection operator (LASSO), we identified prognostic factors and constructed a prognostic miRNA signature. The accuracy of the signature was evaluated by the receiver operating characteristic (ROC) curve. RESULT: In general, in the training set, six miRNAs (hsa-mir-425, hsa-let-7b, hsa-mir-23a, hsa-mir-3074, hsa-mir-424 and hsa-mir-505) displayed good prognostic power as markers of overall survival for EAC patients. Relative to patients in the low-risk group, those assigned to the high-risk group according to their risk scores of the designed miRNA model displayed reduced overall survival. This 6-miRNA model was validated in test and entire set. The area under curve (AUC) for ROC at 3 years was 0.959, 0.840, and 0.868 in training, test, and entire set, respectively. Molecular functional analysis and pathway enrichment analysis indicated that the target messenger RNAs associated with 6-miRNA signature were closely related to several pathways involved in carcinogenesis, especially cell cycle. CONCLUSION: In summary, a novel 6-miRNA expression-based prognostic signature derived from the EAC data of TCGA was constructed and validated for predicting the prognosis of EAC.