OTUB2 Promotes Cancer Metastasis via Hippo-Independent Activation of YAP and TAZ.

The transcriptional regulators YAP and TAZ play important roles in development, physiology, and tumorigenesis and are negatively controlled by the Hippo pathway. It is yet unknown why the YAP/ TAZ proteins are frequently activated in human malignancies in which the Hippo pathway is still active. Here, by a gain-of-function cancer metastasis screen, we discovered OTUB2 as a cancer stemness and metastasis-promoting factor that deubiquitinates and activates YAP/TAZ. We found OTUB2 to be poly-SUMOylated on lysine 233, and this SUMOylation enables it to bind YAP/TAZ. We also identified a yet-unknown SUMO-interacting motif (SIM) in YAP and TAZ required for their association with SUMOylated OTUB2. Importantly, EGF and oncogenic KRAS induce OTUB2 poly-SUMOylation and thereby activate YAP/TAZ. Our results establish OTUB2 as an essential modulator of YAP/TAZ and also reveal a novel mechanism via which YAP/TAZ activity is induced by oncogenic KRAS.

Polymorphisms of FGFR1 in HBV-related hepatocellular carcinoma.

Hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers in China. It is important to understand the genetic mechanisms underlying the development and progression of HBV-related HCC and to identify new biomarkers for clinical treatment. The important role of fibroblast growth factor receptors (FGFRs) has been widely recognized in many types of cancers, but the association between FGFR polymorphisms and HCC carcinogenesis has been rarely reported. In this study, 199 patients with HBV-associated cirrhosis, 203 with HBV-associated HCC, and 184 healthy controls with no liver diseases were enrolled as participants. Using SNaPshot assays, five SNPs (rs13317, rs7825208, rs1047057, rs1047111, and rs1966265) of growth factor receptor genes were genotyped. Our results showed that the G/A and G/G genotypes at rs7825208 of FGFR1 were negatively correlated with HBV-related HCC (odds ratio (OR) = 0.45, 95% confidence interval (CI) = 0.22-0.93, P = 0.027). However, after Bonferroni correction, these significant differences no longer existed (P > 0.05). Our results indicated that these five polymorphisms of fibroblast growth factor receptor genes do not play any independent roles in the tumorigenesis and progression of HBV-related HCC in Han Chinese patients.

Bioinformatic analysis shows the correlation of hsa_circ_0006220-miR-221/222-3p-ESR1/KDR axis with sorafenib resistance of hepatocellular carcinoma.

Sorafenib resistance is a major obstacle influencing its therapeutic efficacy in advanced hepatocellular carcinoma (HCC). The knowledge of circular RNAs (circRNAs), a group of novel endogenous non-coding RNAs, in sorafenib resistance of HCC is still inadequate. In this study, a series of bioinformatic analyses and validation were performed. Firstly, a dataset GSE101850 was included for screening out differentially expressed circRNAs between sorafenib resistant and sensitive HCC, after which the structural patterns and binding microRNAs (miRNAs) of these candidate circRNAs were acquired. By combination of the results from expression, prognosis and diagnosis analysis, miR-221-3p and miR-222-3p were selected as the most potential binding miRNAs of hsa_circ_0006220, which was correlated with sorafenib resistance of HCC. Next, the target genes of miR-221-3p and miR-222-3p were predicted. Subsequently, ESR1 was identified as the top one hub gene among all these target genes. By conducting survival analysis and correlation analysis, ESR1 and KDR were considered as the most potential genes associated with sorafenib resistance of HCC. Collectively, we elucidated a potential hsa_circ_0006220-miR-221/222-3p-ESR1/KDR regulatory axis linked to sorafenib resistance of HCC.

Lack of association between genetic polymorphisms in cytokine genes and tumor recurrence in patients with hepatocellular carcinoma undergoing transplantation.

BACKGROUND: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains one of the most common causes of poor long-term survival. However, the host genetic factors affecting increased risk of tumor recurrence after transplantation have not been thoroughly elucidated. The present study was designed to investigate the association of cytokine gene polymorphisms with the risk of tumor recurrence in LT patients for HCC. METHODS: Eleven single-nucleotide polymorphisms within the promoter regions of 7 cytokine genes, i.e., the IL-1 family (IL-1alpha and IL-1beta), IL-6, IL-8, IL-10, TNF-alpha, and TGF-beta1, were genotyped in 93 HCC patients treated with LT using DNA sequencing. The association between these polymorphisms and the risk of tumor recurrence was evaluated while controlling confounding clinical variables. RESULTS: The genotype frequency of IL-10 -1082 A/G in patients with and without recurrence of HCC was AA 83.3%, GA 16.7% and AA 97.6%, GA 2.4%, respectively. The association between IL-10 -1082 GA and recurrence was significant (P=0.033). No other single-nucleotide polymorphism in the cytokine gene was found to be associated with recurrence. Kaplan-Meier survival curves showed that the homozygous AA patients had a significantly longer mean recurrence-free survival than heterozygous GA patients (23.5 vs 5.7 months, P=0.001). However, multivariate analysis failed to reveal that the GA genotype of IL-10 -1082 A/G was an independent indicator of recurrence. CONCLUSIONS: This study suggests the lack of association of selected cytokine gene polymorphisms with HCC recurrence after LT in the Han Chinese population. The finding does not exclude the idea that other cytokine polymorphisms could act as candidate biomarkers of disease prognosis.

In silico whole-transcriptome analysis reveals a potential hsa_circ_0000375-miR-424-5p-TPM2/SRPX/SRGAP1 regulatory network related to liver metastasis of colorectal cancer.

Liver metastasis is the main lethal cause of colorectal cancer (CRC). The knowledge of role and mechanism of circular RNA (circRNA) in liver metastasis of CRC is still inadequate. In this study, whole-transcriptome analysis was performed using three datasets (GSE147597, GSE147602 and GSE147603). A total of 14 potential circRNAs were identified, after which their structural patterns and binding miRNAs were obtained. Next, 45 differentially expressed miRNAs (DEmiRNAs) between CRC without and with liver metastasis were acquired, consisting 38 upregulated and 7 downregulated miRNAs. After conducting intersection analysis, expression validation and correlation analysis, miR-761 and miR-424-5p were selected as the most potential miRNAs linked to liver metastasis of CRC. Subsequently, the target genes of miR-761 or miR-424-5p were predicted and differentially expressed genes (DEGs) between CRC without and with liver metastasis were obtained. 257 genes that were commonly appeared in predicted genes and DEGs were significantly enriched in "epithelial-to-mesenchymal transition" and "signaling by Robo receptor". Among these enriched genes, only TPM2, SRPX and SRGAP1 were significantly negatively correlated with miR-424-5p and were positively linked to hsa_circ_0000375 in CRC without or with liver metastasis. Collectively, the current findings elucidated a potential hsa_circ_0000375-miR-424-5p-TPM2/SRPX/SRGAP1 network contributing to liver metastasis of CRC.

Pathological complete response rate and clinical outcome after neoadjuvant therapy of HER2-low breast cancer: A National Cancer Database Analysis.

BACKGROUND: The interest in breast cancer with low HER2 expression as a distinct subtype is increasing. We aimed to explore the differences between HER2-low and HER2-zero breast cancer in their prognosis and rate of pathological complete response (pCR) after neoadjuvant therapy. METHODS: The National Cancer Database (NCDB) was used to select patients with breast cancer who received neoadjuvant therapy from 2004 to 2017. Logistic regression model was constructed for analysis of pCR. Cox proportional hazards regression model and Kaplan-Meier method were used for survival analysis. RESULTS: A total of 41500 breast cancer patients were included, among which 14814 (35.7%) had HER2-zero tumors and 26686 (64.3%) had HER2-low. HER2-low tumors were more commonly HR-positive in comparison with HER2-zero (66.3% versus 47.1%, P < 0.001). A lower rate of pCR was observed in HER2-low tumors than in HER2-zero tumors after neoadjuvant therapy in the total cohort (OR = 0.90; 95% CI [0.86-0.95]; P < 0.001) and in the subset of HR-positive (OR = 0.87; 95% CI [0.81-0.94]; P < 0.001). Patients with HER2-low tumors had a significantly superior survival than those with HER2-zero tumors (HR = 0.90; 95% CI [0.86-0.94]; P < 0.001), regardless of the HR status. Additionally, a marginal survival difference was also observed between HER2 IHC1+ and HER2 IHC2+/ISH-negative (HR = 0.91; 95% CI [0.85-0.97]; P = 0.003) cohorts. CONCLUSION: HER2-low tumors are a clinically relevant breast cancer subtype that is distinct from HER2-zero tumors. These findings may provide clues to appropriate therapeutic strategies for this subtype in the future.

Cyclin-dependent kinase inhibitor 3 is overexpressed in hepatocellular carcinoma and promotes tumor cell proliferation.

Cyclin-dependent kinase inhibitor 3 (CDKN3) belongs to the protein phosphatases family and has a dual function in cell cycling. The function of this gene has been studied in several kinds of cancers, but its role in human hepatocellular carcinoma (HCC) remains to be elucidated. In this study, we found that CDKN3 was frequently overexpressed in both HCC cell lines and clinical samples, and this overexpression was correlated with poor tumor differentiation and advanced tumor stage. Functional studies showed that overexpression of CDKN3 could promote cell proliferation by stimulating G1-S transition but has no impact on cell apoptosis and invasion. Microarray-based co-expression analysis identified a total of 61 genes co-expressed with CDKN3, with most of them involved in cell proliferation, and BIRC5 was located at the center of CDKN3 co-expression network. These results suggest that CDKN3 acts as an oncogene in human hepatocellular carcinoma and antagonism of CDKN3 may be of interest for the treatment of HCC.

Perioperative dynamic alterations in peripheral regulatory T and B cells in patients with hepatocellular carcinoma.

BACKGROUND: Intratumoral and circulating regulatory T cells (Tregs) have been shown to be critical in the pathogenesis of hepatocellular carcinoma (HCC). However there is limited knowledge on the alterations of regulatory B cells (Bregs). We here investigated perioperative dynamic alterations of peripheral circulating Tregs and Bregs in HCC patients to reveal the relationship between regulatory lymphocytes and its clinical implications. METHODS: 36 patients with HCC, 6 with chronic hepatitis B infection and 10 healthy donors were enrolled for this study. Frequencies of peripheral Tregs and Bregs were measured by flow cytometry with antibodies against CD4, CD25, CD127, CD19 and IL-10 before, and after radical surgery. Then, clinical informatics of HCC patients was achieved through Digital Evaluation Score System (DESS) for the assessment of disease severity. Finally, we analysed correlations between digitalized clinical features and kinetics of circulating regulatory lymphocytes. RESULTS: Level of circulating CD4+CD25+CD127- Tregs in HCC patients was significantly lower than that in healthy donors and patients with chronic hepatitis B infection before surgery, but was increased after surgery. Preoperative level of CD19+ IL-10+ Bregs in HCC patients was also significantly lower than the other groups. However it dramatically was elevated right after surgery and remained elevated compared to controls (about 7 days after surgery, P = 0.04). Frequency of circulating Tregs was correlated with circulating leukocytes, ferritin, and clinical features suggesting tumor aggressiveness including portal vein thrombosis, hepatic vein involvement and advanced clinical stages. Frequency of circulating Bregs was associated with Hepatitis B e Antigen (HBeAg) and Hepatitis B virus (HBV) DNA copy number. In addition, DESS was significantly and positively correlated with other staging systems. CONCLUSION: Frequencies of peripheral Tregs and Bregs in HCC patients increased after surgery. These results suggest that a postoperative combination of therapies against Tregs and Bregs may be beneficial for better outcome of HCC patients after resection.

Research on correlations of miR-585 expression with progression and prognosis of triple-negative breast cancer.

Triple-negative breast cancer is a special type of breast cancer, characterized by younger onset age, shorter survival period, higher malignant degree, higher mortality, recurrence and metastasis. Triple-negative breast cancer is more harmful to women's life and health, compared with other types of breast cancer. This paper mainly studied the role of miR-585 in triple-negative breast cancer. Real-time quantitative PCR was used to detect the expression of miR-585 in triple-negative breast cancer cell lines and tissues. Kaplan-Meier curve and Cox proportional hazards model analysis were used to investigate the prognostic value of miR-585 in triple-negative breast cancer. CCK-8 and Transwell assays were used to detect cell proliferation, invasion and migration. miR-585 was significantly down-regulated in triple-negative breast cancer cells and tissues. The low expression of miR-585 has been shown to be significantly associated with poor prognosis in triple-negative breast cancer patients. Abnormally low expression of miR-585 can promote cell proliferation, migration and invasion. Overall, abnormally low expression of miR-585 is associated with prognosis and progression of triple-negative breast cancer. miR-585 may serve as a prognostic biomarker for patients with triple-negative breast cancer and it is expected to be a new method and strategy for the treatment of triple-negative breast cancer.

Sox15 Methylation Inhibits Cell Proliferation Through Wnt Signaling in Hepatocellular Carcinoma.

The expression of the SRY-Box Transcription Factor 15 (Sox15) is reduced by DNA methylation, and its progression is suppressed within numerous tumors. However, its effect on hepatocellular carcinoma (HCC) remains unknown. In the present work, the clinical importance and function of Sox15, as well as the underlying molecular mechanism, were explored within HCC. The expression of Sox15 is reduced and positively correlated with prognosis in HCC as analyzed by GEPIA (Gene Expression Profiling Interactive Analysis) and OncoLnc. Meanwhile, the hypermethylated Sox15 promoter CpG-site predicted a dismal HCC prognosis. Besides, ectopic Sox15 expression within the HCC cells (LM3, HUH7, SK-hep-1) remarkably inhibited in vitro cell growth and inhibited xenograft tumorigenesis in the nude mice. Moreover, Sox15 inactivated the Wnt pathway under both in vivo and in vitro conditions. To summarize, Sox15 played a tumor suppressor role within the HCC via the inactivated Wnt pathway. Sox15 and CpG-site methylation of its promoter are the factors that independently predict the prognosis of HCC.

Global Burden of Female Breast Cancer: Age-Period-Cohort Analysis of Incidence Trends From 1990 to 2019 and Forecasts for 2035.

Introduction: This study aimed to describe the latest epidemiology of female breast cancer globally, analyze the change pattern of the incidence rates and the disease's association with age, period, and birth cohort, and subsequently present a forecast of breast cancer incidence. Methods: Data for analysis were obtained from Global Burden of Disease (GBD) Study 2019 and World Population Prospects 2019 revision by the United Nations (UN). We described the age-standardized incidence rates (ASIRs) from 1990 to 2019 and then calculated the relative risks of period and cohort using an age-period-cohort model, and predicted the trends of ASIRs to 2035. Results: In 2019, the global incidence of breast cancer in women increased to 1,977,212 (95% uncertainty interval = 1 807 615 to 2 145 215), with an ASIR of 45.86 (41.91 to 49.76) per 100 000 person-year. Among the six selected countries facing burdensome ASIRs, only the USA showed a downward trend from 1990 to 2019, whereas the others showed an increasing or stable trend. The overall net drift was similar in Japan (1.78%), India (1.66%), and Russia (1.27%), reflecting increasing morbidity from 1990 to 2019. The increase in morbidity was particularly striking in China (2.60%) and not significant in Germany (0.42%). The ASIRs were predicted to continue to increase globally, from 45.26 in 2010 to 47.36 in 2035. In most countries and regions, the age specific incidence rate is the highest in those aged over 70 years and will increase in all age groups until 2035. In high-income regions, the age specific incidence rates are expected to decline in women aged over 50 years. Conclusions: The global burden of female breast cancer is becoming more serious, especially in developing countries. Raising awareness of the risk factors and prevention strategies for female breast cancer is necessary to reduce future burden.

Global, regional, and national childhood cancer burden, 1990-2019: An analysis based on the Global Burden of Disease Study 2019.

INTRODUCTION: Cancer is the leading cause of death among children. OBJECTIVES: We report on the latest estimates of the burden of cancer among children at the global, regional, and national levels from 1990 to 2019. METHODS: Based on the Global Burden of Disease Study 2019, children's cancer data were analyzed by sex, age, year, and location. Age-standardized rates were used to compare the burdens among regions and nations. Joinpoint analysis was applied to assess the temporal trend of the global childhood cancer burden. RESULTS: In 2019, 291,319 (95% uncertainty interval [UI], 254,239 to 331,993) new cases and 98,834 (86,124 to 113,581) deaths from childhood cancer were documented globally. Further, 8,302,464 (7,230,447 to 9,555,118) DALYs and 1,806,630 (1,567,808 to 2,089,668) prevalent cases were recorded in the same year. Age-standardized incidence and prevalence rates of childhood cancer were greatest in higher SDI settings and increased most significantly in Australasia and Southern Latin America over the last 30 years. However, although age-standardized death and DALY rates of childhood cancer have remarkably decreased in all regions since 1990, countries with a lower SDI showed the highest rates in 2019, particularly in countries in Eastern Sub-Saharan Africa. Among all cancers, leukemia has shown the largest decrease in burden since 1990. Despite this, leukemia was still the most common cancer and the leading cause of death among children in 2019, followed by brain and central nervous system cancer. CONCLUSIONS: On a global scale, the childhood cancer burden has significantly fallen over the last 30 years, but is still higher in lower SDI countries. Effective interventions and collaborations among nations should be facilitated to improve healthcare among children with cancer in countries with lower SDI.

DEPTOR stabilizes ErbB2 to promote the proliferation and survival of ErbB2-positive breast cancer cells.

Rationale: Dysregulation of the PI3K/AKT/mTOR pathway occurs frequently in cancers, providing an attractive therapeutic target for anticancer treatments. DEPTOR plays essential roles in regulation of cell proliferation and survival by directly modulating mTOR activity. However, whether DEPTOR regulates the growth of ErbB2-positive breast cancer cells remains unknown. Methods: DEPTOR expression was determined by TCGA data analysis and immunohistochemistry of human breast tissue microarrays. The membrane localization of DEPTOR was demonstrated by immunofluorescence and subcellular fractionation. The interaction of DEPTOR with ErbB2 was determined by immunoprecipitation. Furthermore, the biological significance of this interaction was assessed by ATPlite cell growth, clonogenic survival, and flow cytometry-based apoptosis assays. Results: DEPTOR promoted the proliferation and survival of ErbB2-positive breast cancer cells by directly interacting with and stabilizing ErbB2. Specifically, DEPTOR translocates to cell membrane and interacts with ErbB2 to disrupt ErbB2 polyubiquitination and degradation promoted by ß-TrCP, an E3 ubiquitin ligase. DEPTOR knockdown destabilizes ErbB2 by shortening its protein half-life to inactivate ErbB2-PI3K-AKT-mTOR signaling, leading to the suppression of cell proliferation and survival by inducing apoptosis. Ectopic expression of a constitutively active ErbB2 mutant completely rescued the reduction in cell proliferation and survival by DEPTOR knockdown. Importantly, DEPTOR expression is increased in human breast cancer tissues and its overexpression correlates with poor patient survival. Moreover, DEPTOR is located on the cell membrane in ErbB2-positive breast cancer tissues, but not in tumor-adjacent normal tissues, indicating that DEPTOR may contribute to the oncogenic characteristics of ErbB2. Conclusions: Our study reveals a novel mechanism by which DEPTOR promotes breast cancer cell proliferation and survival by stabilizing ErbB2.

Impact of Preoperative vs Postoperative Radiotherapy on Overall Survival of Locally Advanced Breast Cancer Patients.

BACKGROUND: The treatment for locally advanced breast cancer (LABC) is a severe clinical problem. The postoperative radiotherapy is a conventional treatment method for patients with LABC, whereas the effect of preoperative radiotherapy on outcome of LABC remains controversial. This study aimed to examine and compare the overall survival (OS) in patients with LABC who underwent preoperative radiotherapy or postoperative radiotherapy. METHODS: This retrospective cohort study included 41,618 patients with LABC from the National Cancer Database (NCDB) between 2010 and 2014. We collected patients' demographic, clinicopathologic, treatment and survival information. Propensity score was used to match patients underwent pre-operative radiotherapy with those who underwent post-operative radiotherapy. Cox proportional hazard regression model was performed to access the association between variables and OS. Log-rank test was conducted to evaluate the difference in OS between groups. RESULTS: The estimated median follow-up of all included participants was 69.6 months (IQR: 42.84-60.22); 70.1 months (IQR: 46.85-79.97) for postoperative radiotherapy, 68.5 (IQR: 41.13-78.23) for preoperative radiotherapy, and 67.5 (IQR: 25.92-70.99) for no radiotherapy. The 5-year survival rate was 80.01% (79.56-80.47) for LABC patients who received postoperative radiotherapy, 64.08% (57.55-71.34) for preoperative radiotherapy, and 59.67% (58.60-60.77) for no radiotherapy. Compared with no radiation, patients receiving postoperative radiotherapy had a 38% lower risk of mortality (HR=0.62, 95%CI: 0.60-0.65, p<0.001), whereas those who received preoperative radiotherapy had no significant survival benefit (HR=0.88, 95%CI: 0.70-1.11, p=0.282). Propensity score matched analysis indicated that patients treated with preoperative radiotherapy had similar outcomes as those treated with postoperative radiotherapy (AHR=1.23, 95%CI: 0.88-1.72, p=0.218). Further analysis showed that in C0 (HR=1.45, 95%CI: 1.01-2.07, p=0.044) and G1-2 (AHR=1.74, 95%CI: 1.59-5.96, p=0.001) subgroup, patients receiving preoperative radiotherapy showed a worse OS than those who received postoperative radiotherapy. CONCLUSIONS: Patients with LABC underwent postoperative radiotherapy had improved overall survival, whereas no significant survival benefit was observed in patients receiving preoperative radiotherapy. Preoperative radiotherapy did not present a better survival than postoperative radiotherapy for LABC patients.

Identification of a glycolysis-related gene signature for survival prediction of ovarian cancer patients.

BACKGROUND: Ovarian cancer (OV) is deemed the most lethal gynecological cancer in women. The aim of this study was to construct an effective gene prognostic model for predicting overall survival (OS) in patients with OV. METHODS: The expression profiles of glycolysis-related genes (GRGs) and clinical data of patients with OV were extracted from The Cancer Genome Atlas (TCGA) database. Univariate, multivariate, and least absolute shrinkage and selection operator Cox regression analyses were conducted, and a prognostic signature based on GRGs was constructed. The predictive ability of the signature was analyzed using training and test sets. RESULTS: A gene risk signature based on nine GRGs (ISG20, CITED2, PYGB, IRS2, ANGPTL4, TGFBI, LHX9, PC, and DDIT4) was identified to predict the survival outcome of patients with OV. The signature showed a good prognostic ability for OV, particularly high-grade OV, in the TCGA dataset, with areas under the curve (AUC) of 0.709 and 0.762 for 3- and 5-year survival, respectively. Similar results were found in the test sets, and the AUCs of 3-, 5-year OS were 0.714 and 0.772 in the combined test set. And our signature was an independent prognostic factor. Moreover, a nomogram combining the prediction model and clinical factors was developed. CONCLUSION: Our study established a nine-GRG risk model and nomogram to better predict OS in patients with OV. The risk model represents a promising and independent prognostic predictor for patients with OV. Moreover, our study on GRGs could offer guidance for the elucidation of underlying mechanisms in future studies.

Dietary Risk-Related Colorectal Cancer Burden: Estimates From 1990 to 2019.

Background: Colorectal cancer remains a public health problem worldwide. Dietary risk factors play a key role in the carcinogenesis and progression of colorectal cancer. This study aimed to explore the geographical and temporal trends in various dietary factor-related colorectal cancers. Methods: Data were extracted from the Global Burden of Disease (GBD) 2019 study, including the deaths, disability-adjusted life-years (DALYs), age-standardized rate (ASR), and summary exposure value (SEV) among 4 world regions, 11 age groups, 21 regions, and 204 countries and territories between 1990 and 2019. The estimated annual percentage changes (EAPCs) were calculated to evaluate the variation trend of ASR. Results: Dietary factors were the leading cause of colorectal cancer death and DALY rate, regardless of age. Dietary factor-related deaths and DALYs accounted for 32 and 34% of global colorectal cancer, respectively. Further analysis showed that low whole grain intake remained the leading cause of cancer death and DALY rate, followed by milk and calcium. Diets that were low in whole grains, milk, and calcium accounted for 81.61% of deaths and 81.64% of DALYs. Deaths and DALYs of dietary factors related to colorectal cancer grew by half from 1990 to 2019. All ASRs remained higher for men than women. Asia carried the highest colorectal cancer burden attributed to dietary risks, especially for East Asia [age-standardized death rate (ASDR): EAPC = 1.15, 95% CI:0.88-1.42; DALY: EAPC = 1.08, 95% CI:0.82-1.34]. The heavy burden also existed in high-middle and middle socio-demographic index (SDI) quintiles. China has always had the highest deaths and DALYs of colorectal cancer attributable to dietary risks, followed by the USA, India, and Japan. Conclusions: Large variations existed in the dietary risk-related colorectal cancer burdens among sexes, regions, and countries. More targeted interventions to address modifiable dietary risk factors would save 32% of deaths and 34% of DALYs for colorectal cancer.

Effects of Antihypertensive Drugs Use on Risk and Prognosis of Colorectal Cancer: A Meta-Analysis of 37 Observational Studies.

Background: Antihypertensive drugs might play a key role in the risk and poor prognosis of colorectal cancer. However, current epidemiologic evidence remains inconsistent. The aim of this study is to quantify the association between antihypertensive drugs and colorectal cancer. Methods: To identify available studies, we systematically searched electronic databases: PubMed, Web of Science, Embase, Cochrane Library. The risk estimates and their corresponding 95% confidence intervals (CIs) were collected and analyzed by using random-effects models. Heterogeneity test and sensitivity analysis were also performed. Results: Overall, 37 observational studies were included in this analysis (26 studies with cohort design, three studies with nested case-control design, and 8 studies with case-control design). Antihypertensive drugs did not present a significant effect on the risk or overall survival of patients with colorectal cancer [Risk ratio (RR) = 1.00, 95% CI: 0.95-1.04; Hazard ratio (HR) = 0.93, 95% CI: 0.84-1.02]. In the subgroup analysis, diuretics use was significantly associated with a worse overall survival of patients with colorectal cancer (HR = 1.27; 95% CI: 1.14-1.40). However, use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers was associated with improved progression-free survival of patients who suffered from colorectal cancer (HR = 0.83; 95% CI: 0.72-0.95). Conclusion: Antihypertensive drug usage did not influence the risk and overall survival of patients with colorectal cancer in general. Further investigation reminded us that diuretics use might reduce the overall survival time in colorectal cancer patients, whereas those who took Angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers had a longer progression-free survival.

Tracheal, bronchus, and lung cancer burden and related risk factors in the United States and China.

Tracheal, bronchus, and lung (TBL) cancer is the most common malignant tumor worldwide. This study aims to grasp the characteristics of the TBL cancer burden in China and the United States (USA). Data included incidence, deaths, and disability-adjusted life years (DALYs) as well as their age-standardized rates (ASRs) among different gender, age and risk factors. Joinpoint Regression Model and Age-period-cohort (APC) analysis were used to evaluate the variation tendency and effect of the risk factors. China and USA bore almost half of the TBL cancer burden, especially for males. ASRs of TBL cancer increased in China, but decreased in USA. In China, three factors related to TBL cancer deaths and DALYs related were tobacco, air pollution, and diet low in fruits; in USA, these are tobacco, occupational carcinogens, and high fasting plasma glucose. The younger the population, the less impact of birth cohort on morbidity and mortality. According to APC analysis, age effect played a key role in morbidity and mortality of TBL cancer, and the risk increased with age. Period effect kept increasing over time, while cohort effect decreased with the time of birth. Tobacco was always the top risk factor of death and DALYs in both countries. The policy should be tilted towards air pollution and a diet low in fruits in China, as well as occupational carcinogens and high fasting plasma glucose in USA. Healthcare reform in both countries should focus on planning how its health system could effectively prevent and manage TBL cancer at low cost.

Association of vitamin C intake with breast cancer risk and mortality: a meta-analysis of observational studies.

The association between vitamin C intake and breast cancer is unclear. This meta-analysis aimed to precisely assess the association of vitamin C intake with breast cancer risk and mortality. We searched the PubMed, Embase, and Web of Science databases up to June 2020 and found 69 studies relevant to breast cancer risk (54 studies) and survival (15 studies). Relative risks and 95% confidence intervals were calculated using the random-effects models. Pooled results suggested that the highest versus lowest vitamin C intake was significantly associated with a lower risk of breast cancer incidence (Relative Risk = 0.86; 95% confidence interval, 0.81-0.92). Dietary vitamin C but not supplements was found to reduce breast cancer risk (Relative Risk = 0.89; 95% confidence interval, 0.82-0.96). For the highest versus lowest vitamin C intake, the pooled hazard risk for breast cancer-specific mortality was 0.78 (95% confidence interval, 0.69-0.88), totality mortality was 0.82 (95% confidence interval, 0.74-0.91), and recurrence was 0.81 (95% confidence interval, 0.67-0.99). Our analysis suggests that higher vitamin C intake is significantly associated with reduced breast cancer incidence and mortality. However, the intake of vitamin C supplements has no significant effect on breast cancer prevention.

Prediction of Overall Survival Among Female Patients With Breast Cancer Using a Prognostic Signature Based on 8 DNA Repair-Related Genes.

Importance: Breast cancer (BC), a common malignant tumor, ranks first among cancers in terms of morbidity and mortality among female patients. Currently, identifying effective prognostic models has a significant association with the prediction of the overall survival of patients with BC and guidance of clinicians in early diagnosis and treatment. Objectives: To identify a potential DNA repair-related prognostic signature through a comprehensive evaluation and to further improve the accuracy of prediction of the overall survival of patients with BC. Design, Setting, and Participants: In this prognostic study, conducted from October 9, 2019, to February 3, 2020, the gene expression profiles and clinical data of patients with BC were collected from The Cancer Genome Atlas database. This study consisted of a training set from The Cancer Genome Atlas database and 2 validation cohorts from the Gene Expression Omnibus, which included 1096 patients with BC. A prognostic signature based on 8 DNA repair-related genes (DRGs) was developed to predict overall survival among female patients with BC. Main Outcomes and Measures: Primary screening prognostic biomarkers were analyzed using univariate Cox proportional hazards regression analysis and the least absolute shrinkage and selection operator Cox proportional hazards regression. A risk model was completely established through multivariate Cox proportional hazards regression analysis. Finally, a prognostic nomogram, combining the DRG signature and clinical characteristics of patients, was constructed. To examine the potential mechanisms of the DRGs, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed. Results: In this prognostic study based on samples from 1096 women with BC (mean [SD] age, 59.6 [13.1] years), 8 DRGs (MDC1, RPA3, MED17, DDB2, SFPQ, XRCC4, CYP19A1, and PARP3) were identified as prognostic biomarkers. The time-dependent receiver operating characteristic curve analysis suggested that the 8-gene signature had a good predictive accuracy. In the training cohort, the areas under the curve were 0.708 for 3-year survival and 0.704 for 5-year survival. In the validation cohort, the areas under the curve were 0.717 for 3-year survival and 0.772 for 5-year survival in the GSE9893 data set and 0.691 for 3-year survival and 0.718 for 5-year survival in the GSE42568 data set. This DRG signature mainly involved some regulation pathways of vascular endothelial cell proliferation. Conclusions and Relevance: In this study, a prognostic signature using 8 DRGs was developed that successfully predicted overall survival among female patients with BC. This risk model provides new clinical evidence for the diagnostic accuracy and targeted treatment of BC.