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Abstract Cytokines are critical in regulating immune responses and cellular behavior, playing dual roles in both normal physiology and the pathology of diseases such as cancer. These molecules, including interleukins, interferons, tumor necrosis factors, chemokines, and growth factors like TGF-β, VEGF, and EGF, can promote or inhibit tumor growth, influence the tumor microenvironment, and impact the efficacy of cancer treatments. Recent advances in targeting these pathways have shown promising therapeutic potential, offering new strategies to modulate the immune system, inhibit tumor progression, and overcome resistance to conventional therapies. In this review, we summarized the current understanding and therapeutic implications of targeting cytokine and chemokine signaling pathways in cancer. By exploring the roles of these molecules in tumor biology and the immune response, we highlighted the development of novel therapeutic agents aimed at modulating these pathways to combat cancer. The review elaborated on the dual nature of cytokines as both promoters and suppressors of tumorigenesis, depending on the context, and discussed the challenges and opportunities this presents for therapeutic intervention. We also examined the latest advancements in targeted therapies, including monoclonal antibodies, bispecific antibodies, receptor inhibitors, fusion proteins, engineered cytokine variants, and their impact on tumor growth, metastasis, and the tumor microenvironment. Additionally, we evaluated the potential of combining these targeted therapies with other treatment modalities to overcome resistance and improve patient outcomes. Besides, we also focused on the ongoing research and clinical trials that are pivotal in advancing our understanding and application of cytokine- and chemokine-targeted therapies for cancer patients.

Abstract Background Basal-like breast cancer (BLBC) is the most aggressive subtype of breast cancer due to its aggressive characteristics and lack of effective therapeutics. However, the mechanism underlying its aggressiveness remains largely unclear. S-adenosylmethionine decarboxylase proenzyme (AMD1) overexpression occurs specifically in BLBC. Here, we explored the potential molecular mechanisms and functions of AMD1 promoting the aggressiveness of BLBC. Methods The potential effects of AMD1 on breast cancer cells were tested by western blotting, colony formation, cell proliferation assay, migration and invasion assay. The spermidine level was determined by high performance liquid chromatography. The methylation status of CpG sites within the AMD1 promoter was evaluated by bisulfite sequencing PCR. We elucidated the relationship between AMD1 and Sox10 by ChIP assays and quantitative real-time PCR. The effect of AMD1 expression on breast cancer cells was evaluated by in vitro and in vivo tumorigenesis model. Results In this study, we showed that AMD1 expression was remarkably elevated in BLBC. AMD1 copy number amplification, hypomethylation of AMD1 promoter and transcription activity of Sox10 contributed to the overexpression of AMD1 in BLBC. AMD1 overexpression enhanced spermidine production, which enhanced eIF5A hypusination, activating translation of TCF4 with multiple conserved Pro-Pro motifs. Our studies showed that AMD1-mediated metabolic system of polyamine in BLBC cells promoted tumor cell proliferation and tumor growth. Clinically, elevated expression of AMD1 was correlated with high grade, metastasis and poor survival, indicating poor prognosis of breast cancer patients. Conclusion Our work reveals the critical association of AMD1-mediated spermidine-eIF5A hypusination-TCF4 axis with BLBC aggressiveness, indicating potential prognostic indicators and therapeutic targets for BLBC.

Abstract Prolonged extremely warm ocean temperatures have great impacts on both natural ecosystems and human communities. These phenomena (i.e., marine heatwaves) could be easily monitored globally by satellite-based sea surface temperatures; however, the choice of datasets may lead to potential uncertainties in the marine heatwave assessment. Here we compared the marine heatwaves using three commonly used satellite products to illustrate the uncertainties over Asia and the Indo-Pacific. Distinct differences were found in the occurrence, duration, and long-term trend of marine heatwaves over both coastal and open oceans, while some discrepancies could become comparable with the obtained metrics themselves. Although differences in mean sea surface temperatures or their variances among datasets could not explain the abovementioned discrepancies, different sensors, procedures, and sea ice treatments in each dataset may contribute partially. Overall, our study suggests that the use of multiple datasets is crucial for evaluations of extreme events.

The sedimentary total organic carbon (TOC) in mangrove ecosystems plays an essential role in the global carbon storage. Nevertheless, little information is available about the pattern of TOC in sediments varying from bare and flat to those beneath mangroves. To find out the roles of new-developing mangroves in sedimentary TOC accumulation, a serials of sediment samples were collected from the creek mudflat zone (CMZ) through the fringe mangrove zone (FMZ) to the interior mangrove zone (IMZ) in young mangrove system of Nanliu River Delta in China. Sediment compositions, TOC, total nitrogen (TN), molar C/N ratios, and carbon stable isotopes (δ13C) were analyzed to examine the accumulation processes. The results revealed the distinct differences in the sedimentary TOC values, with an obvious increasing trend from the CMZ and FMZ to the IMZ. We quantified that terrestrials, marine-derived and mangrove-derived sources contributed 39.2-74.1%, 24.7-63.1% and 0.9-6.9%, respectively, to the sedimentary TOC in the mangrove ecosystems. The organic carbon accumulation rates ranged from 2.59 to 269.60 g•m-2•a-1, with values of 8.77 ± 19.87, 24.78 ± 12.53, 167.19 ± 57.79 g•m-2•a-1 for CMZ, FMZ and IMZ. Our work highlights information showing that young mangrove forests of the tropical delta have important potential for carbon storage.

Abstract Phosphorylation proteomics is the basis for the study of abnormally activated kinase signaling pathways in breast cancer, which facilitates the discovery of new oncogenic agents and drives the discovery of potential targets for early diagnosis and therapy of breast cancer. In this study, we have explored the aberrantly active kinases in breast cancer development and to elucidate the role of PRKCD_pY313 in triple negative breast cancer (TNBC) progression. We collected 47 pairs of breast cancer and paired far-cancer normal tissues and analyzed phosphorylated tyrosine (pY) peptides by Superbinder resin and further enriched the phosphorylated serine/threonine (pS/pT) peptides using TiO2 columns. We mapped the kinases activity of different subtypes of breast cancer and identified PRKCD_pY313 was upregulated in TNBC cell lines. Gain-of-function assay revealed that PRKCD_pY313 facilitated the proliferation, enhanced invasion, accelerated metastasis, increased the mitochondrial membrane potential and reduced ROS level of TNBC cell lines, while Y313F mutation and low PRKCD_pY313 reversed these effects. Furthermore, PRKCD_pY313 significantly upregulated Src_pY419 and p38_pT180/pY182, while low PRKCD_pY313 and PRKCD_Y313F had opposite effects. Dasatinib significantly inhibited the growth of PRKCD_pY313 overexpression cells, and this effect could be enhanced by Adezmapimod. In nude mice xenograft model, PRKCD_pY313 significantly promoted tumor progression, accompanied by increased levels of Ki-67, Bcl-xl and Vimentin, and decreased levels of Bad, cleaved caspase 3 and ZO1, which was opposite to the trend of Y313F group. Collectively, the heterogeneity of phosphorylation exists in different molecular subtypes of breast cancer. PRKCD_pY313 activates Src and accelerates TNBC progression, which could be inhibited by Dasatinib.

ABSTRACTReduced riverine sediment supply and sea-level rise (SLR) threaten land building and ecosystem in deltas. However, the sediment-morphodynamic processes in a channel-shoal complex are not well understood. Here, based on bathymetry and the Delft3D model, geomorphic changes and suspended sediment budgets in the South Passage, Nanhui and Jiuduansha Shoal in the mega-Changjiang Delta were examined. Results reveal that with riverine suspended sediment concentration (SSC) decreased by 75%, the net sediment deposition rate was reduced from 4.20 cm/yr in 1979–1990 to 3.21 cm/yr in 1990–2003, and further declined to 2.21 cm/yr in 2003–2013 and 0.40 cm/yr in 2013–2020. Severe erosion occurred along the upper South Passage and extended toward the mouth bar. Strong accretions accumulated in the Nanhui and Jiuduansha Shoal. After river SSC declined from 0.53 kg/m3 to 0.35 kg/m3, 0.16 kg/m3, and 0.12 kg/m3, net suspended sediment deposition was lowered by 3.13%, 7.35% and 8.67%, respectively. Moreover, SLR of 5 cm, 15 cm, 25 cm, and 50 cm resulted in a further 1.11%, 4.18%, 4.16%, and 14.79% reduction in sediment trapping efficiency. Our findings highlight the strong likelihood that reduced river sediment input, SLRs and intensified anthropogenic effects will exacerbate sediment deficit and erosion in mega fluvial-tidal deltas.

Background Breast carcinoma (BRCA) is a life-threatening malignancy in women and shows a poor prognosis. Cuproptosis is a novel mode of cell death but its relationship with BRCA is unclear. This study attempted to develop a cuproptosis-relevant prognostic gene signature for BRCA. Methods Cuproptosis-relevant subtypes of BRCA were obtained by consensus clustering. Differential expression analysis was implemented using the ‘limma’ package. Univariate Cox and multivariate Cox analyses were performed to determine a cuproptosis-relevant prognostic gene signature. The signature was constructed and validated in distinct datasets. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) were also conducted using the prognostic signature to uncover the underlying molecular mechanisms. ESTIMATE and CIBERSORT algorithms were applied to probe the linkage between the gene signature and tumor microenvironment (TME). Immunotherapy responsiveness was assessed using the Tumor Immune Dysfunction and Exclusion (TIDE) web tool. Real-time quantitative PCR (RT-qPCR) was performed to detect the expressions of cuproptosis-relevant prognostic genes in breast cancer cell lines. Results Thirty-eight cuproptosis-associated differentially expressed genes (DEGs) in BRCA were mined by consensus clustering and differential expression analysis. Based on univariate Cox and multivariate Cox analyses, six cuproptosis-relevant prognostic genes, namely SAA1, KRT17, VAV3, IGHG1, TFF1, and CLEC3A, were mined to establish a corresponding signature. The signature was validated using external validation sets. GSVA and GSEA showed that multiple cell cycle-linked and immune-related pathways along with biological processes were associated with the signature. The results ESTIMATE and CIBERSORT analyses revealed significantly different TMEs between the two Cusig score subgroups. Finally, RT-qPCR analysis of cell lines further confirmed the expressional trends of SAA1, KRT17, IGHG1, and CLEC3A. Conclusion Taken together, we constructed a signature for projecting the overall survival of BRCA patients and our findings authenticated the cuproptosis-relevant prognostic genes, which are expected to provide a basis for developing prognostic molecular biomarkers and an in-depth understanding of the relationship between cuproptosis and BRCA.

Abstract Purpose To assess the efficacy of neoadjuvant endocrine therapy in female HR‐positive/HER2‐negative breast cancer patients. Data and Methods We identified female patients aged ≥18 years with cT1‐4N0‐XM0, HR(+), and HER2(−) breast cancer from the National Cancer Database. The patients who underwent surgery first were categorized as “surgery‐first,” while those who received NET before surgery were classified as “NET.” Propensity score‐matching, Cox proportional‐hazard model, variance inflation factors, and interaction analysis were employed to estimate the correlation between NET and survival outcomes. Results Among 432,387 cases, 2914 NET patients and 2914 surgery‐first patients were matched. Compared with the surgery‐first group, the NET group received less adjuvant chemotherapy (p

Abstract Immunotherapies have revolutionized the treatment paradigms of various types of cancers. However, most of these immunomodulatory strategies focus on harnessing adaptive immunity, mainly by inhibiting immunosuppressive signaling with immune checkpoint blockade, or enhancing immunostimulatory signaling with bispecific T cell engager and chimeric antigen receptor (CAR)-T cell. Although these agents have already achieved great success, only a tiny percentage of patients could benefit from immunotherapies. Actually, immunotherapy efficacy is determined by multiple components in the tumor microenvironment beyond adaptive immunity. Cells from the innate arm of the immune system, such as macrophages, dendritic cells, myeloid-derived suppressor cells, neutrophils, natural killer cells, and unconventional T cells, also participate in cancer immune evasion and surveillance. Considering that the innate arm is the cornerstone of the antitumor immune response, utilizing innate immunity provides potential therapeutic options for cancer control. Up to now, strategies exploiting innate immunity, such as agonists of stimulator of interferon genes, CAR-macrophage or -natural killer cell therapies, metabolic regulators, and novel immune checkpoint blockade, have exhibited potent antitumor activities in preclinical and clinical studies. Here, we summarize the latest insights into the potential roles of innate cells in antitumor immunity and discuss the advances in innate arm-targeted therapeutic strategies.

Revealing the coordinated correlation between chemical industry development and the water environment is essential for promoting high-quality development in the Yangtze River Economic Belt. Based on the data in the Yangtze River Economic Belt from 2011 to 2021, this study explores the spatial–temporal evolution and influencing factors of the coupled coordination between chemical industry development and the water environment by using the global entropy method, a coupling coordination model, and the Tobit model. The results indicate a general upward trend in the comprehensive indices of chemical industry development and water environment systems, albeit with distinct spatial patterns. A mismatch between the two systems is observed in terms of spatial distribution. Regarding the coupling coordination degree, the relationship shows an upward trend, primarily at a mild-to-moderate coupling stage, exhibiting a spatial pattern of “downstream > midstream > upstream”. Moreover, a trend of increasing coordination and narrowing disparities between high- and low-level regions can be observed. The model results suggest that environmental regulation, economic development, government capacity, and urbanization play a crucial role in promoting the coupled development of the chemical industry and the water environment. However, openness to external markets may not enhance coupled coordination. These findings may provide policy guidance for the development status of two subsystems in other locations.

Abstract Background High fasting plasma glucose (FPG) has been listed as one of the risk factors for bladder cancer. We here estimated the global, regional, and national levels of bladder cancer burden attributable to high FPG from 1990 to 2019. Methods Bladder cancer data attributable to high FPG were extracted from the Global Burden of Disease Study 2019, and analyzed by age, sex, year, and location. Age‐standardized rates were utilized to evaluate the burden between different populations. The temporal trend of the burden was estimated through the Joinpoint analysis. Results In 2019, high FPG contributed to 22,823.33 (95% uncertainty interval [UI], 4694.88–48,962.26) deaths and 399,654.91 (95% UI, 81,609.35–865,890.95) disability‐adjusted life years (DALYs) of bladder cancer globally. Since 1990, the global age‐standardized death and DALY rates of bladder cancer attributable to high FPG increased apparently by 39.18% and 41.48%, respectively. During the last 30 years, high FPG‐related age‐standardized death and DALY rates of bladder cancer have increased in all countries. In 2019, Central Europe showed the greatest high FPG‐related age‐standardized death and DALY rates of bladder cancer, but Andean Latin America had the lowest rates. Nationally, Lebanon showed the greatest high FPG‐related age‐standardized death and DALY rates of bladder cancer in 2019. High FPG‐attributable deaths and DALYs of bladder cancer were more considerable among males and older people. Countries with high SDI showed higher levels of age‐standardized death and DALY rates of bladder cancer due to high FPG and presented remarkable upward trends in rates in the last 30 years. Conclusions Globally, the high FPG‐associated bladder cancer burden has remarkably increased in all countries, and showed a higher level among countries with higher SDI. Monitoring FPG levels among patients with bladder cancer is critical to lower the corresponding burden.

Abstract Breast cancer is the most common malignancy and the second leading cause of cancer-related death in women. Recent studies have indicated that aberrant activation of Rho GTPases relates to the malignant properties of breast cancer cells. As the guanine nucleotide exchange factor of Rho GTPases, the role of ECT2 (epithelial cell transforming 2) in breast cancer is still unclear. Tissue microarrays and multiple public databases were utilized to investigate the relationship between ECT2 level and clinical-pathological features of breast cancer patients. Kaplan Meier-plotter online tool and tissue microarray with survival information were used to investigate the predictive value for breast cancer. Here, we found increased ECT2 level was highly associated with advanced TNM stage, poor differentiation, and loss of hormone receptors of breast cancer. Gene expression profile showed that ECT2 level was closely correlated to cell-proliferation-associated pathways. Integration analysis using public databases and tissue microarray indicated that high ECT2 was an adverse prognostic factor for breast cancer patients. We believe the ECT2 level might be a valuable complement for commercially available predictors such as the 21 genes test. Furthermore, ECT2 would be a novel target for drug development for breast cancer.

Designing appropriate similarity metrics (distance) and estimating the optimal number of clusters have been two important issues in cluster analysis. This study proposed an improved k-means clustering algorithm involving a Weighted Distance and a novel Internal Validation index (WeDIV). The weighted distance, EP_dis, was designed by considering the relative contribution between Euclidean and Pearson distances with a weighted strategy. This strategy can effectively capture information reflecting the globally spatial correlation and locally variable trend simultaneously in high-dimensional space. The new internal validation index,RCH, inspired by the Calinski-Harabasz (CH) index and the analysis of variance, was developed to automatically estimate the optimal number of clusters. The EP_dis was proved reliable in mathematics and was validated on two simulated datasets. Four simulated datasets representing different properties were used to validate the effectiveness of RCH. Furthermore, We compared the clustering performance of WeDIV with 12 prevailing clustering algorithms on 16 UCI datasets. The results demonstrated that WeDIV outperforms the others regardless of specifying the number of clusters or not.

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.

Abstract Background Basal-like breast cancer (BLBC) is the most aggressive subtype of breast cancer because of its aggressive biological characteristics and no effective targeted agents. However, the mechanism underlying its aggressive behavior remain poorly understood. β1,3-N-acetylglucosaminyltransferase V (B3GNT5) overexpression occurs specifically in BLBC. Here, we studied the possible molecular mechanisms of B3GBT5 promoting the aggressiveness of BLBC. Methods The potential effects of B3GNT5 on breast cancer cells were tested by colony formation, mammosphere formation, cell proliferation assay, flow cytometry and Western blotting. The glycosylation patterns of B3GNT5 and associated functions were determined by Western blotting, quantitative real-time PCR and flow cytometry. The effect of B3GNT5 expression on BLBC was assessed by in vitro and in vivo tumorigenesis model. Results In this study, we showed that B3GNT5 copy number amplification and hypomethylation of B3GNT5 promoter contributed to the overexpression of B3GNT5 in BLBC. Knockout of B3GNT5 strongly reduced surface expression of SSEA-1 and impeded cancer stem cell (CSC)-like properties of BLBC cells. Our results also showed that B3GNT5 protein was heavily N-glycosylated, which is critical for its protein stabilization. Clinically, elevated expression of B3GNT5 was correlated with high grade, large tumor size and poor survival, indicating poor prognosis of breast cancer patients. Conclusions Our work uncovers the critical association of B3GNT5 overexpression and glycosylation with enhanced CSCs properties in BLBC. These findings suggest that B3GNT5 has the potential to become a prognostic marker and therapeutic target for BLBC.

Background: Breast cancer (BRCA) is a life-threatening malignancy in women with an unsatisfactory prognosis. The purpose of this study was to explore the prognostic biomarkers and a risk signature based on ferroptosis-related RNA-binding proteins (FR-RBPs).Methods: FR-RBPs were identified using Spearman correlation analysis. Differentially expressed genes (DEGs) were identified by the “limma” R package. The univariate Cox and multivariate Cox analyses were executed to determine the prognostic genes. The risk signature was constructed and verified with the training set, testing set, and validation set. Mutation analysis, immune checkpoint expression analysis in high- and low-risk groups, and correlation between risk signature and chemotherapeutic agents were conducted using the “maftools” package, “ggplot2” package, and the CellMiner database respectively. The Human Protein Atlas (HPA) database was employed to confirm protein expression trends of prognostic genes in BRCA and normal tissues. The expression of prognostic genes in cell lines was verified by Real-time quantitative polymerase chain reaction (RT-qPCR). Kaplan-meier (KM) plotter database analysis was applied to predict the correlation between the expression levels of signature genes and survival statuses.Results: Five prognostic genes (GSPT2, RNASE1, TIPARP, TSEN54, and SAMD4A) to construct an FR-RBPs-related risk signature were identified and the risk signature was validated by the International Cancer Genome Consortium (ICGC) cohort. Univariate and multivariate Cox regression analysis demonstrated the risk score was a robust independent prognostic factor in overall survival prediction. The Tumor Mutational Burden (TMB) analysis implied that the high- and low-risk groups responded differently to immunotherapy. Drug sensitivity analysis suggested that the risk signature may serve as a chemosensitivity predictor. The results of GSEA suggested that five prognostic genes might be related to DNA replication and the immune-related pathways. RT-qPCR results demonstrated that the expression trends of prognostic genes in cell lines were consistent with the results from public databases. KM plotter database analysis suggested that high expression levels of GSPT2, RNASE1, and SAMD4A contributed to poor prognoses.Conclusion: In conclusion, this study identified the FR-RBPs-related prognostic genes and developed an FR-RBPs-related risk signature for the prognosis of BRCA, which will be of great significance in developing new therapeutic targets and prognostic molecular biomarkers for BRCA.

Background Identifying the cell types using unsupervised methods is essential for scRNA-seq research. However, conventional similarity measures introduce challenges to single-cell data clustering because of the high dimensional, high noise, and high dropout. Methods We proposed a clustering method for small ScRNA-seq data based on Subspace and Weighted Distance (SSWD), which follows the assumption that the sets of gene subspace composed of similar density-distributing genes can better distinguish cell groups. To accurately capture the intrinsic relationship among cells or genes, a new distance metric that combines Euclidean and Pearson distance through a weighting strategy was proposed. The relative Calinski-Harabasz (CH) index was used to estimate the cluster numbers instead of the CH index because it is comparable across degrees of freedom. Results We compared SSWD with seven prevailing methods on eight publicly scRNA-seq datasets. The experimental results show that the SSWD has better clustering accuracy and the partitioning ability of cell groups. SSWD can be downloaded at https://github.com/ningzilan/SSWD.

This study used a two-stage network data envelopment analysis model to measure the water use efficiency of 108 cities in the Yangtze River Economic Belt in the initial water use and wastewater treatment phases from 2009 to 2019. We divided the urban water use efficiency of six significant urban clusters in the Yangtze River Economic Belt using the Dagum Gini coefficient. We also tested the convergence characteristics of urban water use efficiency in six significant urban clusters in the Yangtze River Economic Belt using convergence and convergence kinds. According to this report, the Yangtze River Economic Zone’s cities often have low levels of water use efficiency, which is primarily due to ineffective wastewater treatment. The 108 cities in the Yangtze River Economic Zone are divided into four types based on the average values of water use efficiency in the initial use and wastewater treatment phases; the highest number of cities are in the double-low category, with low average values of water use efficiency in the initial use and wastewater treatment phases. During the study period, spatial differences in urban water use efficiency in the Yangtze River Economic Zone narrowed, with the differences stemming mainly from hyperdensity, followed by intra- and inter-regional differences. Meanwhile, there is convergence in urban water use efficiency in the Yangtze River Economic Belt, significant β convergence in the urban agglomerations of the Yangtze River Delta, Jianghuai, middle reaches of the Yangtze River, Chengdu–Chongqing, and Central Yunnan, and insignificant β convergence in the Central Qian urban agglomeration. After considering control factors, such as industrial structure, financial development level, environmental regulation, economic development level, and science and education development level, the water use efficiency of the six major urban clusters in the Yangtze River Economic Belt converges faster, but the influence of these control factors on the water use efficiency of each urban cluster is heterogeneous. Research results have reference value for the development of improvement strategies on differentiated urban water use efficiency in the Yangtze River Economic Belt. By measuring the regional differences in water use efficiency of urban agglomerations in the Yangtze River Economic Belt and clarifying their convergence mechanism, it provides a basis for analyzing the spatial pattern of water use efficiency in urban agglomerations and has reference value for formulating differentiated urban water use efficiency improvement strategies in the Yangtze River Economic Belt.

Abstract 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.

ObjectivesWhile timely assessment of long-term survival for patients with breast cancer is essential for evaluation on early detection and screening programs, those data are extremely scant in China. We aimed to derive most up-to-date survival estimates and to predict future survival using the cancer registry data from Taizhou city, Eastern China.MethodsPatients diagnosed with breast cancer during 2004-2018 from four cancer registries with high-quality data from Taizhou, Eastern China were included. Period analysis was used to calculate 5-year relative survival (RS) for the overall population and according to the stratification factors sex, age at diagnosis and geographic region. We further predict the upcoming 5-year RS during 2019-2023, using continuous data from three 5-year periods (2004-2008, 2009-2013 and 2014-2018) and a model-based period approach.ResultsOverall 6159 patients diagnosed with breast cancer during 2004-2018 were enrolled. The 5-year RS for breast cancer in 2014-2018 reached 88.8%, while women were higher compared to men (90.5% versus 83.7%) and urban areas were higher compared to rural areas (91.9% versus 86.7%). Additionally, we found a clear gradient by age at diagnosis, ranging from 94.8% for age74 years. Projected overall 5-year RS for the upcoming 2019-2023 could reach 91.5% (84.8% for men and 93.5% for women).ConclusionsWe provided, for first time in China, using period analysis, most up-to-date 5-year RS (88.8%) for patients with breast cancer from Taizhou, Eastern China. We also demonstrate the 5-year RS has improved greatly over last 15 years, which has important implications for timely evaluation of early detection and screening programs.

Background Agents blocking programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) have been approved for triple-negative breast cancer (TNBC). However, the response rate of anti-PD-1/PD-L1 is still unsatisfactory, partly due to immunosuppressive factors such as transforming growth factor-beta (TGF-β). In our previous pilot study, the bispecific antibody targeting TGF-β and murine PD-L1 (termed YM101) showed potent antitumor effect. In this work, we constructed a bispecific antibody targeting TGF-β and human PD-L1 (termed BiTP) and explored the antitumor effect of BiTP in TNBC.Methods BiTP was developed using Check-BODYTM bispecific platform. The binding affinity of BiTP was measured by surface plasmon resonance, ELISA, and flow cytometry. The bioactivity was assessed by Smad and NFAT luciferase reporter assays, immunofluorescence, western blotting, and superantigen stimulation assays. The antitumor activity of BiTP was explored in humanized epithelial-mesenchymal transition-6-hPDL1 and 4T1-hPDL1 murine TNBC models. Immunohistochemical staining, flow cytometry, and bulk RNA-seq were used to investigate the effect of BiTP on immune cell infiltration.Results BiTP exhibited high binding affinity to dual targets. In vitro experiments verified that BiTP effectively counteracted TGF-β-Smad and PD-L1-PD-1-NFAT signaling. In vivo animal experiments demonstrated that BiTP had superior antitumor activity relative to anti-PD-L1 and anti-TGF-β monotherapy. Mechanistically, BiTP decreased collagen deposition, enhanced CD8+ T cell penetration, and increased tumor-infiltrating lymphocytes. This improved tumor microenvironment contributed to the potent antitumor activity of BiTP.Conclusion BiTP retains parent antibodies’ binding affinity and bioactivity, with superior antitumor activity to parent antibodies in TNBC. Our data suggest that BiTP might be a promising agent for TNBC treatment.

BackgroundBreast cancer is one of the most important diseases in women around the world. Glycosylation modification correlates with carcinogenesis and roles of glycogenes in the clinical outcome and immune microenvironment of breast cancer are unclear.MethodsA total of 1297 breast cancer and normal cases in the TCGA and GTEx databases were enrolled and the transcriptional and survival information were extracted to identify prognostic glycogenes using Univariate Cox, LASSO regression, Multivariate Cox analyses and Kaplan-Meier method. The immune infiltration pattern was explored by the single sample gene set enrichment method. The HLA and immune checkpoint genes expression were also compared in different risk groups. The expressions of a glycogene MGAT5 as well as its products were validated by immunohistochemistry and western blotting in breast cancer tissues and cells.ResultsA 19-glycogene signature was identified to separate breast cancer patients into high- and low-risk groups with distinct overall survival rates (P < 0.001). Compared with the high-risk group, proportion of naive B cells, plasma cells and CD8+ T cells increased in the low-risk group (P < 0.001). Besides, expressions of HLA and checkpoint genes, such as CD274, CTLA4, LAG3 and TIGIT3, were upregulated in low-risk group. Additionally, highly expressed MGAT5 was validated in breast cancer tissues and cells. Downstream glycosylation products of MGAT5 were all increased in breast cancer.ConclusionsWe identified a 19-glycogene signature for risk prediction of breast cancer patients. Patients in the low-risk group demonstrated a higher immune infiltration and better immunotherapy response. The validation of MGAT5 protein suggests a probable pathway and target for the development and treatment of breast cancer.

The roles of ubiquitin-related genes in hepatocellular carcinoma (HCC) have not been thoroughly investigated. This study aimed to systematically examine ubiquitin-related genes and identify subtypes and stratify prognosis of HCC by using ubiquitin-related signatures. Survival, biological processes, tumor microenvironment (TME), and genomic alterations of the HCC subtypes were investigated. Patients with HCC were classified into two subtypes (clusters 1 and 2) with distinct survival outcomes, pathways, and genomic alterations. Cluster 2 had better prognosis than did cluster 1. Hepatitis B, hepatitis C, Janus tyrosine kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, and natural killer cell-mediated cytotoxicity were enriched in cluster 1. Moreover, cluster 2 had a higher immune score and immune cell infiltrations, whereas cluster 1 had a lower immune score and immune infiltrations. Additionally, mutations, amplifications, and deletions among the phosphatidylinositol 3-kinase (PI3K)-AKT, p53, and receptor tyrosine kinase (RTK)-RAS pathways more frequently occurred in cluster 1, while those among the Hippo, MYC, and Notch signaling pathways were found in cluster 2. Finally, a prognostic signature, consisting of eight ubiquitin-related genes, was established and validated. In brief, our study established a new classification and developed a prognostic signature for HCC.

IntroductionThis 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.MethodsData 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.ResultsIn 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.ConclusionsThe 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.

Summary: Background: Accumulative evidences have shown that dysregulation of biological pathways contributed to the initiation and progression of malignant tumours. Several methods for pathway activity measurement have been proposed, but they are restricted to making comparisons between groups or sensitive to experimental batch effects. Methods: We introduced a novel method for individualized pathway activity measurement (IPAM) that is based on the ranking of gene expression levels in individual sample. Taking advantage of IPAM, we calculated the pathway activity of 318 pathways from KEGG database in the 10528 tumour/normal samples of 33 cancer types from TCGA to identify characteristic dysregulated pathways among different cancer types. Findings: IPAM precisely quantified the level of activity of each pathway in pan-cancer analysis and exhibited better performance in cancer classification and prognosis prediction over five widely used tools. The average ROC-AUC of cancer diagnostic model using tumour-educated platelets (TEPs) reached 92.84%, suggesting the potential of our algorithm in early diagnosis of cancer. We identified several pathways significantly deregulated and associated with patient survival in a large fraction of cancer types, such as tyrosine metabolism, fatty acid degradation, cell cycle, p53 signalling pathway and DNA replication. We also confirmed the dominant role of metabolic pathways in cancer pathway dysregulation and identified the driving factors of specific pathway dysregulation, such as PPARA for branched-chain amino acid metabolism and NR1I2, NR1I3 for fatty acid metabolism. Interpretation: Our study will provide novel clues for understanding the pathological mechanisms of cancer, ultimately paving the way for personalized medicine of cancer. Funding: A full list of funding can be found in the Acknowledgements section.

Mangrove forests grow on tropical and subtropical coastlines and play a significant role in reducing hydrodynamic energy. However, little information is known about the mechanism of wave attenuation caused by mangroves of different ages, even though the effects of mangroves on wave damping have received widespread concern. Here, a series of systemic biohydrological data were collected along a cross-shore transect through mangroves with different ages of native Aegiceras corniculatum (AC) distribution in the Nanliu Delta of China and were analyzed to investigate wave attenuation over mangroves during different tidal conditions. The results showed that the wave height decreased nearly 58.33%, with a transport distance of 275 m in the AC seedling-sapling region, and approximately 80%, with a transport distance of 1,000 m in the sapling-adult region, on average. The largest wave height attenuation rate of 3 × 10−3 was found in the measured time period and occurred in the seedling-sapling section during the neap tide, while the sapling-adult region had a basically constant reduction rate of 0.8 × 10−3 under changing tidal conditions. Moreover, the drag coefficient calculation indicated that an AC seedling with a height of nearly 0.55 m was more effective in attenuating wave energy than the stem part of a grown tree with a height of nearly 1.2 m. AC seedlings and saplings have significant impacts on wave damping, even though the stem part of an adult AC could produce a decline in wave energy. Moreover, differences in the drag coefficient caused by stems and canopies were responsible for wave attenuation, and the degree of AC inundation volume induced by water level fluctuation might affect the wave damping effect. Our results documented distinct differences in the wave attenuation process by mangroves of different ages, which can inform superior designs of mangroves along coasts against a background of sea-level rise and the occurrence of frequent typhoons.

Abstract Circular RNAs (circRNAs) are a new class of endogenous regulatory RNAs characterized by covalently closed cyclic structure lacking poly-adenylated tails, and are capable of regulating gene expression at transcription or post-transcription levels. Recently, plentiful circRNAs have been discovered in breast cancer and some circRNAs expression profiles are specifically involved in the triple-negative breast cancer (TNBC). TNBC is a type of malignant tumor defined by the lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. Considering its clinical characteristics of high invasion, metastasis, poor prognosis, and lack of effective response to conventional chemotherapies or targeted therapies, it could be a promosing option to discover specific circRNAs as new targets for TNBC treatment. Meanwhile, accumulating evidence has demonstrated that circRNAs are dysregulated in TNBC tissues and are correlated with clinicopathological features and prognosis of TNBC patients. Furthermore, looking for circRNAs with high specificity and sensitivity will provide a new opportunity for the early diagnosis, clinical treatment, and prognosis monitoring of TNBC. Herein, we reviewed the biogenesis, regulatory mechanisms, and biological functions of circRNAs in TNBC and summarized the relationship between circRNAs expression and the clinicopathology, diagnosis, and prognosis of patients with TNBC.

Previous studies of correlations of microRNA (miR)-499 rs3746444 and miR-196a-2 rs11614913 polymorphisms with glioma risk have yielded inconsistent results. In this study, relationships between these two polymorphisms and glioma risk and survival were evaluated. In total, 605 patients and 1,300 controls were genotyped. rs3746444 increased glioma risk in five genetic models (GA versus AA, odds ratio [OR], 95% confidence interval [CI] = 1.31 [1.05–1.66], p = 0.02; GG versus AA, OR [95% CI] = 10.70 [6.13–18.69], p < 0.0001; GA + GG versus AA, OR [95% CI] = 1.82 [1.47–2.24], p < 0.0001; GG versus AA + GA, OR [95% CI] = 9.99 [5.74–17.40], p < 0.0001; G versus A, OR [95% CI] = 2.18 [1.82–2.60], p < 0.0001). rs11614913 decreased glioma risk in a recessive model (OR [95% CI] = 0.79 [0.64–0.97], p = 0.03). No relationships between either SNP and survival were found. rs3746444 in the miR-499 seed region could affect target recognition. Bioinformatics analyses indicated that miR-499 rs3746444 is involved in various biological processes and pathways, including “cell adhesion molecule binding,” “positive regulation of catabolic process,” “NF-kappa B pathway,” and “PI3K-Akt pathway,” by targeting mRNAs. Our results suggested that miR-499 rs3746444 and miR-196a-2 rs11614913 have crucial roles in glioma susceptibility.

Abstract The prognosis of patients with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) is a research hotspot. This study aimed to incorporate important factors obtained from SEER database to construct and validate a nomogram for predicting the cancer-specific survival (CSS) of patients with HCC and ICC. We obtained patient data from SEER database. The nomogram was constructed base on six prognostic factors for predicting CSS rates in HCC patients. The nomogram was validated by concordance index (C-index), the receiver operating characteristic (ROC) curve and calibration curves. A total of 3227 patients diagnosed with HCC (3038) and ICC (189) between 2010 and 2015 were included in this study. The C-index of the nomogram for HCC patients was 0.790 in the training cohort and 0.806 in the validation cohort. The 3- and 5-year AUCs were 0.811 and 0.793 in the training cohort. The calibration plots indicated that there was good agreement between the actual observations and predictions. In conclusion, we constructed and validated a nomogram for predicting the 3- and 5-year CSS in HCC patients. We have confirmed the precise calibration and excellent discrimination power of our nomogram.

Abstract Background The epidemiology of esophageal cancer (EC) can elucidate its causes and risk factors and help develop prevention strategies. We aimed to provide an overview of the burden, trends, and risk factors of EC in China from 1990 to 2017. We also investigated the differences between China, Japan, and South Korea and discussed the possible causes of the disparities. Methods We used the Global Burden of Disease Study 2017 to obtain data on incident cases, deaths, disability-adjusted life-year (DALY) cases, age-standardized incidence rate (ASIR), age-standardized death rate (ASDR), and age-standardized DALY rate of EC in China, Japan, and South Korea from 1990 to 2017. Trend analysis was performed using joinpoint analysis. We measured the associations between ASIR, ASDR, and age-standardized DALY rate and the socio-demographic index (SDI) for 1990–2017. We also analyzed the risk factors associated with EC deaths and DALYs. Results China recorded 234,624 (95% uncertainty intervals: 223,240–246,036) incident cases of and 212,586 (202,673–222,654) deaths from EC in 2017. The ASIR and ASDR declined from 1990 to 2017. Until 2017, the ASIR was 12.23, and ASDR was 11.25 per 100,000 persons. The DALYs were 4,464,980 (4,247,816–4,690,846) with an age-standardized rate of 222.58 per 100,000 persons in 2017. The ASIR, ASDR, and age-standardized DALY rate in China were twice those of Japan and South Korea. These three indicators showed a decreasing trend, whereas SDI increased, in all three countries from 1990 to 2017. Tobacco and alcohol use remained the major risk factors for EC death and DALYs, especially for men in China and women in Japan and South Korea. High body mass index (BMI) and low-fruit diet were the main risk factors for women in China. Conclusions The incident cases and deaths of EC in China, Japan, and South Korea increased from 1990 to 2017, whereas the ASIR, ASDR, and age-standardized DALY rate declined. China had the greatest burden of EC among three countries. SDI and aging along with tobacco use, alcohol use, high BMI, and low-fruit diet were the main risk factors of death and DALYs and should be paid more attention.

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.

Human papillomavirus (HPV) is a clear etiology of cervical cancer (CC). However, the associations between HPV infection and DNA methylation have not been thoroughly investigated. Additionally, it remains unknown whether HPV‐related methylation signatures can identify subtypes of CC and stratify the prognosis of CC patients. DNA methylation profiles were obtained from The Cancer Genome Atlas to identify HPV‐related methylation sites. Unsupervised clustering analysis of HPV‐related methylation sites was performed to determine the different CC subtypes. CC patients were categorized into cluster 1 (Methylation‐H), cluster 2 (Methylation‐M), and cluster 3 (Methylation‐L). Compared to Methylation‐M and Methylation‐L, Methylation‐H exhibited a significantly improved overall survival (OS). Gene set enrichment analysis (GSEA) was conducted to investigate the functions that correlated with different CC subtypes. GSEA indicated that the hallmarks of tumors, including KRAS signaling, TNFα signaling via NF‐κB, inflammatory response, epithelial–mesenchymal transition, and interferon‐gamma response, were enriched in Methylation‐M and Methylation‐L. Based on mutation and copy number variation analyses, we found that aberrant mutations, amplifications, and deletions among the MYC, Notch, PI3K‐AKT, and RTK‐RAS pathways were most frequently detected in Methylation‐H. Additionally, mutations, amplifications, and deletions within the Hippo, PI3K‐AKT, and TGF‐β pathways were presented in Methylation‐M. Genes within the cell cycle, Notch, and Hippo pathways possessed aberrant mutations, amplifications, and deletions in Methylation‐L. Moreover, the analysis of tumor microenvironments revealed that Methylation‐H was characterized by a relatively low degree of immune cell infiltration. Finally, a prognostic signature based on six HPV‐related methylation sites was developed and validated. Our study revealed that CC patients could be classified into three heterogeneous clusters based on HPV‐related methylation signatures. Additionally, we derived a prognostic signature using six HPV‐related methylation sites that stratified the OS of patients with CC into high‐ and low‐risk groups.

Abstract Background LncRNA MEG3 expressed abnormally in various cancers including breast cancer, but no studies reported the correlation between MEG3 SNPs and breast cancer susceptibility among Chinese women. Methods This study is aimed to explore the association between three SNPs of MEG3 (rs3087918, rs7158663, rs11160608) and breast cancer. The study is a population-based case-control study including 434 breast cancer patients and 700 healthy controls. Genotyping was performed using Sequenom MassArray technique. Function prediction of rs3087918 were based on RNAfold and lncRNASNP2 databases. Results Pooled analysis indicated that rs3087918 was related to a decreased risk of breast cancer [GG vs. TT: OR (95%) = 0.67(0.45–0.99), P = 0.042; GG vs. TT + TG: OR (95%) = 0.69(0.48–0.99), P = 0.046], especially for women aged

Abstract Background Investigations of disease incidence, mortality, and disability-adjusted life years (DALYs) are valuable for facilitating preventive measures and health resource planning. We examined the tracheal, bronchus, and lung (TBL) cancer burdens worldwide according to sex, age, and social development index (SDI) at the global, regional, and national levels. Methods We assessed the TBL cancer burden using data from the Global Burden of Disease (GBD) database, including 21 regions, 195 countries, and territories in the diagnostic period 1990–2017. The data of TBL cancer-related mortality and DALYs attributable to all known risk factors were also analyzed. Age-standardized rates (ASRs) and their estimated annual percentage changes (EAPCs) were calculated. Results Incident cases, deaths, and DALYs of TBL cancer increased worldwide (100.44%, 82.30%, and 61.27%, respectively). The age-standardized incidence rate (ASIR) was stable (EAPC = 0.02, 95% confidence interval [CI] − 0.03 to 0.08), but the age-standardized death (EAPC = − 0.34, 95%CI − 0.38 to − 0.3) and DALY rate decreased generally (EAPC = − 0.74, 95%CI − 0.8 to − 0.68). However, the change trend of ASIR and ASDR among sexes was on the contrary. China and the USA always had the highest incidence, mortality, and DALYs of TBL cancer. Significant positive correlations between ASRs and SDI were observed, especially among females. High (36.86%), high-middle (28.78%), and middle SDI quintiles (24.91%) carried the majority burden of TBL cancer. Tobacco remained the top cause of TBL cancer death and DALYs, followed by air pollution, the leading cause in the low-middle and low-SDI quintiles. Metabolic risk-related TBL cancer mortality and DALYs among females increased but was stable among males. The main ages of TBL cancer onset and death were > 50 years, and the DALYs concentrated in 50 − 69 years. Conclusions To significantly reduce the growing burden of TBL cancer, treatment resources need to be skewed according to factors such as risks and geography, especially for high-risk groups and high-burden areas. Asia had the greatest TBL cancer burden, followed by high-income North America. Tobacco remains the leading cause of death and DALYs, followed by air pollution. Effective prevention measures against tobacco and air pollution should be strengthened.

Glioma is the most common tumor of the central nervous system; variation in susceptibility and prognosis worldwide suggests that there are molecular and genetic differences among individuals. The H19 gene plays a dual role in carcinogenesis. In this study, associations between H19 polymorphisms and susceptibility as well as prognosis in glioma were evaluated. In total, 605 patients with glioma and 1,300 cancer-free subjects were enrolled in the study. Individuals with the rs3741219 A>G allele were less likely to develop glioma (relative risk [RR] = 0.54, 95% confidence interval [95% CI] = 0.45–0.63, p < 0.001), whereas rs217727 G>A and rs2839698 G>A genotypes were not associated with glioma risk. The associations between H19 polymorphisms and prognosis were assessed, including overall survival and progression-free survival. Three focused H19 polymorphisms did not show a significant effect on survival. Further analysis based on false-positive report probability validated these significant results. In the haplotype analysis, individuals with the Grs217727Ars2839698Grs3741219 haplotype were less likely to develop glioma (odds ratio [OR] = 0.33, 95% CI = 0.23–0.46, p = 0.02). Overall, carriers of the rs3741219 AG or GG genotype of H19 have a decreased susceptibility to glioma, but polymorphisms in this gene are not related to prognosis.

Although genome-wide association studies (GWASs) have successfully identified thousands of risk variants for human complex diseases, understanding the biological function and molecular mechanisms of the associated SNPs involved in complex diseases is challenging. Here we developed a framework named integrative multi-omics network-based approach (IMNA), aiming to identify potential key genes in regulatory networks by integrating molecular interactions across multiple biological scales, including GWAS signals, gene expression-based signatures, chromatin interactions and protein interactions from the network topology. We applied this approach to breast cancer, and prioritized key genes involved in regulatory networks. We also developed an abnormal gene expression score (AGES) signature based on the gene expression deviation of the top 20 rank-ordered genes in breast cancer. The AGES values are associated with genetic variants, tumor properties and patient survival outcomes. Among the top 20 genes, RNASEH2A was identified as a new candidate gene for breast cancer. Thus, our integrative network-based approach provides a genetic-driven framework to unveil tissue-specific interactions from multiple biological scales and reveal potential key regulatory genes for breast cancer. This approach can also be applied in other complex diseases such as ovarian cancer to unravel underlying mechanisms and help for developing therapeutic targets.

Prediction of phenotypes from genotypes is an important objective to fulfill the promises of genomics, precision medicine and agriculture. Although it’s now possible to account for the majority of genetic variation through model fitting, prediction of phenotypes remains a challenge, especially across populations that have diverged in the past. In this study, we designed simulation experiments to specifically investigate the role of genetic interactions in failure of polygenic prediction. We found that non-additive genetic interactions can significantly reduce the accuracy of polygenic prediction. Our study demonstrated the importance of considering genetic interactions in genetic prediction.

Abstract Background Statistical data on the incidence, mortality, and burden of breast cancer and the relevant risk factors are valuable for policy-making. We aimed to estimate breast cancer incidence, deaths, and disability-adjusted life years (DALYs) by country, gender, age group, and social-demographic status between 1990 and 2017. Methods We extracted breast cancer data from the 2017 Global Burden of Disease (GBD) study from 1990 through 2017 in 195 countries and territories. Data about the number of breast cancer incident cases, deaths, DALYs, and the age-standardized rates were collected. We also estimated the risk factors attributable to breast cancer deaths and DALYs using the comparative risk assessment framework of the GBD study. Results In 2017, the global incidence of breast cancer increased to 1,960,681 cases. The high social-development index (SDI) quintile included the highest number of breast cancer death cases. Between 2007 and 2017, the ASDR of breast cancer declined globally, especially in high SDI and high middle SDI countries. The related DALYs were 17,708,600 in 2017 with high middle SDI quintile as the highest contributor. Of the deaths and DALYs, alcohol use was the greatest contributor in most GBD regions and other contributors included high body mass index (BMI) and high fasting plasma glucose. Conclusion The increasing global breast cancer burden is mainly observed in lower SDI countries; in higher SDI countries, the breast cancer burden tends to be relieving. Therefore, steps against attributable risk factors should be taken to reduce breast cancer burden in lower SDI countries.

MicroRNAs bind to the 3′ untranslated regions of mRNAs, affecting translation, tumorigenesis, and apoptosis. This study evaluated the role of TYMS (rs1059394, C > T, and rs2847153, G > A), RYR3 (rs1044129, G > A), KIAA0423 (rs1053667, T > C), and GOLGA7 (rs11337, G > T) polymorphisms for assessment of glioma risk and prognosis among the Chinese Han population. Five single-nucleotide polymorphisms were assessed in 605 glioma patients and 1,300 controls. We found a significant correlation between rs1059394 and glioma susceptibility in the homozygote and dominant genetic models (TT versus CC, odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.52–0.97, p = 0.03; CT+TT versus CC, OR = 0.74, 95% CI = 0.55–0.99, p = 0.04). The results of the Kaplan-Meier and log rank tests revealed that the rs11337 GG genotype correlated with better overall survival of glioma patients (p = 0.017) than the GT genotype. Multivariate Cox regression analysis results also showed that the rs11337 GT genotype correlated with worse overall survival (p = 0.017, hazard ratio [HR] = 1.25, 95% CI = 1.04–1.5) than the GG genotype. These results suggest that GOLGA7 (rs11337) polymorphism may play a role in the prognosis of glioma patients and that TYMS (rs1059394) is associated with glioma risk. Keywords: GOLGA7, rs11337, polymorphism, cancer risk, prognosis, microRNA-binding site

Abstract DNA polymerase kappa (POLK), one of the specialized Y family DNA polymerases, functions in translesion synthesis and is suggested to be related with cancers. Single nucleotide polymorphisms (SNPs) in specialized DNA polymerases have been demonstrated to be associated with cancer risk. To evaluate the association of two common POLK variants (rs3213801 C>T and rs5744533 C>T) with glioma, we conducted a case‐control study and genotyped these two POLK variants in 605 patients and 1300 healthy controls. The association analysis revealed no significant correlations were observed between these two POLK SNPs and glioma risk. However, the POLK rs3213801 CT genotype was found to be higher in older glioma patients (≥40) than in younger patients (P = .026). Compared with patients harboring the CC genotype, the frequencies of POLK rs5744533 CT and CT+TT genotypes were increased in patients with lower World Health Organization (WHO) grade glioma (P = .028, 0.044, respectively). According to Kaplan‐Meier analysis and log‐rank tests, POLK SNPs were not correlated with either the overall survival or progression‐free survival. Nevertheless, multivariate analysis revealed that the age (≥40) could increase the risk of death in glioma patients (P

Abstract Background Hodgkin lymphoma (HL) is an uncommon B cell lymphoma. We assessed the global, regional, and national burden of HL from 1990 to 2017, by gender, age, and social-demographic index (SDI). Methods Data on HL, including incidence, mortality, and disability adjusted life-years (DALY), from 1990 to 2017 were obtained from the 2017 Global Burden of Disease study. Estimated annual percentage changes (EAPCs) were calculated to assess incidence rate, mortality, and DALY trends. Results HL incidences increased by 38.66%, from 72,937 in 1990 to 101,133 in 2017, while the age-standardized incidence rate (ASIR) was relatively stable. ASIR decreased in the low SDI regions (EAPC = − 2.58; 95% CI, from − 2.66 to − 2.49) and was stable in the other four SDI regions. Incidence showed a bimodal distribution with peak values in patients aged 20–39 years and patients aged 60 years or higher. The number of death cases and DALYs were stable. The age-standardized death rate decreased by 2.36% (95% CI, from − 2.43% to − 2.30%) per year. The annual age-standardized DALY rate decreased by 2.29% (95% CI, from − 2.36% to − 2.21%). The incidence and mortality in male subjects was higher than that in female subjects. The incidence in male and female subjects aged 15–30 years old was close, whereas the biggest difference existed in patients aged

Background: Exposure to ambient particulate matter pollution (APMP) is a global health issue that directly affects the human respiratory system. Thus, we estimated the spatiotemporal trends in the burden of APMP-related respiratory diseases from 1990 to 2019.Methods: Based on the Global Burden of Disease Study 2019, data on the burden of APMP-related respiratory diseases were analyzed by age, sex, cause, and location. Joinpoint regression analysis was used to analyze the temporal trends in the burden of different respiratory diseases over the 30 years.Results: Globally, in 2019, APMP contributed the most to chronic obstructive pulmonary disease (COPD), with 695.1 thousand deaths and 15.4 million disability-adjusted life years (DALYs); however, the corresponding age-standardized death and DALY rates declined from 1990 to 2019. Similarly, although age-standardized death and DALY rates since 1990 decreased by 24% and 40%, respectively, lower respiratory infections (LRIs) still had the second highest number of deaths and DALYs attributable to APMP. This was followed by tracheal, bronchus, and lung (TBL) cancer, which showed increased age-standardized death and DALY rates during the past 30 years and reached 3.78 deaths per 100,000 persons and 84.22 DALYs per 100,000 persons in 2019. Among children aged < 5 years, LRIs had a huge burden attributable to APMP, whereas for older people, COPD was the leading cause of death and DALYs attributable to APMP. The APMP-related burdens of LRIs and COPD were relatively higher among countries with low and low-middle socio-demographic index (SDI), while countries with high-middle SDI showed the highest burden of TBL cancer attributable to APMP.Conclusions: APMP contributed substantially to the global burden of respiratory diseases, posing a significant threat to human health. Effective actions aimed at air pollution can potentially avoid an increase in the PM2.5-associated disease burden, especially in highly polluted areas.

BackgroundThe 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.MethodsThis 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.ResultsThe 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

Beach intra-tidal bed level changes are of significance to coastal protection amid global climate changes. However, due to the limitation of instruments and the disturbance induced by wave motions superimposed on water levels, it was difficult to detect the high-frequency oscillation of the submerged beach bed level. In this study, an observation, lasting for 12 days and covering the middle tide to the following spring tide, was conducted on a meso-macro tidal beach, Yintan Beach, to simultaneously detect the characteristics and influence mechanism of bed level changes at intra-tidal and tidal cycle scales. The collected data included water depth, suspended sediment concentration (SSC), waves, high-frequency three-dimensional (3-D) velocity, and the distance of the seabed to the acoustic Doppler velocimeter (ADV) probe, which were measured by an optical backscatter sensor, two Tide & Wave Recorder-2050s, and an ADV, respectively. The results showed that the tidal cycle-averaged bed level decreased by 58.8 mm, increased by 12.6 mm, and increased by 28.9 mm during neap, middle, and spring tides in succession, respectively, compared with the preceding tidal regimes. The net erosion mainly resulted from large incident wave heights and the consequent strong offshore-directed sediment transport induced by undertows. Moreover, the variations in the bed level were more prominent during a neap to middle tides than during middle to spring tides, which were jointly caused by the wave-breaking probability regulated by water depth and the relative residence times of shoaling wave, breaker, and surf zones that were determined by relative tidal range. In terms of the intra-tidal bed level, it displayed an intra-tidal tendency of increase during floods and decrease during ebb tides, i.e., the intra-tidal bed level changes were controlled by water depth, which modulated the effects of waves on sediment resuspension and vertical sediment exchange. To be specific, waves and SSC were responsible for the intra-tidal bed level changes under low-energy wave conditions, while mean current and bedform exerted important influences on the variations of the intra-tidal bed level under moderate wave conditions, which broke the foregoing interrelation between bed level, waves, and SSC. This study, therefore, emphasizes the usage of ADV measurement to investigate bed level changes in sandy coasts.

BackgroundEpidemiological trends of type 2 diabetes mellitus attributable to fine particulate matter (PM2.5) pollution remain unclear. Here, we estimated spatiotemporal trends of type 2 diabetes mellitus burden attributable to PM2.5 pollution, including ambient particulate matter pollution (APMP) and household air pollution (HAP), from 1990–2019.MethodsData were obtained from the Global Burden of Disease Study 2019 and were analyzed by age, sex, year, and location. Joinpoint regression analysis was applied in the analysis of temporal trends in type 2 diabetes mellitus burden over the 30 years.ResultsGlobally, PM2.5 pollution contributed to 292.5 thousand deaths and 13 million disability-adjusted life-years (DALYs) in 2019. APMP ranked third among all risk factors, causing an increase in type 2 diabetes mellitus burden from 1990, whereas the impact of HAP significantly fell during the same period. Both APMP and HAP contributed the most to deaths and DALYs of type 2 diabetes mellitus among older people. However, the age-standardized death and DALY rates of type 2 diabetes mellitus attributable to APMP were greater among males and people in the middle socio-demographic index countries, especially in Southern Sub-Saharan Africa. For HAP, type 2 diabetes mellitus burden was modestly higher in females and was highest in Oceania, which was the only region with an increase from 1990.ConclusionsPM2.5 pollution resulted in substantial and increasing type 2 diabetes mellitus burden worldwide. Hence, governments and health systems should take steps to reduce air pollution to mitigate this increasing burden.

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.

BackgroundChronic kidney disease (CKD) is a public health problem largely caused by diabetes. The epidemiology of diabetes mellitus–related CKD (CKD-DM) could provide specific support to lessen global, regional, and national CKD burden.MethodsData were derived from the GBD 2019 study, including four measures and age-standardized rates (ASRs). Estimated annual percentage changes and 95% CIs were calculated to evaluate the variation trend of ASRs.ResultsDiabetes caused the majority of new cases and patients with CKD in all regions. All ASRs for type 2 diabetes–related CKD increased over 30 years. Asia and Middle socio-demographic index (SDI) quintile always carried the heaviest burden of CKD-DM. Diabetes type 2 became the second leading cause of CKD and CKD-related death and the third leading cause of CKD-related DALYs in 2019. Type 2 diabetes–related CKD accounted for most of the CKD-DM disease burden. There were 2.62 million incident cases, 134.58 million patients, 405.99 thousand deaths, and 13.09 million disability-adjusted life-years (DALYs) of CKD-DM worldwide in 2019. Age-standardized incidence (ASIR) and prevalence rate (ASPR) of type 1 diabetes–related CKD increased, whereas age-standardized death rate (ASDR) and DALY rate decreased for females and increased for males. In high SDI quintile, ASIR and ASPR of type 1 diabetes–related CKD remained the highest, with the slowest increase, whereas the ASDR and age-standardized DALY rate remained the lowest there. In high SDI quintile, ASIR of type 2 diabetes–related CKD was the highest, with the lowest increasing rate. In addition, type 2 diabetes–related CKD occurred most in people aged 80-plus years worldwide. The main age of type 2 diabetes–related CKD patients was 55–64 years in Asia and Africa. The prevalence, mortality, and DALY rate of type 2 diabetes–related CKD increased with age. As for incidence, there was a peak at 80 years, and after age of 80, the incidence declined. CKD-DM-related anemia was mainly in mild to moderate grade.ConclusionsIncreasing burden of CKD-DM varied among regions and countries. Prevention and treatment measures should be strengthened according to CKD-DM epidemiology, especially in middle SDI quintile and Asia.

Background: The prevalence rate of hypertension and breast cancer increases with advancing age. Renin-angiotensin system inhibitors (RASIs), β-blockers (BBs), calcium channel blockers (CCBs), and diuretics are widely used to treat patients with hypertension. Although, the association between the use of antihypertensive medication and breast cancer has been highly debated, recent evidence supporting this association remains controversial.Objective: To evaluate the association between the use of antihypertensive medication and the risk of breast cancer and its prognosis.Methods: This study was conducted using data from the PubMed, Embase, and Cochrane Library databases retrieved for the period from January 2000 to April 2021. Articles and their references were checked and summary effects were calculated using random- and fixed-effects models. Heterogeneity test and sensitivity analysis were also performed.Results: This meta-analysis included 57 articles, which were all related to breast cancer risk or prognosis. Assessment of breast cancer risk using the pooled data showed that the use of BBs or CCBs or diuretics was associated with increased cancer risk [BB: relative risk (RR) = 1.20, 95% confidence interval (CI) = 1.09–1.32; CCBs: RR = 1.06, 95% CI 1.03–1.08; diuretics: RR = 1.06, 95% CI 1.01–1.11]. Long-term use of diuretic increased the risk of breast cancer (RR = 1.10, 95% CI 1.01–1.20), whereas long-term RASIs treatment reduced the risk (RR = 0.78, 95% CI 0.68–0.91). In addition, we found that diuretic users may be related to elevated breast cancer-specific mortality [hazard ratio (HR) = 1.18, 95% CI 1.04–1.33], whereas using other antihypertensive medications was not associated with this prognosis in patients with breast cancer.Conclusion: Using CCBs, BBs, and diuretics increased the risk of breast cancer. In addition, diuretics may elevate the risk of breast cancer-specific mortality. The long-term use of RASIs was associated with a significantly lower breast cancer risk, compared with non-users. Thus, this analysis provides evidence to support the benefits of the routine use of RASIs in patients with hypertension, which has important public health implications.

Abstract Introduction It remains unclear whether marital status could affect the breast cancer‐caused special survival (BCSS) of patients with breast cancer. Therefore, we sought to explore the influence of demographic and pathological factors on prognosis of patients with breast cancer. Materials and methods We selected patients meeting the eligibility criteria from the Surveillance, Epidemiology, and End Results (SEER) cancer registry program. We assessed the effect of marital status on overall survival (OS) and BCSS using Kaplan‐Meier curve and multivariate Cox proportional hazards regression. Results Compared with divorced/separated/widowed (DSW) patients, the married (AHR 0.7483, 95% CI: 0.729‐0.7682, P