FBXO32-mediated degradation of PTEN promotes lung adenocarcinoma progression.

FBXO32, a member of the F-box protein family, is known to play both oncogenic and tumor-suppressive roles in different cancers. However, the functions and the molecular mechanisms regulated by FBXO32 in lung adenocarcinoma (LUAD) remain unclear. Here, we report that FBXO32 is overexpressed in LUAD compared with normal lung tissues, and high expression of FBXO32 correlates with poor prognosis in LUAD patients. Firstly, we observed with a series of functional experiments that FBXO32 alters the cell cycle and promotes the invasion and metastasis of LUAD cells. We further corroborate our findings using in vivo mouse models of metastasis and confirmed that FBXO32 positively regulates LUAD tumor metastasis. Using a proteomic-based approach combined with computational analyses, we found a positive correlation between FBXO32 and the PI3K/AKT/mTOR pathway, and identified PTEN as a FBXO32 interactor. More important, FBXO32 binds PTEN via its C-terminal substrate binding domain and we also validated PTEN as a bona fide FBXO32 substrate. Finally, we demonstrated that FBXO32 promotes EMT and regulates the cell cycle by targeting PTEN for proteasomal-dependent degradation. In summary, our study highlights the role of FBXO32 in promoting the PI3K/AKT/mTOR pathway via PTEN degradation, thereby fostering lung adenocarcinoma progression.

Identification of significant m6A regulators and immune microenvironment characterization in ischemic stroke.

The role of m6A modification in the regulation of the immune microenvironment (IME) of ischemic stroke (IS) is barely known. Thus, we aim to investigate the impact of m6A modification on the IME of IS and its diagnostic value in IS. We comprehensively assessed the m6A modification patterns, the relationship between these modification patterns and the characteristics of the IME. The m6A modification patterns of individual IS sample were quantified by m6Ascore. The performance of m6A phenotype-related genes as potential biomarkers was evaluated by the area under the receiver operating characteristic curve. Experimental validation was also performed by qRT-PCR. Six dysregulated m6A regulators were identified and a classification model consisting of four key m6A regulators (METLL3, RBMX, RBM15B, YTDHF3) could distinguish IS and healthy control samples well. METTL3 and YTHDF3 are closely related to circulating neutrophil abundance. Two distinct m6A modification patterns were determined which differed in immunocyte abundance. We also identified six m6A phenotype-related genes (APOBEC3A, PTMA, FCGR3A, LOC440926, LOC649946, and FTH1L11), and further explored their biological function. Among them, APOBEC3A, FCGR3A, and FTH1L11 were positively associated with neutrophil abundance. APOBEC3A and FCGR3A were stable diagnostic m6A-associated genes in both the discovery and validation cohorts. This study reveals that m6A modification plays a non-negligible role in the formation of a diversified and complex IME in IS. The m6A phenotype-related genes could be diagnostic biomarkers of IS.

Identification and validation of eight lysosomes-related genes signatures and correlation with immune cell infiltration in lung adenocarcinoma.

Lung cancer is the leading cause of cancer-related death. Lysosomes are key degradative compartments that maintain protein homeostasis. In current study, we aimed to construct a lysosomes-related genes signature to predict the overall survival (OS) of patients with Lung Adenocarcinoma (LUAD). Differentially expressed lysosomes-related genes (DELYs) were analyzed using The Cancer Genome Atlas (TCGA-LUAD cohort) database. The prognostic risk signature was identified by Least Absolute Shrinkage and Selection Operator (LASSO)-penalized Cox proportional hazards regression and multivariate Cox analysis. The predictive performance of the signature was assessed by Kaplan-Meier curves and Time-dependent receiver operating characteristic (ROC) curves. Gene set variant analysis (GSVA) was performed to explore the potential molecular biological function and signaling pathways. ESTIMATE and single sample gene set enrichment analysis (ssGSEA) were applied to estimate the difference of tumor microenvironment (TME) between the different risk subtypes. An eight prognostic genes (ACAP3, ATP8B3, BTK, CAV2, CDK5R1, GRIA1, PCSK9, and PLA2G3) signature was identified and divided patients into high-risk and low-risk groups. The prognostic signature was an independent prognostic factor for OS (HR > 1, p < 0.001). The molecular function analysis suggested that the signature was significantly correlated with cancer-associated pathways, including angiogenesis, epithelial mesenchymal transition, mTOR signaling, myc-targets. The low-risk patients had higher immune cell infiltration levels than high-risk group. We also evaluated the response to chemotherapeutic, targeted therapy and immunotherapy in high- and low-risk patients with LUAD. Furthermore, we validated the expression of the eight gene expression in LUAD tissues and cell lines by qRT-PCR. LYSscore signature provide a new modality for the accurate diagnosis and targeted treatment of LUAD and will help expand researchers' understanding of new prognostic models.

Cross-talk between necroptosis-related lncRNAs to construct a novel signature and predict the immune landscape of lung adenocarcinoma patients.

Background: As a new style of cell death, necroptosis plays a crucial role in tumor immune microenvironment. LncRNAs have been identified to act as competitive RNAs to influence genes involved in necroptosis. Therefore, we aim to create a signature based on necroptosis-related lncRNAs to predict the prognosis and immune landscape of lung adenocarcinoma (LUAD) patients in this study. Methods: TCGA database was used to acquire RNA sequencing (RNA-Seq) data and clinical information for 59 lung normal samples and 535 lung adenocarcinoma samples. The Pearson correlation analysis, univariate cox regression analysis and least absolute shrinkage and selection operator (LASSO) cox regression were performed to construct the prognostic NRlncRNAs signature. Then we used Kaplan-Meier (K-M) analysis, time-dependent ROC curves, univariate and multivariate cox regression analysis, and nomogram to validate this signature. In addition, GO, KEGG, and GSVA were analyzed to investigate the potential molecular mechanism. Moreover, we analyzed the relationship between our identified signature and immune microenvironment, TMB, and some clinical characteristics. Finally, we detected the expression of the six necroptosis-related lncRNAs in cells and tissues. Results: We constructed a NRlncRNAs signature consisting of six lncRNAs (FRMD6-AS1, LINC01480, FAM83A-AS1, FRMD6-AS1, MED4-AS1, and LINC01415) in LUAD. LUAD patients with high risk scores had lower chance of survival with an AUC of 0.739, 0.709, and 0.733 for 1-year, 3-year, and 5-year respectively. The results based on GO, KEGG, and GSVA enrichment analysis demonstrated that NRlncRNAs signature-related genes were mainly correlated with immune pathways, metabolic-and cell growth-related pathways, cell cycle, and apoptosis. Moreover, the risk score was correlated with the immune status of LUAD patients. Patients with higher risk scores had lower ESTIMATE scores and higher TIDE scores. The risk score was positively correlated with TMB. LINC01415, FRMD6-AS1 and FAM83A-AS1 were significantly overexpressed in lung adenocarcinoma, while the expression levels of MED4-AS1 and LINC01480 were lower in lung adenocarcinoma. Conclusion: Overall, an innovative prognostic signature based on NRlncRNAs was developed for LUAD through comprehensive bioinformatics analysis, which can act as a predictor of immunotherapy and may provide guidance for clinicians.

Identification of OTUD6B as a new biomarker for prognosis and immunotherapy by pan-cancer analysis.

Background: Ovarian-tumor (OTU) domain-containing protein 6B (OTUD6B), one of newly identified OTU deubiquitylating enzyme families, is proved to be associated with tumor progression. However, whether it plays a key role in pan-cancer still remains unknown. Methods: The profiles of OTUD6B expression in multiple cancers were analyzed using The Cancer Genome Atlas (TCGA) database. Information of protein expression was performed based on the HPA, GeneCards, and String databases. K-M plotter and survival data analysis were used to analyze the prognostic value of OTUD6B expression, including overall survival (OS), disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI). R package "clusterProfiler" was used for enrichment analysis of OTUD6B. Furthermore, we analyzed the correlation between the expression of OTUD6B, immune infiltration, and immune-related genes. Additionally, we preliminarily validated its tumorigenic effect in lung cancer cell lines. Findings: OTUD6B expression was upregulated in most cancers, such as COAD, CHOL, and LUAD, and predicted poor prognosis in most cancers in TCGA. Results showed that OTUD6B expression was positively correlated with memory CD4+ T cells, Th1 CD4+ T cells, and CD8+ T cells. In terms of the immune-related genes, OTUD6B was found to be associated with most types of genes, such as immunostimulatory genes KDR, TGFBR1, and IL-10. Moreover, for most types of tumors, the immune score was found to be negatively correlated with OTUD6B expression. In addition, lung cancer cell lines with OTUD6B knockdown significantly inhibited proliferation and invasion ability of lung cancer cells. Conclusions: The study indicated that OTUD6B is an oncogene and may serve as a new potential biomarker in various tumors. OTUD6B may play a part in TIME, which could be applied as a new target for cancer therapy.

DNA methylation regulators-related molecular patterns and tumor immune landscape in hepatocellular carcinoma.

Increasing evidence showed that the dysregulation of DNA methylation regulators is a decisive feature of almost all cancer types and affects tumor progressions. However, few studies focused on the underlying influences of DNA methylation regulators-related genes (DMRegs) in immune cell-infiltration characteristics, tumor microenvironment (TME) and immunotherapy in HCC patients. In our study, the alterations of DNA methylation regulators modification patterns (DMRPs) were clustered from hepatocellular carcinoma (HCC) samples based on the expression of DNA methylation regulators as well as genetic and transcriptional features. In addition, based on molecular identification of three distinct molecular subtypes, we found that different DMRPs alterations were related to different clinicopathological characteristics, prognosis, and immune cells infiltration features. Moreover, we constructed and validated a DNA methylation regulators-related genes score (DMRegs_score) to predict the survival of HCC patients. A high DMRegs _score, which was characterized by more TP53 wild mutation, high expression of PD-1, CTLA-4, and remarkable immunity activation, was indicative of poor prognosis. Furthermore, we validated the expression of eight genes which were used for the prognostic signature in this risk score by RT-qPCR using tissues from our center. More importantly, DMRegs_score was highly correlated with targeted drug sensitivity. Additionally, we developed a highly accurate scoring system that could be used to improve the clinical applicability of DMRegs _score. In conclusion, these findings may contribute to a better understanding of DNA methylation regulators and provide new strategies for evaluating prognosis and developing more effective combination therapy for HCC patients.

Comprehensive analysis of the prognostic value and immune infiltration of FGFR family members in gastric cancer.

Background: Fibroblast growth factor receptors (FGFRs) modulate numerous cellular processes in tumor cells and tumor microenvironment. However, the effect of FGFRs on tumor prognosis and tumor-infiltrating lymphocytes in gastric cancer (GC) remains controversial. Methods: The expression of four different types of FGFRs was analyzed via GEPIA, TCGA-STAD, and GTEX databases and our 27 pairs of GC tumor samples and the adjacent normal tissue. Furthermore, the Kaplan-Meier plot and the TCGA database were utilized to assess the association of FGFRs with clinical prognosis. The R software was used to evaluate FGFRs co-expression genes with GO/KEGG Pathway Enrichment Analysis. In vitro and in vivo functional analyses and immunoblotting were performed to verify FGFR4 overexpression consequence. Moreover, the correlation between FGFRs and cancer immune infiltrates was analyzed by TIMER and TCGA databases. And the efficacy of anti-PD-1 mAb treatment was examined in NOG mouse models with overexpressed FGFR1 or FGFR4. Results: The expression of FGFRs was considerably elevated in STAD than in the normal gastric tissues and was significantly correlated with poor OS and PFS. ROC curve showed the accuracy of the FGFRs in tumor diagnosis, among which FGFR4 had the highest ROC value. Besides, univariate and multivariate analysis revealed that FGFR4 was an independent prognostic factor for GC patients. According to a GO/KEGG analysis, the FGFRs were implicated in the ERK/MAPK, PI3K-AKT and extracellular matrix (ECM) receptor signaling pathways. In vivo and in vitro studies revealed that overexpression of FGFR4 stimulated GC cell proliferation, invasion, and migration. In addition, FGFR1 expression was positively correlated with infiltrating levels of CD8+ T-cells, CD4+ T-cells, macrophages, and dendritic cells in STAD. In contrast, FGFR4 expression was negatively correlated with tumor-infiltrating lymphocytes. Interestingly, overexpression of FGFR1 in the NOG mouse model improved the immunotherapeutic impact of GC, while overexpression of FGFR4 impaired the effect. When combined with an FGFR4 inhibitor, the anti-tumor effect of anti-PD-1 treatment increased significantly in a GC xenograft mouse model with overexpressed FGFR4. Conclusions: FGFRs has critical function in GC and associated with immune cell infiltration, which might be a potential prognosis biomarker and predictor of response to immunotherapy in GC.

Identification of an Endoplasmic Reticulum Stress-Related Gene Signature to Evaluate the Immune Status and Predict the Prognosis of Hepatocellular Carcinoma.

Liver cancer is the sixth most frequently diagnosed primary malignancy and ranks as the third leading cause of cancer-related death worldwide in 2020. ER stress also plays a vital role in the pathogenesis of malignancies. In the current study, we aimed to construct an endoplasmic reticulum stress-related genes (ERGs) signature to predict the overall survival (OS) of patients with HCC. Differentially expressed ERGs (DE-ERGs) were analyzed using The Cancer Genome Atlas (TCGA-LIHC cohort) and International Cancer Genome Consortium (ICGC-LIRI-JP cohort) databases. The prognostic gene signature was identified by the univariate Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO)-penalized Cox proportional hazards regression analysis. The predictive ability of the model was evaluated by utilizing Kaplan-Meier curves and time-dependent receiver operating characteristic (ROC) curves. Gene set variant analysis (GSVA) was performed to explore the underlying biological processes and signaling pathways. CIBERPORT and single-sample Gene Set Enrichment Analysis (ssGSEA) were implemented to estimate the immune status between the different risk groups. A total of 113 DE-ERGs were identified between 50 normal samples and 365 HCC samples in the TCGA-LIHC cohort, and 48 DE-ERGs were associated with OS through the univariate Cox regression. A six DE-ERGs (PPARGC1A, SQSTM1, SGK1, PON1, CDK1, and G6PD) signature was constructed and classified patients into high-risk and low-risk groups. The risk score was an independent prognostic indicator for OS (HR > 1, p < 0.001). The function enrichment analysis indicated that cell cycle, RNA degradation, protein localization, and cell division were the main biological processes. The high-risk group had higher immune cell infiltration levels than those of the low-risk group. We predicted the response to targeted therapy in high- and low-risk patients with HCC and found that the high-risk patients were more sensitive to pazopanib. At last, we verified the expression of the six gene patterns in HCC tissues by qRT-PCR and immunohistochemistry. This signature may be a potential tool to provide a choice for prognosis prediction and personal management of patients with HCC.

LINC00891 regulated by miR-128-3p/GATA2 axis impedes lung cancer cell proliferation, invasion and EMT by inhibiting RhoA pathway.

Long non-coding RNA (lncRNA) LINC00891 knockdown is associated with poor prognosis of lung adenocarcinoma, but the underlying mechanism remains to be further explored. Here, we found that LINC00891 expression is downregulated in lung cancer tissues and cell lines compared with that in adjacent normal tissues and normal lung epithelial cells. LINC00891 overexpression impedes cell proliferation, invasion, migration and epithelial-to-mesenchymal transition (EMT) process in lung cancer cells. Mechanistic research showed that GATA2 directly binds to LINC00891 promoter and transcriptionally regulates LINC00891 expression. Meanwhile, GATA2 was identified as a target of miR-128-3p, and it is negatively regulated by miR-128-3p. Moreover, overexpression of GATA2 suppresses lung cancer cell proliferation, invasion, migration, and EMT process. Furthermore, LINC00891 restrains the RhoA pathway activity, and treatment with CCG-1423 (a specific RhoA pathway inhibitor) antagonizes the promoting effect of LINC00891 knockdown on cell malignant behaviors. Additionally, silencing of LINC00891 promotes xenograft tumor growth, which can be reversed by administration with CCG-1423. In summary, LINC00891 regulated by the miR-128-3p/GATA2 axis restrains lung cancer cell malignant progression and hinders xenograft tumor growth by suppressing the RhoA pathway.

Anisodamine Enhances Macrophage M2 Polarization through Suppressing G9a-Mediated Interferon Regulatory Factor 4 Silencing to Alleviate Lipopolysaccharide-Induced Acute Lung Injury.

Acute lung injury (ALI) is a serious inflammatory lung disease. Imbalances in the polarization of classically activated (M1) and alternatively activated (M2) macrophages are closely related to ALI. Anisodamine has a promising therapeutic effect for septic shock. Nevertheless, the role of anisodamine in progression of ALI remains to be investigated. Our results showed that anisodamine significantly reduced lung damage, myeloperoxidase (MPO) activity, lung wet/dry ratio, total cell number, and protein concentrations in bronchoalveolar lavage fluid and decreased interleukin (IL)-6 level and the levels of M1 phenotypic markers, whereas it increased IL-10 level and the levels of M2 phenotypic markers in mice with a nasal instillation of lipopolysaccharide (LPS). Bone marrow-derived macrophages (BMDMs) were stimulated or transfected with LPS plus anisodamine or LPS plus G9a short hairpin RNA. Anisodamine and downregulation of G9a both promoted BMDM M2 polarization caused by IL-4 treatment and inhibited M1 polarization resulting from LPS treatment. Chromatin immunoprecipitation assay revealed that anisodamine inhibited G9a-mediated methylation and expression suppression on interferon regulatory factory 4 (IRF4). Overexpression of G9a or silence of IRF4 reversed the improvement effect of anisodamine on lung tissue injury, evidenced by an increase of MPO activity and the restoration of LPS-induced alterations of M1 and M2 polarization. In conclusion, anisodamine protected against LPS-induced ALI, during which anisodamine suppressed the LPS-stimulated alterations of macrophage M1 and M2 polarization through inhibiting G9a-mediated methylation of IRF4, suggesting that anisodamine was a potential therapeutic drug to alleviate ALI. SIGNIFICANCE STATEMENT: Anisodamine treatment was able to attenuate lung injury and pulmonary edema caused by lipopolysaccharide (LPS) stimulation, and the specific mechanism was that anisodamine reversed the LPS-induced alterations of M1 and M2 polarization by inhibiting G9a-mediated methylation and expression suppression of interferon regulatory factor 4, which suggests that anisodamine has the potential to alleviate acute lung injury.

Identification and validation of prognosis-associated DNA repair gene signatures in colorectal cancer.

Colorectal cancer (CRC) is the third most common malignant tumor. DNA damage plays a crucial role in tumorigenesis, and abnormal DNA repair pathways affect the occurrence and progression of CRC. In the current study, we aimed to construct a DNA repair-related gene (DRG) signature to predict the overall survival (OS) of patients with CRC patients. The differentially expressed DRGs (DE-DRGs) were analyzed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The prognostic gene signature was identified by univariate Cox regression and least absolute shrinkage and selection operator (LASSO)-penalized Cox proportional hazards regression analysis. The predictive ability of the model was evaluated using the Kaplan-Meier curves and time-dependent receiver operating characteristic (ROC) curves. The gene set enrichment analysis (GSEA) was performed to explore the underlying biological processes and signaling pathways. ESTIMATE and CIBERSORT were implemented to estimate the tumor immune score and immune cell infiltration status between the different risk group. The half-maximal inhibitory concentration (IC50) was evaluated to representing the drug response of this signature. Nine DE-DRGs (ESCO2, AXIN2, PLK1, CDC25C, IGF1, TREX2, ALKBH2, ESR1 and MC1R) signatures was constructed to classify patients into high- and low-risk groups. The risk score was an independent prognostic indicator of OS (hazard ratio > 1, P < 0.001). The genetic alteration analysis indicated that the nine DE-DRGs in the signature were changed in 63 required samples (100%), and the major alteration was missense mutation. Function enrichment analysis revealed that the immune response and mtotic sister chromatid segregation were the main biological processes. The high-risk group had higher immune score than the low-risk group. What's more, low-risk patients were more sensitive to selumetinib and dasatinib. The nine DE-DRGs signature was significantly associated with OS and provided a new insight for the diagnosis and treatment of CRC.

Association of methylenetetrahydrofolate reductase (MTHFR) rs1801133 (677C>T) gene polymorphism with ischemic stroke risk in different populations: An updated meta-analysis.

Background: Recently, increasing evidence has implicated methylenetetrahydrofolate reductase (MTHFR) gene mutation as a risk factor for ischemic stroke (IS) in the general population. However, studies have been inconclusive and lack evidence on specific populations. We aim to determine whether the rs1801133 (NC_000001.11 (MTHFR):g. 677C>T (p.Ala222Val) variant, we termed as MTHFR rs1801133 (677 C>T), is linked to an increased risk of IS in different age groups and ancestry groups. Methods: The literature relevant to our study was found by searching the PubMed, Cochrane Library, Web of Science, EMBASE, and CNKI databases. A random effect model analysis was used to calculate the pooled odds ratio (OR) and 95% confidence interval (CI) to evaluate any possible association. We conducted a subgroup analysis based on the age and ancestry groups of the included populations. Results: As of March 2022, 1,925 citations had been identified in electronic databases, of which 96 studies involving 34,814 subjects met our eligibility criteria. A strong link was found between IS and the MTHFR gene rs1801133 (677C>T) polymorphism in all genetic models [dominant genetic model (OR = 1.47; 95%CI = 1.33-1.61; p < 0.001), recessive genetic model (OR = 1.52; 95%CI = 1.36-1.71; p < 0.001), heterozygous model (OR = 1.36; 95%CI = 1.24-1.48; p < 0.001), homozygous model (OR = 1.82; 95%CI = 1.58-2.11; p < 0.001), and T allelic genetic model (OR = 1.37; 95%CI = 1.27-1.48; p < 0.001)]. Further subgroup analyses indicated that the MTHFR rs1801133 (677C>T) variant may increase the risk of IS in Asian, Hispanic, or Latin population, middle-aged, and elderly populations (p < 0.001). Conclusion: Our results implied that mutation of the T allele of MTHFR rs1801133 (677C>T) could be a risk factor for IS. A significant association was found among Asian, Hispanic, or Latin population, middle-aged, and elderly people.

Association of folate intake and plasma folate level with the risk of breast cancer: a dose-response meta-analysis of observational studies.

Epidemiological studies showing the correlation between folate and the breast cancer risk have revealed inconsistent results. Hence, we conducted a dose-response meta-analysis of observational studies to obtain more reliable conclusions. We searched PubMed and Embase for studies published before April 2019 and identified 39 studies on folate intake and 12 studies on plasma folate level. The combined odds ratios (ORs) and 95% confidence intervals (CIs) were extracted to estimate the breast cancer risk. Folate intake was inversely correlated with the breast cancer risk when the highest and lowest categories (OR = 0.85, 95% CI = 0.79-0.92) were compared, and the dose-response result showed that folate intake had a linear correlation with the breast cancer risk. Moreover, a higher folate intake correlated with a lower breast cancer risk in premenopausal women (OR = 0.80, 95% CI = 0.66-0.97), but not in postmenopausal women (OR = 0.94, 95% CI = 0.83-1.06). However, plasma folate levels were not correlated with the breast cancer risk (OR = 0.98, 95% CI = 0.82-1.17). Folate intake was negatively correlated with the breast cancer risk; however, its practical clinical significance requires further study. Furthermore, additional folate supplements should be considered carefully.

Global Burden of Thyroid Cancer From 1990 to 2017.

Importance: Thyroid cancer is the most pervasive endocrine cancer worldwide. Studies examining the association between thyroid cancer and country, sex, age, sociodemographic index (SDI), and other factors are lacking. Objective: To examine the thyroid cancer burden and variation trends at the global, regional, and national levels using data on sex, age, and SDI. Design, Setting, and Participants: In this cross-sectional study, epidemiologic data were gathered using the Global Health Data Exchange query tool, covering persons of all ages with thyroid cancer in 195 countries and 21 regions from January 1, 1990, to December 31, 2017; data analysis was completed on October 1, 2019. All participants met the Global Burden of Disease Study inclusion criteria. Main Outcomes and Measures: Outcomes included incidence, deaths, and disability-adjusted life-years (DALYs) of thyroid cancer. Measures were stratified by sex, region, country, age, and SDI. The estimated annual percentage changes (EAPCs) and age-standardized rates were calculated to evaluate the temporal trends. Results: Increases of thyroid cancer were noted in incident cases (169%), deaths (87%), and DALYs (75%). Age-standardized incidence rate (ASIR) showed an upward trend over time, with an EAPC of 1.59 (95% CI, 1.51-1.67); decreases were noted in EAPCs of age-standardized death rate (-0.15; 95% CI, -0.19 to -0.12) and age-standardized DALY rate (-0.11; 95% CI, -0.15 to -0.08). Almost half (41.73% for incidence, 50.92% for deaths, and 54.39% for DALYs) of the thyroid cancer burden was noted in Southern and Eastern Asia. In addition, females accounted for most of the thyroid cancer burden (70.22% for incidence, 58.39% for deaths, and 58.68% for DALYs) and increased by years in this population, although the ASIR of males with thyroid cancer (EAPC, 2.18; 95% CI, 2.07-2.28) increased faster than that of females (EAPC, 1.38; 95% CI, 1.30-1.46). A third (34%) of patients with thyroid cancer resided in countries with a high SDI, and most patients were aged 50 to 69 years, which was older than the age in other quintiles (high SDI quintile compared with all other quintiles, P<.05). The most common age at onset of thyroid cancer worldwide was 15 to 49 years in female individuals compared with 50 to 69 years in male individuals (P<.05). Death from thyroid cancer was concentrated in participants aged 70 years or older and increased by years (average annual percentage change, 0.10; 95% CI, 0.01-0.21; P<.05). Furthermore, people in lower SDI quintiles developed thyroid cancer and died from it earlier than those in other quintiles (high and high-middle SDI vs low and low-middle SDI, P<.05). Conclusions and Relevance: Data from this study suggest considerable heterogeneity in the epidemiologic patterns of thyroid cancer across sex, age, SDI, region, and country, providing information for governments that may help improve national and local cancer control policies.

Meta-analysis of the association between nut consumption and the risks of cancer incidence and cancer-specific mortality.

Previous studies have indicated a correlation between nut intake and cancer risk in humans. This meta-analysis aimed to determine the relationship between nut consumption and the risks of cancer incidence and mortality. The PubMed, Embase, and Web of Science databases were searched up to August 2019. Relative risks and 95% confidence intervals were calculated using random-effects and fixed-effects models. We included 38 studies on nut consumption and cancer risk and 9 studies on cancer-specific mortality. Compared with no nut intake, nut intake was associated with a lower cancer risk (Relative Risk=0.90; 95% confidence interval, 0.86-0.94). Inverse associations were observed with colorectal cancer, gastric cancer, pancreatic cancer, and lung cancer in subgroup analyses. Tree nut consumption was found to reduce cancer risk (Relative Risk=0.88; 95% confidence interval, 0.79-0.99). Dose-response curves suggested that protective benefits against cancer increased with increased nut intake (P=0.005, P-nonlinearity=0.0414). An inverse correlation with cancer-specific mortality (Odd Ratio=0.90; 95% confidence interval, 0.88-0.92) was observed. In conclusion, nut consumption is inversely associated with the risks of cancer incidence and mortality; a higher intake is significantly associated with a lower cancer risk.

Incidence and disease burden of prostate cancer from 1990 to 2017: Results from the Global Burden of Disease Study 2017.

BACKGROUND: The patterns of the incidence and mortality of prostate cancer (PC) have been changing over the years. In addition, the unclear etiology of PC necessitates further studies into the geographic distribution and age composition of patients with PC. This study was aimed at examining the patterns of the epidemiology of PC to help policymakers to allocate the limited resources of the health care system accordingly. METHODS: Annual case data and age-standardized rates (ASRs) were obtained for the incidence, mortality, and disability-adjusted life-years (DALYs) of PC according to age from 1990 to 2017 and for 21 regions, including 195 countries and territories. The estimated annual percentage changes (EAPCs) of ASRs were calculated to evaluate the incidence and mortality trends of PC. RESULTS: Worldwide, the age-standardized incidence rate (ASIR) of PC increased from 30.5 cases per 100,000 population in 1990 to 37.9 cases per 100,000 population in 2017 with an EAPC of 0.59 (95% confidence interval [CI], 0.49-0.7), whereas the mortality decreased with an EAPC of -0.73 (95% CI, -0.80 to -0.67). The ASIR was positively associated with the sociodemographic index (SDI) in most regions, and the increase in the ASIR was steeper with a higher SDI. The proportion of patients younger than 65 years increased from 23.6% in 1990 to 27.3% in 2017. CONCLUSIONS: The incidence of PC has been increasing globally, whereas its mortality and DALYs have been decreasing. These trends are particularly significant in developed regions and vary across geographic regions. Adjustments to the medical strategy by governments and medical institutions are required.

Global burden of larynx cancer, 1990-2017: estimates from the global burden of disease 2017 study.

Larynx cancer is one of the most common cancers in head and neck. This study aimed to investigate the health burden of larynx cancer at global, regional, and national levels. We collected data of larynx cancer between 1990 and 2017 from the Global Burden of Disease study, including incidence, mortality, and disability adjusted life-years (DALYs). Estimated annual percentage changes (EAPCs) were calculated to assess the changes in age-standardized rate (ASR) of larynx cancer. From 1990 to 2017, LC incident cases increased by 58.67%; however, age-standardized incidence rate (ASIR) decreased, with an EAPC of -0.99. Additionally, the incident cases and ASIR of LC were 6-fold higher for male than those for female in 2017. Over the past 28 years, deaths and DALYs of larynx cancer increased by 33.84% and 25%. Contrarily, age-standardized death and DALY rate showed a downward trend. Incidence, death, and DALYs of larynx cancer were always the highest in people aged 50-69 years. Overall, all the ASRs showed downward trends globally. The majority of larynx cancer burden was observed in men, especially among male aged 50-69 years. South and East Asia carried the heaviest burden of larynx cancer worldwide.

Antihypertensive medications are associated with the risk of kidney and bladder cancer: a systematic review and meta-analysis.

Several studies have indicated that the use of antihypertensive medications may influence the incidence of bladder/kidney cancer, with some scholars refuting any such association. Hence, a systematic review is needed to verify this linkage. we comprehensively searched PubMed, Embase, Web of Science, and the Cochrane Library for original studies reporting a relationship between antihypertensive medications and risk of bladder/kidney cancer. We included 31 articles comprising 3,352,264 participants. We found a significant association between the risk of kidney cancer and any antihypertensive medications use (relative risk (RR) = 1.45, 95% CI 1.20-1.75), as well as angiotensin-converting enzyme inhibitors (RR = 1.24, 95% CI 1.04-1.48), angiotensin II receptor blockers (ARB) (RR = 1.29, 95% CI:1.22-1.37), beta-blockers (RR = 1.36, 95% CI 1.11-1.66), calcium-channel blockers (RR = 1.65, 95% CI 1.54-1.78) and diuretics (RR = 1.34, 95% CI 1.19-1.51). In case of bladder cancer, a statistical significance was observed with the use of ARB (RR = 1.07, 95% CI 1.03-1.11) but not with the other antihypertensive medications. There was a linear association between the duration of antihypertensive medications and the risk of kidney cancer (P = 0.061 for a non-linear trend) and the pooled RR for the per year increase in antihypertensive medications duration of use was 1.02 (95% CI: 1.01-1.02). Our results indicate that there is a significant association between each class of antihypertensive medications and the risk of kidney cancer, and this trend presented as a positive linear association. Furthermore, the use of ARB has been linked to the risk of bladder cancer.

Global burden of breast cancer and attributable risk factors in 195 countries and territories, from 1990 to 2017: results from the Global Burden of Disease Study 2017.

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.

Vitamin D intake, blood vitamin D levels, and the risk of breast cancer: a dose-response meta-analysis of observational studies.

Epidemiological studies have indicated that blood vitamin D levels are linked to cancer. Here we conducted a dose-response meta-analysis based on published observational studies to evaluate the association of vitamin D intake and blood vitamin D levels with breast cancer susceptibility. PubMed, EMBASE, and Web of Science databases were searched up to January 2019. The pooled odds ratio (OR) and 95% confidence intervals (CIs) were extracted to estimate the risk. We identified 70 relevant studies on blood vitamin D levels (50 studies) and vitamin D intake (20 studies), respectively. Linear and nonlinear trend analyses were performed and showed that an increase in blood vitamin D levels by 5 nmol/l was associated with a 6% decrease in breast cancer risk (OR = 0.94, 95% CI = 0.93-0.96). Similar results were obtained for premenopausal (OR = 0.96, 95% CI = 0.93-0.99) and postmenopausal women (OR = 0.96, 95% CI = 0.94-0.98). The pooled OR of breast cancer risk for a 400IU/day increase in vitamin D intake was 0.97 (95% CI = 0.92-1.02). In conclusion, we found that breast cancer risk was inversely related to blood vitamin D levels; however, no significant association was observed in vitamin D intake.