Fresh fruit, dried fruit, raw vegetables, and cooked vegetables consumption associated with progression trajectory of type 2 diabetes: a multi-state analysis of a prospective cohort.

PURPOSE: To examine the effects of fresh fruit, dried fruit, raw vegetables, and cooked vegetables on type 2 diabetes (T2D) progression trajectory. METHODS: We included 429,886 participants in the UK Biobank who were free of diabetes and diabetes complications at baseline. Food groups were determined using a validated food frequency questionnaire. Outcomes were T2D incidence, complications, and mortality. Multi-state model was used to analyze the effects of food groups on T2D progression. RESULTS: During a follow-up of 12.6 years, 10,333 incident T2D cases were identified, of whom, 3961 (38.3%) developed T2D complications and 1169 (29.5%) died. We found that impacts of four food groups on T2D progression varied depending on disease stage. For example, compared to participants who ate less than one piece of dried fruit per day, the hazard ratios and 95% confidence intervals for those who ate ≥ 2 pieces of dried fruit per day were 0.82 (0.77, 0.87), 0.88 (0.85, 0.92), and 0.86 (0.78, 0.95) for transitions from diabetes-free state to incident T2D, from diabetes-free state to total death, and from incident T2D to T2D complications, respectively. Higher intake of fresh fruit was significantly associated with lower risk of disease progression from diabetes-free state to all-cause death. Higher intake of raw and cooked vegetables was significantly associated with lower risks of disease progression from diabetes-free state to incident T2D and to total death. CONCLUSIONS: These findings indicate that higher intake of fresh fruit, dried fruit, raw vegetables, and cooked vegetables could be beneficial for primary and secondary prevention of T2D.

Associations of glycosylated hemoglobin, pre-diabetes, and type 2 diabetes with incident lung cancer: A large prospective cohort study.

BACKGROUND: The association of pre-diabetes and type 2 diabetes (T2D) with incident lung cancer is uncertain, and the incident risk across the glycemic spectrum is unclear. We aimed to explore the associations of glycosylated hemoglobin (HbA1c), pre-diabetes, and T2D with incident lung cancer in a large prospective cohort. METHODS: Leveraging a total of 210,779 cancer-free adults recruited in the UK Biobank between 2006 and 2010. We performed multivariable Cox proportional hazards models and restricted cubic spline methods to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the associations of HbA1c, pre-diabetes, and T2D with incident lung cancer. RESULTS: During a median follow-up of 11.06 years, 1738 incident lung cancer cases were ascertained. The incidence of lung cancer was 20% higher among people with diabetes (HR: 1.20, 95% CI: 1.02 to 1.42) and 38% higher among people with pre-diabetes (HR: 1.38, 95% CI: 1.15 to 1.65). After dividing people with diabetes by whether taking antidiabetic medications, the incidence was 28% higher among people with diabetes without medications (HR: 1.28, 95% CI: 1.02 to 1.61) and 15% higher among people with diabetes with medications (HR: 1.15, 95% CI: 0.93 to 1.41). The increased risk of incident lung cancer for each standard deviation (6.45 mmol/mol) increase in HbA1c was more pronounced across HbA1c values of 32-42 mmol/mol (HR: 1.37, 95% CI: 1.18 to 1.59). The risk was more pronounced among participants <60 years. CONCLUSIONS: Pre-diabetes and T2D are associated with an increased incidence of lung cancer. The increased risk of incident lung cancer is more pronounced across HbA1c values of 32-42 mmol/mol, which are currently considered normal values.

Conditional survival probability of distant-metastatic hepatocellular carcinoma: A population-based study.

BACKGROUND: The prognosis of many patients with distant metastatic hepatocellular carcinoma (HCC) improved after they survived for several months. Compared with traditional survival analysis, conditional survival (CS) which takes into account changes in survival risk could be used to describe dynamic survival probabilities. AIM: To evaluate CS of distant metastatic HCC patients. METHODS: Patients diagnosed with distant metastatic HCC between 2010 and 2015 were extracted from the Surveillance, Epidemiology and End Results database. Univariate and multivariate Cox regression analysis were used to identify risk factors for overall survival (OS), while competing risk model was used to identify risk factors for cancer-specific survival (CSS). Six-month CS was used to calculate the probability of survival for an additional 6 mo at a specific time after initial diagnosis, and standardized difference (d) was used to evaluate the survival differences between subgroups. Nomograms were constructed to predict CS. RESULTS: Positive α-fetoprotein expression, higher T stage (T3 and T4), N1 stage, non-primary site surgery, non-chemotherapy, non-radiotherapy, and lung metastasis were independent risk factors for actual OS and CSS through univariate and multivariate analysis. Actual survival rates decreased over time, while CS rates gradually increased. As for the 6-month CS, the survival difference caused by chemotherapy and radiotherapy gradually disappeared over time, and the survival difference caused by lung metastasis reversed. Moreover, the influence of age and gender on survival gradually appeared. Nomograms were fitted for patients who have lived for 2, 4 and 6 mo to predict 6-month conditional OS and CSS, respectively. The area under the curve (AUC) of nomograms for conditional OS decreased as time passed, and the AUC for conditional CSS gradually increased. CONCLUSION: CS for distant metastatic HCC patients substantially increased over time. With dynamic risk factors, nomograms constructed at a specific time could predict more accurate survival rates.

Road traffic death coding quality in the WHO Mortality Database.

Objective: To evaluate the precision and dependability of road traffic mortality data recorded in the World Health Organization Mortality Database and investigate how uncorrected data influence vital mortality statistics used in traffic safety programmes worldwide. Methods: We assessed country and territory-specific data quality from 2015 to 2020 by calculating the proportions of five types of nonspecific cause of death codes related to road traffic mortality. We compared age-adjusted road traffic mortality and changes in the average annual mortality rate before and after correcting the deaths with nonspecific codes. We generated road traffic mortality projections with both corrected and uncorrected codes, and redistributed the data using the proportionate method. Findings: We analysed data from 124 countries and territories with at least one year of mortality data from 2015 to 2020. The number of countries and territories reporting more than 20% of deaths with ill-defined or unknown cause was 2; countries reporting injury deaths with undetermined intent was 3; countries reporting unspecified unintentional injury deaths was 21; countries reporting unspecified transport crash deaths was 3; and countries reporting unspecified unintentional road traffic deaths was 30. After redistributing deaths with nonspecific codes, road traffic mortality changed by greater than 50% in 7% (5/73) to 18% (9/51) of countries and territories. Conclusion: Nonspecific codes led to inaccurate mortality estimates in many countries. We recommend that injury researchers and policy-makers acknowledge the potential pitfalls of relying on raw or uncorrected road traffic mortality data and instead use corrected data to ensure more accurate estimates when improving road traffic safety programmes.

Dietary Diversity and Inflammatory Diet Associated with All-Cause Mortality and Incidence and Mortality of Type 2 Diabetes: Two Prospective Cohort Studies.

A higher dietary diversity score (DDS) and a lower energy-adjusted dietary inflammatory index (E-DII) may be associated with lower risks of type 2 diabetes (T2D) and mortality. This cohort study aimed to investigate the associations of DDS and E-DII with all-cause mortality, incidence of T2D, and mortality of T2D, as well as the joint effects of these two dietary factors. A total of 181,360 participants without all types of diabetes at baseline from the UK Biobank and 42,139 participants from the US NHANES were included. Cox proportional hazards models were used to assess the associations of DDS and E-DII with outcomes. In the UK Biobank data, 8338 deaths, 3416 incident T2D cases, and 353 T2D deaths occurred during a median follow-up of 12.5 years. In the US NHANES data, 6803 all-cause deaths and 248 T2D-specific deaths were recorded during a median follow-up of 9.6 years. We observed that higher DDS and lower E-DII were significantly associated with lower risks of total mortality and incident T2D. Compared with low DDS, the hazard ratios (HRs) and 95% confidence intervals (CIs) of high DDS were 0.69 (0.64, 0.74) for all-cause mortality, 0.79 (0.70, 0.88) for incident T2D in the UK Biobank, and 0.69 (0.61, 0.78) for all-cause mortality in the US NHANES. Compared with participants in tertile 3 of E-DII, those in tertile 1 had a lower risk of overall death [HR 0.86 (95% CI: 0.81, 0.91) in UK Biobank; 0.83 (0.77, 0.88) in US NHANES] and incident T2D [0.86 (0.79, 0.94)] in UK Biobank. No evidence was observed of the interactive effects of DDS and E-DII on either all-cause mortality or the incidence and mortality of T2D. There was no significant association found between any exposure and T2D mortality in this study. In conclusion, our results revealed that higher DDS and lower E-DII were associated with both total mortality and incident T2D in UK and US adults.

The effects of long-term exposure to air pollution on incident mental disorders among patients with prediabetes and diabetes: Findings from a large prospective cohort.

BACKGROUND: The association between air pollution and mental disorders has been widely documented in the general population. However, the evidence among susceptible populations, such as individuals with prediabetes or diabetes, is still insufficient. METHODS: We analyzed data from 48,515 participants with prediabetes and 24,393 participants with diabetes from the UK Biobank. Annual pollution data were collected for fine particulate matter (PM2.5), inhalable particulate matter (PM10), nitrogen dioxide (NO2), and nitrogen dioxides (NOx) during 2006-2021. The exposure to air pollution and temperature for each participant were estimated by the bilinear interpolation approach and time-weighted method based on their geocoded home addresses and time spent at each address. We employed the generalized propensity score model based on the generalized estimating equation and the time-varying covariates Cox model to assess the effects of air pollution. RESULTS: We observed causal links between air pollutants and mental disorders among both prediabetic and diabetic participants, with stronger effects among those with diabetes than prediabetes. The hazard ratios were 1.18 (1.12, 1.24), 1.15 (1.10, 1.20), 1.18 (1.13, 1.23), and 1.15 (1.11, 1.19) in patients with prediabetes, and 1.21 (1.13, 1.29), 1.17 (1.11, 1.24), 1.19 (1.13, 1.25), and 1.17 (1.12, 1.23) in patients with diabetes per interquartile range elevation in PM2.5, PM10, NO2, and NOx. Furthermore, the effects were more pronounced among people who were older, alcohol drinkers, and living in urban areas. CONCLUSIONS: Our study indicates the potential causal links between long-term exposure to air pollution and incident mental disorders among those with prediabetes and diabetes. Reducing air pollution levels would significantly benefit this vulnerable population by reducing the incidence of mental disorders.

Product-related injury morbidity among Americans aged 0-19 years, 2001-2020.

INTRODUCTION: This study examined changes in product-related injury morbidity among under-20 Americans between 2001 and 2020. METHOD: Product-related injury morbidity data came from the National Electronic Injury Surveillance System (NEISS). Using age-standardized morbidity rates, the authors performed Joinpoint regression models to identify time periods with significant changes between 2001 and 2020 and quantified the annual magnitude of morbidity changes with annual percent changes (APCs) in rates and 95 % confidence intervals (CIs). RESULTS: Age-standardized product-related injury morbidity declined consistently among under-20 Americans from 2001 to 2020 (from 7449.3 to 4023.5 per 100,000 persons; APC = -1.5 %, 95 % CI: -2.3 %, -0.7 %), with the most striking morbidity drop in 2019-2020 (-1576.8 per 100,000 persons). Sports and recreation equipment and home were the most common product and location, respectively, for nonfatal pediatric product-related injuries. Large morbidity differences and varying spectrum by product and by occurring location existed across sex and age groups. CONCLUSIONS: Product-related injury morbidity declined significantly among under-20 Americans between 2001 and 2020, but large variations remained across sex and age groups. PRACTICAL APPLICATIONS: Further research is recommended to understand causal factors contributing to the observed decrease in product-related injury morbidity over the past 20 years and to understand product-related injury morbidity disparities across sex and age groups. Understanding of causal factors could lead to implementation of additional interventions to reduce product-related injury among children and adolescents.

Recent advances in understanding DNA methylation of prostate cancer.

Epigenetic modifications, such as DNA methylation, is widely studied in cancer. DNA methylation patterns have been shown to distinguish between benign and malignant tumors in various cancers, including prostate cancer. It may also contribute to oncogenesis, as it is frequently associated with downregulation of tumor suppressor genes. Aberrant patterns of DNA methylation, in particular the CpG island hypermethylator phenotype (CIMP), have shown associative evidence with distinct clinical features and outcomes, such as aggressive subtypes, higher Gleason score, prostate-specific antigen (PSA), and overall tumor stage, overall worse prognosis, as well as reduced survival. In prostate cancer, hypermethylation of specific genes is significantly different between tumor and normal tissues. Methylation patterns could distinguish between aggressive subtypes of prostate cancer, including neuroendocrine prostate cancer (NEPC) and castration resistant prostate adenocarcinoma. Further, DNA methylation is detectable in cell-free DNA (cfDNA) and is reflective of clinical outcome, making it a potential biomarker for prostate cancer. This review summarizes recent advances in understanding DNA methylation alterations in cancers with the focus on prostate cancer. We discuss the advanced methodology used for evaluating DNA methylation changes and the molecular regulators behind these changes. We also explore the clinical potential of DNA methylation as prostate cancer biomarkers and its potential for developing targeted treatment of CIMP subtype of prostate cancer.

Ambient air pollution and incidence, progression to multimorbidity and death of hypertension, diabetes, and chronic kidney disease: A national prospective cohort.

BACKGROUND: The link between ambient air pollution and the incidence of hypertension, diabetes, and chronic kidney disease (CKD) has been widely studied. However, the associations of air pollution with the dynamic progression to multimorbidity and mortality of these diseases are unknown. METHODS: This study included 162,334 participants from the UK Biobank. Multimorbidity was defined as the coexistence of at least two of hypertension, diabetes, and CKD. Land use regression was used to estimate annual concentrations of particulate matter (PM2.5), PM10, nitrogen dioxide (NO2), and nitrogen oxides (NOx). Multi-state models were used to assess the association between ambient air pollutants and the dynamic progression of hypertension, diabetes, and CKD. RESULTS: During a median follow-up of 11.7 years, 18,496 participants experienced at least one of hypertension, diabetes, and CKD, 2216 experienced multimorbidity, and 302 died afterwards. We observed differential associations of four air pollutants on different transitions from healthy status to incident disease (hypertension, diabetes, or CKD), to multimorbidity, and to death. The hazard ratios (HRs) of each IQR increment in PM2.5, PM10, NO2, and NOx for the transition to incident disease were 1.07 [95 % confidence intervals (CI): 1.04, 1.09], 1.02 (1.00, 1.03), 1.07 (1.04, 1.09), and 1.05 (1.03, 1.07), but the associations with the transition to death were significant for NOx only [HR: 1.04 (95 % CI: 1.01, 1.08)]. CONCLUSIONS: Air pollution exposure might be one important determinant for the incidence and dynamic progression of hypertension, diabetes, and CKD, suggesting that more attention should be paid to ambient air pollution control in the prevention of hypertension, diabetes, and CKD, as well as their progression.

Histological types of lung cancer attributable to fine particulate, smoking, and genetic susceptibility.

BACKGROUND: Fine particulate matter (PM2.5), smoking, and genetic factors are associated with lung cancer. However, the relationship between PM2.5, smoking and subtypes of lung cancer remains unclear. Moreover, it is unclear whether genetic risk modifies the impact of PM2.5 and smoking on incident lung cancer. METHODS: A total of 298,069 participants from the UK Biobank study without lung cancer at baseline were included in this study. Hazard ratios (HRs) with 95 % confidence intervals (CIs) were estimated using multivariable Cox proportional models for the association of lung cancer and its subtypes with PM2.5, smoking, and genetic risk. Potential gene-smoking or gene-PM2.5 interactions were also estimated. We further estimated population attributable fractions for incident lung cancer. RESULTS: During 10.4 years of follow-up, 1683 incident lung cancer cases were identified. Our analysis found that genetic variants, smoking, and PM2.5 were significantly associated with incident lung cancer. For different histological types of lung cancer, the HRs for squamous cell lung carcinoma associated with PM2.5 (per 5 µg/m3 increment) and current smoking were 2.76 (95 % CI: 1.72, 4.42, p < 0.001) and 48.64 (95 % CI: 27.96, 84.61, p < 0.001), while the HRs for lung adenocarcinoma were 1.59 (95 % CI: 1.13, 2.23, p < 0.001) and 9.89 (95 % CI: 7.91, 12.36, p < 0.001), respectively. We further found that participants with high levels of PM2.5 pollution and high genetic risk had the highest risk of incident lung cancer (HR = 1.81, 95 % CI: 1.39, 2.35, p < 0.001), while the interaction between PM2.5 and genetic risk was not statistically significant. We observed that the population attributable fractions of lung cancer attributable to current smoking and high PM2.5 exposure were estimated to be 67.45 % and 17.59 %. CONCLUSION: Genetic susceptibility, smoking, and PM2.5 are important risk factors for lung cancer. Both smoking and PM2.5 are more closely associated with an elevated risk of squamous cell lung cancer.

The Global Burden of Appendicitis in 204 Countries and Territories from 1990 to 2019.

Objective: Appendicitis is a common surgical emergency. This study aimed to estimate the worldwide burden and trends of appendicitis from 1990 to 2019. Methods: Data on appendicitis were derived from the Global Burden of Disease 2019. Incidence and disability-adjusted life-years (DALYs) data were analyzed at global, regional, and national levels and stratified by sex, age, and socio-demographic index. The estimated annual percentage change and relative change were used to assess changing trends. Pearson's correlation test was used to assess the correlation between different measures. Results: Global incidence grew by 63.55% between 1990 and 2019, age-standardized incidence rate climbed by an estimated percentage change of 0.58 per year, whereas the number of DALY declined by 31.93% during the same period, with an estimated annual percentage change of -2.77. In 2019, the areas of Andean Latin America and the Caribbean had the highest age-standardized rates of incidence and DALYs. While South Asia saw the largest increase in age-standardized incidence rates, Andean Latin America saw the biggest decline in age-standardized rates of incidence and DALYs. At the national level, Bangladesh, Bhutan, and Peru were the top three countries in terms of age-standardized incidence rates in 2019, and Honduras, Haiti, and the Central African Republic held the highest age-standardized DALY rates. Ethiopia experienced the most age-standardized incidence rate increase, and Peru saw the largest decline in age-standardized rate of incidence and DALYs. Significant negative correlations between age-standardized DALY rates and socio-demographic index, between estimated annual percentage change and age-standardized incidence rates, were observed at the national level. Conclusion: Appendicitis remains a major global health concern. Although the trends in DALYs decreased, the burden of incidence increased from 1990 to 2019. Policymakers should create health policies adapted to local conditions to manage the burden of appendicitis globally.

The 5-Hydroxymethylcytosine Landscape of Prostate Cancer.

Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease. SIGNIFICANCE: In prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880.

The cell-free DNA methylome captures distinctions between localized and metastatic prostate tumors.

Metastatic prostate cancer remains a major clinical challenge and metastatic lesions are highly heterogeneous and difficult to biopsy. Liquid biopsy provides opportunities to gain insights into the underlying biology. Here, using the highly sensitive enrichment-based sequencing technology, we provide analysis of 60 and 175 plasma DNA methylomes from patients with localized and metastatic prostate cancer, respectively. We show that the cell-free DNA methylome can capture variations beyond the tumor. A global hypermethylation in metastatic samples is observed, coupled with hypomethylation in the pericentromeric regions. Hypermethylation at the promoter of a glucocorticoid receptor gene NR3C1 is associated with a decreased immune signature. The cell-free DNA methylome is reflective of clinical outcomes and can distinguish different disease types with 0.989 prediction accuracy. Finally, we show the ability of predicting copy number alterations from the data, providing opportunities for joint genetic and epigenetic analysis on limited biological samples.

Automated whole-slide images assessment of immune infiltration in resected non-small-cell lung cancer: towards better risk-stratification.

BACKGROUND: High immune infiltration is associated with favourable prognosis in patients with non-small-cell lung cancer (NSCLC), but an automated workflow for characterizing immune infiltration, with high validity and reliability, remains to be developed. METHODS: We performed a multicentre retrospective study of patients with completely resected NSCLC. We developed an image analysis workflow for automatically evaluating the density of CD3+ and CD8+ T-cells in the tumour regions on immunohistochemistry (IHC)-stained whole-slide images (WSIs), and proposed an immune scoring system "I-score" based on the automated assessed cell density. RESULTS: A discovery cohort (n = 145) and a validation cohort (n = 180) were used to assess the prognostic value of the I-score for disease-free survival (DFS). The I-score (two-category) was an independent prognostic factor after adjusting for other clinicopathologic factors. Compared with a low I-score (two-category), a high I-score was associated with significantly superior DFS in the discovery cohort (adjusted hazard ratio [HR], 0.54; 95% confidence interval [CI] 0.33-0.86; P = 0.010) and validation cohort (adjusted HR, 0.57; 95% CI 0.36-0.92; P = 0.022). The I-score improved the prognostic stratification when integrating it into the Cox proportional hazard regression models with other risk factors (discovery cohort, C-index 0.742 vs. 0.728; validation cohort, C-index 0.695 vs. 0.685). CONCLUSION: This automated workflow and immune scoring system would advance the clinical application of immune microenvironment evaluation and support the clinical decision making for patients with resected NSCLC.

Coding quality of deaths and its impact on elderly unintentional fall mortality data from 1990 to 2019: a retrospective analysis of the WHO Mortality Database.

BACKGROUND: Several studies have assessed the reporting quality of all-cause mortality data from the WHO Mortality Database, but little is known about coding quality and its impact on elderly unintentional fall mortality data worldwide. We aimed to assess the coding quality of deaths and its impact on elderly unintentional fall mortality. METHODS: Using data from the WHO Mortality Database, 1990-2019, we calculated the number of countries/territories that had mortality data in the database, and the proportion of deaths with five types of problematic codes based on the 10th International Classification of Disease (unspecified deaths, injury deaths with undetermined intent, unspecified unintentional injury, unintentional falls with unspecified mechanism, unintentional falls with unknown occurrence place). We estimated age-adjusted unintentional fall mortality before and after correcting problematic codes. RESULTS: Only 64% (124/194) of WHO member states had at least 1 year of mortality data in the database during 1990-2019, and data unavailability was more common for underdeveloped countries/territories than for developed countries/territories. Coding quality was poor for many countries/territories. Among the study years when countries/territories possessed mortality data, 80, 53, 51, and 63% had a proportion of unintentional fall deaths with unspecified mechanism over 50% in low-income, lower middle-income, upper middle-income, and high-income countries/territories, respectively; comparable proportions for unintentional fall deaths with unknown occurrence place were 100, 42, 71, and 62%. Among the 94 countries/territories having mortality data, problematic codes caused a relative mortality difference ≥ 50% in 59 countries/territories (63%). After correcting problematic codes, 5 of 55 countries/territories with data witnessed a reverse in mortality changes between 2005 and 2015. Among the 82 countries/territories with mortality data for 5 or more years, 18 countries/territories (22%) experienced a directional reverse in linear regression coefficient. CONCLUSIONS: The availability and coding quality of global data related to elderly unintentional fall mortality was poor between 1990 and 2019. When data are available, varying coding quality across countries/territories and over time have a substantial impact on mortality estimates and mortality comparisons. Global agencies plus each individual government should be aware of the importance of collecting and sharing high-quality mortality data, and take action to improve data quality for inclusion in the WHO Mortality Database.

An integrated functional and clinical genomics approach reveals genes driving aggressive metastatic prostate cancer.

Genomic sequencing of thousands of tumors has revealed many genes associated with specific types of cancer. Similarly, large scale CRISPR functional genomics efforts have mapped genes required for cancer cell proliferation or survival in hundreds of cell lines. Despite this, for specific disease subtypes, such as metastatic prostate cancer, there are likely a number of undiscovered tumor specific driver genes that may represent potential drug targets. To identify such genetic dependencies, we performed genome-scale CRISPRi screens in metastatic prostate cancer models. We then created a pipeline in which we integrated pan-cancer functional genomics data with our metastatic prostate cancer functional and clinical genomics data to identify genes that can drive aggressive prostate cancer phenotypes. Our integrative analysis of these data reveals known prostate cancer specific driver genes, such as AR and HOXB13, as well as a number of top hits that are poorly characterized. In this study we highlight the strength of an integrated clinical and functional genomics pipeline and focus on two top hit genes, KIF4A and WDR62. We demonstrate that both KIF4A and WDR62 drive aggressive prostate cancer phenotypes in vitro and in vivo in multiple models, irrespective of AR-status, and are also associated with poor patient outcome.

Changes in Six-Month Prevalence of Circulatory System Diseases among People Aged 20 Years and Older between 2013 and 2018 in Hunan, China.

Recent changes in population-based prevalence for circulatory system diseases (CSDs) remain unreported either nationally or locally for China. Data were from the two-round health service household interview survey of Hunan Province, China, in 2013 and 2018. A Rao-Scott chi-square test was performed to examine prevalence differences across socio-demographic variables. The overall age-standardized prevalence of CSDs increased substantially between 2013 and 2018 for inhabitants aged 20 years and older (14.25% vs. 21.25%; adjusted odds ratio (OR) = 1.59, 95% CI: 1.24-2.04). Hypertensive disease was the most prevalent type of CSD, accounting for 87.24% and 83.83% of all CSDs in 2013 and in 2018, respectively. After controlling for other socio-demographic factors, the prevalence of CSDs was significantly higher in 2018 (adjusted OR = 1.40), urban residents (adjusted OR = 1.43), females (adjusted OR = 1.12) and older age groups (adjusted OR = 5.36 for 50-59 years, 9.51 for 60-69 years, 15.19 for 70-79 years, and 12.90 for 80 years and older) than in 2013, rural residents, males and the youngest age group (20-49 years). The recent increase in the overall age-standardized CSD prevalence and the large prevalence disparities across urban/rural residents, sex and age groups merit the attention of policymakers and researchers. Further prevention efforts are needed to curb the increasing tendency and to reduce the prevalence of disparities across socio-demographic groups.

CRISPRi screens reveal a DNA methylation-mediated 3D genome dependent causal mechanism in prostate cancer.

Prostate cancer (PCa) risk-associated SNPs are enriched in noncoding cis-regulatory elements (rCREs), yet their modi operandi and clinical impact remain elusive. Here, we perform CRISPRi screens of 260 rCREs in PCa cell lines. We find that rCREs harboring high risk SNPs are more essential for cell proliferation and H3K27ac occupancy is a strong indicator of essentiality. We also show that cell-line-specific essential rCREs are enriched in the 8q24.21 region, with the rs11986220-containing rCRE regulating MYC and PVT1 expression, cell proliferation and tumorigenesis in a cell-line-specific manner, depending on DNA methylation-orchestrated occupancy of a CTCF binding site in between this rCRE and the MYC promoter. We demonstrate that CTCF deposition at this site as measured by DNA methylation level is highly variable in prostate specimens, and observe the MYC eQTL in the 8q24.21 locus in individuals with low CTCF binding. Together our findings highlight a causal mechanism synergistically driven by a risk SNP and DNA methylation-mediated 3D genome architecture, advocating for the integration of genetics and epigenetics in assessing risks conferred by genetic predispositions.