Socioeconomic characteristics, cancer mortality, and universal health coverage: A global analysis.

BACKGROUND: Achieving universal health coverage (UHC) involves all individuals attaining accessible health interventions at an affordable cost. We examined current patterns and temporal trends of cancer mortality and UHC across sociodemographic index (SDI) settings, and quantified these association. METHODS: We used data from the Global Burden of Disease Study 2019 and Our World in Data. The UHC effective coverage index was obtained to assess the potential population health gains delivered by health systems. The estimated annual percentage change (EAPC) with a 95% confidence interval (CI) was calculated to quantify the trend of cancer age-standardized mortality rate (ASMR). A generalized linear model was applied to estimate the association between ASMR and UHC. FINDINGS: The high (EAPC = -0.9% [95% CI, -1.0%, -0.9%]) and high-middle (-0.9% [-1.0%, -0.8%]) SDI regions had the fastest decline in ASMR (per 100,000) for total cancers from 1990 to 2019. The overall UHC effective coverage index increased by 27.9% in the high-SDI quintile to 62.2% in the low-SDI quintile. A negative association was observed between ASMR for all-cancer (adjusted odds ratio [OR] = 0.87 [0.76, 0.99]), stomach (0.73 [0.56, 0.95]), breast (0.64 [0.52, 0.79]), cervical (0.42 [0.30, 0.60]), lip and oral cavity (0.55 [0.40, 0.75]), and nasopharynx (0.42 [0.26, 0.68]) cancers and high UHC level (the lowest as the reference). CONCLUSIONS: Our findings strengthen the evidence base for achieving UHC to improve cancer outcomes. FUNDING: This work is funded by the China National Natural Science Foundation and Chinese Academy of Medical Sciences Innovation Fund for Medical Science.

Survey of hepatitis B virus infection for liver cancer screening in China: A population-based, cross-sectional study.

BACKGROUND: Hepatitis B virus (HBV) infection is the primary cause of hepatocellular carcinoma (HCC) in China. The target population for HCC screening comprises individuals who test positive for hepatitis B surface antigen (HBsAg). However, current data on the prevalence of HBV infection among individuals who are eligible for HCC screening in China are lacking. We aimed to assess the seroepidemiology of HBV infection among Chinese individuals eligible for HCC screening to provide the latest evidence for appropriate HCC screening strategies in China. METHODS: Questionnaires including information of sex, age, ethnicity, marital status, educational level, source of drinking water, as well as smoking and alcohol consumption history and serum samples were collected from females aged 45-64 years and males aged 35-64 years in 21 counties from 4 provinces in eastern and central China between 2015 and 2023. Enzyme-linked immunosorbent assay methods were used to detect the serum HBV marker HBsAg. RESULTS: A total of 603,082 individuals were enrolled, and serum samples were collected for analysis from January 1, 2015 to December 31, 2023. The prevalence of HBsAg positive in the study population was 5.23% (31,528/603,082). The prevalence of HBsAg positive was greater in males than in females (5.60% [17,660/315,183] vs . 4.82% [13,868/287,899], χ 2  = 187.52, P  <0.0001). The elderly participants exhibited a greater prevalence of HBV infection than younger participants (χ 2  = 41.73, P  <0.0001). Birth cohort analysis revealed an overall downward trend in HBV prevalence for both males and females. Individuals born in more recent cohorts exhibited a lower prevalence of HBV infection as compared to those born earlier. CONCLUSIONS: The current prevalence of HBV infection remains above 5% in populations eligible for HCC screening in China. Further efforts should be made to increase the accessibility of HCC screening among individuals with HBV infection.

Combining fecal immunochemical testing and questionnaire-based risk assessment in selecting participants for colonoscopy screening in the Chinese National Colorectal Cancer Screening Programs: A population-based cohort study.

BACKGROUND: Screening reduces colorectal cancer (CRC) burden by allowing early resection of precancerous and cancerous lesions. An adequate selection of high-risk individuals and a high uptake rate for colonoscopy screening are critical to identifying people more likely to benefit from screening and allocating healthcare resources properly. We evaluated whether combining a questionnaire-based interview for risk factors with fecal immunochemical test (FIT) outcomes for high-risk assessment is more efficient and economical than a questionnaire-based interview-only strategy. METHODS AND FINDINGS: In this multicenter, population-based, prospective cohort study, we enrolled community residents aged 40 to 74 years in 29 provinces across China. From 2016 to 2020, a total of 1,526,824 eligible participants were consecutively enrolled in the Cancer Screening Program in Urban China (CanSPUC) cohort, and 940,605 were enrolled in the Whole Life Cycle of Cancer Screening Program (WHOLE) cohort, with follow-up to December 31, 2022. The mean ages were 56.89 and 58.61 years in CanSPUC and WHOLE, respectively. In the WHOLE cohort, high-risk individuals were identified by combining questionnaire-based interviews to collect data on risk factors (demographics, diet history, family history of CRC, etc.) with FIT outcomes (RF-FIT strategy), whereas in the CanSPUC cohort, high-risk individuals were identified using only interview-based data on risk factors (RF strategy). The primary outcomes were participation rate and yield (detection rate of advanced neoplasm, early-stage detection rate of CRCs [stage I/II], screening yield per 10,000 invitees), which were reported for the entire population and for different gender and age groups. The secondary outcome was the cost per case detected. In total, 71,967 (7.65%) and 281,985 (18.47%) individuals were identified as high-risk and were invited to undergo colonoscopy in the RF-FIT group and RF group, respectively. The colonoscopy participation rate in the RF-FIT group was 26.50% (19,071 of 71,967) and in the RF group was 19.54% (55,106 of 281,985; chi-squared test, p < 0.001). A total of 102 (0.53%) CRCs and 2,074 (10.88%) advanced adenomas were detected by the RF-FIT, versus 90 (0.16%) and 3,593 (6.52%) by the RF strategy (chi-squared test, both p < 0.001). The early-stage detection rate using the RF-FIT strategy was significantly higher than that by the RF strategy (67.05% versus 47.95%, Fisher's exact test, p = 0.016). The cost per CRC detected was $24,849 by the RF-FIT strategy versus $55,846 by the RF strategy. A limitation of the study was lack of balance between groups with regard to family history of CRC (3.5% versus 0.7%). CONCLUSIONS: Colonoscopy participation and screening yield were better with the RF-FIT strategy. The association with CRC incidence and mortality reduction should be evaluated after long-term follow-up.

Benefits and harms of polygenic risk scores in organised cancer screening programmes: a cost-effectiveness analysis.

Background: While polygenic risk scores (PRS) could enable the streamlining of organised cancer screening programmes, its current discriminative ability is limited. We conducted a cost-effectiveness analysis to trade-off the benefits and harms of PRS-stratified cancer screening in China. Methods: The validated National Cancer Center (NCC) modelling framework for six cancers (lung, liver, breast, gastric, colorectum, and oesophagus) was used to simulate cancer incidence, progression, stage-specific cancer detection, and risk of death. We estimated the number of cancer deaths averted, quality-adjusted life-years (QALY) gained, number needed to screen (NNS), overdiagnosis, and incremental cost-effectiveness ratio (ICER) of one-time PRS-stratified screening strategy (screening 25% of PRS-defined high-risk population) for a birth cohort at age 60 in 2025, compared with unstratified screening strategy (screening 25% of general population) and no screening strategy. We applied lifetime horizon, societal perspective, and 3% discount rate. An ICER less than $18,364 per QALY gained is considered cost-effective. Findings: One-time cancer screening for population aged 60 was the most cost-effective strategy compared to screening at other ages. Compared with an unstratified screening strategy, the PRS-stratified screening strategy averted more cancer deaths (61,237 vs. 40,329), had a lower NNS to prevent one death (307 vs. 451), had a slightly higher overdiagnosis (14.1% vs. 13.8%), and associated with an additional 130,045 QALYs at an additional cost of $1942 million, over a lifetime horizon. The ICER for all six cancers combined was $14,930 per QALY gained, with the ICER varying from $7928 in colorectal cancer to $39,068 in liver cancer. ICER estimates were sensitive to changes in risk threshold and cost of PRS tools. Interpretation: PRS-stratified screening strategy modestly improves clinical benefit and cost-effectiveness of organised cancer screening programmes. Reducing the costs of polygenic risk stratification is needed before PRS implementation. Funding: The Chinese Academy of Medical Sciences, the Jing-jin-ji Special Projects for Basic Research Cooperation, and the Sanming Project of the Medicine in Shenzhen.

Risk-Adapted Starting Age of Personalized Lung Cancer Screening: A Population-Based, Prospective Cohort Study in China.

BACKGROUND: The current one-size-fits-all screening strategy for lung cancer is not suitable for personalized screening. RESEARCH QUESTION: What is the risk-adapted starting age of lung cancer screening with comprehensive consideration of risk factors? STUDY DESIGN AND METHODS: The National Lung Cancer Screening program, a multicenter, population-based, prospective cohort study, was analyzed. Information on risk factor exposure was collected during the baseline risk assessment. A Cox proportional hazards model was used to estimate the association between risk factors and lung cancer incidence. Age-specific 10-year cumulative risk was calculated to determine the age at which individuals with various risk factors reached the equivalent risk level as individuals aged ≥ 50 years with active tobacco use and a ≥ 20 pack-year smoking history. RESULTS: Of the 1,031,911 participants enrolled in this study, 3,908 demonstrated lung cancer after a median follow-up of 3.8 years. We identified seven risk factors for lung cancer, including pack-years of smoking, secondhand smoke exposure, family history of lung cancer in first-degree relatives, history of respiratory diseases, occupational hazardous exposure, BMI, and diabetes. The 10-year cumulative risk of lung cancer for people aged ≥ 50 years with active tobacco use and a ≥ 20 pack-year smoking history was 1.37%, which was treated as the risk threshold for screening. Individuals who never smoked and those with active tobacco use and a < 30-pack-year history of smoking reached the equivalent risk level 1 to 14 years later compared with the starting age of 50 years. Men with active tobacco use, a ≥ 30-pack-year history of smoking, and concurrent respiratory diseases or diabetes should be screened 1 year earlier at the age of 49 years. INTERPRETATION: The personalized risk-adapted starting ages for lung cancer screening, based on the principle of equal management of equal risk, can served as an optimized screening strategy to identify high-risk individuals.

Cisplatin-activated ERß/DCAF8 positive feedback loop induces chemoresistance in non-small cell lung cancer via PTEN/Akt axis.

High levels of the estrogen receptor ß (ERß) predict poor prognosis following platinum-containing adjuvant chemotherapies in patients with non-small cell lung cancer (NSCLC). However, the precise role of ERß remains elusive. In this study, we demonstrated that targeting ERß could significantly increase the cytotoxicity of cisplatin both in vitro and in vivo. Mechanically, cisplatin directly binds to ERß, which facilitates its homodimerization and nuclear translocation. ERß activation transcriptionally represses the expression of DCAF8, an adaptor of CRL4 E3 ubiquitin ligase, which in turn attenuates the proteasomal degradation of ERß, leading to ERß accumulation; this positive feedback loop results in Akt activation and eventually cisplatin resistance in NSCLC through PTEN inhibition. Moreover, low expression of DCAF8 and high expression of ERß are associated with treatment resistance in patients receiving cisplatin-containing adjuvant chemotherapy. The present results provide insights into the underlying mechanism of ERß-induced cisplatin resistance and offer an alternative therapeutic strategy to improve the efficacy of platinum-based chemotherapy in patients with NSCLC.

Association Between Socioeconomic Status and Adherence to Fecal Occult Blood Tests in Colorectal Cancer Screening Programs: Systematic Review and Meta-Analysis of Observational Studies.

BACKGROUND: Screening adherence is important in reducing colorectal cancer (CRC) incidence and mortality. Disparity in CRC screening adherence was observed in populations of different socioeconomic status (SES), but the direction and strength of the association remained unclear. OBJECTIVE: We aimed to systematically review all the observational studies that have analyzed the association between SES and adherence to organized CRC screening based on fecal occult blood tests. METHODS: We systematically reviewed the studies in PubMed, Embase, and Web of Science and reference lists of relevant reviews from the inception of the database up until June 7, 2023. Individual SES, neighborhood SES, and small-area SES were included, while any SES aggregated by geographic areas larger than neighbors were excluded. Studies assessing SES with any index or score combining indicators of income, education, deprivation, poverty, occupation, employment, marital status, cohabitation, and others were included. A random effect model meta-analysis was carried out for pooled odds ratios (ORs) and relative risks for adherence related to SES. RESULTS: Overall, 10 studies, with a total of 3,542,379 participants and an overall adherence rate of 64.9%, were included. Compared with low SES, high SES was associated with higher adherence (unadjusted OR 1.73, 95% CI 1.42-2.10; adjusted OR 1.53, 95% CI 1.28-1.82). In the subgroup of nonindividual-level SES, the adjusted association was significant (OR 1.57, 95% CI 1.26-1.95). However, the adjusted association was insignificant in the subgroup of individual-level SES (OR 1.46, 95% CI 0.98-2.17). As for subgroups of the year of print, not only was the unadjusted association significantly stronger in the subgroup of early studies (OR 1.97, 95% CI 1.59-2.44) than in the subgroup of late studies (OR 1.43, 95% CI 1.31-1.56), but also the adjusted one was significantly stronger in the early group (OR 1.86, 95% CI 1.43-2.42) than in the late group (OR 1.26, 95% CI 1.14-1.39), which was consistent and robust. Despite being statistically insignificant, the strength of the association seemed lower in studies that did not adjust for race and ethnicity (OR 1.31, 95% CI 1.21-1.43) than the overall estimate (OR 1.53, 95% CI 1.28-1.82). CONCLUSIONS: The higher-SES population had higher adherence to fecal occult blood test-based organized CRC screening. Neighborhood SES, or small-area SES, was more competent than individual SES to be used to assess the association between SES and adherence. The disparity in adherence between the high SES and the low SES narrowed along with the development of interventions and the improvement of organized programs. Race and ethnicity were probably important confounding factors for the association.

Geographic disparities in trends of thyroid cancer incidence and mortality from 1990 to 2019 and a projection to 2030 across income-classified countries and territories.

Background: The rising incidence of thyroid cancer (TC) has generated growing concern globally; yet there are no studies examining whether this incidence was followed by a rise in related mortality. We aimed to comprehensively quantify current trends and future projections of TC incidence and mortality, and to explore the association between the TC burden and socioeconomic inequality in different income strata. Methods: We obtained incidence and mortality data on TC and population from the 2019 Global Burden of Disease (GBD) study and the United Nations' World Population Prospects 2022. We applied an age-period-cohort (APC) model to estimate the overall annual percentage change (net drift) and age, period, and cohort effects from 1990 to 2019, and also constructed a Bayesian APC model to predict the TC burden through 2030. Results: Over a third of global TC cases belonged to the high-income group. From 1990 to 2019, net drifts of TC incidence were >0 in all income groups, while a modest reduction (net drift <0) in mortality was observed in most income groups, except for the lower-middle-income group. Unfavourable age, period, and cohort effects were most notable in Vietnam, China, and Korea. The age-standardised incidence rate (ASIR) is predicted to increase whereas the age-standardized mortality rate (ASMR) is expected to decrease globally between 2020 and 2030, with geographic heterogeneity being detected across income groups. We observed a positive correlation between ASIR and universal health coverage index and health worker density, but a negative one between ASMR and the two indicators, primarily in upper-middle-income and high-income countries. Conclusions: Opposite patterns in incidence and mortality of TC raise concerns about overdiagnosis, particularly in upper-middle-income and high-income countries. Discrepancies in the distribution of health service accessibility, including diagnostic techniques and therapeutic care, should be addressed by narrowing health inequalities in the TC burden across countries.

CRISPR-based m6A modification and its potential applications in telomerase regulation.

Telomerase determines cell lifespan by controlling chromosome stability and cell viability, m6A epigenetic modification plays an important role in the regulation of telomerase activity. Using CRISPR epigenome editing to analyze specific m6A modification sites in telomerase will provide an important tool for analyzing the molecular mechanism of m6A modification regulating telomerase activity. In this review, we clarified the relevant applications of CRISPR system, paid special attention to the regulation of m6A modification in stem cells and cancer cells based on CRISPR system, emphasized the regulation of m6A modification on telomerase activity, pointed out that m6A modification sites regulate telomerase activity, and discussed strategies based on telomerase activity and disease treatment, which are helpful to promote the research of anti-aging and tumor related diseases.

A strategy to reduce the false-positive rate after low-dose computed tomography in lung cancer screening: A multicenter prospective cohort study.

BACKGROUND: The ability of lung cancer screening to manage pulmonary nodules was limited because of the high false-positive rate in the current mainstream screening method, low-dose computed tomography (LDCT). We aimed to reduce overdiagnosis in Chinese population. METHODS: Lung cancer risk prediction models were constructed using data from a population-based cohort in China. Independent clinical data from two programs performed in Beijing and Shandong, respectively, were used as the external validation set. Multivariable logistic regression models were used to estimate the probability of lung cancer incidence in the whole population and in smokers and nonsmokers. RESULTS: In our cohort, 1,016,740 participants were enrolled between 2013 and 2018. Of 79,581 who received LDCT screening, 5165 participants with suspected pulmonary nodules were allocated into the training set, of which, 149 lung cancer cases were diagnosed. In the validation set, 1815 patients were included, and 800 developed lung cancer. The ages of patients and radiologic factors of nodules (calcification, density, mean diameter, edge, and pleural involvement) were included in our model. The area under the curve (AUC) values of the model were 0.868 (95% CI: 0.839-0.894) in the training set and 0.751 (95% CI: 0.727-0.774) in the validation set. The sensitivity and specificity were 70.5% and 70.9%, respectively, which could reduce the 68.8% false-positive rate in simulated LDCT screening. There was no substantial difference between smokers' and nonsmokers' prediction models. CONCLUSION: Our models could facilitate the diagnosis of suspected pulmonary nodules, effectively reducing the false-positive rate of LDCT for lung cancer screening.

Disturbance of gut microbiota aggravates cadmium-induced neurotoxicity in zebrafish larvae through V-ATPase.

Cadmium (Cd) is a harmful environmental pollutant that causes damage to the nervous system, and exposure to Cd also disrupts the gut microbiota. However, it is still unclear whether Cd-induced neurotoxicity is related to alteration of the microbiota. In this study, we first established a germ-free (GF) zebrafish model to avoid the effects of gut microbiota disturbances caused by Cd exposure, and found that Cd-induced neurotoxic effects were weak in GF zebrafish. RNA sequencing showed that expression levels of V-ATPase family genes (atp6v1g1, atp6v1b2, and atp6v0cb) were significantly decreased in Cd-treated conventionally reared (CV) zebrafish, while this inhibition could be avoided in GF zebrafish. Overexpression of atp6v0cb in the V-ATPase family could partially rescue Cd-induced neurotoxicity. Our study shows that the disturbance of gut microbiota aggravates Cd-induced neurotoxicity, and that this may be associated with the expression of several genes in the V-ATPase family.

Metabolic biomarkers in lung cancer screening and early diagnosis (Review).

Late diagnosis is one of the major contributing factors to the high mortality rate of lung cancer, which is now the leading cause of cancer-associated mortality worldwide. At present, low-dose CT (LDCT) screening in the high-risk population, in which lung cancer incidence is higher than that of the low-risk population is the predominant diagnostic strategy. Although this has efficiently reduced lung cancer mortality in large randomized trials, LDCT screening has high false-positive rates, resulting in excessive subsequent follow-up procedures and radiation exposure. Complementation of LDCT examination with biofluid-based biomarkers has been documented to increase efficacy, and this type of preliminary screening can potentially reduce potential radioactive damage to low-risk populations and the burden of hospital resources. Several molecular signatures based on components of the biofluid metabolome that can possibly discriminate patients with lung cancer from healthy individuals have been proposed over the past two decades. In the present review, advancements in currently available technologies in metabolomics were reviewed, with particular focus on their possible application in lung cancer screening and early detection.

Modifiable risk-attributable and age-related burden of lung cancer in China, 1990-2019.

BACKGROUND: There were limited studies on the quantification of the modifiable and nonmodifiable lung cancer burden over time in China. Furthermore, the potential effect of risk factor reduction for lung cancer on gains in life expectancy (LE) remains unknown. METHODS: This study explored temporal trends in lung cancer deaths and disability-adjusted life years (DALY) attributable to modifiable risk factors from 1990 to 2019, based on the 2019 Global Burden of Disease Study. The abridged period life table method was used to quantify the effect of risk factors on LE. The authors used the decomposition approach to estimate contributions of aging metrics to change in the lung cancer burden. RESULTS: Nationally, the majority of lung cancer deaths and DALYs were attributable to behavioral and environmental risk clusters. Potential gains in life expectancy (PGLE) at birth would be 0.78 years for males and 0.35 years for females if the exposure to risk factors was mitigated to the theoretical minimum level. Tobacco use had the most robust impact on LE for both sexes (PGLE: 0.71 years for males and 0.19 years for females). From 1990 to 2019, risk-attributable age-standardized death and DALY rates of lung cancer showed an increasing trend in both sexes; adult population growth imposed 245.9 thousand deaths and 6.2 million DALYs for lung cancer. CONCLUSIONS: The modifiable risk-attributable lung cancer burden remains high in China. Effective tobacco control is the critical step toward addressing the lung cancer burden. Adult population growth was the foremost driver of transition in the age-related lung cancer burden. PLAIN LANGUAGE SUMMARY: We estimate the lung cancer burden attributable to modifiable and nonmodifiable contributors and the effect of risk factor reduction for lung cancer on the life expectancy in China. The findings suggest that the majority of lung cancer deaths and disability-adjusted life years were attributable to behavioral risk clusters, and the risk-attributable lung cancer burden increased nationally from 1990 to 2019. The average gains in life expectancy would be 0.78 years for males and 0.35 years for females if the exposure to risk factors for lung cancer was reduced to the theoretical minimum risk exposure level. Adult population growth was identified as the foremost driver of variation in the aging lung cancer burden.

TTT (Tel2-Tti1-Tti2) Complex, the Co-Chaperone of PIKKs and a Potential Target for Cancer Chemotherapy.

The heterotrimeric Tel2-Tti1-Tti2 or TTT complex is essential for cell viability and highly observed in eukaryotes. As the co-chaperone of ATR, ATM, DNA-PKcs, mTOR, SMG1, and TRRAP, the phosphatidylinositol 3-kinase-related kinases (PIKKs) and a group of large proteins of 300-500 kDa, the TTT plays crucial roles in genome stability, cell proliferation, telomere maintenance, and aging. Most of the protein kinases in the kinome are targeted by co-chaperone Cdc37 for proper folding and stability. Like Cdc37, accumulating evidence has established the mechanism by which the TTT interacts with chaperone Hsp90 via R2TP (Rvb1-Rvb2-Tah1-Pih1) complex or other proteins for co-translational maturation of the PIKKs. Recent structural studies have revealed the α-solenoid structure of the TTT and its interactions with the R2TP complex, which shed new light on the co-chaperone mechanism and provide new research opportunities. A series of mutations of the TTT have been identified that cause disease syndrome with neurodevelopmental defects, and misregulation of the TTT has been shown to contribute to myeloma, colorectal, and non-small-cell lung cancers. Surprisingly, Tel2 in the TTT complex has recently been found to be a target of ivermectin, an antiparasitic drug that has been used by millions of patients. This discovery provides mechanistic insight into the anti-cancer effect of ivermectin and thus promotes the repurposing of this Nobel-prize-winning medicine for cancer chemotherapy. Here, we briefly review the discovery of the TTT complex, discuss the recent studies, and describe the perspectives for future investigation.

Primary vaginal signet ring cell carcinoma.

Primary vaginal cancer is rare, accounting for only 2% of all gynecological malignant tumors. Primary vaginal cell carcinoma is mainly squamous cell carcinoma, accounting for about 90%, and adenocarcinoma only accounts for 8-10%. Primary signet ring cell carcinoma of vagina is rare and has not been reported in the literature. This paper reports a case of signet ring cell carcinoma in vagina.

Evaluation of the oxidative toxicity induced by lead, manganese, and cadmium using genetically modified nrf2a-mutant zebrafish.

Heavy metal pollution has become a serious environmental concern and a threat to public health. Three of the most common heavy metals are cadmium (Cd), lead (Pb), and manganese (Mn). Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor activated in the response to oxidative stress. In this study, mutant zebrafish with an nrf2a deletion of 7 bp were constructed by the CRISPR/Cas9 system to investigate the oxidative toxicity of these three heavy metals. The results of general toxicity tests showed that Pb exposure did not cause significant damage to mutant zebrafish compared with wild-type (WT) zebrafish. However, high Mn exposure increased mortality and malformation rates in mutant zebrafish. Of concern, Cd exposure caused significant toxic damage, including increased mortality and malformation rates, apoptosis of brain neurons, and severe locomotor behavior aberration in mutant zebrafish. The results of qRT-PCR indicated that Cd exposure could induce the activation of genes related to oxidative stress resistance in WT zebrafish, while the expression of these genes was inhibited in mutant zebrafish. This study showed that of the three heavy metals, Cd had the strongest oxidative toxicity, Mn had medium toxicity, and Pb had the weakest toxicity.

Risk-Adapted Starting Age for Personalized Colorectal Cancer Screening: Validated Evidence From National Population-Based Studies.

BACKGROUND & AIMS: A one-size-fits-all approach to colorectal cancer (CRC) screening that does not account for CRC risk factors is not conducive to personalized screening. On the basis of the principle of equal management of equal risks, we aimed to tailor and validate risk-adapted starting ages of CRC screening for individuals with different CRC risk factors. METHODS: A multi-center community-based population cohort (N = 3,165,088) was used to evaluate the starting age of CRC screening with comprehensive consideration of risk factors. Age-specific 10-year cumulative risk curves were used to determine when individuals at greater risk for CRC reached the same risk level as the 50-year-old general population, which is currently the recommended starting age for CRC screening in China. RESULTS: During the study follow-up period (2013-2021), 4,840 incident CRCs were recorded. Family history of CRC, adverse lifestyle, and comorbidities demonstrated heterogeneous associations with CRC risk (hazard ratios, 1.05-1.55; P < .05). Men and women with CRC family history and at least 2 risk factors reached the standard benchmark risk (0.28%) for screening at the age of 40, 10 years earlier than their peers without risk factors in the general population. Proposed starting ages for CRC screening were validated in an independent community-based population cohort (N = 1,023,367). CONCLUSIONS: We determined a risk-adapted CRC screening starting age for individuals with various CRC risk factors. Earlier, personalized screening based on these findings could allow for scarce health resources to be dedicated to individuals who benefit most.

Risk-stratified Approach for Never- and Ever-Smokers in Lung Cancer Screening: A Prospective Cohort Study in China.

Rationale: Over 40% of lung cancer cases occurred in never-smokers in China. However, high-risk never-smokers were precluded from benefiting from lung cancer screening as most screening guidelines did not consider them. Objectives: We sought to develop and validate prediction models for 3-year lung cancer risks for never- and ever-smokers, named the China National Cancer Center Lung Cancer models (China NCC-LCm2021 models). Methods: 425,626 never-smokers and 128,952 ever-smokers from the National Lung Cancer Screening program were used as the training cohort and analyzed using multivariable Cox models. Models were validated in two independent prospective cohorts: one included 369,650 never-smokers and 107,678 ever-smokers (841 and 421 lung cancers), and the other included 286,327 never-smokers and 78,469 ever-smokers (503 and 127 lung cancers). Measurements and Main Results: The areas under the receiver operating characteristic curves in the two validation cohorts were 0.698 and 0.673 for never-smokers and 0.728 and 0.752 for ever-smokers. Our models had higher areas under the receiver operating characteristic curves than other existing models and were well calibrated in the validation cohort. The China NCC-LCm2021 ⩾0.47% threshold was suggested for never-smokers and ⩾0.51% for ever-smokers. Moreover, we provided a range of threshold options with corresponding expected screening outcomes, screening targets, and screening efficiency. Conclusion: The construction of the China NCC-LCm2021 models can accurately reflect individual risk of lung cancer, regardless of smoking status. Our models can significantly increase the feasibility of conducting centralized lung cancer screening programs because we provide justified thresholds to define the high-risk population of lung cancer and threshold options to adapt different configurations of medical resources.

Iron Vacancy Tunable Superconductor-Insulator Transition in FeSe/SrTiO_{3} Monolayer.

The Fe_{4}Se_{5} with a sqrt[5]×sqrt[5] Fe vacancy order is suggested to be a Mott insulator and the parent state of bulk FeSe superconductor. The iron vacancy ordered state has been considered as a Mott insulator and the parent compound of bulk FeSe-based superconductors. However, for the superconducting FeSe/SrTiO_{3} monolayer (FeSe/STO) with an interface-enhanced high transition temperature (T_{c}), the electronic evolution from its Fe vacancy ordered parent phase to the superconducting state, has not been explored due to the challenge to realize an Fe vacancy order in the FeSe/STO monolayer, even though important to the understanding of superconductivity mechanism. In this study, we developed a new method to generate Fe vacancies within the FeSe/STO monolayer in a tunable fashion, with the assistance of atomic hydrogen. As a consequence, an insulating sqrt[5]×sqrt[5] Fe vacancy ordered monolayer is realized as the parent state. By using scanning tunneling microscopy and scanning tunneling spectroscopy, the spectral evolution from superconductivity to insulator is fully characterized. Surprisingly, a prominent spectral weight transfer occurs, thus implying a strong electron correlation effect. Moreover, the Fe vacancy induced insulating gap exhibits no Mott gap-like features. This work provides new insights in understanding the high-T_{c} superconductivity in FeSe/STO monolayer.

Use of Breast Cancer Risk Factors to Identify Risk-Adapted Starting Age of Screening in China.

Importance: Although current guidelines highlight the need for earlier screening in women at increased risk of breast cancer in China, data on risk-adapted starting ages of screening are limited. Objective: To explore the risk-adapted starting age of breast cancer screening in China, with comprehensive consideration of breast cancer risk factors. Design, Setting, and Participants: A multicenter community-based cohort study was conducted under the framework of the Cancer Screening Program in Urban China. Data were collected from January 1, 2013, to December 31, 2018, for unscreened community-dwelling women aged 40 to 74 years without a history of cancer, kidney dysfunction, or severe heart, brain, or lung disease. Data analysis was performed from October 1, 2021, to August 16, 2022. Exposures: Baseline characteristics associated with breast cancer, including first-degree family history of breast cancer, benign breast disease, breastfeeding, age at menarche, and body mass index. Main Outcomes and Measures: Outcomes included breast cancer diagnosis and age at diagnosis. Risk-adapted starting age of screening was defined as the age at which women with different levels of breast cancer risk attained a 10-year cumulative risk level similar to women aged 50 years in the general population. Results: Of the 1 549 988 women enrolled in this study, 3895 had breast cancer (median follow-up, 4.47 [IQR, 3.16-6.35] years). Participants were divided into different risk groups according to breast cancer risk scores (driven by risk factors including first-degree family history of breast cancer, benign breast disease, breastfeeding, age at menarche, and body mass index). Using the 10-year cumulative risk of breast cancer at age 50 years in the general population as a benchmark (2.65% [95% CI, 2.50%-2.76%]), the optimal starting age of screening for women with high, medium, or low risk of breast cancer was identified as 43, 48, or after 55 years, respectively. An online calculator was developed to calculate an individual's optimal starting age of screening. Conclusions and Relevance: This study identifies the risk-adapted starting age of breast cancer screening based on the principle of equal management of equal risks, which may inform updates of current screening guidelines.