Polygenic risk-stratified screening for nasopharyngeal carcinoma in high-risk endemic areas of China: a cost-effectiveness study.

Background: Nasopharyngeal carcinoma (NPC) has an extremely high incidence rate in Southern China, resulting in a severe disease burden for the local population. Current EBV serologic screening is limited by false positives, and there is opportunity to integrate polygenic risk scores for personalized screening which may enhance cost-effectiveness and resource utilization. Methods: A Markov model was developed based on epidemiological and genetic data specific to endemic areas of China, and further compared polygenic risk-stratified screening [subjects with a 10-year absolute risk (AR) greater than a threshold risk underwent EBV serological screening] to age-based screening (EBV serological screening for all subjects). For each initial screening age (30-34, 35-39, 40-44, 45-49, 50-54, 55-59, 60-64, and 65-69 years), a modeled cohort of 100,000 participants was screened until age 69, and then followed until age 79. Results: Among subjects aged 30 to 54 years, polygenic risk-stratified screening strategies were more cost-effective than age-based screening strategies, and almost comprised the cost-effectiveness efficiency frontier. For men, screening strategies with a 1-year frequency and a 10-year absolute risk (AR) threshold of 0.7% or higher were cost-effective, with an incremental cost-effectiveness ratio (ICER) below the willingness to pay (¥203,810, twice the local per capita GDP). Specifically, the strategies with a 10-year AR threshold of 0.7% or 0.8% are the most cost-effective strategies, with an ICER ranging from ¥159,752 to ¥201,738 compared to lower-cost non-dominated strategies on the cost-effectiveness frontiers. The optimal strategies have a higher probability (29.4-35.8%) of being cost-effective compared to other strategies on the frontier. Additionally, they reduce the need for nasopharyngoscopies by 5.1-27.7% compared to optimal age-based strategies. Likewise, for women aged 30-54 years, the optimal strategy with a 0.3% threshold showed similar results. Among subjects aged 55 to 69 years, age-based screening strategies were more cost-effective for men, while no screening may be preferred for women. Conclusion: Our economic evaluation found that the polygenic risk-stratified screening could improve the cost-effectiveness among individuals aged 30-54, providing valuable guidance for NPC prevention and control policies in endemic areas of China.

Efficient organized colorectal cancer screening in Shenzhen: a microsimulation modelling study.

BACKGROUND: Colorectal cancer (CRC) is a global health issue with noticeably high incidence and mortality. Microsimulation models offer a time-efficient method to dynamically analyze multiple screening strategies. The study aimed to identify the efficient organized CRC screening strategies for Shenzhen City. METHODS: A microsimulation model named CMOST was employed to simulate CRC screening among 1 million people without migration in Shenzhen, with two CRC developing pathways and real-world participation rates. Initial screening included the National Colorectal Polyp Care score (NCPCS), fecal immunochemical test (FIT), and risk-stratification model (RS model), followed by diagnostic colonoscopy for positive results. Several start-ages (40, 45, 50 years), stop-ages (70, 75, 80 years), and screening intervals (annual, biennial, triennial) were assessed for each strategy. The efficiency of CRC screening was assessed by number of colonoscopies versus life-years gained (LYG). RESULTS: The screening strategies reduced CRC lifetime incidence by 14-27 cases (30.9-59.0%) and mortality by 7-12 deaths (41.5-71.3%), yielded 83-155 LYG, while requiring 920 to 5901 colonoscopies per 1000 individuals. Out of 81 screening, 23 strategies were estimated efficient. Most of the efficient screening strategies started at age 40 (17 out of 23 strategies) and stopped at age 70 (13 out of 23 strategies). Predominant screening intervals identified were annual for NCPCS, biennial for FIT, and triennial for RS models. The incremental colonoscopies to LYG ratios of efficient screening increased with shorter intervals within the same test category. Compared with no screening, when screening at the same start-to-stop age and interval, the additional colonoscopies per LYG increased progressively for FIT, NCPCS and RS model. CONCLUSION: This study identifies efficient CRC screening strategies for the average-risk population in Shenzhen. Most efficient screening strategies indeed start at age 40, but the optimal starting age depends on the chosen willingness-to-pay threshold. Within insufficient colonoscopy resources, efficient FIT and NCPCS screening strategies might be CRC initial screening strategies. We acknowledged the age-dependency bias of the results with NCPCS and RS.

In vitro digestion and fecal fermentation of selenocompounds: impact on gut microbiota, antioxidant activity, and short-chain fatty acids.

Selenium bioavailability is critically influenced by gut microbiota, yet the interaction dynamics with selenocompounds remain unexplored. Our study found that L-Selenomethionine (SeMet) and Se-(Methyl)seleno-L-cysteine (MeSeCys) maintained stability during in vitro gastrointestinal digestion. In contrast, Selenite and L-Selenocystine (SeCys2) were degraded by approximately 13% and 35%. Intriguingly, gut microflora transformed MeSeCys, SeCys2, and Selenite into SeMet. Moreover, when SeCys2 and Selenite incubated with gut microbiota, they produced red selenium nanoparticles with diameters ranging between 100 and 400 nm and boosted glutathione peroxidase activity. These changes were positively associated with an increased relative abundance of unclassified_g__Blautia (Family Lachnospiraceae), Erysipelotrichaceae_UCG-003 (Family Erysipelatoclostridiaceae), and uncultured_bacterium_g__Subdoligranulum (Family Ruminococcaceae). Our findings implied that differential microbial sensitivities to selenocompounds, potentially attributable to their distinct mechanisms governing selenium uptake, storage, utilization, and excretion.

Tailoring the composition, antioxidant activity, and prebiotic potential of apple peel by Aspergillus oryzae fermentation.

Apple peel is a typical lignocellulosic food by-product rich in functional components. In this work, apple peel was solid-state fermented with Aspergillus oryzae with an aim to modulate its composition and bioactivity. The results showed that A. oryzae fermentation substantially tailored the composition, improved the antioxidant activity and prebiotic potential of apple peel. Upon the fermentation, 1) free phenolics increased and antioxidant activity improved; 2) the pectin substances degraded significantly, along with a decrease in soluble dietary fiber while an increase in insoluble dietary fiber; 3) the in vitro fermentability increased as indicated by the increase in total acid production. The gut microbiota was shaped with more health-promoting potentials, such as higher abundances of Lactobacillus, Bifidobacterium, Megamonas and Prevotella-9 as well as lower abundances of Enterobacter and Echerichia-Shigella. This work is conducive to the modification of apple peel as a potential ingredient in food formulations.

Thioredoxin-2 suppresses hydrogen peroxide-activated nuclear factor kappa B signaling via alleviating oxidative stress in bovine adipocytes.

During the periparturient period, both oxidative stress, and inflammation of adipose tissue are considered high risk factors for metabolic disorder of dairy cows. Oxidative stress can activate transcription factor nuclear factor kappa B (NF-κB), which lead to the upregulation of genes involved in inflammatory pathways. Thioredoxin-2 (TXN2) is a mitochondrial protein that regulates cellular redox by suppressing mitochondrial reactive oxygen species (ROS) generation in nonruminant, whereas the function of TXN2 in bovine adipocytes was unclear. Thus, the objective of this study was to evaluate how or by which mechanisms TXN2 regulates oxidative stress and NF-κB signaling pathway in bovine adipocytes. Bovine pre-adipocytes isolated from 5 healthy Holstein cows were differentiated and used for (1) treatment with different concentrations of hydrogen peroxide (H2O2; 0, 25, 50, 100, 200, or 400 µM) for 2 h; (2) transfection with or without TXN2 small interfering RNA (si-TXN2) for 48 h and then treated with or without 200 µM H2O2 for 2 h; (3) transfection with scrambled negative control siRNA (si-control) or si-TXN2 for 48 h, and then treatment with or without 10 mM N-acetylcysteine (NAC) for 2 h; (4) transfection with or without TXN2-overexpressing plasmid for 48 h and then treatment with or without 200 µM H2O2 for 2 h. High concentrations of H2O2 (200 and 400 µM) decreased protein and mRNA abundance of TXN2, reduced total antioxidant capacity (T-AOC) and ATP content in adipocytes. Moreover, 200 and 400 µM H2O2 reduced protein abundance of inhibitor of kappa B α (IκBα), increased phosphorylation of NF-κB and upregulated mRNA abundance of tumor necrosis factor-α (TNFA) and interleukin-1B (IL-1B), suggesting that H2O2-induced oxidative stress and activated NF-κB signaling pathway. Silencing of TXN2 increased intracellular ROS content, phosphorylation of NF-κB and mRNA abundance of TNFA and IL-1B, decreased ATP content and protein abundance of IκBα in bovine adipocytes. Knockdown of TXN2 aggravated H2O2-induced oxidative stress and inflammation. In addition, treatment with antioxidant NAC ameliorated oxidative stress and inhibited NF-κB signaling pathway in adipocytes transfected with si-TXN2. In bovine adipocytes treated with H2O2, overexpression of TXN2 reduced the content of ROS and elevated the content of ATP and T-AOC. Overexpression of TXN2 alleviated H2O2-induced inflammatory response in adipocytes, as demonstrated by decreased expression of phosphorylated NF-κB, TNFA, IL-1B, as well as increased expression of IκBα. Furthermore, the protein and mRNA abundance of TXN2 was lower in adipose tissue of dairy cows with clinical ketosis. Overall, our studies contribute to the understanding of the role of TXN2 in adipocyte oxidative stress and inflammatory response.

Environmental factors affecting the risk of generalization for ocular-onset myasthenia gravis: a nationwide cohort study.

BACKGROUND: The environmental effects on the prognosis of ocular myasthenia gravis (OMG) remain largely unexplored. AIM: To investigate the association between specific environmental factors and the generalization of OMG. DESIGN: The cohort study was conducted in China based on a nationwide multicenter database. METHODS: Adult patients with OMG at onset, who were followed up for at least 2 years until May 2022, were included. We collected data on demographic and clinical factors, as well as environmental factors, including latitude, socioeconomic status (per capita disposable income [PDI] at provincial level and education) and smoking. The study outcome was the time to the development of generalized myasthenia gravis (GMG). Cox models were employed to examine the association between environmental exposures and generalization. Restricted cubic spline was used to model the association of latitude with generalization risk. RESULTS: A total of 1396 participants were included. During a median follow-up of 5.15 (interquartile range [IQR] 3.37-9.03) years, 735 patients developed GMG within a median of 5.69 (IQR 1.10-15.66) years. Latitude of 20-50°N showed a U-shaped relation with generalization risk, with the lowest risk at around 30°N; both higher and lower latitudes were associated with the increased risk (P for non-linearity <0.001). Living in areas with lower PDI had 1.28-2.11 times higher risk of generalization. No significant association was observed with education or smoking. CONCLUSIONS: Latitude and provincial-level PDI were associated with the generalization of OMG in China. Further studies are warranted to validate our findings and investigate their potential applications in clinical practice and health policy.

Modifiable Risk Factors in High-Risk Groups of Colorectal Cancer Screening: A Cross-Sectional Study with Propensity Score Method.

Aim: The rising incidence and death rate of colorectal cancer (CRC) have posed a severe danger to the lives and health of residents. Individuals at high risk of CRC are drawing growing attention as the majority of the population impacted by CRC. Hence, it is imperative to examine the detection rates and modifiable factors affecting the populations at high risk for CRC in Shenzhen. Methods: The multi-stage stratified cluster sampling method was used to select residents aged 45-74 years old from September 2020 to December 2021. The community-based CRC screening was attended by a total of 30,921 residents from urban and suburb regions. The association between modifiable risk factors and the detection rate of high-risk groups was analyzed using multinomial logistic regression with the inverse probability treatment weighting (IPTW) based on the propensity score. Results: The cross-sectional analysis included 24,613 people after excluding 6308 people who had missing or invalid fecal occult blood test (FOBT) results. The detection rate for high-risk groups during CRC screening was 28.50%. Higher rate of high-risk groups was detected among those who were male, aged 60 or above, college or above, other marital status, and living in urban (P < 0.05). Demographic characteristics after IPTW showed a weak correlation coefficient with the detection rate of CRC high-risk both in high-risk and general-risk groups (SMD < 0.1), suggesting a balanced group of participants. The results of logistic regression with IPTW indicated that smoking, drinking, obesity, lack of exercise, vegetable or fruit eating infrequently, red meat, processed meat, cereal food and their clustering status were more inclined to be risk indicators of CRC (P < 0.05). Conclusion: The detection rate for high-risk CRC groups was comparatively high in Shenzhen. The distribution characteristics of lifestyle and dietary risk factors of high-risk groups should be given consideration when adopting individualized intervention measures and comprehensive prevention and control strategies.

Estimating the economic burden of colorectal cancer in China, 2019-2030: A population-level prevalence-based analysis.

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers worldwide. Comprehensive data on the economic burden of CRC at a population-level is critical in informing policymaking, but such data are currently limited in China. METHODS: From a societal perspective, the economic burden of CRC in 2019 was estimated, including direct medical and nonmedical expenditure, disability, and premature-death-related indirect expenditure. Data on disease burden was taken from the GBD 2019 and analyzed using a prevalence-based approach. The per-person direct expenditure and work loss days were from a multicenter study; the premature-death-related expenditure was estimated using a human capital approach. Projections were conducted in different simulated scenarios. All expenditure data were in Chinese Yuan (CNY) and discounted to 2019. RESULTS: In 2019, the estimated overall economic burden of CRC in China was CNY170.5 billion (0.189% of the local GDP). The direct expenditure was CNY106.4 billion (62.4% of the total economic burden), 91.4% of which was a direct medical expenditure. The indirect expenditure was CNY64.1 billion, of which 63.7% was related to premature death. The predicted burden would reach CNY560.0 billion in 2030 given constant trends for disease burden; however, it would be alternatively reduced to

Impact of changing the prevalence of smoking, alcohol consumption and overweight/obesity on cancer incidence in China from 2021 to 2050: a simulation modelling study.

Background: Smoking, alcohol consumption and overweight/obesity are key cancer risk factors contributing to the cancer burden in China. We aimed to quantify the cancer burden in China associated with smoking, alcohol consumption and overweight/obesity, and estimate the potential effect for cancer prevention interventions under different scenarios. Methods: We used a macro-simulation approach called Prevent Model to estimate for a 30-year study period (2021-2050) numbers and proportions of future avoidable cancer cases under different scenarios of reducing the prevalence of smoking, alcohol consumption and overweight/obesity in Chinese adults. Cancer incidence was predicted under three scenarios: elimination, ambitious target (between elimination and manageable target) and manageable target (from national policy or global action plan). Risk factor prevalence was obtained from China Chronic Disease and Risk Factor Surveillance, and cancer incidence data were derived from the China Cancer Registry Annual Report. Relative risks were obtained from several recent large-scale studies or high-quality meta-analysis. Population data were extracted from the China Population & Employment Statistical Yearbook, China Health Statistical Yearbook and World Population Prospects. Findings: Estimates of the avoidable cancer burden varied with different scenarios. In the theoretical maximum intervention scenario, where the prevalence of smoking, alcohol consumption and overweight/obesity would be eliminated, 9.17% (males: 13.50%; females: 1.47%) of smoking-related cancer cases, 7.06% (males: 11.49%; females: 1.00%) of cancer cases related to alcohol consumption and 8.22% (males: 7.91%; females: 8.52%) of overweight/obesity-related cancer cases were estimated to be avoidable during 2021-2050. Other scenarios, with more moderate goals in the exposure prevalence of smoking, alcohol use and overweight/obesity were also found to be associated with substantial reductions in the future cancer burden. Interpretation: Our results suggested that a substantial number of future cancer cases could be avoided in Chinese adults by reducing the prevalence of smoking, alcohol consumption and overweight/obesity. Funding: National Science & Technology Fundamental Resources Investigation Program of China; Sanming Project of Medicine in Shenzhen.

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.

Inhibition of cluster antigen 36 protects against fatty acid-induced lipid accumulation, oxidative stress, and inflammation in bovine hepatocytes.

When ketosis occurs, supraphysiological concentrations of nonesterified fatty acids (NEFA) display lipotoxicity and are closely related to the occurrence of hepatic lipid accumulation, oxidative stress, and inflammation, resulting in hepatic damage and exacerbating the progression of ketosis. However, the mechanism of these lipotoxic effects caused by high concentrations of NEFA in ketosis is still unclear. Cluster antigen 36 (CD36), a fatty acid transporter, plays a vital role in the development of hepatic pathological injury in nonruminants. Thus, the aim of this study was to investigate whether CD36 plays a role in NEFA-induced hepatic lipotoxicity in dairy cows with clinical ketosis. Liver tissue and blood samples were collected from healthy (n = 10) and clinically ketotic (n = 10) cows at 3 to 15 d in milk. In addition, hepatocytes isolated from healthy calves were treated with 0, 0.6, 1.2, or 2.4 mM NEFA for 12 h; or infected with CD36 expressing adenovirus or CD36 silencing small interfering RNA for 48 h and then treated with 1.2 mM NEFA for 12 h. Compared with healthy cows, clinically ketotic cows had greater concentrations of serum NEFA and ß-hydroxybutyrate and activities of aspartate aminotransferase and alanine aminotransferase but lower serum glucose. In addition, dairy cows with clinical ketosis displayed excessive hepatic lipid accumulation. More importantly, these alterations were accompanied by an increased abundance of hepatic CD36. In the cell culture model, exogenous NEFA (0, 0.6, 1.2, or 2.4 mM) treatment could dose-dependently increase the abundance of CD36. Meanwhile, NEFA (1.2 mM) increased the content of triacylglycerol, reactive oxygen species and malondialdehyde, and decreased the activities of glutathione peroxidase and superoxide dismutase. Moreover, NEFA upregulated phosphorylation levels of nuclear factor κB (NF-κB) and the inhibitor of NF-κB (IκB) α, along with the upregulation of protein abundance of NLR family pyrin domain containing 3 (NLRP3) and caspase-1, and mRNA abundance of IL1B, IL6, and tumor necrosis factor α (TNFA). These alterations induced by NEFA in bovine hepatocytes were associated with increased lipid accumulation, oxidative stress and inflammation, which could be further aggravated by CD36 overexpression. Conversely, silencing CD36 attenuated these NEFA-induced detriments. Overall, these data suggest that CD36 may be a potential therapeutic target for NEFA-induced hepatic lipid accumulation, oxidative stress, and inflammation in dairy cows.

Low abundance of insulin-induced gene 1 contributes to SREBP-1c processing and hepatic steatosis in dairy cows with severe fatty liver.

Fatty liver is a major metabolic disorder of high-producing dairy cows during the transition period. In nonruminants, it is well established that insulin-induced gene 1 (INSIG1) plays a crucial role in regulating hepatic lipogenesis by controlling the anchoring of sterol regulatory element-binding protein 1 (SREBP-1) on the endoplasmic reticulum along with SREBP cleavage-activating protein (SCAP). Whether the INSIG1-SCAP-SREBP-1c transport axis is affected in cows experiencing fatty liver is unknown. Thus, the aim of this study was to investigate the potential role of INSIG1-SCAP-SREBP-1c axis in the progression of fatty liver in dairy cows. For in vivo experiments, 24 dairy cows at the start of their fourth lactation (median; range 3-5) and 8 d in milk (median; range 4-12 d) were selected into a healthy group [n = 12; triglyceride (TG) content <1%] and a severe fatty liver group (n = 12; TG content >10%) according to their hepatic TG content. Blood samples were collected for detecting serum concentrations of free fatty acids, ß-hydroxybutyrate, and glucose. Compared with healthy cows, cows with severe fatty liver had higher serum concentrations of ß-hydroxybutyrate and free fatty acids and lower concentration of glucose. Liver biopsies were used to detect the status of INSIG1-SCAP-SREBP-1c axis, and the mRNA expression of SREBP-1c-target lipogenic genes acetyl-CoA carboxylase α (ACACA), fatty acid synthase (FASN), and diacylglycerol acyltransferase 1 (DGAT1). Cows with severe fatty liver had lower protein expression of INSIG1 in the hepatocyte endoplasmic reticulum fraction, greater protein expression of SCAP and precursor SREBP-1c in the hepatocyte Golgi fraction, and greater protein expression of mature SREBP-1c in the hepatocyte nuclear fraction. In addition, the mRNA expression of SREBP-1c-target lipogenic genes ACACA, FASN, and DGAT1 was greater in the liver of dairy cows with severe fatty liver. In vitro experiments were conducted on hepatocytes isolated from 5 healthy 1-d-old female Holstein calves, and hepatocytes from each calf were run independently. First, hepatocytes were treated with 0, 200, or 400 µM palmitic acid (PA) for 12 h. Exogenous PA treatment decreased INSIG1 protein abundance, enhanced the endoplasmic reticulum to Golgi export of SCAP-precursor SREBP-1c complex and the nuclear translocation of mature SREBP-1c, all of which was associated with increased transcriptional activation of lipogenic genes and TG synthesis. Second, hepatocytes were transfected with INSIG1-overexpressing adenovirus for 48 h and treated with 400 µM PA 12 h before the end of transfection. Overexpressing INSIG1 inhibited PA-induced SREBP-1c processing, upregulation of lipogenic genes, and TG synthesis in hepatocytes. Overall, the present in vivo and in vitro results indicated that the low abundance of INSIG1 contributed to SREBP-1c processing and hepatic steatosis in dairy cows. Thus, the INSIG1-SCAP-SREBP-1c axis may be a novel target for treatment of fatty liver in dairy cows.

Trends in Incidence Rates, Mortality Rates, and Age-Period-Cohort Effects of Female Breast Cancer - China, 2003-2017.

Introduction: This study reported the trends in female breast cancer incidence and mortality rates in China, and analyzed the corresponding age-period-cohort effects. Methods: Data from 22 population-based cancer registries in China between 2003 and 2017 were analyzed. Age-standardized incidence rates (ASIR) and mortality rates (ASMR) were calculated using Segi's world standard population. Joinpoint regression was employed to evaluate trends, and age-period-cohort effects were examined using the intrinsic estimator method. Results: The ASIR for female breast cancer exhibited a more rapid increase in rural areas compared to urban areas across all age groups. The most substantial increase was observed in the 20-34 age group in rural areas [annual percent change (APC)=9.0%, 95% confidence interval (CI): 7.0%-11.0%, P<0.001]. The ASMR for females under 50 years old remained stable from 2003 to 2017 in both urban and rural areas. However, the ASMR for females over 50 in rural areas and those over 65 in urban areas demonstrated a significant increase, with the most pronounced increase observed among females over 65 in rural areas (APC=4.9%, 95% CI: 2.8%-7.0%, P<0.001). Age-period-cohort analysis revealed increasing period effects and decreasing cohort effects for female breast cancer incidence and mortality rates in both urban and rural settings. Notably, the cohort effect for incidence displayed a slight upward trend for females born between 1983 and 1992 in rural areas. Conclusions: Our study revealed a rapid increase in breast cancer incidence among younger generations and an accelerated mortality rate in older populations residing in rural areas. To effectively address the growing burden of female breast cancer in China, it is essential to develop and implement targeted intervention strategies.

Stomach cancer burden in China: Epidemiology and prevention.

In 2020, stomach cancer was the fifth most commonly diagnosed cancer and the fourth leading cause of cancer-related death worldwide. Due to the relatively huge population base and the poor survival rate, stomach cancer is still a threat in China, and accounts for nearly half of the cases worldwide. Fortunately, in China, the incidence and mortality rates of stomach cancer presented a declining trend owing to the change of individual life styles and the persistent efforts to prevent stomach cancer from the governments at all levels. Helicobacter pylori (H. pylori) infection, poor eating habits, smoking, history of gastrointestinal disorders, and family history of stomach cancer are the main risk factors for stomach cancer in China. As a result, by taking risk factors for stomach cancer into account, specific preventive measures, such as eradicating H. pylori and implementing stomach cancer screening projects, should be taken to better prevent and decrease the burden of stomach cancer.

Narirutin activates TFEB (transcription factor EB) to protect against Acetaminophen-induced liver injury by targeting PPP3/calcineurin.

Acetaminophen (APAP) overdose is the predominant cause of drug-induced liver injury worldwide. The macroautophagy/autophagy-lysosomal pathway (ALP) is involved in the APAP hepatotoxicity. TFEB (transcription factor EB) promotes the expression of genes related to autophagy and lysosomal biogenesis, thus, pharmacological activation of TFEB-mediated ALP may be an effective therapeutic approach for treating APAP-induced liver injury. We aimed to reveal the effects of narirutin (NR), the main bioactive constituents isolated from citrus peels, on APAP hepatotoxicity and to explore its underlying mechanism. Administration of NR enhanced activities of antioxidant enzymes, improved mitochondrial dysfunction and alleviated liver injury in APAP-treated mice, whereas NR did not affect APAP metabolism and MAPK/JNK activation. NR enhanced TFEB transcriptional activity and activated ALP in an MTOR complex 1 (MTORC1)-independent but PPP3/calcineurin-dependent manner. Moreover, knockout of Tfeb or knockdown of PPP3CB/CNA2 (protein phosphatase 3, catalytic subunit, beta isoform) in the liver abolished the beneficial effects of NR on APAP overdose. Mechanistically, NR bound to PPP3CB via PRO31, LYS61 and PRO347 residues and enhanced PPP3/calcineurin activity, thereby eliciting dephosphorylation of TFEB and promoting ALP, which alleviated APAP-induced oxidative stress and liver injury. Together, NR protects against APAP-induced liver injury by activating a PPP3/calcineurin-TFEB-ALP axis, indicating NR may be a potential agent for treating APAP overdose.Abbreviations: ALP: autophagy-lysosomal pathway; APAP: acetaminophen; APAP-AD: APAP-protein adducts; APAP-Cys: acetaminophen-cysteine adducts; CAT: catalase; CETSA: cellular thermal shift assay; CQ: chloroquine; CYP2E1: cytochrome P450, family 2, subfamily e, polypeptide 1; CYCS/Cyt c: cytochrome c, somatic; DARTS: drug affinity responsive target stability assay; ENGASE/NAG: endo-beta-N-acetylglucosaminidase; GOT1/AST: glutamic-oxaloacetic transaminase 1, soluble; GPT/ALT: glutamic pyruvic transaminase, soluble; GSH: glutathione; GPX/GSH-Px: glutathione peroxidase; KD: dissociation constant; Leu: leupeptin; MCOLN1: mucolipin 1; MTORC1: MTOR complex 1; NAC: N-acetylcysteine; NAPQI: N-acetyl-p-benzoquinoneimine; NFAT: nuclear factor of activated T cells; NR: narirutin; OA: okadaic acid; RRAG: Ras related GTP binding; ROS: reactive oxygen species; PPP3CB/CNA2: protein phosphatase 3, catalytic subunit, beta isoform; PPP3R1/CNB1: protein phosphatase 3, regulatory subunit B, alpha isoform (calcineurin B, type I); SOD: superoxide dismutase; SPR: surface plasmon resonance analysis; TFEB: transcription factor EB.

Comparison between mono-tacrolimus and mono-glucocorticoid in the treatment of myasthenia gravis.

OBJECTIVE: Use of tacrolimus in mild to moderate myasthenia gravis (MG) is generally limited to glucocorticoid-refractory cases; the advantage of mono-tacrolimus over mono-glucocorticoids is unknown. METHODS: We included mild to moderate MG patients treated with mono-tacrolimus (mono-TAC) or mono-glucocorticoids (mono-GC). The correlation between the immunotherapy options and the treatment efficacy and side effects were examined in 1:1 propensity-score matching. The main outcome was time to minimal manifestations status or better (MMS or better). Secondary outcomes include time to relapse, the mean changes in Myasthenia Gravis-specific Activities of Daily Living (MG-ADL) scores and the rate of adverse events. RESULTS: Baseline characteristics showed no difference between matched groups (49 matched pairs). There were no differences in median time to MMS or better between the mono-TAC group and mono-GC group (5.1 vs. 2.8 months: unadjusted hazard ratio [HR], 0.73; 95% CI, 0.46-1.16; p = 0.180), as well as in median time to relapse (data unavailable for the mono-TAC group since 44 of 49 [89.8%] participants remained in MMS or better; 39.7 months in mono-GC group: unadjusted HR, 0.67; 95% CI, 0.23-1.97; p = 0.464). Changes in MG-ADL scores between the two groups were similar (mean differences, 0.3; 95% CI, -0.4 to 1.0; p = 0.462). The rate of adverse events was lower in the mono-TAC group compared to the mono-GC group (24.5% vs. 55.1%, p = 0.002). INTERPRETATION: Mono-tacrolimus performs superior tolerability with non-inferior efficacy compared to mono-glucocorticoids in mild to moderate myasthenia gravis patients who refuse or have a contraindication to glucocorticoids.

Liver fibrosis is a common pathological change in the liver of dairy cows with fatty liver.

Fatty liver (i.e., hepatic lipidosis) is a prevalent metabolic disorder in dairy cows during the transition period, characterized by excess hepatic accumulation of triglyceride (TG), tissue dysfunction, and cell death. Detailed pathological changes, particularly hepatic fibrosis, during fatty liver remain to be determined. Liver fibrosis occurs as a consequence of liver damage, resulting from the excessive accumulation of extracellular matrix, which distorts the architecture of the normal liver, compromising its normal synthetic and metabolic functions. Thus, we aimed to investigate liver fibrosis status and its potential causal factors including oxidative stress, hepatocyte apoptosis, and production of inflammatory cytokines in the liver of cows with fatty liver. Forty-five dairy cows (parity, 3-5) were selected, and liver biopsy and blood were collected on the second week postpartum (days in milk, 10-14 d). On the basis of the degree of lipid accumulation in liver, selected cows were categorized into normal (n = 25; TG <1% wet wt), mild fatty liver (n = 15; 1% ≤ TG <5% wet wt), and moderate fatty liver (n = 5; 5% ≤ TG <10% wet wt). Compared with normal cows, blood concentrations of nonesterified fatty acids and ß-hydroxybutyrate, along with alanine aminotransferase and aspartate aminotransferase activities, were greater in the cows with fatty liver (mild and moderate). Hepatic extracellular matrix deposition, as indicated by Picrosirius red staining, was greater in cows with fatty liver than those with normal ones. In addition, we observed an increased proportion of collagen type I fiber in extracellular matrix with increased lipid accumulation in the liver. Compared with normal cows, the area of α-smooth muscle actin (α-SMA)-positive staining along with the mRNA abundance of collagen type I α 1 (COL1A1), ACTA2 (gene encoding α-SMA), and transforming growth factor-ß (TGFB) were greater in cows with fatty liver. Compared with normal cows, hepatic contents of malondialdehyde, glutathione disulfide, and 8-isoprostane were greater, whereas total antioxidant capacity, the hepatic content of glutathione, and activities of antioxidant indicators, including superoxide dismutase, glutathione peroxidase, and catalase, were lower in cows with fatty liver. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells and abundance of apoptosis-related molecules BAX, CASP3, CASP8, and CASP9 were greater in cows with fatty liver. However, mRNA abundance of the anti-apoptotic gene BCL2 did not differ. The mRNA abundance of pro-inflammatory cytokines including tumor necrosis factor-α (TNFA), interleukin-1ß (IL1B), and interleukin-6 (IL6) was greater in the liver of cows with fatty liver. Overall, the present study indicated that fibrosis is a common pathological response to liver damage and is associated with oxidative stress, hepatocyte death, and inflammation.

Circadian Disruption and Breast Cancer Risk: Evidence from a Case-Control Study in China.

Studies had suggested an association between circadian disruptors (including night shift work, domestic light exposure at night, sleep duration, and circadian gene polymorphism) and breast cancer, while rare studies had been conducted in the Chinese population. This study was a case-control study conducted to explore the impact of circadian disruptors on the risk of breast cancer in China. Four hundred and sixty-four cases and 464 controls, admitted from the Department of Breast Surgery, Cancer Hospital, Chinese Academy of Medical Sciences, were included in this study. Adjusting age, BMI group, smoking, alcohol consumption, menopausal status, family history of breast cancer, duration of breastfeeding, age at menarche, number of pregnancies, age at first full-term pregnancy, use of estrogen and use of oral contraceptive, multivariate logistic regression analysis showed that the risk of breast cancer was higher in short sleep duration group (OR = 4.86, 95%CI: 1.73-17.33). Meanwhile, rs2292912 in CRY2, rs2253820 in PER1, rs2289591 in PER1 and rs3027188 in PER1 were positively associated with the risk of breast cancer. This study supported that the short duration of sleep and four SNPs in crucial circadian genes played a role in the development of breast cancer.

Real-World Practice of Gastric Cancer Prevention and Screening Calls for Practical Prediction Models.

INTRODUCTION: Some gastric cancer prediction models have been published. Still, the value of these models for application in real-world practice remains unclear. We aim to summarize and appraise modeling studies for gastric cancer risk prediction and identify potential barriers to real-world use. METHODS: This systematic review included studies that developed or validated gastric cancer prediction models in the general population. RESULTS: A total of 4,223 studies were screened. We included 18 development studies for diagnostic models, 10 for prognostic models, and 1 external validation study. Diagnostic models commonly included biomarkers, such as Helicobacter pylori infection indicator, pepsinogen, hormone, and microRNA. Age, sex, smoking, body mass index, and family history of gastric cancer were frequently used in prognostic models. Most of the models were not validated. Only 25% of models evaluated the calibration. All studies had a high risk of bias, but over half had acceptable applicability. Besides, most studies failed to clearly report the application scenarios of prediction models. DISCUSSION: Most gastric cancer prediction models showed common shortcomings in methods, validation, and reports. Model developers should further minimize the risk of bias, improve models' applicability, and report targeting application scenarios to promote real-world use.

Nuciferine Ameliorates Nonesterified Fatty Acid-Induced Bovine Mammary Epithelial Cell Lipid Accumulation, Apoptosis, and Impaired Migration via Activating LKB1/AMPK Signaling Pathway.

High blood concentrations of nonesterified fatty acids (NEFAs) provoke various metabolic disorders and are associated with mammary tissue injury and decreased milk production in dairy cows. Nuciferine, an alkaloid found in Nelumbo nucifera leaves, has great potential for correcting lipid metabolism derangements and lipotoxicity. In this study, we evaluated the lipotoxicity induced by excessive NEFA in bovine mammary epithelial cells (bMECs) and investigated whether nuciferine alleviates NEFA-induced lipotoxicity and the underlying molecular mechanisms. We found that excessive NEFA (1.2 and 2.4 mM) induced lipid accumulation, apoptosis, and migration ability impairment in bMECs, whereas nuciferine could ameliorate these disarrangements, as indicated by decreasing triglyceride content, protein abundance of SREBP-1c, cytoplasmic cytochrome c, and cleaved caspase-3 and increasing protein abundance of PPARα and migration ability. Moreover, nuciferine could reverse NEFA-induced LKB1/AMPK signaling inhibition, and the protective effect of nuciferine on lipotoxicity caused by NEFA was abrogated by AMPK inhibitor dorsomorphin. Furthermore, transfection with LKB1 siRNA (si-LKB1) largely abolished the activation effect of nuciferine on AMPK. Overall, nuciferine can protect bMECs from excessive NEFA-induced lipid accumulation, apoptosis, and impaired migration by activating LKB1/AMPK signaling pathway.