Profound primary prevention of liver cancer following a natural experiment in China: A 50-year perspective and public health implications.

Liver cancer causes upwards of 1 million cancer deaths annually and is projected to rise by at least 55% over the next 15 years. Two of the major risk factors contributing to liver cancer have been well documented by multiple epidemiologic studies and the hepatitis B virus (HBV) and aflatoxin show a synergy that increases by more than 8-fold the risk of liver cancer relative to HBV alone. Using the population-based cancer registry established by the Qidong Liver Cancer Institute in 1972 and aflatoxin-specific biomarkers, we document that reduction of aflatoxin exposure has likely contributed to a nearly 70% decline in age-standardized liver cancer incidence over the past 30 years despite an unchanging prevalence of HBV infection in cases. A natural experiment of economic reform in the 1980s drove a rapid switch from consumption of heavily contaminated corn to minimally, if any, contaminated rice and subsequent dietary diversity. Aflatoxin consumption appears to accelerate the time to liver cancer diagnosis; lowering exposure to this carcinogen adds years of life before a cancer diagnosis. Thus, in 1990 the median age of diagnosis was 48 years, while increasing to 67 years by 2021. These findings have important translational public health implications since up to 5 billion people worldwide might be routinely exposed to dietary aflatoxin, especially in societies using corn as the staple food. Interventions against aflatoxin are an achievable outcome leading to a reduction in liver cancer incidence and years of delay of its nearly always fatal diagnosis.

Wheel-Running Exercise Alleviates Anxiety-Like Behavior via Down-Regulating S-Nitrosylation of Gephyrin in the Basolateral Amygdala of Male Rats.

Physical exercise has beneficial effect on anxiety disorders, but the underlying molecular mechanism remains largely unknown. Here, it is demonstrated that physical exercise can downregulate the S-nitrosylation of gephyrin (SNO-gephyrin) in the basolateral amygdala (BLA) to exert anxiolytic effects. It is found that the level of SNO-gephyrin is significantly increased in the BLA of high-anxiety rats and a downregulation of SNO-gephyrin at cysteines 212 and 284 produced anxiolytic effect. Mechanistically, inhibition of SNO-gephyrin by either Cys212 or Cys284 mutations increased the surface expression of GABAAR γ2 and the subsequent GABAergic neurotransmission, exerting anxiolytic effect in male rats. On the other side, overexpression of neuronal nitric oxide synthase in the BLA abolished the anxiolytic-like effects of physical exercise. This study reveals a key role of downregulating SNO-gephyrin in the anxiolytic effects of physical exercise, providing a new explanation for protein post-translational modifications in the brain after exercise.

Prognostic significance of systemic immune inflammatory index in NSCLC: a meta-analysis.

Aim: The aim of this meta-analysis was to investigate the relationship between the baseline systemic immune inflammatory index (SII) and prognosis in patients with NSCLC. Materials & methods: The relation between pretreatment SII and overall survival, disease-free survival, cancer-specific survival, progression-free survival and recurrence-free survival in NSCLC patients was analyzed combined with hazard ratio and 95% CI. Results: The results showed that high SII was significantly correlated with overall survival and progression-free survival of NSCLC patients, but not with disease-free survival, cancer-specific survival and recurrence-free survival. Conclusion: The study suggests that a higher SII has association with worse prognosis in NSCLC patients. PROSPERO registration number: CRD42022336270.

Engineered hsa-miR-455-3p-Abundant Extracellular Vesicles Derived from 3D-Cultured Adipose Mesenchymal Stem Cells for Tissue-Engineering Hyaline Cartilage Regeneration.

Efforts are made to enhance the inherent potential of extracellular vesicles (EVs) by utilizing 3D culture platforms and engineered strategies for functional cargo-loading. Three distinct types of adipose mesenchymal stem cells-derived EVs (ADSCs-EVs) are successfully isolated utilizing 3D culture platforms consisting of porous gelatin methacryloyl (PG), PG combined with sericin methacryloyl (PG/SerMA), or PG combined with chondroitin sulfate methacryloyl (PG/ChSMA). These correspond to PG-EVs, PG/SerMA-EVs, and PG/ChSMA-EVs, respectively. Unique microRNA (miRNA) profiles are observed in each type of ADSCs-EVs. Notably, PG-EVs encapsulate higher levels of hsa-miR-455-3p and deliver more hsa-miR-455-3p to chondrocytes, which results in the activation of the hsa-miR-455-3p/PAK2/Smad2/3 axis and the subsequent hyaline cartilage regeneration. Furthermore, the functionality of PG-EVs is optimized through engineered strategies, including agomir/lentivirus transfection, electroporation, and Exo-Fect transfection. These strategies, referred to as Agomir-EVs, Lentivirus-EVs, Electroporation-EVs, and Exo-Fect-EVs, respectively, are ranked based on their efficacy in encapsulating hsa-miR-455-3p, delivering hsa-miR-455-3p to chondrocytes, and promoting cartilage formation via the hsa-miR-455-3p/PAK2/Smad2/3 axis. Notably, Exo-Fect-EVs exhibit the highest efficiency. Collectively, the 3D culture conditions and engineered strategies have an impact on the miRNA profiles and cartilage regeneration capabilities of ADSCs-EVs. The findings provide valuable insights into the mechanisms underlying the promotion of cartilage regeneration by ADSCs-EVs.

Mitochondrial fission drives neuronal metabolic burden to promote stress susceptibility in male mice.

Neurons are particularly susceptible to energy fluctuations in response to stress. Mitochondrial fission is highly regulated to generate ATP via oxidative phosphorylation; however, the role of a regulator of mitochondrial fission in neuronal energy metabolism and synaptic efficacy under chronic stress remains elusive. Here, we show that chronic stress promotes mitochondrial fission in the medial prefrontal cortex via activating dynamin-related protein 1 (Drp1), resulting in mitochondrial dysfunction in male mice. Both pharmacological inhibition and genetic reduction of Drp1 ameliorates the deficit of excitatory synaptic transmission and stress-related depressive-like behavior. In addition, enhancing Drp1 fission promotes stress susceptibility, which is alleviated by coenzyme Q10, which potentiates mitochondrial ATP production. Together, our findings unmask the role of Drp1-dependent mitochondrial fission in the deficits of neuronal metabolic burden and depressive-like behavior and provides medication basis for metabolism-related emotional disorders.

Survival of 48866 cancer patients: results from Nantong area, China.

Objective: This study aimed to provide a realistic observation of survival by major site for 48,866 cancer patients treated at a tertiary cancer hospital in a rural area of China. Methods: Patients with cancer registered between 2007 and 2017 in the Nantong rural area were followed up. The starting date for survival calculation was the date of the first diagnosis of cancer at the Nantong Tumor Hospital, and the closing date was December 31, 2020. Observed survival (OS) was analyzed according to ICD-10 site, sex, age, region, and hospitalization period using the life table method and compared using the Wilcoxon (Gehan) statistic. Results: The overall 5-year OS rate was 40.48% for all 48,866 patients, 30.19% for males, and 51.90% for females. The top five cancer sites, accounting for 60.51% of the total cases, were the esophagus, lung, stomach, liver, and cervix, with 5-year OS rates of 33.72%, 18.64%, 32.10%, 19.04%, and 71.51%, respectively. The highest 5-year OS was observed in the thyroid (87.52%) and the lowest was in the pancreas (6.37%). Survival was significantly higher in younger patients than in older patients, with 5-year OSs of 69.26% and 19.84% in those aged 20-29 and 90-99 years, respectively. Five-year OSs improved significantly from 39.35% in 2007-2011 to 41.26% in 2012-2017. Conclusion: Overall survival improved over the years, although the improvement at some sites was not significant. The observed survival varies from region to region, reflecting differences in the patterns of major sites, disparities in proportions of hospitalization, and demographic characteristics.

Cancer survival: left truncation and comparison of results from hospital-based cancer registry and population-based cancer registry.

Background: Cancer survival is an important indicator for evaluating cancer prognosis and cancer care outcomes. The incidence dates used in calculating survival differ between population-based registries and hospital-based registries. Studies examining the effects of the left truncation of incidence dates and delayed reporting on survival estimates are scarce in real-world applications. Methods: Cancer cases hospitalized at Nantong Tumor Hospital during the years 2002-2017 were traced with their records registered in the Qidong Cancer Registry. Survival was calculated using the life table method for cancer patients with the first visit dates recorded in the hospital-based cancer registry (HBR) as the diagnosis date (OSH), those with the registered dates of population-based cancer (PBR) registered as the incidence date (OSP), and those with corrected dates when the delayed report dates were calibrated (OSC). Results: Among 2,636 cases, 1,307 had incidence dates registered in PBR prior to the diagnosis dates of the first hospitalization registered in HBR, while 667 cases with incidence dates registered in PBR were later than the diagnosis dates registered in HBR. The 5-year OSH, OSP, and OSC were 36.1%, 37.4%, and 39.0%, respectively. The "lost" proportion of 5-year survival due to the left truncation for HBR data was estimated to be between 3.5% and 7.4%, and the "delayed-report" proportion of 5-year survival for PBR data was found to be 4.1%. Conclusion: Left truncation of survival in HBR cases was demonstrated. The pseudo-left truncation in PBR should be reduced by controlling delayed reporting and maximizing completeness. Our study provides practical references and suggestions for evaluating the survival of cancer patients with HBR and PBR.

BNIP3L/NIX-mediated mitophagy alleviates passive stress-coping behaviors induced by tumor necrosis factor-α.

Recent studies based on animal models of various neurological disorders have indicated that mitophagy, a selective autophagy that eliminates damaged and superfluous mitochondria through autophagic degradation, may be involved in various neurological diseases. As an important mechanism of cellular stress response, much less is known about the role of mitophagy in stress-related mood disorders. Here, we found that tumor necrosis factor-α (TNF-α), an inflammation cytokine that plays a particular role in stress responses, impaired the mitophagy in the medial prefrontal cortex (mPFC) via triggering degradation of an outer mitochondrial membrane protein, NIP3-like protein X (NIX). The deficits in the NIX-mediated mitophagy by TNF-α led to the accumulation of damaged mitochondria, which triggered synaptic defects and behavioral abnormalities. Genetic ablation of NIX in the excitatory neurons of mPFC caused passive coping behaviors to stress, and overexpression of NIX in the mPFC improved TNF-α-induced synaptic and behavioral abnormalities. Notably, ketamine, a rapid on-set and long-lasting antidepressant, reversed the TNF-α-induced behavioral abnormalities through activation of NIX-mediated mitophagy. Furthermore, the downregulation of NIX level was also observed in the blood of major depressive disorder patients and the mPFC tissue of animal models. Infliximab, a clinically used TNF-α antagonist, alleviated both chronic stress- and inflammation-induced behavioral abnormalities via restoring NIX level. Taken together, these results suggest that NIX-mediated mitophagy links inflammation signaling to passive coping behaviors to stress, which underlies the pathophysiology of stress-related emotional disorders.

Resveratrol reduces lactate production and modifies the ovarian cancer immune microenvironment.

Tumor cells show deregulated metabolism leading to an enrichment of lactate in the tumor microenvironment (TME). This lactate-rich environment has been reported to impair effector T cells. However, T-regulatory cells (Tregs) show metabolic advantages in lactate-rich TME that maintain a strong suppression of effector T cells, which leads to tumor immune evasion. Therefore, the glycolytic process of tumors could represent a therapeutic target, and agents that modify the energy metabolism of tumor cells have therapeutic potential. Resveratrol is a naturally occurring polyphenol that has been confirmed to suppress tumor cells' glycolytic metabolism. In this study, we show that resveratrol induces metabolic reprogramming in ovarian cancer cells. Resveratrol increases oxidative and decreases glycolysis, in association with decreased lactate production both in vitro and in vivo. Lactate reduction in TME weakens the suppressive function of Tregs, and subsequently restores anti-tumor immunity. Significantly, combined resveratrol and PD-1 blockade promote anti-tumor efficacy. These data suggest that resveratrol's anti-tumor actions in ovarian cancer could be explained, in part, through modification of the anti-tumor immunity, and indicate a novel treatment strategy for improving immune checkpoint blockade therapy using resveratrol.

Assessing the Validity of Normalizing Aflatoxin B1-Lysine Albumin Adduct Biomarker Measurements to Total Serum Albumin Concentration across Multiple Human Population Studies.

The assessment of aflatoxin B1 (AFB1) exposure using isotope-dilution liquid chromatography-mass spectrometry (LCMS) of AFB1-lysine adducts in human serum albumin (HSA) has proven to be a highly productive strategy for the biomonitoring of AFB1 exposure. To compare samples across different individuals and settings, the conventional practice has involved the normalization of raw AFB1-lysine adduct concentrations (e.g., pg/mL serum or plasma) to the total circulating HSA concentration (e.g., pg/mg HSA). It is hypothesized that this practice corrects for technical error, between-person variance in HSA synthesis or AFB1 metabolism, and other factors. However, the validity of this hypothesis has been largely unexamined by empirical analysis. The objective of this work was to test the concept that HSA normalization of AFB1-lysine adduct concentrations effectively adjusts for biological and technical variance and improves AFB1 internal dose estimates. Using data from AFB1-lysine and HSA measurements in 763 subjects, in combination with regression and Monte Carlo simulation techniques, we found that HSA accounts for essentially none of the between-person variance in HSA-normalized (R2 = 0.04) or raw AFB1-lysine measurements (R2 = 0.0001), and that HSA normalization of AFB1-lysine levels with empirical HSA values does not reduce measurement error any better than does the use of simulated data (n = 20,000). These findings were robust across diverse populations (Guatemala, China, Chile), AFB1 exposures (105 range), HSA assays (dye-binding and immunoassay), and disease states (healthy, gallstones, and gallbladder cancer). HSA normalization results in arithmetic transformation with the addition of technical error from the measurement of HSA. Combined with the added analysis time, cost, and sample consumption, these results suggest that it may be prudent to abandon the practice of normalizing adducts to HSA concentration when measuring any HSA adducts-not only AFB1-lys adducts-when using LCMS in serum/plasma.

Deficiency of Glycosylated α-Dystroglycan in Ventral Hippocampus Bridges the Destabilization of Gamma-Aminobutyric Acid Type A Receptors With the Depressive-like Behaviors of Male Mice.

BACKGROUND: Depression is a common psychiatric disorder associated with defects in GABAergic (gamma-aminobutyric acidergic) neurotransmission. α-Dystroglycan (α-DG), a cell adhesion molecule known to be essential for skeletal muscle integrity, is also present at inhibitory synapses in the central nervous system and forms a structural element in certain synapses. However, the role of α-DG in the regulation of depressive-like behaviors remains largely unknown. METHODS: Depressive-like behaviors were induced by chronic social defeat stress in adult male mice. Surface protein was extracted by a biotin kit, and the expression of protein was detected by Western blotting. Intrahippocampal microinjection of the lentivirus or adeno-associated virus or agrin intervention was carried out using a stereotaxic instrument and followed by behavioral tests. Miniature inhibitory postsynaptic currents were recorded by whole-cell patch-clamp techniques. RESULTS: The expression of α-DG and glycosylated α-DG in the ventral hippocampus was significantly lower in chronic social defeat stress-susceptible male mice than in control mice, accompanied by a decreased surface expression of GABAA receptor γ2 subunit and reduced GABAergic neurotransmission. RNA interference-mediated knockdown of Dag1 increased the susceptibility of mice to subthreshold stress. Both in vivo administration of agrin and overexpression of like-acetylglucosaminyltransferase ameliorated depressive-like behaviors and restored the decrease in surface expression of GABAA receptor γ2 subunit and the amplitude of miniature inhibitory postsynaptic currents in chronic social defeat stress-exposed mice. CONCLUSIONS: Our findings demonstrate that glycosylated α-DG plays a role in the pathophysiological process of depressive-like behaviors by regulating the surface expression of GABAA receptor γ2 subunit and GABAergic neurotransmission in the ventral hippocampus.

N-acetylcysteine facilitates extinction of cued fear memory in rats via reestablishing basolateral amygdala glutathione homeostasis.

Individual differences in the development of uncontrollable fear in response to traumatic stressors have been observed in clinic, but the underlying mechanisms remain unknown. In the present study we first conducted a meta-analysis of published clinical data and found that malondialdehyde, an oxidative stress biomarker, was significantly elevated in the blood of patients with fear-related anxiety disorders. We then carried out experimental study in rats subjected to fear conditioning. We showed that reestablishing redox homeostasis in basolateral amygdale (BLA) after exposure to fear stressors determined the capacity of learned fear inhibition. Intra-BLA infusion of buthionine sulfoximine (BSO) to deplete the most important endogenous antioxidant glutathione (GSH) blocked fear extinction, whereas intra-BLA infusion of dithiothreitol or N-acetylcysteine (a precursor of GSH) facilitated extinction. In electrophysiological studies conducted on transverse slices, we showed that fear stressors induced redox-dependent inhibition of NMDAR-mediated synaptic function, which was rescued by extinction learning or reducing agents. Our results reveal a novel pharmacological strategy for reversing impaired fear inhibition and highlight the role of GSH in the treatment of psychiatric disorders.

Liver Cancer Survival: A Real World Observation of 45 Years with 32,556 Cases.

BACKGROUND AND AIMS: To explore the long-term trend of liver cancer survival, based on the real-world data (RWD) in the past 45 years from a population-based cancer registry, in Qidong, China. METHODS: A number of 32,556 patients with liver cancer were registered during the period of 1972 to 2016. Mixed methods by active and passive follow-up were performed. Life table method was employed for survival analysis by SPSS22 software. Wilcoxon (Gehan) statistics was considered as a significant test. Relative survival was calculated by using SURV software, and its annual percent change (APC) was estimated by the Joinpoint Regression Program. RESULTS: The overall observed survival (OS) rates of 1-, 5-, 10-, and 20-year rates from the data series were 18.51%, 6.28%, 4.03%, and 2.84%, and their relative survival (RS) rates were 18.88%, 6.95%, 4.96%, and 4.49%, respectively. For 24,338 male cases, the 5-year OS and RS rates were 5.93% and 6.54%, and for 8218 female cases, 7.34% and 8.15%, respectively, with P values less than 0.01. Survival rates of liver cancer from three 15-year periods of 1972-1986, 1987-2001, and 2002-2016 have increased significantly, with 5-year OS rates of 2.02%, 4.40%, and 10.76%, 5-year RS rates of 2.18%, 4.83%, and 12.18%; 10-year OS and RS rates of 0.95%, 3.00%, and 7.02%, vs 1.13%, 3.65%, and 8.96%, respectively, showing a very significant upward trend (P<0.01). There are significant differences among age groups (P<0.01): those aged 55-64 demonstrated the best OS and RS rates of 5-year, being 8.44% and 9.09%, respectively. CONCLUSION: There are significant gender and age differences in the survival rate of liver cancer in Qidong. RWD indicates the relative lower survival rate of liver cancer in this area, but great improvement has been achieved over the past decades.

The emerging roles of absent in melanoma 2 (AIM2) inflammasome in central nervous system disorders.

As a double-stranded DNA (dsDNA) sensor, the PYHIN family member absent in melanoma 2 (AIM2) is an essential component of the inflammasome families. Activation of AIM2 by dsDNA leads to the assembly of cytosolic multimolecular complexes termed the AIM2 inflammasome, resulting in activation of caspase-1, the maturation and secretion of pro-inflammatory cytokines interleukin (IL)-1ß and IL-18, and pyroptosis. Multiple central nervous system (CNS) diseases are accompanied by immune responses and inflammatory cascade. As the resident macrophage cells, microglia cells act as the first and main form of active immune defense in the CNS. AIM2 is highly expressed in microglia as well as astrocytes and neurons and is essential in neurodevelopment. In this review, we highlight the recent progress on the role of AIM2 inflammasome in CNS disorders, including cerebral stroke, brain injury, neuropsychiatric disease, neurodegenerative diseases, and glioblastoma.

ABO blood groups and liver cancer: prospective results from an HBsAg cohort study.

OBJECTIVE: The association between ABO blood group and risk of liver cancer is unclear, although few studies have reported positive results. This study examined the relationship between ABO blood group and liver cancer in hepatitis B surface antigen (HBsAg)-positive individuals. DESIGN: A high-risk population-based cohort study. SETTING: The study was started in 2007 and closed in 2019; the number of observed person-years as obtained by ABO blood group. PARTICIPANTS: The study included 3663 individuals with positive HBsAg, including men aged 30-70 and women aged 40-70. OUTCOME MEASURES: The frequencies of ABO group in the cohort population and patients with liver cancer were calculated, respectively. χ2 test was used to compare differences, and the relative risk (95% CI) for development of liver cancer was evaluated. RESULTS: The frequency distribution of blood types A, B, O and AB was 1118 (30.52%), 1073 (29.29%), 1104 (30.14%) and 368 (10.05%), respectively, among 3663 cohort individuals. In the cohort, patients with liver cancer (n=336) were of the following frequencies: type A: 104 (30.95%); type B: 97 (28.87%); type O: 95 (28.27%); and type AB: 40 (11.90%). No significant difference was found between patients with liver cancer and other individuals. The annual incidence rate of liver cancer was 906.34 per 100 000 person-years, and for blood type A, B, O and AB the rates were 917.76, 893.78, 846.02 and 1093.43 per 100 000 person-years, respectively. The relative risk (95% CI) was 0.97 (0.74 to 1.29), 0.92 (0.70 to 1.22) and 1.19 (0.82 to 1.72) for blood types B, O and AB, respectively, compared with blood type A. CONCLUSION: There were no significant differences in the frequency distribution of ABO blood groups in patients with liver cancer within this high-risk cohort, which demonstrates lack of positive association between ABO blood group and risk of liver cancer.

Biomonitoring of Ambient Outdoor Air Pollutant Exposure in Humans Using Targeted Serum Albumin Adductomics.

Outdoor air pollution, a spatially and temporally complex mixture, is a human carcinogen. However, ambient measurements may not reflect subject-level exposures, personal monitors do not assess internal dose, and spot assessments of urinary biomarkers may not recapitulate chronic exposures. Nucleophilic sites in serum albumin-particularly the free thiol at Cys34-form adducts with electrophiles. Due to the 4-week lifetime of albumin in circulation, accumulating adducts can serve as intermediate- to long-residence biomarkers of chronic exposure and implicate potential biological effects. Employing nanoflow liquid chromatography-high-resolution mass spectrometry (nLC-HRMS) and parallel reaction monitoring (PRM), we have developed and validated a novel targeted albumin adductomics platform capable of simultaneously monitoring dozens of Cys34 adducts per sample in only 2.5 µL of serum, with on-column limits of detection in the low-femtomolar range. Using this platform, we characterized the magnitude and impact of ambient outdoor air pollution exposures with three repeated measurements over 84 days in n = 26 nonsmoking women (n = 78 total samples) from Qidong, China, an area with a rising burden of lung cancer incidence. In concordance with seasonally rising ambient concentrations of NO2, SO2, and PM10 measured at stationary monitors, we observed elevations in concentrations of Cys34 adducts of benzoquinone (p < 0.05), benzene diol epoxide (BDE; p < 0.05), crotonaldehyde (p < 0.01), and oxidation (p < 0.001). Regression analysis revealed significant elevations in oxidation and BDE adduct concentrations of 300% to nearly 700% per doubling of ambient airborne pollutant levels (p < 0.05). Notably, the ratio of irreversibly oxidized to reduced Cys34 rose more than 3-fold during the 84-day period, revealing a dramatic perturbation of serum redox balance and potentially serving as a portent of increased pollution-related mortality risk. Our targeted albumin adductomics assay represents a novel and flexible approach for sensitive and multiplexed internal dosimetry of environmental exposures, providing a new strategy for personalized biomonitoring and prevention.

Liver cancer mortality over six decades in an epidemic area: what we have learned.

BACKGROUND AND AIMS: Liver cancer is one of the most dominant malignant tumors in the world. The trends of liver cancer mortality over the past six decades have been tracked in the epidemic region of Qidong, China. Using epidemiological tools, we explore the dynamic changes in age-standardized rates to characterize important aspects of liver cancer etiology and prevention. METHODS: Mortality data of liver cancer in Qidong from 1958 to 1971 (death retrospective survey) and from 1972 to 2017 (cancer registration) were tabulated for the crude rate (CR), and age-standardized rate and age-birth cohorts. The average annual percentage change was calculated by the Joinpoint Regression Program. RESULTS: The natural death rate during 1958-2017 decreased from 9‰ to 5.4‰ and then increased to 8‰ as the population aged; cancer mortality rates rose continuously from 57/105 to 240/105. Liver cancer mortality increased from 20/105 to 80/105, and then dropped to less than 52/105 in 2017. Liver cancer deaths in 1972-2017 accounted for 30.53% of all cancers, with a CR of 60.48/105, age-standardized rate China (ASRC) of 34.78/105, and ASRW (world) of 45.71/105. Other key features were the CR for males and females of 91.86/105 and 29.92/105, respectively, with a sex ratio of 3.07:1. Period analysis showed that the ASRs for mortality of the age groups under 54 years old had a significant decreasing trend. Importantly, birth cohort analysis showed that the mortality rate of liver cancer in 40-44, 35-39, 30-34, 25-29, 20-24, 15-19 years cohort decreased considerably, but the rates in 70-74, and 75+ increased. CONCLUSIONS: The crude mortality rate of liver cancer in Qidong has experienced trends from lower to higher levels, and from continued increase at a high plateau to most recently a gradual decline, and a change greatest in younger people. Many years of comprehensive prevention and intervention measures have influenced the decline of the liver cancer epidemic in this area. The reduction of intake levels of aflatoxin might be one of the most significant factors as evidenced by the dramatic decline of exposure biomarkers in this population during the past three decades.

Response by the authors.

Response to comments on Cui Q-Q et al: "Hippocampal CD 39/ENTPD 1 promotes mouse depression-like behavior through hydrolyzing extracellular ATP".

Elevated MYO10 Predicts Poor Prognosis and its Deletion Hampers Proliferation and Migration Potentials of Cells Through Rewiring PI3K/Akt Signaling in Cervical Cancer.

MYO10, recognized as an important regulator of cytoskeleton remodeling, has been reported to be associated with tumorigenesis. However, its functional implication in cervical cancer and potential mechanism still remain to be undetermined currently. MYO10 level in cervical cancer tissues was analyzed by using data retrieved from The Cancer Genome Atlas and ONCOMINE databases. Messenger RNA and protein expression levels were determined by quantitative real-time polymerase chain reaction and Western blotting. Small-interfering RNA and overexpressing plasmid were used for MYO10 silencing and overexpression, and cell proliferation was analyzed by CCK-8. Transwell assays were performed to investigate the ability of cell migration and invasion. MYO10 was upregulated in cervical cancer tissues and cells when compared to normal controls, and survival analysis showed patients with high MYO10 expression had worse overall survival. Moreover, knockdown/overexpression of MYO10 significantly inhibited/enhanced the proliferation, invasion, and migration capabilities of cervical cells transfected with siRNAs/overexpressing plasmid. Additionally, MYO10 silencing inhibited PI3K/Akt signaling pathway by decreasing the phosphorylation status of PI3K and AKT. Data from the present study indicated that MYO10 were overexpressed in patients with cervical cancer and positively linked with poor prognosis. Experimental results suggested that MYO10 induced a significant encouraging effect in cervical cancer cell proliferation, invasion, and migration, linked with involvement of PI3K/Akt signaling. Collectively, these results emphasize a novel role for MYO10 overexpression in cervical cancer and provide a potent therapeutic strategy against cervical cancer.

Dietary habits and risk of hepatocellular carcinoma among hepatitis B surface antigen carriers: A prospective cohort study in China.

OBJECTIVE: In this prospective cohort study, we aimed to evaluate the association between dietary habits and the risk of developing hepatocellular carcinoma (HCC) in hepatitis B surface antigen (HBsAg)-positive carriers in Qidong, an hepatitis B virus (HBV)-epidemic area in China. METHODS: A total of 3199 HBsAg carriers aged 30-70 years in a prospective cohort in Qidong, China from 2007 to 2011 were included in the study. At baseline, all participants self-reported their dietary habits in a questionnaire interview. A follow-up check-up was performed every 6 months to identify HCC cases until November 2017. Cox's regression analysis and an interaction analysis were performed to estimate the relative risks of HCC in terms of baseline diet. RESULTS: Among 3199 HBsAg-positive participants, 270 developed HCC (143.86/100 000 person-years [PYs]). Compared with participants who rarely consume garlic, the risk of HCC in those who consumed it ≥ once per week decreased along with the increase in frequency (HR = 1.00, 0.90 and 0.62 in those who consumed it rarely vs those who consumed it 1-6 times per week and ≥ 7 times per week, respectively). This study found a synergistic effect between garlic and tea consumption on the risk of HCC (P = 0.039 for a multiplicative interaction). CONCLUSIONS: HBsAg carriers should improve their diet. Regular consumption of garlic and tea drinking may reduce the HCC incidence in HBsAg carriers.