Frailty mediating the causality between leucocyte telomere length and mortality: a cohort study of 440,551 UK Biobank participants.

Introduction: Previous studies reported leucocyte telomere length (LTL) and frailty were associated with mortality, but it remains unclear whether frailty serves as a mediator in the relationship between leucocyte telomere length and mortality risk. This study aimed to evaluate how measuring LTL and frailty can support early monitoring and prevention of risk of mortality from the prospective of predictive, preventive, and personalized medicine (PPPM/3PM). Methods: We included 440,551 participants from the UK Biobank between the baseline visit (2006-2010) and November 30, 2022. The time-dependent Cox proportional hazards model was conducted to assess the association between LTL and frailty index with the risk of mortality. Furthermore, we conducted causal mediation analyses to examine the extent to which frailty mediated the association between LTL and mortality. Results: During a median follow-up of 13.74 years, each SD increase in LTL significantly decreased the risk of all-cause [hazard ratio (HR): 0.94, 95% confidence interval (CI): 0.93-0.95] and CVD-specific mortality (HR: 0.92, 95% CI: 0.90-0.95). The SD increase in FI elevated the risk of all-cause (HR: 1.35, 95% CI: 1.34-1.36), CVD-specific (HR: 1.47, 95% CI: 1.44-1.50), and cancer-specific mortality (HR: 1.22, 95% CI: 1.20-1.24). Frailty mediated approximately 10% of the association between LTL and all-cause and CVD-specific mortality. Conclusions: Our results indicate that frailty mediates the effect of LTL on all-cause and CVD-specific mortality. There findings might be valuable to predict, prevent, and reduce mortality through primary prevention and healthcare in context of PPPM. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00355-7.

Association between inflammatory bowel disease and cancer risk: evidence triangulation from genetic correlation, Mendelian randomization, and colocalization analyses across East Asian and European populations.

BACKGROUND: Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), has been associated with several cancer risks in observational studies, but the observed associations have been inconsistent and may face the bias of confounding and reverse causality. The potential causal relationships between IBD and the risk of cancers remain largely unclear. METHODS: We performed genome-wide linkage disequilibrium score regression (LDSC), standard two-sample Mendelian randomization (MR), and colocalization analyses using summary genome-wide association study (GWAS) data across East Asian and European populations to evaluate the causal relationships between IBD and cancers. Sensitivity analyses for the MR approach were additionally performed to explore the stability of the results. RESULTS: There were no significant genetic correlations between IBD, CD, or UC and cancers (all P values > 0.05) in East Asian or European populations. According to the main MR analysis, no significant causal relationship was observed between IBD and cancers in the East Asian population. There were significant associations between CD and ovarian cancer (odds ratio [OR] = 0.898, 95% CI = 0.844-0.955) and between UC and nonmelanoma skin cancer (OR = 1.002, 95% CI = 1.000-1.004, P = 0.019) in the European population. The multivariable MR analysis did not find any of the above significant associations. There was no shared causal variant to prove the associations of IBD, CD, or UC with cancers in East Asian or European populations using colocalization analysis. CONCLUSIONS: We did not provide robust genetic evidence of causal associations between IBD and cancer risk. Exposure to IBD might not independently contribute to the risk of cancers, and the increased risk of cancers observed in observational studies might be attributed to factors accompanying the diagnosis of IBD.

Vascular endothelial growth factor and risk of malignant brain tumor: A genetic correlation and two-sample Mendelian randomization study.

Objective: The relationship between vascular endothelial growth factor (VEGF) and the risk of malignant brain tumors has always been a concern in the medical field. However, the causal inferences from published observational studies on this issue may be affected by confounders, coinheritability and reverse causality. We aimed to investigate the causal relationship between VEGF and different types of malignant brain tumors. Methods: Using publicly available summary data from genome-wide association studies (GWAS) of VEGF (n=16,112) and different types of malignant brain tumors (n=174,097-174,646), we adopted a standard two-sample bidirectional Mendelian randomization (MR) to estimate potential causal associations of circulating VEGF levels and the risk of malignant brain tumors. Inverse variance weighted (IVW) was used as the primary analysis method to estimate causality. MR-Egger regression, weighted median (WM), penalty weighted median (PWM), MR robust adjusted profile score (MR.RAPS) and causal analysis using summary effect estimates (CAUSE) methods were used in sensitivity analyses to verify the robustness of the findings. Meanwhile, we applied the MR pleiotropy residual sum and outlier (MR-PRESSO) test and PhenoScanner tool to identify and remove potential horizontal pleiotropic single nucleotide polymorphisms (SNPs). Additionally, linkage disequilibrium score regression (LDSC) analysis was conducted to assess the coinheritability of exposure and outcome. Results: A total of 6 (VEGF), 12 (malignant brain tumor), 13 (brain glioblastoma) and 12 (malignant neoplasm of meninges) SNPs were identified as valid instrumental variables. No evidence supported a causal relationship between circulating VEGF levels and the risk of malignant brain tumors (forwards: odds ratio (OR) = 1.277, 95% confidence interval (CI), 0.812~2.009; reversed: ß = 0.005, 95% CI, -0.029~0.038), brain glioblastoma (forwards: OR (95% CI) = 1.278(0.463~3.528); reversed: ß = 0.010, 95% CI, -0.002~0.022) and malignant neoplasm of meninges (forwards: OR (95% CI) = 0.831(0.486~1.421); reversed: ß = 0.010, 95% CI, -0.030~0.050) using the main IVW method. Outliers and pleiotropy bias were not detected by sensitivity analyses and pleiotropy-robust methods in any estimates. LDSC failed to identify genetic correlations between VEGF and different types of malignant brain tumors. Conclusions: Our findings reported no coinheritability and failed to provide evidence for causal associations between VEGF and the risk of different types of malignant brain tumors. However, certain subtypes of VEGF for which genetic predictors have not been identified may play a role and need to be further investigated.

Survival of gastric cancer in China from 2000 to 2022: A nationwide systematic review of hospital-based studies.

Background: Gastric cancer (GC) mortality continues to fall in industrialized countries, but still remains a public health concern in China, accounting for more than 370 000 deaths. We aimed to evaluate the survival of GC in China from 2000 to 2022 through a nationwide systematic review of hospital-based studies and to identify whether hospital-based studies show higher survival rates than population-based studies. Methods: We searched PubMed, Embase, Web of Science, and the Chinese databases of CNKI and Wanfang for hospital-based studies on GC survival published between January 1, 2000, and January 20, 2022. We calculated the nationwide GC survival rate (SR) and its 95% confidence interval (CI) and conducted subgroup analyses on histologic type, subsite, tumour node metastasis (TNM) stage, therapy type, study design, and participant region. The study protocol was registered in PROSPERO (CRD-42019121559). Results: The initial literature search returned 36 613 publications, among which 664 studies (180 798 participants) matched the inclusion criteria and were included in the meta-analysis. The pooled one-, two-, three- and five-year SRs of GC were 75.4% (95% CI = 74.0%-76.8%), 54.3% (95% CI = 50.1%-58.6%), 53.4% (95% CI = 50.4%-56.4%), and 44.5% (95% CI = 41.5%-47.5%), respectively. Subgroup analyses revealed an increase in three- and five-year SRs from 2006 to 2022. The five-year SR was highest among patients without lymph node metastasis (pooled SR = 67.8%, 95% CI = 62.8%-72.7%) and lowest among those with distant metastasis (pooled SR = 8.4%, 95% CI = 5.1%-11.7%). Conclusions: Our findings illustrate that the long-term survival of GC has improved in China since 2000. Hospital-based studies have presented higher SRs than population-based surveillance.

Prevalence, awareness, treatment and control of type 2 diabetes and its determinants among Mongolians in China: a cross-sectional analysis of IMAGINS 2015-2020.

OBJECTIVES: This study aims to estimate the prevalence, awareness, treatment and control rates of type 2 diabetes (T2D) and pre-diabetes as well as to identify its associated factors among Mongolians living in the Inner Mongolia Autonomous Region, China. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: This sample included 11 361 Mongolian participants from the Inner Mongolian Healthy Aging Intervention Study, a population-based screening project consisting of 141 255 adults aged above 35 years in Inner Mongolia from 2015 to 31 December 2020. OUTCOME MEASURES: The prevalence and 95% CIs of T2D and pre-diabetes were calculated. Factors associated with the prevalence, awareness, treatment and control of T2D were explored by a binomial logistic regression. RESULTS: A total of 17.2% (95% CI 16.5% to 17.9%) of the sample had T2D, of whom 34.0% (95% CI 31.9% to 36.1%) were aware of their diagnosis, 24.7% (95% CI 22.8% to 26.6%) were taking prescribed antidiabetic medications, 6.7% (95% CI 5.6% to 7.8%) had achieved control and 27.5% (95 % CI 26.7% to 28.3%) had pre-diabetes. The prevalence of T2D increased with increasing age, male, lower education level, smoking, obesity and a history of hypertension or dyslipidaemia (all p<0.05). CONCLUSIONS: T2D is highly prevalent, with suboptimal awareness, treatment and control rates, and an escalating health challenge among the Mongolian population. Broad-based strategies, including diabetes prevention education, better screening and affordable treatment, should be implemented to raise awareness, treatment and control rates of T2D in Inner Mongolia.

The Glu69Asp Polymorphism of EME1 Gene is Associated with an Increased Risk of Hepatocellular Carcinoma in Guangxi Population, China.

Background: The dysfunction of Essential meiotic endonuclease 1 homolog 1 (EME1) can lead to genomic instability and tumorigenesis. Single nucleotide polymorphisms (SNPs) in the EME1 gene have been reported to be associated with the risk of several cancers, but its association with hepatocellular carcinoma (HCC) has not been investigated. This study aimed to determine the association between EME1 SNPs and the risk of HCC. Methods: This study included 645 HCC patients and 649 healthy controls from a Guangxi population of Southern China, and genotyped three functional SNPs (Glu69Asp: rs3760413A>C, Ile350Thr: rs12450550T>C, and rs11868055A>G) of the EME1 gene utilizing the Agena MassARRAY platform. Results: The rs3760413C variant genotypes (AC+CC: Glu/Asp+Asp/Asp) conferred a 1.419-fold risk of HCC compared to the AA (Glu/Glu) genotype (adjusted OR = 1.419, 95% CI = 1.017-1.980), and the allele C increased the risk of HCC in a dose-dependent manner (P trend = 0.017). Moreover, the effects of the rs3760413C variant genotypes were more pronounced in individuals who drank pond/ditch water (adjusted OR = 3.956, 95% CI = 1.413-11.076) than in those who never drank (P = 0.033). We further observed that a potential carcinogen microcystin-LR induced more DNA oxidative damages in peripheral blood mononuclear cells from the carriers of rs3760413C variant genotypes than those from the subjects with AA genotype (P = 0.006). A nomogram was also constructed combining the rs3760413A>C polymorphism and environmental risk factors for predicting HCC risk with a good discriminatory ability (concordance index = 0.892, 95% CI: 0.874-0.911) and good calibration (mean absolute error = 0.005). Conclusion: Our data suggest that the Glu69Asp missense polymorphism (rs3760413) of EME1 gene is associated with the risk of HCC, which may be a susceptible biomarker of HCC in the Guangxi population.

Characterization and determinant factors of critical illness and in-hospital mortality of COVID-19 patients: A retrospective cohort of 1,792 patients in Kenya.

Limited data is available on the coronavirus disease 2019 (COVID-19), critical illness rate, and in-hospital mortality in the African setting. This study investigates determinants of critical illness and in-hospital mortality among COVID-19 patients in Kenya. We conducted a retrospective cohort study at Kenyatta National Hospital (KNH) in Kenya. Multivariate logistic regression and Cox proportional hazard regression were employed to determine predictor factors for intensive care unit (ICU) admission and in-hospital mortality, respectively. In addition, the Kaplan-Meier model was used to compare the survival times using log-rank tests. As a result, 346 (19.3%) COVID-19 patients were admitted to ICU, and 271 (15.1%) died. The majority of those admitted to the hospital were male, 1,137 (63.4%) and asymptomatic, 1,357 (75.7%). The most prevalent clinical features were shortness of breath, fever, and dry cough. In addition, older age, male, health status, patient on oxygen (O2), oxygen saturation levels (SPO2), headache, dry cough, comorbidities, obesity, cardiovascular diseases (CVDs), diabetes, chronic lung disease (CLD), and malignancy/cancer can predicate the risk of ICU admission, with an area under the receiver operating characteristic curve (AUC-ROC) of 0.90 (95% confidence interval [CI]: 0.88-0.92). Survival analysis indicated 271 (15.1%) patients died and identified older age, male, headache, shortness of breath, health status, patient on oxygen, SPO2, headache, comorbidity, CVDs, diabetes, CLD, malignancy/cancer, and smoking as risk factors for mortality (AUC-ROC: 0.90, 95% CI: 0.89-0.91). This is the first attempt to explore predictors for ICU admission and hospital mortality among COVID-19 patients in Kenya.

Placental lesions and differential expression of pro-and anti-angiogenic growth mediators and oxidative DNA damage marker in placentae of Ghanaian suboptimal and optimal health status pregnant women who later developed preeclampsia.

BACKGROUND: Angiogenic growth mediators (AGMs) and oxidative stress (OS) both play essential roles in normal placental vascular development and as such, placental alterations in these factors contribute to pre-eclampsia (PE). Suboptimal health status (SHS), an intermediate between health and disease, has been associated with imbalanced AGMs and OS biomarkers. Thus, SHS pregnant women may be at increased risk of developing PE and may present abnormal placental alteration and expression of AGMs and OS compared to optimal health status (OHS) pregnant women. We examined the histopathological morphology, immunohistochemical expression of AGMs antibodies and oxidative DNA damage marker in the placentae of SHS and OHS pregnant women who developed early-onset PE (EO-PE) and late-onset (LO-PE) compared to normotensive pregnancy (NTN-P). METHODS: This nested case-control study recruited 593 singleton normotensive pregnant women at baseline (10-20 weeks gestation) from the Ghanaian Suboptimal Health Status Cohort Study (GHOACS) undertaken at the Komfo Anokye Teaching Hospital, Ghana. Socio-demographic, clinical and obstetrics data were collected, and a validated SHS questionnaire-25 (SHSQ-25) was used in classifying participants into SHS (n = 297) and OHS (n = 296). Participants were followed until the time of PE diagnosis and delivery (32-42 weeks gestation). Blood samples were collected at the two-time points and were assayed for AGMs; soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PIGF), vascular endothelial growth factor-A (VEGF-A), and soluble endoglin (sEng), and OS biomarkers; 8-hydroxydeoxyguanosine (8-OHdG), 8-epiprostaglandinF2-alpha (8- epi-PGF2α) and total antioxidant capacity (TAC) using ELISA. Placental samples were collected for histopathological and immunohistochemical analysis. RESULTS: Of the 593 pregnant women, 498 comprising 248 SHS and 250 OHS women returned for delivery and were included in the final analysis. Of the 248 SHS women, 56, 97 and 95 developed EO-PE, LO-PE and NTN-P, respectively, whereas 14, 30 and 206 of the 250 OHS mothers developed EO-PE, LO-PE and NTN-P, respectively. At baseline, SHS_NTN pregnant women had a significant imbalance in AGMs and OS biomarkers compared to OHS_NTN pregnant women (p<0.0001). At the time of PE diagnosis, SHS_NTN-P women who developed EO-PE, LO-PE, and NTN-P had lower serum levels of P1GF, VEGF-A and TAC and correspondingly higher levels of sEng, sFlt-1, 8-epiPGF2α, and 8-OHdG than OHS-NTN-P women who developed EO-PE and LO-PE, NTN-P (p<0.0001). A reduced placental size, increased foetal/placental weight ratio, and a significantly higher proportion of fibrinoid necrosis, infarction, villous fibrin, syncytial knots, calcification, chorangiosis, tunica media/vascular wall hypertrophy and chorioamnionitis was associated with the SHS group who developed PE (EO-PE>LO-PE) more than OHS groups who developed PE (EO-PE>LO-PE) when all were compared to NTN-P (p<0.0001). The intensity of antibody expression of PIGF and VEGF-A were significantly reduced, whereas Flt-1, Eng and 8-OHdG were significantly increased in placentae from SHS-pregnant women who developed EO-PE>LO-PE more than OHS- pregnant women who developed EO-PE>LO-PE when all were compared to NTN-P (p<0.0001). CONCLUSION: Increased lesions, oxidative DNA damage, and imbalanced expression between pro-and anti-AGMs are associated more with SHS-embodied PE placentae rather than OHS-embodied PE subtypes, thus potentially allowing differential evaluation of PE.

Population-Based Incidence of Guillain-Barré Syndrome During Mass Immunization With Viral Vaccines: A Pooled Analysis.

Misunderstanding temporal coincidence of adverse events during mass vaccination and invalid assessment of possible safety concerns have negative effects on immunization programs, leading to low immunization coverage. We conducted this systematic review and meta-analysis to identify the incidence rates of GBS that are temporally associated with viral vaccine administration but might not be attributable to the vaccines. By literature search in Embase and PubMed, we included 48 publications and 2,110,441,600 participants. The pooled incidence rate of GBS was 3.09 per million persons (95% confidence interval [CI]: 2.67 to 3.51) within six weeks of vaccination, equally 2.47 per 100,000 person-year (95%CI: 2.14 to 2.81). Subgroup analyses illustrated that the pooled rates were 2.77 per million persons (95%CI: 2.47 to 3.07) for individuals who received the influenza vaccine and 2.44 per million persons (95%CI: 0.97 to 3.91) for human papillomavirus (HPV) vaccines, respectively. Our findings evidence the GBS-associated safety of virus vaccines. We present a reference for the evaluation of post-vaccination GBS rates in mass immunization campaigns, including the SARS-CoV-2 vaccine.

Genetic Variant of PP2A Subunit Gene Confers an Increased Risk of Primary Liver Cancer in Chinese.

BACKGROUND: Protein phosphatase 2A (PP2A, a serine/threonine phosphatase) is frequently inactivated in many types of cancer, including primary liver cancer (PLC). Genetic variations in PP2A subunits have been reported to be associated with the risk of many types of cancer but rarely in PLC. This study aims to assess the association between functional polymorphisms of PP2A subunit genes and the risk of PLC in Chinese. METHODS: In a case-control study with a total of 541 PLC patients and 547 controls in Guangxi province of Southern China, we genotyped six putatively functional polymorphisms (rs10421191G>A, rs11453459del>insG, rs1560092T>G, rs7840855C>T, rs1255722G>A and rs10151527A>C) of three PP2A subunit genes (PPP2R1A, PPP2R2A and PPP2R5E) using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry platform. RESULTS: The rs11453459insG variant genotypes (ins/ins+del/ins) of PPP2R1A were found to be significantly associated with an increased risk of PLC compared with the del/del genotype (adjusted OR = 1.290, 95% CI = 1.009-1.650), and the number of insert G allele worked in a dose-dependent manner (P trend= 0.007). The stratified analysis showed that the effects of rs11453459insG variant genotypes were more evident in the subgroup who drink pond-ditch water (adjusted OR = 3.051, 95% CI = 1.264-7.364) than those never drink (P = 0.041). The carriers of rs11453459 del/ins genotype had a significantly lower level of PPP2R1A mRNA expression in liver cancer tissues than those of the del/del genotype (P = 0.021). Furthermore, we used microcystin-LR, a carcinogen presents in the pond-ditch water, to treat human peripheral blood mononuclear cells and found that the cells from carriers of rs11453459insG variant genotypes induced more DNA oxidative damages than those from the del/del genotype carriers (P < 0.001). CONCLUSION: These findings suggest that the PPP2R1A rs11453459del>insG polymorphism is associated with an increased risk of PLC, especially for persons with a history of drinking pond-ditch water. This insertion/deletion polymorphism may be a susceptible biomarker for PLC in Chinese.

All around suboptimal health - a joint position paper of the Suboptimal Health Study Consortium and European Association for Predictive, Preventive and Personalised Medicine.

First two decades of the twenty-first century are characterised by epidemics of non-communicable diseases such as many hundreds of millions of patients diagnosed with cardiovascular diseases and the type 2 diabetes mellitus, breast, lung, liver and prostate malignancies, neurological, sleep, mood and eye disorders, amongst others. Consequent socio-economic burden is tremendous. Unprecedented decrease in age of maladaptive individuals has been reported. The absolute majority of expanding non-communicable disorders carry a chronic character, over a couple of years progressing from reversible suboptimal health conditions to irreversible severe pathologies and cascading collateral complications. The time-frame between onset of SHS and clinical manifestation of associated disorders is the operational area for an application of reliable risk assessment tools and predictive diagnostics followed by the cost-effective targeted prevention and treatments tailored to the person. This article demonstrates advanced strategies in bio/medical sciences and healthcare focused on suboptimal health conditions in the frame-work of Predictive, Preventive and Personalised Medicine (3PM/PPPM). Potential benefits in healthcare systems and for society at large include but are not restricted to an improved life-quality of major populations and socio-economical groups, advanced professionalism of healthcare-givers and sustainable healthcare economy. Amongst others, following medical areas are proposed to strongly benefit from PPPM strategies applied to the identification and treatment of suboptimal health conditions:Stress overload associated pathologiesMale and female healthPlanned pregnanciesPeriodontal healthEye disordersInflammatory disorders, wound healing and pain management with associated complicationsMetabolic disorders and suboptimal body weightCardiovascular pathologiesCancersStroke, particularly of unknown aetiology and in young individualsSleep medicineSports medicineImproved individual outcomes under pandemic conditions such as COVID-19.

Prevention of dementia using mobile phone applications (PRODEMOS): protocol for an international randomised controlled trial.

INTRODUCTION: Profiles of high risk for future dementia are well understood and are likely to concern mostly those in low-income and middle-income countries and people at greater disadvantage in high-income countries. Approximately 30%-40% of dementia cases have been estimated to be attributed to modifiable risk factors, including hypertension, smoking and sedentary lifestyle. Tailored interventions targeting these risk factors can potentially prevent or delay the onset of dementia. Mobile health (mHealth) improves accessibility of such prevention strategies in hard-to-reach populations while at the same time tailoring such approaches. In the current study, we will investigate the effectiveness and implementation of a coach-supported mHealth intervention, targeting dementia risk factors, to reduce dementia risk. METHODS AND ANALYSIS: The prevention of dementia using mobile phone applications (PRODEMOS) randomised controlled trial will follow an effectiveness-implementation hybrid design, taking place in the UK and China. People are eligible if they are 55-75 years old, of low socioeconomic status (UK) or from the general population (China); have ≥2 dementia risk factors; and own a smartphone. 2400 participants will be randomised to either a coach-supported, interactive mHealth platform, facilitating self-management of dementia risk factors, or a static control platform. The intervention and follow-up period will be 18 months. The primary effectiveness outcome is change in the previously validated Cardiovascular Risk Factors, Ageing and Incidence of Dementia dementia risk score. The main secondary outcomes include improvement of individual risk factors and cost-effectiveness. Implementation outcomes include acceptability, adoption, feasibility and sustainability of the intervention. ETHICS AND DISSEMINATION: The PRODEMOS trial is sponsored in the UK by the University of Cambridge and is granted ethical approval by the London-Brighton and Sussex Research Ethics Committee (reference: 20/LO/01440). In China, the trial is approved by the medical ethics committees of Capital Medical University, Beijing Tiantan Hospital, Beijing Geriatric Hospital, Chinese People's Liberation Army General Hospital, Taishan Medical University and Xuanwu Hospital. Results will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ISRCTN15986016.

CDK5 positively regulates Notch1 signaling in pancreatic cancer cells by phosphorylation.

The marked overexpression of cyclin-dependent kinase 5 (CDK5) or Notch1 receptor, which plays critical roles in pancreatic ductal adenocarcinoma (PDAC) development, has been detected in numerous PDAC cell lines and tissues. Although, a previous study has demonstrated that CDK5 inhibition disrupts Notch1 functions in human umbilical vein endothelial cells, the mechanism underlying Notch1 activation regulated by CDK5 remains unclear. Herein, we identified a physical interaction between CDK5 and Notch1 in PDAC cells, with the Notch1 peptide phosphorylated by CDK5/p25 kinase. CDK5 blockade resulted in the profound inhibition of Notch signaling. Accordingly, CDK5 inhibition sensitized PDAC cell proliferation and migration following Notch inhibition. In conclusion, CDK5 positively regulates Notch1 function via phosphorylation, which in turn promotes cell proliferation and migration. The combinational inhibition of CDK5 and Notch signaling may be an effective strategy in the treatment of PDAC.

Association of IgG Glycosylation and Esophageal Precancerosis Beyond Inflammation.

This study aimed to investigate the association of IgG glycosylation and esophageal precancerosis for squamous cell carcinoma and determine its role in inflammation. Primary glycans selected by the least absolute shrinkage and selection operator (LASSO) algorithm were validated using univariate and multivariate logistics models plus restricted cubic spline functions. In total, 24 direct glycans and 27 derived traits were detected, among which four glycans and three derived traits were primarily selected. Then, GP5 (adjusted OR: 0.805), GP17 (adjusted OR: 1.305), G12n (adjusted OR: 1.271), Gal_1 (adjusted OR: 0.776) and Fuc (adjusted OR: 0.737) were validated and significantly associated with esophageal precancerosis. In addition, there was a consistent positive association in GP17 and G12n and a negative association in GP5, Gal_1, and Fuc by restricted cubic spline function. Compared with esophageal inflammation, GP17, G12n, and Fuc were still independently associated with precancerosis. In brief, the IgG glycosylation profile was independently associated with esophageal precancerosis beyond inflammation, which could be an early biomarker for esophageal cancer.Prevention Relevance: IgG glycosylation profile is associated with esophageal precancerosis and specific IgG glycans involves in the early stage of esophageal cancer, which is independent of inflammation.

Corrigendum: Association Between Night-Shift Work and Cancer Risk: Updated Systematic Review and Meta-Analysis.

[This corrects the article DOI: 10.3389/fonc.2020.01006.].

Glycomics: Immunoglobulin G N-Glycosylation Associated with Mammary Gland Hyperplasia in Women.

Mammary gland hyperplasia (MGH) is very common, especially among young and middle-aged women. New diagnostics and biomarkers for MGH are needed for rational clinical management and precision medicine. We report, in this study, new findings using a glycomics approach, with a focus on immunoglobulin G (IgG) N-glycosylation. A cross-sectional study was conducted in a community-based population sample in Beijing, China. A total of 387 participants 40-65 years of age were enrolled in this study, including 194 women with MGH (cases) and 193 women who had no MGH (controls). IgG N-glycans were characterized in the serum by ultra-performance liquid chromatography. The levels of the glycan peaks (GPs) GP2, GP5, GP6, and GP7 were lower in the MGH group compared with the control group, whereas GP14 was significantly higher in the MGH group (p < 0.05). A predictive model using GP5, GP21, and age was established and a receiver operating characteristic curve analysis was performed. The sensitivity and specificity of the model for MGH was 61.3% and 63.2%, respectively, likely owing to receptor mechanisms and/or inflammation regulation. To the best of our knowledge, this is the first study reporting on an association between IgG N-glycosylation and MGH. We suggest person-to-person variations in IgG N-glycans and their combination with multiomics biomarker strategies offer a promising avenue to identify novel diagnostics and individuals at increased risk of MGH.

Association Between Night-Shift Work and Cancer Risk: Updated Systematic Review and Meta-Analysis.

Background: Nightshift work introduces light at night and causes circadian rhythm among night workers, who are considered to be at increased risk of cancer. However, in the last 2 years, nine population-based studies reported insignificant associations between night-shift work and cancer risks. We aimed to conduct an updated systematic review and meta-analysis to ascertain the effect of night-shift work on the incidence of cancers. Methods: Our protocol was registered in PROSPERO and complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Embase, PubMed, and Web of Science databases were used to comprehensively search studies published up to May 31, 2019. The random-effect model (Der Simonian-Laird method) was carried out to combine the risk estimates of night-shift work for cancers. The dose-response meta-analysis was performed to verify whether the association was in a dose-dependent manner. Results: Our literature searching retrieved 1,660 publications. Included in the meta-analyses were 57 eligible studies with 8,477,849 participants (mean age 55 years; 2,560,886 men, 4,220,154 women, and 1,696,809 not mentioned). The pooled results showed that night-shift work was not associated with the risk of breast cancer (OR = 1.009, 95% CI = 0.984-1.033), prostate cancer (OR = 1.027, 95% CI = 0.982-1.071), ovarian cancer (OR = 1.027, 95% CI = 0.942-1.113), pancreatic cancer (OR = 1.007, 95% CI = 0.910-1.104), colorectal cancer (OR = 1.016, 95% CI = 0.964-1.068), non-Hodgkin's lymph (OR = 1.046, 95% CI = 0.994-1.098), and stomach cancer (OR = 1.064, 95% CI = 0.971-1.157), while night-shift work was associated with a reduction of lung cancer (OR = 0.949, 95% CI = 0.903-0.996), and skin cancer (OR = 0.916, 95% CI = 0.879-0.953). The dose-response meta-analysis found that cancer risk was not significantly elevated with the increased light exposure of night- shift work. Conclusion: This systematic review of 57 observational studies did not find an overall association between ever-exposure to night-shift work and the risk of breast, prostate ovarian, pancreatic, colorectal, non-Hodgkin's lymph, and stomach cancers.

Modelling biological age based on plasma peptides in Han Chinese adults.

Age-related disease burdens increased over time, and whether plasma peptides can be used to accurately predict age in order to explain the variation in biological indicators remains inadequately understood. Here we first developed a biological age model based on plasma peptides in 1890 Chinese Han adults. Based on mass spectrometry, 84 peptides were detected with masses in the range of 0.6-10.0 kDa, and 13 of these peptides were identified as known amino acid sequences. Five of these thirteen plasma peptides, including fragments of apolipoprotein A-I (m/z 2883.99), fibrinogen alpha chain (m/z 3060.13), complement C3 (m/z 2190.59), complement C4-A (m/z 1898.21), and breast cancer type 2 susceptibility protein (m/z 1607.84) were finally included in the final model by performing a multivariate linear regression with stepwise selection. This biological age model accounted for 72.3% of the variation in chronological age. Furthermore, the linear correlation between the actual age and biological age was 0.851 (95% confidence interval: 0.836-0.864) and 0.842 (95% confidence interval: 0.810-0.869) in the training and validation sets, respectively. The biological age based on plasma peptides has potential positive effects on primary prevention, and its biological meaning warrants further investigation.

Evaluation of the relationship between cognitive impairment and suboptimal health status in a northern Chinese population: a cross-sectional study.

BACKGROUND: Suboptimal health status (SHS) is an intermediate health status between ideal health and illness. As a determinant of cardiovascular disease and stroke, SHS is hypothesized to be associated with the development of cognitive impairment and dementia. This study aimed to investigate whether individuals with SHS have poor cognitive ability based on a community-based cohort in northern Chinese population. METHODS: 3524 participants who were enrolled in Jidong cohort 2015 in Tangshan City were investigated in this study. Cognitive function was measured with the Mini-Mental State Examination (MMSE). SHS level was evaluated using a self-reporting Suboptimal Health Status Questionnaire-25 (SHSQ-25). The relationship between SHS and cognitive function was analyzed with logistic regression analysis, by which odds ratio (OR) and 95% confidence interval (CI) were calculated. RESULTS: The prevalence of cognitive impairment was 3.4% (121/3524) in our study, with the prevalence rates of 1.9% (34/1750) among men and 4.9% (87/1774) in women. The medians of total score of MMSE were 28 (interquartile range (IQR) = 27-29) in the SHS group, and 29 (IQR = 27-30) in the ideal health group. Logistic regression analysis showed that SHS was significantly correlated with cognitive impairment (adjusted OR = 2.936, 95% CI = 1.428-6.033). With regard to gender, the OR was 5.067 (95% CI = 1.346-19.068) in men, which was higher than that in women (OR = 2.324, 95% CI = 1.130-4.779). CONCLUSIONS: SHS might be a risk factor for cognitive function in northern Chinese population. Early screening of SHS individuals, as well as urgent treatment of SHS might contribute to the prevention of cognitive impairment.

The Association Between Cancer and Dementia: A National Cohort Study in Sweden.

Background: Previous studies have found that the incidence of dementia is lower in patients with cancer. However, the impact of survival bias, as well as the confounding by medical treatment, have not been fully addressed. We aimed to explore the subsequent risk of dementia in different follow-up intervals among patients with cancer, as well as the risk before the diagnosis of cancer. Methods: By using the Swedish Cancer Register and the Swedish Hospital Discharge Register, we systematically examined the risk of dementia among patients diagnosed with 35 different types of cancer. Standardized incidence ratios (SIRs) were used to calculate the relative risk. Results: The subsequent risk of dementia in patients with cancer decreased by 21% compared to matched cancer-free controls (SIR = 0.79, 95% CI 0.78-0.80). For specific cancer sites, 21 of them had a significantly lower risk of subsequent dementia. The decreased risk of dementia was also significant before the diagnosis of cancer. However, the risk was higher among patients with cancer who survived for more than 10 years' post-diagnosis (SIR = 1.37, 95% CI 1.32-1.41). Conclusions: In this population-based study, we found that the risk of dementia was lower among patients with cancer, and the risk was also lower before the diagnosis of cancer. This suggests that lower dementia risk is not simply due to bias. However, the underlying mechanisms need to be explored further.