New insights of metabolite abnormalities in the thalamus of rats with iminodiproprionitrile-induced tic disorders.

Introduction: This study aimed to investigate pathological changes in the "Glutamate (Glu)-γ-aminobutyric acid (GABA)" loop and apply widely targeted metabolomic analysis technology to comprehensively explore metabolite abnormalities/ in the thalamus of rats with tic disorders (TD). Methods: Wistar rats were randomized into control, TD, and tiapride (Tia) groups. Iminodipropionitrile (IDPN) was used to induce TD in rats. The Tia group was administered tiapride. Neurotransmitter levels in the thalamus of rats in the three groups were measured using UPLC-3Q MS. And, the protein expression levels of Glu decarboxylase (GAD65/67) and GABA transporter protein (GAD-T) were measured using western blotting. The mRNA expression levels of these genes were evaluated using real-time polymerase chain reaction. Lastly, other metabolites in the thalamus were detected by widely targeted metabolomic analysis between TD and Control group rats. Results: The Glu level, Glu/GABA ratio, and Asp level in the TD group were significantly higher (all p < 0.001) than those of the Control group, whereas the GABA and Gly levels were lower (p < 0.001 and p = 0.009, respectively). The Tia group exhibited a significant reduction in the Glu level (p = 0.001) compared with the TD group. The protein expression level of GAD67 in TD group was higher (p = 0.009) and the mRNA expression levels of GAD65, GAD67, and GAT-1 were lower (p < 0.05) than those of the Control group. The Tia group did not display any differences in GAD65, GAD67, or GAT-1 expression. Widely targeted metabolomic analysis revealed that 34 substances were abnornal between the TD and Control groups (9 upregulated and 25 downregulated). Neurosteroids (progesterone, corticosterone) exhibited distinct differences. Metabolite analysis using the Kyoto encyclopedia for genes and genomes indicated that the steroid hormone biosynthesis pathway may be involved in TD pathogenesis. Conclusion: This study revealed metabolic abnormalities in the thalamus of rats with TD. The interaction between neurotransmitters and neurosteroid biosynthesis represents a new direction for future studies.

Botanical characteristics, chemical components, biological activity, and potential applications of mangosteen.

Garcinia mangostana L. (Mangosteen), a functional food, belongs to the Garcinaceae family and has various pharmacological effects, including anti-oxidative, anti-inflammatory, anticancer, antidiabetic, and neuroprotective effects. Mangosteen has abundant chemical constituents with powerful pharmacological effects. After searching scientific literature databases, including PubMed, Science Direct, Research Gate, Web of Science, VIP, Wanfang, and CNKI, we summarized the traditional applications, botanical features, chemical composition, and pharmacological effects of mangosteen. Further, we revealed the mechanism by which it improves health and treats disease. These findings provide a theoretical basis for mangosteen's future clinical use and will aid doctors and researchers who investigate the biological activity and functions of food.

Neuropsychiatric sequelae after liver transplantation and their possible mechanism via the microbiota-gut-liver-brain axis.

Patients after liver transplantation are often impacted by mental and even neuropsychiatric disorders, including depression, sleep disorders, anxiety, and post-traumatic stress disorder. Neuropsychiatric sequelae have an adverse impact on rehabilitation and can even incapacitate people, reducing their quality of life. Despite screening tools and effective treatments, neuropsychiatric sequelae after liver transplantation (NSALT) have not been fully diagnosed and treated. Current research suggests that NSALT may be partly related to intestinal microbial variation, but the detailed mechanism remains unclear. In this review, we describe the clinical and diagnostic features, prevalence, prediction, clinical course and outcome, management, and treatment of NSALT; we also summarize their mechanisms through the microbiota-gut-liver-brain axis. Finally, we propose to improve NSALT on the basis of adjusting the gastrointestinal flora, immune inflammation or vagus nerve (VN), providing a novel strategy for clinical prevention and treatment.

Risk of malignant lymphomas in patients with inflammatory bowel disease: a population-based cohort study.

OBJECTIVE: To estimate the risk of non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL) in patients with inflammatory bowel disease (IBD). DESIGN: We undertook a two-country population cohort study with all patients diagnosed with IBD in Norway and Sweden from 1987 and 1993 through 2015 and 2016, respectively, and analysed the risk of NHL and HL. In Sweden, we also analysed prescriptions of thiopurines and anti-tumour necrosis factor (TNF)-α therapy from 2005. We calculated standardised incidence ratios (SIRs) with 95% CIs using the general populations as reference. RESULTS: Among 131 492 patients with IBD with a medium follow-up of 9.6 years, we identified 369 cases of NHL and 44 cases of HL. The SIR of NHL was 1.3 (95% CI 1.1 to 1.5) in ulcerative colitis and 1.4 (95% CI 1.2 to 1.7) in Crohn's disease. We found no compelling heterogeneity in analyses stratified by patient characteristics. We found a similar pattern and magnitude of excess risks for HL. At 10 years, cumulative incidence was 0.26% (95% CI 0.23% to 0.30%) and 0.06% (95% CI 0.04% to 0.08%) for NHL and HL, respectively. Higher excess risks were found among patients with NHL with concomitant primary sclerosing cholangitis (SIR 3.4; 95% CI 2.1 to 5.2) and in those prescribed thiopurines alone (SIR 2.8; 95% CI 1.4 to 5.7) or with anti-TNF-α agents (SIR 5.7; 95% CI 2.7 to 11.9). CONCLUSION: Patients with IBD have a statistically significant increased risk of malignant lymphomas compared with the general population, but the absolute risk remains low.

Insights into the pharmacological and therapeutic effects of apigenin in liver injuries and diseases.

Background: Liver diseases are a spectrum of diseases that include hepatic steatosis, nonalcoholic fatty liver disease, hepatitis, liver fibrosis, cirrhosis, and hepatic cancer. These diseases not only severely decrease the quality of life for patients, but also cause financial burden. Although apigenin (APG) has recently become the primary treatment for liver injuries and diseases (LIADs), there has been no systematic review of its use. Purpose: To review the existing literature and put forward novel strategies for future APG research on LIADs. Methods: A search was conducted in PubMed, Science Direct, Research Gate, Web of Science, VIP, Wanfang, and CNKI, and 809 articles were obtained. After applying inclusion and exclusion criteria, 135 articles were included. Results: APG is promising in treating LIADs via various mechanisms arising from its anti-inflammation, anti-proliferation, anti-infection, anti-oxidation, and anti-cancer properties. Conclusion: This review summarizes the evidence supporting the use of APG as a treatment for LIADs and provides an insight into the intestinal microbiota, which may have important implications in its future clinical use.

Cardiovascular disease and subsequent risk of psychiatric disorders: a nationwide sibling-controlled study.

Background: The association between cardiovascular disease (CVD) and selected psychiatric disorders has frequently been suggested while the potential role of familial factors and comorbidities in such association has rarely been investigated. Methods: We identified 869,056 patients newly diagnosed with CVD from 1987 to 2016 in Sweden with no history of psychiatric disorders, and 910,178 full siblings of these patients as well as 10 individually age- and sex-matched unrelated population controls (N = 8,690,560). Adjusting for multiple comorbid conditions, we used flexible parametric models and Cox models to estimate the association of CVD with risk of all subsequent psychiatric disorders, comparing rates of first incident psychiatric disorder among CVD patients with rates among unaffected full siblings and population controls. Results: The median age at diagnosis was 60 years for patients with CVD and 59.2% were male. During up to 30 years of follow-up, the crude incidence rates of psychiatric disorder were 7.1, 4.6, and 4.0 per 1000 person-years for patients with CVD, their siblings and population controls. In the sibling comparison, we observed an increased risk of psychiatric disorder during the first year after CVD diagnosis (hazard ratio [HR], 2.74; 95% confidence interval [CI], 2.62-2.87) and thereafter (1.45; 95% CI, 1.42-1.48). Increased risks were observed for all types of psychiatric disorders and among all diagnoses of CVD. We observed similar associations in the population comparison. CVD patients who developed a comorbid psychiatric disorder during the first year after diagnosis were at elevated risk of subsequent CVD death compared to patients without such comorbidity (HR, 1.55; 95% CI, 1.44-1.67). Conclusions: Patients diagnosed with CVD are at an elevated risk for subsequent psychiatric disorders independent of shared familial factors and comorbid conditions. Comorbid psychiatric disorders in patients with CVD are associated with higher risk of cardiovascular mortality suggesting that surveillance and treatment of psychiatric comorbidities should be considered as an integral part of clinical management of newly diagnosed CVD patients. Funding: This work was supported by the EU Horizon 2020 Research and Innovation Action Grant (CoMorMent, grant no. 847776 to UV, PFS, and FF), Grant of Excellence, Icelandic Research Fund (grant no. 163362-051 to UV), ERC Consolidator Grant (StressGene, grant no. 726413 to UV), Swedish Research Council (grant no. D0886501 to PFS), and US NIMH R01 MH123724 (to PFS).

Poor dental health and risk of pancreatic cancer: a nationwide registry-based cohort study in Sweden, 2009-2016.

BACKGROUND: Previous studies have reported inconsistent results regarding the association between poor dental health and pancreatic cancer risk. This study aimed to assess this association using a well-functioning nationwide dental health registry in Sweden. METHODS: Information of exposures (dental caries, root canal infection, mild inflammation, and periodontitis; the number of teeth) was ascertained from the Swedish Dental Health Register, and occurrence of pancreatic cancer was identified from both cancer and cause of death registries. Hazard ratios (HRs) were estimated using Cox models. RESULTS: During a median of 7.2 years of follow-up, 10,081 pancreatic cancers were identified among 5,889,441 individuals. Compared with the healthy status, a higher risk of pancreatic cancer was observed in individuals with root canal infection, mild inflammation, and periodontitis in the <50 age group (P for trend <0.001). In the 50-70 age group, only the subgroup with periodontitis had an excess risk (multivariable-adjusted HR = 1.20, 95% confidence interval [CI] 1.11-1.29). No positive association with statistical significance was observed in the 70+ age group. Individuals with fewer teeth tended to have a higher risk in all age groups. CONCLUSIONS: Our results confirmed the association between poor dental health and pancreatic cancer risk, which warrants further studies on underlying mechanisms.

Poor Oral Health and Esophageal Cancer Risk: A Nationwide Cohort Study.

BACKGROUND: Previous research indicates that poor dental health increases risks for certain types of cancers, including esophageal cancer. This study aimed to investigate the association with esophageal cancer using Swedish Dental Health Register. METHODS: This is a prospective cohort study. The exposures were dental diagnoses classified into healthy, caries, root canal infection, mild inflammation, and periodontitis, as well as number of remaining teeth, at baseline and during multiple visits. The outcome was the incidence of esophageal cancer, which was further divided into esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). Cox proportional hazards models were used to estimate hazard ratios (HR) and its corresponding confidence intervals (CI). RESULTS: A total of 5,042,303 individuals were included in the study and 1,259 EAC and 758 ESCC cases were identified. Root canal infection at baseline was associated with 41% higher risk for EAC (HR, 1.41; 95% CI, 1.10-1.82), whereas periodontitis at baseline was linked to 32% and 45% higher risks for respective histopathological subtypes (HR for EAC, 1.32; 95% CI, 1.13-1.53; HR for ESCC, 1.45; 95% CI, 1.20-1.75). Fewer remaining teeth at baseline also increased the risks for both histopathological types of esophageal cancer, with a dose-response effect (Ptrend < 0.01). Cox regression analyses with time-varying exposures corroborated the above-mentioned results. CONCLUSIONS: Impaired dental health before cancer diagnosis is associated with excess risks for both histopathological subtypes of esophageal cancer. IMPACT: Our study provided corroborating evidence for the association between poor oral health and esophageal cancer risk.

Risk of hepato-pancreato-biliary cancer is increased by primary sclerosing cholangitis in patients with inflammatory bowel disease: A population-based cohort study.

BACKGROUND: There is continued uncertainty regarding the risks of hepato-pancreato-biliary cancers in patients with inflammatory bowel disease (IBD) with or without concomitant primary sclerosing cholangitis (PSC). OBJECTIVE: To give updated estimates on risk of hepato-pancreato-biliary cancers in patients with IBD, including pancreatic cancer, hepatocellular carcinoma, gall bladder cancer, and intra - and extrahepatic cholangiocarcinoma. METHODS: In a population-based cohort study, we included all patients diagnosed with IBD in Norway and Sweden from 1987 to 2016. The cohort comprised of 141,960 patients, identified through hospital databases and the National Patient Register. Participants were followed through linkage to national cancer, cause of death, and population registries. We calculated absolute risk and standardized incidence ratios (SIRs) of hepato-pancreato-biliary cancers by PSC and other clinical characteristics. RESULTS: Of the 141,960 IBD patients, 3.2% were diagnosed with PSC. During a median follow-up of 10.0 years, we identified 443 biliary tract cancers (SIR 5.2, 95% confidence interval [CI] 4.8-5.7), 161 hepatocellular carcinomas (SIR 2.4, 95% CI 2.0-2.7) and 282 pancreatic cancers (SIR 1.3, 95% CI 1.2-1.5). The relative risks were considerably higher in PSC-IBD patients, with SIR of 140 (95% CI 123-159) for biliary tract, 38.6 (95% CI 29.2-50.0) for hepatocellular, and 9.0 (95% CI 6.3-12.6) for pancreatic cancer. The SIRs were still slightly increased in non-PSC-IBD patients, compared to the general population. For biliary tract cancer, the cumulative probability at 25 years was 15.6% in PSC-IBD patients, and 0.4% in non-PSC-IBD patients. CONCLUSIONS: The dramatically increased risks of hepato-pancreato-biliary cancers in PSC-IBD patients support periodic surveillance for these malignancies. While much lower, the excess relative risks in non-PSC-IBD patients were not trivial compared to non-IBD related risk factors.

Exploring impacts of COVID-19 on city-wide taxi and ride-sourcing markets: Evidence from Ningbo, China.

The outbreak of the COVID-19 epidemic has brought enormous impacts and changes to human mobility. To better understand and quantify the impacts of COVID-19 on city-wide ride-sourcing and taxi markets, we present exploratory evidence on the factors such as coronavirus cases related attributes, policy-related attributes, operational status of transportation, socio-economic status related variables, demographics related variables, and other factors. Based on 5-month real-world ride-sourcing and taxi datasets in Ningbo, China, including 37-million trips, we study the temporal variations of drivers' working characteristics and productivity of ride-sourcing and taxi fleets. The spatial heterogeneity of the impacts of COVID-19 on taxi and ride-sourcing trips is demonstrated in terms of traffic analysis zones (TAZs). Regression models are established to examine the impacts of a variety of explanatory variables, including COVID-19 related variables, on the district-level productivity of taxi and ride-sourcing services. The results show that the accumulated cured coronavirus cases, policy of closed management, operational status of mass transit, and average fee spent on transportation per capita significantly impact the productivity of the taxi and ride-sourcing fleets. This paper empirically reveals the influence of the epidemic on ride-sourcing and taxi markets and the temporal and spatial variations. The findings can support decision-making to restore the ride-sourcing and taxi markets and benefit other COVID-19 related research efforts.

Gastric Mucosal Abnormality and Risk of Pancreatic Cancer: A Population-Based Gastric Biopsy Cohort Study in Sweden.

BACKGROUND: It remains open whether gastric precancerous lesions are associated with an elevated risk of pancreatic cancer. Our aim was to investigate the association between gastric mucosal status and pancreatic cancer risk. METHODS: Patients with gastric biopsies [normal, minor changes, superficial gastritis, and atrophic gastritis/intestinal metaplasia/dysplasia (AG/IM/Dys)] from the Swedish histopathology registers during 1979 to 2011 were included. Cross-linkages with several nationwide registries allowed complete follow-up and identification of pancreatic cancer cases until 2014. Standardized incidence ratios (SIR) and HRs were estimated. RESULTS: During 3,438,248 person-years of follow-up with 318,653 participants, 3,540 cases of pancreatic cancer were identified. The same pattern of excess risk of pancreatic cancer compared with the general population was observed across all groups: a peak of 12- to 21-fold excess risk in the first year after biopsy [e.g., normal: SIR = 17.4; 95% confidence interval (CI), 15.7-19.3; AG/IM/Dys: SIR = 11.5; 95% CI, 9.9-13.4], which dropped dramatically during the second and third years, followed by 20% to 30% increased risk after the third year (e.g., normal: SIR = 1.2; 95% CI, 1.1-1.4; AG/IM/Dys: SIR = 1.3; 95% CI, 1.1-1.5). However, no significant excess risk was observed with the normal gastric mucosa as reference. CONCLUSIONS: This unique, large pathologic cohort study did not find evidence that abnormal gastric mucosal status is causally associated with a long-term pancreatic cancer risk. However, a highly increased short-term risk was observed for people undergoing gastroscopy with biopsy sampling compared with the general population. IMPACT: Further studies for a long-term risk of pancreatic cancer in patients with gastric biopsies are needed, with further adjustments.

Risk of esophageal and gastric adenocarcinoma in men receiving androgen deprivation therapy for prostate cancer.

The aim of this study was to explore the male predominance in esophageal and gastric adenocarcinoma by evaluating the preventive potential of androgen deprivation therapy (ADT). This matched cohort study was based on a national Swedish database of prostate cancer patients in 2006-2013. Prostate cancer patients receiving ADT were the exposed group. Prostate cancer-free men from the general population were randomly selected and matched to the index case by birth year and county of residence, forming the unexposed control group. The participants were followed until a diagnosis of esophageal or gastric cancer, death, emigration, or end of the study period. The risk of esophageal adenocarcinoma, cardia gastric adenocarcinoma, non-cardia gastric adenocarcinoma, and esophageal squamous-cell carcinoma among ADT-exposed compared to unexposed was calculated by multivariable Cox proportional hazard regression. The hazard ratios (HRs) and 95% confidence intervals (CIs) were adjusted for confounders. There was a risk reduction of non-cardia gastric adenocarcinoma among ADT-users compared to non-users (HR 0.49 [95% CI 0.24-0.98]). No such decreased risk was found for esophageal adenocarcinoma (HR 1.17 [95% CI 0.60-2.32]), cardia gastric adenocarcinoma (HR 0.99 [95% CI 0.40-2.46]), or esophageal squamous cell carcinoma (HR 0.99 [95% CI 0.31-3.13]). This study indicates that androgen deprivation therapy decreases the risk of non-cardia gastric adenocarcinoma, while no decreased risk was found for esophageal adenocarcinoma, cardia gastric adenocarcinoma, or esophageal squamous-cell carcinoma.

Burden of pancreatic cancer along with attributable risk factors in Europe between 1990 and 2019, and projections until 2039.

Projecting the burden of pancreatic cancer over time provides essential information to effectively plan measures for its management and prevention. Here, we obtained data from the Global Burden of Disease (GBD) Study between 1990 and 2019, to model how pancreatic cancer will affect the 27 countries of the European Union (EU) plus the United Kingdom (the pre-Brexit EU-28) until 2039 by conducting the Bayesian age-period-cohort analysis. The number of new pancreatic cancer cases in the EU-28 was 59 000 in 1990, 109 000 in 2019 and projected to be 147 000 in 2039. This corresponded to 60 000, 109 000 and 155 000 for deaths, and a loss of 1.3 million, 2.0 million and 2.7 million for disability-adjusted life years (DALYs), respectively. The most pronounced increase of the crude incidence rate was observed and projected to be in the population older than 80 years. The age-standardized rate (ASR) of incidence, however, increased from 8.6 to 10.1 per 100 000 person-years during 1990-2019 but was projected to remain stable during 2019-2039. At the same time, our models only predicted a mild increase in the ASR of mortality until 2039. The fraction of pancreatic cancer mortality attributable to tobacco consumption decreased during 1990-2019, but we found upward trends for the attributable fractions for high fasting plasma glucose and high body mass index. In conclusion, a substantial increase in counts of incidence, mortality and DALYs lost of pancreatic cancer in the EU-28 is projected over the next two decades, which indicates the need for future health policies and interventions.

A nomogram for screening esophageal squamous cell carcinoma based on environmental risk factors in a high-incidence area of China: a population-based case-control study.

BACKGROUND: Selection of high-risk subjects for endoscopic screening of esophageal squamous cell carcinoma (ESCC) lacks individual predictive tools based on environmental risk factors. METHODS: We performed a large population-based case-control study of 1418 ESCC cases and 1992 controls in a high-risk area of China. Information on potential risk factors was collected via face-to-face interview using an electronic structured questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models, and predictive nomograms were established accordingly. A weighted analysis was further conducted to introduce age into predictive nomograms due to frequency matching study design. RESULTS: Most cases were usually exposed to 4 to 6 risk factors, but most controls were usually exposed to 3 to 5 risk factors. The AUCs of male and female predictive nomograms were 0.75 (95%CI: 0.72, 0.77) and 0.76 (95%CI: 0.73, 0.79), respectively. The weighted analysis adding age in the predictive model improved the AUC in both men and women (0.81 (95%CI: 0.79, 0.84) and 0.88 (95%CI: 0.85, 0.90), respectively). CONCLUSIONS: An easy-to-use preclinical predictive tool is provided to select candidate population with high ESCC risk for endoscopic screening. Its usefulness needs to be further evaluated in future screening practice.

Total mercury concentration in placental tissue, a good biomarker of prenatal mercury exposure, is associated with risk for neural tube defects in offspring.

OBJECTIVE: To examine the role of total mercury (T-Hg) in placenta as a biomarker of prenatal mercury (Hg) exposure and determine the association between prenatal Hg exposure and risk for neural tube defects (NTDs) in offspring. METHODS: Total Hg concentrations in placental tissue were detected in 408 NTD cases and 593 healthy controls enrolled in Shanxi province in northern China. Methylmercury (MeHg) and T-Hg were also detected in the umbilical cord of 147 NTD cases and 140 healthy controls. In addition, MeHg and T-Hg were detected in fetal kidney, liver, and brain tissues of 51 NTD cases. Spearman's rank correlation (rs) was used to evaluate the correlations between placental T-Hg and T-Hg in umbilical cord and fetal kidney, liver, and brain tissues. The Wilcoxon rank-sum test was used to compare T-Hg amounts between case and control groups. Logistic regression was used to examine the association between placental T-Hg and risk for NTDs. RESULTS: Placental T-Hg was significantly correlated with T-Hg in umbilical cord (rs = 0.479), kidney (rs = 0.718), liver (rs = 0.656), and brain (rs = 0.512) tissues (all p < 0.001). The median (25th percentile-75th percentile) concentration for placental T-Hg in the NTD case group was 8.91 (5.00-17.1) ng/g dry weight (d.w.), significantly higher than that in the healthy control group (4.99 [3.26-7.93] ng/g d.w., p < 0.001). After adjusting for potential confounders, higher levels of T-Hg in placenta were associated with increased risk for NTDs in offspring (OR = 1.76, 95% CI: 1.13-2.76), and a dose-response relationship was found (p < 0.001). CONCLUSION: The concentration of T-Hg in placenta is a good biomarker for estimating prenatal Hg exposure, which is associated with increased risk for NTDs.

Targeted proteomics-derived biomarker profile develops a multi-protein classifier in liquid biopsies for early detection of esophageal squamous cell carcinoma from a population-based case-control study.

BACKGROUND: Early diagnosis of esophageal squamous cell carcinoma (ESCC) remains a challenge due to the lack of specific blood biomarkers. We aimed to develop a serum multi-protein signature for the early detection of ESCC. METHODS: We selected 70 healthy controls, 30 precancerous patients, 60 stage I patients, 70 stage II patients and 70 stage III/IV ESCC patients from a completed ESCC case-control study in a high-risk area of China. Olink Multiplex Oncology II targeted proteomics panel was used to simultaneously detect the levels of 92 cancer-related proteins in serum using proximity extension assay. RESULTS: We found that 10 upregulated and 13 downregulated protein biomarkers in serum could distinguish the early-stage ESCC from healthy controls, which were validated by the significant dose-response relationships with ESCC pathological progression. Applying least absolute shrinkage and selection operator (LASSO) regression and backward elimination algorithm, ANXA1 (annexin A1), hK8 (kallikrein-8), hK14 (kallikrein-14), VIM (vimentin), and RSPO3 (R-spondin-3) were kept in the final model to discriminate early ESCC cases from healthy controls with an area under curve (AUC) of 0.936 (95% confidence interval: 0.899 ~ 0.973). The average accuracy rates of the five-protein classifier were 0.861 and 0.825 in training and test data by five-fold cross-validation. CONCLUSIONS: Our study suggested that a combination of ANXA1, hK8, hK14, VIM and RSPO3 serum proteins could be considered as a potential tool for screening and early diagnosis of ESCC, especially with the establishment of a three-level hierarchical screening strategy for ESCC control.

A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. METHODS: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. RESULTS: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E-06 in 1D approach and a Local Moran's Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8-a lncRNA associated with pancreatic carcinogenesis-with a lowest p value = 6.91E-05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1-a major regulator of the ER stress and unfolded protein responses in acinar cells-identified by 3D; all of them with a strong in silico functional support. CONCLUSIONS: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.

Plasma protein biomarkers for early detection of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, mainly due to late diagnosis at advanced tumor stages. In this study, we aimed to identify plasma protein biomarkers for early detection of PDAC. Totally, 135 PDAC patients (early PDAC, Stage I/II, n = 71; advanced PDAC, Stage III/IV, n = 64), 13 benign lesions/chronic pancreatitis patients and 72 healthy individuals, with corresponding plasma samples from a case-control study in Sweden were included. A proximity extension assay was used to detect 92 cancer-related proteins, and an enzyme-linked immunosorbent assay/electrochemiluminescence immunoassay was used to detect CA19-9. Predictive features were selected from these 93 candidate proteins and three covariates in the Swedish participants, and then validated in Spanish participants, including 37 early PDAC patients, 38 advanced PDAC patients, 19 chronic pancreatitis patients and 36 healthy controls. A panel of eight proteins discriminating early PDAC from healthy individuals was identified, and the cross-validated area under the curves (AUCs) were 0.85 (95% confidence interval, 95% CI, 0.78-0.91) and 0.81 (95% CI, 0.70-0.92) in the Swedish and Spanish participants, respectively. Another eight-protein panel was predictive for classifying advanced PDAC from healthy controls in two populations, with cross-validated AUCs of 0.89 (95% CI, 0.83-0.95) and 0.90 (95% CI, 0.83-0.98), respectively. In conclusion, eight protein biomarkers were identified and externally validated, potentially allowing early detection of PDAC patients if validated in additional prospective studies.

Lead-Free BiFeO3-BaTiO3 Ceramics with High Curie Temperature: Fine Compositional Tuning across the Phase Boundary for High Piezoelectric Charge and Strain Coefficients.

BiFeO3-BaTiO3 is a promising high-temperature piezoelectric ceramic that possesses both good electromechanical properties and a Curie temperature (TC). Here, the piezoelectric charge constants (d33) and strain coefficients (d*33) of (1 - x)BiFeO3-xBaTiO3 (BF-xBT; 0.20 ≤ x ≤ 0.50) lead-free piezoelectrics were investigated at room temperature. The results showed a maximum d33 of 225 pC/N in the BF-0.30BT ceramic and a maximum d*33 of 405 pm/V in the BF-0.35BT ceramic, with TCs of 503 and 415 °C, respectively. To better understand the performance enhancement mechanisms, a phase diagram was established using the results of XRD, piezoresponse force microscopy, TEM, and electrical property measurements. The superb d33 of the BF-0.30BT ceramic arose because of its location in the optimum point in the morphotropic phase boundary, low oxygen vacancy (VO··) concentration, and domain heterogeneity. The superior d*33 of the BF-0.35BT ceramic was attributed to a weak relaxor behavior between coexisting macrodomains and polar nanoregions. The presented strategy provides guidelines for designing high-temperature BF-BT ceramics for different applications.

Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analyses.

OBJECTIVES: To characterise the association between type 2 diabetes mellitus (T2DM) subtypes (new-onset T2DM (NODM) or long-standing T2DM (LSDM)) and pancreatic cancer (PC) risk, to explore the direction of causation through Mendelian randomisation (MR) analysis and to assess the mediation role of body mass index (BMI). DESIGN: Information about T2DM and related factors was collected from 2018 PC cases and 1540 controls from the PanGenEU (European Study into Digestive Illnesses and Genetics) study. A subset of PC cases and controls had glycated haemoglobin, C-peptide and genotype data. Multivariate logistic regression models were applied to derive ORs and 95% CIs. T2DM and PC-related single nucleotide polymorphism (SNP) were used as instrumental variables (IVs) in bidirectional MR analysis to test for two-way causal associations between PC, NODM and LSDM. Indirect and direct effects of the BMI-T2DM-PC association were further explored using mediation analysis. RESULTS: T2DM was associated with an increased PC risk when compared with non-T2DM (OR=2.50; 95% CI: 2.05 to 3.05), the risk being greater for NODM (OR=6.39; 95% CI: 4.18 to 9.78) and insulin users (OR=3.69; 95% CI: 2.80 to 4.86). The causal association between T2DM (57-SNP IV) and PC was not statistically significant (ORLSDM=1.08, 95% CI: 0.86 to 1.29, ORNODM=1.06, 95% CI: 0.95 to 1.17). In contrast, there was a causal association between PC (40-SNP IV) and NODM (OR=2.85; 95% CI: 2.04 to 3.98), although genetic pleiotropy was present (MR-Egger: p value=0.03). Potential mediating effects of BMI (125-SNPs as IV), particularly in terms of weight loss, were evidenced on the NODM-PC association (indirect effect for BMI in previous years=0.55). CONCLUSION: Findings of this study do not support a causal effect of LSDM on PC, but suggest that PC causes NODM. The interplay between obesity, PC and T2DM is complex.