The ergodicity question when imaging DNA conformation using liquid cell electron microscopy.

Assessing the ergodicity of graphene liquid cell electron microscope measurements, we report that loop states of circular DNA interconvert reversibly and that loop numbers follow the Boltzmann distribution expected for this molecule in bulk solution, provided that the electron dose is low (80-keV electron energy and electron dose rate 1-20 e- Å-2 s-1). This imaging technique appears to act as a "slow motion" camera that reveals equilibrated distributions by imaging the time average of a few molecules without the need to image a spatial ensemble.

Alterations in gut microbiota and bile acids by proton-pump inhibitor use and possible mediating effects on elevated glucose levels and insulin resistance.

Several observational studies have suggested that proton-pump inhibitor (PPI) use might increase diabetes risk, but the mechanism remains unclear. This study aimed to investigate the effects of PPI use on gut microbiota and bile acids (BAs) profiles, and to explore whether these changes could mediate the association of PPIs use with fasting blood glucose (FBG) levels and insulin resistance (IR) in Chinese population. A cross-sectional study was conducted in Shenzhen, China, from April to August 2021, enrolled 200 eligible patients from the local hospital. Participants completed a questionnaire and provided blood and stool samples. Gut microbiome was measured by16S rRNA gene sequencing, and bile acids were quantified by UPLC-MS/MS. Insulin resistance (IR) was assessed using the Homeostasis Model Assessment 2 (HOMA2-IR). PPI use was positively associated with higher levels of FBG and HOMA2-IR after controlling for possible confounders. PPI users exhibited a decreased Firmicutes and an increase in Bacteroidetes phylum, alongside higher levels of glycoursodeoxycholic acid (GUDCA) and taurochenodeoxycholic acid (TCDCA). Higher abundances of Bacteroidetes and Fusobacterium as well as higher levels of TCDCA in PPI users were positively associated with elevated FBG or HOMA2-IR. Mediation analyses indicated that the elevated levels of FBG and HOMA2-IR with PPI use were partially mediated by the alterations in gut microbiota and specific BAs (i.e., Fusobacterium genera and TCDCA). Long-term PPI use may increase FBG and HOMA2-IR levels, and alterations in gut microbiota and BAs profiles may partially explain this association.

Adherence to a Mediterranean diet is associated with a lower risk of diabetic kidney disease among individuals with hyperglycemia: a prospective cohort study.

BACKGROUND: Type 2 diabetes is associated with a variety of complications, including micro- and macrovascular complications, neurological manifestations and poor wound healing. Adhering to a Mediterranean Diet (MED) is generally considered an effective intervention in individuals at risk for type 2 diabetes mellitus (T2DM). However, little is known about its effect with respect to the different specific manifestations of T2DM. This prompted us to explore the effect of MED on the three most significant microvascular complications of T2DM: diabetic retinopathy (DR), diabetic kidney disease (DKD), and vascular diabetic neuropathies (DN). METHODS: We examined the association between the MED and the incidence of these microvascular complications in a prospective cohort of 33,441 participants with hyperglycemia free of microvascular complications at baseline, identified in the UK Biobank. For each individual, we calculated the Alternate Mediterranean Diet (AMED) score, which yields a semi-continuous measure of the extent to which an individual's diet can be considered as MED. We used Cox proportional hazard models to analyze hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for demographics, lifestyle factors, medical histories and cardiovascular risk factors. RESULTS: Over a median of 12.3 years of follow-up, 3,392 cases of microvascular complications occurred, including 1,084 cases of diabetic retinopathy (DR), 2,184 cases of diabetic kidney disease (DKD), and 632 cases of diabetic neuropathies (DN), with some patients having 2 or 3 microvascular complications simultaneously. After adjusting for confounders, we observed that higher AMED scores offer protection against DKD among participants with hyperglycemia (comparing the highest AMED scores to the lowest yielded an HR of 0.79 [95% CIs: 0.67, 0.94]). Additionally, the protective effect of AMED against DKD was more evident in the hyperglycemic participants with T2DM (HR, 0.64; 95% CI: 0.50, 0.83). No such effect, however, was seen for DR or DN. CONCLUSIONS: In this prospective cohort study, we have demonstrated that higher adherence to a MED is associated with a reduced risk of DKD among individuals with hyperglycemia. Our study emphasizes the necessity for continued research focusing on the benefits of the MED. Such efforts including the ongoing clinical trial will offer further insights into the role of MED in the clinical management of DKD.

Highly stable mixed-phase Cs-Cu-I films with tunable optoelectronic properties for UVB photodetector applications.

Ultraviolet (UV) photodetector plays an important role in military, civilian and people's daily life, and is an indispensable part of spectral detection. However, photodetectors target at the UVB region (280-320 nm) are rarely reported, and the devices detected by medium-wave UV light generally have problems such as low detection rate, low sensitivity, and poor stability, which are difficult to meet the market application needs. Herein, Cs-Cu-I films with mixed-phase have been prepared by vacuum thermal evaporation. By adjusting the proportion of evaporation sources (CsI and CuI), the optical bandgaps of mixed-phase Cs-Cu-I films can be tuned between 3.7 eV and 4.1 eV. This absorption cut-off edge is exactly at both ends of the UVB band, which indicating its potential application in the field of UVB detection. Finally, the photodetectors based on Cs-Cu-I/n-Si heterojunction are fabricated. The photodetector shows good spectral selectivity for UVB band, and has a photoresponsivity of 22 mA/W, a specific detectivity of 1.83*1011 Jones, an EQE over 8.7% and an on/off ratio above 20.

Dermal papilla cell-secreted biglycan regulates hair follicle phase transit and regeneration by activating Wnt/ß-catenin.

Alopecia is a prevalent problem of cutaneous appendages and lacks effective therapy. Recently, researchers have been focusing on mesenchymal components of the hair follicle, i.e. dermal papilla cells, and we previously identified biglycan secreted by dermal papilla cells as the key factor responsible for hair follicle-inducing ability. In this research, we hypothesized biglycan played an important role in hair follicle cycle and regeneration through regulating the Wnt signalling pathway. To characterize the hair follicle cycle and the expression pattern of biglycan, we observed hair follicle morphology in C57BL/6 mice on Days 0, 3, 5, 12 and 18 post-depilation and found that biglycan is highly expressed at both mRNA and protein levels throughout anagen in HFs. To explore the role of biglycan during the phase transit process and regeneration, local injections were administered in C57BL/6 and nude mice. Results showed that local injection of biglycan in anagen HFs delayed catagen progression and involve activating the Wnt/ß-catenin signalling pathway. Furthermore, local injection of biglycan induced HF regeneration and up-regulated expression of key Wnt factors in nude mice. In addition, cell analyses exhibited biglycan knockdown inactivated the Wnt signalling pathway in early-passage dermal papilla cell, whereas biglycan overexpression or incubation activated the Wnt signalling pathway in late-passage dermal papilla cells. These results indicate that biglycan plays a critical role in regulating HF cycle transit and regeneration in a paracrine and autocrine fashion by activating the Wnt/ß-catenin signalling pathway and could be a potential treatment target for hair loss diseases.

Regular use of paracetamol and risk of liver cancer: a prospective cohort study.

BACKGROUND: Paracetamol induces hepatotoxicity and subsequent liver injury, which may increase the risk of liver cancer, but epidemiological evidence remains unclear. We conducted this study to evaluate the association between paracetamol use and the risk of liver cancer. METHODS: This prospective study included 464,244 participants free of cancer diagnosis from the UK Biobank. Incident liver cancer was identified through linkage to cancer and death registries and the National Health Service Central Register using the International Classification of Diseases (ICD)-10 codes (C22). An overlap-weighted Cox proportional hazards model was utilized to calculate the hazard ratio (HR) and 95% confidence interval (CI) for the risk of liver cancer associated with paracetamol use. The number needed to harm (NNH) was calculated at 10 years of follow-up. RESULTS: During a median of 12.6 years of follow-up, 627 cases of liver cancer were identified. Paracetamol users had a 28% higher risk of liver cancer than nonusers (HR 1.28, 95% CI 1.06-1.54). This association was robust in several sensitivity analyses and subgroup analyses, and the quantitative bias analysis indicated that the result remains sturdy to unmeasured confounding factors (E-value 1.88, lower 95% CI 1.31). The NNH was 1106.4 at the 10 years of follow-up. CONCLUSION: The regular use of paracetamol was associated with a higher risk of liver cancer. Physicians should be cautious when prescribing paracetamol, and it is recommended to assess the potential risk of liver cancer to personalize the use of paracetamol.

Lipidomic markers for the prediction of progression from mild cognitive impairment to Alzheimer's disease.

Dementia is a well-known syndrome and Alzheimer's disease (AD) is the main cause of dementia. Lipids play a key role in the pathogenesis of AD, however, the prediction value of serum lipidomics on AD remains unclear. This study aims to construct a lipid score system to predict the risk of progression from mild cognitive impairment (MCI) to AD. First, we used the least absolute shrinkage and selection operator (LASSO) Cox regression model to select the lipids that can signify the progression from MCI to AD based on 310 older adults with MCI. Then we constructed a lipid score based on 14 single lipids using Cox regression and estimated the association between the lipid score and progression from MCI to AD. The prevalence of AD in the low-, intermediate- and high-score groups was 42.3%, 59.8%, and 79.8%, respectively. The participants in the intermediate- and high-score group had a 1.65-fold (95% CI 1.10 to 2.47) and 3.55-fold (95% CI 2.40 to 5.26) higher risk of AD, respectively, as compared to those with low lipid scores. The lipid score showed moderate prediction efficacy (c-statistics > 0.72). These results suggested that the score system based on serum lipidomics is useful for the prediction of progression from MCI to AD.

Genetic risk, adherence to healthy lifestyle behaviors, and risk of cholelithiasis: A population-based cohort study.

OBJECTIVE: Genetic and lifestyles contribute to cholelithiasis, but the impact of adhering to healthy lifestyle on cholelithiasis risk remains uncertain. We aimed to assess combined lifestyle factors and a polygenic risk score on incident cholelithiasis. METHODS: We utilized cholelithiasis genome-wide association study (GWAS) data from FinnGen study, constructing varied polygenic risk score (PRS), and applied them to 317,640 UK Biobank participants. The relative and absolute risk of incident cholelithiasis associated with six well-established lifestyle risk factors, was evaluated and stratified by PRS (low risk [quintile 1], intermediate risk [quintiles 2-4] and high risk [quintile 5]). Lifestyle score was also categorized into favorable, intermediate, and unfavorable groups. RESULTS: The PRS derived from 13 single nucleotide polymorphisms (p ≤ 5 × 10-6, r2 < 0.001) showed the best performance. A significant gradient of increase in risk of cholelithiasis was observed across the quintiles of the polygenic risk score (p < 0.001). Compared to participants with low genetic risk, those with intermediate or high genetic risk had a 10% (95% confidence interval [CI] = 1.05-1.17) and 24% (95% CI = 1.16-1.32) higher risk of cholelithiasis. An unfavorable lifestyle was associated with an approximately 50% higher risk of cholelithiasis than a favorable lifestyle. Participants with high genetic risk and an unfavorable lifestyle had 98% (Hazard ratio [HR]: 1.98; 95% CI: 1.67-2.35) higher risk of cholelithiasis than those with low genetic risk and a favorable lifestyle. CONCLUSIONS: Our study highlights the importance of lifestyle behaviors intervention on cholelithiasis risk regardless of the genetic risk in White European population.

Metabolic syndrome increases osteoarthritis risk: findings from the UK Biobank prospective cohort study.

OBJECTIVE: The association between Metabolic Syndrome (MetS), its components, and the risk of osteoarthritis (OA) has been a topic of conflicting evidence in different studies. The aim of this present study is to investigate the association between MetS, its components, and the risk of OA using data from the UK Biobank. METHODS: A prospective cohort study was conducted in the UK Biobank to assess the risk of osteoarthritis (OA) related to MetS. MetS was defined according to the criteria set by the International Diabetes Federation (IDF). Additionally, lifestyle factors, medications, and the inflammatory marker C-reactive protein (CRP) were included in the model. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI). The cumulative risk of OA was analyzed using Kaplan-Meier curves and log-rank tests. To explore potential nonlinear associations between MetS components and OA risk, a restricted cubic splines (RCS) model was employed. In addition, the polygenic risk score (PRS) of OA was calculated to characterize individual genetic risk. RESULTS: A total of 45,581 cases of OA were identified among 370,311 participants, with a median follow-up time of 12.48 years. The study found that individuals with MetS had a 15% higher risk of developing OA (HR = 1.15, 95%CI:1.12-1.19). Additionally, central obesity was associated with a 58% increased risk of OA (HR = 1.58, 95%CI:1.5-1.66), while hyperglycemia was linked to a 13% higher risk (HR = 1.13, 95%CI:1.1-1.15). Dyslipidemia, specifically in triglycerides (HR = 1.07, 95%CI:1.05-1.09) and high-density lipoprotein (HR = 1.05, 95%CI:1.02-1.07), was also found to be slightly associated with OA risk. When stratified by PRS, those in the high PRS group had a significantly higher risk of OA compared to those with a low PRS, whereas no interaction was found between MetS and PRS on OA risks. Furthermore, the presence of MetS significantly increased the risk of OA by up to 35% in individuals with elevated CRP levels (HR = 1.35, 95% CI:1.3-1.4). CONCLUSION: MetS and its components have been found to be associated with an increased risk of OA, particularly in individuals with elevated levels of CRP. These findings highlight the significance of managing MetS as a preventive and intervention measure for OA.

Safety of propofol-assisted deep extubation in the dental treatment of children-a retrospective, observational study.

PURPOSE: Awake extubation and deep extubation are commonly used anesthesia techniques. In this study, the safety of propofol-assisted deep extubation in the dental treatment of children was assessed. MATERIALS AND METHODS: Children with severe caries who received dental treatment under general anesthesia and deep extubation between January 2017 and June 2023 were included in this study. Data were collected on the following variables: details and time of anesthesia, perioperative vital signs, and incidence of postoperative complications. The incidence of laryngeal spasm (LS) was considered to be the primary observation indicator. RESULTS: The perioperative data obtained from 195 children undergoing dental treatment was reviewed. The median age was 4.2 years (range: 2.3 to 9.6 years), and the average duration of anesthesia was 2.56 h (range 1 to 4.5 h). During intubation with a videoscope, purulent mucus was found in the pharyngeal cavity of seven children (3.6%); LS occurred in five of them (2.6%), and one child developed a fever (T = 37.8 °C) after discharge. Five children (2.6%) experienced emergence agitation (EA) in the recovery room. Also, 13 children (6.7%) experienced epistaxis; 10 had a mild experience and three had a moderate experience. No cases of airway obstruction (AO) and hypoxemia were recorded. The time to open eyes (TOE) was 16.3 ± 7.2 min. The incidence rate of complications was 23/195 (11.8%). Emergency tracheal reintubation was not required. Patients with mild upper respiratory tract infections showed a significantly higher incidence of complications (P < 0.001). CONCLUSIONS: Propofol-assisted deep extubation is a suitable technique that can be used for pediatric patients who exhibited non-cooperation in the outpatient setting. Epistaxis represents the most frequently encountered complication. Preoperative upper respiratory tract infection significantly increases the risk of complications. The occurrence of EA was notably lower than reported in other studies.

Proteasome-associated autoinflammatory syndrome 2 in a neonate.

Proteasome-associated autoinflammatory syndrome-2 (PRAAS2) is characterized by early onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity. We report the case of a premature baby (GA 35+5 weeks) born with disseminated and confluent red papules, diagnosed with PRAAS2. A novel de novo frameshift proteasome maturation protein (POMP) mutation (c.333delT (p.t111fs)) was detected, confirming the diagnosis.

Associations of maternal and personal smoking with all-cause and cause-specific mortality risk and life expectancy: a prospective cohort study.

OBJECTIVES: The aim of this study was to evaluate the individual and combined effects of maternal smoking during pregnancy (MSDP) and personal smoking on mortality and life expectancy. STUDY DESIGN: A prospective cohort study based on the UK Biobank, with a median follow-up of 12.47 years. METHODS: This study employed multivariate Cox regression to determine the relative risks of mortality from all causes and specific diseases according to maternal and/or personal smoking status and pack-years of smoking (0, 1-20, 21-30, >30). Additionally, this study estimated the additive interaction between the two exposures. Life table analyses were performed using the estimated age-specific mortality rates to forecast life expectancy. RESULTS: Results indicated that MSDP elevated the risk of all-cause mortality (HR = 1.12, 95% CI: 1.09-1.15) and mortality due to neoplasms (HR = 1.10, 95% CI: 1.06-1.12), circulatory (HR = 1.13, 95% CI: 1.06-1.19), respiratory (HR = 1.27, 95% CI: 1.16-1.40) and digestive system diseases (HR = 1.22, 95% CI: 1.08-1.38). Notably, both multiplicative and additive interactions were observed between maternal and personal smoking, with Relative Excess Risk due to Interaction (RERI) values for mortality from all causes, neoplasms, circulatory, and respiratory diseases being 0.21, 0.22, 0.16, and 0.76, respectively. This study also found a trend towards shorter gained life expectancy when maternal smoking and increasing pack-years of personal smoking were combined. CONCLUSIONS: In this cohort study of UK Biobank, MSDP was associated with an increased risk of all-cause mortality and reduced life expectancy, suggesting that quitting smoking during pregnancy might have health and longevity benefits for both generations.

Tailoring Near-Infrared-IIb Fluorescence of Thulium(III) by Nanocrystal Structure Engineering.

Currently, mainstream lanthanide probes with fluorescence located in the second near-infrared subwindow of 1500-1700 nm (NIR-IIb) are predominantly Er(III)-based nanoparticles (NPs). Here we report a newly developed NIR-IIb fluorescent nanoprobe, α-Tm NP (cubic-phase NaYF4@NaYF4:Tm@NaYF4), with an emission at 1630 nm. We activate the 1630 nm emission of Tm(III) in α-Tm NP through the large spread of the Stark split sublevels induced by the crystal-field effect of the α-NaYF4 host. Further, we systematically investigated the effect of crystalline structure of the host NaYF4 NP (cubic phase (α) or hexagonal phase (ß)), the type and concentrations of dopants (Yb(III), Tm(III), and Ca(II) ions) in the α-phase host, and the thicknesses of the interlayer and inert shell on the NIR-IIb fluorescence of Tm(III). The ultimate nanostructure presents a significant enhancement factor of the NIR-IIb photoluminescence intensity of Tm(III) up to ∼315. With this bright NIR-IIb fluorescent nanoprobe, we demonstrate high-spatial-resolution time-coursing imaging of breast cancer bone metastasis.

Knockdown of the ABCG23 Gene Disrupts the Development and Lipid Accumulation of Panonychus citri (Acari/Tetranychidae).

Panonychus citri is a worldwide citrus pest that is currently controlled through the use of insecticides. However, alternative strategies are required to manage P. citri. Recent studies suggest that the ATP-binding cassette (ABC) transporter G subfamily plays a crucial role in transporting cuticular lipids, which are essential for the insect's barrier function against microbial penetration. Therefore, investigating the potential of the ABC transporter G subfamily as a control measure for P. citri could be a promising approach. Based on the genome database, the gene was cloned, and the transcriptional response of ABCG23 for the different developmental stages of P. citri and under spirobudiclofen stress was investigated. Our results showed that the expression level of ABCG23 was significantly lower in adult females exposed to treatment compared to the control and was higher in females than males. The knockdown of ABCG23 using RNAi led to a decrease in the survival rate, fecundity, and TG contents of P. citri. Additionally, a lethal phenotype was characterized by body wrinkling and darkening. These results indicate that ABCG23 may be involved in cuticular lipid transportation and have adverse effects on the development and reproduction of P. citri, providing insight into the discovery of new targets for pest management based on the insect cuticle's penetration barrier function.

TMEM119 (c.G143A, p.S48L) Mutation Is Involved in Primary Failure of Eruption by Attenuating Glycolysis-Mediated Osteogenesis.

Primary failure of eruption (PFE) is a rare oral disease with an incidence rate of 0.06%. It is characterized by abnormal eruption mechanisms that disrupt tooth eruption. The underlying pathogenic genetic variant and mechanism of PFE remain largely unknown. The purpose of this study was to explore the role of a novel transmembrane protein 119 (TMEM119) mutation in two PFE patients in a Chinese family. Information collection was performed on the family with a diagnosis of PFE, and blood samples from patients and healthy family members were extracted. Whole-exome sequencing was performed. Bioinformatics analysis revealed that a heterozygous variant in the TMEM119 gene (c.G143A, p.S48L) was a disease-associated mutation in this family. Recombinant pcDNA3.1 plasmid-containing wild-type and mutant TMEM119 expression cassettes were successfully constructed and transfected into MC3T3-E1 cells, respectively. The results of in vitro analysis suggested that the subcellular distribution of the TMEM119 protein was transferred from the cell cytoplasm to the nucleus, and the ability of cells to proliferate and migrate as well as glycolytic and mineralized capacities were reduced after mutation. Furthermore, rescue assays showed that activating transcription factor 4 (ATF4) overexpression rescued the attenuated glycolysis and mineralization ability of cells. Results of in vivo analysis demonstrated that TMEM119 was mainly expressed in the alveolar bone around the mouse molar germs, and the expression level increased with tooth eruption, demonstrated using immunohistochemistry and immunofluorescence. Collectively, the novel TMEM119 mutation is potentially pathogenic in the PFE family by affecting the glucose metabolism and mineralized function of osteoblasts, including interaction with ATF4. Our findings broaden the gene mutation spectrum of PFE and further elucidate the pathogenic mechanism of PFE.

Deep learning-based detection of irreversible pulpitis in primary molars.

BACKGROUND: Changes in healthy and inflamed pulp on periapical radiographs are traditionally so subtle that they may be imperceptible to human experts, limiting its potential use as an adjunct clinical diagnostic feature. AIM: This study aimed to investigate the feasibility of an image-analysis technique based on the convolutional neural network (CNN) to detect irreversible pulpitis in primary molars on periapical radiographs (PRs). DESIGN: This retrospective study was performed in two health centres. Patients who received indirect pulp therapy at Peking University Hospital for Stomatology were retrospectively identified and randomly divided into training and validation sets (8:2). Using PRs as input to an EfficientNet CNN, the model was trained to categorise cases into either the success or failure group and externally tested on patients who presented to our affiliate institution. Model performance was evaluated using sensitivity, specificity, accuracy and F1 score. RESULTS: A total of 348 PRs with deep caries were enrolled from the two centres. The deep learning model achieved the highest accuracy of 0.90 (95% confidence interval: 0.79-0.96) in the internal validation set, with an overall accuracy of 0.85 in the external test set. The mean greyscale value was higher in the failure group than in the success group (p = .013). CONCLUSION: The deep learning-based model could detect irreversible pulpitis in primary molars with deep caries on PRs. Moreover, this study provides a convenient and complementary method for assessing pulp status.

The short-term impact of comprehensive caries treatment on the supragingival microbiome of severe early childhood caries.

BACKGROUND: Children affected by severe early childhood caries (S-ECC) usually need comprehensive caries treatment due to the extensive of caries. How the oral microbiome changes after caries therapy within the short-term warrant further study. AIM: This study aimed to investigate the short-term impact of comprehensive caries treatment on the supragingival plaque microbiome of S-ECC children. DESIGN: Thirty-three children aged 2-4 years with severe caries (dt > 7) were recruited. Comprehensive caries treatment was performed under general anesthesia in one session and included restoration, pulp treatment, extraction, and fluoride application. Supragingival plaque was sampled pre- and 1-month posttreatment. The genomic DNA of the supragingival plaque was extracted, and bacterial 16S ribosomal RNA gene sequencing was performed. RESULTS: Our data showed that the microbial community evenness significantly decreased posttreatment. Furthermore, comprehensive caries treatment led to more diverse microbial structures among the subjects. The interbacterial interactions reflected by the microbial community's co-occurrence network tended to be less complex posttreatment. Caries treatment increased the relative abundance of Corynebacterium matruchotii, Corynebacterium durum, Actinomyces naeslundii, and Saccharibacteria HMT-347, as well as Aggregatibacter HMT-458 and Haemophilus influenzae. Meanwhile, the relative abundance of Streptococcus mutans, three species from Leptotrichia, Neisseria bacilliformis, and Provotella pallens significantly decreased posttreatment. CONCLUSION: Our results suggested that comprehensive caries treatment may contribute to the reconstruction of a healthier supragingival microbiome.

Confounded association between proton pump inhibitor use and risk of biliary tract cancer: Result from three cohorts.

Recent epidemiological studies suggested that proton pump inhibitor (PPI) use was associated with an increased risk of biliary tract cancer (BTC), however, confounders were not adequately controlled. Our study aimed to evaluate PPI use and subsequent risk of BTC and its subtypes in three well-established cohorts. We conducted a pooled analysis of the subjects free of cancers in UK Biobank (n = 463 643), Nurses' Health Study (NHS, n = 80 235) and NHS II (n = 95 869). Propensity score weighted Cox models were used to estimate marginal HRs of PPIs use on BTC risk, accounting for potential confounders. We documented 284 BTC cases in UK Biobank (median follow-up: 7.6 years), and 91 cases in NHS and NHS II cohorts (median follow-up: 15.8 years). In UK biobank, PPI users had a 96% higher risk of BTC compared to nonusers in crude model (HR 1.96, 95% CI 1.44-2.66), but the effect was attenuated to null after adjusting for potential confounders (HR 0.95, 95% CI 0.60-1.49). PPI use was not associated with risk of BTC in the pooled analysis of three cohorts (HR 0.93, 95% CI 0.60-1.43). We also observed no associations between PPI use with risk of intrahepatic (HR 1.00, 95% CI 0.49-2.04), extrahepatic bile duct (HR 1.09, 95% CI 0.52-2.27) and gallbladder cancers (HR 0.66, 95% CI 0.26-1.66) in UK Biobank. In summary, regular use of PPIs was not associated with the risk of BTC and its subtypes.

Genetic factors, adherence to healthy lifestyle behaviors, and risk of bladder cancer.

BACKGROUND: Genetic and lifestyle factors both contribute to the pathogenesis of bladder cancer, but the extent to which the increased genetic risk can be mitigated by adhering to a healthy lifestyle remains unclear. We aimed to investigate the association of combined lifestyle factors with bladder cancer risk within genetic risk groups. METHODS: We conducted a prospective study of 375 998 unrelated participants of European ancestry with genotype and lifestyle data and free of cancer from the UK biobank. We generated a polygenic risk score (PRS) using 16 single nucleotide polymorphisms and a healthy lifestyle score based on body weight, smoking status, physical activity, and diet. Cox models were fitted to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of genetic and lifestyle factors on bladder cancer. RESULTS: During a median follow-up of 11.8 years, 880 participants developed bladder cancer. Compared with those with low PRS, participants with intermediate and high PRS had a higher risk of bladder cancer (HR 1.29, 95% CI 1.07-1.56; HR 1.63, 95% CI 1.32-2.02, respectively). An optimal lifestyle was associated with an approximately 50% lower risk of bladder cancer than a poor lifestyle across all genetic strata. Participants with a high genetic risk and a poor lifestyle had 3.6-fold elevated risk of bladder cancer compared with those with a low genetic risk and an optimal lifestyle (HR 3.63, 95% CI 2.23 -5.91). CONCLUSIONS: Adhering to a healthy lifestyle could substantially reduce the bladder cancer risk across all genetic strata, even for high-genetic risk individuals. For all populations, adopting an intermediate lifestyle is more beneficial than a poor one, and adhering to an optimal lifestyle is the ideal effective strategy for bladder cancer prevention.

Exosomes-mediated transfer of LINC00691 regulates the formation of CAFs and promotes the progression of gastric cancer.

OBJECTIVE: Gastric cancer (GC) is one of the malignant tumors with the highest mortality worldwide. Our previous studies have revealed that LINC00691 is up-regulated in serum of GC patients as a novel potential biomarker for GC diagnosis and prognosis. However, the roles of serum exosomal LINC00691 in GC has not been clarified. This study aimed to find the expression pattern of serum exosomal LINC00691 in GC patients and the correlation between the level of serum exosomal LINC00691 and the pathology of gastric cancer patients. METHODS: We collected the serum of 94 GC patients before surgery and extracted exosomes to detect the expression level of exosomal LINC00691, with 21 healthy volunteers and 17 patients with benign gastric diseases as controls. Surgical GC tissues and paired healthy tissues were collected to culture primary cancer-associated fibroblasts (CAFs) and normal fibroblasts (NFs). We then treated NFs with LINC00691-rich GC cell culture supernatant or exosomes and detected the activation markers and biological functions of the fibroblasts. RESULTS: The results of real-time qPCR indicated that the serum exosomal LINC00691 of GC patients was significantly higher than that of healthy subjects and patients with benign gastric diseases, and was associated with the clinicopathology of GC patients. More interestingly, when the NFs were treated with GC exosomes, the level of LINC00691 was significantly increased, the cell proliferation and migration were noticeably enhanced, and the ability to accelerate GC cell proliferation and invasion was promoted, which means that the induced fibroblasts gained the properties of CAFs. In addition, we found that knockdown of LINC00691 and the use of the JAK2/STAT3 signaling pathway inhibitor ruxolitinib effectively deprived exosome-containing GC cell supernatants of the effects on NFs. CONCLUSION: Our study suggested that exosomal LINC00691 promoted NFs to gained the properties of CAFs depending on JAK2/STAT3 signaling pathway as a potential diagnostic biomarker for GC.