An early-onset specific polygenic risk score optimizes age-based risk estimate and stratification of prostate cancer: population-based cohort study.

BACKGROUND: Early-onset prostate cancer (EOPC, ≤ 55 years) has a unique clinical entity harboring high genetic risk, but the majority of EOPC patients still substantial opportunity to be early-detected thus suffering an unfavorable prognosis. A refined understanding of age-based polygenic risk score (PRS) for prostate cancer (PCa) would be essential for personalized risk stratification. METHODS: We included 167,517 male participants [4882 cases including 205 EOPC and 4677 late-onset PCa (LOPC)] from UK Biobank. A General-, an EOPC- and an LOPC-PRS were derived from age-specific genome-wide association studies. Weighted Cox proportional hazard models were applied to estimate the risk of PCa associated with PRSs. The discriminatory capability of PRSs were validated using time-dependent receiver operating characteristic (ROC) curves with additional 4238 males from PLCO and TCGA. Phenome-wide association studies underlying Mendelian Randomization were conducted to discover EOPC linking phenotypes. RESULTS: The 269-PRS calculated via well-established risk variants was more strongly associated with risk of EOPC [hazard ratio (HR) = 2.35, 95% confidence interval (CI) 1.99-2.78] than LOPC (HR = 1.95, 95% CI 1.89-2.01; I2 = 79%). EOPC-PRS was dramatically related to EOPC risk (HR = 4.70, 95% CI 3.98-5.54) but not to LOPC (HR = 0.98, 95% CI 0.96-1.01), while LOPC-PRS had similar risk estimates for EOPC and LOPC (I2 = 0%). Particularly, EOPC-PRS performed optimal discriminatory capability for EOPC (area under the ROC = 0.613). Among the phenomic factors to PCa deposited in the platform of ProAP (Prostate cancer Age-based PheWAS; https://mulongdu.shinyapps.io/proap ), EOPC was preferentially associated with PCa family history while LOPC was prone to environmental and lifestyles exposures. CONCLUSIONS: This study comprehensively profiled the distinct genetic and phenotypic architecture of EOPC. The EOPC-PRS may optimize risk estimate of PCa in young males, particularly those without family history, thus providing guidance for precision population stratification.

Differences in gut microbiota and its metabolic function among different fasting plasma glucose groups in Mongolian population of China.

BACKGROUND: Many studies reported the association between gut microbiota and type 2 diabetes mellitus (T2D), but it is still unclear which bacterial genus plays a key role and how the metabolic function of gut microbiota changes in the occurrence and development of T2D. Besides, there is a high diabetic prevalence in Mongolian population, which may be partly affected by their high calorie diet. This study identified the main bacterial genus influencing T2D in Mongolian population, and analyzed the changes of metabolic function of gut microbiome. The association between dietary factors and the relative abundance of main bacterial genus and its metabolic function was also studied. METHODS: Dietary surveys and gut microbiota test were performed on 24 Mongolian volunteers that were divided into T2D (6 cases), PRET2D (6 cases) and Control group (12 cases) according to fasting plasma glucose (FPG) values. The relative abundance and metabolic function of gut microbiome from their fecal samples were measured by metagenomic analysis. Statistic method was used to evaluate the association between dietary factors and the relative abundance of the main bacterial genus or its metabolic function. RESULTS: This study found that the Clostridium genus may be one of the key bacterial genera affecting the process of T2D. First, the relative abundance of Clostridium genus was significantly different among the three groups. Second, there was a higher relative abundance of metabolic enzymes of gut bacteria in PRET2D and T2D group than that in Control group. Third, a strong correlation between Clostridium genus and many metabolic enzymes was uncovered, many of which may be produced by the Clostridium. Last, carotene intake daily was negatively correlated with the Clostridium but positively correlated with tagaturonate reductase catalyzing interconversions of pentose and glucuronate. CONCLUSIONS: The gut Clostridium genus may play an important role in the development of T2D and it could be a potential biomarker for T2D in Mongolian population. Meanwhile, the metabolic function of gut bacteria has changed during the early stage of T2D and the changes in carbohydrate, amino acid, lipid or energy metabolism of Clostridium genus may play a critical role. In addition, the carotene intake may affect reproduction and metabolic function of Clostridium genus.

[Hyperuricemia among Mongolian adults and the related factors in Inner Mongolia Autonomous Region from 2018 to 2020].

OBJECTIVE: To understand the epidemiological characteristics of hyperuricemia(HUA) in Mongolian adults in Inner Mongolia Autonomous Region, and to explore the related factors. METHODS: Using multi-stage stratified and population proportional cluster random sampling investigated 2301 Mongolian population aged 18 and older living in Inner Mongolia Autonomous Region from August 2018 to August 2020. The participant general demographic data, personal life and behavior history and diet were collected, and participant physical examination and blood biochemical tests were performed. The prevalence of HUA was counted, and the risk factors were analyzed by Logistic regression analysis and decision tree model. RESULTS: The prevalence rate of HUA in Mongolian adult population was 19.74%, and the standardized prevalence rate was 21.07%. Male(26.3%) was higher than female(15.6%), and there were significant differences in the prevalence rate among populations with different height, weight, occupation, education level and regions(P<0.05), Logistic regression analysis showed that the occurrence of HUA and overweight and obesity(OR=2.002, 95%CI 1.519-2.638), and dyslipidemia(OR=1.620, 95%CI 1.271-2.064), abnormal blood glucose(OR=1.563, 95%CI 1.195-2.046), pork(OR=1.231, 95%CI 1.139-1.330), mutton(OR=1.287, 95%CI 1.179-1.404), poultry meat(OR=1.111, 95%CI 1.024-1.206), alcohol drinking alcohol(OR=1.145, 95%CI 1.008-1.302) showed a positive correlation. It was negatively associated with women(OR=0.641, 95%CI 0.498-0.827), manual labor(OR=0.629, 95%CI 0.477-0.829), beans and their products(OR=0.889, 95%CI 0.811-0.976), milk and milk intake(OR=0.854, 95%CI 0.785-0.921). The result of decision tree model showed that pork intake, overweight and obesity, dyslipidemia, mutton intake and gender were the variables affecting HUA. CONCLUSION: The prevalence of HUA in the Mongolian population was relatively high, and the gender, occupation, body mass index, blood lipid, blood glucose and some dietary factors were all associated with HUA.

Alcohol Advertisements, Hazard Warnings, Knowledge of Alcohol-Related Harm and Health-Profession Students' Drinking in Inner Mongolia.

Background: Consumption of alcohol among adults in Inner Mongolia is high even among health professionals. Little is known of the alcohol consumption patterns of health-profession students. Objectives: To assess the association of knowledge of alcohol-related harm (KAH), and exposure to media-based promotional alcohol sales advertisements (PASA) and alcohol hazard warnings (AHW) with drinking frequency of health-profession university students. Methods: Health-profession students (N = 1277) in the Medical University of Inner Mongolia were interviewed in 2017 regarding their alcohol drinking frequency, KAH, and exposure to PASA and AHW. Multinomial logistic regression was used to evaluate associations between exposure and drinking frequency. Results: Overall, 9% were nondrinkers, 35% occasional drinkers, and 56% frequent drinkers. Females were slightly less commonly drinkers but more commonly frequent drinkers. The prevalence of drinking decreased with age. Mongolians were more commonly frequent drinkers than Han. A majority of students had low KAH. Exposure to PASA was more common among drinkers, and exposure to AHW more common among nondrinkers. The main reason for drinking was social gathering. The relative probability of being an occasional or frequent drinker was lower among older students, those with higher KAH, and those exposed to AHW on television and internet but higher among those exposed to PASA in mini-supermarkets on campus. Conclusions: Students' drinking behavior was associated with low KAH and exposure to alcohol advertisements and warning media messages. Prevalence of frequent drinking might be reduced by wider use of AHW on internet and television and improving the level of knowledge of alcohol-related harm.

Downregulation of miR-33b promotes non-small cell lung cancer cell growth through reprogramming glucose metabolism miR-33b regulates non-small cell lung cancer cell growth.

Glucose metabolism is a common target for cancer regulation and microRNAs (miRNAs) are important regulators of this process. Here we aim to investigate a tumor-suppressing miRNA, miR-33b, in regulating the glucose metabolism of non-small cell lung cancer (NSCLC). In our study, quantitative real-time polymerase chain reaction (qRT-PCR) showed that miR-33b was downregulated in NSCLC tissues and cell lines, which was correlated with increased cell proliferation and colony formation. Overexpression of miR-33b through miR-33b mimics transfection suppressed NSCLC proliferation, colony formation, and induced cell-cycle arrest and apoptosis. Meanwhile, miR-33b overexpression inhibited glucose metabolism in NSCLC cells. Luciferase reporter assay confirmed that miR-33b directly binds to the 3'-untranslated region of lactate dehydrogenase A (LDHA). qRT-PCR and Western blot analysis showed that miR-33b downregulated the expression of LDHA. Moreover, introducing LDHA mRNA into cells over-expressing miR-33b attenuated the inhibitory effect of miR-33b on the growth and glucose metabolism in NSCLC cells. Taken together, these results confirm that miR-33b is an anti-oncogenic miRNA, which inhibits NSCLC cell growth by targeting LDHA through reprogramming glucose metabolism.

Delphinidin-induced autophagy protects pancreatic ß cells against apoptosis resulting from high-glucose stress via AMPK signaling pathway.

Hyperglycemia, a diagnostic characteristic of diabetes mellitus, is detrimental to pancreatic ß cells. Delphinidin, a member of the anthocyanin family, inhibits glucose absorption, increases glucagon-like peptide-1 (GLP-1) secretion, and improves insulin secretion in diabetes. However, whether delphinidin plays a protective role in pancreatic ß-cell mass and function is not clear. In this study, delphinidin was found to decrease the high-glucose-induced apoptosis of RIN-m5F pancreatic ß cells. In addition, delphinidin induced autophagy in RIN-m5F cells under the normal and high-glucose conditions, while 3-methyladenine (3-MA) inhibition of autophagy significantly diminished the protective role of delphinidin against high-glucose-induced apoptosis of pancreatic ß cells. Delphinidin also decreased the level of cleaved caspase 3 and increased the phosphorylation level of AMP-activated protein kinase α (AMPKα) Thr172. Compound C, an AMPK inhibitor, was found to decrease the ratio of LC3-II/LC3-I, and the apoptotic rate of high-glucose-injured cells was increased after treatment with delphinidin, indicating that delphinidin attenuated the negative effects of high-glucose stress to cells. In conclusion, our data demonstrate that delphinidin protects pancreatic ß cells against high-glucose-induced injury by autophagy regulation via the AMPK signaling pathway. These findings might shed light on the underlying mechanisms of diabetes and help improve the prevention and therapy of this common disease.

TRPM2 exacerbates airway inflammation by regulating oxidized-CaMKâ ¡ in allergic asthma.

Background: Airway epithelial cells play important roles in allergic asthma. Transient receptor potential melastatin-related 2 (TRPM2) and oxidized Ca2+/calmodulin-dependent protein kinase Ⅱ (ox-CaMKⅡ) participate in the airway inflammation. This study aimed to analyze the effects of TRPM2 on ox-CaMKⅡ in the airway epithelial cells during allergic asthma. Methods: BEAS-2B cells were treated with different dose of IL-13 (0, 5, 10, 20 ng/mL) for 24 h to analyze the changes of TRPM2 and ox-CaMKⅡ protein. Cells expressing different level of TRPM2 were obtained by transfection of TRPM2 siRNA or TRPM2-short cDNA. The transfected cells were treated with 10 ng/mL of IL-13 to analyze the effects of TRPM2 on the ox-CaMKⅡ. A CaMKⅡ inhibitor KN-93 was used to confirm the effects of TRPM2 on levels of ox-CaMKⅡ, p-MEK and p-ERK in the IL-13-treated BEAS-2B cells. Wild-type (WT) mice and TRPM2-knockout (TRPM2-/-) mice were induced by ovalbumin (OVA) to compare the differences of inflammation, levels of ox-CaMKII, p-MEK and p-ERK in airways. Results: Cell viability was clearly decreased by the 20 ng/mL of IL-13. The levels of TRPM2 and ox-CaMKII protein in cells were increased with increasing doses of IL-13. Transfection of TRPM2 siRNA or TRPM2-short cDNA respectively decreased or increased the levels of ox-CaMKⅡ in the IL-13-stimulated cells. The results of KN-93 treatment were similar to the results of TRPM2 siRNA transfection, that the levels of ox-CaMKⅡ, p-MEK and p-ERK were significantly decreased in the IL-13-treated cells. Compared with the OVA-induced WT mice, levels of inflammation, ox-CaMKⅡ, p-MEK and p-ERK in the airways were significantly weakened in the OVA-induced TRPM2-/- mice. Conclusions: TRPM2 plays a vital role in regulating ox-CaMKⅡ in airway epithelial cells during allergic asthma.

Including the rare cubane cluster cobalt coordination polymer as the fluorescent sensing material for selectively and sensitively detecting the nitrofurantoin antibiotic.

More and more attention has been paid to food safety. Due to the overuse and misuse of antibiotics, the problem of antibiotic residues in animal food is one of the important challenges to ensure food safety. The development of a feasible strategy to detect antibiotic residues in animal food has become desirable. In this paper, we creatively synthesize a water-stable fluorescence sensing material, namely, Co(Ⅱ)-Coordination polymer [Co2(CA) (L)0.5 (H2O)3] n (L = 1,4-bis(imidazole-1-ylmethyl) benzene, CA= Citric acid). The single crystal X-ray diffraction shows that it crystallizes in tetragonal space group I-4. It is worth mentioning that there exists the rare Co4(µ3-O)4 cubane cluster structure and Co8 cluster units. Those adjacent Co8 cluster units are connected into an infinite two-dimensional net structure by four flexible bridged L ligands. Finally, the Co(Ⅱ)-Coordination polymer (CP) further develops into the three-dimensional supramolecular structure via the hydrogen bonds of O-H⋯O and C-H⋯O. It could selectively detect the antibiotic-nitrofurantoin (NFT) residue by way of fluorescence quenching, Co-CP for the detection of NFT shows broad linearity from 0 to 200 µM, with a detection limit of 0.13 µM and strong anti-interference ability. It is used to detect the NFT residual of tap water and milk with a spiked recovery of 86.35-112.47 %.

The lactate-to-albumin ratio relationship with all-cause mortality in cerebral infarction patients: analysis from the MIMIC-IV database.

Objective: To examine the association of lactate-to-albumin ratio (LAR) with 30-day and 90-day mortality in patients with cerebral infarction admitted to the intensive care unit (ICU). Methods: In this retrospective observational study, 1,089 patients with cerebral infarction were recruited. The concentration of blood lactate and serum albumin on the first day of ICU admission were recorded. The relationship between LAR levels and mortality was evaluated through univariate and multivariate Cox regression analyses, four-knot multivariate restricted cubic spline regression, and Kaplan-Meier (KM) curves. Results: The overall 30-day and 90-day mortality rates in the entire cohort were 27.3 and 35.8%, respectively. KM analysis revealed a significant relationship between high LAR index and the risk of all-cause mortality (log-rank p < 0.001). Furthermore, multivariate Cox proportional risk analysis showed that the LAR index independently predicted the risk of 30-day mortality (HR: 1.38, 95% CI 1.15-1.64, p = 0.004) and 90-day mortality (HR: 1.53, 95% CI 1.32-1.77, p < 0.001) in the study population. Furthermore, a higher LAR exceeding 0.53 was positively correlated with the risk of 30-day and 90-day mortalities. Subsequent subgroup analyses demonstrated that LAR could predict the primary outcome. Conclusion: In summary, the LAR index is a reliable and independent predictor of increased mortality among critically ill patients suffering from cerebral infarction. Nonetheless, there is a need for additional comprehensive prospective studies to validate these findings.

Interplay between Catalyst Corrosion and Homogeneous Reactive Oxygen Species in Electrochemical Ozone Production.

Electrochemical ozone production (EOP), a six-electron water oxidation reaction, offers promising avenues for creating value-added oxidants and disinfectants. However, progress in this field is slowed by a dearth of understanding of fundamental reaction mechanisms. In this work, we combine experimental electrochemistry, spectroscopic detection of reactive oxygen species (ROS), oxygen-anion chemical ionization mass spectrometry, and computational quantum chemistry calculations to determine a plausible reaction mechanism on nickel- and antimony-doped tin oxide (Ni/Sb-SnO2, NATO), one of the most selective EOP catalysts. Antimony doping is shown to increase the conductivity of the catalyst, leading to improved electrochemical performance. Spectroscopic analysis and electrochemical experiments combined with quantum chemistry predictions reveal that hydrogen peroxide (H2O2) is a critical reaction intermediate. We propose that leached Ni4+ cations catalyze hydrogen peroxide into solution phase hydroperoxyl radicals (•OOH); these radicals are subsequently oxidized to ozone. Isotopic product analysis shows that ozone is generated catalytically from water and corrosively from the catalyst oxide lattice without regeneration of lattice oxygens. Further quantum chemistry calculations and thermodynamic analysis suggest that the electrochemical corrosion of tin oxide itself might generate hydrogen peroxide, which is then catalyzed to ozone. The proposed pathways explain both the roles of dopants in NATO and its lack of stability. Our study interrogates the possibility that instability and electrochemical activity are intrinsically linked through the formation of ROS. In doing so, we provide the first mechanism for EOP that is consistent with computational and experimental results and highlight the central challenge of instability as a target for future research efforts.

Probiotic Characteristics and Anti-Inflammatory Effects of Limosilactobacillus fermentum 664 Isolated from Chinese Fermented Pickles.

Limosilactobacillus fermentum (L. fermentum) is widely used in industrial food fermentations, and its probiotic and health-promoting roles attracted much attention in the past decades. In this work, the probiotic potential of L. fermentum 664 isolated from Chinese fermented pickles was assessed. In addition, the anti-inflammatory properties and mechanisms were investigated using lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Results indicated that L. fermentum 664 demonstrated excellent acid and bile salt tolerance, adhesion capability, antimicrobial activity, and safety profile. L. fermentum 664 downregulated the release of inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and cyclooxygenase-2 (COX-2) stimulated with LPS. Moreover, L fermentum 664 inhibited the nuclear translocation of the nuclear factor κB (NF-κB) and the activation of mitogen-activated protein kinases (MAPKs) induced by LPS. This action was associated with a reduction in reactive oxygen species (ROS) levels and an enhanced expression of heme oxygenase-1 (HO-1) protein. Additionally, whole genome sequencing indicated that L. fermentum 664 contained genes that encode proteins with antioxidant and anti-inflammatory functions, including Cytochrome bd ubiquinol oxidase subunit I (CydA), Cytochrome bd ubiquinol oxidase subunit II (CydB), and NAD(P)H dehydrogenase quinone 1 (NQO1). In conclusion, our study suggested that L. fermentum 664 has the potential to become a probiotic and might be a promising strategy for the prevention of inflammation.

[An in vitro self-ligation-based method for constructing infectious DNA clone of porcine circovirus type 2].

The aim of this study was to establish a rapid method for constructing infectious clones of porcine circovirus type 2 (PCV2). In this study, we constructed circular infectious clones of PCV2 by seamless cloning technology, using the clinically isolated strain PCV2-LX as a template. Meanwhile, this method was compared with the conventional restriction-ligation approach, focusing on the in vitro circularization (self-ligation) process of the genome and the growth characteristics of rescued viruses. The results showed that this method eliminates the need to analyze and introduce restriction endonuclease sites, thus avoiding the complexities associated with traditional restriction enzyme-based cloning steps. It offers a simple and rapid operation, enabling more efficient editing of the PCV2 genome. The infectious clones constructed using this method could be successfully rescued through liposome transfection, resulting in the production of recombinant viruses that could be stably passaged. Moreover, the recombinant viruses rescued by this method exhibited enhanced proliferative capacity in PK-15 cells and 3D4/31 cells (immortalized porcine alveolar macrophages). In conclusion, this study has established a novel reverse genetics system for PCV2, providing a new strategy for the development of PCV2 genetic engineering vaccines. Additionally, it serves as a reference for the construction of infectious clones for other emerging circoviruses such as PCV3 and PCV4.

Dual modal improved enzyme-linked immunosorbent assay for aflatoxin B1 detection inspired by the interaction of amines with Prussian blue nanoparticles.

This work reports an improved enzyme-linked immunosorbent assay (ELISA) via the interaction between prussian blue nanoparticles (PBNPs) and amines for aflatoxin B1 (AFB1) detection. The effect of different amines on the structure and properties of PBNPs was systematically investigated. Amines with pKb < 7, like ethylenediamine (EDA), can decompose structure of PBNPs, leading to the reduction of extinction coefficient and photothermal effect. Whereas, amines with large pKb > 7, such as o-phenylenediamine (OPD), could undergo catalytic oxidation by PBNPs, resulting in the production of fluorescent and colored oxidation products. Accordingly, EDA and OPD were used to construct improved ELISA. Specifically, silica nanoparticles, on which AFB1 aptamer and amino binding agent (ethylenediaminetetraacetic acid disodium salt, EDTA•2Na) were previously assembled via carboxyl-amino linkage, are anchored to microplates by AFB1 and antibody. EDA concentration can be regulated by EDTA•2Na to affect extinction coefficient and photothermal effect of PBNPs, thereby achieving visual colorimetric and portable photothermal signal readout (Model 1). OPD concentration can also be controlled by EDTA•2Na, thus generating colorimetric and ultrasensitive fluorescent signals through PBNPs catalysis (Model 2). The proposed strategy not only opens new avenue for signal readout mode of biosensing, but also provides universal technique for hazards.

Genetic variant in a BaP-activated super-enhancer increases prostate cancer risk by promoting AhR-mediated FAM227A expression.

Genetic variants in super-enhancers (SEs) are increasingly implicated as a disease risk-driving mechanism. Previous studies have reported an associations between benzo[a]pyrene (BaP) exposure and some malignant tumor risk. Currently, it is unclear whether BaP is involved in the effect of genetic variants in SEs on prostate cancer risk, nor the associated intrinsic molecular mechanisms. In the current study, by using logistic regression analysis, we found that rs5750581T>C in 22q-SE was significantly associated with prostate cancer risk (odds ratio = 1.26, P = 7.61 × 10 -5). We also have found that the rs6001092T>G, in a high linkage disequilibrium with rs5750581T>C ( r 2 = 0.98), is located in a regulatory aryl hydrocarbon receptor (AhR) motif and may interact with the FAM227A promoter in further bioinformatics analysis. We then performed a series of functional and BaP acute exposure experiments to assess biological function of the genetic variant and the target gene. Biologically, the rs6001092-G allele strengthened the transcription factor binding affinity to AhR, thereby upregulating FAM227A, especially upon exposure to BaP, which induced the malignant phenotypes of prostate cancer. The current study highlights that AhR acts as an environmental sensor of BaP and is involved in the SE-mediated prostate cancer risk, which may provide new insights into the etiology of prostate cancer associated with the inherited SE variants under environmental carcinogen stressors.

Benzo[a]pyrene exposure affects colorectal cancer susceptibility by regulating ERß-mediated LINC02977 transcription.

Environmental pollutants known as polycyclic aromatic hydrocarbons (PAHs) are produced through the incomplete combustion of organic material. While PAHs have been investigated as genotoxicants, they can also operate through nongenotoxic pathways in estrogen-dependent malignancies, such as breast, cervical and ovarian cancer. However, whether PAHs induce colorectal cancer (CRC) risk through estrogenic effects is still illusive. Here, we systematically investigated the abnormal expression and activation of estrogen receptor beta (ERß) regulated by PAHs in CRC as well as the underlying mechanisms of ERß-mediated CRC risk. Based on the 300 plasma samples from CRC patients and healthy controls detected by GC-MS/MS, we found that the plasma concentrations of benzo[a]pyrene (BaP) were significantly higher in CRC cases than in healthy controls, with significant estrogenic effects. Moreover, histone deacetylase 2 (HDAC2)-induced deacetylation of the promoter decreases ERß expression, which is associated with poor overall survival and advanced tumor stage. The study also revealed that BaP and estradiol (E2) had different carcinogenic effects, with BaP promoting cell proliferation and inhibiting apoptosis, while E2 had the opposite effects. Additionally, this study mapped ERß genomic binding regions by performing ChIP-seq and ATAC-seq and identified genetic variants of rs1411680 and its high linkage disequilibrium SNP rs6477937, which were significantly associated with CRC risk through meta-analysis of two independent Chinese population genome-wide association studies comprising 2,248 cases and 3,173 controls and then validation in a large-scale European population. By integrating data from functional genomics, we validated the regulatory effect of rs6477937 as an ERß binding-disrupting SNP that mediated allele-specific expression of LINC02977 in a long-range chromosomal interaction manner, which was found to be highly expressed in CRC tissues. Overall, this study suggests that the different active effects on ERß by PAHs and endogenous E2 may play a crucial role in the development and progression of CRC and highlights the potential of targeting ERß and its downstream targets for CRC prevention and treatment.

Correlations of SDF-1ɑ and XRCC1 gene polymorphisms with the risk of renal cancer development and bioinformatics studies of SDF-1α and XRCC1 and the prognosis of renal cancer.

To study the relationships between stromal cell-derived factor-1 (SDF-1ɑ) and renal cell carcinoma (RCC) susceptibility and the presence of single nucleotide polymorphisms in the human X-ray cross-complementary repair gene (XRCC1). Compare SDF-1 based on RCC related data in the TCGA database α, The expression difference of XRCC1 between RCC tissue and normal tissue; Collect 166 newly diagnosed RCC cases and 166 healthy individuals who underwent physical examinations during the same period, and detect genotype using iMLDR method. The results The rs1801157 locus (C:T) of the SDF-1α gene was not significantly associated with the pathohistological type, the rs1799782 locus (G:A) of the XRCC1 gene was associated with the pathohistological type of RCC, and there were interactions between rs1799782 and smoking, alcohol consumption, pesticide exposure, hair dye, and urine holding. The rs1799782 locus of the XRCC1 gene may be a key factor in the pathogenesis and pathological development of RCC. High SDF-1ɑ expression is a protective factor for the overall survival of patients with RCC, and SDF-1ɑ and XRCC1 may be important for the treatment of RCC.

Meta-analysis of the accuracy for RASSF1A methylation in bronchial aspirates for the diagnosis of lung cancer.

OBJECTIVE: To establish the diagnostic accuracy of RASSF1A (Ras association domain family 1 isoform) methylation using bronchial aspirates as an auxiliary method for diagnosing lung cancer through a systematic review and meta-analysis. METHODS: Studies published prior to October 30, 2022, were retrieved from the Embase, PubMed, Web of Science, and Wan Fang databases using the keywords "lung cancer", "RASSF1A", "methylation", and "bronchial aspirates". A fixed or random effect model was used to calculate the combined sensitivity, specificity, positive likelihood ratios (LR), negative LR, diagnostic odds ratio (DOR), along with the respective 95% confidence intervals (CIs) and the area under the curve (AUC) with Q index. The threshold effect was defined by using the Spearman correlation coefficient, and the Deeks funnel plot was generated to evaluate publication bias. RESULTS: Among the 12 trials that met the inclusion criteria, a total of 2388 participants were involved. The pooled results for the diagnosis of lung cancer were as follows, when compared to the pathological diagnosis: sensitivity of 0.47 (95% CI: 0.45-0.50), specificity of 0.96 (95% CI: 0.95-0.97), positive LR of 12.18 (95% CI: 8.96-16.55), negative LR of 0.56 (95% CI: 0.52-0.61), DOR of 24.05 (95% CI: 17.29-33.47), and AUC of 0.78 (Q index = 0.72), respectively. The sensitivity of the RASSF1A methylation assay was relatively low in a detailed subgroup analysis, fluctuating between 0.39 and 0.90, indicating a limitation in its diagnostic value for lung cancer. The RASSF1A methylation assay, on the other hand, demonstrated excellent specificity, suggesting a high exclusion value. Of note, the diagnostic sensitivity, specificity, DOR, and AUC for small cell lung cancer were 0.90 (0.84-0.94), 0.95 (0.94-0.97), 249.5 (103.94-598.8), and 0.98, respectively, showing that RASSF1A methylation was a promising biomarker for diagnosing small cell lung cancer with both high diagnostic and exclusion value. Furthermore, RASSF1A methylation using bronchial washings and bronchial aspirates showed a high AUC of 0.998 and 0.93, respectively, indicating excellent diagnostic performance. CONCLUSIONS: The methylation of RASSF1A in bronchial aspirates demonstrated a high level of diagnostic accuracy and has the potential to be a valuable supplementary diagnostic method, especially for identifying small cell lung cancer.

Analysis of Crack Propagation Behaviors in RPV Dissimilar Metal Welded Joints Affected by Residual Stress.

In severe service environments, the presence of high local residual stress, significant organizational gradient, and nonlinear changes in material properties often leads to stress corrosion cracking (SCC) in dissimilar metal welded (DMW) joints. To accurately predict the crack growth rate, researching the initiation and propagation behavior of SCC cracks in DMW joints under residual stress (RS) is one of the most important methods to ensure the safe operation of nuclear power plants. Using the extended finite element method (XFEM), the crack propagation behaviors in DMW joints under different RS states are predicted and compared. The effects of RS, crack location, and initial crack length on crack propagation behavior are investigated. The crack in a DMW joint without RS deflects to the material of low yield strength. High residual stress urges the crack growing direction to deflect toward the material of high yield strength. Young's modulus has little impact on the crack deflection paths. The distance between the specimen symmetric line and the boundary line has little effect on the crack initiation and propagation within the RS field. A long initial crack is more likely to initiate and propagate than a short crack. To a long crack and the crack that is far from the interface of two materials, the impact of residual stress on the crack propagation path is significant when it is located in a material with high yield strength, while when the initial crack is located in the material with low yield strength, RS has a great influence on the deflection of a short crack growth direction on the condition that the crack is adjacent to the interface.

Sequential release of vascular endothelial growth factor-A and bone morphogenetic protein-2 from osteogenic scaffolds assembled by PLGA microcapsules: A preliminary study in vitro.

Bone regeneration is a complex process sequentially regulated by multiple cytokines at different stages. Vascular endothelial growth factor-A (VEGF-A) and bone morphogenetic protein-2 (BMP-2) are the two most important factors involved in this process, and the combination of the two can achieve better bone regeneration by coupling angiogenesis and osteogenesis. In this study, poly(lactic-co-glycolic acid) (PLGA) microspheres with core-shell structure (microcapsules) encapsulating VEGF-A or BMP-2 were prepared by coaxial channel injection and continuous fluid technology. The sequential release of two cytokines by microcapsules with different PLGA molecular weight and shell thickness and its performance in vitro were explored. It was demonstrated that the molecular weight of PLGA significantly affected the degradation and release kinetics of microcapsules, while the thickness of the shell can regulate the release in a finer level. VEGF-A encapsulated microcapsules with low molecular weight can induce vascular endothelial cells to form lumens structures in vitro at an early stage. And BMP-2 encapsulated microcapsules could promote osteogenic differentiation, but the effect could be delayed when the microcapsules were prepared with PLGA of 150 kDa. In conclusion, the core-shell PLGA microcapsules in this study can sequentially release VEGF-A and BMP-2 at different stages to simulate natural bone repair.

Causal Associations Between Tobacco, Alcohol Use and Risk of Infectious Diseases: A Mendelian Randomization Study.

INTRODUCTION: The causal effects of smoking and alcohol use on the risk of infectious diseases are unclear, and it is hard investigate them in an observational study due to the potential confounding factors. The aim of this study was to use Mendelian randomization (MR) techniques to assess the causalities between smoking, alcohol use and risk of infectious diseases. METHODS: Univariable and multivariable MR analyses were performed using genome-wide association data for the age of initiation of regular smoking (AgeSmk, N = 341,427), smoking initiation (SmkInit, N = 1,232,091), cigarettes per day (CigDay, N = 337,334), lifetime smoking (LifSmk, N = 462,690), drinks per week (DrnkWk, N = 941,280), sepsis (N = 486,484), pneumonia (N = 486,484), upper respiratory tract infection (URTI, N = 486,484) and urinary tract infection (UTI, N = 486,214) among individuals of European ancestry. Independent genetic variants that were significantly (P < 5 × 10-8) associated with each exposure were considered as instruments. The inverse-variance-weighted method was used in the primary analysis, which was followed by a series of sensitivity analyses. RESULTS: Genetically predicted SmkInit was associated with an increased risk of sepsis (OR 1.353, 95% CI 1.079-1.696, P = 0.009), pneumonia (OR 1.770, 95% CI 1.464-2.141, P = 3.8 × 10-9) and UTI (OR 1.445, 95% CI 1.184-1.764, P = 3 × 10-4). Moreover, genetically predicted CigDay was associated with a higher risk of sepsis (OR 1.403, 95% CI 1.037-1.898, P = 0.028) and pneumonia (OR 1.501, 95% CI 1.167-1.930, P = 0.00156). Furthermore, genetically predicted LifSmk was associated with an increased risk of sepsis (OR 2.200, 95% CI 1.583-3.057, P = 2.63 × 10-6), pneumonia (OR 3.462, 95% CI 2.798-4.285, P = 3.28 × 10-30), URTI (OR 2.523, 95% CI 1.315-4.841, P = 0.005) and UTI (OR 2.036, 95% CI 1.585-2.616, P = 3.0 × 10-8). However, there was no significant causal evidence for genetically predicted DrnkWk in sepsis, pneumonia, URTI or UTI. Multivariable MR analyses and sensitivity analyses showed that the above results for causal association estimations were robust. CONCLUSION: In this MR study, we demonstrated the causal association between tobacco smoking and risk of infectious diseases. However, no evidence was found to support causality between alcohol use and the risk of infectious diseases.