Two Mn(II)-Bridged Silverton-Type [UMo12O42]8- Polyoxometalates with Catalytic Activity for the Synthesis of Pyrazoles.

Two Mn(II)-bridged Silverton-type {UMo12O42}-based polyoxomolybdates with different three-dimensional structures, Na6(H2O)12[Mn(UMo12O42)] (NaMn) and (NH4)2[K2Na6(µ4-O)2(H2O)1.2Mn(UMo12O42)]·4.6H2O (KMn), were hydrothermally synthesized and further characterized, demonstrating a feasible strategy for the assembly of Silverton-type polyoxomolybdates. Additionally, NaMn is demonstrated to be a good heterogeneous catalyst in the condensation cyclization reaction of hydrazines and 1,3-diketones, and a range of valuable pyrazoles were produced in up to 99% yield.

Two Different Three-Dimensional Uranium-Containing Polymolybdates Based on Zn(II) for the Heterogeneous Catalytic Construction of C-N Bond.

The introduction of transition metal (TM) ions into polyoxometalates (POMs) cannot only bring about interesting structural diversities but also enable changes in properties. However, TM-containing Silverton-type polyoxomolybdates are still lacking in terms of structural diversity and application development. Herein, two Zn(II)-containing Silverton-type {UMo12O42}-based polyoxomolybdates, H1.89Na4.11(H2O)9Zn[UMo12O42]·4.5H2O (Zn-1) and H1.8Na4.2(H2O)12Zn[UMo12O42] (Zn-2) were hydrothermally synthesized, demonstrating a practical strategy to assembly of TM-containing Silverton-type POMs. Zn-1 is proven to be an excellent and recyclable heterogeneous catalyst in cross-dehydrogenation coupling of 1,4-naphthoquinones with amines reactions, and a series of 2-amino-1,4-naphthoquinones with potential medicinal value have been constructed.

Three Polyoxometalate-Based Ag-Organic Compounds as Heterogeneous Catalysts for the Synthesis of Benzimidazoles.

Three new POM-based compounds, with formulae [Na0.63Ag3(Htba)2.37(tba)0.63(H2O)2(PMo12O40)]·4H2O (Ag3PMo), [Ag4(Htba)4(H2O)2(PMo12O40)](NO3)·H2O (Ag4PMo), and [Ag3(Htba)2(tba)(PW12O40)0.5](NO3)0.5·13H2O (Ag3PW), were prepared with a 3-(4H-1,2,4-triazol-4-yl)benzoic acid (Htba) ligand, Keggin-type anions ([PMo12O40]3-/[PW12O40]3-), and a silver ion (Ag+). The structural features of these compounds are particularly different from the multinuclear subunits, which are [Ag3(tba)3] clusters in Ag3PMo, [Ag4(tba)3] chains in Ag4PMo, and [Ag3(tba)3]2 clusters in Ag3PW, connected by multidonor atom tba ligands and Ag+ ions. Meanwhile, in these compounds, polyanions act as polydentate ligands to link adjacent Ag-tba metal-organic units and expand their spatial dimensions. These compounds, as heterogeneous catalysts, exhibit high stability and excellent catalytic activity to construct benzimidazoles. Ag3PMo could efficiently catalyze the condensation of benzene-1,2-diamines and benzaldehydes and produce benzimidazoles in good yields. In addition, Ag3PMo could be reused up to 7 times and was suitable for gram-scale reactions.

High Cytomegalovirus Viral Load Is Associated With 182-Day All-Cause Mortality in Hospitalized People With Human Immunodeficiency Virus.

BACKGROUND: Cytomegalovirus (CMV) infection is associated with increased mortality in persons with HIV (PWH). It is less clear whether CMV infection is still associated with mortality when routinely screened and adequately treated. METHODS: This retrospective cohort study recruited 1003 hospitalized adults with HIV with CD4 cell counts <200 cells/µL from May 2017 to June 2021. Blood CMV DNA was routinely measured and CMV DNAemia was treated if end-organ disease occurred. CMV viral load was categorized into below the limit of quantification (BLQ; <500 IU/mL), low viral load (LVL; 500-10 000 IU/mL), and high viral load (HVL; ≥10 000 IU/mL) groups. We compared the 182-day all-cause mortality among different groups. RESULTS: The median (IQR) CD4 cell count of patients was 33 (13-84) cells/µL. The prevalence of CMV DNAemia was 39.8% (95% CI: 36.7-42.9%) and was significantly associated with CD4 cell count. The 182-day all-cause mortality was 9.9% (95% CI: 8.0-11.7%). Univariable analysis showed that, compared with BLQ, LVL and HVL were associated with 1.73-fold and 3.81-fold increased risks of mortality, respectively (P = .032 and P < .001). After adjustment for predefined confounding factors, HVL but not LVL was still associated with increased risk of mortality (adjusted hazard ratio: 2.63; 95% CI: 1.61-4.29; P < .001). However, for patients on effective antiretroviral therapy, the impact of HVL on 182-day mortality was not significant (P = .713). CONCLUSIONS: High CMV viral load in hospitalized PWH was associated with higher mortality, even when identified early by screening. Optimalization of the management for those patients needs to be explored in future studies.

Emergence of two AcrB substitutions conferring multidrug resistance to Salmonella spp.

AcrAB-TolC is a major tripartite multidrug efflux pump conferring resistance to a wide variety of compounds in Gram-negative pathogens. Many AcrB mutants have been constructed through site-directed mutagenesis to probe the mechanism of AcrB function in antibiotic resistance. However, much less is known about the actual drug resistance related mutants that naturally occur in clinically isolated pathogens. Here, we report two novel AcrB substitutions, M78I and P319L, in clinically isolated Salmonella strains with high-level ciprofloxacin resistance. Plasmids expressing the detected acrB mutations were constructed and introduced into SL1344△acrB Antimicrobial susceptibility assay showed that all AcrB M78I, AcrB P319L and AcrB M78I/319L conferred reduced susceptibilities to multiple substrates, including fluoroquinolones, erythromycin, tetracyclines, bile salts and dyes. Site-directed mutagenesis and MIC results revealed that increased hydrophobicity of M78I was one of the reasons why AcrB M78I had lower susceptibility to fluoroquinolones. Fluorescence labeling experiments suggested that the AcrB M78I substitution enhanced the binding of substrates to certain amino acid sites in the efflux pathway (e.g., site Q89, E673 and F617) and weakened the binding to other amino acids (e.g., S134 and N274). Structural modeling disclosed the increased flexibility of Leu was favorable for the functional rotation of AcrB compared to the original Pro. AcrA 319L makes the functional rotation of AcrB more flexible, this enables substrate efflux more efficiently. In order to understand the mechanism of AcrAB-TolC drug efflux well, interaction between AcrA and AcrB in the role of substrate efflux of AcrAB-TolC should be further investigated.

Systematic evaluation of narrow-sense validity of polygenic risk score for prostate cancer in a Chinese prostate biopsy cohort.

The aim of this study was to assess the narrow-sense validity of polygenic risk score (PRS) for prostate cancer (PCa) in a Chinese prostate biopsy cohort. We performed an observational prospective study with 2640 men who underwent prostate biopsy. Germline DNA samples were genotyped and PRS was calculated for each subject using 17 PCa risk-associated genetic variants. Additional GWAS data of the ChinaPCa dataset was also used to compliment the evaluation process. The mean PRS was 1.02 in patients with negative biopsy results, which met the baseline benchmark. The mean PRS was significantly higher in the PCa cases (1.32 vs. 1.02, p = 5.56 × 10-17 ). Significant dose-response associations between PRS values and odds ratios for PCa were observed. However, the raw calibration slope was 0.524 and the average bias score between the observed risk and uncorrected PRS value was 0.307 in the entire biopsy cohort. After applying a correction factor derived from a training set, the corrected calibration slope improved to 1.002 in a testing set. Similar and satisfied results were also seen in the ChinaPCa dataset and two datasets combined, while the calibration results were inaccurate when the calibration process were performed mutually between two different study populations. In conclusion, assessing the narrow-sense validity of PRS is necessary prior to its clinical implementation for accurate individual risk assessment.

Two-Fold Interpenetrated Binuclear Nickel Metal-Organic Framework as a Heterogeneous Catalyst for N-Heterocycle Synthesis.

A binuclear Ni(II)-based metal-organic framework {[Ni2(btb)1.333(H2O)3.578(py)1.422]·(DMF)(H2O)3.25}n (Nibtb) was solvothermally synthesized (H3btb = 1,3,5-tri(4-carboxylphenyl)benzene, py = pyridine, DMF = N,N-dimethylformamide). Nibtb shows a rare 2-fold interpenetrating (3,4)-connected 3D network with a point symbol of (83)4(86)3 based on binuclear Ni(II) clusters. Nibtb as a heterogeneous catalyst combines the high stability of MOFs and excellent catalytic activity of nickel, which exhibits excellent catalytic activity for the synthesis of benzimidazoles and pyrazoles under mild conditions. Moreover, the catalyst can be easily separated and reused for seven successive cycles and maintains high catalytic activity.

Impact of inactivated COVID-19 vaccines on lung injury in B.1.617.2 (Delta) variant-infected patients.

BACKGROUND: Chest computerized tomography (CT) scan is an important strategy that quantifies the severity of COVID-19 pneumonia. To what extent inactivated COVID-19 vaccines could impact the COVID-19 pneumonia on chest CT is not clear. METHODS: This study recruited 357 SARS-COV-2 B.1.617.2 (Delta) variant-infected patients admitted to the Second Hospital of Nanjing from July to August 2021. An artificial intelligence-assisted CT imaging system was used to quantify the severity of COVID-19 pneumonia. We compared the volume of infection (VOI), percentage of infection (POI) and chest CT scores among patients with different vaccination statuses. RESULTS: Of the 357 Delta variant-infected patients included for analysis, 105 were unvaccinated, 72 were partially vaccinated and 180 were fully vaccinated. Fully vaccination had the least lung injuries when quantified by VOI (median VOI of 222.4 cm3, 126.6 cm3 and 39.9 cm3 in unvaccinated, partially vaccinated and fully vaccinated, respectively; p < 0.001), POI (median POI of 7.60%, 3.55% and 1.20% in unvaccinated, partially vaccinated and fully vaccinated, respectively; p < 0.001) and chest CT scores (median CT score of 8.00, 6.00 and 4.00 in unvaccinated, partially vaccinated and fully vaccinated, respectively; p < 0.001). After adjustment for age, sex, comorbidity, time from illness onset to hospitalization and viral load, fully vaccination but not partial vaccination was significantly associated with less lung injuries quantified by VOI {adjust coefficient[95%CI] for "full vaccination": - 106.10(- 167.30,44.89); p < 0.001}, POI {adjust coefficient[95%CI] for "full vaccination": - 3.88(- 5.96, - 1.79); p = 0.001} and chest CT scores {adjust coefficient[95%CI] for "full vaccination": - 1.81(- 2.72, - 0.91); p < 0.001}. The extent of reduction of pulmonary injuries was more profound in fully vaccinated patients with older age, having underlying diseases, and being female sex, as demonstrated by relatively larger absolute values of adjusted coefficients. Finally, even within the non-severe COVID-19 population, fully vaccinated patients were found to have less lung injuries. CONCLUSION: Fully vaccination but not partially vaccination could significantly protect lung injury manifested on chest CT. Our study provides additional evidence to encourage a full course of vaccination.

Copper-Containing Polyoxometalate-Based Metal-Organic Frameworks as Heterogeneous Catalysts for the Synthesis of N-Heterocycles.

Three new polyoxometalate-based metal-organic frameworks (POMOFs) [Cu4(µ3-OH)2(tba)3(H2O)5(SiW12O40)0.5](H2SiW12O40)0.5·2.5H2O (CuSiW), [Cu3(µ3-OH)(tba)3(Htba)(H2O)2(HPMo12O40)]·7H2O (CuPMo), and [Cu4(µ3-OH)2(tba)3(H2O)3(PW12O40)0.5]2(PW12O40)·0.5H2O (CuPW) were constructed using multinuclear copper clusters, 3-(4H-1,2,4-triazol-4-yl)benzoic acid (Htba), and Keggin polyoxometalates (POMs). Different POMs regulate the formation of different multinuclear copper clusters ("boat" tetranuclear clusters in CuSiW, trinuclear clusters in CuPMo, and "chair" tetranuclear clusters in CuPW) and different topological structures of CuSiW, CuPMo, and CuPW (3-connected two-dimensional (2D) network for CuSiW, 4-connected 2D network for CuPMo, and (4,6)-connected three-dimensional network for CuPW). CuSiW, CuPMo, and CuPW as heterogeneous catalysts combine the high stability of MOFs in polar solvents and excellent catalytic activity of POMs and could be used for the synthesis of nitrogen-heterocycle compounds. The condensation cyclization reactions of 2-aminophenols/benzenesulfonyl hydrazines with 1,3-diketones produce benzoazoles and pyrazoles in good to excellent yields under the catalysis of CuPMo. Moreover, the catalyst could be reused at least for 7 runs, and this protocol was suitable for gram-scale reactions.

Genetic polymorphisms at 19q13.33 are associated with [-2]proPSA (p2PSA) levels and provide additional predictive value to prostate health index for prostate cancer.

BACKGROUND: Prostate health index (phi), a derivative of [-2]proPSA (p2PSA), has shown better accuracy than prostate-specific antigen (PSA) in prostate cancer (PCa) detection. The present study was to investigate whether previously identified PSA-associated single nucleotide polymorphisms (SNPs) influence p2PSA or phi levels and lead to potential clinical utility. METHODS: We conducted an observational prospective study with 2268 consecutive patients who underwent prostate biopsy in three tertiary medical centers from August 2013 to March 2019. Genotyping data of the 46 candidate genes with a ± 100 kb window were tested for association with p2PSA and phi levels using linear regression. Multivariable logistic regression models were performed and internally validated using repeated tenfold cross-validation. We further calculated personalized phi cutoff values based on the significant genotypes. Discriminative performance was assessed using decision curve analysis and net reclassification improvement (NRI) index. RESULTS: We detected 11 significant variants at 19q13.33 which were p2PSA-associated independent of PCa. The most significant SNP, rs198978 in KLK2 (Pcombined = 5.73 × 10-9 ), was also associated with phi values (Pcombined = 3.20 × 10-6 ). Compared to the two commonly used phi cutoffs of 27.0 and 36.0, the personalized phi cutoffs had a significant NRI for PCa ranged from 5.23% to 9.70% among men carrying variant types (all p < .01). CONCLUSION: Rs198978, is independently associated with p2PSA values, and can improve the diagnostic ability of phi for PCa using personalized cutoff values.

Ultrasensitive and Simultaneous SERS Detection of Multiplex MicroRNA Using Fractal Gold Nanotags for Early Diagnosis and Prognosis of Hepatocellular Carcinoma.

Sensitive and simultaneous detection of multiple cancer-related biomarkers in serum is essential for diagnosis, therapy, prognosis, and staging of cancer. Herein, we proposed a magnetically assisted sandwich-type surface-enhanced Raman scattering (SERS)-based biosensor for ultrasensitive and multiplex detection of three hepatocellular carcinoma-related microRNA (miRNA) biomarkers. The biosensor consists of an SERS tag (probe DNA-conjugated DNA-engineered fractal gold nanoparticles, F-AuNPs) and a magnetic capture substrate (capture DNA-conjugated Ag-coated magnetic nanoparticles, AgMNPs). The proposed strategy achieved simultaneous and sensitive detection of three miRNAs (miRNA-122, miRNA-223, and miRNA-21), and the limits of detection of the three miRNAs in human serum are 349 aM for miRNA-122, 374 aM for miRNA-223, and 311 aM for miRNA-21. High selectivity and accuracy of the SERS biosensor were proved by practical analysis in human serum. Moreover, the biosensor exhibited good practicability in multiplex detection of three miRNAs in 92 clinical sera from AFP-negative patients, patients before and after hepatectomy, recurred and relapse-free patients after hepatectomy, and hepatocellular carcinoma patients at distinct Barcelona clinic liver cancer stages. The experiment results demonstrate that our SERS-based assay is a promising candidate in clinical application and exhibited potential for the prediction, diagnosis, monitoring, and staging of cancers.

Broad- and narrow-sense validity performance of three polygenic risk score methods for prostate cancer risk assessment.

BACKGROUND: Several polygenic risk score (PRS) methods are available for measuring the cumulative effect of multiple risk-associated single nucleotide polymorphisms (SNPs). Their performance in predicting risk at the individual level has not been well studied. METHODS: We compared the performance of three PRS methods for prostate cancer risk assessment in a clinical trial cohort, including genetic risk score (GRS), pruning and thresholding (P + T), and linkage disequilibrium prediction (LDpred). Performance was evaluated for score deciles (broad-sense validity) and score values (narrow-sense validity). RESULTS: A training process was required to identify the best P + T model (397 SNPs) and LDpred model (3 011 362 SNPs). In contrast, GRS was directly calculated based on 110 established risk-associated SNPs. For broad-sense validity in the testing population, higher deciles were significantly associated with higher observed risk; Ptrend was 7.40 × 10-11 , 7.64 × 10-13 , and 7.51 × 10-10 for GRS, P + T, and LDpred, respectively. For narrow-sense validity, the calibration slope (1 is best) was 1.03, 0.77, and 0.87, and mean bias score (0 is best) was 0.09, 0.21, and 0.10 for GRS, P + T, and LDpred, respectively. CONCLUSIONS: The performance of GRS was better than P + T and LDpred. Fewer and well-established SNPs of GRS also make it more feasible and interpretable for genetic testing at the individual level.

Emergence of ciprofloxacin heteroresistance in foodborne Salmonella enterica serovar Agona.

BACKGROUND: Bacterial heteroresistance has been increasingly identified as an important phenomenon for many antibiotic/bacterium combinations. OBJECTIVES: To investigate ciprofloxacin heteroresistance in Salmonella and characterize mechanisms contributing to ciprofloxacin heteroresistance. METHODS: Ciprofloxacin-heteroresistant Salmonella were identified by population analysis profiling (PAP). Target mutations and the presence of PMQR genes were detected using PCR and sequencing. Expression of acrB, acrF and qnrS was conducted by quantitative RT-PCR. Competition ability and virulence were also compared using pyrosequencing, blue/white screening, adhesion and invasion assays and a Galleria model. Two subpopulations were whole-genome sequenced using Oxford Nanopore and Illumina platforms. RESULTS: PAP identified one Salmonella from food that yielded a subpopulation demonstrating heteroresistance to ciprofloxacin at a low frequency (10-9 to 10-7). WGS and PFGE analyses confirmed that the two subpopulations were isogenic, with six SNPs and two small deletions distinguishing the resistant from the susceptible. Both subpopulations possessed a T57S substitution in ParC and carried qnrS. The resistant subpopulation was distinguished by overexpression of acrB and acrF, a deletion within rsxC and altered expression of soxS. The resistant population had a competitive advantage against the parental population when grown in the presence of bile salts but was attenuated in the adhesion and invasion of human intestinal cells. CONCLUSIONS: We determined that heteroresistance resulted from a combination of mutations in fluoroquinolone target genes and overexpression of efflux pumps associated with a deletion in rsxC. This study warns that ciprofloxacin heteroresistance exists in Salmonella in the food chain and highlights the necessity for careful interpretation of antibiotic susceptibility.

Concept and benchmarks for assessing narrow-sense validity of genetic risk score values.

BACKGROUND: While higher genetic risk score (GRS) has been statistically associated with increased disease risk (broad-sense validity), the concept and tools for assessing the validity of reported GRS values from tests (narrow-sense validity) are underdeveloped. METHODS: We propose two benchmarks for assessing the narrow-sense validity of GRS. The baseline benchmark requires that the mean GRS value in a general population approximates 1.0. The calibration benchmark assesses the agreement between observed risks and estimated risks (GRS values). We assessed benchmark performance for three prostate cancer (PCa) GRS tests, derived from three SNP panels with increasing stringency of selection criteria, in a PCa chemoprevention trial where 714 of 3225 men were diagnosed with PCa during the 4-year follow-up. RESULTS: GRS from Panels 1, 2, and 3 were all statistically associated with PCa risk; P = 5.58 × 10-3 , P = 1 × 10-3 , and P = 1.5 × 10-13 , respectively (broad-sense validity). For narrow-sense validity, the mean GRS value among men without PCa was 1.33, 1.09, and 0.98 for Panels 1, 2, and 3, respectively (baseline benchmark). For assessing the calibration benchmark, observed risks were calculated for seven groups of men with GRS values <0.3, 0.3-0.79, 0.8-1.19, 1.2-1.49, 1.5-1.99, 2-2.99, and ≥3. The calibration slope (higher is better) was 0.15, 0.12, and 0.60, and the bias score (lower is better) between the observed risks and GRS values was 0.08, 0.08, and 0.02 for Panels 1, 2, and 3, respectively. CONCLUSION: Performance differed considerably among GRS tests. We recommend that all GRS tests be evaluated using the two benchmarks before clinical implementation for individual risk assessment.

Germline mutations in DNA repair genes are associated with bladder cancer risk and unfavourable prognosis.

OBJECTIVES: To perform a systematic evaluation of whether germline DNA repair gene mutations in bladder cancer (BCa) are associated with increased risk of BCa and aggressive disease. MATERIALS AND METHODS: Germline DNA from 98 patients with BCa was analysed for 54 DNA repair genes using a customized targeted sequencing panel. Population control data were obtained from the public databases the Exome Aggregation Consortium database and the Genome Aggregation Database. Mutation pathogenicity was annotated based on American College of Medical Genetics criteria, mutation frequencies in the general population and the ClinVar database. Mutation frequencies were compared based on case-control and case-case designs for disease risks, disease aggressiveness and outcomes. RESULTS: The frequency of pathogenic/likely pathogenic germline DNA repair gene mutations was 10.2% among patients with BCa. Within the subset of patients with carcinoma invading the bladder muscle, the frequency was 15.8%, ~2.4-fold higher than in patients with non-muscle invasive BCa (6.67%). The mutation frequency among patients with early-onset disease (at age <45 years) was ~3-fold higher than among those diagnosed after age 45 years (28.57% vs 8.79%). Mutation carriers had a significantly higher frequency of unfavourable clinical outcomes (disease recurrence or progression to metastatic BCa) than non-carriers (50.0% vs 13.64%; P = 0.013). CONCLUSION: Pathogenic and likely pathogenic mutations in DNA repair genes were associated with unfavourable prognosis of BCa.

[Preparation optimization of extract of Moringa oleifera leaves and its immune regulation effect on immunosuppressed mice].

With total flavonoid content and dry extract yield as the observation indexes, the optimal extraction conditions of Moringa oleifera leaves were determined by using single factor test and orthogonal test, and cyclophosphamide modeling method was used to establish immunosuppressed mice models, so as to investigate the effects of M. oleifera leaves extract on immune regulation in mice. The results showed that the optimal preparation conditions were as follows: extraction with 70% ethanol, material-liquid ratio 1:15, extraction temperature 80 °C, three times, 1.5 hours for each time. Under these conditions, the content of total flavonoids from M. oleifera leaves was 15.64 mg·g⁻¹, which can significantly enhance macrophage phagocytosis and immune organ index, promote the synthesis of serum immunoglobulin IgG and hemolysin, and decrease AST activity, with regulation effect on immune dysfunction.

TEX15: A DNA repair gene associated with prostate cancer risk in Han Chinese.

BACKGROUND: Both common and rare genetic variants may contribute to risk of developing prostate cancer. Genome-wide association studies (GWASs) have identified ∼100 independent, common variants associated with prostate cancer risk. However, little is known about the association of rare variants (minor allele frequency [MAF] <1%) in the genome with prostate cancer risk. METHODS: A two-stage study was used to test the association of rare, deleterious coding variants, annotated using predictive algorithms, with prostate cancer risk in Chinese men. Predicted rare, deleterious coding variants in the Illumina HumanExome-12 v1.1 beadchip were first evaluated in 1343 prostate cancer patients and 1008 controls. Significant variants were then validated in an additional 1816 prostate cancer patients and 1549 controls. RESULTS: In the discovery stage, 14 predicted rare, deleterious coding variants were significantly associated with prostate cancer risk (P < 0.01). In the confirmation stage, Q1631H in TEX15 (rs142485241), a DNA repair gene, was significantly associated with prostate cancer risk (P = 0.0069). The estimated odds ratio (OR) of the variant in the combined analysis was 3.24 (95% Confidence Interval 1.85-6.06), P = 8.81 × 10-5 . Additionally, rs28756990 (V741F) at MLH3 (P = 0.06) and rs2961144 (I126V) at OR2A5 (P = 0.065) were marginally associated with prostate cancer risk in the replication stage. CONCLUSIONS: Our study provided preliminary evidence that the rare variant Q1631H in DNA repair gene TEX15 is associated with prostate cancer risk. This finding complements known common prostate cancer risk-associated variants and suggests the possible role of DNA repair genes in prostate cancer development.

Reclassification of prostate cancer risk using sequentially identified SNPs: Results from the REDUCE trial.

BACKGROUND: Although the clinical validity of risk-associated single nucleotide polymorphisms (SNPs) for assessment of disease susceptibility has been consistently established, risk reclassification from increasing numbers of implicated risk-associated SNPs raises concern that it is premature for clinical use. Our objective is to assess the degree and impact of risk reclassification with the increasing number of SNPs. METHODS: A total of 3239 patients from the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial were included. Four genetic risk scores (GRSs) were calculated based on sets of sequentially discovered prostate cancer (PCa) risk-associated SNPs (17, 34, 51, and 68 SNPs). RESULTS: Pair-wise correlation coefficients between sets of GRSs increased as more SNPs were included in the GRS: 0.80, 0.86, and 0.95 for 17 versus 34 SNPs, 34 versus 51 SNPs, and 51 versus 68 SNPs, respectively. Using a GRS of 1.5 as a cutoff for higher versus lower risk, reclassification rates of PCa risk decreased: 14.11%, 12.04%, and 8.15% for 17 versus 34 SNPs, 34 versus 51 SNPs, and 51 versus 68 SNPs, respectively. Evolving GRSs, nevertheless, provide a tool for further refining risk assessment. When all four sequential GRSs were considered, the detection rates of PCa for men whose GRSs were consistently <1.5, reclassified, and consistently ≥1.5 were 20.8%, 29.67%, and 39.26%, respectively (Ptrend = 1.12 × 10-8 ). In comparison, the detection rates of PCa in men with negative or positive family history were 23.75% and 31.78%, respectively. CONCLUSIONS: Risk assessment using currently available SNPs is justified. Multiple GRS values from evolving sets of SNPs provide a valuable tool for better refining risk.

An evaluation study of reported pancreatic adenocarcinoma risk-associated SNPs from genome-wide association studies in Chinese population.

BACKGROUND: Previous genome-wide association studies (GWAS), and a pathway study of pancreatic ductal adenocarcinoma (PDAC) identified 14 significantly associated single nucleotide polymorphisms (SNPs) along with another 7 promising loci in European, Japanese, and Chinese descents. In this study, we aimed to evaluate the potential association of these SNPs with PDAC risk in the Chinese population. METHODS: In this Chinese population-based case-control study with 254 cases and 1200 controls, we tested 20 PDAC risk associated SNPs from previous GWAS and one SNP from a pathway-based study. RESULTS: All 21 SNPs were polymorphic in the Chinese population. Twenty SNPs were included in the final analysis after the quality check (QC). Among these SNPs, three were significantly associated with PDAC risk after Bonferroni correction (P < 2.5E-03) including rs7779540 (at 7q36.2, P = 3.89E-06, OR = 2.59, 95%CI: 1.73-3.87), rs10919791 (at 1q32.1, P = 6.07E-05, OR = 1.52, 95%CI: 1.24-1.86) and rs401681 (at 5p15.33, P = 5.15E-04, OR = 1.42, 95%CI: 1.17-1.73). Rs2255280 (at 5p13.1, P = 8.16E-03, OR = 1.31, 95%CI: 1.07-1.6) showed significant association at the p < 0.05 level. The directions of effect of these SNPs were consistent with previous studies. CONCLUSION: Four PDAC risk-associated SNPs identified in GWAS of various populations are associated with PDAC risk in the Chinese population. Information on PDAC risk-associated SNPs and their ORs may facilitate risk assessment of PDAC risk in the Chinese population.

MiR-23b controls TGF-ß1 induced airway smooth muscle cell proliferation via direct targeting of Smad3.

BACKGROUND: MicroRNAs are small yet versatile gene tuners that regulate a variety of cellular processes, including cell growth and proliferation. Here we report that miR-23b inhibited airway smooth muscle cells (ASMCs) proliferation through directly targeting of Smad3. METHODS: We obtained ASMCs by laser capture microdissection of normal and asthmatic mice lung tissues. Mice ASMCs were cultured and induced by TGF-ß1. The implication between TGF-ß1 and miR-23b in ASMCs were detected by RT-PCR. The effects of miR-23b on ASMCs proliferation and apoptosis were assessed by transient transfection of miR-23b mimics and inhibitor. The expression of Smad3 in ASMCs were detected by RT-PCR and Western blotting analysis. Dual-Luciferase Reporter Assay System will be applied to identify whether Smad3 is a target gene of miR-23b. RESULTS: TGF-ß1 and miR-23b mRNA expression of in-situ bronchial ASMCs collected by laser capture microdissection were increased in asthmatic mice compared to non-asthma controls. This is accompanied by an increase in miR-23b mRNA expression in TGF-ß1 induced ASMCs. miR-23b up-regulation significantly inhibited TGF-ß1-induced ASMCs proliferation and promoted apoptosis. MiR-23b negatively regulates the expression of Smad3 in ASMCs. Dual-Luciferase Reporter Assay System demonstrated that Smad3 was a direct target of miR-23b. CONCLUSIONS: MiR-23b may function as an inhibitor of asthma airway remodeling by suppressing ASMCs proliferation via direct targeting of Smad3.