Pace of Aging in older adults matters for healthspan and lifespan.

As societies age, policy makers need tools to understand how demographic aging will affect population health and to develop programs to increase healthspan. The current metrics used for policy analysis do not distinguish differences caused by early-life factors, such as prenatal care and nutrition, from those caused by ongoing changes in people's bodies due to aging. Here we introduce an adapted Pace of Aging method designed to quantify differences between individuals and populations in the speed of aging-related health declines. The adapted Pace of Aging method, implemented in data from N=13,626 older adults in the US Health and Retirement Study, integrates longitudinal data on blood biomarkers, physical measurements, and functional tests. It reveals stark differences in rates of aging between population subgroups and demonstrates strong and consistent prospective associations with incident morbidity, disability, and mortality. Pace of Aging can advance the population science of healthy longevity.

[Disseminated nocardiosis caused by Nocardia otitidiscaviarum in an immunocompetent host: a case report].

Nocardiosis can be caused by various Nocardia spp., including Nocardia asteroides, Nocardia brasiliensis, Nocardia cyriacigeorgica, Nocardia farcinica and Nocardia otitidiscaviarum. As compared with the other Nocardia spp., Nocardia otitidiscaviarum appears to be rare which can spread through the bloodstream and affect multiple organs. The disease is usually seen in immunocompromised patients' but may also occur in immunocompetent patients. The clinical symptoms and laboratory and imaging examinations of the disease are nonspecific.Here, we reported a case of disseminated nocardiosis caused by infection with Nocardiosis otitidiscaviarum in an immunocompetent host to improve the knowledge and diagnosis of nocardiosis.

Association between Dried Fruit Intake and DNA Methylation: A Multivariable Mendelian Randomization Analysis.

OBJECTIVES: Observational studies have reported associations between dried fruit intake and DNA methylation(DNAm). However, inherent flaws in observational study designs make them susceptible to confounding and reverse causality bias. Consequently, it is unclear whether a causal association exists. In the present study, we aimed to investigate the causal associations between dried fruit intake and DNAm. METHODS: We performed two-sample Mendelian randomization (MR) using the IEU Open GWAS database aggregated data. Forty-three single nucleotide polymorphisms (SNPs) associated with dried fruit intake as instrumental variables (IVs) were selected as exposure. DNAm outcomes include Gran (estimated granulocyte proportions); AgeAccelGrim(GrimAge acceleration); Hannum (Hannum age acceleration); IEAA(Intrinsic epigenetic age acceleration), AgeAccelPheno( PhenoAge acceleration), and DNAmPAIadjAge (DNAm-estimated plasminogen activator inhibitor-1 levels). We used the MR pleiotropy residual sum and outlier test (MRPRESSO) and Radial-MR test to identify any level of multi-effect outliers and assessed the causal effect estimates(after removing outliers). The primary causal effects were estimated using inverse-variance weighted (IVW) method and undertook sensitivity analyses using MR methods robust to horizontal pleiotropy.The direct effects of dried fruit intake on DNAm were estimated using multivariable mendelian randomization (MVMR). RESULTS: Leveraging two-sample MR analysis, we observed statistically significant associations between dried fruit intake with a lower AgeAccelGrim(ß=-1.365, 95% confidence intervals [CI] -2.266 to -0.464, PIVW=2.985×10-3) and AgeAccelPheno (ß= -1.933, 95% CI -3.068 to -0.798, PIVW=8.371×10-4). By contrast, the effects level on Gran (ß=0.008, PIVW=0.430), Hannum(ß=-0.430, PIVW=0.357), IEAA(ß=-0.184, PIVW=0.700), and DNAmPAIadjAge (ß=-1.861, PIVW=0.093) were not statistically significant. MVMR results adjusting for the potential effects of confounders showed that the causal relationship between dried fruit intake and AgeAccelGrim(ß= -1.315, 95% CI -2.373 to -0.258, PIVW=1.480×10-2) and AgeAccelPheno(ß= -1.595, 95% CI -2.987 to -0.202, PIVW=2.483×10-2) persisted. No significant horizontal polymorphism was found in the sensitivity analysis. CONCLUSION: Our MR study suggested that increased dried fruit intake is associated with slower AgeAccelGrim and AgeAccelPheno. It can providing a promising avenue for exploring the beneficial effects of dried fruit intake on lifespan extension.

[Efficacy of plasma exchange in severe crescentic IgA nephropathy: A multicentered, cohort study].

OBJECTIVE: To evaluate the efficacy of plasma exchange therapy on crescentic IgA nephropathy (IgAN). METHODS: A retrospective analysis was performed in a cohort of patients with crescentic IgAN from January 2012 to September 2020 at 9 sites across China. Clinical and pathological data, as well as therapeutic regimens, were collected. In order to minimize the effect of potential confounders in baseline characteristics, propensity score matching using a 1 ∶1 ratio nearest neighbor algorithm was performed between the adjunctive plasma exchange therapy group and the intensive immunosuppressive therapy group. The primary outcome was end-stage of kidney disease (ESKD). Kaplan-Meier method was used to compare the difference in renal survival between the two groups. RESULTS: A total of 95 crescentic IgAN patients with acute kidney disease were included in this study, including 37 (38.9%) patients receiving adjunctive plasma exchange therapy, and 58 (61.1%) patients receiving intensive immunosuppressive therapy. In the whole cohort, the baseline eGFR was 12.77 (7.28, 21.29) mL/(min·1.73 m2), 24-hour urinary protein quantification was 5.9 (4.0, 8.9) g, and crescent percentage was 64.71% (54.55%, 73.68%). In the study, 23 patients in each group were matched after propensity score matching The median follow-up time was 7 (1, 26) months. As a whole, 29 patients (63.0%) reached ESKD, including 16 patients (69.6%) in the adjunctive plasma exchange therapy group and 13 (56.5%) patients in the intensive immunosuppressive therapy group.. There were no stastical difference between the two groups in terms of baseline eGFR [14.30 (9.31, 17.58) mL/(min·1.73 m2) vs. 11.45 (5.59, 20.79) mL/(min·1.73 m2)], 24-hour urinary protein (7.4±3.4) g vs. (6.6±3.8) g, crescent percentage 64.49%±13.23% vs. 66.41%±12.65% and the proportion of patients received steroid therapy[23 (100.0%) vs. 21 (91.3%)] (All P>0.05). Kaplan-Meier survival analysis demonstrated that there was no significant difference in renal survival rate between the two groups (Log-rank test, P=0.933). CONCLUSION: The adjunctive plasma exchange therapy in addition to conventional intense immunosuppressive therapy did not additionally improve the prognosis of crescentic IgA nephropathy.

Long-term particulate matter 2.5 exposure and dementia: a systematic review and meta-analysis.

OBJECTIVES: This study aimed to analyse the existing evidence on the association between particulate matter 2.5 (PM2.5) and dementia, including two of its subtypes, namely, Alzheimer's disease (AD) and vascular dementia (VaD). STUDY DESIGN: This was a systematic review and meta-analysis. METHODS: The PubMed, EMBASE, Cochrane and Web of Science databases were comprehensively searched for articles published between January 1900 and June 2022. All cohort studies that reported the influence of long-term exposure to PM2.5 on dementia, together with its subtypes, in adults aged ≥40 years, without any regional restriction were included. A random effects model was used to pool the hazard ratios (HRs) of PM2.5 for dementia, AD and VaD. Funnel plots, sensitivity analyses and subgroup analyses were performed to test publication bias and result stability. In addition, an explanation for the heterogeneity of the results was suggested. RESULTS: In total, 20 articles were selected for review; 18 included results on the long-term effects of PM2.5 on dementia, 13 on AD, and eight on VaD. Three group meta-analyses were performed to obtain the HRs and 95% confidence intervals (CIs). The pooled HRs were 1.40 (95% CI 1.23, 1.60) for dementia, 1.47 (95% CI 1.22, 1.78) for AD and 2.00 (95% CI 1.30, 3.08) for VaD per 10.0 µg/m3 PM2.5 increase. CONCLUSIONS: Long-term exposure to PM2.5 may increase the risk of dementia, including AD and VaD. These results highlight the need for further study on the detrimental impact of PM2.5 and the importance of strategies to mitigate increasing air pollution.

[Research progress on health hazards and occupational protection of prolymethylmethacrylate bone cement in the operating room].

There are many occupational risk factors in operating room work. Polymethyl methacrylate (PMMA) , as a kind of common bone filling and repairing material, is widely used in the fixation of artificial joints, oral braces and orthopedic prosthesis. However, PMMA will release methyl methacrylate (MMA) monomer when it is implanted into human tissues and polymerized to harden, which is toxic to the body. This paper analyzes harmful factors in using PMMA bone cement, and then explores corresponding occupational protection knowledge, in order to reduce the occurrence of occupational hazards related to PMMA bone cement and enhance the self-protection ability of the operation room medical staff.

[Role of PNPT1 in cardiomyocyte apoptosis induced by oxygen-glucose deprivation].

OBJECTIVE: To explore the effect of inhibiting polyribonucleotide nucleotidyl-transferase 1 (PNPT1) on oxygen-glucose deprivation (OGD)-induced apoptosis of mouse atrial myocytes. METHODS: Cultured mouse atrial myocytes (HL-1 cells) with or without OGD were transfected with PNPT1-siRNA or a negative control siRNA (NC-siRNA group), and the cell survival rate was detected using CCK-8 assay. The expression levels of ACTB and TUBA mRNA were detected with qPCR, and the protein expression of PNPT1 was detected with Western blotting. The apoptosis rate of the treated cells was determined with flow cytometry, the mitochondrial membrane potential was detected using JC-1 kit, and the mitochondrial morphology was observed using transmission electron microscope. RESULTS: With the extension of OGD time, the protein expression levels of PNPT1 increased progressively in the cytoplasm of HL-1 cells (P < 0.05). Transfection with PNPT1-siRNA significantly reduced PNPT1 expression in HL-1 cells (P < 0.05). Exposure to OGD significantly enhanced degradation of ACTB and TUBA mRNA (P < 0.05) and markedly increased the apoptosis rate of HL-1 cells (P < 0.05), and these changes were significantly inhibited by transfection with PNPT1-siRNA (P < 0.05), which obviously increased mitochondrial membrane potential and improved mitochondrial morphology of HL-1 cells exposed to OGD. CONCLUSION: Inhibition of PNPT1 improves mitochondrial damage and reduces degradation of apoptotic-associated mRNAs to alleviate OGD-induced apoptosis of mouse atrial myocyte.

Prevalence and potential risk factors of chronic pruritus among community middle-aged and older population in Beijing, China.

BACKGROUND: Chronic pruritus is a common problem among older adults, with a significant impact on their quality of life. However, it is under-studied epidemiologically, especially among Chinese older adults. OBJECTIVE: The aim of this study was to identify the prevalence and explore the risk factors of chronic pruritus among the middle-aged and older adults in Beijing, China. METHODS: A total of 929 participants aged ≥35 years from six communities in Beijing, China, were interviewed. The survey collected the demographic characteristics, the experience of chronic pruritus (>6 weeks), chronic disease history, the level of physical activities and sleep quality. A population-based case-control study was conducted, including 178 chronic pruritus cases and 697 controls. A multivariate logistic regression model was performed to explore the risk factors of chronic pruritus. Additionally, a random forest algorithm was used to rank the importance of potential risk factors and analyse the overall interpretation of risk factors. RESULTS: The prevalence of chronic pruritus was 19.48% (181/929) among the Beijing middle-aged and elderly population. The findings indicated that older adults aged 65 years old or above, male, with college or higher degree, alcohol drinking, hypertension, hyperlipidaemia, chronic lung disease, cardiovascular disease, digestive system disease and osteoarthritis/rheumatism, and middle or low sleep quality were associated with the increased risk of chronic pruritus respectively. Physical activity level (≥3000 Met) was associated with a decreased risk of chronic pruritus. The rank according to the most contribution of chronic pruritus risk was sleep quality, education, physical activity level, osteoarthritis/rheumatism, age and gender. CONCLUSION: Prevalence of chronic pruritus was high among the Chinese middle-aged and elderly population. Age, gender, high education, alcohol drinking, hypertension, hyperlipidaemia, chronic lung disease, cardiovascular disease, digestive system disease, osteoarthritis /rheumatism and poor sleep quality may serve as risk factors of chronic pruritus. Moderate and high physical activity levels may serve as protective factors of chronic pruritus risk.

[Influence of metabolic syndrome on activities of daily living in middle-aged and elderly population in China: a prospective cohort study].

Objective: To examine the associations between metabolic syndrome (MS) and the risks for impaired activities of daily living (ADL) in the middle-aged and elderly population in China and provide basis for improving healthy life expectancy. Methods: Prospective cohort study design was used in this study. Based the data of China Health and Retirement Longitudinal Study (CHARLS) from 2011 to 2018 and the baseline data in 2011, the follow up for ADL outcomes was conducted in 2013, 2015 and 2018 respectively, and the participants recruited in 2013 and 2015 were new baseline populations. The participants with impaired ADL in three baseline populations were excluded. Cox proportional hazard model was used to estimate the effect of different components and number of MS components on the risk for ADL impairment in the middle-aged and elderly population in China. Results: In 59 795 person-years of follow-up, a total of 1 011 cases of ADL impairments were recorded. The incidence density of ADL impairment was 16.91 per 1 000 person-year; The findings of Cox regression analysis showed that compared with the middle aged and elderly people without MS, the risk for ADL impairments was 1.29 times higher (95%CI: 1.12-1.50) for those with one component of MS, 1.32 times higher (95%CI:1.07-1.64) for those with hyperlipemia complicated with diabetes, 1.78 times higher (95%CI: 1.22-2.59) for those with obesity and one component of MS, 2.48 times higher (95%CI:1.59-3.85) for those with hypertension complicated with hyperlipemia, 3.51 times higher (95%CI:1.66-7.43) for those with hypertension complicated with diabetes, 1.80 times higher (95%CI: 1.40-2.32) for those with ≥3 MS, respectively. Compared with the middle-aged and elderly population without MS, the risk for impaired ADL increased by 30% (HR=1.30, 95%CI: 1.13-1.51), 54% (HR=1.54, 95%CI: 1.28-1.85) and 87% (HR=1.87, 95%CI:1.45-2.41), respectively, in the middle-aged and elderly with one, two, and more than three components of MS, with a significant dose-response relationship that ADL impaired risks increased as the number of MS components increased (P<0.001). Conclusions: Our findings suggested that MS is a risk factor for ADL impairment in middle-aged and elderly population in China. Prevention and early intervention of obesity, hypertension, hyperlipemia, diabetes and metabolic syndrome could help to reduce or delay the incidence of ADL impairment.

[Matching in observational research: from the directed acyclic graph perspective].

Matching is a standard method for selecting research objects regarding the observational research, which controls confounding factors and improves statistical efficiency. However, its role in controlling confounding is not consistent in different observational studies. Matching can eliminate the confounding bias of matching variables in cohort studies, but checking on itself cannot eliminate confounding bias in case-control studies. In matched case-control studies, researchers may not accurately judge whether the variable is a confounder. Sometimes the variables that are not confounders are mistakenly matched. In that case, it will result in overmatching, which will lead to the decline of statistical efficiency or the introduction of unavoidable bias or increase of workload. If the real confounding factors are omitted, it will cause confounding bias. Therefore, researchers should consider what kind of matching variable selection criteria should be formulated. A directed acyclic graph is a visual graphic language that can show the complicated causality among different epidemiological research designs. This article analyzes the role of Matching in different observational research designs from the perspective of the directed acyclic graph, formulates the selection criteria for matching variables in matched case-control studies, and provides some reference suggestions for future epidemiological research design.

Assessment of community pharmacists' communication and comfort levels when interacting with Deaf and hard of hearing patients.

BACKGROUND: Deaf and hard of hearing patients who use sign language face considerable communication barriers while accessing pharmacy services. Low comfort-levels between community pharmacists and Deaf and hard of hearing patients result in poor interactions and increase patient safety risks. OBJECTIVE: 1) To examine the way community pharmacists interact with Deaf and hard of hearing patients in Malaysia, and their level of comfort in such interactions. 2) To examine how comfort-levels vary by the preferred communication methods, resources and employer support. METHODS: This cross-sectional study was conducted among registered community pharmacists practicing in Malaysia. Questionnaire items included comfort-levels of community pharmacists when interacting with Deaf and hard of hearing patients, used and preferred communication methods, necessary resources, and perceived employer's level of support. Based on the list of registered pharmacies, the questionnaire with a pre-paid return envelope was mailed out while pharmacies close to the university were approached in person. This questionnaire was distributed online using Google Form. Comparisons between comfort-levels and study parameters were analyzed using independent t-tests and ANOVA. RESULTS: A total of 297 community pharmacists responded (response rate 29.2%). Higher comfort-levels were reported in those who had received between 1 to 5 prescriptions as compared to those who did not receive prescriptions from Deaf and hard of hearing patients (MD= -0.257, SD=0.104, p=0.042). More than 80% used written information and only 3.4% had used the services of a qualified sign language interpreter throughout their community pharmacist career. Significantly lower comfort-levels (p=0.0004) were reported in community pharmacists who perceived training in sign language as a necessity to interact with Deaf and hard of hearing patients (M=3.6, SD=0.9) versus those who were not interested in sign language training (M=3.8, SD=0.6). CONCLUSIONS: The results suggest that community pharmacists were neither extremely comfortable nor averse when interacting with Deaf and hard of hearing patients. The lack of significant findings in terms of comfort-levels may indicate other potential drivers for their choice of communication method when interacting with Deaf and hard of hearing patients.

Assessment of community pharmacists’ communication and comfort levels when interacting with Deaf and hard of hearing patients

Background: Deaf and hard of hearing patients who use sign language face considerable communication barriers while accessing pharmacy services. Low comfort-levels between community pharmacists and Deaf and hard of hearing patients result in poor interactions and increase patient safety risks. Objective: 1) To examine the way community pharmacists interact with Deaf and hard of hearing patients in Malaysia, and their level of comfort in such interactions. 2) To examine how comfort-levels vary by the preferred communication methods, resources and employer support. Methods: This cross-sectional study was conducted among registered community pharmacists practicing in Malaysia. Questionnaire items included comfort-levels of community pharmacists when interacting with Deaf and hard of hearing patients, used and preferred communication methods, necessary resources, and perceived employer’s level of support. Based on the list of registered pharmacies, the questionnaire with a pre-paid return envelope was mailed out while pharmacies close to the university were approached in person. This questionnaire was distributed online using Google Form. Comparisons between comfort-levels and study parameters were analyzed using independent t-tests and ANOVA. Results: A total of 297 community pharmacists responded (response rate 29.2%). Higher comfort-levels were reported in those who had received between 1 to 5 prescriptions as compared to those who did not receive prescriptions from Deaf and hard of hearing patients (MD= -0.257, SD=0.104, p=0.042). More than 80% used written information and only 3.4% had used the services of a qualified sign language interpreter throughout their community pharmacist career. Significantly lower comfort-levels (p=0.0004) were reported in community pharmacists who perceived training in sign language as a necessity to interact with (AU)

Recent progress on the Chinese space programme and radiation research.

Manned space exploration was initiated in China in 1992, and substantial progress has been made. The next step is to build the Chinese Space Station (CSS), which is planned to be launched in 2020. The CSS will provide an on-orbit laboratory for experimental studies including space radiation research. The health risk of space radiation, especially carcinogenesis, is a major concern for long-term space exploration. Establishing a risk assessment system suitable for Chinese astronauts and developing effective countermeasures are major tasks for Chinese space radiobiologists. The Institute of Space Life Sciences, Soochow University has focused on these topics for years. We established cancer models with low-dose-rate exposure of alpha particles, and elucidated a microRNA-TGFß network regulating bystander effects and a lncRNA-cytoskeleton network regulating genomic instability induced by ionising radiation. We also confirmed the radioresistance of quiescent cells, which inspires a potential strategy to improve individual radioresistance during long-term space travel. However, we believe that a multi-disciplinary strategy must be developed to protect astronauts from highly energised space radiation.

[Co-prevalence relationship analysis on different metabolic syndrome scores and behavioral risk factors in adults from Urumqi based].

Objective: To investigate the influence of the prevalence and co-prevalence of risk factors for metabolic syndrome on the scores of different levels of metabolic syndrome in people receiving physical examination in Urumqi. Methods: Using the 2017 Xinjiang Health Examination Database, a total of 175 927 people from 7 districts and 1 county in Urumqi were selected as subjects. Face-to-face survey and body measurements were used to collect cardiovascular risk factors and metabolic syndrome scores. Metabolic syndrome scores were used. For the 0-5 points at 6 levels, χ(2), χ(2) trend test, correlation analysis of ordered variable Kendall's tau-b, and logistic regression analysis of ordered results were used to analyze the influence of prevalence and co-prevalence of behavioral risk factors on the MS scores. Results: The percentages of 6 metabolic syndrome scores in the sample population were 23.82%, 27.87%, 22.41%, 16.03%, 8.02%, and 1.85%, respectively. The scores of metabolic syndrome were different in different age groups, ethnic groups, groups with different drinking rates, and groups with different dietary types, with the differences all significant (P<0.05).The MS score in men increased with the increase of oil/salt rate and excessive drinking rate (P<0.01). The score in women increased with the increase of the current smoking rate, oil/salt rate, and increased with the decrease of physical activity (P≤0.01). There was no significant difference in the distribution of regular drinking rates between different score groups (P>0.05). The scores of metabolic syndrome increased with the increase of risk factors (P<0.05). Ordered results logistic analysis found that in the men with ≥3 risk factors and the metabolic syndrome score was 1.15 (1.06-1.26) times higher than that in the men without risk factor, as well as in women with 2 risk factors and≥3 risk factors. The metabolic syndrome scores were 1.38 (1.22-1.55), 2.02 (1.53-2.66) times higher than those in the women without risk factors. Conclusions: The physical examination group in Urumqi, the more the metabolic syndrome disease behavior risk factors clustered, the higher the metabolic syndrome score was. Therefore, comprehensive intervention measures should be taken to control the different forms of metabolic syndrome to prevent the occurrence and progress of the disease.

Alterations in folate-dependent one-carbon metabolism as colon cell transition from normal to cancerous.

Folate-dependent one-carbon cycle metabolism (FOCM) plays a critical role in maintaining genomic stability through regulating DNA biosynthesis, repair and methylation. Folate metabolites as well as other metabolites in the FOCM are hypothesized to be altered when cells transition from normal to cancerous state. Using cells at different stages in their development into colorectal cancer, the FOCM metabolites were profiled as an effort to phenotype the cells, and the metabolite levels were compared to the expressions of related genes. Here, we investigate whether there is a correlation between the metabolite levels, DNA methylation levels and the expression of the related genes that drive the levels of these metabolites. Using CRL1459, APC10.1, HCT116 and Caco-2, we show for the first time that FOCM metabolites correlate with the gene expression patterns. These differences follow a trend that may facilitate distinguishing colon cells at the different stages as they transition into cancerous state. The folate distribution and methionine levels were found to be key in determining the staging of the colon cells in CRC development. Also, expression of CBS, MTRR and MAT genes may facilitate distinguishing between untransformed and transformed colon cells.

Using a Dedicated Interventional Pulmonology Practice Decreases Wait Time Before Treatment Initiation for New Lung Cancer Diagnoses.

PURPOSE: While there is significant mortality and morbidity with lung cancer, early stage diagnoses carry a better prognosis. As lung cancer screening programs increase with more pulmonary nodules detected, expediting definitive treatment initiation for newly diagnosed patients is imperative. The objective of our analysis was to determine if the use of a dedicated interventional pulmonology practice decreases time delay from new diagnosis of lung cancer or metastatic disease to the chest to treatment initiation. METHODS: Retrospective chart analysis was done of 87 consecutive patients with a new diagnosis of primary lung cancer or metastatic cancer to the chest from our interventional pulmonology procedures. Demographic information and time intervals from abnormal imaging to procedure and to treatment initiation were recorded. RESULTS: Patients were older (mean age 69) and former or current smokers (72%). A median of 27 days (1-127 days) passed from our diagnostic biopsy to treatment initiation. A median of 53 total days (2-449 days) passed from abnormal imaging to definitive treatment. Endobronchial ultrasound-guided transbronchial needle aspiration was the most commonly used diagnostic procedure (59%), with non-small cell lung cancer the majority diagnosis (64%). For surgical patients, all biopsy-negative lymph nodes from our procedures were cancer-free at surgical excision. CONCLUSIONS: Compared to prior reports from international and United States cohorts, obtaining a tissue biopsy diagnosis through a gatekeeper interventional pulmonology practice decreases median delay from abnormal imaging to treatment initiation. This finding has the potential to positively impact patient outcomes and requires further evaluation.

SPOP suppresses osteosarcoma invasion via PI3K/AKT/NF-κB signaling pathway.

OBJECTIVE: Speckle-type POZ protein (SPOP), is an E3 ubiquitin ligase adaptor that is frequently mutated in prostate and endometrial cancers. SPOP has been shown to be responsible for oncogene SRC-3 ubiquitination and proteolysis in prostate cancers.  However, whether SPOP plays a role in osteosarcoma (OS) is unknown. In this study, we investigated the inhibitory effect of SPOP on invasion and migration of OS cells. PATIENTS AND METHODS: Real-time PCR and Western blot were used to detect the expression of SPOP in human OS samples and cell lines. Short hairpin RNA (shRNA) was used to silencing the expression of SPOP. Small scale Real-time PCR screen was used to identify the matrix metalloproteases (MMP) family members responsible for the phenotype caused by SPOP depletion. Matrigel-coated invasion chambers were used to detect the invasion ability of SPOP in OS cells. RESULTS: We found that SPOP was down-regulated in clinic OS samples and cultured OS cells. Furthermore, we showed that silencing of SPOP promoted cell migratory and invasive ability of OS cells in vitro, whereas restored the expression of SPOP achieved the opposite effects. At the molecular level, we found that SPOP regulated the activity of "PI3K/Akt/NF-κB" signaling pathway in OS cells. CONCLUSIONS: Our results suggested that down-regulation of SPOP promoted OS cells migratory and invasive ability via modulating the "PI3K/Akt/NF-κB" signaling pathway. Thus, SPOP could be a promising drug target for the treatment of OS invasion.

[Safety and feasibility of sheathless transfemoral aortic valve implantation].

Objective: To investigate the safety and feasibility of sheathless transfemoral aortic valve replacement (TAVR). Methods: In this prospective study, we enrolled 23 patients with severe aortic stenosis (AS) who were inoperable or at high-risk for surgical aortic valve replacement operation in Fuwai hospital From September 2012 to June 2015. Multislice spiral CT and angiography of femoral artery showed that all patients had minimal femoral artery diameters (<6.5 mm) and severe calcification which was not suitable for transfemoral TAVR through sheath. We attempted to apply the sheathless transfemoral TAVR using Venus-A prosthesis without sheath insertion, and procedure related complication during the procedure and hospital stay were observed. Results: The 6 mm×30 mm balloon was used for femoral artery predilation in 1 patient with iliofemoral artery stenosis before delivery system was transported. In the other 22 patients, the delivery system was transported directly. A total of 21 patients finished TAVR with transfemoral sheathless technique. In 2 patients, prosthesis was unable to fully expand after release due to severe valve calcification, and patients received urgent surgical aortic valve replacement. One patient had valve dislocation into the ascending aorta that was not related to the sheathless replacement technique, and delivery system and Venus-A valve were removed after femoral artery was opened surgically, and repeated sheathless TAVR implantation was performed and was successful. Moderate aortic regurgitation occurred in 2 patients immediately after procedure, and trace or mild aortic regurgitation was detected in rest of the patients. One patient had puncture site rupture and bleeding after procedure, and was successfully treated by balloon compression without blood transfusion. Complete atrioventricular block occurred in 3 patients within 24 hours after procedure and lasted after 48-72 hours, permanent pacemakers were implanted in these patients. Conclusion: The sheathless transfemoral technique in TAVR is safe and feasible in severe aortic stenosis patients with small access vessel diameter.

3D-QSAR pharmacophore-based virtual screening, molecular docking and molecular dynamics simulation toward identifying lead compounds for NS2B-NS3 protease inhibitors.

NS2B-NS3 protease has been identified to serve as lead drug design target due to its significant role in West Nile viral (WNV) and dengue virus (DENV) reproduction and replication. There are currently no approved chemotherapeutic drugs and effective vaccines to inhibit DENV and WNV infections. In this work, 3D-QSAR pharmacophore model has been developed to discover potential inhibitory candidates. Validation through Fischer's model and decoy test indicate that the developed 3D pharmacophore model is highly predictive for DENV inhibitors, which was then employed to screen ZINC chemical library to obtain reasonable hits. Following ADMET filtering, 15 hits were subjected to further filter through molecular docking and CoMFA modeling. Finally, top three hits were identified as lead compounds or potential inhibitory candidates with IC50 values of ∼0.4637 µM and fitness of ∼57.73. It is implied from CoMFA modeling that substituents at the side site of benzotriazole such as a p-nitro group (e.g. biphenyl head) and a carbonyl (e.g. carboxylate function) at the side site of furan or amino group may improve bioactivity of ZINC85645245, respectively. Molecular dynamics simulations (MDS) were performed to discover new interactions and reinforce the binding modes from docking for the hits also. The QSAR and MDS results obtained from this work should be useful in determining structural requirements for inhibitor development as well as in designing more potential inhibitors for NS2B-NS3 protease.

Long Non-coding RNA-mRNA Correlation Analysis Reveals the Potential Role of HOTAIR in Pathogenesis of Sporadic Thoracic Aortic Aneurysm.

OBJECTIVE/BACKGROUND: Long non-coding RNA (lncRNA) play important roles in many diseases. However, their roles in sporadic thoracic aortic aneurysm (STAA) are unclear. Therefore, the objective of this study was to construct an lncRNA-mRNA network and dissect lncRNAs that might contribute to the pathogenesis of STAA. METHODS: Differentially expressed lncRNAs and mRNAs between four ascending aortic specimens derived from STAA and four controls from patients who had undergone coronary artery bypass graft (CABG) were identified by microarray analysis. Gene Ontology (GO) enrichment and lncRNA-mRNA correlation analysis were implemented with differentially expressed genes. An lncRNA in the correlation network HOX transcript antisense intergenic RNA (HOTAIR) was selected as a candidate. HOTAIR expression was examined by quantitative real time polymerase chain reaction in STAA (n = 24) and controls (n = 24 [CABG, n = 22; heart transplant donors, n = 2]). HOTAIR expression was knocked down with siRNA in order to evaluate its role in apoptosis, cell proliferation, and expression of collagen types I and III. RESULTS: Five percent of lncRNAs were significantly differentially expressed in STAA patient samples compared with controls. GO enrichment analysis suggested differentially expressed genes were significantly enriched in the process of extracellular matrix organisation and leukocyte migration. lncRNA-mRNA interaction network revealed HOTAIR was associated with genes involved in extracellular matrix organisation. Moreover, HOTAIR expression was significantly decreased in STAA specimens and it negatively correlated with aortic diameter. HOTAIR knockdown induced early and late apoptosis and reduced cell proliferation. Furthermore, both mRNA and protein levels of collagen types I and III expression were suppressed after HOTAIR knockdown. CONCLUSION: Transcriptomic and lncRNA-mRNA correlation analysis revealed HOTAIR was downregulated in STAA and associated with genes involved in extracellular matrix remodelling. In vitro experiments confirmed that knockdown of HOTAIR could induce apoptosis and suppress collagen types I and III expression in human aortic smooth muscle cells.