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Severe pneumonia occurs commonly in children and is the main cause of clinical infant mortality. This study tested the expression pattern of long noncoding RNA cancer susceptibility candidate 2 (CASC2) in the serum of children with severe pneumonia and explored its clinical values.Serum levels of CASC2 were detected in 145 children with severe pneumonia. All cases were divided into two groups based on their respiratory failure (RF) condition. Receiver operating characteristic (ROC) and Kaplan-Meier (K-M) curves were plotted for the diagnostic and prognostic ability evaluation. Multivariate cox regression analysis was done for the examination of independent influence factors.The serum levels of CASC2 significantly decreased in children with severe pneumonia in contrast with healthy individuals and reached the lowest value in those with RF. Serum CASC2 can distinguish severe pneumonia and predicted the development of RF. Based on the 28-day survival data, cases with low CASC2 levels had a poor survival rate. CASC2 (hazard ratio [HR] = 0.068, 95% confidence interval [CI] = 0.016-0.292, P 0.001) and age (HR = 2.806, 95% CI = 1.240-6.394, P 0.001) were independent influence factor for the poor prognosis of children with severe pneumonia.Downregulation of serum CASC2 was related to the occurrence of RF in children with severe pneumonia and may be a predictor of the poor prognosis. This study will provide a potential biomarker for severe pneumonia treatment in clinic.

Background Snail control is critical to schistosomiasis control efforts in China. However, re-emergence of Oncomelania hupensis is challenging the achievements of schistosomiasis control. The present study aimed to test whether the amphibious snails can spread across watersheds using a combination of population genetics and geographic statistics. Methods The digital maps and attributes of snail habitats were obtained from the national survey on O. hupensis. Snail sampling was performed in 45 counties of Sichuan Province. The cox1 gene of specimens was characterized by sequencing. Unique haplotypes were found for phylogenetic inference and mapped in a geographical information system (GIS). Barriers of gene flow were identified by Monmonier’s maximum difference algorithm. The watercourses and watersheds in the study area were determined based on a digital elevation model (DEM). Plain areas were defined by a threshold of slope. The slope of snail habitats was characterized and the nearest distance to watercourses was calculated using a GIS platform. Spatial dynamics of high-density distributions were observed by density analysis of snail habitats. Results A total of 422 cox1 sequences of O. hupensis specimens from 45 sampling sites were obtained and collapsed into 128 unique haplotypes or 10 clades. Higher haplotype diversity in the north of the study area was observed. Four barriers to gene flow, leading to five sub-regions, were found across the study area. Four sub-regions ran across major watersheds, while high-density distributions were confined within watersheds. The result indicated that snails were able to disperse across low-density areas. A total of 63.48% habitats or 43.29% accumulated infested areas were distributed in the plain areas where the overall slope was < 0.94°. Approximately 90% of snail habitats were closer to smaller watercourses. Historically, high-density areas were mainly located in the plains, but now more were distributed in hilly region. Conclusions Our study showed the cross-watershed distribution of Oncomelania snails at a large scale. Natural cross-watershed spread in plains and long-distance dispersal by humans and animals might be the main driver of the observed patterns. We recommend cross-watershed joint control strategies for snail and schistosomiasis control. Graphical Abstract

Steroid-induced necrosis of femoral head (SINFH) is a femoral head necrotic disease caused by prolonged use of hormones. The detailed pathogenesis has not been fully demonstrated. In this study, we employed the bioinformatics approach to probe the roles of SINFH inhibitors. Core dysfunction modules related to SINFH was obtained. Meanwhile, GO and KEGG analysis of genes in dysfunction modules are carried out. Furthermore, the pivot prediction analysis of dysfunction modules related to ncRNA and transcription factor (TF) has been performed. The functions of the enriched modules were focused on multiple perspectives, including circulation, gland development, bone development and reconstruction, calcium production, and fatty acid metabolism regulation. The ncRNAs and TFs analysis showed that miR-322-5p, miR-124-3p, miR-125a-3p, and Ctnnb1 were important members of SINFH dysfunction. Drug targets suggested that Zinc and adenosine monophosphate may have an impact on SINFH dysfunction. SINFH was closely related to bone development and reconstruction.

Background: Osteoarthritis (OA) is a kind of chronic disease relating to joints, which seriously affectsthe daily life activities of the elderly and can also lead to disability. However, the pathogenesis of OA is still unclear, which leads to limited treatment and the therapeutic effect far from people's expectations. This study aims to filter out key genes in the pathogenesis of OA and explore their potential role in the occurrence and development of OA. Methods: The dataset of GSE117999 was obtained and analyzed in order to identify the differentially expressed genes (DEGs), hub genes and key genes. We also identified potential miRNAs which may play a major role in the pathogenesis of OA, and verified their difference in OA by real-time quantitative PCR (RT-qPCR). DGldb was found to serve as an indicator to identify drugs with potential therapeutic effects on key genes and Receiver Operating Characteristic (ROC) analysis was used for identifying underlying biomarkers of OA. Results: We identified ten key genes, including MDM2, RB1, EGFR, ESR1, UBE2E3, WWP1, BCL2, OAS2, TYMS and MSH2. Then, we identified hsa-mir-3613-3p, hsa-mir-548e-5p and hsamir- 5692a to be potentially related to key genes. In addition, RT-qPCR confirmed the differential expression of identified genes in mouse cartilage with or without OA. We then identified Etoposide and Everolimus, which were potentially specific to the most key genes. Finally, we speculated that ESR1 might be a potential biomarker of OA. Conclusions: In this study, potential key genes related to OA and their biological functions were identified, and their potential application value in the diagnosis and treatment of OA has been demonstrated, which will help us to improve the therapeutic effect of OA.

The association between socioeconomic status (SES) and bone mineral density (BMD) in men remains controversial. We showed that SES was positively associated with BMD in American men. Confounding factors like race/ethnicity and age could affect the association.Based on the data from the National Health and Nutrition Examination Survey (NHANES), 2011-2020, this article aims to investigate the association of SES (poverty income ratio (PIR) and education level) with the BMD in American men.We evaluated the association of SES with BMD in 4446 men aged ≥ 20 years (mean age, 41.0 ± 13.4 years) from the NHANES 2011-2020. BMD was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine. We used multivariate linear regression models to examine the relationship between SES and total spine BMD, adjusted for a large range of confounding factors.Compared with other PIR quarters, individuals in the highest quarter of PIR were more likely to be older and white and had fewer smoking or drinking behaviors. After adjusting for race/ethnicity, age, drinking and smoking behavior, body mass index (BMI), total protein, serum calcium, serum uric acid, cholesterol, serum phosphorus, and blood urea nitrogen, PIR was positively correlated with total spine BMD (β = 0.004 95% CI: 0.001-0.007, P = 0.006). Individuals with the highest degree (college degree or above) had a 0.057 g/cmOur study indicates that SES was positively associated with the lumbar BMD among American men. Clinicians, healthcare providers, and policymakers should consider the unequal SES of men when implementing osteoporosis prevention and treatment strategies.

The incidence and mortality of primary liver cancer are very high and resection of tumor is the most crucial treatment for it. We aimed to assess the efficacy and safety of combined use of transversus abdominis plane (TAP) block and laryngeal mask airway (LMA) during implementing Enhanced Recovery After Surgery (ERAS) programs for patients with primary liver cancer. This was a prospective, evaluator-blinded, randomized, controlled parallel-arm trial. A total of 96 patients were enrolled (48 in each group). Patients in the control group received general anesthesia with endotracheal intubation, while patients in the TAP + LMA group received general anesthesia with LMA and an ultrasound-guided subcostal TAP block. The primary end-point was postoperative time of readiness for discharge. The secondary end-points were postoperative pain intensity, time to first flatus, quality of recovery (QoR), complications and overall medical cost. Postoperative time of readiness for discharge in the TAP + LMA group [7 (5–11) days] was shorter than that of the control group [8 (5–13) days, P = 0.004]. The postoperative apioid requirement and time to first flatus was lower in the TAP + LMA group [(102.8 ± 12.4) µg, (32.7 ± 5.8) h, respectively] than the control group [(135.7 ± 20.1) µg, P = 0.000; (47.2 ± 7.6) h, P = 0.000; respectively]. The QoR scores were significantly higher in the TAP + LMA group than the control group. The total cost for treatment in the TAP + LMA group [(66,608.4 ± 6,268.4) CNY] was lower than that of the control group [(84,434.0 ± 9,436.2) CNY, P = 0.000]. There was no difference in complications between these two groups. The combined usage of a TAP block and LMA is a simple, safe anesthesia method during implementing ERAS programs for patients with primary liver cancer. It can alleviate surgical stress, accelerate recovery and reduce medical cost.

The current study was aimed at exploring the potential roles and possible mechanisms of miR-10a-5p in osteoarthritis (OA). We performed RT-qPCR, Western blot, CCK8, EdU Assay, and flow cytometry assay to clarify the roles of miR-10a-5p in OA. Furthermore, the whole transcriptome sequencing together with integrated bioinformatics analyses were conducted to elucidate the underlying mechanisms of miR-10a-5p involving in OA. Our results demonstrated that miR-10a-5p was upregulated in OA and acted as a significant contributing factor for OA. A large number of circRNAs, lncRNAs, miRNAs, and mRNAs were identified by overexpressing miR-10a-5p. Functional enrichment analyses indicated that these differentially-expressed genes were enriched in some important terms including PPAR signaling pathway, PI3K-Akt signaling pathway, and p53 signaling pathway. A total of 42 hub genes were identified in the protein-protein interaction network including SERPINA1, TTR, APOA1, and A2M. Also, we constructed the network regulatory interactions across coding and noncoding RNAs triggered by miR-10a-5p, which revealed the powerful regulating effects of miR-10a-5p. Moreover, we found that HOXA3 acted as the targeted genes of miR-10a-5p and miR-10a-5p contributed to the progression of OA by suppressing HOXA3 expression. Our findings shed insight on regulatory mechanisms of miR-10a-5p, which might provide novel therapeutic targets for OA.

Due to age and gender, patients awaiting total knee or hip arthroplasty (TKA/THA) are at a higher risk of osteoporosis. In joint arthroplasty, low bone mineral density (BMD) is a risk factor for implant osseointegration, durability, and prosthesis complications. This study aims to investigate the prevalence and treatment rate of osteoporosis in patients undergoing total joint arthroplasty (TJA).We applied a comprehensive literature search through PubMed, Cochrane Library, and EMBASE from inception to July 10, 2021, for studies investigating the prevalence and treatment rate of osteoporosis in TJA patients. The aggregated prevalence was calculated with the random-effects model, and the heterogeneity between studies was checked by Cochran's Q test and quantified by the IOf 4561 citations identified by the search strategy, 11 studies including 3462 patients were eligible for inclusion. The pooled prevalence of osteoporosis and osteopenia in TJA patients was 24.8% (95%CI: 14.1-37.2%) and 38.5% (95%CI: 29.3-48.0%), respectively. The prevalence of osteoporosis/osteopenia in TJA patients was 64.0% (95%CI: 45.8-80.3%). In terms of gender, the pooled prevalence of osteoporosis in males, females, and postmenopausal females were 5.5% (95%CI: 1.5-11.4%), 29.0% (95%CI: 18.3-41.1%), and 38.3% (95%CI: 13.2-67.1%), respectively. The treatment rate of osteoporosis in TJA patients was 32.9% (95%CI: 15.2-53.1%) by a random-effects model.Osteoporosis is highly prevalent in patients undergoing TJA, especially in postmenopausal females. However, the treatment rate of osteoporosis is low. Considering the possibility of surgical complications, clinicians should strengthen their awareness of pre-operative BMD assessment and manage osteoporosis in high-risk patients.

Background Rheumatoid arthritis (RA) is a chronic autoimmune disease, which commonly affects women. Accumulating evidence shows that differentially expressed circular RNAs (circRNAs) play crucial roles in the progress of RA. However, the roles of circRNAs in female RA remains unclear. This study explores potential role and diagnostic value of hsa_circ_0140271 from peripheral blood mononuclear cells (PBMC) in female RA. Methods Differential expression of circRNAs was determined by RNA-sequencing in PBMC from 4 healthy controls (HC) and 4 RA patients, and we further measured the level of hsa_circ_0140271 in a validation cohort consisting of 47 RA and 47 HC via RT-qPCR. Besides, correlation studies with clinical variables were also examined. What’s more, we performed bioinformatics analysis to predict the potential role of hsa_circ_0140271. Results PBMC expression of hsa_circ_0140271 of female RA was significantly higher than that of female HC, and it was positively correlated with antistreptolysin (ASO). Furthermore, the receiver operating characteristic (ROC) curve indicated that hsa_circ_0140271 could distinguish female RA from female HC and female patients with ankylosing spondylitis (AS) or osteoarthritis (OA). Besides, the combined diagnosis anti-cyclic citrullinated peptide (Anti-CCP) + hsa_circ_0140271 could improve diagnostic accuracy with an area under the curve (AUC) of 0.818 to compared with Anti-CCP. Furthermore, KEGG pathway enrichment analysis indicated hsa_circ_0140271 may act as microRNA sponge and participate in fatty acid metabolism pathways. Conclusion Hsa_circ_0140271 was likely to be used as a promising diagnostic biomarker for female RA; it may act as microRNA sponge to regulate fatty acid metabolism pathways in RA.

Background The optimal treatment of Pauwels type III femoral neck fracture (FNF) in young patients remains a worldwide challenge in orthopedic surgery. Methods Finite element models of four internal fixations were developed to treat Pauwels type III FNF: a: the traditional inverted triangular parallel cannulated screw (PCS) model, b: the F-technique cannulated screw model, c: the modified F-technique cannulated screw model using a fully threaded screw instead of a partially threaded distally, d: the dynamic hip screw coupled with derotational screw (DHS + DS) model. Under the same conditions, finite element analyses were carried out to compare the displacement and von Mises stress distribution of four internal fixations and femurs, the maximum crack distances of the fracture surfaces, Z axis displacements of four models as well as the stress distribution in the subtrochanteric region. Results The modified F-technique configuration resulted in a more stable fixation as compared to the other three configurations, with respect to the maximum displacement and stress peaks of femur and internal fixations, the maximum crack distances of the fracture surfaces, Z axis displacements of four configurations as well as the stress distribution in the subtrochanteric region. Conclusions Our results suggested that modified F-technique configuration show a better performance in resisting shearing and rotational forces in treating Pauwels type III FNF compared to those using traditional inverted triangular PCS, the F-technique configuration or DHS + DS, providing a new choice for the treatment of FNFs.

To evaluate the efficacy and safety of tranexamic acid (TXA) in patients with adolescent idiopathic scoliosis undergoing corrective surgery.A literature search of PubMed, Embase, and Cochrane Library was performed to identify studies published from inception to February 2019. After study selection and data extraction, statistical analysis was performed. Odds ratios and weighted mean differences (WMDs) with 95% confidence intervals (CIs) for all available clinical outcomes were analyzed using fixed-effects or random-effects models.Twelve studies comprising 2500 patients were included. Intravenous TXA use was associated with significantly fewer patients received blood transfusions (odds ratio, 0.12; 95% CI, 0.06 to 0.22; P0.001), less intraoperative estimated blood loss (WMD, -470.07; 95% CI, -645.23 to -294.90; P0.001), less intraoperative estimated blood loss per segment (WMD, -27.40; 95% CI, -32.80 to -22.00; P0.001), less cell salvage blood transfusion (WMD, -106.02; 95% CI, -170.84 to -41.20; P = 0.001), and shorter surgical time (WMD, -26.18; 95% CI, -46.91 to -5.46; P = 0.010). No significant difference was found in postoperative hemoglobin (WMD, 0.39; 95% CI, -0.07 to 0.86; P = 0.100) and hemoglobin change (WMD, -0.92; 95% CI, -2.90 to 1.07; P = 0.360) between TXA and control groups. No renal, thromboembolic, or other major complications associated with TXA were noted in included studies.TXA was effective in reducing surgical time, intraoperative estimated blood loss, and blood transfusion without increasing complications in patients undergoing corrective surgery for adolescent idiopathic scoliosis. TXA had no influence on postoperative hemoglobin and hemoglobin change.

To evaluate the incidence and risk factors associated with proximal junctional kyphosis (PJK) in patients with adolescent idiopathic scoliosis (AIS) after correction surgery.PubMed, Embase, and Cochrane Library were searched from inception until August 2018 to obtain relevant studies. After study selection and data extraction, statistical analysis was performed with RevMan 5.3. The odds ratios (ORs) and weight mean differences (WMDs) with 95% confidence intervals (CIs) for all available factors were analyzed using fixed or random effects models.A total of 7 studies were included in this meta-analysis. The overall incidence of PJK in AIS was 14% (95% CI, 8%-20%). Among the potential risk factors, proximal implants with screws (OR, 1.64; 95% CI, 1.13-2.39; P = 0.010), instrumentation types with all screws (OR, 1.78; 95% CI, 1.19-2.67; P = 0.005), larger preoperative thoracic kyphosis (TK) (WMD, 7.50; 95% CI, 5.75-9.26; P0.001), larger preoperative lumbar lordosis (LL) (WMD, 4.85; 95% CI, 2.79-6.92; P0.001), larger postoperative LL (WMD, 2.00; 95% CI, 0.09-3.91; P = 0.040), greater change in TK (WMD, -6.75; 95% CI, -9.72 to -3.78; P 0.001), and greater change in LL (WMD, -3.26; 95% CI, -5.40 to -1.12; P = 0.003) were identified as risk factors for PJK.The incidence of PJK in patients with AIS was 14%. Proximal implants with screws and instrumentation types with all screws were significantly associated with increased occurrence of PJK. Larger preoperative TK, larger preoperative LL, larger postoperative LL, greater TK change, and greater LL change were also identified as risk factors for PJK in AIS after correction surgery.

Several recent studies have reported an abnormal liver chemistry profile among patients with coronavirus disease 2019 (COVID-19), although its clinical significance remains unknown.This systematic review and meta-analysis identified six studies of 586 patients delineating liver chemistries among patients with severe/critical illness versus mild cases of COVID-19 infection. Patients with severe/critical illness with COVID-19 infection have increased prevalence of coronary artery disease, cerebrovascular disease, and chronic obstructive pulmonary disease as compared with mild cases. A significant association between severe/critical COVID-19 infections with elevations in aspartate aminotransferase (pooled mean difference [MD], 11.70 U/L; 95% confidence interval [CI], 2.97, 20.43; P = 0.009), elevated total bilirubin (pooled MD, 0.14 mg/dL; 95% CI, 0.06, 0.22; P = 0.0005), and decreased albumin (pooled MD, -0.68 g/L; 95% CI, -0.81, -0.55; P 0.00001) was noted. There was also a trend toward elevated alanine aminotransferase levels among these severe cases (pooled MD, 8.84 U/L; 95% CI, -2.28, 19.97; P = 0.12); however, this did not reach statistical significance. More severe/critically ill cases were associated with leukocytosis, neutrophilia, lymphopenia, elevated creatinine kinase, elevated lactate dehydrogenase (LDH), and elevated prothrombin time (PT).Comorbidities, including coronary artery disease, cerebrovascular disease and chronic obstructive pulmonary disease, are more prevalent in hospitalized Chinese patients with severe/critical illness from COVID-19, and these patients are more likely to manifest with abnormal liver chemistries. Further prospective studies are crucial to understand the pathophysiologic mechanisms underlying the hepatic manifestations of the novel COVID-19 infection and its clinical significance.

Background: Osteoarthritis (OA) is a degenerative joint disease that seriously affects the quality of life of elderly individuals. Regrettably, the pathological mechanism for OA has not yet been fully elucidated. This study is committed to distinguishing key genes and the underlying mechanisms for OA. Raw data was acquired from the Gene Expression Omnibus (GEO) database. We identified differentially expressed genes (DEGs), hub genes, and key genes through bioinformatics analysis. Subsequently, we predicted the microRNAs (miRNAs) and circular RNAs (circRNAs) associated with these key genes that may play key roles in OA using web tools. We also constructed a protein-drug network and found potentially effective drugs by analyzing the relationships between the drugs and the key genes. Results: The analysis revealed 360 DEGs, 24 hub genes, and 15 key genes enriched in many categories potentially related to the pathological mechanism of OA. hsa-miR-29a-3p, hsa-miR-29b-3p, and hsa-miR-29c-3p were predicted to be important miRNAs for OA, while hsa_circ_0025119, hsa_circ_0025113, hsa_circ_0009897, and hsa_circ_0002447 were predicted to be the most important circRNAs. Further studies indicated that Ocriplasmin and Collagenase clostridium histolyticum may be effective drugs for the treatment of OA. Finally, CD34 and VWF were inferred to be the most meaningful biomarkers for OA. Conclusions: In conclusion, we determined the underlying key genes, miRNAs, and circRNAs for OA, predicted potentially effective drugs, and identified the most meaningful biomarkers for the disease. Our findings may provide insight into the pathological mechanism of OA and guide future research.

Introduction Proximal femoral nail anti-rotation (PFNA) is a routine method to deal with intertrochanteric fractures in the elder population. It is challenging to remove PFNA in some cases as a result of stripping of blade heads. In this case presentation, we describe a novel technique using commonly available instruments that can be used to remove stripped, even broken anti-rotation blade where conventional methods have failed. Methods The subject underwent a PFNA removal surgery 15 months after the previous fixation. We encountered difficulties using the regular instrument to remove the anti-rotation blade. A 5-mm tungsten carbide bur was used to drill a single cortical hole at the end of the blade. Then double-strand steel wire was threaded through the hole, and the distal part was shaped into a circle which could tie to the extraction screw. Slide Hammer was applied to gently knock out the blade along the anatomical direction of the femoral neck. Results The technique helped us successfully remove the anti-rotation blade and provided the patient with a satisfactory result. Conclusion The use of a tungsten reamer and steel wire loop to remove the proximal femoral anti-rotation blade may provide a cost-effective and straightforward method of dealing with extraction failure.

Background Joint stiffness is a common complication after anterior cruciate ligament (ACL) reconstruction, which seriously affects the efficacy of the operation and patient satisfaction. After ACL reconstruction, the identification of joint stiffness’ risk factors can help its prevention. This meta-analysis was conducted to evaluate joint stiffness’ risk factors and incidence after ACL reconstruction and provide guidance on its prevention. Methods PubMed, Embase, and Cochrane Library were searched to obtain relevant studies. The odds ratios (ORs) with 95% confidence intervals (CIs) for all potential risk factors were analyzed using fixed or random-effects meta-analysis in RevMan 5.2. Results In total, there were 37 studies and 113,740 patients that were included in this study. After ACL reconstruction, joint stiffness’ incidence negatively correlated with the studies publication time (R = −0.62, P = 0.0094). After ACL reconstruction, the joint stiffness overall pooled incidence was 3% (95% CI, 3-4%). Gender (OR, 0.51; 95% CI, 0.38-0.68; P < 0.00001) was identified as a risk factor. Potential risk factors, such as trauma to surgery time interval, graft type, and concomitant surgery with meniscus injury, have no significant correlation with joint stiffness after ACL reconstruction. Conclusion This study indicated that joint stiffness’ incidence after ACL reconstruction is 3% and that gender is a risk factor for joint stiffness after ACL reconstruction.

Urbanization increases human mobility in ways that can alter the transmission of classically rural, vector-borne diseases like schistosomiasis. The impact of human mobility on individual-level Schistosoma risk is poorly characterized. Travel outside endemic areas may protect against infection by reducing exposure opportunities, whereas travel to other endemic regions may increase risk. Using detailed monthly travel- and water-contact surveys from 27 rural communities in Sichuan, China, in 2008, we aimed to describe human mobility and to identify mobility-related predictors of S. japonicum infection. Candidate predictors included timing, frequency, distance, duration, and purpose of recent travel as well as water-contact measures. Random forests machine learning was used to detect key predictors of individual infection status. Logistic regression was used to assess the strength and direction of associations. Key mobility-related predictors include frequent travel and travel during July—both associated with decreased probability of infection and less time engaged in risky water-contact behavior, suggesting travel may remove opportunities for schistosome exposure. The importance of July travel and July water contact suggests a high-risk window for cercarial exposure. The frequency and timing of human movement out of endemic areas should be considered when assessing potential drivers of rural infectious diseases.

Backgroud Osteoarthritis (OA) is a common disease caused by chondrocyte dysfunction. KLF10 is a member of the Sp1-like transcription factor family that is involved in regulating osteoblasts, but its expression and regulatory mechanism(s) in chondrocytes are unclear. In the present study, we aimed to investigate the regulatory role of KLF10 on the pathological process of OA. Methods KLF10 expression in the cartilaginous tissue of patients with osteoarthritis (OA) was evaluated by immunohistochemistry (IHC). Next, we generated an OA mouse model, and the histological changes in cartilage tissue were verified using H&E staining, Safranin O-Fast Green staining, and IHC assays. KLF10 expression in the articular chondrocytes of OA mice was determined by qRT-PCR and Western blotting. To investigate the role of KLF10 in regulating cell proliferation and migration, a KLF10 overexpression plasmid was constructed and transfected into primary mouse chondrocytes. Subsequently, we used RNA sequencing (RNA-seq) to screen differentially expressed genes in chondrocytes with or without KLF10 overexpression. qRT-PCR was used for verification purposes. Results We found that KLF10 was upregulated in the cartilaginous tissue of patients with OA as well as in cartilaginous tissue of the OA mouse model. KLF10 overexpression inhibited the proliferation and migration of chondrocytes. Furthermore, RNA sequencing results identified increased expression of Acvr1 and decreased expression of Inhbb in cells overexpressing KLF10. Changes in mRNA expression of Acvr1 and Inhbb were confirmed by qRT-PCR. Conclusions KLF10 inhibits chondrocyte proliferation and migration by regulating the expression of Acvr1 and Inhbb in both human and mouse OA. These data suggest that KLF10 may be a potential therapeutic target for the treatment of OA.

Aims The prostate transmembrane protein, androgen induced 1 (PMEPA1) is differentially expressed in pan-cancer. However, PMEPA1 specific role in cancers has not been fully clarified. This study aims to explore the potential role of Pmepa1 in pan-cancer and specific cancer, with a view to deepening the research on the pathological mechanism of cancer. Main methods The Perl language and R language were used to identify the correlation between PMEPA1 expression level and clinical indicators, prognosis values, tumor microenvironment, immune cells' infiltration, immune checkpoint genes, TMB and MSI. The Therapeutic Target Database was used for identifying potential therapeutic drugs that target the pathways that are significantly affected by PMEPA1 expression. Key findings PMEPA1 differential expression significantly correlated with patients' age, race, tumors' stage and status. PMEPA1 high expression was closely correlated with poor prognosis in many cancer types, excluding prostate adenocarcinoma. PMEPA1 expression was closely related to tumor cells and the immune microenvironment in stromal and immune cells' level, immune cells' infiltration, immune checkpoint genes, tumor mutational burden and microsatellite instability. We also found that the activity of the olfactory transduction pathway was closely related to PMEPA1 expression. In pan-cancer, Trifluoperazine and Halofantrine have the potential to reduce PMEPA1 expression. Significance This study integrated existing data to explore PMEPA1 potential function in cancers, provided insights for the future cancer-related studies.

Supplemental Digital Content is available in the text, Background: Blood transfusions are associated with many adverse outcomes among spine surgery patients, but it remains unclear whether perioperative blood transfusion during spine surgery and postoperative infection are related. Recently, many related cohort studies have been published on this topic. Methods: This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The PubMed, Embase, and Cochrane Library databases were searched for eligible published studies. The Newcastle–Ottawa Scale (NOS) was used to assess the methodological quality of the studies, and a random-effects model was used to calculate the odds ratios (ORs) with 95% CIs. Sensitivity analyses were conducted to explore the source of heterogeneity. Results: The final analysis included 8 cohort studies with a total of 34,185 spine surgery patients. These studies were considered to be of high or moderate quality based on their NOS scores, which ranged from 5 to 9. Pooled estimates indicated that blood transfusion increased the infection rate (OR, 2.99; 95% CI, 1.95 to 4.59; I2 = 86%), which was consistent with the sensitivity analyses. Conclusions: Our results suggest that perioperative blood transfusion is a risk factor for postoperative infection among spine surgery patients. Further study is necessary to identify other influencing factors and to establish the mechanism underlying this relationship. Additional measures may be needed to reduce unnecessary blood transfusions during spine surgery.

Objectives Previous studies showed the effectiveness of negative pressure wound therapy (NPWT) in preventing surgical site infections (SSIs), but current guidelines do not recommend its routine use for surgical wounds. The aim was to compare the effectiveness and safety of NPWT with standard surgical dressing or conventional therapy for preventing SSIs. Methods Pubmed, Embase and the Cochrane Library were systematically searched on 10 April 2019. Also, we searched clinicaltrials.gov and references of relevant studies. Eligibility criteria were randomized controlled trials (RCTs) and adult surgical patients were included. The effectiveness of NPWT versus standard surgical dressing or conventional therapy was investigated. Relative risks (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were used to estimate the pooled effect of dichotomous outcomes and continuous outcomes respectively. The primary outcome was surgical site infections. The quality of included studies and the certainty of the evidence were assessed using the risk of bias tool and the GRADE approach. Results A total of 45 RCTs with 6624 surgical patients were included. NPWT reduced SSIs (RR 0.58; 95% CI 0.49–0.69) and wound dehiscence(17 RCTs; RR 0.80; 95% CI 0.65–1.00). NPWT did not increase the risk of hematoma (9 RCTs; RR 0.91; 95% CI 0.40–2.07) and hospital readmission(9 RCTs; RR 0.77; 95% CI 0.52–1.12) or prolong length of hospital stay(15 RCTs; MD –0.38; 95% CI, –0.78 to 0.02). NPWT significantly increased the risk of all adverse event-related outcomes (10 RCTs; RR 3.21; 95% CI, 1.17–8.78). The level of certainty was identified as low for the primary outcome and very low for all the secondary outcomes. Conclusions Compared with standard wound care, NPWT may reduce the risk of SSIs. We are uncertain whether NPWT reduces or increases the risk of wound dehiscence, haematoma, hospital readmission and all adverse event-related outcomes or if it shortens or prolongs length of hospital stay.

Aims Articular cartilage degeneration has been recognized as the primary pathological change in osteoarthritis (OA). Mechanisms that govern the shift from cartilage homeostasis to OA remain unknown. Previous studies have reported that intrinsic circadian clock in chondrocytes could function to optimize cartilage repair/remodeling to optimum times of day, but little is known about its molecular mechanisms. This study attempted to investigate the potential role and mechanism of circadian gene Clock in OA pathology. Materials and methods The expression of Clock in OA chondrocytes and cartilage was detected by qRT-PCR, western blot and immunohistochemistry. Temporal gene expression changes were analyzed using qRT-PCR in chondrocytes transfected with siClock following dexamethasone synchronization. In addition, the effect of Clock knockdown on senescent phenotypes and autophagic flux was evaluated in chondrocytes treated with siClock or siCntrl. Key findings The expression of Clock was up-regulated in OA cartilage from humans and mouse models. Clock knockdown had no influence on rhythmic expression of the downstream genes in primary chondrocytes. We also found that Clock knockdown elevated antioxidant enzyme activities, diminished reactive oxygen species (ROS) production and attenuated senescence of chondrocytes via restoring autophagic flux. Significance Clock knockdown can attenuate ROS-mediated senescence of chondrocytes through restoring autophagic flux in non-circadian manner, providing a potential therapeutic target for OA.

We aim to investigate the correlations between hemodynamic parameters, penile rigidity grading, and the therapeutic effects of phosphodiesterase type 5 inhibitors using color Doppler flow imaging after intracavernosal injection in patients with erectile dysfunction. This study involved 164 patients. After intracavernosal injection with a mixture of papaverine (60 mg), prostaglandin E1 (10 μg), and lidocaine (2%, 0.5–1 ml), the penile vessels were assessed using color Doppler flow imaging. Penile rigidity was classified based on the Erection Hardness Score system as Grades 4, 3, 2 or 1 (corresponding to Schramek Grades V to II). Then, the patients were given oral sildenafil (50–100 mg) and scored according to the International Index of Erectile Function (IIEF-5) questionnaire. The number of patients with penile rigidities of Schramek Grades II to V was 14, 18, 21, and 111, respectively. The IIEF-5 score was positively correlated with the refilling index of the penile cavernosal artery (r = 0.79, P < 0.05), the peak systolic velocity (r = 0.45, P < 0.05), and penile rigidity (r = 0.75, P < 0.05), and was negatively correlated with the end diastolic velocity (r = −0.74, P < 0.05). For patients with erectile dysfunction, both the IIEF-5 score after sildenafil administration, which is correlated with penile rigidity, and the hemodynamic parameters detected using color Doppler flow imaging may predict the effects of phosphodiesterase type 5 inhibitor treatment and could provide a reasonable model for the targeted-treatment of erectile dysfunction.

Osteoarthritis (OA), a common joint disease in elderly, causes serious social and economic burdens worldwide. Previous studies indicated that some differentially expressed circular RNAs (circRNAs) participated in the initiation and progression of OA. These findings suggested that circRNAs may act as promising diagnostic biomarkers and therapeutic targets for OA. In this review, we summarize the biogenesis and biological functions of circRNAs and explore the underlying roles of circRNAs in OA, which may enlighten further studies and contribute to the early diagnosis and intervention of OA.

With great interest, we read the recent article by Neogi et al entitled, ‘Effect of bisphosphonates on knee replacement (KR) surgery’.1 In the study, the authors concluded that in this population-based cohort of older women with incident knee osteoarthritis (OA), those with incident bisphosphonate users had lower risk of KR than non-users of bisphosphonates, which was further supported by another large cohort study.2 The strengths of this study include a propensity score-matched cohort design, Cox proportional hazards regression to control for potential confounders and sensitivity analyses focused on residual confounding. Meanwhile, the authors acknowledged the limitations of their work. We applaud and congratulate their important work for clinical practice. However, several important points should …

Background While the dispersal of hosts and vectors—through active or passive movement—is known to facilitate the spread and re-emergence of certain infectious diseases, little is known about the movement ecology of Oncomelania spp., intermediate snail host of the parasite Schistosoma japonicum, and its consequences for the spread of schistosomiasis in East and Southeast Asia. In China, despite intense control programs aimed at preventing schistosomiasis transmission, there is evidence in recent years of re-emergence and persistence of infection in some areas, as well as an increase in the spatial extent of the snail host. A quantitative understanding of the dispersal characteristics of the intermediate host can provide new insights into the spatial dynamics of transmission, and can assist public health officials in limiting the geographic spread of infection. Methodology/Principal findings Oncomelania hupensis robertsoni snails (n = 833) were sampled from 29 sites in Sichuan, China, genotyped, and analyzed using Bayesian assignment to estimate the rate of recent snail migration across sites. Landscape connectivity between each site pair was estimated using the geographic distance distributions derived from nine environmental models: Euclidean, topography, incline, wetness, land use, watershed, stream use, streams and channels, and stream velocity. Among sites, 14.4% to 32.8% of sampled snails were identified as recent migrants, with 20 sites comprising >20% migrants. Migration rates were generally low between sites, but at 8 sites, over 10% of the overall host population originated from one proximal site. Greater landscape connectivity was significantly associated with increased odds of migration, with the minimum path distance (as opposed to median or first quartile) emerging as the strongest predictor across all environmental models. Models accounting for land use explained the largest proportion of the variance in migration rates between sites. A greater number of irrigation channels leading into a site was associated with an increase in the site’s propensity to both attract and retain snails. Conclusions/Significance Our findings have important implications for controlling the geographic spread of schistosomiasis in China, through improved understanding of the dispersal capacity of the parasite’s intermediate host., Author Summary In China, human schistosomiasis is caused by infection with the parasitic blood fluke Schistosoma japonicum, which requires snail hosts as a lifecycle intermediary. Snail control efforts have been a key component of China’s schistosomiasis control program, which has reduced human infections from 11 million in the 1950s to approximately 115,000 today. However, schistosomiasis has re-emerged in some areas, and the range of areas infested by or suitable for snail hosts is expanding. Understanding how the physical structure of the environment influences snail migration could aid in understanding how intermediate host mobility contributes to persistence and/or re-emergence of schistosomiasis. Within the 29 sites sampled for snail hosts, we estimated that between 14–33% of snails were recent migrants from another site, and above average inter-site migration rates occurred between sites separated by up to 44 km. Greater landscape connectivity was associated with increased recent migration rates. Connectivity models considering land use patterns explained the largest proportion of the variance in migration rates between sites. An increase in the number of irrigation channels leading into the site was associated with an increase in a site’s propensity to both attract migrant snails and retain snails. Our findings have important implications for understanding and responding to the geographic spread of schistosomiasis.

To understand the endemic situation and impact factors of paragonimiasis in Sichuan Province, so as to provide the evidence for its control work.Four administrative villages from Xuanhan County, Kaijiang County, Pengzhou City and Yucheng District of Ya'an City were selected as regular surveillance sites. In the surveillance sites, ELISA was applied to test the infection situation of residents, questionnaire surveys were performed simultaneously; and water crabs were collected to detect the metacercariae of Paragonimus.From 2011 to 2013, totally 3 666 residents were tested by serum test and 104 of them were positive with a positive rate of 2.8%. Totally 3 671 residents underwent the questionnaire survey and 24.8% of them had heard about paragonimiasis, 36.3% had eaten undercooked water crabs, 56.4% had played with water crabs, and 84.6% had drunk stream water. Totally 2 463 water crabs were dissected, and metacercariae of Paragonimus were found in 620 of them with the infection rate of 25.2% and infectiosity of 4.53 per crab, respectively.The endemic situation of paragonimiasis in natural environments is serious in Sichuan Province. The residents in endemic area practice unhealthy diet behavior, and there is an urgent risk of the breakout of paragonimiasis.

Benzo[a]pyrene (B[a]P), a major human carcinogen in combustion products such as cigarette smoke and diesel exhaust, is metabolically activated into DNA-reactive metabolites via three different enzymatic pathways. The pathways are the anti-(+)-benzo[a]pyrene 7,8-diol 9,10-epoxide pathway (P450/epoxide hydrolase catalyzed) (B[a]PDE), the benzo[a]pyrene o-quinone pathway (aldo ketose reductase (AKR) catalyzed) and the B[a]P radical cation pathway (P450 peroxidase catalyzed). We used a yeast p53 mutagenesis system to assess mutagenesis by B[a]P radical cations. Because radical cations are short-lived, they were generated in situ by reacting B[a]P with cumene hydroperoxide (CuOOH) and horse radish peroxidase (HRP) and then monitoring the generation of the more stable downstream products, B[a]P-1,6-dione and B[a]P-3,6-dione. On the basis of B[a]P-1,6 and 3,6-dione formation, approximately 4 μM of radical cation was generated. In the mutagenesis assays, the radical cations produced in situ showed a dose-dependent increase in mutagenicity from 0.25 μM to 10 μM B[a]P with no significant increase seen with further escalation to 50 μM B[a]P. However, mutagenesis was 200-fold less than with the AKR pathway derived B[a]P, 7-8-dione. Mutant p53 plasmids, which yield red colonies, were recovered from the yeast to study the pattern and spectrum of mutations. The mutation pattern observed was G to T (31%) > G to C (29%) > G to A (14%). The frequency of codons mutated by the B[a]P radical cations was essentially random and not enriched at known cancer hotspots. The quinone products of radical cations, B[a]P-1,6-dione and B[a]P-3,6-dione were more mutagenic than the radical cation reactions, but still less mutagenic than AKR derived B[a]P-7,8-dione. We conclude that B[a]P radical cations and their quinone products are weakly mutagenic in this yeast-based system compared to redox cycling PAH o-quinones.

Furan is a liver toxicant and carcinogen in rodents. It is classified as a possible human carcinogen, but the human health effects of furan exposure remain unknown. The oxidation of furan by cytochrome P450 (P450) enzymes is necessary for furan toxicity. The product of this reaction is the reactive α,β-unsaturated dialdehyde, cis-2-butene-1,4-dial (BDA). To determine whether human liver microsomes metabolize furan to BDA, a liquid chromatography/tandem mass spectrometry method was developed to detect and quantify BDA by trapping this reactive metabolite with N-acetyl-l-cysteine (NAC) and N-acetyl-l-lysine (NAL). Reaction of NAC and NAL with BDA generates N-acetyl-S-[1-(5-acetylamino-5-carboxypentyl)-1H-pyrrol-3-yl]-l-cysteine (NAC-BDA-NAL). Formation of NAC-BDA-NAL was quantified in 21 different human liver microsomal preparations. The levels of metabolism were comparable to that observed in F-344 rat and B6C3F1 mouse liver microsomes, two species known to be sensitive to furan-induced toxicity. Studies with recombinant human liver P450s indicated that CYP2E1 is the most active human liver furan oxidase. The activity of CYP2E1 as measured by p-nitrophenol hydroxylase activity was correlated to the extent of NAC-BDA-NAL formation in human liver microsomes. The formation of NAC-BDA-NAL was blocked by CYP2E1 inhibitors but not other P450 inhibitors. These results suggest that humans are capable of oxidizing furan to its toxic metabolite, BDA, at rates comparable to those of species sensitive to furan exposure. Therefore, humans may be susceptible to furan's toxic effects.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants and are carcinogenic in multiple organs and species. Benzo[a]pyrene (B[a]P) is a representative PAH and has been studied extensively for its carcinogenicity and toxicity. B[a]P itself is chemically inert and requires metabolic activation to exhibit its toxicity and carcinogenicity. Three major metabolic pathways have been well documented. The signature metabolites generated from the radical cation (peroxidase or monooxygenase mediated) pathway are B[a]P-1,6-dione and B[a]P-3,6-dione, the signature metabolite generated from the diol-epoxide (P450 mediated) pathway is B[a]P-r-7,t-8,t-9,c-10-tetrahydrotetrol (B[a]P-tetrol-1), and the signature metabolite generated from the o-quinone (aldo-keto reductase mediated) pathway is B[a]P-7,8-dione. The contributions of these different metabolic pathways to cancer initiation and the exploitation of this information for cancer prevention are still under debate. With the availability of a library of [(13)C(4)]-labeled B[a]P metabolite internal standards, we developed a sensitive stable isotope dilution atmospheric pressure chemical ionization tandem mass spectrometry method to address this issue by quantitating B[a]P metabolites from each metabolic pathway in human lung cells. This analytical method represents a 500-fold increased sensitivity compared with that of a method using HPLC-radiometric detection. The limit of quantitation (LOQ) was determined to be 6 fmol on column for 3-hydroxybenzo[a]pyrene (3-OH-B[a]P), the generally accepted biomarker for B[a]P exposure. This high level of sensitivity and robustness of the method was demonstrated in a study of B[a]P metabolic profiles in human bronchoalveolar H358 cells induced or uninduced with the AhR ligand, 2,3,7,8-tetrachlorodibenzodioxin (TCDD). All the signature metabolites were detected and successfully quantitated. Our results suggest that all three metabolic pathways contribute equally in the overall metabolism of B[a]P in H358 cells with or without TCDD induction. The sensitivity of the method should permit the identification of cell-type differences in B[a]P activation and detoxication and could also be used for biomonitoring human exposure to PAH.

The efficacy of praziquantel for the treatment of Schistosoma japonicum in humans is reported from a cross-sectional survey conducted in 33 villages in Sichuan Province. Infection prevalence was found to be 5.7% (185 infected of 3,269 tested) in a region where 44-73% prevalence was found 9 years before. Collected miracidia were subjected to an in vitro test of praziquantel susceptibility. An effective concentration of praziquantel associated with 50% of miracidia changing shape was found between 10(-8) and 10(-7) M and 10(-7) and 10(-6) M for 10 and 5 minutes of exposure, respectively. After treating infected persons two times with 40-mg/kg doses of praziquantel, only one remained infected. Findings are reported from a 60-household questionnaire on attitudes and behaviors that may be associated with development of drug resistance. The low number of treatment failures and good compliance with treatment despite side effects and repeated annual treatments suggest that, in the near term, praziquantel remains effective in treating human S. japonicum infection in China.

The HIV-1 protease is a validated drug target for the design of antiretroviral drugs to combat AIDS. We previously established the sulfoximine functionality as a valid transition state mimetic (TSM) in the HIV-1 protease inhibitors (PI) design and have identified a lead pseudosymmetric compound with nanomolar enzymatic inhibitory activity. Here, we report the asymmetric synthesis of this compound and its application in the synthesis of sulfoximine-based peptidomimetic HIV-1 protease inhibitors. Molecular modeling revealed the potential mode of binding of the sulfoximine inhibitor as a TSM. The predicted absolute binding free energies suggested similar inhibitory effect as observed in our enzymatic inhibitory studies.

The traditional curriculum of clinical science at the Zhejiang University School of Medicine (ZUSM) was dominated by lectures, and many critical factors in producing competent physicians (such as the development of skills and active learning) were largely neglected. During a four-year period ending in 2007, ZUSM developed and implemented a new model for delivering clinical science education-the integrated clerkship. The principal features of the model are the greater amount of time that students are exposed to and are working in the clinical environment as clerks and the great reduction in lecture hours. Unlike the U.S. model of clerkship, the integrated clerkship at ZUSM is characterized by a progressive process, with intensive preparatory lectures before the clerkship, which is divided into two levels, junior and senior. The junior clerkship is equally divided into didactic activities and clinical practice; the senior clerkship requires students to become an essential part of the work taking place on the wards. A preliminary program evaluation showed that the fundamental goals of the integrated clerkship had been largely attained, especially the mastery of basic clinical skills and retention of medical knowledge. Surveys showed that most of the integrated clerkship students and faculty members were satisfied with the new curriculum; the students felt better prepared to cope with the professional challenges of patient care, and they began to understand how social context affects their patients. As the pilot program in China, the integrated clerkship at ZUSM may serve as a template for medical schools at a similar level, in China and elsewhere.

Furan is a liver toxicant and carcinogen in rodents. On the basis of these observations and the large potential for human exposure, furan has been classified as a possible human carcinogen. The mechanism of tumor induction by furan is unknown. However, the toxicity requires cytochrome P450-catalyzed oxidation of furan. The product of this oxidation, cis-2-butene-1,4-dial (BDA), reacts readily with glutathione, amino acids, and DNA and is a bacterial mutagen in Ames assay strain TA104. Characterization of the urinary metabolites of furan is expected to provide information regarding the structure(s) of the reactive metabolite(s). Recently, several urinary metabolites have been identified. We reported the presence of a monoglutathione-BDA reaction product, N-[4-carboxy-4-(3-mercapto-1H-pyrrol-1-yl)-1-oxobutyl]-l-cysteinylglycine cyclic sulfide. Three additional urinary metabolites of furan were also characterized as follows: R-2-acetylamino-6-(2,5-dihydro-2-oxo-1H-pyrrol-1-yl)-1-hexanoic acid, N-acetyl-S-[1-(5-acetylamino-5-carboxypentyl)-1H-pyrrol-3-yl]-l-cysteine, and its sulfoxide. It was postulated that these three metabolites are derived from degraded protein adducts. However, the possibility that these metabolites result from the reaction of BDA with free lysine and/or cysteine was not ruled out. In this latter case, one might predict that the reaction of thiol-BDA with free lysine would not occur exclusively on the epsilon-amino group. Reaction of BDA with N-acetylcysteine or GSH in the presence of lysine indicated that both the alpha- and the epsilon-amino groups of lysine can be modified by thiol-BDA. The N-acetylcysteine-BDA-N-acetyllysine urinary metabolites were solely linked through the epsilon-amino group of lysine. A GSH-BDA-lysine cross-link was a significant hepatocyte metabolite of furan. In this case, the major product resulted from reaction with the epsilon-amino group of lysine; however, small amounts of the alpha-amino reaction product were also observed. Western analysis of liver and hepatocyte protein extracts using anti-GSH antibody indicated that GSH was covalently linked to proteins in tissues or cells exposed to furan. Our data support the hypothesis that GSH-BDA can react with either free lysine or protein lysine groups. These data suggest that there are multiple pathways by which furan can modify cellular nucleophiles. In one pathway, BDA reacts directly with proteins to form cysteine-lysine reaction products. In another, BDA reacts with GSH to form GSH-BDA conjugates, which then react with cellular nucleophiles like free lysine or lysine moieties in proteins. Both pathways will give rise to N-acetyl-S-[1-(5-acetylamino-5-carboxypentyl)-1H-pyrrol-3-yl]-l-cysteine. Given the abundance of these metabolites in urine of furan-treated rats, these pathways appear to be major pathways of furan biotransformation in vivo.

Furan, a possible human carcinogen, is found in heat treated foods and tobacco smoke. Previous studies have shown that humans are capable of converting furan to its reactive metabolite, cis-2-butene-1,4-dial (BDA), and therefore may be susceptible to furan toxicity. Human risk assessment of furan exposure has been stymied because of the lack of mechanism-based exposure biomarkers. Therefore, a sensitive LC-MS/MS assay for six furan metabolites was applied to measure their levels in urine from furan-exposed rodents as well as in human urine from smokers and nonsmokers. The metabolites that result from direct reaction of BDA with lysine (BDA-N(α)-acetyllysine) and from cysteine-BDA-lysine cross-links (N-acetylcysteine-BDA-lysine, N-acetylcysteine-BDA-N(α)-acetyllysine, and their sulfoxides) were targeted in this study. Five of the six metabolites were identified in urine from rodents treated with furan by gavage. BDA-N(α)-acetyllysine, N-acetylcysteine-BDA-lysine, and its sulfoxide were detected in most human urine samples from three different groups. The levels of N-acetylcysteine-BDA-lysine sulfoxide were more than 10 times higher than that of the corresponding sulfide in many samples. The amount of this metabolite was higher in smokers relative to that in nonsmokers and was significantly reduced following smoking cessation. Our results indicate a strong relationship between BDA-derived metabolites and smoking. Future studies will determine if levels of these biomarkers are associated with adverse health effects in humans.

To understand the changes of schistosomiasis endemic situation in Sichuan Province, the upstream of Yangtze River basin, and the impact on schistosomiasis transmission in Three Gorges Reservoir area after the construction of Three Gorges Reservoir.The annual reports of the schistosomiasis endemic situation in Sichuan Province from 2000-2012, the data of the schistosomiasis surveillance sites in Sichuan Province from 2001-2012, the data of the schistosomiasis sampling survey in Sichuan Province in 2001, and the relevant reference of Three Gorges Reservoir were collected. The schistosomiasis prevalence in human and cattle, and Oncomelania hupensis snail status were investigated. The snail survey was implemented in Qianjin Village, Jianyang City, Sichuan Province, the nearest village to Three Gorges Reservoir Area.The schistosomiasis endemic situation presented a continuous declining state in Sichuan Province from 2000-2012, and reached the criteria of schistosomiasis transmission controlled in 2008. From 2012, 65.07% of endemic counties reached the criteria of schistosomiasis transmission interrupted. From 2006, no schistosome infected snails were found. In Qianjin Village, 1714 m2 environments were surveyed and no snails were found.The schistosomiasis endemic area and snail area are significantly reduced in Sichuan Province, the upstream of Yangtze River basin, after the construction of Three Gorges Reservoir. Therefore, the possibility of schistosomiasis endemic diffusing to Three Gorges Reservoir area is minimum.

// Yang Peng 1, * , Wen Dong 1, 3, * , Tian-xin Lin 1, 3, * , Guang-zheng Zhong 1 , Bei Liao 2 , Bo Wang 1, 3 , Peng Gu 1 , Li Huang 1 , Yun Xie 1 , Fu-ding Lu 1 , Xu Chen 1 , Wei-bin Xie 1 , Wang He 1 , Shao-xu Wu 1 , Jian Huang 1 1 Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China 2 Department of Medical Examination Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China 3 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People’s Republic of China * These authors have contributed equally to this work Corresponding to: Wen Dong, e-mail: wendong1210@hotmail.com Jian Huang, e-mail: urolhj@sina.com Keywords: microRNA-155, bladder cancer, DMTF1, Arf, cell proliferation Received: November 24, 2014 Accepted: April 6, 2015 Published: April 18, 2015 ABSTRACT MicroRNA-155 (miR-155) is dysregulated in human cancers. In this study, we reported that miR-155 was over-expressed in bladder cancer tissues. We found that miR-155 promoted cell proliferation in vitro and tumorigenesis in vivo . MiR-155 directly reduced the expression of the tumor suppressor DMTF1. The expression of DMTF1 was decreased in bladder cancer tissues. Similar to the restoring miR-155 expression, knockdown of DMTF1 promoted cell growth and cell cycle progression, whereas DMTF1 over-expression rescued the effect of miR-155. Moreover, we investigated DMTF1-Arf-p53 pathway and found that DMTF1 worked in both p53-dependent and p53-independent manners. Taken together, our findings suggested that miR-155 functions as a tumor promoter in bladder cancer, which is partially through repressing DMTF1 expression. The identification of miR-155 and its novel target DMTF1 will be valuable in developing diagnostic markers and therapeutic applications for bladder cancer.

Background The translocations of the anaplastic lymphoma kinase (ALK) gene with the echinoderm microtubule-associated protein-like 4 (EML4) gene on chromosome 2p have been identified in non-small-cell lung cancers (NSCLCs) as oncogenic driver mutations. It has been suggested that EML4-ALK fusion is associated with the resistance in NSCLCs to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), such as gefitinib and erlotinib. In contrast, ALK tyrosine kinase inhibitor (ALK TKI) crizotinib has shown superior effects in combating NSCLCs with EML4-ALK. Thus, characterization of EML4-ALK fusion genes and clinical features of resulting carcinomas would be a great benefit to disease diagnosis and designing customized treatment plans. Studies have suggested that EML4-ALK translocation occurs more frequently in never-smokers with NSCLC, especially in female patients. However, it is not clear whether this is the case in male patients, too. In this study, we have determined the frequency of EML4-ALK translocation in male never-smokers with NSCLC in a cohort of Chinese patients. The clinical features associated with EML4-ALK translocation were also investigated. Methods A cohort of 95 Chinese male never-smokers with NSCLC was enrolled in this study. EML4-ALK fusion genes were detected using one-step real time RT-PCR and DNA sequencing. We further determined the expression levels of ALK mRNA by RT-PCR and ALK protein by immunohistochemistry in these specimens. The clinical features of EML4-ALK–positive carcinomas were also determined. Results We have identified EML4-ALK fusion genes in 8 out of 95 carcinoma cases, accounting for 8.42% in Chinese male never-smokers with NSCLC. It is significantly higher than that in all Chinese male patients (3.44%) regardless smoking habit. It is also significantly higher than that in all Chinese smokers (8/356 or 2.25%) or in smokers worldwide (2.9%) by comparing to published data. Interestingly, EML4-ALK fusion genes are more frequently found in younger patients and associated with less-differentiated carcinomas. Conclusions The frequency of EML4-ALK translocation is strongly associated with smoking habits in Chinese male patients with higher frequency in male never-smokers. EML4-ALK translocation is associated with early-onset and less-differentiated carcinomas.

Attenuated primate lentivirus vaccines provide the most consistent protection against challenge with pathogenic simian immunodeficiency virus (SIV). Thus, they provide an excellent model to examine the influence of the route of immunization on challenge outcome and to study vaccine-induced protective anti-SIV immune responses. In the present study, rhesus macaques were immunized with live nonpathogenic simian-human immunodeficiency virus (SHIV) 89.6 either intravenously or mucosally (intranasally or intravaginally) and then challenged intravaginally with pathogenic SIVmac239. The route of immunization did not affect mucosal challenge outcome after a prolonged period of systemic infection with the nonpathogenic vaccine virus. Further, protection from the SIV challenge was associated with the induction of multiple host immune effector mechanisms. A comparison of immune responses in vaccinated-protected and vaccinated-unprotected animals revealed that vaccinated-protected animals had higher frequencies of SIV Gag-specific cytotoxic T lymphocytes and gamma interferon (IFN-γ)-secreting cells during the acute phase postchallenge. Vaccinated-protected animals also had a more pronounced increase in peripheral blood mononuclear cell IFN-α mRNA levels than did the vaccinated-unprotected animals in the first few weeks after challenge. Thus, innate as well as cellular anti-SIV immune responses appeared to contribute to the SHIV89.6-induced protection against intravaginal challenge with pathogenic SIVmac239.

Diet has a strong influence on the intestinal microbiota in both humans and animal models. It is well established that microbial colonization is required for normal development of the immune system and that specific microbial constituents prompt the differentiation or expansion of certain immune cell subsets. Nonetheless, it has been unclear how profoundly diet might shape the primate immune system or how durable the influence might be. We show that breast-fed and bottle-fed infant rhesus macaques develop markedly different immune systems, which remain different 6 months after weaning when the animals begin receiving identical diets. In particular, breast-fed infants develop robust populations of memory T cells as well as T helper 17 (TH17) cells within the memory pool, whereas bottle-fed infants do not. These findings may partly explain the variation in human susceptibility to conditions with an immune basis, as well as the variable protection against certain infectious diseases.

To date, expansion of bone-marrow-derived mesenchymal stem cells (MSCs) is typically carried out on two-dimensional (2D) tissue culture plastic. Since this 2D substratum is very different from the physiological situation, MSCs gradually lose their unique multipotent properties during expansion. Recently, the role of the extracellular matrix (ECM) microenvironment (“niche”) in facilitating and regulating stem cell behavior in vivo has been elucidated. As a result, investigators have shifted their efforts toward developing three-dimensional (3D) scaffolds capable of functioning like the native tissue ECM. In this study, we demonstrated that stromal-cell-derived ECM, formed within a collagen/hydroxyapatite (Col/HA) scaffold to mimic the bone marrow “niche,” promoted MSC proliferation and preserved their differentiation capacity. The ECM was synthesized by MSCs to reconstitute the tissue-specific 3D microenvironment in vitro. Following deposition of the ECM inside Col/HA scaffold, the construct was decellularized and reseeded with MSCs to study their behavior. The data showed that MSCs cultured on the ECM-Col/HA scaffolds grew significantly faster than the cells from the same batch cultured on the regular Col/HA scaffolds. In addition, MSCs cultured on the ECM-Col/HA scaffolds retained their “stemness” and osteogenic differentiation capacity better than MSCs cultured on regular Col/HA scaffolds. When ECM-Col/HA scaffolds were implanted into immunocompromised mice, with or without loading MSCs, it was found that those scaffolds formed less bone as compared with regular Col/HA scaffolds (i.e., without ECM), in both cases of with or without loading MSCs. The in vivo study further confirmed that the ECM-Col/HA scaffold was a suitable mimic of the bone marrow “niche.” This novel 3D stromal-cell-derived ECM system has the potential to be developed into a biomedical platform for regenerative medicine applications.

To evaluate the effect of schistosomiasis control in Lushan earthquake-stricken areas in Sichuan Province, so as to provide the evidence for formulating appropriate measures for schistosomiasis prevention and control.According to the data of historical schistosomiasis prevalence, 5 villages were selected as research sites and field investigations were conducted.The average density of Oncomelania hupensis snails was 0.41 snails/0.1 m2, and there were no schistosome-infected snails. There were no acute schistosomiasis cases in these five villages. For local residents, the health education leaflets were more suitable than warning signs, and for migrant population, they were more concerned about the warning signs.After the implementation of effective prevention and control works, the epidemic risks of schistosomiasis have been controlled. However, the health education, surveillance, and prevention measures for schistosomiasis still need to be persisted in.

Here we provide the first report of protection against a vaginal challenge with a highly virulent simian immunodeficiency virus (SIV) by using a vaccine vector. New poliovirus vectors based on Sabin 1 and 2 vaccine strain viruses were constructed, and these vectors were used to generate a series of new viruses containing SIVgag,pol,env,nef, andtatin overlapping fragments. Two cocktails of 20 transgenic polioviruses (SabRV1-SIV and SabRV2-SIV) were inoculated into seven cynomolgus macaques. All monkeys produced substantial anti-SIV serum and mucosal antibody responses. SIV-specific cytotoxic T-lymphocyte responses were detected in three of seven monkeys after vaccination. All 7 vaccinated macaques, as well as 12 control macaques, were challenged vaginally with pathogenic SIVmac251. Strikingly, four of the seven vaccinated animals exhibited substantial protection against the vaginal SIV challenge. All 12 control monkeys became SIV positive. In two of the seven SabRV-SIV-vaccinated monkeys we found no virological evidence of infection following challenge, indicating that these two monkeys were completely protected. Two additional SabRV-SIV-vaccinated monkeys exhibited a pronounced reduction in postacute viremia to 3copies/ml, suggesting that the vaccine elicited an effective cellular immune response. Three of six control animals developed clinical AIDS by 48 weeks postchallenge. In contrast, all seven vaccinated monkeys remained healthy as judged by all clinical parameters. These results demonstrate the efficacy of SabRV as a potential human vaccine vector, and they show that the use of a vaccine vector cocktail expressing an array of defined antigenic sequences can be an effective vaccination strategy in an outbred population.

The intact cervicovaginal mucosa is a relative barrier to the sexual transmission of human immunodeficiency virus type 1 (HIV-1). In the simian immunodeficiency virus (SIV) macaque model of HIV infection, seronegative transient viremia (STV; virus isolation positive followed by repeated negative cultures) occurs after intravaginal inoculation of a low dose of pathogenic SIVmac251 (C. J. Miller, M. Marthas, J. Torten, N. Alexander, J. Moore, G. Doncel, and A. Hendrickx, J. Virol. 68:6391–6400, 1994). Thirty-one adult female macaques that had been inoculated intravaginally with pathogenic SIVmac251 became transiently viremic. One monkey that had been culture negative for a year after SIV inoculation became persistently viremic and developed simian AIDS. No other STV monkey developed persistent viremia or disease. Results of very sensitive assays showed that 6 of 31 monkeys had weak SIV-specific antibody responses. SIV-specific antibodies were not detected in the cervicovaginal secretions of 10 STV monkeys examined. Twenty of 26 monkeys had lymphocyte proliferative responses to p55 gag and/or gp130 env antigens; 3 of 6 animals, including the monkey that became persistently viremic, had detectable cytotoxic T-lymphocyte (CTL) responses to SIV. At necropsy, lymphoid tissues and vaginal mucosa were virus culture negative, but in 10 of 10 animals, SIV provirus was detected by PCR using gag -specific primer pairs. Fifty percent of the PCR-positive tissue samples were also positive for SIV gag RNA by reverse transcriptase PCR. Thus, transient viremia following intravaginal inoculation of pathogenic SIV is associated with persistent, systemic infection, either latent or very low level productive. Atypical immune responses, characterized by lymphocyte proliferation and some CTL responses in the absence of conventionally detectable antibodies, develop in transiently viremic monkeys.

Recent studies have shown that miR-199a-5p plays opposite roles in cancer initiation and progression of different cancer types, acting as oncogene for some cancer types but as tumor suppressor gene for others. However, the role and molecular mechanism of miR-199a-5p in gastric cancer are largely unknown.In this study, miR-199a-5p expression level in gastric cancer was first analyzed by qPCRand then validated in 103 gastric cancer patients by in situ hybridization (ISH). Gastric cancer cell lines were transfected with miR-199a-5p inhibitor and mimic, and underwent in vitro transwell assays. Target genes (klotho) were identified using Luciferase reporter assay. Immunohistochemical staining was also used to investigate on how miR-199a-5p regulates the tumour-suppressive effects of klotho in gastric cancer.In our present study, we found that miR-199a-5p level was significantly increased in gastric cancer tissues compared to paired normal tissues. We observed that miR-199a-5p could promote migration and invasion of gastric cancer cells. In situ hybridization of miR-199a-5p also confirmed that higher miR-199a-5p expression level was associated with increased likelihood of lymph node metastasis and later TNM stage. Luciferase reporter assay and immunohistochemistry revealed that klotho might be the downstream target of miR-199a-5p.Our present study suggests that miR-199a-5p acts as an oncogene in gastric cancer and functions by targeting klotho.

To assess the impact of the "4 x 20" Lushan Earthquake on the risk of schistosomiasis transmission in Lushan and Tianquan counties, so as to provide the evidence for formulating appropriate measures for schistosomiasis prevention and control.Based on a comprehensive literature review, an analysis of schistosomiasis monitoring data in the earthquake affected counties, and a field investigation, a rapid assessment on the impact of the earthquake on schistosomiasis was conducted.Lushan and Tianquan counties were two endemic areas of schistosomiasis with high transmission level in history, especially Lushan County where Oncomelania snail distribution/density was the highest in Sichuan Province. After the earthquake, the streams and damaged ditches were blocked up, potentially leading to the spread of Oncomelania snails, and the damaged sanitary facilities may also lead to the release of excrement, contaminating the environment where snails resided. Meanwhile, the people who were relocated due to the earthquake may have higher exposures to contaminated environment. In addition, increasing population mobility (e.g. relief workers) also had the potential to bring infection sources in the earthquake affected areas. Further, animals, which may serve as reservoirs for the parasite such as homeless dogs, may also add the complexity of local schistosomiasis transmission.The epidemic risk of schistosomiasis in Lushan and Tianquan counties is high. To prevent the outbreak and epidemic of schistosomiasis, the victim settlements should be established appropriately and the excrement should be managed carefully. Meanwhile, the snail control should be carried out in the high-risk environments. The health education, monitoring, patient treatments and expanded chemotherapy should be carried out and strengthened.

Freshly resected human non-small cell lung cancer (NSCLC) has been successfully transplanted and propagated subcutaneously in nude mice (Cancer Letters 61 (1991) 53-60). We used this model to study the changes of the human metastasis suppressor genes, nm23-H1 and nm23-H2, through the process of propagation and metastasis of human NSCLC. Using a non-radioisotopic Southern analysis, the nm23-H1 and nm23-H2 genes were detected without evidence of deletion in the early generations of the tumor grafts. These genes, however, were absent from the tumor grafts sampled past 4 generations of propagation and from all the propagated metastases originated from the subcutaneous grafts. Further restriction analysis revealed that only mouse DNA, but no human Alu DNA, was present in the tumor specimens which lacked the human nm23 genes. Thus, there is a loss of human DNA but a gain of mouse DNA in the propagated tumors originated from the transplanted human NSCLC. The mechanisms of loss of human DNA in these propagated tumors in nude mice have yet to be delineated.