Search

Background: Glanders is a rare zoonotic disease caused by Burkholderia mallei. Humans can be infected by B. mallei, which causes cutaneous lymphadenitis and pneumonia, leading to sepsis and death in severe cases. Case presentation: We report a case of a 60-year-old male who was diagnosed with glanders. The patient who had a history of diabetes presented with cough, expectoration, and fever. Computed tomography (CT) imaging showed B. mallei infection in the right upper lobe of the lung with mediastinal lymph node involvement and the lingual segment of the left lung. Moreover, the posterior basal segment of the lower lobe of both lungs had inflammation. Subsequently, B. mallei infection was confirmed by lymph node biopsy and bronchoalveolar lavage multiplex PCR-based targeted gene sequencing. After meropenem treatment, the patient was discharged, and CT imaging showed reduced absorption of pulmonary inflammatory lesions. Conclusions: Glanders is a rare disease that can cause skin infection, lymphadenitis, and pneumonia, and in severe cases, it can be life-threatening. The diagnosis of this disease mainly relies on microbiological culture and pathological biopsy. Diagnosis is also facilitated by multiplex PCRbased targeted gene sequencing. Glanders is treated with cephalosporins, carbapenems, and other sensitive antibiotics.

Supplementary Figure 1: PTENP1 and PTEN expression were decreased in human ccRCC samples. Supplementary Figure 2: PTENP1 expression in ACHN and SN12PM6 cells. Supplementary Figure 3: PTENP1 expression activated AKT in ACHN and SN12PM6 cells. Supplementary Figure 4: miR-21 expression in ACHN and SN12PM6 cells. Supplementary Figure 5: PTEN expression in ACHN and SN12PM6 cells. Supplementary Figure 6: 5-10 fold overexpression of PTENP1 increased PTEN expression and suppressed cell proliferation, migration and invasion. Supplementary Figure 7: PTENP1 functions and regulation of PTEN are DICER dependent. Supplementary Figure 8: 5'AZA increased PTENP1 and PTEN expression and suppressed cell proliferation, migration and invasion. Supplementary Figure 9: Cisplatin and gemcitabine treatment increased PTENP1 expression.

Supplementary Figure Legend

Purpose: To assess the pre-operative risk factors for post-operative urosepsis following mini-percutaneous nephrolithotomy (mPCNL) in patients with large kidney stones. Methods：Records of ...

Supplementary Figure from Alternative Splicing of EZH2 pre-mRNA by SF3B3 Contributes to the Tumorigenic Potential of Renal Cancer

Purpose:Deregulation or mutation of the EZH2 gene causes various tumors, including clear cell renal cell carcinoma (ccRCC). Although several splice variants of EZH2 have been identified, little is known about how EZH2 splicing is regulated or the contribution of alternative splicing to its protumorigenic functions.Experimental Design:We conducted RT-PCR, Western blot analysis, and IHC techniques to examine EZH2 and its alternative splicing transcript expression in renal cancer tissue and renal cancer cell lines. Proliferation, migration, clonogenicity, and tumorigenicity of renal cancer cells either exhibiting knockdown of EZH2 or its splicing factor SF3B3 were assessed by CCK8, Transwell assay, and murine xenograft experiments.Results:We found that the inclusion of alternative EZH2 exon 14 was significantly increased in ccRCC samples and renal cancer cell lines. In ccRCC lines, enforced expression of EZH2Δ14 inhibited, and EZH2 promoted, cell growth, migration, proliferation, and tumorigenicity in a xenograft model. Mechanistic studies demonstrated that EZH2Δ14 isoform functions as a dominant-negative inhibitor of full-length EZH2. Coexpression of EZH2Δ14 variant with full-length EZH2 not only abrogated DAB2IP and HOXA9 suppression but also inhibited EZH2-driven tumorigenesis. Strikingly, the splicing factor SF3B3 stimulates inclusion of exon14 and has pro-proliferative activity. Importantly, the upregulation of SF3B3 expression observed in clinical ccRCC samples parallels the increased inclusion of EZH2 exon14, and the SF3B3 level is associated with higher tumor stage and poor overall survival.Conclusions:These results suggest SF3B3 as a key regulator of EZH2 pre-mRNA splicing and SF3B3 may represent a novel prognostic factor and potential therapeutic target in ccRCC.

CD46 is well known to be involved in diverse biological processes. Although several splice variants of CD46 have been identified, little is known about the contribution of alternative splicing to its tumorigenic functions. In this study, we found that exclusion of CD46 exon 13 is significantly increased in bladder cancer (BCa) samples. In BCa cell lines, enforced expression of CD46-CYT2 (exon 13-skipping isoform) promoted, and CD46-CYT1 (exon 13-containing isoform) attenuated, cell growth, migration, and tumorigenicity in a xenograft model. We also applied interaction proteomics to identify exhaustively the complexes containing the CYT1 or CYT2 domain in EJ-1 cells. 320 proteins were identified that interact with the CYT1 and/or CYT2 domain, and most of them are new interactors. Using an internal ribosome entry site (IRES)-dependent reporter system, we established that CD46 could regulate mRNA translation through an interaction with the translation machinery. We also identified heterogeneous nuclear ribonucleoprotein (hnRNP)A1 as a novel CYT2 binding partner, and this interaction facilitates the interaction of hnRNPA1 with IRES RNA to promote IRES-dependent translation of HIF1a and c-Myc. Strikingly, the splicing factor SRSF1 is highly correlated with CD46 exon 13 exclusion in clinical BCa samples. Taken together, our findings contribute to understanding the role of CD46 in BCa development., Graphical Abstract, Aberrant alternative splicing is one of the molecular hallmarks of cancer. In this study, we investigated the contribution of CD46 alternative splicing to bladder cancer development and defined a new role for CD46 in regulation of translation. Next, we showed that SRSF1, by regulating the splicing of CD46, reinforces an aggressive phenotype.

Background Increased hypoxia‐inducible factor 2α (HIF2α) activation is a common event in clear cell renal cell carcinoma (ccRCC) progression. However, the function and underlying mechanism of HIF2α in ccRCC remains uninvestigated. We conducted this study to access the potential link between junction plakoglobin (JUP) and HIF2α in ccRCC. Methods Affinity purification and mass spectrometry (AP‐MS) screening, glutathione‐s‐transferase (GST) pull‐down and co‐immunoprecipitation (Co‐IP) assays were performed to detect the interacting proteins of HIF2α. Quantitative PCR (qPCR) and Western blotting were used to detect the expression of JUP in human ccRCC samples. Luciferase reporter assays, chromatin immunoprecipitation (ChIP), cycloheximide chase assays, and ubiquitination assays were conducted to explore the regulation of JUP on the activity of HIF2α. Cell Counting Kit‐8 (CCK‐8) assays, colony formation assays, transwell assays, and xenograft tumor assays were performed to investigate the effect of JUP knockdown or overexpression on the tumorigenicity of renal cancer cells. Results We identified JUP as a novel HIF2α‐binding partner and revealed an important role of JUP in recruiting von Hippel‐Lindau (VHL) and histone deacetylases 1/2 (HDAC1/2) to HIF2α to regulate its stability and transactivation. JUP knockdown promoted and overexpression suppressed the tumorigenicity of renal cell carcinoma in vitro and in vivo. Importantly, the low expression of JUP was found in clinical ccRCC samples and correlated with enhanced hypoxia scores and poor treatment outcomes. Conclusion Taken together, these data support a role of JUP in modulating HIF2α signaling during ccRCC progression and identify JUP as a potential therapeutic target., We provide a mechanism by which the tumor suppressor JUP interact with the HIF2α transcription factor in ccRCC cells. JUP downregulation is likely to trigger the aberrant upregulation of HIF2α stability and transactivity, which further exerts effects on tumorigenesis in ccRCC. These results have important implications in both the diagnosis and treatment of RCC.

Ginsenosides, phenolic compounds, and polysaccharides are the bioactive constituents of Panax ginseng Meyer. Compound K (CK) is a secondary ginsenoside with better bioavailability. It is also a promising anticancer agent.We aimed to evaluate the effect of CK on prostate cancer (PCa) and its potential mechanisms.The proliferation, migration and cell cycle of PCa cells after CK treatment were assessed in various PCa cell lines. Docetaxel was used as a positive control drug. Unlike other published studies, the potential mechanisms of CK (50 μM) were investigated by an unbiased global transcriptome sequencing in the current study.Key CK related genes (CRGs) with prognostic significance were identified and verified by bioinformatic methods using data from the TCGA dataset and GSE21034 dataset. The role of CDK1 in the effect of CK treatment on PCa cells was investigated by overexpression of CDK1.CK inhibited the proliferation and migration of PCa cells at concentrations (less than 25 μM) without obvious cytotoxicity. Five key CRGs with prognostic significance were identified, including CCNA2, CCNB2, CCNE2, CDK1, and PKMYT1, which are involved in cell cycle pathways. CK inhibited the expression of these 5 genes and the cell cycle of PCa cells. According to the results of bioinformatic analysis, the expression of the five key CRGs was strongly associated with poor prognosis and advanced pathological stage and grade of PCa. In addition, CK could restore androgen sensitivity in castration-resistant PCa cells, probably by inhibiting the expression of CDK1. After CDK1 overexpression, the inhibition of proliferation and migration of PCa cells by CK was decreased. The inhibition on the phosphorylation of AKT by CK was also reduced.CK can inhibit PCa cells, and the mechanisms may be associated with the inhibition of cell cycle pathways through CDK1. CK is also a potential clinical anticancer agent for treating PCa.

The DNA repair enzyme 8-oxoguanine DNA glycosylase-1 (OGG1) is involved in early embryonic development, as well as in multiple conditions, including cardiac fibrosis, diabetes, and neurodegenerative diseases. But, function of OGG1 in pulmonary fibrosis was not entirely clear. In this study, we identified a novel function of OGG1 in the cell transformation process in pulmonary fibrosis. We demonstrated that OGG1 and Smad7 co-localize and interact in A549 cells. Bleomycin-induced pulmonary fibrosis was established in wild-type (WT) and Ogg1-/- mice. Upon treatment with transforming growth factor (TGF)-β1, increased OGG1 expression was observed in WT mice with pulmonary fibrosis as well as in A549 cells, MRC-5 cells, and primary rat type II alveolar epithelial cells. The increased expression of OGG1 promoted cell migration, while OGG1 depletion decreased migration ability. Expression of the transformation-associated markers vimentin and alpha-smooth muscle actin were also affected by OGG1. We also observed that OGG1 promoted TGF-β1-induced cell transformation and activated Smad2/3 by interacting with Smad7. The interaction between OGG1 and the TGF-β/Smad axis modulates the cell transformation process in lung epithelial cells and fibroblasts. Moreover, we demonstrated that Ogg1 deficiency relieved pulmonary fibrosis in bleomycin-treated mice. Ogg1 knockout decreased the bleomycin-induced expression of Smad7 and phosphorylation of Smad2/3 in mice. These findings suggest that OGG1 has multiple biological functions in the pathogenesis of pulmonary fibrosis.

The static–dynamic performance of body-in-prime (BIP) which contains glass was improved by optimizing its beam-like structure parameters. An implicit parametric model of BIP was built using SFE CON...

Background We have reported that heparin-binding epidermal growth factor (HB-EGF) is increased in patients with chronic obstructive pulmonary disease (COPD) and associated with collagen deposition, but the mechanisms remain unclear. In the present study, we aimed to investigated the inflammatory cytokines secreted by bronchial epithelial cells following exposure to HB-EGF that promoted proliferation and migration of human lung fibroblast. Methods HB-EGF–induced inflammatory cytokines were assayed in two airway epithelial cells (primary human bronchial epithelial cells [HBECs] and BEAS-2B cells). Moreover, the culture supernatants derived from HB-EGF-treated HBECs and BEAS-2B cells were added to human primary lung fibroblasts. The effect of culture supernatants on proliferation and migration of fibroblasts was assessed. Results IL-8 expression was significantly increased in bronchial epithelial cells treated with HB-EGF, which was at least partially dependent on NF-kB pathways activation. HB-EGF–induced IL-8 was found to further promote lung fibroblasts proliferation and migration, and the effects were attenuated after neutralizing IL-8. Conclusions These findings suggest that HB-EGF may be involved in the pathology of airway fibrosis by induction of IL-8 from airway epithelium, subsequently causing lung fibroblasts proliferation and migration. Thus, inhibition of HBEGF and/or IL-8 production could prevent the development of airway fibrosis by modulating fibroblast activation.

Dysregulation of the epigenetic status of long noncoding RNAs (lncRNAs) has been linked to diverse human diseases including human cancers. However, the landscape of the whole-genome methylation profile of lncRNAs and the precise roles of these lncRNAs remain elusive in renal cell carcinoma (RCC). We first examined lncRNA expression profiles in RCC tissues and corresponding adjacent normal tissues (NTs) to identify the lncRNA signature of RCC, then lncRNA Promoter Microarray was performed to depict the whole-genome methylation profile of lncRNAs in RCC. Combined analysis of the lncRNAs expression profiles and lncRNAs Promoter Microarray identified a series of downregulated lncRNAs with hypermethylated promoter regions, including NR_023387. Quantitative real-time polymerase chain reaction (RT-PCR) implied that NR_023387 was significantly downregulated in RCC tissues and cell lines, and lower expression of NR_023387 was correlated with shorter overall survival. Methylation-specific PCR, MassARRAY, and demethylation drug treatment indicated that hypermethylation in the NR_023387 promoter contributed to its silencing in RCC. Besides, HNF4A regulated the expression of NR_023387 via transcriptional activation. Functional experiments demonstrated NR_023387 exerted tumor-suppressive roles in RCC via suppressing the proliferation, migration, invasion, tumor growth, and metastasis of RCC. Furthermore, we identified MGP as a putative downstream molecule of NR_023387, which promoted the epithelial-mesenchymal transition of RCC cells. Our study provides the first whole-genome lncRNA methylation profile in RCC. Our combined analysis identifies a tumor-suppressive and prognosis-related lncRNA NR_023387, which is silenced in RCC via promoter hypermethylation and HNF4A deficiency, and may exert its tumor-suppressive roles by downregulating the oncogenic MGP.

Taurine-upregulated gene 1 (TUG1) has been involved in tumorigenesis of several human cancers, but its precise biological role in bladder cancer remains largely elusive. In this study, we found that TUG1 was upregulated in bladder cancer and the expression of TUG1 was positively and negatively correlated with CCND2 and miR-194-5p, respectively. MiR-194-5p expression was frequently decreased through promoter hypermethylation, while it was epigenetically increased following cisplatin and 5-aza-2′-deoxycytidine (5-Aza-DC) treatment. Furthermore, knockdown of TUG1 attenuated the expression of epigenetic regulator Enhancer of zeste homolog 2 (EZH2), and it alleviated the promoter hypermethylation of miR-194-5p and induced its expression. Increased miR-194-5p expression or decreased TUG1 expression significantly sensitized bladder cancer cells to cisplatin, inhibited the proliferation, and induced apoptosis. Besides, CCND2 was a direct target of miR-194-5p, while miR-194-5p was regulated by TUG1. CCND2 could partially restore the tumor-suppressive effects on cell proliferation and cisplatin resistance following TUG1 silencing. Additionally, TUG1 expression was correlated with clinical stage, lymphatic metastasis, and patient prognosis. In conclusion, TUG1 promotes bladder cancer cell growth and chemoresistance by regulating CCND2 via EZH2-associated silencing of miR-194-5p. Our study may be conducive to elucidating the molecular mechanism of and providing novel therapeutic target and biomarker for bladder cancer. Keywords: TUG1, chemoresistance, CCND2, miR-194-5p, bladder cancer, cisplatin resistance, methylation, EZH2

Hypertension is associated with increased risk of stroke and bleeding in patients with atrial fibrillation (AF). In the present study, we aimed to investigate the influence of hypertension status in patients with AF receiving treatment with non-vitamin K antagonist oral anticoagulants (NOACs). PubMed, Embase, and Cochrane Library were searched from the inception of each database to November 2017. Randomized controlled trials (RCTs) that evaluated NOACs versus warfarin in patients with AF and hypertension were identified. A meta-analysis was performed using random- or fixed-effects models according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Five trials (72,967 patients, including 51,378 patients with hypertension) were enrolled. NOACs significantly reduced the risk of stroke and systemic embolism (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.81–0.94, n = 51,378 patients), hemorrhagic stroke (HR 0.55, 95% CI 0.41–0.74, n = 28,818 patients), death from any cause (HR 0.91, 95% CI 0.85–0.97, n = 43,101 patients), major bleeding (HR 0.78, 95% CI 0.74–0.83, n = 51,378 patients) and intracranial bleeding (HR 0.50, 95% CI 0.38–0.67, n = 27,185 patients). The benefits of NOACs in comparison with warfarin were consistent in AF patients with or without hypertension (Pinteraction for all outcomes > 0.05). Our findings suggest that NOACs can be recommended for the prevention of stroke or systemic embolism in patients with AF and hypertension.

Cobalt sulfide (Co1−xS) is studied extensively as an anode material for lithium-ion batteries (LIBs) due to high theoretical capacity, however, low electronic conductivity and large volume change during the discharge/charge process limit its actual application. In this study, we synthesize Co1−xS-reduced graphene oxide (Co1−xS-rGO) composite through a simple solvothermal reaction and then freeze-drying process. The introduction of rGO not only improves electronic conductivity and redox kinetics of electrode material but also prevents Co1−xS nanoparticles from aggregation. At a current density of 200 mA g−1, the discharge capacity of Co1−xS-rGO maintains 643 mAh g−1 after 100 cycles. Even at high current density of 1000 mA g−1, the discharge capacity of 625 mAh g−1 is retained after 200 cycles, which is close to theoretical capacity (683 mAh g−1). And then, Co1−xS-rGO delivers good rate performance and cycling stability. In the meanwhile, in-situ synthesis method is facile. These results indicate that Co1−xS-rGO could be a promising anode material for LIBs.

Path planning is a fundamental problem in the aspect of autonomous driving. A-star (A*) algorithm is a heuristic algorithm for path planning. However, there are two problems need to be solved in the traditional A-star algorithm: firstly, the tracking error caused by vehicle speed and vehicle size are not considered in path planning; secondly, the kinematics constraints of the vehicle itself and the smoothness of the path in the actual driving process are not considered. Therefore, this paper proposes an improved A-star algorithm to address the above deficiencies. By designing the collision cost heuristic function based on the position of obstacles, the vehicle contour and speed are considered and the vehicle safety is improved by setting a safe space around the vehicle, and establishing a steering cost heuristic function based on the control of heading angle difference, the vehicle dynamics constraints are satisfied, so as to improve the feasibility of path planning. The experimental results show that the improved A-star algorithm can avoid vehicle contours collision at different speeds and output a smoother path, and effectively generate higher quality path.

Aiming at the road spectrum simulation test rig of the front subframe of a car, the design of the test rig fixture based on multi-objective Optimization and the simulation prediction of the fatigue life are introduced in detail. Our engineers optimize the stiffness of the test rig by using the finite element software, so that the stiffness of the car body can be accurately simulated, and the force characteristics of the subframe on the test rig are the same as on the real car, thus the validity and accuracy of the bench test results are ensured. The fatigue test of the subframe is simulated by using the fatigue life software FEMFAT and the fatigue life of the subframe is predicted, greatly reducing the test time.

Background Aberrant alternative splicing events play critical roles in carcinogenesis and progression of many cancers, while sparse studies regarding to alternative splicing are available for clear cell renal cell carcinoma (ccRCC). We identified that alternative splicing of coiled-coil domain containing 50 (CCDC50) was dysregulated in ccRCC, whereas the clinical significance of this splicing event and its splicing regulation mechanisms were still elusive. Methods Bioinformatic algorithm was utilized to identify significant exon skipping events in ccRCC via exon sequencing data from The Cancer Genome Atlas. Semi-quantitative real-time polymerase chain reaction and western blot were used to validate the aberrant expression of different transcripts in renal cancer tissues, cell lines and corresponding noncancerous controls. Short hairpin RNA targeting CCDC50 and overexpressing plasmids for each transcript were introduced into ccRCC cell lines, followed by a series of in vitro and in vivo functional experiments. Moreover, a panel of splicing factors were identified and their roles on splicing regulation of CCDC50 precursor mRNA (pre-mRNA) were studied. Furthermore, RNAseq data were analyzed to elucidate downstream molecules of CCDC50. Two-way analysis of variance and unpaired Student t test were used in statistical analysis. Results Pre-mRNA of CCDC50 generated two transcripts, full-length transcript (CCDC50-FL) and truncated transcript (CCDC50-S) with exon 6 skipped. CCDC50-S was overexpressed in ccRCC tissues and cell lines compared to noncancerous counterparts, but CCDC50-FL was only detected in noncancerous tissues and normal renal epithelial cells. Higher percent spliced-in index was associated with better survival in ccRCC patients. In vitro and in vivo functional experiments indicated that CCDC50-S transcript promoted the proliferation, migration, invasion and tumorigenesis of ccRCC, while CCDC50-FL exerted opposite tumor suppressive functions. Besides, we identified that heterogeneous nuclear ribonucleoprotein A1 (HnRNP A1) could promote the skipping of exon 6, which resulted in higher portion of CCDC50-S and oncogenic transformation. Moreover, zinc finger protein 395 (ZNF395) was identified as a downstream protein of CCDC50-S, and the interaction initiated oncogenic pathways which were involved in ccRCC progression. Conclusions Aberrant alternative splicing of CCDC50 is regulated by HnRNP A1 in ccRCC. This splicing event contributes to cancer progression through the downstream pathway involving ZNF395.

Additional file 2. Supplementary figure 1–10.

Additional file 1. Supplementary table 1. The primers used in the study.

s In this study, we determined the spatial variations and potential risks of heavy metals in the sediments of Yueqing Bay by assessing the relationship between metal concentrations and sediment physiochemical factors. We found higher sediment metal concentrations in the inner bay than in the central and outer bay, particularly with respect to Hg, Cu, and Pb concentrations. According to the sediment quality guidelines, the heavy metals had a toxicity incidence probability of 21%. Assessments of heavy metal contamination using the geo-accumulation index and potential ecological risk index suggest that Cr, As, Pb, and Hg likely pose low ecological risks, while Cu, Zn, and Cd were identified as priority pollutants and may pose moderate ecological risks to the ecosystem. Multivariate statistical analysis inferred the high influence of sediment texture, total organic carbon (TOC), and petroleum hydrocarbons (PHCs) on the distribution and fate of metals in sediment.

In Traditional Chinese Medicine, Polygonum multiflorum (PM) is known for its anti-aging properties. A previous study by our group showed that extracts of PM were able to prevent and treat bone loss in vivo, and the active components emodin and 2,3,5,4,-tetrahydroxystilbene-2-O-β-glucoside (TSG) promoted the osteogenic differentiation of mesenchymal stem cells in vitro. The aim of the present study was to investigate the preventive effects of PM on glucocorticoid-induced osteoporosis (GIO) in rats. A crude extract of PM was prepared with 75% ethanol, purified and enriched using a D-101 macroresin column and elution with 30% ethanol, and the material obtained was assessed by high-performance liquid chromatography. Male or female Sprague Dawley rats (n=180) were randomly divided into nine groups: Control, prednisone, prednisone plus calcitriol (CAL), prednisone plus 30% ethanolic eluate of PM [high (H), medium (M) and low (L) dose] and prednisone plus crude extract of PM (H, M and L dose). Prednisone was orally administered to the osteoporosis model rats for 21 weeks, alongside which they received PM extracts. The weight of the viscera, anterior tibial muscle and other tissues was recorded at the end of the experiment. The femur and lumbar vertebra were collected for the measurement of three-dimensional microarchitecture by micro-computed tomography scanning, assessment of biomechanical properties and determination of bone mineral density (BMD). In the 30% ethanolic eluate of the PM extract, the content of TSG and combined anthraquinone was 9.20 and 0.15%, respectively, and that in the crude extract of PM was 2.23 and 0.03%, respectively. Over 6 weeks, the weight of the rats the in prednisone group decreased (P

Long non-coding RNAs (lncRNAs) exert critical regulatory roles in the development and progression of several cancers. Plasmacytoma variant translocation 1 (PVT1), an lncRNA, was shown to be upregulated in clear cell renal cell carcinoma (ccRCC) in our study, while Kaplan-Meier curve and Cox regression analysis showed that high expression of PVT1 was associated with poor overall survival (OS) and disease free survival (DFS) in ccRCC patients. In vitro experiments revealed that PVT1 promoted renal cancer cell proliferation, migration, and invasion, while in vivo studies confirmed its oncogenic roles in ccRCC. Further bioinformatic analysis and RNA immunoprecipitation revealed that PVT1 could function as an oncogenic transcript partly through sponging miR-200s to regulate BMI1, ZEB1 and ZEB2 expression. Besides, a novel splicing variant of PVT1 lacking exon 4 (PVT1ΔE4) was found to have a higher expression in ccRCC and could also promote cell proliferation and invasion as the full-length transcript did. Besides, SRSF1 decreased the inclusion of exon 4 of full-length transcript and increased the relative expression of PVT1ΔE4 in ccRCC. Mechanistic investigations indicated that PVT1ΔE4 could also upregulate the expression of BMI1, ZEB1 and ZEB2 through interacting with miR-200s. Our study helps reveal new molecular events in ccRCC and provides promising diagnostic and therapeutic targets for this disease.

Background: Our previous study identified a novel microRNA, miR-4673, which is upregulated in A549 cells exposed to paclitaxel (PTX). In this study, we investigated the role of miR-4673 in PTX-induced cytotoxicity. Methods: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, apoptosis assay, 5,5’,6,6’-Tetrachloro-1,1’,3,3’-tetraethyl-imidacarbocyanine iodide (JC-1) staining and 2’,7’-Dichlorofluorescein (DCFH) staining were used to evaluate cell viability, apoptosis, mitochondrial membrane potential (MMP) loss and reactive oxygen species (ROS) generation in A549 and H1299 cells. Bioinformatics analysis and Luciferase reporter assay were used to explore whether 8-oxoguanine-DNA glycosylase-1 (OGG1) is a target gene of miR-4673. Results: Enforced expression of miR-4673 decreased cell viability and increased PTX-induced apoptosis, MMP loss and reactive oxygen species (ROS) generation in A549 and H1299 cells. Bioinformatics analysis, which was used to identify potential target of miR-4673, revealed a binding site of miR-4673 in 3’UTR of OGG1. Luciferase reporters assays showed that miR-4673 specifically binds to ‘CUGUUGA’ in 3’UTR of OGG1. Enforced expression of miR-4673 decreased accumulation of OGG1. In addition, silencing OGG1 enhanced inhibitory effects of PTX on apoptosis, MMP loss and ROS generation, which is similar to effects of miR-4673. Moreover, enforced expression of OGG1 compromised promoting effects of miR-4673 on PTX-induced apoptosis, MMP loss and ROS generation. Conclusion: miR-4673 modulates PTX-induced apoptosis, MMP loss and ROS generation by targeting OGG1.

BACKGROUND The histone methyltransferase (HMT) family includes histone lysine methyltransferases (HKMTs) and histone/protein arginine methyltransferases (PRMTs). The role of HMT gene variants in prostate cancer remains unknown. Therefore, this study aimed to evaluate HMT gene variants in the pathogenesis and prognosis of human prostate cancer, using in vitro cell studies and bioinformatics analysis. MATERIAL AND METHODS Integrative bioinformatics analysis of the expression of 51 HMT genes in human prostate cancer was based on datasets from the Cancer Genome Atlas (TCGA). Correlation and regression analysis were used to identify critical HMTs in prostate cancer. Kaplan-Meier and the area under the receiver operating characteristics curve (AUROC) were performed to evaluate the function of the HMTs on prognosis. Gene expression and function of 22Rv1 human prostate carcinoma cells were studied. RESULTS The HMT genes identified to have a role in the pathogenesis of prostate cancer included the EZH2, SETD5, PRDM12, NSD1, SETD6, SMYD1, and the WHSC1L1 gene. The EZH2, SETD5, and SMYD1 genes were selected as a prognostic panel, with the SUV420H2 HMT gene. SETD2, NSD1, and ASH1L were identified as critical genes in the development of castration-resistant prostate cancer (CRPC), similar to mixed-lineage leukemia (MLL) complex family members. Knockdown of the SETD5 gene in 22Rv1 prostate carcinoma cells in vitro inhibited cancer cell growth and migration. CONCLUSIONS HMT gene variants may have a role in the pathogenesis of prostate cancer. Future studies may determine the role of HMT genes as prognostic biomarkers in patients with prostate cancer.

The signaling adaptor sequestosome 1 (SQSTM1)/p62 is frequently overexpressed in tumors and plays an important role in the regulation of tumorigenesis. Although great progress has been made, biological roles of p62 and relevant molecular mechanisms responsible for its pro-tumor activity remain largely unknown. Here, we show that p62 knockdown reduces cell growth and the expression of glycolytic genes in a manner that depends on HIF1α activity in renal cancer cells. Knockdown of p62 decreases HIF1α levels and transcriptional activity by regulating mTORC1 activity and NF-κB nuclear translocation. Furthermore, p62 interacts directly with the von Hippel-Lindau (VHL) E3 ligase complex to modulate the stability of HIF1α. Mechanistically, p62 binds to the VHL complex and competes with HIF1α. Expression of p62 inhibits the interaction of DCNL1 (also known as DCUN1D1) with CUL2 and attenuates the neddylation of CUL2, and thus downregulates the VHL E3 ligase complex activity. Functionally, HIF1α expression is required for p62-induced glucose uptake, lactate production and soft agar colony growth. Taken together, our findings demonstrate that p62 is a crucial positive regulator of HIF1α, which is a facilitating factor in p62-enhanced tumorigenesis., Highlighted Article: p62 is a crucial positive regulator of HIF1α, which is a facilitating factor in p62-enhanced tumorigenesis.

Background and aims Aging-induced bone loss is a multifactorial, age-related, and progressive phenomenon among the general population and may further progress to osteoporosis and increase the risk of fractures. Cycloastragenol (CAG), currently the only compound reported that activates human telomerase, is thought to be able to alleviate or delay the symptoms of aging and chronic diseases. Previous research has suggested that CAG may have the potential to alleviate age-related bone loss. However, to date, no research has specifically focused on this aspect. In this study, we aimed to investigate whether CAG could prevent senile osteoporosis, and further reveal its underlying mechanism. Methods CAG treatment was administrated into two bone loss rat models (D-galactose administration and aging) for 20 weeks and 33 weeks, respectively. Serum biomarkers analyses, bone biomechanical tests, micro-computed tomography assessment, and bone histomorphometry analyses were performed on the bone samples collected at the endpoint, to determine whether CAG could prevent or alleviate age-related bone loss. Proteomic analysis was performed to reveal the changes in protein profiles of the bones, and western blot was used to further verify the identity of the key proteins. The viability, osteoblastic differentiation, and mineralization of MC3T3-E1 cells were also evaluated after CAG treatment in vitro. Results The results suggest that CAG treatment improves bone formation, reduces osteoclast number, alleviates the degradation of bone microstructure, and enhances bone biomechanical properties in both d -galactose- and aging-induced bone loss models. CAG treatment promotes viability, osteoblastic differentiation, and mineralization in MC3T3-E1 cells. Proteomic and western blot analyses revealed that CAG treatment increases osteoactivin (OA) expression to alleviate bone loss. Conclusion The results revealed that CAG alleviates age-related bone loss and improves bone microstructure and biomechanical properties. This may due to CAG-induced increase in OA expression. In addition, the results support preclinical investigations of CAG as a potential therapeutic medicine for the treatment of senile osteoporosis.

Background Information Dysregulated micro‐RNAs have been reported in many human cancers, including renal cell carcinoma. Recent studies indicated that miR‐490 is involved in tumour development and progression. However, the expression profile and function in renal cell carcinoma remains unknown. Results Herein, we showed that miR‐490‐5p was down‐regulated in renal cell carcinoma tissues and cells compared with the adjacent normal tissues and normal cells. We also provided evidence that miR‐490‐5p acts as a tumour suppressor in renal carcinoma in a variety of in vitro and in vivo assays. Mechanistically, miR‐490‐5p was verified to directly bind to 3′ UTR of the PIK3CA mRNA and reduce the expression of PIK3CA at both mRNA and protein levels, which further inhibits phosphatidylinositol 3‐kinase/Akt signalling pathway. We further showed that knockdown of PIK3CA can block the growth inhibitory effect of miR‐490‐5p, and over‐expression of PIK3CA can reverse the inhibitory effect of miR‐490‐5p on renal cancer cell tumourigenicity. Conclusions Taken together, our results indicated for the first time that miR‐490‐5p functions as a tumour suppressor in renal carcinoma by targeting PIK3CA. Significance Our findings suggest that miR‐490‐5p may be a potential gene therapy target for the treatment of renal cell carcinoma.