A site to transform Pubmed publications into these bibliographic reference formats: ADS, BibTeX, EndNote, ISI used by the Web of Knowledge, RIS, MEDLINE, Microsoft's Word 2007 XML.

Yu Long - Top 30 Publications

Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation.

Bromodomain and extraterminal domain (BET) protein inhibitors are emerging as promising anticancer therapies. The gene encoding the E3 ubiquitin ligase substrate-binding adaptor speckle-type POZ protein (SPOP) is the most frequently mutated in primary prostate cancer. Here we demonstrate that wild-type SPOP binds to and induces ubiquitination and proteasomal degradation of BET proteins (BRD2, BRD3 and BRD4) by recognizing a degron motif common among them. In contrast, prostate cancer-associated SPOP mutants show impaired binding to BET proteins, resulting in decreased proteasomal degradation and accumulation of these proteins in prostate cancer cell lines and patient specimens and causing resistance to BET inhibitors. Transcriptome and BRD4 cistrome analyses reveal enhanced expression of the GTPase RAC1 and cholesterol-biosynthesis-associated genes together with activation of AKT-mTORC1 signaling as a consequence of BRD4 stabilization. Our data show that resistance to BET inhibitors in SPOP-mutant prostate cancer can be overcome by combination with AKT inhibitors and further support the evaluation of SPOP mutations as biomarkers to guide BET-inhibitor-oriented therapy in patients with prostate cancer.

Aldehyde dehydrogenase 1 (ALDH1) isoform expression and potential clinical implications in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent and life-threatening malignancies worldwide. There are few diagnostic and prognostic biomarkers and druggable targets for HCC. Aldehyde dehydrogenase 1 (ALDH1) is a marker of stem cells in a variety of cancers, but the mRNA levels and prognostic value of ALDH1 isoforms in HCC patients remain unknown. In the present study, gene ontology annotation of the ALDH1 family was performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID), and the gene pathway analsis was performed using GeneMANIA software. The initial prognostic value of ALDH1 expression in 360 HCC patients was assessed using the OncoLnc database. The expression levels of ALDH1 isoforms in normal liver tissues and clinical specimens of cancer vs. normal control datasets were determined using the GTEx and Oncomine databases, respectively. We then analyzed the prognostic value of ALDH1 expression in 212 hepatitis B virus (HBV)-related HCC patients using the GEO database. We found that the ALDH1 isoform showed high aldehyde dehydrogenase activity. The ALDH1A1, ALDH1B1, and ALDH1L1 genes encoded for the ALDH1 enzyme. High ALDH1B1 expression had protective qualities in HCC patients. Moreover, HBV-related HCC patients who showed high ALDH1L1 gene expression had a better clinical outcomes. In addition, high ALDH1A1 expression was associated with a 57-month recurrence-free survival in HBV-related HCC patients. High ALDH1B1 expression was protective for HCCs with multiple nodules and high serum alpha-fetoprotein (AFP) level. Furthermore, high serum AFP levels contributed to lower ALDH1L1. ALDH1A1, ALDH1B1, and ALDH1L1, all of which were considered promising diagnostic and prognostic markers as well as potential drug targets.

Cyclophilin A Maintains Glioma-Initiating Cell Stemness by Regulating Wnt/β-catenin Signaling.

Glioma-initiating cells (GICs) are glioma stem-like cells that contribute to glioblastoma (GBM) development, recurrence, and resistance to chemotherapy and radiotherapy. They have recently become the focus of novel treatment strategies. Cyclophilin A (CypA) is a cytosolic protein that belongs to the peptidyl-prolyl isomerase (PPIase) family and the major intracellular target of the immunosuppressive drug cyclosporin A (CsA). In this study, we investigate the functions of CypA and its mechanism of action in GICs' development.

Pyramidatine (Z88) Sensitizes Vincristine-Resistant Human Oral Cancer (KB/VCR) Cells to Chemotherapeutic Agents by Inhibition of P- glycoprotein.

Multi-drug resistance (MDR) to anticancer drugs remains a major impediment in cancer therapy. A major goal for scientists is to identify more effective compounds that are able to circumvent MDR and simultaneously have minimal adverse side effects. Here, we reported that Pyramidatine (Z88), a cinnamic acid-derived bisamide compound isolated from the leaves of Aglaia perviridis, had potent anti-MDR activity. The average resistant fold (RF) of Z88 is 0.09 and 0.51 in KB/VCR (vincristine-resistant human oral cancer cells) and MCF-7/ADR (adriamycin-resistant human breast adenocarcinoma) cells. A CCK-8 assay showed that Z88 could enhance the cytotoxicity of VCR toward KB/VCR cells. A FACS analysis revealed that Z88 could enhance the VCR-induced apoptosis as well as G2/M arrest in a dose-dependent manner in KB/VCR cells. Western Blot results showed that the expression levels of PARP, Bax, and Cyclin B1 all increased after treatment with 0.2 μmol/L (μM) of VCR combined with 10 μM of Z88 for 24 h in KB/VCR cells. Z88 also could enhance the accumulation of rhodamine 123. Further studies showed that Z88 could inhibit the verapamil-stimulated P- glycoprotein (P-gp) ATPase activity. Additionally, qPCR detection and western blot assays revealed that Z88 could decrease the RNA transcript level of ABCB1 and the protein expression level of P-gp. In conclusion, Z88 exerted potent anti-MDR activity in vitro and its mechanisms may be associated with dual-inhibition of the function and expression of P-gp. These findings encourage efforts todevelop more effective reversal agents to circumvent MDR.

Molecular Cloning and Characterization of Babesia orientalis Rhoptry Neck 2 BoRON2 Protein.

Babesiosis caused by Babesia orientalis is one of the most prevalent infections of water buffalo transmitted by Rhipicephalus haemaphysaloides causing a parasitic and hemolytic disease. The organelles proteins localized in apical membrane especially rhoptries neck and microneme protein form a complex called moving junction important during invasion process of parasites belonging to apicomplexan group, including Babesia species. A truncated fragment coding a 936 bps fragment was cloned in pMD-19T and subcloned into pET32 (a)(+) expression vector, expressed in E. coli BL21. Purified recombinant BoRON2 was used to produce polyclonal antibody against BoRON2. Here, we identified the full sequence of gene encoding the rhoptry neck 2 protein that we named BoRON2 which is 4035 bp in full-length open reading frame without introns, encoding a polypeptide of 1345 amino acids. Western blot of rBoRON2 probed with buffalo positive serum analysis revealed a band of around 150 kDa in parasite lysates, suggesting an active involvement during invasion process. These findings most likely are constructive in perspective of ongoing research focused particularly on water buffalo babesiosis prevention and therapeutics and globally provide new information for genes comparative analysis.

Distinct prognostic values of alcohol dehydrogenase mRNA expression in pancreatic adenocarcinoma.

Alcohol dehydrogenase (ADH) isoenzymes have been reported as a potential diagnostic marker for pancreatic cancer, but their prognostic value in pancreatic cancer remains unclear. The aim of this investigation was to identify the prognostic value of ADH genes in human patients with pancreatic adenocarcinoma (PAAD).

ALDH1L1 variant rs2276724 and mRNA expression predict post-operative clinical outcomes and are associated with TP53 expression in HBV-related hepatocellular carcinoma.

Aldehyde dehydrogenase 1 family member L1 (ALDH1L1) is downregulated in hepatocellular carcinoma (HCC) tumors, and its decreased expression is associated with the poor prognosis of HCC patients. We, therefore, evaluated the effect of single nucleotide polymorphisms (SNPs) of ALDH1L1, and its mRNA expression on the survival of hepatitis B virus (HBV)‑related HCC patients and the association with tumor protein p53 (TP53) expression. ALDH1L1 SNPs in 415 HBV-related HCC patients were genotyped via direct sequencing. Expression profile chip datasets and survival information were obtained from GSE14520. The C allele (CT/CC) carriers of rs2276724 were significantly associated with a favorable prognosis [adjusted P=0.040; adjusted hazard ratio (HR)=0.725; 95% confidence interval (CI)=0.533-0.986]. Joint-effect analyses suggested that the CT/CC genotype of rs2276724 in TP53-negative patients was significantly associated with a decreased risk of death, compared to the TT genotype of rs2276724 in TP53-positive patients (adjusted P=0.037; adjusted HR=0.621; 95% CI=0.396-0.973). Furthermore, low expression of ALDH1L1 predicted a poor prognosis for the HBV-related HCC patients (adjusted P=0.04 for disease-free survival; adjusted P=0.001 for overall survival). Patients with high ALDH1L1 expression and low TP53 expression were significantly associated with a decreased risk of recurrence and death, and patients with a high TP53 expression were also significantly associated with a decreased risk of death in HBV-related HCC, compared with low ALDH1L1 and low TP53 expression. Our results suggest that ALDH1L1 may be a biomarker for predicting postoperative clinical outcomes. Moreover, ALDH1L1-rs2276724 and mRNA expression were associated with TP53 expression in HBV-related HCC patients.

OsCNGC13 promotes seed-setting rate by facilitating pollen tube growth in stylar tissues.

Seed-setting rate is a critical determinant of grain yield in rice (Oryza sativa L.). Rapid and healthy pollen tube growth in the style is required for high seed-setting rate. The molecular mechanisms governing this process remain largely unknown. In this study, we isolate a dominant low seed-setting rate rice mutant, sss1-D. Cellular examination results show that pollen tube growth is blocked in about half of the mutant styles. Molecular cloning and functional assays reveals that SSS1-D encodes OsCNGC13, a member of the cyclic nucleotide-gated channel family. OsCNGC13 is preferentially expressed in the pistils and its expression is dramatically reduced in the heterozygous plant, suggesting a haploinsufficiency nature for the dominant mutant phenotype. We show that OsCNGC13 is permeable to Ca2+. Consistent with this, accumulation of cytoplasmic calcium concentration ([Ca2+]cyt) is defective in the sss1-D mutant style after pollination. Further, the sss1-D mutant has altered extracellular matrix (ECM) components and delayed cell death in the style transmission tract (STT). Based on these results, we propose that OsCNGC13 acts as a novel maternal sporophytic factor required for stylar [Ca2+]cyt accumulation, ECM components modification and STT cell death, thus facilitating the penetration of pollen tube in the style for successful double fertilization and seed-setting in rice.

Genome-Wide Association Study of MKI67 Expression and its Clinical Implications in HBV-Related Hepatocellular Carcinoma in Southern China.

Hepatocellular carcinoma (HCC) is a common malignant tumor with a high rate of recurrence. Immunohistochemical analysis of the marker of proliferation Ki-67 (MKI67) is used to assess proliferation activity of HCC The regulation of MKI67 expression remains unclear in HCC This study aims to explore the association between MKI67 expression and gene variants.

Epigallocatechin-3-gallate enhances ER stress-induced cancer cell apoptosis by directly targeting PARP16 activity.

Poly(ADP-ribose) polymerases (PARPs) are ADP-ribosylating enzymes and play important roles in a variety of cellular processes. Most small-molecule PARP inhibitors developed to date have been against PARP1, a poly-ADP-ribose transferase, and suffer from poor selectivity. PARP16, a mono-ADP-ribose transferase, has recently emerged as a potential therapeutic target, but its inhibitor development has trailed behind. Here we newly characterized epigallocatechin-3-gallate (EGCG) as a potential inhibitor of PARP16. We found that EGCG was associated with PARP16 and dramatically inhibited its activity in vitro. Moreover, EGCG suppressed the ER stress-induced phosphorylation of PERK and the transcription of unfolded protein response-related genes, leading to dramatically increase of cancer cells apoptosis under ER stress conditions, which was dependent on PARP16. These findings newly characterized EGCG as a potential inhibitor of PARP16, which can enhance the ER stress-induced cancer cell apoptosis, suggesting that a combination of EGCG and ER stress-induced agents might represent a novel approach for cancer therapy or chemoprevention.

CD70, a novel target of CAR-T-cell therapy for gliomas.

Cancer immunotherapy represents a promising treatment approach for malignant-gliomas, but is hampered by the limited number of ubiquitously expressed tumor antigens and the profoundly immunosuppressive tumor microenvironment. We identified CD70 as a novel immunosuppressive ligand and glioma target.

Fabrication of a graphene/C60 nanohybrid via γ-cyclodextrin host-guest chemistry for photodynamic and photothermal therapy.

The wonderful chemical structures and characteristics of low-dimensional carbon materials have exciting applications in life sciences. In the present study, we developed a facile strategy to conjugate C60 with graphene via host-guest chemistry for targeted phototherapy. A versatile carrier based on folic acid-functionalized graphene (GO-FA) and comprising γ-cyclodextrin (γ-CD) at its surface was assembled via π-π interaction, creating hybrid structures with drug storage and tumor targeting properties. This γ-CD-modified graphene (GO-FA/Py-γ-CD) is capable of hosting pristine C60 molecules for the fabrication of a GO-FA/Py-γ-CD/C60 nanohybrid. The hybridization of GO-FA, γ-CD, and C60 hinders the aggregation of C60, promotes cellular uptake, enhances light absorption, and finally demonstrates enhanced phototherapy effects of GO-FA/Py-γ-CD/C60. Under Xe lamp irradiation (2 W cm(-2)) for 4 min, GO-FA/Py-γ-CD/C60 simultaneously causes heating and intracellular ROS production, which further significantly reduces the cell viability to 16.2% at low content of loading (30 μg mL(-1)). Moreover, it represents an excellent tumor killing efficiency, better than that of the other reported graphene/C60 nanohybrids; thus, this material is suitable for applications in phototherapy of cancer.

Knockout of the Nogo-B Gene Attenuates Tumor Growth and Metastasis in Hepatocellular Carcinoma.

Human hepatocellular carcinoma (HCC) is a malignant cancer. It is a challenge to develop anti-HCC drugs due to HCC's extreme aggressiveness and with the sensitivity of the liver to show severe adverse effects. More importantly, the precise mechanisms causing HCC pathogenicity are not known. Our previous study disclosed Nogo-B as a reticulon 4 (Rtn4) family member. In the present study, we first identified that Nogo-B played a critical role in HCC progression. We found, via in vitro and in vivo assays, that Nogo-B was expressed aberrantly in primary HCC tumor tissues and immortal HCC cells but was relatively scarce in the normal liver tissues or cells. Nogo-B knockout, via the CRISPR-Cas9 technique, resulted in significant suppression of HCC cell proliferation and tumor growth. Next-generation sequencing analysis showed that Nogo-B knockout have effects on interleukin-6 (IL-6) signaling pathway. Furthermore, we observed that IL-6 induced phosphorylation of STAT3 (pSTAT3) in wild-type HCC cells, but Nogo-B knockout could reduce IL-6-induced increase of pSTAT3, supporting that Nogo-B affects HCC tumor progression possibly via regulating the IL-6/STAT3 signaling pathway. In conclusion, Nogo-B is expressed aberrantly in HCCs and plays an oncogenic role. These findings support that Nogo-B may be a novel anti-HCC therapeutic target.

Catalytic Oxidation of Chlorobenzene over MnxCe1-xO2/HZSM-5 Catalysts: A Study with Practical Implications.

Industrial-use catalysts usually encounter severe deactivation after long-term operation for catalytic oxidation of chlorinate volatile organic compounds (CVOCs), which becomes a "bottleneck" for large-scale application of catalytic combustion technology. In this work, typical acidic solid-supported catalysts of MnxCe1-xO2/HZSM-5 were investigated for the catalytic oxidation of chlorobenzene (CB). The activation energy (Ea), Brønsted and Lewis acidities, CB adsorption and activation behaviors, long-term stabilities, and surficial accumulation compounds (after aging) were studied using a range of analytical techniques, including XPS, H2-TPR, pyridine-IR, DRIFT, and O2-TP-Ms. Experimental results revealed that the Brønsted/Lewis (B/L) ratio of MnxCe1-xO2/HZSM-5 catalysts could be adjusted by ion exchange of H• (in HZSM-5) with Mn(n+) (where the exchange with Ce(4+) did not distinctly affect the acidity); the long-term aged catalysts could accumulate ca. 14 organic compounds at surface, including highly toxic tetrachloromethane, trichloroethylene, tetrachloroethylene, o-dichlorobenzene, etc.; high humid operational environment could ensure a stable performance for MnxCe1-xO2/HZSM-5 catalysts; this was due to the effective removal of Cl• and coke accumulations by H2O washing, and the distinct increase of Lewis acidity by the interaction of H2O with HZSM-5. This work gives an in-depth view into the CB oxidation over acidic solid-supported catalysts and could provide practical guidelines for the rational design of reliable catalysts for industrial applications.

Tumor associated CD70 expression is involved in promoting tumor migration and macrophage infiltration in GBM.

Tumor migration/metastasis and immunosuppression are major obstacles in effective cancer therapy. Incidentally, these 2 hurdles usually coexist inside tumors, therefore making therapy significantly more complicated, as both oncogenic mechanisms must be addressed for successful therapeutic intervention. Our recent report highlights that the tumor expression of a TNF family member, CD70, is correlated with poor survival for primary gliomas. In this study, we investigated how CD70 expression by GBM affects the characteristics of tumor cells and the tumor microenvironment. We found that the ablation of CD70 in primary GBM decreased CD44 and SOX2 gene expression, and inhibited tumor migration, growth and the ability to attract monocyte-derived M2 macrophages in vitro. In the tumor microenvironment, CD70 was associated with immune cell infiltrates, such as T cells; myeloid-derived suppressor cells; and monocytes/macrophages based on the RNA-sequencing profile. The CD163+ macrophages were far more abundant than T cells were. This overwhelming level of macrophages was identified only in GBM and not in low-grade gliomas and normal brain specimens, implying their tumor association. CD70 was detected only on tumor cells, not on macrophages, and was highly correlated with CD163 gene expression in primary GBM. Additionally, the co-expression of the CD70 and CD163 genes was found to correlate with decreased survival for patients with primary GBM. Together, these data suggest that CD70 expression is involved in promoting tumor aggressiveness and immunosuppression via tumor-associated macrophage recruitment/activation. Our current efforts to target this molecule using chimeric antigen receptor T cells hold great potential for treating patients with GBM.

Pressure-Enabled Synthesis of Hetero-Dimers and Hetero-Rods through Intraparticle Coalescence and Interparticle Fusion of Quantum-Dot-Au Satellite Nanocrystals.

This report presents the fabrication and pressure-driven processing of heterostructural nanocrystal superlattices (HNC-SLs) self-assembled from quantum-dot-Au (QD-Au) satellite-type HNCs. In situ small/wide-angle X-ray scattering and electron microscopic measurements showed that the HNC-SLs underwent structural transformation at both atomic- and mesoscales during the pressure processing. Upon deviatoric stress-driven orientational migration, the intraparticle coalescence of Au satellites at QD surfaces transforms individual HNCs into heterodimers, whereas the interparticle fusion drives assembled HNCs into ordered heterorod arrays. These results demonstrate high-pressure-processing as a clean and fast means for conversion of HNCs into novel heteromaterials that are difficult to achieve through conventional synthetic routes.

Prognostic value of Notch receptors in postsurgical patients with hepatitis B virus-related hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies and a major cause of cancer involved death worldwide. Prognosis remains poor because of high recurrence rates and lack of effective relapse prevention strategies. Notch pathway plays an important role in tumor progression and metastasis, and it is associated with the prognosis of cancer. A total of 465 hepatitis B virus (HBV)-related HCC patients who underwent surgery were enrolled. Single nucleotide polymorphisms (SNP) of Notch pathway receptors were genotyped using Sanger DNA sequencing. Kaplan-Meier curves and the Cox proportional hazards regression model were adopted to analyze the association of polymorphisms and mRNA expression with clinical and pathological features, respectively. Four SNPs (rs1043996 in Notch3 and rs422951, rs520692, rs3830041 in Notch4) were significantly associated with overall survival (OS) (P = 0.023, P = 0.042, P = 0.028, and P = 0.001 respectively). Patients carrying the AA genotype in rs1043996 and TT/TC genotypes in rs422951 and rs520692 significantly decreased risks of death, compared to those carrying the AG/GG genotype in rs1043996 and CC genotype in rs422951 and rs520692, respectively. Patients carrying the TT genotype in rs3830041 showed poorer OS, compared with those carrying the TC/CC genotype. A haplotype block (rs422951 was in strong LD with rs520692, r(2)  = 0.843) was identified in Notch4. Notch3 mRNA expression significantly increased in tumor tissue, compared with nontumor normal tissue (P < 0.0001). Moreover, higher expression of Notch3 was associated with poorer OS (HR = 2.11, 95% CI = 1.32-3.37, P = 0.002) and shorter recurrence time of HBV-related HCC (HR = 1.96, 95% CI = 1.31-2.93, P = 0.001). Our findings collectively indicate that Notch receptors variants (rs1043996 in Notch3 and rs422951, rs520692, rs3830041 in Notch4) are independent predictive targets for OS in HBV-related HCC patients. Notch3 expression is a potential prognostic biomarker of OS and recurrence-free survival (RFS) prediction in HBV-related HCC patients following surgical treatment.

Safety and Efficacy Study of an Ozone Laser Combined Therapy Using Puncture Needle in the Treatment of Patients With Cervical Spondylosis.

Fifty-eight patients with cervical spondylosis (CS) were treated with patented technology of ozone laser combined therapy using puncture needle between August 2008 and February 2010. Visual Analogue Scale (VAS) score changes before and 6 months after surgery and MacNab score criteria 6 months after surgery were analyzed.

NF90 regulates PARP1 mRNA stability in hepatocellular carcinoma.

Poly (ADP-ribose) polymerase 1 (PARP1) is an ADP- ribosylation enzyme and plays important roles in a variety of cellular processes, including DNA damage response and tumor development. However, the post-transcriptional regulation of PARP1 remains largely unknown. In this study, we identified that the mRNA of PARP1 is associated with nuclear factor 90 (NF90) by RNA immunoprecipitation plus sequencing (RIP-seq) assay. The mRNA and protein levels of PARP1 are dramatically decreased in NF90-depleted cells, and NF90 stabilizes PARP1's mRNA through its 3'UTR. Moreover, the expression levels of PARP1 and NF90 are positively correlated in hepatocellular carcinoma (HCC). Finally, we demonstrated that NF90-depleted cells are sensitive to PARP inhibitor Olaparib (AZD2281) and DNA damage agents. Taken together, these results suggest that NF90 regulates PARP1 mRNA stability in hepatocellular carcinoma cells, and NF90 is a potential target to inhibit PARP1 activity.

The Enzymatic and Structural Basis for Inhibition of Echinococcus granulosus Thioredoxin Glutathione Reductase by Gold(I).

New drugs are needed to treat flatworm infections that cause severe human diseases such as schistosomiasis. The unique flatworm enzyme thioredoxin glutathione reductase (TGR), structurally different from the human enzyme, is a key drug target. Structural studies of the flatworm Echinococcus granulosus TGR, free and complexed with Au(I)-MPO, a novel gold inhibitor, together with inhibition assays were performed.

Caspase polymorphisms and prognosis of hepatocellular carcinoma.

The aim of our study was to determine the impact of genetic polymorphisms in the caspase (CASP) genes on prognosis of hepatocellular carcinoma (HCC). We genotyped 7 potentially functional polymorphisms in CASP3, CASP7, CASP8, CASP9, CASP10 genes in 362 HCC patients of receiving surgical resection of HCC tumor. The associations of genotype and haplotype with overall survival (OS) and disease free survival (DFS) were analyzed by using the Cox proportional hazards model. We found that the CASP9 rs4645981 C allele was significantly associated with positive effect on DFS (P = 0.011 and 0.016 for CT+CC vs. TT in univariate and multivariate analysis, respectively), CT genotype was associated with a better OS of HCC than the TT genotype both in univariate and multivariate analysis (P = 0.048 and 0.041, respectively). Moreover, the CASP3 rs2705897 GT genotype showed marginally significant association with decreased OS and DFS, compared with the GG genotype. One haplotype TT/TG in CASP3 (constructed by rs12108497 T>C and rs2705897 T>G) was significantly associated with decreased OS and DFS, compared to the common haplotype TT/TT both in univariate analysis (P = 0.021 and 0.026, respectively) and multivariate analysis (P = 0.025 and 0.030, respectively). The haplotype GT/GT in CASP9 (constructed by rs4645978 A>G and rs4645981 C>T) was significantly associated with decreased DFS both in univariate and multivariate analysis (P = 0.012 and 0.010, respectively). In conclusion, the CASP9 rs4645981 polymorphism, CASP3 and CASP9 haplotypes may be useful prognosis markers for HCC patients with surgical resection of tumor.

Dysregulation of INF2-mediated mitochondrial fission in SPOP-mutated prostate cancer.

Next-generation sequencing of the exome and genome of prostate cancers has identified numerous genetic alternations. SPOP (Speckle-type POZ Protein) was one of the most frequently mutated genes in primary prostate cancer, suggesting SPOP is a potential driver of prostate cancer development and progression. However, how SPOP mutations contribute to prostate cancer pathogenesis remains poorly understood. SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. ER-localized isoform of the formin protein inverted formin 2 (INF2) mediates actin polymerization at ER-mitochondria intersections and facilitates DRP1 recruitment to mitochondria, which is a critical step in mitochondrial fission. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. INF2 mutant escaping from SPOP-mediated ubiquitination is more potent in prompting mitochondrial fission. Moreover, prostate cancer-associated SPOP mutants increase INF2 localization in ER and promote mitochondrial fission, probably through a dominant-negative effect to inhibit endogenous SPOP. Moreover, INF2 is important for SPOP inactivation-induced prostate cancer cell migration and invasion. These findings reveal novel molecular events underlying the regulation of INF2 function and localization, and provided insights in understanding the relationship between SPOP mutations and dysregulation of mitochondrial dynamics in prostate cancer.

miR‑196a‑5p modulates gastric cancer stem cell characteristics by targeting Smad4.

Cancer stem cells (CSCs) are undifferentiated cancer cells with a high tumorigenic activity, the ability to undergo self-renewal, and a multilineage differentiation potential. Clinical evidence suggests that CSCs in a tumor mass are the cellular determinants to promote cancer invasion and metastasis. MicroRNAs (miRNAs) have emerged as important modulators of cancer stem cell characteristics. Unveiling the candidate miRNAs that regulate CSCs may provide novel therapeutic targets against cancer. We analyzed the miRNA expression profiles regulating the cancer stem-like cell characteristics in gastric cancer. Gastric cancer stem cells (GCSCs) were sorted using the stem cell marker CD44 by fluorescence-activated cell sorting. Functional studies revealed that CD44(+) cells formed more sphere colonies and showed higher invasiveness than CD44(-) cells. miRNA microarray analysis revealed that miR‑196a‑5p was significantly upregulated in CD44(+) cells than CD44(-) cells. Suppression of miR‑196a‑5p led to decreased colony formation and invasion of GCSCs. miR‑196a‑5p decreased the expression of Smad4 by targeting 3'-UTR of the mRNA. The expression of Smad4 in gastric cancer tissues was correlated with differentiation state of tumors, TNM stage and depth of invasion. The stimulation of epithelial-mesenchymal transition (EMT) by miR‑196a‑5p in cancer stem-like cells was abolished by overexpression of Smad4. Collectively, these data demonstrate that miR‑196a‑5p has a key role in EMT and invasion by targeting Smad4 in GCSCs. miR‑196a‑5p may serve as a potential target for gastric cancer therapy.

Activated Notch signaling augments cell growth in hepatocellular carcinoma via up-regulating the nuclear receptor NR4A2.

Hepatocellular carcinoma (HCC) is one of the most malignant cancers. Conventional therapies are limited due to the human liver being such a unique organ and easily showing side-effects. The unclear molecular mechanisms are tough challenges for scientists searching for new and effective anti-HCC targeting drugs. We identified that the nuclear receptor NR4A2 is a novel oncogene in HCC progression. In this study, we show that NR4A2 and the notch recceptor Notch1 were expressed highly in primary HCC tissues and immortal HCC cells by using qPCR, western blot and immuno-histochemistry assays. Both genes were observed to stimulate HCC cell proliferation, anti-apoptosis and cell cycle arrest by using cell proliferation assays and FACS assays. We also observed that the four notch receptor subtypes (Notch1-4) displayed different effects on HCC cell growth. The over-expression of Notch1 by transiently transfecting the intracellular domain of Notch1 (ICN1, Notch1 active form) increased the expression of NR4A2, with the knockdown of Notch1 decreasing NR4A2. This indicates that NR4A2 is one of the Notch-mediated downstream genes. Moreover, both NR4A2 and Notch1 suppressed the expression of tumor suppressors p21 and p63. These findings support that Notch1/NR4A2 co-regulate HCC cell functions by playing oncogenic roles and regulating the associated downstream signaling pathways. Novel Notch1/NR4A2-mediated oncogenic signaling may provide us a great opportunity for anti-HCC drug development.

PLCE1 polymorphisms and expression combined with serum AFP level predicts survival of HBV-related hepatocellular carcinoma patients after hepatectomy.

Polymorphisms in the phospholipase C epsilon (PLCE) 1 gene play a crucial role in the development and progression of several types of cancer. The present study investigated the prognostic significance of PLCE1 gene polymorphisms and expression combined with serum α-fetoprotein (AFP) level in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Single nucleotide polymorphisms were genotyped by sequencing DNA isolated from surgically resected tumor samples of 421 HBV-related HCC patients, and expression profiles were generated based on the GSE14520 dataset. A joint-effects analysis of PLCE1 haplotypes (Ars2274223Crs3765524; Grs2274223Trs3765524) with AFP level stratified at 20 ng/ml showed a significant association with overall survival(OS) of HBV-related HCC patients(log-rank P=0.0003). Patients with AC and GT haplotypes with AFP level ≥ 20 ng/ml had an increased risk of death as compared to those with the AC haplotype and AFP level < 20 ng/ml (adjusted P=0.029 and 0.041, respectively). Patients with the GT haplotype and AFP level < 20 ng/ml also had an increased risk of death, although with a non-significant P value (adjusted P=0.092). Joint-effects analysis of PLCE1 mRNA expression with serum AFP level stratified at 300 ng/ml was significantly associated with HBV-related HCC recurrence and OS. Our results demonstrate that PLCE1 haplotypes (including rs2274223 and rs3765524) and expression combined with serum AFP level may predict postoperative outcome of HBV-related HCC patients.

Probable pulmonary Blastomyomycocis in an immunocompetent person.

The current case report presents a 29-year old man who worked as a hotel guard in a city in China. The patient had fever and dry cough before and after hospitalization. Chest X-ray and CT revealed nodular and patchy lesions in both lower lungs. There were no abnormal findings in the examination of sputum and bronchoalveoular lavage fluid (BALF). He was diagnosed with pulmonary blastomycosis by histological examination of lung biopsy and treated with fluconazole. Follow-up chest CT examination demonstrated that the patient was recovered through appropriate antifungal treatment.

Multi-layer mucilage of Plantago ovata seeds: Rheological differences arise from variations in arabinoxylan side chains.

Mucilages are hydrocolloid solutions produced by plants for a variety of functions, including the creation of a water-holding barrier around seeds. Here we report our discovery of the formation of three distinct mucilage layers around Plantago ovata seeds upon their hydration. Each layer is dominated by different arabinoxylans (AXs). These AXs are unusual because they are highly branched and contain β-1,3-linked xylose in their side chains. We show that these AXs have similar monosaccharide and linkage composition, but vary in their polymer conformation. They also exhibit distinct rheological properties in aqueous solution, despite analytical techniques including NMR showing little difference between them. Using enzymatic hydrolysis and chaotropic solvents, we reveal that hydrogen bonding and side chain distribution are key factors underpinning the distinct rheological properties of these complex AXs.

Association of native T1 times with biventricular function and hemodynamics in precapillary pulmonary hypertension.

In precapillary pulmonary hypertension (PH) patients, we sought to (1) investigate the relationship between ventricular insertion point (VIP) T1 times, hemodynamic parameters, and biventricular function, and (2) determine the predictors of anterior and inferior VIP T1 time. Twenty-two patients with precapillary PH underwent 1.5-T cardiac MR, right heart catheterization (RHC), and echocardiography. A group of 10 healthy age- and sex-matched volunteers served as controls. Biventricular function, morphology and mass were obtained from short-axis cine images. Native T1 times at anterior, inferior VIP, septum and LV lateral wall were respectively derived from all subjects. Mixed venous oxygen saturation (SvO2) was the strongest hemodynamic parameters correlating with anterior (rp = -0.67, P = 0.001) and inferior VIP T1 time (rp = -0.81, P < 0.001). Elevated VIP T1 times were associated with reduced right ventricular (RV) ejection fraction, RV longitudinal and transverse motion, and increased RV end-diastolic and end-systolic volume index. LV diastolic function, quantified as mitral E velocity, was negatively correlated with anterior, inferior VIP (rp = -0.55, P = 0.01) and septal T1 times (rp = -0.50, P = 0.02), and positively correlated with RV systolic function and wall motion. In multivariate linear regression analyses, systolic eccentricity index (sEI) was the independent predictor of average VIPs T1 time (β= 0.47, P < 0.01), and remained significant correlation after adjustment of RHC and demographic parameters. In patients with precapillary PH, VIP T1 times are associated with biventricular function and hemodynamic parameters. Among all the parameters, sEI acts as a determinant of average VIPs T1 time.

In-Depth Analysis of Glycoprotein Sialylation in Serum Using a Dual-Functional Material with Superior Hydrophilicity and Switchable Surface Charge.

Sialylation typically occurs at the terminal of glycans, and its aberration often correlates with diseases including neurological diseases and cancer. However, the analysis of glycoprotein sialylation in complex biological samples is still challenging due to their low abundance. Herein, a histidine-bonded silica (HBS) material with a hydrophilic interaction and switchable surface charge was fabricated to enrich sialylated glycopeptides (SGPs) from the digest of proteomics samples. High selectivity toward SGPs was obtained by combining the superior hydrophilicity and switchable-charge characteristics. During the enrichment of sialylated glycopeptides from bovine fetuin digest, seven glycopeptides were detected even at the ratio of 1:5000 with the nonsialylated glycopeptides, demonstrating the high specificity of SGP enrichment by using HBS material. Then, HBS material was further utilized to selectively enrich SGPs from the protein digest of human serum, and 487 glycosites were identified from only 2 μL of human serum; 92.0% of the glycopeptides contained at least one sialic acid, indicating good performance for SGP enrichment by using HBS material. Furthermore, the prepared HBS material also has great potential applications in the analysis of glycoprotein sialylation from other complex biological samples.

Distinctive morphology effects of porous-spherical/yolk-shell/hollow Pd-nitrogen-doped-carbon spheres catalyst for catalytic reduction of 4-nitrophenol.

Pd-nitrogen-doped-carbon nanocatalysts (Pd-C/N) with different morphologies, such as porous spheres, yolk-shell and hollow structures, had been synthesized and compared. The yolk-shell Pd-nitrogen-doped-carbon nanocatalysts (YS-Pd-C/N) and hollow Pd-nitrogen-doped-carbon nanocatalysts (H-Pd-C/N) were prepared through different etch time using SiO2 spheres as hard-templates. The as-prepared catalysts were characterized thoroughly by TEM, BET, XRD, FT-IR, and XPS. Importantly, the catalysts have moderate BET specific surface area in the range from 200 to 300m(2)g(-1) and pore volume between 0.2 and 0.3cm(3)g(-1). The reduction of 4-nitrophenol is chosen as a model reaction to research the morphology effects of these prepared Pd-C/N catalysts with the same chemical compositions. Interestingly, H-Pd-C/N exhibited the best catalytic performance, which could be attributed to its high nitrogen content, the uniform distribution of abundant active sites, as well as the synergistic effect of graphitic C/N shell and Pd species for the catalytic reaction. Especially, the unique hollow morphology and porous shell of H-Pd-C/N made it to be a nanoreactor, which was beneficial to improve the catalytic activities. In addition, H-Pd-C/N nanocatalysts exhibited favorable stability in the recycling reactions.