SETDB1 tumour suppressor roles in near-haploid mesothelioma involve TP53.

BACKGROUND: Mutational inactivation of the SETDB1 histone methyltransferase is found in a subset of mesothelioma, particularly in cases with near-haploidy and TP53 mutations. However, the tumourigenic consequences of SETDB1 inactivation are poorly understood. METHODS: In this study, we investigated SETDB1 tumour suppressor functions in mesothelioma and explored biologic relationships between SETDB1 and TP53. RESULTS: Immunoblotting of early passage cultures showed that SETDB1 was undetectable in 7 of 8 near-haploid mesotheliomas whereas SETDB1 expression was retained in each of 13 near-diploid mesotheliomas. TP53 aberrations were present in 5 of 8 near-haploid mesotheliomas compared to 2 of 13 near-diploid mesotheliomas, and BAP1 inactivation was demonstrated only in near-diploid mesotheliomas, indicating that near-haploid and near-diploid mesothelioma have distinct molecular and biologic profiles. Lentiviral SETDB1 restoration in near-haploid mesotheliomas (MESO257 and MESO542) reduced cell viability, colony formation, reactive oxygen species levels, proliferative marker cyclin A expression, and inhibited growth of MESO542 xenografts. The combination of SETDB1 restoration with pemetrexed and/or cisplatin treatment additively inhibited tumour growth in vitro and in vivo. Furthermore, SETDB1 restoration upregulated TP53 expression in MESO542 and MESO257, whereas SETDB1 knockdown inhibited mutant TP53 expression in JMN1B near-haploid mesothelioma cells. Likewise, TP53 knockdown inhibited SETDB1 expression. Similarly, immunoblotting evaluations of ten near-diploid mesothelioma biopsies and analysis of TCGA expression profiles showed that SETDB1 expression levels paralleled TP53 expression. CONCLUSION: These findings demonstrate that SETDB1 inactivation in near-haploid mesothelioma is generally associated with complete loss of SETDB1 protein expression and dysregulates TP53 expression. Targeting SETDB1 pathways could be an effective therapeutic strategy in these often untreatable tumours.

Comprehensive transcriptomics and metabolomics analyses reveal that hyperhomocysteinemia is a high risk factor for coronary artery disease in a chinese obese population aged 40-65: a prospective cross-sectional study.

BACKGROUND: Clinical observations suggest a complex relationship between obesity and coronary artery disease (CAD). This study aimed to characterize the intermediate metabolism phenotypes among obese patients with CAD and without CAD. METHODS: Sixty-two participants who consecutively underwent coronary angiography were enrolled in the discovery cohort. Transcriptional and untargeted metabolomics analyses were carried out to screen for key molecular changes between obese patients with CAD (CAD obese), without CAD (Non-CAD obese), and Non-CAD leans. A targeted GC-MS metabolomics approach was used to further identify differentially expressed metabolites in the validation cohorts. Regression and receiver operator curve analysis were performed to validate the risk model. RESULTS: We found common aberrantly expressed pathways both at the transcriptional and metabolomics levels. These pathways included cysteine and methionine metabolism and arginine and proline metabolism. Untargeted metabolomics revealed that S-adenosylhomocysteine (SAH), 3-hydroxybenzoic acid, 2-hydroxyhippuric acid, nicotinuric acid, and 2-arachidonoyl glycerol were significantly elevated in the CAD obese group compared to the other two groups. In the validation study, targeted cysteine and methionine metabolomics analyses showed that homocysteine (Hcy), SAH, and choline were significantly increased in the CAD obese group compared with the Non-CAD obese group, while betaine, 5-methylpropanedioic acid, S-adenosylmethionine, 4-PA, and vitamin B2 (VB2) showed no significant differences. Multivariate analyses showed that Hcy was an independent predictor of obesity with CAD (hazard ratio 1.7; 95%CI 1.2-2.6). The area under the curve based on the Hcy metabolomic (HCY-Mtb) index was 0.819, and up to 0.877 for the HCY-Mtb.index plus clinical variables. CONCLUSION: This is the first study to propose that obesity with hyperhomocysteinemia is a useful intermediate metabolism phenotype that could be used to identify obese patients at high risk for developing CAD.

Intermolecular 3D-MoRSE Descriptors for Fast and Accurate Prediction of Electronic Couplings in Organic Semiconductors.

The theoretical rational design of organic semiconductors faces an obstacle in that the performance of organic semiconductors depends very much on their stacking and local morphology (for example, phase domains), which involves numerous molecules. Simulation becomes computationally expensive as intermolecular electronic couplings have to be calculated from density functional theory. Therefore, developing fast and accurate methods for intermolecular electronic coupling estimation is essential. In this work, by developing a series of new intermolecular 3D descriptors, we achieved fast and accurate prediction of electronic couplings in both crystalline and amorphous thin films. Three groups of developed descriptors could perform faster and higher accuracy prediction on electronic couplings than the most advanced state-of-the-art descriptors. This work paves the way for large-scale simulations, high-throughput calculations, and screening of organic semiconductors.

Gallic acid alleviates lipopolysaccharide-induced renal injury in rats by inhibiting cell pro-death and inflammatory response and its mechanism.

The mechanism of gallic acid in improving lipopolysaccharide-induced renal injury in rats was investigated by studying the pro-death and inflammatory response of cells. SPF rats were randomly divided into 4 groups with n=10 in each group. Blank control group: normal saline injection; The model group was injected with LPS induced model (LPS group); Low dose gallic acid group (LPS+L-GA group); Middle dose gallic acid group (LPS+M-GA group). The expression of serum inflammatory factors IL-1, IL-1ß, IL-18, and MCP-1 were detected by Elisa. Western blot assay was used to detect the expression of inflammation-related proteins. The contents of BUN, Scr, SUA, Serum cystatinALB, and ACR were determined by the biochemical analyzer. The pathological tissue sections were used to observe the kidney injury in each group. The renal expressions of NLRP3, Caspase-1, GSDMD, and IL-1ß were detected by immunohistochemistry. The activation of the AMPK/SIRT1 signaling pathway was detected by Western blot assay. The LPS-induced mouse kidney injury model was established successfully. Compared with the model group, different doses of gallic acid can improve the expression of renal biochemical indexes (P<0.05); At the same time, gallic acid can activate AMPK/SIRT1 and reduce kidney injury in mice (P<0.05); Compared with the model group, the expression of pyroptosis gene, the expression of genes related to inflammatory factors and the expression of inflammatory factors were decreased in the gallic acid injection group (P<0.05). By activating the AMPK/SIRT1 signaling pathway, gallic acid can inhibit the scorch death and validation effect in mice, thereby protecting the kidneys of mice.

Molecular modification of MAPbI3 surface: insights from first-principles theory studies.

Molecular surface modification has been widely used to improve the stability and the power conversion efficiency of perovskite solar cells. First-principles studies have played a crucial role in the mechanism of surface modification. However, the design of surface modification molecules lacks theoretical guidelines. Herein, we studied the surface modifications of a series of typical small molecules based on first-principles calculations. The relevance of the calculated properties and experimental performance has been investigated. It was found that molecules with nitrogen-containing groups, including amino, π-conjugated N-heterocycle, and (thio)amide groups, could have strong adsorption energies, and may be suitable modifiers. Molecules such as oxygen-containing six-membered rings and 1,2,4-triazine may induce defect states. Based on our calculations, design guidelines for perovskite surface modification molecules have been proposed based on three aspects: interfacial buffering, defect avoidance, and energy level alignment. This work may shed light on the development of perovskite surface modification molecules towards higher power conversion efficiency and more stable perovskite solar cells.

Concurrent inhibition of CDK2 adds to the anti-tumour activity of CDK4/6 inhibition in GIST.

BACKGROUND: Advanced gastrointestinal stromal tumour (GIST) is characterised by genomic perturbations of key cell cycle regulators. Oncogenic activation of CDK4/6 results in RB1 inactivation and cell cycle progression. Given that single-agent CDK4/6 inhibitor therapy failed to show clinical activity in advanced GIST, we evaluated strategies for maximising response to therapeutic CDK4/6 inhibition. METHODS: Targeted next-generation sequencing and multiplexed protein imaging were used to detect cell cycle regulator aberrations in GIST clinical samples. The impact of inhibitors of CDK2, CDK4 and CDK2/4/6 was determined through cell proliferation and protein detection assays. CDK-inhibitor resistance mechanisms were characterised in GIST cell lines after long-term exposure. RESULTS: We identify recurrent genomic aberrations in cell cycle regulators causing co-activation of the CDK2 and CDK4/6 pathways in clinical GIST samples. Therapeutic co-targeting of CDK2 and CDK4/6 is synergistic in GIST cell lines with intact RB1, through inhibition of RB1 hyperphosphorylation and cell proliferation. Moreover, RB1 inactivation and a novel oncogenic cyclin D1 resulting from an intragenic rearrangement (CCND1::chr11.g:70025223) are mechanisms of acquired CDK-inhibitor resistance in GIST. CONCLUSIONS: These studies establish the biological rationale for CDK2 and CDK4/6 co-inhibition as a therapeutic strategy in patients with advanced GIST, including metastatic GIST progressing on tyrosine kinase inhibitors.

Peptide supplementation relieves stress and enhances glycolytic flux in filamentous fungi during organic acid bioproduction.

Filamentous fungi occupy a uniquely favorable position in the bioproduction of organic acids. Intracellular stress is the main stimulator in filamentous fungi to produce and accumulate organic acids with high flux. However, stress can affect the physiological activities of filamentous fungi, thereby deteriorating their fermentation performance. Herein, we report that peptide supplementation during Rhizopus oryzae fermentation significantly improved fumaric acid production. Specifically, fumaric acid productivity was elevated by approximately 100%, fermentation duration was shortened from 72 to 36 h, while maintaining the final titer. Furthermore, transcriptome profile analysis and biochemical assays indicated that the overall capabilities of the stress defense systems (enzymatic and nonenzymatic) were significantly improved in R. oryzae. Consequently, glycolytic metabolism was distinctly enhanced, which eventually resulted in improved fumaric acid production and reduced fermentation duration. We expect our findings and efforts to provide essential insights into the optimization of the fermentation performance of filamentous fungi in industrial biotechnology and fermentation engineering.

SALL4 Oncogenic Function in Cancers: Mechanisms and Therapeutic Relevance.

SALL4, a member of the SALL family, is an embryonic stem cell regulator involved in self-renewal and pluripotency. Recently, SALL4 overexpression was found in malignant cancers, including lung cancer, hepatocellular carcinoma, breast cancer, gastric cancer, colorectal cancer, osteosarcoma, acute myeloid leukemia, ovarian cancer, and glioma. This review updates recent advances of our knowledge of the biology of SALL4 with a focus on its mechanisms and regulatory functions in tumors and human hematopoiesis. SALL4 overexpression promotes proliferation, development, invasion, and migration in cancers through activation of the Wnt/ß-catenin, PI3K/AKT, and Notch signaling pathways; expression of mitochondrial oxidative phosphorylation genes; and inhibition of the expression of the Bcl-2 family, caspase-related proteins, and death receptors. Additionally, SALL4 regulates tumor progression correlated with the immune microenvironment involved in the TNF family and gene expression through epigenetic mechanisms, consequently affecting hematopoiesis. Therefore, SALL4 plays a critical oncogenic role in gene transcription and tumor growth. However, there are still some scientific hypotheses to be tested regarding whether SALL4 is a therapeutic target, such as different tumor microenvironments and drug resistance. Thus, an in-depth understanding and study of the functions and mechanisms of SALL4 in cancer may help develop novel strategies for cancer therapy.

Bullatine A exerts anti-inflammatory effects by inhibiting the ROS/JNK/NF-κB pathway and attenuating systemic inflammatory responses in mice.

CONTEXT: Aconiti brachypodi Radix (Xue-shang-yi-zhi-hao) is a traditional Chinese herbal medicine that is capable of anti-analgesic and anti-inflammatory effects. Bullatine A (BA) is one of the major active ingredients of this plant, and most of the previous studies reported that it has anti-analgesic effects. However, the mechanism of BA anti-inflammatory remains unclear. OBJECTIVE: This study investigates the anti-inflammatory activities of BA, both in vitro and in vivo, and elucidates its mechanism. MATERIALS AND METHODS: In vitro, BA (10, 20, 40 and 80 µM) was added to 1 µg/mL of lipopolysaccharide (LPS)-activated microglia BV2 cells and immortalized murine bone marrow-derived macrophages, respectively. After 6 h, the mRNA and protein levels of inflammatory factors were determined by real-time quantitative PCR and western blotting. In vivo, C57BL/6 mice were randomly divided into control, model (5 mg/kg dose of LPS) and treated groups (LPS with 5, 10 or 20 mg/kg dose of BA) to evaluate the anti-inflammatory efficacy of BA. RESULTS: BA significantly inhibited LPS-induced expression of inflammatory factors, such as IL-1ß, IL-6, TNF-α, inducible nitric oxide synthase (iNOS) and COX-2. Further investigations showed that BA reduced the translocation of NF-κB p65 (38.5%, p < 0.01). BA also reduced the phosphorylation of c-Jun N-terminal kinase (JNK) (11.2%, p < 0.05) and reactive oxygen species (ROS) generation (24.2%, p < 0.01). Furthermore, BA treatment attenuated the LPS-primed inflammatory response and liver and lung damage in vivo. CONCLUSIONS: BA can inhibit the inflammatory response in part through the ROS/JNK/NF-κB signalling pathway, providing a theoretical basis for the clinical application of BA in the treatment of periphery inflammatory diseases.

WITHDRAWN: Effects of cancer-associated point mutations on the structure, function, and stability of succinate dehydrogenase A.

This article has been withdrawn by the authors. Some of the SDHA enzyme activity data were flawed and were not performed and analyzed correctly. The withdrawing authors are in the process of correcting the data and re-evaluating them for resubmission.

Coordinated targeting of CK2 and KIT in gastrointestinal stromal tumours.

BACKGROUND: Most gastrointestinal stromal tumours (GIST) are driven by activating oncogenic mutations of KIT/PDGFRA, which provide a compelling therapeutic target. Our previous studies showed that CDC37, regulated by casein kinase 2 (CK2), is a crucial HSP90 cofactor for KIT oncogenic function and a promising and more selective therapeutic target in GIST. METHODS: Biologic mechanisms of CK2-mediated CDC37 regulation were assessed in GISTs by immunoblotting, immunoprecipitations, knockdown and inactivation assays. The effects of a combination of KIT and CK2 inhibition were assessed by immunoblotting, cell viability, colony growth, cell cycle analysis, apoptosis, migration and invasiveness. RESULTS: CK2 overexpression was demonstrated by immunoblotting in GIST cell lines and patient biopsies. Treatment with a specific CK2 inhibitor, CX4945, leads to CDC37 dephosphorylation and inhibits KIT signalling in imatinib-sensitive and in imatinib-resistant GIST cell lines. Immunoprecipitation demonstrated that CK2 inhibition blocks KIT:HSP90:CDC37 interaction in GIST cells. Coordinated inhibition of CK2 and KIT by CX4945 (or CK2 shRNA) and imatinib, respectively, leads to increased apoptosis, anti-proliferative effects and cell cycle arrest and decreased p-AKT and p-S6 expression, migration and invasiveness in all GIST cell lines compared with either intervention alone, indicating additive effects of inhibiting these two important regulators of GIST biology. CONCLUSION: Our findings suggest that combinatorial inhibition of CK2 and KIT warrants evaluation as a novel therapeutic strategy in GIST, especially in imatinib-resistant GIST.

Citronellal prevents endothelial dysfunction and atherosclerosis in rats.

BACKGROUND: Atherosclerosis is a chronical inflammatory disease in arterial walls, which is involved in oxidative stress and endothelial dysfunction. Aromatherapy is one of the complementary therapies that use essential oils as the major therapeutic agents to treat several diseases. Citronellal (CT) is a monoterpene predominantly formed by the secondary metabolism of plants, producing antithrombotic, antiplatelet, and antihypertensive activities. AIM: The aim of the present study is to explore whether aromatherapy with CT improves endothelial function to prevent the formation of atherosclerotic plaque in vivo. METHODS: An AS model in carotid artery was induced by balloon injury and vitamin D3 injection in rats fed with a high-fat diet. The size of the carotid atherosclerotic plaque was determined by ultrasound, oil red, and hematoxylin-eosin staining. Endothelial function was assessed by measuring acetylcholine-induced vessel relaxation in an organ chamber. RESULTS: Administrations of CT (50, 100, and 150 mg/kg) as well as lovastatin dramatically reduced the size of carotid atherosclerotic plaque in rats in a dose-dependent manner, compared with atherosclerotic rats fed with a high-fat diet plus balloon injury and vitamin D3. Mechanically, CT improved endothelial dysfunction, increased cell migration, and suppressed oxidative stress and inflammation in vascular endothelium in rats feeding on the high-fat diet plus balloon injury. Further, CT downregulated the protein levels of sodium-hydrogen exchanger 1 in rats with atherosclerosis. CONCLUSION: CT improves endothelial dysfunction and prevents the growth of atherosclerosis in rats by reducing oxidative stress. Clinically, CT is potentially considered as a medicine to treat patients with atherosclerosis.

Administration of losartan improves aortic arterial stiffness and reduces the occurrence of acute coronary syndrome in aged patients with essential hypertension.

BACKGROUNDS AND AIMS: Increased arterial stiffness may increase cardiovascular morbidity and mortality. Angiotensin II type 1 receptor blocker losartan is potentially useful in controlling the central blood pressure and arterial stiffness in mild to moderate essential hypertension, while the effects of losartan in aged patients with essential hypertension are not entirely investigated. METHODS: The carotid-femoral arterial pulse wave velocity (PWV) was measured in aged patients with essential hypertension. RESULTS: In a cross-sectional study, PWV value was significantly higher in these old patients with essential hypertension, compared with patients without essential hypertension. Logistic regression analysis indicated that age, hypertension duration, and losartan treatment are risk factors of arterial stiffness. In a perspective study, long-term administration of losartan (50 mg/d) remarkably reduced PWV in aged patients with essential hypertension. In a longitudinal study, PWV is an independent predictor of the occurrence of acute coronary syndrome (ACS) in elderly patients with essential hypertension by using multivariate analysis. Further, the ACS occurrence was reduced by long-term administration of losartan in aged patients with essential hypertension, compared with the old hypertensive patients without taking losartan. CONCLUSION: Losartan treatment is a negative risk factor of arterial stiffness and reduces the risk of ACS in aged patients with essential hypertension.

ALK oncoproteins in atypical inflammatory myofibroblastic tumours: novel RRBP1-ALK fusions in epithelioid inflammatory myofibroblastic sarcoma.

ALK oncogenic activation mechanisms were characterized in four conventional spindle-cell inflammatory myofibroblastic tumours (IMT) and five atypical IMT, each of which had ALK genomic perturbations. Constitutively activated ALK oncoproteins were purified by ALK immunoprecipitation and electrophoresis, and were characterized by mass spectrometry. The four conventional IMT had TPM3/4-ALK fusions (two cases) or DCTN1-ALK fusions (two cases), whereas two atypical spindle-cell IMT had TFG-ALK and TPM3-ALK fusion in one case each, and three epithelioid inflammatory myofibroblastic sarcomas had RANBP2-ALK fusions in two cases, and a novel RRBP1-ALK fusion in one case. The epithelioid inflammatory myofibroblastic sarcoma with RRBP1-ALK fusion had cytoplasmic ALK expression with perinuclear accentuation, different from the nuclear membranous ALK localization in epithelioid inflammatory myofibroblastic sarcomas with RANBP2-ALK fusions. Evaluation of three additional uncharacterized epithelioid inflammatory myofibroblastic sarcomas with ALK cytoplasmic/perinuclear- accentuation expression demonstrated RRBP1-ALK fusion in two cases. These studies show that atypical spindle-cell IMT can utilize the same ALK fusion mechanisms described previously in conventional IMT, whereas in clinically aggressive epithelioid inflammatory myofibroblastic sarcoma we identify a novel recurrent ALK oncogenic mechanism, resulting from fusion with the RRBP1 gene. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

[Application of flexible bronchoscopy in children with respiratory diseases].

OBJECTIVE: To investigate the significance of flexible bronchoscopy in children with respiratory diseases. METHODS: A retrospective analysis was performed for the clinical data of 80 children who were hospitalized due to respiratory diseases (including severe pneumonia, Mycoplasma pneumoniae pneumonia with atelectasis/lung consolidation/local emphysema, protracted pneumonia, coughing and wheezing of unknown cause, chronic cough of unknown cause, and laryngeal stridor) and who underwent flexible bronchoscopy/alveolar lavage. RESULTS: Bronchoscopy found that all the 80 children had endobronchial inflammation, among whom 28 children had severe airway obstruction by secretion. Twenty-four children had congenital airway dysplasia besides endobronchial inflammation, and three children had bronchial foreign bodies. In the children with coughing and wheezing of unknown cause and laryngeal stridor, some had congenital airway dysplasia or bronchial foreign bodies. Among the 27 children with Mycoplasma pneumoniae pneumonia, 26 had severe airway obstruction/embolization by secretion; 25 children (93%) underwent chest imaging again at 2 weeks after alveolar lavage, and the results showed complete or partial lung recruitment. Among the 80 children who underwent bronchoscopy, 3 had severe hypoxemia during surgery, 1 had epistaxis, 1 had minor bleeding during alveolar lavage, 3 had transient bronchospasm, and 5 had postoperative fever; these children were all improved after symptomatic treatment. CONCLUSIONS: Flexible bronchoscopy is safe and reliable in children with respiratory diseases. Early alveolar lavage under a flexible bronchoscope is recommended for children with severe/refractory Mycoplasma pneumoniae pneumonia to improve prognosis. Flexible bronchoscopy is recommended for children with recurrent coughing and wheezing and persistent laryngeal stridor, in order to directly observe the throat and airway under an endoscope.

Co-targeting of FAK and MDM2 triggers additive anti-proliferative effects in mesothelioma via a coordinated reactivation of p53.

BACKGROUND: Improved mesothelioma patient survival will require development of novel and more effective pharmacological interventions. TP53 genomic mutations are uncommon in mesothelioma, and recent data indicate that p53 remains functional, and therefore is a potential therapeutic target in these cancers. In addition, the tumour suppressor NF2 is inactivated by genomic mechanisms in more than 80% of mesothelioma, causing upregulation of FAK activity. Because FAK is a negative regulator of p53, NF2 regulation of FAK-p53-MDM2 signalling loops were evaluated. METHODS: Interactions of FAK-p53 or NF2-FAK were evaluated by phosphotyrosine-p53 immunoaffinity purification and tandem mass spectrometry, and p53, FAK, and NF2 immunoprecipitations. Activation and/or expression of FAK, p53, and NF2 were also evaluated in mesotheliomas. Effects of combination MDM2 and FAK inhibitors/shRNAs were assessed by measuring mesothelioma cell viability/growth, expression of cell cycle checkpoints, and cell cycle alterations. RESULTS: We observed constitutive activation of FAK, a known negative regulator of p53, in each of 10 mesothelioma cell lines and each of nine mesothelioma surgical specimens, and FAK was associated with p53 in five of five mesothelioma cell lines. In four mesotheliomas with wild-type p53, FAK silencing by RNAi induced expression and phosphorylation of p53. However, FAK regulation of mesothelioma proliferation was not restricted to p53-dependent pathways, as demonstrated by immunoblots after FAK knockdown in JMN1B mesothelioma cells, which have mutant/inactivated p53, compared with four mesothelioma cell lines with nonmutant p53. Additive effects were obtained through a coordinated reactivation of p53, by FAK knockdown/inhibition and MDM2 inhibition, as demonstrated by immunoblots, cell viability, and cell-cycle analyses, showing increased p53 expression, apoptosis, anti-proliferative effects, and cell-cycle arrest, as compared with either intervention alone. Our results also indicate that NF2 regulates the interaction of FAK-p53 and MDM2-p53. CONCLUSIONS: These findings highlight novel therapeutic opportunities in mesothelioma.

Correlations between MDM2 gene SNP309 polymorphism and susceptibility to leukemia.

BACKGROUND: The objective of this study was to perform a systematic review of correlations between the single-nucleotide polymorphism at nucleotide 309 (single-nucleotide polymorphism, SNP309) in the murine double-minute 2 (MDM2) gene promoter and susceptibility to leukemia. MATERIAL/METHODS: We performed a computer search of relevant case-control studies published from January 1990 to Jan 2014 in databases such as Ovid, EBSCO, PubMed, CNKI, CBMDISC, VIP, and WanFang Data. The literature was screened based on inclusion and exclusion criteria. The data were retrieved, and the quality of the methodology used in the studies was evaluated. A meta-analysis was performed by calculating the combined odds ratios (OR) and 95% confidence intervals (CI) using RevMan 5.0 and Stata 10.0 software. Sensitivity was analyzed and publication bias was assessed. RESULTS: A total of ten case-control studies from nine research papers were selected in this study, which included 1889 cases and 5707 controls. Meta-analysis showed that people who carried the G allele had increased susceptibility to leukemia compared to people who carried the T allele [OR=1.24, 95% CI (1.06, 1.45), P=0.007]. In a recessive model, the GG homozygotic population had a higher risk of leukemia than the heterozygotic GT+TT population [OR=1.47, 95% CI (1.11, 1.96), P=0.008]. We did not find significant difference in a dominant model [GG+GT vs. TT: OR=1.22, 95% CI (0.98, 1.52), P=0.07]. Publication bias was not significant. CONCLUSIONS: SNP309 polymorphism in the MDM2 gene is associated with susceptibility to leukemia. The G allele may be a risk factor for leukemia.

Toxicity induced by Basic Violet 14, Direct Red 28 and Acid Red 26 in zebrafish larvae.

Basic Violet 14, Direct Red 28 and Acid Red 26 are classified as carcinogenic dyes in the European textile ecology standard, despite insufficient toxicity data. In this study, the toxicity of these dyes was assessed in a zebrafish model, and the underlying toxic mechanisms were investigated. Basic Violet 14 and Direct Red 28 showed acute toxicity with a LC50 value at 60.63 and 476.84 µg ml(-1) , respectively, whereas the LC50 of Acid Red 26 was between 2500 and 2800 µg ml(-1) . Treatment with Basic Violet 14, Direct Red 28 and Acid Red 26 resulted in common developmental abnormalities including delayed yolk sac absorption and swimming bladder deflation. Hepatotoxicity was observed in zebrafish treated with Basic Violet 14, and cardiovascular toxicity was found in zebrafish treated with Acid Red 26 at concentrations higher than 2500 µg ml(-1) . Basic Violet 14 also caused significant up-regulation of GCLC gene expression in a dose-dependent manner whereas Acid Red 26 induced significant up-regulation of NKX2.5 and down-regulation of GATA4 at a high concentration in a dose-dependent manner. These results suggest that Basic Violet 14, Direct Red 28 and Acid Red 26 induce developmental and organ-specific toxicity, and oxidative stress may play a role in the hepatotoxicity of Basic Violet 14, the suppressed GATA4 expression may have a relation to the cardiovascular toxicity of Acid Red 26.

14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma.

14-3-3 proteins are ubiquitously expressed regulators of various cellular functions, including proliferation, metabolism, and differentiation, and altered 14-3-3 expression is associated with development and progression of cancer. We report a transforming 14-3-3 oncoprotein, which we identified through conventional cytogenetics and whole-transcriptome sequencing analysis as a highly recurrent genetic mechanism in a clinically aggressive form of uterine sarcoma: high-grade endometrial stromal sarcoma (ESS). The 14-3-3 oncoprotein results from a t(10;17) genomic rearrangement, leading to fusion between 14-3-3ε (YWHAE) and either of two nearly identical FAM22 family members (FAM22A or FAM22B). Expression of YWHAE-FAM22 fusion oncoproteins was demonstrated by immunoblot in t(10;17)-bearing frozen tumor and cell line samples. YWHAE-FAM22 fusion gene knockdowns were performed with shRNAs and siRNAs targeting various FAM22A exons in an t(10;17)-bearing ESS cell line (ESS1): Fusion protein expression was inhibited, with corresponding reduction in cell growth and migration. YWHAE-FAM22 maintains a structurally and functionally intact 14-3-3ε (YWHAE) protein-binding domain, which is directed to the nucleus by a FAM22 nuclear localization sequence. In contrast to classic ESS, harboring JAZF1 genetic fusions, YWHAE-FAM22 ESS display high-grade histologic features, a distinct gene-expression profile, and a more aggressive clinical course. Fluorescence in situ hybridization analysis demonstrated absolute specificity of YWHAE-FAM22A/B genetic rearrangement for high-grade ESS, with no fusions detected in other uterine and nonuterine mesenchymal tumors (55 tumor types, n = 827). These discoveries reveal diagnostically and therapeutically relevant models for characterizing aberrant 14-3-3 oncogenic functions.

Aberrant AKT activation drives well-differentiated liposarcoma.

Well-differentiated liposarcoma (WDLPS), one of the most common human sarcomas, is poorly responsive to radiation and chemotherapy, and the lack of animal models suitable for experimental analysis has seriously impeded functional investigation of its pathobiology and development of effective targeted therapies. Here, we show that zebrafish expressing constitutively active Akt2 in mesenchymal progenitors develop WDLPS that closely resembles the human disease. Tumor incidence rates were 8% in p53 wild-type zebrafish, 6% in p53 heterozygotes, and 29% in p53-homozygous mutant zebrafish (P = 0.013), indicating that aberrant Akt activation collaborates with p53 mutation in WDLPS pathogenesis. Analysis of primary clinical specimens of WDLPS, and of the closely related dedifferentiated liposarcoma (DDLPS) subtype, revealed immunohistochemical evidence of AKT activation in 27% of cases. Western blot analysis of a panel of cell lines derived from patients with WDLPS or DDLPS revealed robust AKT phosphorylation in all cell lines examined, even when these cells were cultured in serum-free media. Moreover, BEZ235, a small molecule inhibitor of PI3K and mammalian target of rapamycin that effectively inhibits AKT activation in these cells, impaired viability at nanomolar concentrations. Our findings are unique in providing an animal model to decipher the molecular pathogenesis of WDLPS, and implicate AKT as a previously unexplored therapeutic target in this chemoresistant sarcoma.