Discovery of a Promising CBP/p300 Degrader XYD129 for the Treatment of Acute Myeloid Leukemia.

The epigenetic target CREB (cyclic-AMP responsive element binding protein) binding protein (CBP) and its homologue p300 were promising therapeutic targets for the treatment of acute myeloid leukemia (AML). Herein, we report the design, synthesis, and evaluation of a class of CBP/p300 PROTAC degraders based on our previously reported highly potent and selective CBP/p300 inhibitor 5. Among the compounds synthesized, 11c (XYD129) demonstrated high potency and formed a ternary complex between CBP/p300 and CRBN (AlphaScreen). The compound effectively degraded CBP/p300 proteins and exhibited greater inhibition of growth in acute leukemia cell lines compared to its parent compound 5. Furthermore, 11c demonstrated significant inhibition of tumor growth in a MOLM-16 xenograft model (TGI = 60%) at tolerated dose schedules. Our findings suggest that 11c is a promising lead compound for the treatment of AML.

Discovery of Highly Potent and Efficient CBP/p300 Degraders with Strong In Vivo Antitumor Activity.

The transcriptional coactivator cAMP response element binding protein (CREB)-binding protein (CBP) and its homologue p300 have emerged as attractive therapeutic targets for human cancers such as acute myeloid leukemia (AML). Herein, we report the design, synthesis, and biological evaluation of a series of cereblon (CRBN)-recruiting CBP/p300 proteolysis targeting chimeras (PROTACs) based on the inhibitor CCS1477. The representative compounds 14g (XYD190) and 14h (XYD198) potently inhibited the growth of AML cells with low nanomolar IC50 values and effectively degraded CBP and p300 proteins in a concentration- and time-dependent manner. Mechanistic studies confirmed that 14g and 14h can selectively bind to CBP/p300 bromodomains and induce CBP and p300 degradation in bromodomain family proteins in a CRBN- and proteasome-dependent manner. 14g and 14h displayed remarkable antitumor efficacy in the MV4;11 xenograft model (TGI = 88% and 93%, respectively). Our findings demonstrated that 14g and 14h are useful lead compounds and deserve further optimization and activity evaluation for the treatment of human cancers.

Discovery of Novel Phenoxyaryl Pyridones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with High Selectivity for the Second Bromodomain (BD2) to Potentially Treat Acute Myeloid Leukemia.

Bromodomain-selective BET inhibition has emerged as a promising strategy to improve the safety profiles of pan-BET inhibitors. Herein, we report the discovery of potent phenoxyaryl pyridones as highly BD2-selective BET inhibitors. Compound 23 (IC50 = 2.9 nM) exhibited a comparable BRD4 BD2 inhibitory activity relative to 10 (IC50 = 1.0 nM) and remarkably improved selectivity over BRD4 BD1 (23: 2583-fold; 10: 344-fold). This lead compound significantly inhibited the proliferation of acute myeloid leukemia (AML) cell lines through induction of G0/G1 arrest and apoptosis in vitro. Excellent in vivo antitumor efficacy with 23 was achieved in an MV;411 mouse xenograft model. Pleasingly, compound 23 (hERG IC50 > 30 µM) mitigated the inhibition of the human ether-à-go-go-related gene (hERG) ion channel compared with 10 (hERG IC50 = 2.8 µM). This work provides a promising BD2-selective lead for the development of more effective and safe BET inhibitors as anticancer agents.

CTGF regulates mineralization in human mature chondrocyte by controlling Pit-1 and modulating ANK via the BMP/Smad signalling.

OBJECTIVE: Connective tissue growth factor (CTGF) exhibits potent proliferative, differentiated, and mineralizing effects, and is believed to be contribute to cartilage mineralization in Osteoarthritis (OA). However, the underlying mechanism of chondrocyte mineralization induced by CTGF remains obscure. As a key regulator of mineral responses, type III phosphate transporter 1 (Pit-1) has been associated with the pathogenesis of articular mineralization. Therefore, the primary objective of this study was to investigate whether CTGF influences the development of mature chondrocyte mineralization and the underlying mechanisms governing such mineralization. METHODS: The effect of Connective tissue growth factor (CTGF) on human C-28/I2 chondrocytes were investigated. The chondrocytes were treated with CTGF or related inhibitors, and transfected with Overexpression and siRNA transfection of Type III Phosphate Transporter 1(Pit-1). Subsequently, the cells were subjected to Alizarin red S staining, PiPer Phosphate Assay Kit, Alkaline Phosphatase Diethanolamine Activity Kit, ELISA, RT-PCR or Western blot analysis. RESULTS: Stimulation with Connective tissue growth factor (CTGF) significantly upregulated the expression of the Type III Phosphate Transporter 1(Pit-1) and mineralization levels in chondrocytes through activation of α5ß1 integrin and BMP/Samd1/5/8 signaling pathways. Furthermore, treatment with overexpressed Pit-1 markedly increased the expression of Multipass Transmembrane Ankylosis (ANK) transporter in the cells. The inhibitory effect of CTGF receptor blockade using α5ß1 Integrin blocking antibody was demonstrated by significantly suppressed the expression of Pit-1 and ANK transporter, as well as chondrocyte mineralization. CONCLUSIONS: Our data indicate that Connective tissue growth factor (CTGF) plays a critical role inchondrocyte mineralization, which is dependent on the expression of the Type III Phosphate Transporter 1(Pit-1) and Multipass Transmembrane Ankylosis (ANK) transporter. Consequently, inhibition of CTGF activity may represent a novel therapeutic approach for the management of Osteoarthritis (OA).

Discovery of a potent and selective CBP bromodomain inhibitor (Y08262) for treating acute myeloid leukemia.

The bromodomain of CREB (cyclic-AMP response element binding protein) binding protein (CBP) is an epigenetic "reader" and plays a key role in transcriptional regulation. CBP bromodomain is considered to be a promising therapeutic target for acute myeloid leukemia (AML). Herein, we report the discovery of a series of 1-(indolizin-3-yl)ethan-1-one derivatives as potent, and selective CBP bromodomain inhibitors focused on improving cellular potency. One of the most promising compounds, 7e (Y08262), inhibits the CBP bromodomain at the nanomolar level (IC50 = 73.1 nM) with remarkable selectivity. In addition, the new inhibitor also displays potent inhibitory activities in AML cell lines. Collectively, this study provides a new lead compound for further validation of CBP bromodomain as a molecular target for AML drug development.

An evaluation of the protective effects of chlorogenic acid on broiler chickens in a dextran sodium sulfate model: a preliminary investigation.

This study was conducted to investigate the protective effects of chlorogenic acid (CGA) on broilers subjected to dextran sodium sulfate (DSS)-induced intestinal damage. One hundred and forty-four 1-day-old male Arbor Acres broiler chicks were allocated into one of 3 groups with 6 replicates of eight birds each for a 21-d trial. The treatments included: 1) Control group: normal birds fed a basal diet; 2) DSS group: DSS-treated birds fed a basal diet; and 3) CGA group: DSS-treated birds fed a CGA-supplemented control diet. An oral DSS administration via drinking water was performed from 15 to 21 d of age. Compared with the control group, DSS administration reduced 21-d body weight and weight gain from 15 to 21 d, but increased absolute weight of jejunum and absolute and relative weight of ileum (P < 0.05). DSS administration elevated circulating D-lactate concentration and diamine oxidase activity (P < 0.05), which were partially reversed when supplementing CGA (P < 0.05). The oral administration with DSS decreased villus height and villus height/crypt depth ratio, but increased crypt depth in jejunum and ileum (P < 0.05). Compared with the control group, DSS administration increased serum glutathione level and jejunal catalase activity and malonaldehyde accumulation, but decreased jejunal glutathione level (P < 0.05). In contrast, feeding a CGA-supplemented diet normalized serum glutathione and jejunal malonaldehyde levels, and increased jejunal glutathione concentration in DSS-administrated birds (P < 0.05). Additionally, CGA supplementation reduced ileal malonaldehyde accumulation in DSS-treated birds (P < 0.05). DSS challenge increased levels of serum interferon-γ and interleukin-6, jejunal interleukin-1ß, tumor necrosis factor-α, and interleukin-6, and ileal interleukin-1ß and interleukin-6 when compared with the control group (P < 0.05). The elevated serum interferon-γ and ileal interleukin-6 levels were normalized to control values when supplementing CGA (P < 0.05). The results suggested that CGA administration could partially prevent DSS-induced increased intestinal permeability, oxidative damage, and inflammation in broilers, although it did not improve their growth performance and intestinal morphology.

Structural insights revealed by the cocrystal structure of CCS1477 in complex with CBP bromodomain.

Inhibition of the bromodomain of the CREB (cyclic-AMP response element-binding protein) binding protein (CBP) is a particularly promising new therapeutic approach for cancer. Benzimidazole derivatives CCS1477 and its analogues (8 and 9) are highly potent and selective CBP bromodomain inhibitors, with Kd values of 26.4, 37.0, and 34.3 nM in ITC assay, respectively. Among these compounds, CCS1477 is undergoing phase Ib/IIa clinical trials for the treatment of various cancers. Thus, we determined the co-crystal structures of CCS1477 and its analogues in complex with CBP bromodomain and revealed the detailed binding modes. Furthermore, overlapping with other reported co-crystal structures allowed us to identify that interaction with Arg1173, LPF shelf, and ZA channel was critical for keeping strong biological activity and selectivity. Collectively, this study provided a structural basis for CBP bromodomain inhibitors design.

Integrated Bioinformatics Analysis Identifies a New Stemness Index-Related Survival Model for Prognostic Prediction in Lung Adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is one of the most lethal malignancies and is currently lacking in effective biomarkers to assist in diagnosis and therapy. The aim of this study is to investigate hub genes and develop a risk signature for predicting prognosis of LUAD patients. METHODS: RNA-sequencing data and relevant clinical data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was performed to identify hub genes associated with mRNA expression-based stemness indices (mRNAsi) in TCGA. We utilized LASSO Cox regression to assemble our predictive model. To validate our predictive model, me applied it to an external cohort. RESULTS: mRNAsi index was significantly associated with the tissue type of LUAD, and high mRNAsi scores may have a protective influence on survival outcomes seen in LUAD patients. WGCNA indicated that the turquoise module was significantly correlated with the mRNAsi. We identified a 9-gene signature (CENPW, MCM2, STIL, RACGAP1, ASPM, KIF14, ANLN, CDCA8, and PLK1) from the turquoise module that could effectively identify a high-risk subset of these patients. Using the Kaplan-Meier survival curve, as well as the time-dependent receiver operating characteristic (tdROC) analysis, we determined that this gene signature had a strong predictive ability (AUC = 0.716). By combining the 9-gene signature with clinicopathological features, we were able to design a predictive nomogram. Finally, we additionally validated the 9-gene signature using two external cohorts from GEO and the model proved to be of high value. CONCLUSION: Our study shows that the 9-gene mRNAsi-related signature can predict the prognosis of LUAD patient and contribute to decisions in the treatment and prevention of LUAD patients.

Discovery, optimization and evaluation of 1-(indolin-1-yl)ethan-1-ones as novel selective TRIM24/BRPF1 bromodomain inhibitors.

TRIM24 (tripartite motif-containing protein 24) and BRPF1 (bromodomain and PHD finger containing protein 1) are epigenetics "readers" and potential therapeutic targets for cancer and other diseases. Here we describe the structure-guided design of 1-(indolin-1-yl)ethan-1-ones as novel TRIM24/BRPF1 bromodomain inhibitors. The representative compound 20l (Y08624) is a new TRIM24/BRPF1 dual inhibitor, with IC50 values of 0.98 and 1.16 µM, respectively. Cellular activity of 20l was validated by viability assay in prostate cancer (PC) cell lines. In PC xenograft models, 20l suppressed tumor growth (50 mg/kg/day, TGI = 53%) without exhibiting noticeable toxicity. Compound 20l represents a versatile starting point for the development of more potent TRIM24/BRPF1 inhibitors.

Structure-Based Discovery and Optimization of Furo[3,2-c]pyridin-4(5H)-one Derivatives as Potent and Second Bromodomain (BD2)-Selective Bromo and Extra Terminal Domain (BET) Inhibitors.

Pan-bromodomain and extra terminal (Pan-BET) inhibitors show profound efficacy but exhibit pharmacology-driven toxicities in clinical trials. The development of domain-selective BET inhibitors to separate efficacy and toxicity is urgently needed. Herein, we report a series of furo[3,2-c]pyridin-4(5H)-one derivatives as novel BD2-selective BET inhibitors. The representative compound 8l (XY153) potently bound to BRD4 BD2 with an half-maximum inhibitory concentration (IC50) value of 0.79 nM and displayed 354-fold selectivity over BRD4 BD1. Besides, 8l exhibited 6-fold BRD4 BD2 domain selectivity over other BET BD2 domains. Compound 8l displayed potent antiproliferative activity against multiple tumor cell lines, especially MV4-11 (IC50 = 0.55 nM), while showing weak cytotoxicity against the normal lung fibroblast cell line. It highlights the safety profile of this series of BD2 inhibitors. 8l also demonstrated good metabolic stability in vitro. These data indicate that 8l may serve as a new and valuable lead compound for the development of potential therapeutics against acute myeloid leukemia (AML).

High Expression Levels of SLC38A1 Are Correlated with Poor Prognosis and Defective Immune Infiltration in Hepatocellular Carcinoma.

Solute Carrier Family 38 Member 1 (SLC38A1) is a principal transporter of glutamine and plays a crucial role in the transformation of neoplastic cells. However, the correlation between SLC38A1 expression, prognosis, and immune infiltration in hepatocellular carcinoma (HCC) has yet to be elucidated. We used two independent patient cohorts, namely, a Cancer Genome Atlas (TCGA) cohort and a Clinical Proteomic Tumor Analysis Consortium (CPTAC) cohort, to analyze the role of SLC38A1 in HCC at the mRNA and protein levels, respectively. In these two cohorts, SLC38A1 mRNA and protein expression levels were higher in HCC tissues than in adjacent nontumor tissues. Both SLC38A1 mRNA and protein expression were positively associated with clinicopathological characteristics (clinical stage, T stage, pathological grade, tumor size, and tumor thrombus), were negatively associated with survival, and were independent prognostic factors in HCC patients. Functional enrichment analyses further indicated that SLC38A1 was involved in multiple pathways related to amino acid metabolism, tumors, and immunity. High expression levels of SLC38A1 were inversely proportional to CD8+ T cells and directly proportional to macrophages M0, neutrophils, programmed cell death-1/programmed cell death ligand 1 (PD-1/PD-L1), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). Moreover, we used immunohistochemical analysis of tissue samples and other online databases to further validate the expression levels and prognostic significance of SLC38A1 in HCC. Collectively, our study demonstrated that the upregulated expression of SLC38A1 was related to an unfavorable prognosis and defective immune infiltration in HCC.

Osthole inhibits proliferation of kainic acid­activated BV­2 cells by modulating the Notch signaling pathway.

Epilepsy is a syndrome involving chronic recurrent transient brain dysfunction. Activation and proliferation of microglia serve important roles in epilepsy pathogenesis and may be targets for treatment. Although osthole, an active constituent isolated from Cnidium monnieri (L.) Cusson, has been demonstrated to improve epilepsy in rats, its underlying mechanism remains to be elucidated. The present study investigated the effect of osthole on proliferation of kainic acid (KA)­activated BV­2 cells and explored the molecular mechanism by which it inhibited their proliferation. Using Cell Counting Kit­8, enzyme­linked immunosorbent assay, reverse transcription­quantitative PCR, western blot analysis and immunofluorescence staining, it was identified that following exposure of KA­activated BV­2 cells to 131.2 µM osthole for 24 h, cell proliferation and release of tumor necrosis factor α, interleukin 6 and nitric oxide synthase/induced nitric oxide synthase were significantly inhibited (P<0.05). Further experiments revealed that osthole significantly downregulated mRNA and protein levels of Notch signaling components in KA­activated BV­2 cells (P<0.05). Therefore, it was hypothesized that osthole inhibited the proliferation of microglia by modulating the Notch signaling pathway, which may be useful for the treatment of epilepsy and other neurodegenerative diseases characterized by Notch upregulation.

NLRP3 inflammasome and related cytokines reflect the immune status of patients with HBV-ACLF.

BACKGROUND: The NLRP3 inflammasome has been suggested to play a crucial role in host antiviral defense, including against hepatitis B virus (HBV) infection. In the present study, we measured expression of NLRP3 and its related cytokines in patients with different stages of HBV-related acute-on-chronic liver failure (HBV-ACLF), a pattern of end-stage liver disease that occurs frequently in patients with chronic HBV (CHB) infection or HBV-related cirrhosis. METHODS: A total of 75 subjects including 30 HBV-ACLF patients, 30 CHB patients, and 15 healthy controls (HCs) were enrolled. The NLRP3 inflammasome and its components (caspase-1, interleukin (IL)-1ß, and IL-18) were measured in peripheral blood mononuclear cells (PBMCs), macrophages, and liver using flow cytometry, quantitative real-time polymerase chain reaction (RT-PCR), western blot, and immunohistochemistry. The LPS was used to evaluate changes in NLRP3 and its related cytokines in CD14+ monocytes which may reflect immune status. Cytokine expression was measured using RT-PCR. RESULTS: Patients with HBV-ACLF had lower NLRP3 inflammasome expression in peripheral CD14+ monocytes, particularly in the middle-to-late stage, but higher expression in liver macrophages compared to CHB and HCs. Compared with H-LPS or L-LPS alone, L-LPS sequential H-LPS can significantly inhibit the expression of NLRP3 and its related cytokines. CONCLUSION: Differential expression patterns of the NLRP3 inflammasome in the periphery and liver might be related to immune dysfunction and recruitment of monocytes to the injured liver during disease progression. Persistent systemic inflammation is likely a cause of compromised immune status in patients with HBV-ACLF.

MicroRNA-124a contributes to glucocorticoid resistance in acute-on-chronic liver failure by negatively regulating glucocorticoid receptor alpha.

INTRODUCTION AND OBJECTIVES: Glucocorticoid resistance frequently associating with inflammation, may severely compromise the therapeutic effect of glucocorticoids. In this study, we aimed to investigate the regulation of glucocorticoid resistance by microRNA-124a (miR-124a) in patients with acute-on-chronic liver failure (ACLF). MATERIALS AND METHODS: The miR-124a levels and glucocorticoid receptor alpha (GRα) expressions in peripheral blood monocytes and liver tissues were measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), flow cytometry, and western blot analyses in the following four groups: healthy controls (HC), moderate chronic hepatitis B (CHB) patients, hepatitis B virus-related ACLF (HBV-ACLF) patients, and alcohol-induced ACLF (A-ACLF) patients. In addition, the serum miR-124a levels and multiple biochemical indices were determined. The effects of miR-124a transfection on GRα expression were assayed by qRT-PCR and western blotting in U937 and HepG2 cells stimulated with lipopolysaccharide (LPS). RESULTS: Compared with the CHB patients and HC, the miR-124a levels in HBV-ACLF and A-ACLF patients increased, while GRα expressions decreased. No significant differences in miR-124a levels and GRα expressions were observed between the HBV-ACLF and A-ACLF patients. For the ACLF patients, miR-124a level was negatively related to GRα expression in monocytes and positively correlated with the inflammatory factors such as interleukin-1 beta (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). In U937 and HepG2 cells, LPS stimulated miR-124a levels but inhibited GRα expressions; meanwhile, increasing miR-124a levels reduced GRα expressions, and inhibiting miR-124a levels increased GRα expressions. CONCLUSIONS: This study provides evidence that GRα expression was negatively regulated by miR-124a, which primarily determines the extent of acquired glucocorticoid resistance in ACLF.

Osthole inhibits proliferation and induces apoptosis in BV-2 microglia cells in kainic acid-induced epilepsy via modulating PI3K/AKt/mTOR signalling way.

CONTEXT: Osthole is a natural coumarin compound most frequently extracted from plants of the Apiaceae family such as Cnidium monnieri (L.) Cusson, Angelica pubescens Maxin.f., and Peucedanum ostruthium (L.). Osthole is considered to have potential therapeutic applications for the treatment of diseases including epilepsy. However, the mechanism of osthole induced-apoptosis in BV-2 microglia cells is not yet clear. OBJECTIVE: To investigate the molecular mechanisms underlying the effect of osthole on PI3K/AKt/mTOR expression in kainic acid (KA)-activated BV-2 microglia cells. MATERIALS AND METHODS: Optimal culture concentration and time of osthole were investigated by MTT assay. The concentration of osthole was tested from 10 to 400 µM and the culture time was tested from 2 to 72 h. Ultrastructure difference among control, KA and osthole group was analyzed under transmission electron microscope. The mRNA expression of PI3K/AKt/mTOR was investigated using reverse transcription (RT)-PCR and the protein expression was investigated using western blotting and immunofluorescence assay. Apoptosis rate of BV-2 cells between each group was measured by flow cytometry. RESULTS: IC50 for cell viability of BV-2 cells by osthole was 157.7 µM. Treated with osthole (140 µM) for 24 h significantly increased the inhibition rate. Pretreatment with osthole inhibited the KA-induced PI3K/AKt/mTOR mRNA and protein expression. The results of flow cytometry analysis showed that the apoptotic rate of osthole group was obviously higher than KA group. CONCLUSIONS: Date showed that osthole may be useful in the treatment of epilepsy and other neurodegenerative diseases that are characterized by over expression of PI3K/Akt/mTOR.

Cure and prevention strategy for postoperative gastrointestinal fistula after esophageal and gastric cardiac cancer surgery.

Gastrointestinal fistula is the most serious complication of esophageal and gastric cardiac cancer surgery. According to occurrence of organ, gastrointestinal fistula can be divided into anastomotic fistula, gastric fistula; According to occurrence site, fistula can be divided into cervical fistula, thoracic fistula; According to time of occurrence, can be divided into early, middle and late fistula. There are special types of fistula including 'thoracic cavity'-stomach-bronchial fistula, 'thoracic cavity'-stomach-aortic fistula. Early diagnosis needs familiarity with various types of clinical gastrointestinal fistulas. However, Prevention of gastrointestinal fistula is better than cure, including perioperative nutritional support, respiratory tract management, and acid suppression, positive treatment of complications, antibiotic prophylaxis, and gastrointestinal decompression and eating timing. Prevention can effectively reduce the incidence of postoperative gastrointestinal fistula. Collectively, early diagnosis and treatment, nutritional supports are key to reducing mortality of gastrointestinal fistula.

Giant primary cystic mediastinal lymphangioma: A case report.

Cystic lymphangioma mainly occurs in children. Cystic mediastinal lymphangioma (CML) originates from mediastinal tissues and is an extremely uncommon cystic lymphangioma that develops from the lymphatic vessels. The present study reports the case of 46-year-old male patient with a giant CML that was surgically resected by video-assisted thoracoscopy. The largest diameter of the CML was 18.0 cm, and ~400 ml of pale yellow fluid was removed from the cystic cavity during surgery. The postoperative pathological reports on the cystic wall showed that the neoplasm was a CML. At present, at the one-year postoperative follow-up, there are no signs of recurrence. In conclusion, complete surgical resection may prevent recurrence.

Association between P(16INK4a) promoter methylation and non-small cell lung cancer: a meta-analysis.

BACKGROUND: Aberrant methylation of CpG islands acquired in tumor cells in promoter regions plays an important role in carcinogenesis. Accumulated evidence demonstrates P(16INK4a) gene promoter hypermethylation is involved in non-small cell lung carcinoma (NSCLC), indicating it may be a potential biomarker for this disease. The aim of this study is to evaluate the frequency of P(16INK4a) gene promoter methylation between cancer tissue and autologous controls by summarizing published studies. METHODS: By searching Medline, EMBSE and CNKI databases, the open published studies about P(16INK4a) gene promoter methylation and NSCLC were identified using a systematic search strategy. The pooled odds of P(16INK4A) promoter methylation in lung cancer tissue versus autologous controls were calculated by meta-analysis method. RESULTS: Thirty-four studies, including 2 652 NSCLC patients with 5 175 samples were included in this meta-analysis. Generally, the frequency of P(16INK4A) promoter methylation ranged from 17% to 80% (median 44%) in the lung cancer tissue and 0 to 80% (median 15%) in the autologous controls, which indicated the methylation frequency in cancer tissue was much higher than that in autologous samples. We also find a strong and significant correlation between tumor tissue and autologous controls of P(16INK4A) promoter methylation frequency across studies (Correlation coefficient 0.71, 95% CI:0.51-0.83, P<0.0001). And the pooled odds ratio of P(16INK4A) promoter methylation in cancer tissue was 3.45 (95% CI: 2.63-4.54) compared to controls under random-effect model. CONCLUSION: Frequency of P(16INK4a) promoter methylation in cancer tissue was much higher than that in autologous controls, indicating promoter methylation plays an important role in carcinogenesis of the NSCLC. Strong and significant correlation between tumor tissue and autologous samples of P(16INK4A) promoter methylation demonstrated a promising biomarker for NSCLC.

Extrathoracic malignant peripheral nerve sheath tumor of the lateral chest wall locally recurred and metastasized to peritoneum: Report of a case.

Malignant peripheral nerve sheath tumors (MPNSTs) are rare, with an expected incidence of 0.0001% per year in the general population and 4.6% in patients with von Recklinghausen's disease. They are defined as any malignant tumors arising or differentiating from cells of the peripheral nerve sheath. MPNSTs can develop in various sites including the trunk and head/neck region. However, its onset on the chest wall is very rare. Here we report a case of MPNST growing outside the thorax on the chest wall. The patient developed a local recurrence twice, which caused multiple metastases to the lung and peritoneum.

[Sodium nitrite improves epithelial-mesenchymal transition of hepatoma cells in mice bearing H22].

This study is to report the determination of the effect of sodium nitrite induced oxygen species (ROS) on the epithelial-mesenchymal transition in hepatoma cells in mice bearing H22 and investigation of its role in hypoxia-inducible factor 1alpha (HIF-1alpha) in this process. Mice hepatocarcinoma cell line H22 was inoculated subcutaneously into right axillary of sixty male Kunming mice and then randomly divided into four groups: control group; low-dose sodium nitrite group (10 mg x kg(-1)), medium-dose sodium nitrite group (20 mg x kg(-1)) and high-dose sodium nitrite group (30 mg x kg(-1)). Sodium nitrite group was given (ig) sodium nitrite with 10-30 mg x kg(-1) x d(-1) for 21 days. Compared with control group, there was no obvious difference between the two groups in the volume or weight of xenografts, but in sodium nitrite treatment group, the activity of SOD and CAT decreased and contents of MDA or nitrite increased in tumor tissue of mice bearing H22; epithelial-mesenchymal transition (EMT) of hepatoma cells was induced, the EMT-phenotype tumors displayed a greater degree of local aggressiveness, with dissection through adjacent fascia and skeletal muscle. The increased expression of HIF-la and vimentin and declination of E-cadherin were confirmed by immunohistochemistry and Western blotting. These data indicate sodium nitrite treatment could improve the epithelial-mesenchymal transition of xenografts in mice bearing H22, which might relate to the fact that ROS mediated signal pathway increased the expression of HIF-1alpha.