Inactivated cGAS-STING Signaling Facilitates Endocrine Resistance by Forming a Positive Feedback Loop with AKT Kinase in ER+HER2- Breast Cancer.

Endocrine-resistant ER+HER2- breast cancer (BC) is particularly aggressive and leads to poor clinical outcomes. Effective therapeutic strategies against endocrine-resistant BC remain elusive. Here, analysis of the RNA-sequencing data from ER+HER2- BC patients receiving neoadjuvant endocrine therapy and spatial transcriptomics analysis both show the downregulation of innate immune signaling sensing cytosolic DNA, which primarily occurs in endocrine-resistant BC cells, not immune cells. Indeed, compared with endocrine-sensitive BC cells, the activity of sensing cytosolic DNA through the cGAS-STING pathway is attenuated in endocrine-resistant BC cells. Screening of kinase inhibitor library show that this effect is mainly mediated by hyperactivation of AKT1 kinase, which binds to kinase domain of TBK1, preventing the formation of a trimeric complex TBK1/STING/IRF3. Notably, inactivation of cGAS-STING signaling forms a positive feedback loop with hyperactivated AKT1 to promote endocrine resistance, which is physiologically important and clinically relevant in patients with ER+HER2- BC. Blocking the positive feedback loop using the combination of an AKT1 inhibitor with a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of endocrine-resistant tumors in humanized mice models, providing a potential strategy for treating patients with endocrine-resistant BC.

Decreased Nrf2 protein level and low sperm quality in intractable spermatocystitis.

ABSTRACT: To investigate the molecular etiology of low sperm quality in patients with intractable spermatocystitis, spermatozoa samples from patients with persistent hematospermia undergoing transurethral seminal vesiculoscopy and healthy volunteers were utilized. Spermatozoa samples were collected from the seminal vesicles through transurethral seminal vesiculoscopy or by masturbation ejaculation. Sperm quality was analyzed by a WLJY-9000 color semen analysis system. Measurement of tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) in the seminal plasma was performed using enzyme-linked immunosorbent assay (ELISA). Measurement of H2O2 in the seminal plasma was performed with a hydrogen peroxide kit. The protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and phosphorylated-Nrf2 (p-Nrf2) were measured by western blot analysis and immunofluorescence assays. Low sperm quality parameters and increased levels of inflammatory cytokines (TNFα, IL-6, and H2O2) in the seminal plasma were detected among the semen samples from the patients with persistent hematospermia. Nrf2 and p-Nrf2 were strongly expressed in the nucleus and periphery of human sperm cells, according to the results of the immunofluorescence assays. The protein levels of Nrf2 and p-Nrf2 were significantly lower in the spermatozoa samples from patients with persistent hematospermia than in those from healthy volunteers with normal sperm motility. The results suggested that Nrf2 signaling might play a role in the low sperm quality of patients with intractable spermatocystitis.

Puerarin prevents calcium oxalate crystal-induced renal epithelial cell autophagy by activating the SIRT1-mediated signaling pathway.

Calcium oxalate (CaOx) crystals can activate autophagy, causing damage to renal tubular epithelial cells (TECs). Puerarin has been shown to have protective and therapeutic effects against a variety of diseases by inhibiting autophagy activation. However, the protective effect of puerarin against CaOx crystals and the underlying molecular mechanisms are unclear. Cell Counting Kit-8 (CCK-8) assays were used to evaluate the effects of puerarin on cell viability. Intracellular reactive oxygen species (ROS) levels were measured by the cell-permeable fluorogenic probe 2,7-dichlorofluorescein diacetate (DCFH-DA). Immunofluorescence, immunohistochemistry, and western blotting were used to examine the expression of SIRT1, Beclin1, p62, and LC3, and explore the underlying molecular mechanisms in vivo and in vitro. Puerarin treatment significantly attenuated CaOx crystal-induced autophagy of TECs and CaOx cytotoxicity to TECs by altering SIRT1 expression in vitro and in vivo, whereas the SIRT1-specific inhibitor EX527 exerted contrasting effects. In addition, we found that the protective effect of puerarin was related to the SIRT1/AKT/p38 signaling pathway. The findings suggest that puerarin regulates CaOx crystal-induced autophagy by activating the SIRT1-mediated signaling pathway, and they suggest a series of potential therapeutic targets and strategies for treating nephrolithiasis.

Association between socioeconomic status and chronic obstructive pulmonary disease in Jiangsu province, China: a population-based study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common public health problem worldwide. Recent studies have reported that socioeconomic status (SES) is related to the incidence of COPD. This study aimed to investigate the association between SES and COPD among adults in Jiangsu province, China, and to determine the possible direct and indirect effects of SES on the morbidity of COPD. METHODS: A cross-sectional study was conducted among adults aged 40 years and above between May and December of 2015 in Jiangsu province, China. Participants were selected using a multistage sampling approach. COPD, the outcome variable, was diagnosed by physicians based on spirometry, respiratory symptoms, and risk factors. Education, occupation, and monthly family average income (FAI) were used to separately indicate SES as the explanatory variable. Mixed-effects logistic regression models were introduced to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for examining the SES-COPD relationship. A pathway analysis was conducted to further explore the pulmonary function impairment of patients with different SES. RESULTS: The mean age of the 2421 participants was 56.63 ±â€Š9.62 years. The prevalence of COPD was 11.8% (95% CI: 10.5%-13.1%) among the overall sample population. After adjustment for age, gender, residence, outdoor and indoor air pollution, body weight status, cigarette smoking, and potential study area-level clustering effects, educational attainment was negatively associated with COPD prevalence in men; white collars were at lower risk (OR: 0.60, 95% CI: 0.43-0.83) of experiencing COPD than blue collars; compared with those within the lower FAI subgroup, participants in the upper (OR: 0.68, 95% CI: 0.49-0.97) tertiles were less likely to experience COPD. Such negative associations between all these three SES indicators and COPD were significant among men only. Education, FAI, and occupation had direct or indirect effects on pulmonary function including post-bronchodilator forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC), FEV1, FVC, and FEV1 percentage of predicted. Education, FAI, and occupation had indirect effects on pulmonary function indices of all participants mainly through smoking status, indoor air pollution, and outdoor air pollution. We also found that occupation could affect post-bronchodilator FEV1/FVC through body mass index. CONCLUSIONS: Education, occupation, and FAI had an adverse relationship with COPD prevalence in Jiangsu province, China. SES has both direct and indirect associations with pulmonary function impairment. SES is of great significance for COPD morbidity. It is important that population-based COPD prevention strategies should be tailored for people with different SES.

An integrated pan-cancer analysis of TFAP4 aberrations and the potential clinical implications for cancer immunity.

Studies have shown that transcription factor activating enhancer binding protein 4 (TFAP4) plays a vital role in multiple types of cancer; however, the TFAP4 expression profile is still unknown, as is its value within the human pan-cancer analysis. The present study comprehensively analysed TFAP4 expression patterns from 33 types of malignancies, along with the significance of TFAP4 for prognosis prediction and cancer immunity. TFAP4 displayed inconsistent levels of gene expression across the diverse cancer cell lines, and displayed abnormal expression within most malignant tumours, which closely corresponded to overall survival. More importantly, the TFAP4 level was also significantly related to the degree of tumour infiltration. TFAP4 was correlated using gene markers in tumour-infiltrating immune cells and immune scores. TFAP4 expression was correlated with tumour mutation burden and microsatellite instability in different cancer types, and enrichment analyses identified TFAP4-associated terms and pathways. The present study comprehensively analysed the expression of TFAP4 across 33 distinct types of cancers, which revealed that TFAP4 may possibly play a vital role during cancer formation and development. TFAP4 is related to differing degrees of immune infiltration within cancers, which suggests the potential of TFAP4 as an immunotherapy target in cancers. Our study demonstrated that TFAP4 plays an important role in tumorigenesis as a prognostic biomarker, which highlights the possibility of developing new targeted treatments.

Clinical Implications of Aberrant PD-1 and CTLA4 Expression for Cancer Immunity and Prognosis: A Pan-Cancer Study.

Combination therapy with inhibitors of cytotoxic T lymphocyte-associated protein (CTLA)4 and programmed death (PD)-1 has demonstrated efficacy in cancer patients. However, there is little information on CTLA4 and PD-1 expression levels and their clinical significance across diverse cancers. In this study, we addressed this question by analyzing PD-1 and CTLA4 levels in 33 different types of cancer along with their prognostic significance using The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia datasets. Liver hepatocellular carcinoma (LIHC) patients receiving cytokine-induced killer cell (CIK) immunotherapy at Sun Yat-sen University cancer center were enrolled for survival analysis. The correlation between PD-1/CTLA4 expression and cancer immunity was also analyzed. The results showed that PD-1 and CTLA4 transcript levels varied across cancer cell lines, with aberrant expression detected in certain cancer types; Kaplan-Meier analysis with the Cox proportional hazards model showed that this was closely related to overall survival in breast invasive carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, acute myeloid leukemialymphoma, uterine corpus endometrial carcinoma, and uveal melanoma in TCGA. High serum PD-1 and CTLA4 levels predicted better survival in LIHC patients receiving CIK therapy. PD-1 and CTLA4 levels were found to be significantly correlated with the degree of tumor cell infiltration using Tumor Immune Estimation Resource, Estimating Relative Subsets of RNA Transcripts, and Estimation of Stromal and immune Cells in Malignant Tumor Tissues Using Expression Data as well as with tumor-infiltrating lymphocyte marker expression; they were also related to tumor mutation burden, microsatellite instability, mismatch repair, and the expression of DNA methyltransferases in some cancer types. Gene set enrichment analysis of 33 cancer types provided further evidence for associations between PD-1/CTLA4 levels and cancer development and immunocyte infiltration. Thus, PD-1 and CTLA4 play important roles in tumorigenesis and tumor immunity and can serve as prognostic biomarkers in different cancer types.

Rosiglitazone Suppresses Calcium Oxalate Crystal Binding and Oxalate-Induced Oxidative Stress in Renal Epithelial Cells by Promoting PPAR-γ Activation and Subsequent Regulation of TGF-ß1 and HGF Expression.

Peroxisome proliferator-activated receptor- (PPAR-) γ is a ligand-dependent transcription factor, and it has become evident that PPAR-γ agonists have renoprotective effects, but their influence and mechanism during the development of calcium oxalate (CaOx) nephrolithiasis remain unknown. Rosiglitazone (RSG) was used as a representative PPAR-γ agonist in our experiments. The expression of transforming growth factor-ß1 (TGF-ß1), hepatocyte growth factor (HGF), c-Met, p-Met, PPAR-γ, p-PPAR-γ (Ser112), Smad2, Smad3, pSmad2/3, and Smad7 was examined in oxalate-treated Madin-Darby canine kidney (MDCK) cells and a stone-forming rat model. A CCK-8 assay was used to evaluate the effects of RSG on cell viability. In addition, intracellular reactive oxygen species (ROS) levels were monitored, and lipid peroxidation in renal tissue was detected according to superoxide dismutase and malondialdehyde levels. Moreover, the location and extent of CaOx crystal deposition were evaluated by Pizzolato staining. Our results showed that, both in vitro and in vivo, oxalate impaired PPAR-γ expression and phosphorylation, and then accumulative ROS production was observed, accompanied by enhanced TGF-ß1 and reduced HGF. These phenomena could be reversed by the addition of RSG. RSG also promoted cell viability and proliferation and decreased oxidative stress damage and CaOx crystal deposition. However, these protective effects of RSG were abrogated by the PPAR-γ-specific inhibitor GW9662. Our results revealed that the reduction of PPAR-γ activity played a critical role in oxalate-induced ROS damage and CaOx stone formation. RSG can regulate TGF-ß1 and HGF/c-Met through PPAR-γ to exert antioxidant effects against hyperoxaluria and alleviate crystal deposition. Therefore, PPAR-γ agonists may be expected to be a novel therapy for nephrolithiasis, and this effect is related to PPAR-γ-dependent suppression of oxidative stress.

Improved accuracy of hemimandibular reconstructions involving the condyle by utilizing hydroformed reconstruction plates rather than hand-bent stock plates.

BACKGROUND: Computer-aided design/computer-aided manufacturing (CAD/CAM) surgical templates allow precise mandibular reconstructive surgery. However, their clinical accuracy is limited by manual plate bending. Digitally hydroformed plates maintain a digital workstream in virtual planning. METHODS: Twelve patients with Brown's class IIc mandibular defects were randomized into two groups: group I (experimental), the reconstruction plate was digitally hydroformed, and group II (control), surgeries were performed CAD/CAM guided with the reconstruction plate manually prebent. The linear and angular deviations of reconstruction outcomes were compared to surgical simulation in both groups. RESULTS: The mean linear and angular deviations of middle and posterior segments were 2.14 ± 0.79 mm, 3.71 ± 0.95 mm, 8.73° ± 1.91°, and 9.06° ± 0.96° in group I and 4.31 ± 0.78 mm, 6.74 ± 1.40 mm, 16.35° ± 0.72°, and 31.48° ± 3.38° in group II, respectively. Measurements in group I were significantly lower than group II (P < .005). CONCLUSION: Digital hydroforming for plate prebent is a reliable method that helps improving the clinical accuracy of CAD/CAM-guided mandibular reconstruction surgery.

Randomized control trial comparing the titanium osteosynthesis and the biodegradable osteosynthesis in mandibulotomy access.

BACKGROUND: The clinical degradation rate and strength of biodegradable implant exposed to postoperative radiotherapy (PORT) are unknown. METHODS: A prospective randomized control trial of 40 consecutive mandibulotomy patients randomly divided into titanium and biodegradable cohorts. All patients received PORT. The following parameters were compared: maximal mouth opening, occlusal force, center of force trajectory, occlusal status, radiographic evidence of bony union, mandibular function impairment questionnaire (MFIQ), overall satisfaction score, and complication rates. RESULTS: Both the mandibular function and occlusal status parameter of the biodegradable and the titanium groups were not significantly difference. Biodegradable cohort showed better MFIQ scores (P = .08) and overall satisfaction scores (P = .64) but was not statistically significant. Of note, 40% of patients in the titanium cohort complained of plate palpability/cold intolerance and required plate removal (P = .02); 10% of patients in the titanium cohort developed osteoradionecrosis. CONCLUSION: Biodegradable osteosynthesis is as reliable as titanium osteosynthesis for mandibulotomy fixation. PORT did not increase the complication rate in the biodegradable group.

WITHDRAWN: A Randomized Controlled Trial Comparing Between Titanium Osteosynthesis and Biodegradable Osteosynthesis in Access Mandibulotomy for Oral Malignancy.

Available online April 7, 2018. This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Modified maxillary reconstruction technique for Brown's class III defects by subdividing a rhomboid shaped iliac crest into 2 subunits.

BACKGROUND: Men and women share a common maxillary morphology with heterogeneity in size. This indicated that our technique of reconstruction with a rhomboid-shaped iliac crest bone flap incorporating a 30° vertical wedge osteotomy may be widely used for Brown's class III maxillectomy defect reconstruction among a population with class I skeletal profile. The reconstruction of Brown's class III maxillary defects is extremely challenging. The purpose of this study was to closely study the maxilla geometrically in order to establish a standardized maneuver, which facilitates conversion of the iliac bone flap into a natural maxilla's contours. METHODS: We evaluated the geometries of 40 adult maxillas. The perimeter lengths of perinasal and infraorbital subunits were analyzed, in addition to the intersecting angle (δ) of both subunits. Sex variation was evaluated using the Student's t test. RESULTS: In the 80 studied unilateral maxillas (40 maxillas from 18 men and 22 women), there were no significant sex differences for δ (P = .1527). In addition, both sexes shared common morphological features, hence, in surgical reconstruction, the δ can be constantly set at 150°. Perimeter of bone segments had a greater intersubject variability (coefficient of variation [CV] of approximately 4.5-11). From both cadaveric dissections and clinical applications, our results have shown that our standard maneuver was reproducible and reliable in reestablishing natural facial contours. CONCLUSION: Our standard maneuver can serve as a universal guideline, with individualized perimeter manipulations, to yield an aesthetically natural and functional outcome.

A three-lncRNA signature derived from the Atlas of ncRNA in cancer (TANRIC) database predicts the survival of patients with head and neck squamous cell carcinoma.

OBJECTIVE: Long non-coding RNAs (lncRNAs) have important biological functions and can be used as prognostic biomarkers in cancer. To identify a lncRNA prognostic signature for head and neck squamous cell carcinoma (HNSCC). METHOD: We analysed RNA-seq data derived from the TANRIC database to identify a lncRNA prognostic signature model using the orthogonal partial least squares discrimination analysis (OPLS-DA) and 1.5-fold expression change criterion methods. The prognosis prediction model based on the lncRNA signatures and clinical parameters were evaluated using the 5-fold cross validation method. RESULTS: A total of 84 out of 3199 lncRNAs were significantly associated with the survival of patients with HNSCC (log-rank test P<0.01). Using the OPLS-DA and 1.5-fold change selection criterion, 5 lncRNAs (KTN1-AS1, LINC00460, GUSBP11, LINC00923 and RP5-894A10.6) were further selected. The prediction power of each combination of the 5 lncRNAs was evaluated through the receiver operating characteristic (ROC) curve and a three-lncRNA panel (KTN1-AS1, LINC00460 and RP5-894A10.6) achieved the highest prognostic prediction power (AUC 0.68, 95% CI 0.60-0.76, P<0.0001) in the cohort. The patients were categorized into high- and low-risk groups based on their three-lncRNA profiles. Patients with high-risk scores had worse overall survival than those with low risk scores in the cohort (log-rank test P=0.0003). Multivariable Cox regression analyses showed that the lncRNA signature and tumour grade were independent prognostic factors for patients with HNSCC. CONCLUSIONS: Our findings showed that the three-lncRNA signature might be a novel biomarker for the accurate prognosis prediction of patients with HNSCC.

Analysis of the differences of serum protein mass spectrometry in patients with triple negative breast cancer and non-triple negative breast cancer.

The objective of the present study was to investigate differences of serum protein mass spectrometry in patients with triple negative breast cancer (TNBC) and non-TNBC and thus to search for candidate serum protein biomarkers for identification and diagnosis of TNBC. Thirty serum samples from patients with TNBC without any treatment and 30 serum samples from patients with non-TNBC without any treatment were detected by using two-dimensional gel electrophoresis and matrix-assisted laser dissociation tandem time-of-flight mass spectrometry (MALDI-TOF-MS). PDQest 7.0 software of Bio-Rad was adopted to screen differentially expressed proteins. Protein ID retrieval was conducted by using Mascot software to confirm the results of differential proteins. Two-dimensional gel electrophoresis profiles were obtained successfully. A total of 16 differential protein loci were discovered by analyzing patient sera of the two groups using two-dimensional gel electrophoresis analysis software. Ten differential proteins were identified by mass spectrometric analysis in the 16 differential proteins. Combined with database and literature search results, it is speculated that the specifically upregulated proteins and downregulated proteins including transthyretin, haptoglobin, and antitrypsin may be the potential markers for early diagnosis of TNBC. Comparing the TNBC patients with the non-TNBC patients, there are differences in serum protein compositions. The ten differential proteins discovered in the present study provide reference basis for further improving early diagnosis and identification and diagnosis index of TNBC. Especially, transthyretin, haptoglobin, and antitrypsin show dramatic significances for the early diagnosis of TNBC.

Adiponectin protects the genioglossus of rats against chronic intermittent hypoxia-induced injury via inhibition of endoplasmic reticulum stress.

BACKGROUND: Obstructive sleep apnea hypopnea syndrome, characterized by chronic intermittent hypoxia (CIH), is closely correlated with genioglossus dysfunction. CIH has been identified to mediate mitochondrial damage in genioglossus. It has been reported that endoplasmic reticulum stress (ERS) could be induced by mitochondrial dysfunction. This study aimed to investigate the role of ERS in CIH-induced genioglossus injury, as well as the possible intervention effect of adiponectin (Ad) supplement in rats. METHODS: Forty-five male Wistar rats were randomly divided into three groups and submitted to room air (group A, n=15) as a control or CIH (groups B and C, n=15, respectively). Throughout the exposure period, intravenous Ad was given in group C; while intravenous normal saline was simultaneously given in groups A and B. After 35-day exposure, genioglossus samples were obtained from the pentobarbital-anaesthetized rats via surgical dissection, following blood sampling. Western blotting was applied to detect expressions of ERS signals and associated apoptotic pathways in genioglossus. Serum adiponectin levels were assessed via enzyme-linked immunosorbent assay (ELISA). RESULTS: Significant hypoadiponectinemia was revealed in group B only (P < 0.05). Compared to those in groups A and C, expressions of markers involved in ERS, such as glucose regulated protein 78 (GRP78), p-PERK, phosphorylated eukaryotic initiation factor 2a (p-eIF2a), phosphorylated inositol-requiring transmembrane kinase/endoribonuclease 1a (p-IRE1a), spliced X-Box binding protein 1 (XBP1s) and activating transcription factor 6 (ATF6), were significantly enhanced in group B (all P < 0.01); while no significant difference was shown between groups A and C (all P > 0.05). ERSassociated apoptotic pathways were remarkably activated in group B. The involved markers detected as the expression of CCAAT/enhancer binding protein homologous protein (CHOP), B-cell lymphoma/leukemia associatied X protein (BAX) and caspase-12 were significantly elevated (all P < 0.01). Transvenous adiponectin supplement improved the above CIHinduced pathological changes in group C. CONCLUSION: Beyond hypoadiponectinemia, CIH could enhance ERS and induce activation of ERS-associated apoptotic pathways in genioglossus, which could be significantly improved by adiponectin supplement.

Clinicopathologic characteristics and prognostic factors in patients with operable HER-2 overexpressing breast cancer.

OBJECTIVE: To study the relationship between clinical pathologic characteristics, treatment modalities and prognostic factors in HER-2 (Human Epidermal growth factor Receptor-2) overexpressed breast carcinoma. MATERIALS AND METHODS: Major clinico-pathological factors including therapeutic modalities and survival status of 371 breast cancer patients with HER2 over-expression, teated at Yantai Yuhuangding Hospital from March of 2002 to December of 2010 were retrospectively studied, with special attention focused on survival-related factors. RESULTS: The median age of the total 371 patients in this study was 48 years at time of diagnosis, among which, the leading pathological type was infiltrating ductal carcinoma (92.5%); 62.8% presented with a primary tomor larger than 2 cm in diameter at diagnosis, 51.0% had axillary lymph node (ALN) metastases; ER (Estrogen receptor) /PR (Progesterone receptor) double negative occured in 52.8% of cases, and PCNA (proliferation cell nuclear antigen) (+ + +) was found in 55.1%. HER-2 overexpressed patients were usually in advanced stage when the diagnosis was made (72.8% at stages IIA~IIIC). The prognosis and survival were assessed in 259 patients with complete follow-up data. 5-year DFS (disease-free survival) and OS (overall survival) rate was 68.0% and 78.0% respectively. Univariate analysis revealed that age, tumor size, ALN metastases, LVSI (lymph-vascular space involvement), PCNA status, hormonal therapy, chemotherapy cycles, and HER-2 overexpression, correlated closely with the prognosis. ALN metastases, LVSI, PCNA status and chemotherapy cycles were independent predictors of survival. CONCLUSIONS: HER-2 overexpressed breast cancer has special clinical and pathological characteristics, with advanced clinical stages and high rate of ER/PR double negative. Lymph node metastases, LVSI, PCNA and chemotherapy cycles are independent predictors of prognosis.

The impact of E-cadherin expression on non-small cell lung cancer survival: a meta-analysis.

E-cadherin has been implicated in invasiveness and metastasis. However, the clinical prognostic value of decreased E-cadherin expression in patients with non-small cell lung cancer (NSCLC) remains unsettled. A meta-analysis of eligible studies was performed to quantitatively review the correlation of decreased E-cadherin expression with survival in patients with NSCLC. Thirteen studies, including 2,274 patients, were subjected to final analysis. The rate of decreased E-cadherin expression was 47.6 % overall and 41.4 % for stage I disease. The combined hazard ratio (HR) was 1.41 (95 % CI 0.18-1.65; P = 0.001), indicating that decreased E-cadherin expression had an unfavorable impact on the survival of patients with NSCLC. Further, in the stratified analysis by ethnicity, the combined HR in Asians was 1.49 (95 % CI 1.27-1.71) and in non-Asians was 1.01 (95 % CI 1.00-1.02). However, when only the stage I studies were considered, the combined HR was 1.19 (95 % CI 0.90-1.47; P = 0.576), suggesting that decreased E-cadherin expression has no impact on survival. Decreased E-cadherin expression was associated with poor survival in patients with NSCLC, especially among Asians, but was not significantly correlated with survival for stage I NSCLC patients.

Rhabdastrellic acid-A induced autophagy-associated cell death through blocking Akt pathway in human cancer cells.

BACKGROUND: Autophagy is an evolutionarily conserved protein degradation pathway. A defect in autophagy may contribute to tumorigenesis. Autophagy inducers could have a potential function in tumor prevention and treatment. METHODOLOGY/PRINCIPAL FINDINGS: Our results showed that Rhabdastrellic acid-A, an isomalabaricane triterpenoid isolated from the sponge Rhabdastrella globostellata, inhibited proliferation of human cancer cell lines Hep3B and A549 and induced caspase-independent cell death in both the cell lines. Further investigation showed that Rhabdastrellic acid-A induced autophagy of cancer cells determined by YFP-LC3 punctation and increased LC3-II. The pretreatment with autophagy inhibitor 3-MA inhibited Rhabdastrellic acid-A-induced cell death. Knockdown of autophagy-related gene Atg5 inhibited Rhabdastrellic acid-A-induced cell death in A549 cells. Also, phospho-Akt and its downstream targets significantly decreased after treatment with Rhabdastrellic acid-A in both cancer cell lines. Transfection of constitutive active Akt plasmid abrogated autophagy and cell death induced by Rhabdastrellic acid-A. CONCLUSIONS/SIGNIFICANCE: These results suggest that Rhabdastrellic acid-A could induce autophagy-associated cell death through blocking Akt pathway in cancer cells. It also provides the evidence that Rhabdastrellic acid-A deserves further investigation as a potential anticancer or cancer preventive agent.

The effect of oxidative stress in myocardial cell injury in mice exposed to chronic intermittent hypoxia.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is an important risk factor for cardiovascular diseases. Chronic intermittent hypoxia (CIH) is considered to be one of the most important causes of cardiovascular diseases in OSA patients. This repeated hypoxia and reoxygenation cycle is similar to hypoxia-reperfusion injury, which initiates oxidative stress. In this study, we observed cardiocytes injury induced by CIH and the effect of N-acetylcysteine (NAC). METHODS: Thirty ICR mice were randomly assigned to 3 groups: control, CIH and NAC (CIH + NAC) groups. Malondialdehyde (MDA) and superoxide dismutase (SOD) of cardiocyte homogenates were measured. Serum lipids were measured by an instrument method. Serum cardiac troponin I (cTnI) was detected by enzyme-linked immunosorbent assays (ELISA). Myocardium pathological sections were observed. RESULTS: (1) The SOD activity and MDA concentration of cardiocyte homogenates in the CIH group were significantly higher than in other groups (P < 0.005). The MDA concentration of the NAC group was lower than that of the control group (P < 0.01). (2) The serum cTnI concentration of the CIH and NAC groups was significantly higher than that of the control group (P < 0.01). (3) Serum triglyceride levels in the NAC group were lower than in the other groups (P < 0.01), while there were no significant differences in low density lipoprotein and high density lipoprotein among the three groups. (4) The degeneration of myocardium, transverse striation blurred, and fabric effusion were observed in tissue sections in the CIH and NAC groups. However, normal tissue was found in the control group. CONCLUSION: The oxidative stress induced by CIH can injure cardiocytes and the injury effect can be partially inhibited by NAC.

Rhabdastrellic acid-A inhibited PI3K/Akt pathway and induced apoptosis in human leukemia HL-60 cells.

Increasing evidence suggests that aberrant activation of PI3K/Akt is involved in many human cancers, and that inhibition of the PI3K/Akt pathway might be a promising strategy for cancer treatment. Our investigation indicates that Rhabdastrellic acid-A, an isomalabaricane triterpenoid isolated from the sponge, Rhabdastrella globostellata, inhibits proliferation of HL-60 cells with an IC(50) value of 0.68mug/ml, and induces apoptosis. Rhabdastrellic acid-A also induces cleavage of the death substrate poly (ADP-ribose) polymerase (PARP) and caspase-3. Pretreatment of HL-60 cells with the caspase-3 specific inhibitor, DEVD-CHO, prevents Rhabdastrellic acid-A-induced DNA fragmentation and PARP cleavage. Activated PI3K and Akt significantly decreases after treatment with Rhabdastrellic acid-A in HL-60 cells. Expression levels of protein bcl-2, bax remain unchanged in response to Rhabdastrellic acid-A treatment in HL-60 cells. These results suggest that Rhabdastrellic acid-A inhibits PI3K/Akt pathway and induces caspase-3 dependent-apoptosis in HL-60 human leukemia cells.