Microtubule associated protein 4 (MAP4) phosphorylation reduces cardiac microvascular density through NLRP3-related pyroptosis.

Phosphorylation of MAP4 (p-MAP4) causes cardiac remodeling, with the cardiac microvascular endothelium being considered a vital mediator of this process. In the current study, we investigated the mechanism underlying p-MAP4 influences on cardiac microvascular density. We firstly confirmed elevated MAP4 phosphorylation in the myocardium of MAP4 knock-in (KI) mice. When compared with the corresponding control group, we detected the decreased expression of CD31, CD34, VEGFA, VEGFR2, ANG2, and TIE2 in the myocardium of MAP4 KI mice, accompanied by a reduced plasma concentration of VEGF. Moreover, we observed apoptosis and mitochondrial disruption in the cardiac microvascular endothelium of MAP4 KI animals. Consistently, we noted a decreased cardiac microvascular density, measured by CD31 and lectin staining, in MAP4 KI mice. To explore the underlying mechanism, we targeted the NLRP3-related pyroptosis and found increased expression of the corresponding proteins, including NLRP3, ASC, mature IL-1ß, IL-18, and GSDMD-N in the myocardium of MAP4 KI mice. Furthermore, we utilized a MAP4 (Glu) adenovirus to mimic cellular p-MAP4. After incubating HUVECs with MAP4 (Glu) adenovirus, the angiogenic ability was inhibited, and NLRP3-related pyroptosis were significantly activated. Moreover, both cytotoxicity and PI signal were upregulated by the MAP4 (Glu) adenovirus. Finally, NLRP3 inflammasome blockage alleviated the inhibited angiogenic ability induced by MAP4 (Glu) adenovirus. These results demonstrated that p-MAP4 reduced cardiac microvascular density by activating NLRP3-related pyroptosis in both young and aged mice. We thus managed to provide clues explaining MAP4 phosphorylation-induced cardiac remodeling and enriched current knowledge regarding the role of MAP4.

Geranylgeranyl diphosphate synthase 1 knockout ameliorates ventilator-induced lung injury via regulation of TLR2/4-AP-1 signaling.

OBJECTIVE: To investigate the role of geranylgeranyl diphosphate synthase 1 (GGPPS1) in ventilator-induced lung injury along with the underlying mechanism. METHODS: A murine VILI model was induced by high-tidal volume ventilation in both wild-type and GGPPS1 knockout mice. GGPPS1 expression was detected in the bronchoalveolar lavage fluid (BALF) supernatants of acute respiratory distress syndrome (ARDS) patients and healthy volunteers, as well as in lung tissues and BALF supernatants of the VILI mice using enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcription polymerase chain reaction (qRT-PCR), western bolt and immunohistochemical (IHC). The wet/dry ratio, total BALF proteins, and lung injury score were analyzed. The percentage of neutrophils was detected by flow cytometry and IHC. Inflammatory cytokine levels were measured by ELISA and qRT-PCR. The related expression of Toll-like receptor (TLR)2/4 and its downstream proteins was evaluated by western blot. RESULTS: GGPPS1 in BALF supernatants was upregulated in ARDS patients and the VILI mice. Depletion of GGPPS1 significantly alleviated the severity of ventilator induced lung injury in mice. Total cell count, neutrophils and inflammatory cytokines (interleukin [IL]-6, IL-1ß, IL-18 and tumor necrosis factor-α) levels in BALF were reduced after GGPPS1 depletion. Moreover, addition of exogenous GGPP in GGPPS-deficient mice significantly exacerbated the severity of ventilator induced lung injury as compared to the PBS treated controls. Mechanistically, the expression of TLR2/4, as well as downstream proteins including activator protein-1 (AP-1) was suppressed in lung tissues of GGPPS1-deficient mice. CONCLUSION: GGPPS1 promoted the pathogenesis of VILI by modulating the TLR2/4-AP-1 signaling pathway, and GGPPS1 knockout significantly alleviated the lung injury and inflammation in the VILI mice.

Tumor necrosis factor receptor-associated protein 1 regulates hypoxia-induced apoptosis through a mitochondria-dependent pathway mediated by cytochrome c oxidase subunit II.

BACKGROUND: Tumor necrosis factor receptor-associated protein 1 (TRAP1) plays a protective effect in hypoxic cardiomyocytes, but the precise mechanisms are not well clarified. The study is aimed to identify the mechanism of TRAP1 on hypoxic damage in cardiomyocytes. METHODS: In this study, the effects of TRAP1 and cytochrome c oxidase subunit II (COXII) on apoptosis in hypoxia-induced cardiomyocytes were explored using overexpression and knockdown methods separately. RESULTS: Hypoxia induced cardiomyocyte apoptosis, and TRAP1 overexpression notably inhibited apoptosis induced by hypoxia. Conversely, TRAP1 silencing promoted apoptosis in hypoxic cardiomyocytes. Further investigation revealed that the proapoptotic effects caused by the silencing of TRAP1 were prevented by COXII overexpression, whereas COXII knockdown reduced the antiapoptotic function induced by TRAP1 overexpression. Additionally, changes in the release of cytochrome c from mitochondria into the cytosol and the caspase-3 activity in the cytoplasm, as well as reactive oxygen species production, were found to be correlated with the changes in apoptosis. CONCLUSIONS: The current study uncovered that TRAP1 regulates hypoxia-induced cardiomyocyte apoptosis through a mitochondria-dependent apoptotic pathway mediated by COXII, in which reactive oxygen species presents as an important component.

Carcinoembryonic antigen in pleural effusion of patients with lung adenocarcinoma: a predictive marker for EGFR mutation.

BACKGROUND: Carcinoembryonic antigen (CEA) can reflect tumor growth, recurrence and metastasis, and also predict the clinical efficacy of the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). In the present study, we investigated the association between CEA in serum and pleural effusion (PE) and EGFR mutations in patients with lung adenocarcinoma. METHODS: We retrospectively investigated 114 lung adenocarcinoma patients with malignant pleural effusion (MPE). CEA levels in serum and MPE were measured by immunoradiometric assay, we analysed the correlation between CEA and EGFR mutation status. RESULTS: Fifty-three cases had EGFR mutation (46.5%). EGFR mutations were more common in females, patients with high levels of PE (≥107.2 ng/mL) and serum CEA (≥87 ng/mL). There was no significant difference in EGFR mutation rate between in tumor tissue and PE samples (49.3% vs. 41.9%, P=0.440). The result of receiver operating characteristic (ROC) indicated that the cut off value of CEA in MPE was 107.2 ng/mL, which had the highest sensitivity (SEN) and specificity (SPE) for predicting EGFR mutation [SEN 66%, and SPE 62.3%, AUC =0.668, 95% confidence interval (CI): 0.569-0.767, P=0.025]. The combination of gender, smoking history, serum and MPE CEA level had a higher calculated AUC (0.718, 95% CI: 0.622-0.813, P=0.000). Moreover, multivariate analysis showed that CEA level in MPE but not in serum was confirmed as the only independent factor associated with EGFR gene mutation status (P=0.026) with an odds ratio of 2.885 (95% CI: 1.137-7.317). CONCLUSIONS: MPE CEA can probably serve as a predictive marker for EGFR mutation in advanced lung adenocarcinoma. Combining gender, smoking history, and CEA has a relatively better predictive value. However, detecting EGFR mutations in lung adenocarcinomas is necessary for determining EGFR-TKI treatment in clinic.

Efficacy and Safety of Neurokinin-1 Receptor Antagonists for Prevention of Chemotherapy-Induced Nausea and Vomiting: Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVES: Can addition of neurokinin-1 receptor antagonists (NK1-RAs) be considered as an ideal strategy for the prevention of chemotherapy-induced nausea and vomiting (CINV)? Researchers differ on this question. MATERIALS AND METHODS: Electronic databases were searched for randomized control trials (RCTs) that evaluated the effectiveness and safety of NK1-RAs in preventing CINV. The primary end point was complete response (CR) in the acute, delayed, and overall phases after chemotherapy. Subgroup analyses evaluated the types of NK1-RAs, routines of administration, types of malignancies, regimens used in combination with NK1-RAs, and age of patients included in the studies. The incidences of different types of adverse events were also extracted to estimate the safety of NK1-RAs. RESULTS: A total of 38 RCTs involving 13,923 patients were identified. The CR rate of patients receiving NK-RAs was significantly higher than patients in the control groups during overall phase (70.8% vs 56.0%, <0.001), acute phase (85.1% vs 79.6%, <0.001), and delayed phase (71.4% vs 58.2%, <0.001). There were three studies including patients of children or adolescents, the CR rate was also significantly higher in the treatment group (overall phase: OR=2.807, <0.001; acute phase: OR=2.863, P =0.012; delayed phase: OR=2.417, <0.001). For all the other outcomes, patients in the NK1-RAs groups showed improvements compared to the control groups (incidence of nausea: 45.2% vs 45.9%, <0.001; occurrence of vomiting: 22.6% vs 38.9%, <0.001; usage of rescue drugs: 23.5% vs 34.1%, <0.001). The pooled side effects from NK1-RAs did not significantly differ from previous reports and the toxicity rates in patients less than eighteen years old also did not diff between the two groups (P=0.497). However, we found that constipation and insomnia were more common in the patients of control groups, whereas diarrhea and hiccups were more frequently detected in patients receiving NK1-RAs. CONCLUSIONS: NK1-RAs improved the CR rate of CINV. They are effective for both adults and children. The use of NK1-RAs might be associated with the appearance of diarrhea and hiccups, while decreasing the possibility of constipation and insomnia.

Neuroprotective effects of tetrandrine against vascular dementia.

Tetrandrine is one of the major active ingredients in Menispermaceae Stephania tetrandra S. Moore, and has specific therapeutic effects in ischemic cerebrovascular disease. Its use in vascular dementia has not been studied fully. Here, we investigated whether tetrandrine would improve behavioral and cellular impairments in a two-vessel occlusion rat model of chronic vascular dementia. Eight weeks after model establishment, rats were injected intraperitoneally with 10 or 30 mg/kg tetrandrine every other day for 4 weeks. Behavioral assessment in the Morris water maze showed that model rats had longer escape latencies in training trials, and spent less time swimming in the target quadrant in probe trials, than sham-operated rats. However, rats that had received tetrandrine showed shorter escape latencies and longer target quadrant swimming time than untreated model rats. Hematoxylin-eosin and Nissl staining revealed less neuronal necrosis and pathological damage, and more living cells, in the hippocampus of rats treated with tetrandrine than in untreated model rats. Western blot assay showed that interleukin-1ß expression, and phosphorylation of the N-methyl-D-aspartate 2B receptor at tyrosine 1472, were lower in model rats that received tetrandrine than in those that did not. The present findings suggest that tetrandrine may be neuroprotective in chronic vascular dementia by reducing interleukin-1ß expression, N-methyl-D-aspartate receptor 2B phosphorylation at tyrosine 1472, and neuronal necrosis.

Predictive and prognostic significance of circulating endothelial cells in advanced non-small cell lung cancer patients.

The aim of this study was to evaluate the predictive and prognostic values of circulating endothelial cells (CECs) in patients with advanced non-small cell lung cancer (NSCLC). A total of 102 newly diagnosed advanced NSCLC patients were enrolled in this study. The amount of CECs was enumerated by flow cytometry (CD45- CD31+ CD146+) at baseline. CEC counts of 56 patients were detected before and after two cycles of chemotherapy. We correlated the baseline and reduction of CECs after therapy with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The CEC level was significantly higher in advanced NSCLC patients, ranging from 57 to 1300 cells/10(5) cells (mean ± SD = 299 ± 221 cells/10(5) cells), than in patients with benign lesions (205 ± 97 cells/10(5) cells) and healthy volunteers (117 ± 33 cells/10(5) cells). When the cutoff value of CEC counts was 210 cells/10(5) cells, there was no significant association between CEC counts and OR/PFS/OS of the enrolled patients. However, patients with CEC response after chemotherapy have more chances to achieve OR (P < 0.001), and such patients showed longer PFS (P = 0.048) and OS (P = 0.018) than those without CEC response. In the multivariate analysis, the independent prognostic roles of brain metastasis (HR 6.165, P = 0.001), and CEC response (HR 0.442, P = 0.044) were found. The CEC counts could be considered as diagnostic biomarker for advanced NSCLC patients. And the reduction of CECs after treatment might be more ideal than the baseline CEC counts as a predictive or prognostic factor in patients treated with chemotherapy or anti-angiogenic therapy.

Prognostic value of the ratio of ground glass opacity on computed tomography in small lung adenocarcinoma: A meta-analysis.

INTRODUCTION: Lung cancer is the leading cause of cancer-associated death. In many countries, adenocarcinoma is the most common histologic type in lung cancer. Previously, few factors are identified to be prognostic indicators for the patients with small lung adenocarcinoma. Recently, the ground glass opacity (GGO) area found on high-resolution computed tomography (HRCT) scanning was identified as a prognostic indicator in some studies. But no clear consensus has been defined. METHODS: The PubMed/MEDLINE, EMBASE, Cochrane library and SpringerLink electronic databases were searched for articles related to ground glass opacity on computed tomography in patients with small lung adenocarcinoma. Data was extracted and analyzed independently by two investigators. An estimate of the hazard ratio (HR) for comparing high GGO ratio with low GGO ratio was extracted. The respective HRs was combined into a pooled HR, and 95% confidence interval (CI) was calculated for each study. The publication heterogeneity was assessed graphically using performing Beggs' funnel plot. All the statistical tests used in our meta-analysis were performed with STATA version 11. RESULTS: Thirteen studies, encompassing 2,027 patients, were included in our meta-analysis. Ten of these studies revealed that the GGO ratio in small lung adenocarcinoma is a good prognostic indicator. Seven studies were combined in a meta-analysis using overall survival (OS) as the end point of interest. The weighted HR of 7 studies was 0.85, with relative 95% CI ranging from 0.78 to 0.93 (P=0.009). For the surgical patient population, the primary endpoint of relapse-free survival (RFS) was superior with high GGO area on computed tomography (The combined HR 0.82, 95% CI 0.74-0.90; P=0.007). CONCLUSIONS: The result of our meta-analysis suggested that the GGO area measured on HRCT had a prognostic value of overall survival and relapse-free survival in small lung adenocarcinoma. The GGO ratio may be an independent prognostic factor for small lung adenocarcinoma.

Baseline and decline of serum ADAM28 during chemotherapy of advanced non-small cell lung cancer: a probable predictive and prognostic factor.

ADAM28 (a disintegrin and metalloproteinase 28) is over-expressed in non-small cell lung cancer (NSCLC) with correlation to cancer proliferation, tumor size and lymph node metastasis. In the present study, we investigated the predictive and prognostic value of ADAM28 during chemotherapy in patients with advanced NSCLC. 122 advanced NSCLC cases, 37 patients with benign lung disease and 40 healthy controls were enrolled in the study. The serum levels of ADAM28 were measured by enzymelinked immunosorbent assays. Data were correlated with diagnosis, radiologic objective response and survival. Serum levels of ADAM28 in advanced NSCLC group were significantly elevated compared to benign lung disease group (P<0.001) and healthy controls (P<0.001). And the expression of ADAM28 had relationship to the tumor size and lymph metastasis in NSCLC patients. When the cut-off value of ADAM28 was 225.54 pg/ml, the area under the ROC curve was 0.843 (95% confidence interval [CI]: 0.784-0.902); the sensitivity (SEN) and specificity (SPE) were both the best, with a SEN of 76% and a SPE of 83%. The patients who had ADAM28-response and no ADAM28-response had significantly difference in objective response to treatment (P<0.001). The median Progression-free survival from response assessment was 5 months. In the multivariate analysis, performance status (hazard ratio [HR], 1.68; 95% CI: 1.06-2.67), the level of serum ADAM28 (HR, 1.01; 95% CI: 1.01-1.02), and ADAM28-responses (HR, 047; 95% CI, 0.26-0.83), were significant correlated with prognosis. The levels of ADAM28 and ADAM28-responses appeared to be reliable surrogate markers to predict tumor response and survival in patients with advanced NSCLC.

Efficacy and safety of Abraxane in treatment of progressive and recurrent non-small cell lung cancer patients: A retrospective clinical study.

BACKGROUND: Abraxane is a novel Cremophor-free nanoparticle paclitaxel that has been demonstrated to improve efficacy in the treatment of solid tumors. We undertook this retrospective study to evaluate the efficacy and safety of Abraxane in the progressive or recurrent non-small cell lung cancer (NSCLC) patients. METHODS: From August 2009 to April 2011, 33 patients who were diagnosed with progressive or recurrent NSCLC and treated with one or more prior platinum-based chemotherapies, were enrolled. The patients were injected with Abraxane, 260 mg/m2 , d1, and were evaluated for efficacy and safety. The treatment was repeated every three weeks unless progressive lesions or unacceptable toxicities were found. RESULTS: There were no complete response and 11 partial responses (33.3%). Patients with squamous cell carcinoma showed better responses than those with adenocarcinoma (41.7% and 21.1%, respectively). Fourteen patients had stable disease, and the disease control rate was 75.8%. The median progression-free survival was five months (95% confidence interval [CI]: 3.5-6.5). Four patients (12.1%) experienced grade 3-4 hematologic toxicities; one anemia (3.0%), two leucopenia (6.1%) and one thrombocytopenia (3.0%). Six patients (18.2%) experienced grade 3-4 non-hematologic toxicities; two abnormal hepatic functions (6.1%), one fatigue (3.0%), one peripheral neuropathy (3.0%), and two alopecia (6.1%). CONCLUSION: Recurrent and progressive NSCLC patients pretreated with platinum-based chemotherapy might benefit from Abraxane with tolerable adverse events.

Diagnostic performance of integrated positron emission tomography/computed tomography for mediastinal lymph node staging in non-small cell lung cancer: a bivariate systematic review and meta-analysis.

INTRODUCTION: Accurate clinical staging of mediastinal lymph nodes (MLNs) of patients with non-small cell lung cancer (NSCLC) is important in determining therapeutic options and prognoses. Integrated positron emission tomography and computed tomography (PET/CT) scanning is becoming widely used for MLN staging in patients with NSCLC. We performed a bivariate meta-analysis to determine the pooled sensitivity (SEN) and specificity (SPE) of this imaging modality. METHODS: The PubMed/MEDLINE, Embase, and SpringerLink databases were searched for articles related to PET/CT for MLN staging in patients with NSCLC. SEN and SPE were calculated for every study. Hierarchical summary receiver operating characteristic curves were used to summarize overall test performance and assess study quality. Potential between-study heterogeneity was explored by subgroup analyses. RESULTS: Fourteen of 330 initially identified reports were included in the meta-analysis. When we did not consider the unit of analysis, the pooled weighted SEN and SPE were 0.73 (95% confidence interval [CI]: 0.65-0.79) and 0.92 (95% CI: 0.88-0.94), respectively. In the patient-based data analysis, the pooled weighted SEN was 0.76 (95% CI: 0.65-0.84) and the pooled weighted SPE was 0.88 (95% CI: 0.82-0.92). In the MLN-based data analysis, the pooled SEN was 0.68 (95% CI: 0.56-0.78) and the pooled SPE was 0.95 (95% CI: 0.91-0.97). CONCLUSIONS: Integrated PET/CT is a relatively accurate noninvasive imaging technique, with excellent specificity for MLN staging in patients with NSCLC. Nevertheless, current evidence suggests that we should not depend on the results of PET/CT completely for MLN staging in patients with NSCLC.