HDAC6-specific inhibitor suppresses Th17 cell function via the HIF-1α pathway in acute lung allograft rejection in mice.

Background: Previous animal experiments and clinical studies indicated the critical role of Th17 cells in lung transplant rejection. Therefore, the downregulation of Th17 cell function in lung transplant recipients is of great interest. Methods: We established an orthotopic mouse lung transplantation model to investigate the role of histone deacetylase 6-specific inhibitor (HDAC6i), Tubastatin A, in the suppression of Th17 cells and attenuation of pathologic lesions in lung allografts. Moreover, mechanism studies were conducted in vitro. Results: Tubastatin A downregulated Th17 cell function in acute lung allograft rejection, prolonged the survival of lung allografts, and attenuated acute rejection by suppressing Th17 cell accumulation. Consistently, exogenous IL-17A supplementation eliminated the protective effect of Tubastatin A. Also, hypoxia-inducible factor-1α (HIF-1α) was overexpressed in a lung transplantation mouse model. HIF-1α deficiency suppressed Th17 cell function and attenuated lung allograft rejection by downregulating retinoic acid-related orphan receptor γt (ROR γt) expression. We showed that HDAC6i downregulated HIF-1α transcriptional activity under Th17-skewing conditions in vitro and promoted HIF-1α protein degradation in lung allografts. HDAC6i did not affect the suppression of HIF-1α-/- naïve CD4+ T cell differentiation into Th17 cell and attenuation of acute lung allograft rejection in HIF-1α-deficient recipient mice. Conclusion: These findings suggest that Tubastatin A downregulates Th17 cell function and suppresses acute lung allograft rejection, at least partially, via the HIF-1α/ RORγt pathway.

Dynamic Behaviors of Condensing Clusters Based on Rayleigh Scattering Experiment.

Condensation is a common physical process which widely exists in natural phenomena and thermal energy systems. In a condensation process, cluster is considered as the important bridge between vapor body and condensates. However, limited by the minimum imaging dimension of traditional measurements, early experimental studies about initial stages of condensation process are not sufficient. This paper provides a powerful optical platform for the study of dynamic clusters process. Based on the Rayleigh law, optical experiments were firstly introduced to investigate the clusters spatial distribution close to and far from condensation surface. The results show that clusters are mainly generated in the vicinity of the condensation surface within the thickness of 200 µm. When they move away from the condensation surface, clusters progressively vanish and they have a life cycle of a fraction of a millisecond. Though scattering intensity is proportional to the 6th power of cluster radius r and cluster number density N c theoretically, the scattering intensity does not increase sharply with the increase of subcooling degree from the experimental results, so we can infer that the cluster number density plays a dominate role in this process and the effect of cluster radius almost can be ignored.Zhong Lan and Di Wang contributed equally to this work.

Increased expression of the long non-coding RNA ANRIL promotes lung cancer cell metastasis and correlates with poor prognosis.

BACKGROUND: Emerging evidences indicate that dysregulated long non-coding RNAs (lncRNAs) are implicated in cancer tumorigenesis and progression. LncRNA ANRIL has been shown to promote the progression of gastric cancer. However, the role of lncRNA ANRIL in human non-small cell lung cancer (NSCLC) remains unclear. METHODS: Expression of lncRNA ANRIL was analyzed in 87 NSCLC tissues and three lung cancer cell lines by quantitative real-time PCR (qRT-PCR). The correlation of lncRNA ANRIL with clinicopathological features and prognosis was analyzed. Suppression of lncRNA ANRIL using siRNA treatment was performed in order to explore its role in tumor progression. RESULTS: The expression level of lncRNA ANRIL was higher in NSCLC tissues and lung cancer cells than in adjacent non-tumor tissues and normal human bronchial epithelial cells. Higher expression of lncRNA ANRIL in NSCLC tissues was associated with higher TNM stage and advanced lymph node metastasis. Patients with high lncRNA ANRIL expression had poorer overall survival compared with low lncRNA ANRIL group. Univariate and multivariate analyses suggested that high expression of lncRNA ANRIL was an independent poor prognostic indicator for NSCLC patients. Moreover, knockdown of lncRNA ANRIL expression could inhibit lung cancer cell proliferation, migration and invasion in vitro. CONCLUSIONS: Our results suggested that lncRNA ANRIL was a potential biomarker for NSCLC prognosis, and the dysregulation of lncRNA ANRIL may play an important role in NSCLC progression. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1707061287149690 .

[Pulmonary benign metastasizing leiomyoma: a clinicopathological study of 5 cases].

Pulmonary benign metastasizing leiomyoma (PBML) is a rare and often to be misdiagnosed disease. In this study, we want to investigate the diseased of the clinicopathological characteristics, diagnosis, treatment and prognosis. The retrospective analysis were performed on the clinicopathological data of 5 patients with PBML. All 5 cases were female, mean age 46.8 years old, and were found with single nodule. One case was found with left kidney metastasis. Surgical procedures includes: VATS biopsy (3 cases), resection of superior lobe of left lung (1 case), resection of superior lobe of right lung and wedge resection of middle and inferior lobe of right lung (1 case). The residual nodules in lung were stable in all cases with followup 3-48 mo. PBML is dominated occurring in females with history of uterine leiomyoma, preferential to metastasize to lung, and surgery is the primary therapy. Since it is hormone dependent, hormonal therapy may be suggested in these patients.

Screening of critical genes in lung adenocarcinoma via network analysis of gene expression profile.

Biomarker discovery is of great importance in diagnosis and treatment of diseases. In present study, a number of differentially expressed genes (DEGs) were identified for lung adenocarcinoma via comparative analysis of gene expression data. A gene expression core signature was generated for four types of lung adenocarcinoma (EGFR-mutated, KRAS-mutated, ALK-mutated and triple-negative adenocarcinoma). Functional enrichment analysis with DAVID tools revealed that up-regulated genes were mainly associated with cell cycle while down-regulated genes were mainly involved in vasculature development and cell adhesion. Then it was used to retrieve relevant small molecule drugs with Connectivity map and trichostatin A was predicted to be the top candidate drug for treatment of lung cancer. Network clustering was performed with MCL in cytoscape to identify sub-networks and several hub genes were obtained: CDC25C, ICT1, TK1 and EZH2. These genes play important roles in the progression of lung cancer and some have been suggested as potential biomarkers. Therefore, our findings are beneficial in deepening the understandings about the pathogenesis and providing directions for future researches.

A systematic review and meta-analysis of herbal medicine on chronic obstructive pulmonary diseases.

Herbal medicine (HM) as an adjunct therapy has been shown to be promising for the chronic obstructive pulmonary disease (COPD). However, the role of herbs in COPD remains largely unexplored. In this present study, we conducted the systematic review to evaluate the efficacy of herbs in COPD. 176 clinical studies with reporting pulmonary function were retrieved from English and Chinese database. Commonly used herbs for acute exacerbations stage (AECOPD) and stable COPD stage (SCOPD) were identified. A meta-analysis conducted from 15 high quality studies (18 publications) showed that HM as an adjunct therapy had no significant improvement in pulmonary function (FEV1, FEV%, FVC, and FEV1/FVC) compared to conventional medicine. The efficacy of the adjunct HM on improving the arterial blood gas (PaCO2 and PaO2) for AECOPD and SCOPD remains inconclusive due to the heterogeneity among the studies. However, HM as an adjunct therapy improved clinical symptoms and quality of life (total score, activity score, and impact score of St. George's Respiratory Questionnaire). Studies with large-scale and double-blind randomized controlled trials are required to confirm the role of the adjunct HM in the management of COPD.

Comparison of short and long-term results between sleeve resection and pneumonectomy in lung cancer patients over 70 years old: 10 years experience from a single institution in China.

BACKGROUND: The aim of this study was to compare the short and long-term results between sleeve resection (SR) and pneumonectomy (PN) in lung cancer patients over 70 years of age. METHODS: We retrospectively reviewed 105 lung cancer patients over 70 years of age who had undergone SR or PN at Shanghai Chest Hospital from January 2003 to December 2012. RESULTS: The SR group showed a higher frequency of airway clearance via bronchoscopy (48.6% vs. 25.7%, P = 0.04), longer surgical time (162.7 vs. 140.9 minutes, P = 0.01), and shorter postoperative stay (13.7 vs. 18.1 days, P = 0.02) than the PN group. There was no difference in hospital mortality (P = 1.00) or morbidity (P = 0.40) between the two groups. A logistic regression model showed that preoperative predicted forced expiratory volume in 1 second was the only independent risk factor for overall morbidity (P = 0.04). In survival analysis, SR showed better prognosis than PN (median 50.0 vs. 20.0 months, P < 0.01). In subgroup analysis, SR showed better survival in N0 (P = 0.03) and N1 (P < 0.01) cases, but not in N2 cases (P = 0.36). It also showed better survival in stage I + II patients (P = 0.03), but not in stage III patients (P = 0.10). CONCLUSIONS: Although PN could be carried out as safely as SR in patients over 70 years of age with a good pulmonary reservoir, SR is still recommended as a less traumatic procedure, sparing lung parenchyma with better long-term results.

Four common vascular endothelial growth factor polymorphisms (-2578C>A, -460C>T, +936C>T, and +405G>C) in susceptibility to lung cancer: a meta-analysis.

BACKGROUND AND OBJECTIVE: Vascular endothelial growth factor (VEGF) is one of the key initiators and regulators of angiogenesis and it plays a vital role in the onset and development of malignancy. The association between VEGF gene polymorphisms and lung cancer risk has been extensively studied in recent years, but currently available results remain controversial or ambiguous. The aim of this meta-analysis is to investigate the associations between four common VEGF polymorphisms (i.e., -2578C>A, -460C>T, +936C>T and +405C>G) and lung cancer risk. METHODS: A comprehensive search was conducted to identify all eligible studies to estimate the association between VEGF polymorphisms and lung cancer risk. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of this association. RESULTS: A total of 14 published case-control studies with 4,664 cases and 4,571 control subjects were identified. Our meta-analysis provides strong evidence that VEGF -2578C>A polymorphism is capable of increasing lung cancer susceptibility, especially among smokers and lung squamous cell carcinoma (SCC) patients. Additionally, for +936C>T polymorphism, increased lung cancer susceptibility was only observed among lung adenocarcinoma patients. In contrast, VEGF -460C>T polymorphism may be a protective factor among nonsmokers and SCC patients. Nevertheless, we did not find any association between +405C>G polymorphism and lung cancer risk, even when the groups were stratified by ethnicity, smoking status or histological type. CONCLUSION: This meta-analysis recommends more investigations into the relationship between -2578C>A and -460C>T lung cancer risks. More detailed and well-designed studies should be conducted to identify the causal variants and the underlying mechanisms of the possible associations.

[Correlation analysis between imaging features and lymph node metastasis in T1a lung adenocarcinoma].

OBJECTIVE: To analyze the data of patients with clinical stage T1a lung adenocarcinoma and find the predictive factors associated with lymph node metastasis. METHODS: From January to June 2012, 271 patients with small nodules of peripheral lung adenocarcinoma were enrolled in the retrospective review. There were 105 male and 112 female patients, with an average age of (61 ± 11)years (range 32-85 years). The data were collected including age, gender, smoking history, carcinoembryonic antigen(CEA), imaging findings, surgical procedure, pleural involvement, symptoms, tumor size, pathological classification, pathologic stage, maximum standardized uptake value(SUVmax) and lymph node metastasis. The predictive factors of lymph node metastasis in clinical factors were detected by univariate and multivariate analysis. RESULTS: By preoperative thin-section CT, 35 patients were categorized as pure ground-grass opacity(GGO), 11 cases of atypical adenomatous hyperplasia, 24 cases of adenocarcinoma in situ, with no lymph node metastasis. Categorized as mixed ground-glass opacities in 89 patients, 84 patients (94.4%) had no lymph node metastasis, only 5 patients (6.0%) with lymph node metastasis. Categorized as solid nodules in 93 patients, a total of 28 cases (30.1%) had lymph node metastasis. There were statistically significant difference between three groups (χ(2) = 23.41, P < 0.001) . By univariate analysis, we found that the predictive factors of lymph node metastasis were as follows: tumor size > 1 cm (χ(2) = 9.021, P < 0.003) , imaging performance with mixed GGO or solid nodules (χ(2) = 23.41, P < 0.000) , CEA > 5 µg/L (χ(2) = 15.541, P < 0.000) and PET-CT SUVmax > 5 (χ(2) = 0.644, P < 0.000). By multivariate analysis, we found that imaging performance (mixed GGO or solid nodules) was the independent predictor of lymph node metastasis in clinical factors (OR = 166.116, 95%CI:18.161-25.19, P < 0.001) . CONCLUSIONS: Patients of pure GGO generally do not have lymph node metastasis. Tumor diameter > 1 cm, imaging findings with the mixed GGO or solid nodules, carcinoembryonic antigen CEA > 5 µg/L, PET-CT SUVmax > 5 are predictive factors of lymph node metastasis in which imaging is independent predictor.

[Study on the effects of hematopoiesis of anemic mice after marrow-suppressed treated by tonifying kidney, invigorating spleen, and removing blood stasis].

OBJECTIVE: To observe the effects of tonifying kidney,tonifying spleen,invigorating the circulation of blood on the expression of hematopooietic cytokines of bone marrow suppression induced by chemotherapy. METHODS: Automated blood analyzer was used to detect the level of RBC and HGB, 14th and 28 days, while real time quantitative RT-PCR was used to detect EPO, EPOR mRNA expression. RESULTS: Liuwei Dihuang Tang, Buzhong Yiqi Tang and Compound Danshen Decoction group could increase the level of RBC and HGB significantly. Liuwei Dihuang Tang and Buzhong Yiqi Tang groups could increase the mRNA expression level of EPO and EPOR significantly. However, there was no significantly difference when Compound Danshen Decoction group compared with control group on EPO, EPOR mRNA expression level. CONCLUSION: The tonifying kidney, tonifying spleen, invigorate the circulation of blood are stable and reliable as to enhance the role of peripheral blood; tonifying kidney, tonifying spleen can improve EPO, EPOR mRNA expression levels, and promote the proliferation of bone marrow hematopoietic stem cells, and promote the differentiation of erythroid blood cells to increase red blood cell line; And invigorate the circulation of blood promote hematopoietic mechanisms have to be further studied.

Protective effects on myelosuppression mice treated by three different classic Chinese medicine formulae.

BACKGROUND: In order to observe the protective therapeutic action and mechanism of Liuwei Dihuang Decoction, Buzhong Yiqi Decoction, and Compound Danshen Decoction on Myelosuppression induced by cyclophosphamide. MATERIALS AND METHODS: The mice model was established by intraperitoneal injected with 100 mg/kg cyclophosphamide by human and mice dose conversion on the 9(th), 11(th), 13(th) days during the experiment. Flow cytometry (FCM) was used for detecting the number of cells and investigating bone marrow cell cycles. Spleen was taken out and the mRNA expression level of thrombopoietin (TPO) and c-Mpl were detected by Q-PCR, and c-Mpl in spleen in order to discuss the mechanism of myelosuppression and the protective effects of traditional Chinese medicine. RESULTS: Both Liuwei Dihuang Decoction Group and Buzhong Yiqi Decoction Group can accelerate bone marrow hematopoietic stem progenitor cells (HSPCs) in marrow-suppressed mice and enhance cell proliferation by promoting cell cycles from G0/G1 phase to access into S, G2/M phase. And at the same time these Chinese decoctions can increase the mRNA expression level of TPO and c-Mpl in spleen. CONCLUSION: Researched showed that Chinese formula take effect by affecting these genes on myelosuppressed mice.

[Immunosuppressive therapy after human lung transplantation].

OBJECTIVE: To summarize the diagnosis and treatment of acute rejection after lung transplantation and to discuss optimized immunosuppressive therapy. METHODS: Between November 2002 and June 2006, 16 patients underwent operations on lung transplantation, 7 cases on single-lung transplantation and 9 cases on bilateral-lung transplantation. Immunosuppressive therapy was new triple drug maintenance regimen including tacrolimus (Tac), mycophenolate mofetil (MMF) and steroids, and (or) daclizumab. RESULTS: Eight cases in new triple drug maintenance regimen with daclizumab. There is no acute rejection in 6 months. Except 2 of the 8 cases died of early post-lung transplantation sever pulmonary edema and dysfunction, 3 of the rest 6 cases underwent acute rejection incident about 21.4% (3/14). CONCLUSION: In this group the new triple drug maintenance regimen including tacrolimus (Tac), mycophenolate mofetil (MMF) and steroids, and (or) daclizumab acquired beneficial effect in preventing acute rejection after lung transplantation.

[Causes and prevention of anastomotic leakage after esophagectomy and reconstruction through different routes for esophageal cancer].

OBJECTIVE: To compare the anastomotic leakage rates after esophagectomy and reconstruction through different routes for esophageal cancer and analyze the causes for higher anastomotic leakage rate after esophagectomy, systemic lymph node dissection and reconstruction through retrosternal route and its prevention. METHODS: Data of 1105 cases of esophagectomy were reviewed retrospectively. Patients in group A (n=229) underwent esophagectomy through left thoracotomy and intrathoracic anastomosis, patients in group B (n=716), esophagectomy through right anterio-lateral thoracotomy and cervical reconstruction through posterior mediastinal route, patients in group C (n=160) esophagectomy, systemic lymph node dissection and cervical anastomosis through the retrosternal route. RESULTS: The leakage rate was significantly higher (19.4%) in group C than that in group B (11.9%, P< 0.05) and much significantly higher than that in group A (2.2%, P< 0.01). In group C, there was no significant difference in leakage rate between the patients with hand-sewn or mechanical anastomosis (22.2% vs.11.6%, P=0.133), between the patients who had whole stomach or tube-typed gastric reconstruction (25% vs.15.6%, P=0.146). The leakage rate was significantly decreased from 23.3% to 9.1% after prolonged nasal-gastric drainage for seven days (P< 0.05). CONCLUSION: The high anastomotic leakage rate after retrosternal reconstruction is mainly due to compression of the stomach in the anterior mediastinum. Prolonged nasogastric drainage is an effective way to decrease the leakage rate after systemic lymphadenectomy.