Hapln1 promotes dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping.

Hyaluronan and proteoglycan link protein 1 (Hapln1) supports active cardiomyogenesis in zebrafish hearts, but its regulation in mammal cardiomyocytes is unclear. This study aimed to explore the potential regulation of Hapln1 in the dedifferentiation and proliferation of cardiomyocytes and its therapeutic value in myocardial infarction with human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) and an adult mouse model of myocardial infarction. HiPSC-CMs and adult mice with myocardial infarction were used as in vitro and in vivo models, respectively. Previous single-cell RNA sequencing data were retrieved for bioinformatic exploration. The results showed that recombinant human Hapln1 (rhHapln1) promotes the proliferation of hiPSC-CMs in a dose-dependent manner. As a physical binding protein of Hapln1, versican interacted with Nodal growth differentiation factor (NODAL) and growth differentiation factor 11 (GDF11). GDF11, but not NODAL, was expressed by hiPSC-CMs. GDF11 expression was unaffected by rhHapln1 treatment. However, this molecule was required for rhHapln1-mediated activation of the transforming growth factor (TGF)-ß/Drosophila mothers against decapentaplegic protein (SMAD)2/3 signaling in hiPSC-CMs, which stimulates cell dedifferentiation and proliferation. Recombinant mouse Hapln1 (rmHapln1) could induce cardiac regeneration in the adult mouse model of myocardial infarction. In addition, rmHapln1 induced hiPSC-CM proliferation. In conclusion, Hapln1 can stimulate the dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping and subsequent activation of the TGF-ß/SMAD2/3 signaling pathway. Hapln1 might be an effective hiPSC-CM dedifferentiation and proliferation agent and a potential reagent for repairing damaged hearts.

A quantitative study of airway ultrasound in predicting difficult laryngoscopy: A prospective study.

PURPOSE: As common clinical screening tests cannot effectively predict a difficult airway, and unanticipated difficult laryngoscopy remains a challenge for physicians. We herein used ultrasound to develop some point-of-care predictors for difficult laryngoscopy. METHODS: This prospective observational study included 502 patients who underwent laryngoscopy and a detailed sonographic assessment. Patients under 18 years old, or with maxillofacial deformities or fractures, limited mouth opening, limited neck movement or history of neck surgery were excluded from the study. Laryngoscopic views of all patients were scored and grouping using the modified Cormack-Lehane (CL) scoring system. The measurements acquired comprised tongue width, the longitudinal cross-sectional area of the tongue, tongue volume, the mandible-hyoid bone distance, the hyoid bone-glottis distance, the mandible-hyoid bone-glottis angle, the skin-thyrohyoid membrane distance, the glottis-superior edge of the thyroid cartilage distance (DGTC), the skin-hyoid bone distance, and the epiglottis midway-skin distance. ANOVA and Chi-square were used to compare differences between groups. Logistic regression was used to identify risk factors for difficult laryngoscopy and it was visualized by receiver operating characteristic curves and nomogram. R version 3.6.3 and SPSS version 26.0 were used for statistical analyses. RESULTS: Difficult laryngoscopy was indicated in 49 patients (CL grade Ⅲ - Ⅳ) and easy laryngoscopy in 453 patients (CL grade Ⅰ - Ⅱ). The ultrasound-measured mandible-hyoid bone-glottis angle and DGTC significantly differed between the 2 groups (p < 0.001). Difficult laryngoscopy was predicted by an area under the curve (AUC) of 0.930 with a threshold mandible-hyoid bone-glottis angle of 125.5° and by an AUC of 0.722 with a threshold DGTC of 1.22 cm. The longitudinal cross-sectional area of the tongue, tongue width, tongue volume, the mandible-hyoid distance, and the hyoid-glottis distance did not significantly differ between the groups. CONCLUSION: Difficult laryngoscopy may be anticipated in patients in whom the mandible-hyoid bone-glottis angle is smaller than 125.5° or DGTC is larger than 1.22 cm.

Expression level of epithelial cell adhesion molecule (EpCAM) of circulating tumor cells (CTCs) of patients with NSCLC as an early indicator to monitor the effects of postoperative adjuvant chemotherapy.

BACKGROUND: An early indicator for monitoring the effect of adjuvant treatment after lung cancer surgery is urgently needed. The study was to explore the effects of epithelial cell adhesion molecule (EpCAM) of circulating tumor cells (CTCs) in NSCLC patients with postoperative adjuvant chemotherapy. METHODS: Two drugs (platinum-containing chemotherapeutics + platinum-free chemotherapeutics) first-line chemotherapy regimen were given after surgery. MRNA of EpCAM was detected. Chest computed tomography, head computed tomography and abdominal B-ultrasound were reviewed before the first and third chemotherapy. RESULTS: EpCAM in CTCs from peripheral blood between the recurrent group and the non-recurrent group at 1 day before surgery, first, second and third adjuvant chemotherapy were no significant differences (P>0.05). Only one day before the fourth adjuvant chemotherapy treatment, it showed significant difference between the recurrent group and the non-recurrent group (P=0.008). There was a significant difference between the time of imaging diagnosis of recurrence or metastasis and the time of monitoring the expression level of EpCAM in CTCs from peripheral blood (P<0.0001). CONCLUSIONS: EpCAM in CTCs from peripheral blood during postoperative adjuvant chemotherapy was related to recurrence or metastasis of NSCLC patients.

The volume threshold of 300 versus 100 ml/day for chest tube removal after pulmonary lobectomy: a meta-analysis.

OBJECTIVES: In this meta-analysis, we conducted a pooled analysis of clinical studies comparing the efficacy of a volume threshold of 300 ml/day before removing a chest tube (CT) versus 100 ml/day after a lobectomy. METHODS: According to the recommendations of the Cochrane Collaboration, we established a rigorous study protocol. We performed a systematic electronic search of PubMed, Embase, Cochrane Library, Web of Science databases, CNKI, the Wanfang database, CBMdisc and Google Scholar to identify articles to include in our meta-analysis. A literature search was performed using relevant keywords. A meta-analysis was performed using RevMan© software. RESULTS: Five studies, published between 2014 and 2015, including 615 patients (314 patients who had the CT removed when daily drainage was <300 ml and 301 patients who had the CT removed when daily drainage was <100 ml) met the selection criteria. From the available data, the patients using the volume threshold of 300 ml/day had a significantly decreased duration of drainage [MD = -44.07; 95% confidence interval (CI) -64.45 to -23.68; P < 0.0001] and hospital stay after operation (MD = -2.25; 95% CI -3.52 to -0.97; P = 0.0006) compared with patients using a volume threshold of 100 ml/day after a pulmonary lobectomy. However, no significant differences were observed in postoperative complications, such as pleural fluid reaccumulation [Odds ratio (OR) = 1.73; 95% CI = 0.74-4.07; P = 0.21] and atelectasis (OR = 0.97; 95% CI = 0.52-1.81; P = 0.93). Thoracentesis rates after removing the CT also showed no significant difference (OR = 1.53; 95% CI 0.55-4.22; P = 0.41). CONCLUSIONS: Our results showed that a higher volume threshold, up to 300 ml/day, is effective in reducing hospitalization times and duration of drainage in patients who undergo a lobectomy. Moreover, the volume threshold of 300 ml/day does not increase the occurrence of postoperative atelectasis, pleural fluid reaccumulation and thoracentesis rates. However, this review is limited by the methodological quality of the included trials, and additional studies according to the recommendations of Cochrane Library are appreciated.

Biomimetically inspired asymmetric total synthesis of (+)-19-dehydroxyl arisandilactone A.

Complex natural products are a proven and rich source of disease-modulating drugs and of efficient tools for the study of chemical biology and drug discovery. The architectures of complex natural products are generally considered to represent significant barriers to efficient chemical synthesis. Here we describe a concise and efficient asymmetric synthesis of 19-dehydroxyl arisandilactone A-which belongs to a family of architecturally unique, highly oxygenated nortriterpenoids isolated from the medicinal plant Schisandra arisanensis. This synthesis takes place by means of a homo-Michael reaction, a tandem retro-Michael/Michael reaction, and Cu-catalysed intramolecular cyclopropanation as key steps. The proposed mechanisms for the homo-Michael and tandem retro-Michael/Michael reactions are supported by density functional theory (DFT) calculation. The developed chemistry may find application for the synthesis of its other family members of Schisandraceae nortriterpenoids.

The clinicopathological significance of hMLH1 hypermethylation in non-small-cell lung cancer: a meta-analysis and literature review.

The hMLH1 gene plays an essential role in DNA repair. Methylation of the hMLH1 gene is common in many types of cancer and can lead to the loss of hMLH1 expression. However, the association and clinicopathological significance between hMLH1 promoter hypermethylation and non-small-cell lung cancer (NSCLC) is elusive. Here, we investigated the correlation of hMLH1 promoter hypermethylation and NSCLC using 13 studies by comprising 1,056 lung cancer patients via a meta-analysis. We observed that 1) loss of hMLH1 protein expression was significantly associated with its promoter hypermethylation, 2) hMLH1 gene inactivation through hypermethylation contributed to the tumorigenesis of NSCLC, which could be a decisive factor for the pathogenesis of NSCLC due to its high occurrence in NSCLC tissues compared to normal lung tissues, 3) a correlation exists between histologic subtypes/disease stages (TNM I+II vs III+IV) and hypermethylation status of hMLH1 gene, and 4) NSCLC patients with hMLH1 hypermethylation and subsequent low expression levels of hMLH1 have a short overall survival period than those patients with normal expression of hMLH1 gene. hMLH1 mRNA predicts patient survival in lung cancer, and this was confirmed by using a public database. We then discussed the tumor suppressor function of hMLH1 and the clinicopathological significance of hMLH1 in NSCLC. We concluded that hMLH1 hypermethylation should be an early diagnostic marker for NSCLC and also a prognostic index for NSCLC. hMLH1 is an interesting therapeutic target in human lung cancers.

Clinicopathological significance and a potential drugtarget of RARß in non-small-cell lung carcinoma: a meta-analysis and a systematic review.

Lung cancer is the leading cause of cancer-related mortality in men worldwide. Aberrant RARß promoter methylation has been frequently investigated in non-small-cell lung carcinoma (NSCLC), the most common form of lung cancer. The aim of present study was to carry out a meta-analysis and a systematic review to evaluate clinicopathological significance of RARß promoter hypermethylation in NSCLC. A systematic literature search was carried out. The data were extracted and assessed by two reviewers independently. The Cochrane software Review Manager 5.2 was used to conduct the review. Odds ratios (ORs) with 95% corresponding confidence intervals (CIs) were calculated. A total of 18 relevant articles were available for meta-analysis which included 1,871 participants. The frequency of RARß hypermethylation was significantly increased in NSCLC than in nonmalignant lung tissue, and the pooled OR was 5.69 (P<0.00001). RARß hypermethylation was significantly more frequently observed in adenocarcinoma (AC) than in squamous cell carcinoma (SCC), and the pooled OR was 1.47 (P=0.005). Hypermethylation of RARß gene in NSCLC was 2.46 times higher in smoking than in nonsmoking individuals, and the pooled OR was 2.46 (P=0.0002). RARß hypermethylation rate was not significantly correlated with stage of the disease and sex. RARß gene methylation status was not associated with prognosis of patients with NSCLC. In conclusion, RARß promoter hypermethylation significantly increased in NSCLC than in non-neoplastic lung tissue and is predominant in AC, suggesting that RARß methylation contributes to the development of NSCLC, especially AC. RARß gene is a potential novel target for development of personalized therapy in patients with NSCLC, and is promising in restoration of retinoic acid-target gene induction via demethylation of RARß1' promoter.

Correlation between expression of cell adhesion molecules CD44 v6 and E-cadherin and lymphatic metastasis in non- small cell lung cancer.

OBJECTIVE: To explore the relationship between expressions of cell adhesion molecules CD44 v6 and E-cadherin (E-cad) and lymphatic metastasis in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Eighty- seven tissue samples obtained from patients with primary NSCLC were collected in our hospital from Dec., 2007 to Dec., 2012, and the expressions of CD44 v6 and E-cad gene proteins in these samples were detected by immunohistochemical method. RESULTS: In the tissue without lymphatic metastasis, the positive expression rate of CD44 v6 was significantly lower, whereas the normal expression rate of E-cad was notably higher than that with lymphatic metastasis (55.6% vs. 78.4%, 47.2% vs. 21.6%), and both differences had statistical significance (P<0.05). Besides, CD44 v6 and E-cad expressions had a significant correlation in the NSCLC tissue with lymphatic metastasis (P<0.05). CONCLUSIONS: The positive expression of CD44 v6 and abnormal expression of E-cad may play a very important role in promoting lymphatic metastasis of NSCLC, with synergistic effect. Hence, detection of CD44 v6 and E-cad expressions is conductive to judging the lymphatic metastasis in NSCLC.

[Primary sinus histiocytosis of the trachea: a case report and review of literature].

OBJECTIVE: To study the clinicopathological features, diagnosis and prognosis of primary sinus histiocytosis (Rosai-Dorfman disease, RDD) of the trachea by case report and review of the literature. METHODS: A 63 year old man with a space-occupying lesion of the trachea firstly diagnosed as a malignant tumor was admitted to this hospital for further evaluation and treatment. The lesion was removed by surgery and the final diagnosis was primary RDD. The clinical data of the case was analyzed and the related literatures were reviewed. The literature review was carried out respectively with"Rosai-Dorfman disease" and "sinus histiocytosis"as the key words in Wanfang Med Online and with"Rosai-Dorfman disease","sinus histiocytosis","trachea or lung"as the key words in PubMed database by July 2012. RESULTS: The chest computerized tomography of the case showed that the mass was located at the right side of the trachea with heterogeneous density and contrast enhancement. Bronchoscopy revealed a neoplasma occluding the distal trachea. The lesion was excised by surgery. Microscopic histology showed that in the dark-staining area a large number of lymphocytes and plasma cells were noted while the light-staining area was formed by giant histiocytes. The pathological changes invaded the tracheal wall and eroded the cartilages. Intact lymphocytes and plasma cells were observed within the eosinophilic cytoplasm of the histiocytes. Immunohistochemistry showed that the giant histiocytes were strongly positive for S-100 protein and CD68 protein. Primary RDD of trachea was confirmed. The patient remained well without any other treatment or evidence of progression for 11 months. A total of 13 literatures and 26 cases were retrieved from Wanfang Med Online and Pubmed, including 21 cases of primary RDD of the upper respiratory tract and 4 cases of primary RDD of the lung. A total of 5 literatures and 5 cases of RDD affecting the trachea were retrieved from Wanfang Med Online and Pubmed. There was only one case of primary RDD of the trachea in Pubmed. A 39-year-old female patient with 1 month of dyspnea was misdiagnosed as having bronchial asthma and was unresponsive to empirical corticosteroid and bronchodilator therapy. The chest computerized tomography revealed an ill-defined irregular soft tissue in the trachea. A tracheal ring sleeve resection and reanastomosis was performed to prevent asphyxia. The mass was confirmed to be primary RDD of the trachea according to histopathology and immunohistochemistry. The patient was well without any treatment for 12 months. CONCLUSIONS: Primary RDD of the trachea is an extremely rare disease, with dyspnoea as a feature of the disease. When it is completely removed, the prognosis is good. Typical histopathology and immunohistochemistry are needed to make a definite diagnosis. The positive immunohistochemistry staining for S-100 and CD68 protein in giant histiocytes and lymphocyteemperipolesis are essential for the diagnosis. The differential diagnosis includes other benign or malignant space-occupying lesions of the trachea.

[Video-assisted thoracoscopic surgery bronchial sleeve lobectomy for lung cancer].

OBJECTIVE: To discuss the feasibility of video-assisted thoracoscopic surgery(VATS) bronchial sleeve lobectomy for NSCLC,and to describe this treatment method and the major Indications. METHOD: Between September 2010 and December 2012, 10 patients in our hospital underwent VATS bronchial sleeve lobectomy.The patients were one female and nine males.Included 3 cases on the right upper lobe, 3 cases on the right lower lobe, 1 case on the right middle lobe, 2 cases on the left upper lobe, 1 case on the left lower lobe.2 cases underwent VATS bronchial sleeve lobectomy and sleeve resection of the pulmonary artery. RESULTS: 10 cases were finished by Video-Assisted Thoracoscopic Surgery.They all recovered well.No patient showed bronchopleural fistula, empyema and atelectasis.There was no perioperative death. CONCLUSIONS: Video-assisted thoracoscopic surgery (VATS) lobectomy including bronchial sleeve lobectomy is therefore considered to be a feasible surgical modality for the treatment of patients with NSCLC.

Research on the relationship between serum levels of inflammatory cytokines and non-small cell lung cancer.

AIMS: This study was conducted to evaluate the levels of TNF-α, IL-6, IL-8 and VEGF in serum of patients with non- small cell lung cancer, for assessing their possible diagnostic and prognostic roles. METHODS: We enrolled 48 patients newly diagnosed with non-small cell lung cancer and 40 healthy controls. TNF- α, IL-6 and IL-8 levels were measured in the serum of all the subjects with specific radioimmunoassay kits, while EGF was analyzed by sandwich enzyme immunoassay techniques. RESULTS: A statistically significant difference was observed between lung cancer patients and the control group regarding the values of TNF-α, IL-6, IL-8 and VEGF in serum. Moreover, TNF-α, IL-8 and VEGF levels were higher in patients with advanced stages compared to early stages. In addition, higher serum levels of TNF-α, IL-6, IL-8 and VEGF were found in smokers than in non-smokers, both in patients and controls. CONCLUSION: Serum levels of TNF-α, IL-6, IL-8 and VEGF were all elevated in lung cancer patients, suggesting that inflammatory cytokines could be jointly used as a screening tool. Though TNF-α, IL-8 and VEGF levels were related to advanced disease, long-term survival studies of NSCLC patients should be performed to confirm whether they can act as biomarkers of advanced disease. In addition, smoking would be an important contributor to the processes of inflammation and lung cancer.

Application of hyperbranched rolling circle amplification for direct detection of mycobacterium tuberculosis in clinical sputum specimens.

BACKGROUND: Global tuberculosis (TB) control is encumbered by the lack of a rapid and simple detection method for diagnosis, especially in low-resource areas. An isothermal amplification method, hyperbranched rolling circle amplification (HRCA), was optimized to detect Mycobacterium tuberculosis (Mtb) in clinical sputum specimens. METHODS: A clinical validation study was performed to assess the diagnostic accuracy of HRCA. In order to analyze the detection limit of HRCA under optimal conditions, the method was initially used to detect purified H37Rv strain DNA and culture suspensions. Next, three strains of Mycobacterium tuberculosis complex (MTC) and eight strains of non-tuberculosis mycobacterium (NTM) were analyzed in order to evaluate specificity. Sputum specimens from 136 patients with diagnosed pulmonary TB, 38 lung cancer patients, and 34 healthy donors were tested by HRCA to validate the clinical application of HRCA for the rapid detection of Mtb. RESULTS: The detection limit of HRCA for purified H37Rv DNA and culture suspensions was 740 aM and 200cfu/ml, respectively. The results of all MTC strains were positive in contrast to the NTM specimens which were all negative. The detection sensitivity for the 136 sputum specimens from TB patients was 77.2% (105/136), which was slightly lower than that of quantitative real-time PCR(79.4%, 108/136) and culture (80.9%,110/136). The sensitivity of all three methods was statistically higher than smear microscopy (44.9%, 61/136). The overall specificity of HRCA was 98.6% (71/72) which was similar to that of quantitative real-time PCR (qRT-PCR) and smear/culture methods (100%, 72/72). CONCLUSIONS: Use of the HRCA assay for detection of Mtb within clinical sputum specimens was demonstrated to be highly sensitive and specific. Moreover, the performance of HRCA is simple and cost-effective compared with qRT-PCR and is less time consuming than culture. Therefore, HRCA is a promising TB diagnostic tool that can be used routinely in low-resource clinical settings.

Expression of CD40 and growth-inhibitory activity of CD40 agonist in ovarian carcinoma cells.

The CD40 receptor is a member of the tumour necrosis factor receptor family and is widely expressed on various cell types. The antitumour activity of CD40 agonist antibody has been observed in B-cell-derived malignancies, but its activity on ovarian cancer remains unclear. However, in this paper, we first confirmed that the anti-CD40 agonist antibody could inhibit the growth of ovarian cancer cells and induce apoptosis. This study investigated the expression of CD40 by ovarian carcinoma tissues and cell lines, at the same time, we evaluated the effect of a recombinant soluble human CD40L (rshCD40L) and an anti-CD40 agonist antibody on cell growth and apoptosis. Flow cytometry and immunohistochemistry assay demonstrated that CD40 was expressed on ovarian carcinoma cell lines and primary ovarian carcinoma cells derived from ascites, as well as on ovarian carcinoma tissues. The growth inhibition of rshCD40L and the anti-CD40 agonist antibody on ovarian carcinoma cells was examined by MTT assay, and the proportion of apoptotic tumour cells was analysed by flow cytometry and Hoechst staining. Our study showed that CD40 was expressed on all ovarian carcinoma cell lines and was examined in 86.2% (162/188) of ovarian cancer tissue samples, but not in normal ovarian tissues (n = 20). Treatment with rshCD40L or anti-CD40 agonist antibody significantly inhibited ovarian carcinoma cell growth and induced apoptosis. Theses results suggest that CD40 is expressed on ovarian carcinoma cells, moreover, that rshCD40L and anti-CD40 agonist antibody have therapeutic potential to inhibit human ovarian cancer growth.

CREB is a positive transcriptional regulator of gamma interferon in latent but not active tuberculosis infections.

Gamma interferon (IFN-gamma) is a crucial cytokine for protection against Mycobacterium tuberculosis, but the mechanism of IFN-gamma transcription is still unclear. The cyclic AMP (cAMP) responsive element binding (CREB) proteins belong to the bZip (basic leucine zipper) family of transcription factors and are essential for T-cell function and cytokine production. This study focused on the capacity of CREB proteins to regulate IFN-gamma transcription in CD3(+) T cells obtained from tuberculosis (TB) patients and persons with latent tuberculosis infection (LTBI) in China. The electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), and Western blotting were used to demonstrate the regulatory role of CREB. EMSA (in vitro) and ChIP (in vivo) experiments suggested CREB could bind to the IFN-gamma proximal promoter in persons with LTBI, whereas no binding was detected in TB patients. Western blotting confirmed the expression of CREB proteins, especially serine-133-phosphorylated CREB, was markedly reduced in TB patients compared with persons with LTBI. These results suggested that CREB could promote the transcription and production of IFN-gamma through binding with the IFN-gamma proximal promoter, but the regulatory role of CREB was decreased in tuberculosis patients owing to diminished expression of CREB proteins, which in turn reduced the IFN-gamma production.

[Expression of HDGF and its implication in stage I non-small cell lung cancer].

OBJECTIVE: To evaluate the expression of HDGF and its implication in patients who undergone radical resection for stage I non-small cell lung cancer. METHODS: Immunohistochemical technique was applied to detect the expression of HDGF in 118 lung cancer tissues and 30 normal lung tissues as control. At the same time, the expression of VEGF and Ki-67 labeling rate of the tumors was evaluated. RESULTS: HDGF expression was observed in all cases, and significantly higher than that in normal lung tissues (52.23 +/- 10.35 vs. 156.73 +/- 70.95, P < 0.01). Expresson of HDGF was closely related to histological classification, and the expression in adenocarcinoma was much stronger than that in squamous cell cancers (P = 0.001), but not related to other clinicopathological factors. VEGF expression was closely related to the expression of HDGF. HDGF expression in the VEGF high expression group was much higher than that in VEGF low expression group (171.77 +/- 81.07 vs. 142.81 +/- 59.84, P = 0.028). Ki-67 expression was also closely related to the expression of HDGF, the labeling rate of Ki-67 in high HDGF expression group was much higher than that in low HDGF expression group (30.49% +/- 7.88% vs. 17.80% +/- 5.63%, P = 0.001). Univariate analysis showed that the patients with high HDGF expression had a shorter overall survival than that with low HDGF expression (40.0% vs. 77.5%, P = 0.008), and multivariate Cox regression analysis showed that HDGF was a significantly independent predictive factors for patients with stage I NSCLC (RR = 1.011, P = 0.002). CONCLUSION: HDGF expression is upgraded in postoperative stage I non-small cell lung cancer patients. HDGF is a significantly independent predictive factor for patients with stage I NSCLC. HDGF may play an important role on carcinogenesis and development of stage I NSCLC through promoting cell proliferation and neoangiogenesis of the tumor.