VEGFR endocytosis regulates the angiogenesis in a mouse model of hindlimb ischemia.

BACKGROUND: The regulation of angiogenesis in the treatment of cardiovascular diseases has been widely studied and the vascular endothelial growth factor (VEGF) families and VEGF receptor (VEGFR) have been proven to be one of the key regulators. The VEGFR endocytosis has been recently proved to be involved in the regulation of angiogenesis. Our previous study showed that the upregulation of VEGFR endocytosis enhanced angiogenesis in vitro. In this research, we utilized mice with induced hindlimb ischemia, as a model to investigate the role of VEGFR endocytosis in the regulation of angiogenesis in vivo. Our goal was to observe the effect of revascularization with different degrees of VEGFR endocytosis after injecting atypical protein kinase C inhibitor (αPKCi) and dynasore, which could respectively promote and inhibit the VEGFR endocytosis. METHODS: We induced the hindlimb ischemia in adult male mice by ligating the hindlimb artery. By directly injecting the ischemic muscles with endothelial progenitor cells (EPCs) alone or EPCs + αPKCi/EPCs + dynasore or control medium (sham group), we divided the mice into four groups and detected lower limb blood flow using a laser Doppler blood perfusion imager. We also measured the immunohistochemistry (IHC) of markers for angiogenesis, such as CD31 and alpha smooth muscle actin (α-SMA) in the ischemic hindlimb tissues. RESULTS: We demonstrated VEGFR endocytosis played an important role in the angiogenesis of the ischemic hindlimb model in vivo. By using atypical PKC inhibitor that increase the VEGFR endocytosis, the angiogenesis in the mice model was promoted. Treatment with EPCs + αPKCi showed greater effects on blood perfusion recovery and increased the α-SMA-positive vessels. CONCLUSIONS: The regulation of VEGFR endocytosis represents a valuable method of improving angiogenesis and thus revascularization in ischemic disease model.

The role of the Wnt/ß-catenin signaling pathway in the proliferation of gold nanoparticle-treated human periodontal ligament stem cells.

BACKGROUND: Several studies have confirmed that gold nanoparticles (AuNPs) of specific concentration and size exert a boosting effect on cell proliferation; however, the mechanism through which this effect occurs remains unknown. This study explores the canonical Wnt signaling pathway in AuNP promotion of human periodontal ligament stem cell (hPDLSC) proliferation. METHODS: MTS was employed to evaluate hPDLSC proliferation. The interference of LRP5 and ß-catenin was steered by shRNA plasmids and siRNA, respectively, at which point the expression of MYC, CCND1, AXIN2, and POU5F1 had been estimated via real-time PCR. The expressions of LRP5 and ß-catenin were detected via western blot assay. RESULTS: The proliferation of hPDLSCs treated with 60 nm AuNPs at 56 µM was clearly elevated. In contrast, ß-catenin siRNA significantly decreased cell viability. The LRP5 shRNA plasmid did not consistently impact cells. The expressions of these four genes downstream of the Wnt/ß-catenin signaling pathway were not significantly overexpressed in response to the interference of shRNA plasmid/siRNA with the treatment of AuNPs. CONCLUSIONS: These results suggest that the Wnt/ß-catenin signaling pathway plays a significant role in the process of AuNP promotion of hPDLSC proliferation.

Prognostic value of platelet-to-lymphocyte ratio in pancreatic cancer: a comprehensive meta-analysis of 17 cohort studies.

BACKGROUND AND AIMS: Several studies were conducted to explore the prognostic value of platelet-to-lymphocyte ratio (PLR) in pancreatic cancer and have reported contradictory results. This study aims to summarize the prognostic role of PLR in pancreatic cancer. MATERIALS AND METHODS: Embase, PubMed and Cochrane Library were completely searched. The cohort studies focusing on the prognostic role of PLR in pancreatic cancer were eligible. The overall survival (OS) and progression-free survival (PFS) were analyzed. RESULTS: Fifteen papers containing 17 cohort studies with pancreatic cancer were identified. The results showed patients that with low PLR might have longer OS when compared to the patients with high PLR (hazard ratio=1.28, 95% CI=1.17-1.40, P<0.00001; I2=42%). Similar results were observed in the subgroup analyses of OS, which was based on the analysis model, ethnicity, sample size and cut-off value. Further analyses based on the adjusted potential confounders were conducted, including CA199, neutrophil-to-lymphocyte ratio, modified Glasgow Prognostic Score, albumin, C-reactive protein, Eastern Cooperative Oncology Group, stage, tumor size, nodal involvement, tumor differentiation, margin status, age and gender, which confirmed that low PLR was a protective factor in pancreatic cancer. In addition, low PLR was significantly associated with longer PFS when compared to high PLR in pancreatic cancer (hazard ratio=1.27, 95% CI=1.03-1.57, P=0.03; I2=33%). CONCLUSION: In conclusion, it was found that high PLR is an unfavorable predictor of OS and PFS in patients with pancreatic cancer, and PLR is a promising prognostic biomarker for pancreatic cancer.

The prognostic value of high LncRNA AFAP1-AS1 expression in various cancers: A systematic review and meta-analysis containing 21 studies.

BACKGROUNDS: Plenty of studies have been conducted to explore the prognostic value of LncRNA AFAP1-AS1 in various cancers, however, with contradictory outcomes. The aim of the current study was to explore the prognostic value of high LncRNA AFAP1-AS1 expression in various cancers. METHODS: PubMed, EMBASE, Web of Science, Cochrane library, China National Knowledge Internet (CNKI) and Wan-fang database were comprehensively retrieved, and all the relevant studies were included into the study. RESULTS: A total of 21 studies involving 2179 patients were finally included into the systematic review and meta-analysis. Compared to low LncRNA AFAP1-AS1 expression, high LncRNA AFAP1-AS1 expression was significantly related to shorter OS (HR = 2.02, 95%CI = 1.51-2.70, P < 0.001; I2 = 78%), DFS(HR = 1.80, 95%CI = 1.16-2.80, P = 0.009; I2 = 0%), RFS (HR = 2.90, 95%CI = 1.79-4.69, P < 0.001; I2 = 38%)and PFS(HR = 2.18, 95%CI = 1.62-2.92, P < 0.001; I2 = 0%) in patients with various cancers. Besides, high LncRNA AFAP1-AS1 expression was significantly associated with smoking (P < 0.001), advanced clinical stage (P < 0.001), larger tumor size (P < .001), earlier tumor metastasis (P < 0.001), earlier lymph nodal involvement (P = 0.002) and vascular invasion (P < 0.001) in various cancers. CONCLUSIONS: Cancer patients with high LncRNA AFAP1-AS1 expression had shorter OS, DFS, RFS and PFS compared to those with low expression. Moreover, high LncRNA AFAP1-AS1 expression was significantly related to advanced clinical stage, larger tumor size, earlier tumor metastasis, earlier lymph nodal involvement and vascular invasion. High LncRNA AFAP1-AS1 expression was an unfavorable prognostic factor in various cancers.

The Role of Grb2 in Cancer and Peptides as Grb2 Antagonists.

BACKGROUND: Growth factor receptor-bound protein 2 (Grb2) is a 25 kDa adaptor protein, which was originally discovered to accomplish basic cellular events such as cell growth, cell proliferation, and metabolism. However, recent studies evidenced that Grb2 was largely involved in multiple tumor malignancies. The mature Grb2 is a 217 amino acid sequence, which consists of one Src homology 2 (SH2) domain flanked by two Src homology 3 (SH3) domains. Using these binding motives, the ubiquitously expressed Grb2 acts as an intermediate between cell-surface activated receptors and downstream targets. OBJECTIVES: Consequently, the Grb2 becomes the key element of this oncogenesis and launched a number of defected signaling cascades. Therefore, vast concern of the Grb2 in multiple cancer patterns makes it an attractive therapeutic target. In this review, we have compiled the maximum tumor conformations caused by the involvement of the Grb2, the central role of Grb2 in numerous oncogenic pathways and particular approaches that can be useful to downregulate the Grb2 overexpression. We will discuss in details the activity of different types of novel peptides, their high affinity for the Grb2 protein and blockade of Grb2 mediated signaling pathways by targeting the SH2/SH3 binding sites. METHODS & RESULTS: There is a three-fold aspect to this review: Grb2 protein introduction, Grb2 protein involvement in cancer, and the role of peptides as Grb2 antagonists. First, Grb2 and compiled maximum tumor conformations induced by Grb2 involvement were introduced. Secondly, several oncogenic pathways of Grb2 involvement and particular approaches potentially useful to downregulate Grb2 overexpression were outlined. The activity of different types of novel peptides for the Grb2 protein was also detailed. Last but not least, the blockade of Grb2-mediated signaling pathways by targeting SH2/SH3 binding sites were summarized. CONCLUSION: We have epitomized the utmost cancer malignancies caused by abnormal signaling of the Grb2 adaptor molecule. Indeed, Grb2's enormous involvement in the progression and development of different cancers broaden our tactics to build anticancer drug candidates. Depending on the high affinity and increased specificity we have described the major potent peptides which may efficiently target and block the SH2 or SH3 arms of the Grb2. It may be of benefit for developing novel anticancer peptides. However, further work is needed to pinpoint more binding motives of Grb2 to generate efficacious anticancer agents for diverse human cancers in the near future.

Neutrophil-to-Lymphocyte Ratio Is a Potential Prognostic Biomarker in Patients with Ovarian Cancer: A Meta-Analysis.

BACKGROUND AND AIMS: Plenty of studies were conducted to explore the prognostic significance of neutrophil-to-lymphocyte ratio (NLR) in ovarian cancer with contradictory results. This study aims to summarize the prognostic significance of NLR in patients with ovarian cancer. METHODS: A literature search in PubMed, Cochrane Library, and Embase was conducted. The endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: Eleven studies involving a total of 2,892 patients were identified. The results indicated that patients with high NLR had shorter PFS compared to patients with low NLR in ovarian cancer (HR = 1.55, 95% CI = 1.15-2.08, p = 0.004, and I2 = 61%). Similarly, high NLR was related to shorter OS (HR = 1.51, 95% CI = 1.03-2.23, p = 0.04, and I2 = 85%). Moreover, high NLR was significantly associated with shorter PFS when the NLR cut-off was less than 3.3 (p = 0.03) or when treatment is operation (p = 0.002). In addition, high NLR was distinctly related to worse OS in Asian people (p = 0.04) or operation (p = 0.04). CONCLUSION: High NLR was associated with shorter PFS and shorter OS in ovarian cancer. NLR is potentially a promising prognostic biomarker in patients with ovarian cancer.

Prognostic role of platelet to lymphocyte ratio in hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Several studies were conducted to explore the prognostic significance of platelet to lymphocyte ratio (PLR) in hepatocellular carcinoma (HCC), however, contradictory results across most reports were documented. To this end, we present a systematic review that aims to summarize the prognostic significance of PLR in patients with HCC. RESULTS: A total of 10 studies involving a total of 2,315 patients were identified. The Newcastle-Ottawa Quality Assessment Scale (NOS) of each included study was greater than or equal to 5. The results indicated that high PLR was significantly associated with a worse OS when compared to the low PLR (HR = 1.60, 95% CI = 1.23-2.08, p = 0.0005; I2 = 88%, p < 0.00001). Similar results were detected in the subgroup analysis of the analysis model, cut-off value, ethnicity, sample size and therapy. However, no obvious correlation between the PLR and DFS/RFS in patients with HCC was observed (HR = 1.21, 95% CI = 0.87-1.67, p = 0.26; I2 = 61%, p = 0.07). MATERIALS AND METHODS: A complete literature search in the PubMed, Cochrane Library and Embase database was performed. Retrospective and prospective studies focusing on the role of PLR on the prognosis in HCC were all deemed as "suitable" for our scope. The endpoints determined were: the overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS) and the progress free survival (PFS). CONCLUSIONS: The study revealed that high PLR is an unfavorable predictor of OS in patients with HCC, and high PLR is a promising prognostic biomarker for HCC, especially for patients in Asia.

Case report: improvement of cardiac remodeling with shock wave therapy of a patient with ischemic cardiomyopathy.

Percutaneous coronary intervention (PCI) and coronary-artery bypass grafting (CABG) are two major preferred reperfusion strategies to restore the ischemic-related artery patency, but PCI and CABG do not necessarily guarantee the recovery of post-procedure left ventricular (LV) dysfunction and release of symptoms. Moreover, there is no definitive effective way to enhance microcirculations. Theoretically, shock wave therapy (SWT) is an option. We report here a case of patient who received SWT. The patient's medical history was characterized by chest pain for 20 years, having received CABG 13 years ago. The follow-up angiography showed all blood vessels are stiff and rigid therefore no chance for a second CABG. After cardiac SWT treatment for 1 year, the patient's symptoms of chest pain and chronic heart failure significantly improved, the odds of cardiac muscle survival increased, the cardiac remodeling was also improved. What's more, left ventricular ejection fraction (LVEF) was improved from 34% to 51% and 43% in half year and 1 year after SWT which is indicated by single-photon emission computed tomography (SPECT), respectively. To our knowledge, this is the first report of 2-cycle cardiac SWT treatments over 1 year with a complete follow-up, indicating that SWT can not only improve the symptoms of chronic heart failure, but also improve LVEF and cardiac remodeling caused by ischemic cardiomyopathy.