Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in adults and children worldwide. NAFLD has become a severe health issue and it can progress towards a more severe form of the disease, the non-alcoholic steatohepatitis (NASH). A combination of environmental factors, host genetics, and gut microbiota leads to excessive accumulation of lipids in the liver (steatosis), which may result in lipotoxicity and trigger hepatocyte cell death, liver inflammation, fibrosis, and pathological angiogenesis. NASH can further progress towards liver cirrhosis and cancer. Over the last few years, cell-derived extracellular vesicles (EVs) have been identified as effective cell-to-cell messengers that transfer several bioactive molecules in target cells, modulating the pathogenesis and progression of NASH. In this review, we focused on recently highlighted aspects of molecular pathogenesis of NASH, mediated by EVs via their bioactive components. The studies included in this review summarize the state of art regarding the role of EVs during the progression of NASH and bring novel insight about the potential use of EVs for diagnosis and therapeutic strategies for patients with this disease.
Adult ; Cell Death ; Child ; Diagnosis ; Fatty Liver* ; Fibrosis ; Genetics ; Hepatocytes ; Humans ; Inflammation ; Liver ; Liver Cirrhosis ; Liver Diseases ; Microbiota ; Neovascularization, Pathologic

Animals ; Male ; Neovascularization, Pathologic ; diagnosis ; Vasa Vasorum ; physiology

BACKGROUNDAccumulating evidence indicates a potential role of adventitial vasa vasorum (VV) dysfunction in the pathophysiology of restenosis. However, characterization of VV vascularization in restenotic arteries with primary lesions is still missing. In this study, we quantitatively evaluated the response of adventitial VV to vascular injury resulting from balloon angioplasty in diseased arteries.

METHODSPrimary atherosclerotic-like lesions were induced by the placement of an absorbable thread surrounding the carotid artery of New Zealand rabbits. Four weeks following double-injury induced that was induced by secondary balloon dilation, three-dimensional patterns of adventitial VV were reconstructed; the number, density, and endothelial surface of VV were quantified using micro-computed tomography. Histology and immunohistochemistry were performed in order to examine the development of intimal hyperplasia.

RESULTSResults from our study suggest that double injured arteries have a greater number of VV, increased luminal surface, and an elevation in the intima/media ratio (I/M), along with an accumulation of macrophages and smooth muscle cells in the intima, as compared to sham or single injury arteries. I/M and the number of VV were positively correlated (R2 = 0.82, P < 0.001).

CONCLUSIONSExtensive adventitial VV neovascularization occurs in injured arteries after balloon angioplasty, which is associated with intimal hyperplasia. Quantitative assessment of adventitial VV response may provide insight into the basic biological process of postangioplasty restenosis.

Angioplasty, Balloon, Coronary ; Animals ; Male ; Neovascularization, Pathologic ; diagnosis ; Rabbits ; Vasa Vasorum ; physiology ; X-Ray Microtomography

BACKGROUND: Angiogenesis is important for the proliferation and survival of multiple myeloma (MM) cells. Bone marrow (BM) microvessel density (MVD) is a useful marker of angiogenesis and is determined by immunohistochemical staining with anti-CD34 antibody. This study investigated the prognostic impact of MVD and demonstrated the relationship between MVD and previously mentioned prognostic factors in patients with MM. METHODS: The study included 107 patients with MM. MVD was assessed at initial diagnosis in a blinded manner by two hematopathologists who examined three CD34-positive hot spots per patient and counted the number of vessels in BM samples. Patients were divided into three groups according to MVD tertiles. Cumulative progression-free survival (PFS) and overall survival (OS) curves, calculated by using Kaplan-Meier method, were compared among the three groups. Prognostic impact of MVD was assessed by calculating Cox proportional hazard ratio (HR). RESULTS: Median MVDs in the three groups were 16.8, 33.9, and 54.7. MVDs were correlated with other prognostic factors, including beta2-microglobulin concentration, plasma cell percentage in the BM, and cancer stage according to the International Staging System. Multivariate Cox regression analysis showed that high MVD was an independent predictor of PFS (HR=2.57; 95% confidence interval, 1.22-5.42; P=0.013). PFS was significantly lower in the high MVD group than in the low MVD group (P=0.025). However, no difference was observed in the OS (P=0.428). CONCLUSIONS: Increased BM MVD is a marker of poor prognosis in patients newly diagnosed with MM. BM MVD should be assessed at the initial diagnosis of MM.
Aged ; Antigens, CD34/metabolism ; Bone Marrow/metabolism/*pathology ; Disease-Free Survival ; Female ; Humans ; Immunohistochemistry ; Kaplan-Meier Estimate ; Male ; Microvessels/*physiopathology ; Middle Aged ; Multiple Myeloma/*diagnosis/mortality ; Neoplasm Staging ; Neovascularization, Pathologic ; Plasma Cells/cytology ; Prognosis ; Proportional Hazards Models ; Regression Analysis ; Risk Factors

OBJECTIVETo study the changes in quantitative kinetic parameters in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) during radiotherapy and their value for efficacy evaluation in patients with nasopharyngeal carcinoma (NPC).

METHODSTwenty-four patients with NPC that had been pathologically confirmed as poorly differentiated squamous cell carcinoma underwent conventional MRI and DCE-MRI scans 1-2 days before radiotherapy (Pre-RT), during radiotherapy (RT 50 Gy), and upon completion of radiotherapy (RT 70 Gy). Based on the two-compartment model and using the arterial input function deconvolution technique, we calculated the quantitative kinetic parameters of DCE-MRI (K(trans), kep, and Ve) of the tumor tissues, examined the correlation between the tumor regression rate (RS0-50) and the parameters on Pre-RT and RT 50 Gy, and compared the parameters for RT 70 Gy among the groups with different prognosis.

RESULTSThe K(trans) value of the tumor tissue decreased after radiotherapy and showed a significant difference between Pre-RT and RT 70 Gy, but not between Pre-RT and RT 50 Gy. The kep value decreased and Ve value increased after radiotherapy. The tumor regression rate was found to be positively correlated with the K(trans) value for Pre-RT (P=0.005) but negatively with the K(trans) value for RT 50 Gy (P=0.001). During the follow-up for 3 years, 5 patients died and 3 patients had distant metastases. No statistical differences in K(trans), kep, or Ve were found between the groups with different prognosis.

CONCLUSIONSThe kinetic parameters in DCE-MRI, which vary significantly during radiotherapy, allow monitoring of tumor angiogenesis and vascular permeability and quantitative assessment of treatment efficacy for NPC. K(trans) value for Pre-RT and RT 50 Gy can serve as an indicator for early efficacy assessment of radiotherapy and for treatment adjustment, but its relation with the long-term outcomes awaits further study.

Algorithms ; Capillary Permeability ; Carcinoma ; Carcinoma, Squamous Cell ; diagnosis ; Humans ; Magnetic Resonance Imaging ; Nasopharyngeal Neoplasms ; blood supply ; radiotherapy ; Neovascularization, Pathologic ; Prognosis ; Treatment Outcome

This study investigated the relationship between carotid plaque neovascularization and diabetes mellitus (DM) by using contrast-enhanced ultrasonography. Contrast-enhanced ultrasonography was performed in 104 patients with carotid plaque thicker than 2.0 mm. There were 36 patients with DM and 68 patients without DM. The enhanced intensity in the plaque and the ratio of enhanced intensity in the plaque to that in the lumen of the carotid artery in patients with DM were significantly greater than those in patients without DM. Our study demonstrated that the enhanced intensity in patients with DM is greater than that their counterparts without DM, suggesting that carotid plaque in DM patients may have more neovessels and may be more vulnerable.
Aged ; Carotid Arteries ; diagnostic imaging ; physiopathology ; Contrast Media ; Diabetes Mellitus ; physiopathology ; Female ; Humans ; Image Enhancement ; methods ; Male ; Middle Aged ; Neovascularization, Pathologic ; diagnosis ; diagnostic imaging ; physiopathology ; Plaque, Atherosclerotic ; diagnosis ; diagnostic imaging ; physiopathology ; Reproducibility of Results ; Sensitivity and Specificity ; Ultrasonography ; methods

OBJECTIVETo review the current status and progress on nuclear medical molecular imaging of angiogenesis.

DATA SOURCESA literature search was performed in Medline and PubMed published in English up to May 31, 2012. The search terms were molecular imaging, nuclear medicine and angiogenesis.

STUDY SELECTIONArticles studying molecular imaging of angiogenesis using radionuclide were selected and reviewed.

RESULTSMolecular imaging has been used for studying angiogenesis by targeting integrin αVβ3, VEGF/VEGFR, and matrix metalloproteinases (MMPs) with radionuclide-labeled tracers. The technology has been shown to be able to assess the angiogenesis status and/or predict the efficacy of anti-angiogenic therapy. Future directions of the research on the molecular imaging of angiogenesis include development of new tracers with better tumor targeting efficacy, desirable pharmacokinetics, and easy translation to clinical applications.

CONCLUSIONAdvances in molecular imaging of angiogenesis using radioculcide will make the technology a valuable tool for personalized anti-angiogenesis treatment.

Humans ; Integrins ; analysis ; Matrix Metalloproteinases ; analysis ; Neoplasms ; blood supply ; Neovascularization, Pathologic ; diagnosis ; Receptors, Vascular Endothelial Growth Factor ; analysis ; Vascular Endothelial Growth Factor A ; analysis

PURPOSE: To investigate the correlations between parameters of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and prognostic factors in rectal cancer. MATERIALS AND METHODS: We studied 29 patients with rectal cancer who underwent gadolinium contrast-enhanced, T1-weighted DCE-MRI with a three Tesla scanner prior to surgery. Signal intensity on DCE-MRI was independently measured by two observers to examine reproducibility. A time-signal intensity curve was generated, from which four semiquantitative parameters were calculated: steepest slope (SLP), time to peak (Tp), relative enhancement during a rapid rise (Erise), and maximal enhancement (Emax). Morphologic prognostic factors including T stage, N stage, and histologic grade were identified. Tumor angiogenesis was evaluated in terms of microvessel count (MVC) and microvessel area (MVA) by morphometric study. As molecular factors, the mutation status of the K-ras oncogene and microsatellite instability were assessed. DCE-MRI parameters were correlated with each prognostic factor using bivariate correlation analysis. A p-value of <0.05 was considered significant. RESULTS: Erise was significantly correlated with N stage (r=-0.387 and -0.393, respectively, for two independent data), and Tp was significantly correlated with histologic grade (r=0.466 and 0.489, respectively). MVA was significantly correlated with SLP (r=-0.532 and -0.535, respectively) and Erise (r=-0.511 and -0.446, respectively). MVC was significantly correlated with Emax (r=-0.435 and -0.386, respectively). No significant correlations were found between DCE-MRI parameters and T stage, K-ras mutation, or microsatellite instability. CONCLUSION: DCE-MRI may provide useful prognostic information in terms of histologic differentiation and angiogenesis in rectal cancer.
Adult ; Aged ; Aged, 80 and over ; Cell Differentiation ; Contrast Media/*pharmacology ; DNA Mutational Analysis ; Female ; Gadolinium/pharmacology ; Genes, ras ; Humans ; Magnetic Resonance Imaging/*methods ; Male ; Microcirculation ; Microsatellite Instability ; Middle Aged ; Neoplasm Staging ; Neovascularization, Pathologic ; Prognosis ; Rectal Neoplasms/*diagnosis/genetics/*pathology ; Retrospective Studies ; Time Factors

OBJECTIVE: To determine whether quantitative perfusion parameters of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) correlate with immunohistochemical markers of angiogenesis in rectal cancer. MATERIALS AND METHODS: Preoperative DCE-MRI was performed in 63 patients with rectal adenocarcinoma. Transendothelial volume transfer (Ktrans) and fractional volume of the extravascular-extracellular space (Ve) were measured by Interactive Data Language software in rectal cancer. After surgery, microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression scores were determined using immunohistochemical staining of rectal cancer specimens. Perfusion parameters (Ktrans, Ve) of DCE-MRI in rectal cancer were found to be correlated with MVD and VEGF expression scores by Spearman's rank coefficient analysis. T stage and N stage (negative or positive) were correlated with perfusion parameters and MVD. RESULTS: Significant correlation was not found between any DCE-MRI perfusion parameters and MVD (rs = -0.056 and p = 0.662 for Ktrans; rs = -0.103 and p = 0.416 for Ve), or between any DCE-MRI perfusion parameters and the VEGF expression score (rs = -0.042, p = 0.741 for Ktrans ; r = 0.086, p = 0.497 for Ve) in rectal cancer. TN stage showed no significant correlation with perfusion parameters or MVD (p > 0.05 for all). CONCLUSION: DCE-MRI perfusion parameters, Ktrans and Ve, correlated poorly with MVD and VEGF expression scores in rectal cancer, suggesting that these parameters do not simply denote static histological vascular properties.
Adult ; Aged ; Aged, 80 and over ; Contrast Media/*diagnostic use ; Female ; Follow-Up Studies ; Humans ; Immunohistochemistry ; Magnetic Resonance Imaging/*methods ; Male ; Middle Aged ; Neoplasm Staging ; Neovascularization, Pathologic/diagnosis/metabolism ; Rectal Neoplasms/blood supply/*diagnosis/metabolism ; Retrospective Studies ; Tumor Markers, Biological/biosynthesis ; Vascular Endothelial Growth Factor A/*biosynthesis

This study aims to find good markers for predicting the prognosis of patients with esophageal squamous cell carcinoma (ESCC). Vasculogenic mimicry (VM) and the expression of hypoxia inducible factor-lα (HIF-lα)/E-cad protein in ESCC were investigated by immunostaining. The association between VM, HIF-lα/E-cad and clinicopathologic characteristics and 5-year-survival rate of patients with ESCC was analyzed. A total of 160 ESCC specimens were involved in this study and 28 specimens of normal esophageal mucosa served as controls. VM channels were identified in 78 (48.75%) of the 160 ESCC specimens and none of the normal esophageal mucosa was found to have VM. The rates of high-expression of HIF-lα and E-cad in ESCC were 43.75% and 38.75%, while the rates in control were 17.86% and 71.43%, respectively (P<0.05 for all). VM and the expression levels of HIF-lα and E-cad were significantly related to lymph node metastasis, serosa infiltration, PTNM staging and 5-year-survival rates of patients with ESCC (P<0.05 for all). VM was positively correlated with HIF-lα but negatively with E-cad, and HIF-lα was negatively correlated with E-cad (P<0.001 for all). The 5-year-survival rate of patients with ESCC was 6.41% (5/78) in VM group and 65% (52/82) in non-VM group, 7.14% (5/70) in high HIF-lα expression group and 57.78% (52/90) in low HIF-lα expression group. Oppositely, the 5-year-survival rate in high E-cad expression group was 80.65% (50/62) and that in low E-cad expression group was 7.37% (7/98) (P<0.05 for all). Cox multifactor regression analysis indicated that lymph node metastasis, PTNM stage, VM and expression levels of HIF-lα and E-cad were independent risk factors of patients with ESCC (P<0.05 for all). Combined detection of VM, HIF-lα and E-cad plays an important role in predicting the invasion, metastasis and prognosis of patients with ESCC.
Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor ; metabolism ; Cadherins ; metabolism ; Carcinoma, Squamous Cell ; diagnosis ; metabolism ; Esophageal Neoplasms ; diagnosis ; metabolism ; Female ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; metabolism ; Male ; Middle Aged ; Neovascularization, Pathologic ; diagnosis ; metabolism ; Prognosis ; Reproducibility of Results ; Sensitivity and Specificity ; Survival Rate