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1.
Objectives
Deficient microvascular blood flow control is thought to cause tumor hypoxia and increase resistance to therapy. In glioma patients, we tested whether perfusion-weighted MRI (PWI) based indices of microvascular flow control provide more information on tumor grade and patient outcome than does the established PWI angiogenesis marker, cerebral blood volume (CBV).Material and Methods
Seventy-two glioma patients (sixty high-grade, twelve low-grade gliomas) were included. Capillary transit time heterogeneity (CTH) and the coefficient of variation (COV), its ratio to blood mean transit time, provide indices of microvascular flow control and the extent to which oxygen can be extracted by tumor tissue. The ability of these parameters and CBV to differentiate tumor grade were assessed by receiver operating characteristic curves and logistic regression. Their ability to predict time to progression and overall survival was examined by the Cox proportional-hazards regression model, and by survival curves using log-rank tests.Results
The best prediction of grade (AUC = 0.876; p < 0.05) was achieved by combining knowledge of CBV and CTH in the enhancing tumor and peri-focal edema, and patients with glioblastoma multiforme were identified best by CTH (AUC = 0.763; p<0.001). CTH outperformed CBV and COV in predicting time to progression and survival in all gliomas and in a subgroup consisting of only high-grade gliomas.Conclusion
Our study confirms the importance of microvascular flow control in tumor growth by demonstrating that determining CTH improves tumor grading and outcome prediction in glioma patients compared to CBV alone. 相似文献2.
Background
Malignant gliomas represent one group of tumors that poorly respond to ionizing radiation (IR) alone or combined with chemotherapeutic agents because of the intrinsic or acquired resistance. In this study, TIP-1 was identified as one novel protein that confers resistance of glioma cells to IR.Methodology/Principal Findings
Meta-analysis indicated that high TIP-1 expression levels correlate with the poor prognosis of human malignant gliomas after radiotherapy. Studies with established human glioma cell lines demonstrated that TIP-1 depletion with specific shRNAs sensitized the cells to IR, whereas an ectopic expression of TIP-1 protected the glioma cells from the IR-induced DNA damage and cell death. Biochemical studies indicated that TIP-1 protein promoted p53 ubiquitination and resulted in a reduced p53 protein level. Furthermore, p53 and its ubiquitination are required for the TIP-1 regulated cellular response to IR. A yeast two-hybrid screening identified that TIP-1, through its single PDZ domain, binds to the carboxyl terminus of LZAP that has been studied as one tumor suppressor functioning through ARF binding and p53 activation. It was revealed that the presence of TIP-1 enhances the protein association between LZAP and ARF and modulates the functionality of ARF/HDM2 toward multi-ubiquitination of p53, while depleting TIP-1 rescued p53 from polyubiquitination and degradation in the irradiated glioma cells. Studies with a mouse xenograft model indicated that depleting TIP-1 within D54 cells improved the tumor growth control with IR.Conclusions/Significance
This study provided the first evidence showing that TIP-1 modulates p53 protein stability and is involved in the radioresistance of malignant gliomas, suggesting that antagonizing TIP-1 might be one novel approach to sensitize malignant gliomas to radiotherapy. 相似文献3.
Shen Yuntian Chen Hua Zhang Jinshi Chen Yanming Wang Mengyao Ma Jiawei Hong Lei Liu Ning Fan Qiuhong Lu Xueguan Tian Ye Wang Aidong Jun Dong Lan Qing Huang Qiang 《PloS one》2015,10(11)
Background
Host malignant stromal cells induced by glioma stem/progenitor cells were revealed to be more radiation-resistant than the glioma stem/progenitor cells themselves after malignant transformation in nude mice. However, the mechanism underlying this phenomenon remains unclear.Methods
Malignant stromal cells induced by glioma stem/progenitor cell 2 (GSC-induced host brain tumor cells, ihBTC2) were isolated and identified from the double color-coded orthotopic glioma nude mouse model. The survival fraction at 2 Gy (SF2) was used to evaluate the radiation resistance of ihBTC2, the human glioma stem/progenitor cell line SU3 and its radiation-resistant sub-strain SU3-5R and the rat C6 glioma cell line. The mRNA of Notch 1 and Hes1 from ihBTC2 cells were detected using qPCR before and after 4 Gy radiation. The expression of the Notch 1, pAkt and Bcl-2 proteins were investigated by Western blot. To confirm the role of the Notch pathway in the radiation resistance of ihBTC2, Notch signaling blocker gamma secretase inhibitors (GSIs) were used.Results
The ihBTC2 cells had malignant phenotypes, such as infinite proliferation, hyperpentaploid karyotype, tumorigenesis in nude mice and expression of protein markers of oligodendroglia cells. The SF2 of ihBTC2 cells was significantly higher than that of any other cell line (P<0.05, n = 3). The expression of Notch 1 and Hes1 mRNAs from ihBTC2 cells was significantly increased after radiation. Moreover, the Notch 1, pAkt and Bcl-2 proteins were significantly increased after radiation (P<0.05, n = 3). Inhibition of Notch signaling markedly enhanced the radiosensitivity of ihBTC2 cells.Conclusions
In an orthotopic glioma model, the malignant transformation of host stromal cells was induced by glioma stem/progenitor cells. IhBTC2 cells are more radiation-resistant than the glioma stem/progenitor cells, which may be mediated by activation of the Notch signaling pathway. 相似文献4.
Zahra Moinfar Hannes Dambach Bodo Schoenebeck Eckart F?rster Nora Prochnow Pedro Michael Faustmann 《PloS one》2016,11(2)
Introduction
Glioma is the most common malignant primary brain tumour with male preponderance and poor prognosis. Glioma cells express variable amounts of connexin 43 (Cx43) and estrogen receptors (ERs). Both, Cx43 and ERs, play important roles in cell proliferation and migration. Therefore, we investigated the effects of 17-ß estradiol (E2) on Cx43 expression in two glioma cell lines with variable native expression of Cx43.Materials and Methods
F98 and C6 rat glioma cells were cultured for 24 h in the presence of 10 nM or 100 nM E2, and the E2-antagonist, Fulvestrant. An MTT assay was performed to evaluate cell viability. ERα, ERβ and Cx43 protein expressions were analysed by western blotting and Cx43 mRNA expression was analysed by real-time polymerase chain reaction. To quantify cell migration, an exclusive zone migration assay was used. Functional coupling of cells via gap junctions was examined using whole-cell patch-clamp technique.Results
E2 reduced Cx43 expression in C6 cells, but increased Cx43 expression in F98 cultures. These effects were mediated via ERs. Moreover, E2 promoted C6 cell migration, but it did not affect F98 cell migration. The expression level of ERα was found to be high in C6, but low in F98 cells. ERβ was exclusively expressed in C6 cells. In addition, E2 treatment induced a significant decrease of ERβ in C6 cultures, while it decreased ERα expression in F98 glioma cells.Discussion
These findings show that E2 differentially modulates Cx43 expression in F98 and C6 glioma cells, likely due to the differential expression of ERs in each of these cell lines. Our findings point to the molecular mechanisms that might contribute to the gender-specific differences in the malignancy of glioma and could have implications for therapeutic strategies against glioma. 相似文献5.
Theodoros N. Sergentanis Georgios Tsivgoulis Christina Perlepe Ioannis Ntanasis-Stathopoulos Ioannis-Georgios Tzanninis Ioannis N. Sergentanis Theodora Psaltopoulou 《PloS one》2015,10(9)
Objective
This meta-analysis aims to examine the association between being overweight/obese and risk of meningiomas and gliomas as well as overall brain/central nervous system (CNS) tumors.Study Design
Potentially eligible publications were sought in PubMed up to June 30, 2014. Random-effects meta-analysis and dose-response meta-regression analysis was conducted. Cochran Q statistic, I-squared and tau-squared were used for the assessment of between-study heterogeneity. The analysis was performed using Stata/SE version 13 statistical software.Results
A total of 22 studies were eligible, namely 14 cohort studies (10,219 incident brain/CNS tumor cases, 1,319 meningioma and 2,418 glioma cases in a total cohort size of 10,143,803 subjects) and eight case-control studies (1,009 brain/CNS cases, 1,977 meningioma cases, 1,265 glioma cases and 8,316 controls). In females, overweight status/obesity was associated with increased risk for overall brain/CNS tumors (pooled RR = 1.12, 95%CI: 1.03–1.21, 10 study arms), meningiomas (pooled RR = 1.27, 95%CI: 1.13–1.43, 16 study arms) and gliomas (pooled RR = 1.17, 95%CI: 1.03–1.32, six arms). Obese (BMI>30 kg/m2) females seemed particularly aggravated in terms of brain/CNS tumor (pooled RR = 1.19, 95%CI: 1.05–1.36, six study arms) and meningioma risk (pooled RR = 1.48, 95%CI: 1.28–1.71, seven arms). In males, overweight/obesity status correlated with increased meningioma risk (pooled RR = 1.58, 95%CI: 1.22–2.04, nine study arms), whereas the respective association with overall brain/CNS tumor or glioma risk was not statistically significant. Dose-response meta-regression analysis further validated the findings.Conclusion
Our findings highlight obesity as a risk factor for overall brain/CNS tumors, meningiomas and gliomas among females, as well as for meningiomas among males. 相似文献6.
Xinwei Shi Hao Liu Jing Cao Qing Liu Guiju Tang Wanlu Liu Haiyi Liu Dongrui Deng Fuyuan Qiao Yuanyuan Wu 《PloS one》2015,10(8)
Objective
Extravillous trophoblast (EVT) cells invade the endometrium and the maternal spiral arterioles during the first trimester. Mammary Serine Protease Inhibitor (Maspin, SERPINB5) plays a putative role in regulating the invasive activity of cytotrophoblasts. The maspin gene is silenced in various cancers by an epigenetic mechanism that involves aberrant cytosine methylation. We investigated the effect of the methylation status of the maspin promoter on the maspin expression and the aggressiveness of EVT cells.Methods
Western blotting was used to detect the maspin protein expression in EVT cells upon hypoxia. The proliferative ability, the apoptosis rate and the migration and invasiveness were measured with Cell Counting Kit-8 assay, Flow Cytometry technology and Transwell methods. Subsequently, we treated cells with recombinant maspin protein. The methylation degree of maspin promoter region upon hypoxia/ decitabine was detected by bisulfite sequencing PCR and methylation-specific PCR. Finally, we explored the effects of decitabine on maspin protein expression and the aggressiveness of EVT cells.Results
Hypoxia effectively increased maspin protein expression in EVT cells and significantly inhibited their aggressiveness. The addition of recombinant maspin protein inhibited this aggressiveness. Decitabine reduced the methylation in the maspin promoter region and effectively increased the maspin protein expression, which significantly weakened the migration and invasiveness of EVT cells.Discussion
The methylation status of the maspin promoter is an important factor that affects the migration and invasion of EVT cells during early pregnancy. A decrease in the methylation status can inhibit the migration and invasion of EVT cells to affect placentation and can result in the ischemia and hypoxia of placenta. 相似文献7.
Fomchenko EI Dougherty JD Helmy KY Katz AM Pietras A Brennan C Huse JT Milosevic A Holland EC 《PloS one》2011,6(7):e20605
Background
Gliomas are thought to form by clonal expansion from a single cell-of-origin, and progression-associated mutations to occur in its progeny cells. Glioma progression is associated with elevated growth factor signaling and loss of function of tumor suppressors Ink4a, Arf and Pten. Yet, gliomas are cellularly heterogeneous; they recruit and trap normal cells during infiltration.Methodology/Principal Findings
We performed lineage tracing in a retrovirally mediated, molecularly and histologically accurate mouse model of hPDGFb-driven gliomagenesis. We were able to distinguish cells in the tumor that were derived from the cell-of-origin from those that were not. Phenotypic, tumorigenic and expression analyses were performed on both populations of these cells. Here we show that during progression of hPDGFb-induced murine gliomas, tumor suppressor loss can expand the recruited cell population not derived from the cell-of-origin within glioma microenvironment to dominate regions of the tumor, with essentially no contribution from the progeny of glioma cell-of-origin. Moreover, the recruited cells can give rise to gliomas upon transplantation and passaging, acquire polysomal expression profiles and genetic aberrations typically present in glioma cells rather than normal progenitors, aid progeny cells in glioma initiation upon transplantation, and become independent of PDGFR signaling.Conclusions/Significance
These results indicate that non-cell-of-origin derived cells within glioma environment in the mouse can be corrupted to become bona fide tumor, and deviate from the generally established view of gliomagenesis. 相似文献8.
Qingbin Li Baoshi Chen Jinquan Cai Ying Sun Guangzhi Wang Yongli Li Ruiyan Li Yan Feng Bo Han Jianlong Li Yu Tian Liye Yi Chuanlu Jiang 《PloS one》2016,11(3)
Background
Glioblastoma multiform (GBM) is the most common malignant primary brain tumor in adults. Radiotherapy plus concomitant and adjuvant TMZ chemotherapy is the current standard of care for patients with GBM. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, are key modulators of tumor invasion and metastasis due to their ECM degradation capacity. The aim of the present study was to identify the most informative MMP member in terms of prognostic and predictive ability for patients with primary GBM.Method
The mRNA expression profiles of all MMP genes were obtained from the Chinese Glioma Genome Atlas (CGGA), the Repository for Molecular Brain Neoplasia Data (REMBRANDT) and the dataset. MGMT methylation status was also examined by pyrosequencing. The correlation of MMP9 expression with tumor progression was explored in glioma specimens of all grades. Kaplan–Meier analysis and Cox proportional hazards regression models were used to investigate the association of MMP9 expression with survival and response to temozolomide. GSE16011Results
MMP9 was the only significant prognostic factor in three datasets for primary glioblastoma patients. Our results indicated that MMP9 expression is correlated with glioma grade (p<0.0001). Additionally, low expression of MMP9 was correlated with better survival outcome (OS: p = 0.0012 and PFS: p = 0.0066), and MMP9 was an independent prognostic factor in primary GBM (OS: p = 0.027 and PFS: p = 0.032). Additionally, the GBM patients with low MMP9 expression benefited from temozolomide (TMZ) chemotherapy regardless of the MGMT methylation status.Conclusions
Patients with primary GBMs with low MMP9 expression may have longer survival and may benefit from temozolomide chemotherapy. 相似文献9.
Li-Nien Chien Quinn T. Ostrom Haley Gittleman Jia-Wei Lin Andrew E. Sloan Gene H. Barnett J. Bradley Elder Christopher McPherson Ronald Warnick Yung-Hsiao Chiang Chieh-Min Lin Lisa R. Rogers Hung-Yi Chiou Jill S. Barnholtz-Sloan 《PloS one》2015,10(6)
Background
High grade gliomas are the most common type of malignant brain tumor, and despite their rarity, cause significant morbidity and mortality. This study aimed to compare the treatment patterns of high grade glioma to examine survival patterns in patients who receive specific treatments between cohorts in Ohio and Taiwan.Method
Patients aged 18 years and older at age of diagnosis with World Health Organization (WHO) grade III or IV astrocytoma from 2007-2012 were selected from the Ohio Brain Tumor Study and the Taiwan Cancer Registry. The treatment information was derived from medical chart reviews in Ohio and National Health Insurance Research Data in Taiwan. Treatment examined included surgical procedure (brain biopsy and/or resection), radiotherapy (radiation and/or radiosurgery), and alkylating chemotherapy. Kaplan-Meier and parametric survival models were used to examine the effect of treatment on survival, adjusted for age, sex, and comorbidities.Results
294 patients in Ohio and 1,097 patients in Taiwan met the inclusion criteria. 70.3% patients in Ohio and 51.4% in Taiwan received surgical resection, followed by concurrent chemoradiation. Patients who received this treatment had the highest survival rate, with a 1-year survival rate of 72.8% in Ohio and 73.4% in Taiwan. Patients who did not receive surgical resection, followed by concurrent chemoradiation had an increased risk of death (hazard ratio of 5.03 [95% confidence interval (CI): 3.61-7.02] in Ohio and 1.49 [95% CI: 1.31-1.71] in Taiwan) after adjustment for age, sex, and comorbidities.Conclusion
Surgical resection followed by concurrent chemoradiation was associated with higher survival rate of patients with high grade glioma in both Ohio and Taiwan; however, one-third of patients in Ohio and half in Taiwan did not receive this treatment. 相似文献10.
Background
Glioblastoma Multiforme (GBM) is the most lethal form of brain tumor. Efficient DNA repair and anti-apoptotic mechanisms are making glioma treatment difficult. Proteases such as MMP9, cathepsin B and urokinase plasminogen activator receptor (uPAR) are over expressed in gliomas and contribute to enhanced cancer cell proliferation. Non-homologous end joining (NHEJ) repair mechanism plays a major role in double strand break (DSB) repair in mammalian cells.Methodology/Principal Findings
Here we show that silencing MMP9 in combination with uPAR/cathepsin B effects NHEJ repair machinery. Expression of DNA PKcs and Ku70/80 at both mRNA and protein levels in MMP9-uPAR (pMU) and MMP9-cathepsin B (pMC) shRNA-treated glioma xenograft cells were reduced. FACS analysis showed an increase in apoptotic peak and proliferation assays revealed a significant reduction in the cell population in pMU- and pMC-treated cells compared to untreated cells. We hypothesized that reduced NHEJ repair led to DSBs accumulation in pMU- and pMC-treated cells, thereby initiating cell death. This hypothesis was confirmed by reduced Ku70/Ku80 protein binding to DSB, increased comet tail length and elevated γH2AX expression in treated cells compared to control. Immunoprecipitation analysis showed that EGFR-mediated lowered DNA PK activity in treated cells compared to controls. Treatment with pMU and pMC shRNA reduced the expression of DNA PKcs and ATM, and elevated γH2AX levels in xenograft implanted nude mice. Glioma cells exposed to hypoxia and irradiation showed DSB accumulation and apoptosis after pMU and pMC treatments compared to respective controls.Conclusion/Significance
Our results suggest that pMU and pMC shRNA reduce glioma proliferation by DSB accumulation and increase apoptosis under normoxia, hypoxia and in combination with irradiation. Considering the radio- and chemo-resistant cancers favored by hypoxia, our study provides important therapeutic potential of MMP9, uPAR and cathepsin B shRNA in the treatment of glioma from clinical stand point. 相似文献11.
Eliene Bogaerts Femke Heindryckx Lindsey Devisscher Annelies Paridaens Yves-Paul Vandewynckel Anja Van den Bussche Xavier Verhelst Louis Libbrecht Leo A. van Grunsven Anja Geerts Hans Van Vlierberghe 《PloS one》2015,10(3)
Background & Aims
Expression of liver progenitor cell (LPC) characteristics has been proposed as a negative prognostic marker in primary liver tumors. Hypoxia has been linked to activation of the Notch pathway which is responsible for activation and proliferation of LPCs and hypoxia-induced LPC activation has been shown in hepatocellular carcinoma. Our aim was to elucidate the time-dependent effects of hypoxia on the LPC niche in hepatocellular carcinoma which could aid in determining a safe time frame for use of hypoxia inducing therapies.Methods
We used dimethyloxaloylglycine to mimic a hypoxic reaction in mice by stabilizing hypoxia-inducible factor 1 alpha at three distinct time points in diethylnitrosamine induced hepatocarcinogenesis. LPC, metastasis and Notch pathway markers were determined by quantitative PCR and (immune)histochemistry (heamatoxillin-eosin, reticulin, Sirius red and cytokeratin 19 staining).Results
Activating the hypoxia inducible pathway early in hepatocarcinogenesis resulted in an increased incidence of both cholangioma and hepatocellular lesions, associated with high expression of LPC, metastatic and Notch pathway markers. Adversely, activating the hypoxic response during tumor development resulted in decreased incidence of hepatocellular lesions and increased cholangioma incidence, with an unaltered gene expression profile of LPC-, Notch pathway- and metastatic markers. A hypoxic insult at advanced stages of hepatocarcinogenesis severely increased the expression of LPC characteristics, however without increased expression of actors of the Notch pathway and metastatic markers and minor changes in incidence of hepatocellular and cholangioma lesions.Conclusion
Our results indicate that increased hypoxia at the onset of tumor development has detrimental effects on tumor progression; patients with HCC developed in a background of fibrosis/cirrhosis might therefore represent a more difficult treatment group. In contrast, hypoxia during tumor development appears to favor tumor outcome, highlighting the importance of early detection. Finally, hypoxia in advanced stages resulted in increased expression of LPC characteristics indicating poor outcome. 相似文献12.
Zhen Li Zhou Tan Shiying Hao Bo Jin Xiaohong Deng Guang Hu Xiaodan Liu Jie Zhang Hua Jin Min Huang John T. Kanegaye Adriana H. Tremoulet Jane C. Burns Jianmin Wu Harvey J. Cohen Xuefeng B. Ling Emergency Medicine Kawasaki Disease Research Group 《PloS one》2016,11(2)
Objectives
Kawasaki disease (KD) is an acute pediatric vasculitis of infants and young children with unknown etiology and no specific laboratory-based test to identify. A specific molecular diagnostic test is urgently needed to support the clinical decision of proper medical intervention, preventing subsequent complications of coronary artery aneurysms. We used a simple and low-cost colorimetric sensor array to address the lack of a specific diagnostic test to differentiate KD from febrile control (FC) patients with similar rash/fever illnesses.Study Design
Demographic and clinical data were prospectively collected for subjects with KD and FCs under standard protocol. After screening using a genetic algorithm, eleven compounds including metalloporphyrins, pH indicators, redox indicators and solvatochromic dye categories, were selected from our chromatic compound library (n = 190) to construct a colorimetric sensor array for diagnosing KD. Quantitative color difference analysis led to a decision-tree-based KD diagnostic algorithm.Results
This KD sensing array allowed the identification of 94% of KD subjects (receiver operating characteristic [ROC] area under the curve [AUC] 0.981) in the training set (33 KD, 33 FC) and 94% of KD subjects (ROC AUC: 0.873) in the testing set (16 KD, 17 FC). Color difference maps reconstructed from the digital images of the sensing compounds demonstrated distinctive patterns differentiating KD from FC patients.Conclusions
The colorimetric sensor array, composed of common used chemical compounds, is an easily accessible, low-cost method to realize the discrimination of subjects with KD from other febrile illness. 相似文献13.
Sven R. Kantelhardt Wouter Caarls Anthony H. B. de Vries Guy M. Hagen Thomas M. Jovin Walter Schulz-Schaeffer Veit Rohde Alf Giese Donna J. Arndt-Jovin 《PloS one》2010,5(6)
Background
The current therapy of malignant gliomas is based on surgical resection, radio-chemotherapy and chemotherapy. Recent retrospective case-series have highlighted the significance of the extent of resection as a prognostic factor predicting the course of the disease. Complete resection in low-grade gliomas that show no MRI-enhanced images are especially difficult. The aim in this study was to develop a robust, specific, new fluorescent probe for glioma cells that is easy to apply to live tumor biopsies and could identify tumor cells from normal brain cells at all levels of magnification.Methodology/Principal Findings
In this investigation we employed brightly fluorescent, photostable quantum dots (QDs) to specifically target epidermal growth factor receptor (EGFR) that is upregulated in many gliomas. Living glioma and normal cells or tissue biopsies were incubated with QDs coupled to EGF and/or monoclonal antibodies against EGFR for 30 minutes, washed and imaged. The data include results from cell-culture, animal model and ex vivo human tumor biopsies of both low-grade and high-grade gliomas and show high probe specificity. Tumor cells could be visualized from the macroscopic to single cell level with contrast ratios as high as 1000: 1 compared to normal brain tissue.Conclusions/Significance
The ability of the targeted probes to clearly distinguish tumor cells in low-grade tumor biopsies, where no enhanced MRI image was obtained, demonstrates the great potential of the method. We propose that future application of specifically targeted fluorescent particles during surgery could allow intraoperative guidance for the removal of residual tumor cells from the resection cavity and thus increase patient survival. 相似文献14.
Minna M. Wieck Ryan G. Spurrier Daniel E. Levin Salvador Garcia Mojica Michael J. Hiatt Raghava Reddy Xiaogang Hou Sonia Navarro Jooeun Lee Amber Lundin Barbara Driscoll Tracy C. Grikscheit 《PloS one》2016,11(2)
Rationale
Neonatal respiratory distress syndrome is a restrictive lung disease characterized by surfactant deficiency. Decreased vascular endothelial growth factor (VEGF), which demonstrates important roles in angiogenesis and vasculogenesis, has been implicated in the pathogenesis of restrictive lung diseases. Current animal models investigating VEGF in the etiology and outcomes of RDS require premature delivery, hypoxia, anatomically or temporally limited inhibition, or other supplemental interventions. Consequently, little is known about the isolated effects of chronic VEGF inhibition, started at birth, on subsequent developing lung structure and function.Objectives
To determine whether inducible, mesenchyme-specific VEGF inhibition in the neonatal mouse lung results in long-term modulation of AECII and whole lung function.Methods
Triple transgenic mice expressing the soluble VEGF receptor sFlt-1 specifically in the mesenchyme (Dermo-1/rtTA/sFlt-1) were generated and compared to littermate controls at 3 months to determine the impact of neonatal downregulation of mesenchymal VEGF expression on lung structure, cell composition and function. Reduced tissue VEGF bioavailability has previously been demonstrated with this model.Measurements and Main Results
Triple transgenic mice demonstrated restrictive lung pathology. No differences in gross vascular development or protein levels of vascular endothelial markers was noted, but there was a significant decrease in perivascular smooth muscle and type I collagen. Mutants had decreased expression levels of surfactant protein C and hypoxia inducible factor 1-alpha without a difference in number of type II pneumocytes.Conclusions
These data show that mesenchyme-specific inhibition of VEGF in neonatal mice results in late restrictive disease, making this transgenic mouse a novel model for future investigations on the consequences of neonatal RDS and potential interventions. 相似文献15.
Background
Glioblastoma can be classified into four distinct molecular subtypes (Proneural, Neural, Classical and Mesenchymal), based on gene expression profiling. This study aimed to investigate the prevalence, clinicopathologic features and overall survival (OS) of the four molecular subtypes among all malignant gliomas.Methods
A total of 941 gene expression arrays with clinical data were obtained from the Rembrandt, and CGGA datasets. Molecular subtypes were predicted with a prediction analysis of microarray. GSE16011Results
Among 941 malignant gliomas, 32.73% were Proneural, 15.09% Neural, 19.77% Classical and 32.41% Mesenchymal. The Proneural and Neural subtypes occurred largely in low-grade gliomas, while the Classical and Mesenchymal subtypes were more frequent in high-grade gliomas. A survival analysis showed that the Proneural subtype displayed a good prognosis, Neural had an intermediate correlation with overall survival, Mesenchymal had a worse prognosis than Neural, and Classical had the worst clinical outcome. Furthermore, oligodendrocytomas were preferentially assigned to the Proneural subtype, while the Mesenchymal subtype included a higher percentage of astrocytomas, compared with oligodendrocytomas. Additionally, nearly all classical gliomas harbored EGFR amplifications. Classical anaplastic gliomas have similar clinical outcomes as their glioblastoma counterparts and should be treated more aggressively.Conclusions
Molecular subtypes exist stably in all histological malignant gliomas subtypes. This could be an important improvement to histological diagnoses for both prognosis evaluations and clinical outcome predictions. 相似文献16.
Jialiang Wang Hui Wang Zhizhong Li Qiulian Wu Justin D. Lathia Roger E. McLendon Anita B. Hjelmeland Jeremy N. Rich 《PloS one》2008,3(11)
Background
Malignant gliomas rank among the most lethal cancers. Gliomas display a striking cellular heterogeneity with a hierarchy of differentiation states. Recent studies support the existence of cancer stem cells in gliomas that are functionally defined by their capacity for extensive self-renewal and formation of secondary tumors that phenocopy the original tumors. As the c-Myc oncoprotein has recognized roles in normal stem cell biology, we hypothesized that c-Myc may contribute to cancer stem cell biology as these cells share characteristics with normal stem cells.Methodology/Principal Findings
Based on previous methods that we and others have employed, tumor cell populations were enriched or depleted for cancer stem cells using the stem cell marker CD133 (Prominin-1). We characterized c-Myc expression in matched tumor cell populations using real time PCR, immunoblotting, immunofluorescence and flow cytometry. Here we report that c-Myc is highly expressed in glioma cancer stem cells relative to non-stem glioma cells. To interrogate the significance of c-Myc expression in glioma cancer stem cells, we targeted its expression using lentivirally transduced short hairpin RNA (shRNA). Knockdown of c-Myc in glioma cancer stem cells reduced proliferation with concomitant cell cycle arrest in the G0/G1 phase and increased apoptosis. Non-stem glioma cells displayed limited dependence on c-Myc expression for survival and proliferation. Further, glioma cancer stem cells with decreased c-Myc levels failed to form neurospheres in vitro or tumors when xenotransplanted into the brains of immunocompromised mice.Conclusions/Significance
These findings support a central role of c-Myc in regulating proliferation and survival of glioma cancer stem cells. Targeting core stem cell pathways may offer improved therapeutic approaches for advanced cancers. 相似文献17.
Yong Yan Lei Zhang Tao Xu Jinxu Zhou Rong Qin Chao Chen Yongxiang Zou Da Fu Guohan Hu Juxiang Chen Yicheng Lu 《PloS one》2013,8(11)
Objectives
To study the expression pattern and prognostic significance of SAMSN1 in glioma.Methods
Affymetrix and Arrystar gene microarray data in the setting of glioma was analyzed to preliminarily study the expression pattern of SAMSN1 in glioma tissues, and Hieratical clustering of gene microarray data was performed to filter out genes that have prognostic value in malignant glioma. Survival analysis by Kaplan-Meier estimates stratified by SAMSN1 expression was then made based on the data of more than 500 GBM cases provided by The Cancer Genome Atlas (TCGA) project. At last, we detected the expression of SAMSN1 in large numbers of glioma and normal brain tissue samples using Tissue Microarray (TMA). Survival analysis by Kaplan-Meier estimates in each grade of glioma was stratified by SAMSN1 expression. Multivariate survival analysis was made by Cox proportional hazards regression models in corresponding groups of glioma.Results
With the expression data of SAMSN1 and 68 other genes, high-grade glioma could be classified into two groups with clearly different prognoses. Gene and large sample tissue microarrays showed high expression of SAMSN1 in glioma particularly in GBM. Survival analysis based on the TCGA GBM data matrix and TMA multi-grade glioma dataset found that SAMSN1 expression was closely related to the prognosis of GBM, either PFS or OS (P<0.05). Multivariate survival analysis with Cox proportional hazards regression models confirmed that high expression of SAMSN1 was a strong risk factor for PFS and OS of GBM patients.Conclusion
SAMSN1 is over-expressed in glioma as compared with that found in normal brains, especially in GBM. High expression of SAMSN1 is a significant risk factor for the progression free and overall survival of GBM. 相似文献18.
Object
Our objective was to explore the protective effects of hypoxic preconditioning on induced Schwann cells exposed to an environment with low concentrations of oxygen. It has been observed that hypoxic preconditioning of induced Schwann cells can promote axonal regeneration under low oxygen conditions.Method
Rat bone marrow mesenchymal stem cells (MSCs) were differentiated into Schwann cells and divided into a normal oxygen control group, a hypoxia-preconditioning group and a hypoxia group. The ultrastructure of each of these groups of cells was observed by electron microscopy. In addition, flow cytometry was used to measure changes in mitochondrial membrane potential. Annexin V-FITC/PI staining was used to detect apoptosis, and Western blots were used to detect the expression of Bcl-2/Bax. Fluorescence microscopic observations of axonal growth in NG-108 cells under hypoxic conditions were also performed.Results
The hypoxia-preconditioning group maintained mitochondrial cell membrane and crista integrity, and these cells exhibited less edema than the hypoxia group. In addition, the cells in the hypoxia-preconditioning group were found to be in early stages of apoptosis, whereas cells from the hypoxia group were in the later stages of apoptosis. The hypoxia-preconditioning group also had higher levels of Bcl-2/Bax expression and longer NG-108 cell axons than were observed in the hypoxia group.Conclusion
Hypoxic preconditioning can improve the physiological state of Schwann cells in a severe hypoxia environment and improve the ability to promote neurite outgrowth. 相似文献19.
Weibei Dou Mingyu Zhang Xiaojie Zhang Yuan Li Hongyan Chen Shaowu Li Min Lu Jianping Dai Jean-Marc Constans 《PloS one》2015,10(9)