bluuebunny/crossref_metadata_2025_split huggingface dataset:
Susceptible Stages in Schwann Cells for NF1-Associated Plexiform Neurofibroma Development
Authors: Le Lu Q. , Liu Chiachi , Shipman Tracey , Chen Zhiguo , Suter Ueli , Parada Luis F. 
Published: May 2011

AbstractStem cells are under strict regulation by both intrinsic factors and the microenvironment. There is increasing evidence that many cancers initiate through acquisition of genetic mutations (loss of intrinsic control) in stem cells or their progenitors, followed by alterations of the surrounding microenvironment (loss of extrinsic control). In neurofibromatosis type 1 (NF1), deregulation of Ras signaling results in development of multiple neurofibromas, complex tumors of the peripheral nerves. Neurofibromas arise from the Schwann cell lineage following loss of function at the NF1 locus, which initiates a cascade of interactions with other cell types in the microenvironment and additional cell autonomous modifications. In this study, we sought to identify whether a temporal “window of opportunity” exists during which cells of the Schwann cell lineage can give rise to neurofibromas following loss of NF1. We showed that acute loss of NF1 in both embryonic and adult Schwann cells can lead to neurofibroma formation. However, the embryonic period when Schwann cell precursors and immature Schwann cells are most abundant coincides with enhanced susceptibility to plexiform neurofibroma tumorigenesis. This model has important implications for understanding early cellular events that dictate neurofibroma development, as well as for the development of novel therapies targeting these tumors. Cancer Res; 71(13); 4686–95. ©2011 AACR.
Association of CHFR Promoter Methylation with Disease Recurrence in Locally Advanced Colon Cancer
Authors: Tanaka Motofumi , Chang Ping , Li Yanan , Li Donghui , Overman Michael , Maru Dipen M. , Sethi Salil , Phillips Jonathan , Bland Gail L. , Abbruzzese James L. , Eng Cathy 
Published: May 2011

Abstract
Purpose: This study was designed to determine whether DNA methylation biomarkers are associated with recurrence and survival in colon cancer patients.
Experimental Design: A retrospective analysis of 82 patients who received curative surgical resection for American Joint Committee on Cancer (AJCC) high-risk stage II or III colon cancer (1999–2007) was conducted. DNA methylation status was quantitatively evaluated by the pyrosequencing method. We preselected three tumor suppressor genes and one locus of interest; CHFR, ID4, RECK, and MINT1. Mean methylation levels of multiple CpG sites in the promoter regions were used for analysis; 15% or more was defined as methylation positive. The association of recurrence-free survival (RFS) and overall survival (OS) with methylation status was analyzed by the log-rank test, Kaplan–Meier method, and Cox proportional hazards model.
Results: Methylation levels of ID4, MINT1, and RECK did not correlate with RFS or OS. CHFR was methylation positive in 63% patients. When methylation status was dichotomized (negative or low: &lt;30%, high: ≥30%), patients with CHFR methylation-high (44%) had worse RFS (P = 0.006) and reduced OS (P = 0.069). When stratified by stage, CHFR methylation-high was associated with reduced RFS (P = 0.004) and OS (P = 0.010) in stage III patients. CHFR methylation-high was commonly associated with N2 disease (P = 0.04) and proximal tumors (P = 0.002). Multivariate analysis indicated AJCC T4 disease and CHFR methylation-high (P = 0.001 and P = 0.015, respectively) were independent predictors for recurrence.
Conclusions: The extent of CHFR promoter methylation correlates with RFS, indicating it is a promising epigenetic marker for recurrence. Clin Cancer Res; 17(13); 4531–40. ©2011 AACR.
Foretinib (GSK1363089), an Orally Available Multikinase Inhibitor of c-Met and VEGFR-2, Blocks Proliferation, Induces Anoikis, and Impairs Ovarian Cancer Metastasis
Authors: Zillhardt Marion , Park Sun-Mi , Romero Iris L. , Sawada Kenjiro , Montag Anthony , Krausz Thomas , Yamada S. Diane , Peter Marcus E. , Lengyel Ernst 
Published: May 2011

Abstract
Purpose: Currently, there are no approved targeted therapies for the treatment of ovarian cancer, despite the fact that it is the most lethal gynecological malignancy. One proposed target is c-Met, which has been shown to be an important prognostic indicator in a number of malignancies, including ovarian cancer. The objective of this study was to determine whether an orally available multikinase inhibitor of c-Met and vascular endothelial growth factor receptor-2 (foretinib, GSK1363089) blocks ovarian cancer growth.
Experimental Design: The effect of foretinib was tested in a genetic mouse model of endometrioid ovarian cancer, several ovarian cancer cell lines, and an organotypic 3D model of the human omentum.
Results: In the genetic mouse model, treatment with foretinib prevented the progression of primary tumors to invasive adenocarcinoma. Invasion through the basement membrane was completely blocked in treated mice, whereas in control mice, invasive tumors entirely replaced the normal ovary. In 2 xenograft mouse models using human ovarian cancer cell lines, the inhibitor reduced overall tumor burden (86% inhibition, P &lt; 0.0001) and metastasis (67% inhibition, P &lt; 0.0001). The mechanism of inhibition by foretinib involved (a) inhibition of c-Met activation and downstream signaling, (b) reduction of ovarian cancer cell adhesion, (c) a block in migration and invasion, (d) reduced proliferation mediated by a G2–M cell-cycle arrest, and (e) induction of anoikis.
Conclusions: This study shows that foretinib blocks tumorigenesis and reduces invasive tumor growth in different models of ovarian cancer by affecting several critical tumor functions. We believe that it provides a rationale for the further clinical development of foretinib for the treatment of ovarian cancer. Clin Cancer Res; 17(12); 4042–51. ©2011 AACR.
E7080 Suppresses Hematogenous Multiple Organ Metastases of Lung Cancer Cells with Nonmutated Epidermal Growth Factor Receptor
Authors: Ogino Hirokazu , Hanibuchi Masaki , Kakiuchi Soji , Trung Van The , Goto Hisatsugu , Ikuta Kenji , Yamada Tadaaki , Uehara Hisanori , Tsuruoka Akihiko , Uenaka Toshimitsu , Wang Wei , Li Qi , Takeuchi Shinji , Yano Seiji , Nishioka Yasuhiko , Sone Saburo 
Published: May 2011

Abstract
While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors improve the prognosis of patients with EGFR mutant lung cancer, the prognosis of patients with nonmutant EGFR lung cancer, especially those with metastases, is still extremely poor. We have assessed the therapeutic efficacy of E7080, an orally available inhibitor of multiple tyrosine kinases including VEGF receptor 2 (VEGFR-2) and VEGFR-3, in experimental multiple organ metastasis of lung cancer cell lines without EGFR mutations. E7080 markedly inhibited the in vitro proliferation of VEGF-stimulated microvascular endothelial cells. Intravenous inoculation into natural killer cell–depleted severe combined immunodeficient mice of the small cell lung cancer cell lines H1048 (producing low amounts of VEGF) and SBC-5 (producing intermediate amounts of VEGF) resulted in hematogenous metastases into multiple organs, including the liver, lungs, kidneys, and bones, whereas intravenous inoculation of PC14PE6, a non–small cell lung cancer cell line producing high amounts of VEGF, resulted in lung metastases followed by massive pleural effusion. Daily treatment with E7080 started after the establishment of micrometastases significantly reduced the number of large (&gt;2 mm) metastatic nodules and the amount of pleural effusion, and prolonged mouse survival. Histologically, E7080 treatment reduced the numbers of endothelial and lymph endothelial cells and proliferating tumor cells and increased the number of apoptotic cells in metastatic nodules. These results suggest that E7080 has antiangiogenic and antilymphangiogenic activity and may be of potential therapeutic value in patients with nonmutant EGFR lung cancer and multiple organ metastases. Mol Cancer Ther; 10(7); 1218–28. ©2011 AACR.
Sorafenib Enhances the Antitumor Effects of Chemoradiation Treatment by Downregulating ERCC-1 and XRCC-1 DNA Repair Proteins
Authors: Yadav Arti , Kumar Bhavna , Teknos Theodoros N. , Kumar Pawan 
Published: May 2011

Abstract
Head and neck squamous cell carcinoma remains a challenging clinical problem because of the persisting high rate of local and distant failure due to the acquisition of chemo- and radioresistance. In this study, we examined if treatment with sorafenib, a potent inhibitor of Raf kinase and VEGF receptor, could reverse the resistant phenotype in tumor and tumor-associated endothelial cells, thereby enhancing the therapeutic efficacy of currently used chemoradiation treatment. We used both in vitro and in vivo models to test the efficacy of sorafenib either as a single agent or in combination with chemoradiation. Sorafenib, as a single agent, showed antitumor and angiogenesis properties, but the effects were more pronounced when used in combination with chemoradiation treatment. Sorafenib significantly enhanced the antiproliferative effects of chemoradiation treatment by downregulating DNA repair proteins (ERCC-1 and XRCC-1) in a dose-dependent manner. In addition, combination treatment significantly inhibited tumor cell colony formation, tumor cell migration, and tumor cell invasion. Combination treatment was also very effective in inhibiting VEGF-mediated angiogenesis in vitro. In a severe combined immunodeficient mouse xenograft model, combination treatment was very well tolerated and significantly inhibited tumor growth and tumor angiogenesis. Interestingly, following combination treatment, low-dose sorafenib treatment alone was highly effective as a maintenance regimen. Taken together, our results suggest a potentially novel strategy to use sorafenib to overcome chemo- and radioresistance in tumor and tumor-associated endothelial to enhance the effectiveness of the chemoradiation therapy. Mol Cancer Ther; 10(7); 1241–51. ©2011 AACR.
Chemotherapy Dosing Schedule Influences Drug Resistance Development in Ovarian Cancer
Authors: De Souza Raquel , Zahedi Payam , Badame Rose M. , Allen Christine , Piquette-Miller Micheline 
Published: May 2011

Abstract
Drug resistance leads to chemotherapy failure and is responsible for the death of a great majority of patients with metastatic, late-stage ovarian cancer. The present study addressed whether changes in the chemotherapy dosing schedule affect the development, further worsening, or circumvention of drug resistance in chemosensitive and chemoresistant ovarian cancer. Severe combined immunodeficient mice bearing HeyA8 and HeyA8-MDR xenografts were treated with docetaxel intermittently (1×/wk or 3×/wk) or continuously for 21 days. Tumor mRNA expression of genes implicated in docetaxel resistance was measured by quantitative real-time-PCR. Analyzed genes included those encoding for the drug efflux transporters mdr1 and mrp7 and for molecules that interfere with or overcome the effects of docetaxel, including β-tubulinIII, actinin4, stathmin1, bcl2, rpn2, thoredoxin, and akt2. In both models, continuous docetaxel resulted in greater antitumor efficacy than 1×/wk or 3×/wk dosing and did not induce upregulation of any analyzed genes. Once weekly dosing caused upregulation of various drug resistance–related genes, especially in chemoresistant xenografts. More frequent, 3×/wk dosing diminished this effect, although levels of various genes were higher than for continuous chemotherapy. Drug efflux transporter expression was further examined by Western blotting, confirming that intermittent, but not continuous, docetaxel induced significant upregulation. Overall, our results show that the presence and length of treatment-free intervals contribute to the development of drug resistance. Elimination of these intervals by continuous dosing resulted in superior antitumor efficacy and prevented drug resistance induction in chemosensitive and chemoresistant disease. These results encourage the clinical implementation of continuous chemotherapy to overcome and/or prevent drug resistance in newly diagnosed and recurrent, refractory ovarian cancer. Mol Cancer Ther; 10(7); 1289–99. ©2011 AACR.
Sarcomere Gene Mutations in Isolated Left Ventricular Noncompaction Cardiomyopathy Do Not Predict Clinical Phenotype
Authors: Probst Susanne , Oechslin Erwin , Schuler Pia , Greutmann Matthias , Boyé Philipp , Knirsch Walter , Berger Felix , Thierfelder Ludwig , Jenni Rolf , Klaassen Sabine 
Published: May 2011

Background—
Left ventricular noncompaction of the myocardium (LVNC) has been recognized as a cardiomyopathy with a genetic etiology. Mutations in genes encoding sarcomere proteins were shown to be associated with LVNC. We evaluated the potential clinical impact of genetic analysis of sarcomere genes in patients with LVNC.

Methods and Results—

We identified 5 mutations in cardiac myosin-binding protein C (
MYBPC3
) and 2 mutations in α-tropomyosin (
TPM1
) in a cohort of unrelated adult probands with isolated LVNC. The mutations in
MYBPC3
and
TPM1
and in 6 other previously reported sarcomere genes in this cohort resulted in a total of 18 (29%) heterozygous mutations in 63 probands. β-myosin heavy chain (
MYH7
) was the most prevalent disease gene and accounts for 13% of cases, followed by
MYBPC3
(8%). Comparing sarcomere mutation-positive and mutation-negative LVNC probands showed no significant differences in terms of average age, myocardial function, and presence of heart failure or tachyarrhythmias at initial presentation or at follow-up. Familial disease was found in 16 probands of whom 8 were sarcomere mutation positive. Nonpenetrance was detected in 2 of 8 mutation-positive families with LVNC.

Conclusions—
Mutations in sarcomere genes account for a significant (29%) proportion of cases of isolated LVNC in this cohort. The distribution of disease genes confirms genetic heterogeneity and opens new perspectives in genetic testing in patients with LVNC and their relatives at high risk of inheriting the cardiomyopathy. The presence or absence of a sarcomere gene mutation in LVNC cannot be related to the clinical phenotype.
Noninvasive Vascular Function Measurement in the Community
Authors: Schnabel Renate B. , Schulz Andreas , Wild Philipp S. , Sinning Christoph R. , Wilde Sandra , Eleftheriadis Medea , Herkenhoff Stephanie , Zeller Tanja , Lubos Edith , Lackner Karl J. , Warnholtz Ascan , Gori Tommaso , Blankenberg Stefan , Münzel Thomas 
Published: May 2011

Background—
Several methods of noninvasive vascular function testing have been suggested for cardiovascular risk screening in the community. A direct comparison of the different methods and their relation to classical cardiovascular risk factors in a large cohort is missing.

Methods and Results—

In 5000 individuals (mean age, 55.5±10.9 years; age range, 35 to 74 years; women, 49.2%) of the population-based Gutenberg Heart Study, we performed simultaneous measurement of flow-mediated dilation (FMD) and peripheral arterial volume pulse determined by infrared photo (reflection index) and pneumatic plethysmography (PAT) and explored their associations. All function measures were recorded at baseline and after reactive hyperemia induced by 5-minute brachial artery occlusion. Correlations between different measures of vascular function were statistically significant but moderate. The strongest association for hyperemic response variables was observed for PAT ratio and FMD (Spearman
r
=0.17; age- and sex-adjusted partial correlation, 0.068). Classical risk factors explained between 15.8% (baseline reflection index) and 58.4% (brachial artery diameter) of the baseline values but only accounted for 3.2% (reflection index), 15.4% (FMD), and 13.9% (PAT ratio) of the variability of reflective hyperemic response. Regression models varied in their relations to classical risk factors for the individual vascular function measures. Consistently associated with different vascular function methods were age, sex, body mass index, and indicators of hypertension. Peripheral tonometry also showed a relation to fasting glucose concentrations.

Conclusions—
Noninvasive measures of conduit artery and peripheral arterial function are modestly correlated, differ in their relation to classical cardiovascular risk factors, and may thus reflect different pathologies.
Latitudinal prevalence gradient of multiple sclerosis in Latin America
Authors: Risco J , Maldonado H , Luna L , Osada J , Ruiz P , Juarez A , Vizcarra D 
Published: May 2011

Background: Multiple sclerosis (MS) has a unique geographical distribution that reflects both genetic and environmental factors. Many studies have shown a positive correlation between MS frequency and latitude across both large and small geographical regions. However, scarce data have been published on the epidemiology of MS in Latin America and no study has evaluated latitudinal variation. Objective: To evaluate the effect of latitude on MS prevalence in Latin America. Methods: We conducted a systematic review of MS prevalence during January 2011. Prevalence rates were collected from eligible publications. The effect of latitude on prevalence was analyzed using linear regression. Results: A total of ten studies were eligible for analysis, corresponding to six countries, spanning from Panama to Argentina. The crude prevalence of MS ranged from 0.75 to 21.5 per 100,000. We found a strong and significant association between prevalence and latitude ( r2 0.8; p < 0.001) and determined an increase in prevalence of 0.33 per 100,000 per degree latitude. Conclusion: Our findings suggest a latitudinal prevalence gradient of MS in Latin American countries between Panama and Argentina.
Risk prediction of incident coronary heart disease in the Netherlands: re-estimation and improvement of the SCORE risk function
Authors: Merry Audrey HH , Boer Jolanda MA , Schouten Leo J , Ambergen Ton , Steyerberg Ewout W , Feskens Edith JM , Verschuren WM Monique , Gorgels Anton PM , van den Brandt Piet A 
Published: May 2011

Aims: To re-estimate the SCORE risk function using individual data on risk factors and coronary heart disease (CHD) incidence from the Dutch Cardiovascular Registry Maastricht (CAREMA) population-based cohort study; to evaluate changes that may improve risk prediction after re-estimation; and to compare the performance of the resulting CAREMA risk function with that of existing risk scores. Methods and results: The cohort consisted of 21,148 participants, born in 1927–1977 and randomly sampled from the Maastricht region in 1987–1997. After follow-up (median 10.9 years), 783 incident CHD cases occurred. Model performance was assessed by discrimination and calibration. The additional value of including other risk factors or current risk factors in a different manner was evaluated using the net reclassification index (NRI). The c statistic of the re-estimated SCORE model was 0.799 (95% CI 0.782–0.816). Separating the total/high-density lipoprotein (HDL) cholesterol ratio into total and HDL cholesterol levels did not improve the c statistic ( p = 0.22), but reclassified 6.0% of the participants into a more appropriate risk category ( p < 0.001) compared with the re-estimated model. The resulting CAREMA function reclassified 28% of the participants into a more appropriate risk category than the Framingham score. Compared with the SCORE functions for high- and low-risk regions, the NRIs were 28% and 35%, respectively, which can largely be explained by the difference in outcome definition (CHD incidence vs. CHD mortality). Conclusion: In this Dutch population, a re-estimated SCORE function with total and HDL cholesterol levels instead of the cholesterol ratio can be used for the risk prediction of CHD incidence.
The RacGAP ArhGAP15 is a master negative regulator of neutrophil functions
Authors: Costa Carlotta , Germena Giulia , Martin-Conte Erica L. , Molineris Ivan , Bosco Eleonora , Marengo Stefano , Azzolino Ornella , Altruda Fiorella , Ranieri V. Marco , Hirsch Emilio 
Published: May 2011

AbstractIn phagocytes, GTPases of the Rac family control crucial antimicrobial functions. The RacGAP ArhGAP15 negatively modulates Rac activity in leukocytes, but its in vivo role in innate immunity remains largely unknown. Here we show that neutrophils and macrophages derived from mice lacking ArhGAP15 presented higher Rac activity but distinct phenotypes. In macrophages, the loss of ArhGAP15 induced increased cellular elongation and membrane protrusions but did not modify chemotactic responses. Conversely, the lack of ArhGAP15 in neutrophils affected critical Rac-dependent antimicrobial functions, specifically causing enhanced chemotactic responses, straighter directional migration, amplified reactive oxygen species production, increased phagocytosis, and improved bacterial killing. In vivo, in a model of severe abdominal sepsis, these effects contributed to increase neutrophil recruitment to the site of infection, thereby limiting bacterial growth, controlling infection spread, reducing systemic inflammation, and ultimately improving survival in ArhGAP15-null mice. Altogether, these results demonstrate the relevance of ArhGAP15 in the selective regulation of multiple neutrophil functions, suggesting that ArhGAP15 targeting might be beneficial in specific pathologic settings like severe sepsis.
Modulation of microRNA expression in human T-cell development: targeting of NOTCH3 by miR-150
Authors: Ghisi Margherita , Corradin Alberto , Basso Katia , Frasson Chiara , Serafin Valentina , Mukherjee Subhamoy , Mussolin Lara , Ruggero Katia , Bonanno Laura , Guffanti Alessandro , De Bellis Gianluca , Gerosa Gino , Stellin Giovanni , D'Agostino Donna M. , Basso Giuseppe , Bronte Vincenzo , Indraccolo Stefano , Amadori Alberto , Zanovello Paola 
Published: May 2011

Abstract
Ontogenesis of T cells in the thymus is a complex process whose molecular control is poorly understood. The present study investigated microRNAs involved in human thymocyte differentiation by comparing the microRNA expression profiles of thymocytes at the double-positive, single-positive CD4+ and single-positive CD8+ maturation stages. Microarray analysis showed that each thymocyte population displays a distinct microRNA expression profile that reflects their developmental relationships. Moreover, analysis of small-RNA libraries generated from human unsorted and double-positive thymocytes and from mature peripheral CD4+ and CD8+ T lymphocytes, together with the microarray data, indicated a trend toward up-regulation of microRNA expression during T-cell maturation after the double-positive stage and revealed a group of microRNAs regulated during normal T-cell development, including miR-150, which is strongly up-regulated as maturation progresses. We showed that miR-150 targets NOTCH3, a member of the Notch receptor family that plays important roles both in T-cell differentiation and leukemogenesis. Forced expression of miR-150 reduces NOTCH3 levels in T-cell lines and has adverse effects on their proliferation and survival. Overall, these findings suggest that control of the Notch pathway through miR-150 may have an important impact on T-cell development and physiology.