bluuebunny/crossref_metadata_2025_split huggingface dataset:
miR-124 Inhibits STAT3 Signaling to Enhance T Cell–Mediated Immune Clearance of Glioma
Authors: Wei Jun , Wang Fei , Kong Ling-Yuan , Xu Shuo , Doucette Tiffany , Ferguson Sherise D. , Yang Yuhui , McEnery Kayla , Jethwa Krishan , Gjyshi Olsi , Qiao Wei , Levine Nicholas B. , Lang Frederick F. , Rao Ganesh , Fuller Gregory N. , Calin George A. , Heimberger Amy B. 
Published: May 2013

Abstract
miRNAs (miR) have been shown to modulate critical gene transcripts involved in tumorigenesis, but their role in tumor-mediated immunosuppression is largely unknown. On the basis of miRNA gene expression in gliomas using tissue microarrays, in situ hybridization, and molecular modeling, miR-124 was identified as a lead candidate for modulating STAT3 signaling, a key pathway mediating immunosuppression in the tumor microenvironment. miR-124 is absent in all grades and pathologic types of gliomas. Upon upregulating miR-124 in glioma cancer stem cells (gCSC), the STAT3 pathway was inhibited, and miR-124 reversed gCSC-mediated immunosuppression of T-cell proliferation and induction of forkhead box P3 (Foxp3)+ regulatory T cells (Treg). Treatment of T cells from immunosuppressed glioblastoma patients with miR-124 induced marked effector response including upregulation of interleukin (IL)-2, IFN-γ, and TNF-α. Both systemic administration of miR-124 or adoptive miR-124–transfected T-cell transfers exerted potent anti-glioma therapeutic effects in clonotypic and genetically engineered murine models of glioblastoma and enhanced effector responses in the local tumor microenvironment. These therapeutic effects were ablated in both CD4+- and CD8+-depleted mice and nude mouse systems, indicating that the therapeutic effect of miR-124 depends on the presence of a T-cell–mediated antitumor immune response. Our findings highlight the potential application of miR-124 as a novel immunotherapeutic agent for neoplasms and serve as a model for identifying miRNAs that can be exploited as immunotherapeutics. Cancer Res; 73(13); 3913–26. ©2013 AACR.
Targeting the CD20 and CXCR4 Pathways in Non-Hodgkin Lymphoma with Rituximab and High-Affinity CXCR4 Antagonist BKT140
Authors: Beider Katia , Ribakovsky Elena , Abraham Michal , Wald Hanna , Weiss Lola , Rosenberg Evgenia , Galun Eithan , Avigdor Abraham , Eizenberg Orly , Peled Amnon , Nagler Arnon 
Published: May 2013

AbstractPurpose: Chemokine axis CXCR4/CXCL12 is critically involved in the survival and trafficking of normal and malignant B lymphocytes. Here, we investigated the effect of high-affinity CXCR4 antagonist BKT140 on lymphoma cell growth and rituximab-induced cytotoxicity in vitro and in vivo.Experimental Design: In vitro efficacy of BKT140 alone or in combination with rituximab was determined in non-Hodgkin lymphoma (NHL) cell lines and primary samples from bone marrow aspirates of patients with NHL. In vivo efficacy was evaluated in xenograft models of localized and disseminated NHL with bone marrow involvement.Results: Antagonizing CXCR4 with BKT140 resulted in significant inhibition of CD20+ lymphoma cell growth and in the induction of cell death, respectively. Combination of BKT140 with rituximab significantly enhanced the apoptosis against the lymphoma cells in a dose-dependent manner. Moreover, rituximab induced CXCR4 expression in lymphoma cell lines and primary lymphoma cells, suggesting the possible interaction between CD20 and CXCR4 pathways in NHL. Primary bone marrow stromal cells (BMSC) further increased CXCR4 expression and protected NHL cells from rituximab-induced apoptosis, whereas BKT140 abrogated this protective effect. Furthermore, BKT140 showed efficient antilymphoma activity in vivo in the xenograft model of disseminated NHL with bone marrow involvement. BKT140 treatment inhibited the local tumor progression and significantly reduced the number of NHL cells in the bone marrow. Combined treatment of BKT140 with rituximab further decreased the number of viable lymphoma cells in the bone marrow, achieving 93% reduction.Conclusions: These findings suggest the possible role of CXCR4 in NHL progression and response to rituximab and provide the scientific basis for the development of novel CXCR4-targeted therapies for refractory NHL. Clin Cancer Res; 19(13); 3495–507. ©2013 AACR.
Triptolide Induces the Expression of miR-142-3p: A Negative Regulator of Heat Shock Protein 70 and Pancreatic Cancer Cell Proliferation
Authors: MacKenzie Tiffany N. , Mujumdar Nameeta , Banerjee Sulagna , Sangwan Veena , Sarver Aaron , Vickers Selwyn , Subramanian Subbaya , Saluja Ashok K. 
Published: May 2013

Abstract
Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest malignancies, is resistant to current chemotherapies. We previously showed that triptolide inhibits PDAC cell growth in vitro and blocks metastatic spread in vivo. Triptolide downregulates HSP70, a molecular chaperone upregulated in several tumor types. This study investigates the mechanism by which triptolide inhibits HSP70. Because microRNAs (miRNA) are becoming increasingly recognized as negative regulators of gene expression, we tested whether triptolide regulates HSP70 via miRNAs. Here, we show that triptolide as well as quercetin, but not gemcitabine, upregulated miR-142-3p in PDAC cells (MIA PaCa-2, Capan-1, and S2-013). Ectopic expression of miR-142-3p inhibited cell proliferation, measured by electric cell-substrate impedance sensing, and decreased HSP70 expression, measured by real-time PCR and immunoblotting, compared with controls. We showed that miR-142-3p directly binds to the 3′UTR of HSP70, and that this interaction is important as HSP70 overexpression rescued miR–142-3p-induced cell death. We found that miR–142-3p regulates HSP70 independently of heat shock factor 1. Furthermore, Minnelide, a water-soluble prodrug of triptolide, induced the expression of miR-142-3p in vivo. This is the first description of an miRNA-mediated mechanism of HSP70 regulation in cancer, making miR-142-3p an attractive target for PDAC therapeutic intervention. Mol Cancer Ther; 12(7); 1266–75. ©2013 AACR.
Impact of Tumor Vascularity on Responsiveness to Antiangiogenesis in a Prostate Cancer Stem Cell-Derived Tumor Model
Authors: Zhang Kexiong , Waxman David J. 
Published: May 2013

Abstract
Drugs that target the tumor vasculature and inhibit angiogenesis are widely used for cancer treatment. Individual tumors show large differences in vascularity, but it is uncertain how these differences affect responsiveness to antiangiogenesis. We investigated this question using two closely related prostate cancer models that differ markedly in tumor vascularity: PC3, which has very low vascularity, and the PC3-derived cancer stem-like cell holoclone PC3/2G7, which forms tumors with high microvessel density, high tumor blood flow, and low hypoxia compared with parental PC3 tumors. Three angiogenesis inhibitors (axitinib, sorafenib, and DC101) all induced significantly greater decreases in tumor blood flow and microvessel density in PC3/2G7 tumors compared with PC3 tumors, as well as significantly greater decreases in tumor cell proliferation and cell viability and a greater increase in apoptosis. The increased sensitivity of PC3/2G7 tumors to antiangiogenesis indicates they are less tolerant of low vascularity and suggests they become addicted to their oxygen- and nutrient-rich environment. PC3/2G7 tumors showed strong upregulation of the proangiogenic factors chemokine ligand 2 (CCL2) and VEGFA compared with PC3 tumors, which may contribute to their increased vascularity, and they have significantly lower endothelial cell pericyte coverage, which may contribute to their greater sensitivity to antiangiogenesis. Interestingly, high levels of VEGF receptor-2 were expressed on PC3 but not PC3/2G7 tumor cells, which may contribute to the growth static response of PC3 tumors to VEGF-targeted antiangiogenesis. Finally, prolonged antiangiogenic treatment led to resumption of PC3/2G7 tumor growth and neovascularization, indicating these cancer stem-like cell-derived tumors can adapt and escape from antiangiogenesis. Mol Cancer Ther; 12(5); 787–98. ©2013 AACR.
Bowman Birk Inhibitor Concentrate and Oral Leukoplakia: A Randomized Phase IIb Trial
Authors: Armstrong William B. , Taylor Thomas H. , Kennedy Ann R. , Melrose Raymond J. , Messadi Diana V. , Gu Mai , Le Anh D. , Perloff Marjorie , Civantos Francisco , Goodwin William Jarrard , Wirth Lori J. , Kerr Alexander Ross , Meyskens Frank L. 
Published: May 2013

Abstract
Oral premalignancy serves as an ideal model for study of chemopreventive agents. Although 13-cis-retinoic acid showed reversal of oral premalignancy, toxicity, and reversal of clinical response after cessation of therapy obviated its widespread use. A search for nontoxic agents with cancer preventive activity led us to evaluate Bowman Birk Inhibitor (BBI) formulated as BBI Concentrate (BBIC). We previously reported encouraging results in a phase IIa trial of BBIC in patients with oral leukoplakia with measurable clinical responses and favorable biomarker changes. On the basis of these results, we undertook a randomized, placebo controlled phase IIb trial with patients receiving BBIC or placebo for 6 months, with assessment of clinical response and change in lesion area as primary end point and an intent-to-treat analysis. One hundred and thirty two subjects were randomized; and 89 subjects completed six months on study drug or placebo. Both placebo and BBIC showed a statistically significant decrease in mean lesion area of 17.1% and 20.6%, respectively, and partial or greater clinical responses of 30% and 28% respectively. No significant difference between placebo and study drug arms was observed. Histologic review, review of photographs of lesions, and comparison of serum neu protein and oral mucosal cell protease activity also did not show significant differences between study arms. Probable reasons for these negative results were considered, are discussed, and include a placebo with non-BBIC clinical activity and reduced pharmacokinetic availability of the second batch of BBIC. This experience should be a strong cautionary note to those considering “Green” chemoprevention. Cancer Prev Res; 6(5); 410–8. ©2013 AACR.
Not Significant But Important
Authors: Mulshine James L. , Ondrey Frank G. 
Published: May 2013

Abstract
Armstrong and colleagues report the result of a large Phase IIb randomized trial evaluating the effectiveness of a preparation of the Bowman Birk Inhibitor compared with an oral placebo in reversing the extent of oral leukoplakia as measured visually by pathology or a battery of intermediate end points. In this editorial, we review the report of this negative clinical trials result to highlight the clinical trial process used in evaluating this previously promising chemoprevention agent. Publishing this report is important to address concerns with publication bias. The challenges in running a chemoprevention trial are reviewed with suggestions to enhance progress going forward. Conceptually, developing drugs to intercept the early stages of carcinogenesis is very attractive, but progress in this area has been slow. Two opportunities to overcome this reality are discussed. These measures include the broader use of neoadjuvant, window-of-opportunity trials with new candidate chemoprevention agents to get more textured information about the mechanistic impact of the drug exposure in previously untreated early tumor tissue. In addition, we discuss the use of new intermediate end point markers such as with optical imaging tools to obtain a more objective and quantitative assessment of drug response. Cancer Prev Res; 6(5); 371–4. ©2013 AACR.
Elevated plasma factor VIII enhances venous thrombus formation in rabbits: Contribution of factor XI, von Willebrand factor and tissue factor
Authors: Sugita Chihiro , Yamashita Atsushi , Matsuura Yunosuke , Iwakiri Takashi , Okuyama Nozomi , Matsuda Shuntaro , Matsumoto Tomoko , Inoue Osamu , Harada Aya , Kitazawa Takehisa , Hattori Kunihiro , Shima Midori , Asada Yujiro 
Published: May 2013

SummaryElevated plasma levels of factor VIII (FVIII) are associated with increased risk of deep venous thrombosis. The aim of this study is to elucidate how elevated FVIII levels affect venous thrombus formation and propagation in vivo. We examined rabbit plasma FVIII activity, plasma thrombin generation, whole blood coagulation, platelet aggregation and venous wall thrombogenicity before and one hour after an intravenous infusion of recombinant human FVIII (rFVIII). Venous thrombus induced by the endothelial denudation of rabbit jugular veins was histologically assessed. Thrombus propagation was evaluated as indocyanine green fluorescence intensity. Argatroban, a thrombin inhibitor, and neutralised antibodies for tissue factor (TF), factor XI (FXI), and von Willebrand factor (VWF) were infused before or after thrombus induction to investigate their effects on venous thrombus formation or propagation. Recombinant FVIII (100 IU/kg) increased rabbit plasma FVIII activity two-fold and significantly enhanced whole blood coagulation and total plasma thrombin generation, but did not affect initial thrombin generation time, platelet aggregation and venous wall thrombogenicity. The rFVIII infusion also increased the size of venous thrombus 1 hour after thrombus induction. Argatroban and the antibodies for TF, FXI or VWF inhibited such enhanced thrombus formation and all except TF suppressed thrombus propagation. In conclusion, elevated plasma FVIII levels enhance venous thrombus formation and propagation. Excess thrombin generation by FXI and VWF-mediated FVIII recruitment appear to contribute to the growth of FVIII-driven venous thrombus.
Thin-Capped Atheromata With Reduced Collagen Content in Pigs Develop in Coronary Arterial Regions Exposed to Persistently Low Endothelial Shear Stress
Authors: Koskinas Konstantinos C. , Sukhova Galina K. , Baker Aaron B. , Papafaklis Michail I. , Chatzizisis Yiannis S. , Coskun Ahmet U. , Quillard Thibaut , Jonas Michael , Maynard Charles , Antoniadis Antonios P. , Shi Guo-Ping , Libby Peter , Edelman Elazer R. , Feldman Charles L. , Stone Peter H. 
Published: May 2013

Objective—
The mechanisms promoting the focal formation of rupture-prone coronary plaques in vivo remain incompletely understood. This study tested the hypothesis that coronary regions exposed to low endothelial shear stress (ESS) favor subsequent development of collagen-poor, thin-capped plaques.

Approach and Results—
Coronary angiography and 3-vessel intravascular ultrasound were serially performed at 5 consecutive time points in vivo in 5 diabetic, hypercholesterolemic pigs. ESS was calculated along the course of each artery with computational fluid dynamics at all 5 time points. At follow-up, 184 arterial segments with previously identified in vivo ESS underwent histopathologic analysis. Compared with other plaque types, eccentric thin-capped atheromata developed more in segments that experienced lower ESS during their evolution. Compared with lesions with higher preceding ESS, segments persistently exposed to low ESS (<1.2 Pa) exhibited reduced intimal smooth muscle cell content; marked intimal smooth muscle cell phenotypic modulation; attenuated procollagen-I gene expression; increased gene and protein expression of the interstitial collagenases matrix-metalloproteinase-1, -8, -13, and -14; increased collagenolytic activity; reduced collagen content; and marked thinning of the fibrous cap.

Conclusions—
Eccentric thin-capped atheromata, lesions particularly prone to rupture, form more frequently in coronary regions exposed to low ESS throughout their evolution. By promoting an imbalance of attenuated synthesis and augmented collagen breakdown, low ESS favors the focal evolution of early lesions toward plaques with reduced collagen content and thin fibrous caps—2 critical determinants of coronary plaque vulnerability.
Rating Method for Dilated Virchow–Robin Spaces on Magnetic Resonance Imaging
Authors: Adams Hieab H.H. , Cavalieri Margherita , Verhaaren Benjamin F.J. , Bos Daniel , van der Lugt Aad , Enzinger Christian , Vernooij Meike W. , Schmidt Reinhold , Ikram M. Arfan 
Published: May 2013

Background and Purpose—
Dilated Virchow–Robin spaces are an emerging neuroimaging biomarker, but their assessment on MRI needs standardization.

Methods—
We developed a rating method for dilated Virchow–Robin spaces in 4 brain regions (centrum semiovale, basal ganglia, hippocampus, and mesencephalon) and tested its reliability in a total of 125 MRI scans from 2 population-based studies. Six investigators with varying levels of experience performed the ratings. Intraclass correlation coefficients were calculated to determine intra- and interrater reliability.

Results—
Intrarater reliability was excellent for all 4 regions (intraclass correlation coefficient, >0.8). Interrater reliability was excellent for the centrum semiovale and hippocampus (intraclass correlation coefficient, >0.8) and good for the basal ganglia and mesencephalon (intraclass correlation coefficient, 0.6–0.8). This did not differ between the cohorts or experience levels.

Conclusions—
We describe a reliable rating method that can facilitate pathogenic and prognostic research on dilated Virchow–Robin spaces using MRI.
Warm Winter Storms in Central Chile
Authors: Garreaud R. 
Published: May 2013

Abstract
Central Chile is a densely populated region along the west coast of subtropical South America (30°–36°S), limited to the east by the Andes. Precipitation is concentrated in austral winter, mostly associated with the passage of cold fronts. The freezing level over central Chile is typically between 1500 and 2500 m when precipitation is present. In about a third of the cases, however, precipitation occurs accompanied by warm temperatures and freezing levels above 3000 m, leading to a sizeable increment in the pluvial area of Andean basins and setting the stage for hydrometeorological hazards. Here, warm winter storms in central Chile are studied, including a statistical description of their occurrence and an estimate of their hydrological impacts. Remote-sensed data and high-resolution reanalysis are used to explore the synoptic-scale environment of a typical case, generalized later by a compositing analysis. The structure of warm storms is also contrasted with that of the more recurrent cold cases. Precipitation during warm events occurs in the warm sector of a slow-moving cold front because of the intense moisture flux against the mountains in connection with a land-falling atmospheric river. This is in turn driven by a strong zonal jet aloft and reduced mechanical blocking upstream of the Andes. On a broader scale, a key element is the presence of a slowly moving anticyclone over the south Pacific, fostering advection of cold air into midlatitudes. The intense and persistent zonal jet stretches a moist-air corridor from the central Pacific to the west coast of South America.
Exploring the Perceptions of Success in an Exercise Referral Scheme
Authors: Mills Hayley , Crone Diane , James David V. B. , Johnston Lynne H. 
Published: May 2013

Background: Exercise referral schemes feature as one of the prevalent primary care physical activity interventions in the United Kingdom, without extensive understanding of how those involved in providing and participating view success. The present research explores and reveals the constituents of “success,” through comparison, contradiction, and integration of qualitative and quantitative research findings. Method: A population-based cohort design formed the basis for a mixed method approach to the research. The quantitative component used a three-stage binary logistic regression to identify patient sociodemographic characteristics and referral reasons associated with three outcomes ( n = 1,315). The qualitative component ( n = 28) comprised four focus groups with patients ( n = 17), individual interviews with exercise providers ( n = 4), and referring health professionals ( n = 7). The research components were compared at discussion stage to offer insights into the concept of “success.” Results: The integrated findings highlighted the multidimensional nature of the concept of success, containing a wide range of concepts such as empowerment, inclusion, and confidence. The traditional notions of success such as, attendance, weight loss, and blood pressure reduction featured amid a more holistic view which incorporated psychological and social aspects as both influences and outcomes. Conclusion: These findings can enable future development of more representative evaluations of the benefits of exercise referral. This mixed methods research approach can facilitate the development of sophisticated, tailored, evidence-based interventions in the future.
Value of D-dimer and protein S for diagnosis of portal vein thrombosis in patients with liver cirrhosis
Authors: Zhang Dong-Lei , Hao Jian-Yu , Yang Ning 
Published: May 2013

Objective To investigate the value of D-dimer and protein S plasma concentrations for diagnosis of portal vein thrombosis (PVT) in patients with liver cirrhosis. Methods D-dimer and protein S were quantified, PVT was diagnosed by dynamic enhanced computed tomography and liver function was classified using the Child–Pugh system. Receiver operating curve analysis was performed. Results D-dimer increased, and protein S decreased, with decreasing liver function in the total study population ( n = 188). D-dimer concentrations were significantly higher and protein S concentrations were significantly lower in patients with ( n = 51) than those without PVT ( n = 137). D-dimer had high specificity and negative predictive value (NPV) in Child–Pugh class A or B patients (cut-off values>0.56 mg/l and >1.18 mg/l, respectively). In class C patients>0.77 mg/l D-dimer had high sensitivity and NPV. Protein S had high sensitivity but low specificity in class A or B patients (cut-off values < 17.4 mg/l and <19.2 mg/l, respectively). Conclusion Plasma D-dimer and protein S are potential biomarkers for PVT diagnosis in patients with cirrhosis. PVT can be excluded when D-dimer is low and protein S is elevated.