bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost‐Effectiveness of a School‐Based Emotional Health Screening Program
Authors: Kuo Elena , Stoep Ann Vander , McCauley Elizabeth , Kernic Mary A. 
Published: May 2009

ABSTRACTBackground:  School‐based screening for health conditions can help extend the reach of health services to underserved populations. Screening for mental health conditions is growing in acceptability, but evidence of cost‐effectiveness is lacking. This study assessed costs and effectiveness associated with the Developmental Pathways Screening Program, in which students undergo universal classroom emotional health screening and those who have positive screens are provided with on‐site clinical evaluation and referral.Methods:  Costs are enumerated for screening and clinical evaluation in terms of labor and overhead and summarized as cost per enrolled student, per positive screen, and per referral. Cost‐effectiveness is summarized as cost per student successfully linked to services. School demographics are used to generate a predictive formula for estimating the proportion of students likely to screen positive in a particular school, which can be used to estimate program cost.Results:  Screening costs ranged from $8.88 to $13.64 per enrolled student, depending on the prevalence of positive screens in a school. Of students referred for services, 72% were linked to supportive services within 6 weeks. Cost‐effectiveness was estimated to be $416.90 per successful linkage when 5% screened positive and $106.09 when 20% screened positive. A formula to estimate the proportion of students screening positive proved accurate to within 5%.Conclusion:  Information concerning costs and effectiveness of school‐based emotional health screening programs can guide school districts in making decisions concerning resource allocation.
Ewing Sarcoma Fusion Protein EWSR1/FLI1 Interacts with EWSR1 Leading to Mitotic Defects in Zebrafish Embryos and Human Cell Lines
Authors: Embree Lisa J. , Azuma Mizuki , Hickstein Dennis D. 
Published: May 2009

Abstract
The mechanism whereby the fusion of EWSR1 with the ETS transcription factor FLI1 contributes to malignant transformation in Ewing sarcoma remains unclear. We show that injection of human or zebrafish EWSR1/FLI1 mRNA into developing zebrafish embryos leads to mitotic defects with multipolar and disorganized mitotic spindles. Expression of human EWSR1/FLI1 in HeLa cells also results in mitotic defects, along with mislocalization of Aurora kinase B, a key regulator of mitotic progression. Because these mitotic abnormalities mimic those observed with the knockdown of EWSR1 in zebrafish embryos and HeLa cells, we investigated whether EWSR1/FLI1 interacts with EWSR1 and interferes with its function. EWSR1 coimmunoprecipitates with EWSR1/FLI1, and overexpression of EWSR1 rescues the mitotic defects in EWSR1/FLI1-transfected HeLa cells. This interaction between EWSR1/FLI1 and EWSR1 in Ewing sarcoma may induce mitotic defects leading to genomic instability and subsequent malignant transformation. [Cancer Res 2009;69(10):4363–71]
RLIP76: A Target for Kidney Cancer Therapy
Authors: Singhal Sharad S. , Singhal Jyotsana , Yadav Sushma , Sahu Mukesh , Awasthi Yogesh C. , Awasthi Sanjay 
Published: May 2009

AbstractRLIP76 is a multifunctional transporter protein that serves as an energy-dependent efflux mechanism for endogenously generated toxic metabolites as well as exogenous toxins, including chemotherapy drugs. Our recent studies in cultured cells, syngeneic animal tumor model, and in xenograft model have shown that RLIP76 serves a major cancer-specific antiapoptotic role in a wide variety of histologic types of cancer, including leukemia, melanoma, colon, lung, prostate, and ovarian cancer. Results of present studies in cell culture and xenograft model of Caki-2 cells show that RLIP76 is an important anticancer for kidney cancer because inhibition of RLIP76 function by antibody or its depletion by small interfering RNA or antisense DNA caused marked and sustained regression of established human kidney xenografts of Caki-2 cells in nude mouse. [Cancer Res 2009;69(10):4244–51]
An Imaging-Based Rapid Evaluation Method for Complement-Dependent Cytotoxicity Discriminated Clinical Response to Rituximab-Containing Chemotherapy
Authors: Mishima Yuji , Sugimura Natsuhiko , Matsumoto-Mishima Yuko , Terui Yasuhito , Takeuchi Kengo , Asai Suzuka , Ennishi Daisuke , Asai Hiroaki , Yokoyama Masahiro , Kojima Kiyotsugu , Hatake Kiyohiko 
Published: May 2009

Abstract
Purpose: Rituximab has greatly improved the efficacy of chemotherapy regimens for CD20-positive non-Hodgkin's lymphoma. However, although several mechanisms of action of rituximab have been identified, the exact therapeutic functions of these mechanisms remains to be clarified. In addition, there is no established prognostic marker to predict an individual response. This study verified the validity of ex vivo complement-dependent cytotoxicity (CDC) susceptibility as a predictor of pathologic tumor regression in patients undergoing rituximab-containing chemotherapy and examined whether CDC contributes to the mechanism of action of rituximab.
Experimental Design: A rapid assay system was established to evaluate the tumoricidal activity of rituximab using a living cell–imaging technique. We analyzed lymph node biopsies obtained from 234 patients with suspected lymphomas and estimated the association between CDC susceptibility and the response to rituximab-containing chemotherapy in diffuse large B-cell lymphoma and follicular lymphoma.
Results: This study revealed that CDC susceptibility of lymphoma cells freshly obtained from patients was strongly associated with response to rituximab-containing chemotherapy in both diffuse large B-cell lymphoma and follicular lymphoma. This correlation was not apparent in cases that received chemotherapy without rituximab.
Conclusions: The system that we have established allows a successful assessment of rituximab-induced CDC and can distinguish cases refractory to rituximab-containing chemotherapy. The association between CDC susceptibility and therapy response suggests that CDC is pivotal in the ability of chemotherapy including rituximab to induce remission.
Trk Receptor Expression and Inhibition in Neuroblastomas
Authors: Brodeur Garrett M. , Minturn Jane E. , Ho Ruth , Simpson Anisha M. , Iyer Radhika , Varela Carly R. , Light Jennifer E. , Kolla Venkatadri , Evans Audrey E. 
Published: May 2009

Abstract
Neuroblastoma, the most common and deadly solid tumor in children, exhibits heterogeneous clinical behavior, from spontaneous regression to relentless progression. Current evidence suggests that the TRK family of neurotrophin receptors plays a critical role in these diverse behaviors. Neuroblastomas expressing TrkA are biologically favorable and prone to spontaneous regression or differentiation, depending on the absence or presence of its ligand (NGF) in the microenvironment. In contrast, TrkB-expressing tumors frequently have MYCN amplification and are very aggressive and often fatal tumors. These tumors also express the TrkB ligand (BDNF), resulting in an autocrine or paracrine survival pathway. Exposure to BDNF promotes survival, drug resistance, and angiogenesis of TrkB-expressing tumors. Here we review the role of Trks in normal development, the different functions of Trk isoforms, and the major Trk signaling pathways. We also review the roles these receptors play in the heterogeneous biological and clinical behavior of neuroblastomas, and the activation of Trk receptors in other cancers. Finally we address the progress that has been made in developing targeted therapy with Trk-selective inhibitors to treat neuroblastomas and other tumors with activated Trk expression.
A Vasculature-Targeting Regimen of Preoperative Docetaxel with or without Bevacizumab for Locally Advanced Breast Cancer: Impact on Angiogenic Biomarkers
Authors: Baar Joseph , Silverman Paula , Lyons Janice , Fu Pingfu , Abdul-Karim Fadi , Ziats Nicholas , Wasman Jay , Hartman Paul , Jesberger John , Dumadag Leda , Hohler Erin , Leeming Rosemary , Shenk Robert , Chen Helen , McCrae Keith , Dowlati Afshin , Remick Scot C. , Overmoyer Beth 
Published: May 2009

Abstract
Purpose: Taxanes have effects on angiogenesis causing difficulties in separating biological effects of chemotherapy from those due to angiogenesis inhibitors. This randomized phase II trial was designed to evaluate the additional biomarker effect on angiogenesis when bevacizumab is added to docetaxel.
Experimental Design: Patients with inoperable breast cancer were randomized to either 2 cycles of preoperative docetaxel (D) 35 mg/m2 i.v. weekly for 6 weeks, followed by a 2-week break; or docetaxel with bevacizumab 10 mg/kg i.v. every other week for a total of 16 weeks (DB). Plasma and serum markers of endothelial damage, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and tumor microvessel density were assessed before treatment and at the end of each preoperative cycle.
Results: Forty-nine patients were randomized (DB, 24; D, 25). There was no difference in overall clinical response, progression-free survival, or overall survival. Vascular endothelial growth factor increased during treatment; more so with DB (P &lt; 0.0001). Vascular cell adhesion molecule-1 (VCAM-1) also increased (P &lt; 0.0001); more so with DB (P = 0.069). Intercellular adhesion molecule increased (P = 0.018) and E-selectin decreased (P = 0.006) overall. Baseline levels of VCAM-1 and E-selectin correlated with clinical response by univariate analysis. DCE-MRI showed a greater decrease in tumor perfusion calculated by initial area under the curve for the first 90 seconds in DB (P = 0.024). DCE-MRI also showed an overall decrease in tumor volume (P = 0.012).
Conclusion: Bevacizumab plus docetaxel caused a greater increase in vascular endothelial growth factor and VCAM-1, and a greater reduction in tumor perfusion by DCE-MRI compared with docetaxel. Clinical outcomes of inoperable breast cancer were predicted by changes in VCAM-1 and E-selectin.
Assessment of GS-9219 in a Pet Dog Model of Non-Hodgkin's Lymphoma
Authors: Vail David M. , Thamm Douglas H. , Reiser Hans , Ray Adrian S. , Wolfgang Grushenka H.I. , Watkins William J. , Babusis Darius , Henne Ilana N. , Hawkins Michael J. , Kurzman Ilene D. , Jeraj Robert , Vanderhoek Matt , Plaza Susan , Anderson Christie , Wessel Mackenzie A. , Robat Cecilia , Lawrence Jessica , Tumas Daniel B. 
Published: May 2009

Abstract
Purpose: To assess, in dogs with naturally occurring non-Hodgkin's lymphoma, pharmacokinetics, safety, and activity of GS-9219, a prodrug of the nucleotide analogue 9-(2-phosphonylmethoxyethyl) guanine (PMEG), which delivers PMEG and its phosphorylated metabolites to lymphoid cells with preferential cytotoxicity in cells with a high proliferation index such as lymphoid malignancies.
Experimental Design: To generate proof-of-concept, a phase I/II trial was conducted in pet dogs (n = 38) with naturally occurring non-Hodgkin's lymphoma using different dose schedules of GS-9219. A subset of dogs was further evaluated with 3′-deoxy-3′-18F-fluorothymidine positron emission tomography/computed tomography imaging before and after treatment.
Results: The prodrug had a short plasma half-life but yielded high and prolonged intracellular levels of the cytotoxic metabolite PMEG diphosphate in peripheral blood mononuclear cells in the absence of detectable plasma PMEG. Dose-limiting toxicities were generally manageable and reversible and included dermatopathy, neutropenia, and gastrointestinal signs. Antitumor responses were observed in 79% of dogs and occurred in previously untreated dogs and dogs with chemotherapy-refractory non-Hodgkin's lymphoma. The median remission durations observed compare favorably with other monotherapies in dogs with non-Hodgkin's lymphoma. High 3′-deoxy-3′-18F-fluorothymidine uptake noted in lymphoid tissues before treatment decreased significantly after treatment (P = 0.016).
Conclusions: GS-9219 was generally well tolerated and showed significant activity against spontaneous non-Hodgkin's lymphoma as modeled in pet dogs and, as such, supports clinical evaluation in humans.
Imatinib blocks migration and invasion of medulloblastoma cells by concurrently inhibiting activation of platelet-derived growth factor receptor and transactivation of epidermal growth factor receptor
Authors: Abouantoun Thamara J. , MacDonald Tobey J. 
Published: May 2009

Abstract
Platelet-derived growth factor (PDGF) receptor (PDGFR) expression correlates with metastatic medulloblastoma. PDGF stimulation of medulloblastoma cells phosphorylates extracellular signal-regulated kinase (ERK) and promotes migration. We sought to determine whether blocking PDGFR activity effectively inhibits signaling required for medulloblastoma cell migration and invasion. DAOY and D556 human medulloblastoma cells were treated with imatinib mesylate (Gleevec), a PDGFR tyrosine kinase inhibitor, or transfected with small interfering RNA (siRNA) to PDGFRB to test the effects of blocking PDGFR phosphorylation and expression, respectively. PDGFR cell signaling, migration, invasion, survival, and proliferation following PDGF-BB stimulation, with and without PDGFR inhibition, were measured. PDGF-BB treatment of cells increased PDGFRB, Akt and ERK phosphorylation, and transactivated epidermal growth factor receptor (EGFR), which correlated with enhanced migration, survival, and proliferation. Imatinib (1 μmol/L) treatment of DAOY and D556 cells inhibited PDGF-BB- and serum-mediated migration and invasion at 24 and 48 h, respectively, and concomitantly inhibited PDGF-BB activation of PDGFRB, Akt, and ERK but increased PTEN expression and activity. Imatinib treatment also induced DAOY cell apoptosis at 72 h and inhibited DAOY and D556 cell proliferation at 48 h. siRNA silencing of PDGFRB similarly inhibited signaling, migration, and survival and both siRNA and imatinib treatment inhibited PDGF-BB-mediated EGFR transactivation, indicating that the effects of imatinib treatment are specific to PDGFRB target inhibition. These results indicate that PDGFRB tyrosine kinase activity is critical for migration and invasion of medulloblastoma cells possibly by transactivating EGFR; thus, imatinib may represent an important novel therapeutic agent for the treatment of medulloblastoma. [Mol Cancer Ther 2009;8(5):1137–47]
A novel human monoclonal antibody that binds with high affinity to mesothelin-expressing cells and kills them by antibody-dependent cell-mediated cytotoxicity
Authors: Feng Yang , Xiao Xiaodong , Zhu Zhongyu , Streaker Emily , Ho Mitchell , Pastan Ira , Dimitrov Dimiter S. 
Published: May 2009

Abstract
Mesothelin is a potential new target for cancer immunotherapy because it is present at relatively low levels only in mesothelial cells of pleura, peritoneum, and pericardium of healthy people, but is significantly elevated in a number of tumors, including mesothelioma, ovarian, pancreatic, and lung cancers. However, all currently available antibodies against mesothelin are either murine or chimeric, which could limit their use because of increased likelihood of immunogenicity compared with fully human antibodies. Here, we report the identification and characterization of a novel fully human monoclonal antibody, m912, which was isolated from a human Fab library by panning against recombinant mesothelin. This antibody in scFv, Fab, and IgG1 formats bound specifically and with high affinity (equilibrium dissociation constant in the nmol/L range) to cell surface-associated human mesothelin and to recombinant mesothelin. It specifically lysed cancer cells engineered to express mesothelin in the presence of peripheral blood mononuclear cells isolated from healthy donors most likely by antibody-dependent cellular cytotoxicity. M912 is the first reported fully human monoclonal antibody to mesothelin, which has potential for cancer treatment and diagnosis. [Mol Cancer Ther 2009;8(5):1113–8]
Ligation of cancer cell surface GRP78 with antibodies directed against its COOH-terminal domain up-regulates p53 activity and promotes apoptosis
Authors: Misra Uma Kant , Mowery Yvonne , Kaczowka Steven , Pizzo Salvatore Vincent 
Published: May 2009

Abstract
Binding of activated α2-macroglobulin to GRP78 on the surface of human prostate cancer cells promotes proliferation by activating signaling cascades. Autoantibodies directed against the activated α2-macroglobulin binding site in the NH2-terminal domain of GRP78 are receptor agonists, and their presence in the sera of cancer patients is a poor prognostic indicator. We now show that antibodies directed against the GRP78 COOH-terminal domain inhibit [3H]thymidine uptake and cellular proliferation while promoting apoptosis as measured by DNA fragmentation, Annexin V assay, and clonogenic assay. These antibodies are receptor antagonists blocking autophosphorylation and activation of GRP78. Using 1-LN and DU145 prostate cancer cell lines and A375 melanoma cells, which express GRP78 on their cell surface, we show that antibodies directed against the COOH-terminal domain of GRP78 up-regulate the tumor suppressor protein p53. By contrast, antibody directed against the NH2-terminal domain of GRP78 shows negligible effects on p53 expression. PC-3 prostate cancer cells, which do not express GRP78 on their cell surface, are refractory to the effects of anti-GRP78 antibodies directed against either the COOH- or NH2-terminal domains. However, overexpression of GRP78 in PC-3 cells causes translocation of GRP78 to the cell surface and promotes apoptosis when these cells are treated with antibody directed against its COOH-terminal domain. Silencing GRP78 or p53 expression by RNA interference significantly blocked the increase in p53 induced by antibodies. Antibodies directed against the COOH-terminal domain may play a therapeutic role in cancer patients whose tumors trigger the production of autoantibodies directed against the NH2-terminal domain of GRP78. [Mol Cancer Ther 2009;8(5):1350–62]
Dual targeting of AKT and mammalian target of rapamycin: A potential therapeutic approach for malignant peripheral nerve sheath tumor
Authors: Zou Changye Y. , Smith Kerrington D. , Zhu Quan-Sheng , Liu Jun , McCutcheon Ian E. , Slopis John M. , Meric-Bernstam Funda , Peng Zhenghong , Bornmann William G. , Mills Gordon B. , Lazar Alexander J. , Pollock Raphael E. , Lev Dina 
Published: May 2009

Abstract
The mammalian target of rapamycin (mTOR) pathway may constitute a potential target for the treatment of malignant peripheral nerve sheath tumors (MPNST). However, investigations of other cancers suggest that mTOR blockade can paradoxically induce activation of prosurvival, protumorigenic signaling molecules, especially upstream AKT. Consequently, we hypothesized that dual phosphatidylinositol 3-kinase (PI3K)/AKT-mTOR blockade might be applicable for MPNST treatment. Expression of activated mTOR downstream targets (p4EBP1 and pS6RP) and pAKT was evaluated immunohistochemically in a tissue microarray of human MPNSTs (n = 96) and benign neurofibromas (n = 31). Results were analyzed by Wilcoxon rank-sum tests. mTOR and AKT pathways in human MPNST cell lines, and the effects of rapamycin (mTOR inhibitor), LY294002 (dual PI3K/mTOR inhibitor), and PI-103 (potent dual PI3K/AKT-mTOR inhibitor) on pathway activation were evaluated by Western blot. Effects on cell growth were evaluated via MTS and colony formation assays. Cell cycle progression and apoptosis were assessed by propidium iodide/fluorescence-activated cell sorting staining and Annexin V assays. Acridine orange staining/fluorescence-activated cell sorting analysis, electron microscopy, and Western blot evaluated autophagy induction. p4EBP1, pS6Rp, and pAKT levels were found to be significantly higher in MPNST versus neurofibroma (P &lt; 0.05 for all markers). mTOR and AKT pathways were found to be highly activated in MPNST cell lines. MPNST cells were sensitive to rapamycin; however, rapamycin enhanced pAKT and peIF4E expression. PI-103 abrogated MPNST cell growth and induced G1 cell cycle arrest potentially through repression of cyclin D1. PI-103 did not elicit apoptosis but significantly induced autophagy in MPNST cells. These results suggest further study of combined PI3K/AKT and mTOR inhibition as a novel therapy for patients harboring MPNST. [Mol Cancer Ther 2009;8(5):OF1–12]
Potentin vitroandin vivoanticancer activities of des-methyl, des-amino pateamine A, a synthetic analogue of marine natural product pateamine A
Authors: Kuznetsov Galina , Xu Qunli , Rudolph-Owen Lori , TenDyke Karen , Liu Junke , Towle Murray , Zhao Nanding , Marsh Joanne , Agoulnik Sergei , Twine Natalie , Parent Lana , Chen Zhihong , Shie Jue-Lon , Jiang Yimin , Zhang Huiming , Du Hong , Boivin Roch , Wang Yuan , Romo Daniel , Littlefield Bruce A. 
Published: May 2009

AbstractWe report here that des-methyl, des-amino pateamine A (DMDA-PatA), a structurally simplified analogue of the marine natural product pateamine A, has potent antiproliferative activity against a wide variety of human cancer cell lines while showing relatively low cytotoxicity against nonproliferating, quiescent human fibroblasts. DMDA-PatA retains almost full in vitro potency in P-glycoprotein-overexpressing MES-SA/Dx5-Rx1 human uterine sarcoma cells that are significantly resistant to paclitaxel, suggesting that DMDA-PatA is not a substrate for P-glycoprotein-mediated drug efflux. Treatment of proliferating cells with DMDA-PatA leads to rapid shutdown of DNA synthesis in the S phase of the cell cycle. Cell-free studies show that DMDA-PatA directly inhibits DNA polymerases α and γ in vitro albeit at concentrations considerably higher than those that inhibit cell proliferation. DMDA-PatA shows potent anticancer activity in several human cancer xenograft models in nude mice, including significant regressions observed in the LOX and MDA-MB-435 melanoma models. DMDA-PatA thus represents a promising natural product-based anticancer agent that warrants further investigation.[Mol Cancer Ther 2009;8(5):1250–60]