bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antiphosphatidylserine Antibody Combined with Irradiation Damages Tumor Blood Vessels and Induces Tumor Immunity in a Rat Model of Glioblastoma
Authors: He Jin , Yin Yi , Luster Troy A. , Watkins Linda , Thorpe Philip E. 
Published: November 2009

AbstractPurpose: The vascular targeting antibody bavituximab is being combined with chemotherapy in clinical trials in cancer patients. Bavituximab targets the membrane phospholipid, phosphatidylserine, complexed with 2-glycoprotein I. Phosphatidylserine is normally intracellular but becomes exposed on the luminal surface of vascular endothelium in tumors. Phosphatidylserine exposure on tumor vessels is increased by chemotherapy and irradiation. Here, we determined whether treatment with the murine equivalent of bavituximab, 2aG4, combined with irradiation can suppress tumor growth in a rat model of glioblastoma.Experimental Design: F98 glioma cells were injected into the brains of syngeneic rats where they grow initially as a solid tumor and then infiltrate throughout the brain. Rats with established tumors were treated with 10 Gy whole brain irradiation and 2aG4.Results: Combination treatment doubled the median survival time of the rats, and 13 of animals were rendered disease free. Neither treatment given individually was as effective. We identified two mechanisms. First, irradiation induced phosphatidylserine exposure on tumor blood vessels and enhanced antibody-mediated destruction of tumor vasculature by monocytes/macrophages. Second, the antibody treatment induced immunity to F98 tumor cells, which are normally weakly immunogenic. Surviving rats were immune to rechallenge with F98 tumor cells. In vitro, 2aG4 enhanced the ability of dendritic cells (DCs) to generate F98-specific cytotoxic T cells. Phosphatidylserine exposure, which is induced on tumor cells by irradiation, likely suppresses tumor antigen presentation, and 2aG4 blocks this tolerogenic effect.Conclusion: Bavituximab combined with radiotherapy holds promise as a vascular targeting and immune enhancement strategy for the treatment of human glioblastoma. (Clin Cancer Res 2009;15(22):687180)
Homozygous Deletion of MTAP Gene as a Poor Prognosticator in Gastrointestinal Stromal Tumors
Authors: Huang Hsuan-Ying , Li Shau-Hsuan , Yu Shih-Chen , Chou Fong-Fu , Tzeng Ching-Cherng , Hu Tsung-Hui , Uen Yih-Huei , Tian Yu-Fang , Wang Yu-Hui , Fang Fu-Min , Huang Wen-Wei , Wei Yu-Ching , Wu Jing-Mei , Li Chien-Feng 
Published: November 2009

Abstract
Purpose: Chromosome 9 is frequently deleted in high-risk gastrointestinal stromal tumors (GISTs), whereas its specific tumor suppressor genes (TSGs) are less understood. We did an integrative study of MTAP gene at 9p21 to analyze its implication in GISTs.
Experimental Design: To search TSGs on chromosome 9, we used ultrahigh-resolution array comparative genomic hybridization to profile DNA copy number alterations of 22 GISTs, with special attention to MTAP gene. MTAP immunoexpression was assessable for 306 independent GISTs on tissue microarrays, with 146 cases analyzed for MTAP homozygous deletion, 181 for mutations of KIT and PDGFRA receptor tyrosine kinase genes, and 7 for MTAP hypermethylation.
Results: Array comparative genomic hybridization identified 11 candidate TSGs on 9p and six on 9q. MTAP and/or CDKN2A/CDKN2B at 9p21.3 were deleted in one intermediate-risk (11) and seven high-risk (70) GISTs with two cases homozygously codeleted at both loci. MTAP homozygous deletion, present in 25 of 146 cases, was highly associated with larger size and higher mitotic rate, Ki-67 index, and risk level (all P &lt; 0.01) but not with receptor tyrosine kinase genotypes. Whereas MTAP homozygous deletion correlated with MTAP protein loss (P &lt; 0.001), 7 of 30 GISTs without MTAP expression did not show homozygous deletion, including three MTAP-hypermethylated cases. MTAP homozygous deletion was univariately predictive of decreased disease-free survival (P &lt; 0.0001) and remained multivariately independent (P = 0.0369, hazard ratio = 2.166), together with high-risk category (P &lt; 0.0001), Ki-67 index &gt;5 (P = 0.0106), and nongastric location (P = 0.0416).
Conclusions: MTAP homozygous deletion, the predominant mechanism to deplete protein expression, is present in 17 of GISTs. It correlates with important prognosticators and independently predicts worse outcomes, highlighting the role in disease progression. (Clin Cancer Res 2009;15(22):696372)
Phase II Study of Androgen Synthesis Inhibition with Ketoconazole, Hydrocortisone, and Dutasteride in Asymptomatic Castration-Resistant Prostate Cancer
Authors: Taplin Mary-Ellen , Regan Meredith M. , Ko Yoo-Joung , Bubley Glenn J. , Duggan Stephen E. , Werner Lillian , Beer Tomasz M. , Ryan Christopher W. , Mathew Paul , Tu Shi-Ming , Denmeade Samuel R. , Oh William K. , Sartor Oliver , Mantzoros Christos S. , Rittmaster Roger , Kantoff Philip W. , Balk Steven P. 
Published: November 2009

Abstract
Purpose: Increasing evidence indicates that enhanced intratumoral androgen synthesis contributes to prostate cancer progression after androgen deprivation therapy. This phase II study was designed to assess responses to blocking multiple steps in androgen synthesis with inhibitors of CYP17A1 (ketoconazole) and type I and II 5-reductases (dutasteride) in patients with castration-resistant prostate cancer (CRPC).
Experimental Design: Fifty-seven men with CRPC were continued on gonadal suppression and treated with ketoconazole (400 mg thrice daily), hydrocortisone (30 mg/AM, 10 mg/PM), and dutasteride (0.5 mg/d).
Results: Prostate-specific antigen response rate (50 decline) was 56 (32 of 57; 95 confidence interval, 42.4-69.3); the median duration of response was 20 months. In patients with measurable disease, 6 of 20 (30) responded by the Response Evaluation Criteria in Solid Tumors. Median duration of treatment was 8 months; 9 patients remained on therapy with treatment durations censored at 18 to 32 months. Median time to progression was 14.5 months. Grade 3 toxicities occurred in 32 with only one reported grade 4 (thrombosis) toxicity. Dehydroepiandrosterone sulfate declined by 89, androstenedione by 56, and testosterone by 66, and dihydrotestosterone declined to below detectable levels compared with baseline levels with testicular suppression alone. Median baseline levels and declines in dehydroepiandrosterone sulfate, androstenedione, testosterone, and dihydrotestosterone were not statistically different in the responders versus nonresponders, and hormone levels were not significantly increased from nadir levels at relapse.
Conclusion: The response proportion to ketoconazole, hydrocortisone, and dutasteride was at least comparable with previous studies of ketoconazole alone, whereas time to progression was substantially longer. Combination therapies targeting multiple steps in androgen synthesis warrant further investigation. (Clin Cancer Res 2009;15(22):7099105)
A Multimarker Prognostic Assay for Primary Cutaneous Melanoma
Authors: Kashani-Sabet Mohammed , Venna Suraj , Nosrati Mehdi , Rangel Javier , Sucker Antje , Egberts Friederike , Baehner Frederick L. , Simko Jeff , Leong Stanley P.L. , Haqq Chris , Hauschild Axel , Schadendorf Dirk , Miller James R. , Sagebiel Richard W. 
Published: November 2009

AbstractPurpose: To determine the prognostic significance of a multimarker assay incorporating expression levels of three molecular markers in primary cutaneous melanoma.Experimental Design: We assessed expression levels of NCOA3, SPP1, and RGS1 using immunohistochemical analysis in a tissue microarray cohort of 395 patients. For each marker, we identified optimal cut-points for expression intensity to predict disease-specific survival (DSS) and, as a secondary endpoint, sentinel lymph node (SLN) status. The cumulative overexpression of all three markers was embodied in a multimarker index, and its prognostic effect on DSS and SLN status was assessed using Cox regression, Kaplan-Meier analysis, and logistic regression. The prognostic effect of this multimarker assay on DSS was assessed in an independent cohort of 141 patients, in which marker expression levels were scored using immunohistochemical analysis of stained tissue sections.Results: Increasing multimarker index scores were significantly predictive of reduced DSS and increased SLN metastasis in the 395-patient cohort. Multivariate logistic regression analysis revealed multimarker expression scores as an independent predictor of SLN status (P = 0.001). Multivariate Cox regression analysis showed the independent effect of the multimarker index on DSS (P &lt; 0.001). The multimarker index was the most significant factor predicting DSS when compared with other clinical and histologic factors, including SLN status (P = 0.002). Multimarker expression scores were also the most significantly predictive of DSS in the independent cohort (P = 0.01).Conclusions: These results describe a multimarker assay with independent prognostic effect on the prediction of survival associated with melanoma in two distinct cohorts. (Clin Cancer Res 2009;15(22):698792)
Involvement of the HER2 pathway in repair of DNA damage produced by chemotherapeutic agents
Authors: Boone Julien J.M. , Bhosle Jaishree , Tilby Mike J. , Hartley John A. , Hochhauser Daniel 
Published: November 2009

AbstractHER2 (ErbB2) is overexpressed in up to 30% of human breast cancers. Preclinical and clinical studies suggest synergy between some chemotherapeutic agents and the humanized anti-HER2 antibody trastuzumab (Herceptin). This study investigated the effects of etoposide and cisplatin on the repair of DNA damage in breast cancer cell lines. We examined the potential significance of HER2 nuclear expression in DNA repair. MCF-7, SK-BR-3, and MDA-MB-453 cells were treated with cisplatin and etoposide. Repair of DNA interstrand crosslinks (ICL) and strand breaks, following incubation with cisplatin and etoposide, respectively, were quantitated by the single-cell gel electrophoresis (comet) assay. Intrastrand crosslinks produced by cisplatin were assessed by ELISA. The effects of trastuzumab were measured in combination with these drugs. Similar experiments were done using HER2-negative MDA-MB-468 cells transfected with HER2 and a construct lacking the nuclear localization sequence. Incubation of breast cancer cell lines with trastuzumab delayed the repair of ICL produced by cisplatin. There were no effects on the repair of intrastrand crosslinks produced by cisplatin, or repair of DNA strand breaks following etoposide treatment. Transfection of HER2 into MDA-MB-468 cells inhibited the repair of cisplatin-induced ICL, whereas transfection of a HER2 construct lacking the nuclear localization sequence did not affect DNA repair. These results indicate that HER2 expression modulates the repair of specific DNA lesions produced by chemotherapy. The effect on ICL repair requires nuclear expression of HER2. Understanding the mechanisms of interaction between DNA-interacting agents and HER2 inhibitors will inform the design of clinical trials and optimize the therapeutic effects of these combinations. [Mol Cancer Ther 2009;8(11):3015–23]
Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents
Authors: Hirai Hiroshi , Iwasawa Yoshikazu , Okada Megumu , Arai Tsuyoshi , Nishibata Toshihide , Kobayashi Makiko , Kimura Toshifumi , Kaneko Naoki , Ohtani Junko , Yamanaka Kazunori , Itadani Hiraku , Takahashi-Suzuki Ikuko , Fukasawa Kazuhiro , Oki Hiroko , Nambu Tadahiro , Jiang Jian , Sakai Takumi , Arakawa Hiroharu , Sakamoto Toshihiro , Sagara Takeshi , Yoshizumi Takashi , Mizuarai Shinji , Kotani Hidehito 
Published: November 2009

AbstractWee1 is a tyrosine kinase that phosphorylates and inactivates CDC2 and is involved in G2 checkpoint signaling. Because p53 is a key regulator in the G1 checkpoint, p53-deficient tumors rely only on the G2 checkpoint after DNA damage. Hence, such tumors are selectively sensitized to DNA-damaging agents by Wee1 inhibition. Here, we report the discovery of a potent and selective small-molecule inhibitor of Wee1 kinase, MK-1775. This compound inhibits phosphorylation of CDC2 at Tyr15 (CDC2Y15), a direct substrate of Wee1 kinase in cells. MK-1775 abrogates G2 DNA damage checkpoint, leading to apoptosis in combination with DNA-damaging chemotherapeutic agents such as gemcitabine, carboplatin, and cisplatin selectively in p53-deficient cells. In vivo, MK-1775 potentiates tumor growth inhibition by these agents, and cotreatment does not significantly increase toxicity. The enhancement of antitumor effect by MK-1775 was well correlated with inhibition of CDC2Y15 phosphorylation in tumor tissue and skin hair follicles. Our data indicate that Wee1 inhibition provides a new approach for treatment of multiple human malignancies. [Mol Cancer Ther 2009;8(11):2992–3000]
Mcl-1 is an important determinant of the apoptotic response to the BH3-mimetic molecule HA14-1 in cisplatin-resistant ovarian carcinoma cells
Authors: Simonin Karin , Brotin Emilie , Dufort Sandrine , Dutoit Soizic , Goux Didier , N'Diaye Monique , Denoyelle Christophe , Gauduchon Pascal , Poulain Laurent 
Published: November 2009

Abstract
Chemoresistance of ovarian carcinoma has been associated previously to the absence of Bcl-xL expression downregulation in response to cisplatin. Among BH3-mimetic molecules constituting promising anticancer agents able to inhibit the activity of antiapoptotic Bcl-2 family proteins, we evaluated the effect of one of them, HA14-1, on various ovarian carcinoma cell lines. In response to HA14-1, the cisplatin-resistant IGROV1-R10 cell line underwent massive cell death, whereas other cell lines presented a partial response (IGROV1, SKOV3, and A2780) or did not respond to this molecule (OAW42 and OAW42-R). However, the expression of HA14-1 targets (Bcl-2 and Bcl-xL) did not correlate to these different responses. In contrast, cell death was associated with the disappearance of Mcl-1 after exposure to HA14-1. We showed that, in the HA14-1 nonresponsive cell lines (SKOV3 and OAW42), small interfering RNA–mediated Mcl-1 downregulation allowed HA14-1–induced massive apoptosis in the absence of chemotherapy. Furthermore, cisplatin-induced Mcl-1 downregulation was also able to sensitize highly chemoresistant SKOV3 cells to HA14-1. Taken together, these results show that Bcl-xL and Mcl-1 are able to cooperate to protect ovarian carcinoma cells against oncogenic stress or chemotherapy-induced apoptosis and suggest that the development of multitargeted strategies directed against these two antiapoptotic proteins may constitute a major challenge for the therapeutic care of chemoresistant ovarian carcinomas. BH3-mimetic compounds represent promising tools for this purpose either on their own (direct or indirect pan-inhibitors) or in combination with new drugs aiming to inactivate Mcl-1. [Mol Cancer Ther 2009;8(11):3162–70]
MUC1 oncoprotein is a druggable target in human prostate cancer cells
Authors: Joshi Maya Datt , Ahmad Rehan , Yin Li , Raina Deepak , Rajabi Hasan , Bubley Glenn , Kharbanda Surender , Kufe Donald 
Published: November 2009

Abstract
Human prostate cancers are dependent on the androgen receptor for their progression. The MUC1 heterodimeric oncoprotein is aberrantly overexpressed in prostate cancers; however, it is not known if MUC1 is of functional importance to these tumors. To assess dependence on MUC1, we synthesized an inhibitor, designated GO-201, which interacts directly with the MUC1-C subunit at its oligomerization domain. Treatment of MUC1-positive DU145 and PC3 prostate cancer cells with GO-201, and not an altered version, resulted in inhibition of proliferation. GO-201 also induced necrotic cell death that was associated with increases in reactive oxygen species, loss of mitochondrial transmembrane potential, and depletion of ATP. By contrast, GO-201 had no effect against MUC1-negative LNCaP, CWR22Rv1, and MDA-PCa-2b prostate cancer cells. Significantly, GO-201 treatment of DU145 and PC3 xenografts growing in nude mice resulted in complete tumor regression and prolonged lack of recurrence. These findings indicate that certain prostate cancer cells are dependent on MUC1-C for growth and survival and that directly targeting MUC1-C results in their death in vitro and in tumor models. [Mol Cancer Ther 2009;8(11):3056–65]
A Commentary: A Communication about a Communication
Authors: Hartman Lars 
Published: November 2009

AbstractTo analyze some possible foci of a commentator's work a model of interpretation is applied: through Text (the commentary) a Sender/the Interpreter (the commentator) interprets a Text (the biblical text) to Recipients (the readers of the commentary) as the Message of Sender (the biblical author) with a certain Purpose to a Recipient (the addressee in the early church) who is in a given Situation (in the early church).
Velocity and Temperature Structure Functions in the Upper Troposphere and Lower Stratosphere from High-Resolution Aircraft Measurements
Authors: Wroblewski Donald E. , Coté Owen R. , Hacker Jorg M. , Dobosy Ronald J. 
Published: November 2009

Abstract
High-resolution measurements obtained from NOAA “best” atmospheric turbulence (BAT) probes mounted on an EGRETT high-altitude research aircraft were used to characterize turbulence in the upper troposphere and lower stratosphere at scales from 2 m to 20 km, focusing on three-dimensional behavior in the sub-kilometer-scale range. Data were analyzed for 129 separate level flight segments representing 41 h of flight time and 12 600 km of wind-relative flight distances. The majority of flights occurred near the tropopause layer of the winter subtropical jet stream in the Southern Hemisphere. Second-order structure functions for velocity and temperature were analyzed for the separate level-flight segments, individually and in various ensembles. A 3D scaling range was observed at scales less than about 100 m, with power-law exponents for the structure functions of the velocity component in the flight direction varying mostly between 0.4 and 0.75 for the separate flight segments, but close to ⅔ for the ensemble-averaged curves for all levels and for various subensembles. Structure functions in the 3D scaling range were decoupled from those at scales greater than 10 km, with the large-scale structure functions showing less variation than those at smaller scales. Weakly anisotropic behavior was observed in the 3D range, with structure parameters for the lateral and vertical velocities on the same order as those in the flight direction but deviating from the expected isotropic value. Anisotropy was correlated with turbulence intensity, with greater anisotropy associated with weaker turbulence.
Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting
Authors: Sánchez-Abarca Luis I. , Gutierrez-Cosio Silvia , Santamaría Carlos , Caballero-Velazquez Teresa , Blanco Belen , Herrero-Sánchez Carmen , García Juan L. , Carrancio Soraya , Hernández-Campo Pilar , González Francisco J. , Flores Teresa , Ciudad Laura , Ballestar Esteban , del Cañizo Consuelo , San Miguel Jesus F. , Pérez-Simon Jose A. 
Published: November 2009

AbstractCytokine genes are targets of multiple epigenetic mechanisms in T lymphocytes. 5-azacytidine (5-azaC) is a nucleoside-based DNA methyltransferase inhibitor that induces demethylation and gene reactivation. In the current study, we analyzed the effect of 5-azaC in T-cell function and observed that 5-azaC inhibits T-cell proliferation and activation, blocking cell cycle in the G0 to G1 phase and decreasing the production of proinflammatory cytokines such as tumor necrosis factor-α and interferon-γ. This effect was not attributable to a proapoptotic effect of the drug but to the down-regulation of genes involved in T-cell cycle progression and activation such as CCNG2, MTCP1, CD58, and ADK and up-regulation of genes that induce cell-growth arrest, such as DCUN1D2, U2AF2, GADD45B, or p53. A longer exposure to the drug leads to demethylation of FOXP3 promoter, overexpression of FOXP3, and expansion of regulatory T cells. Finally, the administration of 5-azaC after transplantation prevented the development of graft-versus-host disease, leading to a significant increase in survival in a fully mismatched bone marrow transplantation mouse model. In conclusion, the current study shows the effect of 5-azaC in T lymphocytes and illustrates its role in the allogeneic transplantation setting as an immunomodulatory drug, describing new pathways that must be explored to prevent graft-versus-host disease.
Epigenetic chromatin states uniquely define the developmental plasticity of murine hematopoietic stem cells
Authors: Weishaupt Holger , Sigvardsson Mikael , Attema Joanne L. 
Published: November 2009

Abstract
Heritable epigenetic signatures are proposed to serve as an important regulatory mechanism in lineage fate determination. To investigate this, we profiled chromatin modifications in murine hematopoietic stem cells, lineage-restricted progenitors, and CD4+ T cells using modified genome-scale mini-chromatin immunoprecipitation technology. We show that genes involved in mature hematopoietic cell function associate with distinct chromatin states in stem and progenitor cells, before their activation or silencing upon cellular maturation. Many lineage-restricted promoters are associated with bivalent histone methylation and highly combinatorial histone modification patterns, which may determine their selective priming of gene expression during lineage commitment. These bivalent chromatin states are conserved in mammalian evolution, with a particular overrepresentation of promoters encoding key regulators of hematopoiesis. After differentiation into progenitors and T cells, activating histone modifications persist at transcriptionally repressed promoters, suggesting that these transcriptional programs might be reactivated after lineage restriction. Collectively, our data reveal the epigenetic framework that underlies the cell fate options of hematopoietic stem cells.
Assessment of angiogenesis by CD105 antigen in epithelial salivary gland neoplasms with diverse metastatic behavior
Authors: Cardoso Sergio V , Souza Kelen Christine N , Faria Paulo R , Eisenberg Ana Lucia A , Dias Fernando L , Loyola Adriano M 
Published: November 2009

Abstract

Background
Information on the biology of metastasis development in salivary gland tumors is scarce. Since angiogenesis seems associated with this phenomenon in other tumors, we sought to compare salivary gland tumors with diverse metastatic behavior in order to improve the knowledge and management of these lesions.

Methods
Samples from the most important salivary gland tumors were segregated according to its metastatic behavior and submitted to routine immunohistochemistry to identify vessels positive for CD105 expression. Frequency of positive cases and intratumoral microvessel density (IMD) was compared among the group of lesions.

Results
CD105 positive vessels were absent in normal salivary gland tissue, were rare in pleomorphic adenomas and adenoid cystic carcinomas (ACC), more common in polymorphous low-grade adenocarcinomas and highest in mucoepidermoid carcinomas. Only ACC with such feature were metastatic. IMD was higher in malignant rather than benign tumors.

Conclusion
Immunostaining of CD105 in salivary gland tumors implies participation of angiogenesis in the development of malignant lesions, as well as some role for myoepithelial cells in the control of new vessel formation. In addition, suggest that ACC with positive CD105 vessels are at higher risk for metastasis.