bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of the Microenvironment for Radiosensitization by Patupilone
Authors: Bley Carla Rohrer , Jochum Wolfram , Orlowski Katrin , Furmanova Polina , Vuong Van , McSheehy Paul M.J. , Pruschy Martin 
Published: February 2009

Abstract
Purpose: The combined treatment modality of ionizing radiation (IR) and the clinically relevant microtubule-stabilizing compound patupilone (epothilone B, EPO906) is a promising approach for anticancer therapy. Here, we investigated the role of the tumor microenvironment for the supra-additive in vivo response in tumor xenografts derived from patupilone-sensitive and patupilone-resistant non-small cell lung cancer cells.
Experimental Design: The treatment response to a combined regimen of patupilone and IR was investigated in vitro and in tumor xenografts derived from wild-type A549 and A549.EpoB40 cells, which are resistant to patupilone due to a β-tubulin mutation.
Results: In both A549 and A549.EpoB40 cells, proliferative activity and clonogenicity were reduced in response to IR, whereas patupilone, as expected, inhibited proliferation of the mutant cell line with reduced potency. Combined treatment with patupilone and IR induced a cytotoxic effect in vitro in an additive way in A549 cells but not in the tubulin-mutated, patupilone-resistant A549.EpoB40 cells. A supra-additive tumor growth delay was induced by combined treatment in xenografts derived from A549 cells but not in xenografts derived from A549.EpoB40 cells. Histologic analysis revealed a significant decrease in tumor cell proliferation (Ki-67) and microvessel density and a treatment-dependent change of tumor hypoxia in A549 but not A549.EpoB40 xenografts.
Conclusions: Using a genetically defined patupilone-sensitive and patupilone-resistant tumor model, we here showed that the major cytotoxic effect of the combined treatment modality of IR and patupilone is directed against the tumor cell compartment. The induced antiangiogenic effect derives indirectly from the tumor cell.
A TaqMan Low-Density Array to Predict Outcome in Advanced Hodgkin's Lymphoma Using Paraffin-Embedded Samples
Authors: Sánchez-Espiridión Beatriz , Sánchez-Aguilera Abel , Montalbán Carlos , Martin Carmen , Martinez Rafael , González-Carrero Joaquín , Poderos Concepción , Bellas Carmen , Fresno Manuel F. , Morante Cesar , Mestre Maria J. , Mendez Miguel , Mazorra Francisco , Conde Eulogio , Castaño Angel , Sánchez-Godoy Pedro , Tomas José F. , Morente Manolo M. , Piris Miguel A. , García Juan F. ,   for the Spanish Hodgkin's Lymphoma Study Group
Published: February 2009

Abstract
Purpose: Despite major advances in the treatment of classic Hodgkin's lymphoma (cHL), ∼30% of patients in advanced stages may eventually die as result of the disease, and current methods to predict prognosis are rather unreliable. Thus, the application of robust techniques for the identification of biomarkers associated with treatment response is essential if new predictive tools are to be developed.
Experimental Design: We used gene expression data from advanced cHL patients to identify transcriptional patterns from the tumoral cells and their nonneoplastic microenvironment, associated with lack of maintained treatment response. Gene-Set Enrichment Analysis was used to identify functional pathways associated with unfavorable outcome that were significantly enriched in either the Hodgkin's and Reed-Sternberg cells (regulation of the G2-M checkpoint, chaperones, histone modification, and signaling pathways) or the reactive cell microenvironment (mainly represented by specific T-cell populations and macrophage activation markers).
Results: To explore the pathways identified previously, we used a series of 52 formalin-fixed paraffin-embedded advanced cHL samples and designed a real-time PCR-based low-density array that included the most relevant genes. A large majority of the samples (82.7%) and all selected genes were analyzed successfully with this approach.
Conclusions: The results of this assay can be combined in a single risk score integrating these biological pathways associated with treatment response and eventually used in a larger series to develop a new molecular outcome predictor for advanced cHL.
Preclinical Studies in Support of Defibrotide for the Treatment of Multiple Myeloma and Other Neoplasias
Authors: Mitsiades Constantine S. , Rouleau Cecile , Echart Cinara , Menon Krishna , Teicher Beverly , Distaso Maria , Palumbo Antonio , Boccadoro Mario , Anderson Kenneth C. , Iacobelli Massimo , Richardson Paul G. 
Published: February 2009

Abstract
Purpose of the Study: Defibrotide, an orally bioavailable polydisperse oligonucleotide, has promising activity in hepatic veno-occlusive disease, a stem cell transplantation–related toxicity characterized by microangiopathy. The antithrombotic properties of defibrotide and its minimal hemorrhagic risk could serve for treatment of cancer-associated thrombotic complications. Given its cytoprotective effect on endothelium, we investigated whether defibrotide protects tumor cells from cytotoxic antitumor agents. Further, given its antiadhesive properties, we evaluated whether defibrotide modulates the protection conferred to multiple myeloma cells by bone marrow stromal cells.
Methods-Results: Defibrotide lacks significant single-agent in vitro cytotoxicity on multiple myeloma or solid tumor cells and does not attenuate their in vitro response to dexamethasone, bortezomib, immunomodulatory thalidomide derivatives, and conventional chemotherapeutics, including melphalan and cyclophosphamide. Importantly, defibrotide enhances in vivo chemosensitivity of multiple myeloma and mammary carcinoma xenografts in animal models. In cocultures of multiple myeloma cells with bone marrow stromal cells in vitro, defibrotide enhances the multiple myeloma cell sensitivity to melphalan and dexamethasone, and decreases multiple myeloma–bone marrow stromal cell adhesion and its sequelae, including nuclear factor-κB activation in multiple myeloma and bone marrow stromal cells, and associated cytokine production. Moreover, defibrotide inhibits expression and/or function of key mediators of multiple myeloma interaction with bone marrow stromal cell and endothelium, including heparanase, angiogenic cytokines, and adhesion molecules.
Conclusion: Defibrotide's in vivo chemosensitizing properties and lack of direct in vitro activity against tumor cells suggest that it favorably modulates antitumor interactions between bone marrow stromal cells and endothelia in the tumor microenvironment. These data support clinical studies of defibrotide in combination with conventional and novel therapies to potentially improve patient outcome in multiple myeloma and other malignancies.
Overexpression of Class III β-Tubulin Predicts Good Response to Taxane-Based Chemotherapy in Ovarian Clear Cell Adenocarcinoma
Authors: Aoki Daisuke , Oda Yoshinao , Hattori Satoshi , Taguchi Ken-ichi , Ohishi Yoshihiro , Basaki Yuji , Oie Shinji , Suzuki Nao , Kono Suminori , Tsuneyoshi Masazumi , Ono Mayumi , Yanagawa Takashi , Kuwano Michihiko 
Published: February 2009

AbstractPurpose: Of the various microtubule-associated molecules, β-tubulin III has been reported to be closely associated with the therapeutic efficacy of taxane-based chemotherapy against ovarian cancer. Stathmin and microtubule-associated protein 4 (MAP4) have been reported to play an important role in microtubule stabilization. In this study, we investigated whether expression of these microtubule-associated factors affects the therapeutic efficacy of taxane-based chemotherapy in ovarian clear cell adenocarcinoma.Experimental Design: Drug sensitivity of paclitaxel or cisplatin was assessed in ovarian cancer cell lines treated with small interfering RNA of tubulin isoforms, MAP4, and stathmin. We examined 94 surgically resected ovarian clear cell adenocarcinoma specimens from patients treated with taxane-containing regimens (n = 44) and with taxane-free regimens (n = 50), using immunohistochemistry to detect expression of β-tubulin III, stathmin, and MAP4.Results: Knockdown of β-tubulin III and IV specifically conferred drug resistance to paclitaxel in one ovarian cancer cell line, but not to other molecules. Estimated overall survival revealed a significant synergistic effect between taxane and β-tubulin III in patients with ovarian clear cell adenocarcinoma. Of three microtubule-related molecules, among the taxane-based chemotherapy group, cases with higher β-tubulin III expression were associated with a significantly more favorable prognosis compared with those having lower β-tubulin III expression. By contrast, there was no statistical significance in the synergistic relationships between stathmin and taxane or between MAP4 and taxane.Conclusions: Taxane-based chemotherapy was effective for patients with ovarian clear cell adenocarcinomas who were positive for β-tubulin III but not for those who were negative for these proteins.
Pharmacologic Unmasking of Epigenetically Silenced Genes in Breast Cancer
Authors: Ostrow Kimberly Laskie , Park Hannah Lui , Hoque Mohammad Obaidul , Kim Myoung Sook , Liu Junwei , Argani Pedram , Westra William , Criekinge Wim Van , Sidransky David 
Published: February 2009

AbstractPurpose: Aberrant promoter hypermethylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of various cancers including breast cancer. Many epigenetically inactivated genes involved in breast cancer development remain to be identified. Therefore, in this study we used a pharmacologic unmasking approach in breast cancer cell lines with 5-aza-2′-deoxycytidine (5-aza-dC) followed by microarray expression analysis to identify epigenetically inactivated genes in breast cancer.Experimental Design: Breast cancer cell lines were treated with 5-aza-dC followed by microarray analysis to identify epigenetically inactivated genes in breast cancer. We then used bisulfite DNA sequencing, conventional methylation-specific PCR, and quantitative fluorogenic real-time methylation-specific PCR to confirm cancer-specific methylation in novel genes.Results: Forty-nine genes were up-regulated in breast cancer cells lines after 5-aza-dC treatment, as determined by microarray analysis. Five genes (MAL, FKBP4, VGF, OGDHL, and KIF1A) showed cancer-specific methylation in breast tissues. Methylation of at least two was found at high frequency only in breast cancers (40 of 40) as compared with normal breast tissue (0 of 10; P &lt; 0.0001, Fisher's exact test).Conclusions: This study identified new cancer-specific methylated genes to help elucidate the biology of breast cancer and as candidate diagnostic markers for the disease.
Curcumin Inhibits Prosurvival Pathways in Chronic Lymphocytic Leukemia B Cells and May Overcome Their Stromal Protection in Combination with EGCG
Authors: Ghosh Asish K. , Kay Neil E. , Secreto Charla R. , Shanafelt Tait D. 
Published: February 2009

AbstractPurpose: Chronic lymphocytic leukemia (CLL) is incurable with current chemotherapy treatments. Curcumin (diferuloylmethane), an active ingredient in the spice turmeric, inhibits tumor metastasis, invasion, and angiogenesis in tumor cell lines. We evaluated the effects of curcumin on the viability of primary CLL B cells and its ability to overcome stromal mediated protection.Experimental Design: The in vitro effect of curcumin on primary CLL B cells was evaluated using fluorescence activated cell sorter analysis and Western blotting. For some experiments, CLL B cells were cocultured with human stromal cells to evaluate the effects of curcumin on leukemia cells cultured in their microenvironment. Finally, the effect of curcumin in combination with the green tea extract epigallocatechin-3 gallate (EGCG) was evaluated.Results: Curcumin induced apoptosis in CLL B cells in a dose-dependent (5-20 μmol/L) manner and inhibited constitutively active prosurvival pathways, including signal transducers and activators of transcription 3 (STAT3), AKT, and nuclear factor κB. Moreover, curcumin suppressed expression of the anti-apoptotic proteins Mcl-1 and X-linked inhibitor of apoptosis protein (XIAP), and up-regulated the pro-apoptotic protein BIM. Coculture of CLL B cells with stromal cells resulted in elevated levels of STAT3, increased expression of Mcl-1 and XIAP, and decreased sensitivity to curcumin. When curcumin was administered simultaneously with EGCG, antagonism was observed for most patient samples. In contrast, sequential administration of these agents led to substantial increases in CLL B-cell death and could overcome stromal protection.Conclusions: Curcumin treatment was able to overcome stromal protection of CLL B cells on in vitro testing and to synergize with EGCG when administered in a sequential fashion. Additional evaluation of curcumin as a potential therapeutic agent for treatment of CLL seems warranted.
Soy-Derived Isoflavones Inhibit the Growth of Canine Lymphoid Cell Lines
Authors: Jamadar-Shroff Vahbiz , Papich Mark G. , Suter Steven E. 
Published: February 2009

AbstractPurpose: This study aimed to evaluate the in vitro effects of genistein, both pure genistein and a commercially available form of genistein called Genistein Combined Polysacharride (GCP), against two canine B-cell lymphoid cell lines and determine the oral bioavailability of GCP when fed to normal dogs.Experimental Design: The in vitro effect of genistein and GCP was evaluated using cell proliferation and apoptotic assays. The IC50 of both compounds was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation assay and propidium idodide staining. Apoptosis was evaluated using Annexin V staining, caspase 3 and 9 staining, and DNA laddering. Cell cycle analysis and Bcl-2/Bax ratios were also examined. An initial dose escalating pharmacokinetic study was used to determine if therapeutic serum levels of genistein could be reached with oral dosing of GCP in normal dogs.Results: The 72-hour in vitro IC50 of genistein and GCP against the GL-1 and 17-71 cells were both 10 μg/mL and 20 μg/mL, respectively. GCP led to cell death in both cell lines via apoptosis and treated cells exhibited increased Bax:Bcl-2 ratios. The serum concentrations of genistein in normal dogs given increasing oral doses of GCP did not reach the 72-hour in vitro IC50 in a dose escalation study.Conclusions: The results of these studies support the notion that canine high-grade B-cell lymphoma may represent a relevant large animal model of human non-Hodgkin's lymphoma to investigate the utility of GCP in chemopreventive and/or treatment strategies that may serve as a prelude to human clinical lymphoma trials.
A Genetic Expression Profile Associated with Oral Cancer Identifies a Group of Patients at High Risk of Poor Survival
Authors: Méndez Eduardo , Houck John R. , Doody David R. , Fan Wenhong , Lohavanichbutr Pawadee , Rue Tessa C. , Yueh Bevan , Futran Neal D. , Upton Melissa P. , Farwell D. Gregory , Heagerty Patrick J. , Zhao Lue Ping , Schwartz Stephen M. , Chen Chu 
Published: February 2009

Abstract
Purpose: To determine if gene expression signature of invasive oral squamous cell carcinoma (OSCC) can subclassify OSCC based on survival.
Experimental Design: We analyzed the expression of 131 genes in 119 OSCC, 35 normal, and 17 dysplastic mucosa to identify cluster-defined subgroups. Multivariate Cox regression was used to estimate the association between gene expression and survival. By stepwise Cox regression, the top predictive models of OSCC-specific survival were determined and compared by receiver operating characteristic analysis.
Results: The 3-year overall mean ± SE survival for a cluster of 45 OSCC patients was 38.7 ± 0.09% compared with 69.1 ± 0.08% for the remaining patients. Multivariate analysis adjusted for age, sex, and stage showed that the 45 OSCC patient cluster had worse overall and OSCC-specific survival (hazard ratio, 3.31; 95% confidence interval, 1.66-6.58 and hazard ratio, 5.43; 95% confidence interval, 2.32-12.73, respectively). Stepwise Cox regression on the 131 probe sets revealed that a model with a term for LAMC2 (laminin γ2) gene expression best identified patients with worst OSCC-specific survival. We fit a Cox model with a term for a principal component analysis-derived risk score marker and two other models that combined stage with either LAMC2 or PCA. The area under the curve for models combining stage with either LAMC2 or PCA was 0.80 or 0.82, respectively, compared with 0.70 for stage alone (P = 0.013 and 0.008, respectively).
Conclusions: Gene expression and stage combined predict survival of OSCC patients better than stage alone.
Combining the Endoplasmic Reticulum Stress–Inducing Agents Bortezomib and Fenretinide as a Novel Therapeutic Strategy for Metastatic Melanoma
Authors: Hill David S. , Martin Shaun , Armstrong Jane L. , Flockhart Ross , Tonison Joge J. , Simpson Dominic G. , Birch-Machin Mark A. , Redfern Christopher P.F. , Lovat Penny E. 
Published: February 2009

AbstractPurpose: Single-agent chemotherapy is largely the treatment of choice for systemic therapy of metastatic melanoma, but survival rates are low, and novel adjuvant and systemic therapies are urgently required. Endoplasmic reticulum (ER) stress is a potential therapeutic target, and two relatively new drugs, fenretinide and bortezomib (Velcade), each acting via different cellular mechanisms, induce ER stress leading to apoptosis in melanoma cells. The aim of this study was to test the hypothesis that apoptosis of melanoma cells may be increased by combining clinically achievable concentrations of fenretinide and bortezomib.Experimental Design: Three human melanoma cell lines were used to assess changes in viability and the induction of apoptosis in response to fenretinide, bortezomib, or both drugs together. A s.c. xenograft model was used to test responses in vivo.Results: Fenretinide and bortezomib synergistically decreased viability and increased apoptosis in all three melanoma lines at clinically achievable concentrations. This was also reflected by increased expression of GADD153, a marker of ER stress-induced apoptosis. In vivo, fenretinide in combination with bortezomib gave a marked reduction in xenograft tumor volume and an increase in apoptosis compared with fenretinide or bortezomib alone. The cell cycle stage of tumor cells in vivo were similar to that predicted from the effects of each drug or the combination in vitro.Conclusions: These results suggest that fenretinide and bortezomib, both of which are available in clinical formulation, warrant clinical evaluation as a combination therapy for metastatic melanoma.
Q 4:24 revisited
Authors: Witztum Joseph 
Published: February 2009

AbstractQ 4:24 has presented a challenge to classical exegetes and modern scholars alike. Examining Quranic evidence and the exegetical tradition, this article offers a textual analysis of this verse and suggests a new reading. I argue that the first part of Q 4:24 is an independent sentence; that an erroneous reading of it as a continuation of the previous verse led to the replacement of the original meaning of muhsināt (chaste women) with married women; and that there is a strong case for understanding the second part of the verse as addressing mut'a.
Sources of Moral Obligation to non-Muslims in the "Jurisprudence of Muslim Minorities" (Fiqh al-aqalliyyāt) Discourse
Authors: March Andrew 
Published: February 2009

AbstractThis article surveys four approaches towards moral obligation to non-Muslims found in Islamic legal thought. I refer to the first three approaches as the "revelatory-deontological," the "contractualist-constructivist" and the "consequentialist-utilitarian." The main argument is that present in many contemporary works on the "jurisprudence of Muslim minorities" (fiqh al-aqalliyyāt) is an attempt to provide an Islamic foundation for a relatively thick and rich relationship of moral obligation and solidarity with non-Muslims. This attempt takes the form of a fourth "comprehensive-qualitative" approach to political ethics that appeals not to juridical reasoning of the type "is x permissible and in which conditions?" but rather to Islamic ideals of what it means to live a good life, of what believing, normatively-committed Muslims want to pursue in this world. This meta-ethical approach builds on and goes beyond the first three. This fourth "comprehensive-qualitative" approach to moral obligation to non-Muslims is novel, emergent and not found in the writings of outright reformers but in those of conservative, "neo-classical," sharī'a-minded—even Muslim Brotherhood-affiliated—Muslim scholars. What adds to the force of this argument is that the other meta-ethical discourses, particularly of contract and utility (maslaha), already get these scholars quite far towards a doctrine of "loyal resident alienage" in non-Muslim societies. That even orthodox Muslim scholars go further shows that they have some interest in giving a theological or principled foundation to a much thicker and richer form of moral obligation to non-Muslims, a relationship which involves recognizing non-Muslims qua non-Muslims and contributing to their well-being.
Feminei Furores. Prudentius' Hamartigenia and the Epigramma Paulini
Authors: Chiappiniello Roberto 
Published: February 2009

AbstractThe Epigramma Paulini is a late antique Gallo-Roman poem of uncertain authorship which contains a dialogue structured on the model of the first Vergilian Eclogue. It is an unusual pastoral poem as it blends pastoral with satire. Recent scholarship has focused on the way the author of the Epigramma Paulini adapts the Vergilian model to suit his Christian message. The aim of this paper is to explore more fully the satirical section of the poem and, in particular, the lines focusing on Roman vices which contain a striking attenuation of the topos of misogyny. I seek to show through verbal and thematic similarities that the model for this part of the poem is the Hamartigenia of Prudentius.
Cloning and expression of PKG, a candidate foraging regulating gene in Vespula vulgaris
Authors: Tobback Julie , Heylen Kevin , Gobin Bruno , Wenseleers Tom , Billen Johan , Arckens Lut , Huybrechts Roger 
Published: February 2009

Abstract
In honey bees, enhancement of cGMP-dependent protein kinase (PKG) expression accompanies a behavioural transition from in-hive working nursing bees towards outdoors foraging worker bees. Accordingly this gene was named amfor or Apis mellifera foraging gene. In the red harvester ant Pogonomyrmex barbatus a gene homologue affected food seeking behaviour as well, but in this species PKG expression decreased from the onset of foraging behaviour. Since the wasp Vespula vulgaris is phylogenetically positioned between ants and bees, in this paper we tried to elucidate whether the involvement of PKG in foraging behaviour can be extended to this species and if so, whether its expression is enhanced or decreased by the transition from nursing to foraging. To enable this candidate gene approach, we first had to clone the PKG homologue from the common wasp. QPCR indicated a relevantly higher expression of Vvfor in nursing versus foraging wasps although interpretation of the results was hampered by a remarkable degree of variation as could be predicted from wasps captured in the wild as a source for mRNA extraction and quantification.