bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inverse Correlation between Tumoral Indoleamine 2,3-Dioxygenase Expression and Tumor-Infiltrating Lymphocytes in Endometrial Cancer: Its Association with Disease Progression and Survival
Authors: Ino Kazuhiko , Yamamoto Eiko , Shibata Kiyosumi , Kajiyama Hiroaki , Yoshida Norio , Terauchi Mikio , Nawa Akihiro , Nagasaka Tetsuro , Takikawa Osamu , Kikkawa Fumitaka 
Published: April 2008

Abstract
Purpose: Tumor escape from host immune systems is a crucial mechanism for disease progression. We recently showed that the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) is a prognostic indicator for endometrial cancer. The purpose of the present study was to investigate the relationship between IDO expression and tumor-infiltrating lymphocytes (TIL) or natural killer (NK) cells and to clarify their prognostic effect in endometrial cancer.
Experimental Design: Immunohistochemical staining for IDO expression in endometrial cancer tissues (n = 65) was done. Tumor-infiltrating CD3+ and CD8+ lymphocytes, as well as CD57+ NK cells, were counted in serial tissue sections.
Results: High IDO expression in tumor cells was found in 32 of 65 cases and was positively correlated with myometrial invasion, nodal metastasis, and lymph-vascular space involvement. We also found a significant correlation between high IDO expression and reduced numbers of CD3+, CD8+, and CD57+ cells infiltrating into both the tumor epithelium and stroma. Patients with high IDO expression, a low number of stromal CD3 (&lt;60), low intraepithelial CD8 (&lt;25), or low stromal CD8 (&lt;40) had significantly impaired progression-free survival. On multivariate analysis, IDO expression and the number of stromal CD3+ TILs were independent prognostic factors for impaired progression-free survival.
Conclusions: Tumoral IDO expression correlated with a reduced number of TILs and NK cells in endometrial cancer, possibly contributing to disease progression and impaired clinical outcome. These findings suggest that targeting IDO to restore host antitumor immunity may be a therapeutic strategy for endometrial cancer.
Vascularization in Primary Breast Carcinomas: Its Prognostic Significance and Relationship with Tumor Cell Dissemination
Authors: Dhakal Hari Prasad , Naume Bjørn , Synnestvedt Marit , Borgen Elin , Kaaresen Rolf , Schlichting Ellen , Wiedswang Gro , Bassarova Assia , Giercksky Karl-Erik , Nesland Jahn M. 
Published: April 2008

Abstract
Purpose: The interaction between tumor cells, stroma, and endothelial cells is important for the dissemination of tumor cells. The aim of the present study is to examine vascularity in primary breast carcinomas and its prognostic significance and relationship with tumor cell dissemination.
Experimental Design: A total of 498 invasive breast carcinomas were analyzed. Representative tumor sections were stained for CD34 and CD105, and vascularity was quantified by the Chalkley method. The relationship between Chalkley counts, vascular invasion, disseminated tumor cells (DTC) in the bone marrow, other clinicopathologic variables, and clinical outcome was evaluated.
Results: High vascular grades determined by Chalkley counts were significantly associated with shorter distant disease–free survival and breast cancer–specific survival in all patients (P &lt; 0.001, log-rank) and in node-negative patients not receiving adjuvant systemic therapy (P &lt; 0.05). In multivariate analysis, both CD34 and CD105 Chalkley counts showed prognostic significance for distant disease–free survival (P = 0.014 and P = 0.026), whereas CD34 also showed prognostic significance for breast cancer–specific survival (P = 0.007). Vascular invasion and DTCs in the bone marrow showed independent prognostic significance. DTC did not discriminate survival for CD34 low Chalkley counts, whereas a very poor prognosis was observed for DTC-positive patients with high CD34 counts. In node-negative patients not receiving systemic chemotherapy, high CD34 and high CD105 counts in combination identified patients with unfavorable outcome, as opposed to all other CD34/CD105 combinations.
Conclusions: Improved identification of risk groups could be obtained by adding CD34 and CD105 vascular analysis to DTC, vascular invasion, and other primary tumor factors. This may facilitate the selection of candidates for adjuvant systemic therapy.
Treatment of Cancer with a Novel Dual-Targeted Conditionally Replicative Adenovirus Armed with mda-7/IL-24 Gene
Authors: Luo Jingjing , Xia Qingmei , Zhang Rui , Lv Chen , Zhang Wei , Wang Yingxin , Cui Qiang , Liu Li , Cai Rong , Qian Cheng 
Published: April 2008

Abstract
Purpose: Recent studies showed that oncolytic adenoviruses not only have capacity for destruction of tumors but also can be used as potential vectors to express therapeutic genes for therapy of cancer. However, better specificity and mode of transgene expression are required to improve the efficacy and safety if this vector is applied for clinical application.
Experimental Design: In this study, we have created adenoviral replication-based transgene expression system by replacement of 6.7K/gp19K of E3 genes with EGFP and IL-24 genes so that expression of transgenes should be controlled by adenoviral E3 promoter. Transgene expression, viral replication capacity, and cytotoxicity have been studied in tumor and normal cells. Antitumor efficacy was evaluated in animal model with established tumor.
Results: Our data showed that expression of IL-24 could be detected at 6 h and reached the maximal level at 48 h after infection in tumor cells. The expression level was 14 times higher than that induced by cytomegalovirus promoter. Low level of IL-24 could be detected in normal cells only until 72 h after infection. The substitution of 6.7K/gp19K of E3 genes with transgenes did not affect viral replication in tumor cells. Strong cytotoxicity was observed only in tumor cells after infection with AdCN205-IL-24. Treatment of the established tumors induced high level of local expression of IL-24 in tumor cells and resulted in tumor regression.
Conclusions: Our data showed that AdCN205-IL-24 can provide potent and safe vector for the therapy of cancer.
Epidermal Growth Factor Receptor Controls Flat Dysplastic Aberrant Crypt Foci Development and Colon Cancer Progression in the Rat Azoxymethane Model
Authors: Dougherty Urszula , Sehdev Amikar , Cerda Sonia , Mustafi Reba , Little Nathaniel , Yuan Weihua , Jagadeeswaran Sujatha , Chumsangsri Anusara , Delgado Jorge , Tretiakova Maria , Joseph Loren , Hart John , Cohen Ezra E.W. , Aluri Lata , Fichera Alessandro , Bissonnette Marc 
Published: April 2008

AbstractPurpose: Colonic carcinogenesis deranges growth-regulating epidermal growth factor receptors (EGFR). We previously showed that EGFR signals were up-regulated in human aberrant crypt foci (ACF), putative colon cancer precursors. The azoxymethane model of colon cancer recapitulates many aspects of human colonic tumors. Recent studies indicate that flat dysplastic ACF with increased β-catenin are tumor precursors in this model. We asked, therefore, if EGFR signals are required for flat dysplastic ACF development and cancer progression.Experimental Design: Rats received azoxymethane or saline, and standard chow or chow supplemented with gefitinib, an EGFR inhibitor, for 44 weeks. EGFR signals were quantified in normal colon, flat ACF, and tumors by computerized analysis of immunostains and Western blots. K-ras mutations were assessed by PCR and mRNA for egfr ligands by quantitative real-time PCR.Results: EGFR inhibition with gefitinib decreased the incidence of flat dysplastic ACF from 66% to 36% and tumors from 71% to 22% (P &lt; 0.05). This inhibitor also reduced the overexpressions of cyclin D1 and Cox-2 in flat ACF. Furthermore, in flat ACF, EGFR blockade decreased the up-regulation of c-Jun, FosB, phosphorylated active signal transducers and activators of transcription 3, and CCAAT/enhancer binding protein-β, potential regulators of cyclin D1 and Cox-2. In colonic tumors, EGFR blockade significantly decreased angiogenesis, proliferation, and progression while also increasing apoptosis (P &lt; 0.05). Gefitinib also inhibited the activations of extracellular signal–regulated kinase, Src, and AKT pathways in tumors.Conclusions: We have shown for the first time that EGFR promotes the development of flat dysplastic ACF and the progression of malignant colonic tumors. Furthermore, we have mechanistically identified several transcription factors and their targets as EGFR effectors in colonic carcinogenesis.
Sensitizing estrogen receptor–negative breast cancer cells to tamoxifen with OSU-03012, a novel celecoxib-derived phosphoinositide-dependent protein kinase-1/Akt signaling inhibitor
Authors: Weng Shu-Chuan , Kashida Yoko , Kulp Samuel K. , Wang Dasheng , Brueggemeier Robert W. , Shapiro Charles L. , Chen Ching-Shih 
Published: April 2008

AbstractTamoxifen is a mainstay in the treatment of estrogen receptor (ER)–positive breast cancer patients. Although the efficacy of tamoxifen has been attributed to induction of tumor cell growth arrest and apoptosis by inhibition of ER signaling, recent evidence indicates that tamoxifen possesses ER-independent antitumor activities. Here, we use OSU-03012, a small-molecule inhibitor of phosphoinositide-dependent protein kinase-1 (PDK-1) to address the hypothesis that PDK-1/Akt signaling represents a therapeutically relevant target to sensitize ER-negative breast cancer to tamoxifen. OSU-03012 sensitized both ER-positive MCF-7 and ER-negative MDA-MB-231 cells to the antiproliferative effects of tamoxifen in an ER-independent manner. Flow cytometric analysis of phosphatidylserine externalization revealed that this augmented suppression of cell viability was attributable to a marked enhancement of tamoxifen-induced apoptosis by OSU-03012. Mechanistically, this OSU-03012-mediated sensitization was associated with suppression of a transient tamoxifen-induced elevation of Akt phosphorylation and enhanced modulation of the functional status of multiple Akt downstream effectors, including FOXO3a, GSK3α/β, and p27. The growth of established MDA-MB-231 tumor xenografts was suppressed by 50% after oral treatment with the combination of tamoxifen (60 mg/kg) and OSU-03012 (100 mg/kg), whereas OSU-03012 and tamoxifen alone suppressed growth by 30% and 0%, respectively. These findings indicate that the inhibition of PDK-1/Akt signaling to sensitize ER-negative breast cancer cells to the ER-independent antitumor activities of tamoxifen represents a feasible approach to extending the use of tamoxifen to a broader population of breast cancer patients. Considering the urgent need for novel therapeutic strategies for ER-negative breast cancer patients, this combinatorial approach is worthy of continued investigation. [Mol Cancer Ther 2008;7(4):800–8]
SUMOylation of HMGA2: selective destabilization of promyelocytic leukemia protein via proteasome
Authors: Cao Xuefei , Clavijo Carlos , Li Xu , Lin H. Helen , Chen Yuan , Shih Hsiu-Ming , Ann David K. 
Published: April 2008

Abstract
The HMGA2 architectural protein functions in a variety of cellular processes, such as cell growth, transcription regulation, neoplastic transformation, and progression. Up-regulation of HMGA2 protein is observed in many tumors and is associated with advanced cancers with poor prognoses. Although the expression and biochemical properties of HMGA2 protein are regulated by microRNA and phosphorylation, it is unknown whether HMGA2 activity can also be regulated by SUMOylation, and that is what is investigated in this report. We identified HMGA2 as a SUMOylation target and showed that the expression of wild-type HMGA2, but not SUMOylation-defective HMGA2(2K/R), selectively lowered the steady-state level of PML protein. Consequently, the HMGA2-elicited PML down-regulation rendered a reduction in the average number of PML nuclear bodies per cell and the volume of PML assembled per PML nuclear body. Using small interfering RNA to suppress endogenous ubiquitin expression and proteasome inhibitor to repress ubiquitin-mediated protein degradation, we showed that HMGA2 confers PML down-regulation through ubiquitin-proteasome–dependent protein degradation. Importantly, arsenic trioxide treatment stimulated HMGA2 SUMOylation, leading to the formation of HMGA2 nuclear foci surrounding PML nuclear bodies and the stimulation of PML degradation. Collectively, our results unveil a previously unrecognized effect by HMGA2 on the modulation of PML protein level, providing a novel mechanism underlying HMGA2 function and underscoring the molecular basis for oncogenic progression by HMGA2. [Mol Cancer Ther 2008;7(4):923–34]
Molecular analysis of metaplastic breast carcinoma: high EGFR copy number via aneusomy
Authors: Gilbert Judith A. , Goetz Matthew P. , Reynolds Carol A. , Ingle James N. , Giordano Karin F. , Suman Vera J. , Blair Hilary E. , Jenkins Robert B. , Lingle Wilma L. , Reinholz Monica M. , Adjei Alex A. , Ames Matthew M. 
Published: April 2008

Abstract
Metaplastic breast carcinoma, a rare tumor composed of adenocarcinomatous and nonglandular growth patterns, is characterized by a propensity for distant metastases and resistance to standard anticancer therapies. We sought confirmation that this tumor is a basal-like breast cancer, expressing epidermal growth factor receptor (EGFR) and stem cell factor receptor (KIT). EGFR activating mutations and high copy number (associated with response to tyrosine kinase inhibitor gefitinib) and KIT activating mutations (associated with imatinib sensitivity) were then investigated. Seventy-seven metaplastic cases were identified (1976-2006); 38 with tumor blocks available underwent pathologic confirmation before EGFR and KIT immunohistochemical analyses. A tissue microarray of malignant glandular and metaplastic elements was constructed and analyzed immunohistochemically for cytokeratin 5/6, estrogen receptor, progesterone receptor, and p63, and by fluorescence in situ hybridization for EGFR and HER-2/neu. DNA isolated from individual elements was assessed for EGFR and KIT activating mutations. All assessable cases were negative for estrogen receptor, progesterone receptor, and (except one) HER2. The majority were positive for cytokeratin 5/6 (58%), p63 (59%), and EGFR overexpression (66%); 24% were KIT positive. No EGFR or KIT activating mutations were present; 26% of the primary metaplastic breast carcinomas were fluorescence in situ hybridization-positive, displaying high EGFR copy number secondary to aneusomy (22%) and amplification (4%). We report here that metaplastic breast carcinoma is a basal-like breast cancer lacking EGFR and KIT activating mutations but exhibiting high EGFR copy number (primarily via aneusomy), suggesting that EGFR tyrosine kinase inhibitors should be evaluated in this molecular subset of breast carcinomas. [Mol Cancer Ther 2008;7(4):944–51]
Genome-wide DNA copy number predictors of lapatinib sensitivity in tumor-derived cell lines
Authors: Greshock Joel , Cheng Jie , Rusnak David , Martin Anne Marie , Wooster Richard , Gilmer Tona , Lee Kwan , Weber Barbara L. , Zaks Tal 
Published: April 2008

Abstract
A common aim of pharmacogenomic studies that use genome-wide assays on panels of cancers is the unbiased discovery of genomic alterations that are associated with clinical outcome and drug response. Previous studies of lapatinib, a selective dual-kinase inhibitor of epidermal growth factor receptor (EGFR) and HER2 tyrosine kinases, have shown predictable relationships between the activity of these target genes and response. Under the hypothesis that additional genes may play a role in drug sensitivity, a predictive model for lapatinib response was constructed from genome-wide DNA copy number data from 24 cancer cell lines. An optimal predictive model which consists of aberrations at nine distinct genetic loci, includes gains of HER2, EGFR, and loss of CDKN2A. This model achieved an area under the receiver operating characteristic curve of ∼0.85 (80% confidence interval, 0.70–0.98; P &lt; 0.01), and correctly classified the sensitivity status of 8 of 10 head and neck cancer cell lines. This study shows that biomarkers predictive for lapatinib sensitivity, including the previously described copy number gains of EGFR and HER2, can be discovered using novel genomic assays in an unbiased manner. Furthermore, these results show the utility of DNA copy number profiles in pharmacogenomic studies. [Mol Cancer Ther 2008;7(4):935–43]
The proximal promoter region of the human vascular endothelial growth factor gene has a G-quadruplex structure that can be targeted by G-quadruplex–interactive agents
Authors: Sun Daekyu , Liu Wei-Jun , Guo Kexiao , Rusche Jadrian J. , Ebbinghaus Scot , Gokhale Vijay , Hurley Laurence H. 
Published: April 2008

Abstract
Previous studies on the functional analysis of the human vascular endothelial growth factor (VEGF) promoter using the full-length VEGF promoter reporter revealed that the proximal 36-bp region (−85 to −50 relative to transcription initiation site) is essential for basal or inducible VEGF promoter activity in several human cancer cells. This region consists of a polypurine (guanine) tract that contains four runs of at least three contiguous guanines separated by one or more bases, thus conforming to a general motif capable of forming an intramolecular G-quadruplex. Here, we show that the G-rich strand in this region is able to form an intramolecular propeller-type parallel-stranded G-quadruplex structure in vitro by using the electrophoretic mobility shift assay, dimethyl sulfate footprinting technique, the DNA polymerase stop assay, circular dichroism spectroscopy, and computer-aided molecular modeling. Two well-known G-quadruplex–interactive agents, TMPyP4 and Se2SAP, stabilize G-quadruplex structures formed by this sequence in the presence of a potassium ion, although Se2SAP is at least 10-fold more effective in binding to the G-quadruplex than TMPyP4. Between these two agents, Se2SAP better suppresses VEGF transcription in different cancer cell lines, including HEC1A and MDA-MB-231. Collectively, our results provide evidence that specific G-quadruplex structures can be formed in the VEGF promoter region, and that the transcription of this gene can be controlled by ligand-mediated G-quadruplex stabilization. Our results also provide further support for the idea that G-quadruplex structures may play structural roles in vivo and therefore might provide insight into novel methodologies for rational drug design. [Mol Cancer Ther 2008;7(4):880–9]
Histone tail modifications and noncanonical functions of histones: perspectives in cancer epigenetics
Authors: Hadnagy Annamaria , Beaulieu Raymond , Balicki Danuta 
Published: April 2008

Abstract
Over the past few years, the histone deacetylase (HDAC) inhibitors have occupied an important place in the effort to develop novel, but less toxic, anticancer therapy. HDAC inhibitors block HDACs, which are the enzymes responsible for histone deacetylation, and therefore they modulate gene expression. The cellular effects of HDAC inhibitors include growth arrest and the induction of differentiation. Early successes in cancer therapeutics obtained using these drugs alone or in combination with other anticancer drugs emphasize the important place of posttranslational modifications of histones in cancer therapy. Histone tail modifications along with DNA methylation are the most studied epigenetic events related to cancer progression. Moreover, extranuclear functions of histones have also been described. Because HDAC inhibitors block HDACs and thereby increase histone acetylation, we propose a model wherein exogenous acetylated histones or other related acetylated proteins that are introduced into the nucleus become HDAC substrates and thereby compete with endogenous histones for HDACs. This competition may lead to the increased acetylation of the endogenous histones, as in the case of HDAC inhibitor therapy. Moreover, other mechanisms of action, such as binding to chromatin and modulating gene expression, are also possible for exogenously introduced histones. [Mol Cancer Ther 2008;7(4):740–8]
Operational Multiple-Doppler Wind Retrieval Inferred from Long-Range Radial Velocity Measurements
Authors: Bousquet Olivier , Tabary Pierre , Parent du Châtelet Jacques 
Published: April 2008

Abstract
The recent deployment of an innovative triple pulse rise time (PRT) scheme within the French operational radar network allows for the simultaneous collection of reflectivity and radial velocity measurements up to a range of 250 km with no ambiguity. This achievement brings new perspectives in terms of operational exploitation of Doppler measurements including the capability to consistently perform multiple-Doppler wind synthesis in a fully operational framework. Using real and simulated Doppler observations, the authors show that the 3D wind fields retrieved in that framework can definitely be relied upon to achieve a consistent and detailed mapping of the airflow structure in various precipitation regimes despite radar baselines averaging ∼180 km and very limited scanning strategies. This achievement could be easily transposed to other operational networks and represents a remarkable opportunity to add further value to operational Doppler velocity measurements.
A Probabilistic Analysis of the Dynamics and Predictability of Tropical Cyclogenesis
Authors: Sippel Jason A. , Zhang Fuqing 
Published: April 2008

Abstract
Using methods unique for tropical cyclone studies in peer-reviewed literature, this study examines the dynamics and predictability of a nondeveloping tropical disturbance in the Gulf of Mexico during the 2004 hurricane season. Short-range ensemble forecasts are performed with a mesoscale model at low resolution with parameterized moist convection and at high resolution with explicit convection. Taking advantage of discrepancies between ensemble members, statistical correlation is used to elucidate why some ensemble members strengthen the disturbance into a tropical cyclone or hurricane and others do not.
It is found that the two most important factors in the initial conditions for genesis in this case are the presence of deep moisture and high CAPE. These factors combine to yield more active initial convection and a quick spinup during the first 6–12 h. Because these factors result in quicker genesis in some ensemble members than others, they are also the primary source for spread early in the ensemble. Discrepancies after 12 h are amplified by differences in convection that are related to fluxes of sensible and latent heat. Eventually the wind-induced surface heat exchange mechanism results in even larger ensemble spread.