bluuebunny/crossref_metadata_2025_split huggingface dataset:
The p50 Subunit of NF-κB Is Critical for In Vivo Clearance of the Noninvasive Enteric PathogenCitrobacter rodentium
Authors: Dennis Alison , Kudo Takahiro , Kruidenier Laurens , Girard Francis , Crepin Valerie F. , MacDonald Thomas T. , Frankel Gad , Wiles Siouxsie 
Published: August 2008

ABSTRACTCitrobacter rodentium, a natural mouse pathogen, belongs to the family of extracellular enteric pathogens that includes enteropathogenicEscherichia coli(EPEC) and enterohemorrhagicE. coli(EHEC).C. rodentiumshares many virulence factors with EPEC and EHEC and relies on attaching-and-effacing lesion formation for colonization and infection of the gut. In vivo,C. rodentiuminfection is characterized by increased epithelial cell proliferation, mucosal thickening, and a TH1-type immune response, but with protective immunity believed to be mediated by serum immunoglobulin G (IgG). In this work, we characterize the immune response and pathology of mice lacking the p50 subunit of the transcription factor nuclear factor kappa B (NF-κB) duringC. rodentiuminfection. We show that p50−/−mice are unable to clearC. rodentiuminfection. Furthermore, these animals show a reduced influx of immune cells into infected colonic tissue and greater levels of mucosal hyperplasia and the cytokines tumor necrosis factor alpha and gamma interferon. Surprisingly, despite being unable to eliminate infection, p50−/−mice showed markedly higher levels of anti-CitrobacterIgG and IgM, suggesting that antibody alone is not responsible for bacterial clearance. These data also demonstrate that non-NF-κB-dependent defenses are insufficient to controlC. rodentiuminfection, and hence, the NF-κB p50 subunit is critical for defense against this noninvasive pathogen.
Analysis of Competing Risks of Causes of Death and their Variation Over Different Time Periods in Hodgkin's Disease
Authors: Provencio Mariano , Millán Isabel , España Pilar , Sánchez Antonio C. , Sánchez José J. , Cantos Blanca , Vargas Juan A. , Bellas Carmen , García Vanesa , Sabin Pilar , Bonilla Félix 
Published: August 2008

Abstract
Purpose: Hodgkin's disease is considered a model of curable illness. However, long-term studies show excessive mortality in relation to the general population. We studied the various causes of death by use of competing risks and their evolution over the years.
Experimental Design: All patients diagnosed with Hodgkin's disease at our institution between 1967 and 2003 were included. The competing risks of causes of death and their vital situation were examined in three time periods: cohort A with patients treated before 1980, cohort B with patients treated from 1981 to 1986, and cohort C with patients treated from 1986 onwards.
Results: We studied 534 patients, with a median follow-up time of 9.1 years for the whole cohort. The 5-year, 15-year, and 20-year Kaplan-Meier survival estimates for all patients were 81%, 72%, and 65%, respectively. At the close of the study, 337 (63.1%) were alive and 170 (31.8%) patients had died. The most common cause of death was the progression of Hodgkin's disease, followed by deaths due to a second tumor. Survival was significantly worse in the first period than in the other two (P &lt; 0.001), and in the three periods, the main cause of death was tumor progression.
Conclusions: The progression of Hodgkin's disease is the main cause of death. Over time, a reduction in death related to infection and the acute toxicity of treatment was seen. A lot of patients still die for reasons linked to delayed side effects of radiotherapy, such as second tumors and heart disease, which is important to plan preventive activities and clinical research.
Proteasome Inhibition Activates Epidermal Growth Factor Receptor (EGFR) and EGFR-Independent Mitogenic Kinase Signaling Pathways in Pancreatic Cancer Cells
Authors: Sloss Callum M. , Wang Fang , Liu Rong , Xia Lijun , Houston Michael , Ljungman David , Palladino Michael A. , Cusack James C. 
Published: August 2008

Abstract
Purpose: In the current study, we investigate the activation of antiapoptotic signaling pathways in response to proteasome inhibitor treatment in pancreatic cancer and evaluate the use of concomitant inhibition of these pathways to augment proteasome inhibitor treatment responses.
Experimental Design: Pancreatic cancer cell lines and mouse flank xenografts were treated with proteasome inhibitor alone or in combination with chemotherapeutic compounds (gemcitabine, erlotinib, and bevacizumab), induction of apoptosis and effects on tumor growth were assessed. The effect of bortezomib (a first-generation proteasome inhibitor) and NPI-0052 (a second-generation proteasome inhibitor) treatment on key pancreatic mitogenic and antiapoptotic pathways [epidermal growth factor receptor, extracellular signal-regulated kinase, and phosphoinositide-3-kinase (PI3K)/AKT] was determined and the ability of inhibitors of these pathways to enhance the effects of proteasome inhibition was assessed in vitro and in vivo.
Results: Our data showed that proteasome inhibitor treatment activates antiapoptotic and mitogenic signaling pathways (epidermal growth factor receptor, extracellular signal-regulated kinase, c-Jun-NH2-kinase, and PI3K/AKT) in pancreatic cancer. Additionally, we found that activation of these pathways impairs tumor response to proteasome inhibitor treatment and inhibition of the c-Jun-NH2-kinase and PI3K/AKT pathways increases the antitumor effects of proteasome inhibitor treatment.
Conclusion: These preclinical studies suggest that targeting proteasome inhibitor–induced antiapoptotic signaling pathways in combination with proteasome inhibition may augment treatment response in highly resistant solid organ malignancies. Further evaluation of these novel treatment combinations in clinical trials is warranted.
High Expression of Neuropeptide Y1 Receptors in Ewing Sarcoma Tumors
Authors: Körner Meike , Waser Beatrice , Reubi Jean Claude 
Published: August 2008

AbstractPurpose: Peptide receptors are frequently overexpressed in human tumors, allowing receptor-targeted scintigraphic imaging and therapy with radiolabeled peptide analogues. Neuropeptide Y (NPY) receptors are new candidates for these applications, based on their high expression in specific cancers. Because NPY receptors are expressed in selected sarcoma cell lines and because novel treatment options are needed for sarcomas, this study assessed the NPY receptor in primary human sarcomas.Experimental Design: Tumor tissues of 88 cases, including Ewing sarcoma family of tumors (ESFT), synovial sarcomas, osteosarcomas, chondrosarcomas, liposarcomas, angiosarcomas, rhabdomyosarcomas, leiomyosarcomas, and desmoid tumors, were investigated for NPY receptor protein with in vitro receptor autoradiography using 125I-labeled NPY receptor ligands and for NPY receptor mRNA expression with in situ hybridization.Results: ESFT expressed the NPY receptor subtype Y1 on tumor cells in remarkably high incidence (84%) and density (mean, 5,314 dpm/mg tissue). Likewise, synovial sarcomas expressed Y1 on tumor cells in high density (mean, 7,497 dpm/mg; incidence, 40%). The remaining tumors expressed NPY receptor subtypes Y1 or Y2 at lower levels. Moreover, many of the sarcomas showed Y1 expression on intratumoral blood vessels. In situ hybridization for Y1 mRNA confirmed the autoradiography results.Conclusions: NPY receptors are novel molecular markers for human sarcomas. Y1 may inhibit growth of specific sarcomas, as previously shown in an in vivo mouse model of human ESFT. The high Y1 expression on tumor cells of ESFT and synovial sarcomas and on blood vessels in many other sarcomas represents an attractive basis for an in vivo tumor targeting.
Overexpression of Stromal Cell–Derived Factor 1 and Its Receptor CXCR4 Induces Autocrine/Paracrine Cell Proliferation in Human Pituitary Adenomas
Authors: Barbieri Federica , Bajetto Adriana , Stumm Ralf , Pattarozzi Alessandra , Porcile Carola , Zona Gianluigi , Dorcaratto Alessandra , Ravetti Jean-Louis , Minuto Francesco , Spaziante Renato , Schettini Gennaro , Ferone Diego , Florio Tullio 
Published: August 2008

Abstract
Purpose: Hypothalamic or locally produced growth factors and cytokines control pituitary development, functioning, and cell division. We evaluated the expression of the chemokine stromal cell–derived factor 1 (SDF1) and its receptor CXCR4 in human pituitary adenomas and normal pituitary tissues and their role in cell proliferation.
Experimental Design: The expression of SDF1 and CXCR4 in 65 human pituitary adenomas and 4 human normal pituitaries was determined by reverse transcription-PCR, immunohistochemistry, and confocal immunofluorescence. The proliferative effect of SDF1 was evaluated in eight fibroblast-free human pituitary adenoma cell cultures.
Results: CXCR4 mRNA was expressed in 92% of growth hormone (GH)-secreting pituitary adenomas (GHoma) and 81% of nonfunctioning pituitary adenomas (NFPA), whereas SDF1 was identified in 63% and 78% of GHomas and NFPAs, respectively. Immunostaining for CXCR4 and SDF1 showed a strong homogenous labeling in all tumoral cells in both GHomas and NFPAs. In normal tissues, CXCR4 and SDF1 were expressed only in a subset of anterior pituitary cells, with a lower expression of SDF1 compared with its cognate receptor. CXCR4 and SDF1 were not confined to a specific cell population in the anterior pituitary but colocalized with discrete subpopulations of GH-, prolactin-, and adrenocorticorticotropic hormone–secreting cells. Conversely, most of the SDF1-containing cells expressed CXCR4. In six of eight pituitary adenoma primary cultures, SDF1 induced a statistically significant increase in DNA synthesis that was prevented by the treatment with the CXCR4 antagonist AMD3100 or somatostatin.
Conclusions: CXCR4 and SDF1 are overexpressed in human pituitary adenomas and CXCR4 activation may contribute to pituitary cell proliferation and, possibly, to adenoma development `in humans.
Biological Processes Associated with Breast Cancer Clinical Outcome Depend on the Molecular Subtypes
Authors: Desmedt Christine , Haibe-Kains Benjamin , Wirapati Pratyaksha , Buyse Marc , Larsimont Denis , Bontempi Gianluca , Delorenzi Mauro , Piccart Martine , Sotiriou Christos 
Published: August 2008

Abstract
Purpose: Recently, several prognostic gene expression signatures have been identified; however, their performance has never been evaluated according to the previously described molecular subtypes based on the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2), and their biological meaning has remained unclear. Here we aimed to perform a comprehensive meta-analysis integrating both clinicopathologic and gene expression data, focusing on the main molecular subtypes.
Experimental Design: We developed gene expression modules related to key biological processes in breast cancer such as tumor invasion, immune response, angiogenesis, apoptosis, proliferation, and ER and HER2 signaling, and then analyzed these modules together with clinical variables and several prognostic signatures on publicly available microarray studies (&gt;2,100 patients).
Results: Multivariate analysis showed that in the ER+/HER2− subgroup, only the proliferation module and the histologic grade were significantly associated with clinical outcome. In the ER−/HER2− subgroup, only the immune response module was associated with prognosis, whereas in the HER2+ tumors, the tumor invasion and immune response modules displayed significant association with survival. Proliferation was identified as the most important component of several prognostic signatures, and their performance was limited to the ER+/HER2− subgroup.
Conclusions: Although proliferation is the strongest parameter predicting clinical outcome in the ER+/HER2− subtype and the common denominator of most prognostic gene signatures, immune response and tumor invasion seem to be the main molecular processes associated with prognosis in the ER−/HER2− and HER2+ subgroups, respectively. These findings may help to define new clinicogenomic models and to identify new therapeutic strategies in the specific molecular subgroups.
Nonredundant Functions for Tumor Protein D52-Like Proteins Support Specific Targeting of TPD52
Authors: Shehata Mona , Bièche Ivan , Boutros Rose , Weidenhofer Judith , Fanayan Susan , Spalding Lisa , Zeps Nikolajs , Byth Karen , Bright Robert K. , Lidereau Rosette , Byrne Jennifer A. 
Published: August 2008

Abstract
Purpose: Tumor protein D52 (TPD52 or D52) is frequently overexpressed in breast and other cancers and present at increased gene copy number. It is, however, unclear whether D52 amplification and overexpression target specific functional properties of the encoded protein.
Experimental Design: The expression of D52-like genes and MAL2 was compared in breast tissues using quantitative reverse transcription-PCR. The functions of human D52 and D53 genes were then compared by stable expression in BALB/c 3T3 fibroblasts and transient gene knockdown in breast carcinoma cell lines. In situ D52 and MAL2 protein expression was analyzed in breast tissue samples using tissue microarray sections.
Results: The D52 (8q21.13), D54 (20q13.33), and MAL2 (8q24.12) genes were significantly overexpressed in breast cancer tissue (n = 95) relative to normal breast (n = 7; P ≤ 0.005) unlike the D53 gene (6q22.31; P = 0.884). Subsequently, D52-expressing but not D53-expressing 3T3 cell lines showed increased proliferation and anchorage-independent growth capacity, and reduced D52 but not D53 expression in SK-BR-3 cells significantly increased apoptosis. High D52 but not MAL2 expression was significantly associated with reduced overall survival in breast carcinoma patients (log-rank test, P &lt; 0.001; n = 357) and was an independent predictor of survival (hazard ratio, 2.274; 95% confidence interval, 1.228-4.210; P = 0.009; n = 328).
Conclusion: D52 overexpression in cancer reflects specific targeting and may contribute to a more proliferative, aggressive tumor phenotype in breast cancer.
Circulating Tumor Cells and Bone Marrow Micrometastasis
Authors: Alix-Panabières Catherine , Riethdorf Sabine , Pantel Klaus 
Published: August 2008

Abstract
Sensitive immunocytochemical and molecular assays allow the detection of single circulating tumor cells (CTC) in the peripheral blood and disseminated tumor cells (DTC) in the bone marrow as a common and easily accessible homing organ for cells released by epithelial tumors of various origins. The results obtained thus far have provided direct evidence that tumor cell dissemination starts already early during tumor development and progression. Tumor cells are frequently detected in the blood and bone marrow of cancer patients without clinical or even histopathologic signs of metastasis. The detection of DTC and CTC yields important prognostic information and might help to tailor systemic therapies to the individual needs of a cancer patient. In the present review, we provide a critical review of (a) the current methods used for detection of CTC/DTC and (b) data on the molecular characterization of CTC/DTC with a particular emphasis on tumor dormancy, cancer stem cell theory, and novel targets for biological therapies; and we pinpoint to (c) critical issues that need to be addressed to establish CTC/DTC measurements in clinical practice.
C19orf48Encodes a Minor Histocompatibility Antigen Recognized by CD8+ Cytotoxic T Cells from Renal Cell Carcinoma Patients
Authors: Tykodi Scott S. , Fujii Nobuharu , Vigneron Nathalie , Lu Sharon M. , Mito Jeffrey K. , Miranda Maureen X. , Chou Jeffrey , Voong Lilien N. , Thompson John A. , Sandmaier Brenda M. , Cresswell Peter , Van den Eynde Benoît , Riddell Stanley R. , Warren Edus H. 
Published: August 2008

AbstractPurpose: Tumor regression has been observed in some patients with metastatic renal cell carcinoma (RCC) after nonmyeloablative allogeneic hematopoietic cell transplantation (HCT). Cellular and molecular characterization of antigens recognized by tumor-reactive T cells isolated from responding patients could potentially provide insight into the mechanisms of tumor regression.Experimental Design: CD8+ CTL clones that recognized a novel RCC-associated minor histocompatibility (H) antigen presented by HLA-A*0201 were isolated from two patients with metastatic RCC who experienced tumor regression or stable disease following nonmyeloablative allogeneic HCT. These clones were used to screen a cDNA library and isolate the unique cDNA encoding the antigen.Results: An alternative open reading frame in the C19orf48 gene located on chromosome 19q13 encodes the HLA-A*0201–restricted minor H antigen recognized by the RCC-reactive T cells. The differential T-cell recognition of donor- and recipient-derived target cells is attributable to a nonsynonymous single-nucleotide polymorphism within the nucleotide interval that encodes the antigenic peptide. Assays for gene expression and CTL recognition showed that the C19orf48-encoded peptide is widely expressed in renal tumors and solid tumors of other histologies. The antigenic peptide can be processed for CTL recognition via both TAP-dependent and TAP-independent pathways.Conclusions: Donor T-cell responses against the HLA-A*0201–restricted minor H antigen encoded by C19orf48 may contribute to RCC regression after MHC-matched allogeneic HCT.
HER3 Is a Determinant for Poor Prognosis in Melanoma
Authors: Reschke Markus , Mihic-Probst Daniela , van der Horst Edward Htun , Knyazev Pjotr , Wild Peter J. , Hutterer Markus , Meyer Stefanie , Dummer Reinhard , Moch Holger , Ullrich Axel 
Published: August 2008

Abstract
Purpose: The epidermal growth factor receptor family member HER3 is overexpressed in diverse human cancers and has been associated with poor prognosis in breast, lung, and ovarian cancer. However, the relevance of HER3 with regard to its prognostic significance and function in primary melanoma and metastases remains largely elusive.
Experimental Design: HER3 protein expression was analyzed immunohistochemically using tissue microarrays of 130 primary melanoma and 87 metastases relative to established clinical variables. The possibility of an influence of HER3 on melanoma cell proliferation, migration, invasion, and chemotherapy-induced apoptosis was studied in human melanoma cell lines.
Results: We show that HER3 is frequently expressed in malignant melanoma and metastases at elevated levels. High HER3 expression may serve as a prognostic marker because it correlates with cell proliferation, tumor progression, and reduced patient survival. Suppression of HER3 expression by RNA interference reduces melanoma cell proliferation, migration, and invasion in vitro. In addition, down-regulation of HER3 synergistically enhances dacarbazine-induced apoptosis. Moreover, monoclonal antibodies specific for the extracellular portion of HER3 efficiently block heregulin-induced proliferation, migration, and invasion of melanoma cell lines.
Conclusion: Our results provide novel insights into the role of HER3 in melanoma and point out new possibilities for therapeutic intervention.
Novel Molecular Subtypes of Serous and Endometrioid Ovarian Cancer Linked to Clinical Outcome
Authors: Tothill Richard W. , Tinker Anna V. , George Joshy , Brown Robert , Fox Stephen B. , Lade Stephen , Johnson Daryl S. , Trivett Melanie K. , Etemadmoghadam Dariush , Locandro Bianca , Traficante Nadia , Fereday Sian , Hung Jillian A. , Chiew Yoke-Eng , Haviv Izhak ,   Australian Ovarian Cancer Study Group, Gertig Dorota , deFazio Anna , Bowtell David D.L. 
Published: August 2008

AbstractPurpose: The study aim to identify novel molecular subtypes of ovarian cancer by gene expression profiling with linkage to clinical and pathologic features.Experimental Design: Microarray gene expression profiling was done on 285 serous and endometrioid tumors of the ovary, peritoneum, and fallopian tube. K-means clustering was applied to identify robust molecular subtypes. Statistical analysis identified differentially expressed genes, pathways, and gene ontologies. Laser capture microdissection, pathology review, and immunohistochemistry validated the array-based findings. Patient survival within k-means groups was evaluated using Cox proportional hazards models. Class prediction validated k-means groups in an independent dataset. A semisupervised survival analysis of the array data was used to compare against unsupervised clustering results.Results: Optimal clustering of array data identified six molecular subtypes. Two subtypes represented predominantly serous low malignant potential and low-grade endometrioid subtypes, respectively. The remaining four subtypes represented higher grade and advanced stage cancers of serous and endometrioid morphology. A novel subtype of high-grade serous cancers reflected a mesenchymal cell type, characterized by overexpression of N-cadherin and P-cadherin and low expression of differentiation markers, including CA125 and MUC1. A poor prognosis subtype was defined by a reactive stroma gene expression signature, correlating with extensive desmoplasia in such samples. A similar poor prognosis signature could be found using a semisupervised analysis. Each subtype displayed distinct levels and patterns of immune cell infiltration. Class prediction identified similar subtypes in an independent ovarian dataset with similar prognostic trends.Conclusion: Gene expression profiling identified molecular subtypes of ovarian cancer of biological and clinical importance.
An Initial Report of a Radiation Dose-Escalation Trial in Patients with One to Five Sites of Metastatic Disease
Authors: Salama Joseph K. , Chmura Steven J. , Mehta Neil , Yenice Kamil M. , Stadler Walter M. , Vokes Everett E. , Haraf Daniel J. , Hellman Samuel , Weichselbaum Ralph R. 
Published: August 2008

Abstract
Purpose: Previous investigations have suggested that a subset of patients with metastatic cancer in a limited number of organs may benefit from local treatment. We investigated whether cancer patients with limited sites of metastatic disease (oligometastasis) who failed standard therapies could be identified and safely treated at one to five known sites of low-volume disease with radiotherapy.
Experimental Design: Patients with one to five sites of metastatic cancer with a life expectancy of &gt;3 months and good performance status received escalating doses of radiation to all known sites of cancer with hypofractionated radiation therapy. Patients were followed radiographically with computed tomography scans of the chest, abdomen, and pelvis and metabolically with [18F]fluorodeoxyglucose-positron emission tomography 1 month following treatment and then every 3 months. Acute toxicities were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 and late toxicities were scored using the Radiation Therapy Oncology Group late toxicity scoring system.
Results: Twenty-nine patients with 56 metastatic lesions were enrolled from November 2004 to March 2007, with a median follow-up of 14.9 months. Two patients experienced acute (radiation pneumonitis and nausea) and one experienced chronic (gastrointestinal hemorrhage) grade ≥3 toxicity. Fifty-nine percent of patients responded to protocol therapy. Twenty-one percent of patients have not progressed following protocol treatment. Fifty-seven percent of treated lesions have not progressed at last follow-up. Progression was amenable to further local therapy in 48% of patients.
Conclusions: Patients with low-volume metastatic cancer can be identified, safely treated, and may benefit from radiotherapy.