bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of the Major Antigenic Protein of
Helicobacter cinaedi
and Its Immunogenicity in Humans with
H. cinaedi
Infections
Authors: Iwashita Hirofumi , Fujii Shigemoto , Kawamura Yoshiaki , Okamoto Tatsuya , Sawa Tomohiro , Masaki Takayuki , Nishizono Akira , Higashi Shuichi , Kitamura Toshio , Tamura Fumio , Sasaki Yutaka , Akaike Takaaki 
Published: January 2008

ABSTRACT

Helicobacter cinaedi
infection is now recognized as an increasingly important emerging disease. Its pathogenesis and epidemiological features are not fully understood, however. Here, we investigated the antigenic protein of
H. cinaedi
and the immunological response to it in
H. cinaedi
-infected patients. We constructed a genomic library of
H. cinaedi
from an
H. cinaedi
clinical isolate, and various
H. cinaedi
recombinant proteins were expressed. We identified the 30-kDa protein, encoded in an 822-bp
H. cinaedi
genome, as a major antigen, which was specifically recognized by serum from an
H. cinaedi
-immunized rabbit and
H. cinaedi
-infected patients. The gene encoding this 30-kDa antigen had high sequence similarity with genes encoding putative membrane proteins of bacteria. To evaluate whether the 30-kDa protein can be applied in serological testing for
H. cinaedi
infections, the recombinant protein was expressed in
Escherichia coli
as a His-tagged fusion protein and purified by Ni
2+
affinity chromatography. Western blot analysis revealed strong immunoreactivity of the 31-kDa fusion protein with serum antibody from patients infected with
H. cinaedi
, but such an immunoreaction was absent or was very weak with uninfected control serum. An enzyme-linked immunosorbent assay using this
H. cinaedi
major antigen showed significantly high antibody titers for
H. cinaedi
-infected subjects compared with those of various control groups. We therefore conclude that the 30-kDa putative membrane protein is a major antigen of
H. cinaedi
and is useful for immunological and serological testing for clinical diagnosis and for further epidemiological study of
H. cinaedi
infection in humans.
A Macrophage Gene Expression Signature Defines a Field Effect in the Lung Tumor Microenvironment
Authors: Stearman Robert S. , Dwyer-Nield Lori , Grady Michael C. , Malkinson Alvin M. , Geraci Mark W. 
Published: January 2008

Abstract
One area of intensive investigation is to understand complex cellular and signaling interactions in the tumor microenvironment. Using a novel, although straightforward, microarray approach, we defined a gene expression signature from the lung tumor microenvironment in the murine A/J-urethane model of human lung adenocarcinoma. The tumor microenvironment is reflected by the composition of the cell types present and alterations in mRNA levels, resulting in a “Field Effect” around the tumor. The genes composing the Field Effect expression signature include proteases and their inhibitors, inflammation markers, and immune signaling molecules. By several criteria, the Field Effect expression signature can be attributed to the macrophage lineage, suggesting a qualitative change in the expression pattern of tumor-associated macrophages (TAM) observed in lung tumors. The protein expression levels for a number of Field Effect genes were verified by Western blot analysis of lung homogenates, and for their expression in macrophages and parenchymal cells outside of the tumors by immunohistochemistry. In addition, the Field Effect expression signature was used to classify bronchoalveolar lavage (BAL) cells from tumor-bearing or age-matched control mice. Using a variety of statistical measures, the Field Effect expression signature correctly classified the BAL cells &gt;94% of the time. Finally, the protein levels for several Field Effect genes were higher in cell-free BAL fluid, indicating they may be secreted by the TAMs. This work suggests that TAMs generate a unique gene expression signature within the tumor microenvironment, and this signature could potentially be used for identifying lung cancer from BAL cells and/or fluid. [Cancer Res 2008;68(1):34–43]
Specific Genes Expressed in Association with Progesterone Receptors in Meningioma
Authors: Claus Elizabeth B. , Park Peter J. , Carroll Rona , Chan Jennifer , Black Peter M. 
Published: January 2008

Abstract
An association between hormones and meningioma has been postulated. No data exist that examine gene expression in meningioma by hormone receptor status. The data are surgical specimens from 31 meningioma patients undergoing neurosurgical resection at Brigham and Women's Hospital from March 15, 2004 to May 10, 2005. Progesterone and estrogen hormone receptors (PR and ER, respectively) were measured via immunohistochemistry and compared with gene expression profiling results. The sample is 77% female with a mean age of 55.7 years. Eighty percent were grade 1 and the mean MIB was 6.2, whereas 33% and 84% were ER+ and PR+, respectively. Gene expression seemed more strongly associated with PR status than with ER status. Genes on the long arm of chromosome 22 and near the neurofibromatosis type 2 (NF2) gene (22q12) were most frequently noted to have expression variation, with significant up-regulation in PR+ versus PR− lesions, suggesting a higher rate of 22q loss in PR− lesions. Pathway analyses indicated that genes in collagen and extracellular matrix pathways were most likely to be differentially expressed by PR status. These data, although preliminary, are the first to examine gene expression for meningioma cases by hormone receptor status and indicate a stronger association with PR than with ER status. PR status is related to the expression of genes near the NF2 gene, mutations in which have been identified as the initial event in many meningiomas. These findings suggest that PR status may be a clinical marker for genetic subgroups of meningioma and warrant further examination in a larger data set. [Cancer Res 2008;68(1):314–22]
CARM1 Regulates Estrogen-Stimulated Breast Cancer Growth through Up-regulation of E2F1
Authors: Frietze Seth , Lupien Mathieu , Silver Pamela A. , Brown Myles 
Published: January 2008

Abstract
Estrogen receptor α (ERα) mediates breast cancer proliferation through transcriptional mechanisms involving the recruitment of specific coregulator complexes to the promoters of cell cycle genes. The coactivator-associated arginine methyltransferase CARM1 is a positive regulator of ERα-mediated transcriptional activation. Here, we show that CARM1 is essential for estrogen-induced cell cycle progression in the MCF-7 breast cancer cell line. CARM1 is specifically required for the estrogen-induced expression of the critical cell cycle transcriptional regulator E2F1 whereas estrogen stimulation of cyclin D1 is CARM1 independent. Upon estrogen stimulation, the E2F1 promoter is subject to CARM1-dependent dimethylation on histone H3 arginine 17 (H3R17me2) in a process that parallels the recruitment of ERα. Additionally, we find that the recruitment of CARM1 and subsequent histone arginine dimethylation are dependent on the presence of the oncogenic coactivator AIB1. Thus, CARM1 is a critical factor in the pathway of estrogen-stimulated breast cancer growth downstream of ERα and AIB1 and upstream of the cell cycle regulatory transcription factor E2F1. These studies identify CARM1 as a potential new target in the treatment of estrogen-dependent breast cancer. [Cancer Res 2008;68(1):301–6]
Paxillin Is a Target for Somatic Mutations in Lung Cancer: Implications for Cell Growth and Invasion
Authors: Jagadeeswaran Ramasamy , Surawska Hanna , Krishnaswamy Soundararajan , Janamanchi Varalakshmi , Mackinnon A. Craig , Seiwert Tanguy Y. , Loganathan Sivakumar , Kanteti Rajani , Reichman Trevor , Nallasura Vidya , Schwartz Stuart , Faoro Leonardo , Wang Yi-Ching , Girard Luc , Tretiakova Maria S. , Ahmed Salman , Zumba Osvaldo , Soulii Lioubov , Bindokas Vytas P. , Szeto Livia L. , Gordon Gavin J. , Bueno Raphael , Sugarbaker David , Lingen Mark W. , Sattler Martin , Krausz Thomas , Vigneswaran Wickii , Natarajan Viswanathan , Minna John , Vokes Everett E. , Ferguson Mark K. , Husain Aliya N. , Salgia Ravi 
Published: January 2008

Abstract
Lung cancer is characterized by abnormal cell growth and invasion, and the actin cytoskeleton plays a major role in these processes. The focal adhesion protein paxillin is a target of a number of oncogenes involved in key signal transduction and important in cell motility and migration. In lung cancer tissues, we have found that paxillin was highly expressed (compared with normal lung), amplified (12.1%, 8 of 66) and correlated with increased MET and epidermal growth factor receptor (EGFR) gene copy numbers, or mutated (somatic mutation rate of 9.4%, 18 of 191). Paxillin mutations (19 of 21) were clustered between LD motifs 1 and 2 and the LIM domains. The most frequent point mutation (A127T) enhanced lung cancer cell growth, colony formation, focal adhesion formation, and colocalized with Bcl-2 in vitro. Gene silencing from RNA interference of mutant paxillin led to reduction of cell viability. A murine in vivo xenograft model of A127T paxillin showed an increase in tumor growth, cell proliferation, and invasion. These results establish an important role for paxillin in lung cancer. [Cancer Res 2007;68(1):132–42]
Osteopontin Promotes Vascular Endothelial Growth Factor–Dependent Breast Tumor Growth and Angiogenesis via Autocrine and Paracrine Mechanisms
Authors: Chakraborty Goutam , Jain Shalini , Kundu Gopal C. 
Published: January 2008

Abstract
Angiogenesis is the hallmark of cancer, and development of aggressiveness of primary tumor depends on de novo angiogenesis. Here, using multiple in vitro and in vivo models, we report that osteopontin (OPN) triggers vascular endothelial growth factor (VEGF)–dependent tumor progression and angiogenesis by activating breast tumor kinase (Brk)/nuclear factor–inducing kinase/nuclear factor-κB (NF-κB)/activating transcription factor-4 (ATF-4) signaling cascades through autocrine and paracrine mechanisms in breast cancer system. Our results revealed that both exogenous and tumor-derived OPN play significant roles in VEGF-dependent tumor angiogenesis. Clinical specimen analysis showed that OPN and VEGF expressions correlate with levels of neuropilin-1, Brk, NF-κB, and ATF-4 in different grades of breast cancer. Consequently, OPN plays essential role in two key aspects of tumor progression: VEGF expression by tumor cells and VEGF-stimulated neovascularization. Thus, targeting OPN and its regulated signaling network could be a novel strategy to block tumor angiogenesis and may develop an effective therapeutic approach for the management of breast cancer. [Cancer Res 2008;68(1):152–61]
PAX5/TEL Acts as a Transcriptional Repressor Causing Down-modulation of CD19, Enhances Migration to CXCL12, and Confers Survival Advantage in pre-BI Cells
Authors: Fazio Grazia , Palmi Chiara , Rolink Antonius , Biondi Andrea , Cazzaniga Giovanni 
Published: January 2008

Abstract
PAX5 is a transcription factor essential for B-cell development. Recently, it has been found as a frequent target of aberrancies in childhood acute lymphoblastic leukemia (ALL; 30% of B cell ALL cases), showing monoallelic loss, point mutations, or chromosomal translocations. The role of these aberrancies is still poorly understood. We previously cloned the PAX5/TEL fusion gene in a patient affected by B-cell precursor ALL with a t(9;12) translocation. This is the first report investigating the molecular and functional roles of PAX5/TEL protein in vitro from murine wild-type pre-BI cells. We showed that PAX5/TEL protein acts as an aberrant transcription factor with repressor function, recruiting mSin3A, down-regulating B220, CD19, BLNK, MB-1, FLT3, and μ heavy chain expression, thus suggesting a block on B-cell differentiation. In a PAX5-deficient context, the presence of PAX5/TEL did not replace PAX5 functions. PAX5/TEL protein enhances cell migration towards CXCL12, with the overexpression of CXCR4. Moreover, the presence of the fusion gene overcomes interleukin-7 withdrawal and interferes with transforming growth factor-β1 pathway, inducing resistance and conferring cells an advantage in proliferation and survival. Thus, in vitro, the PAX5/TEL protein has a dominant effect on wild-type PAX5, interferes with the process of B-cell differentiation and migration, and induces resistance to apoptosis. Taken together, these phenomena likely represent key events in the process of B-cell transformation. [Cancer Res 2008;68(1):181–9]
Natriuretic Peptide Receptor A as a Novel Anticancer Target
Authors: Kong Xiaoyuan , Wang Xiaoqin , Xu Weidong , Behera Sumita , Hellermann Gary , Kumar Arun , Lockey Richard F. , Mohapatra Subhra , Mohapatra Shyam S. 
Published: January 2008

Abstract
The receptor for atrial natriuretic peptide (ANP), natriuretic peptide receptor A (NPRA), is expressed in cancer cells, and natriuretic peptides have been implicated in cancers. However, the direct role of NPRA signaling in tumorigenesis remains elusive. Here, we report that NPRA expression and signaling is important for tumor growth. NPRA-deficient mice showed significantly reduced antigen-induced pulmonary inflammation. NPRA deficiency also substantially protected C57BL/6 mice from lung, skin, and ovarian cancers. Furthermore, a nanoparticle-formulated interfering RNA for NPRA attenuated B16 melanoma tumors in mice. Ectopic expression of a plasmid encoding NP73-102, the NH2-terminal peptide of the ANP prohormone, which down-regulates NPRA expression, also suppressed lung metastasis of A549 cells in nude mice and tumorigenesis of Line 1 cells in immunocompetent BALB/c mice. The antitumor activity of NP73-102 was in part attributed to apoptosis of tumor cells. Western blot and immunohistochemistry staining indicated that the transcription factor, nuclear factor-κB, was inactivated, whereas the level of tumor suppressor retinoblastoma protein was up-regulated in the lungs of NPRA-deficient mice. Furthermore, expression of vascular endothelial growth factor was down-regulated in the lungs of NPRA-deficient mice compared with that in wild-type mice. These results suggest that NPRA is involved in tumor angiogenesis and represents a new target for cancer therapy. [Cancer Res 2008;68(1):249–56]
Circulating Colony Stimulating Factor-1 and Breast Cancer Risk
Authors: Tamimi Rulla M. , Brugge Joan S. , Freedman Matthew L. , Miron Alexander , Iglehart J. Dirk , Colditz Graham A. , Hankinson Susan E. 
Published: January 2008

Abstract
Colony stimulating factor-1 (CSF1) and its receptor (CSF1-R) are important in mammary gland development and have been implicated in breast carcinogenesis. In a nested case-control study in the Nurses' Heath Study of 726 breast cancer cases diagnosed between June 1, 1992, and June 1, 1998, and 734 matched controls, we prospectively evaluated whether circulating levels of CSF1 (assessed in 1989–1990) are associated with breast cancer risk. The association varied by menopausal status (Pheterogeneity = 0.009). CSF1 levels in the highest quartile (versus lowest) were associated with an 85% reduced risk of premenopausal breast cancer [relative risk (RR), 0.15; 95% confidence interval (95% CI), 0.03–0.85; Ptrend = 0.02]. In contrast, CSF1 levels in the highest quartile conferred a 33% increased risk of postmenopausal breast cancer (RR, 1.33; 95% CI, 0.96–1.86; Ptrend = 0.11), with greatest risk for invasive (RR, 1.45; 95% CI, 1.02–2.07; Ptrend = 0.06) and ER+/PR+ tumors (RR, 1.72; 95% CI, 1.11–2.66; Ptrend = 0.04). Thus, the association of circulating CSF1 levels and breast cancer varies by menopausal status. [Cancer Res 2008;68(1):18–21]
Evaluation of Promoter Hypermethylation Detection in Body Fluids as a Screening/Diagnosis Tool for Head and Neck Squamous Cell Carcinoma
Authors: Carvalho André Lopes , Jeronimo Carmen , Kim Michael M. , Henrique Rui , Zhang Zhe , Hoque Mohammad O. , Chang Steve , Brait Mariana , Nayak Chetan S. , Jiang Wei-Wen , Claybourne Quia , Tokumaru Yutaka , Lee Juna , Goldenberg David , Garrett-Mayer Elizabeth , Goodman Steven , Moon Chul-so , Koch Wayne , Westra William H. , Sidransky David , Califano Joseph A. 
Published: January 2008

Abstract
Purpose: To evaluate aberrant promoter hypermethylation of candidate tumor suppressor genes as a means to detect epigenetic alterations specific to solid tumors, including head and neck squamous cell carcinoma (HNSCC).
Experimental Design: Using promoter regions identified via a candidate gene and discovery approach, we evaluated the ability of an expanded panel of CpG-rich promoters known to be differentially hypermethylated in HNSCC in detection of promoter hypermethylation in serum and salivary rinses associated with HNSCC. We did preliminary evaluation via quantitative methylation-specific PCR (Q-MSP) using a panel of 21 genes in a limited cohort of patients with HNSCC and normal controls. Using sensitivity and specificity for individual markers as criteria, we selected panels of eight and six genes, respectively, for use in salivary rinse and serum detection and tested these in an expanded cohort including up to 211 patients with HNSCC and 527 normal controls.
Results: Marker panels in salivary rinses showed improved detection when compared with single markers, including a panel with 35% sensitivity and 90% specificity and a panel with 85% sensitivity and 30% specificity. A similar pattern was noted in serum panels, including a panel with 84.5% specificity with 50.0% sensitivity and a panel with sensitivity of 81.0% with specificity of 43.5%. We also noted that serum and salivary rinse compartments showed a differential pattern of methylation in normal subjects that influenced the utility of individual markers.
Conclusions: Q-MSP detection of HNSCC in serum and salivary rinses using multiple targets offers improved performance when compared with single markers. Compartment-specific methylation in normal subjects affects the utility of Q-MSP detection strategies.
Phase I Pharmacokinetic/Pharmacodynamic Study of EKB-569, an Irreversible Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase, in Combination with Irinotecan, 5-Fluorouracil, and Leucovorin (FOLFIRI) in First-Line Treatment of Patients with Metastatic Colorectal Cancer
Authors: Folprecht Gunnar , Tabernero Josep , Köhne Claus-Henning , Zacharchuk Charles , Paz-Ares Luis , Rojo Federico , Quinn Susan , Casado Esther , Salazar Ramon , Abbas Richat , Lejeune Chantal , Marimón Irene , Andreu Jordi , Ubbelohde Ulrike , Cortes-Funes Hernan , Baselga Jose 
Published: January 2008

Abstract
Purpose: To determine the recommended dose (RD) of EKB-569, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with FOLFIRI chemotherapy in patients with metastatic colorectal cancer (mCRC).
Methods: Patients with previously untreated mCRC received FOLFIRI and EKB-569 at doses of 10, 25, 50, and 75 mg/day (EKB started on day 3). Three sequential skin biopsies were obtained in selected patients to assess the pharmacodynamic effects on EGFR signaling of FOLFIRI alone and with EKB-569. Complete pharmacokinetic sampling and tumor biopsies, when feasible, were conducted.
Results: Forty-seven patients were enrolled. Dose-limiting toxicities (grade 3 diarrhea or asthenia) were observed in 1/7 patients at 50 mg EKB-569 and in 2/3 at 75 mg. Two additional dose levels (35 mg EKB-569/day and 50 mg EKB-569/day plus modified FOLFIRI) were evaluated. The RD was 25 mg EKB-569/full dose FOLFIRI. Grades 3 to 4 toxicities in &gt;10% of patients were diarrhea (30%), neutropenia (21%), and asthenia (17%). Twenty-one patients had an objective response [48%; 95% confidence interval (95% CI), 32-65%]. The median time to tumor progression was 7.7 months. At the RD, EKB-569 resulted in complete inhibition of phosphorylated EGFR (pEGFR) and downstream receptor signaling in skin and tumor samples. FOLFIRI alone did not affect pEGFR, but inhibited epidermal proliferation and activated mitogen-activated protein kinase (MAPK) and induced p27 expression in the skin.
Conclusion: The RD of EKB-569 is 25 mg/day when combined with FOLFIRI and results in complete EGFR inhibition. Chemotherapy alone interferes with pharmacodynamic markers, an observation to be taken into account in future studies of targeted agents with chemotherapy.
Combining Agents that Target the Tumor Microenvironment Improves the Efficacy of Anticancer Therapy
Authors: Blansfield Joseph A. , Caragacianu Diana , Alexander H. Richard , Tangrea Michael A. , Morita Shane Y. , Lorang Dominique , Schafer Peter , Muller George , Stirling David , Royal Richard E. , Libutti Steven K. 
Published: January 2008

AbstractPurpose: Over the past 60 years, cytotoxic chemotherapy has targeted the cancer cell. Despite this, there have been few cancer cures. A new approach to cancer therapy is to target the multicellular biological entity of the tumor microenvironment.Experimental Design: Lenalidomide, an immunomodulatory drug, sunitinib, a tyrosine kinase inhibitor, and low-dose metronomic cyclophosphamide, were tested alone and in combination for their abilities to inhibit endothelial cell tube formation, rat aortic ring outgrowth, tumor growth, and metastatic development in mice. In addition, ectopic tumor lysates were evaluated for the presence of proangiogenic proteins.Results: The three agents alone were shown to significantly inhibit endothelial cells' ability to form tubes and significantly inhibit the multicellular microenvironment in the rat aortic ring assay (P &lt; 0.01 and P &lt; 0.001). This effect was also significantly augmented when the agents were combined. Furthermore, the three-drug combination was able halt the progression of tumor growth almost completely in xenograft models of ocular melanoma, colon cancer, pancreatic cancer, and cutaneous melanoma. These agents significantly decrease the number of proliferating cells in tumors, significantly increase the number of cells undergoing active cell death in tumors, and significantly decrease the number of blood vessels in treated tumors (P &lt; 0.05). Combination therapy shows a decrease in the compensatory up-regulation of proangiogenic proteins after treatment when compared with single-agent therapy.Conclusions: This combination of agents causes an inhospitable microenvironment for tumor cells and shows great promise for use in the clinic.