bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene Expression Profiling in Uveal Melanoma Reveals Two Molecular Classes and Predicts Metastatic Death
Authors: Onken Michael D. , Worley Lori A. , Ehlers Justis P. , Harbour J. William 
Published: September 2005

Abstract
Melanomas are notoriously difficult to classify because of a lack of discrete clinical and pathological stages. Here, we show that primary uveal melanomas surprisingly cluster into two distinct molecular classes based on gene expression profile. Genes that discriminate class 1 (low-grade) from class 2 (high-grade) include highly significant clusters of down-regulated genes on chromosome 3 and up-regulated genes on chromosome 8q, which is consistent with previous cytogenetic studies. A three-gene signature allows biopsy-size tumor samples to be assigned accurately to tumor classes using either array or PCR platforms. Most importantly, this molecular classification strongly predicts metastatic death and outperforms other clinical and pathological prognostic indicators. These studies offer new insights into melanoma pathogenesis, and they provide a practical foundation for effective clinical predictive testing.
Human Polynucleotide Phosphorylase (
hPNPase

old-35
)
Authors: Sarkar Devanand , Lebedeva Irina V. , Emdad Luni , Kang Dong-chul , Baldwin Albert S. , Fisher Paul B. 
Published: September 2005

Abstract
Chronic inflammation is a characteristic feature of aging, and the relationship between cellular senescence and inflammation, although extensively studied, is not well understood. An overlapping pathway screen identified human polynucleotide phosphorylase (hPNPaseold-35), an evolutionary conserved 3′,5′-exoribonuclease, as a gene up-regulated during both terminal differentiation and cellular senescence. Enhanced expression of hPNPaseold-35 via a replication-incompetent adenovirus (Ad.hPNPaseold-35) in human melanoma cells and normal human melanocytes results in a characteristic senescence-like phenotype. Reactive oxygen species (ROS) play a key role in the induction of both in vitro and in vivo senescence. We now document that overexpression of hPNPaseold-35 results in increased production of ROS, leading to activation of the nuclear factor (NF)-κB pathway. Ad.hPNPaseold-35 infection promotes degradation of IκBα and nuclear translocation of NF-κB and markedly increases binding of the transcriptional activator p50/p65. The generation of ROS and activation of NF-κB by hPNPaseold-35 are prevented by treatment with a cell-permeable antioxidant, N-acetyl-l-cysteine. Infection with Ad.hPNPaseold-35 enhances the production of interleukin (IL)-6 and IL-8, two classical NF-κB-responsive cytokines, and this induction is inhibited by N-acetyl-l-cysteine. A cytokine array reveals that Ad.hPNPaseold-35 infection specifically induces the expression of proinflammatory cytokines, such as IL-6, IL-8, RANTES, and matrix metalloproteinase (MMP)-3. We hypothesize that hPNPaseold-35 might play a significant role in producing pathological changes associated with aging by generating proinflammatory cytokines via ROS and NF-κB. Understanding the relationship between hPNPaseold-35 and inflammation and aging provides a unique opportunity to mechanistically comprehend and potentially intervene in these physiologically important processes.
Proinvasive Properties of Ovarian Cancer Ascites-Derived Membrane Vesicles
Authors: Graves Laura E. , Ariztia Edgardo V. , Navari Jason R. , Matzel Heather J. , Stack M. Sharon , Fishman David A. 
Published: September 2005

Abstract
Malignant ovarian ascites are rich in cellular components, membrane-bound vesicles, and soluble proteins. This study focused on the structure of membrane-bound vesicles and their ability to promote invasion in cultured malignant ovarian epithelium. Membrane vesicles were derived from women with stage I–IV malignant ovarian ascites and from nonmalignant gynecologic ascites. Isolated vesicles were characterized by immunofluorescence and Western blot analysis. Using gel zymography for matrix metalloproteinase (MMP) detection and a colorimetric assay for urokinase-type plasminogen activator (uPA) analysis, we analyzed the proteinase activities of MMP-2, MMP-9, and uPA from the prepared vesicles, whole cells isolated from ascites, and the cell-free ultracentrifuged supernatant. The invasiveness of established cultured malignant ovarian epithelium on addition of ascites-derived vesicles was tested using a Matrigel-based invasion assay. Fractionation of malignant ascites revealed that extracellular matrix-degrading proteinases including MMPs and uPA are localized preferentially in membrane vesicles. All malignant vesicles tested, regardless of cancer stage, stimulated invasion. Furthermore, the combination of ovarian cancer cells and membrane vesicles resulted in greater uPA activation than that of cells or vesicles alone. Membrane vesicles from malignant ascites were also found to contain activated MMP-2, MMP-9, and uPA. Our data suggest that vesicle-stimulated proteinase activation leads to increased extracellular matrix degradation, which may facilitate tumor cell invasion and metastasis.
A Novel RARβ Isoform Directed by a Distinct Promoter P3 and Mediated by Retinoic Acid in Breast Cancer Cells
Authors: Peng Xinjian , Maruo Takeshi , Cao Yanxia , Punj Vasu , Mehta Rajeshwari , Das Gupta Tapas K. , Christov Konstantin 
Published: September 2005

Abstract
Retinoids regulate gene transcription through activating retinoic acid receptors (RARs)/retinoic X receptors (RXRs). Of the three RAR receptors (α, β, and γ), RARβ has been considered a tumor suppressor gene. Here, we identified a novel RARβ isoform-RARβ5 in breast epithelial cells, which could play a negative role in RARβ signaling. Similar to RARβ2, the first exon (59 bp) of RARβ5 is RARβ5 isoform specific, whereas the other exons are common to all of the RARβ isoforms. The first exon of RARβ5 does not contain any translation start codon, and therefore its protein translation begins at an internal methionine codon of RARβ2, lacking the A, B, and part of C domain of RARβ2. RARβ5 protein was preferentially expressed in estrogen receptor-negative breast cancer cells and normal breast epithelial cells that are relatively resistant to retinoids, whereas estrogen receptor-positive cells that did not express detectable RARβ5 protein were sensitive to retinoid treatment, suggesting that this isoform may affect the cellular response to retinoids. RARβ5 isoform is unique among all of the RARs, because a corresponding isoform was not detectable for either RARα or RARγ. RARβ5 mRNA was variably expressed in normal and cancerous breast epithelial cells. Its transcription was under the control of a distinct promoter P3, which can be activated by all-trans-retinoic acid (atRA) and other RAR/RXR selective retinoids in MCF-7 and T47D breast cancer cells. We mapped the RARβ5 promoter and found a region -302/-99 to be the target region of atRA. In conclusion, we identified and initially characterized RARβ5 in normal, premalignant, and malignant breast epithelial cells. RARβ5 may serve as a potential target of retinoids in prevention and therapy studies.
From Mice to Humans
Authors: Hu Yuhui , Sun Hongxia , Drake Jeffrey , Kittrell Frances , Abba Martin C. , Deng Li , Gaddis Sally , Sahin Aysegul , Baggerly Keith , Medina Daniel , Aldaz C. Marcelo 
Published: September 2005

AbstractGenetically engineered mouse mammary cancer models have been used over the years as systems to study human breast cancer. However, much controversy exists on the utility of such models as valid equivalents to the human cancer condition. To perform an interspecies gene expression comparative study in breast cancer we used a mouse model that most closely resembles human breast carcinogenesis. This system relies on the transplant of p53 null mouse mammary epithelial cells into the cleared mammary fat pads of syngeneic hosts. Serial analysis of gene expression (SAGE) was used to obtain gene expression profiles of normal and tumor samples from this mouse mammary cancer model (&gt;300,000 mouse mammary-specific tags). The resulting mouse data were compared with 25 of our human breast cancer SAGE libraries (&gt;2.5 million human breast-specific tags). We observed significant similarities in the deregulation of specific genes and gene families when comparing mouse with human breast cancer SAGE data. A total of 72 transcripts were identified as commonly deregulated in both species. We observed a systematic and significant down-regulation in all of the tumors from both species of various cytokines, including CXCL1 (GRO1), LIF, interleukin 6, and CCL2. All of the mouse and most human mammary tumors also displayed decreased expression of genes known to inhibit cell proliferation, including NFKBIA (IKBα), GADD45B, and CDKN1A (p21); transcription-related genes such as CEBP, JUN, JUNB, and ELF1; and apoptosis-related transcripts such as IER3 and GADD34/PPP1R15A. Examples of overexpressed transcripts in tumors from both species include proliferation-related genes such as CCND1, CKS1B, and STMN1 (oncoprotein 18); and genes related to other functions such as SEPW1, SDFR1, DNCI2, and SP110. Importantly, abnormal expression of several of these genes has not been associated previously with breast cancer. The consistency of these observations was validated in independent mouse and human mammary cancer sets.This is the first interspecies comparison of mammary cancer gene expression profiles. The comparative analysis of mouse and human SAGE mammary cancer data validates this p53 null mouse tumor model as a useful system closely resembling human breast cancer development and progression. More importantly, these studies are allowing us to identify relevant biomarkers of potential use in human studies while leading to a better understanding of specific mechanisms of human breast carcinogenesis.
Caspase-Independent Cell Death by Arsenic Trioxide in Human Cervical Cancer Cells
Authors: Kang Young-Hee , Yi Min-Jung , Kim Min-Jung , Park Moon-Taek , Bae Sangwoo , Kang Chang-Mo , Cho Chul-Koo , Park In-Chul , Park Myung-Jin , Rhee Chang Hun , Hong Seok-Il , Chung Hee Yong , Lee Yun-Sil , Lee Su-Jae 
Published: September 2005

Abstract
Although mechanisms of arsenic trioxide (As2O3)-induced cell death have been studied extensively in hematologic cancers, those in solid cancers have yet to be clearly defined. In this study, we showed that the translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus is required for As2O3-induced cell death in human cervical cancer cells. We also showed that reactive oxygen species (ROS)-mediated poly(ADP-ribose) polymerase-1 (PARP-1) activation is necessary for AIF release from mitochondria. The treatment of human cervical cancer cells with As2O3 induces dissipation of mitochondrial membrane potential (Δψm), translocation of AIF from mitochondria to the nucleus, and subsequent cell death. Small interfering RNA targeting of AIF effectively protects cervical cancer cells against As2O3-induced cell death. As2O3 also induces an increase of intracellular ROS level and a marked activation of PARP-1. N-acetyl-l-cystein, a thiol-containing antioxidant, completely blocks As2O3-induced PARP-1 activation, Δψm loss, nuclear translocation of AIF from mitochondria, and the consequent cell death. Furthermore, pretreatment of 1,5-dihydroxyisoquinoline or 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone, PARP-1 inhibitors, effectively attenuates the loss of Δψm, AIF release, and cell death. These data support a notion that ROS-mediated PARP-1 activation signals AIF release from mitochondria, resulting in activation of a caspase-independent pathway of cell death in solid tumor cells by As2O3 treatment.
Myeloperoxidase Genotype, Fruit and Vegetable Consumption, and Breast Cancer Risk
Authors: Ahn Jiyoung , Gammon Marilie D. , Santella Regina M. , Gaudet Mia M. , Britton Julie A. , Teitelbaum Susan L. , Terry Mary Beth , Neugut Alfred I. , Josephy P. David , Ambrosone Christine B. 
Published: September 2005

Abstract
Myeloperoxidase (MPO), an antimicrobial enzyme in the breast, generates reactive oxygen species (ROS) endogenously. An MPO G463A polymorphism exists in the promoter region, with the variant A allele conferring lower transcription activity than the common G allele. Because oxidative stress may play a role in breast carcinogenesis, we evaluated MPO genotypes in relation to breast cancer risk among 1,011 cases and 1,067 controls from the Long Island Breast Cancer Study Project (1996–1997). We also assessed the potential modifying effects of dietary antioxidants and hormonally related risk factors on these relationships. Women over 20 years with incident breast cancer who were residents of Nassau and Suffolk Counties, NY, were identified as potential cases. Population-based controls were frequency matched by 5-year age groups. Genotyping was performed with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) technology, and suspected breast cancer risk factors and usual dietary intake were assessed during an in-person interview. Unconditional logistic regression was used to estimate odds ratios and 95% confidence intervals. Having at least one A allele was associated with an overall 13% reduction in breast cancer risk. When consumption of fruits and vegetables and specific dietary antioxidants were dichotomized at the median, inverse associations with either GA or AA genotypes were most pronounced among women who consumed higher amounts of total fruits and vegetables (odds ratio, 0.75; 95% confidence interval, 0.58–0.97); this association was not noted among the low-consumption group (P for interaction = 0.04). Relationships were strongest among premenopausal women. Results from this first study of MPO genotypes and breast cancer risk indicate that MPO variants, related to reduced generation of ROS, are associated with decreased breast cancer risk, and emphasize the importance of fruit and vegetable consumption in reduction of breast cancer risk.
Proliferation of Transformed Somatotroph Cells Related to Low or Absent Expression of Protein Kinase A Regulatory Subunit 1A Protein
Authors: Lania Andrea G. , Mantovani Giovanna , Ferrero Stefano , Pellegrini Caterina , Bondioni Sara , Peverelli Erika , Braidotti Paola , Locatelli Marco , Zavanone Mario L. , Ferrante Emanuela , Bosari Silvano , Beck-Peccoz Paolo , Spada Anna 
Published: September 2005

Abstract
The two regulatory subunits (R1 and R2) of protein kinase A (PKA) are differentially expressed in cancer cell lines and exert diverse roles in growth control. Recently, mutations of the PKA regulatory subunit 1A gene (PRKAR1A) have been identified in patients with Carney complex. The aim of this study was to evaluate the expression of the PKA regulatory subunits R1A, R2A, and R2B in a series of 30 pituitary adenomas and the effects of subunit activation on cell proliferation. In these tumors, neither mutation of PRKAR1A nor loss of heterozygosity was identified. By real-time PCR, mRNA of the three subunits was detected in all of the tumors, R1A being the most represented in the majority of samples. By contrast, immunohistochemistry documented low or absent R1A levels in all tumors, whereas R2A and R2B were highly expressed, thus resulting in an unbalanced R1/R2 ratio. The low levels of R1A were, at least in part, due to proteasome-mediated degradation. The effect of the R1/R2 ratio on proliferation was assessed in GH3 cells, which showed a similar unbalanced pattern of R subunits expression, and in growth hormone-secreting adenomas. The R2-selective cAMP analog 8-Cl cAMP and R1A RNA silencing, stimulated cell proliferation and increased Cyclin D1 expression, respectively, in human and rat adenomatous somatotrophs. These data show that a low R1/R2 ratio promoted proliferation of transformed somatotrophs and are consistent with the Carney complex model in which R1A inactivating mutations further unbalance this ratio in favor of R2 subunits. These results suggest that low expression of R1A protein may favor cAMP-dependent proliferation of transformed somatotrophs.
Failed Adoptive Immunotherapy with Tumor-Specific T Cells
Authors: Roychowdhury Sameek , May Kenneth F. , Tzou Katherine S. , Lin Teresa , Bhatt Darshna , Freud Aharon G. , Guimond Martin , Ferketich Amy K. , Liu Yang , Caligiuri Michael A. 
Published: September 2005

AbstractAdoptive immunotherapy with tumor-specific T cells has emerged as a valid approach for prevention or treatment of diseases, such as melanoma and EBV-associated lymphoma. As interleukin (IL) 15 promotes survival of CD8+ memory CTLs, we hypothesized that it could be used to enhance antitumor immunity in vivo through the maintenance of adoptively transferred memory CTL. To test this, we treated mice bearing P1A+ tumors with adoptively transferred T cells possessing a transgenic Vα8+ T-cell receptor specific for the P1A tumor antigen (called P1CTL). Mice were then randomized to receive daily low-dose IL-15 (0.5 μg/day) or PBS. Mice receiving the transgenic P1CTL and IL-15 experienced a significantly delayed tumor relapse or complete tumor regression (P &lt; 0.002 compared with PBS), with a striking persistence of the CD8+ Vα8+ P1CTL compared with mice receiving the CD8+ Vα8+ P1CTL and PBS vehicle (26.3 versus 5.1% P &lt; 10−5). Animals exhibiting complete tumor regression had a significant population of CD8+ Vα8+ P1CTL (46%) that persisted with IL-15 treatment until 140 days after adoptive transfer and successfully defended them against tumor rechallenge without IL-15. Low-dose IL-2 afforded no protection over vehicle and resulted in lower percentages of T cells with an activated memory phenotype, lower Bcl-2 expression, and lower ex vivo antitumor cytotoxicity compared with mice treated with IL-15. Collectively, the data support the notion that exogenous low-dose IL-15 therapy can enhance and even reverse the limited efficacy of adoptively transferred tumor-specific T-cell therapy and may do so in a fashion that is superior and distinct from exogenous IL-2 therapy.
STAT1
Authors: Thomas Michelle , Finnegan Clodagh E. , Rogers Katherine M.-A. , Purcell James W. , Trimble Anne , Johnston Patrick G. , Boland Marion P. 
Published: September 2005

Abstract
The anthracyclines, such as doxorubicin, are widely used in the treatment of breast cancer. Previously, we showed that these drugs could activate the transcription factor, nuclear factor κB, in a DNA damage-dependent manner. We now show that these drugs can potentiate the activation of signal transducer and activator of transcription 1 (STAT1) in MDA-MB 435 breast cancer cells treated with IFN-γ. We observed that key markers of STAT1 activation, including tyrosine 701 and serine 727 phosphorylation, were enhanced in the presence of doxorubicin. This potentiation resulted in enhanced nuclear localization of activated STAT1 and led to an increase in the nuclear binding of activated STAT complexes. The observed potentiation was specific for STAT1 and IFN-γ, as no effects were observed with either STAT3 or STAT5. Furthermore, the type I IFNs (α and β) had little or no effect. The observed effects on STAT1 phosphorylation have previously been linked with maximal transcriptional activation and apoptosis. Cell viability was assessed by crystal violet staining followed by analysis with CalcuSyn to determine combination index values, a measure of synergy. We confirmed that significant synergy existed between IFN-γ and doxorubicin (combination index = 0.34) at doses lower than IC50 values for this drug (0.67 μmol/L). In support of this, we observed that apoptotic cell death was also enhanced by measuring poly(ADP-ribose) polymerase and caspase-3 cleavage. Finally, suppression of STAT1 expression by small-interfering RNA resulted in a loss of synergistic apoptotic cell death compared with cells, where no suppression of STAT1 expression was attained with scrambled small-interfering RNA control. We conclude that doxorubicin potentiates STAT1 activation in response to IFN-γ, and that this combination results in enhanced apoptosis in breast cancer cells.
Plakophilin 3 Oncogene as Prognostic Marker and Therapeutic Target for Lung Cancer
Authors: Furukawa Chiyuki , Daigo Yataro , Ishikawa Nobuhisa , Kato Tatsuya , Ito Tomoo , Tsuchiya Eiju , Sone Saburo , Nakamura Yusuke 
Published: September 2005

Abstract
We investigated gene expression profiles of non–small cell lung carcinomas (NSCLC) to screen candidate molecules that might be useful as diagnostic markers or for development of novel molecular-targeting therapies. Here we report evidence that a member of the armadillo protein family, plakophilin 3 (PKP3), is a potential molecular target for treatment of lung cancers and might also serve as a prognostic indicator. We documented elevated expression of PKP3 in the great majority of NSCLC samples examined. Treatment of NSCLC cells with small interfering RNAs of PKP3 suppressed growth of the cancer cells; on the other hand, induction of exogenous expression of PKP3 conferred growth-promoting activity on COS-7 cells and enhanced their mobility in vitro. To investigate its function, we searched for PKP3-interacting proteins and identified dynamin 1-like, which was also activated in NSCLC. In addition, a high level of PKP3 expression was associated with poor survival as well as disease stage and node status for patients with lung adenocarcinoma, suggesting an important role of the protein in development and progression of this disease. As our data imply that up-regulation of PKP3 is a frequent and important feature of lung carcinogenesis, we suggest that targeting the PKP3 molecule might hold promise for development of a new therapeutic and diagnostic strategy for clinical management of lung cancers.
Soluble Tumor Necrosis Factor-Like Weak Inducer of Apoptosis Overexpression in HEK293 Cells Promotes Tumor Growth and Angiogenesis in Athymic Nude Mice
Authors: Ho David H. , Vu Hong , Brown Sharron A. N. , Donohue Patrick J. , Hanscom Heather N. , Winkles Jeffrey A. 
Published: September 2005

Abstract
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily of structurally related cytokines. TWEAK acts on responsive cells via binding to a cell surface receptor named Fn14. Recent studies have demonstrated that TWEAK can stimulate numerous cellular responses including cell proliferation, migration, and proinflammatory molecule production. It has also been reported that TWEAK can stimulate blood vessel formation in the rat cornea angiogenesis assay, but it is presently unknown whether this cytokine could play a role in the pathological angiogenesis associated with human diseases such as cancer, rheumatoid arthritis, and diabetic retinopathy. In the present study we investigated whether TWEAK was expressed in human tumors and whether it could promote tumor growth and angiogenesis in vivo. TWEAK mRNA expression was detected in many tumor types by cDNA array hybridization analysis, and TWEAK protein expression was confirmed in human colon cancer tissue by immunohistochemistry. As an initial approach to address whether TWEAK might act as a tumor angiogenesis factor, we established several human embryonic kidney cell lines that constitutively secrete a soluble TWEAK protein and examined their growth properties in vitro and in vivo. We found that although TWEAK-overexpressing cells do not have a growth advantage in vitro, they form larger and more highly vascularized tumors in athymic mice when compared with control, vector-transfected cells. This result suggests that the TWEAK-Fn14 signaling system may be a potential regulator of human tumorigenesis.