bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene Expression Changes in an Animal Melanoma Model Correlate with Aggressiveness of Human Melanoma Metastases
Authors: Xu Lei , Shen Steven S. , Hoshida Yujin , Subramanian Aravind , Ross Ken , Brunet Jean-Philippe , Wagner Stephan N. , Ramaswamy Sridhar , Mesirov Jill P. , Hynes Richard O. 
Published: May 2008

Abstract
Metastasis is the deadliest phase of cancer progression. Experimental models using immunodeficient mice have been used to gain insights into the mechanisms of metastasis. We report here the identification of a “metastasis aggressiveness gene expression signature” derived using human melanoma cells selected based on their metastatic potentials in a xenotransplant metastasis model. Comparison with expression data from human melanoma patients shows that this metastasis gene signature correlates with the aggressiveness of melanoma metastases in human patients. Many genes encoding secreted and membrane proteins are included in the signature, suggesting the importance of tumor-microenvironment interactions during metastasis. (Mol Cancer Res 2008;6(5):760–9)
Impairment of the DNA Repair and Growth Arrest Pathways by p53R2 Silencing Enhances DNA Damage–Induced Apoptosis in a p53-Dependent Manner in Prostate Cancer Cells
Authors: Devlin Hong-Lin , Mack Phillip C. , Burich Rebekah A. , Gumerlock Paul H. , Kung Hsing-Jien , Mudryj Maria , deVere White Ralph W. 
Published: May 2008

Abstract
p53R2 is a p53-inducible ribonucleotide reductase that contributes to DNA repair by supplying deoxynucleotide triphosphate pools in response to DNA damage. In this study, we found that p53R2 was overexpressed in prostate tumor cell lines compared with immortalized prostatic epithelial cells and that the protein was induced upon DNA damage. We investigated the effects of p53R2 silencing on DNA damage in LNCaP cells (wild-type p53). Silencing p53R2 potentiated the apoptotic effects of ionizing radiation and doxorubicin treatment as shown by increased sub-G1 content and decreased colony formation. This sensitizing effect was specific to DNA-damaging agents. Comet assay and γ-H2AX phosphorylation status showed that the decreased p53R2 levels inhibited DNA repair. Silencing p53R2 also reduced the levels of p21WAF1/CIP1 at the posttranscriptional level, suggesting links between the p53-dependent DNA repair and cell cycle arrest pathways. Using LNCaP sublines stably expressing dominant-negative mutant p53, we found that the sensitizing effect of p53R2 silencing is mediated by p53-dependent apoptosis pathways. In the LNCaP sublines (R273H, R248W, and G245S) that have defects in inducing p53-dependent apoptosis, p53R2 silencing did not potentiate DNA damage–induced apoptosis, whereas p53R2 silencing was effective in a LNCaP subline (P151S) which retains the ability to induce p53-dependent apoptosis. This study shows that p53R2 is a potential therapeutic target that could be used to enhance the effectiveness of ionizing radiation or DNA-damaging chemotherapy in a subset of patients with prostate cancer. (Mol Cancer Res 2008;6(5):808–18)
Growth Factor Regulation of Estrogen Receptor Coregulator PELP1 Functions via Protein Kinase A Pathway
Authors: Nagpal Jatin K. , Nair Sujit , Chakravarty Dimple , Rajhans Rajib , Pothana Saikumar , Brann Darrell W. , Tekmal Rajeshwar Rao , Vadlamudi Ratna K. 
Published: May 2008

Abstract
PELP1 (proline-rich, glutamic acid–rich, and leucine-rich protein-1) is a potential proto-oncogene that functions as a coregulator of estrogen receptor (ER), and its expression is deregulated during breast cancer progression. Emerging evidence suggests growth factor signaling crosstalk with ER as one possible mechanism by which breast tumors acquire resistance to therapy. In this study, we examined mechanisms by which growth factors modulate PELP1 functions, leading to activation of ER. Using in vivo labeling assays, we have found that growth factors promote phosphorylation of PELP1. Utilizing a panel of substrate-specific phosphorylated antibodies, we discovered that growth factor stimulation promotes phosphorylation of PELP1 that is recognized by a protein kinase A (PKA) substrate–specific antibody. Accordingly, growth factor–mediated PELP1 phosphorylation was effectively blocked by PKA-specific inhibitor H89. Utilizing purified PKA enzyme and in vitro kinase assays, we obtained evidence of direct PELP1 phosphorylation by PKA. Using deletion and mutational analysis, we identified PELP1 domains that are phosphorylated by PKA. Interestingly, site-directed mutagenesis of the putative PKA site in PELP1 compromised growth factor–induced activation and subnuclear localization of PELP1 and also affected PELP1-mediated transactivation function. Utilizing MCF-7 cells expressing a PELP1 mutant that cannot be phosphorylated by PKA, we provide mechanistic insights by which growth factor signaling regulates ER transactivation in a PELP1-dependent manner. Collectively, these findings suggest that growth factor signals promote phosphorylation of ER coactivator PELP1 via PKA pathway, and such modification may have functional implications in breast tumors with deregulated growth factor signaling. (Mol Cancer Res 2008;6(5):851–61)
TLS-ERG Leukemia Fusion Protein Deregulates Cyclin-Dependent Kinase 1 and Blocks Terminal Differentiation of Myeloid Progenitor Cells
Authors: Pan Jing , Zou Junhui , Wu Daniel Y. , Roberson Rachael S. , Hennings Leah J. , Ma Xiaoyun , Yared Marwan , Blackburn Michael L. , Chansky Howard A. , Yang Liu 
Published: May 2008

Abstract
TLS-ERG fusion protein is derived from the t(16;21) translocation found in human myeloid leukemia. Here, we show that retroviral transduction of TLS-ERG confers a growth advantage to L-G myeloid progenitor cells and blocks terminal differentiation. We found that the level of cyclin-dependent kinase 1 (Cdk1) protein was significantly decreased in controls but unchanged in TLS-ERG–expressing cells after granulocyte colony-stimulating factor treatment or interleukin-3 withdrawal. Injection of TLS-ERG–expressing L-G cells induced rapid development of a leukemia-like disease in syngeneic mice. Through site-directed mutagenesis, we showed that transformation and deregulation of Cdk1 by TLS-ERG require an intact ets DNA-binding domain within the fusion protein. Interestingly, treatment of TLS-ERG–expressing L-G cells with 5-aza-2′-deoxycytidine (Decitabine) or trichostatin A resulted in down-regulation of Cdk1 and induction of terminal differentiation. To investigate whether Cdk1 deregulation is indeed responsible for transformation by TLS-ERG, we constructed lentiviral vectors for delivery of Cdk1 mutants and small interfering RNA (siRNA). Both dominant-negative inhibition and siRNA knockdown of Cdk1 were able to restore the ability of TLS-ERG–expressing L-G cells to undergo terminal differentiation. In addition, siRNA knockdown of Cdk1 in YNH-1 cells derived from a t(16;21) acute myelogenous leukemia patient also resulted in terminal differentiation. As restoration of terminal myeloid differentiation to TLS-ERG cells is dependent on cell cycle arrest, our findings suggest an important role for Cdk1 in cellular transformation and may be useful in the search for new treatments of TLS-ERG–associated myeloid leukemia. (Mol Cancer Res 2008;6(5):862–72)
A Functional Screen Identifies miR-34a as a Candidate Neuroblastoma Tumor Suppressor Gene
Authors: Cole Kristina A. , Attiyeh Edward F. , Mosse Yael P. , Laquaglia Michael J. , Diskin Sharon J. , Brodeur Garrett M. , Maris John M. 
Published: May 2008

Abstract
MicroRNAs are small noncoding RNAs that have critical roles in regulating a number of cellular functions through transcriptional silencing. They have been implicated as oncogenes and tumor suppressor genes (oncomirs) in several human neoplasms. We used an integrated genomics and functional screening strategy to identify potential oncomirs in the pediatric neoplasm neuroblastoma. We first identified microRNAs that map within chromosomal regions that we and others have defined as frequently deleted (1p36, 3p22, and 11q23-24) or gained (17q23) in high-risk neuroblastoma. We then transiently transfected microRNA precursor mimics or inhibitors into a panel of six neuroblastoma cell lines that we characterized for these genomic aberrations. The majority of transfections showed no phenotypic effect, but the miR-34a (1p36) and miR-34c (11q23) mimics showed dramatic growth inhibition in cell lines with 1p36 hemizygous deletion. In contrast, there was no growth inhibition by these mimics in cell lines without 1p36 deletions. Quantitative reverse transcription-PCR showed a perfect correlation of absent miR-34a expression in cell lines with a 1p36 aberration and phenotypic effect after mimetic add-back. Expression of miR-34a was also decreased in primary tumors (n = 54) with 1p36 deletion (P = 0.009), but no mutations were discovered in resequencing of the miR-34a locus in 30 neuroblastoma cell lines. Flow cytometric time series analyses showed that the likely mechanism of miR-34a growth inhibition is through cell cycle arrest followed by apoptosis. BCL2 and MYCN were identified as miR-34a targets and likely mediators of the tumor suppressor phenotypic effect. These data support miR-34a as a tumor suppressor gene in human neuroblastoma. (Mol Cancer Res 2008;6(5):735–42)
The Biphasic Role of the Hypoxia-Inducible Factor Prolyl-4-Hydroxylase, PHD2, in Modulating Tumor-Forming Potential
Authors: Lee KangAe , Lynd Jeremy D. , O'Reilly Sandra , Kiupel Matti , McCormick J. Justin , LaPres John J. 
Published: May 2008

Abstract
Hypoxia is a common feature of solid tumors. The cellular response to hypoxic stress is controlled by a family of prolyl hydroxylases (PHD) and the transcription factor hypoxia-inducible factor 1 (HIF1). To investigate the relationship between PHD and HIF1 activity and cellular transformation, we characterized the expression levels of PHD isoforms across a lineage of cell strains with varying transformed characteristics. We found that PHD2 is the primary functional isoform in these cells and its levels are inversely correlated to tumor-forming potential. When PHD2 levels were altered with RNA interference in nontumorigenic fibroblasts, we found that small decreases can lead to malignant transformation, whereas severe decreases do not. Consistent with these results, direct inhibition of PHD2 was also shown to influence tumor-forming potential. Furthermore, we found that overexpression of PHD2 in malignant fibroblasts leads to loss of the tumorigenic phenotype. These changes correlated with HIF1α activity, glycolytic rates, vascular endothelial growth factor expression, and the ability to grow under hypoxic stress. These findings support a biphasic model for the relationship between PHD2 activity and malignant transformation. (Mol Cancer Res 2008;6(5):829–42)
Zebrafish as a Cancer Model
Authors: Feitsma Harma , Cuppen Edwin 
Published: May 2008

Abstract
The zebrafish has developed into an important model organism for biomedical research over the last decades. Although the main focus of zebrafish research has traditionally been on developmental biology, keeping and observing zebrafish in the lab led to the identification of diseases similar to humans, such as cancer, which subsequently became a subject for study. As a result, about 50 articles have been published since 2000 in which zebrafish were used as a cancer model. Strategies used include carcinogenic treatments, transplantation of mammalian cancer cells, forward genetic screens for proliferation or genomic instability, reverse genetic target-selected mutagenesis to inactivate known tumor suppressor genes, and the generation of transgenics to express human oncogenes. Zebrafish have been found to develop almost any tumor type known from human, with similar morphology and, according to gene expression array studies, comparable signaling pathways. However, tumor incidences are relatively low, albeit highly comparable between different mutants, and tumors develop late in life. In addition, tumor spectra are sometimes different when compared with mice and humans. Nevertheless, the zebrafish model has created its own niche in cancer research, complementing existing models with its specific experimental advantages and characteristics. Examples of these are imaging of tumor progression in living fish by fluorescence, treatment with chemical compounds, and screening possibilities not only for chemical modifiers but also for genetic enhancers and suppressors. This review aims to provide a comprehensive overview of the state of the art of zebrafish as a model in cancer research. (Mol Cancer Res 2008;6(5):685–94)
Signal Transducer and Activator of Transcription-3: A Molecular Hub for Signaling Pathways in Gliomas
Authors: Brantley Emily C. , Benveniste Etty N. 
Published: May 2008

AbstractGlioblastoma is the most common and severe primary brain tumor in adults. Its aggressive and infiltrative nature renders the current therapeutics of surgical resection, radiation, and chemotherapy relatively ineffective. Accordingly, recent research has focused on the elucidation of various signal transduction pathways in glioblastoma, particularly aberrant activation. This review focuses on the signal transducer and activator of transcription-3 (STAT-3) signal transduction pathway in the context of this devastating tumor. STAT-3 is aberrantly activated in human glioblastoma tissues, and this activation is implicated in controlling critical cellular events thought to be involved in gliomagenesis, such as cell cycle progression, apoptosis, angiogenesis, and immune evasion. There are no reports of gain-of-function mutations in glioblastoma; rather, the activation of STAT-3 is thought to be a consequence of either dysregulation of upstream kinases or loss of endogenous inhibitors. This review provides detailed insight into the multiple mechanisms of STAT-3 activation in glioblastoma, as well as describing endogenous and chemical inhibitors of this pathway and their clinical significance. In glioblastoma, STAT-3 acts a molecular hub to link extracellular signals to transcriptional control of proliferation, cell cycle progression, and immune evasion. Because STAT-3 plays this central role in glioblastoma signal transduction, it has significant potential as a therapeutic target. (Mol Cancer Res 2008;6(5):675–84)
The Fibroblast Growth Factor–Inducible 14 Receptor Is Highly Expressed in HER2-Positive Breast Tumors and Regulates Breast Cancer Cell Invasive Capacity
Authors: Willis Amanda L. , Tran Nhan L. , Chatigny Julie M. , Charlton Nichole , Vu Hong , Brown Sharron A.N. , Black Michael A. , McDonough Wendy S. , Fortin Shannon P. , Niska Joshua R. , Winkles Jeffrey A. , Cunliffe Heather E. 
Published: May 2008

Abstract
Genomic characterization is beginning to define a molecular taxonomy for breast cancer; however, the molecular basis of invasion and metastasis remains poorly understood. We report a pivotal role for the fibroblast growth factor–inducible 14 (Fn14) receptor in this process. We examined whether Fn14 and its ligand tumor necrosis factor–like weak inducer of apoptosis (TWEAK) were expressed in breast tumors and whether deregulation of Fn14 levels affected malignant behavior of breast cancer cell lines. Analysis of TWEAK and Fn14 in publicly available gene expression data indicated that high Fn14 expression levels significantly correlated with several poor prognostic indicators (P &lt; 0.05). Fn14 expression was highest in the HER2-positive/estrogen receptor–negative (HER2+/ER−) intrinsic subtype (P = 0.0008). An association between Fn14 and HER2 expression in breast tumors was confirmed by immunohistochemistry. Fn14 levels were elevated in invasive, ER− breast cancer cell lines. Overexpression of Fn14 in weakly invasive MCF7 and T47D cells resulted in a marked induction of invasion and activation of nuclear factor-κB (NF-κB) signaling. Ectopic expression of Fn14tCT, a Fn14 deletion mutant that cannot activate NF-κB signaling, was not able to induce invasion. Moreover, ectopic expression of Fn14tCT in highly invasive MDA-MB-231 cells reduced their invasive capability. RNA interference–mediated inhibition of Fn14 expression in both MDA-MB-231 and MDA-MB-436 cells reduced invasion. Expression profiling of the Fn14-depleted cells revealed deregulation of NF-κB activity. Our findings support a role for Fn14-mediated NF-κB pathway activation in breast tumor invasion and metastasis. (Mol Cancer Res 2008;6(5):725–34)
Optimal levels of the essential amino acids histidine, lysine and threonine in Caenorhabditis elegans maintenance medium
Authors: Lu Nancy , Xiong Xiaoyan 
Published: May 2008

AbstractCurrent Caenorhabditis elegans Maintenance Medium (C-CeMM) is used to cultivate the free-living nematode, C. elegans. In C-CeMM, ten amino acids (AA) were found to be nutritionally essential. The optimal requirements of seven of these ten essential AA were determined previously. The objectives of the present study were to determine the optimal requirements of the remaining three essential AA: histidine, lysine and threonine. The Optimal Caenorhabditis elegans Maintenance Medium (O-CeMM) was formulated using the levels of all essential AA that supported the optimal population growth for C. elegans from previous quantitative studies and from the results obtained in the first part of this study. The efficacy of O-CeMM, C-CeMM, as well as Egg CeMM (E-CeMM), based on the essential AA ratio in hen's egg, was studied. The optimal requirements (mg ml–1) of histidine, lysine and threonine were determined to be 2.26 (8× C-CeMM), 1.03-2.06 (1× to 2× C-CeMM), and 0.717-2.86 (1× to 4× C-CeMM), respectively. It was found that O-CeMM supported a significantly higher (1.55 ∼ 1.60×) population growth (number of nematodes/ml) when compared with C-CeMM and E-CeMM. For both O-CeMM and C-CeMM, the AA efficiency ratio (AAER; g dry weight (wt) gain of C. elegans/g of total AA) was determined to be 0.18, which was significantly higher than the 0.15 that was determined in E-CeMM. Although the O-CeMM supported a significantly higher population growth, a higher level of histidine and consequently higher total AA were used in O-CeMM than in C-CeMM. Therefore, based on the findings on AAER, it was concluded that both the O-CeMM and C-CeMM were equally efficient for the cultivation of C. elegans.
Nematodes of the order Dorylaimida from Andalucía Oriental, Spain. The genus Enchodelus Thorne, 1939. 2. Description of three known species with rounded tail and long odontostyle
Authors: Peña-Santiago Reyes , Guerrero Pablo , Liébanas Gracia 
Published: May 2008

AbstractNew observations on three similar species of the genus Enchodelus, namely E. groenlandicus, E. macrodorus and E. saxifragae, are provided on the basis of material collected in the southern Iberian Peninsula. Enchodelus groenlandicus is redescribed, this being the first record of the species after its original description 80 years ago. An emended diagnosis is given for E. macrodorus in addition to a compendium and analysis of its previous records. Enchodelus saxifragae, certainly the most widely distributed species in the studied area, is also redescribed. Measurements, illustrations, including LM and SEM, and remarks on the identity of the three species, are presented. Together with E. distinctus and E. microdoroides, the three species form a species group characterised by a long odontostyle (>35 μm), flanged odontophore, tripartite uterus and short, rounded tail. These five species are compared in detail and a key to their identification provided.
Meloidogyne phaseoli n. sp. (Nematoda: Meloidogynidae), a root-knot nematode parasitising bean in Brazil
Authors: Charchar Maria Jose , Eisenback Jonathan , Boiteux Maria Esther , Charchar João 
Published: May 2008

AbstractMeloidogyne phaseoli n. sp. is described and illustrated from specimens parasitising bean cv. Carioca in Brasilia, Brazil. The perineal pattern of the female is rounded to oval-shaped with a dorsal arch that is flattened to moderately high and squarish, sometimes with rounded shoulders. The striae are moderately spaced and often distinctly forked in the lateral field. The female stylet is 14-19 μm long and has broad, distinctly set-off knobs and several small, rounded projections on the shaft. The excretory pore opens 34-82 μm from the head near the level of metacorpus. Males are 999-2105 μm in length and have a high, wide head cap that slopes posteriorly. The labial disc and medial lips are partially fused to form an elongated lip structure. The robust stylet is 20-26 μm long and has wide knobs that are distinctly set-off from the shaft which is marked by several small, round projections. Mean second-stage juvenile length is 464 μm. The head region is not annulated and the large labial disc and crescent-shaped medial lips are fused to form a dumbbell-shaped head cap. The stylet is 10.5-12 μm long and has rounded, posteriorly sloping knobs. The slender tail, 46-64 μm long, has large irregular-sized annules in the posterior region and a slightly rounded tip. The hyaline tail terminus is long, 10.5-19.3 μm. The esterase isozyme is a unique E3 phenotype having one weak and two strong bands. Tomato, tobacco, bean and pea are good hosts, corn is a very poor host, whilst pepper, watermelon, peanut, cotton and soybean are non-hosts.
Pathogenicity and reproductive fitness of Pratylenchus brachyurus on cowpea
Authors: Maria Simões de Siqueira Kércya , Inomoto Mário Massayuki 
Published: May 2008

AbstractThe lesion nematode Pratylenchus brachyurus is widespread in cowpea plantations throughout the tropics and sub-tropics. However, the pathogenicity of P. brachyurus on cowpea has been scarcely studied. In this work, it was demonstrated in two glasshouse experiments that an isolate (Pb20) of P. brachyurus was pathogenic to cowpea cv. IPA-206, adversely affecting the plant growth and pod formation and filling. Initial population levels of 5000 and 15 000 nematodes per plant caused reduction of root growth and typical decay of root tissue. The third experiment demonstrated that all six cowpea cultivars selected for evaluation supported reproduction of three isolates of P. brachyurus (Pb20, Pb21 and Pb23) in their roots, although the reproduction factor values obtained indicated that they were dissimilar in their reproductive fitness. Low resistance to P. brachyurus was reported for at least one tested cultivar, but apparently of an insufficient degree to be effective for field management of the nematode.
Meloidogyne pisi n. sp. (Nematoda: Meloidogynidae), a root-knot nematode parasitising pea in Brazil
Authors: Charchar João , Charchar Maria Jose , Eisenback Jonathan , Boiteux Maria Esther 
Published: May 2008

AbstractMeloidogyne pisi n. sp. is described and illustrated from specimens obtained from roots of pea cv. Mikado in Brasilia, Brazil. The female perineal pattern is variable in shape, most are rounded to ovoid, whereas others have a moderately high, squarish dorsal arch, and can be marked with several striae parallel to the vulva or may be nearly free of striae. Lateral fields may contain a few irregular, wavy, transverse striae or be difficult to discern. Female medial lips are wide and long, sometimes with distinctly indented outer margins; the lateral lips are large and triangular, head annule is wide and marked by incomplete annulations and transverse folds. Stylet is 13-17 μm long with large, elongated knobs and a shaft that is cylindrical, straight and thick. Lumen lining of pharynx containing numerous rounded cuticular thickenings throughout its length; excretory pore located between base of stylet and median bulb. Males are 893-2510 μm long with a 19-26 μm long stylet bearing large elongated knobs, shaft marked with small, rounded projections. Second-stage juveniles are 374-463 μm long with medial lips often indented medially and 10-11 μm long stylet. Tail slender, 42-66 μm long with large irregular annules in posterior region, a slightly pointed tip and hyaline region 9-17 μm long. Many galls and egg masses are produced on tomato, tobacco and varieties of pea and bean. Few galls occur on watermelon and corn and reproduction is poor on pepper. No reproduction occurs on peanut, cotton or soybean.