bluuebunny/crossref_metadata_2025 huggingface dataset:
Pathway-Based Feature Selection Algorithm for Cancer Microarray Data
Authors: Bandyopadhyay Nirmalya , Kahveci Tamer , Goodison Steve , Sun Y. , Ranka Sanjay
Published: March 2010

Classification of cancers based on gene expressions produces better accuracy
when compared to that of the clinical markers. Feature selection improves
the accuracy of these classification algorithms by reducing the chance
of overfitting that happens due to large number of features. We develop a
new feature selection method called Biological Pathway-based Feature Selection (BPFS) for microarray data. Unlike most of the existing methods,
our method integrates signaling and gene regulatory pathways with gene
expression data to minimize the chance of overfitting of the method and to
improve the test accuracy. Thus, BPFS selects a biologically meaningful feature
set that is minimally redundant. Our experiments on published breast
cancer datasets demonstrate that all of the top 20 genes found by our method
are associated with cancer. Furthermore, the classification accuracy of our
signature is up to 18% better than that of vant Veers 70 gene signature,
and it is up to 8% better accuracy than the best published feature selection
method, I-RELIEF.
Fabrication of Highly Porous Alumina‐Based Ceramics with Connected Spaces by Employing PMMA Microspheres as a Template
Authors: Kamitani Kazutaka , Hyodo Takeo , Shimizu Yasuhiro , Egashira Makoto
Published: March 2010

Highly porous alumina‐based ceramics were fabricated by a slip casting method by employing polymethylmethacrylate (PMMA) microspheres having different diameters as a template and MgO or SiC powder as a sintering aid and subsequent calcination at 1600∘C. Spherical pores reflecting the morphology of the PMMA microspheres could be fabricated. In addition, the formation of much smaller connected space among the pores was observed on the pore′s inner walls of all ceramics. In this method, porous structure, for example, pore diameter, shape (open or closed), and mechanical properties, could be controlled by varying the particle size of PMMA microspheres and its concentration in alumina‐based slurries. Highly porous and mechanically strong alumina‐based ceramics having an open porosity of 62%, a connected space size of 1.3 μm, and a compressive strength of 147.6 MPa could be fabricated by employing PMMA microspheres with a mean particle size of 22.6 μm and an appropriate amount of SiC.
Soft Tissue Extramedullary Plasmacytoma
Authors: Ruiz Santiago Fernando , Tello Moreno Manuel , Martín Castro Aurelio , Guzmán Álvarez Luis , Navarrete González Pedro
Published: March 2010

We present the uncommon case of a subcutaneous fascia-based extramedullary plasmacytoma in the leg, which was confirmed by the pathology report and followed up until its remission. We report the differential diagnosis with other more common soft tissue masses. Imaging findings are nonspecific but are important to determine the tumour extension and to plan the biopsy.
Unicity of Meromorphic Function Sharing One Small Function with Its Derivative
Authors: Chen Ang , Wang Xiuwang , Zhang Guowei
Published: March 2010

We deal with the problem of uniqueness of a meromorphic function sharing one small function with its k′s derivative and obtain some results.
Advances in Structural Control in Civil Engineering in China
Authors: Li Hongnan , Huo Linsheng
Published: March 2010

In the recent years, much attention has been paid to the research and development of structural control techniques with particular emphasis on alleviation of wind and seismic responses of buildings and bridges in China. Structural control in civil engineering has been developed from the concept into a workable technology and applied into practical engineering structures. The aim of this paper is to review a state of the art of researches and applications of structural control in civil engineering in China. It includes the passive control, active control, hybrid controland semiactive control. Finally, the possible future directions of structural control in civil engineering in China are presented.
Preclinical Evaluation of Radiation and Perifosine in a Genetically and Histologically Accurate Model of Brainstem Glioma
Authors: Becher Oren J. , Hambardzumyan Dolores , Walker Talia R. , Helmy Karim , Nazarian Javad , Albrecht Steffen , Hiner Rebecca L. , Gall Sarah , Huse Jason T. , Jabado Nada , MacDonald Tobey J. , Holland Eric C.
Published: March 2010

Brainstem gliomas (BSG) are a rare group of central nervous system tumors that arise mostly in children and usually portend a particularly poor prognosis. We report the development of a genetically engineered mouse model of BSG using the RCAS/tv-a system and its implementation in preclinical trials. Using immunohistochemistry, we found that platelet-derived growth factor (PDGF) receptor α is overexpressed in 67% of pediatric BSGs. Based on this observation, we induced low-grade BSGs by overexpressing PDGF-B in the posterior fossa of neonatal nestin tv-a mice. To generate high-grade BSGs, we overexpressed PDGF-B in combination with Ink4a-ARF loss, given that this locus is commonly lost in high-grade pediatric BSGs. We show that the likely cells of origin for these mouse BSGs exist on the floor of the fourth ventricle and cerebral aqueduct. Irradiation of these high-grade BSGs shows that although single doses of 2, 6, and 10 Gy significantly increased the percent of terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL)–positive nuclei, only 6 and 10 Gy significantly induce cell cycle arrest. Perifosine, an inhibitor of AKT signaling, significantly induced TUNEL-positive nuclei in this high-grade BSG model, but in combination with 10 Gy, it did not significantly increase the percent of TUNEL-positive nuclei relative to 10 Gy alone at 6, 24, and 72 hours. Survival analysis showed that a single dose of 10 Gy significantly prolonged survival by 27% (P = 0.0002) but perifosine did not (P = 0.92). Perifosine + 10 Gy did not result in a significantly increased survival relative to 10 Gy alone (P = 0.23). This PDGF-induced BSG model can serve as a preclinical tool for the testing of novel agents. Cancer Res; 70(6); 2548–57
Oncogenic Potential of Retinoic Acid Receptor-γ in Hepatocellular Carcinoma
Authors: Yan Ting-Dong , Wu Hua , Zhang Hai-Ping , Lu Na , Ye Ping , Yu Feng-Hai , Zhou Hu , Li Wen-Gang , Cao Xihua , Lin Ya-Yu , He Jia-You , Gao Wei-Wei , Zhao Yi , Xie Lei , Chen Jie-bo , Zhang Xiao-kun , Zeng Jin-Zhang
Published: March 2010

Retinoic acid receptors (RAR; α, β, and γ), members of the nuclear receptor superfamily, mediate the pleiotropic effects of the vitamin A metabolite retinoic acid (RA) and derivatives (retinoids) in normal and cancer cells. Abnormal expression and function of RARs are often involved in the growth and development of cancer. However, the underlying molecular mechanisms remain largely elusive. Here, we report that levels of RARγ were significantly elevated in tumor tissues from a majority of human hepatocellular carcinoma (HCC) and in HCC cell lines. Overexpression of RARγ promoted colony formation by HCC cells in vitro and the growth of HCC xenografts in animals. In HepG2 cells, transfection of RARγ enhanced, whereas downregulation of RARγ expression by siRNA approach impaired, the effect of RA on inducing the expression of α-fetoprotein, a protein marker of hepatocarcinogenesis. In studying the possible mechanism by which overexpression of RARγ contributed to liver cancer cell growth and transformation, we observed that RARγ resided mainly in the cytoplasm of HCC cells, interacting with the p85α regulatory subunit of phosphatidylinositol 3-kinase (PI3K). The interaction between RARγ and p85α resulted in activation of Akt and NF-κB, critical regulators of the growth and survival of cancer cells. Together, our results show that overexpression of RARγ plays a role in the growth of HCC cells through nongenomic activation of the PI3K/Akt and NF-κB signaling pathways. Cancer Res; 70(6); 2285–95
Downregulation of Notch Pathway by a γ-Secretase Inhibitor Attenuates AKT/Mammalian Target of Rapamycin Signaling and Glucose Uptake in an ERBB2 Transgenic Breast Cancer Model
Authors: Efferson Clay L. , Winkelmann Christopher T. , Ware Christopher , Sullivan Timothy , Giampaoli Saverio , Tammam Jennifer , Patel Shailendra , Mesiti Giuseppe , Reilly John F. , Gibson Raymond E. , Buser Carolyn , Yeatman Timothy , Coppola Domenico , Winter Christopher , Clark Edwin A. , Draetta Giulio F. , Strack Peter R. , Majumder Pradip K.
Published: March 2010

ERBB2/neu and Notch signaling are known to be deregulated in many human cancers. However, pathway cross-talk and dependencies are not well understood. In this study, we use an ERBB2-transgenic mouse model of breast cancer (neuT) to show that Notch signaling plays a critical role in tumor maintenance. Inhibition of the Notch pathway with a γ-secretase inhibitor (GSI) decreased both the Notch and the mammalian target of rapamycin/AKT pathways. Antitumor activity resulting from GSI treatment was associated with decreased cell proliferation as measured by Ki67 and decreased expression of glucose transporter Glut1. Positron emission tomography (PET) imaging showed that the functional consequences of decreased Glut1 translated to reduced glucose uptake and correlated with antitumor effects as measured by micro-computed tomography imaging. The decrease of Glut1 in neuT tumors was also observed in several human breast cancer cell lines following GSI treatment. We provide evidence that ∼27% of ERBB2-positive human breast cancer specimens display high expression of HES1, phospho-S6RP, and GLUT1. Together, these results suggest that pathways downstream of Notch signaling are, at least in part, responsible for promoting tumor growth in neuT and also active in both neuT and a subset of human breast cancers. These findings suggest that GSI may provide therapeutic benefit to a subset of ERBB2-positive breast cancers and that [18F]FDG-PET imaging may be useful in monitoring clinical response. Cancer Res; 70(6); 2476–84
Hsp27 Promotes Insulin-Like Growth Factor-I Survival Signaling in Prostate Cancer via p90Rsk-Dependent Phosphorylation and Inactivation of BAD
Authors: Zoubeidi Amina , Zardan Anousheh , Wiedmann Romina M. , Locke Jennifer , Beraldi Eliana , Fazli Ladan , Gleave Martin E.
Published: March 2010

Hsp27 is highly expressed in castrate-resistant prostate cancer. Although its overexpression confers resistance to androgen ablation and chemotherapy, the mechanisms by which Hsp27 inhibits treatment-induced apoptosis are incompletely defined. Castrate-resistance often correlates with increased activity of autocrine and/or paracrine growth/survival stimulatory loops including the mitogen-activated protein kinase (MAPK) and Akt pathways and insulin-like growth factor (IGF) axis components. Because Hsp27 can be activated by both MAPK and Akt pathways, it is possible that interactions between IGF-I signaling and Hsp27 phosphoactivation function to promote castrate-resistant progression. Here, we report that Hsp27 expression and phosphorylation levels correlate with IGF-I signaling and castrate-resistant progression in human prostate cancer specimens and cell lines. IGF-I induces Hsp27 phosphorylation in a time- and dose-dependent manner via p90Rsk, which interacts directly with and phosphorylates Hsp27 in vitro and in vivo. Conversely, p90Rsk inhibition using short interfering RNA or a dominant negative mutant abolishes IGF-I–induced Hsp27 phosphorylation. Hsp27 overexpression increases IGF-I–induced phosphorylation of Erk, p90Rsk, and Akt. Conversely, Hsp27 knockdown abrogates IGF-I–induced phosphorylation of Erk, p90Rsk, and Akt, thereby destabilizing Bad/14-3-3 complexes and increasing apoptotic rates. These data elucidate the interactions between Hsp27 phosphorylation and the IGF-I receptor signaling pathway and support targeting Hsp27 as a therapeutic strategy for castrate-resistant prostate cancer. Cancer Res; 70(6); 2307–17
Jun Proteins Are Starvation-Regulated Inhibitors of Autophagy
Authors: Yogev Orli , Goldberg Rachel , Anzi Shira , Yogev Ohad , Shaulian Eitan
Published: March 2010

The growing number of biological functions affected by autophagy ascribes a special significance to identification of factors regulating it. The activator protein-1 (AP-1) transcription factors are involved in most aspects of cellular proliferation, death, or survival, yet no information regarding their involvement in autophagy is available. Here, we show that the AP-1 proteins JunB and c-Jun, but not JunD, c-Fos, or Fra-1, inhibit autophagy. JunB inhibits autophagy induced by starvation, overexpression of a short form of ARF (smARF), a potent inducer of autophagy, or even after rapamycin treatment. In agreement, acute repression of JunB expression, by JunB knockdown, potently induces autophagy. As expected from autophagy-inhibiting proteins, Jun B and c-Jun expression is reduced by starvation. Decrease in JunB mRNA expression and posttranscriptional events downregulate JunB protein expression after starvation. The inhibition of autophagy by JunB is not mediated by mammalian target of rapamycin (mTOR) regulation, as it occurs also in the absence of mTOR activity, and autophagy induced by JunB knockdown is not correlated with changes in mTOR activity. Nevertheless, the transcriptional activities of c-Jun and JunB are required for autophagy inhibition, and JunB incapable of heterodimerizing is a less effective inhibitor of autophagy. Most importantly, inhibition of autophagy in starved HeLa cells by JunB enhances apoptotic cell death. We suggest that JunB and c-Jun are regulators of autophagy whose expression responds to autophagy-inducing signals. Cancer Res; 70(6); 2318–27
Plasma Homocysteine and Cysteine and Risk of Breast Cancer in Women
Authors: Lin Jennifer , Lee I-Min , Song Yiqing , Cook Nancy R. , Selhub Jacob , Manson JoAnn E. , Buring Julie E. , Zhang Shumin M.
Published: March 2010

Homocysteine and cysteine are associated with oxidative damage and metabolic disorders, which may lead to carcinogenesis. Observational studies assessing the association between circulating homocysteine or cysteine and breast cancer are very limited, and findings have been inconsistent. We prospectively evaluated plasma levels of homocysteine and cysteine in relation to breast cancer risk among 812 incident cases of invasive breast cancer and 812 individually matched control subjects from 28,345 women in the Women's Health Study; these women were ≥45 years old, provided blood samples, and had no history of cancer and cardiovascular disease at baseline. Logistic regression controlling for matching factors and risk factors for breast cancer was used to estimate relative risks (RR) and 95% confidence intervals (95% CI). All statistical tests were two sided. Homocysteine levels were not associated with overall risk for breast cancer. However, we observed a positive association between cysteine levels and breast cancer risk; the multivariate RR for the highest quintile group relative to the lowest quintile was 1.65 (95% CI, 1.04–2.61; P for trend = 0.04). In addition, women with higher levels of homocysteine and cysteine were at a greater risk for developing breast cancer when their folate levels were low (P for interaction = 0.04 and 0.002, respectively). Although our study offers little support for an association between circulating homocysteine and overall breast cancer risk, higher homocysteine levels may be associated with an increased risk for breast cancer among women with low folate status. The increased risk of breast cancer associated with high cysteine levels warrants further investigation. Cancer Res; 70(6); 2397–405
Mesalazine Reduces Mutations in Transforming Growth Factor β Receptor II and Activin Type II Receptor by Improvement of Replication Fidelity in Mononucleotide Repeats
Authors: Campregher Christoph , Honeder Clemens , Chung Heekyung , Carethers John M. , Gasche Christoph
Published: March 2010

Purpose: Mesalazine (5-aminosalicylic acid, 5-ASA) has chemopreventive properties in colitis-associated cancer. In vitro, it improves replication fidelity at (CA)13 microsatellites independent of mismatch repair proficiency. Therefore, 5-ASA might be advantageous in patients with hereditary nonpolyposis colorectal cancer. At this point, however, it is uncertain whether this improvement of replication fidelity is specific for (CA)13 repetitive sequences. Here, we tested the effect of 5-ASA on replication fidelity in mononucleotide, dinucleotide, and tetranucleotide repeats.

Experimental Design: HCT116 and HCT116+chr3 cells were transfected with pIREShyg2-EGFP reporter plasmids harboring the following microsatellites: A10, G10, (CA)13, (CA)26, (AAAG)17, poly-A tracts, and their flanking sequences of transforming growth factor β receptor II (TGFBR2; A10) and activin type II receptor (ACVR2; A8). Stably transfected single-cell clones were selected, characterized by Southern blotting, sorted into six-well plates, and cultured with or without 5-ASA. Frameshift mutations that shift the enhanced green fluorescence protein into its proper reading frame were quantified by flow cytometry.

Results: In HCT116, 5-ASA reduced the mutant fraction at (CA)13 by 48.3%, at A10 by 35.6-43.6%, at G10 by 74.9-83.6%, and at (AAAG)17 by 37.6-44.4%. Similar results were observed in hMLH1-proficient HCT116+chr3 cells. Moreover, the presence of 5-ASA significantly reduced mutations in TGFBR2 (A10) and ACVR2 (A8) by 39.9% and 46.2%, respectively.

Conclusions: 5-ASA increases replication fidelity in mononucleotide, dinucleotide, and tetranucleotide repeats and reduces mutations in tumor suppressor genes TGFBR2 and ACVR2, a finding that may provoke in vivo studies for the prevention of colorectal cancer in hereditary nonpolyposis colorectal cancer. Clin Cancer Res; 16(6); 1950–6
SB939, a Novel Potent and Orally Active Histone Deacetylase Inhibitor with High Tumor Exposure and Efficacy in Mouse Models of Colorectal Cancer
Authors: Novotny-Diermayr Veronica , Sangthongpitag Kanda , Hu Chang Yong , Wu Xiaofeng , Sausgruber Nina , Yeo Pauline , Greicius Gediminas , Pettersson Sven , Liang Ai Leng , Loh Yung Kiang , Bonday Zahid , Goh Kee Chuan , Hentze Hannes , Hart Stefan , Wang Haishan , Ethirajulu Kantharaj , Wood Jeanette Marjorie
Published: March 2010

Although clinical responses in liquid tumors and certain lymphomas have been reported, the clinical efficacy of histone deacetylase inhibitors in solid tumors has been limited. This may be in part due to the poor pharmacokinetic of these drugs, resulting in inadequate tumor concentrations of the drug. SB939 is a new hydroxamic acid based histone deacetylase inhibitor with improved physicochemical, pharmaceutical, and pharmacokinetic properties. In vitro, SB939 inhibits class I, II, and IV HDACs, with no effects on other zinc binding enzymes, and shows significant antiproliferative activity against a wide variety of tumor cell lines. It has very favorable pharmacokinetic properties after oral dosing in mice, with >4-fold increased bioavailability and 3.3-fold increased half-life over suberoylanilide hydroxamic acid (SAHA). In contrast to SAHA, SB939 accumulates in tumor tissue and induces a sustained inhibition of histone acetylation in tumor tissue. These excellent pharmacokinetic properties translated into a dose-dependent antitumor efficacy in a xenograft model of human colorectal cancer (HCT-116), with a tumor growth inhibition of 94% versus 48% for SAHA (both at maximum tolerated dose), and was also effective when given in different intermittent schedules. Furthermore, in APCmin mice, a genetic mouse model of early-stage colon cancer, SB939 inhibited adenoma formation, hemocult scores, and increased hematocrit values more effectively than 5-fluorouracil. Emerging clinical data from phase I trials in cancer patients indicate that the pharmacokinetic and pharmacologic advantages of SB939 are translated to the clinic. The efficacy of SB939 reported here in two very different models of colorectal cancer warrants further investigation in patients. Mol Cancer Ther; 9(3); 642–52
Doxorubicin Resistance in a NovelIn vitroModel of Human Pleomorphic Liposarcoma Associated with Alternative Lengthening of Telomeres
Authors: Mitchell Marcy A. , Johnson Jay E. , Pascarelli Kara , Beeharry Neil , Chiourea Maria , Gagos Sarantis , Lev Dina , von Mehren Margaret , Kipling David , Broccoli Dominique
Published: March 2010

Soft tissue sarcomas are a diverse set of fatal human tumors where few agents have demonstrable clinical efficacy, with the standard therapeutic combination of doxorubicin and ifosfamide showing only a 25% to 30% response rate in large multi-institutional trials. Although liposarcomas are the most common histologic form of adult soft tissue sarcomas, research in this area is severely hampered by the lack of experimentally tractable in vitro model systems. To this end, here we describe a novel in vitro model for human pleomorphic liposarcoma. The cell line (LS2) is derived from a pleomorphic liposarcoma that uses the alternative lengthening of telomeres (ALT) mechanism of telomere maintenance, which may be important in modulating the response of this tumor type to DNA-damaging agents. We present detailed baseline molecular and genomic data, including genome-wide copy number and transcriptome profiles, for this model compared with its parental tumor and a panel of liposarcomas covering multiple histologies. The model has retained essentially all of the detectable alterations in copy number that are seen in the parental tumor, and shows molecular karyotypic and expression profiles consistent with pleomorphic liposarcomas. We also show the utility of this model, together with two additional human liposarcoma cell lines, to investigate the relationship between topoisomerase 2A expression and the sensitivity of ALT-positive liposarcomas to doxorubicin. This model, together with its associated baseline data, provides a powerful new tool to develop treatments for this clinically poorly tractable tumor and to investigate the contribution that ALT makes to modulating sensitivity to doxorubicin. Mol Cancer Ther; 9(3); 682–92
2-Methoxyestradiol Inhibits Barrett's Esophageal Adenocarcinoma Growth and Differentiation through Differential Regulation of the β-Catenin–E-Cadherin Axis
Authors: Kambhampati Suman , Banerjee Snigdha , Dhar Kakali , Mehta Smita , Haque Inamul , Dhar Gopal , Majumder Monami , Ray Gibanananda , Vanveldhuizen Peter J. , Banerjee Sushanta K.
Published: March 2010

The purpose of this study was to evaluate whether 2-methoxyestradiol (2-ME2), a promising anticancer agent, modulates Barrett's esophageal adenocarcinoma (BEAC) cell growth and behavior through a cellular pathway involving β-catenin in partnership with E-cadherin, which seems to play a critical role in the induction of antitumor responses in cancer cells. We found that 2-ME2 markedly reduced the BEAC cell proliferation through regulating apoptotic machinery such as Bcl-2 and Bax. It may nullify the aggressive behavior of the cells by reducing the migratory behavior. Expressions of β-catenin and E-cadherin and binding of these two proteins is activated in a 2-ME2–dependent fashion in Bic-1 cells. Moreover, overexpressions of these two proteins may be due to the stabilization of these proteins by 2-ME2. We found that 2-ME2–induced antimigratory effects are mediated through the β-catenin–E-cadherin signaling pathways. In view of these results, we determined whether 2-ME2 reduces BEAC tumor growth. Administration of 2-ME2 significantly decreased the growth of BEAC cells xenografted on the flank of nude mice. The evidence presented points out that the effect of 2-ME2 on β-catenin–orchestrated signal transduction plausibly plays a multifaceted functional role to inhibit the proliferation and cell migration of 2-ME2–treated malignant cells and it could be a potential candidate in novel treatment strategies for Barrett's esophageal adenocarcinoma. Mol Cancer Ther; 9(3); 523–34
Sorafenib Inhibits STAT3 Activation to Enhance TRAIL-Mediated Apoptosis in Human Pancreatic Cancer Cells
Authors: Huang Shengbing , Sinicrope Frank A.
Published: March 2010

Signal transducers and activators of transcription 3 (STAT3) is constitutively active in human pancreatic cancer cells and can promote cell growth and apoptosis resistance that contribute to tumorigenesis. We determined if sorafenib, a multikinase inhibitor, can induce apoptosis by targeting STAT3 signaling to enhance apoptosis induction by tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). Human pancreatic cancer cell lines (PANC-1 and BxPC-3) were preincubated with sorafenib (Nexavar) alone or followed by TRAIL. Apoptosis was determined by Annexin V labeling, caspase cleavage, and Bax/Bak activation. Protein expression was analyzed by immunoblotting. Knockdown of STAT3, Mcl-1, and Bim were achieved by lentiviral small hairpin RNA. Adenoviral dominant-negative or retroviral constitutively active (CA) STAT3 were also used. Sorafenib inhibited constitutive STAT3 phosphorylation (Tyr705) and suppressed Mcl-1 and Bcl-xL proteins in a dose- and time-dependent manner. CA-STAT3 overexpression was shown to attenuate caspase-3 cleavage and suppression of Mcl-1 by sorafenib. STAT3 knockdown or a DN STAT3 was shown to downregulate Mcl-1 and Bcl-xL and to sensitize cells to TRAIL-mediated apoptosis. Treatment with sorafenib enhanced TRAIL-induced Annexin V staining and release of mitochondrial cytochrome c and AIF. Because the BH3-only Bim protein is a potent inducer of mitochondrial apoptosis, Bim knockdown was shown to attenuate caspase-3, caspase-9 cleavage, and Bax/Bak activation by sorafenib plus TRAIL. The suppression of STAT3 by genetic means or using sorafenib was shown to downregulate Mcl-1 and Bcl-xL and to sensitize cells to TRAIL-mediated apoptosis. These data indicate that targeting STAT3 may enhance treatment efficacy against pancreatic cancer. Mol Cancer Ther; 9(3); 742–50
Skp2 Directs Myc-Mediated Suppression of p27Kip1 yet Has Modest Effects on Myc-Driven Lymphomagenesis
Authors: Old Jennifer B. , Kratzat Susanne , Hoellein Alexander , Graf Steffi , Nilsson Jonas A. , Nilsson Lisa , Nakayama Keiichi I. , Peschel Christian , Cleveland John L. , Keller Ulrich B.
Published: March 2010

The universal cyclin-dependent kinase inhibitor p27Kip1 functions as a tumor suppressor, and reduced levels of p27Kip1 connote poor prognosis in several human malignancies. p27Kip1 levels are predominately regulated by ubiquitin-mediated turnover of the protein, which is marked for destruction by the E3 ubiquitin ligase SCFSkp2 complex following its phosphorylation by the cyclin E–cyclin-dependent kinase 2 complex. Binding of phospho-p27Kip1 is directed by the Skp2 F-box protein, and this is greatly augmented by its allosteric regulator Cks1. We have established that programmed expression of c-Myc in the B cells of Eμ-Myc transgenic mice triggers p27Kip1 destruction by inducing Cks1, that this response controls Myc-driven proliferation, and that loss of Cks1 markedly delays Myc-induced lymphomagenesis and cancels the dissemination of these tumors. Here, we report that elevated levels of Skp2 are a characteristic of Eμ-Myc lymphomas and of human Burkitt lymphoma that bear MYC/Immunoglobulin chromosomal translocations. As expected, Myc-mediated suppression of p27Kip1 was abolished in Skp2-null Eμ-Myc B cells. However, the effect of Skp2 loss on Myc-driven proliferation and lymphomagenesis was surprisingly modest compared with the effects of Cks1 loss. Collectively, these findings suggest that Cks1 targets, in addition to p27Kip1, are critical for Myc-driven proliferation and tumorigenesis. Mol Cancer Res; 8(3); 353–62
PAX5α Enhances the Epithelial Behavior of Human Mammary Carcinoma Cells
Authors: Vidal Laurent J-P , Perry Jo K. , Vouyovitch Cecile M. , Pandey Vijay , Brunet-Dunand Severine E. , Mertani Hichem C. , Liu Dong-Xu , Lobie Peter E.
Published: March 2010

Deregulated PAX5 expression has been associated with metastatic mammary carcinoma, although the precise role of PAX5 in cancer progression is unclear. Stable forced expression of PAX5α in the mammary carcinoma cell lines MCF-7 and MDA-MB-231 reduced cell cycle progression, cell survival, and anchorage-independent cell growth. In xenograft studies, forced expression of PAX5α was associated with a significant reduction in tumor volume. Furthermore, forced expression of PAX5α in mammary carcinoma cells resulted in altered cell morphology with resultant enhancement of epithelial cell characteristics. Morphologic changes were associated with localization of β-CATENIN at cell-cell junctions and with altered mRNA expression of mesenchymal markers in mammary carcinoma cells. In addition, forced expression of PAX5α in MCF-7 and MDA-MB-231 cells significantly reduced cell migration and invasion. Concomitantly, small interfering RNA–mediated depletion of PAX5α increased MCF-7 total cell number, cell motility, migration, and invasion. These studies show that PAX5α enhances the epithelial characteristics of mammary carcinoma cells, reminiscent of mesenchymal to epithelial transition. Mol Cancer Res; 8(3); 444–56
Hormones and Genes of Importance in Bone Physiology and Their Influence on Bone Mineralization and Growth in Turner Syndrome
Authors: Andrade Anenisia C. , Baron Jeffrey , Manolagas Stavros C. , Shaw Nick J. , Rappold Gudrun A. , Donaldson Malcolm D.C. , Gault Emma Jane , Sävendahl Lars
Published: March 2010

This mini review summarizes papers presented in a Joint Symposium between the Bone, Growth Plate and Turner Syndrome Working Groups of the European Society for Paediatric Endocrinology (ESPE) that was held on September 9, 2009, in New York.The program had been composed to give an update on hormones and genes of importance in bone physiology and their influence on bone mineralization and growth in Turner syndrome. This paper summarizes the data and highlights the main topics and discussions related to each presentation.
Analyses of Treatment Variables for Patients with Childhood Craniopharyngioma – Results of the Multicenter Prospective Trial KRANIOPHARYNGEOM 2000 after Three Years of Follow-Up
Authors: Müller Hermann L. , Gebhardt Ursel , Schröder Sabine , Pohl Fabian , Kortmann Rolf-Dieter , Faldum Andreas , Zwiener Isabella , Warmuth-Metz Monika , Pietsch Torsten , Calaminus Gabriele , Kolb Reinhard , Wiegand Christoph , Sörensen Niels
Published: March 2010

Background: Controversies surround various treatment variables for patients with childhood craniopharyngioma such as growth hormone (GH) replacement, which some believe can exacerbate recurrence/progression. We prospectively assessed the risk of tumor recurrence/progression in survivors of childhood craniopharyngioma. Methods: Multivariable analyses of risk factors (age at diagnosis, degree of resection, irradiation, GH treatment and gender) and descriptive analyses of overall survival (OS) and event-free survival (EFS) rates were performed in 117 patients, recruited prospectively and evaluated after 3 years of follow-up in the German, Austrian and Swiss multicenter trial KRANIOPHARYNGEOM 2000. Results: We observed a 3-year OS of 0.97 and a 3-year EFS of 0.46, indicating high recurrence rates after complete resection (CR) (n = 47; 3-year-EFS: 0.64) and high progression rates after incomplete resection (IR) (n = 64; 3-year EFS: 0.31). The risk of an event decreased by 80% after CR compared to IR (hazard ratio = 0.20; p < 0.001). Irradiation had protective effects on EFS: irradiated patients had an 88% lower risk of recurrence/progression compared to patients without/before irradiation (hazard ratio = 0.12; p < 0.001). GH treatment had no impact on 3-year EFS rates. Conclusions: Tumor recurrences/progressions are frequent and occur early after initial treatment of childhood craniopharyngioma. A radical resection preserving the integrity of hypothalamic structures appears optimal at original diagnosis. Irradiation was efficient in preventing recurrences/progressions. GH treatment had no impact on the low 3-year EFS observed in our study. However, further conclusions on the influence of GH on recurrence rates have to be refined to long-term follow-up studies of patients with childhood craniopharyngioma.
Tall Stature and Gonadal Dysgenesis in a Non-Mosaic Girl 45,X
Authors: Fernandez Rosa , Pasaro Eduardo
Published: March 2010

Turner’s syndrome, also known as ‘monosomy X’, is a genetic disorder that occurs in 1/2,500 female births and is hypothesized to result from haploinsufficiency of certain genes expressed from both sex chromosomes that escape X inactivation. While the classic karyotype related to Turner’s syndrome is 45,X, the majority of those affected actually have a mosaic chromosomal complement, most often with a second normal cell line (46,XX). The resulting phenotype is variable and related to the underlying chromosomal pattern, but it is characterized by three cardinal features: short stature (around 100%), ovarian failure (>90%) and congenital lymphedema (>80%). In this paper we report a molecular and cytogenetic investigation of a 26-year-old female with non-mosaic 45,X karyotype, who has a stature of 170 cm without GH treatment, and whose only apparent Turner feature is gonadal dysgenesis. The only possible explanation for the absence of Turner phenotype is the hidden mosaicism combined with an untreated gonadal dysgenesis. Our results support the theory that significant ascertainment bias exists in our understanding of Turner’s syndrome.
Unusual Phenotypical Variations in a Boy with McCune-Albright Syndrome
Authors: Mamkin Irene , Philibert Pascal , Anhalt Henry , Ten Svetlana , Sultan Charles
Published: March 2010

Background: McCune-Albright syndrome (MAS) typically comprises the constellation of polyostotic fibrous dysplasia, café-au-lait spots, and associated endocrinopathies including gonadotropin-independent precocious puberty, excessive growth hormone production and gigantism, hyperthyroidism, and hyperparathyroidism. Objective: We report the unique case of a boy with the diagnostic criteria of MAS accompanied by atypical short stature and macroorchidism without precocious puberty. Patient: An 8.4-year-old prepubertal boy presented with a history of recurrent bone fractures, multiple café-au-lait spots, bilateral macroorchidism, and short stature. X-ray of the extremities was consistent with polyostotic fibrous dysplasia. Serum inhibin B (IB) and anti-müllerian hormone (AMH) were elevated; testosterone, LH, and FSH were normal for age. Results: PCR-based DNA analysis of bone tissue revealed a substitution of arginine for cysteine at position 201 in the Gsα protein resulting in activation of the Gsα subunit. Conclusions: We report a second case of MAS associated with macroorchidism. In this case, isolated Sertoli cell hyperfunction was also associated with microlithiasis and was not associated with peripheral precocious puberty. Short stature not associated with GH-IGF-1 axis abnormality was a second anomalous finding in this case. Our experience suggests that the phenotypic variation in MAS is wider than previously described.
Development of an e-Learning Portal for Pediatric Endocrinology: Educational Considerations
Authors: Grijpink-van den Biggelaar K. , Drop S.L.S. , Schuwirth L.
Published: March 2010

Background: Global accessibility and dissemination of developments in pediatric endocrinology prompted to examine how to develop an educational interactive e-SPE web portal. Methods: A systematic approach was used to identify the relevant aspects of accessibility and dissemination. An orientation at the big idea was made, executed by an analysis of the needs of student and teacher pediatric endocrinologists, a definition of the learning objectives, a research in educational literature and an exploration of ICT design specifications. Results: The intensive collaboration between medical, educational and information technology disciplines resulted in a portal design. The portal meets requirements of adult learning, stresses interaction between partners in learning and offers direct feedback during the learning process. The portal supports the development of not only knowledge but also competences both at junior and advanced levels. Conclusion: When the e-SPE portal is completed, the options for summative assessment will be examined as a medium for international certification in conjunction with local and national requirements (http://espe.elearning.nl).
Characteristics and Prognosis of Childhood Atopic Dermatitis: A Multicenter Study in Turkey
Authors: Yuksel Hasan , Can Demet , Reisli İsmail , Uzuner Nevin , Orhan Fazil , Cevit Omer , Tahan Fulya , Canitez Yakup , Kuyucu Semanur , Boz Aysen Bingol , Akcay Ahmet , Yılmaz Ozge
Published: March 2010

Background:Childhood atopic dermatitis (AD) is classically accepted as initial finding of atopic march; however, nonatopic cases do not follow this course. The aim of this study was to determine the characteristics and prognosis of AD in childhood in Turkey. Methods:The study included 531 children with AD that presented to pediatric allergy departments in 11 different regions of Turkey. Age at diagnosis, total serum and inhalant-specific immunoglobulin E (IgE) levels and allergen skin prick test results were recorded retrospectively. Clinical characteristics like additional allergic diseases at presentation or during follow-up were recorded as well as duration of follow-up. Results:Mean age at diagnosis was 37.8 ± 36.2 months. Mean IgE level was 318.3 ± 677.8 IU/ml (median 100 IU/ml). Skin prick tests yielded positive results in 47% of children. At presentation, 31.6% of children reported additional allergic disease, while 11.7% developed allergic disease during follow-up. Among all, 46.6% had additional allergic disease at any point. IgE levels were significantly higher in children with additional allergic diseases (p = 0.001). Allergen skin prick test positivity and family history of allergic diseases increased the risk of additional allergic diseases significantly (OR = 3.90, 95% CI = 2.3–6.6 and OR = 1.89, 95% CI = 1.3–2.8, respectively). Conclusions: Allergic sensitization is not present in all cases of AD. Coexistence of additional allergic diseases is not as high as expected but more common in children who have been demonstrated to have atopic sensitization with high IgE levels and allergen skin prick test positivity.
Concordance of Lateral Flow and Skin Prick Tests in the Assessment of Allergen Sensitisation in the Epidemiological Field in Children
Authors: Sanchez-Bahillo Maria , Garcia-Marcos Luis , Martinez-Torres Antonia Elena , Perez-Fernandez Virginia , Sanchez-Solis Manuel
Published: March 2010

Background: A new lateral flow test (LFT) for office use provides information about sensitisation to common allergens. Concordance between LFT and skin-prick test (SPT) has not been assessed in epidemiological studies. The aim of this study is to determine LFT-SPT concordance in this field. Methods: Plasma samples (n = 270) from children aged 9–12 years previously SPT tested were used for the analysis. We selected 180 samples from children SPT positive to any of the 6 allergens which were common to SPT and LFT (cat, birch, timothy-grass, olive, pellitoryand Dermatophagoides pteronyssinus), and 90 samples from children SPT negative. The intensity of the LFT colour line which indicates a positive reaction was rated from 0 to 4. Results: Only results on cat, olive and D. pteronyssinus were analysed, as only these had an acceptable number of individuals. When atopy was defined as at least 1 wheal with a mean diameter ≧3 mm, agreement was excellent (Cohen’s ĸ = 0.81) when a lightly visible line was considered positive in the LFT, and dropped substantially (Cohen’s ĸ = 0.68) when this value of LFT was considered negative. The correlation between the SPT wheal diameter and the intensity of the LFT line was 0.71 for cat, 0.81 for olive and 0.78 for D. pteronyssinus.Conclusions: As compared to SPT, LFT is a reliable method to screen for sensitisation to cat dander, olive pollen and D. pteronyssinus in the epidemiological field among schoolchildren. There is a good correlation between the SPT wheal diameter and the intensity of the LFT line.
Two Newly Diagnosed HLA Class II-Deficient Patients Identified by Rapid Vector-Based Complementation Analysis Reveal Discoordinate Invariant Chain Expression Levels
Authors: Schmetterer Klaus G. , Seidel Markus G. , Körmöczi Ulrike , Rottal Arno , Schwarz Klaus , Matthes-Martin Susanne , Steinberger Peter , Pickl Winfried F.
Published: March 2010

Background: Primary immunodeficiencies represent the ‘molecular Achilles’ heels’ of human immunity. Detailed analyses of primary immunodeficiencies extend our knowledge of pivotal immunological processes, lead to novel diagnostic algorithms and shorten the time to diagnosis. Methods: Clinical/immunological phenotypes of 2 unrelated patients from Austria with combined immunodeficiency were determined. Leukocyte subpopulations of these patients, their parents and healthy controls were analyzed by flow cytometry. Patient-derived Epstein-Barr virus (EBV)-transformed B cell lines were established and complemented by candidate cDNAs. Suspected mutations were confirmed by DNA sequencing. Results: Phenotyping revealed a lack of constitutive human leukocyte antigen (HLA) class II expression on antigen-presenting cells of both patients, compatible with MHC class II deficiency. Rapid vector-based complementation analysis of the patients’ B cells identified HLA class II transactivator (CIITA) deficiency in patient VIP1 and regulatory factor X (RFX)AP deficiency in patient VIP2. CIITA deficiency was caused by a homozygous p.Glu381X mutation. RFXAP deficiency resulted from a homozygous p.Ser123ThrfsX15 mutation, not described in the Middle European population so far. Of note, HLA class II-associated invariant chain (Ii) expression levels were significantly reduced in VIP1 and 3 additional EBV-transformed B cell lines of CIITA-deficient patients but normal in EBV-transformed B cells from VIP2. In addition, peripheral blood B cells from the parents of VIP1 showed significantly reduced HLA-DR and -DP expression levels compared to healthy controls. Conclusions: Analysis of patients’ intracellular Ii and their parents’ surface HLA class II expression levels might help to identify CIITA-deficient patients already during initial phenotyping.
Autoimmune Response of IgE Antibodies to Cellular Self-Antigens in Systemic Lupus Erythematosus
Authors: Atta Ajax Mercês , Santiago Mittermayer Barreto , Guerra Fernanda Garcia , Pereira Mariana Menezes , Sousa Atta Maria Luiza B.
Published: March 2010

Background: Systemic lupus erythematosus (SLE) patients may exhibit high total IgE and antinuclear IgE antibodies (ANA-IgE). Here, we investigated the specificity of ANA-IgE in SLE patients and the involvement of cytokines in this immune response. Methods: Sera from 92 SLE patients and 68 healthy controls were evaluated for the presence of antinuclear IgE antibodies by immunoperoxidase with HEp-2,000® cells and immunoblotting with IgG-depleted sera. Total IgE, IgE specific to allergens, and serum cytokine levels were determined by ELISA. Results: Antinuclear IgE antibodies were detected only in SLE patients (29/92, 31.5%). High total IgE was associated with ANA-IgE (p < 0.0001), but was not associated with IgE antibodies to allergens. In the immunoblotting, ANA-IgE reacted with nucleosomes (23/29, 79.3%), dsDNA (14/29, 48.3%), SS-A/Ro (14/29, 48.3%), SS-B/La (2/29, 18.7%), Sm (14/29, 48.3%) and RNP (18/29, 62.1%). Patients with ANA-IgE had very low serum IL-4, less IL-5 than controls (p < 0.05), more IL-10 than seronegative patients (p < 0.05), and unaltered IFN-γ levels. The IL-5/IL-10 ratio was lower in ANA-IgE seropositive patients in comparison with either seronegative patients (p < 0.05) or healthy controls (p = 0.001). Controls displayed higher IL-5/IFN-γ ratios than either SLE patients with ANA-IgE (p < 0.05) or patients without these immunoglobulins (p < 0.01). Conclusions: We conclude that IgE antibodies against cell autoantigens involved in protein expression, cellular proliferation, and cell death are present in patients with SLE. Interleukin-10 seems to down-regulate this IgE autoimmune response in SLE.
Disappearing Myelodysplastic Syndrome-Associated Hemolytic Anemia in Leukemic Transformation
Authors: Tabata Rie , Tabata Chiharu , Omori Konosuke , Nagai Tomoko
Published: March 2010

Background: Here we report 2 rare cases of acute myeloid leukemia (AML) complicated with hemolytic anemia limited to the myelodysplastic syndrome (MDS) stage, and disappearing in leukemic transformation. Methods/Results: A 66-year-old man with MDS-RAEB-2 was admitted to hospital for severe anemia with increased reticulocyte counts. Hemolytic anemia was suspected, and it was ameliorated by methylprednisolone pulse therapy. Although anemia grew worse when steroids were tapered off, later improvement coincided with an increase in myeloblasts in the peripheral blood, i.e. with leukemic transformation. In another case, a 68-year-old man was admitted to hospital when laboratory findings showed a white blood cell count of 24,800/µl with increased myeloblasts (62.5%), leading to the diagnosis of AML with multilineage dysplasia. Following a decrease in blasts due to anti-cancer drugs, supporting the MDS-RAEB-2 status, severe anemia with increased reticulocytes and positive direct antiglobulin test was diagnosed, suggesting the existence of autoimmune hemolytic anemia, which was then ameliorated by steroid therapy. Conclusions: The simultaneous loss of autoimmunity and leukemic cell expansion observed in our cases may possibly suggest a common underlying mechanism.
Early Detection of Alzheimer’s Disease with PET Imaging
Authors: Berti V. , Osorio R.S. , Mosconi L. , Li Y. , De Santi S. , de Leon M.J.
Published: March 2010

Preclinical diagnosis of Alzheimer’s disease (AD) is one of the major challenges for the prevention of AD. AD biomarkers are needed not only to reveal preclinical pathologic changes, but also to monitor progression and therapeutics. PET neuroimaging can reliably assess aspects of the molecular biology and neuropathology of AD. The aim of this article is to review the use of FDG-PET and amyloid PET imaging in the early detection of AD.
Human Analogue of the Morris Water Maze for Testing Subjects at Risk of Alzheimer’s Disease
Authors: Laczó J. , Andel R. , Vyhnalek M. , Vlcek K. , Magerova H. , Varjassyova A. , Tolar M. , Hort J.
Published: March 2010

Background: Patients with Alzheimer’s disease (AD) and amnestic mild cognitive impairment (MCI) have difficulties with spatial orientation. Objective: To test hypothesis that spatial navigation is impaired early in MCI patients representing the presymptomatic stage of AD. Methods: We tested patients with probable AD (n = 21), MCI, further classified according to Petersen’s criteria as amnestic MCI (aMCI) single domain (n = 11), aMCI multiple domain (n = 31), or nonamnestic MCI (n = 7). The aMCI group was also stratified using cued recall according to Dubois’ criteria into memory impairment of the hippocampal type (n = 10) and isolated memory retrieval impairment-nonhippocampal (n = 32) and also according to ApoE4 status into E4+ (n = 12) and E4– (n = 30). These patients and controls (n = 28) were tested in the human variant of the Morris water maze. Depending on the subtest, the subjects could use the egocentric or allocentric (hippocampus-dependent) navigation. Results: The AD and aMCI multiple domain groups were impaired in all subtests. The aMCI single domain group was impaired in allocentric subtests. The hippocampal MCI group performed poorer than the nonhippocampal MCI group and similarly to the AD group. The ApoE4+ group was as bad as the AD group when compared with the E4– group. Conclusion: aMCI subjects represent a very heterogeneous population, and spatial memory or cued recall examination can add more value to aMCI classification. ApoE4+ patients are more impaired than ApoE4– patients.