bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental Human Cell and Tissue Models of Pemphigus
Authors: van der Wier Gerda , Pas Hendri H. , Jonkman Marcel F.
Published: May 2010

Pemphigus is a chronic mucocutaneous autoimmune bullous disease that is characterized by loss of cell‐cell contact in skin and/or mucous membranes. Past research has successfully identified desmosomes as immunological targets and has demonstrated that acantholysis is initiated through direct binding of IgG. The exact mechanisms of acantholysis, however, are still missing. Experimental model systems have contributed considerably to today′s knowledge and are still a favourite tool of research. In this paper we will describe to what extent human cell and tissue models represent the in vivo situation, for example, organ cultures of human skin, keratinocyte cultures, and human skin grafted on mice and, furthermore, how suitable they are to study the pathogenesis of pemphigus. Organ cultures closely mimic the architecture of the epidermis but are less suitable to answer posed biochemical questions. Cultured keratinocyte monolayers are convenient in this respect, but their desmosomal make‐up in terms of adhesion molecules does not exactly reflect the in vivo situation. Reconstituted skin is a relatively new model that approaches organ culture. In models of human skin grafted on mice, acantholysis can be studied in actual human skin but now with all the advantages of an animal model.
Leptospirosis: An Unusual Cause of ARDS
Authors: Clavel Marc , Lhéritier Gwenaelle , Weinbreck Nicolas , Guerlin Antoine , Dugard Anthony , Denes Eric , Vignon Philippe
Published: May 2010

Severe leptospirosis usually associates shock, jaundice, renal failure, and thrombocytopenia. Massive hemoptysis due to diffuse alveolar haemorrhage may rarely occur leading to an acute respiratory failure and multiple organ failure. We present the case of an acute respiratory distress syndrome caused by a severe leptospirosis. The severity of the respiratory failure contrasted with the absence of significant liver or renal dysfunction. Bedside open lung biopsy was only consistent with a postinfectious BOOP. The diagnosis was retrospective when the niece of the patient presented with similar inaugural symptoms ten days later after being scratched by a wild rat which was considered by our patient as a pet.
Video Quality Prediction Models Based on Video Content Dynamics for H.264 Video over UMTS Networks
Authors: Khan Asiya , Sun Lingfen , Ifeachor Emmanuel , Fajardo Jose-Oscar , Liberal Fidel , Koumaras Harilaos
Published: May 2010

The aim of this paper is to present video quality prediction models for objective non-intrusive, prediction of H.264 encoded video for all content types combining parameters both in the physical and application layer over Universal Mobile Telecommunication Systems (UMTS) networks. In order to characterize the Quality of Service (QoS) level, a learning model based on Adaptive Neural Fuzzy Inference System (ANFIS) and a second model based on non-linear regression analysis is proposed to predict the video quality in terms of the Mean Opinion Score (MOS). The objective of the paper is two-fold. First, to find the impact of QoS parameters on end-to-end video quality for H.264 encoded video. Second, to develop learning models based on ANFIS and non-linear regression analysis to predict video quality over UMTS networks by considering the impact of radio link loss models. The loss models considered are 2-state Markov models. Both the models are trained with a combination of physical and application layer parameters and validated with unseen dataset. Preliminary results show that good prediction accuracy was obtained from both the models. The work should help in the development of a reference-free video prediction model and QoS control methods for video over UMTS networks.
Identifying and Improving Knowledge Deficits of Emergency Airway Management of Tracheotomy and Laryngectomy Patients: A Pilot Patient Safety Initiative
Authors: El-Sayed Ivan H. , Ryan Susan , Schell Hildy , Rappazini Rosanne , Wang Steven J.
Published: May 2010

Objectives. To evaluate the knowledge base of hospital staff regarding emergent airway management of tracheotomy and laryngectomy patients, and the impact of the introduction of a bedside airway form.Methods. Cross-sectional surveys of physicians, nurses, and respiratory therapists at a tertiary care hospital prior to and 24 months after introduction of a bedside Emergency Airway Access (EAA) form.Results. Pre- and postintervention surveys revealed several knowledge deficits. Preintervention, 37% of medical internists and 19% overall did not know that laryngectomy patients cannot be orally ventilated, and 67% of internists could not identify the purpose of stay sutures in recently created tracheotomies. Postintervention, these numbers improved for all groups. Furthermore, 80% of respiratory therapists reported encountering the EAA form in an emergent situation and found it useful.Conclusion. A knowledge deficit is identified in caregivers expected to provide emergency management of patients with airway anatomy altered by subspecialty surgeons. Safety initiatives such as the EAA form may improve knowledge among providers.
Population-Based Estimate of the Contribution of TP53 Mutations to Subgroups of Early-Onset Breast Cancer: Australian Breast Cancer Family Study
Authors: Mouchawar Judy , Korch Christopher , Byers Tim , Pitts Todd M. , Li Efang , McCredie Margaret R.E. , Giles Graham G. , Hopper John L. , Southey Melissa C.
Published: May 2010

Although germline TP53 mutations have been identified in women with breast cancer from families meeting Li-Fraumeni criteria, their contribution to breast cancer per se is not well known, but is thought to be minimal. We aimed to determine the prevalence of germline TP53 mutations in subgroups of early-onset breast cancer. Germline TP53 mutation status was assessed by DNA sequencing, screening for heterozygous single-nucleotide polymorphisms, and Multiplex Ligation-Dependent Probe Amplification analyses. From an Australian population-based series of invasive breast cancers, we studied (a) 52 women diagnosed before age 30 years unselected for family history [very early-onset (VEO)] and (b) 42 women diagnosed in their 30s with two or more first- or second-degree relatives with breast or ovarian cancer [early-onset family history (EO-FH)]. Of the VEO group, two (4%) had a mutation: G13203A (exon 6 missense) in a 24-year-old and a large 5,338-bp genomic deletion in a 26-year-old. Neither had a family cancer history that met Li-Fraumeni criteria. Of the EO-FH group, three (7%) had a mutation: T13240G (a known intron 5 splicing mutation) in a 36-year-old from a classic Li-Fraumeni family; G12299A (exon 4 missense) in a 33-year-old from a Li-Fraumeni–like family; and 14058delG (exon 7 frame-shift) in a 39-year-old with a family cancer history that did not meet Li-Fraumeni criteria. Germline TP53 mutations play a larger role in early-onset breast cancer than previously thought, and in this context, can be evident outside clinically defined Li-Fraumeni families. Cancer Res; 70(12); 4795–800. ©2010 AACR.
Role of Peroxisome Proliferator-Activated Receptor-γ and Its Coactivator DRIP205 in Cellular Responses to CDDO (RTA-401) in Acute Myelogenous Leukemia
Authors: Tsao Twee , Kornblau Steven , Safe Stephen , Watt Julie C. , Ruvolo Vivian , Chen Wenjing , Qiu Yihua , Coombes Kevin R. , Ju Zhenlin , Abdelrahim Maen , Schober Wendy , Ling Xiaoyang , Kardassis Dimitris , Meyer Colin , Schimmer Aaron , Kantarjian Hagop , Andreeff Michael , Konopleva Marina
Published: May 2010

Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear receptor (NR) family of transcription factors with important regulatory roles in cellular growth, differentiation, and apoptosis. Using proteomic analysis, we showed expression of PPARγ protein in a series of 260 newly diagnosed primary acute myelogenous leukemia (AML) samples. Forced expression of PPARγ enhanced the sensitivity of myeloid leukemic cells to apoptosis induced by PPARγ agonists 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and 15-deoxy-12,14-15DPGJ2, through preferential cleavage of caspase-8. No effects on cell cycle distribution or differentiation were noted, despite prominent induction of p21 in PPARγ-transfected cells. In turn, antagonizing PPARγ function by small interfering RNA or pharmacologic PPARγ inhibitor significantly diminished apoptosis induction by CDDO. Overexpression of coactivator protein DRIP205 resulted in enhanced differentiation induction by CDDO in AML cells through PPARγ activation. Studies with DRIP205 deletion constructs showed that the NR boxes of DRIP205 are not required for this coactivation. In a phase I clinical trial of CDDO (RTA-401) in leukemia, CDDO induced an increase in PPARγ mRNA expression in six of nine patient samples; of those, induction of differentiation was documented in four patients and that of p21 in three patients, all expressing DRIP205 protein. In summary, these findings suggest that cellular levels of PPARγ regulate induction of apoptosis via caspase-8 activation, whereas the coactivator DRIP205 is a determinant of induction of differentiation, in response to PPARγ agonists in leukemic cells. Cancer Res; 70(12); 4949–60. ©2010 AACR.
Arrest Defective 1 Autoacetylation Is a Critical Step in Its Ability to Stimulate Cancer Cell Proliferation
Authors: Seo Ji Hae , Cha Jong-Ho , Park Ji-Hyeon , Jeong Chul-Ho , Park Zee-Yong , Lee Hye-Suk , Oh Seung Hyun , Kang Ju-Hee , Suh Se Won , Kim Kyoung Hoon , Ha Jun Yong , Han Sang Hee , Kim Se-Hee , Lee Ji-Won , Park Jeong Ae , Jeong Joo-Won , Lee Kong-Joo , Oh Goo Taeg , Lee Mi-Ni , Kwon Sung Won , Lee Seung-Ki , Chun Kwang-Hoon , Lee Su-Jae , Kim Kyu-Won
Published: May 2010

The N-acetyltransferase arrest defective 1 (ARD1) is an important regulator of cell growth and differentiation that has emerged recently as a critical molecule in cancer progression. However, the regulation of the enzymatic and biological activities of human ARD1 (hARD1) in cancer is presently poorly understood. Here, we report that hARD1 undergoes autoacetylation and that this modification is essential for its functional activation. Using liquid chromatography-tandem mass spectrometry and site-directed mutational analyses, we identified K136 residue as an autoacetylation target site. K136R mutation abolished the ability of hARD1 to promote cancer cell growth in vitro and tumor xenograft growth in vivo. Mechanistic investigations revealed that hARD1 autoacetylation stimulated cyclin D1 expression through activation of the transcription factors β-catenin and activator protein-1. Our results show that hARD1 autoacetylation is critical for its activation and its ability to stimulate cancer cell proliferation and tumorigenesis. Cancer Res; 70(11); 4422–32. ©2010 AACR.
Novel Dyskerin-Mediated Mechanism of p53 Inactivation through Defective mRNA Translation
Authors: Montanaro Lorenzo , Calienni Maria , Bertoni Sara , Rocchi Laura , Sansone Pasquale , Storci Gianluca , Santini Donatella , Ceccarelli Claudio , Taffurelli Mario , Carnicelli Domenica , Brigotti Maurizio , Bonafè Massimiliano , Treré Davide , Derenzini Massimo
Published: May 2010

In up to 60% of human cancers, p53 gene mutations are responsible for direct inactivation of the tumor suppressor function of p53. Alternative mechanisms of p53 inactivation described thus far mainly affect its posttranslational regulation. In X-linked dyskeratosis congenita, a multisystemic syndrome characterized by increased cancer susceptibility, mutations of the DKC1 gene encoding dyskerin cause a selective defect in the translation of a subgroup of internal ribosome entry site (IRES)–containing cellular mRNAs. In this study, we show that impairment of dyskerin function can cause p53 inactivation due to a defect in p53 mRNA translation. siRNA-mediated reduction of dyskerin levels caused a decrease of p53 mRNA translation, protein levels, and functional activity, both in human breast cancer cells and in primary mammary epithelial progenitor cells. These effects seemed to be independent of the known role of dyskerin in telomerase function, and they were associated with a specific impairment of translation initiation mediated by IRES elements present in p53 mRNA. In a series of human primary breast cancers retaining wild-type p53, we found that low levels of dyskerin expression were associated with reduced expression of p53-positive target genes. Our findings suggest that a dyskerin-mediated mechanism of p53 inactivation may occur in a subset of human tumors. Cancer Res; 70(11); 4767–77. ©2010 AACR.
Oncogenic Ras Promotes Reovirus Spread by Suppressing IFN-β Production through Negative Regulation of RIG-I Signaling
Authors: Shmulevitz Maya , Pan Lu-Zhe , Garant Katy , Pan Da , Lee Patrick W.K.
Published: May 2010

Reovirus is the first naturally occurring human virus reported to exploit activated Ras signaling in the host cell for infection, and is currently undergoing clinical trials as a cancer therapeutic. Recent evidence suggests that Ras transformation promotes three reoviral replication steps during the first round of infection: uncoating of the incoming virion, generation of progeny viruses with enhanced infectivity, and virus release through enhanced apoptosis. Whether oncogenic Ras also enhances reovirus spread in subsequent rounds of infection through other mechanisms has not been examined. Here, we show that compared with nontransformed cells, Ras-transformed cells are severely compromised not only in their response to IFN-β, but also in the induction of IFN-β mRNA following reovirus infection. Defects in both IFN-β production and response allow for efficient virus spread in Ras-transformed cells. We show that the MEK/ERK pathway downstream of Ras is responsible for inhibiting IFN-β expression by blocking signaling from the retinoic acid–inducible gene I (RIG-I) which recognizes viral RNAs. Overexpression of wild-type RIG-I restores INF-β expression in reovirus-infected Ras-transformed cells. In vitro–synthesized viral mRNAs also invoke robust RIG-I–mediated IFN-β production in transfected nontransformed cells, but not in Ras-transformed cells. Collectively, our data suggest that oncogenic Ras promotes virus spread by suppressing viral RNA–induced IFN-β production through negative regulation of RIG-I signaling. Cancer Res; 70(12); 4912–21. ©2010 AACR.
14-3-3 Binding Sites in the Snail Protein Are Essential for Snail-Mediated Transcriptional Repression and Epithelial-Mesenchymal Differentiation
Authors: Hou Zhaoyuan , Peng Hongzhuang , White David E. , Wang Pu , Lieberman Paul M. , Halazonetis Thanos , Rauscher Frank J.
Published: May 2010

The Snail transcription factor is a repressor and a master regulator of epithelial-mesenchymal transition (EMT) events in normal embryonic development and during tumor metastases. Snail directly regulates genes affecting cell adhesion, motility, and polarity. Invasive tumor cells express high levels of Snail, which is a marker for aggressive disease and poor prognosis. Transcriptional repression and EMT induction by Snail requires binding to its obligate corepressor, the LIM protein Ajuba. It is unclear how this complex is assembled and maintained on Snail target genes. Here we define functional 14-3-3 binding motifs in Snail and Ajuba, which selectively bind 14-3-3 protein isoforms. In Snail, an NH2-terminal motif in the repression domain cooperates with a COOH-terminal, high-affinity motif for binding to 14-3-3 proteins. Coordinate mutation of both motifs abolishes 14-3-3 binding and inhibits Snail-mediated gene repression and EMT differentiation. Snail, 14-3-3 proteins, and Ajuba form a ternary complex that is readily detected through chromatin immunoprecipitation at the endogenous E-cadherin promoter. Collectively, these data show that 14-3-3 proteins are new components of the Snail transcriptional repression machinery and mediate its important biological functions. Cancer Res; 70(11); 4385–93. ©2010 AACR.
Reversal of Chemotherapy-Induced Leukopenia Using Granulocyte Macrophage Colony-Stimulating Factor Promotes Bone Metastasis That Can Be Blocked with Osteoclast Inhibitors
Authors: Dai Jinlu , Lu Yi , Yu Chunyan , Keller Jill M. , Mizokami Atsushi , Zhang Jian , Keller Evan T.
Published: May 2010

Hematopoietic growth factors are used to reverse chemotherapy-induced leukopenia. However, some factors such as granulocyte macrophage colony-stimulating factor (GM-CSF) induce osteoclast-mediated bone resorption that can promote cancer growth in the bone. Accordingly, we evaluated the ability of GM-CSF to promote bone metastases of breast cancer or prostate cancer in a mouse model of chemotherapy-induced leukopenia. In this model, GM-CSF reversed cyclophosphamide-induced leukopenia but also promoted breast cancer and prostate cancer growth in the bone but not in soft tissue sites. Bone growth was associated with the induction of osteoclastogenesis, yet in the absence of tumor GM-CSF, it did not affect osteoclastogenesis. Two osteoclast inhibitors, the bisphosphonate zoledronic acid and the RANKL inhibitor osteoprotegerin, each blocked GM-CSF–induced tumor growth in the bone but did not reverse the ability of GM-CSF to reverse chemotherapy-induced leukopenia. Our findings indicate that it is possible to dissociate the bone-resorptive effects of GM-CSF, to reduce metastatic risk, from the benefits of this growth factor in reversing leukopenia caused by treatment with chemotherapy. Cancer Res; 70(12); 5014–23. ©2010 AACR.
L1 Cell Adhesion Molecule Is a Novel Therapeutic Target in Intrahepatic Cholangiocarcinoma
Authors: Min Jeong-Ki , Kim Jin-Man , Li Shengjin , Lee Jung Whoi , Yoon Hyunho , Ryu Chun Jeih , Jeon Soung Hoo , Lee Jae-Hyek , Kim Jin Young , Yoon Hee Kwan , Lee Young Kwan , Kim Bong-Hui , Son Yeon Sung , Choi Hong Seo , Lim Nam-Kyu , Kim Dae-Ghon , Hong Hyo Jeong
Published: May 2010

Purpose: Intrahepatic cholangiocarcinoma (ICC), a highly malignant hepatobiliary cancer, has a poor prognosis and is refractory to conventional therapies. The aim of this study is to discover a novel molecular target for the treatment of ICC.

Experimental Design: To discover novel cancer-associated membrane antigens expressed in ICC cells, we generated monoclonal antibodies (mAb) by immunizing mice with intact ICC cell lines and screened for those that bind to the plasma membrane of ICC cells but not to normal cells. The mAb A10-A3 was selected and its target antigen was identified as the L1 cell adhesion molecule. Expression of L1 in ICC was evaluated by immunohistochemical analysis of tumor samples from 42 ICC patients. The functional significance of L1 expression in the tumor progression of ICC was investigated by L1 suppression, L1 overexpression, and antibody treatment.

Results: L1 was not expressed in normal hepatocytes and intrahepatic bile duct epithelium but highly expressed in 40.5% of ICC patients, remarkably at the invasive front of the tumors. Suppression of L1 with short hairpin RNA significantly decreased proliferation, migration, and invasion of ICC cells in vitro. Consistently, L1 overexpression in ICC cells enhanced proliferation, migration, invasion, and apoptosis resistance. In addition, L1 short hairpin RNA or anti-L1 mAb significantly reduced the tumor growth in nude mice bearing ICC xenograft.

Conclusions: We identified that L1 is expressed in ICC. L1 plays an important role in the tumor progression of ICC by enhancing cell proliferation, migration, invasion, and survival. L1 may represent a novel therapeutic target for ICC. Clin Cancer Res; 16(14); 3571–80. ©2010 AACR.
A Pharmacodynamic Study of Rapamycin in Men with Intermediate- to High-Risk Localized Prostate Cancer
Authors: Armstrong Andrew J. , Netto George J. , Rudek Michelle A. , Halabi Susan , Wood David P. , Creel Patricia A. , Mundy Kelly , Davis S. Lindsay , Wang Ting , Albadine Roula , Schultz Luciana , Partin Alan W. , Jimeno Antonio , Fedor Helen , Febbo Phillip G. , George Daniel J. , Gurganus Robin , De Marzo Angelo M. , Carducci Michael A.
Published: May 2010

Purpose: Given discrepancies between preclinical and clinical observations of mammalian target of rapamycin (mTOR) inhibition in prostate cancer, we sought to determine the pharmacodynamic effects of the mTOR/TORC1 inhibitor rapamycin in men with intermediate- to high-risk prostate cancer undergoing radical prostatectomy.

Experimental Design: Rapamycin was given at 3 or 6 mg orally for 14 days before radical prostatectomy in men with multifocal Gleason sum ≥7 prostate cancer; 10 untreated control subjects were included. The primary outcome was inhibition of phosphorylation of ribosomal S6 in posttreatment radical prostatectomy versus pretreatment biopsy tumor tissue, evaluated using a Simon two-stage design for pharmacodynamic efficacy.

Results: Thirty-two subjects were accrued: 20 at 3 mg, 2 at 6 mg, and 10 controls. No dose-limiting toxicities were observed at 3 mg; however, two of two men enrolled at 6 mg experienced dose-limiting toxicities including thrombocytopenia and fever with grade 3 stomatitis. Adverse events observed at 3 mg included stomatitis, rash, ileus, and neutropenia. Pharmacodynamic studies showed tumor S6 phosphorylation inhibition in 50% of 10 evaluable rapamycin-treated men with sufficient paired tissue [median 58% inhibition (P = 0.049) versus 2% inhibition in controls (P = 0.75)] with no significant effect on AKT activity. We observed no change in Ki-67 or caspase-3 cleavage but noted a reduction in cytoplasmic p27 staining with increased nuclear localization with rapamycin treatment. Prostate tissue rapamycin concentrations were 3- to 4-fold higher than blood.

Conclusions: At 3 mg daily, rapamycin successfully and safely inhibited prostate cancer S6 phosphorylation and achieved relatively high prostate tissue concentrations. No effect on AKT phosphorylation, tumor proliferation, or apoptosis was observed. Clin Cancer Res; 16(11); 3057–66. ©2010 AACR.
Angiogenin Regulation by Estradiol in Breast Tissue: Tamoxifen Inhibits Angiogenin Nuclear Translocation and Antiangiogenin Therapy Reduces Breast Cancer Growth In vivo
Authors: Nilsson Ulrika W. , Abrahamsson Annelie , Dabrosin Charlotta
Published: May 2010

Purpose: Angiogenin, a 14.2-kDa polypeptide member of the RNase A superfamily, has potent angiogenic effects. Nuclear accumulation of angiogenin is essential for its angiogenic activity. Increased angiogenin expression has been associated with the transition of normal breast tissue into invasive breast carcinoma. In this article, we investigated whether estradiol (E2) affected angiogenin in breast tissue.

Experimental Design: We used microdialysis for sampling of extracellular angiogenin in vivo. In vitro cultures of whole normal breast tissue, breast cancer cells, and endothelial cells were used.

Results: We show that extracellular angiogenin correlated significantly with E2 in normal human breast tissue in vivo and that exposure of normal breast tissue biopsies to E2 stimulated angiogenin secretion. In breast cancer patients, the in vivo angiogenin levels were significantly higher in tumors compared with the adjacent normal breast tissue. In estrogen receptor–positive breast cancer cells, E2 increased and tamoxifen decreased angiogenin secretion. Moreover, E2-induced angiogenin derived from cancer cells significantly increased endothelial cell proliferation. Tamoxifen reversed this increase as well as inhibited nuclear translocation of angiogenin. In vivo, in experimental breast cancer, tamoxifen decreased angiogenin levels and decreased angiogenesis. Additionally, treating tumor-bearing mice with an antiangiogenin antibody resulted in tumor stasis, suggesting a role for angiogenin in estrogen-dependent breast cancer growth.

Conclusion: Our results suggest previously unknown mechanisms by which estrogen and antiestrogen regulate angiogenesis in normal human breast tissue and breast cancer. This may be important for estrogen-driven breast cancer progression and a molecular target for therapeutic interventions. Clin Cancer Res; 16(14); 3659–69. ©2010 AACR.
AACR-FDA-NCI Cancer Biomarkers Collaborative Consensus Report: Advancing the Use of Biomarkers in Cancer Drug Development
Authors: Khleif Samir N. , Doroshow James H. , Hait William N.
Published: May 2010

Recent discoveries in cancer biology have greatly increased our understanding of cancer at the molecular and cellular level, but translating this knowledge into safe and effective therapies for cancer patients has proved to be challenging. There is a growing imperative to modernize the drug development process by incorporating new techniques that can predict the safety and effectiveness of new drugs faster, with more certainty, and at lower cost. Biomarkers are central to accelerating the identification and adoption of new therapies, but currently, many barriers impede their use in drug development and clinical practice. In 2007, the AACR-FDA-NCI Cancer Biomarkers Collaborative stepped into the national effort to bring together disparate stakeholders to clearly delineate these barriers, to develop recommendations for integrating biomarkers into the cancer drug development enterprise, and to set in motion the necessary action plans and collaborations to see the promise of biomarkers come to fruition, efficiently delivering quality cancer care to patients. Clin Cancer Res; 16(13); 3299–318. ©2010 AACR.
Induction of Clusterin by AKT—Role in Cytoprotection against Docetaxel in Prostate Tumor Cells
Authors: Zhong Bin , Sallman David A. , Gilvary Danielle L. , Pernazza Daniele , Sahakian Eva , Fritz Dillon , Cheng Jin Q. , Trougakos Ioannis , Wei Sheng , Djeu Julie Y.
Published: May 2010

Clusterin (CLU), in its cytoplasmic form, is abundant in many advanced cancers and has been established to be cytoprotective against chemotherapeutic agents including docetaxel. However, little is known of the mechanism of its induction. Here, we provide evidence that AKT plays a critical role in upregulating cytoplasmic/secretory sCLU, which is responsible for docetaxel resistance. Western blot analysis indicated that docetaxel-resistant sublines derived from DU145 and PC3 prostate tumor cell lines displayed a markedly increased phospho-AKT level closely accompanied by heightened sCLU expression when compared with parental cells. To examine if AKT has a role in sCLU expression, AKT blockade was done by treatment with a specific inhibitor, API-2, or dominant-negative AKT transduction before analysis of sCLU gene expression. Loss of AKT function resulted in loss of sCLU and was accompanied by chemosensitization to docetaxel and increased cell death via a caspase-3–dependent pathway. To confirm that AKT affected resistance to docetaxel through sCLU and not through other mediators, tumor cells were first transfected with full-length CLU for overexpression and then treated with the AKT inhibitor API-2. We found that once sCLU was overexpressed, API-2 could not chemosensitize the tumor cells to docetaxel. Thus, the chemoresistance to docetaxel is mediated by sCLU and it can be induced by AKT. Lastly, AKT was found to mediate sCLU induction via signal transducer and activator of transcription 1 activation, which we have earlier shown to drive sCLU gene expression. These results identify a previously unrecognized pathway linking AKT to cytoprotection by sCLU in tumor cells. Mol Cancer Ther; 9(6); 1831–41. ©2010 AACR.
Preclinical Evaluation of Differentially Targeting Dual Virotherapy for Human Solid Cancer
Authors: Sakai Ryo , Kagawa Shunsuke , Yamasaki Yasumoto , Kojima Toru , Uno Futoshi , Hashimoto Yuuri , Watanabe Yuichi , Urata Yasuo , Tanaka Noriaki , Fujiwara Toshiyoshi
Published: May 2010

Multimodal approaches combining drugs that differentially function is the most popular regimen for treating human cancer. Understanding the molecular mechanisms underlying the synergistic, potentiative, and antagonistic effects of drug combinations could facilitate the discovery of novel efficacious combinations. We previously showed that telomerase-specific replication-competent adenovirus (Telomelysin, OBP-301), in which the human telomerase reverse transcriptase promoter controls the adenoviral E1 gene expression, induces a selective antitumor effect in human cancer cells. Here, using E1-deleted replication-deficient adenovirus expressing the p53 tumor suppressor gene (Advexin, Ad-p53) and OBP-301, we investigate how these adenoviruses that kill tumor cells with different mechanisms could work in combination on human cancer. We found that E1-deficient Ad-p53 could kill cancer cells more efficiently in the presence of OBP-301 than Ad-p53 alone or OBP-301 alone, because Ad-p53 could become replication-competent by being supplied adenoviral E1 from coinfected OBP-301 in trans. Ad-p53 plus OBP-301 induced high levels of p53 protein expression without p21 induction, resulting in apoptotic cell death documented by active caspase-3 expression with a cytometric bead array and an increased subdiploid apoptotic fraction of the cell cycle. For in vivo evaluation, nude mice xenografted with human lung tumors received intratumoral injection of OBP-301 and/or Ad-p53. Analysis of the growth of implanted tumors showed an enhanced antitumor effect in combination therapy. Our data show that Ad-p53 in combination with OBP-301 induces not only oncolytic but also apoptotic cancer cell death and enhances antitumor activity in vitro and in vivo, providing potential merits as a multimodal treatment for human cancer. Mol Cancer Ther; 9(6); 1884–93. ©2010 AACR.
Sprouty-4 Inhibits Transformed Cell Growth, Migration and Invasion, and Epithelial-Mesenchymal Transition, and Is Regulated by Wnt7A through PPARγ in Non–Small Cell Lung Cancer
Authors: Tennis Meredith A. , Van Scoyk Michelle M. , Freeman Scott V. , Vandervest Katherine M. , Nemenoff Raphael A. , Winn Robert A.
Published: May 2010

Sprouty proteins are potent receptor tyrosine kinase inhibitors that antagonize growth factor signaling and are involved in lung development. However, little is known about the regulation or targets of Sprouty-4 (Spry4) in lung cancer. Our study aimed to determine the role of Spry4 in non–small cell lung cancer (NSCLC). We found that Spry4 mRNA expression was decreased in NSCLC cell lines and in dysplastic lung cell lines compared with a nontransformed cell line, suggesting that Spry4 has tumor-suppressing activity. When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21. Changes in epithelial and mesenchymal markers indicated that Spry4 expression induces a reversal of the epithelial to mesenchymal transition characteristic of tumor cells. Treatment of a nontransformed lung epithelial cell line with short hairpin RNA to Spry4 led to the decreased expression of epithelial markers and increased cell growth, supporting the concept of Spry4 acting as a tumor suppressor. We showed that the activity of the Spry4 promoter is increased by Wnt7A/Fzd9 signaling through peroxisome proliferator–activated receptor γ. These data present previously undescribed targets of Spry4 and suggest that Spry4 is a downstream target of Wnt7A/Fzd 9 signaling. Spry4 may have efficacy in the treatment of NSCLC. Mol Cancer Res; 8(6); 833–43. ©2010 AACR.
Combination Effects of Salvianolic Acid B with Low-Dose Celecoxib on Inhibition of Head and Neck Squamous Cell Carcinoma Growth In vitro and In vivo
Authors: Zhao Yuan , Hao Yubin , Ji Hongguang , Fang Yayin , Guo Yinhan , Sha Wei , Zhou Yanfei , Pang Xiaowu , Southerland William M. , Califano Joseph A. , Gu Xinbin
Published: May 2010

Head and neck squamous cell carcinoma (HNSCC) development is closely associated with inflammation. Cyclooxygenase-2 (COX-2) is an important mediator of inflammation. Therefore, celecoxib, a selective inhibitor of COX-2, was hailed as a promising chemopreventive agent for HNSCC. Dose-dependent cardiac toxicity limits long-term use of celecoxib, but it seems likely that this may be diminished by lowering its dose. We found that salvianolic acid B (Sal-B), isolated from Salvia miltiorrhiza Bge, can effectively suppress COX-2 expression and induce apoptosis in a variety of cancer cell lines. In this study, we report that combination of Sal-B with low-dose celecoxib results in a more pronounced anticancer effect in HNSCC than either agent alone. The combination effects were assessed in four HNSCC cell lines (JHU-06, JHU-011, JHU-013, and JHU-022) by evaluating cell viability, proliferation, and tumor xenograft growth. Cell viability and proliferation were significantly inhibited by both the combined and single-agent treatments. However, the combination treatment significantly enhanced anticancer efficacy in JHU-013 and JHU-022 cell lines compared with the single treatment regimens. A half-dose of daily Sal-B (40 mg/kg/d) and celecoxib (2.5 mg/kg/d) significantly inhibited JHU-013 xenograft growth relative to mice treated with a full dose of Sal-B or celecoxib alone. The combination was associated with profound inhibition of COX-2 and enhanced induction of apoptosis. Taken together, these results strongly suggest that combination of Sal-B, a multifunctional anticancer agent, with low-dose celecoxib holds potential as a new preventive strategy in targeting inflammatory-associated tumor development. Cancer Prev Res; 3(6); 787–96. ©2010 AACR.
Berries and Ellagic Acid Prevent Estrogen-Induced Mammary Tumorigenesis by Modulating Enzymes of Estrogen Metabolism
Authors: Aiyer Harini S. , Gupta Ramesh C.
Published: May 2010

To determine whether dietary berries and ellagic acid prevent 17β-estradiol (E2)–induced mammary tumors by altering estrogen metabolism, we randomized August-Copenhagen Irish rats (n = 6 per group) into five groups: sham implant + control diet, E2 implant + control diet (E2-CD), E2 + 2.5% black raspberry (E2-BRB), E2 + 2.5% blueberry (E2-BB), and E2 + 400 ppm ellagic acid (E2-EA). Animals were euthanized at early (6 wk), intermediate (18 wk), and late (24 wk) phases of E2 carcinogenesis, and the mammary tissue was analyzed for gene expression changes using quantitative real-time PCR. At 6 weeks, E2 treatment caused a 48-fold increase in cytochrome P450 1A1 (CYP1A1; P < 0.0001), which was attenuated by both BRB and BB diets to 12- and 21-fold, respectively (P < 0.001). E2 did not alter CYP1B1 levels, but both berry and EA diets significantly suppressed it by 11- and 3.5-fold, respectively, from baseline (P < 0.05). There was a 5-fold increase in 17β-hydroxysteroid dehydrogenase 7 (17βHSD7), and this was moderately abrogated to ∼2-fold by all supplementation (P < 0.05). At 18 weeks, CYP1A1 was elevated by 15-fold in E2-CD and only E2-BB reduced this increase to 7-fold (P < 0.05). Catechol-O-methyltransferase expression was elevated 2-fold by E2 treatment (P < 0.05), and all supplementation reversed this. At 24 weeks, CYP1A1 expression was less pronounced but still high (8-fold) in E2-treated rats. This increase was reduced to 3.2- and 4.6-fold by E2-BRB and E2-EA, respectively (P < 0.05), but not by E2-BB. Supplementation did not alter the effect of E2 on steroid receptors. The diets also significantly suppressed mammary tumor incidence (10-30%), volume (41-67%), and multiplicity (38-51%; P < 0.05). Berries may prevent mammary tumors by suppressing the levels of E2-metabolizing enzymes during the early phase of E2 carcinogenesis. Cancer Prev Res; 3(6); 727–37. ©2010 AACR.
A Girl with Tomboy Behavior: Lesson from Misdiagnosis in a Baby with Ambiguous Genitalia
Authors: Dati E. , Baldinotti F. , Conidi M.E. , Simi P. , Baroncelli G.I. , Bertelloni S.
Published: May 2010

5α-Reductase-2 deficiency is a rare 46,XY disorder of sex differentiation caused by mutations in the 5α-reductase type 2 gene. It presents at birth with variable degree of undervirilization. Here, a baby with 5α-reductase-2 deficiency and misdiagnosis of complete androgen insensitivity syndrome, female sex assignment and early gonadectomy is described. During primary school, the girl developed tomboy behavior. Molecular analysis demonstrated compound heterozygosity for 5α-reductase type 2 gene mutations (exon 2: Q126R; exon 4: H230P). This child underlines the need for adequate endocrine and genetic testing for a definite diagnosis before gender is assigned in children with ambiguous genitalia and surgical interventions are carried out. Inadequate work-up may result in inappropriate gender assignment in infancy with possible inferences on outcome.
Primary Tracheoesophageal Puncture in Stapler-Assisted Total Laryngectomy
Authors: Leahy Kevin P. , Tufano Ralph P.
Published: May 2010

Background/Aims: The purpose of this article was to present a novel technique for primary tracheoesophageal puncture (TEP) in patients undergoing stapler-assisted laryngectomy. Methods: A case series of 10 consecutive patients treated with stapler-assisted laryngectomy that underwent primary TEP at the time of the initial surgery was conducted. The technique involves the use of a flexible esophagoscope and a modified Seldinger technique to safely create the TEP under direct visualization without disrupting the stapler closure. This series was performed at a single academic institution. The primary outcome measured was ability of alaryngeal speech. Results: A total of 10 consecutive patients had the procedure done. All patients achieved alaryngeal speech and there were no complications. Conclusion: This method allows for a safe and efficient TEP creation at the time of stapler-assisted laryngectomy, obviating the need for secondary procedures, either in the office or operating room.
Translocation and Deletion around SOX9 in a Patient with Acampomelic Campomelic Dysplasia and Sex Reversal
Authors: Jakubiczka S. , Schröder C. , Ullmann R. , Volleth M. , Ledig S. , Gilberg E. , Kroisel P. , Wieacker P.
Published: May 2010

Campomelic dysplasia (MIM 114290) is a severe malformation syndrome frequently accompanied by male-to-female sex reversal. Causative are mutations within the SOX9 gene on 17q24.3 as well as chromosomal aberrations (translocations, inversions or deletions) in the vicinity of SOX9. Here, we report on a patient with muscular hypotonia, craniofacial dysmorphism, cleft palate, brachydactyly, malformations of thoracic spine, and gonadal dysgenesis with female external genitalia and müllerian duct derivatives in the presence of a male karyotype. X-ray examination and clinical examinations revealed no signs of campomelia. The combination of molecular cytogenetic analysis and array CGH revealed an unbalanced translocation between one chromosome 7 and one chromosome 17 [46,XY,t(7;17)(q33;q24).ish t(7;17)(wcp7+,wcp17+;wcp7+wcp17+)] with a deletion of approximately 4.2 Mb located about 0.5 Mb upstream of SOX9. STS analysis confirmed the deletion of chromosome 17, which has occurred de novo on the paternal chromosome. The proximal breakpoint on chromosome 17 is localized outside the known breakpoint cluster regions. The deletion on chromosome 17q24 removes several genes. Among these genes PRKAR1A is deleted. Inactivating mutations of PRKAR1A cause Carney complex. To our knowledge, this is the first report of a patient with acampomelic campomelic dysplasia, carrying both a deletion and a translocation.
Obstacles to Good Work in Indian International Relations
Authors: Bajpai Kanti
Published: May 2010

This article suggests that, from 1947 to the late 1980s, Indian International Relations (IIR) led the developing world and certainly Asian IR. Since then, China, Korea and Japan seem to have taken the lead. The article defines the nature of ‘good work’ as ‘good published work’ and argues that there are five key obstacles to better published work in IIR: the neglect of theory; the failure to define a series of animating puzzles, problematiques and problem-solving agendas; the lack of methodological training; the quality of teaching; and the mismanagement of professional life. Three reasons are advanced for the origins and persistence of these obstacles: post-colonial parochialism; the influence of the formative moment of the field in India; and the relationship of Political Science/IR to the Indian state. The article concludes that the remedies are primarily in the hands of Indian scholars and not with the government.
Development of International Relations Theory in India
Authors: Mallavarapu Siddharth
Published: May 2010

The article seeks to do an audit of the state of International Relations theory (IRT) in India. It examines three facets of IRT in this connection. The first relates to the possibility of a tradition of thinking on issues of universal theoretical significance. The second pertains to an exploration of scholarly reflection on an important principle of Indian foreign policy, namely, non-alignment and the limits of theorizing it. The final facet examines the concerns that inform theorization by Indian scholars since the 1990s. In regard to the first facet, the article argues that there exists an Indian tradition of thinking on issues of order, justice and cosmopolitanism, even though it may not have been expressed in the language of IRT. With regard to non-alignment, the article argues that while it did not result in broader theoretical formulations, it raised a number of first order issues for further theorizing. Finally, it suggests that recent IRT invocations by Indian scholars reflect a more receptive conjuncture for such work, both in terms of India’s own changing stature in the world system as well as an acknowledgement of more eclectic methods and possibilities in the broader world of the social sciences.
Marshall’s Scale Economies and Jacobs’ Externality in Korea: the Role of Age, Size and the Legal Form of Organisation of Establishments
Authors: Bun Song Lee  , Jang Soomyung , Sung Hyo Hong
Published: May 2010

This paper revisits the concept of agglomeration economies by estimating the effects of localisation, urbanisation and local competition on labour productivity using establishment-level data in Korean manufacturing industries. It is found that, when an establishment locates in a more localised/specialised, more urbanised/diversified and more competitive area, its workers become more productive due to external benefits from agglomeration. Issues of self-selection bias and omitted variable bias are addressed by instrumenting the variables measuring localisation economies and controlling for the fixed effects of establishments/location and industries/year. However, the external effects from the spatial proximity of other establishments vary across the categories of industry type, age, size and legal form of organisation of establishments. Establishments in traditional heavy manufacturing industries receive more external benefits in a less diversified area, while those in transport equipment manufacturing industries enjoy the largest benefits from localisation. Externalities exist for establishments aged between 2 and 7 years, having at least 10 workers, being corporate and having multiplants (or not being headquarters). Establishments in relatively young industries rely more on diversified environments, while establishments in relatively old industries receive greater external benefits in the same industry cluster. This result supports the product life-cycle location theory of Duranton and Puga.
Road Pricing and Relocation Decisions of Dutch Households
Authors: Tillema Taede , van Wee Bert , Ettema Dick
Published: May 2010

Using stated preference data collected among Dutch respondents, this paper explores the effects of kilometre and cordon charges on the decision to move house or change jobs. About 5 per cent of the respondents indicated a reasonably high probability of moving house if a road pricing measure were to be implemented; with respect to job change, this was about 13.5 per cent. On the basis of an ordered probit analysis, it was possible to identify several important variables that help to explain these figures. The variables that affect people’s decision to move house or change jobs are more or less the same. Somewhat unexpectedly, the price level of the road pricing measure does not seem to have a significant impact.
Idiopathic Intracranial Hypertension in Two Patients With Alagille Syndrome
Authors: Mouzaki Marialena , Nichter Charles , Qureshi Muhammad , Rountree Bart , Furuya Katryn N.
Published: May 2010

Alagille syndrome is an autosomal dominant condition with incomplete penetrance that is associated mostly with hepatic, cardiac, and skeletal abnormalities. In addition, the association of Alagille syndrome with ocular abnormalities is well known and is considered one of the characteristic features of this condition. Most commonly, posterior embryotoxon, glaucoma, or retinopathy has been identified in these children. The authors present 2 patients with Alagille syndrome who, before the age of 3 years old, developed idiopathic intracranial hypertension with documented increased intracranial pressure by lumbar puncture and papilledema, which was responsive to acetazolamide.
Schema Effects of Rape Myth Acceptance on Judgments of Guilt and Blame in Rape Cases: The Role of Perceived Entitlement to Judge
Authors: Eyssel Friederike , Bohner Gerd
Published: May 2010

Two experiments ( N = 330) examined conditions that facilitate biasing effects of rape myth acceptance (RMA) on judgments of blame in rape cases. In both experiments, participants read a short vignette depicting a rape case. In Experiment 1, the amount of case-irrelevant information about defendant and plaintiff was varied. As predicted, high-RMA (vs. low-RMA) participants were less likely to blame the defendant the more irrelevant information they had read. In Experiment 2, participants in a social judgeability condition were made to believe that they had been subliminally exposed to additional case information although in fact no additional information had been presented. As predicted, compared to a control condition, participants’ blame judgments were more biased by their RMA under social judgeability. Our findings reveal that the mechanism underlying the biasing effects of RMA may be the subjective feeling of entitlement to judge.
Ethical Message of the Mahabharata in the Wake of the Global Financial Crisis
Authors: Chakravarti Sitansu S.
Published: May 2010

This article deals with the concept of greed as pertaining to Business Ethics in today’s world, considered part of the system of the study Ethics as such, in the backdrop of the recent happenings in the financial world in the USA, whose repercussions have been felt all over. The analysis draws inspiration from the words in the Mahabharata, both with a view to improving the existing theories in place in the West today, as well as having a handle on greed management so needed to set liberalism on the right footing. The article brings into focus the secular spirituality imbedded in the epic relating to the concept harmony, without recourse to God parlance, a virtue around which the ethical considerations move, bringing a needed improvement on the Virtue Ethics of today, and harmonizing the three conflicting ethical theories of the day. Greed management is effective only when we look beyond science to the area of values putting the right emphasis on Virtue Ethics.