bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Expression of HER3 Is Associated with a Decreased Survival in Gastric Cancer
Authors: Hayashi Mikiko , Inokuchi Mikito , Takagi Yoko , Yamada Hiroyuki , Kojima Kazuyuki , Kumagai Jiro , Kawano Tatsuyuki , Sugihara Kenichi 
Published: December 2008

Abstract
Background: The role of human epidermal growth factor receptor (HER) 3 and HER4 has been elucidated in gastric cancer. HER1 and HER2 overexpression are regarded as prognostic factors and targets of treatment. The dimerization of the HER family receptors activates downstream signal pathways and promotes tumor progression. This study investigated the positive correlation between HER1 and HER4 expression and the prognosis of patients with gastric cancers.
Experimental Design: Tumor samples were obtained from gastric adenocarcinomas of 134 patients who underwent a gastrectomy from 1999 to 2002. The expression of each HER was analyzed in the tumor by immunohistochemical staining. Parametric correlations were done between HER expression and the clinicopathologic findings. A multivariate analysis was done with the overall survival.
Results: HER3 expression was significantly associated with parameters involved with tumor progression, including the depth of tumor invasion (T1 versus T2-T4; P = 0.000), involved lymph nodes (P = 0.000), distant metastasis (P = 0.008), tumor stage (P = 0.000), and recurrent disease (P = 0.000). HER1 was also significantly associated with those factors excluding distant metastasis. A significant relationship was observed between the expression of HER1 and HER3 (P = 0.000). HER3 overexpression was associated with a significantly worse survival (P = 0.0000) and was an independent prognostic factor in the multivariate analysis (hazard ratio, 2.382; 95% confidence interval, 1.009-5.625; P = 0.048).
Conclusions: HER3 overexpression is strongly associated with tumor progression and poor prognosis of patients with gastric cancer. It may become a new prognostic factor and a target of treatment.
Single Nucleotide Polymorphisms of microRNA Machinery Genes Modify the Risk of Renal Cell Carcinoma
Authors: Horikawa Yohei , Wood Christopher G. , Yang Hushan , Zhao Hua , Ye Yuanqing , Gu Jian , Lin Jie , Habuchi Tomonori , Wu Xifeng 
Published: December 2008

Abstract
Purpose: MicroRNAs (miRNA) are a class of small noncoding RNA molecules that have been implicated in a wide variety of basic cellular functions through posttranscriptional regulations on their target genes. Compelling evidence has shown that miRNAs are involved in cancer initiation and progression. We hypothesized that genetic variations of the miRNA machinery genes could be associated with the risk of renal cell carcinoma.
Experimental Design: We genotyped 40 single nucleotide polymorphisms (SNP) from 11 miRNA processing genes (DROSHA, DGCR8, XPO5, RAN, DICER1, TARBP2, AGO1, AGO2, GEMIN3, GEMIN4, HIWI) and 15 miRNA genes in 279 Caucasian patients with renal cell carcinoma and 278 matched controls.
Results: We found that two SNPs in the GEMIN4 gene were significantly associated with altered renal cell carcinoma risks. The variant-containing genotypes of Asn929Asp and Cys1033Arg exhibited significantly reduced risks, with odds ratios (OR) of 0.67 [95% confidence interval (95% CI), 0.47-0.96] and 0.68 (95% CI, 0.47-0.98), respectively. Haplotype analysis showed that a common haplotype of GEMIN4 was associated with a significant reduction in the risk of renal cell carcinoma (OR, 0.66; 95% CI, 0.45-0.97). We also conducted a combined unfavorable genotype analysis including five promising SNPs showing at least a borderline significant risk association. Compared with the low-risk reference group with one unfavorable genotype, the median-risk and high-risk groups exhibited a 1.55-fold (95% CI, 0.96-2.50) and a 2.49-fold (95% CI, 1.58-3.91) increased risk of renal cell carcinoma, respectively (P for trend &lt; 0.001).
Conclusions: Our results suggested that genetic polymorphisms of the miRNA-machinery genes may affect renal cell carcinoma susceptibility individually and jointly.
Phase I Study of the Poly(ADP-Ribose) Polymerase Inhibitor, AG014699, in Combination with Temozolomide in Patients with Advanced Solid Tumors
Authors: Plummer Ruth , Jones Christopher , Middleton Mark , Wilson Richard , Evans Jeffrey , Olsen Anna , Curtin Nicola , Boddy Alan , McHugh Peter , Newell David , Harris Adrian , Johnson Patrick , Steinfeldt Heidi , Dewji Raz , Wang Diane , Robson Lesley , Calvert Hilary 
Published: December 2008

Abstract
Purpose: One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA. Poly(ADP-ribose) polymerase (PARP)-1 is a nuclear enzyme involved in base excision repair, one of the five major repair pathways. PARP inhibitors are emerging as a new class of agents that can potentiate chemotherapy and radiotherapy. The article reports safety, efficacy, pharmacokinetic, and pharmacodynamic results of the first-in-class trial of a PARP inhibitor, AG014699, combined with temozolomide in adults with advanced malignancy.
Experimental Design: Initially, patients with solid tumors received escalating doses of AG014699 with 100 mg/m2/d temozolomide × 5 every 28 days to establish the PARP inhibitory dose (PID). Subsequently, AG014699 dose was fixed at PID and temozolomide escalated to maximum tolerated dose or 200 mg/m2 in metastatic melanoma patients whose tumors were biopsied. AG014699 and temozolomide pharmacokinetics, PARP activity, DNA strand single-strand breaks, response, and toxicity were evaluated.
Results: Thirty-three patients were enrolled. PARP inhibition was seen at all doses; PID was 12 mg/m2 based on 74% to 97% inhibition of peripheral blood lymphocyte PARP activity. Recommended doses were 12 mg/m2 AG014699 and 200 mg/m2 temozolomide. Mean tumor PARP inhibition at 5 h was 92% (range, 46-97%). No toxicity attributable to AG014699 alone was observed. AG014699 showed linear pharmacokinetics with no interaction with temozolomide. All patients treated at PID showed increases in DNA single-strand breaks and encouraging evidence of activity was seen.
Conclusions: The combination of AG014699 and temozolomide is well tolerated, pharmacodynamic assessments showing proof of principle of the mode of action of this new class of agents.
Heat Shock Protein 90 Overexpression Independently Predicts Inferior Disease-Free Survival with Differential Expression of the α and β Isoforms in Gastrointestinal Stromal Tumors
Authors: Li Chien-Feng , Huang Wen-Wei , Wu Jing-Mei , Yu Shih-Chen , Hu Tsung-Hui , Uen Yih-Huei , Tian Yu-Fang , Lin Ching-Nan , Lu David , Fang Fu-Min , Huang Hsuan-Ying 
Published: December 2008

Abstract
Purpose: Most gastrointestinal stromal tumors harbor a mutated KIT or PDGFRA receptor tyrosine kinase (RTK). Heat shock protein 90 (Hsp90) is a chaperone mediating the folding and stabilization of many oncoproteins, including KIT. An Hsp90 inhibitor, 17-AAG, can attenuate KIT activation and proliferation of gastrointestinal stromal tumor cell lines. We further evaluated Hsp90 immunoexpression and the difference between α and β isoforms in gastrointestinal stromal tumor specimens.
Experimental Design: Hsp90 immunostain was assessable in 306 cases on tissue microarrays of primary gastrointestinal stromal tumors and correlated with various variables and disease-free survival (DFS). RTK mutation variants, confirmed in 142 cases by sequencing with or without precedent denaturing high pressure liquid chromatography screening, were dichotomized into two prognostically different groups. Differential expression of transcript and protein isoforms was measured by real-time reverse transcription-PCR and Western blotting in 16 and 6 cases, respectively.
Results: Hsp90 overexpression (55%) significantly correlated with larger size, nongastric location, higher mitotic count and NIH risk level, Ki-67 overexpression (all P ≤ 0.001), and unfavorable RTK genotypes (P = 0.020). It strongly portended inferior DFS univariately (P &lt; 0.0001) and remained independent in multivariate analysis (P = 0.031; risk ratio, 2.44), along with high-risk category, Ki-67 overexpression, and old age. For both mRNA and protein, Hsp90β was more abundant than Hsp90α, whereas the latter was significantly higher in high-risk cases.
Conclusions: Hsp90 overexpression represents a poor prognosticator that correlates with several adverse parameters, highlighting its role in disease progression and alternative therapy for high-risk, imatinib-resistant gastrointestinal stromal tumors. Hsp90α seems more relevant to the intrinsic aggressiveness of gastrointestinal stromal tumors, albeit less abundant than Hsp90β.
Distinct Subcellular Expression Patterns of Neutral Endopeptidase (CD10) in Prostate Cancer Predict Diverging Clinical Courses in Surgically Treated Patients
Authors: Fleischmann Achim , Schlomm Thorsten , Huland Hartwig , Köllermann Jens , Simon Philipp , Mirlacher Martina , Salomon Georg , Chun Felix H.K. , Steuber Thomas , Simon Ronald , Sauter Guido , Graefen Markus , Erbersdobler Andreas 
Published: December 2008

Abstract
Purpose: Neutral endopeptidase (CD10), an ectopeptidase bound to the cell surface, is thought to be a potential prognostic marker for prostate cancer.
Experimental Design: Prostate cancer patients (N = 3,261) treated by radical prostatectomy at a single institution were evaluated by using tissue microarray. Follow-up data were available for 2,385 patients. The cellular domain (membranous, membranous-cytoplasmatic, and cytoplasmatic only) of CD10 expression was analyzed immunohistochemically and correlated with various clinical and histopathologic features of the tumors.
Results: CD10 expression was detected in 62.2% of cancer samples and occurred preferentially in higher Gleason pattern (P &lt; 0.0001). CD10 expression positively correlated with adverse tumor features such as elevated preoperative prostate-specific antigen (PSA), higher Gleason score, and advanced stage (P &lt; 0.0001 each). Survival analyses showed that PSA recurrence was significantly associated with the staining pattern of CD10 expression. Outcome significantly declined from negative over membranous, membranous-cytoplasmatic, to exclusively cytoplasmatic CD10 expression (P &lt; 0.0001). In multivariate analysis, CD10 expression was an independent predictor for PSA failure (P = 0.0343).
Conclusions: CD10 expression is an unfavorable independent risk factor in prostate cancer. The subcellular location of CD10 protein is associated with specific clinical courses, suggesting an effect on different important biological properties of prostate cancer cells. The frequent expression of CD10 in prostate cancer and the strong association of CD10 with unfavorable tumor features may qualify this biomarker for targeted therapies.
Ascites Specific Inhibition of CD1d-Mediated Activation of Natural Killer T Cells
Authors: Webb Tonya J. , Giuntoli Robert L. , Rogers Ophelia , Schneck Jonathan , Oelke Mathias 
Published: December 2008

AbstractPurpose: Natural killer T (NKT) cells recognize lipid antigen presented by CD1 molecules. NKT cells can both directly, through cytotoxicity, and indirectly, through activation of other effector cells, mediate antitumor immunity. It has been shown, however, that tumor-associated lipids are frequently shed into the tumor microenvironment, which can mediate immunosuppressive activity. Given that ovarian cancer–associated ascites has been reported to have increased levels of gangliosides, we examined the effect of tumor-associated and other ascites on CD1d-mediated antigen presentation to NKT cells.Experimental Design: To investigate the effects of ascites on NKT cell activation, we pretreated CD1d-expressing cells with the ascites and measured their ability to stimulate cytokine production in NKT cells. To determine whether antigen processing or editing was necessary, CD1d-immunoglobulin–based artificial antigen presenting cells (aAPC) were also incubated with ascites. In addition, to examine specificity, we analyzed whether ascites fluid could influence the activation of classic CD8+ T cells.Results: Pretreatment of CD1d-expressing cells with ascites from the majority of patients inhibited the ability of the cells to stimulate/activate NKT cells in a dose-dependent manner. Ascites treatment also partially blocked the ability of α-galactosylceramide–loaded CD1d-immunoglobulin–based aAPC to activate NKT cells. In addition, our data show that treatment with ascites does not inhibit HLA-A2–mediated activation of classic CD8+ T cells.Conclusions: Together, these data suggest that ovarian and other cancers may have developed immune evasion mechanisms specifically targeting the CD1/NKT cell system.
Claudin-18 Splice Variant 2 Is a Pan-Cancer Target Suitable for Therapeutic Antibody Development
Authors: Sahin Ugur , Koslowski Michael , Dhaene Karl , Usener Dirk , Brandenburg Gunda , Seitz Gerhard , Huber Christoph , Türeci Özlem 
Published: December 2008

Abstract
Purpose: Antibody-based cancer therapies have emerged as the most promising therapeutics in oncology. The purpose of this study was to discover novel targets for therapeutic antibodies in solid cancer.
Experimental Design: We combined data mining and wet-bench experiments to identify strictly gastrocyte lineage–specific cell surface molecules and to validate them as therapeutic antibody targets.
Results: We identified isoform 2 of the tight junction molecule claudin-18 (CLDN18.2) as a highly selective cell lineage marker. Its expression in normal tissues is strictly confined to differentiated epithelial cells of the gastric mucosa, but it is absent from the gastric stem cell zone. CLDN18.2 is retained on malignant transformation and is expressed in a significant proportion of primary gastric cancers and the metastases thereof. In addition to its orthotopic expression, we found frequent ectopic activation of CLDN18.2 in pancreatic, esophageal, ovarian, and lung tumors, correlating with distinct histologic subtypes. The activation of CLDN18.2 depends on the binding of the transcription factor cyclic AMP–responsive element binding protein to its unmethylated consensus site. Most importantly, we were able to raise monoclonal antibodies that bind to CLDN18.2 but not to its lung-specific splice variant and recognize the antigen on the surface of cancer cells.
Conclusions: Its highly restricted expression pattern in normal tissues, its frequent ectopic activation in a diversity of human cancers, and the ability to specifically target this molecule at the cell surface of tumor cells qualify CLDN18.2 as a novel, highly attractive pan-cancer target for the antibody therapy of epithelial tumors.
Perilobar Nephrogenic Rests Are Nonobligate Molecular Genetic Precursor Lesions of Insulin-Like Growth Factor-II-Associated Wilms Tumors
Authors: Vuononvirta Raisa , Sebire Neil J. , Dallosso Anthony R. , Reis-Filho Jorge S. , Williams Richard D. , Mackay Alan , Fenwick Kerry , Grigoriadis Anita , Ashworth Alan , Pritchard-Jones Kathy , Brown Keith W. , Vujanic Gordan M. , Jones Chris 
Published: December 2008

Abstract
Purpose: Perilobar nephrogenic rests (PLNRs) are abnormally persistent foci of embryonal immature blastema that have been associated with dysregulation at the 11p15 locus by genetic/epigenetic means and are thought to be precursor lesions of Wilms tumor. The precise genomic events are, however, largely unknown.
Experimental Design: We used array comparative genomic hybridization to analyze a series of 50 PLNRs and 25 corresponding Wilms tumors characterized for 11p15 genetic/epigenetic alterations and insulin-like growth factor-II expression.
Results: The genomic profiles of PLNRs could be subdivided into three categories: those with no copy number changes (22 of 50, 44%); those with single, whole chromosome alterations (8 of 50, 16%); and those with multiple gains/losses (20 of 50, 40%). The most frequent aberrations included 1p- (7 of 50, 14%) +18 (6 of 50, 12%), +13 (5 of 50, 10%), and +12 (3 of 50, 6%). For the majority (19 of 25, 76%) of cases, the rest harbored a subset of the copy number changes in the associated Wilms tumor. We identified a temporal order of genomic changes, which occur during the insulin-like growth factor-II/PLNR pathway of Wilms tumorigenesis, with large-scale chromosomal alterations such as 1p-, +12, +13, and +18 regarded as “early” events. In some of the cases (24%), the PLNRs harbored large-scale copy number changes not observed in the concurrent Wilms tumor, including +10p, +14q, and +18.
Conclusions: These data suggest that although the evidence for PLNRs as precursors is compelling, not all lesions must necessarily undergo malignant transformation.
Chemokine Markers Predict Biochemical Recurrence of Prostate Cancer following Prostatectomy
Authors: Blum David L. , Koyama Tatsuki , M'Koma Amosy E. , Iturregui Juan M. , Martinez-Ferrer Magaly , Uwamariya Consolate , Smith Joseph A. , Clark Peter E. , Bhowmick Neil A. 
Published: December 2008

AbstractPurpose: Stratifying patients who have a high risk of prostate cancer recurrence following prostatectomy can potentiate the use of adjuvant therapy at an early stage. Inflammation has emerged as a mediator of prostate cancer metastatic progression. We hypothesized that chemokines can be biomarkers for distinguishing patients with high risk for biochemical recurrence of prostate cancer.Experimental Design: In a nested case-control study, 82 subjects developed biochemical recurrence within 5 years of prostatectomy. Prostate tissues from 98 age-matched subjects who were recurrence-free following prostatectomy in the same period were the controls. A high-throughput lectin-based enrichment of prostate tissue enabled multiplex ELISA to identify the expression of three chemokines to discriminate the two patient populations.Results: The expression of CX3CL1 and IL-15 in prostate tissue was associated with 5-year biochemical recurrence-free survival following prostatectomy. However, the expression of chemokine ligand 4 (CCL4) was associated with biochemical recurrence. Multivariable logistic regression model combining preoperative prostate-specific antigen, Gleason score, surgical margin, and seminal vesicle status with the three chemokines doubled the specificity of prediction at 90% sensitivity compared with use of the clinicopathologic variables alone (P &lt; 0.0001). Survival analysis yielded a nomogram that supported the use of CX3CL1, IL-15, and CCL4 in predicting 1-, 3-, and 5-year recurrence-free survival after prostatectomy.Conclusions: Each of the three chemokines can serve as independent predictors of biochemical recurrence. However, the combination of chemokine biomarkers plus clinicopathologic variables discriminated prostatectomy subjects for the probability of biochemical recurrence significantly better than clinicopathologic variables alone.
Globalization, Linguistic Diversity, and Information Dissemination in Malawi
Authors: Kamwendo Gregory 
Published: December 2008

AbstractIn a linguistically heterogeneous country, one of the critical challenges is to make information accessible to all people. Various communication media can be used: television, radio, telephone, the Internet and others. Malawi needs to embrace Information Communication Technologies (ICTs) in order to achieve development in all spheres of human life. Malawi's use of ICTs ranks low. The critical challenge, therefore, is to promote an increased use of ICTs with the aim of improving people's access to information. Given that only a minority of Malawians have access to ICTs, that television has not significantly penetrated into rural areas where 80 % of the population lives, and that there is also a high illiteracy rate, the radio becomes the most accessible form of technology for information dissemination in Malawi.
The Global Development Learning Network (GDLN) and Tertiary Education in Africa: Opportunities and Predicaments of Centralized Knowledge Broadcasting Programs on the World Scale
Authors: Assié-Lumumba N'Dri 
Published: December 2008

AbstractIn the context of the increasing use of ICTs as a medium for higher education delivery across national borders, the World Bank established the Global Development Learning Network (GDLN). GDLN's official mission was to facilitate rapid and simultaneous dissemination of knowledge to audiences in various socio-geographic spaces and the expansion of the opportunity for tertiary education in developing countries. Using the case of Centre d'Education à Distance de Côte d'Ivoire, one of the GDLN national institutional affiliates in Africa, this study illustrates the agendas of liberalization and globalization through ICTs in spite of the potential for local educational gains.
Mapping Moroccan Literature: The Spatial Practices of Modernity in 'Abdelmajīd Ben Jallūn's Fī al-Tufūla
Authors: Campbell Ian 
Published: December 2008

AbstractThis article addresses 'Abdelmajīd Ben Jallūn's 1956 autobiographical novel Fī al-Tufūla from the perspective of the spatial theories of the French cultural geographer Henri Lefebvre. Ben Jallūn spent his early childhood in England and brought the sociospatial practices of 20th-century Britain—what Lefebvre would term "abstract space"—to Morocco with him, where he encounters a profoundly different set of sociospatial practices. The paper describes these Moroccan practices and defines them as "labyrinthine space" by examining the differences Ben Jallūn's childhood alter ego encounters when trying to make his way through the city and receive an education. As he grows into adolescence, Ben Jallūn adapts to the labyrinthine spaces of traditional Islamic culture in Morocco and creates a hybrid space of his own; this enables him to have a bird's-eye view of the nascent Moroccan literary scene. He uses this space and the perspective it provides him to create a map of Moroccan literature and in effect creates the idea of "Moroccan literature" as opposed to literatures by authors from various Moroccan cities. Yet this act is itself a political act, an accrual of power to Ben Jallūn.
The Portrayal of Paul's Outer Appearance in the Acts of Paul and Thecla. Re-Considering the Correspondence between Body and Personality in Ancient Literature
Authors: Omerzu Heike 
Published: December 2008

AbstractThis essay claims that Paul's description in Acts Paul Thecl. 3, if read against the background of Graeco-Roman physiognomics, i.e., the belief in the coherence between outer appearance and inner qualities of a person, is not derogative as assumed in older research but agreeable. The positive interpretation of Paul's outer appearance is corroborated by an analysis of the reactions he evokes in followers (Onesiphorus, Thecla) as well as opponents (Theoclia, Thamyris). It is demonstrated that Paul's physiognomy corresponds to his apostolic identity.
Making Tradition of an Ass. Zênôn the Alexandrian, a White Donkey, and Conversion to Hellenism
Authors: Wellman Tennyson Jacob 
Published: December 2008

AbstractModern discussions of religious change in the ancient Mediterranean have frequently focused on the steady increase in Christian authority and numbers, and the related decrease in the number of 'pagans.' This is frequently paired with a supercessionist logic that suggests Christianity is a new thing in contrast to the older, static, Jewish and pagan cultures. Looking at an invented conversion ritual (one moving from Judaism to Hellenism), we can begin to question the standard ideas of tradition and innovation in Late Antique religious cultures, and to see the ways that some Jews and Hellenes used Christian discourses to assert their own independence and agency.