The CXCR2 antagonist, SCH-527123, shows antitumor activity and sensitizes cells to oxaliplatin in preclinical colon cancer models

Colorectal cancer is the second most common cause of cancer-related death in the United States. Recent studies showed that interleukin-8 (IL-8) and its receptors (CXCR1 and CXCR2) are significantly upregulated in both the tumor and its microenvironment, and act as key regulators of proliferation, angiogenesis, and metastasis. Our previous study showed that IL-8 overexpression in colorectal cancer cells triggers the upregulation of the CXCR2-mediated proliferative pathway. The aim of this study was to investigate whether the CXCR2 antagonist, SCH-527123, inhibits colorectal cancer proliferation and if it can sensitize colorectal cancer cells to oxaliplatin both in vitro and in vivo. SCH-527123 showed concentration-dependent antiproliferative effects in HCT116, Caco2, and their respective IL-8-overexpressing variants colorectal cancer cell lines. Moreover, SCH-527123 was able to suppress CXCR2-mediated signal transduction as shown through decreased phosphorylation of the NF-κB/mitogen-activated protein kinase (MAPK)/AKT pathway. These findings corresponded with decreased cell migration and invasion, while increased apoptosis in colorectal cancer cell lines. In vivo results verified that SCH-527123 treatment decreased tumor growth and microvessel density when compared with vehicle-treated tumors. Importantly, these preclinical studies showed that the combination of SCH-527123 and oxaliplatin resulted in a greater decrease in cell proliferation, tumor growth, apoptosis, and angiogenesis that was superior to single-agent treatment. Taken together, these findings suggest that targeting CXCR2 may block tumor proliferation, migration, invasion, and angiogenesis. In addition, CXCR2 blockade may further sensitize colorectal cancer to oxaliplatin treatment.

Influence of sex on the survival of patients with esophageal cancer

PURPOSE: The prognostic value of sex for esophageal cancer survival is currently unclear, and growing data suggest that hormonal influences may account for incidence disparities between men and women. Therefore, moving from the hypothesis that hormones could affect the prognosis of patients with esophageal cancer, we investigated the primary hypothesis that sex is associated with survival and the secondary hypotheses that the relationship between sex and survival depends, at least in part, on age, histology, and race/ethnicity.

PATIENTS AND METHODS: By using the SEER databases from 1973 to 2007, we identified 13,603 patients (34%) with metastatic esophageal cancer (MEC) and 26,848 patients (66%) with locoregional esophageal cancer (LEC). Cox proportional hazards model for competing risks were used for analyses.

RESULTS: In the multivariate analysis, women had longer esophageal cancer-specific survival (ECSS) than men in both MEC (hazard ratio [HR], 0.949; 95% CI, 0.905 to 0.995; P = .029) and LEC (HR, 0.920; 95% CI, 0.886 to 0.955; P < .001) cohorts. When age and histology were accounted for, there was no difference for ECSS between men and women with adenocarcinoma. In contrast, women younger than age 55 years (HR, 0.896; 95% CI, 0.792 to 1.014; P = .081) and those age 55 years or older (HR, 0.905; 95% CI, 0.862 to 0.950; P < .001) with squamous cell LEC had longer ECSS than men. In the squamous cell MEC cohort, only women younger than age 55 years had longer ECSS (HR, 0.823; 95% CI, 0.708 to 0.957; P = .011) than men.

CONCLUSION: Sex is an independent prognostic factor for patients with LEC or MEC. As secondary hypotheses, in comparison with men, women age 55 years or older with squamous cell LEC and women younger than age 55 years with squamous cell MEC have a significantly better outcome. These last two findings need further validation.

Plastin Polymorphisms Predict Gender- and Stage-Specific Colon Cancer Recurrence after Adjuvant Chemotherapy

Tumor recurrence after curative resection remains a major problem in patients with locally advanced colorectal cancer treated with adjuvant chemotherapy. Genetic single-nucleotide polymorphisms (SNP) may serve as useful molecular markers to predict clinical outcomes in these patients and identify targets for future drug development. Recent in vitro and in vivo studies have demonstrated that the plastin genes PLS3 and LCP1 are overexpressed in colon cancer cells and play an important role in tumor cell invasion, adhesion, and migration. Hence, we hypothesized that functional genetic variations of plastin may have direct effects on the progression and prognosis of locally advanced colorectal cancer. We tested whether functional tagging polymorphisms of PLS3 and LCP1 predict time to tumor recurrence (TTR) in 732 patients (training set, 234; validation set, 498) with stage II/III colorectal cancer. The PLS3 rs11342 and LCP1 rs4941543 polymorphisms were associated with a significantly increased risk for recurrence in the training set. PLS3 rs6643869 showed a consistent association with TTR in the training and validation set, when stratified by gender and tumor location. Female patients with the PLS3 rs6643869 AA genotype had the shortest median TTR compared with those with any G allele in the training set [1.7 vs. 9.4 years; HR, 2.84; 95% confidence interval (CI), 1.32-6.1; P = 0.005] and validation set (3.3 vs. 13.7 years; HR, 2.07; 95% CI, 1.09-3.91; P = 0.021). Our findings suggest that several SNPs of the PLS3 and LCP1 genes could serve as gender- and/or stage-specific molecular predictors of tumor recurrence in stage II/III patients with colorectal cancer as well as potential therapeutic targets.

Common cancer stem cell gene variants predict colon cancer recurrence

PURPOSE: Recent evidence suggests that cancer stem cells (CSC) are responsible for key elements of colon cancer progression and recurrence. Germline variants in CSC genes may result in altered gene function and/or activity, thereby causing interindividual differences in a patient's tumor recurrence capacity and chemoresistance. We investigated germline polymorphisms in a comprehensive panel of CSC genes to predict time to tumor recurrence (TTR) in patients with stage III and high-risk stage II colon cancer.

EXPERIMENTAL DESIGN: A total of 234 patients treated with 5-fluorouracil-based chemotherapy at the University of Southern California were included in this study. Whole blood samples were analyzed for germline polymorphisms in genes that have been previously associated with colon CSC (CD44, Prominin-1, DPP4, EpCAM, ALCAM, Msi-1, ITGB1, CD24, LGR5, and ALDH1A1) by PCR-RFLP or direct DNA-sequencing.

RESULTS: The minor alleles of CD44 rs8193 C>T, ALCAM rs1157 G>A, and LGR5 rs17109924 T>C were significantly associated with increased TTR (9.4 vs. 5.4 years; HR, 0.51; 95% CI: 0.35-0.93; P = 0.022; 11.3 vs. 5.7 years; HR, 0.56; 95% CI: 0.33-0.94; P = 0.024, and 10.7 vs. 5.7 years; HR, 0.33; 95% CI: 0.12-0.90; P = 0.023, respectively) and remained significant in the multivariate analysis stratified by ethnicity. In recursive partitioning, a specific gene variant profile including LGR5 rs17109924, CD44 rs8193, and ALDH1A1 rs1342024 represented a high-risk subgroup with a median TTR of 1.7 years (HR, 6.71, 95% CI: 2.71-16.63, P < 0.001).

CONCLUSION: This is the first study identifying common germline variants in colon CSC genes as independent prognostic markers for stage III and high-risk stage II colon cancer patients.

Pharmacogenetic angiogenesis profiling for first-line Bevacizumab plus oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer

PURPOSE: There is substantial germline genetic variability within angiogenesis pathway genes, thereby causing interindividual differences in angiogenic capacity and resistance to antiangiogenesis therapy. We investigated germline polymorphisms in genes involved in VEGF-dependent and -independent angiogenesis pathways to predict clinical outcome and tumor response in metastatic colorectal cancer (mCRC) patients treated with bevacizumab and oxaliplatin-based chemotherapy.

EXPERIMENTAL DESIGN: A total of 132 patients treated with first-line bevacizumab and FOLFOX or XELOX were included in this study. Genomic DNA was isolated from whole-blood samples by PCR-RFLP or direct DNA sequencing. The endpoints of the study were progression-free survival (PFS), overall survival (OS), and response rate (RR).

RESULTS: The minor alleles of EGF rs444903 A>G and IGF-1 rs6220 A>G were associated with increased OS and remained significant in multivariate Cox regression analysis (HR: 0.52; 95% CI: 0.31-0.87; adjusted P = 0.012 and HR: 0.60; 95% CI: 0.36-0.99; adjusted P = 0.046, respectively). The minor allele of HIF1α rs11549465 C>T was significantly associated with increased PFS but lost its significance in multivariate analysis. CXCR1 rs2234671 G>C, CXCR2 rs2230054 T>C, EGFR rs2227983 G>A, and VEGFR-2 rs2305948 C>T predicted tumor response, with CXCR1 rs2234671 G>C remaining significant in multiple testing (P(act) = 0.003).

CONCLUSION: In this study, we identified common germline variants in VEGF-dependent and -independent angiogenesis genes predicting clinical outcome and tumor response in patients with mCRC receiving first-line bevacizumab and oxaliplatin-based chemotherapy.

Molecular predictors of response to antiangiogenesis therapies

Angiogenesis is a crucial component of tumor growth and metastasis. Targeting the vascular endothelial growth factor pathway represents therapeutic potentials for treating cancer. To date, 3 Food and Drug Administration-approved agents targeting angiogenesis have been developed, bevacizumab, sunitinib, and sorafenib. However, no validated biomarkers are available to identify those patients who are likely to benefit from antiangiogenesis therapy. Molecular biomarker research in antiangiogenesis inhibition is an actively growing field. Although current data are extremely promising, it is still uncertain which biomarker(s) can reliably predict their efficacy. With increasing numbers of inhibitors being developed, the need for biomarkers is more critical than ever. This review will focus on translational research that strives to identify molecular biomarkers (tissue, circulating and genomic) for approved antiangiogenesis therapies that can indicate benefit, resistance, and toxicity.

A matter of time: Phases of customer co-creation community participation and their impact on customer behavior

Despite the growing relevance of co-creating customer communities only little scientific evidence is available on their impact on transactional behavior of participants. Previous research has mostly used self-reported data or distinguished only between during and pre-community phases obtaining mixed results. However, the author proposes that co-creating community activity takes place in five distinguishable phases and changes in transactional behavior are limited to certain phases. Using 33 months of transactional data of a Dutch online auction provider a study was conducted covering all five phases of the community co-creation process from community planning over community set-up, co-development and co-testing to post-launch. The overall results indicate mixed effects of community participation on the different transactional variables during the co-creation process. Community participation had positive effects on auctions listing behavior at the community set-up, co-development and post-launch phases, whereby the number of auctions listed peaked during the community set-up phase. These results suggest that the impact on transactional behavior differs between co-creation phases and different psychological mechanism limited to certain phases might trigger the respective changes.

Keyword Competition and Determinants of Ad Position in Sponsored Search Advertising

Given the significant growth of the Internet in recent years, marketers have been striving for new techniques and strategies to prosper in the online world. Statistically, search engines have been the most dominant channels of Internet marketing in recent years. However, the mechanics of advertising in such a market place has created a challenging environment for marketers to position their ads among their competitors. This study uses a unique cross-sectional dataset of the top 500 Internet retailers in North America and hierarchical multiple regression analysis to empirically investigate the effect of keyword competition on the relationship between ad position and its determinants in the sponsored search market. To this end, the study utilizes the literature in consumer search behavior, keyword auction mechanism design, and search advertising performance as the theoretical foundation. This study is the first of its kind to examine the sponsored search market characteristics in a cross-sectional setting where the level of keyword competition is explicitly captured in terms of the number of Internet retailers competing for similar keywords. Internet retailing provides an appropriate setting for this study given the high-stake battle for market share and intense competition for keywords in the sponsored search market place. The findings of this study indicate that bid values and ad relevancy metrics as well as their interaction affect the position of ads on the search engine result pages (SERPs). These results confirm some of the findings from previous studies that examined sponsored search advertising performance at a keyword level. Furthermore, the study finds that the position of ads for web-only retailers is dependent on bid values and ad relevancy metrics, whereas, multi-channel retailers are more reliant on their bid values. This difference between web-only and multi-channel retailers is also observed in the moderating effect of keyword competition on the relationships between ad position and its key determinants. Specifically, this study finds that keyword competition has significant moderating effects only for multi-channel retailers.

Realitätsnähe von Kinderfernsehprogrammen und geschlechterspezifische Fernsehnutzungspräferenzen

Überblick über die Arbeit: "Die Notwendigkeit deutscher Kinderfernseh- und -filmproduktion ist unbestritten. Sie sind die Voraussetzung dafür, dass Kinder im Fernsehen ihre eigene Lebenswirklichkeit wiederfinden und zur Reflexion dieser Wirklichkeit angeregt werden."(Rosenbaum 2000) Kinderfernsehexperten wie Uwe Rosenbaum (Landessenderdirektor des Südwestrundfunks Rheinland-Pfalz) oder Armin Maiwald (Geschäftsführer der Flash Filmstudio GmbH, Produzent und Regisseur vieler Sachgeschichten der Sendung mit der Maus) vertreten die Meinung, dass in Deutschland mehr Kinderprogramm mit Kindern produziert werden müsse, die in Deutschland wohnen. Sie sind dabei auch der Meinung, Realprogramm sei qualitativ hochwertiger und damit für Kinder besser, als einseitiges, triviales Zeichentrickprogramm. Der Teil 1 greift diesen Diskurs auf und beschreibt ihn. Einen Beitrag zu diesem Diskurs möchte die Frageleisten, welche Darstellungsformen von Welt vom expliziten Kinderfernsehen angeboten werden und welche davon Kinder bevorzugen. Das Material einer systematischen Fernsehprogrammanalyse, die von den Nutzungspräferenzen der Kinder ausgeht, kann dabei helfen. Dabei konzentriere ich mich auf die zwei Aspekte "Animation" und "real", da der Diskurs Realfilm als qualitativ hochwertig ansieht und Animation in dieser Hinsicht das genaue Gegenteil darstellt. Dabei ist ein zentrales Ergebnis der Analyse, dass sich die Nutzungspräferenzen der Jungen und Mädchen in bezug auf realitätsnahes Programm sehr unterscheiden: Jungen sehen eher Zeichentrickprogramm und Mädchen sehen eher Realformate wie z.B. Soap-Operas. Das legt nahe, die Diskussion um Realitätsnähe im Kinderfernsehen aus geschlechterspezifischer Sicht zu betrachten und die Fragestellung der Arbeit dahingehend neu zu formulieren. Der zweite Teil der Arbeit sortiert zunächst die Begriffe "Realitätsnähe", "Realfilm" und "Zeichentrick", die im ersten Teil eingeführt wurden und trennt sie von einander. Die "Jährliche Bestandsaufnahme zum Kinderfernsehen - qualitative und quantitative Fernsehprogrammanalyse in der Sicht der Kinder" dient dazu, im Kinderfernsehen die Spuren des Diskurses wieder zu finden. Die systematische Suche nach solchen Programmen macht es nötig, mit Hilfe operationalisierter Begriffe, Fernsehprogramm zu kodieren. Dabei bieten sich bereits vorhandene Kodes zur Realitätsnähe an. Für die Auswertung sind zudem auch Zugänge über weitere Kodes wie z.B. Information/ Unterhaltung oder Fiction/ Non-Fiction möglich. Die Ansätze in Teil 1 und 2 waren bis dahin umgangssprachliche Formulierungen, deshalb folgt im dritten Teil der Arbeit ein Exkurs in die Theorie, um den Begriff der Realitätsnähe im Fernsehen theoretisch zu begründen und um Realfilm und Animation theoretisch zu beschreiben. Zwei Themenfelder sind hierbei wesentlich: Das erste Themenfeld behandelt die Wirklichkeitskonstruktion im Fernsehen mit den Autoren Alfred Schütz, Thomas Luckmann und Jürgen Fritz. Das Wesentliche in diesem Abschnitt ist der Versuch Realfilm und Zeichentrick als geschlossene Sinngebiete wie "reale Welt" und "Spielwelt" zu verstehen, da geschlossenen Sinngebieten spezifische, eigene Erlebnis- und Erkenntnisstile zugrunde liegen. Fazit dieser Überlegung ist, dass Realfilm und Zeichentrick einander nicht über- oder untergeordnet sind, sondern formal nebeneinander mit unterschiedlichen Erkenntnis- und Erlebnisstilen in Erscheinung treten, bzw. in ihnen unterschiedliche Erlebnis- und Erkenntnisstile angelegt sind. Das zweite Themenfeld widmet sich der von David Buckingham so genannten "Perceived Reality", die nach der Wahrnehmung der Kinder von Wirklichkeit im Fernsehen fragt. Dabei geht es um die Frage, wie Kinder die Realität des Fernsehens beurteilen. Ein Fazit ist hierbei, dass Kinder an Fernsehsendungen keine allgemeingültige Messlatte anlegen, um die Realitätsnähe zu bestimmen, sondern Kinder handeln die Realitätsnähe von Sendungen und deren Bewertung in sozialen Kontexten mit Peers und Erwachsenen je nach Situation aus. Der vierte Teil der Arbeit wertet die Kodierung aus dem zweiten Teil aus und präsentiert Ergebnisse. In diesem Teil werden verschiedene Auswertungsverfahren ausprobiert, um Muster in der Rezeption und im Ein- und Ausschaltverhalten der Kinder in bezug auf Realitätsnähe zu finden. Nachdem Überblick über das Angebot an realitätsnahem Kinderfernsehprogramm, folgt die Auswertung der Nutzung des Kinderprogramms. Hierbei steht die Frage im Vordergrund, in welchem Ausmaß Kinder realitätsnahe Programme nutzen und welche geschlechterspezifischen Unterschiede es in der Nutzung Formate "Animation" und "real" gibt. Im Groben werden in diesem Kapitel zahlreiche Listen präsentiert, Sendungen beschrieben und vor allem unterschiedliche Altersgruppen sowie Geschlechter berücksichtigt. Eines der auffälligsten Merkmale wird sein, dass Jungen in Bezug auf die eingangs eröffneten Begriffe andere Präferenzen und Fernsehnutzungsmuster zeigen als Mädchen. Im Gegensatz zu Mädchen sehen die Jungen eher weniger Realprogramm und eher mehr Animationsprogramm. Kinder im Fernsehen stehen stellvertretend für Muster und Typen von Kindern der realen Welt. Das legitimiert anhand der Typologie der Kinder nach Freizeitmustern , nach diesen Kindertypen im Fernsehen und bei den Zuschauern zu suchen. Ein Ergebnis bestätigte die Beobchtung, dass Mädchen neben Realprogramm auch Zeichentrick sehen, und Jungen nur Zeichentrick. Anhand der bis dort gewonnenen Ergebnisse und zweier Beispiele aus dem Schulalltag folgt abschließend in Teil 5 ein pädagogisches Fazit. Der Umgang von Jungen mit Medien wird häufig problematisiert und so wie es sich in den Ergebnissen dieser und anderer Arbeiten wie der PISA2000-Studie oder in der Typologie der Freizeitmuster darstellt, könnte man durchaus den Eindruck gewinnen, dass Jungen eine schwierige Beziehung zu Medien haben. Deshalb muss man sich vermutlich zunächst eingestehen, dass Jungen eher Zeichentrick und Mädchen eher Soaps gucken, um danach Jungen emphatisch in Bezug auf ihre Mediennutzungsmuster zu begegnen und ihre Vorlieben nicht zu trivialisieren oder zu verurteilen. Das hat pädagogische Bedeutung für die Schule, wie die beiden Beispiele zeigen.

La pelota no se mancha: Un estudio histórico sobre el desarrollo y la política en FIFA

Esta investigación se centra en la Fédération Internationale de Football Association (FIFA) como organización política. Intenta responder dos interrogantes primordiales: 1) ¿cómo la FIFA ha constituido el poder que tiene actualmente y, así, hacerse del monopolio indiscutido del fútbol? Y 2) ¿cómo ha cambiado en el tiempo la política interna de FIFA y su vínculo con la política internacional? Para lograr esto, se realiza un estudio histórico, basado principalmente en documentos, que intenta caracterizar y analizar los cambios de la organización en el tiempo. Se enfatizan las últimas dos presidencias de FIFA, de João Havelange y Joseph Blatter, como casos de estudio.