bluuebunny/crossref_metadata_2025_split huggingface dataset:
Meeting Report: NCI Think Tanks in Cancer Biology
Authors: Sogn John A. , Anton-Culver Hoda , Singer Dinah S. 
Published: October 2005

Abstract
Over the past year and a half, the Division of Cancer Biology of NCI has been assessing the state of cancer biology, with the goal of developing a research agenda for the near future that would accelerate progress in cancer research. Our goal was to identify emerging concepts and promising opportunities for investigation across nine scientific areas with unusual promise for rapid progress. A series of meetings called Think Tanks was convened, each involving a panel of 15-25 experts. In all, over 160 leaders in cancer research and related fields discussed the current state of science in their disciplines, projected its trajectory and recommended what NCI could or should do to facilitate progress. In addition to emphasizing the importance of continued support for investigator-initiated research, the Think Tanks permitted identification of a number of overarching themes. Critical among them was the need to support the development of integrative cancer biology and to encourage studies of the tumor microenvironment by establishing an infrastructure for interactive research. There was also consensus about the importance of comparative studies of normal and tumor states, and development of mechanisms for supporting collaborative, interdisciplinary research and training.
Hyperplastic Gastric Tumors with Spasmolytic Polypeptide–Expressing Metaplasia Caused by Tumor Necrosis Factor-α–Dependent Inflammation in Cyclooxygenase-2/Microsomal Prostaglandin E Synthase-1 Transgenic Mice
Authors: Oshima Masanobu , Oshima Hiroko , Matsunaga Akihiro , Taketo Makoto Mark 
Published: October 2005

AbstractWe showed recently that Helicobacter infection induces expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in the mouse stomach, and that transgenic mice expressing both cyclooxygenase-2 and microsomal prostaglandin E synthase-1 (K19-C2mE mice) develop hyperplastic gastric tumors with inflammatory histopathology. To investigate possible roles of proinflammatory cytokines and acquired immunity in the gastric hyperplasia of K19-C2mE mice, we introduced knockout mutations for tumor necrosis factor-α (TNF-α; Tnf), interleukin-1 receptor-α chain (Il1r1), and Rag2 genes, respectively. Among the compound mutants, only the Tnf (−/−) K19-C2mE mice showed significant suppression of hyperplastic tumors with reduced cell proliferation. In contrast, tumorigenesis remained unaffected in either compound mutants of K19-C2mE containing Il1r1 or Rag2 mutation, indicating that neither interleukin-1β signaling nor T cell/B cell response was required for the development of hyperplastic tumors. Importantly, spasmolytic polypeptide/trefoil factor 2–expressing metaplasia (SPEM) in the K19-C2mE stomach was also suppressed in the Tnf (−/−) K19-C2mE mice, indicating that TNF-α–dependent inflammation is responsible for SPEM development. Because gastric metaplasia to the SPEM lineage is considered as a preneoplastic lesion of gastric cancer, it is possible that inhibition of TNF-α–dependent inflammation, together with eradication of Helicobacter, can be an effective prevention strategy for gastric cancer.
Association between Acquired Uniparental Disomy and Homozygous Gene Mutation in Acute Myeloid Leukemias
Authors: Fitzgibbon Jude , Smith Lan-Lan , Raghavan Manoj , Smith Matthew L. , Debernardi Silvana , Skoulakis Spyros , Lillington Debra , Lister T. Andrew , Young Bryan D. 
Published: October 2005

Abstract
Genome-wide single nucleotide polymorphism analysis has revealed large-scale cryptic regions of acquired homozygosity in the form of segmental uniparental disomy in ∼20% of acute myeloid leukemias. We have investigated whether such regions, which are the consequence of mitotic recombination, contain homozygous mutations in genes known to be mutational targets in leukemia. In 7 of 13 cases with uniparental disomy, we identified concurrent homozygous mutations at four distinct loci (WT1, FLT3, CEBPA, and RUNX1). This implies that mutation precedes mitotic recombination which acts as a “second hit” responsible for removal of the remaining wild-type allele, as has recently been shown for the JAK2 gene in myeloproliferative disorders.
Anti–Prostate Stem Cell Antigen Monoclonal Antibody 1G8 Induces Cell Death In vitro and Inhibits Tumor Growth In vivo via a Fc-Independent Mechanism
Authors: Gu Zhennan , Yamashiro Joyce , Kono Evelyn , Reiter Robert E. 
Published: October 2005

Abstract
Prostate stem cell antigen (PSCA), a 123–amino acid cell surface glycoprotein, is highly expressed in both local and metastatic prostate cancers as well as in a large proportion of bladder and pancreatic cancers. PSCA overexpression correlates with a high risk of recurrence after primary therapy for prostate cancer. We have reported previously that anti-PSCA monoclonal antibody (mAb) 1G8 inhibits tumor growth, prevents metastasis, and prolongs the survival of mice inoculated with human prostate cancer cell lines and xenografts. The current study was undertaken to elucidate the mechanism of action of anti-PSCA antibody therapy. In particular, we asked whether antitumor activity resulted from recruitment of an immune response or a direct effect on the tumor cell itself. In vitro assays show that both intact 1G8 and F(ab′)2 fragments of 1G8 induce prostate cancer cell death. The anti-PSCA antibody-induced cell death is caspase independent and requires antigen cross-linking. These results were confirmed in in vivo models in which both 1G8 and F(ab′)2 fragments were able to inhibit prostate tumor formation and growth equally. These results suggest that the anti-PSCA mAb 1G8 acts by a direct, Fc-independent mechanism to inhibit prostate tumor growth both in vitro and in vivo.
p27kip1 in Intestinal Tumorigenesis and Chemoprevention in the Mouse
Authors: Yang WanCai , Bancroft Laura , Liang Jiao , Zhuang Min , Augenlicht Leonard H. 
Published: October 2005

Abstract
Targeted inactivation of p27kip1 was sufficient for intestinal tumor formation in mice, but this was strictly a function of diet: tumors formed in p27+/− or p27−/− mice fed control AIN-76A diet and were increased by a western-style diet but did not develop in mice fed standard chow diet. When crossed with the Apc1638N+/− mouse, Apc+/−,p27+/− or Apc+/−,p27−/− mice not only formed twice as many tumors than the sum of the tumors from mutation at either locus alone, but on AIN76A diet also developed intestinal intussusception, a tumor-associated pathology in patients leading to intestinal blockage that has not been reported for intestinal cancer in mouse models. Moreover, the frequency of intussusception was increased when the compound mutant mice were maintained on the western diet, leading to early death. Despite this more aggressive tumor phenotype generated by inactivation of p27 than by inactivation of another cyclin-dependent kinase inhibitor, p21WAF1/cip1, the nonsteroidal anti-inflammatory drug sulindac was still effective in inhibiting intestinal tumor formation in Apc+/−,p27+/− or Apc+/−,p27−/− mice, which contrasts with the abrogation of the effects of sulindac in Apc+/−,p21+/− or Apc+/−,p21−/− mice, indicating that p27 is not necessary for tumor inhibition by sulindac. Furthermore, tumor inhibition by sulindac was linked to the induction of p21 expression by the drug, regardless of p27 status, leading to suppression of cell proliferation and promotion of cell differentiation and apoptosis in the intestinal mucosa.
Sleep Duration and Breast Cancer: A Prospective Cohort Study
Authors: Verkasalo Pia K. , Lillberg Kirsi , Stevens Richard G. , Hublin Christer , Partinen Markku , Koskenvuo Markku , Kaprio Jaakko 
Published: October 2005

Abstract
Breast cancer incidence has increased during recent decades for reasons that are only partly understood. Prevalence of sleeping difficulties and sleepiness has increased, whereas sleeping duration per night has decreased. We hypothesized that there is an inverse association between sleep duration and breast cancer risk, possibly due to greater overall melatonin production in longer sleepers. This population-based study includes information from women born in Finland before 1958. Sleep duration, other sleep variables, and breast cancer risk factors were assessed by self-administered questionnaires given in 1975 and in 1981. Breast cancer incidence data for 1976 to 1996 was obtained from the Finnish Cancer Registry. Hazard ratios (HR) and 95% confidence intervals (CI) were obtained from Cox proportional hazards models adjusting for potential confounders. Altogether, 242 cases of breast cancer occurred over the study period among the 12,222 women with sleep duration data in 1975. For these women, the HRs for breast cancer in the short (≤6 hours), average (7-8 hours), and long sleep (≥9 hours) duration groups were 0.85 (CI, 0.54-1.34), 1.0 (referent), and 0.69 (CI, 0.45-1.06), respectively. Analysis restricted to the 7,396 women (146 cases) whose sleep duration in 1975 and 1981 were in the same duration group (stable sleepers) yielded HRs of 1.10 (CI, 0.59-2.05), 1.0, and 0.28 (CI, 0.09-0.88), with a decreasing trend (P = 0.03). This study provides some support for a decreased risk of breast cancer in long sleepers.
Ku86 Modulates DNA Topoisomerase I–Mediated Radiosensitization, but not Cytotoxicity, in Mammalian Cells
Authors: Shih Shyh-Jen , Erbele Tara , Chen Allan Y. 
Published: October 2005

AbstractKu86 is an integral component of the nonhomologous end-joining (NHEJ) pathway of cellular double-strand break repair. In the current study, we investigated the role of Ku86 in DNA topoisomerase I–mediated radiosensitization induced by camptothecin in mammalian cells. Interestingly, as examined by clonogenic survival assay, a 30-minute camptothecin treatment induced significantly higher levels of radiosensitization in the Ku86-deficient Chinese hamster ovary xrs-6 cells than in the hamster Ku86-complemented xrs-6+hamKu86 cells, albeit exhibiting similar drug toxicity in these two cell lines. To confirm these findings, similar studies were conducted in two pairs of transfectant sublines established from the Ku86-deficient Chinese hamster lung fibroblast XR-V15B cells. Compared with the vector-alone sublines, radiation resistance was restored in the human Ku86-complemented sublines without alteration of cell cycle distributions. Again, significantly higher levels of camptothecin-induced radiosensitization were observed in the vector-alone sublines than in the Ku86-complemented XR-V15B sublines. In contrast, camptothecin treatments, ranging from 0.5 to 24 hours, induced similar cytotoxicities in both vector-alone and Ku86-complemented sublines. Because neither the DNA-damaging etoposide and cisplatin nor the tubulin-binder vinblastine induced enhanced levels of radiosensitization in the Ku86-deficient cells, Ku86 seems to uniquely affect topoisomerase I–mediated radiosensitization induced by camptothecin. Furthermore, cotreatment with DNA replication inhibitor aphidicolin abolished both camptothecin-induced cytotoxicity and radiosensitization in the vector-alone, as well as the Ku86-complemented subline cells, indicating both events are initiated by replication-dependent topoisomerase I–mediated DNA damages. Taken together, our data show a novel role of Ku86 in modulating topoisomerase I–mediated radiosensitization, but not cytotoxicity, in mammalian cells.
Molecular Portraits and 70-Gene Prognosis Signature Are Preserved throughout the Metastatic Process of Breast Cancer
Authors: Weigelt Britta , Hu Zhiyuan , He Xiaping , Livasy Chad , Carey Lisa A. , Ewend Matthew G. , Glas Annuska M. , Perou Charles M. , van't Veer Laura J. 
Published: October 2005

Abstract
Microarray analysis has been shown to improve risk stratification of breast cancer. Breast tumors analyzed by hierarchical clustering of expression patterns of “intrinsic” genes have been reported to subdivide into at least four molecular subtypes that are associated with distinct patient outcomes. Using a supervised method, a 70-gene expression profile has been identified that predicts the later appearance or absence of clinical metastasis in young breast cancer patients. Here, we show that distant metastases display both the same molecular breast cancer subtype as well as the 70-gene prognosis signature as their primary tumors. Our results suggest that the capacity to metastasize is an inherent feature of most breast cancers. Furthermore, our data imply that poor prognosis breast carcinomas classified either by the intrinsic gene set or the 70 prognosis genes represent distinct disease entities that seem sustained throughout the metastatic process.
Weaknesses in the classification criteria for antithrombotic-related major bleeding events
Authors: Gregory Elliott C. , Stoddard Gregory , Haug Peter , Lagor Charles 
Published: October 2005

SummaryWe asked two physicians to review the medical records (electronic and paper) of 100 patients on antithrombotics. The physicians used published classification criteria to identify all of the bleeding events that the patients experienced. The goal of the review was to investigate whether the physicians would identify the same antithrombotic related major bleeding events (ARMBEs) for each patient. The correct identification and classification of multiple bleeding events is a prerequisite for studies of antithrombotic treatment practices during hospitalization that predispose patients to ARMBEs. In addition, we were interested in the reasons for disagreement between the physicians, so that we could find ways of improving their agreement. The reviewers identified 299 bleeding events for the 100 patients. They disagreed on whether 29 of the events represented an ARMBE occurring during hospitalization. With a kappa statistic of 0.49 (95% confidence interval, 0.31 to 0.66) the agreement was moderate. The reviewers most often disagreed either because they misinterpreted the data (12 events) or because the classification criteria for ARMBEs were not explicit enough (9 events). Disagreement took two main forms: either the reviewers disagreed on ARMBEs by not identifying the same bleeds (11 events) or by not applying the severity criteria appropriately (7 events). Because the main type of disagreement was not identifying the same bleeds, a study investigating the antithrombotic treatment practices that predispose patients to ARMBEs would be threatened. We therefore proposed supplementing the existing classification criteria with additional rules to avoid ambiguities in patients with multiple events.
Analyses of cellular multimerin 1 receptors: in vitro evidence of binding mediated by αΙΙbβ3 and αvβ3
Authors: Adam Frédéric , Zheng Shilun , Joshi Nilesh , Kelton David , Sandhu Amin , Suehiro Youko , Jeimy Samira , Santos Aurelio , Massé Jean-Marc , Kelton John , Cramer Elisabeth , Hayward Catherine 
Published: October 2005

SummaryMultimerin 1 (MMRN1) is a large, soluble, polymeric, factor V binding protein and member of the EMILIN protein family.In vivo, MMRN1 is found in platelets, megakaryocytes, endothelium and extracellular matrix fibers, but not in plasma. To address the mechanism of MMRN1 binding to activated platelets and endothelial cells, we investigated the identity of the major MMRN1 receptors on these cells using wild-type and RGE-forms of recombinant MMRN1. Ligand capture, cell adhesion, ELISA and flow cytometry analyses of platelet-MMRN1 binding, indicated that MMRN1 binds to integrins αIIbβ3 and αvβ3. Endothelial cell binding to MMRN1 was predominantly mediated by αvβ3 and did not require the MMRN1 RGD site or cellular activation. Like many other αvβ3 ligands, MMRN1 had the ability to support adhesion of additional cell types, including stimulated neutrophils. Expression studies, using a cell line capable of endothelial-like MMRN1 processing, indicated that MMRN1 adhesion to cellular receptors enhanced its extracellular matrix fiber assembly. These studies implicate integrin-mediated binding in MMRN1 attachment to cells and indicate that MMRN1 is a ligand for αIIbβ3 and αvβ3.
Plasma markers of angiogenesis in pregnancy induced hypertension
Authors: Nadar Sunil , Karalis Ioannis , Al Yemeni Eman , Blann Andrew , Lip Gregory 
Published: October 2005

SummaryThis study tests the hypothesis that abnormalities in plasma indices of angiogenesis, such as Vascular Endothelial Growth Factor (VEGF) and angiopoietins (Ang-1, Ang-2), as well as their soluble receptors Flt-1 (sflt-1) and Tie 2 (sTie-2) respectively, are present in women with in pregnancy-induced hypertension (PIH). We also measured platelet levels of VEGF and Ang-1 (pVEGF and pAng-1 respectively). We studied 69 consecutive women with PIH (34 without proteinuria, and 35 with proteinuria, i.e. preeclampsia) who were compared to 64 consecutive women with normotensive pregnancies and 30 normotensive non-pregnant women, in a cross-sectional study. Using ELISA, we measured levels of plasma VEGF, Ang-1 &2, Tie-2 and sflt-1, and also the levels of angiogenic markers within the platelet [platelet VEGF (pVEGF) and platelet Ang-1 (pAng1)] by lysing a fixed number of platelets with 0.5% tween. Results show that levels of plasma VEGF, Ang-1, Ang2, sFlt-1 and Tie-2 were significantly different between the study groups. Post hoc analyses revealed plasma Ang-1 was highest in the preeclampsia group (p<0.001), whilst Ang-2 was highest in the normotensive pregnant group (p-=0.018). Plasma Tie-2 was highest in the PIH group. VEGF levels were significantly different between the preeclampsia group and the PIH group (p<0.05). Platelet VEGF levels were higher in the non-pregnant group than in the pregnant group, but there were no significant differences in the platelet levels of Ang-1 between the different groups. Ang-2, sFlt-1 and Tie-2 were undetectable in the platelet lysate in any of the patient groups or controls. Blood pressure was a major determinant of the different angiogenic factors studied. Abnormal indices of angiogenesis are evident in PIH and preeclampsia, with higher levels of sFlt-1 and lower levels ofVEGF; in PIH, increased levels of Ang-1 and Tie-2, but reduced Ang-2, are evident compared to normal pregnancy. These abnormalities may have implications for the pathogenesis of PIH and preeclampsia.
Modulation of systemic hemostatic parameters by enoxaparin during gestation in women with thrombophilia and pregnancy loss
Authors: Blumenfeld Zeev , Leiba Ronit , Lanir Naomi , Brenner Benjamin , Sarig Galit 
Published: October 2005

SummaryRecurrent pregnancy loss (PL) is associated with maternal thrombophilia and prophylaxis with low molecular weight heparin (LMWH) can improve pregnancy outcome in this setting. The aim of this study was to investigate the modulation of systemic hemostatic parameters by enoxaparin in women with recurrent PL and to evaluate plasmatic parameters that would potentially enable monitoring LMWH prophylaxis effect during pregnancy. Study group included 87 women with thrombophilia and PL treated with enoxaparin 40 mg daily vs. 40 mg twice daily. The control group comprised 40 women with normal pregnancies. Blood samples have been collected throughout the period starting at 5-10 weeks of gestation until 6-10 weeks postpartum. The determined plasmatic markers included: anti-Xa activity, total and free tissue factor pathway inhibitor (TFPI), D-dimer, prothrombin fragment 1+2 (PT1+2), activated protein C resistance (APC-SR) and free protein S. Successful pregnancy outcome was recorded in 70 (80.5%) women treated with enoxaparin, with-out correlation to enoxaparin dosage. Seventeen women (19.5%) had pregnancy loss at 16±7 (6-32) weeks of gestation. Anti-Xa levels at 10-15 weeks of gestation were higher (0.39±0.38 u/ml) in the successful pregnancy outcome group compared to the abortion group (0.22±0.2 u/ml). Prophylactic anti-Xa activity levels (0.28±0.13 u/ml) were documented from 15 weeks of gestation until delivery in the successful pregnancy outcome group. Significant increase in anti-Xa, total TFPI and free TFPI levels (P<0.001) was achieved after beginning of LMWH prophylaxis in successful pregnancy outcome group but not in the abortion group. D-dimer and PT1+2 levels appeared to be significantly increased while APC-SR and free protein S levels gradually decreased during pregnancy, with no difference between study groups. These results suggest that LMWH prophylaxis during pregnancy enables modulation of systemic hemostatic parameters via inhibition of factor Xa and increase in plasmatic total and free TFPI levels.
Homocysteine and thrombosis: from basic science to clinical evidence
Authors: Brożek Jan , Szczeklik Andrzej , Undas Anetta 
Published: October 2005

SummaryHomocysteine is a sulfhydryl-containing amino acid formed during the metabolism of methionine. Rapidly accumulating evidence links elevated homocysteine levels to thrombosis via several mechanisms such as increased tissue factor expression, attenuated anticoagulant processes, enhanced platelet reactivity, increased thrombin generation, augmented factor V activity, impaired fibrinolytic potential, and vascular injury, including endothelial dysfunction. Molecular mechanisms underlying prothrombotic actions of homocysteine are incompletely understood and involve oxidative stress, DNA hypomethylation, and proinflammatory effects. Current evidence from retrospective and prospective studies supports the concept that higher total plasma homocysteine concentration is associated with increased risk of coronary artery disease, stroke, and venous thromboembolism. Hyperhomocysteinemia is currently considered a relatively weak prothrombotic factor. It is still unclear whether administration of vitamins, that reduce homocysteine levels acting as cofactors of the enzymes involved in the methionine metabolism, may decrease the risk of arterial and/or venous thromboembolic events. Ongoing clinical trials might help clarify this issue.
Plasma concentrations and importance of high mobility group box protein in the prognosis of organ failure in patients with disseminated intravascular coagulation
Authors: Hatada Tsuyoshi , Nobori Tsutomu , Okabayashi Kazuhiro , Maruyama Kazuo , Abe Yasunori , Uemoto Shinji , Yamada Shingo , Maruyama Ikuro , Wada Hideo 
Published: October 2005

SummaryHigh Mobility Group Box chromosomal protein 1 (HMGB1) is a nuclear DNA-binding protein acting as a proinflammatory cytokine when released in the extracellular space from necrotic cells, activated macrophages and dendritic cells. HMGB1 acts on a specific receptor, RAGE (receptor for advanced glycation endproducts), and induces prolonged inflammation, organ failure, septicaemia and death. The aim of the study was to determine the diagnostic value of plasma HMGB1 concentration and its role in the development of organ failure in patients with disseminated intravascular coagulation (DIC). Plasma HMGB-1 levels were measured in patients with suspected DIC and their relationships with DIC, organ failure and clinical outcome were determined. The study took place at the intensive care facility, Mie University School of Medicine and comprised 201 patients with suspected DIC. Plasma HMGB1 was below the detection limit in normal subjects, but moderately elevated in patients with infectious diseases (4.54 ± 8.18 ng/ml, mean±SD), malignancies (2.15 ± 5.34 ng/ml), and traumas (6.47 ± 13.13 ng/ml). DIC was associated with significantly high plasma HMGB1 (14.05 ± 12.56 ng/ml) in these patients. The highest HMGBI levels were in patients with organ failure (8.29 ± 10.99 ng/ml) and non-survivors (16.58 ± 11.01 ng/ml). HMGB1 plasma levels correlated with the DIC score and sepsis-related organ failure assessment (SOFA) score. In conclusion, our data suggest that HMGB-1 is a potentially suitable prognostic marker of OF or DIC.