bluuebunny/crossref_metadata_2025_split huggingface dataset:
Colitis-Associated Cancer Is Dependent on the Interplay between the Hemostatic and Inflammatory Systems and Supported by Integrin αMβ2 Engagement of Fibrinogen
Authors: Steinbrecher Kris A. , Horowitz Netanel A. , Blevins Elizabeth A. , Barney Kelley A. , Shaw Maureen A. , Harmel-Laws Eleana , Finkelman Fred D. , Flick Matthew J. , Pinkerton Malinda D. , Talmage Kathryn E. , Kombrinck Keith W. , Witte David P. , Palumbo Joseph S. 
Published: March 2010

Abstract
A link between colitis and colon cancer is well established, but the mechanisms regulating inflammation in this context are not fully defined. Given substantial evidence that hemostatic system components are powerful modulators of both inflammation and tumor progression, we used gene-targeted mice to directly test the hypothesis that the coagulation factor fibrinogen contributes to colitis-associated colon cancer in mice. This fundamental provisional matrix protein was found to be an important determinant of colon cancer. Fibrinogen deficiency resulted in a dramatic diminution in the number of colonic adenomas formed following azoxymethane/dextran sodium sulfate challenge. More detailed analyses in mice expressing a mutant form of fibrinogen that retains clotting function, but lacks the leukocyte integrin receptor αMβ2 binding motif (Fibγ390-396A), revealed that αMβ2-mediated engagement of fibrin(ogen) is mechanistically coupled to local inflammatory processes (e.g., interleukin-6 elaboration) and epithelial alterations that contribute to adenoma formation. Consistent with these findings, the majority of Fibγ390-396A mice developed no discernable adenomas, whereas penetrance was 100% in controls. Furthermore, the adenomas harvested from Fibγ390-396A mice were significantly smaller than those from control mice and less proliferative based on quantitative analyses of mitotic indices, suggesting an additional role for fibrin(ogen) in the growth of established adenomas. These studies show, for the first time, a unique link between fibrin(ogen) and the development of inflammation-driven malignancy. Given the importance of antecedent inflammation in the progression of numerous cancers, these studies suggest that therapies targeting fibrin(ogen)-αMβ2 interactions may be useful in preventing and/or treating this important subset of malignancies. Cancer Res; 70(7); 2634–43
Phase I Evaluation of Telatinib, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Combination with Irinotecan and Capecitabine in Patients with Advanced Solid Tumors
Authors: Langenberg Marlies H.G. , Witteveen Petronella O. , Roodhart Jeanine M. , Verheul Henk M.W. , Mergui-Roelvink Marja , van der Sar Jana , Brendel Erich , Laferriere Nicole , Schellens Jan H.M. , Voest Emile E. 
Published: March 2010

Abstract
Purpose: We studied the safety and tolerability of telatinib, an orally available, small-molecule tyrosine kinase inhibitor of the vascular endothelial growth factor receptor (VEGFR-2/VEGFR-3), platelet-derived growth factor receptor β, and c-Kit in combination with capecitabine and irinotecan.
Experimental Design: Telatinib twice daily continuously, irinotecan once every 3 weeks, and capecitabine oral twice daily on day 1 to 14 were administered in cycles of 21 days in escalating doses in successive cohorts. Toxicity was evaluated to conform to the Common Terminology Criteria for Adverse Events version 3.0. Pharmacokinetic and (circulating) endothelial (progenitor) cell measurements were done. Tumor efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors.
Results: Twenty-three patients were included in this phase I trial. Most frequently (&gt;25%) reported adverse events of any grade were vomiting, nausea, fatigue, diarrhea, alopecia, and hand-foot syndrome. A silent myocardial infarction and two cases of decreased left ventricular ejection fraction were reported; both were reversible. Cardiac monitoring of the subsequent patients did not reveal other abnormalities. The study was terminated when the recommended single agent phase II doses of telatinib (900 mg twice daily) and capecitabine/irinotecan was reached. Pharmacokinetic profiles showed no clinically relevant changes upon coadministration of the three drugs. (Circulating) endothelial (progenitor) cell levels stabilized during treatment. Five of 23 patients had partial remission and 9 of 23 patients showed stable disease.
Conclusions: Continuous administration of 900 mg telatinib twice daily can be safely combined with irinotecan (180 mg/m2) and capecitabine (1,000 mg/m2 twice daily, day 1-14) and is the recommended schedule for further phase II studies. Tumor shrinkage and disease stabilization was observed. Cardiac toxicity needs further investigation in following studies. Clin Cancer Res; 16(7); 2187–97. ©2010 AACR.
In vitro and In vivo Selective Antitumor Activity of Edelfosine against Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia Involving Lipid Rafts
Authors: Mollinedo Faustino , de la Iglesia-Vicente Janis , Gajate Consuelo , de Mendoza Ander Estella-Hermoso , Villa-Pulgarin Janny A. , de Frias Mercè , Roué Gaël , Gil Joan , Colomer Dolors , Campanero Miguel A. , Blanco-Prieto Maria J. 
Published: March 2010

Abstract
Purpose: Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) remain B-cell malignancies with limited therapeutic options. The present study investigates the in vitro and in vivo effect of the phospholipid ether edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) in MCL and CLL.
Experimental Design: Several cell lines, patient-derived tumor cells, and xenografts in severe combined immunodeficient mice were used to examine the anti-MCL and anti-CLL activity of edelfosine. Furthermore, we analyzed the mechanism of action and drug biodistribution of edelfosine in MCL and CLL tumor-bearing severe combined immunodeficient mice.
Results: Here, we have found that the phospholipid ether edelfosine was the most potent alkyl-lysophospholipid analogue in killing MCL and CLL cells, including patient-derived primary cells, while sparing normal resting lymphocytes. Alkyl-lysophospholipid analogues ranked edelfosine &gt; perifosine ≫ erucylphosphocholine ≥ miltefosine in their capacity to elicit apoptosis in MCL and CLL cells. Edelfosine induced coclustering of Fas/CD95 death receptor and rafts in MCL and CLL cells. Edelfosine was taken up by malignant cells, whereas normal resting lymphocytes hardly incorporated the drug. Raft disruption by cholesterol depletion inhibited drug uptake, Fas/CD95 clustering, and edelfosine-induced apoptosis. Edelfosine oral administration showed a potent in vivo anticancer activity in MCL and CLL xenograft mouse models, and the drug accumulated dramatically and preferentially in the tumor.
Conclusions: Our data indicate that edelfosine accumulates and kills MCL and CLL cells in a rather selective way, and set coclustering of Fas/CD95 and lipid rafts as a new framework in MCL and CLL therapy. Our data support a selective antitumor action of edelfosine. Clin Cancer Res; 16(7); 2046–54. ©2010 AACR.
The Core Circadian GeneCryptochrome 2Influences Breast Cancer Risk, Possibly by Mediating Hormone Signaling
Authors: Hoffman Aaron E. , Zheng Tongzhang , Yi Chun-Hui , Stevens Richard G. , Ba Yue , Zhang Yawei , Leaderer Derek , Holford Theodore , Hansen Johnni , Zhu Yong 
Published: March 2010

AbstractAs transcriptional regulators, circadian genes have the potential to influence a variety of biological pathways, including many cancer-related processes. Cryptochrome 2 (CRY2) is essential for proper circadian timing and is a key component of the circadian regulatory feedback loop. Here, we report findings from genetic, epigenetic, loss-of-function, and transcriptional profiling analyses of CRY2 in breast cancer. Six single-nucleotide polymorphisms in CRY2 were identified for genotyping in a case-control population (n = 441 cases and n = 479 controls), and three single-nucleotide polymorphisms (rs11038689, rs7123390, and rs1401417) were significantly associated with postmenopausal breast cancer risk, with significant effect modification by menopausal status [dominant model for rs11038689: odds ratio (OR), 0.71; 95% confidence interval (95% CI), 0.51-0.99; P for trend = 0.028; homozygous variants for rs7123390: OR, 0.44; 95% CI, 0.22-0.86; P for trend = 0.028; and rs1401417: OR, 0.44; 95% CI, 0.21-0.92; P for trend = 0.017]. Interestingly, this association was only evident in women with estrogen and progesterone receptor (ER/PR)–negative breast tumors but not with ER/PR-positive tumors. Breast cancer patients also had significantly higher levels of CRY2 promoter methylation relative to controls, which is consistent with tissue array data showing lower levels of CRY2 expression in tumor tissue relative to adjacent normal tissue. Furthermore, in vitro analyses identified several breast cancer–relevant genes that displayed altered expression following CRY2 knockdown. These findings suggest a role for CRY2 in breast tumorigenesis and provide further evidence that the circadian system may be an important modulator of hormone-related cancer susceptibility. Cancer Prev Res; 3(4); 539–48. ©2010 AACR.
5-Deoxykaempferol Plays a Potential Therapeutic Role by Targeting Multiple Signaling Pathways in Skin Cancer
Authors: Lee Kyung Mi , Lee Ki Won , Byun Sanguine , Jung Sung Keun , Seo Sang Kwon , Heo Yong-Seok , Bode Ann M. , Lee Hyong Joo , Dong Zigang 
Published: March 2010

Abstract
Nontoxic small molecules with multitargeting effects are believed to have potential in cancer prevention. Dietary phytochemicals were shown to exhibit cancer-preventive effects attributed to their antioxidant capacities. In this report, we show that the natural compound 5-deoxykaempferol (5-DK) exerts a chemopreventive effect on UVB-induced skin carcinogenesis by targeting multiple signaling molecules. 5-DK suppressed the UVB-induced expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor in mouse skin epidermal JB6 P+ cells. Moreover, 5-DK inhibited phosphorylation of MKK3/6, MKK4, and Akt, but had no effect on phosphorylation of Src, extracellular signal–regulated kinases, or ribosomal S6 kinase (RSK). However, 5-DK affected multiple targets by reducing Src, phosphoinositide 3-kinase (PI3K), and RSK2 activities. In particular, pull-down assays revealed that 5-DK specifically bound to and competed with ATP for binding with Src, PI3K, and RSK2. Exposure to 5-DK significantly suppressed UVB-induced tumorigenesis in mouse skin in a dose-dependent manner, and it inhibited the UVB-induced expression of COX-2, proliferating cell nuclear antigen, vascular endothelial growth factor, and matrix metalloproteinase-9. Our data suggest that 5-DK docks at the ATP-binding site of Src, PI3K, and RSK2. For RSK2, the ATP-binding site is located between the N- and C-lobes of the kinase domain. Taken together, our results indicate that 5-DK holds promise for the treatment of UVB-induced skin cancer by targeting Src, PI3K, and RSK2 signaling. Cancer Prev Res; 3(4); 454–65. ©2010 AACR.
Illuminating User Experience of a Website for the Relatives of Persons With Depression
Authors: Stjernswärd Sigrid , Östman Margareta 
Published: March 2010

Background: The aim of the study was to illuminate users’ experiences of a website aimed at helping relatives of persons with depression. Material: Data was collected through forum posts, a usability scale and focus groups, and was analyzed using content analysis. Discussion: The diary and forum seemed to fill different and valuable functions (i.e. think tank, exchange of stories), allowing communication with the self and others. Conclusions: The website www.sommarregn.se has the potential to work as an empowering self-help instrument online, representing a viable medium to help relatives cope. Its usability can be enhanced through further development.
Quantifying the effects of climate change and risk level on peak load design in buildings
Authors: Watkins R. , Levermore GJ 
Published: March 2010

Good building design aims to balance providing a comfortable internal environment for as much of the time as possible within a variety of constraints. An important factor is the expected weather, but in a changing climate this poses additional challenges to engineers and architects. This paper examines the effects of increased external temperature on the size of the central air conditioning and heating plant for an example building. It is found that for each 1°C rise in external temperatures, the peak cooling load increases approximately by 10%, the chiller power by 14% and fan power for distribution by 30-50%. These are relatively large increases in power needed to counteract rising external temperature and the paper considers the choice of risk level for sizing building plant. From HadRM3 data, the future frequency distribution of higher external temperatures is examined to evaluate the effects on plant size of designing to a fixed percentile of risk. Projected changes in absolute humidity are also discussed. Practical applications: Climate change is an important topic for building services engineers, resulting in the UK in the new, performance-based Building Regulations Part L. New, future weather data will also become available with different climate change scenarios. This paper examines the implications of both climate change and the risk level on the peak load for natural ventilation or air conditioning and heating that is used in the design of systems.
Generation of iPSCs from cultured human malignant cells
Authors: Carette Jan E. , Pruszak Jan , Varadarajan Malini , Blomen Vincent A. , Gokhale Sumita , Camargo Fernando D. , Wernig Marius , Jaenisch Rudolf , Brummelkamp Thijn R. 
Published: March 2010

AbstractInduced pluripotent stem cells (iPSCs) can be generated from various differentiated cell types by the expression of a set of defined transcription factors. So far, iPSCs have been generated from primary cells, but it is unclear whether human cancer cell lines can be reprogrammed. Here we describe the generation and characterization of iPSCs derived from human chronic myeloid leukemia cells. We show that, despite the presence of oncogenic mutations, these cells acquired pluripotency by the expression of 4 transcription factors and underwent differentiation into cell types derived of all 3 germ layers during teratoma formation. Interestingly, although the parental cell line was strictly dependent on continuous signaling of the BCR-ABL oncogene, also termed oncogene addiction, reprogrammed cells lost this dependency and became resistant to the BCR-ABL inhibitor imatinib. This finding indicates that the therapeutic agent imatinib targets cells in a specific epigenetic differentiated cell state, and this may contribute to its inability to fully eradicate disease in chronic myeloid leukemia patients.
Mast cells and the neurofibroma microenvironment
Authors: Staser Karl , Yang Feng-Chun , Clapp D. Wade 
Published: March 2010

Abstract
Neurofibromatosis type 1 (NF1) is the most common genetic disorder with a predisposition to malignancy and affects 1 in 3500 persons worldwide. NF1 is caused by a mutation in the NF1 tumor suppressor gene that encodes the protein neurofibromin. Patients with NF1 have cutaneous, diffuse, and plexiform neurofibromas, tumors comprised primarily of Schwann cells, blood vessels, fibroblasts, and mast cells. Studies from human and murine models that closely recapitulate human plexiform neurofibroma formation indicate that tumorigenesis necessitates NF1 loss of heterozygosity in the Schwann cell. In addition, our most recent studies with bone marrow transplantation and pharmacologic experiments implicate haploinsufficiency of Nf1 (Nf1+/−) and c-kit signaling in the hematopoietic system as required and sufficient for tumor progression. Here, we review recent studies implicating the hematopoietic system in plexiform neurofibroma genesis, delineate the physiology of stem cell factor–dependent hematopoietic cells and their contribution to the neurofibroma microenvironment, and highlight the application of this research toward the first successful, targeted medical treatment of a patient with a nonresectable and debilitating neurofibroma. Finally, we emphasize the importance of the tumor microenvironment hypothesis, asserting that tumorigenic cells in the neurofibroma do not arise and grow in isolation.
Contrasting effects of Sox17- and Sox18-sustained expression at the onset of blood specification
Authors: Serrano Alicia G. , Gandillet Arnaud , Pearson Stella , Lacaud Georges , Kouskoff Valerie 
Published: March 2010

AbstractWe have previously shown that Sox7 was transiently expressed at the onset of blood specification and was implicated in the regulation of cell survival, proliferation, and maturation of hematopoietic precursors. Here, we assessed, using embryonic stem cell differentiation as a model system, whether Sox17 and Sox18, 2 close homologs of Sox7, may act similarly to Sox7 at the onset of hematopoietic development. Sox18-enforced expression led to the enhanced proliferation of early hematopoietic precursors while blocking their maturation, phenotype highly reminiscent of Sox7-enforced expression. In striking contrast, Sox17-enforced expression dramatically increased the apoptosis of these early precursors. Similarly to Sox7, Sox18 was transiently expressed during early hematopoiesis, but its expression was predominantly observed in CD41+ cells, contrasting with Sox7, mostly expressed in Flk1+ cells. Conversely, Sox17 remained marginally expressed during blood specification. Overall, our data uncover contrasting effect and expression pattern for Sox18 and Sox17 at the onset of hematopoiesis specification.
End-of-life experience of children undergoing stem cell transplantation for malignancy: parent and provider perspectives and patterns of care
Authors: Ullrich Christina K. , Dussel Veronica , Hilden Joanne M. , Sheaffer Jan W. , Lehmann Leslie , Wolfe Joanne 
Published: March 2010

Abstract
The end-of-life (EOL) experience of children who undergo stem cell transplantation (SCT) may differ from that of other children with cancer. To evaluate perspectives and patterns of EOL care after SCT, we surveyed 141 parents of children who died of cancer (response rate, 64%) and their physicians. Chart review provided additional information. Children for whom SCT was the last cancer therapy (n = 31) were compared with those for whom it was not (n = 110). SCT parents and physicians recognized no realistic chance for cure later than non-SCT peers (both P < .001) and were more likely to have a primary goal of cure at death (parents, P < .001; physicians, P = .02). SCT children were more likely to suffer highly from their last cancer therapy and die in the intensive care unit (both P < .001), with less opportunity for EOL preparation. SCT parents who recognized no realistic chance for cure more than 7 days before death along with the physician were more likely to prepare for EOL, and if their primary goal was to reduce suffering, to achieve this (P < .001). SCT is associated with significant suffering and less opportunity to prepare for EOL. Children and families undergoing SCT may benefit from ongoing discussions regarding prognosis, goals, and opportunities to maximize quality of life.
Complementary transcriptomic, lipidomic, and targeted functional genetic analyses in cultured Drosophila cells highlight the role of glycerophospholipid metabolism in Flock House virus RNA replication
Authors: Castorena Kathryn M , Stapleford Kenneth A , Miller David J 
Published: March 2010

Abstract

Background
Cellular membranes are crucial host components utilized by positive-strand RNA viruses for replication of their genomes. Published studies have suggested that the synthesis and distribution of membrane lipids are particularly important for the assembly and function of positive-strand RNA virus replication complexes. However, the impact of specific lipid metabolism pathways in this process have not been well defined, nor have potential changes in lipid expression associated with positive-strand RNA virus replication been examined in detail.

Results
In this study we used parallel and complementary global and targeted approaches to examine the impact of lipid metabolism on the replication of the well-studied model alphanodavirus Flock House virus (FHV). We found that FHV RNA replication in cultured Drosophila S2 cells stimulated the transcriptional upregulation of several lipid metabolism genes, and was also associated with increased phosphatidylcholine accumulation with preferential increases in lipid molecules with longer and unsaturated acyl chains. Furthermore, targeted RNA interference-mediated downregulation of candidate glycerophospholipid metabolism genes revealed a functional role of several genes in virus replication. In particular, we found that downregulation of Cct1 or Cct2, which encode essential enzymes for phosphatidylcholine biosynthesis, suppressed FHV RNA replication.

Conclusion
These results indicate that glycerophospholipid metabolism, and in particular phosphatidylcholine biosynthesis, plays an important role in FHV RNA replication. Furthermore, they provide a framework in which to further explore the impact of specific steps in lipid metabolism on FHV replication, and potentially identify novel cellular targets for the development of drugs to inhibit positive-strand RNA viruses.
Functional analysis of B and C class floral organ genes in spinach demonstrates their role in sexual dimorphism
Authors: Sather D Noah , Jovanovic Maja , Golenberg Edward M 
Published: March 2010

Abstract

Background
Evolution of unisexual flowers entails one of the most extreme changes in plant development. Cultivated spinach, Spinacia oleracea L., is uniquely suited for the study of unisexual flower development as it is dioecious and it achieves unisexually by the absence of organ development, rather than by organ abortion or suppression. Male staminate flowers lack fourth whorl primordia and female pistillate flowers lack third whorl primordia. Based on theoretical considerations, early inflorescence or floral organ identity genes would likely be directly involved in sex-determination in those species in which organ initiation rather than organ maturation is regulated. In this study, we tested the hypothesis that sexual dimorphism occurs through the regulation of B class floral organ gene expression by experimentally knocking down gene expression by viral induced gene silencing.

Results
Suppression of B class genes in spinach resulted in the expected homeotic transformation of stamens into carpels but also affected the number of perianth parts and the presence of fourth whorl. Phenotypically normal female flowers developed on SpPI-silenced male plants. Suppression of the spinach C class floral organ identity gene, SpAG, resulted in loss of reproductive organ identity, and indeterminate flowers, but did not result in additional sex-specific characteristics or structures. Analysis of the genomic sequences of both SpAP3 and SpPI did not reveal any allelic differences between males and females.

Conclusion
Sexual dimorphism in spinach is not the result of homeotic transformation of established organs, but rather is the result of differential initiation and development of the third and fourth whorl primordia. SpAG is inferred to have organ identity and meristem termination functions similar to other angiosperm C class genes. In contrast, while SpPI and SpAP3 resemble other angiosperms in their essential functions in establishing stamen identity, they also appear to have an additional function in regulating organ number and identity outside of the third whorl. We present a model for the evolution of dioecy in spinach based on the regulation of B class expression.