bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Innate Production Capacity of Proinflammatory Cytokines Increases Risk for Death from Cancer: Results of the PROSPER Study
Authors: Trompet Stella , de Craen Anton J.M. , Mooijaart Simon , Stott David J. , Ford Ian , Sattar Naveed , Jukema Wouter , Westendorp Rudi G.J. 
Published: December 2009

AbstractPurpose: Various lines of evidence suggest that proinflammatory factors may play a role in tumor growth and metastasis, the leading cause of cancer-related mortality. However, most evidence originates from animal models, only few human studies reported an association between proinflammatory cytokines and death from cancer. Here, we investigated the association between circulating levels and innate production capacity of proinflammatory cytokines and cancer incidence and mortality in the PROspective Study on Pravastatin in the Elderly at Risk (PROSPER).Experimental Design: Circulating levels of interleukin 6 (IL-6) and C-reactive protein were measured in all 5,804 participants of the PROSPER study. The innate production capacity of IL-6, IL-1β, and tumor necrosis factor α (TNF-α) were measured in a random sample of 403 subjects.Results: We showed that high circulating inflammatory markers were associated with an increased risk for cancer incidence and death from cancer during follow-up (all P &lt; 0.05). Moreover, high innate proinflammatory cytokine production capacity is associated with an increased risk for death from cancer (all P &lt; 0.04) but not with higher cancer incidence during follow-up (all P &gt; 0.6).Conclusions: High innate production capacity of proinflammatory cytokines is associated with an increased risk for death from cancer, probably because of increased tumor growth and metastasis. Because there was no association between innate production capacity and cancer incidence, the association between circulating levels and cancer incidence at least partially reflects reversed causality. (Clin Cancer Res 2009;15(24):7744–8)
Inhibition of Functional Hyaluronan-CD44 Interactions in CD133-positive Primary Human Ovarian Carcinoma Cells by Small Hyaluronan Oligosaccharides
Authors: Slomiany Mark G. , Dai Lu , Tolliver Lauren B. , Grass G. Daniel , Zeng Yiping , Toole Bryan P. 
Published: December 2009

Abstract
Purpose: CD44 is one of the most common markers used for identification of highly tumorigenic subpopulations of human carcinoma cells, but little is known about the function of CD44 or its major ligand, hyaluronan, in these cells. The purpose of this study was to investigate the involvement of hyaluronan and its interaction with CD44 in the properties of a tumorigenic subpopulation of primary ovarian carcinoma cells.
Experimental Design: A tumorigenic subpopulation was identified in ascites fluids from ovarian carcinoma patients by expression of high CD133 levels. Treatment with small hyaluronan oligosaccharides, which dissociate constitutive hyaluronan polymer-CD44 interactions, was used to test the importance of hyaluronan-CD44 interaction in assembly of multidrug and monocarboxylate transporters and receptor tyrosine kinases in the plasma membrane of cells with high CD133 levels, and in the tumorigenic capacity of the CD133-high subpopulation.
Results: Although total CD44 levels were similar in cells with high or low CD133 expression, CD44 was present in close association with transporters, receptor tyrosine kinases, and emmprin (CD147) in the plasma membrane of cells with high CD133 levels. Treatment with small hyaluronan oligosaccharides reduced association of the transporters and receptor tyrosine kinases with CD44 in the plasma membrane, diminished drug transporter activity, and inhibited i.p. tumorigenesis in these cells.
Conclusions: We conclude that hyaluronan-CD44 interaction plays an important role in the properties of highly tumorigenic cells by stabilizing oncogenic complexes in their plasma membrane, and that treatment with hyaluronan-CD44 antagonists provides a logical therapeutic approach for abrogating the properties of these cells. (Clin Cancer Res 2009;15(24):7593–601)
Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and paclitaxel have cooperative in vivo effects against glioblastoma multiforme cells
Authors: Dorsey Jay F. , Mintz Akiva , Tian Xiaobing , Dowling Melissa L. , Plastaras John P. , Dicker David T. , Kao Gary D. , El-Deiry Wafik S. 
Published: December 2009

Abstract
Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in conjunction with microtubule-targeting agents may be a promising novel anticancer treatment strategy. In vitro studies have suggested that relatively low concentrations of TRAIL enhance the lethality of paclitaxel (Taxol) against human cancer cells. The increased efficacy may be due to the triggering of caspase activation, resulting in mitotic checkpoint abrogation and catastrophe. We show here that wild-type p53 protects cells from caspase-dependent death induced by this therapeutic combination in vitro. We have now also developed an imaging-based model system to test the in vivo efficacy of combined TRAIL and Taxol, in which tumor growth and treatment response can be monitored noninvasively and in real-time. We further utilize bioluminescence, F18-fluorodeoxyglucose-positron emission tomography, and microscale computed tomography imaging to confirm the effects of combined treatment on tumors. These studies together provide the first in vivo confirmation that combined TRAIL plus paclitaxel results in better tumor control compared with either TRAIL or paclitaxel alone, and with no discernable increased normal tissue toxicity in the mouse. Interestingly, the in vivo antitumor response elicited by combined treatment was not affected by the p53 status of the tumor cells. These preclinical observations together suggest the therapeutic potential of combining TRAIL plus paclitaxel in cancer treatment, and support further preclinical and future clinical testing. [Mol Cancer Ther 2009;8(12):3285–95]
Inhibition of Y-box binding protein-1 slows the growth of glioblastoma multiforme and sensitizes to temozolomide independent O6-methylguanine-DNA methyltransferase
Authors: Gao Yuanyuan , Fotovati Abbas , Lee Cathy , Wang Michelle , Cote Gilbert , Guns Emma , Toyota Brian , Faury Damien , Jabado Nada , Dunn Sandra E. 
Published: December 2009

Abstract
Glioblastoma multiforme (GBM) is an aggressive type of brain tumor where &lt;3% of newly diagnosed cases in the patients will survive &gt;5 years. In adults, GBM is the most common type of brain tumor. It is rarer in children, where it constitutes ∼15% of all brain tumors diagnosed. These tumors are often invasive, making surgical resection difficult. Further, they can be refractory to current therapies such as temozolomide. The current dogma is that temozolomide resistance rests on the expression of O6-methylguanine-DNA methyltransferase (MGMT) because it cleaves methylated DNA adducts formed by the drug. Our laboratory recently reported that another drug resistance gene known as the Y-box binding protein-1 (YB-1) is highly expressed in primary GBM but not in normal brain tissues based on the evaluation of primary tumors. We therefore questioned whether GBM depend on YB-1 for growth and/or response to temozolomide. Herein, we report that YB-1 inhibition reduced tumor cell invasion and growth in monolayer as well as in soft agar. Moreover, blocking this protein ultimately delayed tumor onset in mice. Importantly, inhibiting YB-1 enhanced temozolomide sensitivity in a manner that was independent of MGMT in models of adult and pediatric GBM. In conclusion, inhibiting YB-1 may be a novel way to improve the treatment of GBM. [Mol Cancer Ther 2009;8(12):3276–84]
Natural product derivative Bis(4-fluorobenzyl)trisulfide inhibits tumor growth by modification of β-tubulin at Cys 12 and suppression of microtubule dynamics
Authors: Xu Wanhong , Xi Biao , Wu Jieying , An Haoyun , Zhu Jenny , Abassi Yama , Feinstein Stuart C. , Gaylord Michelle , Geng Baoqin , Yan Huifang , Fan Weimin , Sui Meihua , Wang Xiaobo , Xu Xiao 
Published: December 2009

Abstract
Bis(4-fluorobenzyl)trisulfide (BFBTS) is a synthetic molecule derived from a bioactive natural product, dibenzyltrisulfide, found in a subtropical shrub, Petiveria allieacea. BFBTS has potent anticancer activities to a broad spectrum of tumor cell lines with IC50 values from high nanomolar to low micromolar and showed equal anticancer potency between tumor cell lines overexpressing multidrug-resistant gene, MDR1 (MCF7/adr line and KBv200 line), and their parental MCF7 line and KB lines. BFBTS inhibited microtubule polymerization dynamics in MCF7 cells, at a low nanomolar concentration of 54 nmol/L, while disrupting microtubule filaments in cells at low micromolar concentration of 1 μmol/L. Tumor cells treated with BFBTS were arrested at G2-M phase, conceivably resulting from BFBTS-mediated antimicrotubule activities. Mass spectrometry studies revealed that BFBTS bound and modified β-tubulin at residue Cys12, forming β-tubulin-SS-fluorobenzyl. The binding site differs from known antimicrotubule agents, suggesting that BFBTS functions as a novel antimicrotubule agent. BFBTS at a dose of 25 mg/kg inhibited tumor growth with relative tumor growth rates of 19.91%, 18.5%, and 23.42% in A549 lung cancer, Bcap-37 breast cancer, and SKOV3 ovarian cancer xenografts, respectively. Notably, BFBTS was more potent against MDR1-overexpressing MCF7/adr breast cancer xenografts with a relative tumor growth rate of 12.3% than paclitaxel with a rate of 43.0%. BFBTS displays a novel antimicrotubule agent with potentials for cancer therapeutics. [Mol Cancer Ther 2009;8(12):3318–30]
Abcc2 (Mrp2), Abcc3 (Mrp3), and Abcg2 (Bcrp1) are the main determinants for rapid elimination of methotrexate and its toxic metabolite 7-hydroxymethotrexate in vivo
Authors: Vlaming Maria L. H. , van Esch Anita , Pala Zeliha , Wagenaar Els , van de Wetering Koen , van Tellingen Olaf , Schinkel Alfred H. 
Published: December 2009

Abstract
The multidrug transporters ABCC2, ABCC3, and ABCG2 can eliminate potentially toxic compounds from the body and have overlapping substrate specificities. To investigate the overlapping functions of Abcc2, Abcc3, and Abcg2 in vivo, we generated and characterized Abcc3;Abcg2−/− and Abcc2;Abcc3;Abcg2−/− mice. We subsequently analyzed the relative impact of these transport proteins on the pharmacokinetics of the anticancer drug methotrexate (MTX) and its main, toxic, metabolite 7-hydroxymethotrexate (7OH-MTX) after i.v. administration of MTX (50 mg/kg). Whereas in single and double knockout mice, the plasma and liver concentrations of MTX and 7OH-MTX decreased rapidly after MTX administration, in the Abcc2;Abcc3;Abcg2−/− mice, they remained very high. One hour after administration, 67% of the MTX dose was still present in livers of Abcc2;Abcc3;Abcg2−/− mice as MTX or 7OH-MTX versus 7% in wild-type, showing dramatic liver accumulation of these toxic compounds when Abcc2, Abcc3, and Abcg2 were all absent. Furthermore, the urinary and fecal excretion of the nephrotoxic metabolite 7OH-MTX were increased 27- and 7-fold, respectively, in Abcc2;Abcc3;Abcg2−/− mice. Thus, Abcc2, Abcc3, and Abcg2 together mediate the rapid elimination of MTX and 7OH-MTX after i.v. administration and can to a large extent compensate for each other's absence. This may explain why it is still comparatively safe to use a toxic drug such as MTX in the clinic, as the risk of highly increased toxicity due to dysfunctioning of ABCC2, ABCC3, or ABCG2 alone is limited. Nevertheless, cotreatment with possible inhibitors of ABCC2, ABCC3, and ABCG2 should be done with utmost caution when treating patients with methotrexate. [Mol Cancer Ther 2009;8(12):3350–9]
Antimitotic effect of the retinoid 4-oxo-fenretinide through inhibition of tubulin polymerization: a novel mechanism of retinoid growth–inhibitory activity
Authors: Appierto Valentina , Tiberio Paola , Cavadini Elena , Casalini Patrizia , Cappelletti Graziella , Formelli Franca 
Published: December 2009

Abstract
The retinoid 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR), a metabolite of fenretinide (4-HPR) present in plasma of 4-HPR–treated patients, is very effective in inducing growth inhibition and apoptosis in several cancer cell lines. 4-Oxo-4-HPR and 4-HPR have different mechanisms of action because 4-oxo-4-HPR, unlike 4-HPR, causes marked cell accumulation in G2-M phase. Here, we investigated the molecular events involving 4-oxo-4-HPR–induced cell cycle perturbation in ovarian (A2780 and IGROV-1) and breast (T47D, estrogen receptor+ and BT-20, estrogen receptor-) cancer cells. 4-Oxo-4-HPR induced a delay of mitosis (with mitotic index increasing 5- to 6-fold in all cell lines) without progression beyond the anaphase, as shown by cyclin B1 expression. 4-Oxo-4-HPR induced multipolar spindle formation and phosphorylation of BUBR1, resulting in activation of the spindle checkpoint. Multipolar spindles were not due to impairment of pole-focusing process, loss of centrosome integrity, or modulation of the expression levels of molecules associated with spindle aberrations (Kif 1C, Kif 2A, Eg5, Tara, tankyrase-1, centractin, and TOGp). We show here that 4-oxo-4-HPR targets microtubules because, in treated cells, it interfered with the reassembly of cold-depolymerized spindle microtubules and decreased the polymerized tubulin fraction. In cell-free assays, 4-oxo-4-HPR inhibited tubulin polymerization (50% inhibition of microtubule assembly at 5.9 μmol/L), suggesting a direct molecular interaction with tubulin. In conclusion, by showing that 4-oxo-4-HPR causes mitotic arrest through antimicrotubule activities, we delineate a new molecular mechanism for a retinoid. [Mol Cancer Ther 2009;8(12):3360–8]
Tamoxifen Inhibits TRPV6 Activity via Estrogen Receptor–Independent Pathways in TRPV6-Expressing MCF-7 Breast Cancer Cells
Authors: Bolanz Katrin A. , Kovacs Gergely Gy. , Landowski Christopher P. , Hediger Matthias A. 
Published: December 2009

Abstract
The epithelial calcium channel TRPV6 is upregulated in breast carcinoma compared with normal mammary gland tissue. The selective estrogen receptor modulator tamoxifen is widely used in breast cancer therapy. Previously, we showed that tamoxifen inhibits calcium uptake in TRPV6-transfected Xenopus oocytes. In this study, we examined the effect of tamoxifen on TRPV6 function and intracellular calcium homeostasis in MCF-7 breast cancer cells transiently transfected with EYFP-C1-TRPV6. TRPV6 activity was measured with fluorescence microscopy using Fura-2. The basal calcium level was higher in transfected cells compared with nontransfected cells in calcium-containing solution but not in nominally calcium-free buffer. Basal influxes of calcium and barium were also increased. In transfected cells, 10 μmol/L tamoxifen reduced the basal intracellular calcium concentration to the basal calcium level of nontransfected cells. Tamoxifen decreased the transport rates of calcium and barium in transfected cells by 50%. This inhibitory effect was not blocked by the estrogen receptor antagonist, ICI 182,720. Similarly, a tamoxifen-induced inhibitory effect was also observed in MDA-MB-231 estrogen receptor–negative cells. The effect of tamoxifen was completely blocked by activation of protein kinase C. Inhibiting protein kinase C with calphostin C decreased TRPV6 activity but did not alter the effect of tamoxifen. These findings illustrate how tamoxifen might be effective in estrogen receptor–negative breast carcinomas and suggest that the therapeutic effect of tamoxifen and protein kinase C inhibitors used in breast cancer therapy might involve TRPV6-mediated calcium entry. This study highlights a possible role of TRPV6 as therapeutic target in breast cancer therapy. (Mol Cancer Res 2009;7(12):2000–10)
Emerging Roles of the EBF Family of Transcription Factors in Tumor Suppression
Authors: Liao Daiqing 
Published: December 2009

Abstract
Alterations in various developmental pathways are common themes in cancer. The early B-cell factors (EBF) are a family of four highly conserved DNA-binding transcription factors with an atypical zinc-finger and helix-loop-helix motif. They are involved in the differentiation and maturation of several cell lineages including B-progenitor lymphoblasts, neuronal precursors, and osteoblast progenitors. During B-cell development, EBF1 is required for the expression of Pax5, an essential factor for the production of antibody-secreting cells. Accumulating evidence indicates that genomic deletion of the EBF1 gene contributes to the pathogenesis, drug resistance, and relapse of B-progenitor acute lymphoblastic leukemia (ALL). Epigenetic silencing and genomic deletion of the EBF3 locus in chromosome 10q are very frequent in glioblastoma (GBM). Strikingly, the frequency of EBF3 loss in GBM is similar to that of the loss of Pten, a key suppressor of gliomagenesis. Cancer-specific somatic mutations were detected in EBF3 in GBM and in both EBF1 and EBF3 in pancreatic ductal adenocarcinoma. These missense mutations occur in the DNA-binding domain or the conserved IPT/TIG domain, suggesting that they might disrupt the functions of these two proteins. Functional studies revealed that EBF3 represses the expression of genes required for cell proliferation [e.g., cyclins and cyclin-dependent kinases (CDK)] and survival (e.g., Mcl-1 and Daxx) but activates those involved in cell cycle arrest (e.g., p21 and p27), leading to growth suppression and apoptosis. Therefore, EBFs represent new tumor suppressors whose inactivation blocks normal development and contributes to tumorigenesis of diverse types of human cancer. (Mol Cancer Res 2009;7(12):1893–901)
Substance Use Motives Related to Social Reinforcement among People with a History of Incarceration
Authors: Redman Dina 
Published: December 2009

• Summary: Motivational factors have been viewed as central to both the initiation and perpetuation of substance abuse. Until now, the relationship of substance use motives to previous life experiences has yet to be fully explored. This mixed methods study investigated the association between social reinforcement-type substance use motives and stressful events, as well as patterns and consequences of use among 68 men and women with a history of incarceration. • Findings: Themes coded from the respondents’ narratives yielded three principal motivational categories: social reinforcement, coping, and enhancement. Discriminant analyses revealed that social reinforcement motives were associated with drinking in greater quantities, alcohol and drug dependence, parental divorce or separation, and greater perceived stress at fathers’ and siblings’ deaths. • Applications : Social work practice implications are discussed including conducting a comprehensive motivational assessment at the inception of substance abuse treatment along with interventions focused on enhancing social support, increasing the capacity for attachment, and the utilization of role models.
Accounting for the Clients’ Troublesome Behaviour in a Supported Housing Unit
Authors: Juhila Kirsi , Hall Christopher , Raitakari Suvi 
Published: December 2009

• Summary: The article studies how professionals working in a Finnish supported housing unit explain the behaviour of clients which they define as troublesome in regard to rehabilitation expectations. The clients of the unit suffer from mental health and substance abuse problems. The research data consist of 23 meetings where clients’ progress is discussed and were analysed using accounts analysis. • Findings: There were 225 episodes where the professionals explain clients’ troublesome behaviour. Three ways of accounting appeared with similar frequency: 1) blaming clients for their behaviour, 2) excusing clients’ behaviour, 3) excusing clients and blaming others for the clients’ behaviour. Detailed analysis of the data shows how these ways of accounting are used in the meeting talk and how blame, excuses and responsibility are combined in different ways. Another important finding is that the same troublesome behaviour can be accounted for in several ways in the course of meeting conversations. • Applications : The analysis displays the complex ways in which policy imperatives and professional ethics are routinely managed in everyday situations. While concepts like self-determination and choice promote clients’ control of their care, in practice client careers are affected by locally negotiated judgements. The study of policy implementation can benefit from discourse-oriented approaches.
Explaining Social Work Practice — The CAIMeR Theory
Authors: Blom Björn , Morén Stefan 
Published: December 2009

• Summary: This article presents the CAIMeR theory, consisting of a conceptual framework and a theoretical model, which can help explain how results in social work practice arise from interventions and its contextual contingencies. The theory has been developed over several years in connection with empirical studies, and together with social workers. • Findings: The article starts from the meta-theoretical perspective critical realism and its notion of explanative knowledge as a stepping stone to open up the so-called black box. A fundamental concept in critical realism, generative mechanisms, is discussed and elaborated. • Applications : The CAIMeR theory can be used in several contexts: social work practice, and for evaluation of social work, and, moreover, for organization development in social work. We argue that social workers, evaluators and decision-makers need accurate theory about the core activity (work with clients) within its contextual conditions. The CAIMeR theory pays attention to generative mechanisms at different levels, which is necessary if one wants to understand what is going on in a certain agency, and explain the results in a more qualified way. The theory can also be useful for researchers and university students that need a comprehensive explanative framework when studying phenomena in social work practice.
Impaired clot retraction in factor XIII A subunit–deficient mice
Authors: Kasahara Kohji , Souri Masayoshi , Kaneda Mizuho , Miki Toshiaki , Yamamoto Naomasa , Ichinose Akitada 
Published: December 2009

AbstractFactor XIII (FXIII) is a plasma transglutaminase that cross-links fibrin monomers, α2-plasmin inhibitor, and so forth. Congenital FXIII deficiency causes lifelong bleeding symptoms. To understand the molecular pathology of FXIII deficiency in vivo, its knockout mice have been functionally analyzed. Because prolonged bleeding times, a sign of defective/abnormal primary hemostasis, were commonly observed in 2 separate lines of FXIII A subunit (FXIII-A) knockout mice, a possible role or roles of FXIII in platelet-related function was investigated in the present study. Although platelet aggregation induced by adenosine diphosphate or collagen was normal, clot retraction (CR) was lost in the platelet-rich plasma (PRP) of FXIII-A knockout mice. In contrast, there was no CR impairment in the PRP of tissue transglutaminase-knockout mice compared with that of wild-type mice. Furthermore, a transglutaminase inhibitor, cystamine, halted CR in the PRP of wild-type mice. These results indicate that the enzymatic activity of FXIII is necessary for CR, at least in mice.