bluuebunny/crossref_metadata_2025_split huggingface dataset:
Direct Ex Vivo Analyses of HLA-DR1 Transgenic Mice Reveal an Exceptionally Broad Pattern of Immunodominance in the Primary HLA-DR1-Restricted CD4 T-Cell Response to Influenza Virus Hemagglutinin
Authors: Richards Katherine A. , Chaves Francisco A. , Krafcik Frederick R. , Topham David J. , Lazarski Christopher A. , Sant Andrea J. 
Published: May 2007

ABSTRACTThe recent threat of an avian influenza pandemic has generated significant interest in enhancing our understanding of the events that dictate protective immunity to influenza and in generating vaccines that can induce heterosubtypic immunity. Although antigen-specific CD4 T cells are known to play a key role in protective immunity to influenza through the provision of help to B cells and CD8 T cells, little is known about the specificity and diversity of CD4 T cells elicited after infection, particularly those elicited in humans. In this study, we used HLA-DR transgenic mice to directly and comprehensively identify the specificities of hemagglutinin (HA)-specific CD4 T cells restricted to a human class II molecule that were elicited following intranasal infection with a strain of influenza virus that has been endemic in U.S. human populations for the last decade. Our results reveal a surprising degree of diversity among influenza virus-specific CD4 T cells. As many as 30 different peptides, spanning the entire HA protein, were recognized by CD4 T cells, including epitopes genetically conserved among H1, H2, and H5 influenza A viruses. We also compared three widely used major histocompatibility class II algorithms to predict HLA-DR binding peptides and found these as yet inadequate for identifying influenza virus-derived epitopes. The results of these studies offer key insights into the spectrum of peptides recognized by HLA-DR-restricted CD4 T cells that may be the focus of immune responses to infection or to experimental or clinical vaccines in humans.
Medical report from the 2006 FIFA World Cup Germany
Authors: Dvorak Jiri , Junge Astrid , Grimm Katharina , Kirkendall Donald 
Published: May 2007

Objective:To continue the injury surveillance of FIFA-sponsored football tournaments and report on other medical aspects of the 2006 FIFA World Cup.Design:Prospective epidemiological injury surveillance and descriptive summary of additional medical aspects.Setting:Major international football tournament.Participants:National team players, doctors and referees at the 2006 FIFA World Cup Germany.Main outcome measures:Injury type, location and rate.Results:145 injuries were reported for the 64 matches of the 2006 FIFA World Cup Germany—an overall injury rate of 68.7 per 1000 match hours (95% CI 57.5 to 79.9) or 2.3 injuries per match, in comparison with 2.7 injuries per match in the 2002 FIFA World Cup (p = NS). Physical examinations before participation uncovered no hidden cardiovascular problems. Once the tournament started, no referees were unable to complete their duties. There were no positive doping tests.Conclusions:The injury rate for this World Cup was below that of 2002, but consistent with the overall injury rate per match since data collection began in 1998. There continues to be no evidence of systematic doping in international football.
Career-ending injuries to professional jockeys in British horse racing (1991–2005)
Authors: Balendra G , Turner M , McCrory P 
Published: May 2007

Background:It has been previously shown that professional jump and flat racing jockeys suffer a high incidence of injury as a consequence of their profession. This paper specifically examines career-ending injuries to professional jockeys in Great Britain.Aims:To investigate career-ending injuries in professional jockeys.Method:Analysis of prospectively collected injury database on professional jockeys.Results:The majority of injuries in this study occurred to the head, shoulder or torso. Fractures were the most common type of injury that led to a decision to end a career, followed by neurological injury to the head and/or spine.Conclusion:Injuries to the head are the most common career-ending injuries, and consideration of injury counter measures could be an important strategy in equestrian sports.
No difference in insulin sensitivity between healthy postmenopausal women with or without sarcopenia: a pilot study
Authors: Goulet Eric D.B. , Lord Christine , Chaput Jean-Philippe , Aubertin-Leheudre Mylène , Brochu Martin , Dionne Isabelle J. 
Published: May 2007

Insulin plays a pivotal role in skeletal muscle protein metabolism and its action decreases with age. A loss of muscle mass, termed sarcopenia, also occurs with age. The age-associated decline in insulin sensitivity (IS) may negatively alter muscle protein metabolism and, therefore, be implicated in the aetiology of sarcopenia. However, no studies have yet compared the level of IS between older individuals with or without sarcopenia. Thus, in this study, we compared the IS of 20 class I sarcopenics (CIS), 8 class II sarcopeniscs (CIIS), and 16 non-sarcopenics (NS), among a group of otherwise healthy, non-obese, postmenopausal women. IS was estimated with the quantitative IS check index (QUICKI). Muscle mass index (MMI), which was used to determine sarcopenia, was calculated as follows: (appendicular muscle mass × 1.19) – 1.01/h2, where h = height. Fat-free mass (FFM), fat mass (FM), and trunk FM (TFM) were measured by dual-energy X-ray absorptiometry. Accelerometry and indirect calorimetry were used to estimate resting (REE), daily (DEE), and physical activity (PAEE) energy expenditure. A 3 d food record was used to determine total energy, protein (animal and vegetal), and carbohydrate intakes. As expected, MMI and FFM differed significantly among groups. However, no significant differences were found among groups for IS, FM, TFM, REE, DEE, PAEE, or total energy, protein (both animal and vegetable), and carbohydrate intakes. Using QUICKI, a surrogate measure of IS, the present results suggest that the action of insulin does not play an important role in the development and maintenance of sarcopenia in healthy, non-obese, postmenopausal women.
Epidemiological studies of exercise in diabetes prevention
Authors: Hu Gang , Lakka Timo A. , Kilpeläinen Tuomas O. , Tuomilehto Jaakko 
Published: May 2007

Type 2 diabetes is one of the fastest growing public health problems in both developed and developing countries. It is estimated that the number of people with diabetes in the world will double in coming years, from 171 million in 2000 to 366 million in 2030. Cardiovascular disease accounts for more than 70% of total mortality among patients with type 2 diabetes. The associations of physical activity, physical fitness, and changes in the lifestyle with the risk of type 2 diabetes have been assessed by a number of prospective studies and clinical trials in the past decade. Several studies have also evaluated the joint associations of physical activity, body mass index, and glucose levels with the risk of type 2 diabetes. Prospective studies and clinical trials have shown that moderate or high levels of physical activity or physical fitness and changes in the lifestyle (dietary modification and increase in physical activity) can prevent type 2 diabetes. Our review of the scientific evidence confirms that 30 min/d of moderate- or high-level physical activity is an effective and safe way to prevent type 2 diabetes in all populations.
Tumor Angiogenesis Promoted by Ex vivo Differentiated Endothelial Progenitor Cells Is Effectively Inhibited by an Angiogenesis Inhibitor, TK1-2
Authors: Oh Ho-Kyun , Ha Jung-Min , O Eunju , Lee Byung Hun , Lee Suk Keun , Shim Byoung-Shik , Hong Yong-Kil , Joe Young Ae 
Published: May 2007

Abstract
Neovascularization plays a critical role in the growth and metastatic spread of tumors and involves recruitment of circulating endothelial progenitor cells (EPC) from bone marrow as well as sprouting of preexisting endothelial cells. In this study, we examined if EPCs could promote tumor angiogenesis and would be an effective cellular target for an angiogenesis inhibitor, the recombinant kringle domain of tissue-type plasminogen activator (TK1-2). When TK1-2 was applied in the ex vivo culture of EPCs isolated from human cord blood, TK1-2 inhibited adhesive differentiation of mononuclear EPCs into endothelial-like cells. In addition, it inhibited the migration of ex vivo cultivated EPCs and also inhibited their adhesion to fibronectin matrix or endothelial cell monolayer. When A549 cancer cells were coimplanted along with ex vivo cultivated EPCs s.c. in nude mice, the tumor growth was increased. However, the tumor growth and the vascular density of tumor tissues increased by coimplanted EPCs were decreased upon TK1-2 treatment. Accordingly, TK1-2 treatment reduced the remaining number of EPCs in tumor tissues and their incorporation into the host vascular channels. In addition, overall expression levels of vascular endothelial growth factor (VEGF) and von Willebrand factor in tumor tissues were decreased upon TK1-2 treatment. Interestingly, strong VEGF expression by implanted EPCs was decreased by TK1-2. Finally, we confirmed in vitro that TK1-2 inhibited VEGF secretion of EPCs. TK1-2 also inhibited endothelial cell proliferation and migration induced by the conditioned medium of EPCs. Therefore, we concluded that EPCs, as well as mature endothelial cells, could be an important target of TK1-2. [Cancer Res 2007;67(10):4851–9]
Copper-Transporting P-Type ATPase, ATP7A, Confers Multidrug Resistance and Its Expression Is Related to Resistance to SN-38 in Clinical Colon Cancer
Authors: Owatari Satsuki , Akune Satoshi , Komatsu Masaharu , Ikeda Ryuji , Firth Stephen D. , Che Xiao-Fang , Yamamoto Masatatsu , Tsujikawa Kazutake , Kitazono Masaki , Ishizawa Takashi , Takeuchi Toru , Aikou Takashi , Mercer Julian F.B. , Akiyama Shin-ichi , Furukawa Tatsuhiko 
Published: May 2007

AbstractWe and others have shown that the copper transporters ATP7A and ATP7B play a role in cellular resistance to cis-diaminedichloroplatinum (II) (CDDP). In this study, we found that ATP7A transfection of Chinese hamster ovary cells (CHO-K1) and fibroblasts isolated from Menkes disease patients enhanced resistance not only to CDDP but also to various anticancer drugs, such as vincristine, paclitaxel, 7-ethyl-10-hydroxy-camptothecin (SN-38), etoposide, doxorubicin, mitoxantron, and 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11). ATP7A preferentially localized doxorubicin fluorescence to the Golgi apparatus in contrast to the more intense nuclear staining of doxorubicin in the parental cells. Brefeldin A partially and monensin completely altered the distribution of doxorubicin to the nuclei in the ATP7A-expressing cells. ATP7A expression also enhanced the efflux rates of doxorubicin and SN-38 from cells and increased the uptake of SN-38 in membrane vesicles. These findings strongly suggested that ATP7A confers multidrug resistance to the cells by compartmentalizing drugs in the Golgi apparatus and by enhancing efflux of these drugs, and the trans-Golgi network has an important role of ATP7A-related drug resistance. ATP7A was expressed in 8 of 34 (23.5%) clinical colon cancer specimens but not in the adjacent normal epithelium. Using the histoculture drug response assay that is useful for the prediction of drug sensitivity of clinical cancers, ATP7A-expressing colon cancer cells were significantly more resistant to SN-38 than ATP7A-negative cells. Thus, ATP7A confers resistance to various anticancer agents on cancer cells and might be a good index of drug resistance in clinical colon cancers. [Cancer Res 2007;67(10):4860–7]
HMGA1 Controls Transcription of Insulin Receptor to Regulate Cyclin D1 Translation in Pancreatic Cancer Cells
Authors: Kolb Sebastian , Fritsch Ralph , Saur Dieter , Reichert Maximilian , Schmid Roland M. , Schneider Günter 
Published: May 2007

Abstract
The HMGA1 proteins act as architectural transcription factors and are involved in the regulation of genes important in the process of carcinogenesis. Although HMGA1 proteins are overexpressed in most types of cancer, signaling circuits regulated by HMGA1 are not clarified in detail. In this study, we show that HMGA1 proteins promote proliferation of pancreatic cancer cells by accelerating G1 phase progression. Transfection of HMGA1-specific small interfering RNA (siRNA) activates the RB-dependent G1-phase checkpoint due to the impaired expression of cyclin D1. Down-regulation of cyclin D1 after the HMGA1 knockdown is due to translational control and involves the repressor of the eukaryotic translation initiation factor 4E (eIF4E) 4E-BP1. We show that 4E-BP1 and cyclin D1 act downstream of the insulin receptor (IR) in pancreatic cancer cells. At the molecular level transcription of the IR is controlled by a CAAT/enhancer binding protein β (C/EBPβ)/HMGA1 complex. Together, this work defines a novel pathway regulated by HMGA1, which contributes to the proliferation of pancreatic cancer cells. [Cancer Res 2007;67(10):1–8]
Intraprostatic Androgens and Androgen-Regulated Gene Expression Persist after Testosterone Suppression: Therapeutic Implications for Castration-Resistant Prostate Cancer
Authors: Mostaghel Elahe A. , Page Stephanie T. , Lin Daniel W. , Fazli Ladan , Coleman Ilsa M. , True Lawrence D. , Knudsen Beatrice , Hess David L. , Nelson Colleen C. , Matsumoto Alvin M. , Bremner William J. , Gleave Martin E. , Nelson Peter S. 
Published: May 2007

AbstractAndrogen deprivation therapy (ADT) remains the primary treatment for advanced prostate cancer. The efficacy of ADT has not been rigorously evaluated by demonstrating suppression of prostatic androgen activity at the target tissue and molecular level. We determined the efficacy and consistency of medical castration in suppressing prostatic androgen levels and androgen-regulated gene expression. Androgen levels and androgen-regulated gene expression (by microarray profiling, quantitative reverse transcription-PCR, and immunohistochemistry) were measured in prostate samples from a clinical trial of short-term castration (1 month) using the gonadotropin-releasing hormone antagonist, Acyline, versus placebo in healthy men. To assess the effects of long-term ADT, gene expression measurements were evaluated at baseline and after 3, 6, and 9 months of neoadjuvant ADT in prostatectomy samples from men with localized prostate cancer. Medical castration reduced tissue androgens by 75% and reduced the expression of several androgen-regulated genes (NDRG1, FKBP5, and TMPRSS2). However, many androgen-responsive genes, including the androgen receptor (AR) and prostate-specific antigen (PSA), were not suppressed after short-term castration or after 9 months of neoadjuvant ADT. Significant heterogeneity in PSA and AR protein expression was observed in prostate cancer samples at each time point of ADT. Medical castration based on serum testosterone levels cannot be equated with androgen ablation in the prostate microenvironment. Standard androgen deprivation does not consistently suppress androgen-dependent gene expression. Suboptimal suppression of tumoral androgen activity may lead to adaptive cellular changes allowing prostate cancer cell survival in a low androgen environment. Optimal clinical efficacy will require testing of novel approaches targeting complete suppression of systemic and intracrine contributions to the prostatic androgen microenvironment. [Cancer Res 2007;67(10):5033–41]
Side Population in Human Lung Cancer Cell Lines and Tumors Is Enriched with Stem-like Cancer Cells
Authors: Ho Maria M. , Ng Alvin V. , Lam Stephen , Hung Jaclyn Y. 
Published: May 2007

Abstract
Stem cells have been isolated by their ability to efflux Hoechst 33342 dye and are referred to as the “side population” (SP). In this study, we used flow cytometry and Hoechst 33342 dye efflux assay to isolate and characterize SP cells from six human lung cancer cell lines (H460, H23, HTB-58, A549, H441, and H2170). Nonobese diabetic/severe combined immunodeficiency xenograft experiments showed that SP cells were enriched in tumor-initiating capability compared with non-SP cells. Matrigel invasion assay showed that SP cells also have higher potential for invasiveness. Further characterization of this SP phenotype revealed several stem cell properties. We found evidence for repopulating ability by SP to regenerate a population resembling the original population. SP displayed elevated expression of ABCG2 as well as other ATP-binding cassette transporters and showed resistance to multiple chemotherapeutic drugs. Human telomerase reverse transcriptase expression was higher in the SP, suggesting that this fraction may represent a reservoir with unlimited proliferative potential for generating cancer cells. mRNA levels of minichromosome maintenance (MCM) 7, a member of the MCM family of proteins critical to the DNA replication complex, were lower in SP cells, suggesting that a majority of the SP fraction was in the G0 quiescent state. Sixteen clinical lung cancer samples also displayed a smaller but persistent SP population. These findings indicate that SP is an enriched source of lung tumor–initiating cells with stem cell properties and may be an important target for effective therapy and a useful tool to investigate the tumorigenic process. [Cancer Res 2007;67(10):4827–33]
Faithful Companions: A Proposal for Neurooncology Trials in Pet Dogs
Authors: Kimmelman Jonathan , Nalbantoglu Josephine 
Published: May 2007

Abstract
Although relatively rare, malignant glioma (MG) is frequently used for testing novel cancer treatments. However, human MG trials have often been initiated on the basis of preclinical models that involve numerous discontinuities with the human disease. Below, we discuss various limitations of the mainstay model used in MG preclinical research, the murine orthotopic xenograft. After discussing alternative model systems like transgenic mouse models and canine xenografts, we argue that companion animals with spontaneous brain cancers offer a scientifically and ethically attractive system for preclinical testing of novel MG interventions. Ethical advantages and practical challenges of companion animal brain cancer trials are briefly discussed. [Cancer Res 2007;67(10):4541–4]
Chimeric NKG2D Receptor–Bearing T Cells as Immunotherapy for Ovarian Cancer
Authors: Barber Amorette , Zhang Tong , DeMars Leslie R. , Conejo-Garcia Jose , Roby Katherine F. , Sentman Charles L. 
Published: May 2007

Abstract
Despite advancements in the treatment of ovarian cancer, this disease continues to be a leading cause of cancer death in women. Adoptive transfer of tumor-reactive T cells is a promising antitumor therapy for many cancers. We designed a chimeric receptor linking NKG2D, a natural killer (NK) cell–activating receptor, to the CD3ζ chain of the T-cell receptor to target ovarian tumor cells. Engagement of chimeric NKG2D receptors (chNKG2D) with ligands for NKG2D, which are commonly expressed on tumor cells, leads to T-cell secretion of proinflammatory cytokines and tumor cytotoxicity. In this study, we show that &gt;80% of primary human ovarian cancer samples expressed ligands for NKG2D on the cell surface. The tumor samples expressed MHC class I–related protein A, MICB, and UL-16 binding proteins 1 and 3. ChNKG2D-expressing T cells lysed ovarian cancer cell lines. We show that T cells from ovarian cancer patients that express chNKG2D secreted proinflammatory cytokines when cultured with autologous tumor cells. In addition, we show that chNKG2D T cells can be used therapeutically in a murine model of ovarian cancer. These data indicate that treatment with chNKG2D-expressing T cells is a potential immunotherapy for ovarian cancer. [Cancer Res 2007;67(10):5003–8]
The Proteasome Inhibitor PS-341 (Bortezomib) Up-Regulates DR5 Expression Leading to Induction of Apoptosis and Enhancement of TRAIL-Induced Apoptosis Despite Up-Regulation of c-FLIP and Survivin Expression in Human NSCLC Cells
Authors: Liu Xiangguo , Yue Ping , Chen Shuzhen , Hu Liping , Lonial Sagar , Khuri Fadlo R. , Sun Shi-Yong 
Published: May 2007

Abstract
The proteasome inhibitor PS-341 (bortezomib or Velcade), an approved drug for treatment of patients with multiple myeloma, is currently being tested in clinical trials against various malignancies, including lung cancer. Preclinical studies have shown that PS-341 induces apoptosis and enhances tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–induced apoptosis in human cancer cells with undefined mechanisms. In the present study, we show that PS-341 induced caspase-8–dependent apoptosis, cooperated with TRAIL to induce apoptosis, and up-regulated death receptor 5 (DR5) expression in human non–small cell lung cancer (NSCLC) cells. DR5 induction correlated with the ability of PS-341 to induce apoptosis. Blockage of PS-341–induced DR5 up-regulation using DR5 small interfering RNA (siRNA) rendered cells less sensitive to apoptosis induced by either PS-341 or its combination with TRAIL, indicating that DR5 up-regulation mediates PS-341–induced apoptosis and enhancement of TRAIL-induced apoptosis in human NSCLC cells. We exclude the involvement of c-FLIP and survivin in mediating these events because c-FLIP (i.e., FLIPS) and survivin protein levels were actually elevated on exposure to PS-341. Reduction of c-FLIP with c-FLIP siRNA sensitized cells to PS-341–induced apoptosis, suggesting that c-FLIP elevation protects cells from PS-341–induced apoptosis. Thus, the present study highlights the important role of DR5 up-regulation in PS-341–induced apoptosis and enhancement of TRAIL-induced apoptosis in human NSCLC cells. [Cancer Res 2007;67(10):4981–8]
Nucleophosmin Mediates Mammalian Target of Rapamycin–Dependent Actin Cytoskeleton Dynamics and Proliferation in Neurofibromin-Deficient Astrocytes
Authors: Sandsmark Danielle K. , Zhang Huabiao , Hegedus Balazs , Pelletier Corey L. , Weber Jason D. , Gutmann David H. 
Published: May 2007

Abstract
Neurofibromatosis type 1 (NF1) is a common autosomal dominant tumor predisposition syndrome in which affected individuals develop astrocytic brain tumors (gliomas). To determine how the NF1 gene product (neurofibromin) regulates astrocyte growth and motility relevant to glioma formation, we have used Nf1-deficient primary murine astrocytes. Nf1−/− astrocytes exhibit increased protein translation and cell proliferation, which are mediated by Ras-dependent hyperactivation of the mammalian target of rapamycin (mTOR) protein, a serine/threonine protein kinase that regulates ribosomal biogenesis, protein translation, actin cytoskeleton dynamics, and cell proliferation. In this study, we show that Nf1-deficient astrocytes have fewer actin stress fibers and exhibit increased cell motility compared with wild-type astrocytes, which are rescued by pharmacologic and genetic mTOR inhibition. We further show that mTOR-dependent regulation of actin stress fiber formation, motility, and proliferation requires rapamycin-sensitive activation of the Rac1 GTPase but not elongation factor 4E-binding protein 1/S6 kinase. Nf1−/− astrocytes also exhibit increased protein translation and ribosomal biogenesis through increased expression of the nucleophosmin (NPM) nuclear-cytoplasmic shuttling protein. We found that NPM expression in Nf1−/− astrocytes was blocked by rapamycin in vitro and in vivo and that expression of a dominant-negative NPM mutant protein in Nf1−/− astrocytes rescued actin stress fiber formation and restored cell motility and proliferation to wild-type levels. Together, these data show that neurofibromin regulates actin cytoskeleton dynamics and cell proliferation through a mTOR/Rac1-dependent signaling pathway and identify NPM as a critical mTOR effector mediating these biological properties in Nf1-deficient astrocytes. [Cancer Res 2007;67(10):4790–9]