bluuebunny/crossref_metadata_2025 huggingface dataset:
Attenuation correction of PET cardiac data with low‐dose average CT in PET/CT
Authors: Pan Tinsu , Mawlawi Osama , Luo Dershan , Liu Hui H. , Chi Pai‐chun M. , Mar Martha V. , Gladish Gregory , Truong Mylene , Erasmus Jeremy , Liao Zhongxing , Macapinlac H. A.
Published: October 2006

We proposed a low‐dose average computer tomography (ACT) for attenuation correction (AC) of the PET cardiac data in PET/CT. The ACT was obtained from a cine CT scan of over one breath cycle per couch position while the patient was free breathing. We applied this technique on four patients who underwent tumor imaging with in PET/CT, whose PET data showed high uptake of in the heart and whose CT and PET data had misregistration. All four patients did not have known myocardiac infarction or ischemia. The patients were injected with of and scanned after injection. The helical CT (HCT) data were acquired in for the coverage of . The PET acquisition was per bed of . The duration of cine CT acquisition per was . We used a fast gantry rotation cycle time of to minimize motion induced reconstruction artifacts in the cine CT images, which were averaged to become the ACT images for AC of the PET data. The radiation dose was about for cine duration. The selection of was based on our analysis of the respiratory signals of 600 patients; 87% of the patients had average breath cycles of less than and 90% had standard deviations of less than in the period of breath cycle. In all four patient studies, registrations between the CT and the PET data were improved. An increase of average uptake in the anterior and the lateral walls up to 48% and a decrease of average uptake in the septal and the inferior walls up to 16% with ACT were observed. We also compared ACT and conventional slow scan CT (SSCT) of duration in one patient study and found ACT was better than SSCT in depicting average respiratory motion and the SSCT images showed motion‐induced reconstruction artifacts. In conclusion, low‐dose ACT improved registration of the CT and the PET data in the heart region in our study of four patients. ACT was superior than SSCT for depicting average respiration motion in a patient study.
Helical tomotherapy dynamic quality assurance
Authors: Balog John , Holmes Tim , Vaden Richard
Published: October 2006

A multifaceted tomotherapy quality assurance procedure has been developed. This procedure tests most of the features inherent in the tomotherapy Hi‐Art device. This includes the megavoltage imaging quality, spatial and temporal accuracy of the dynamic delivery properties, as well as more traditional beam output characteristics. This is accomplished with a specialized multichannel electrometer that measures collected charge every and a Virtual Water cylindrical phantom that holds many ion chambers and differing density insert plugs. Both devices are offered with the Hi‐Art product. These tests are presented as well as their sensitivity to beam and delivery variations.
The costs of fatal and non-fatal falls among older adults
Authors: Stevens J A , Corso P S , Finkelstein E A , Miller T R
Published: October 2006

Objective:To estimate the incidence and direct medical costs for fatal and non-fatal fall injuries among US adults aged ⩾65 years in 2000, for three treatment settings stratified by age, sex, body region, and type of injury.

Methods:Incidence data came from the 2000 National Vital Statistics System, 2001 National Electronic Injury Surveillance System-All Injury Program, 2000 Health Care Utilization Program National Inpatient Sample, and 1999 Medical Expenditure Panel Survey. Costs for fatal falls came fromIncidence and economic burden of injuries in the United States; costs for non-fatal falls were based on claims from the 1998 and 1999 Medicare fee-for-service 5% Standard Analytical Files. A case crossover approach was used to compare the monthly costs before and after the fall.

Results:In 2000, there were almost 10 300 fatal and 2.6 million medically treated non-fatal fall related injuries. Direct medical costs totaled $0.2 billion dollars for fatal and $19 billion dollars for non-fatal injuries. Of the non-fatal injury costs, 63% ($12 billion) were for hospitalizations, 21% ($4 billion) were for emergency department visits, and 16% ($3 billion) were for treatment in outpatient settings. Medical expenditures for women, who comprised 58% of the older adult population, were 2–3 times higher than for men for all medical treatment settings. Fractures accounted for just 35% of non-fatal injuries but 61% of costs.

Conclusions:Fall related injuries among older adults, especially among older women, are associated with substantial economic costs. Implementing effective intervention strategies could appreciably decrease the incidence and healthcare costs of these injuries.
Determining objective injury prevention priorities
Authors: Wiebe D J , Nance M L , Branas C C
Published: October 2006

Background and objective:Finite injury prevention resources make the establishment of prevention priorities essential. Toward this end, the US National Trauma Data Bank (NTDB) for 2000 to 2004 was accessed and four injury prevention priority scores (one previously defined and three new scores) were computed.

Methods:An injury prevention priority score (IPPS) was calculated based on the frequency of an injury mechanism and the median injury severity score. In addition, a mortality priority score (Mort-PS), a hospital charge priority score (Charge-PS), and a years of potential life lost (YPLL-PS) priority score were calculated for the 13 most common injury mechanisms.

Results:There was variability across the four scores, but motor vehicle traffic, firearm related, and fall injuries ranked high on all four of the priority criteria. Multiple criteria should be considered when assessing injury burden.

Conclusions:The methods presented here can help prioritize injuries and support more objective public policies.
Reducing hazard related falls in people 75 years and older with significant visual impairment: how did a successful program work?
Authors: La Grow S J , Robertson M C , Campbell A J , Clarke G A , Kerse N M
Published: October 2006

Background:In a randomized controlled trial testing a home safety program designed to prevent falls in older people with severe visual impairment, it was shown that the program, delivered by an experienced occupational therapist, significantly reduced the numbers of falls both at home and away from home.

Objectives:To investigate whether the success of the home safety assessment and modification intervention in reducing falls resulted directly from modification of home hazards or from behavioral modifications, or both.

Methods:Participants were 391 community living women and men aged 75 years and older with visual acuity 6/24 meters or worse; 92% (361 of 391) completed one year of follow up. Main outcome measures were type and number of hazards and risky behavior identified in the home and garden of those receiving the home safety program, compliance with home safety recommendations reported at six months, location of all falls for all study participants during the trial, and environmental hazards associated with each fall.

Results:The numbers of falls at home related to an environmental hazard and those with no hazard involved were both reduced by the home safety program (n = 100 participants) compared with the group receiving social visits (n = 96) (incidence rate ratios = 0.40 (95% confidence interval, 0.21 to 0.74) and 0.43 (0.21 to 0.90), respectively).

Conclusions:The overall reduction in falls by the home safety program must result from some mechanism in addition to the removal or modification of hazards or provision of new equipment.
Intentional injury mortality in the European Union: how many more lives could be saved?
Authors: Stone D H , Jeffrey S , Dessypris N , Kyllekidis S , Chishti P , Papadopoulos F C , Petridou E T
Published: October 2006

Objective:To explore the scope for reducing the number of intentional injury deaths, hypothesizing that all European Union (EU) countries are able to match the experience of the country with the lowest mortality rate for intentional injuries.

Design:Intentional injury mortality data for the three last available years and denominator population estimates were obtained from the World Health Organisation mortality database for the 22 EU countries with more than one million population. To estimate the potential saving of lives, the yearly average age adjusted injury mortality rates were calculated. This issue done for children (0–14), adults (15–64), and elderly people (65 and over), both including and excluding deaths from undetermined cause.

Main outcome measures:Number of lives that might potentially be saved if all EU member states matched the lowest intentional injury rate reported by an EU member state.

Results:Over 73% of all intentional injury deaths could have been avoided if all EU countries matched the country with the lowest intentional injury mortality rate. EU member states would have suffered about 600 fewer intentional injury deaths in children, about 40 000 fewer adult deaths, and over 14 000 fewer intentional injury deaths in the elderly. This amounts to over 55 000 lives in a single year.

Conclusions:Many lives lost through injury might be saved if all countries were to achieve the lowest intentional injury mortality rates reported in the EU. How this theoretical observation might be translated into practice needs to be further explored as the international variation in intentional injury mortality rates in the EU results from a range of factors.
DC ELECTRICAL PROPERTIES OF CuO SUBSTITUTED LEAD VANADATE GLASS SYSTEM
Authors: RAMESH K. V. , SASTRY D. L.
Published: October 2006

Glasses of the system x( CuO )(50-x) PbO :50 V 2 O 5 were prepared by melt quenching in the range x=0 mol % to 15 mol%. Measurements are reported for DC electrical conductivity for the above compositions in the temperature range 300–500 K. The experimental results are analyzed with reference to various theoretical models proposed for DC electrical conduction in amorphous semiconductors. The analysis shows that at high temperatures the temperature dependence of DC conductivity is consistent with Mott's model of phonon-assisted hopping conduction, variable range hopping mechanism and Schnakenberg's model mechanism. The high-temperature thermoelectric power was satisfactorily explained by Heikes' relation and the data also showed evidence of small polaron formation in these glasses.
THE QUASI-CONFINED OPTICAL PHONONS IN WURTZITE SYMMETRY MULTIPLE QUANTUM WELLS
Authors: HUANG WEN-DENG , WEI SHU-YI , REN YA-JIE
Published: October 2006

Within the framework of the dielectric-continuum model and Loudon's uniaxial crystal model, the equation of motion for p-polarization field in wurtzite multiplayer symmetry heterostructures are solved for the quasi-confined phonon (QC) modes. The polarization eigenvector, the dispersion relation, and the electron-QC interaction Fröhlich-like Hamiltonian are derived by using the transfer-matrix method. The analytical theory and formulas can be directly applied to the single quantum well (QW) and multiple quantum wells (QWs), and superlattices (SLs). The dispersion relations and the electron-QC coupling strength are investigated for a wurtzite GaN/Al 0.15 Ga 0.85 N single QW. The results show that there are infinite branches of the dispersion curve with definite symmetry with respect to the center of the QW structure. The confinement of the quasi-confined phonons in the QW leads to a quantization of qz,j characterized by an integer m that defines the order of corresponding quasi-confined modes. The QC modes are more dispersive for decreasing m. The QC modes display an interface behavior in the barrier and a confined behavior in the well. When q⊥ is small, the symmetric modes have more contribution to electron-QC interaction than the antisymmetric modes.
Parameter estimation of feedback gain in a stochastic model of renal hemodynamics: differences between spontaneously hypertensive and Sprague-Dawley rats
Authors: Ditlevsen Susanne , Yip Kay-Pong , Marsh Donald J. , Holstein-Rathlou Niels-Henrik
Published: October 2006

Proximal tubular pressure shows periodic self-sustained oscillations in normotensive rats but highly irregular fluctuations in spontaneously hypertensive rats (SHR). Although we have suggested that the irregular fluctuations in SHR represent low-dimensional deterministic chaos in tubuloglomerular feedback (TGF), they could also arise from other mechanisms, such as intrinsic instabilities in preglomerular vessels or inputs from neighboring, coupled nephrons. To test this possibility, we applied a parameter estimation procedure to a model of TGF, where a stochastic process was added to represent mechanisms not included explicitly in the model. In its deterministic version, the model can have chaotic dynamics arising from TGF. The model introduces random fluctuations into a parameter that determines the gain of TGF. The model shows a rich variety of dynamics ranging from low-dimensional deterministic oscillations and chaos to high-dimensional random fluctuations. To fit the data from normotensive rats, the model must introduce only a small variation in the feedback gain, and its estimates of that gain agree well with experimental values. These results support the use of the deterministic model of nephron dynamics in normotensive rats. In contrast, the irregular tubular pressure fluctuations in SHR were best described by a model dominated by random parameter fluctuations. The results point to the failure of simple mathematical models of nephron dynamics adequately to describe processes that are important for the irregular tubular pressure fluctuations and the need to consider other factors, such as differences in vascular function or nephron-nephron interactions, in further work on this problem.
Angiopoietin-1 and vascular endothelial growth factor induce expression of inflammatory cytokines before angiogenesis
Authors: Aplin Alfred C. , Gelati Maurizio , Fogel Eric , Carnevale Edvige , Nicosia Roberto F.
Published: October 2006

The purpose of this study was to identify novel transcriptional events occurring in the aortic wall before angiogenesis. We used a defined tissue culture system that takes advantage of the capacity of rat aortic rings to generate neovessels ex vivo in response to angiogenic factor stimulation. Total RNA isolated from aortic rings 18 h posttreatment with angiopoietin (Ang)-1 or vascular endothelial growth factor (VEGF) was used to probe oligonucleotide microarrays. Many genes were up- or downregulated by either Ang-1 or VEGF, with a subset being affected by treatment with both growth factors. Grouping of genes by biological function revealed that Ang-1 and VEGF both upregulated a host of immune-related genes including many inflammatory cytokines. A mixture of the Ang-1- and VEGF-induced cytokines stimulated the spontaneous angiogenic response of aortic rings and was synergistic with a low dose of recombinant VEGF. This effect was associated with enhanced recruitment of adventitial macrophages and dendritic cells in the angiogenic outgrowths. Thus Ang-1 and VEGF activate the innate immune system of the vessel wall, stimulating the production of proangiogenic inflammatory cytokines before the emergence of neovessels. This hitherto unreported feature of the angiogenic response might represent an important early component of the cellular and molecular cascade responsible for the angiogenic response of the aortic wall.
The Synovial Sarcoma–Associated SS18-SSX2 Fusion Protein Induces Epigenetic Gene (De)Regulation
Authors: de Bruijn Diederik R.H. , Allander Susanne V. , van Dijk Anke H.A. , Willemse Marieke P. , Thijssen Jose , van Groningen Jan J.M. , Meltzer Paul S. , Geurts van Kessel Ad
Published: October 2006

Fusion of the SS18 and either one of the SSX genes is a hallmark of human synovial sarcoma. The SS18 and SSX genes encode nuclear proteins that exhibit opposite transcriptional activities. The SS18 protein functions as a transcriptional coactivator and is associated with the SWI/SNF complex, whereas the SSX proteins function as transcriptional corepressors and are associated with the polycomb complex. The domains involved in these opposite transcriptional activities are retained in the SS18-SSX fusion proteins. Here, we set out to determine the direct transcriptional consequences of conditional SS18-SSX2 fusion protein expression using complementary DNA microarray-based profiling. By doing so, we identified several clusters of SS18-SSX2–responsive genes, including a group of genes involved in cholesterol synthesis, which is a general characteristic of malignancy. In addition, we identified a group of SS18-SSX2–responsive genes known to be specifically deregulated in primary synovial sarcomas, including IGF2 and CD44. Furthermore, we observed an uncoupling of EGR1, JUNB, and WNT signaling in response to SS18-SSX2 expression, suggesting that the SWI/SNF-associated coactivation functions of the SS18 moiety are impaired. Finally, we found that SS18-SSX2 expression affects histone modifications in the CD44 and IGF2 promoters and DNA methylation levels in the IGF2 imprinting control region. Together, we conclude that the SS18-SSX2 fusion protein may act as a so-called transcriptional “activator-repressor,” which induces downstream target gene deregulation through epigenetic mechanisms. Our results may have implications for both the development and clinical management of synovial sarcomas. (Cancer Res 2006; 66(19): 9474-82)
In Melanoma, RAS Mutations Are Accompanied by Switching Signaling from BRAF to CRAF and Disrupted Cyclic AMP Signaling
Authors: Dumaz Nicolas , Hayward Robert , Martin Jan , Ogilvie Lesley , Hedley Douglas , Curtin John A. , Bastian Boris C. , Springer Caroline , Marais Richard
Published: October 2006

Melanocytes require the RAS/RAF/MEK/ERK and the cyclic AMP (cAMP) signaling pathways to maintain the fine balance between proliferation and differentiation. We have investigated how cross-talk between these pathways affects melanoma progression. We show that cAMP suppresses CRAF activity in melanocytes and that this is essential to suppress the oncogenic potential of CRAF in these cells. As a consequence, BRAF alone is responsible for signaling to MEK. However, when RAS is mutated in melanoma, the cells switch their signaling from BRAF to CRAF. This switch is accompanied by dysregulated cAMP signaling, a step that is necessary to allow CRAF to signal to MEK. Thus, a fundamental switch in RAF isoform usage occurs when RAS is mutated in melanoma, and this occurs in the context of disrupted cAMP signaling. These data have important implications for the development of therapeutic strategies to treat this life-threatening disease. (Cancer Res 2006; 66(19): 9483-91)
Transgenic Mice Expressing the p75 CCAAT-Displacement Protein/Cut Homeobox Isoform Develop a Myeloproliferative Disease–Like Myeloid Leukemia
Authors: Cadieux Chantal , Fournier Sylvie , Peterson Alan C. , Bédard Christian , Bedell Barry J. , Nepveu Alain
Published: October 2006

The p75 CCAAT-displacement protein/Cut homeobox (CDP/Cux) isoform was previously reported to be overexpressed in human breast cancers. To investigate its oncogenic potential, we engineered two transgenic mouse lines expressing p75 CDP/Cux under the control of the mouse mammary tumor virus-long terminal repeat. The FVB strain of mouse is generally used in the generation of mouse models for breast cancer. The transgene was introduced into the hprt locus of 129/Ola embryonic stem cells and, following germ line passage, was backcrossed onto the FVB and C57BL/6 mouse strains. Here, we describe the phenotype of p75 CDP/Cux transgenic virgin female mice of the first backcross generations. We report that after a long latency period, ∼33% of mice from two independent transgenic lines and from backcrosses into either the FVB or the C57BL/6 strains succumbed to a similar disease characterized by splenomegaly, hepatomegaly, and frequent infiltration of leukocytes into nonhematopoietic organs like the kidneys and lungs. Although an excess of B or T cells was observed in three diseased mice, in 17 other cases, histologic and flow cytometry analyses revealed the expansion of a population of neutrophils in the blood, spleen, and bone marrow. The increase in neutrophils correlated with signs of anemia and thrombocytopenia, whereas there was no indication of a reactive process. Therefore, p75 CDP/Cux transgenic mice displayed heightened susceptibility to a disease defined as a myeloproliferative disease–like myeloid leukemia. These results indicate that the overexpression of p75 CDP/Cux could alter homeostasis in the hematopoietic compartment. (Cancer Res 2006; 66(19): 9492-501)
Oxidative Stress Induces ADAM9 Protein Expression in Human Prostate Cancer Cells
Authors: Sung Shian-Ying , Kubo Hiroyuki , Shigemura Katsumi , Arnold Rebecca S. , Logani Sanjay , Wang Ruoxiang , Konaka Hiroyuki , Nakagawa Masayuki , Mousses Spiro , Amin Mahul , Anderson Cynthia , Johnstone Peter , Petros John A. , Marshall Fray F. , Zhau Haiyen E. , Chung Leland W.K.
Published: October 2006

The ADAM (a disintegrin and metalloprotease) family is a group of transmembrane proteins containing cell adhesive and proteolytic functional domains. Microarray analysis detected elevated ADAM9 during the transition of human LNCaP prostate cancer cells from an androgen-dependent to an androgen-independent and metastatic state. Using a prostate tissue array (N = 200), the levels of ADAM9 protein expression were also elevated in malignant as compared with benign prostate tissues. ADAM9 protein expression was found in 43% of benign glands with light staining and 87% of malignant glands with increasing intensity of staining. We found that ADAM9 mRNA and protein expressions were elevated on exposure of human prostate cancer cells to stress conditions such as cell crowding, hypoxia, and hydrogen peroxide. We uncovered an ADAM9-like protein, which is predominantly induced together with the ADAM9 protein by a brief exposure of prostate cancer cells to hydrogen peroxide. Induction of ADAM9 protein in LNCaP or C4-2 cells can be completely abrogated by the administration of an antioxidant, ebselen, or genetic transfer of a hydrogen peroxide degradative enzyme, catalase, suggesting that reactive oxygen species (ROS) are a common mediator. The induction of ADAM9 by stress can be inhibited by both actinomycin D and cycloheximide through increased gene transcription and protein synthesis. In conclusion, intracellular ROS and/or hydrogen peroxide, generated by cell stress, regulate ADAM9 expression. ADAM9 could be responsible for supporting prostate cancer cell survival and progression. By decreasing ADAM9 expression, we observed apoptotic cell death in prostate cancer cells. (Cancer Res 2006; 66(19): 9519-26)
HOXB7, a Homeodomain Protein, Is Overexpressed in Breast Cancer and Confers Epithelial-Mesenchymal Transition
Authors: Wu Xinyan , Chen Hexin , Parker Belinda , Rubin Ethel , Zhu Tao , Lee Ji Shin , Argani Pedram , Sukumar Saraswati
Published: October 2006

Epithelial-mesenchymal transition (EMT) is increasingly recognized as a mechanism whereby cells in primary noninvasive tumors acquire properties essential for migration and invasion. Microarray analyses of microdissected epithelial cells from bone metastasis revealed a HOXB7 overexpression that was 3-fold higher than in primary breast carcinomas and 18-fold higher compared with normal breast. This led us to investigate the role of HOXB7 in neoplastic transformation of breast cells. Expression of HOXB7 in both MCF10A and Madin-Darby canine kidney (MDCK) epithelial cells resulted in the acquisition of both phenotypic and molecular attributes typical of EMT. Loss of epithelial proteins, claudin 1 and claudin 7, mislocalization of claudin 4 and E-cadherin, and the expression of mesenchymal proteins, vimentin and α-smooth muscle actin, were observed. MDCK cells expressing HOXB7 exhibited properties of migration and invasion. Unlike MDCK vector–transfected cells, MDCK-HOXB7 cells formed highly vascularized tumors in mice. MDCK-HOXB7 cells overexpressed basic fibroblast growth factor (bFGF), had more active forms of both Ras and RhoA proteins, and displayed higher levels of phosphorylation of p44 and p42 mitogen-activated protein kinase (MAPK; extracellular signal–regulated kinases 1 and 2). Effects initiated by HOXB7 were reversed by specific inhibitors of FGF receptor and the Ras-MAPK pathways. These data provide support for a function for HOXB7 in promoting tumor invasion through activation of Ras/Rho pathway by up-regulating bFGF, a known transcriptional target of HOXB7. Reversal of these effects by HOXB7-specific siRNA further suggested that these effects were mediated by HOXB7. Thus, HOXB7 overexpression caused EMT in epithelial cells, accompanied by acquisition of aggressive properties of tumorigenicity, migration, and invasion. (Cancer Res 2006; 66(19): 9527-34)
Common Genetic Variants in Proinflammatory and Other Immunoregulatory Genes and Risk for Non-Hodgkin Lymphoma
Authors: Wang Sophia S. , Cerhan James R. , Hartge Patricia , Davis Scott , Cozen Wendy , Severson Richard K. , Chatterjee Nilanjan , Yeager Meredith , Chanock Stephen J. , Rothman Nathaniel
Published: October 2006

Profound disruption of immune function is an established risk factor for non-Hodgkin lymphoma. We report here a large-scale evaluation of common genetic variants in immune genes and their role in lymphoma. We genotyped 57 single nucleotide polymorphisms (SNP) from 36 candidate immune genes in 1,172 non-Hodgkin lymphoma cases and 982 population-based controls from a US multicenter study. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) for the association between individual SNP and haplotypes with non-Hodgkin lymphoma overall and five well-defined subtypes. A haplotype comprising SNPs in two proinflammatory cytokines, tumor necrosis factor-α and lymphotoxin-α (rs1800629, rs361525, rs1799724, rs909253, and rs2239704), increased non-Hodgkin lymphoma risk overall (OR, 1.31; 95% CI, 1.06-1.63; P = 0.01) and notably for diffuse large B cell (OR, 1.64; 95% CI, 1.23-2.19; P = 0.0007). A functional nonsynonymous SNP in the innate immune gene Fcγ receptor 2A (FCGR2A; rs1801274) was also associated with non-Hodgkin lymphoma; AG and AA genotypes were associated with a 1.26-fold (95% CI, 1.01-1.56) and 1.41-fold (95% CI, 1.10-1.81) increased risk, respectively (Ptrend = 0.006). Among non-Hodgkin lymphoma subtypes, the association with FCGR2A was pronounced for follicular and small lymphocytic lymphomas. In conclusion, common variants in genes influencing proinflammatory and innate immune responses were associated with non-Hodgkin lymphoma risk overall and their effects could vary by subtype. Our results require replication but potentially provide important clues for investigating common genetic variants as susceptibility factors and in disease outcomes, treatment responses, and immunotherapy targets. (Cancer Res 2006; 66(19): 9771-80)
Increased Fibroblast Growth Factor-Inducible 14 Expression Levels Promote Glioma Cell Invasion via Rac1 and Nuclear Factor-κB and Correlate with Poor Patient Outcome
Authors: Tran Nhan L. , McDonough Wendy S. , Savitch Benjamin A. , Fortin Shannon P. , Winkles Jeffrey A. , Symons Marc , Nakada Mitsutoshi , Cunliffe Heather E. , Hostetter Galen , Hoelzinger Dominique B. , Rennert Jessica L. , Michaelson Jennifer S. , Burkly Linda C. , Lipinski Christopher A. , Loftus Joseph C. , Mariani Luigi , Berens Michael E.
Published: October 2006

Glial tumors progress to malignant grades by heightened proliferation and relentless dispersion throughout the central nervous system. Understanding genetic and biochemical processes that foster these behaviors is likely to reveal specific and effective targets for therapeutic intervention. Our current report shows that the fibroblast growth factor-inducible 14 (Fn14), a member of the tumor necrosis factor (TNF) receptor superfamily, is expressed at high levels in migrating glioma cells in vitro and invading glioma cells in vivo. Forced Fn14 overexpression stimulates glioma cell migration and invasion, and depletion of Rac1 by small interfering RNA inhibits this cellular response. Activation of Fn14 signaling by the ligand TNF-like weak inducer of apoptosis (TWEAK) stimulates migration and up-regulates expression of Fn14; this TWEAK effect requires Rac1 and nuclear factor-κB (NF-κB) activity. The Fn14 promoter region contains NF-κB binding sites, which mediate positive feedback causing sustained overexpression of Fn14 and enduring glioma cell invasion. Furthermore, Fn14 gene expression levels increase with glioma grade and inversely correlate with patient survival. These results show that the Fn14 cascade operates as a positive feedback mechanism for elevated and sustained Fn14 expression. Such a feedback loop argues for aggressive targeting of the Fn14 axis as a unique and specific driver of glioma malignant behavior. (Cancer Res 2006; 66(19): 9535-42)
TSLC1 Is a Tumor Suppressor Gene Associated with Metastasis in Nasopharyngeal Carcinoma
Authors: Lung Hong Lok , Leung Cheung Arthur Kwok , Xie Dan , Cheng Yue , Kwong Fung Mei , Murakami Yoshinori , Guan Xin-Yuan , Sham Jonathan Shuntong , Chua Daniel , Protopopov Alexey I. , Zabarovsky Eugene R. , Tsao Sai Wah , Stanbridge Eric J. , Lung Maria Li
Published: October 2006

In up to 87% of nasopharyngeal carcinoma (NPC) clinical tumor specimens, there was either down-regulation or loss of TSLC1 gene expression. Using a tissue microarray and immunohistochemical staining, the frequency of down-regulated or loss of expression of TSLC1 in metastatic lymph node NPC was 83% and the frequency of loss of expression of TSLC1 was 35%, which was significantly higher than that in primary NPC (12%). To examine the possible growth-suppressive activity of TSLC1 in NPC, three NPC cell lines, HONE1, HNE1, and CNE2, were transfected with the wild-type TSLC1 gene cloned into the pCR3.1 expression vector; a reduction of colony formation ability was observed for all three cell lines. A tetracycline-inducible expression vector, pETE-Bsd, was also used to obtain stable transfectants of TSLC1. There was a dramatic difference between colony formation ability in the presence or absence of doxycycline when the gene is shut off or expressed, respectively, with the tetracycline-inducible system. Tumorigenicity assay results show that the activation of TSLC1 suppresses tumor formation in nude mice and functional inactivation of this gene is observed in all the tumors derived from tumorigenic transfectants. Further studies indicate that expression of TSLC1 inhibits HONE1 cell growth in vitro by arresting cells in G0-G1 phase in normal culture conditions, whereas in the absence of serum, TSLC1 induced apoptosis. These findings suggest that TSLC1 is a tumor suppressor gene in NPC, which is significantly associated with lymph node metastases. (Cancer Res 2006; 66(19): 9385-92)
Small-Molecule MDM2 Antagonists as a New Therapy Concept for Neuroblastoma
Authors: Van Maerken Tom , Speleman Frank , Vermeulen Joëlle , Lambertz Irina , De Clercq Sarah , De Smet Els , Yigit Nurten , Coppens Vicky , Philippé Jan , De Paepe Anne , Marine Jean-Christophe , Vandesompele Jo
Published: October 2006

Circumvention of the p53 tumor suppressor barrier in neuroblastoma is rarely caused by TP53 mutation but might arise from inappropriately increased activity of its principal negative regulator MDM2. We show here that targeted disruption of the p53-MDM2 interaction by the small-molecule MDM2 antagonist nutlin-3 stabilizes p53 and selectively activates the p53 pathway in neuroblastoma cells with wild-type p53, resulting in a pronounced antiproliferative and cytotoxic effect through induction of G1 cell cycle arrest and apoptosis. A nutlin-3 response was observed regardless of MYCN amplification status. Remarkably, surviving SK-N-SH cells adopted a senescence-like phenotype, whereas CLB-GA and NGP cells underwent neuronal differentiation. p53 dependence of these alternative outcomes of nutlin-3 treatment was evidenced by abrogation of the effects when p53 was knocked down by lentiviral-mediated short hairpin RNA interference. The diversity of cellular responses reveals pleiotropic mechanisms of nutlins to disable neuroblastoma cells and exemplifies the feasibility of exploiting, by a single targeted intervention, the multiplicity of anticancer activities exerted by a key tumor suppressor as p53. The observed treatment effects without the need of imposing a genotoxic burden suggest that selective MDM2 antagonists might be beneficial for treatment of neuroblastoma patients with and without MYCN amplification. (Cancer Res 2006; 66(19): 9646-55)
Activation of Aminoflavone (NSC 686288) by a Sulfotransferase Is Required for the Antiproliferative Effect of the Drug and for Induction of Histone γ-H2AX
Authors: Meng Ling-hua , Shankavaram Uma , Chen Chi , Agama Keli , Fu Hai-qing , Gonzalez Frank J. , Weinstein John , Pommier Yves
Published: October 2006

Aminoflavone (AF) is entering clinical trials. We recently reported that AF induces DNA-protein cross-links (DPC) and γ-H2AX in MCF-7 human breast cancer cells. To elucidate the mechanism of action of AF and provide biomarkers indicative of AF activity, we correlated AF activity profile (GI50) with gene expression patterns in the NCI-60 cell lines. Sulfotransferases (SULT) showed the highest positive correlation coefficients among ∼14,000 probe sets analyzed (r = 0.537, P < 0.001). Stable transfection of SULT1A1 into AF-resistant MDA-MB-231 cells sensitized these cells to AF. AF produced DPCs, γ-H2AX foci, and S-phase arrest in the SULT1A1-transfected but not in the parent MDA-MB-231 cells. Conversely, cells in which SULT1A1 was knocked down by small interfering RNA failed to induce γ-H2AX. Inhibition of SULTs and cytochrome P450 (CYP) enzymes by natural flavonoids blocked the antiproliferative activity of AF and the formation of AF-DNA adducts. AF also induces SULT1A1 and CYP expression in MCF-7 cells, suggesting the existence of an aryl hydrocarbon receptor–mediated positive feedback for AF activation by CYP and SULT1A1. Metabolism studies showed that AF can be oxidized by CYP at two amino groups to form N-hydroxyl metabolites that are substrates for bioactivation by SULTs. We propose that both N-sulfoxy-groups can be further converted to nitrenium ions that form adducts with DNA and proteins. The results reported here show the importance of SULT1A1 and CYP for AF activation and anticancer activity. They also suggest using SULT1A1 and γ-H2AX as biomarkers for prediction of AF activity during patient selection and monitoring of clinical trials. (Cancer Res 2006; 66(19): 9656-64)
Host and Direct Antitumor Effects and Profound Reduction in Tumor Metastasis with Selective EP4 Receptor Antagonism
Authors: Yang Li , Huang Yuhui , Porta Rut , Yanagisawa Kiyoshi , Gonzalez Adriana , Segi Eric , Johnson David H. , Narumiya Shuh , Carbone David P.
Published: October 2006

Prostaglandin E2 (PGE2), one of the major metabolites of cyclooxygenase-2, has been implicated in tumorigenesis and tumor progression in several human cancers, including colorectal and lung. Here, we show that one of the PGE2 receptors, the EP4 receptor, plays an important role in metastasis in both of these tumor types. Using i.v. injected Lewis lung carcinoma (3LL), we found that tumor metastasis to lung was significantly reduced when mice were treated with a specific EP4 antagonist ONO-AE3-208 or when EP4 receptor expression was knocked down in the tumor cells using RNA interference technology. Host EP4 receptors also contributed to tumor metastasis and tumor growth with decreased metastasis and tumor growth observed in EP4 receptor knockout animals. In vitro tumor cell adhesion, motility, invasion, colony formation, and Akt phosphorylation were all significantly inhibited when 3LL cells were treated with the EP4 receptor–specific antagonist. When the cells were treated with an EP4-specific agonist (AE1-734), we observed a worsening of these same features in vitro. Treatment with ONO-AE3-208 also profoundly decreased liver metastases after intrasplenic injection of MC26 colon cancer cells. Our data show that selective antagonism of EP4 receptor signaling results in a profound reduction in lung and colon cancer metastasis. Selective antagonism of the EP4 receptor may thus represent a novel therapeutic approach for the treatment of cancer and especially its propensity to metastasize. (Cancer Res 2006; 66(19): 9665-72)
The Neuromedin U-Growth Hormone Secretagogue Receptor 1b/Neurotensin Receptor 1 Oncogenic Signaling Pathway as a Therapeutic Target for Lung Cancer
Authors: Takahashi Koji , Furukawa Chiyuki , Takano Atsushi , Ishikawa Nobuhisa , Kato Tatsuya , Hayama Satoshi , Suzuki Chie , Yasui Wataru , Inai Kouki , Sone Saburo , Ito Tomoo , Nishimura Hitoshi , Tsuchiya Eiju , Nakamura Yusuke , Daigo Yataro
Published: October 2006

Using a genome-wide cDNA microarray to search for genes that were specifically up-regulated in non–small cell lung cancers (NSCLC), we identified an abundant expression of neuromedin U (NMU) in the great majority of lung cancers. Immunohistochemical analysis showed a significant association of NMU expression with poorer prognosis of patients with NSCLC. Treatment of NSCLC cells with short interfering RNA against NMU suppressed its expression and inhibited the growth of the cells; on the other hand, the induction of exogenous expression of NMU conferred growth-promoting activity and enhanced cell mobility in vitro. We found that two G protein–coupled receptors, growth hormone secretagogue receptor 1b and neurotensin receptor 1, were also overexpressed in NSCLC cells, and that a heterodimer complex of these receptors functioned as an NMU receptor. The NMU-receptor interaction subsequently induced the generation of a second messenger, cyclic AMP, to activate its downstream genes including transcription factors and cell cycle regulators. Treatment of NSCLC cells with short interfering RNAs for growth hormone secretagogue receptor or neurotensin receptor 1 suppressed the expression of those genes and the growth of NSCLC cells. These data strongly implied that targeting the NMU signaling pathway would be a promising therapeutic strategy for the treatment of lung cancers. (Cancer Res 2006; 66(19): 9408-19)
Tumor-Induced Activation of Lymphatic Endothelial Cells via Vascular Endothelial Growth Factor Receptor-2 Is Critical for Prostate Cancer Lymphatic Metastasis
Authors: Zeng Yiping , Opeskin Kenneth , Goad Jeremy , Williams Elizabeth D.
Published: October 2006

Prostate cancer disseminates initially and primarily to regional lymph nodes. However, the nature of interactions between tumor cells and lymphatic endothelial cells (LEC) is poorly understood. In the current study, we have isolated prostate LECs and developed a series of two-dimensional and three-dimensional in vitro coculture systems and in vivo orthotopic prostate cancer models to investigate the interactions of prostate cancer cells with prostate LECs. In vitro, highly lymph node metastatic prostate cancer cell lines (PC-3 and LNCaP) and their conditioned medium enhanced prostate LEC tube formation and migration, whereas poorly lymph node metastatic prostate cancer cells (DU145) or normal prostate epithelial cells (RWPE-1) or their conditioned medium had no effect. In vivo, the occurrence of lymphatic invasion and lymph node metastasis was observed in PC-3 and LNCaP xenografts but not in DU145 xenografts. Furthermore, vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 is expressed by prostate LECs, and its ligands VEGF-A, VEGF-C, and VEGF-D are up-regulated in highly lymph node metastatic prostate cancer cells. Recombinant VEGF-A and VEGF-C, but not VEGF-C156S, potently promoted prostate LEC tube formation, migration, and proliferation in vitro, indicating that signaling via VEGFR-2 rather than VEGFR-3 is involved in these responses. Consistent with this, blockade of VEGFR-2 significantly reduced tumor-induced activation of LECs. These results show that the interaction of prostate tumor cells with LECs via VEGFR-2 modulates LEC behavior and is related to the ability of tumor cells to form lymph node metastases. (Cancer Res 2006; 66(19): 9566-75)
The CXCR5 Chemokine Receptor Is Expressed by Carcinoma Cells and Promotes Growth of Colon Carcinoma in the Liver
Authors: Meijer Joost , Zeelenberg Ingrid S. , Sipos Bence , Roos Ed
Published: October 2006

The chemokine receptor CXCR5 is expressed by B cells and certain T cells and controls their migration into and within lymph nodes. Its ligand BCA-1/CXCL13 is present in lymph nodes and spleen and also in the liver. Surprisingly, we detected CXCR5 in several mouse and human carcinoma cell lines. CXCR5 was particularly prominent in pancreatic carcinoma cell lines and was also detected by immunohistochemistry in 7 of 18 human pancreatic carcinoma tissues. Expression in CT26 colon carcinoma was low in vitro, up-regulated in vivo, and rapidly lost when cells were explanted in vitro. CXCL13 strongly promoted proliferation of CXCR5-transfected CT26 cells in vitro. In the liver, after intrasplenic injection, these CXCR5 transfectants initially grew faster than controls, but the growth rate of control tumors accelerated later to become similar to the transfectants, likely due to the up-regulation of CXCR5. Inhibition of CXCR5 function, by trapping CXCR5 in the endoplasmic reticulum using a CXCL13-KDEL “intrakine,” had no effect on initial growth of liver foci but later caused a prolonged growth arrest. In contrast, s.c. and lung tumors of CXCR5- and intrakine-transfected cells grew at similar rates as controls. We conclude that expression of CXCR5 on tumor cells promotes the growth of tumor cells in the liver and, at least for CT26 cells, seems to be required for outgrowth to large liver tumors. Given the limited expression on normal cells, CXCR5 may constitute an attractive target for therapy, particularly for pancreatic carcinoma. (Cancer Res 2006; 66(19): 9576-82)
High-resolution Global Genomic Survey of 178 Gliomas Reveals Novel Regions of Copy Number Alteration and Allelic Imbalances
Authors: Kotliarov Yuri , Steed Mary Ellen , Christopher Neil , Walling Jennifer , Su Qin , Center Angela , Heiss John , Rosenblum Mark , Mikkelsen Tom , Zenklusen Jean C. , Fine Howard A.
Published: October 2006

Primary brain tumors are the fourth leading cause of cancer mortality in adults under the age of 54 years and the leading cause of cancer mortality in children in the United States. Therapy for the most common type of primary brain tumors, gliomas, remains suboptimal. The development of new and more effective treatments will likely require a better understanding of the biology of these tumors. Here, we show that use of the high-density 100K single-nucleotide polymorphism arrays in a large number of primary tumor samples allows for a much higher resolution survey of the glioma genome than has been previously reported in any tumor type. We not only confirmed alterations in genomic areas previously reported to be affected in gliomas, but we also refined the location of those sites and uncovered multiple, previously unknown regions that are affected by copy number alterations (amplifications, homozygous and heterozygous deletions) as well as allelic imbalances (loss of heterozygosity/gene conversions). The wealth of genomic data produced may allow for the development of a more rational molecular classification of gliomas and serve as an important starting point in the search for new molecular therapeutic targets. (Cancer Res 2006; 66(19): 9428-36)
Mechanism of Reoxygenation after Antiangiogenic Therapy Using SU5416 and Its Importance for Guiding Combined Antitumor Therapy
Authors: Ansiaux Réginald , Baudelet Christine , Jordan Bénédicte F. , Crokart Nathalie , Martinive Philippe , DeWever Julie , Grégoire Vincent , Feron Olivier , Gallez Bernard
Published: October 2006

Emerging preclinical studies support the concept of a transient “normalization” of tumor vasculature during the early stage of antiangiogenic treatment, with possible beneficial effects on associated radiotherapy or chemotherapy. One key issue in this area of research is to determine whether this feature is common to all antiangiogenic drugs and whether the phenomenon occurs in all types of tumors. In the present study, we characterized the evolution of the tumor oxygenation (in transplantable liver tumor and FSAII tumor models) after administration of SU5416, an antagonist of the vascular endothelial growth factor receptor. SU5416 induced an early increase in tumor oxygenation [measured by electronic paramagnetic resonance (EPR)], which did not correlate with remodeling of the tumor vasculature (assessed by CD31 labeling using immunohistochemistry) or with tumor perfusion (measured by dynamic contrast enhanced-magnetic resonance imaging). Inhibition of mitochondrial respiration (measured by EPR) was responsible for this early reoxygenation. Consistent with these unique findings in the tumor microenvironment, we found that SU5416 potentiated tumor response to radiotherapy but not to chemotherapy. In addition to the fact that the characterization of the tumor oxygenation is essential to enable correct application of combined therapies, our results show that the long-term inhibition of oxygen consumption is a potential novel target in this class of compounds. (Cancer Res 2006; 66(19): 9698-704)
Squamous Cell Carcinoma Related Oncogene/DCUN1D1 Is Highly Conserved and Activated by Amplification in Squamous Cell Carcinomas
Authors: Sarkaria Inderpal , O-charoenrat Pornchai , Talbot Simon G. , Reddy Pabbathi G. , Ngai Ivan , Maghami Ellie , Patel Kepal N. , Lee Benjamin , Yonekawa Yoshihiro , Dudas Maria , Kaufman Andrew , Ryan Russell , Ghossein Ronald , Rao Pulivarthi H. , Stoffel Archontoula , Ramanathan Y. , Singh Bhuvanesh
Published: October 2006

Chromosomal amplification at 3q is common to multiple human cancers, but has a specific predilection for squamous cell carcinomas (SCC) of mucosal origin. We identified and characterized a novel oncogene, SCC-related oncogene (SCCRO), which is amplified along the 3q26.3 region in human SCC. Amplification and overexpression of SCCRO in these tumors correlate with poor clinical outcome. The importance of SCCRO amplification in malignant transformation is established by the apoptotic response to short hairpin RNA against SCCRO, exclusively in cancer cell lines carrying SCCRO amplification. The oncogenic potential of SCCRO is underscored by its ability to transform fibroblasts (NIH-3T3 cells) in vitro and in vivo. We show that SCCRO regulates Gli1—a key regulator of the hedgehog (HH) pathway. Collectively, these data suggest that SCCRO is a novel component of the HH signaling pathway involved in the malignant transformation of squamous cell lineage. (Cancer Res 2006; 66(19): 9437-44)