bluuebunny/crossref_metadata_2025 huggingface dataset:
Macrophage Migration Inhibitory Factor: A Multifunctional Cytokine in Rheumatic Diseases
Authors: Kasama Tsuyoshi , Ohtsuka Kumiko , Sato Michihito , Takahashi Ryo , Wakabayashi Kuninobu , Kobayashi Kazuo
Published: January 2011

Macrophage migration inhibitory factor (MIF) was originally identified in the culture medium of activated T lymphocytes as a soluble factor that inhibited the random migration of macrophages. MIF is now recognized to be a multipotent cytokine involved in the regulation of immune and inflammatory responses. Moreover, the pivotal nature of its involvement highlights the importance of MIF to the pathogenesis of various inflammatory disorders and suggests that blocking MIF may be a useful therapeutic strategy for treating these diseases. This paper discusses the function and expressional regulation of MIF in several rheumatic diseases and related conditions.
Existence of Solution and Positive Solution for a Nonlinear Third-Order "Equation missing" -Point BVP
Authors: Sun Jian-Ping , Jin Fan-Xia
Published: January 2011

In this paper, we are concerned with the following nonlinear third-order "Equation missing"-point boundary value problem: "Equation missing", "Equation missing", "Equation missing", "Equation missing", "Equation missing". Some existence criteria of solution and positive solution are established by using the Schauder fixed point theorem. An example is also included to illustrate the importance of the results obtained.
High Temperature Resonant Ultrasound Spectroscopy: A Review
Authors: Li G. , Gladden J. R.
Published: January 2011

The measurement of elastic constants plays an important role in condensed matter physics and materials characterization. This paper presents the resonant ultrasound spectroscopy (RUS) method for the determination of elastic constants in a single crystal or amorphous solid. In RUS, the measured resonance spectrum of a properly prepared sample and other information such as geometry, density, and initial estimated elastic constants are used to determine the elastic constants of the material. We briefly present the theoretical background and applications to specific materials; however, the focus of this review is on the technical applications of RUS, especially those for high-temperature measurements.
Immunotherapy for Renal Cell Carcinoma
Authors: Itsumi Momoe , Tatsugami Katsunori
Published: January 2011

Immunotherapy plays a significant role in the management of renal cell carcinoma (RCC) patients with metastatic disease because RCC is highly resistant to both chemotherapy and radiation therapy. Many reports illustrate various approaches to the treatment of RCC, such as cytokine‐, antigen‐ or dendritic cell‐ (DC‐) based immunotherapy, and the safety and effectiveness of immunotherapy have been highlighted by multiple clinical trials. Although antitumor immune responses and clinically significant outcomes have been achieved in these trials, the response rate is still low, and very few patients show long‐term clinical improvement. Recently, the importance of immune regulation by antigen‐presenting cells (APC) and regulatory T cells (Treg cells) has also been discussed. The authors outline the principles of cell‐mediated tumor immunotherapy and discuss clinical trials of immunotherapy for RCC.
Measures of Noncircularity and Fixed Points of Contractive Multifunctions
Authors: Marrero Isabel
Published: January 2011

In analogy to the Eisenfeld-Lakshmikantham measure of nonconvexity and the Hausdorff measure of noncompactness, we introduce two mutually equivalent measures of noncircularity for Banach spaces satisfying a Cantor type property, and apply them to establish a fixed point theorem of Darbo type for multifunctions. Namely, we prove that every multifunction with closed values, defined on a closed set and contractive with respect to any one of these measures, has the origin as a fixed point.
Intravenous Sphingosylphosphorylcholine Protects Ischemic and Postischemic Myocardial Tissue in a Mouse Model of Myocardial Ischemia/Reperfusion Injury
Authors: Herzog Christine , Schmitz Martina , Levkau Bodo , Herrgott Ilka , Mersmann Jan , Larmann Jan , Johanning Kai , Winterhalter Michael , Chun Jerold , Müller Frank Ulrich , Echtermeyer Frank , Hildebrand Reinhard , Theilmeier Gregor
Published: January 2011

HDL, through sphingosine-1-phosphate (S1P), exerts direct cardioprotective effects on ischemic myocardium. It remains unclear whether other HDL-associated sphingophospholipids have similar effects. We therefore examined if HDL-associated sphingosylphosphorylcholine (SPC) reduces infarct size in a mouse model of transient myocardial ischemia/reperfusion. Intravenously administered SPC dose-dependently reduced infarct size after 30 minutes of myocardial ischemia and 24 hours reperfusion compared to controls. Infarct size was also reduced by postischemic, therapeutical administration of SPC. Immunohistochemistry revealed reduced polymorphonuclear neutrophil recruitment to the infarcted area after SPC treatment, and apoptosis was attenuated as measured by TUNEL.In vitro, SPC inhibited leukocyte adhesion to TNFα-activated endothelial cells and protected rat neonatal cardiomyocytes from apoptosis. S1P3was identified as the lysophospholipid receptor mediating the cardioprotection by SPC, since its effect was completely absent in S1P3-deficient mice. We conclude that HDL-associated SPC directly protects against myocardial reperfusion injuryin vivovia the S1P3receptor.
Occupational Health and Safety Issues in Ontario Sawmills and Veneer/Plywood Plants: A Pilot Study
Authors: Verma Dave K. , Demers Cecil , Shaw Don , Verma Paul , Kurtz Lawrence , Finkelstein Murray , des Tombe Karen , Welton Tom
Published: January 2011

A pilot study was conducted within the Ontario sawmill and veneer/plywood manufacturing industry. Information was collected by postal questionnaire and observational walk-through surveys. Industrial hygiene walk-through surveys were conducted at 22 work sites, and measurements for wood dust, noise, and bioaerosol were taken. The aim of the study was to obtain data on the current status regarding health and safety characteristics and an estimate of wood dust, noise, and bioaerosol exposures. The occupational exposure to wood dust and noise are similar to what has been reported in this industry in Canada and elsewhere. Airborne wood dust concentration ranged between 0.001 mg/m3and 4.87 mg/m3as total dust and noise exposure ranged between 55 and 117 dB(A). The study indicates the need for a more comprehensive industry-wide study of wood dust, noise, and bioaersols.
Low-Power, High Data Rate Transceiver System for Implantable Prostheses
Authors: Kahn A. R. , Chow E. Y. , Abdel-Latief O. , Irazoqui P. P.
Published: January 2011

Wireless telemetry is crucial for long-term implantable neural recording systems. RF-encoded neurological signals often require high data-rates to transmit information from multiple electrodes with a sufficient sampling frequency and resolution. In this work, we quantify the effects of interferers and tissue attenuation on a wireless link for optimal design of future systems. The wireless link consists of an external receiver capable of demodulating FSK/OOK transmission at speeds up to 8 Mbps, with <1e-5 bit-error rate (BER) without error correction, and a fully implanted transmitter consuming about 1.05 mW. The external receiver is tested with the transmitterin vivoto show demodulation efficacy of the transcutaneous link at high data-rates. Transmitter/Receiver link BER is quantified in typical and controlled RF environments for ex vivo andin vivoperformance.
Power Coupling Efficiency Enhancement in Multimode Step-Index Fiber Using Refractive and Diffractive Microlenses
Authors: Selvanandan S. , Anbarasan P. M.
Published: January 2011

A novel study has been undertaken for the coupling efficiency enhancement on planar (refractive and diffractive) microlenses as coupling elements with various geometrical shapes in fibre optics communication. When the dispersion of the planar diffractive microlens is expressed in terms of an Abbe number, it is easy to solve for the refractive and diffractive power coupling efficiency that result in a single material. Coupling loss is reduced with microlens used as coupler even when increasing wavelength of the Gaussian beam. A slight difference of power coupling efficiency is observed with the different direction of electric polarisation for a Gaussian beam of large spot size at its waist due to coupling property has been discussed and shown to agree well with theoretical model.
Laser Rapid Manufacturing of Stainless Steel 316L/Inconel718 Functionally Graded Materials: Microstructure Evolution and Mechanical Properties
Authors: Wu Dongjiang , Liang Xiaokang , Li Qian , Jiang Lijia
Published: January 2011

Two patterns of functionally graded materials (FGMs) were successfully fabricated whose compositions gradually varied from 100% stainless steel 316L to 100% Inconel718 superalloy using laser engineered net shaping process. The microstructure characterization, composition analysis, and microhardness along the graded direction were investigated. The comparison revealed the distinctions in solidification behavior, microstructure evolution of two patterns. In the end, the abrasive wear resistance of the material was investigated.
Effect of Combination Therapy with Sodium Ozagrel and Panax Ginseng on Transient Cerebral Ischemia Model in Rats
Authors: Park Sang In , Jang Dong-Kyu , Han Young-Min , Sunwoo Yun-Young , Park Moon-Seo , Chung Yong-An , Maeng Lee-So , Im Ruth , Kim Min-Wook , Jeun Sin-Soo , Jang Kyung-Sool
Published: January 2011

Sodium ozagrel (SO) prevents platelet aggregation and vasoconstriction in the cerebral ischemia. It plays an important role in the prevention of brain damage induced by cerebral ischemia/reperfusion. Recently, many animal studies have suggested that thePanax ginseng(PG) has neuroprotective effects in the ischemic brain. In this study, we assessed the neuroprotective effects that come from a combination therapy of SO and PG in rat models with middle cerebral artery occlusion (MCAO). Animals with MCAO were assigned randomly to one of the following four groups: (1) control (Con) group, (2) SO group (3 mg/kg, intravenously), (3) PG group (200 mg/kg, oral feeding), and (4) SO + PG group. The rats were subjected to a neurobehavior test including adhesive removal test and rotarod test at 1, 3, 7, 10, and 15 days after MCAO. The cerebral ischemic volume was quantified by Metamorph imaging software after 2-3-5-triphenyltetrazolium (TTC) staining. The neuronal cell survival and astrocytes expansion were assessed by immunohistofluorescence staining. In the adhesive removal test, the rats of PG or SO + PG group showed significantly better performance than those of the control group (Con:88.1±24.8, PG:43.6±11, SO + PG:11.8±7,P<.05). Notably, the combination therapy group (SO + PG) showed better performance than the SO group alone (SO:56±12, SO + PG:11.8±7,P<.05). In TTC staining for infarct volume, cerebral ischemic areas were also significantly reduced in the PG group and SO + PG group (Con:219±32, PG:117±8, SO + PG:99±11,P<.05). Immunohistofluorescence staining results showed that the group which received SO + PG group therapy had neuron cells in the normal range. They also had a low number of astrocytes and apoptotic cells compared with the control or SO group in the peri-infarction area. During astrocytes staining, compared to the SO + PG group, the PG group showed only minor differences in the number of NeuN-positive cells and quantitative analysis of infarct volume. In conclusion, these studies showed that in MCAO rat models, the combination therapy with SO and PG may provide better neuroprotective effects such as higher neuronal cell survival and inhibition of astrocytes expansion than monotherapy with SO alone.
Glycogen Storage Disease Type Ia in Canines: A Model for Human Metabolic and Genetic Liver Disease
Authors: Specht Andrew , Fiske Laurie , Erger Kirsten , Cossette Travis , Verstegen John , Campbell-Thompson Martha , Struck Maggie B. , Lee Young Mok , Chou Janice Y. , Byrne Barry J. , Correia Catherine E. , Mah Cathryn S. , Weinstein David A. , Conlon Thomas J.
Published: January 2011

A canine model of Glycogen storage disease type Ia (GSDIa) is described. Affected dogs are homozygous for a previously described M121I mutation resulting in a deficiency of glucose‐6‐phosphatase‐α. Metabolic, clinicopathologic, pathologic, and clinical manifestations of GSDIa observed in this model are described and compared to those observed in humans. The canine model shows more complete recapitulation of the clinical manifestations seen in humans including “lactic acidosis”, larger size, and longer lifespan compared to other animal models. Use of this model in preclinical trials of gene therapy is described and briefly compared to the murine model. Although the canine model offers a number of advantages for evaluating potential therapies for GSDIa, there are also some significant challenges involved in its use. Despite these challenges, the canine model of GSDIa should continue to provide valuable information about the potential for generating curative therapies for GSDIa as well as other genetic hepatic diseases.
Experimental Model of Zymosan‐Induced Arthritis in the Rat Temporomandibular Joint: Role of Nitric Oxide and Neutrophils
Authors: Chaves Hellíada Vasconcelos , Ribeiro Ronaldo de Albuquerque , de Souza André Mattos Brito , Silva Antonio Alfredo Rodrigues e , Gomes Antoniella Souza , Vale Mariana Lima , Bezerra Mirna Marques , Brito Gerly Anne de Castro
Published: January 2011

Aims. To establish a new model of zymosan‐induced temporomandibular joint (TMJ) arthritis in the rat and to investigate the role of nitric oxide.Methods. Inflammation was induced by an intra‐articular injection of zymosan into the left TMJ. Mechanical hypernociception, cell influx, vascular permeability, myeloperoxidase activity, nitrite levels, and histological changes were measured in TMJ lavages or tissues at selected time points. These parameters were also evaluated after treatment with the nitric oxide synthase (NOS) inhibitors L‐NAME or 1400 W.Results. Zymosan‐induced TMJ arthritis caused a time‐dependent leucocyte migration, plasma extravasation, mechanical hypernociception, and neutrophil accumulation between 4 and 24 h. TMJ immunohistochemical analyses showed increased inducible NOS expression. Treatment with L‐NAME or 1400 W inhibited these parameters.Conclusion. Zymosan‐induced TMJ arthritis is a reproducible model that may be used to assess both the mechanisms underlying TMJ inflammation and the potential tools for therapies. Nitric oxide may participate in the inflammatory temporomandibular dysfunction mechanisms.
Fetal Cell Microchimerism and Cancer: A Nexus of Reproduction, Immunology, and Tumor Biology
Authors: Kallenbach Lisa R. , Johnson Kirby L. , Bianchi Diana W.
Published: January 2011

Fetal cell microchimerism (FCM) is the persistence of fetal cells in the maternal circulation and organs following pregnancy. Proposed hypotheses about the function of fetal cells in the pathogenesis of maternal cancer include promotion of tumorigenesis, protection by providing immunosurveillance, and participation in tissue repair. To date, studies of FCM and cancer have been primarily descriptive and quantitative. More research is needed to understand the cellular phenotype of the microchimeric cells in maternal tumors and whether they have a functional role. This research will require further study using a multidisciplinary approach, incorporating knowledge of the fetomaternal relationship, tumor biology, immunology, and clinical oncology. Cancer Res; 71(1); 8–12. ©2011 AACR.
Carminomycin I Is an Apoptosis Inducer That Targets the Golgi Complex in Clear Cell Renal Carcinoma Cells
Authors: Woldemichael Girma M. , Turbyville Thomas J. , Linehan W. Marston , McMahon James B.
Published: January 2011

Clear cell renal cell carcinoma (CCRCC) evolves due to mutations in the Von Hippel–Lindau (VHL) tumor suppressor gene. Although the loss of VHL enables survival and proliferation of CCRCC cells, it is also expected to introduce vulnerabilities that may be exploited for therapeutics discovery. To this end, we developed a high-throughput screen to identify small molecules derived from plants, microorganisms, and marine organisms to which CCRCC cells are sensitive. Screening over 8,000 compounds using this approach, we report here the identification of the microbially derived compound carminomycin I (CA) as an effective inhibitor of VHL-defective (VHL−/−) CCRCC cell proliferation. CA also induced apoptosis in CCRCC cells by a mechanism independent of p53 or hypoxia-inducible factor 2. We found that P-glycoprotein (P-gp) sequestered CA within the Golgi complex. Interestingly, Golgi sequestration was critical for the antiproliferative effects of CA and P-gp inhibitors abrogated this activity. Furthermore, CA induced cleavage of the Golgi protein p115 and the translocation of its C-terminal fragment to the nucleus. Finally, examination of the activity of the VHL-interacting Golgi protein, endoplasmic reticulum-Golgi intermediate compartment, ERGIC-53 showed that VHL could mediate protection from CA in CCRCC cells. Our natural product–based screening approach has revealed the P-gp–mediated localization of anticancer compounds within the Golgi in CCRCC cells as a potential strategy of targeting VHL-deficient CCRCC cells. Cancer Res; 71(1); 134–42. ©2011 AACR.
Novel Synthetic Antagonists of Canonical Wnt Signaling Inhibit Colorectal Cancer Cell Growth
Authors: Waaler Jo , Machon Ondrej , von Kries Jens Peter , Wilson Steven Ray , Lundenes Elsa , Wedlich Doris , Gradl Dietmar , Paulsen Jan Erik , Machonova Olga , Dembinski Jennifer L. , Dinh Huyen , Krauss Stefan
Published: January 2011

Canonical Wnt signaling is deregulated in several types of human cancer where it plays a central role in tumor cell growth and progression. Here we report the identification of 2 new small molecules that specifically inhibit canonical Wnt pathway at the level of the destruction complex. Specificity was verified in various cellular reporter systems, a Xenopus double-axis formation assay and a gene expression profile analysis. In human colorectal cancer (CRC) cells, the new compounds JW67 and JW74 rapidly reduced active β-catenin with a subsequent downregulation of Wnt target genes, including AXIN2, SP5, and NKD1. Notably, AXIN2 protein levels were strongly increased after compound exposure. Long-term treatment with JW74 inhibited the growth of tumor cells in both a mouse xenograft model of CRC and in ApcMin mice (multiple intestinal neoplasia, Min). Our findings rationalize further preclinical and clinical evaluation of these new compounds as novel modalities for cancer treatment. Cancer Res; 71(1); 197–205. ©2010 AACR.
Higher miRNA Tolerance in Immortal Li-Fraumeni Fibroblasts with Abrogated Interferon Signaling Pathway
Authors: Li Qunfang , Tainsky Michael A.
Published: January 2011

The IFN pathway is abrogated in fibroblasts from Li-Fraumeni syndrome (LFS) patients during spontaneous cellular immortalization, a necessary step in carcinogenesis. Microarray profiling of differentially expressed microRNAs (miRNA) revealed that most miRNAs were upregulated in IFN pathway–defective MDAH087-10 fibroblasts compared with MDAH087-N cells with relatively normal IFN signaling. Overexpression of Dicer, a critical enzyme in miRNA biogenesis, promoted cell growth and colony formation in MDAH087-10 cells. However, double-stranded miRNA produced by Dicer enhanced the expression of IFN-stimulated genes in MDAH087-N cells resulting in significant cell death and reduced cell growth. Furthermore, manipulation of the IFN pathway in immortal LFS fibroblasts through transcription factor IRF7 reversed their response to Dicer overexpression due to changed IFN pathway activity. Dicer overexpressing MDAH087-N cells contained lower levels of miRNA than vector control, and conversely much higher miRNA expression was detected in Dicer-transfected MDAH087-10 cells. Therefore, cells with a defective IFN pathway have a higher miRNA tolerance than cells with normal IFN pathway. This work indicates for the first time that the IFN pathway as mediated through the transcription factor IRF7 must be disrupted to permit miRNA upregulation to occur in early carcinogenesis. The IFN pathway appears to provide a checkpoint for miRNA level tolerance and its abrogation leads to cellular immortalization. Cancer Res; 71(1); 255–65. ©2010 AACR.
Activation and Involvement of Ral GTPases in Colorectal Cancer
Authors: Martin Timothy D. , Samuel Jonathan C. , Routh Elizabeth D. , Der Channing J. , Yeh Jen Jen
Published: January 2011

Current approaches to block KRAS oncogene function focus on inhibition of K-Ras downstream effector signaling. We evaluated the antitumor activity of selumetinib (AZD6244, ARRY-142886), a potent and selective MEK1/2 inhibitor, on a panel of colorectal carcinoma (CRC) cells and found no inhibition of KRAS mutant CRC cell anchorage-independent growth. Although AKT activity was elevated in KRAS mutant cells, and PI3K inhibition did impair the growth of MEK inhibitor-insensitive CRC cell lines, concurrent treatment with selumetinib did not provide additional antitumor activity. Therefore, we speculated that inhibition of the Ral guanine exchange factor (RalGEF) effector pathway may be a more effective approach for blocking CRC growth. RalGEFs are activators of the related RalA and RalB small GTPases and we found activation of both in CRC cell lines and patient tumors. Interfering RNA stable suppression of RalA expression reduced CRC tumor cell anchorage-independent growth, but surprisingly, stable suppression of RalB greatly enhanced soft agar colony size and formation frequency. Despite their opposing activities, both RalA and RalB regulation of anchorage-independent growth required interaction with RalBP1/RLIP76 and components of the exocyst complex. Interestingly, RalA interaction with the Exo84 but not Sec5 exocyst component was necessary for supporting anchorage-independent growth, whereas RalB interaction with Sec5 but not Exo84 was necessary for inhibition of anchorage-independent growth. We suggest that anti-RalA–selective therapies may provide an effective approach for KRAS mutant CRC. Cancer Res; 71(1); 206–15. ©2010 AACR.
MiR-26a Inhibits Cell Growth and Tumorigenesis of Nasopharyngeal Carcinoma through Repression of EZH2
Authors: Lu Juan , He Ming-Liang , Wang Lu , Chen Ying , Liu Xiong , Dong Qi , Chen Yang-Chao , Peng Ying , Yao Kai-Tai , Kung Hsiang-Fu , Li Xiang-Ping
Published: January 2011

Several microRNAs (miRNA) have been implicated in nasopharyngeal carcinoma (NPC), a highly invasive and metastatic cancer that is widely prevalent in southern China. In this study, we report that microRNA miR-26a iscommonly downregulated in NPC specimens and NPC cell lines with important functional consequences. Ectopic expression of miR-26a dramatically suppressed cell proliferation and colony formation by inducing G1-phase cell-cycle arrest. We found that miR-26a strongly reduced the expression of EZH2 oncogene in NPC cells. Similar to the restoring miR-26 expression, EZH2 downregulation inhibited cell growth and cell-cycle progression, whereas EZH2 overexpression rescued the suppressive effect of miR-26a. Mechanistic investigations revealed that miR-26a suppressed the expression of c-myc, the cyclin D3 and E2, and the cyclin-dependent kinase CDK4 and CDK6 while enhancing the expression of CDK inhibitors p14ARF and p21CIP1 in an EZH2-dependent manner. Interestingly, cyclin D2 was regulated by miR-26a but not by EZH2, revealing cyclin D2 asanother direct yet mechanistically distinct target of miR-26a. In clinical specimens, EZH2 was widely overexpressed and its mRNA levels were inversely correlated with miR-26a expression. Taken together, our results indicate that miR-26a functions as a growth-suppressive miRNA in NPC, and that its suppressive effects are mediated chiefly by repressing EZH2 expression. Cancer Res; 71(1); 225–33. ©2010 AACR.
Identification of New MicroRNAs in Paired Normal and Tumor Breast Tissue Suggests a Dual Role for the ERBB2/Her2 Gene
Authors: Persson Helena , Kvist Anders , Rego Natalia , Staaf Johan , Vallon-Christersson Johan , Luts Lena , Loman Niklas , Jonsson Goran , Naya Hugo , Hoglund Mattias , Borg Ake , Rovira Carlos
Published: January 2011

To comprehensively characterize microRNA (miRNA) expression in breast cancer, we performed the first extensive next-generation sequencing expression analysis of this disease. We sequenced small RNA from tumors with paired samples of normal and tumor-adjacent breast tissue. Our results indicate that tumor identity is achieved mainly by variation in the expression levels of a common set of miRNAs rather than by tissue-specific expression. We also report 361 new, well-supported miRNA precursors. Nearly two-thirds of these new genes were detected in other human tissues and 49% of the miRNAs were found associated with Ago2 in MCF7 cells. Ten percent of the new miRNAs are located in regions with high-level genomic amplifications in breast cancer. A new miRNA is encoded within the ERBB2/Her2 gene and amplification of this gene leads to overexpression of the new miRNA, indicating that this potent oncogene and important clinical marker may have two different biological functions. In summary, our work substantially expands the number of known miRNAs and highlights the complexity of small RNA expression in breast cancer. Cancer Res; 71(1); 78–86. ©2011 AACR.
Endothelial Cell–Specific Deletion of Transcription Factor FoxM1 Increases Urethane-Induced Lung Carcinogenesis
Authors: Balli David , Zhang Yufang , Snyder Jonathan , Kalinichenko Vladimir V. , Kalin Tanya V.
Published: January 2011

Vascular endothelial cells provide essential support to the tumor microenvironment, but little is known about the transcriptional control of endothelial functions during tumorigenesis. Here we define a critical role for the Forkhead transcription factor FoxM1 in modulating the development of tumor-associated endothelial cells. Pulmonary tumorigenesis induced by urethane administration was compared in mice genetically deleted for FoxM1 in endothelial cells (enFoxm1−/− mice). Notably, lung tumor number and size were increased in enFoxm1−/− mice. Increased tumorigenesis was associated with increased proliferation of tumor cells and increased expression of c-Myc and cyclin D1. Furthermore, perivascular infiltration by inflammatory cells was elevated and inflammatory cells in BAL fluid were increased. Expression of Flk-1 (vascular endothelial growth factor receptor 2) and FoxF1, known regulators of pulmonary inflammation, was decreased in enFoxm1−/− mice. siRNA-mediated knockdown of FoxM1 in endothelial cells reduced Flk-1 and FoxF1 expression, which was driven by direct transcriptional induction by FoxM1 as target genes. Endothelial specific deletion of FoxM1 in vivo or in vitro also decreased expression of Sfrp1 (secreted frizzled-related protein 1), a known inhibitor of canonical Wnt signaling, in a manner that was associated with increased Wnt signaling. Taken together, our results suggest that endothelial-specific expression of FoxM1 limits lung inflammation and canonical Wnt signaling in lung epithelial cells, thereby restricting lung tumorigenesis. Cancer Res; 71(1); 40–50. ©2011 AACR.
Molecular Pathobiology of Human Cervical High-Grade Lesions: Paracrine STAT3 Activation in Tumor-Instructed Myeloid Cells Drives Local MMP-9 Expression
Authors: Schröer Nadine , Pahne Jennifer , Walch Barbara , Wickenhauser Claudia , Smola Sigrun
Published: January 2011

In many tumors, the switch from precancerous lesions to malignancy critically relies on expression of the matrix-metalloprotease MMP-9, which is predominantly provided by infiltrating inflammatory cells. Our study defines a novel molecular cascade, how human neoplastic cells instruct tumor-associated myeloid cells to produce MMP-9. In biopsies of human papillomavirus–associated precancerous cervical intraepithelial neoplasia (CIN III lesions), we show broad activation of the transcription factor STAT3 and coexpression of MMP-9 in perivascular inflammatory cells. For the first time, we establish a causative link between tumor-mediated paracrine STAT3 activation and MMP-9 production by human tumor-instructed monocytes, whereas NF-κB activation is dispensable for this response. Our data provide evidence that STAT3 does not directly induce MMP-9 but first leads to a strong production of the monocyte chemoattractant protein-1 (CCL2) in the nanogram range. In a second phase, autocrine stimulation of the CCR2 receptor in the tumor-instructed monocytes amplifies MMP-9 expression via intracellular Ca2+ signaling. These findings elucidate a critical mechanism in the molecular pathobiology of cervical carcinogenesis at the switch to malignancy. Particularly in tumors, which are associated with infectious agents, STAT3-driven inflammation may be pivotal to promote carcinogenesis, while at the same time limit NF-κB–dependent immune responses and thus rejection of the infected preneoplastic cells. The molecular cascade defined in this study provides the basis for a rational design of future adjuvant therapies of cervical precancerous lesions. Cancer Res; 71(1); 87–97. ©2011 AACR. Cancer Res; 71(1); 87–97. ©2011 AACR.
Snail2 is an Essential Mediator of Twist1-Induced Epithelial Mesenchymal Transition and Metastasis
Authors: Casas Esmeralda , Kim Jihoon , Bendesky Andrés , Ohno-Machado Lucila , Wolfe Cecily J. , Yang Jing
Published: January 2011

To metastasize, carcinoma cells must attenuate cell–cell adhesion to disseminate into distant organs. A group of transcription factors, including Twist1, Snail1, Snail2, ZEB1, and ZEB2, have been shown to induce epithelial mesenchymal transition (EMT), thus promoting tumor dissemination. However, it is unknown whether these transcription factors function independently or coordinately to activate the EMT program. Here we report that direct induction of Snail2 is essential for Twist1 to induce EMT. Snail2 knockdown completely blocks the ability of Twist1 to suppress E-cadherin transcription. Twist1 binds to an evolutionarily conserved E-box on the proximate Snail2 promoter to induce its transcription. Snail2 induction is essential for Twist1-induced cell invasion and distant metastasis in mice. In human breast tumors, the expression of Twist1 and Snail2 is highly correlated. Together, our results show that Twist1 needs to induce Snail2 to suppress the epithelial branch of the EMT program and that Twist1 and Snail2 act together to promote EMT and tumor metastasis. Cancer Res; 71(1); 245–54. ©2010 AACR.
Long Intergenic Noncoding RNAs: New Links in Cancer Progression
Authors: Tsai Miao-Chih , Spitale Robert C. , Chang Howard Y.
Published: January 2011

The process of cancer metastasis involves a series of sequential and complex steps. Here we give a perspective on recent results regarding noncoding transcription in cancer progression, focusing on the emerging role of long intergenic noncoding RNAs (lincRNAs). LincRNAs target chromatin modification complexes or RNA-binding proteins to alter gene expression programs. Similarly to miRNAs, lincRNAs exhibit distinct gene expression patterns in primary tumors and metastases. We discuss how lincRNAs can be used for cancer diagnosis and prognosis and serve as potential therapeutic targets. Cancer Res; 71(1); 3–7. ©2011 AACR.
Glioblastoma Recurrence after Cediranib Therapy in Patients: Lack of “Rebound” Revascularization as Mode of Escape
Authors: di Tomaso Emmanuelle , Snuderl Matija , Kamoun Walid S. , Duda Dan G. , Auluck Pavan K. , Fazlollahi Ladan , Andronesi Ovidiu C. , Frosch Matthew P. , Wen Patrick Y. , Plotkin Scott R. , Hedley-Whyte E. Tessa , Sorensen A. Gregory , Batchelor Tracy T. , Jain Rakesh K.
Published: January 2011

Recurrent glioblastomas (rGBM) invariably relapse after initial response to anti-VEGF therapy. There are 2 prevailing hypotheses on how these tumors escape antiangiogenic therapy: switch to VEGF-independent angiogenic pathways and vessel co-option. However, direct evidence in rGBM patients is lacking. Thus, we compared molecular, cellular, and vascular parameters in autopsy tissues from 5 rGBM patients who had been treated with the pan-VEGF receptor tyrosine kinase inhibitor cediranib versus 7 patients who received no therapy or chemoradiation but no antiangiogenic agents. After cediranib treatment, endothelial proliferation and glomeruloid vessels were decreased, and vessel diameters and perimeters were reduced to levels comparable to the unaffected contralateral brain hemisphere. In addition, tumor endothelial cells expressed molecular markers specific to the blood–brain barrier, indicative of a lack of revascularization despite the discontinuation of therapy. Surprisingly, in cediranib-treated GBM, cellular density in the central area of the tumor was lower than in control cases and gradually decreased toward the infiltrating edge, indicative of a change in growth pattern of rGBMs after cediranib treatment, unlike that after chemoradiation. Finally, cediranib-treated GBMs showed high levels of PDGF-C (platelet-derived growth factor C) and c-Met expression and infiltration by myeloid cells, which may potentially contribute to resistance to anti-VEGF therapy. In summary, we show that rGBMs switch their growth pattern after anti-VEGF therapy—characterized by lower tumor cellularity in the central area, decreased pseudopalisading necrosis, and blood vessels with normal molecular expression and morphology—without a second wave of angiogenesis. Cancer Res; 71(1); 19–28. ©2011 AACR.
Dose-Dependent Effects of Focal Fractionated Irradiation on Secondary Malignant Neoplasms in Nf1 Mutant Mice
Authors: Nakamura Jean L. , Phong Connie , Pinarbasi Emile , Kogan Scott C. , Vandenberg Scott , Horvai Andrew E. , Faddegon Bruce A. , Fiedler Dorothea , Shokat Kevan , Houseman Benjamin T. , Chao Richard , Pieper Russell O. , Shannon Kevin
Published: January 2011

Secondary malignant neoplasms (SMN) are increasingly common complications of cancer therapy that have proven difficult to model in mice. Clinical observations suggest that the development of SMN correlates with radiation dose; however, this relationship has not been investigated systematically. We developed a novel procedure for administering fractionated cranial irradiation (CI) and investigated the incidence and spectrum of cancer in control and heterozygous Nf1 mutant mice irradiated to a moderate (15 Gy) or high dose (30 Gy). Heterozygous Nf1 inactivation cooperated with CI to induce solid tumors and myeloid malignancies, with mice developing many of the most common SMNs found in human patients. CI-induced malignancies segregated according to radiation dose as Nf1+/− mice developed predominately hematologic abnormalities after 15 Gy, whereas solid tumors predominated at 30 Gy, suggesting that radiation dose thresholds exist for hematologic and nonhematologic cancers. Genetic and biochemical studies revealed discrete patterns of somatic Nf1 and Trp53 inactivation and we observed hyperactive Ras signaling in many radiation-induced solid tumors. This technique for administering focal fractionated irradiation will facilitate mechanistic and translational studies of SMNs. Cancer Res; 71(1); 106–15. ©2011 AACR.
ShRNA-Targeted MAP4K4 Inhibits Hepatocellular Carcinoma Growth
Authors: Liu An-Wen , Cai Jing , Zhao Xiang-Li , Jiang Ting-Hui , He Tian-Feng , Fu Hua-Qun , Zhu Ming-Hua , Zhang Shu-Hui
Published: January 2011

Purpose: Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is overexpressed in many types of cancer. Herein, we aimed to investigate its expression pattern, clinical significance, and biological function in hepatocellular carcinoma (HCC).

Experimental Design: MAP4K4 expression was examined in 20 fresh HCCs and corresponding nontumor liver tissues. Immunohistochemistry for MAP4K4 was performed on additional 400 HCCs, of which 305 (76%) were positive for hepatitis B surface antigens. The clinical significance of MAP4K4 expression was analyzed. MAP4K4 downregulation was performed in HCC cell lines HepG2 and Hep3B with high abundance of MAP4K4, and the effects of MAP4K4 silencing on cell proliferation in vitro and tumor growth in vivo were evaluated. Quantitative real-time PCR arrays were employed to identify the MAP4K4-regulated signaling pathways.

Results: MAP4K4 was aberrantly overexpressed in HCCs relative to adjacent nontumor liver tissues. This overexpression was significantly associated with larger tumor size, increased histologic grade, advanced tumor stage, and intrahepatic metastasis, as well as worse overall survival and higher early recurrence rate. Knockdown of the MAP4K4 expression reduced cell proliferation, blocked cell cycle at S phase, and increased apoptosis. The antitumor effects of MAP4K4 silencing were also observed in vivo, manifested as retarded tumor xenograft growth. Furthermore, multiple tumor progression–related signaling pathways including JNK, NFκB, and toll-like receptors were repressed by MAP4K4 downregulation.

Conclusions: MAP4K4 overexpression is an independent predictor of poor prognosis of HCC patients, and inhibition of its expression might be of therapeutic significance. Clin Cancer Res; 17(4); 1–11. ©2010 AACR.
Serotonin Transporter Bi- and Triallelic Genotypes and Their Relationship with Anxiety and Academic Performance: A Preliminary Study
Authors: Calapoğlu Mustafa , Şahin-Calapoğlu Nilufer , Karaçöp Ataman , Soyöz Mustafa , Elyıldırım Ümit Y. , Avşaroğlu Selahattin
Published: January 2011

Background: Considerable evidence suggests that variation of the serotonin-transporter-linked promoter region (5- HTTLPR) is associated with anxiety-related traits. Academic outcomes are also more closely related to trait anxiety. This preliminary study aimed to explore the association between academic performance and levels of anxiety with respect to the bi- and triallelic classification of 5-HTTLPR polymorphism of the 5-HTT gene in teacher candidates. Methods: In our study, Spielberger’s State-Trait Anxiety Inventory, the Selection Examination for Professional Posts in Public Organizations (KPSS) and 5-HTTLPR genotypes were used to investigate a group of 94 healthy teacher candidates. Results: Higher anxiety scores were significantly associated with the S′S′ genotype. There was no direct, statistically significant association between academic performance and genotypic groups regarding bi- and triallelic classification. However, the students who have L′L′ or LL genotypes had the lowest levels of trait anxiety and the poorest academic performance. Additionally, there was a significant positive correlation between academic performance and anxiety levels. Discussion: These findings support the idea that S and LG alleles are associated with anxiety-related traits, and that the S′S′ genotype may be a good indicator for anxiety-related traits in a sample from the Turkish population. A specific degree of anxiety is considered to be a motivation for learning and high academic performance. However, 5-HTTLPR polymorphism of the 5-HTT gene may be one of the genetic factors affecting academic performance in connection with anxiety levels. Implications for incorporating anxiety management training in the educational process in terms of both environmental and individual factors will have a very important role in improving effective strategies for student personality services, as well as for development and planning.
SCL-90-R Symptom Profile Clusters among Inpatients Undergoing Psychodynamic Group Psychotherapy: Cluster Stability, Associations with Clinical Characteristics and Treatment Outcome
Authors: Kirchmann Helmut , Schreiber-Willnow Karin , Seidler Klaus-Peter , Strauss Bernhard
Published: January 2011

Background/Aims: Based on pretreatment psychopathological symptoms measured with the Symptom Checklist 90 Revised (SCL-90-R), this study investigated whether stable symptom clusters exist among psychotherapy inpatients. Furthermore, it was examined whether the identified clusters would differ with respect to clinical characteristics and treatment outcome. Sampling and Methods: We collected data from a total of 3,688 psychotherapeutic inpatients involved in psychodynamic group psychotherapy from 10 hospitals. Ipsatized SCL-90-R presymptom data were used as input variables for a series of cluster analyses combining hierarchical (Ward algorithm) and non-hierarchical (k-means) procedures. Results: The cluster analyses revealed a 7-cluster solution with the following subgroups: (1) insecure-paranoid, (2) neutralizing, (3) phobic-anxious, (4) aggressive, (5) insecure-phobic, (6) somatizing, and (7) obsessive-depressive. Cross-validation with independent data sets, as well as alternative statistical procedures, confirmed the stability of the 7-cluster solution. Correlations with clinical diagnoses and interpersonal problems indicate the clinical relevance of the cluster differentiation. The cluster insecure-phobic proved to be less beneficial when used as a predictor of treatment outcome. Furthermore, we found moderator effects between cluster assignment and pretreatment interpersonal problems: the overall amount of interpersonal problems seemed to be detrimental to the patients from the clusters insecure-phobic and somatizing, whereas a relatively (ipsatized) heightened level of dominance was advantageous for improving psychopathological complaints of the patients from the cluster aggressive. Conclusions: We could identify typical and clinically meaningful symptom clusters for the population of inpatients undergoing psychodynamic group psychotherapy in Germany. This finding could help strengthen clinical research which is led by the assumption that it is relevant to characterize patients by a specific pattern of psychopathological symptoms rather than or in addition to one (or more) distinct diagnostic categories.
Is Familial Obsessive-Compulsive Disorder Different from Sporadic Obsessive-Compulsive Disorder? A Comparison of Clinical Characteristics, Comorbidity and Treatment Response
Authors: Viswanath Biju , Narayanaswamy Janardhanan C. , Cherian Anish V. , Reddy Y.C. Janardhan , Math Suresh Bada
Published: January 2011

Background: Familial and sporadic subtypes of obsessive-compulsive disorder (OCD) have been proposed, but have not been well studied. The aim of the study was to compare the clinical characteristics, comorbidity and treatment response of familial OCD with sporadic OCD. Sampling and Methods: We reviewed the clinical records of 84 familial OCD patients and 80 randomly selected sporadic OCD patients from a specialty OCD clinic in India. All the subjects had been evaluated using the specially devised topical OCD evaluation proforma, the Yale-Brown Obsessive Compulsive Scale and the Clinical Global Impression scale. A diagnosis of OCD was made according to the DSM-IV criteria. Results: Familial OCD was associated with earlier age at onset, a greater duration of untreated illness and more compulsions, particularly ordering and cognitive types. It was also associated with greater comorbidity, especially depression and other anxiety disorders, and treatment non-response. The sporadic group had more sexual obsessions and predominant obsession subtypes of OCD. In regression analysis, ordering compulsions, cognitive compulsions, absence of sexual obsessions, lifetime comorbidity of major depression and anxiety disorders and a greater duration of untreated illness predicted familial OCD. Conclusions: Our findings support the observation that familial OCD could be phenotypically different from sporadic forms of OCD and therefore a putative subtype of OCD.
Neural Correlates of Belief-Laden Reasoning during Premise Processing: An Event-Related Potential Study
Authors: Luo Junlong , Yang Qun , Du Xiumin , Zhang Qinglin
Published: January 2011

In this study, electrophysiological correlates of belief-laden reasoning were investigated. As subjects, trained participants were required to draw a logical conclusion after being exposed to 4 conditional arguments: the inhibitory content of modus tollens (ICMT), facilitatory content of modus tollens (FCMT), inhibitory content of denial of the antecedent (ICDA) and facilitatory content of denial of the antecedent (FCDA). Event-related potentials were employed to record the processing of minor premises. The results show that in comparison with FCMT, a greater negativity in the ICMT developed during both the 400- to 600- and the 800- to 1,600-ms time windows. A greater anterior cingulate cortex activity observed in the 800- to 1,600-ms time window in ICMT could reflect a detection of the conflict between empirical beliefs and logical rules. However, the components elicited by ICDA and FCDA were not significantly different. The results indicate that logical training influenced MT and DA forms of belief-laden reasoning in different ways and different strategies were likely adopted in the inference processes.
Lack of Association between Testosterone and Suicide Attempts
Authors: Perez-Rodriguez M. Mercedes , Lopez-Castroman Jorge , Martinez-Vigo Maria , Diaz-Sastre Carmen , Ceverino Antonio , Núñez-Beltrán Amparo , Saiz-Ruiz Jeronimo , de Leon Jose , Baca-Garcia Enrique
Published: January 2011

Objective: To determine whether testosterone levels differ in male suicide attempters versus healthy controls and to explore the associations between testosterone levels and time of blood collection, and between testosterone levels and characteristics of suicide attempts. Method: A sample of 112 male suicide attempters was studied. Thirty-seven male blood donors were recruited as controls. Results: The mean testosterone levels were 5.1 ± 2.9 ng/ml in male attempters and 4.6 ± 1.6 ng/ml in controls. Group differences in testosterone levels were not significant when we studied the interaction with time of extraction (F = 0.37; d.f. = 2; p = 0.70) or when matched by age and time of extraction (t = –0.74; d.f. = 26; p = 0.47). When partial correlations were performed correcting for the effect of time of extraction, significant partial correlations were found in testosterone levels with history of aggressive behavior and lethality of the attempt. Conclusions: When circadian variation and age were considered, we found no support for the putative role of testosterone as a biological marker of suicidal behavior. Further research should consider: (1) testosterone and neurosteroids; (2) serial determinations with a minimal time gap between the attempt and the blood extraction; (3) controls within the same time periods, and (4) other variables that may affect testosterone levels, such as body mass index, physical activity and sleep disturbances.
On the Occurrence of the Diabetes-Associated Antigen GAD 65 in Human Sera
Authors: Tilz G.P. , Wiltgen M. , Borkenstein M.
Published: January 2011

Background: Glutamic acid decarboxylase (GAD 65) is involved as an antigen in diabetes mellitus type 1 and is generally considered to be located intracellularly in pancreas β-cells. In this study we demonstrate its appearance in 64 human sera samples representing a cross-section of a blood bank. Method: The proof of GAD 65 in sera was done using an enzyme-linked immunosorbent assay (ELISA) setup where it was detected by interaction with corresponding antibodies labeled with an enzyme. The enzyme catalyzes a substrate reaction, resulting in a change of color, that is used for the quantitative evaluation of the antigen-antibody interaction. Result: The measurements showed that GAD 65 exists in various amounts in the sera of blood donors, with an average concentration of 58.00 ng/ml. The correlation analysis of samples stored at –80°C and at room temperature demonstrates the stability of GAD 65 at room temperature. The correlation coefficient between the GAD 65 concentrations of samples stored at room temperature and of the same samples after 1 week shows that the molecule remains stable. Conclusion: Our results encourage us to propose antigen GAD 65, due to its frequency in human sera in different concentrations and its stability, as a biomarker for the early diagnosis of type 1 diabetes and related inflammations.