bluuebunny/crossref_metadata_2025 huggingface dataset:
GLOBAL EXISTENCE, UNIQUENESS AND OPTIMAL SOLVERS OF DISCRETIZED VISCOELASTIC FLOW MODELS
Authors: LEE YOUNG-JU , XU JINCHAO , ZHANG CHEN-SONG
Published: March 2011

This paper is devoted to studying the well-posedness and optimal solution techniques for a full discretization scheme, proposed by Lee and Xu (2006), for a large class of viscoelastic flow models. By using some special properties of the scheme such that it is stable in the energy norm and it preserves the positivity of the conformation tensor, the global existence and uniqueness of the solution of the discrete scheme is established. Furthermore, it is shown that the solution of the discrete scheme at each time step can be obtained by an iterative procedure that only requires [Formula: see text] operations (with N being the number of nodes of the underlying finite element grid).
TANGENTIAL-DISPLACEMENT AND NORMAL–NORMAL-STRESS CONTINUOUS MIXED FINITE ELEMENTS FOR ELASTICITY
Authors: PECHSTEIN ASTRID , SCHÖBERL JOACHIM
Published: March 2011

In this paper, we introduce new finite elements to approximate the Hellinger Reissner formulation of elasticity. The elements are the vector-valued tangential continuous Nédélec elements for the displacements, and symmetric tensor-valued, normal–normal continuous elements for the stresses. These elements do neither suffer from volume locking as the Poisson ratio approaches ½, nor suffer from shear locking when anisotropic elements are used for thin structures. We present the analysis of the new elements, discuss their implementation, and give numerical results.
Factors influencing the catalytic activity of β-tetrabrominatedmeso-tetra(para-tolyl)porphyrinatomanganese(III) for oxidation of sulfides and olefins with Oxone
Authors: Rayati Saeed , Zakavi Saeed , Kalantari Hossein
Published: March 2011

Effect of different reaction parameters on the catalytic activity of β-tetrabrominated meso-tetra(para-tolyl)porphyrinatomanganese(III), MnT(4-CH3P)PBr4(OAc) , for oxidation of different sulfides and hydrocarbons with tetra-n-butylammonium hydrogen monopersulfate (TBAHS) has been studied. In oxidation of sulfides, the chemoselectivity of reaction has been significantly changed in THF as the solvent compared with the common organic solvents. Also, using nitrogenous bases bearing electron-withdrawing groups ( -Cl or -CN ) clearly increased the ratio of sulfoxide to sulfone relative to the electron-donating ones. Catalytic oxidation of olefins with TBAHS was conducted in protic and aprotic solvents and acetonitrile has been found as the best solvent. A significantly large difference was found between the co-catalytic activity of imidazole (ImH) and pyridine in comparison with that observed in dichloromethane. The competitive oxidation of cis- and trans-stilbene suggests the presence of a high valent manganese oxo as well as a six coordinate (ImH)MnT(4-CH3P)PBr4(HSO5) species as the active oxidants in acetonitrile.
天福宫的领导层、组织与功能(1840–1915): 基于报章资料的研究
Authors: 李勇
Published: March 2011

有关天福宫早期历史的研究每为文献缺略所难，《叻报》等新加坡华文报章却可以提供研究天福宫的不少素材。挖掘、整理、分析这些素材，对于讨论天福宫作为闽帮总机构70余年间，其领导层、组织、结构与功能的发展与演变，以及思考在中西方文化咬合、碰撞的特殊场域，新加坡华人移民“异域”发展的“方言”帮群社会结构、民间社会的组织运作与组织机能问题，尤为必要。全文分三部分：第一部分讨论天福宫组织与领导层的历史沿革；第二部分讨论兼具香火庙宇和闽帮总机构二重特性的天福宫，在承办中元普渡、迎神赛会、圣谕宣讲、兴办教育、对祖籍原乡实施灾荒救济等方面，所发挥的宗教和社区双重功能。最后是对华人社会组织与运作“异域”发展问题的一些初步思考。
中国四个城市吸引海外回流人才比较研究: 政策的视角
Authors: 王苍柏
Published: March 2011

现有关于中国海外回流人才的研究，大多从国家的层次出发，强调中央或国家级的职能部门在指导全国规模的人才引进当中的政策、措施及作用。关于具体城市的人才流动则研究不足；对人才政策的区域性差异也有所忽略。为了弥补以上不足，本文从城市的层次和比较的视野，对海外回流人才政策进行初步分析。作者以中国四个最有代表性的城市—北京、上海、广州和深圳—作为研究重点。通过对这四个城市海外回流人才和政府官员的深入访谈，以及对各个城市所出台的人才政策及相关数据的分析，本研究显示：第一，对海外回流人才的吸引和使用，各个城市往往会根据当地的具体情况，出台“地方化”的人才政策，以增加其吸引力度和灵活性，从而呈现出不同的类型和特色。只有在比较研究的基础上，才能对整个中国的海外人才回流状况有更加真切和深入的了解。第二，有必要把海外人才回流放入一个多元互动的分析框架当中，避免陷入“就政策而政策”式的讨论。从根本上来说，回流人才的聚散取决于一个城市的产业结构所能够提供的就业机会和发展前景，同时受到社会、文化和地域等因素的制约。政策作为这个框架的重要一环，只有与其它因素相互配合，才能充分发挥其调控和疏导的作用。
北西班牙地区华人社区的群体特性及社会融合
Authors: 方晓  , Ardanaz Eduardo Rubio
Published: March 2011

作为世界移民的新兴输入国，自20世纪80年代以来，西班牙吸引了越来越多的华人移民。目前，中国已经成为西班牙外来移民的第十大来源国。与欧洲大部分地区一样，西班牙新华人移民的空间分布也呈现明显的“小集中、大分散”的特征。马德里和巴塞罗那两大都市是最主要的华人移民聚居地，汇集超过半数以上的在西华人移民。与美国、加拿大或欧盟其他部分国家（如法国和德国）的情况相异，西班牙中国新移民结构中技术移民的比例甚小。本文以巴斯克地区为案例，对在西新华人移民的经济活动、家庭组织、教育和社会参与等方面进行分析，归结出社会融入过程中的各种主要问题，并探讨了相关的对策建议。
Mechanisms for increased insulin-stimulated Akt phosphorylation and glucose uptake in fast- and slow-twitch skeletal muscles of calorie-restricted rats
Authors: Sharma Naveen , Arias Edward B. , Bhat Abhijit D. , Sequea Donel A. , Ho Steve , Croff Kelsey K. , Sajan Mini P. , Farese Robert V. , Cartee Gregory D.
Published: March 2011

Calorie restriction [CR; ∼65% of ad libitum (AL) intake] improves insulin-stimulated glucose uptake (GU) and Akt phosphorylation in skeletal muscle. We aimed to elucidate the effects of CR on 1) processes that regulate Akt phosphorylation [insulin receptor (IR) tyrosine phosphorylation, IR substrate 1-phosphatidylinositol 3-kinase (IRS-PI3K) activity, and Akt binding to regulatory proteins (heat shock protein 90, Appl1, protein phosphatase 2A)]; 2) Akt substrate of 160-kDa (AS160) phosphorylation on key phosphorylation sites; and 3) atypical PKC (aPKC) activity. Isolated epitrochlearis (fast-twitch) and soleus (slow-twitch) muscles from AL or CR (6 mo duration) 9-mo-old male F344BN rats were incubated with 0, 1.2, or 30 nM insulin and 2-deoxy-[3H]glucose. Some CR effects were independent of insulin dose or muscle type: CR caused activation of Akt (Thr308and Ser473) and GU in both muscles at both insulin doses without CR effects on IRS1-PI3K, Akt-PP2A, or Akt-Appl1. Several muscle- and insulin dose-specific CR effects were revealed. Akt-HSP90 binding was increased in the epitrochlearis; AS160 phosphorylation (Ser588and Thr642) was greater for CR epitrochlearis at 1.2 nM insulin; and IR phosphorylation and aPKC activity were greater for CR in both muscles with 30 nM insulin. On the basis of these data, our working hypothesis for improved insulin-stimulated GU with CR is as follows: 1) elevated Akt phosphorylation is fundamental, regardless of muscle or insulin dose; 2) altered Akt binding to regulatory proteins (HSP90 and unidentified Akt partners) is involved in the effects of CR on Akt phosphorylation; 3) Akt effects on GU depend on muscle- and insulin dose-specific elevation in phosphorylation of Akt substrates, including, but not limited to, AS160; and 4) greater IR phosphorylation and aPKC activity may contribute at higher insulin doses.
Renin expression in large renal vessels during fetal development depends on functional β1/β2-adrenergic receptors
Authors: Neubauer Björn , Machura Katharina , Schnermann Jürgen , Wagner Charlotte
Published: March 2011

During nephrogenesis, renin expression shifts from large renal arteries toward smaller vessels in a defined spatiotemporal pattern, finally becoming restricted to the juxtaglomerular position. Chronic stimulation in adult kidneys leads to a recruitment of renin expression in the upstream vasculature. The mechanisms that control this characteristic switch-on and switch-off in the immature and adult kidney are not well-understood. Previous studies in mice with juxtaglomerular cell-specific deletion of the adenylyl cyclase-stimulatory G protein Gsα suggested that signaling along the cAMP pathway plays an essential role for renin expression during nephrogenesis and in the adult kidney. To identify the Gsα-dependent receptor that might be involved in activating this pathway, the present studies were performed to compare renin expression in wild types with that in mice with targeted deletions of β1 and β2-adrenoceptors. The sympathetic nervous system is an important regulator of the renin system in the adult kidney so that activation of β-adrenenoceptors may also participate in the activation of renin expression along the developing arterial tree and in upstream vasculature in adulthood. Compared with wild-types, renin expression was found to be significantly lower at all developmental stages in the kidneys of β1/β2 Adr−/− mice. Three-dimensional analysis showed reduced renin expression in all segments of the vascular tree in mutants and a virtual absence of renin expression in the large arcuate arteries. Adult mutant kidneys showed the typical upstream renin expression after chronic stimulation. Tyrosine hydroxylase staining in fetal and postnatal kidneys revealed that sympathetic innervation of renin-producing cells occurs early in fetal development. Our data indicate that genetic disruption of β-adrenergic receptors reduces basal renin expression along the developing preglomerular tree and in adult kidneys. Furthermore, β-adrenergic receptor input is critical for the expression of renin in large renal vessels during early fetal development.
Developmental time course distinguishes changes in spontaneous and light-evoked retinal ganglion cell activity in rd1 and rd10 mice
Authors: Stasheff Steven F. , Shankar Malini , Andrews Michael P.
Published: March 2011

In a subset of hereditary retinal diseases, early photoreceptor degeneration causes rapidly progressive blindness in children. To better understand how retinal development may interact with degenerative processes, we compared spontaneous and light-evoked activity among retinal ganglion cells in rd1 and rd10 mice, strains with closely related retinal disease. In each, a mutation in the Pde6b gene causes photoreceptor dysfunction and death, but in rd10 mice degeneration starts after a peak in developmental plasticity of retinal circuitry and thereafter progresses more slowly. In vitro multielectrode action potential recordings revealed that spontaneous waves of correlated ganglion cell activity comparable to those in wild-type mice were present in rd1 and rd10 retinas before eye opening [postnatal day (P) 7 to P8]. In both strains, spontaneous firing rates increased by P14–P15 and were many times higher by 4–6 wk of age. Among rd1 ganglion cells, all responses to light had disappeared by ∼P28, yet in rd10 retinas vigorous ON and OFF responses were maintained well beyond this age and were not completely lost until after P60. This difference in developmental time course separates mechanisms underlying the hyperactivity from those that alter light-driven responses in rd10 retinas. Moreover, several broad physiological groups of cells remained identifiable according to response polarity and time course as late as P60. This raises hope that visual function might be preserved or restored despite ganglion cell hyperactivity seen in inherited retinal degenerations, particularly if treatment or manipulation of early developmental plasticity were to be timed appropriately.
MicroRNA in central nervous system trauma and degenerative disorders
Authors: Liu Nai-Kui , Xu Xiao-Ming
Published: March 2011

MicroRNAs (miRNAs) are a novel class of small noncoding RNAs that negatively regulate gene expression at the posttranscriptional level by binding to the 3′-untranslated region of target mRNAs leading to their translational inhibition or sometimes degradation. MiRNAs are predicted to control the activity of at least 20–30% of human protein-coding genes. Recent studies have demonstrated that miRNAs are highly expressed in the central nervous system (CNS) including the brain and spinal cord. Although we are currently in the initial stages of understanding how this novel class of gene regulators is involved in neurological biological functions, a growing body of exciting evidence suggests that miRNAs are important regulators of diverse biological processes such as cell differentiation, growth, proliferation, and apoptosis. Moreover, miRNAs are key modulators of both CNS development and plasticity. Some miRNAs have been implicated in several neurological disorders such as traumatic CNS injuries and neurodegenerative diseases. Recently, several studies suggested the possibility of miRNA involvement in neurodegeneration. Identifying the roles of miRNAs and their target genes and signaling pathways in neurological disorders will be critical for future research. miRNAs may represent a new layer of regulators for neurobiology and a novel class of therapeutic targets for neurological diseases.
Nestin Reporter Transgene Labels Multiple Central Nervous System Precursor Cells
Authors: Walker Avery S. , Goings Gwendolyn E. , Kim Yongsoo , Miller Richard J. , Chenn Anjen , Szele Francis G.
Published: March 2011

Embryonic neuroepithelia and adult subventricular zone (SVZ) stem and progenitor cells express nestin. We characterized a transgenic line that expresses enhanced green fluorescent protein (eGFP) specified to neural tissue by the second intronic enhancer of the nestin promoter that had several novel features. During embryogenesis, the dorsal telencephalon contained many and the ventral telencephalon few eGFP+ cells. eGFP+ cells were found in postnatal and adult neurogenic regions. eGFP+ cells in the SVZ expressed multiple phenotype markers, glial fibrillary acidic protein, Dlx, and neuroblast-specific molecules suggesting the transgene is expressed through the lineage. eGFP+ cell numbers increased in the SVZ after cortical injury, suggesting this line will be useful in probing postinjury neurogenesis. In non-neurogenic regions, eGFP was strongly expressed in oligodendrocyte progenitors, but not in astrocytes, even when they were reactive. This eGFP+ mouse will facilitate studies of proliferative neuroepithelia and adult neurogenesis, as well as of parenchymal oligodendrocytes.
A Regenerative Antioxidant Protocol of Vitamin E and α‐Lipoic Acid Ameliorates Cardiovascular and Metabolic Changes in Fructose‐Fed Rats
Authors: Patel Jatin , Matnor Nur Azim , Iyer Abishek , Brown Lindsay
Published: March 2011

Type 2 diabetes is a major cause of cardiovascular disease. We have determined whether the metabolic and cardiovascular changes induced by a diet high in fructose in young adult male Wistar rats could be prevented or reversed by chronic intervention with natural antioxidants. We administered a regenerative antioxidant protocol using two natural compounds: α‐lipoic acid together with vitamin E (α‐tocopherol alone or a tocotrienol‐rich fraction), given as either a prevention or reversal protocol in the food. These rats developed glucose intolerance, hypertension, and increased collagen deposition in the heart together with an increased ventricular stiffness. Treatment with a fixed combination of vitamin E (either α‐tocopherol or tocotrienol‐rich fraction, 0.84 g/kg food) and α‐lipoic acid (1.6 g/kg food) normalized glucose tolerance, blood pressure, cardiac collagen deposition, and ventricular stiffness in both prevention and reversal protocols in these fructose‐fed rats. These results suggest that adequate antioxidant therapy can both prevent and reverse the metabolic and cardiovascular damage in type 2 diabetes.
Hepatic Gene Expression Profiles Are Altered by Dietary Unsalted Korean Fermented Soybean (Chongkukjang) Consumption in Mice with Diet-Induced Obesity
Authors: Soh JuRyoun , Kwon Dae Young , Cha Youn-Soo
Published: March 2011

We found that Chongkukjang, traditional unsalted fermented soybean, has an antiobesity effect in mice with diet-induced obesity and examined the changes in hepatic transcriptional profiles using cDNA microarray. High-fat diet-induced obese C57BL/6J mice were divided into three groups: normal-diet control group (NDcon, 10% of total energy from fat), high-fat diet control group (HDcon, 45% of total energy from fat), and HDcon plus 40% Chongkukjang (HDC) and were fed for 9 weeks. The HDC group mice were pair-fed (isocalorie) with mice in the HDcon group. Final body weight, epididymal fat accumulation, serum total cholesterol, and LDL-cholesterol were improved in HDC group. The cDNA microarray analyses revealed marked alterations in the expression of about 800 genes. Several genes involved in fatty acid catabolism (Acaa2, Mgll, Phyh, Slc27a2, and Slc27a5) were normalized by Chongkukjang consumption. This study showed beneficial effects of Chongkukjang consumption in preventing diet-induced obesity and related metabolic abnormalities.
Acute Exercise Increases Plasma Total Antioxidant Status and Antioxidant Enzyme Activities in Untrained Men
Authors: Berzosa C. , Cebrián I. , Fuentes-Broto L. , Gómez-Trullén E. , Piedrafita E. , Martínez-Ballarín E. , López-Pingarrón L. , Reiter R. J. , García J. J.
Published: March 2011

Antioxidant defences are essential for cellular redox regulation. Since free‐radical production may be enhanced by physical activity, herein, we evaluated the effect of acute exercise on total antioxidant status (TAS) and the plasma activities of catalase, glutathione reductase, glutathione peroxidase, and superoxide dismutase and its possible relation to oxidative stress resulting from exercise. Healthy untrained male subjects (n = 34) performed three cycloergometric tests, including maximal and submaximal episodes. Venous blood samples were collected before and immediately after each different exercise. TAS and enzyme activities were assessed by spectrophotometry. An increase of the antioxidant enzyme activities in plasma was detected after both maximal and submaximal exercise periods. Moreover, under our experimental conditions, exercise also led to an augmentation of TAS levels. These findings are consistent with the idea that acute exercise may play a beneficial role because of its ability to increase antioxidant defense mechanisms through a redox sensitive pathway.
Apoptotic Cell Death and Inhibition of Wnt/β‐Catenin Signaling Pathway in Human Colon Cancer Cells by an Active Fraction (HS7) from Taiwanofungus camphoratus
Authors: Yeh Chi-Tai , Yao Chih-Jung , Yan Jiann-Long , Chuang Shuang-En , Lee Liang-Ming , Chen Chien-Ming , Yeh Chuan-Feng , Li Chi-Han , Lai Gi-Ming
Published: March 2011

Aberrant activation of Wnt/β‐catenin signaling plays an important role in the development of colon cancer. HS7 is an active fraction extracted from Taiwanofungus camphoratus, which had been widely used as complementary medicine for Taiwan cancer patients in the past decades. In this study, we demonstrated the effects of HS7 on the growth inhibition, apoptosis induction, and Wnt/β‐catenin signaling suppression in human colon cancer cells. HS7 significantly inhibited proliferation of HT29, HCT116, and SW480 colon cancer cells in a dose‐ and time‐dependent manner. The apoptosis induction was evidenced by DNA fragmentation and subG1 accumulation, which was associated with increased Bax/Bcl‐2 ratio, activation of caspase‐3 and cleavage of PARP. By using Tcf‐dependent luciferase activity assay, HS7 was found to inhibit the β‐catenin/Tcf transcriptional activities. In addition, HS7 strongly suppressed the binding of Tcf complexes to its DNA‐binding site shown in electrophoretic mobility shift assay. This inhibition was further confirmed by the decreased protein levels of Tcf‐4 and β‐catenin. The β‐catenin/Tcf downstream target genes, such as survivin, c-myc, cyclin D1, MMP7, and MT1-MMP involved in apoptosis, invasion, and angiogenesis were also diminished as well. These results indicate that Taiwanofungus camphoratus may provide a benefit as integrative medicine for the treatment of colon cancer.
Higher Volume at Time of Breast Conserving Surgery Reduces Re-Excision in DCIS
Authors: Wolf J. H. , Wen Y. , Axelrod D. , Roses D. , Guth A. , Shapiro R. , Cohen J. , Singh B.
Published: March 2011

Purpose. The purpose of this study was to compare the surgical and pathological variables which impact rate of re-excision following breast conserving therapy (BCS) with or without concurrent additional margin excision (AM).Methods. The pathology database was queried for all patients with DCIS from January 2004 to September 2008. Pathologic assessment included volume of excision, subtype, size, distance from margin, grade, necrosis, multifocality, calcifications, and ER/PR status.Results. 405 cases were identified and 201 underwent BCS, 151-BCS-AM, and 53-mastectomy. Among the 201 BCS patients, 190 underwent re-excision for close or involved margins. 129 of these were treated with BCS and 61 with BCS-AM (P<.0001). The incidence of residual DCIS in the re-excision specimens was 32% (n=65) for BCS and 22% (n=33) for BCS-AM (P<.05). For both the BCS and the BCS-AM cohorts, volume of tissue excised is inversely correlated to the rate of re-excision (P=.0284). Multifocality (P=.0002) and ER status (P=.0382) were also significant predictors for rate of re-excision and variation in surgical technique was insignificant.Conclusions.The rate of positive margins, re-excision, and residual disease was significantly higher in patients with lower volume of excision. The performance of concurrent additional margin excision increases the efficacy of BCS for DCIS.
Dual Solutions on Thermosolutal Marangoni Forced Convection Boundary Layer with Suction and Injection
Authors: Hamid R. A. , Arifin N. M. , Nazar R. , Ali F. M. , Pop I.
Published: March 2011

This paper considers the extended problem of the thermosolutal Marangoni forced convection boundary layer by Pop et al. (2001) when the wall is permeable, namely, there is a suction or injection effect. The governing system of partial differential equations is transformed into a system of ordinary differential equations, and the transformed equations are solved numerically using the shooting method. The effects of suction or injection parameter
f0 on the velocity, temperature, and concentration profiles are illustrated and presented in tables and figures. It is shown that dual solutions exist for the similarity parameter β less than 0.5.
Acupuncture Treatment for Bortezomib-Induced Peripheral Neuropathy: A Case Report
Authors: Bao Ting , Zhang Ruixin , Badros Ashraf , Lao Lixing
Published: March 2011

Peripheral neuropathy is a common and severe dose-limiting side effect of the chemotherapy agent, bortezomib, in multiple myeloma patients. Treatment with narcotics, antidepressants, and anticonvulsants has limited response and potential significant side effects. Acupuncture has been reported to be effective in treating diabetic neuropathy and chemo-induced peripheral neuropathy. There has not been report on the effect of acupuncture in treating bortezomib-induced peripheral neuropathy specifically. Here, we report a successful case of using acupuncture to relieve bortezomib-induced peripheral neuropathy symptoms.
Heavy Chain Ferritin siRNA Delivered by Cationic Liposomes Increases Sensitivity of Cancer Cells to Chemotherapeutic Agents
Authors: Liu Xiaoli , Madhankumar A.B. , Slagle-Webb Becky , Sheehan Jonas M. , Surguladze Nodar , Connor James R.
Published: March 2011

Approximately half of all gliomas are resistant to chemotherapy, and new therapeutic strategies are urgently needed to treat this cancer. We hypothesized that disrupting iron homeostasis in glioma cells could block tumor growth, based on an acute requirement for high levels of iron to meet energy requirements associated with their rapid growth. Ferritin is best known as an intracellular iron storage protein, but it also localizes to tumor cell nuclei where it seems to protect DNA from oxidative damage and to promote transcription. In this study, we hypothesize that silencing the H-ferritin (heavy chain ferritin) gene could increase tumor sensitivity to chemotoxins. To test this hypothesis, H-ferritin siRNA was delivered to several human cancer cell lines by using cationic liposomes (C-liposome). H-ferritin siRNA decreased protein expression by 80% within 48 hours, and this decrease was associated with more than 50% decrease in the LD50 for DNA-alkylating agent carmustine (BCNU), which is commonly used to treat glioma in clinic. In a subcutaneous mouse model of human glioma, intratumoral injections of liposomes containing H-ferritin siRNA reduced the effective dose of BCNU needed for tumor suppression by more than 50%. A plasmid supercoil relaxation assay showed that H-ferritin specifically and directly protected DNA from BCNU treatment. H-ferritin siRNA additionally seemed to increase apoptosis in glioma cells in vitro upon H-ferritin knockdown. Overall, our results illustrate how silencing H-ferritin can effectively sensitize tumors to chemotherapy and also show the ability of C-liposomes to serve as a novel in vivo delivery tool for siRNAs. Cancer Res; 71(6); 2240–9. ©2011 AACR.
miR-218 Suppresses Nasopharyngeal Cancer Progression through Downregulation of Survivin and the SLIT2-ROBO1 Pathway
Authors: Alajez Nehad M. , Lenarduzzi Michelle , Ito Emma , Hui Angela B.Y. , Shi Wei , Bruce Jeff , Yue Shijun , Huang Shao H. , Xu Wei , Waldron John , O'Sullivan Brian , Liu Fei-Fei
Published: March 2011

Nasopharayngeal carcinoma (NPC) is an Epstein–Barr virus–associated malignancy most common in East Asia and Africa. Here we report frequent downregulation of the microRNA miR-218 in primary NPC tissues and cell lines where it plays a critical role in NPC progression. Suppression of miR-218 was associated with epigenetic silencing of SLIT2 and SLIT3, ligands of ROBO receptors that have been previously implicated in tumor angiogenesis. Exogenous expression of miR-218 caused significant toxicity in NPC cells in vitro and delayed tumor growth in vivo. We used an integrated trimodality approach to identify targets of miR-218 in NPC, cervical, and breast cell lines. Direct interaction between miR-218 and the 3′-untranslated regions (UTR) of mRNAs encoding ROBO1, survivin (BIRC5), and connexin43 (GJA1) was validated in a luciferase-based transcription reporter assay. Mechanistic investigations revealed a negative feedback loop wherein miR-218 regulates NPC cell migration via the SLIT-ROBO pathway. Pleotropic effects of miR-218 on NPC survival and migration were rescued by enforced expression of miR-218–resistant, engineered isoforms of survivin and ROBO1, respectively. In clinical specimens of NPC (n = 71), ROBO1 overexpression was significantly associated with worse overall (P = 0.04, HR = 2.4) and nodal relapse-free survival (P = 0.008, HR = 6.0). Our findings define an integrative tumor suppressor function for miR-218 in NPC and further suggest that restoring miR-218 expression in NPC might be useful for its clinical management. Cancer Res; 71(6); 2381–91. ©2011 AACR.
CREB Is a Novel Nuclear Target of PTEN Phosphatase
Authors: Gu Tingting , Zhang Zhong , Wang Jianli , Guo Junyi , Shen Wen Hong , Yin Yuxin
Published: March 2011

PTEN phosphatase is a potent tumor suppressor that regulates multiple cellular functions. In the cytoplasm, PTEN dephosphorylates its primary lipid substrate, phosphatidylinositol 3,4,5-trisphosphate, to antagonize the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway. It has also become increasingly evident that PTEN functions in the nucleus and may play an important part in transcription regulation, but its nuclear targets remain elusive. In this report, we demonstrate the transcription factor cyclic AMP response element-binding protein (CREB) is a protein target of PTEN phosphatase and that PTEN deficiency leads to CREB phosphorylation independent of the PI3K/AKT pathway. Using confocal immunofluorescence and reciprocal immunoprecipitation, we further show that PTEN colocalizes with CREB and physically interacts with CREB. Moreover, we use both in vitro and in vivo experiments to show PTEN can dephosphorylate CREB in a phosphatase-dependent manner, suggesting that CREB is a substrate of PTEN nuclear phosphatase. Loss of Pten results in an elevated RNA level of multiple CREB transcriptional targets and increased cell proliferation, which can be reversed by a nonphosphorylatable CREB mutant or knockdown of CREB. These data reveal a mechanism for PTEN modulation of CREB-mediated gene transcription and cell growth. Our study thus characterizes PTEN as a nuclear phophatase of a transcription factor and identifies CREB as a novel protein target of PTEN phosphatase, which contributes to better understanding of PTEN function in the nucleus. Cancer Res; 71(8); 2821–5. ©2011 AACR.
Functional Cooperation of RKTG with p53 in Tumorigenesis and Epithelial–Mesenchymal Transition
Authors: Jiang Yuhui , Xie Xiaoduo , Li Zhigang , Wang Zheng , Zhang Yixuan , Ling Zhiqiang , Pan Yi , Wang Zhenzhen , Chen Yan
Published: March 2011

Raf kinase trapping to Golgi (RKTG) is a potential tumor suppressor gene due to its negative roles in regulating Ras/Raf/MEK/ERK (extracellular signal–regulated kinase) pathway and GPCR (G protein–coupled receptor) Gβγ subunit signaling. Interestingly, RKTG-deficient mice are free of tumors, although they are prone to form skin cancer on carcinogen administration. On the other hand, p53 is a well-characterized tumor suppressor gene and p53 heterozygous mice develop sarcoma and other tumors starting from 12 months of age. In RKTG-null mouse embryonic fibroblasts, lypophosphatidic acid (LPA), but not EGF (epidermal growth factor), could stimulate hyperphosphorylation of AKT and GSK3β, accompanied by increases in phosphorylation of p53 at Ser15 and accumulation of p53, as well as its target genes p21 and p16. Spontaneous skin cancer–like tumors were detected in about 25% of RKTG nullizygous and p53 heterozygous mice within 7 months of age. Hyperplasia and epithelial–mesenchymal transition (EMT) were observed in the tumor-overlying epidermis, in which LOH of p53 occurred and EMT features emerged. In p53-mutated A431 epithelial carcinoma cells, knockdown of RKTG led to enhancement of LPA-stimulated AKT and GSK3β phosphorylation, together with increased accumulation of β-catenin and appearance of EMT features that were antagonized by p53 overexpression. In HepG2 epithelial cells, LPA-stimulated AKT phosphorylation and EMT features reached maximum when both RKTG and p53 were simultaneously silenced. In summary, these results not only indicate that RKTG has an in vivo tumor suppressor function to cooperate with p53 in tumorigenesis but also suggest that p53 has an EMT checkpoint function and the loss of this function can combine with loss of RKTG to drive EMT and tumor progression. Cancer Res; 71(8); 2959–68. ©2011 AACR.
A Developmental Taxonomy of Glioblastoma Defined and Maintained by MicroRNAs
Authors: Kim Tae-Min , Huang Wei , Park Richard , Park Peter J. , Johnson Mark D.
Published: March 2011

mRNA expression profiling has suggested the existence of multiple glioblastoma subclasses, but their number and characteristics vary among studies and the etiology underlying their development is unclear. In this study, we analyzed 261 microRNA expression profiles from The Cancer Genome Atlas (TCGA), identifying five clinically and genetically distinct subclasses of glioblastoma that each related to a different neural precursor cell type. These microRNA-based glioblastoma subclasses displayed microRNA and mRNA expression signatures resembling those of radial glia, oligoneuronal precursors, neuronal precursors, neuroepithelial/neural crest precursors, or astrocyte precursors. Each subclass was determined to be genetically distinct, based on the significant differences they displayed in terms of patient race, age, treatment response, and survival. We also identified several microRNAs as potent regulators of subclass-specific gene expression networks in glioblastoma. Foremost among these is miR-9, which suppresses mesenchymal differentiation in glioblastoma by downregulating expression of JAK kinases and inhibiting activation of STAT3. Our findings suggest that microRNAs are important determinants of glioblastoma subclasses through their ability to regulate developmental growth and differentiation programs in several transformed neural precursor cell types. Taken together, our results define developmental microRNA expression signatures that both characterize and contribute to the phenotypic diversity of glioblastoma subclasses, thereby providing an expanded framework for understanding the pathogenesis of glioblastoma in a human neurodevelopmental context. Cancer Res; 71(9); 3387–99. ©2011 AACR.
Targeting Galectin-1 in Carcinoma-Associated Fibroblasts Inhibits Oral Squamous Cell Carcinoma Metastasis by Downregulating MCP-1/CCL2 Expression
Authors: Wu Ming-Heng , Hong Hsiao-Chin , Hong Tse-Ming , Chiang Wei-Fan , Jin Ying-Tai , Chen Yuh-Ling
Published: March 2011

Purpose: Carcinoma-associated fibroblasts (CAFs) in tumor stroma play an important role in tumor progression and have been associated with a poor prognosis in oral squamous cell carcinoma (OSCC). However, how CAFs influence OSCC malignancy and whether normalizing CAFs inhibits cancer progression remain unclear.

Experimental Design: The relationship between the expression of Galectin-1 (Gal-1) and alpha-smooth muscle actin (α-SMA, a CAF marker) in OSCC patient samples and primary cultured CAFs was examined by quantitative real-time PCR, Western blotting, and immunofluorescence. To examine the effect of Gal-1 on CAF activation and CAF-mediated tumor invasion and migration in vitro, Gal-1 expression was knocked down by small hairpin RNA. Finally, cancer cells and CAFs were coimplanted into SCID mice to evaluate the effect of Gal-1 on CAF-modulated tumor progression in vivo.

Results: Gal-1 expression is positively associated with α-SMA in the stroma of OSCC specimens. Gal-1 knockdown decreases activated CAF characteristics, resulting in a decrease in α-SMA expression and extracellular matrix protein production. Notably, blocking Gal-1 expression significantly inhibits CAF-conditioned medium-induced tumor cell migration and invasion, possibly by reducing the production of monocyte chemotactic protein-1 (MCP-1/CCL2). MCP-1 induces the migration of OSCC cells by binding to the receptor CCR2; adding an MCP-1 antibody to CAF-conditioned medium that inhibits the interaction between MCP-1 and CCR2 abolishes migration. Finally, we found that Gal-1 knockdown in CAFs significantly reduces CAF-augmented tumor growth and metastasis in vivo.

Conclusions: Our findings demonstrate that Gal-1 regulates CAF activation and indicate that targeting Gal-1 in CAFs inhibits OSCC metastasis by modulating MCP-1 expression. Clin Cancer Res; 17(6); 1306–16. ©2011 AACR.
Transcription-Induced DNA Double Strand Breaks: Both Oncogenic Force and Potential Therapeutic Target?
Authors: Haffner Michael C. , De Marzo Angelo M. , Meeker Alan K. , Nelson William G. , Yegnasubramanian Srinivasan
Published: March 2011

An emerging model of transcriptional activation suggests that induction of transcriptional programs, for instance by stimulating prostate or breast cells with androgens or estrogens, respectively, involves the formation of DNA damage, including DNA double strand breaks (DSB), recruitment of DSB repair proteins, and movement of newly activated genes to transcription hubs. The DSB can be mediated by the class II topoisomerase TOP2B, which is recruited with the androgen receptor and estrogen receptor to regulatory sites on target genes and is apparently required for efficient transcriptional activation of these genes. These DSBs are recognized by the DNA repair machinery triggering the recruitment of repair proteins such as poly(ADP-ribose) polymerase 1 (PARP1), ATM, and DNA-dependent protein kinase (DNA-PK). If illegitimately repaired, such DSBs can seed the formation of genomic rearrangements like the TMPRSS2-ERG fusion oncogene in prostate cancer. Here, we hypothesize that these transcription-induced, TOP2B-mediated DSBs can also be exploited therapeutically and propose that, in hormone-dependent tumors like breast and prostate cancers, a hormone-cycling therapy, in combination with topoisomerase II poisons or inhibitors of the DNA repair components PARP1 and DNA-PK, could overwhelm cancer cells with transcription-associated DSBs. Such strategies may find particular utility in cancers, like prostate cancer, which show low proliferation rates, in which other chemotherapeutic strategies that target rapidly proliferating cells have had limited success. Clin Cancer Res; 17(12); 3858–64. ©2011 AACR.
Involvement of the TGF-β and β-Catenin Pathways in Pelvic Lymph Node Metastasis in Early-Stage Cervical Cancer
Authors: Noordhuis Maartje G. , Fehrmann Rudolf S.N. , Wisman G. Bea A. , Nijhuis Esther R. , van Zanden Jelmer J. , Moerland Perry D. , Ver Loren van Themaat Emiel , Volders Haukeline H. , Kok Mirjam , ten Hoor Klaske A. , Hollema Harry , de Vries Elisabeth G.E. , de Bock Geertruida H. , van der Zee Ate G.J. , Schuuring Ed
Published: March 2011

Purpose: Presence of pelvic lymph node metastases is the main prognostic factor in early-stage cervical cancer patients, primarily treated with surgery. Aim of this study was to identify cellular tumor pathways associated with pelvic lymph node metastasis in early-stage cervical cancer.

Experimental Design: Gene expression profiles (Affymetrix U133 plus 2.0) of 20 patients with negative (N0) and 19 with positive lymph nodes (N+), were compared with gene sets that represent all 285 presently available pathway signatures. Validation immunostaining of tumors of 274 consecutive early-stage cervical cancer patients was performed for representatives of the identified pathways.

Results: Analysis of 285 pathways resulted in identification of five pathways (TGF-β, NFAT, ALK, BAD, and PAR1) that were dysregulated in the N0, and two pathways (β-catenin and Glycosphingolipid Biosynthesis Neo Lactoseries) in the N+ group. Class comparison analysis revealed that five of 149 genes that were most significantly differentially expressed between N0 and N+ tumors (P < 0.001) were involved in β-catenin signaling (TCF4, CTNNAL1, CTNND1/p120, DKK3, and WNT5a). Immunohistochemical validation of two well-known cellular tumor pathways (TGF-β and β-catenin) confirmed that the TGF-β pathway (positivity of Smad4) was related to N0 (OR: 0.20, 95% CI: 0.06–0.66) and the β-catenin pathway (p120 positivity) to N+ (OR: 1.79, 95%CI: 1.05–3.05).

Conclusions: Our study provides new, validated insights in the molecular mechanism of lymph node metastasis in cervical cancer. Pathway analysis of the microarray expression profile suggested that the TGF-β and p120-associated noncanonical β-catenin pathways are important in pelvic lymph node metastasis in early-stage cervical cancer. Clin Cancer Res; 17(6); 1317–30. ©2011 AACR.
Targeting the BMK1 MAP Kinase Pathway in Cancer Therapy
Authors: Yang Qingkai , Lee Jiing-Dwan
Published: March 2011

The big mitogen activated protein kinase 1 (BMK1) pathway is the most recently discovered and least-studied mammalian mitogen-activated protein (MAP) kinase cascade, ubiquitously expressed in all types of cancer cells tested so far. Mitogens and oncogenic signals strongly activate this cellular MAP kinase pathway, thereby passing down proliferative, survival, chemoresistance, invasive, and angiogenic signals in tumor cells. Recently, several pharmacologic small molecule inhibitors of this pathway have been developed. Among them, the BMK1 inhibitor XMD8–92 blocks cellular BMK1 activation and significantly suppresses tumor growth in lung and cervical tumor models and is well tolerated in animals. On the other hand, MEK5 inhibitors, BIX02188, BIX02189, and compound 6, suppress cellular MEK5 activity, but no data exist to date on their effectiveness in animals. Clin Cancer Res; 17(11); 3527–32. ©2011 AACR.
Drozitumab, a Human Antibody to Death Receptor 5, Has Potent Antitumor Activity against Rhabdomyosarcoma with the Expression of Caspase-8 Predictive of Response
Authors: Kang Zhigang , Chen Jun-Jie , Yu Yunkai , Li Bo , Sun Shi-Yong , Zhang Baolin , Cao Liang
Published: March 2011

Purpose: Rhabdomyosarcoma (RMS) is a common pediatric soft-tissue tumor. In this study, we evaluated the efficacy and selectivity of drozitumab, a death receptor DR5-targeted therapeutic antibody, in RMS preclinical models.

Experimental Design: A panel of 11 RMS cell lines was used for in vitro studies. The molecular marker predictive of response to drozitumab was interrogated. Selected RMS cell lines were injected into the gastrocnemius muscle of mice for in vivo assessment of the potency and selectivity of drozitumab.

Results: We report that DR5, but not DR4, persisted at high levels and on the surface of all RMS cell lines. DR5 antibody drozitumab was effective in vitro against the majority of RMS cell lines. There was a strong correlation between caspase-8 expression and the sensitivity to drozitumab, which induced the rapid assembly of the death-induced signaling complex and the cleavage of caspase-8 only in sensitive cells. More importantly, caspase-8 catalytic activity was both necessary and sufficient for mediating the sensitivity to drozitumab. Furthermore, drozitumab had potent antitumor activity against established RMS xenografts with a specificity predicted from the in vitro analysis and with tumor-free status in half of the treated mice.

Conclusion: Our study provides the first preclinical evaluation of the potency and selectivity of a death receptor antibody in RMS. Drozitumab is effective, in vitro, against the majority of RMS cell lines that express caspase-8 and, in vivo, may provide long-term control of RMS. Clin Cancer Res; 17(10); 3181–92. ©2011 AACR.
Imaging and Therapy with Rituximab Anti-CD20 Immunotherapy in an Animal Model of Central Nervous System Lymphoma
Authors: Muldoon Leslie L. , Lewin Seth J. , Dósa Edit , Kraemer Dale F. , Pagel Michael A. , Doolittle Nancy D. , Neuwelt Edward A.
Published: March 2011

Purpose: To evaluate the effect of rituximab monoclonal antibody (mAb) on MRI tumor volumetrics and efficacy in a rat model of central nervous system (CNS) lymphoma when delivery to the brain was optimized with osmotic blood–brain barrier disruption (BBBD).

Experimental Design: Female nude rats with intracerebral MC116 human B-cell lymphoma xenografts underwent baseline MRI and were randomized into 5 groups (n = 6 per group): (i) BBBD saline control; (ii) methotrexate with BBBD; (iii) rituximab with BBBD; (iv) rituximab and methotrexate with BBBD; and (v) intravenous rituximab. Tumor volumes were assessed by MRI at 1 week, and rats were followed for survival.

Results: BBBD increased delivery of yttrium-90-radiolabeled mAb in the model of CNS lymphoma. Control rats showed 201 ± 102% increase in tumor volume on MRI 1 week after entering the study and median 14-day survival (range: 6–33). Tumor growth on MRI was slowed in the methotrexate treatment group, but survival time (median: 7 days; range: 5–12) was not different from controls. Among 17 evaluable rats treated with rituximab, 10 showed decreased tumor volume on MRI. All rituximab groups had increased survival compared with control, with a combined median of 43 days (range: 20–60, P < 0.001). There were no differences by route of delivery or combination with methotrexate.

Conclusions: Rituximab was effective at decreasing tumor volume and improving survival in a model of CNS lymphoma and was not affected by combination with methotrexate or by BBBD. We suggest that rituximab warrants further study in human primary CNS lymphoma. Clin Cancer Res; 17(8); 2207–15. ©2011 AACR.
Comparison of Corticotropin-Releasing Factor, Dexamethasone, and Temozolomide: Treatment Efficacy and Toxicity in U87 and C6 Intracranial Gliomas
Authors: Moroz Maxim A. , Huang Ruimin , Kochetkov Tatiana , Shi Weiji , Thaler Howard , de Stanchina Elisa , Gamez Idoia , Ryan Robert P. , Blasberg Ronald G.
Published: March 2011

Purpose/Experimental Design: Treatment of cerebral tumors and peritumoral brain edema remains a clinical challenge and is associated with high morbidity and mortality. Dexamethasone is an effective drug for treating brain edema, but it is associated with well-documented side effects. Corticorelin acetate (Xerecept) or human corticotrophin-releasing factor (hCRF) is a comparatively new drug and has been evaluated in two orthotopic glioma models (U87 and C6), by a direct comparison with dexamethasone and temozolomide.

Results: In vitro combination therapy and monotherapy showed a variable response in 6 different glioma cell lines. In vivo studies showed a dose-dependent effect of hCRF (0.03 and 0.1 mg/kg q12h) on survival of U87 intracranial xenograft–bearing animals [median survival: control – 41 days (95% CI 25–61); “low-hCRF” 74.5 days (95% CI 41–88); “high-hCRF” >130 days (95% CI not reached)]. Dexamethasone treatment had no effect on survival, but significant toxicity was observed. A survival benefit was observed with temozolomide and temozolomide + hCRF-treated animals but with significant temozolomide toxicity. C6-bearing animals showed no survival benefit, but there were similar treatment toxicities. The difference in hCRF treatment response between U87 and C6 intracranial gliomas can be explained by a difference in receptor expression. RT-PCR identified CRF2r mRNA in U87 xenografts; no CRF receptors were identified in C6 xenografts.

Conclusions: hCRF was more effective than either dexamethasone or temozolomide in the treatment of U87 xenografts, and results included improved prognosis with long-term survivors and only mild toxicity. The therapeutic efficacy of hCRF seems to be dependent on tumor hCRF receptor (CRFr) expression. These results support further clinical assessment of the therapeutic efficacy of hCRF and levels of CRFr expression in different human gliomas. Clin Cancer Res; 17(10); 3282–92. ©2011 AACR.
BRAFV600E: Implications for Carcinogenesis and Molecular Therapy
Authors: Cantwell-Dorris Emma R. , O'Leary John J. , Sheils Orla M.
Published: March 2011

The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway is frequently mutated in human cancer. This pathway consists of a small GTP protein of the RAS family that is activated in response to extracellular signaling to recruit a member of the RAF kinase family to the cell membrane. Active RAF signals through MAP/ERK kinase to activate ERK and its downstream effectors to regulate a wide range of biological activities including cell differentiation, proliferation, senescence, and survival. Mutations in the v-raf murine sarcoma viral oncogenes homolog B1 (BRAF) isoform of the RAF kinase or KRAS isoform of the RAS protein are found as activating mutations in approximately 30% of all human cancers. The BRAF pathway has become a target of interest for molecular therapy, with promising results emerging from clinical trials. Here, the role of the most common BRAF mutation BRAFV600E in human carcinogenesis is investigated through a review of the literature, with specific focus on its role in melanoma, colorectal, and thyroid cancers and its potential as a therapeutic target. Mol Cancer Ther; 10(3); 385–94. ©2011 AACR.
Apoptosis Is the Essential Target of Selective Pressure against p53, whereas Loss of Additional p53 Functions Facilitates Carcinoma Progression
Authors: Lu Xiangdong , Yang Chunyu , Yin Chaoying , Van Dyke Terry , Simin Karl
Published: March 2011

The high frequency of p53 mutation in human cancers indicates the important role of p53 in suppressing tumorigenesis. It is well established that the p53 regulates multiple, distinct cellular functions such as cell-cycle arrest and apoptosis. Despite intensive studies, little is known about which function is essential, or if multiple pathways are required, for p53-dependent tumor suppression in vivo. Using a mouse brain carcinoma model that shows high selective pressure for p53 inactivation, we found that even partially abolishing p53-dependent apoptosis by Bax inactivation was sufficient to significantly reduce the selective pressure for p53 loss. This finding is consistent with previous reports that apoptosis is the primary p53 function selected against during Eμ-myc–induced mouse lymphoma progression. However, unlike observed in the Eμ-myc–induced lymphoma model, attenuation of apoptosis is not sufficient to phenocopy the aggressive tumor progression associated with complete loss of p53 activity. We conclude that apoptosis is the primary tumor suppressive p53 function and the ablation of additional p53 pleiotropic effects further exacerbates tumor progression. Mol Cancer Res; 9(4); 430–9. ©2011 AACR.