bluuebunny/crossref_metadata_2025 huggingface dataset:
NBM-T-L-BMX-OS01, Semisynthesized from Osthole, Is a Novel Inhibitor of Histone Deacetylase and Enhances Learning and Memory in Rats
Authors: Yang Ying-Chen , Chen Chia-Nan , Wu Carol-Imei , Huang Wei-Jan , Kuo Tsun-Yung , Kuan Ming-Chung , Tsai Tung-Hu , Huang Jing-Shi , Huang Chung-Yang
Published: March 2013

NBM-T-L-BMX-OS01 (BMX) was derived from the semisynthesis of osthole, isolated fromCnidium monnieri(L.) Cuss., and was identified to be a potent inhibitor of HDAC8. This study shows that HDAC8 is highly expressed in the pancreas and the brain. The function of HDAC8 in the brain has not been adequately studied. Because BMX enhances neurite outgrowth and cAMP response element-binding protein (CREB) activation, the effect of BMX on neural plasticity such as learning and memory is examined. To examine declarative and nondeclarative memory, a water maze, a passive one-way avoidance task, and a novel object recognition task were performed. Results from the water maze revealed that BMX and suberoylanilide-hydroxamic-acid-(SAHA-) treated rats showed shorter escape latency in finding the hidden platform. The BMX-treated animals spent more time in the target quadrant in the probe trial performance. An analysis of the passive one-way avoidance results showed that the BMX-treated animals stayed longer in the illuminated chamber by 1 day and 7 days after footshock. The novel object recognition task revealed that the BMX-treated animals showed a marked increase in the time spent exploring novel objects. Furthermore, BMX ameliorates scopolamine-(Sco-) induced learning and memory impairment in animals, indicating a novel role of BMX in learning and memory.
Efficient Removal of Cr(VI) with Fe/Mn Mixed Metal Oxide Nanocomposites Synthesized by a Grinding Method
Authors: Weilong Wang , Xiaobo Fu
Published: March 2013

Fe/Mn mixed metal oxides were synthesized facilely by a grinding method and were characterized by TEM, XRD, XPS, and BET. The characterization results revealed that mixed metal oxides were mainly composed of not highly crystallized Fe2O3 and Mn3O4 nanoparticles with a diameter about 3–5 nm. The specific BET surface areas of the composite were affected by the amounts of KCl diluent in the preparation process and about 268 m2/g of the composite can be achieved. Compared with metal oxide adsorbents existent, the composites showed good adsorption capacity, stability, and regeneration activity for Cr(VI) removal. The enhanced adsorption capacity was speculated to be ascribed to the synergistic effect of the mixed metal oxides. By monitoring the valence change in the adsorption process using XPS characterization, the mechanism for Cr(VI) removal on the composites was found to be a combination of electrostatic attraction and ion exchange. The above results demonstrated that the synthesized metal oxides nanocomposite is of great potential for Cr(VI) removal in the fields of remediation of environmental problems.
A Systems Biology-Based Investigation into the Pharmacological Mechanisms of Wu Tou Tang Acting on Rheumatoid Arthritis by Integrating Network Analysis
Authors: Zhang Yanqiong , Wang Danhua , Tan Shufang , Xu Haiyu , Liu Chunfang , Lin Na
Published: March 2013

Aim. To investigate pharmacological mechanisms of Wu Tou Tang acting on rheumatoid arthritis (RA) by integrating network analysis at a system level.Methods and Results. Drug similarity search tool in Therapeutic Targets Database was used to screen 153 drugs with similar structures to compositive compounds of each ingredient in Wu Tou Tang and to identify 56 known targets of these similar drugs as predicted molecules which Wu Tou Tang affects. The recall, precision, accuracy, and F1-score, which were calculated to evaluate the performance of this method, were, respectively, 0.98, 0.61, 59.67%, and 0.76. Then, the predicted effector molecules of Wu Tou Tang were significantly enriched in neuroactive ligand-receptor interaction and calcium signaling pathway. Next, the importance of these predicted effector molecules was evaluated by analyzing their network topological features, such as degree, betweenness, andk-coreness. We further elucidated the biological significance of nine major candidate effector molecules of Wu Tou Tang for RA therapy and validated their associations with compositive compounds in Wu Tou Tang by the molecular docking simulation.Conclusion. Our data suggest the potential pharmacological mechanisms of Wu Tou Tang acting on RA by combining the strategies of systems biology and network pharmacology.
Optimal Model of Operation Parameters of Gathering Pipeline Network with Triple-Line Process
Authors: Liang Yongtu , Lu Cen , Ren Kuijie , Xiao Qiao , He Guoxi
Published: March 2013

This is a mathematic model for the optimal operation of the gathering pipeline network and its solution provides this gathering pipeline network having a triple-line heat-tracing process, a method for reducing the operational costs and increasing economic benefit. The model consists of an objective function, minimum total operation cost, and 3 constraints including water temperature constraint at pipe nodes, inlet oil temperature constraints, and outlet water temperature constraint. By using a sequential quadratic programming algorithm, the model can be solved and a set of optimal mass rate and the desired temperature of tracing water are attained. The method is here specifically applied to the optimal operation analysis of a gathering pipeline network in North China Oilfield. The result shows its operation cost can be reduced by 2076RMB/d, which demonstrates that this method contributes to the production cost reduction of old oilfields in their high water-cut stage.
A Conflict Avoidance Scheme for WiMedia Wireless Home Networks
Authors: Hur Kyeong , Sohn Won-Sung , Lee YangSun
Published: March 2013

We propose an efficient resource reservation scheme for UWB (Ultrawideband) WPAN (Wireless Personal Area Network) with D-MAC (Distributed Medium Access Control). Since the WiMedia D-MAC supporting DRP (Distributed Reservation Protocol) scheme causes lots of conflicts due to failure of beacon detection in wireless channel environment, overall performances of the WiMedia D-MAC can be deteriorated. Therefore, we propose Relay DRP protocol, which makes a relay path to avoid DRP conflicts or harsh channel conditions through cooperative relay transmission scheme and is compliant with the current WiMedia D-MAC protocol. Simulation results demonstrate performance improvements of the proposed method for throughput and energy consumption.
Conditional Maximum Likelihood Estimation in Polytomous Rasch Models Using SAS
Authors: Christensen Karl Bang
Published: March 2013

IRT models are widely used but often rely on distributional assumptions about the latent variable. For a simple class of IRT models, the Rasch models, conditional inference is feasible. This enables consistent estimation of item parameters without reference to the distribution of the latent variable in the population. Traditionally, specialized software has been needed for this, but conditional maximum likelihood estimation can be done using standard software for fitting generalized linear models. This paper describes an SAS macro %rasch_cml that fits polytomous Rasch models. The macro estimates item parameters using conditional maximum likelihood (CML) estimation and person locations using maximum likelihood estimator (MLE) and Warm's weighted likelihood estimation (WLE). Graphical presentations are included: plots of item characteristic curves (ICCs), and a graphical goodness-of-fit-test is also produced.
Crystalline-Like Keratopathy after Intravenous Immunoglobulin Therapy with Incomplete Kawasaki Disease: Case Report and Literature Review
Authors: Erdem Elif , Kocabas Emine , Taylan Sekeroglu Hande , Özgür Özlem , Yagmur Meltem , Ersoz T. Reha
Published: March 2013

A 7-year-old girl had presented with high body temperature and joint pain which continued for 3 days. Because of the prolonged history of unexplained fever, rash, bilateral nonpurulent conjunctival injection, oropharyngeal erythema, strawberry tongue, and extreme of age, incomplete Kawasaki disease was considered and started on an intravenous immunoglobulin infusion. Six days after this treatment, patient was referred to eye clinic with decreased vision and photophobia. Visual acuity was reduced to 20/40 in both eyes. Slit-lamp examination revealed bilateral diffuse corneal punctate epitheliopathy and anterior stromal haze. Corneal epitheliopathy seemed like crystal deposits. One day after presentation, mild anterior uveitis was added to clinical picture. All ocular findings disappeared in one week with topical steroid and unpreserved artificial tear drops. We present a case who was diagnosed as incomplete Kawasaki disease along with bilateral diffuse crystalline-like keratopathy. We supposed that unusual ocular presentation may be associated with intravenous immunoglobulin treatment.
Understanding Dendritic Cells and Their Role in Cutaneous Carcinoma and Cancer Immunotherapy
Authors: Yanofsky Valerie R. , Mitsui Hiroshi , Felsen Diane , Carucci John A.
Published: March 2013

Dendritic cells (DC) represent a diverse group of professional antigen-presenting cells that serve to link the innate and adaptive immune systems. Their capacity to initiate a robust and antigen-specific immune response has made them the ideal candidates for cancer immunotherapies. To date, the clinical impact of DC immunotherapy has been limited, which may, in part, be explained by the complex nature of DC biology. Multiple distinct subsets of DCs have been identified in the skin, where they can be broadly subcategorized into epidermal Langerhans cells (LC), myeloid-derived dermal dendritic cells (mDC) and plasmacytoid dendritic cells (pDC). Each subset is functionally unique and may activate alternate branches of the immune system. This may be relevant for the treatment of squamous cell carcinoma, where we have shown that the tumor microenvironment may preferentially suppress the activity of mDCs, while LCs remain potent stimulators of immunity. Here, we provide an in depth analysis of DC biology, with a particular focus on skin DCs and their role in cutaneous carcinoma. We further explore the current approaches to DC immunotherapy and provide evidence for the targeting of LCs as a promising new strategy in the treatment of skin cancer.
Research and Development for Botanical Products in Medicinals and Food Supplements Market
Authors: Miroddi Marco , Mannucci Carmen , Mancari Ferdinando , Navarra Michele , Calapai Gioacchino
Published: March 2013

Botanical products sold in the health area are generally intended as drugs, medicinal products, food supplements or substances for therapeutic use. Use of botanicals for improving or to care human health has evolved independently in different countries worldwide. Regulatory issues regarding botanical products designed for the food supplements or medicinal market and their influence on research and development are discussed. European Union (EU) and United States (US) policies regulating these products are focused with comments on the legislations delivered during the last ten years and differences existing in rules between these countries are emphasized. Research and development on botanical products nowdays strongly influenced by the product destination in the market. Addressed and differentiated research for either food supplements or medicinal markets is necessary to purchase data really useful for assessment of safe and effective use for both the categories. The main objective is to catalyze interest of academic and companies' researchers on crucial aspects to be taken into account in the research for the development of botanical products.
Inflammasome in Intestinal Inflammation and Cancer
Authors: Nunes Tiago , de Souza Heitor S.
Published: March 2013

The activation of specific cytosolic pathogen recognition receptors, the nucleotide-binding-oligomerization-domain- (NOD-) like receptors (NLRs), leads to the assembly of the inflammasome, a multimeric complex platform that activates caspase-1. The caspase-1 pathway leads to the upregulation of important cytokines from the interleukin (IL)-1 family, IL-1β, and IL-18, with subsequent activation of the innate immune response. In this review, we discuss the molecular structure, the mechanisms behind the inflammasome activation, and its possible role in the pathogenesis of inflammatory bowel diseases and intestinal cancer. Here, we show that the available data points towards the importance of the inflammasome in the innate intestinal immune response, being the complex involved in the maintenance of intestinal homeostasis, correct intestinal barrier function and efficient elimination of invading pathogens.
Comparative Analysis of Mesenchymal Stromal Cells Biological Properties
Authors: De Luca Angela , Verardi Rosanna , Neva Arabella , Benzoni Patrizia , Crescini Elisabetta , Xia Er , Almici Camillo , Calza Stefano , Dell'Era Patrizia
Published: March 2013

The stromal progenitors of mesodermal cells, mesenchymal stromal cells (MSCs), are a heterogeneous population of plastic adherent fibroblast-like cells with extensive proliferative capacity and differentiation potential. Human MSCs have now been isolated from various tissues including bone marrow, muscle, skin, and adipose tissue, the latter being one of the most suitable cell sources for cell therapy, because of its easy accessibility, minimal morbidity, and abundance of cells. Bone marrow and subcutaneous or visceral adipose tissue samples were collected, digested with collagenase if needed, and seeded in Iscove's medium containing 5% human platelet lysate. Nonadherent cells were removed after 2-3 days and the medium was replaced twice a week. Confluent adherent cells were detached, expanded, and analyzed for several biological properties such as morphology, immunophenotype, growth rate, senescence, clonogenicity, differentiation capacity, immunosuppression, and secretion of angiogenic factors. The results show significant differences between lines derived from subcutaneous fat compared to those derived from visceral fat, such as the higher proliferation rate of the first and the strong induction of angiogenesis of the latter. We are convinced that the identification of the peculiarities of MSCs isolated from different tissues will lead to their more accurate use in cell therapy.
Prediction of Currency Volume Issued in Taiwan Using a Hybrid Artificial Neural Network and Multiple Regression Approach
Authors: Shao Yuehjen E.
Published: March 2013

Because the volume of currency issued by a country always affects its interest rate, price index, income levels, and many other important macroeconomic variables, the prediction of currency volume issued has attracted considerable attention in recent years. In contrast to the typical single-stage forecast model, this study proposes a hybrid forecasting approach to predict the volume of currency issued in Taiwan. The proposed hybrid models consist of artificial neural network (ANN) and multiple regression (MR) components. The MR component of the hybrid models is established for a selection of fewer explanatory variables, wherein the selected variables are of higher importance. The ANN component is then designed to generate forecasts based on those important explanatory variables. Subsequently, the model is used to analyze a real dataset of Taiwan's currency from 1996 to 2011 and twenty associated explanatory variables. The prediction results reveal that the proposed hybrid scheme exhibits superior forecasting performance for predicting the volume of currency issued in Taiwan.
On a Multipoint Boundary Value Problem for a Fractional Order Differential Inclusion on an Infinite Interval
Authors: Nyamoradi Nemat , Baleanu Dumitru , Agarwal Ravi P.
Published: March 2013

We investigate the existence of solutions for the following multipoint boundary value problem of a fractional order differential inclusionD0+αut+Ft,ut,u′t∋0,0<t<+∞,u0=u′0=0,Dα-1u+∞-∑i=1m-2‍βiuξi=0, whereD0+αis the standard Riemann-Liouville fractional derivative,2<α<3,0<ξ1<ξ2<⋯<ξm-2<+∞, satisfies0<∑i=1m-2‍βiξiα-1<Γ(α),  and  F:[0,+∞)×ℝ×ℝ→𝒫(ℝ)is a set-valued map. Several results are obtained by using suitable fixed point theorems when the right hand side has convex or nonconvex values.
Nephrotic Syndrome Associated with Lung Cancer: A Rare Case of Malignancy Associated with AA Amyloidosis
Authors: Gueutin Victor , Langlois Anne-Lyse , Shehwaro Nathalie , Elharraqui Ryme , Rouvier Philippe , Izzedine Hassane
Published: March 2013

Nonhematologic malignancies are rarely reported to be associated with AA amyloidosis. Although the association between renal cell carcinoma and systemic AA amyloidosis has been established, the evidence linking pulmonary cancer to AA amyloidosis is scarce. Here, a case of biopsy-proven renal AA amyloidosis complicated with nephrotic syndrome associated with lung carcinoma is reported.
Alternanthera sessilisRed Ethyl Acetate Fraction Exhibits Antidiabetic Potential on Obese Type 2 Diabetic Rats
Authors: Tan Kok Keong , Kim Kah Hwi
Published: March 2013

The antidiabetic potential ofAlternanthera sessilisRed was investigated using the obese type 2 diabetic rats induced by high fat diet and streptozotocin. Three fractions (hexane, ethyl acetate, and water) were obtained from the crude ethanol extract ofAlternanthera sessilisRed.Alternanthera sessilisRed ethyl acetate fraction (ASEAF) was found to possess the most potent antihyperglycemic effect through oral glucose tolerance test. The ASEAF was subsequently given to the diabetic rats for two weeks. It was found that two-week administration of ASEAF reduces the fasting blood glucose level, triglyceride level, and free fatty acid level of the rats. ASEAF-treated diabetic rats showed higher pancreatic insulin content and pancreatic total superoxide dismutase activity compared to the untreated diabetic rats. Also, the insulin sensitivity indexes suggested that ASEAF ameliorates the insulin resistant state of the diabetic rats. In conclusion, ASEAF could be developed into a potential antidiabetic agent for the management of type 2 diabetes.
The Uptake Mechanism of the Cell‐Penetrating pVEC Peptide
Authors: Akdag Ihsan Omur , Ozkirimli Elif
Published: March 2013

Peptide based drug design efforts have gained renewed interest with the discovery of cargo‐carrying or cell‐penetrating peptides. Understanding the translocation mechanism of these peptides and identifying the residues or elements that contribute to uptake can provide valuable clues toward the design of novel peptides. To this end, we have performed steered molecular dynamics (SMD) simulations on the pVEC peptide from murine vascular endothelial‐cadherin protein and its two variants. Translocation was found to occur in three stages, adsorption via the cationic residues, inclusion of the whole peptide inside the membrane accompanied by formation of a water defect, and exit of both peptide and water molecules from the bilayer. Our simulation results suggest that the precise order in which the hydrophobic, cationic, and the polar regions are located in the amphipathic pVEC peptide contributes to its uptake mechanism. These results present new opportunities for the design of novel cell‐penetrating and antimicrobial peptides.
Levels of Oxidized LDL, Estrogens, and Progesterone in Placenta Tissues and Serum Paraoxonase Activity in Preeclampsia
Authors: Açıkgöz Şerefden , Özmen Bayar Ülkü , Can Murat , Güven Berrak , Mungan Görkem , Doğan Suat , Sümbüloğlu Vildan
Published: March 2013

In vitro literature studies have suggested that atherosclerotic oxidized low density lipoprotein (OxLDL) inhibits trophoblast invasion. The objective of this study was to determine the levels of OxLDL and to examine the relationship between antioxidative estradiol, estriol, and prooxidative progestin in normal and preeclamptic placental tissues and measure the serum activity of antioxidative paraoxonase (PON1). The study included 30 preeclamptic and 32 normal pregnant women. OxLDL was determined with ELISA, estradiol, unconjugated estriol, and progesterone that were determined with chemiluminescence method in placental tissues. Serum PON1 activity was determined with spectrophotometric method. Levels of OxLDL (), estriol (), estradiol (), and progesterone () were lower in the placental tissues of preeclamptic group compared to the normal pregnant women. Serum PON1 activity was higher in preeclamptic group () and preeclamptic group without intrauterine growth restriction () compared to normal pregnant women. Tissue estriol of preeclamptic group without/with IUGR (, ) was lower than the normal group. Results of our study suggest that the events leading to fetoplacental insufficiency lead to a reduction in the levels of estriol limit deposition of OxLDL in placental tissues. The serum PON1 activity is probably important in the inhibition of OxLDL in preeclampsia.
The Relationship of Affective Temperament and Emotional-Behavioral Difficulties to Internet Addiction in Turkish Teenagers
Authors: Ozturk Fatma Ozgun , Ekinci Mine , Ozturk Onder , Canan Fatih
Published: March 2013

The purpose of this study was to investigate the association of affective temperament profiles and emotional and behavioural characteristics with Internet addiction among high school students. The study sample included 303 high school students. A sociodemographic characteristics data form, internet addiction scale (IAS), the strengths and difficulties questionnaire, and the temperament evaluation of Memphis, Pisa, Paris, and San Diego autoquestionnaire were used to collect data. Of the sample, 6.6% were found to be addicted to Internet. Having a computer in the home (P<0.001) and using the Internet for more than two years (P<0.001) were found to be related to higher scores on the IAS. The prevalence rate of anxious temperament for Internet addicts was more than that for nonaddicts (P<0.001). Dysthymic (r=0.199; P<0.01), cyclothymic (r=0.249; P<0.01), hyperthymic (r=0.156; P<0.01), irritable (r=0.254; P<0.01), and anxious (r=0.205; P<0.01) temperaments; conduct problems (r=0.146; P<0.05), hyperactivity-inattention (r=0.133; P<0.05), emotional symptoms (r=0.138; P<0.05), and total difficulties (r=0.160; P<0.01) were found to be correlated with IAS scores. According to these findings, there is a relation between the Internet addiction and affective temperament profiles, especially with anxious temperament. Furthermore, emotional and behavioural problems are more frequent in adolescents who have problematic Internet use.
Myeloid-Derived Suppressor Cells as a Vehicle for Tumor-Specific Oncolytic Viral Therapy
Authors: Eisenstein Samuel , Coakley Brian A. , Briley-Saebo Karen , Ma Ge , Chen Hui-ming , Meseck Marcia , Ward Stephen , Divino Celia , Woo Savio , Chen Shu-Hsia , Pan Ping-Ying
Published: March 2013

One of the several impediments to effective oncolytic virus therapy of cancer remains a lack of tumor-specific targeting. Myeloid-derived suppressor cells (MDSC) are immature myeloid cells induced by tumor factors in tumor-bearing hosts. The biodistribution kinetics of MDSC and other immune cell types in a murine hepatic colon cancer model was investigated through the use of tracking markers and MRI. MDSCs were superior to other immune cell types in preferential migration to tumors in comparison with other tissues. On the basis of this observation, we engineered a strain of vesicular stomatitis virus (VSV), an oncolytic rhabdovirus that bound MDSCs and used them as a delivery vehicle. Improving VSV-binding efficiency to MDSCs extended the long-term survival of mice bearing metastatic colon tumors compared with systemic administration of wild-type VSV alone. Survival was further extended by multiple injections of the engineered virus without significant toxicity. Notably, direct tumor killing was accentuated by promoting MDSC differentiation towards the classically activated M1-like phenotype. Our results offer a preclinical proof-of-concept for using MDSCs to facilitate and enhance the tumor-killing activity of tumor-targeted oncolytic therapeutics. Cancer Res; 73(16); 5003–15. ©2013 AACR.
Loss of TGF-β Adaptor β2SP Activates Notch Signaling and SOX9 Expression in Esophageal Adenocarcinoma
Authors: Song Shumei , Maru Dipen M. , Ajani Jaffer A. , Chan Chia-Hsin , Honjo Soichiro , Lin Hui-Kuan , Correa Arlene , Hofstetter Wayne L. , Davila Marta , Stroehlein John , Mishra Lopa
Published: March 2013

TGF-β and Notch signaling pathways play important roles in regulating self-renewal of stem cells and gastrointestinal carcinogenesis. Loss of TGF-β signaling components activates Notch signaling in esophageal adenocarcinoma, but the basis for this effect has been unclear. Here we report that loss of TGF-β adapter β2SP (SPNB2) activates Notch signaling and its target SOX9 in primary fibroblasts or esophageal adenocarcinoma cells. Expression of the stem cell marker SOX9 was markedly higher in esophageal adenocarcinoma tumor tissues than normal tissues, and its higher nuclear staining in tumors correlated with poorer survival and lymph node invasion in esophageal adenocarcinoma patients. Downregulation of β2SP by lentivirus short hairpin RNA increased SOX9 transcription and expression, enhancing nuclear localization for both active Notch1 (intracellular Notch1, ICN1) and SOX9. In contrast, reintroduction into esophageal adenocarcinoma cells of β2SP and a dominant-negative mutant of the Notch coactivator mastermind-like (dnMAN) decreased SOX9 promoter activity. Tumor sphere formation and invasive capacity in vitro and tumor growth in vivo were increased in β2SP-silenced esophageal adenocarcinoma cells. Conversely, SOX9 silencing rescued the phenotype of esophageal adenocarcinoma cells with loss of β2SP. Interaction between Smad3 and ICN1 via Smad3 MH1 domain was also observed, with loss of β2SP increasing the binding between these proteins, inducing expression of Notch targets SOX9 and C-MYC, and decreasing expression of TGF-β targets p21(CDKN1A), p27 (CDKN1B), and E-cadherin. Taken together, our findings suggest that loss of β2SP switches TGF-β signaling from tumor suppression to tumor promotion by engaging Notch signaling and activating SOX9. Cancer Res; 73(7); 2159–69. ©2013 AACR.
Common Genetic Polymorphisms Modify the Effect of Smoking on Absolute Risk of Bladder Cancer
Authors: Garcia-Closas Montserrat , Rothman Nathaniel , Figueroa Jonine D. , Prokunina-Olsson Ludmila , Han Summer S. , Baris Dalsu , Jacobs Eric J. , Malats Nuria , De Vivo Immaculata , Albanes Demetrius , Purdue Mark P. , Sharma Sapna , Fu Yi-Ping , Kogevinas Manolis , Wang Zhaoming , Tang Wei , Tardón Adonina , Serra Consol , Carrato Alfredo , García-Closas Reina , Lloreta Josep , Johnson Alison , Schwenn Molly , Karagas Margaret R. , Schned Alan , Andriole Gerald , Grubb Robert , Black Amanda , Gapstur Susan M. , Thun Michael , Diver William Ryan , Weinstein Stephanie J. , Virtamo Jarmo , Hunter David J. , Caporaso Neil , Landi Maria Teresa , Hutchinson Amy , Burdett Laurie , Jacobs Kevin B. , Yeager Meredith , Fraumeni Joseph F. , Chanock Stephen J. , Silverman Debra T. , Chatterjee Nilanjan
Published: March 2013

Bladder cancer results from the combined effects of environmental and genetic factors, smoking being the strongest risk factor. Evaluating absolute risks resulting from the joint effects of smoking and genetic factors is critical to assess the public health relevance of genetic information. Analyses included up to 3,942 cases and 5,680 controls of European background in seven studies. We tested for multiplicative and additive interactions between smoking and 12 susceptibility loci, individually and combined as a polygenic risk score (PRS). Thirty-year absolute risks and risk differences by levels of the PRS were estimated for U.S. males aged 50 years. Six of 12 variants showed significant additive gene–environment interactions, most notably NAT2 (P = 7 × 10−4) and UGT1A6 (P = 8 × 10−4). The 30-year absolute risk of bladder cancer in U.S. males was 6.2% for all current smokers. This risk ranged from 2.9% for current smokers in the lowest quartile of the PRS to 9.9% for current smokers in the upper quartile. Risk difference estimates indicated that 8,200 cases would be prevented if elimination of smoking occurred in 100,000 men in the upper PRS quartile compared with 2,000 cases prevented by a similar effort in the lowest PRS quartile (Padditive = 1 × 10−4). Thus, the potential impact of eliminating smoking on the number of bladder cancer cases prevented is larger for individuals at higher than lower genetic risk. Our findings could have implications for targeted prevention strategies. However, other smoking-related diseases, as well as practical and ethical considerations, need to be considered before any recommendations could be made. Cancer Res; 73(7); 2211–20. ©2012 AACR.
Trop-2 Promotes Prostate Cancer Metastasis By Modulating β1 Integrin Functions
Authors: Trerotola Marco , Jernigan Danielle L. , Liu Qin , Siddiqui Javed , Fatatis Alessandro , Languino Lucia R.
Published: March 2013

The molecular mechanisms underlying metastatic dissemination are still not completely understood. We have recently shown that β1 integrin-dependent cell adhesion to fibronectin and signaling is affected by a transmembrane molecule, Trop-2, which is frequently upregulated in human carcinomas. Here, we report that Trop-2 promotes metastatic dissemination of prostate cancer cells in vivo and is abundantly expressed in metastasis from human prostate cancer. We also show here that Trop-2 promotes prostate cancer cell migration on fibronectin, a phenomenon dependent on β1 integrins. Mechanistically, we demonstrate that Trop-2 and the α5β1 integrin associate through their extracellular domains, causing relocalization of α5β1 and the β1-associated molecule talin from focal adhesions to the leading edges. Trop-2 effect is specific as this molecule does not modulate migration on vitronectin, does not associate with the major vitronectin receptor, αvβ3 integrin, and does not affect localization of αvβ3 integrin as well as vinculin in focal adhesions. We show that Trop-2 enhances directional prostate cancer cell migration, through modulation of Rac1 GTPase activity. Finally, we show that Trop-2 induces activation of PAK4, a kinase that has been reported to mediate cancer cell migration. In conclusion, we provide the first evidence that β1 integrin-dependent migratory and metastatic competence of prostate cancer cells is enhanced by Trop-2. Cancer Res; 73(10); 3155–67. ©2013 AACR.
The Multifaceted Role of the Microenvironment in Liver Metastasis: Biology and Clinical Implications
Authors: Van den Eynden Gert G. , Majeed Ali W. , Illemann Martin , Vermeulen Peter B. , Bird Nigel C. , Høyer-Hansen Gunilla , Eefsen Rikke Løvendahl , Reynolds Andrew R. , Brodt Pnina
Published: March 2013

The liver is host to many metastatic cancers, particularly colorectal cancer, for which the last 2 decades have seen major advances in diagnosis and treatment. The liver is a vital organ, and the extent of its involvement with metastatic disease is a major determinant of survival. Metastatic cells arriving in the liver via the bloodstream encounter the microenvironment of the hepatic sinusoid. The interactions of the tumor cells with hepatic sinusoidal and extrasinusoidal cells (endothelial, Kupffer, stellate, and inflammatory cells) determine their fate. The sinusoidal cells can have a dual role, sometimes fatal to the tumor cells but also facilitatory to their survival and growth. Adhesion molecules participate in these interactions and may affect their outcome. Bone marrow–derived cells and chemokines also play a part in the early battle for survival of the metastases. Once the tumor cells have arrested and survived the initial onslaught, tumors can grow within the liver in 3 distinct patterns, reflecting differing host responses, mechanisms of vascularization, and proteolytic activity. This review aims to present current knowledge of the interactions between the host liver cells and the invading metastases that has implications for the clinical course of the disease and the response to treatment. Cancer Res; 73(7); 2031–43. ©2013 AACR.
Oncogenic NRAS, Required for Pathogenesis of Embryonic Rhabdomyosarcoma, Relies upon the HMGA2–IGF2BP2 Pathway
Authors: Li Zhizhong , Zhang Yunyu , Ramanujan Krishnan , Ma Yan , Kirsch David G. , Glass David J.
Published: March 2013

Embryonic rhabdomyosarcoma (ERMS) is the most common soft-tissue tumor in children. Here, we report the identification of the minor groove DNA-binding factor high mobility group AT-hook 2 (HMGA2) as a driver of ERMS development. HMGA2 was highly expressed in normal myoblasts and ERMS cells, where its expression was essential to maintain cell proliferation, survival in vitro, and tumor outgrowth in vivo. Mechanistic investigations revealed that upregulation of the insulin–like growth factor (IGF) mRNA-binding protein IGF2BP2 was critical for HMGA2 action. In particular, IGF2BP2 was essential for mRNA and protein stability of NRAS, a frequently mutated gene in ERMS. shRNA-mediated attenuation of NRAS or pharmacologic inhibition of the MAP–ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) effector pathway showed that NRAS and NRAS-mediated signaling was required for tumor maintenance. Taken together, these findings implicate the HMGA2–IGFBP2–NRAS signaling pathway as a critical oncogenic driver in ERMS. Cancer Res; 73(10); 3041–50. ©2013 AACR.
The 19th Annual Prostate Cancer Foundation Scientific Retreat
Authors: Walia Guneet , Pienta Kenneth J. , Simons Jonathan W. , Soule Howard R.
Published: March 2013

Prostate Cancer Foundation (PCF) convened its 19th Annual Scientific Retreat October 25–27, 2012, in Carlsbad, CA. Each year, this event brings together diverse researchers in a collaborative forum to present and discuss new and largely unpublished findings for prostate cancer diagnosis, prognosis, and treatment and defines the challenges to ending this disease as a threat to life and well-being. Several themes resonated at the multidisciplinary meeting, notably (i) the roles of field cancerization, tumor microenvironment, epithelial plasticity, signal transduction pathways in cancer progression, and disease resistance; (ii) intratumoral heterogeneity and consequences for precision medicine; (iii) resistance mechanisms to androgen axis inhibitors; and (iv) advances in molecular imaging and therapeutics for better detection and treatment. Cancer Res; 73(16); 4988–91. ©2013 AACR.
Cancer Survivors in the United States: Prevalence across the Survivorship Trajectory and Implications for Care
Authors: de Moor Janet S. , Mariotto Angela B. , Parry Carla , Alfano Catherine M. , Padgett Lynne , Kent Erin E. , Forsythe Laura , Scoppa Steve , Hachey Mark , Rowland Julia H.
Published: March 2013

Background: Cancer survivors represent a growing population, heterogeneous in their need for medical care, psychosocial support, and practical assistance. To inform survivorship research and practice, this manuscript will describe the prevalent population of cancer survivors in terms of overall numbers and prevalence by cancer site and time since diagnosis.

Methods: Incidence and survival data from 1975–2007 were obtained from the Surveillance, Epidemiology, and End Results Program and population projections from the United States Census Bureau. Cancer prevalence for 2012 and beyond was estimated using the Prevalence Incidence Approach Model, assuming constant future incidence and survival trends but dynamic projections of the U.S. population.

Results: As of January 1, 2012, approximately 13.7 million cancer survivors were living in the United States with prevalence projected to approach 18 million by 2022. Sixty-four percent of this population have survived 5 years or more; 40% have survived 10 years or more; and 15% have survived 20 years or more after diagnosis. Over the next decade, the number of people who have lived 5 years or more after their cancer diagnosis is projected to increase approximately 37% to 11.9 million.

Conclusions: A coordinated agenda for research and practice is needed to address cancer survivors' long-term medical, psychosocial, and practical needs across the survivorship trajectory.

Impact: Prevalence estimates for cancer survivors across the survivorship trajectory will inform the national research agenda as well as future projections about the health service needs of this population. Cancer Epidemiol Biomarkers Prev; 22(4); 561–70. ©2013 AACR.
Phase I Trial, Pharmacokinetics, and Pharmacodynamics of Vandetanib and Dasatinib in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma
Authors: Broniscer Alberto , Baker Sharyn D. , Wetmore Cynthia , Pai Panandiker Atmaram S. , Huang Jie , Davidoff Andrew M. , Onar-Thomas Arzu , Panetta John C. , Chin Thomas K. , Merchant Thomas E. , Baker Justin N. , Kaste Sue C. , Gajjar Amar , Stewart Clinton F.
Published: March 2013

Purpose: Testing of promising drug combinations is crucial in the treatment of diffuse intrinsic pontine glioma (DIPG). As the VEGF and platelet-derived growth factor (PDGF) pathways are critical in gliomas, we evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of vandetanib, a VEGFR-2 inhibitor, combined with dasatinib, a potent PDGFR inhibitor, during and after radiotherapy in children with newly diagnosed DIPG.

Experimental Design: Dasatinib was started concurrently with radiotherapy. Vandetanib was started 8 days later. We tested increasing doses of vandetanib (65 and 85 mg/m2 once daily) and dasatinib (65 and 85 mg/m2 twice daily). Dose-limiting toxicities were evaluated during the first 6 weeks of therapy. Plasma pharmacokinetics was obtained on days 8 and 42 ± 3 in all patients and concomitantly with cerebrospinal fluid (CSF) when possible. Inhibition of targets of dasatinib in peripheral blood mononuclear cells (PBMC) was evaluated.

Results: Twenty-five patients were treated. Treatment was well tolerated. The median duration of treatment was 184 days. Diarrhea was the most significant toxicity. Three patients experienced substantial myelosuppression. The steady-state plasma pharmacokinetics of vandetanib was comparable with previous studies. Although the plasma exposure to dasatinib decreased from days 8 to 42, it remained similar to adult studies. CSF to plasma exposure of vandetanib and dasatinib were approximately 2% in 2 patients. Phosphorylated 70S6K decreased during therapy in PBMCs.

Conclusions: The MTD of vandetanib and dasatinib in combination was 65 mg/m2 for each drug. Other studies are underway to test dasatinib and other PDGFR inhibitors alone or in combination for this deadly cancer. Clin Cancer Res; 19(11); 3050–8. ©2013 AACR.
The Novel Chk1 Inhibitor MK-8776 Sensitizes Human Leukemia Cells to HDAC Inhibitors by Targeting the Intra-S Checkpoint and DNA Replication and Repair
Authors: Dai Yun , Chen Shuang , Kmieciak Maciej , Zhou Liang , Lin Hui , Pei Xin-Yan , Grant Steven
Published: March 2013

Interactions between the novel Chk1 inhibitor MK-8776 and the histone deacetylase (HDAC) inhibitor (HDACI) vorinostat were examined in human leukemia cells harboring wild-type (wt) or deficient p53. MK-8776 synergistically potentiated vorinostat-mediated apoptosis in various p53-wt or -deficient leukemia cell lines, whereas p53 knockdown by short hairpin RNA (shRNA) sensitized p53-wt cells to lethality of this regimen. Leukemia cell lines carrying FLT3-ITD were also sensitive to the MK-8776/vorinostat regimen. Synergistic interactions were associated with inhibition of Chk1 activity, interference with the intra-S-phase checkpoint, disruption of DNA replication, and downregulation of proteins involved in DNA replication (e.g., Cdt1) and repair (e.g., CtIP and BRCA1), resulting in sharp increases in DNA damage, reflected by enhanced γ-H2A.X formation, and apoptosis. Moreover, leukemia cells expressing kinase-dead Chk1 (D130A) or Chk1 shRNA were significantly more sensitive to HDACIs compared with their wt counterparts and displayed downregulation of CtIP and BRCA1 phosphorylation following HDACI exposure. Finally, the MK-8776/vorinostat regimen was active in primary acute myelogenous leukemia (AML) blasts, particularly against the CD34+/CD38−/CD123+ population enriched for leukemia-initiating cells. In contrast, identical regimens were relatively sparing toward normal cord blood CD34+ cells. Together, these findings indicate that the novel Chk1 inhibitor MK-8776 markedly potentiates HDACI lethality in leukemia cells displaying various genetic backgrounds through mechanisms involving disruption of the intra-S checkpoint, DNA replication, and DNA repair. They also argue that leukemic cells, including those bearing oncogenic mutations associated with poor prognosis, for example, p53 deletion/mutation or FLT3-ITD, may also be susceptible to this strategy. Mol Cancer Ther; 12(6); 878–89. ©2013 AACR.
Potential Advantages of CUDC-101, a Multitargeted HDAC, EGFR, and HER2 Inhibitor, in Treating Drug Resistance and Preventing Cancer Cell Migration and Invasion
Authors: Wang Jing , Pursell Natalie W. , Samson Maria Elena S. , Atoyan Ruzanna , Ma Anna W. , Selmi Abdelkader , Xu Wanlu , Cai Xiong , Voi Maurizio , Savagner Pierre , Lai Cheng-Jung
Published: March 2013

CUDC-101 is a novel, small-molecule, anticancer agent targeting histone deacetylase (HDAC), EGF receptor (EGFR), and HER2. It is currently in phase I clinical development in patients with solid tumors. Previously, we reported that CUDC-101 has potent antiproliferative and proapoptotic activity in cultured tumor cells and in vivo xenograft models. We now show that cancer cells that have acquired resistance to single-target EGFR inhibitors through upregulation of AXL or loss of E-cadherin remain sensitive to CUDC-101, which inhibits MET- and AXL-mediated signaling, restores E-cadherin expression, and reduces cell migration. CUDC-101 also efficiently inhibited the proliferation of MET-overexpressing non–small cell lung cancer and gastric cancer cell lines and inhibited the migration and invasion of invasive tumor cells. Taken together, these results suggest that coupling HDAC and HER2 inhibitory activities to an EGFR inhibitor may potentially be effective in overcoming drug resistance and preventing cancer cell migration. Mol Cancer Ther; 12(6); 925–36. ©2013 AACR.
Profiling Bortezomib Resistance Identifies Secondary Therapies in a Mouse Myeloma Model
Authors: Stessman Holly A.F. , Baughn Linda B. , Sarver Aaron , Xia Tian , Deshpande Raamesh , Mansoor Aatif , Walsh Susan A. , Sunderland John J. , Dolloff Nathan G. , Linden Michael A. , Zhan Fenghuang , Janz Siegfried , Myers Chad L. , Van Ness Brian G.
Published: March 2013

Multiple myeloma is a hematologic malignancy characterized by the proliferation of neoplastic plasma cells in the bone marrow. Although the first-to-market proteasome inhibitor bortezomib (Velcade) has been successfully used to treat patients with myeloma, drug resistance remains an emerging problem. In this study, we identify signatures of bortezomib sensitivity and resistance by gene expression profiling (GEP) using pairs of bortezomib-sensitive (BzS) and bortezomib-resistant (BzR) cell lines created from the Bcl-XL/Myc double-transgenic mouse model of multiple myeloma. Notably, these BzR cell lines show cross-resistance to the next-generation proteasome inhibitors, MLN2238 and carfilzomib (Kyprolis) but not to other antimyeloma drugs. We further characterized the response to bortezomib using the Connectivity Map database, revealing a differential response between these cell lines to histone deacetylase (HDAC) inhibitors. Furthermore, in vivo experiments using the HDAC inhibitor panobinostat confirmed that the predicted responder showed increased sensitivity to HDAC inhibitors in the BzR line. These findings show that GEP may be used to document bortezomib resistance in myeloma cells and predict individual sensitivity to other drug classes. Finally, these data reveal complex heterogeneity within multiple myeloma and suggest that resistance to one drug class reprograms resistant clones for increased sensitivity to a distinct class of drugs. This study represents an important next step in translating pharmacogenomic profiling and may be useful for understanding personalized pharmacotherapy for patients with multiple myeloma. Mol Cancer Ther; 12(6); 1140–50. ©2013 AACR.
Antithrombotic therapy in obesity
Authors: Hernández Vera Rodrigo , Padró Teresa , Vilahur Gemma , Badimon Lina
Published: March 2013

summary

Clinical management of obese subjects to reduce their risk of suffering cardiovascular events is complex. Obese patients typically require preventive strategies, life-style modifications, and multi-drug therapy to address obesity-induced co-morbidities. Data regarding the effects of excess weight on the pharmacokinetics of most drugs is scarce as these individuals are often excluded from clinical trials. However, the physiological alterations observed in obese patients and their lower response to some antiplatelet agents and anticoagulants have suggested that dosage regimes need to be adjusted for these subjects. In this review we will briefly discuss platelet alterations that can contributeto increased thrombotic risk, analyse existing data regarding the effects of obesity on drug pharmacokinetics focusing on antiplatelet agents and anticoagulants, and we will describe the beneficial effects of weight loss on thrombosis.
Nonculprit Coronary Plaque Characteristics of Chronic Kidney Disease
Authors: Kato Koji , Yonetsu Taishi , Jia Haibo , Abtahian Farhad , Vergallo Rocco , Hu Sining , Tian Jinwei , Kim Soo-Joong , Lee Hang , McNulty Iris , Lee Stephen , Uemura Shiro , Jang Yangsoo , Park Seung-Jung , Mizuno Kyoichi , Yu Bo , Jang Ik-Kyung
Published: March 2013

Background—

Chronic kidney disease (CKD) promotes the development of atherosclerosis and increases the risk of cardiovascular disease. The aim of the present study was to compare the coronary plaque characteristics of patients with and without CKD using optical coherence tomography.

Methods and Results—

We identified 463 nonculprit plaques from 287 patients from the Massachusetts General Hospital (MGH) optical coherence tomography registry. CKD was defined as estimated glomerular filtration rate <60 mL/min per 1.73 m
2
. A total of 402 plaques (250 patients) were in the non-CKD group and 61 plaques (37 patients) were in the CKD group. Compared with non-CKD plaques, plaques with CKD had a larger lipid index (mean lipid arc×lipid length, 1248.4±782.8 mm° [non-CKD] versus 1716.1±1116.2 mm° [CKD];
P
=0.003). Fibrous cap thickness was not significantly different between the groups. Calcification (34.8% [non-CKD] versus 50.8% [CKD];
P
=0.041), cholesterol crystals (11.2% [non-CKD] versus 23.0% [CKD];
P
=0.048), and plaque disruption (5.5% [non-CKD] versus 13.1% [CKD];
P
=0.049) were more frequently observed in the CKD group. In the multivariate linear regression model, a lower estimated glomerular filtration rate and diabetes mellitus were independent risk factors for a larger lipid index.

Conclusions—

Compared with non-CKD patients, the patients with CKD had a larger lipid index with a higher prevalence of calcium, cholesterol crystals, and plaque disruption. The multivariate linear regression model demonstrated that a lower estimated glomerular filtration rate was an independent risk factor for a larger lipid index.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01110538.
About the circumscription of Celosia argentea (Amaranthaceae) and the related Linnaean taxa
Authors: IAMONICO DUILIO
Published: March 2013

As part of the revision of the genus Celosia Linnaeus (1753: 205) for the treatment of Amaranthaceae for the Euro+Med plantbase project and the New Flora of Italy (Iamonico, in prep.), it has been necessary to establish the identity of C. argentea Linnaeus (1753: 205) in comparison with the related taxa C. cristata Linnaeus (1753: 205), C. castrensis Linnaeus (1762: 297) and C. margaritacea Linnaeus (1762: 297) (Feng et al. 2009). A first step was the typification of the names (Iamonico & Jarvis 2012). Here the current circumscription of C. argentea in comparison with C. cristata, C. castrensis and C. margaritacea are discussed using relevant literature and morphological data of collections (70 specimens from the Herbaria B, BAR, FI, K, KUFS, PE, RO, LINN andTROY were examined).