bluuebunny/crossref_metadata_2025 huggingface dataset:
Dissociated mean and functional connectivity BOLD signals in visual cortex during eyes closed and fixation
Authors: McAvoy Mark , Larson-Prior Linda , Ludwikow Marek , Zhang Dongyang , Snyder Abraham Z. , Gusnard Debra L. , Raichle Marcus E. , d'Avossa Giovanni
Published: August 2012

We investigated the effects of resting state type on blood oxygen level-dependent (BOLD) signal and functional connectivity in two paradigms: participants either alternated between fixation and eyes closed or maintained fixation or eyes closed throughout each scan. The BOLD signal and functional connectivity of lower and higher tiers of the visual cortical hierarchy were found to be differentially modulated during eyes closed versus fixation. Fixation was associated with greater mean BOLD signals in primary visual cortex and lower mean BOLD signals in extrastriate visual areas than periods of eyes closed. In addition, analysis of thalamocortical functional connectivity during scans in which participants maintained fixation showed synchronized BOLD fluctuations between those thalamic nuclei whose mean BOLD signal was systematically modulated during alternating epochs of eyes closed and fixation, primary visual cortex and the attention network, while during eyes closed negatively correlated fluctuations were seen between the same thalamic nuclei and extrastriate visual areas. Finally, in all visual areas the amplitude of spontaneous BOLD fluctuations was greater during eyes closed than during fixation. The dissociation between early and late tiers of visual cortex, which characterizes both mean and functionally connected components of the BOLD signal, may depend on the reorganization of thalamocortical networks. Since dissociated changes in local blood flow also characterize transitions between different stages of sleep and wakefulness (Braun AR, Balkin TJ, Wesenten NJ, Gwadry F, Carson RE, Varga M, Baldwin P, Belenky G, Herscovitch P. Science 279: 91–95, 1998), our results suggest that dissociated endogenous neural activity in primary and extrastriate cortex may represent a general aspect of brain function.
Self-Inflicted Urethrovesical Foreign Bodies in Children
Authors: Ceran Canan , Uguralp Sema
Published: August 2012

We present two cases of self-inflicted urethrovesical foreign body in children. Case 1 was a 6-year-old girl admitted with a history of self-introduction of a pin. The X-ray revealed the pin as 3.5 cm in length and in the bladder. The foreign body was removed endoscopically. Case 2 was a 13-year-old boy with a self-introduced packing needle, 13 cm in length, partially in the urethra. The end and the tip of the needle passed through the urethra to the surrounding tissues. Foreign body removed via a little skin incision with endoscopic guidance. Foreign bodies are rarely found in the lower urinary tract of children. Definitive treatment is usually the endoscopic removal; however, sometimes surgical intervention may require.
Catheter Ablation of Long-Lasting Accelerated Idioventricular Rhythm in a Patient with Mild Left Ventricular Dysfunction
Authors: Mine Takanao , Hamaoka Mamoru , Kishima Hideyuki , Masuyama Tohru
Published: August 2012

A 35-year-old woman with long-lasting accelerated idioventricular rhythm (AIVR) exhibited palpitation and dyspnea on exertion and mild left ventricular (LV) dysfunction during followup. Symptoms appeared 10 years after the AIVR was first noted, and she underwent catheter ablation for curative therapy of AIVR after 12 years. Radiofrequency ablation of the anteroseptal site of the LV at the earliest activation terminated rhythm. An echocardiogram, taken 1 month after discharge, subsequently revealed that the left ventricular wall motion had normalized. This is a rare case of long-lasting AIVR with mild LV dysfunction.
Saline Agriculture in the 21st Century: Using Salt Contaminated Resources to Cope Food Requirements
Authors: Ladeiro Bruno
Published: August 2012

With the continue increase of the world population the requirements for food, freshwater, and fuel are bigger every day. This way an urgent necessity to develop, create, and practice a new type of agriculture, which has to be environmentally sustainable and adequate to the soils, is arising. Among the stresses in plant agriculture worldwide, the increase of soil salinity is considered the major stress. This is particularly emerging in developing countries that present the highest population growth rates, and often the high rates of soil degradation. Therefore, salt-tolerant plants provide a sensible alternative for many developing countries. These plants have the capacity to grow using land and water unsuitable for conventional crops producing food, fuel, fodder, fibber, resin, essential oils, and pharmaceutical products. In addition to their production capabilities they can be used simultaneously for landscape reintegration and soil rehabilitation. This review will cover important subjects concerning saline agriculture and the crop potential of halophytes to use salt-contaminated resources to manage food requirements.
Crowd Evacuation for Indoor Public Spaces Using Coulomb’s Law
Authors: Kamkarian Pejman , Hexmoor Henry
Published: August 2012

This paper focuses on designing a tool for guiding a group of people out of a public building when they are faced with dangerous situations that require immediate evacuation. Despite architectural attempts to produce safe floor plans and exit door placements, people will still commit to fatal route decisions. Since they have access to global views, we believe supervisory people in the control room can use our simulation tools to determine the best courses of action for people. Accordingly, supervisors can guide people to safety. In this paper, we combine Coulomb’s electrical law, graph theory, and convex and centroid concepts to demonstrate a computer-generated evacuation scenario that divides the environment into different safe boundaries around the locations of each exit door in order to guide people through exit doors safely and in the most expedient time frame. Our mechanism continually updates the safe boundaries at each moment based on the latest location of individuals who are present inside the environment. Guiding people toward exit doors depends on the momentary situations in the environment, which in turn rely on the specifications of each exit door. Our mechanism rapidly adapts to changes in the environment in terms of moving agents and changes in the environmental layout that might be caused by explosions or falling walls.
Bacillus cereusBloodstream Infection in a Preterm Neonate Complicated by Late Meningitis
Authors: Horii Toshinobu , Tamai Kiyoko , Notake Shigeyuki , Yanagisawa Hideji
Published: August 2012

Central nervous system infections caused byBacillus cereushave rarely been reported in infants. In this paper, the case of a 2-month-old low-birth-weight female who developed meningitis 45 days after resolution of a bloodstream infection (BSI) is described. The pulsed-field gel electrophoresis results revealed that the patterns of bothB. cereusisolates responsible for the acute meningitis and for the prior bacteraemic episode were closely related. Although the source of the infection from within the patient was not clear, it is suggested that theB. cereusBSI developed in the neonate was complicated by acute meningitis.
Surgical Bailout Therapy after Implantation of a Medtronic CoreValve Bioprosthesis
Authors: Calé Rita , Neves José , Teles Rui , Brito João , Abecasis Miguel , Almeida Manuel , Nolasco Tiago , Mendes Miguel
Published: August 2012

Moderate-to-severe paraprosthesic leak causing hemodynamic deterioration and left ventricular remodeling can occur after transcatheter aortic valve implantation (TAVI). We present the case of a 75-year-old woman who underwent TAVI with a 26 mm CoreValve prosthesis complicated with an acute left ventricle dilatation due to a severe paravalvular leak. Patient was unresponsive to elective balloon post-dilatation, and therefore she was successfully treated with open-heart surgery to remove the malfunctioning CoreValve bioprosthesis and perform standard aortic valve replacement.
Genetic Background Strongly Influences the Bone Phenotype of P2X7 Receptor Knockout Mice
Authors: Syberg Susanne , Petersen Solveig , Beck Jensen Jens-Erik , Gartland Alison , Teilmann Jenni , Chessell Iain , Steinberg Thomas H. , Schwarz Peter , Jørgensen Niklas Rye
Published: August 2012

The purinergic P2X7 receptor is expressed by bone cells and has been shown to be important in both bone formation and bone resorption. In this study we investigated the importance of the genetic background of the mouse strains on which the P2X7 knock-out models were based by comparing bone status of a new BALB/cJ P2X7−/−strain with a previous one based on the C57BL/6 strain. Female four-month-old mice from both strains were DXA scanned on a PIXImus densitometer; femurs were collected for bone strength measurements and serum for bone marker analysis. Bone-related parameters that were altered only slightly in the B6 P2X7−/−became significantly altered in the BALB/cJ P2X7−/−when compared to their wild type littermates. The BALB/cJ P2X7−/−showed reduced levels of serum C-telopeptide fragment (s-CTX), higher bone mineral density, and increased bone strength compared to the wild type littermates. In conclusion, we have shown that the genetic background of P2X7−/−mice strongly influences the bone phenotype of the P2X7−/−mice and that P2X7 has a more significant regulatory role in bone remodeling than found in previous studies.
Survey of the Synanthropic Flies Associated with Human Habitations in Ubon Ratchathani Province of Northeast Thailand
Authors: Chaiwong Tarinee , Srivoramas Thanyakarn , Sukontason Kom , Sanford Michelle R. , Moophayak Kittikhun , Sukontason Kabkaew L.
Published: August 2012

Synanthropic fly surveys were performed to determine the species composition and abundance in Ubon Ratchathani province in Northeast Thailand. Adult fly collections were conducted in various human habitations from two districts—Muang Ubon Ratchathani and Warinchamrap, at fresh-food markets, garbage piles, restaurants, school cafeterias, and rice paddy fields. Customized reconstructable funnel fly traps baited with 250 g of 1-day tainted beef were used for fly collections from September 2010–February 2011. A total of 3,262 flies were captured, primarily consisting of three families including: Calliphoridae (6 species), Muscidae (3 species), and Sarcophagidae (11 species). The blow fly,Chrysomya megacephala, and the house fly,Musca domestica, were the dominant species collected from both districts at all collection sites.C. megacephalawas predominant in paddy fields, restaurants and garbage piles, whileM. domesticawas numerically dominant in fresh-food markets and school cafeterias. The current survey identified various species of synanthropic flies with close associations to humans and with the ability to transmit human pathogens in Ubon Ratchathani province; providing crucial information that may be used for developing control and sanitation management plans in this particular area.
Melatonin: Bone Metabolism in Oral Cavity
Authors: López-Martínez Fanny , Olivares Ponce Patricia N. , Guerra Rodríguez Miriam , Martínez Pedraza Ricardo
Published: August 2012

Throughout life, bone tissue undergoes a continuous process of resorption and formation. Melatonin, with its antioxidant properties and its ability to detoxify free radicals, as suggested by Conconi et al. (2000) may interfere in the osteoclast function and thereby inhibit bone resorption, as suggested by Schroeder et al. (1981). Inhibition of bone resorption may be enhanced by a reaction of indoleamine in osteoclastogenesis. That it has been observed melatonin, at pharmacological doses, decrease bone mass resorption by suppressing through down regulation of the RANK-L, as suggested by Penarrocha Diago et al. (2005) and Steflik et al. (1994). These data point an osteogenic effect towards that may be of melatonin of clinical importance, as it could be used as a therapeutic agent in situations in which would be advantageous bone formation, such as in the treatment of fractures or osteoporosis or their use as, a bioactive surface on implant as suggested by Lissoni et al. (1991).
Improved Expression for Estimation of Leakage Inductance in E Core Transformer Using Energy Method
Authors: Thondapu Sivananda Reddy , Borage Mangesh B. , Wanmode Yashwant D. , Shrivastava Purushottam
Published: August 2012

This paper proposes a simpler and more accurate expression for estimation of leakage inductance in E core transformer, which is the most widely used transformer structure. The derived expression for leakage inductance accounts for the flux extending into air. The finite element method (FEM) analysis is made on the secondary shorted transformer to observe the H-field pattern. The results obtained from FEM analysis are used for approximating the field that is extending into air to derive an expression for leakage inductance. This expression is experimentally validated on prototype transformers of different core dimensions.
Management Strategies for Aggressive Cushing's Syndrome: From Macroadenomas to Ectopics
Authors: Pozza Carlotta , Graziadio Chiara , Giannetta Elisa , Lenzi Andrea , Isidori Andrea M.
Published: August 2012

Cushing’s syndrome (CS) is a rare but severe clinical condition represented by an excessive endogenous cortisol secretion and hence excess circulating free cortisol, characterized by loss of the normal feedback regulation and circadian rhythm of the hypothalamic-pituitary axis due to inappropriate secretion of ACTH from a pituitary tumor (Cushing’s disease, CD) or an ectopic source (ectopic ACTH secretion, EAS). The remaining causes (20%) are ACTH independent. As soon as the diagnosis is established, the therapeutic goal is the removal of the tumor. Whenever surgery is not curative, management of patients with CS requires a major effort to control hypercortisolemia and associated symptoms. A multidisciplinary approach that includes endocrinologists, neurosurgeons, oncologists, and radiotherapists should be adopted. This paper will focus on traditional and novel medical therapy for aggressive ACTH-dependent CS. Several drugs are able to reduce cortisol levels. Their mechanism of action involves blocking adrenal steroidogenesis (ketoconazole, metyrapone, aminoglutethimide, mitotane, etomidate) or inhibiting the peripheral action of cortisol through blocking its receptors (mifepristone “RU-486”). Other drugs include centrally acting agents (dopamine agonists, somatostatin receptor agonists, retinoic acid, peroxisome proliferator-activated receptorγ“PPAR-γ” ligands) and novel chemotherapeutic agents (temozolomide and tyrosine kinase inhibitors) which have a significant activity against aggressive pituitary or ectopic tumors.
Regulation of ROS Production and Vascular Function by Carbon Monoxide
Authors: Choi Yoon Kyung , Por Elaine D. , Kwon Young-Guen , Kim Young-Myeong
Published: August 2012

Carbon monoxide (CO) is a gaseous molecule produced from heme by heme oxygenase (HO). CO interacts with reduced iron of heme-containing proteins, leading to its involvement in various cellular events via its production of mitochondrial reactive oxygen species (ROS). CO-mediated ROS production initiates intracellular signal events, which regulate the expression of adaptive genes implicated in oxidative stress and functions as signaling molecule for promoting vascular functions, including angiogenesis and mitochondrial biogenesis. Therefore, CO generated either by exogenous delivery or by HO activity can be fundamentally involved in regulating mitochondria-mediated redox cascades for adaptive gene expression and improving blood circulation (i.e., O2delivery) via neovascularization, leading to the regulation of mitochondrial energy metabolism. This paper will highlight the biological effects of CO on ROS generation and cellular redox changes involved in mitochondrial metabolism and angiogenesis. Moreover, cellular mechanisms by which CO is exploited for disease prevention and therapeutic applications will also be discussed.
Combined Effects ofEurycoma longifoliaand Testosterone on Androgen-Deficient Osteoporosis in a Male Rat Model
Authors: Saadiah Abdul Razak Halimatun , Shuid Ahmad Nazrun , Naina Mohamed Isa
Published: August 2012

Androgen-deficient osteoporosis in men is treated with testosterone therapy, which is associated with side effects.Eurycoma longifolia(EL) is known to possess androgenic properties and has been reported to protect bone from androgen-deficient osteoporosis in experimental animal models. The present study aimed to determine the effectiveness of combination therapy of EL and testosterone (T) in treating androgen-deficient osteoporosis. Forty male Sprague-Dawley rats were divided into: sham-operated (SHAM), orchidectomized-control (ORX), orchidectomized with testosterone (ORX + T), orchidectomized with EL (ORX + EL), and orchidectomized with combined T and EL therapy (ORX + T + EL). EL was administered via oral gavages daily at the dose of 15 mg/kg. T was injected intramuscularly at 8 mg/kg and 4 mg/kg for the ORX + T and ORX + T + EL groups, respectively. Following 6 weeks of treatment, the osteocalcin levels of ORX + T and ORX + T + EL groups were significantly lower than the SHAM group (P<0.05). The posttreatment CTX levels of ORX + T and ORX + T + EL groups were significantly lower than their pretreatment levels (P<0.05). Biomechanically, the strain parameter of the ORX + T + EL group was significantly higher than the ORX group (P<0.05). Thus, the combination therapy of EL and low-dose T has potential for treatment of androgen-deficient osteoporosis. The lower T dose is beneficial in reducing the sideeffects of testosterone therapy.
Trends in Nutrition and Exercise Counseling among Adolescents in the Health Care Environment
Authors: Peart Tasha , Crawford Patricia B.
Published: August 2012

Purpose. Obesity is a serious health threat, particularly among racial/ethnic minorities and those who are uninsured, yet little is known about the implementation of nutrition or exercise counseling or the combination of both among these groups. Trends in counseling by race/ethnicity and types of insurance were examined.Methods. Trend analyses were conducted with the California Health Interview Surveys among those ages 12–17 for the period 2003–2009.Results.Race/Ethnicity: Receipt of both counseling methods declined from 2003–2009 for all racial/ethnic groups, except Hispanics and Whites, for whom increases in counseling began after 2007. Hispanics and African Americans generally reported higher levels of nutrition than exercise counseling, while Whites generally reported higher levels of exercise than nutrition counseling for the study period.Insurance Type: Receipt of both counseling methods appeared to decline from 2003–2009 among all insurance types, although after 2007, a slight increase was observed for the low-cost/free insurance group. Those with private health insurance generally received more exercise counseling than nutrition counseling over the study period.Conclusions. Counseling among all racial/ethnic groups and insurance types is warranted, but particularly needed for African Americans, American Indian/Alaska Natives, and the uninsured as they are at highest risk for developing obesity. Institutional and policy changes in the health care environment will be beneficial in helping to promote obesity-related counseling.
A Systematic Review of the Clinimetric Properties of Habitual Physical Activity Measures in Young Children with a Motor Disability
Authors: Oftedal Stina , Bell Kristie L. , Mitchell Louise E. , Davies Peter S. W. , Ware Robert S. , Boyd Roslyn N.
Published: August 2012

Aim. To identify and systematically review the clinimetric properties of habitual physical activity (HPA) measures in young children with a motor disability.Method. Five databases were searched for measures of HPA including: children aged <6.0 years with a neuromuscular disorder, physical activity defined as “bodily movement produced by skeletal muscles causing caloric expenditure”, reported HPA as duration, frequency, intensity, mode or energy expenditure, and evaluated clinimetric properties. The quality of papers was assessed using the COSMIN-checklist. A targeted search of identified measures found additional studies of typically developing young children (TDC).Results. Seven papers assessing four activity monitors met inclusion criteria. Four studies were of good methodological quality. The Minimod had good ability to measure continuous walking but the demonstrated poor ability to measure steps during free-living activities. The Intelligent Device for Energy Expenditure and Activity and Ambulatory Monitoring Pod showed poor ability to measure activity during both continuous walking and free-living activities. The StepWatch showed good ability to measure steps during continuous walking in TDC.Interpretation. Studies assessing the clinimetric properties of measures of HPA in this population are urgently needed to allow assessment of the relationship between HPA and health outcomes in this group.
Synthesis of 2,3‐Dihydro‐6‐methyl‐2‐thiopyrimidin‐4(1H)‐one (6‐Methylthiouracil) Derivatives and Their Reactions
Authors: Barmaki Mohammad , Valiyeva Gulgaz , Maharramovm Abel A. , Allaverdiyev Mirze M.
Published: August 2012

The synthesis and characterization of 2,3‐dihydro‐6‐methyl‐2‐thioxopyrimidin‐(1H)‐one (I) and some of its derivatives has been performed in our lab. Ring‐closing cyclization, as a result of the condensation of ethyl‐3‐oxobutanoate with thiourea in KOH in an ethanol medium produced 2,3‐dihydro‐6‐methy ‐2‐thioxopyrimidin‐(1H)‐one (I). The reaction of compound (I) with 2‐ chloroacetic acid in an alkaline KOH solution produced the carboxylate derivative, 2‐(2,6‐dihydro‐4‐methyl‐6‐oxopyrimidin‐2‐yl‐thio)ethanoic acid (II). The reaction of the resulted derivative of carboxylate (II) with the salt of copper sulphate, produced a new copper salt (III). A substitution reaction between synthesized compound (I) and 2‐chloroethanol in an aqueous solution of KOH, created 2‐(2‐hydroxyethylthio)‐6‐methylpyrimidin‐4(3H)‐one (IV). The reaction of compound (I) with 2‐(chloromethyl)oxirane in the presence of an aqueous solution of KOH, resulted yielded 2‐(3‐chloro‐2‐hydroxy‐propylthio)‐6‐methylpyrimidin‐4(3H)‐one (V). Sodium mercaptide compound (VI), was produced by the reaction of (I) with NaOH and then the sodium salt of 2,3‐dihydro‐6‐methyl‐2‐thioxopyrimidin‐(1H)‐one (VI) was reacted with 2‐(chloromethyl)oxirane to result in 2‐((oxiran‐2‐yl) methyl‐thio)‐6‐methyl‐pyrimidin‐4(3H)‐one (VII). Different acylation reagents (acetyl chloride, benzoyl chloride) were reacted with compound (I), in dimethylformamide, acylation happens on sulfur and furnished S‐acylified derivatives of (VIII‐IX). All the synthesized and obtained products were confirmed by IR, 1H, and 13C NMR and elemental analysis.
An Efficient Approach to the Synthesis of Novel Oxazolidinones as Potential Antimicrobial Agents
Authors: Devi Kavita , Asmat Yumna , Jain Sonika , Sharma Swapnil , Dwivedi Jaya
Published: August 2012

Oxazolidinone, either mononuclear or condensed with other heterocyclics, has established its importance in medicinal chemistry. A variety of biological activities have been reported by oxazolidinone derivatives. The present work describes the synthesis of several oxazolidinone derivatives, 3‐(2‐(7‐chloroquinoline‐4‐ylamino)ethyl)‐2‐imino‐5‐(4‐chloro/nitro/methoxy benzylidene)oxazolidin‐4‐one 4(a–c) and 4‐(2‐(7‐chloroquinolin‐4‐ylamino)ethyl)‐2(4‐chloro/nitro/methoxy‐benzylidene)‐1,6‐diox‐4,9‐di‐azaspiro[4,4]nonane‐3,8‐dione 5(a–c). Synthesized compounds (1, 3, 4a, 5a, and 5c) were screened against bacterial strains such as S. aureus (MTCC 96) and E. coli (MTCC119)
and fungal strains A. niger (MTCC 1344) and C. albicans (MTCC 871) compared with penicillin for bacteria and fluconazole for fungi as reference drugs by disk diffusion method. All synthesized compounds were identified by the means of IR, NMR, and MS.
Fumigant Compounds from the Essential Oil of Chinese Blumea balsamifera Leaves against the Maize Weevil (Sitophilus zeamais)
Authors: Chu Sha Sha , Du Shu Shan , Liu Zhi Long
Published: August 2012

Essential oil of Chinese medicinal herb, Blumea balsamifera leaves, was found to possess fumigant toxicity against the maize weevils, Sitophilus zeamais. The main components of the essential oil of B. balsamifera were 1,8‐cineole (20.98%), borneol (11.99%), β‐caryophyllene (10.38%), camphor (8.06%), 4‐terpineol (6.49%), α‐terpineol (5.91%), and caryophyllene oxide (5.35%). Bioactivity‐guided chromatographic separation of the essential oil on repeated silica gel columns led to isolate five constituent compounds, namely, 1,8‐cineole, borneol, camphor, α‐terpineol, and 4‐terpineol. 1,8‐Cineole, 4‐terpineol, and α‐terpineol showed pronounced fumigant toxicity against S. zeamais adults (LC50 = 2.96 mg/L, 4.79 mg/L, and 7.45 mg/L air, resp.) and were more toxic than camphor (LC50 = 21.64 mg/L air) and borneol (LC50 = 21.67 mg/L air). The crude essential oil also possessed strong fumigant toxicity against S. zeamais adults (LC50 = 10.71 mg/L air).
Batch Study for Insecticide Carbofuran Adsorption onto Palm‐Oil‐Fronds‐Activated Carbon
Authors: Salman Jassem M.
Published: August 2012

The adsorption of insecticide, carbofuran from aqueous solution onto activated carbon derived from palm oil fronds (PFAC) was investigated through batch study. The effects of both initial concentration and pH of the carbofuran over the range of 25 to 250 mg/L and 2 to 12, respectively, on the adsorption of the prepared PFAC were studied in batch experiments. Equilibrium data were fitted to the Langmuir, the Freundlich, and the Temkin isotherm models. The results obtained from application of these models show that the best fits were achieved with the Langmuir model, and a maximum monolayer adsorption capacity of 164 mg/g was obtained at 30°C. The regeneration efficiency of spent activated carbon was studied and it was found to be 90.0–96.4%. The results indicated that PFAC has good capability as adsorbent for the removal of carbofuran from aqueous solutions.
FLT-PET Is Superior to FDG-PET for Very Early Response Prediction in NPM-ALK-Positive Lymphoma Treated with Targeted Therapy
Authors: Li Zhoulei , Graf Nicolas , Herrmann Ken , Jünger Alexandra , Aichler Michaela , Feuchtinger Annette , Baumgart Anja , Walch Axel , Peschel Christian , Schwaiger Markus , Buck Andreas , Keller Ulrich , Dechow Tobias
Published: August 2012

The prognosis of relapsed or refractory aggressive lymphoma is poor. The huge variety of currently evolving targeted treatment approaches would benefit from tools for early prediction of response or resistance. We used various ALK-positive anaplastic large cell lymphoma (ALCL) cell lines to evaluate two inhibitors, the HSP90 inhibitor NVP-AUY922, and the mTOR inhibitor everolimus, both of which have shown to interfere with ALK-dependent oncogenic signal transduction. Their therapeutic effect was determined in vitro by MTT assay, [18F]fluorodeoxyglucose (FDG)- and [18F]fluorothymidine (FLT)-uptake, and by biochemical analysis of ALK-induced signaling. Micro-FDG- and FLT-positron emission tomography (PET) imaging studies in immunodeficient mice bearing ALCL xenotransplants were carried out with the cell lines SUDHL-1 and Karpas299 to assess early treatment response to NVP-AUY922 or everolimus in vivo. SUDHL-1 cells showed sensitivity to both inhibitors in vitro. Importantly, we detected a significant reduction of FLT-uptake in SUDHL-1 bearing animals using both inhibitors compared with baseline as early as 5 days after initiation of targeted therapy. Immunostaining showed a decrease in Ki-67 and an increase in cleaved caspase-3 staining. In contrast, FDG-uptake did not significantly decrease at early time points. Karpas299 xenotransplants, which are resistant to NVP-AUY922 and sensitive to everolimus treatment, showed an increase of mean FLT-uptake on day 2 after administration of NVP-AUY299, but a significant reduction in FLT-uptake upon everolimus treatment. In conclusion, we show that FLT-PET but not FDG-PET is able to predict response to treatment with specific inhibitors very early in the course of treatment and thus enables early prediction of treatment efficacy. Cancer Res; 72(19); 5014–24. ©2012 AACR.
Functional Genomics Identifies Drivers of Medulloblastoma Dissemination
Authors: Mumert Michael , Dubuc Adrian , Wu Xiaochong , Northcott Paul A. , Chin Steven S. , Pedone Carolyn A. , Taylor Michael D. , Fults Daniel W.
Published: August 2012

Medulloblastomas are malignant brain tumors that arise in the cerebellum in children and disseminate via the cerebrospinal fluid to the leptomeningeal spaces of the brain and spinal cord. Challenged by the poor prognosis for patients with metastatic dissemination, pediatric oncologists have developed aggressive treatment protocols, combining surgery, craniospinal radiation, and high-dose chemotherapy, that often cause disabling neurotoxic effects in long-term survivors. Insights into the genetic control of medulloblastoma dissemination have come from transposon insertion mutagenesis studies. Mobilizing the Sleeping Beauty transposon in cerebellar neural progenitor cells caused widespread dissemination of typically nonmetastatic medulloblastomas in Patched+/− mice, in which Shh signaling is hyperactive. Candidate metastasis genes were identified by sequencing the insertion sites and then mapping these sequences back to the mouse genome. To determine whether genes located at transposon insertion sites directly caused medulloblastomas to disseminate, we overexpressed candidate genes in Nestin+ neural progenitors in the cerebella of mice by retroviral transfer in combination with Shh. We show here that ectopic expression of Eras, Lhx1, Ccrk, and Akt shifted the in vivo growth characteristics of Shh-induced medulloblastomas from a localized pattern to a disseminated pattern in which tumor cells seeded the leptomeningeal spaces of the brain and spinal cord. Cancer Res; 72(19); 4944–53. ©2012 AACR.
Abstract 1000: Oncogenic Kras inhibits mitochondrial metabolism by regulating the pyruvate dehydrogenase complex under conditions of nutrient stress
Authors: Jaitin Diego , Sayles Leanne , Goliazova Tereza , Denko Nicholas , Sweet-Cordero Alejandro
Published: August 2012

Kras is one of the most frequently mutated oncogenes in human cancer. Previous studies have suggested a role for oncogenic Kras in regulating glucose metabolism, although the exact mechanism is unclear. By analyzing the transcriptional consequences of Kras mutation under conditions of nutrient stress, a direct role for oncogenic Kras in regulating oxidative phosphorylation was observed. Signaling downstream of Kras via the MEK/ERK pathway inhibits expression of PDP1, a mitochondrial phosphatase that regulates the pyruvate dehydrogenase complex (PDC). PDC is a key enzyme in the conversion of pyruvate into acetyl-CoA. Decreased expression of PDP1 induced by oncogenic Kras leads to increased phosphorylation and thereby inactivation of PDC. Therefore, oncogenic Kras represses mitochondrial function and oxygen consumption by maintaining PDC in an inactive state. This effect is not apparent under the high-glucose conditions in which cells are typically cultured. However, at glucose concentrations more closely reflective of what cells experience in vivo, the effect of oncogenic Kras signaling on PDP1 expression becomes readily apparent. This study demonstrates a novel role for oncogenic Kras in the regulation of mitochondrial metabolism. Further studies underway may clarify a role for this pathway as a target for therapeutic intervention in Kras-mutant tumors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1000. doi:1538-7445.AM2012-1000
Abstract 1015: Mammary stem cells increase late in embryogenesis, facilitating their characterization and revealing links to breast cancer
Authors: Spike Benjamin T. , Engle Dannielle D. , Lin Jennifer C. , La Justin , Cheung Samantha K. , Wahl Geoffrey M.
Published: August 2012

Parallels between embryonic development, stem cells, and cancer have long been recognized. The proliferative and invasive characteristics of the most lethal forms of breast cancer and their lack of differentiated characteristics resemble aspects of embryonic mammogenesis, raising the possibility that they share molecular mechanisms. We have identified, isolated and characterized a fetal mammary population with concentrated mammary stem cell activity and shown that it exhibits gene expression similarities to certain human breast cancer molecular subtypes. Limiting dilution transplantation analyses demonstrate that a robust increase in fetal mammary stem cell (fMaSC) activity is evident after embryonic day 16 (E16), coincident with invasion of the rudiment through the mesenchyme and into the fat pad precursor. Markers used to enrich adult MaSCs enabled isolation of a population at E18.5 that is highly enriched for fMaSCs and capable of serial transplantation in vivo and clonal, multilineage sphere formation in vitro. Genome-wide expression profiling and single cell analyses revealed candidate pathways in both the epithelial and stromal compartments with relevance to fMaSC activity and cancer. Notably, ErbB and FGF signaling were critical and synergistic for the in vitro growth of spheres derived from the fMaSC-enriched population, and fMaSCs expressed elevated ErbB2, 3, and 4 relative to adult MaSC enriched populations. We explored molecular links between fetal mammary development and cancer further by analyzing the expression of fetal gene signatures in archived breast cancer array data and in breast cancer cell lines. We identified gene expression modules correlating with certain cell lines, intrinsic breast cancer subtypes and clinical outcome. These studies advance the attractive hypothesis that regulatory pathways governing fMaSC function and embryonic mammogenesis that are deregulated in certain types of human cancer can be targeted in the development of new therapies and prognostic metrics.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1015. doi:1538-7445.AM2012-1015
Abstract 1018: Epithelial-to-mesenchymal transition (EMT) alters vesiculation of cancer cells expressing oncogenic epidermal growth factor receptor (EGFR): Implications for the aggressive, procoagulant and proangiogenic properties
Authors: Garnier Delphine , Milsom Chloe , Magnus Nathalie , Bentley Victoria , Lee Tae Hoon , Meehan Brian , Montermini Laura , Rak Janusz
Published: August 2012

Cancer cells release elevated amounts of membrane-derived organelles containing complex molecular cargo, and known as extracellular vesicles (EVs). This process (vesiculation) is implicated in intercellular communication, as well as in cancer invasion, metastasis, angiogenesis and activation of the coagulation system. We have previously demonstrated a link between oncogenic transformation mediated by mutant K-ras, epidermal growth factor receptor (EGFR) as well as other genetic lesions and the intensity of cancer cell vesiculation. In the present study we interrogate vesiculation during the superimposed processes of de-differentiation and epithelial-to-mesenchymal transition (EMT). In the EGFR-driven epidermoid cancer cell line A431, EMT can be induced by stimulation with EGFR ligands coupled with blockade of the E-cadherin. Of note, A431 cells express high levels of the Tissue Factor (TF) receptor which renders them procoagulant, and is required for the efficient tumor initiation and proangiogenic signalling. A431 cells emit heterogeneous population of EVs, including subsets containing TF, and EGFR. We observed that induction of EMT in A431 cells is associated with a global increase in vesiculation, as revealed by nanoparticle tracking analysis (NTA/Nanosight). At the same time, EGFR and TF are relocated from the plasma membrane to distinct subcellular microdomains, and this change is associated with a rearrangement in the proteome of EVs emitted by cancer cells, including a significant increase in TF content. Tumor cell-derived, TF-containing EVs are readily taken up by endothelial cells and trigger their procoagulant conversion and angiogenic responses. While forming tumors in vivo A431 cells spontaneously undergo multilineage differentiation and generate EMT-like subpopulations, which release into the circulation a subset of EVs with a distinct molecular signature. Thus, EMT-like processes not only modulate intrinsic cellular properties (cell shape, differentiation), but also trigger a shift in cellular vesiculation that may be detected in EV preparations isolated from peripheral blood. Moreover, EVs that emanate from cancer cells upon their entry into the EMT pathway may acquire the ability to modify the extracellular and vascular milieu, and possibly facilitate tumor initiation, invasion and metastasis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1018. doi:1538-7445.AM2012-1018
Abstract 1034: Upregulation of Ezh2 expression correlates with higher tumor proliferation and grade in non-Hodgkin's B- and T-cell lymphoma
Authors: Al-Kader Lamia Abd , Oka Takashi , Takata Katsuyoshi , Sun Xu , Sato Hiaki , Murakami Ichiro , Kimura Hiroshi , Otte Arie P. , Yoshino Tadashi
Published: August 2012

Polycomb group (PcG) proteins are involved in regulation of hematopoiesis, which include two main members Ezh2 and Bmi-1. Reports on their expression levels in different subtypes of malignant lymphoma and role in lymphomagensis and tumor progression are rather limited. To address this issue, we analyzed a total of 197 patient samples including 10 samples of Hodgkin lymphoma (HL), 109 of B-cell lymphoma (BCL) and 78 of T-cell lymphoma (TCL) by immunohistochemistry. The results showed overall expression in HL, BCL and TCL to be 90%, 56.9% and 84.6% for Ezh2 and 90%, 82.5% and 84.6% for Bmi-1 respectively. Among BCL, highest Ezh2 positivity was seen in Burkitt's lymphoma (BL) followed by high-grade follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). In TCL, Ezh2 expression was observed in all subtypes and seemed more homogenous. Difference in its expression between aggressive and indolent subtypes of BCL was statistically significant (p= 0.000∼0.010). On the other hand, Bmi-1 was rather more consistently expressed in both BCL and TCL up to 100% in 7 subtypes. Difference in its expression between aggressive and indolent subtypes was statistically insignificant. Ki67 showed strong positive correlation with Ezh2 in BCL (Correlation coefficient (Co) =0.983, p= 0.000) and moderate correlation in TCL (Co=0 .629, p= 0.000). This correlation could not be detected in case of Bmi1. These data suggest that out of the two Polycomb group (PcG) proteins, only Ezh2 correlates with tumor proliferation and signals a more aggressive nature.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1034. doi:1538-7445.AM2012-1034
Abstract 1041: Epigenetic regulation of BRAF-HDAC complex in presence of trichostatin A, 5-aza-2′-deoxycytidine and cisplatin in ovarian cancer
Authors: Meng Fanliang , Zhong Mei , Sun Guigin , Yu Yanhong , Brewer Molly A.
Published: August 2012

Objective: To investigate the regulation of the subunits of BRAF-HDAC complex, a gene transcription repression complex, which regulates the interaction of histone methylation, histone acetylation, DNA methylation and DNA repair in response to chemotherapy in ovarian cancer cell lines with different treatment strategies. We hypothesized that combining different epigenetic modifiers with low dose Cisplatin would result in an optimal therapeutic regime for ovarian cancer. Materials and Methods: Two epigenetic modifiers Trichostatin A (TSA), a histone deacetylase inhibitor and 5-aza-2′- deoxycytidine (Decitabine), a demethylating agent were evaluated in different doses alone and in combination with Cisplatin on the expression of subunits of BRAF-HDAC complex, histone methylation, acetylation and the associated pathways affected. Three cell lines, A2780, Hey and SKOV3 were used. Spheroids were grown in serum free medium and injected IP in SCID mice. Western blots confirmed protein expression. Results: Different combinations of TSA, Decitabine and low dose Cisplatin significantly inhibited the expression of the subunits LSD1 and CoREST in the BRAF-HDAC complex, two proteins which together demethylate H3K4 and H3K9. The BRAF-HDAC complex cofactor subunit BRAF35 was also significantly suppressed by the combination treatment. The BRAF-HDAC complex subunit repressor increased significantly after combined treatment. indicating that the combination of TSA, Decitabine and Cisplatin suppresses the expression of H3K4 and H3K9 methylation and increases the expression of Histone H3 lys9/14 and Histone H4 ser1/lys5/lys8/lys12 acetylation. Along with these methylation and acetylation changes, we found a decrease in epithelial-mesenchymal transition, cancer cell proliferation, chemoresistance and pluripotency. Spheroid formation was decreased in vitro and there was no tumor formation in SCID mice in presence of these epigenetic modifiers and low dose Cisplatin. Conclusions: The combination of epigenetic modifiers and low dose Cisplatin can regulate and modify the expression of subunits of BRAF-HDAC complex, resulting in decreased expression of tri- and di- methylated H3K4 and H3K9 and increased acetylation of Histone H3 and H4, subsequently modifying the tumor biology and tumorigenicity of these ovarian cancer cell lines. Further investigation of these mechanisms could provide the development of more effective and less toxic treatment for ovarian cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1041. doi:1538-7445.AM2012-1041
Abstract 1055: Enhancer of Zeste Homologue 2 (EZH2) may relate to progression of intra and extrahepatic cholangiocarcinoma
Authors: Nakagawa Shigeki , Okabe HIrohisa , Beppu Toru , Kuroki Hideyuki , Mima Kousuke , Hayashi Hiromitu , Imai Katsunori , Nitta Hidetoshi , Nakahara Osamu , Ikuta Yoshiaki , Chikamoto Akira , Ishiko Takatoshi , Takamori Hiroshi , Baba Hideo
Published: August 2012

[Background and Aims]Enhancer of Zeste Homolog 2 (EZH2) is one of the polycomb proteins and involved in the progress of several solid tumors by methylating histone3 Lysin27 (H3K27) and silencing various genes. However, the role of EZH2 in cholangiocarcinoma has not been clarified. In this study, we investigated the significance of EZH2 expression in intrahepatic and extrahepatic cholangiocarcinoma progression.[Patients and Methods]Fourty-seven intrahepatic cholangiocarcinoma (ICC) patients and 45 extrahepatic cholangiocarcinoma (ECC) patients treated with curative resection from 1993 to 2010 were enrolled. We examined the EZH2 expression by immunohistochemistry, and relationship between EZH2 expression and clinicopathological factors, such as gender, age, CA19-9, tumor diameter, tumor number, histological vascular invasion, differentiation, lymph node metastasis and prognosis. To assess whether EZH2 relates to angiogenesis and tumor growth, Ki67 expression and microvessel density (MVD) using CD34 were also examined by immunohistochemistry. EZH2 expression was investigated eight cholangiocarcinoma cell lines. Using small interfering RNA against EZH2, the influence of EZH2 knock-down on cholangiocarcinoma cell proliferation and invasion was studied in vitro. [Results]In ICC, 24 patients (51.0%) shows a high expression of EZH2 when the cutoff value was determined to be 10%. The EZH2 high expression is significantly correlated with tumor diameter > 3.5cm (P=0.0113) and MVD score (P=0.039). The high EZH2 expression group showed significantly worse overall survival (p=0.045). In ECC, 19 patients(42.2%) showed a high EZH2 expression. The EZH2 high expression is significantly correlated with positive lymph node metastasis (p=0.0469), high Ki67 expression (P=0.0017). The high EZH2 expression group showed significantly worse overall survival (P=0.0261). All of the eight cholangiocarcinoma cell lines expressed EZH2 in a various level. When we knock down the expression of EZH2 in RBE cells, the expression of H3K27 was reduced and cell growth decreased. However, EZH2 down-regulation didn't affect cell invasion.[Conclusion]EZH2 may relate to the progression of intra and extrahepatic cholangiocarcinoma.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1055. doi:1538-7445.AM2012-1055