bluuebunny/crossref_metadata_2025 huggingface dataset:
Cortical regions involved in the observation of bimanual actions
Authors: Heitger Marcus H. , Macé Marc J.-M. , Jastorff Jan , Swinnen Stephan P. , Orban Guy A.
Published: August 2012

Although we are beginning to understand how observed actions performed by conspecifics with a single hand are processed and how bimanual actions are controlled by the motor system, we know very little about the processing of observed bimanual actions. We used fMRI to compare the observation of bimanual manipulative actions with their unimanual components, relative to visual control conditions equalized for visual motion. Bimanual action observation did not activate any region specialized for processing visual signals related to this more elaborated action. On the contrary, observation of bimanual and unimanual actions activated similar occipito-temporal, parietal and premotor networks. However, whole-brain as well as region of interest (ROI) analyses revealed that this network functions differently under bimanual and unimanual conditions. Indeed, in bimanual conditions, activity in the network was overall more bilateral, especially in parietal cortex. In addition, ROI analyses indicated bilateral parietal activation patterns across hand conditions distinctly different from those at other levels of the action-observation network. These activation patterns suggest that while occipito-temporal and premotor levels are involved with processing the kinematics of the observed actions, the parietal cortex is more involved in the processing of static, postural aspects of the observed action. This study adds bimanual cooperation to the growing list of distinctions between parietal and premotor cortex regarding factors affecting visual processing of observed actions.
Inflammation-induced shift in spinal GABAAsignaling is associated with a tyrosine kinase-dependent increase in GABAAcurrent density in nociceptive afferents
Authors: Zhu Yi , Dua Shiv , Gold Michael S.
Published: August 2012

To account for benzodiazepine-induced spinal analgesia observed in association with an inflammation-induced shift in the influence of the GABAAreceptor antagonist gabazine on nociceptive threshold, the present study was designed to determine whether persistent inflammation is associated with the upregulation of high-affinity GABAAreceptors in primary afferents. The cell bodies of afferents innervating the glabrous skin of the rat hind paw were retrogradely labeled, acutely dissociated, and studied before and after the induction of persistent inflammation. A time-dependent increase in GABAAcurrent density was observed that was more than twofold by 72 h after the initiation of inflammation. This increase in current density included both high- and low-affinity currents and was restricted to neurons in which GABA increased intracellular Ca2+. No increases in GABAAreceptor subunit mRNA or protein were detected in whole ganglia. In contrast, the increased current density was completely reversed by 20-min preincubation with the tyrosine kinase inhibitor genistein and partially reversed with the Src kinase inhibitor PP2. Genistein reversal was partially blocked by the dynamin inhibitor peptide P4. Changes in nociceptive threshold following spinal administration of genistein and muscimol to inflamed rats indicated that the pronociceptive actions of muscimol observed in the presence of inflammation were reversed by genistein. These results suggest that persistent changes in relative levels of tyrosine kinase activity following inflammation provide not only a sensitive way to dynamically regulate spinal nociceptive signaling but a viable target for the development of novel therapeutic interventions for the treatment of inflammatory pain.
Constructing the angiome: a global angiogenesis protein interaction network
Authors: Chu Liang-Hui , Rivera Corban G. , Popel Aleksander S. , Bader Joel S.
Published: August 2012

Angiogenesis is the formation of new blood vessels from pre-existing microvessels. Excessive and insufficient angiogenesis have been associated with many diseases including cancer, age-related macular degeneration, ischemic heart, brain, and skeletal muscle diseases. A comprehensive understanding of angiogenesis regulatory processes is needed to improve treatment of these diseases. To identify proteins related to angiogenesis, we developed a novel integrative framework for diverse sources of high-throughput data. The system, called GeneHits, was used to expand on known angiogenesis pathways to construct the angiome, a protein-protein interaction network for angiogenesis. The network consists of 478 proteins and 1,488 interactions. The network was validated through cross validation and analysis of five gene expression datasets from in vitro angiogenesis assays. We calculated the topological properties of the angiome. We analyzed the functional enrichment of angiogenesis-annotated and associated proteins. We also constructed an extended angiome with 1,233 proteins and 5,726 interactions to derive a more complete map of protein-protein interactions in angiogenesis. Finally, the extended angiome was used to identify growth factor signaling networks that drive angiogenesis and antiangiogenic signaling networks. The results of this analysis can be used to identify genes and proteins in different disease conditions and putative targets for therapeutic interventions as high-ranked candidates for experimental validation.
Renal Preservation Therapy for Renal Cell Carcinoma
Authors: Chiu Yichun , Chiu Allen W.
Published: August 2012

Renal preservation therapy has been a promising concept for the treatment of localized renal cell carcinoma (RCC) for 20 years. Nowadays partial nephrectomy (PN) is well accepted to treat the localized RCC and the oncological control is proved to be the same as the radical nephrectomy (RN). Under the result of well oncological control, minimal invasive method gains more popularity than the open PN, like laparoscopic partial nephrectomy (LPN) and robot assisted laparoscopic partial nephrectomy (RPN). On the other hand, thermoablative therapy and cryoablation also play an important role in the renal preservation therapy to improve the patient procedural tolerance. Novel modalities, but limited to small number of patients, include high-intensity ultrasound (HIFU), radiosurgery, microwave therapy (MWT), laser interstitial thermal therapy (LITT), and pulsed cavitational ultrasound (PCU). Although initial results are encouraging, their real clinical roles are still under evaluation. On the other hand, active surveillance (AS) has also been advocated by some for patients who are unfit for surgery. It is reasonable to choose the best therapeutic method among varieties of treatment modalities according to patients' age, physical status, and financial aid to maximize the treatment effect among cancer control, patient morbidity, and preservation of renal function.
Intensification of Doxorubicin-Related Oxidative Stress in the Heart by Hypothyroidism Is Not Related to the Expression of Cytochrome P450 NADPH-Reductase and Inducible Nitric Oxide Synthase, As Well As Activity of Xanthine Oxidase
Authors: Dudka Jaroslaw , Burdan Franciszek , Korga Agnieszka , Iwan Magdalena , Madej-Czerwonka Barbara , Cendrowska-Pinkosz Monika , Korobowicz-Markiewicz Agnieszka , Jodlowska-Jedrych Barbara , Matysiak Wlodzimierz
Published: August 2012

Cytochrome P450 NADPH-reductase (P450R), inducible synthase (iNOS) and xanthine oxidase play an important role in the antracycline-related cardiotoxicity. The expression of P450R and iNOS is regulated by triiodothyronine. The aim of this study was to evaluate the effect of methimazole-induced hypothyreosis on oxidative stress secondary to doxorubicin administration. 48 hours after methimazole giving cessation, rats were exposed to doxorubicin (2.0, 5.0 and 15 mg/kg). Blood and heart were collected 4, 48 and 96 h after the drug administration. Animals exposed exclusively to doxorubicin or untreated ones were also assessed. The hypothyreosis (0.025% of methimazole) significantly increased the doxorubicin effect on the cardiac carbonyl group and they may increase the glutathione level. An insignificant effect of methimazole was noticed in case of the cardiac lipid peroxidation product, the amount of DNA oxidative damages, iNOS and xanthine oxidase-enzymes responsible for red-ox activation of doxorubicin. However, the concentration of P450R was affected by a lower dose of methimazole in rats administered with doxorubicin. Since in rats receiving doxorubicin changes in oxidative stress caused by methimazole were not accompanied by elevation of bioreductive enzymes, it may be concluded that these changes in the oxidative stress were not related to the tested enzymes.
Fixed Point Theorem for Cyclic Chatterjea Type Contractions
Authors: Karapınar Erdal , Nashine Hemant Kumar
Published: August 2012

We introduce the notion of cyclic weakly Chatterjea type contraction and generalized cyclic weakly Chatterjea type contraction in metric spaces. We discussed the existence of fixed point theorems of (generalized) cyclic weakly Chatterjea type contraction mappings in the context of complete metric spaces. Our main theorems extend and improve some fixed point theorems in the literature.
A Systematic Review of the Recent Quality of Life Studies in Adult Extremity Sarcoma Survivors
Authors: Tang Melissa H. , Pan Donald J. W. , Castle David J. , Choong Peter F. M.
Published: August 2012

Background. Extremity sarcoma represents a heterogeneous group of rare cancers that carries a relatively high morbidity with regards to physical function. Quality of Life (QoL) as an outcome is an important consideration in this cohort. We aimed to identify the correlates of QoL in extremity sarcoma cohorts.Methods. A systematic review of the literature on extremity sarcoma in adults from five databases over the last ten years was undertaken.Results. Twelve articles were chosen and assessed for quality. Physical and social function of extremity sarcoma survivors is below that of the general population. Overall QoL scores of these patients are comparable to those of the general population. Studies that used more recently treated cohorts found that patients who had limb sparing surgery displayed superior functional outcomes over those that underwent amputations. Pain and perceiving that the cancer negatively influenced opportunities was associated with poor outcomes.Conclusion. The available literature regarding QoL in extremity sarcoma patients is heterogeneous in terms of aims and assessment tools. Results need to be interpreted in light of the improved management of extremity sarcoma in more recent patient cohorts.
Design and Analysis of a THz Metamaterial Structure with High Refractive Index at Two Frequencies
Authors: Lu Zan , Camps-Raga Bruno , Islam N. E.
Published: August 2012

The concept of a single frequency band, single high-refractive-index metamaterial has been extended and applied in the design of dual frequency band, dual high-refractive-index metamaterials in the THz regime. The structure design consists of twenty five unit cells with a surface area of 250 um by 250 um and a thickness of 5 um. Each cell has metallic structures embedded in a polyimide substrate. The return loss (S-parameter) analysis shows two strong electric responses at two frequency ranges, and the extracted constitutive parameters suggested high values of simultaneous dielectric constant and permeability at these frequencies. Results retrieved from the S-parameters also show high refractive index values. A first peak refractive index of 61.83 was observed at a resonant frequency of 0.384 THz, and another peak refractive index of 19.2 was observed at the resonant frequency 1.416 THz. Analysis show that higher refractive index at the second resonance frequency band is achievable through redesign of the structures, and modifications could lead to a single structure with multiple frequency, multiple high-refractive-index metamaterials that can be put to practical use.
Modelling and Prediction of Stainless Steel Clad Bead Geometry Deposited by GMAW Using Regression and Artificial Neural Network Models
Authors: Sreeraj P. , Kannan T.
Published: August 2012

To improve the corrosion-resistant properties of carbon steel, usually cladding process is used. It is a process of depositing a thick layer of corrosion-resistant material over carbon steel plate. Most of the engineering applications require high strength and corrosion resistant materials for long-term reliability and performance. Cladding these properties can be achieved with minimum cost. The main problem faced in cladding is the selection of optimum combinations of process parameters for achieving quality clad and hence good clad bead geometry. This paper highlights an experimental study to predict various input process parameters (welding current, welding speed, gun angle, contact tip-to-work distance, andpinch) to getoptimum dilutionin stainless steel cladding of low carbon structural steel plates using Gas Metal Arc Welding (GMAW). Experiments were conducted based on central composite rotatable design with full replication technique, and mathematical models were developed using multiple regression method. The developed models have been checked for adequacy and significance. Using Artificial Neural Network (ANN) the parameters were predicted, and percentage of error was calculated between predicted and actual values. The direct and interaction effects of process parameters on clad bead geometry are presented in graphical form.
The Genetic Basis of Female Mate Preference and Species Isolation inDrosophila
Authors: Laturney Meghan , Moehring Amanda J.
Published: August 2012

The processes that underlie mate choice have long fascinated biologists. With the advent of increasingly refined genetic tools, we are now beginning to understand the genetic basis of how males and females discriminate among potential mates. One aspect of mate discrimination of particular interest is that which isolates one species from another. As behavioral isolation is thought to be the first step in speciation, and females are choosy more often than males in this regard, identifying the genetic variants that influence interspecies female mate choice can enhance our understanding of the process of speciation. Here, we review the literature on female mate choice in the most widely used model system for studies of species isolationDrosophila. Although females appear to use the same traits for both within- and between-species female mate choice, there seems to be a different genetic basis underlying these choices. Interestingly, most genomic regions that cause females to reject heterospecific males fall within areas of low recombination. Likely, candidate genes are those that act within the auditory or olfactory system, or within areas of the brain that process these systems.
Involvement of the Cerebral Monoamine Neurotransmitters System in Antidepressant-Like Effects of a Chinese Herbal Decoction, Baihe Dihuang Tang, in Mice Model
Authors: Chen Meng-Li , Gao Jie , He Xin-Rong , Chen Qian
Published: August 2012

Baihe Dihuang Tang (BDT) is a renowned Chinese herbal formula which is commonly used for treating patients with mental instability, absentmindedness, insomnia, deficient dysphoria, and other psychological diseases. These major symptoms closely associated with the depressive disorders. BDT was widely popular use for treating emotion-thought disorders for many years in China. In the present study, the antidepressant-like effect of BDT in mice was investigated by using the forced swim test (FST) and the tail suspension test (TST). The underlying mechanism was explored by determining the effect of BDT on the level of cerebral monoamine neurotransmitters. BDT (9 and 18 g/kg, p.o. for 14 days) administration significantly reduced the immobility time in both the FST and the TST without changing locomotion in the open field-test (OFT). Moreover, BDT treatment at the dose of 18 g/kg inhibited reserpine-induced ptosis. Meanwhile, BDT enhanced 5-HT and NA levels in mouse cerebrum as well as decreased the ratio of 5-HT compared to its metabolite, 5-HIAA, (turnover, 5-HIAA/5-HT) after TST. The results demonstrated that the antidepressant-like effect of BDT is mediated, at least partially, via the central monoaminergic neurotransmitter system.
Integral Formulae of Bernoulli and Genocchi Polynomials
Authors: Rim Seog-Hoon , Jin Joung-Hee , Jeong Joohee
Published: August 2012

Recently, some interesting and new identities are introduced in the work of Kim et al. (2012). From these identities, we derive some new and interesting integral formulae for Bernoulli and Genocchi polynomials.
Dynamic Modeling and Analysis of the Email Virus Propagation
Authors: Li Yihong , Pan Jinxiao , Jin Zhen
Published: August 2012

A novel deterministic SEIS model for the transmission of email viruses in growing communication networks is formulated. Interestingly, the model is different from classical SEIS models not only in the form, but also in the dynamical features. We study the equilibria and their stability and analyse the bifurcation dynamics of the model. In particular, we find that the virus‐free equilibrium is locally asymptotically stable for any parameter values, which may attribute to the absence of the basic reproduction number. It is shown that the model undergoes a saddle‐node bifurcation and admits the bistable phenomenon. Moreover, on the basis of the Lyapunov function, the domains of attraction of equilibria are estimated by solving an LMI optimization problem. Based on the above theoretical results, some effective strategies are also provided to control the propagation of the email viruses. Additionally, our results are confirmed by numerical simulations.
Immune Response to Lipoproteins in Atherosclerosis
Authors: Samson Sonia , Mundkur Lakshmi , Kakkar Vijay V.
Published: August 2012

Atherosclerosis, the underlying cause of cardiovascular disease, is characterized by chronic inflammation and altered immune response. Cholesterol is a well-known risk factor associated with the development of cardiovascular diseases. Elevated serum cholesterol is unique because it can lead to development of atherosclerosis in animals and humans even in the absence of other risk factors. Modifications of low-density lipoproteins mediated by oxidation, enzymatic degradation, and aggregation result in changes in their function and activate both innate and adaptive immune system. Oxidized low-density lipoprotein (LDL) has been identified as one of the most important autoantigens in atherosclerosis. This escape from self-tolerance is dependent on the formation of oxidized phospholipids. The emerging understanding of the importance of immune responses against oxidized LDL in atherosclerosis has focused attention on the possibility of development of novel therapy for atherosclerosis. This review provides an overview of immune response to lipoproteins and the fascinating possibility of developing an immunomodulatory therapy for atherosclerosis.
Estimation of Natural Variability and Detection of Anthropogenic Signal in Summertime Precipitation over South America
Authors: Talento Stefanie , Barreiro Marcelo
Published: August 2012

We use a coupled model to estimate the natural variability of summertime rainfall over South America and to determine the time horizon when anthropogenic forcing will start having an effect on it. We use a combination of three experiments: preindustrial, 20th century, and the projected changes under A1B scenario. The first empirical orthogonal function of rainfall in December–February is used to characterize summertime variability. The model can display two different regimes of natural variability of this mode. In one regime, there is a strong coupling between the South Atlantic convergence zone (SACZ) and the Atlantic Ocean. In the other regime, the SACZ is dominated by internal atmospheric variability. The detection of the impact of anthropogenic forcing is calculated comparing the probability density functions (pdfs) of the preindustrial run with the one under the A1B scenario. We found that the detection strongly depends on the pdf used to characterize internal climate variability. If the pdf of the mode with coupling between the SACZ and the Atlantic Ocean is used, the anthropogenic influence is felt very early within the future scenario (in less than 30 years). On the contrary, with the pdf that characterizes an SACZ dominated by internal atmospheric variability, the forcing is detected only several (almost 50) years into the scenario.
Statistical Analyses and Modeling of the Implementation of Agile Manufacturing Tactics in Industrial Firms
Authors: AL-Tahat Mohammad D. , Bataineh Khaled M.
Published: August 2012

This paper provides a review and introduction on agile manufacturing. Tactics of agile manufacturing are mapped into different production areas (eight‐construct latent): manufacturing equipment and technology, processes technology and know‐how, quality and productivity improvement, production planning and control, shop floor management, product design and development, supplier relationship management, and customer relationship management. The implementation level of agile manufacturing tactics is investigated in each area. A structural equation model is proposed. Hypotheses are formulated. Feedback from 456 firms is collected using five‐point‐Likert‐scale questionnaire. Statistical analysis is carried out using IBM SPSS and AMOS. Multicollinearity, content validity, consistency, construct validity, ANOVA analysis, and relationships between agile components are tested. The results of this study prove that the agile manufacturing tactics have positive effect on the overall agility level. This conclusion can be used by manufacturing firms to manage challenges when trying to be agile.
Goal-Oriented Respiratory Management for Critically Ill Patients with Acute Respiratory Distress Syndrome
Authors: Barbas Carmen Sílvia Valente , Matos Gustavo Faissol Janot , Amato Marcelo Britto Passos , Carvalho Carlos Roberto Ribeiro
Published: August 2012

This paper, based on relevant literature articles and the authors' clinical experience, presents a goal-oriented respiratory management for critically ill patients with acute respiratory distress syndrome (ARDS) that can help improve clinicians' ability to care for these patients. Early recognition of ARDS modified risk factors and avoidance of aggravating factors during hospital stay such as nonprotective mechanical ventilation, multiple blood products transfusions, positive fluid balance, ventilator-associated pneumonia, and gastric aspiration can help decrease its incidence. An early extensive clinical, laboratory, and imaging evaluation of “at risk patients” allows a correct diagnosis of ARDS, assessment of comorbidities, and calculation of prognostic indices, so that a careful treatment can be planned. Rapid administration of antibiotics and resuscitative measures in case of sepsis and septic shock associated with protective ventilatory strategies and early short-term paralysis associated with differential ventilatory techniques (recruitment maneuvers with adequate positive end-expiratory pressure titration, prone position, and new extracorporeal membrane oxygenation techniques) in severe ARDS can help improve its prognosis. Revaluation of ARDS patients on the third day of evolution (Sequential Organ Failure Assessment (SOFA), biomarkers and response to infection therapy) allows changes in the initial treatment plans and can help decrease ARDS mortality.
Neuroblastoma in the Elderly and SIADH: Case Report and Review of the Literature
Authors: Pellegrino Micaela , Gianotti Laura , Cassibba Sara , Brizio Rodolfo , Terzi Alberto , Borretta Giorgio
Published: August 2012

Objective. To report the rare case of a thymic neuroblastoma, in an elderly woman with SIADH at presentation.Methods. Clinical and biochemical data of the patient are presented and the pertinent literature is reviewed.Results. a 79-year-old woman was admitted into our department with worsening asthenia, severe hyponatremia (114.8 mEq/L), low plasma osmolarity (253 mEq/L), and inappropriate urinary sodium concentration (151 mEq/L). CT scan showed an a large solid inhomogeneous mass in the anterior mediastinum.18F-FDG-PET/CT showed uptake in the mass. On continuous 3% hypertonic saline infusion, sodium gradually increased without achieving normal values. The patient underwent surgery, followed by full normalization of sodium levels. Tumor cells were positive for neuroendocrine markers. Thymic neuroblastoma with SIADH was diagnosed.Conclusions. Neuroblastoma is an extremely rare tumor in the elderly. Contrary to children and younger adults, neuroblastoma in older adults is typically localized in the anterior mediastinum and is often associated with SIADH. Moreover, it has mainly local aggressiveness in this age group, without metastatic spread; thus radical surgery achieves cure in most cases.
Efficient Synthesis of 1‐Amidoalkyl‐2‐Naphthols by One‐Pot, Three‐Component Reaction under Solvent‐Free Conditions
Authors: Karimi-Jaberi Zahed , Jokar Marziyeh , Abbasi S. Zoleykha
Published: August 2012

Two efficient and direct procedures have been developed for the preparation of 1‐amidoalkyl‐2‐naphthols by a one‐pot condensation of aldehydes, 2‐naphthol, and amides in the presence of trichloroacetic acid or cobalt (II) chloride as catalyst. The reactions were carried out under solvent‐free media. High yields, short reaction times, easy workup of the catalyst are advantages of these procedures.
Proteomic Identification of a Direct Role for Cyclin D1 in DNA Damage Repair
Authors: Jirawatnotai Siwanon , Hu Yiduo , Livingston David M. , Sicinski Piotr
Published: August 2012

The human CCND1 gene, which encodes the cell-cycle protein cyclin D1, is one of the most frequently amplified genes in human cancers. Cyclin D1 activates the cyclin-dependent kinases CDK4 and CDK6 and drives cell proliferation. Beyond the cell-cycle role, the full repertoire of cyclin D1 functions in cancer cells is still unclear. Emerging evidence indicates that cyclin D1 may play a role in DNA damage response. In this review, we discuss observations linking cyclin D1 to DNA damage repair and summarize our recent findings, which show a cyclin D1 function in homologous recombination-mediated DNA repair. Cancer Res; 72(17); 4289–93. ©2012 AACR.
Differential Protein Stability and ALK Inhibitor Sensitivity of EML4-ALK Fusion Variants
Authors: Heuckmann Johannes M. , Balke-Want Hyatt , Malchers Florian , Peifer Martin , Sos Martin L. , Koker Mirjam , Meder Lydia , Lovly Christine M. , Heukamp Lukas C. , Pao William , Küppers Ralf , Thomas Roman K.
Published: August 2012

Purpose: ALK rearrangement–positive lung cancers can be effectively treated with ALK inhibitors. However, the magnitude and duration of response is heterogeneous. In addition, acquired resistance limits the efficacy of ALK inhibitors, with most upfront resistance mechanisms being unknown.

Experimental Design: By making use of the Ba/F3 cell line model, we analyzed the cytotoxic efficacy of ALK kinase inhibitors as a function of different EML4-ALK fusion variants v1, v2, v3a, and v3b as well as of three artificially designed EML4-ALK deletion constructs and the ALK fusion genes KIF5b-ALK and NPM1-ALK. In addition, the intracellular localization, the sensitivity to HSP90 inhibition and the protein stability of ALK fusion proteins were studied.

Results: Different ALK fusion genes and EML4-ALK variants exhibited differential sensitivity to the structurally diverse ALK kinase inhibitors crizotinib and TAE684. In addition, differential sensitivity correlated with differences in protein stability in EML4-ALK–expressing cells. Furthermore, the sensitivity to HSP90 inhibition also varied depending on the ALK fusion partner but differed from ALK inhibitor sensitivity patterns. Finally, combining inhibitors of ALK and HSP90 resulted in synergistic cytotoxicity.

Conclusions: Our results might explain some of the heterogeneous responses of ALK-positive tumors to ALK kinase inhibition observed in the clinic. Thus, targeted therapy of ALK-positive lung cancer should take into account the precise ALK genotype. Furthermore, combining ALK and HSP90 inhibitors might enhance tumor shrinkage in EML4-ALK–driven tumors. Clin Cancer Res; 18(17); 4682–90. ©2012 AACR.
A Comparative and Integrative Approach Identifies ATPase Family, AAA Domain Containing 2 as a Likely Driver of Cell Proliferation in Lung Adenocarcinoma
Authors: Fouret Robert , Laffaire Julien , Hofman Paul , Beau-Faller Michèle , Mazieres Julien , Validire Pierre , Girard Philippe , Camilleri-Bröet Sophie , Vaylet Fabien , Leroy-Ladurie François , Soria Jean-Charles , Fouret Pierre
Published: August 2012

Purpose: To identify genetic changes that could drive cancer pathogenesis in never and ever smokers with lung adenocarcinoma.

Experimental Design: We analyzed the copy number and gene expression profiles of lung adenocarcinomas in 165 patients and related the alterations to smoking status. Having found differences in the tumor profiles, we integrated copy number and gene expression data from 80 paired samples.

Results: Amplifications at 8q24.12 overlapping MYC and ATAD2 were more frequent in ever smokers. Unsupervised analysis of gene expression revealed two groups: in the group with mainly never smokers, the tumors expressed genes common to normal lung; in the group with more ever smokers, the tumors expressed “proliferative” and “invasive” gene clusters. Integration of copy number and gene expression data identified one module enriched in mitotic genes and MYC targets. Its main associated modulator was ATAD2, a cofactor of MYC. A strong dose–response relationship between ATAD2 and proliferation-related gene expression was noted in both never and ever smokers, which was verified in two independent cohorts. Both ATAD2 and MYC expression correlated with 8q24.12 amplification and were higher in ever smokers. However, only ATAD2, and not MYC, overexpression explained the behavior of proliferation-related genes and predicted a worse prognosis independently of disease stage in a large validation cohort.

Conclusions: The likely driving force behind MYC contribution to uncontrolled cell proliferation in lung adenocarcinoma is ATAD2. Deregulation of ATAD2 is mainly related to gene amplification and is more frequent in ever smokers. Clin Cancer Res; 18(20); 5606–16. ©2012 AACR.
Mutated BCR-ABL Generates Immunogenic T-cell Epitopes in CML Patients
Authors: Cai Ann , Keskin Derin B. , DeLuca David S. , Alonso Anselmo , Zhang Wandi , Zhang Guang Lan , Hammond Naa Norkor , Nardi Valentina , Stone Richard M. , Neuberg Donna , Sidney John , Brusic Vladimir , Wu Catherine J.
Published: August 2012

Purpose: Characterization of an approach to identify leukemia neoantigens arising in the context of drug resistance.

Experimental Design: We assessed whether leukemia neoantigens could be generated from drug-resistant mutations in BCR-ABL after imatinib relapse in patients with chronic myelogenous leukemia (CML).

Results: We computationally predicted that approximately 70 peptides derived from 26 BCR-ABL mutations would bind eight common alleles of MHC class I (IC50 < 1,000 nmol/L). Seven of nine imatinib-resistant CML patients were predicted to generate at least 1 peptide that binds autologous HLA alleles. We predicted and confirmed that an E255K mutation-derived peptide would bind HLA-A3 with high affinity (IC50 = 28 nmol/L), and showed that this peptide is endogenously processed and presented. Polyfunctional E255K-specific CD8+ T cells were detected in two imatinib-resistant HLA-A3+ CML patients concurrent with an effective anti-CML response to further therapy.

Conclusions: Our in vitro studies support the hypothesis that leukemia-driven genetic alterations are targeted by the immune system in association with a clinical response, and suggest the possibility of immunizing relapsed patients with CML against newly acquired tumor neoantigens. Clin Cancer Res; 18(20); 5761–72. ©2012 AACR.
MicroRNA Regulation of Oncolytic Adenovirus 6 for Selective Treatment of Castration-Resistant Prostate Cancer
Authors: Zhang Zhenwei , Zhang Xuemei , Newman Kam , Liu Xinyuan
Published: August 2012

Almost all patients with advanced prostate cancer progress to castration-resistant stage with limited treatment options. Oncolytic adenoviruses have been actively pursued as potential agents for cancer treatment. Virtually all clinical trials on oncolytic adenovirus are based on serotype 5. However, viral replication in hepatocytes induces severe liver toxicity and limits its systemic administration for metastatic disease. Moreover, rapid clearance of viral particles injected intravenously further hinders the anticancer efficacy. Adenovirus 6 (Ad6) was previously reported to exhibit less liver toxicity and escape Kupffer cells absorption after systemic administration. To further improve its safety, we generated a novel oncolytic adenovirus Ad6miR, in which four copies of binding sites of a liver-specific microRNA miR122 were incorporated into E1A gene of Ad6. miR122 regulation significantly decreased Ad6 replication in hepatocytes and consequently hepatotoxicity because of the negative regulation of miR122. Cytotoxicity assay using primary or established prostate cancer cell lines showed robust oncolytic activity of Ad6miR. Systemic treatment of established tumors with Ad6miR showed strong antitumor activity, comparable with that of Ad6 or Ad5. Although Ad6 evaded Kupffer cells, its blood clearance rate was as rapid as Ad5. The vast majority of Ad6 particles intravenously injected localized in liver sinusoidal endothelial cells rather than previously reported Kupffer cells. Elevating Ad6miR injection dose increased circulating Ad6miR concentration and its antitumor efficacy. miR122 regulation of Ad6 significantly improves its safety profile after systemic administration, which allows increasing therapeutic doses leading to improved anticancer efficacy of systemic treatment of castration-resistant prostate cancer. Mol Cancer Ther; 11(11); 2410–8. ©2012 AACR.
Consistent Neurodegeneration and Its Association with Clinical Progression in Huntington's Disease: A Coordinate-Based Meta-Analysis
Authors: Dogan Imis , Eickhoff Simon B. , Schulz Jörg B. , Shah N. Jon , Laird Angela R. , Fox Peter T. , Reetz Kathrin
Published: August 2012

Background: The neuropathological hallmark of Huntington's disease (HD) is progressive striatal loss starting several years prior to clinical onset. In the past decade, whole-brain magnetic resonance imaging (MRI) studies have provided accumulating evidence for widely distributed cortical and subcortical atrophy in the early course of the disease. Objective: In order to synthesize current morphometric MRI findings and to investigate the impact of clinical and genetic features on structural changes, we performed a coordinate-based meta-analysis of voxel-based morphometry (VBM) studies in HD. Methods: Twenty HD samples derived from 17 studies were integrated in the analysis comparing a total of 685 HD mutation carriers [345 presymptomatic (pre-HD) and 340 symptomatic (symp-HD) subjects] and 507 controls. Convergent findings across studies were delineated using the anatomical likelihood estimation approach. Effects of genetic and clinical parameters on the likelihood of observing VBM findings were calculated by means of correlation analyses. Results: Pre-HD studies featured convergent evidence for neurodegeneration in the basal ganglia, amygdala, thalamus, insula and occipital regions. In symp-HD, cerebral atrophy was more pronounced and spread to cortical regions (i.e. inferior frontal, premotor, sensorimotor, midcingulate, frontoparietal and temporoparietal cortices). Higher cytosine-adenosine-guanosine repeats were associated with striatal degeneration, while parameters of disease progression and motor impairment additionally correlated with cortical atrophy, especially in sensorimotor areas. Conclusion: This first quantitative meta-analysis in HD demonstrates the extent of striatal atrophy and further consistent extrastriatal degeneration before clinical conversion. Sensorimotor areas seem to be core regions affected in symp-HD and, along with widespread cortical atrophy, may account for the clinical heterogeneity in HD.
Securing Dual Ipsilateral Leads through a Single Burr Hole in Deep Brain Stimulation Surgery: Technical Note
Authors: Potts Mathew B. , Larson Paul S.
Published: August 2012

Deep brain stimulation (DBS) surgery typically involves placement of a single lead through a burr hole, either unilaterally or bilaterally. Rare indications, however, call for placement of 2 ipsilateral leads. To date, there have been no technical descriptions of how best to secure dual ipsilateral leads to the skull. We describe a method of placing and securing 2 ipsilateral DBS leads through a single burr hole using standard cranial plating equipment and a simple modification to a burr hole-mounted anchoring ring. This method has been used safely in 6 patients without detectable displacement of the first lead during implantation of the second lead.
Gamma Knife Stereotactic Radiosurgery for Radiation-Induced Meningiomas
Authors: Kuhn Elizabeth N. , Chan Michael D. , Tatter Stephen B. , Ellis Thomas L.
Published: August 2012

Background: Radiation-induced meningiomas present a unique clinical dilemma given the fact that patients with these tumors have often received a prior full course of radiotherapy. As such, traditional radiotherapy is limited by lifetime tissue tolerances to radiation, leaving surgery and radiosurgery as attractive treatment options. Objectives: To ascertain the safety and efficacy of Gamma Knife radiosurgery as a treatment for radiation-induced meningiomas. Methods: A retrospective chart review was conducted to identify patients who received Gamma Knife radiosurgery for a meningioma and met the criteria for this being a radiation-induced tumor. Serial imaging was used to determine the outcome of treatment and clinical notes used to assess for toxicity. Results: We present our series of 12 patients with radiation-induced meningiomas treated with Gamma Knife stereotactic radiosurgery over a 12-year period at our institution. With a median follow-up of 35 months, local control was 100%. Two patients experienced distant brain failure (>2 cm from previous radiosurgical volume). Two patients experienced posttreatment toxicity related to treatment-related edema. A review of data collected from the scientific literature suggests that tumor volume predicts for treatment failure of radiosurgery. Conclusions: Gamma Knife radiosurgery is both a safe and effective treatment for radiation-induced meningiomas.
Weight Change after Globus Pallidus Internus or Subthalamic Nucleus Deep Brain Stimulation in Parkinson’s Disease and Dystonia
Authors: Mills Kelly A. , Scherzer Rebecca , Starr Philip A. , Ostrem Jill L.
Published: August 2012

Background: Weight gain has been described in Parkinson’s disease (PD) patients after subthalamic nucleus (STN) deep brain stimulation (DBS). Objectives: We examined change in weight following DBS in both PD and dystonia patients to further investigate the role of disease and brain target (STN or globus pallidus internus, GPi) specificity. Methods: Data was retrospectively collected on 61 PD DBS patients (STN n = 31 or GPi n = 30) and on 36 dystonia DBS patients (STN n = 9 and GPi n = 27) before and after surgery. Annual change in body mass index (BMI) was evaluated with nonparametric tests between groups and multiple quantile regression. Results: PD patients treated with STN DBS had a small increase in median BMI while those with GPi had a small decrease in BMI. Dystonia patients treated with STN DBS had a greater increase in BMI per year compared to those treated with GPi DBS. Multivariable regression analyses for each disease showed little difference between targets in weight gain in those with PD, but STN target was strongly associated with weight gain in dystonia patients (STN vs. GPi, +7.99 kg, p = 0.012). Conclusions: Our results support previous reports of weight gain after DBS in PD. This is the first report to suggest a target-specific increase in weight following STN DBS in dystonia patients.
Haemostatic effects of levothyroxine and selenomethionine in euthyroid patients with Hashimoto’s thyroiditis
Authors: Okopien Boguslaw , Krysiak Robert
Published: August 2012

The aim of this prospective study was to investigate for the first time whether levothyroxine and selenomethionine, administered alone or in combination, affect coagulation and fibrinolysis in Hashimoto’s thyroiditis patients with normal thyroid function tests. A group of 155 ambulatory women with recently diagnosed and previously untreated Hashimoto’s thyroiditis, of whom 149 completed the study, were randomly assigned in a double-blind fashion to six months of treatment with levothyroxine, selenomethionine, levothyroxine plus selenomethionine, or placebo. The control group included 39 matched healthy women. The prothrombin time ratio, the activated partial thromboplastin time, and plasma levels/activities of fibrinogen, factor VII, von Willebrand factor, factor X and plasminogen activator inhibitor-1 (PAI-1) were assessed at baseline and after three and six months of treatment. Compared with the healthy subjects, Hashimoto’s thyroiditis patients exhibited higher plasma levels/activities of all of the parameters studied, as well as were characterised by the abnormal prothrombin time ratio and activated partial thromboplastin time. All these haemostatic disturbances were reduced or normalised by levothyroxine + selenomethionine treatment, while the effect of levothyroxine or selenomethionine was limited to fibrinogen and PAI-1, respectively. Our results demonstrate that euthyroid women with Hashimoto’s thyroiditis are characterised by abnormal coagulation and fibrinolysis. Levothyroxine and selenomethionine, especially if administered together, produce a beneficial effect on haemostasis in euthyroid patients with this disorder.

Note: This study was in part a sub-study of another trial (ACTRN 12611000238976), which assessed the effect of levothyroxine and selenomethionine, administered alone or in combination, on monocyte and lymphocyte cytokine release in Hashimoto“s thyroiditis patients. Trial no.: ACTRN12612000271808.
Mitotically Inactivated Embryonic Stem Cells Can Be Used as an In Vivo Feeder Layer to Nurse Damaged Myocardium after Acute Myocardial Infarction
Authors: Burt Richard K. , Chen You-hong , Verda Larissa , Lucena Carolina , Navale Shankararao , Johnson Jesse , Han Xiaoqiang , Lomasney Jon , Baker Jessa M. , Ngai Ka-Leung , Kino Aya , Carr James , Kajstura Jan , Anversa Piero
Published: August 2012

Expression of Concern

This article has a related Expression of Concern:

10.1161/RES.0000000000000241 (
Circ Res
. 2018; doi: 10.1161/RES.0000000000000241)
Association Between Coronary Vascular Dysfunction and Cardiac Mortality in Patients With and Without Diabetes Mellitus
Authors: Murthy Venkatesh L. , Naya Masanao , Foster Courtney R. , Gaber Mariya , Hainer Jon , Klein Josh , Dorbala Sharmila , Blankstein Ron , Di Carli Marcelo F.
Published: August 2012

Background—

Diabetes mellitus increases the risk of adverse cardiac outcomes and is considered a coronary artery disease (CAD) equivalent. We examined whether coronary vascular dysfunction, an early manifestation of CAD, accounts for increased risk among diabetics compared with nondiabetics.

Methods and Results—

A total of 2783 consecutive patients (1172 diabetics and 1611 nondiabetics) underwent quantification of coronary flow reserve (CFR; CFR=stress divided by rest myocardial blood flow) by positron emission tomography and were followed up for a median of 1.4 years (quartile 1–3, 0.7–3.2 years). The primary end point was cardiac death. Impaired CFR (below the median) was associated with an adjusted 3.2- and 4.9-fold increase in the rate of cardiac death for diabetics and nondiabetics, respectively (
P
=0.0004). Addition of CFR to clinical and imaging risk models improved risk discrimination for both diabetics and nondiabetics (c index, 0.77–0.79,
P
=0.04; 0.82–0.85,
P
=0.03, respectively). Diabetic patients without known CAD with impaired CFR experienced a rate of cardiac death comparable to that for nondiabetic patients with known CAD (2.8%/y versus 2.0%/y;
P
=0.33). Conversely, diabetics without known CAD and preserved CFR had very low annualized cardiac mortality, which was similar to patients without known CAD or diabetes mellitus and normal stress perfusion and systolic function (0.3%/y versus 0.5%/y;
P
=0.65).

Conclusions—

Coronary vasodilator dysfunction is a powerful, independent correlate of cardiac mortality among both diabetics and nondiabetics and provides meaningful incremental risk stratification. Among diabetic patients without CAD, those with impaired CFR have event rates comparable to those of patients with prior CAD, whereas those with preserved CFR have event rates comparable to those of nondiabetics.
On Convergence Rates of Mixtures of Polynomial Experts
Authors: Mendes Eduardo F. , Jiang Wenxin
Published: August 2012

In this letter, we consider a mixture-of-experts structure where m experts are mixed, with each expert being related to a polynomial regression model of order k. We study the convergence rate of the maximum likelihood estimator in terms of how fast the Hellinger distance of the estimated density converges to the true density, when the sample size n increases. The convergence rate is found to be dependent on both m and k, while certain choices of m and k are found to produce near-optimal convergence rates.
Adaptive Metric Learning Vector Quantization for Ordinal Classification
Authors: Fouad Shereen , Tino Peter
Published: August 2012

Many pattern analysis problems require classification of examples into naturally ordered classes. In such cases, nominal classification schemes will ignore the class order relationships, which can have a detrimental effect on classification accuracy. This article introduces two novel ordinal learning vector quantization (LVQ) schemes, with metric learning, specifically designed for classifying data items into ordered classes. In ordinal LVQ, unlike in nominal LVQ, the class order information is used during training in selecting the class prototypes to be adapted, as well as in determining the exact manner in which the prototypes get updated. Prototype-based models in general are more amenable to interpretations and can often be constructed at a smaller computational cost than alternative nonlinear classification models. Experiments demonstrate that the proposed ordinal LVQ formulations compare favorably with their nominal counterparts. Moreover, our methods achieve competitive performance against existing benchmark ordinal regression models.