bluuebunny/crossref_metadata_2025_split huggingface dataset:
New Strategies in the Molecular Targeting of Glioblastoma: How Do You Hit a Moving Target?
Authors: Cloughesy Timothy F. , Mischel Paul S. 
Published: January 2011

Abstract
Cancer is a molecularly complex, genomically unstable disease. Selection for drug-resistant mutations, activation of feedback loops, and upregulation of cross-talk pathways provide escape routes by which cancer cells maintain signal flux through critical downstream effectors to promote therapeutic resistance. Attempts to target signal transduction pathways in cancer may therefore require investigators to aim at a moving target. We need to anticipate the routes of resistance to guide the selection of drugs that will lead to durable therapeutic response. In this New Strategies article, we discuss the challenges imposed by the complexity and adaptive capacity of cancer and suggest potential new diagnostic strategies to more effectively guide targeted cancer therapy. We focus on glioblastoma, the most common malignant primary brain tumor of adults. Glioblastoma is a model for a pathway-driven, molecularly heterogeneous cancer for which new genomic insights obtained through The Cancer Genome Atlas are ripe for integration with functional biology and incorporation into new molecular diagnostic assays. Clin Cancer Res; 17(1); 6–11. ©2011 AACR.
Antitumor Activity of SNX-2112, a Synthetic Heat Shock Protein-90 Inhibitor, in MET-Amplified Tumor Cells with or without Resistance to Selective MET Inhibition
Authors: Bachleitner-Hofmann Thomas , Sun Mark Y. , Chen Chin-Tung , Liska David , Zeng Zhaoshi , Viale Agnes , Olshen Adam B. , Mittlboeck Martina , Christensen James G. , Rosen Neal , Solit David B. , Weiser Martin R. 
Published: January 2011

Abstract
Purpose: Heat shock protein-90 (HSP-90), a molecular chaperone required by numerous oncogenic kinases [e.g., HER-2, epidermal growth factor receptor (EGFR), Raf-1, v-Src, and AKT] for conformational stability, has attracted wide interest as a novel target for cancer therapy. HSP-90 inhibition induces degradation of HSP-90 client proteins, leading to a combinatorial inhibition of multiple oncogenic signaling pathways with consecutive growth arrest and apoptosis. MET, a tyrosine kinase that is constitutively active in tumor cells with MET oncogene amplification, has recently been identified as another HSP-90 client.
Experimental Design: The aim of our study was to assess the efficacy of SNX-2112, a synthetic HSP-90 inhibitor, in 3 different MET-amplified tumor cell lines (GTL-16, MKN-45, and EBC-1) as well as PR-GTL-16 cells, a GTL-16 subline selected for resistance to the highly selective MET kinase inhibitor PHA-665752.
Results: In all cell lines, SNX-2112 led to degradation of MET, HER-2, EGFR, and AKT, as well as abrogation of Ras/Raf/MEK/MAPK and PI3K/AKT signaling, followed by complete cell cycle arrest. SNX-5542, an orally bioavailable prodrug of SNX-2112, displayed significant antitumor efficacy in vivo in nude mice bearing MET-amplified tumor xenografts. Importantly, HSP-90 inhibition maintained its antitumor efficacy in PR-GTL-16 cells both in vitro and in vivo, suggesting that HSP-90 inhibition could be a particularly valuable strategy in MET-amplified tumors that have acquired resistance to MET kinase inhibition.
Conclusions: Our study provides evidence for the efficacy of HSP-90 inhibition in MET-amplified cancer cells, particularly when MET kinase inhibitor resistance has emerged. Clin Cancer Res; 17(1); 122–33. ©2011 AACR.
Interindividual Variability of Response to Rituximab: From Biological Origins to Individualized Therapies
Authors: Cartron Guillaume , Trappe Ralf Ulrich , Solal-Céligny Philippe , Hallek Michael 
Published: January 2011

AbstractRituximab has markedly changed the treatment of B-cell malignancies. Despite its widespread use, however, its precise mode of action and the impact of host- and tumor-related factors on rituximab-activated biological pathways were only recently clarified. Biological mechanisms resulting in complete resistance to rituximab may exist at both the cellular and subcellular level; however, their frequency and their impact on clinical response are unclear. The identification of Fcγ receptor polymorphisms that can influence anti-CD20 antibody activity has resulted in the development of third-generation anti-CD20 antibodies. However, it is also now appreciated that pharmacokinetic variability is a major factor affecting clinical response to anti-CD20 antibodies. The concept of antigenic mass, which takes into account the total tumor load and the expression levels of the target antigen CD20, is able to explain the correlation between rituximab plasma concentrations and treatment responses. Thus, it can be hypothesized that dosing regimens that take this information into account will help to improve response rates. Clin Cancer Res; 17(1); 19–30. ©2011 AACR.
Phase I Trial of TGF-β2 Antisense GM-CSF Gene-Modified Autologous Tumor Cell (TAG) Vaccine
Authors: Olivares Jairo , Kumar Padmasini , Yu Yang , Maples Phillip B. , Senzer Neil , Bedell Cynthia , Barve Minal , Tong Alex , Pappen Beena O. , Kuhn Joseph , Magee Mitchell , Wallraven Gladice , Nemunaitis John 
Published: January 2011

AbstractPurpose: On the basis of the hypothesis that the combined expression of immunostimulatory granulocyte macrophage colony stimulating factor (GM-CSF) and antitumor suppressor TGF-β2 antisense (AS) transgenes can break tolerance and stimulate immune responses to cancer-associated antigens, we constructed an expression plasmid [the tumor-associated glycoprotein (TAG) plasmid] that coexpresses GM-CSF and TGF-β2 AS nucleotide sequences and which was incorporated into an autologous whole-cell vaccine.Experimental Design: Patients undergoing resection were enrolled. Freshly harvested autologous tumor cells were mechanically and enzymatically disaggregated, then electroporated with the TAG vector. The resulting vaccine was irradiated, then aliquoted and cryopreserved until the time of injection. Patients received a minimum of 5 to a maximum of 12 monthly intradermal injections. Immune function was monitored at baseline and at months 3 and 6.Results: Vaccine manufacturing efficiency was 84% (32/38). Twenty-three patients received at least 1 vaccination. There were no grade 3 or 4 toxicities, and grade 1 and 2 events were local in nature. Seventeen of 21 patients had stable disease (SD) at month 2 or later as their best response, and 1 patient with stage IVa malignant melanoma achieved a complete response (CR) following 11 vaccinations and remains without evidence of disease 2 years following initiation of therapy. Six of 13 patients displayed a positive enzyme-linked immunospot (ELISPOT) response to autologous TAG vaccine at week 12 including 3 patients with prolonged SD or CR. The 3 other patients survived through week 24, as compared with none of the 7 ELISPOT-negative patients.Conclusions: On the basis of safety and clinical and immunologic results, further evaluation of bifunctional vaccines is warranted. Clin Cancer Res; 17(1); 183–92. ©2011 AACR.
Molecular Targeting of Neural Cancer Stem Cells: TTAGGG, You're It!
Authors: Hjelmeland Anita B. , Rich Jeremy N. 
Published: January 2011

Abstract
Telomerase is an important mechanism by which cancers escape replicative senescence. In neural tumors, cancer stem cells express telomerase, suggesting that this may explain their preferential tumorigenesis. Oligonucleotide telomerase targeting selectively disrupts cancer stem cell growth through the induction of differentiation, adding to the armamentarium of anticancer stem cell therapies. Clin Cancer Res; 17(1); 3–5. ©2011 AACR.
α1AMP-Activated Protein Kinase Preserves Endothelial Function During Chronic Angiotensin II Treatment by Limiting Nox2 Upregulation
Authors: Schuhmacher Swenja , Foretz Marc , Knorr Maike , Jansen Thomas , Hortmann Marcus , Wenzel Philip , Oelze Matthias , Kleschyov Andrei L. , Daiber Andreas , Keaney John F. , Wegener Gerhard , Lackner Karl , Münzel Thomas , Viollet Benoit , Schulz Eberhard 
Published: January 2011

Objective—
Besides its well-described metabolic effects, vascular AMP-activated protein kinase (AMPK) can activate endothelial NO synthase, promotes angiogenesis, and limits endothelial cell apoptosis. The current study was designed to study the effects of α1AMPK deletion during vascular disease in vivo.

Methods and Results—
Chronic angiotensin II infusion at low subpressor doses caused a mild endothelial dysfunction that was significantly aggravated in α1AMPK-knockout mice. Unexpectedly, this endothelial dysfunction was not associated with decreased NO content, because NO levels measured by serum nitrite or electron paramagnetic resonance were even increased. However, because of parallel superoxide production, NO was consumed under production of peroxynitrite in angiotensin II–treated α1AMPK-knockout mice, associated with NADPH oxidase activation and Nox2 upregulation. As Nox2 is also a component of phagocyte NADPH oxidases, we found a vascular upregulation of several proinflammatory markers, including inducible NO synthase, vascular cell adhesion molecule-1, and cyclooxygenase-2. Cotreatment with the NADPH oxidase inhibitor apocynin was able to prevent vascular inflammation and also partially restored endothelial function in α1AMPK-knockout mice.

Conclusion—
Our data indicate that in vivo α1AMPK deletion leads to Nox2 upregulation, resulting in endothelial dysfunction and vascular inflammation. This implicates basal AMPK activity as a protective, redox-regulating element in vascular homeostasis.
Distribution and diversity of root-lession nematode (Pratylenchus spp.) associated with Miscanthus × giganteus and Panicum virgatum used for biofuels, and species identification in a multiplex polymerase chain reaction
Authors: Gray Michael , Lopez-Nicora Horacio , Mekete Tesfamariam , Niblack Terry , Reynolds Kimberly 
Published: January 2011

AbstractThe distribution of Pratylenchus spp. from bioenergy field plots in six states (Illinois, Iowa, South Dakota, Kentucky, Tennessee, Georgia) of the USA were surveyed. The species were identified based on morphology and morphometrics and further characterised based on fragment sequences of the 28S rRNA of the D2-D3 region. The region revealed variations in sequencing information that supports the morphological identification. In this work, six Pratylenchus spp. were detected: Pratylenchus brachyurus, P. crenatus, P. hexincisus, P. neglectus, P. penetrans and P. scribneri. Pratylenchus scribneri, P. crenatus, and P. penetrans were distributed most widely, with detection of 34, 29 and 15%, respectively. Pratylenchus hexincisus, P. brachyurus and P. neglectus were distributed sporadically, with detection rates of 10.0, 2.6 and 2.0%, respectively. A one-step multiplex PCR was developed for the simultaneous detection of P. scribneri, P. crenatus and P. penetrans. Sequence data from this research and NCBI were used to generate different primer sets that are species-specific. We have therefore designed three sets of primers that discriminate P. scribneri, P. crenatus and P. penetrans in multiplex PCR. All the tested primers have shown specificity and have no cross-reaction with the non-target species. When used in a uniplex, duplex and triplex PCR, the selected three primers gave a unique electrophoretic DNA banding pattern characterised by a single DNA fragment for P. scribneri (ca 750), P. crenatus (ca 690), and P. penetrans (ca 520). The method could be used for routine diagnostic programmes.
Police Powers of Arres
Authors: Singer M , Francis R D 
Published: January 2011

Prior to the passage of the Crimes (Powers of Arrest) Act 1972 (Vic) which came into operation on 1 July 1972, there existed in Victoria not only the complex common law rules governing instances of arrest, but also a collection of more than 60 legislative provisions contained in more than 30 separate Acts. This paper sets out to examine some effects of this rationalizing Act. This report has an empirical base using records from a large and representative urban police station yielding, in this instance, 200 cases for analysis. It was found that the legislation had no discernible effect in changes of arrest versus summons rates for comparable offences, but a number of distinct features were isolated as being influential in determining the police decision to arrest or to handle matters by means of summons. These factors were found to co-exist prior to and after the implementation of the legislation, and did not appear to change as a result of the legislation. From this study it is concluded that there is an urgent need for some working guidelines to be set out in the relevant powers of arrest legislation. Such guidelines, absent in the present Act, confer on the police an unwarranted, and perhaps unwanted, degree of discretionary power. Proposals for reform are examined, stressing the need to develop an objective system whereby influential factors in the decision to arrest, leading to the suggestion that such systematic control both could and should be formalized by the legislature.
Police Contact and Delinquency: A Relevant Evaluation
Authors: Wellford Charles F , Aultman M G 
Published: January 2011

The data for this study were obtained from a survey in Tallahassee, Florida in March of 1975. A stratifield cluster sampling technique was used to select approximately 1500 students from grades 6 though 12. A self-report technique was used to obtain the responses. The model to be tested includes four variables: contact with police, perception of police, self-esteem, and delinquency. The issue addressed by the research concerns whether contacts with the police have any effect on delinquent behaviour and whether certain intervening variables (ie perception of police and self-esteem) have an effect in the causal process. A comparison of the correlations between age and police contact and between age and delinquency shows that the latter set are much more strongly related than are the former set. This suggests that delinquency occurs more often later in the age cycle than does police contact. This finding is considered to lend support to the causal order. The path analysis shows that contact with police has a considerable effect on subsequent delinquent behaviour. The intervening variable “perception of police” is seen to indicate a more important causal path than does the route predicted by labelling theorists which involves self-esteem as an intervening factor. The total amount of variance explained by this path model is approximately 65%.
Female Status Offenders and Justice Reforms: An International Perspective
Authors: Hancock Linda , Chesney-Lind Meda 
Published: January 2011

Females are treated differently from males in the juvenile justice system. While the majority of males appear in juvenile court on charges of illegal behaviour, most females appear on “status offence” grounds, that is, for behaviour that only juveniles under a particular age can be brought to police or court attention. Females charged on moral or status offences are treated more harshly than males. However, when they are charged with illegal behaviour, females are treated more leniently which is appropriate, since delinquent girls are generally involved in less serious criminal behaviour than boys. In principle, the juvenile court was set up to protect juveniles and, by giving wide powers of discretion to law enforcers, to facilitate decisions in young offenders' best interests. In practice, particular categories of youth are treated more harshly than others. Evidence indicates that those females appearing on status offence charges (often from socially and economically disadvantaged backgrounds) are discriminated against on the basis of their sexual behaviour. This paper describes the present situation and outlines the failures of attempts at legislative changes in the definition and processing of juvenile status offenders in the United States and Australia. These examples show that the double standard of juvenile justice is international; not simply an artifact of one nation's court system. Treating status offence problems within a criminal justice system has destructive and damaging effects which may only intensify the problems from which such youth are ostensibly being protected.
Infanticide: A litmus test for feminist criminological theory
Authors: Laster Kathy 
Published: January 2011

Infanticide is an important and historically prevalent crime. It is also a “female” crime. The challenge for feminist criminological theory is to account for infanticide without falling into the trap of “essentialising” the offence and its perpetrators. Two current broad feminist theoretical positions (the androgynous approach and the social control perspectives) are applied to infanticide. It is argued that their explanatory usefulness is limited since both in various ways distort the “true” dimensions of the crime. The inability of these current perspectives to account for infanticide raises serious questions about their general applicability for feminist criminological theory.
A Systematic Review of Adenotonsillectomy as a Risk Factor for Childhood Obesity
Authors: Jeyakumar Anita , Fettman Nicholas , Armbrecht Eric S. , Mitchell Ron 
Published: January 2011

ObjectiveTonsillectomy is the most common major surgical procedure performed in children. There is evidence that tonsillectomy is associated with weight increase and may contribute to pediatric obesity. The study aimed to review the evidence that tonsillectomy with or without adenoidectomy is a risk factor for future obesity.Data SourcesSystematic literature search was performed using PubMed and Ovid.Review MethodsSystematic analysis of the literature from 1970 to 2009 on patients who underwent adenotonsillectomy (T&A) with preoperative and postoperative weight‐based measurements.ResultsNine studies satisfied inclusion criteria. A total of 795 children were included. Preoperative weight ranged from normal to morbid obesity. In total, 656 children had demographic information recorded, and 53.35% of the children were male. Indication for surgery was not recorded in 336 patients. In 47.7% patients, the indication recorded was sleep‐disordered breathing. The first group included 3 studies involving 127 children, and body mass index (BMI) increased by 5.5% to 8.2%. The second group included 3 studies involving 419 patients; the standardized weight scores increased in 46% to 100% of patients. The third group included 3 studies with 249 patients; the corrected weight increased postoperatively in 50% to 75% of patients. Morbidly obese patients (weight 130%‐260% vs peers) remained unchanged postoperatively.LimitationsEach study was designed with different definitions of overweight and a range of follow‐up periods. Demographic information was limited.ConclusionsA large population of normal and overweight children undergoing T&A gained a greater than expected amount of weight postoperatively, which suggests an association between T&A and weight gain. A significant need exists for a large study with consistent outcomes measured.
An Animal Model for Endotracheal Tube–Related Laryngeal Injury Using Hypoxic Ventilation
Authors: Gordin Arie , Chadha Neil K. , Campisi Paolo , Luginbuehl Igor , Taylor Glenn , Forte Vito 
Published: January 2011

ObjectivesTo explore whether hypoxic ventilation could allow a practical animal model of laryngotracheal injury secondary to endotracheal intubation.Study DesignRandomized controlled animal study.SettingAnimal laboratory in a tertiary pediatric hospital.Subjects and MethodsEight Sus scrofa piglets (15‐18 kg) were anesthetized and intubated for 4 hours, with a 6‐mm cuffed endotracheal tube. They were randomly assigned to either constant hypoxic ventilation (oxygen saturation under 70%) or nonhypoxic ventilation. Endotracheal tube cuff pressure was manually controlled and maintained at a constant level. After 4 hours, fluorescein dye was administered intravenously to highlight areas of hypoperfusion within the larynx. The animals were euthanized at the end of the procedure, and the larynx and trachea were harvested for gross and histological examination. The pathologist was blinded to the ventilation group. The severity of laryngeal injury was graded between 0 and 4 by a senior pathologist.ResultsThe experiment protocol was successfully completed in all animal subjects. The animals undergoing hypoxic ventilation showed a significantly higher median injury grade than the nonhypoxic animals (2 vs 1, respectively; P =. 003). Damage was significantly worse in the hypoxic group at all anatomical sublevels.ConclusionsEndotracheal tube–related laryngeal injury was demonstrated after only 4 hours of intubation using this animal model, and hypoxic ventilation increased the severity of injury. This study therefore provides an animal model that may be suitable for future investigation and prevention of intubation injury.
Glyceraldehyde-3-phosphate dehydrogenase is largely unresponsive to low regulatory levels of hydrogen peroxide in Saccharomyces cerevisiae
Authors: Cyrne Luísa , Antunes Fernando , Sousa-Lopes Ana , Diaz-Bérrio João , Marinho H Susana 
Published: January 2011

Abstract

Background
The reversible oxidation of protein SH groups has been considered to be the basis of redox regulation by which changes in hydrogen peroxide (H2O2) concentrations may control protein function. Several proteins become S-glutathionylated following exposure to H2O2 in a variety of cellular systems. In yeast, when using a high initial H2O2 dose, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was identified as the major target of S-glutathionylation which leads to reversible inactivation of the enzyme. GAPDH inactivation by H2O2 functions to reroute carbohydrate flux to produce NADPH. Here we report the effect of low regulatory H2O2 doses on GAPDH activity and expression in Saccharomyces cerevisiae.

Results
A calibrated and controlled method of H2O2 delivery - the steady-state titration - in which cells are exposed to constant, low, and known H2O2 concentrations, was used in this study. This technique, contrary to the common bolus addition, allows determining which H2O2 concentrations trigger specific biological responses. This work shows that both in exponential- and stationary-phase cells, low regulatory H2O2 concentrations induce a large upregulation of catalase, a fingerprint of the cellular oxidative stress response, but GAPDH oxidation and the ensuing activity decrease are only observed at death-inducing high H2O2 doses. GAPDH activity is constant upon incubation with sub-lethal H2O2 doses, but in stationary-phase cells there is a differential response in the expression of the three GAPDH isoenzymes: Tdh1p is strongly upregulated while Tdh2p/Tdh3p are slightly downregulated.

Conclusions
In yeast GAPDH activity is largely unresponsive to low to moderate H2O2 doses. This points to a scenario where (a) cellular redoxins efficiently cope with levels of GAPDH oxidation induced by a vast range of sub-lethal H2O2 concentrations, (b) inactivation of GAPDH cannot be considered a sensitive biomarker of H2O2-induced oxidation in vivo. Since GAPDH inactivation only occurs at cell death-inducing high H2O2 doses, GAPDH-dependent rerouting of carbohydrate flux is probably important merely in pathophysiological situations. This work highlights the importance of studying H2O2-induced oxidative stress using concentrations closer to the physiological for determining the importance of protein oxidation phenomena in the regulation of cellular metabolism.