bluuebunny/crossref_metadata_2025 huggingface dataset:
Group sequential control of overall toxicity incidents in clinical trials – non-Bayesian and Bayesian approaches
Authors: Yu Jihnhee , Hutson Alan D , Siddiqui Adnan H , Kedron Mary A
Published: March 2012

In some small clinical trials, toxicity is not a primary endpoint; however, it often has dire effects on patients’ quality of life and is even life-threatening. For such clinical trials, rigorous control of the overall incidence of adverse events is desirable, while simultaneously collecting safety information. In this article, we propose group sequential toxicity monitoring strategies to control overall toxicity incidents below a certain level as opposed to performing hypothesis testing, which can be incorporated into an existing study design based on the primary endpoint. We consider two sequential methods: a non-Bayesian approach in which stopping rules are obtained based on the ‘future’ probability of an excessive toxicity rate; and a Bayesian adaptation modifying the proposed non-Bayesian approach, which can use the information obtained at interim analyses. Through an extensive Monte Carlo study, we show that the Bayesian approach often provides better control of the overall toxicity rate than the non-Bayesian approach. We also investigate adequate toxicity estimation after the studies. We demonstrate the applicability of our proposed methods in controlling the symptomatic intracranial hemorrhage rate for treating acute ischemic stroke patients.
Factors Mediating Remote Preconditioning of Trauma in the Rat Heart
Authors: Gross Garrett J. , Hsu Anna , Gross Eric R. , Falck John R. , Nithipatikom Kasem
Published: March 2012

The present study further identified factors involved in the cardioprotective phenomenon of remote preconditioning of trauma (RPCT) with special emphasis on the role of the epoxyeicosatrienoic acids (EETs) in mediating this phenomenon. Remote preconditioning of trauma was produced by an abdominal incision only through the skin. Subsequently, all rats were subjected to 30 minutes of left coronary artery occlusion followed by 2 hours of reperfusion and the infarct size was determined. Remote preconditioning of trauma produced a reduction in infarct size expressed as a percentage of the area at risk from 63.0% ± 1.1% to 44.7% ± 1.4%; P < .01 versus control. To test the 3 major triggers of classical preconditioning in mediating RPCT, blockers of the bradykinin B2 receptor (B2BK), (S)-4-[2-[Bis(cyclohexylamino)methyleneamino]-3-(2-naphthalenyl)-1-oxopropylamino]benzyl tributyl phosphonium (WIN 64338, 1 mg/kg, iv), or HOE 140 (50 μg/kg, iv), the nonselective opioid receptor blocker, naloxone (3 mg/kg, iv), or the adenosine A1 receptor blocker, 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX, 1 mg/kg, iv) were administered 10 minutes prior to RPCT. Only the 2 B2BK selective antagonists blocked RPCT (60.2% ± 1.1%, WIN 64338; 62.3% ± 2.0%, HOE 140). To test EETs in RPCT, we administered the EET receptor antagonist 14,15-Epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, 2.5 mg/kg, iv) or the EET synthesis inhibitor, N-(Methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MSPPOH, 3.0 mg/kg, iv) 10 minutes prior to RPCT. In both groups, the EET antagonists completely blocked RPCT (62.0% ± 0.8%, 14,15-EEZE; 61.8% ± 1.0%, MSPPOH). The EET antagonists also blocked the effect of B2BK activation. We also determined whether the sarcolemmal KATP or the mitochondrial KATP channel mediate RPCT by pretreating rats with 1-[5-[2-(5-Chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3 methylthiourea, sodium salt (HMR 1098) or 5-hydroxydecanoic acid (5-HD), respectively. Interestingly, 5-HD blocked RPCT (64.7% ± 1.3%), whereas, HMR 1098 did not (50.3% ± 1.3%). The 2 EET antagonists completely blocked capsaicin-induced cardioprotection. These results clearly suggest that EETs mediate RPCT-, bradykinin- and capsaicin-induced cardioprotection in rat hearts.
Quality and sensory acceptability of a chilled functional apple ready-dessert
Authors: Keenan DF , Brunton NP , Gormley TR , Butler F
Published: March 2012

An apple and dairy based ready-dessert with an added prebiotic was stored and chill temperatures and number of quality attributes were monitored during chill (4 °C) storage for 30 days. All ready-desserts were thermally processed by sous vide ( P90 > 10 min). The stability of the dairy component in ready-desserts was monitored by measuring volatile free fatty acids. Changes in these components were more evident in prebiotic-enriched samples compared to controls. However, no significant differences were observed over storage in control and prebiotic-enriched ready-desserts. This was supported by sensory analysis that showed no significant changes over storage in control or prebiotic-enriched samples. Of the other quality parameters, the addition of prebiotic inclusions resulted in lower L and b values and dry matter ( p < 0.05), while increasing ( p < 0.05) soluble solids content compared to control samples. Fluctuations in some of the quality parameters were also observed over storage. Rheological characteristics, i.e. flow behaviour ( n), consistency index ( K), storage ( G′), loss ( G″) and complex ( G*) moduli were unaffected by prebiotic inclusion. However, storage affected the rheological characteristics of ready-desserts. A decrease ( p < 0.05) in flow behaviour ( n) led to concomitant increases in consistency index ( K) and complex modulus ( G*) values in control samples.
Advancing the Discussion About Systematic Classroom Behavioral Observation, a Product Review of Tenny, J. (2010). eCOVE Observation Software. Pacific City, OR
Authors: Froiland John Mark , Smith Liana
Published: March 2012

Applied child psychologists and behavioral consultants often use systematic behavioral observations to inform the psychological assessment and intervention development process for children referred for attention and hyperactivity problems. This article provides a review of the 2010 version of the eCOVE classroom observation software in terms of its utility in tracking the progress of children with attention and hyperactive behaviors and its use in evaluating teacher behaviors that may impede or promote children’s attention and positive behavior. The eCOVE shows promise as an efficient tool for psychologists and behavioral consultants who want to evaluate the effects of interventions for children with symptoms of ADHD, ODD, mood disorders and learning disorders; however, some research-based improvements for future models are suggested. The reviewers also share their firsthand experience in using eCOVE to evaluate teacher and student behavior exhibited on a television show about teaching urban high school students and during a movie about an eccentric new kindergarten teacher. Rich examples are provided of using strategic behavioral observations to reveal how to improve the classroom environment so as to facilitate attention, motivation and positive behavior among youth. Broader implications for enhancing the use of systematic behavioral observations in the assessment of children and adolescents with attention disorders and related behavioral problems are discussed. Key issues are examined such as the use of behavioral observations during psychological consultation to prevent the previously found gender bias in referrals for ADHD. Using behavioral observations to enhance differential diagnosis is also discussed.
Toxicological Effects of a Mixture Used in Weight Loss Products: p-Synephrine Associated With Ephedrine, Salicin, and Caffeine
Authors: Schmitt Gabriela C. , Arbo Marcelo D. , Lorensi Andréia L. , Maciel Érica S. , Krahn Carolina L. , Mariotti Kristiane C. , Dallegrave Eliane , Leal Mirna B. , Limberger Renata P.
Published: March 2012

p-Synephrine is an adrenergic amine found in Citrus aurantium L. fruits and has been used for weight loss in dietary supplements. There are commercial products containing this substance associated to caffeine, salicin, and ephedrine. The aim of this study was to evaluate the acute toxicity of this mixture in mice of both sexes. The significative results observed after acute oral administration to male and female mice of 300, 350, and 400 mg/kg total of p-synephrine, ephedrine, salicin, plus caffeine in a 10:4:6:80 w/w ratio included a reduction in locomotor activity and ptosis in all treated groups for both sexes. Seizures were also observed in male (400 mg/kg) and female groups (350 and 400 mg/kg). Gasping and tearing were observed in males. Salivation (400 mg/kg), agitation (350 and 400 mg/kg), and piloerection (all treated groups) were significantly observed only in females. Deaths occurred in males at 350 and 400 mg/kg treated groups and the necropsy showed cardiopulmonary hemorrhage. A reduction in locomotor activity was confirmed through the spontaneous locomotor activity test, in which the number of crossings considerably decreased ( P < .01) in all treated groups. The rotarod test showed a decrease in motor coordination at 400 mg/kg. Body temperature decreased significantly ( P < .01) in all treated groups compared to controls. The results suggested clear signs of toxicity of p-synephrine, ephedrine, salicin, and caffeine association; this toxicity augments the attentiveness on commercial products containing this mixture, given the expressive number of adverse events related to its utilization.
Service Locus of Control and Customer Coproduction
Authors: Büttgen Marion , Schumann Jan H. , Ates Zelal
Published: March 2012

Customer coproduction is highly relevant for service firms and has attracted significant academic attention. Whereas prior research has addressed several drivers of customer coproduction behavior, such as motivation, ability, or knowledge, it has hardly addressed the role of customer control beliefs or their drivers. This research proposes that specific beliefs about the service locus of control (SLOC) influence coproduction behaviors and that SLOC beliefs themselves depend on customers' prior comparable reinforcement experiences and the socialization activities of the service provider. The test of the proposed model includes 2,679 customers of a service firm that provides health-related strength training, a context that relies heavily on coproduction. The results show that SLOC beliefs, especially customers' internal SLOC, drive coproduction. Service providers can influence internal SLOC with organizational socialization activities, particularly when the customer possesses prior experience with the service provider. Prior comparable reinforcement experiences are less relevant drivers though, which emphasizes the importance of proactive, repeated socialization activities by service providers.
Clinical features, survival times and COX-1 and COX-2 expression in cats with transitional cell carcinoma of the urinary bladder treated with meloxicam
Authors: Bommer Nicholas X , Hayes Alison M , Scase Timothy J , Gunn-Moore Danièlle A
Published: March 2012

Records of 11 cats with transitional cell carcinoma of the urinary bladder, which had been treated with meloxicam, were reviewed for signalment, duration of clinical signs prior to diagnosis, results of diagnostic imaging, whether or not concurrent surgery was performed and survival. Immunohistochemical expression of cyclo-oxygenase-1 (COX-1) and cyclo-oxygenase-2 (COX-2) was assessed in the tumours of seven cats. Tumour location varied greatly. The cats had a mean age of 13 years. Three cats had a previous diagnosis of feline idiopathic cystitis of up to 2008 days duration. Ten of the cats showed clinical improvement (reduction of haematuria and/or dysuria), with a mean survival time (MST) of 311 days (range 10–1064); 1-year survival of 50%. All seven bladders assessed for COX staining were COX-1 positive and five were COX-2 positive. The MST for the COX-2-positive cats was 123 days, the MST for the COX-2-negative cases was 375 days.
A case of feline primary inflammatory mammary carcinoma: clinicopathological and immunohistochemical findings
Authors: Millanta Francesca , Verin Ranieri , Asproni Pietro , Giannetti Giovanni , Poli Alesandro
Published: March 2012

The clinicopathological and immunohistochemical findings of a primary feline mammary tumour with features similar to human and canine primary inflammatory carcinoma are described for the first time. The cat presented to the clinic for the rapid onset of oedema, severe erythema, local pain and warmth of the inguinal region, with a pustular-to-nodular cutaneous lesion in association with an ill-defined underlying mass. An epithelial malignant tumour was diagnosed by cytological investigation. Necropsy revealed a thickening of the skin with oedema of the subcutis in the right inguinal area, and regional and distant metastases. Histology showed an unencapsulated tubulopapillary proliferation of malignant epithelial cells, with a massive embolisation in the dermal lymphatics and a mild inflammatory infiltrate. Through immunohistochemistry, the tumour was found to be oestrogen (ER)-alpha-, androgen (AR)- and progesterone (PR)-negative; neoplastic cells were ER-alpha, AR-negative and focally PR-positive. An irregular, mild and focal HER-2 immunoreactivity was present (score +1, non-HER-2 overexpressing). The neoplastic cells were cyclo-oxygenase-2 and vascular endothelial growth factor positive.
Bounded autonomy in deciding to seek medical help: Carer role, the sick role and the case of dementia
Authors: Chrisp TAC , Tabberer S , Thomas BD
Published: March 2012

Social psychological theories of illness and health decision making place the individual with the symptoms at the centre. In the case of dementia it is often a relative who is first to contact health care professionals. The article illustrates how the autonomy of both the individual with symptoms and their carers is bounded by the actions of others. An over arching theme of ‘bounded autonomy in decision making’, and four subthemes emerged. Bounded autonomy is where a person’s actions are constrained or contested by another person. There are implications for interventions to bring forward the point at which diagnosis occurs.
Crosslinguistic influence at the syntax proper: Interrogative subject–verb inversion in heritage Spanish
Authors: Cuza Alejandro
Published: March 2012

This study examines the potential effects of crosslinguistic influence in the acquisition of subject–verb inversion in Spanish matrix and embedded wh-questions among Spanish heritage language learners living in the United States. The results from an acceptability judgment task and a written production task administered to 17 US-born heritage speakers indicate crosslinguistic influence effects. The effects are more evident with embedded interrogatives than with matrix questions. A follow-up study with the heritage speakers also shows less inversion behavior with embedded questions in oral production but higher performance levels than in written production. The findings are discussed in relation to interface vulnerability approaches and current debates on the selective nature of crosslinguistic influence in L2 and bilingual development.
The effect of different weather data sets and their resolution on climate-based daylight modelling
Authors: Iversen A , Svendsen S , Nielsen TR
Published: March 2012

Climate-based daylight modelling is based on the available weather data, which means that the weather data used as input to the daylight simulations are of great importance. In this paper, the effect on the outcome of the daylight simulations of using one weather data file rather than another for the same location was investigated. Furthermore, the effect of using weather data sets with an hourly resolution compared to a one-minute resolution was investigated. The results showed that the lighting dependencies varied by up to 2% depending on the chosen weather data file and indoor illuminance threshold. The energy consumption for artificial lighting was underestimated when simulating with time steps of hourly means compared to one-minute resolution. The findings from this comparison show that the dynamic, short-term effects of the weather have a surprisingly small impact on the simulation outcome.
The Trotter Paterson Lecture 2012: Whatever happened to visual performance?
Authors: Rea MS
Published: March 2012

Visual performance has been studied since the 1930s to help establish a foundation for recommended illuminances. Two approaches were taken to research visual performance, one by Weston in Great Britain and the other by Luckiesh in the United States, leading to different recommended illuminances in the two countries. Because of the energy crisis of the 1970s, applied research into visual performance was undertaken to resolve the discrepancy, resulting in a model of relative visual performance. More recently, a controversy has emerged regarding the value of illuminating roadways. Recent research shows that the incremental improvements in visual performance provided by roadway lighting are correlated with the incremental reductions in night-time crashes, demonstrating that an understanding of visual performance remains important for lighting practice.
Peroxisome proliferator-activated receptor (PPAR α/γ) agonists as a potential target to reduce cardiovascular risk in diabetes
Authors: Nicholls Stephen J , Uno Kiyoko
Published: March 2012

The disappointing results of glucose lowering studies have highlighted the ongoing need to develop new therapeutic strategies to reduce cardiovascular risk in patients with type 2 diabetes. The presence of a range of metabolic abnormalities in diabetic patients presents a number of potential targets for therapeutic intervention. While modulation of peroxisome proliferator activated receptors (PPARs) represents an attractive approach, the results of studies of pharmacological agonists have been variable. The findings of these studies and rationale for development of dual PPAR-α/γ agonists will be reviewed.
Preparation and electrical property evaluation of vapor-grown carbon nanofibers reinforced natural rubber composites
Authors: Jiang Hongxia , Ni Qingqing , Wang Hongfu
Published: March 2012

Natural rubber composites with different contents of 1 wt%, 3 wt%, 5 wt%, 10 wt%, and 20 wt% vapor-grown carbon nanofibers were synthesized using a solvent casting method. The morphology, electrical conductivity, dielectric property, and electromagnetic interference shielding effectiveness of natural rubber/vapor-grown carbon nanofiber composites at room temperature were investigated. The scanning electron microscopy image showed there was an even dispersion of vapor-grown carbon nanofibers in natural rubber. The electrical conductivity increased with the increase in vapor-grown carbon nanofiber content. The percolation threshold of natural rubber/vapor-grown carbon nanofiber composites was about 4.9 wt% according to the power law. The dielectric property of natural rubber/vapor-grown carbon nanofiber composites had frequency dependence and increased along with the addition of vapor-grown carbon nanofibers. The electromagnetic interference shielding effectiveness in X-band microwave frequency of natural rubber/20 wt% vapor-grown carbon nanofiber composite with 1 mm thickness was 12.8 dB.
Preoperative Cardiac Evaluation of the Vascular Surgery Patient—An Anesthesia Perspective
Authors: Omar Hesham R. , Mangar Devanand , Camporesi Enrico M.
Published: March 2012

The morbidity and mortality associated with vascular surgery procedures are largely the results of cardiac events. National guidelines have been regularly proposed and updated by the American College of Cardiology (ACC)/American Heart Association (AHA) to ensure optimal perioperative management and risk stratification. Controversy remains between experts and other cardiology societies regarding several patient care issues including revascularization before surgery, timing of β-blocker therapy, and the administration of antiplatelet therapy. Several landmark articles recently published have helped to modify the guidelines in the hope of improving vascular patient outcomes. In this review, we searched all recent available literature pertaining to perioperative cardiac evaluation before major vascular surgery. We propose an algorithm for preoperative cardiac evaluation, which is a modification to the AHA recommendations. Incorporated in this algorithm are recent published pivotal articles that can help in guiding physicians caring for the vascular patient requiring major operative or endovascular interventions.
Making Decisions
Authors: Gaskins Susan W. , Payne Foster Pamela , Sowell Richard L. , Lewis Timothy L. , Gardner Antonio , Parton Jason M.
Published: March 2012

The purpose of this study was to identify and describe the process of HIV disclosure for rural African American men—a population disproportionately affected by HIV/AIDS. Forty men were interviewed about their experience of making an HIV disclosure. Grounded theory methodology guided data collection and analysis. The core category or variable that emerged from the data was a process—Making Decisions: The Process of HIV Disclosure. Five categories accounted for variations in disclosures: (a) beliefs and knowledge about HIV/AIDS, (b) influencing factors, (c) disclosure decisions, (d) disclosure efficacy, and (e) outcomes of disclosure. Most of the men had disclosed to others; however, the disclosures were selective, and the decisions were iterative. The majority of the men did not disclose their diagnosis for several months to several years. The findings provide a framework of the many factors related to HIV disclosure that can guide health care providers in counseling persons living with HIV/AIDS in making disclosure decisions.
Hopelessness and Sexual Risk Behavior Among Adolescent African American Males in a Low-Income Urban Community
Authors: Kagan Sarah , Deardorff Julianna , McCright Jacqueline , Lightfoot Marguerita , Lahiff Maureen , Lippman Sheri A.
Published: March 2012

African American youth bear a disproportionate burden of sexually transmitted infections. Environmental stressors may lead to increased hopelessness, which in turn can lead to increases in risk-taking behavior. This study explored the hypothesis that as hopelessness increases, sexual risk behavior will increase—specifically, inconsistent condom use and increased number of sex partners. In 2010, 108 African American men 15 to 24 years old responded to sexual behavior questions and Beck’s Hopelessness Scale. The associations between hopelessness and sexual risk behaviors were evaluated with multivariate logistic regression. Increased hopelessness was associated with increased inconsistent condom use with non-main sexual partners (adjusted odds ratio = 2.3, 95% confidence interval = 1.3-4.0). There was no association between hopelessness and condom use with a main partner or sex with more than one partner in the past 3 months. These findings imply that hopelessness may encourage sexual risk-taking behavior in young males.
Combined loss of cRel/p50 subunits of NF-κB leads to impaired innate host response in sepsis
Authors: Courtine Emilie , Cagnard Nicolas , Mazzolini Julie , Antona Marion , Pène Frédéric , Fitting Catherine , Jacques Sébastien , Rousseau Christophe , Niedergang Florence , Gerondakis Steve , Chiche Jean-Daniel , Ouaaz Fatah , Mira Jean-Paul
Published: March 2012

NF-κB, which comprises homo- and hetero-dimers of the five members of the Rel family, plays a crucial role in immunity to infection. The cRel and p50 subunits have been implicated in the development and function of the immune cells, but their in vivo importance remains poorly explored in sepsis. We aimed to study the impact of the combined loss of these two subunits on the innate response to infection in a cecal ligation and puncture model of sepsis. We have explored the possible defects in host defense, including pathogen clearance, bacterial phagocytosis and cytokine plasma release. We also performed gene profiling of cRel−/−p50−/− and wild-type LPS-stimulated peritoneal macrophages. Deficiency of cRel and p50 led to enhanced mortality to sepsis that was associated with defective macrophages phagocytosis, decreased bacterial clearance and moderate cytokine response. Transcription profile analysis revealed a common inflammatory response but a significant down-regulated transcription of genes encoding for pathogen recognition receptors and antimicrobial molecules, supporting the in vivo findings in mice. In conclusion, the cRel and p50 subunits of NF-κB play an important combined role in the innate response and are crucial for survival and pathogen clearance in polymicrobial sepsis.
An analytical model for track cycling
Authors: Lukes Richard , Hart John , Haake Steve
Published: March 2012

This paper presents the full derivation of an analytical model for track cycling. The model takes into account the unique aspects of track cycling associated with riding around a velodrome. These include, riding upon a banked track and the resulting tyre scrubbing effects, and the tipping motion of a cyclist passing through a corner with the resulting centripetal forces. Validation was provided using SRMTM power crank data and split times obtained for an elite national cyclist in a 4 km pursuit competition. Results have shown the model to over-predict cyclist performance with a discrepancy of 0.7 s in a finals event and 4.3 s, less than 2% error, in a qualifying race. It is believed this may be attributable to discrepancies in atmospheric variables. However the model has proved capable of predicting the velocity increase, specifically associated with track cycling, as a cyclist passes through a bend. The model is useful for analysis of the physics of track cycling, and can be used to quantitatively predict performance dependent upon bicycle efficiencies, tyre type and venue conditions, in a racing scenario.
Computational analysis and design of components of protective helmets
Authors: Forero Rueda Manuel A , Gilchrist Michael D
Published: March 2012

Computer methods can assist in understanding the behaviour of the individual components of a helmet, beyond merely the headform output as is usually done in a laboratory environment or for test-house certification purposes. This design study uses a method that we have previously used to analyse the effects of helmet liner material properties. While the helmet liner is of vital importance for energy absorption, other design modifications can also serve to improve its performance. The equestrian helmet model previously developed and analysed by the authors was used in this study. The helmet shell and geometric factors, such as a gap between the liner and shell, ventilation holes and ridges on the helmet liner were studied to observe their influence on helmet performance. By studying helmet design variations in terms of different variables other than headform linear acceleration, it is possible to determine which helmet configurations perform better, why they perform the way they do and how efficiently they perform. This can assist the product design and optimization process by suggesting models which would optimize cost, weight and helmet size.
Modal analysis of composite prosthetic energy-storing-and-returning feet: an initial investigation
Authors: Noroozi Siamak , Sewell Philip , Rahman Abdul Ghaffar Abdul , Vinney John , Chao Ong Zhi , Dyer Bryce
Published: March 2012

The desire of individuals with a lower-limb amputation to participate in sports, coupled with the high demands of athletics, has resulted in the development of energy-storing-and-returning feet, capable of storing energy during stance and returning it to the individual in late stance to assist in forward propulsion. However, little attention has been paid to date to advance the understanding of their dynamic characteristics (natural frequencies, mode shapes and damping) during running. The evaluation of such parameters is now urgently required, as the use of energy-storing-and-returning feet is now being investigated through legal and justice systems to determine participation of amputee athletes using them at the Olympic Games. This paper presents a study of the dynamic characteristics of two commercially available Elite Blade composite feet (solid and split foot). A full modal analysis of the feet was conducted with varying masses attached to them, representing different body masses. The study showed that natural frequencies close to typical running step frequency can be achieved with simple control of the mass or stiffness. It was concluded that further study of the dynamic characteristics could result in a significant change in the design, development and the attitude towards the use of composite prosthetic feet. This initial study has highlighted the key questions that need to be answered to fully understand the dynamic characteristics and inform designers on how to tune a foot to match an amputee’s gait and body condition.
The pan-deacetylase inhibitor panobinostat induces cell death and synergizes with everolimus in Hodgkin lymphoma cell lines
Authors: Lemoine Manuela , Derenzini Enrico , Buglio Daniela , Medeiros L. Jeffrey , Davis R. Eric , Zhang Jiexin , Ji Yuan , Younes Anas
Published: March 2012

The pan-deacetylase inhibitor panobinostat (LBH589) recently has been shown to have significant clinical activity in patients with relapsed Hodgkin lymphoma, but its mechanism of action in Hodgkin lymphoma remains unknown. In this study, we demonstrate that panobinostat has potent antiproliferative activity against Hodgkin lymphoma–derived cell lines. At the molecular level, panobinostat activated the caspase pathway, inhibited STAT5 and STAT6 phosphorylation, and down-regulated hypoxia-inducible factor 1 α and its downstream targets, glucose transporter 1 (GLUT1) and vascular endothelial growth factor. Paradoxically, panobinostat inhibited LKB1 and AMP-activated protein kinase, leading to activation of mammalian target of rapamycin (mTOR) that promotes survival. Combining panobinostat with the mTOR inhibitor everolimus (RAD001) inhibited panobinostat-induced mTOR activation and enhanced panobinostat antiproliferative effects. Collectively, our data demonstrate that panobinostat is a potent deacetylase inhibitor against Hodgkin lymphoma–derived cell lines, and provide a mechanistic rationale for combining panobinostat with mTOR inhibitors for treating Hodgkin lymphoma patients. Furthermore, the effect of panobinostat on GLUT1 expression suggests that panobinostat may modulate the results of clinical diagnostic imaging tests that depend of functional GLUT1, such as fluorodeoxyglucose positron emission tomography.
Leukemia-initiating cells of patient-derived acute lymphoblastic leukemia xenografts are sensitive toward TRAIL
Authors: Castro Alves Catarina , Terziyska Nadia , Grunert Michaela , Gündisch Sibylle , Graubner Ulrike , Quintanilla-Martinez Leticia , Jeremias Irmela
Published: March 2012

Cancer stem cells represent the most important target cells for antitumor therapy. TRAIL (TNF-related apoptosis-inducing ligand) is a potential anticancer agent that induces apoptosis in a wide variety of tumor cells, but its ability to target cancer stem cells is currently unknown. Here we investigated whether TRAIL targets leukemia-initiating cells. Limiting dilution transplantation assays were performed on xenografts from pediatric patients with precursor B-cell acute lymphoblastic leukemia (pre-B ALL) in NSG mice. In vitro treatment of xenograft cells with TRAIL significantly reduced and delayed their engraftment and procrastinated animal death from leukemia. Systemic TRAIL treatment of mice injected with patient-derived pre-B ALL xenograft cells abrogated leukemia in 3 of 5 mice in 1 sample. In conclusion, our data suggest that TRAIL targets leukemia-initiating cells derived from pre-B ALL xenografts in vitro and in vivo, and hence constitutes an attractive candidate drug for treatment of ALL.
The FA pathway counteracts oxidative stress through selective protection of antioxidant defense gene promoters
Authors: Du Wei , Rani Reena , Sipple Jared , Schick Jonathan , Myers Kasiani C. , Mehta Parinda , Andreassen Paul R. , Davies Stella M. , Pang Qishen
Published: March 2012

Oxidative stress has been implicated in the pathogenesis of many human diseases including Fanconi anemia (FA), a genetic disorder associated with BM failure and cancer. Here we show that major antioxidant defense genes are down-regulated in FA patients, and that gene down-regulation is selectively associated with increased oxidative DNA damage in the promoters of the antioxidant defense genes. Assessment of promoter activity and DNA damage repair kinetics shows that increased initial damage, rather than a reduced repair rate, contributes to the augmented oxidative DNA damage. Mechanistically, FA proteins act in concert with the chromatin-remodeling factor BRG1 to protect the promoters of antioxidant defense genes from oxidative damage. Specifically, BRG1 binds to the promoters of the antioxidant defense genes at steady state. On challenge with oxidative stress, FA proteins are recruited to promoter DNA, which correlates with significant increase in the binding of BRG1 within promoter regions. In addition, oxidative stress-induced FANCD2 ubiquitination is required for the formation of a FA-BRG1–promoter complex. Taken together, these data identify a role for the FA pathway in cellular antioxidant defense.
Expression of ABO blood-group genes is dependent upon an erythroid cell–specific regulatory element that is deleted in persons with the Bm phenotype
Authors: Sano Rie , Nakajima Tamiko , Takahashi Keiko , Kubo Rieko , Kominato Yoshihiko , Tsukada Junichi , Takeshita Haruo , Yasuda Toshihiro , Ito Kazuto , Maruhashi Takayuki , Yokohama Akihiko , Isa Kazumi , Ogasawara Kenichi , Uchikawa Makoto
Published: March 2012

The ABO blood group is of great importance in blood transfusion and organ transplantation. However, the mechanisms regulating human ABO gene expression remain obscure. On the basis of DNase I–hypersensitive sites in and upstream of ABO in K562 cells, in the present study, we prepared reporter plasmid constructs including these sites. Subsequent luciferase assays indicated a novel positive regulatory element in intron 1. This element was shown to enhance ABO promoter activity in an erythroid cell–specific manner. Electrophoretic mobility–shift assays demonstrated that it bound to the tissue-restricted transcription factor GATA-1. Mutation of the GATA motifs to abrogate binding of this factor reduced the regulatory activity of the element. Therefore, GATA-1 appears to be involved in the cell-specific activity of the element. Furthermore, we found that a partial deletion in intron 1 involving the element was associated with Bm phenotypes. Therefore, it is plausible that deletion of the erythroid cell–specific regulatory element could down-regulate transcription in the Bm allele, leading to reduction of B-antigen expression in cells of erythroid lineage, but not in mucus-secreting cells. These results support the contention that the enhancer-like element in intron 1 of ABO has a significant function in erythroid cells.
Regulation of acute graft-versus-host disease by microRNA-155
Authors: Ranganathan Parvathi , Heaphy Catherine E. A. , Costinean Stefan , Stauffer Nicole , Na Caroline , Hamadani Mehdi , Santhanam Ramasamy , Mao Charlene , Taylor Patricia A. , Sandhu Sukhinder , He Gang , Shana'ah Arwa , Nuovo Gerard J. , Lagana Alessandro , Cascione Luciano , Obad Susanna , Broom Oliver , Kauppinen Sakari , Byrd John C. , Caligiuri Michael , Perrotti Danilo , Hadley Gregg A. , Marcucci Guido , Devine Steven M. , Blazar Bruce R. , Croce Carlo M. , Garzon Ramiro
Published: March 2012

Acute graft-versus-host disease (aGVHD) remains a major complication of allogeneic hematopoietic stem cell transplant (alloHSCT), underscoring the need to further elucidate its mechanisms and develop novel treatments. Based on recent observations that microRNA-155 (miR-155) is up-regulated during T-cell activation, we hypothesized that miR-155 is involved in the modulation of aGVHD. Here we show that miR-155 expression was up-regulated in T cells from mice developing aGVHD after alloHSCT. Mice receiving miR-155–deficient donor lymphocytes had markedly reduced lethal aGVHD, whereas lethal aGVHD developed rapidly in mice recipients of miR-155 overexpressing T cells. Blocking miR-155 expression using a synthetic anti–miR-155 after alloHSCT decreased aGVHD severity and prolonged survival in mice. Finally, miR-155 up-regulation was shown in specimens from patients with pathologic evidence of intestinal aGVHD. Altogether, our data indicate a role for miR-155 in the regulation of GVHD and point to miR-155 as a novel target for therapeutic intervention in this disease.
Stem cell heterogeneity: implications for aging and regenerative medicine
Authors: Muller-Sieburg Christa E. , Sieburg Hans B. , Bernitz Jeff M. , Cattarossi Giulio
Published: March 2012

For decades, hematopoietic stem cells (HSCs) were thought to be a homogeneous population of cells with flexible behavior. Now a new picture has emerged: The HSC compartment consists of several subpopulations of HSCs each with distinct, preprogrammed differentiation and proliferation behaviors. These programs are epigenetically fixed and are stably bequeathed to all daughter HSCs on self-renewal. HSCs within each subset are remarkably similar in their self- renewal and differentiation behaviors, to the point where their life span can be predicted with mathematical certainty. Three subsets can be distinguished when HSCs are classified by their differentiation capacity: myeloid-biased, balanced, and lymphoid-biased HSCs. The relative number of the HSC subsets is developmentally regulated. Lymphoid-biased HSCs are found predominantly early in the life of an organism, whereas myeloid-biased HSCs accumulate in aged mice and humans. Thus, the discovery of distinct subpopulations of HSCs has led to a new understanding of HCS aging. This finding has implications for other aspects of HSC biology and applications in re-generative medicine. The possibility that other adult tissue stem cells show similar heterogeneity and mechanisms of aging is discussed.
MYC + diffuse large B-cell lymphoma is not salvaged by classical R-ICE or R-DHAP followed by BEAM plus autologous stem cell transplantation
Authors: Cuccuini Wendy , Briere Josette , Mounier Nicolas , Voelker Hans-Ullrich , Rosenwald Andreas , Sundstrom Christer , Cogliatti Sergio , Hirchaud Edouard , Ysebaert Loic , Bron Dominique , Soulier Jean , Gaulard Philippe , Houlgatte Remi , Gisselbrecht Christian , Thieblemont Catherine
Published: March 2012

Approximately 5-10% of diffuse large B-cell lymphomas (DLBCL) harbor a 8q24/MYC rearrangement (MYC+). We determined the prognostic significance of MYC rearrangement in patients with relapsed/refractory DLBCL prospectively treated by R-ICE or R-DHAP followed by high-dose therapy and autologous stem cell transplantation. Twenty-eight (17%) of the 161 patients analyzed presented a MYC+ rearrangement, targeted as either simple hit (25%) or complex hits (n=75%) including MYC/BCL2, MYC/BCL6, and MYC/BCL2/BCL6. Results were statistically highly concordant in matched primary and relapsed biopsies (n = 45). Compared to the MYC− DLBCL patients, the MYC+ DLBCL patients presented with a more elevated lactico-deshydrogenase level (P = .0006) and a more advanced age adjusted international prognostic index (P = .0039). The 4-year PFS and OS were significantly lower in the MYC+ DLBCL patients than those in the MYC− DLBCL patients, with rates of 18% vs 42% (P = .0322), and of 29% vs 62% (P = .0113), respectively. Type of treatment, R-DHAP or R-ICE, had no impact on survivals, with 4-year PFS rates of 17% vs 19% and 4-year OS rates of 26% vs 31%. In conclusion, MYC rearrangement is an early event in DLBCL. MYC+ DLBCL patients have a significant inferior prognosis than MYC− DLBCL patients. Their outcome was not influenced by the proposed salvage therapy.
Reduced intensity conditioning is superior to nonmyeloablative conditioning for older chronic myelogenous leukemia patients undergoing hematopoietic cell transplant during the tyrosine kinase inhibitor era
Authors: Warlick Erica , Ahn Kwang Woo , Pedersen Tanya L. , Artz Andrew , de Lima Marcos , Pulsipher Michael , Akpek Gorgun , Aljurf Mahmoud , Cahn Jean-Yves , Cairo Mitchell , Chen Yi-Bin , Cooper Brenda , Deol Abhinav , Giralt Sergio , Gupta Vikas , Khoury H. Jean , Kohrt Holbrook , Lazarus Hillard M. , Lewis Ian , Olsson Richard , Pidala Joseph , Savani Bipin N. , Seftel Matthew , Socié Gerard , Tallman Martin , Ustun Celaettin , Vij Ravi , Vindeløv Lars , Weisdorf Daniel
Published: March 2012

Tyrosine kinase inhibitors (TKIs) and reduced intensity conditioning (RIC)/nonmyeloablative (NMA) conditioning hematopoietic cell transplants (HCTs) have changed the therapeutic strategy for chronic myelogenous leukemia (CML) patients. We analyzed post-HCT outcomes of 306 CML patients reported to the Center for International Blood and Marrow Transplant Research aged 40 years and older undergoing RIC/NMA HCT from 2001 to 2007: 117 (38%) aged 40 to 49 years, 119 (39%) 50 to 59 years, and 70 (23%) 60 years or older. The majority (74%) had treatment with imatinib before HCT. At HCT, most patients aged 40 to 49 years were in chronic phase (CP) 1 (74%), compared with 31% aged 60 years or older. Siblings were donors for 56% aged 40 to 49 years; older cohorts had more unrelated donors. The majority received peripheral blood grafts and RIC across all age groups. 3 year overall survival (54%, 52%, and 41%), day + 100 grade II-IV acute GVHD (26%, 32%, and 32%), chronic GVHD (58%, 51%, and 43%), and 1-year treatment-related mortality (18%, 20%, and 13%) were similar across ages. The 3-year relapse incidence (36%, 43%, and 66%) and disease-free survival (35%, 32%, and 16%) were inferior in the oldest cohort. Importantly, for CP1 patients, relapse and disease-free survival were similar across age cohorts. Allogeneic RIC HCT for older patients with CML can control relapse with acceptable toxicity and survival in TKI-exposed CML, especially if still in CP1.
A 3-year longitudinal study of sleep disordered breathing in the elderly
Authors: Sforza Emilia , Gauthier Maylis , Crawford-Achour Emilie , Pichot Vincent , Maudoux Delphine , Barthélémy Jean Claude , Roche Frédéric
Published: March 2012

Limited and controversial data exist on the natural evolution of sleep disordered breathing (SDB) in untreated individuals. This study examines the evolution of SDB over a 3-yr period in a community-based sample of elderly subjects.

From the initial cohort of 854 healthy subjects aged mean±sd68.4±0.8 yrs, 519 untreated subjects accepted clinical and instrumental follow-up 3.6±1.6 yrs later. SDB was defined as a respiratory disturbance index (RDI) >15 events·h−1.

At baseline, 202 (39%) subjects had an RDI ≤15 events·h−1and 317 (61%) had an RDI >15 events·h−1. 3 yrs later, 280 (54%) subjects were non-SDB and 239 (46%) had SDB. Between evaluations, the RDI decreased from 22.3±16.2 to 16.4±13.0 events·h−1, with a greater decrease in the number of cases with an RDI >30 events·h−1that in those with RDI ≥30 events·h−1. In the non-SDB group, 81% had a stable RDI and 19% increased their RDI by a mean of 13.7 events·h−1. In the SDB group, the RDI decreased to values ≤15 events·h−1in 36.6% of cases, 63.4% still having SDB. The RDI changes did not depend on weight changes.

In healthy elderly subjects, the prevalence and severity of SDB did not show a tendency toward natural worsening, some cases having improvement or a remission independent of weight changes. These findings also suggest that in the elderly, natural SDB progression is still hypothetical.
Does oxidative stress modulate limb muscle atrophy in severe COPD patients?
Authors: Fermoselle Clara , Rabinovich Roberto , Ausín Pilar , Puig-Vilanova Ester , Coronell Carlos , Sanchez Francisco , Roca Josep , Gea Joaquim , Barreiro Esther
Published: March 2012

Oxidative stress may differentially regulate protein loss within peripheral muscles of severe chronic obstructive pulmonary disease (COPD) patients exhibiting different body composition.

Oxidation levels of proteins, myosin heavy chain (MyHC) and myonuclei, superoxide anion, antioxidants, actin, creatine kinase, carbonic anhydrase-3, ubiquitin–proteasome system, redox-signalling pathways, inflammation and muscle structure, and damage were quantified in limb muscles of severe COPD patients with and without muscle wasting, and in sedentary controls.

Compared with controls, in the quadriceps of muscle-wasted COPD patients, levels of protein carbonylation, oxidation of MyHC and myonuclei, superoxide anion production, superoxide dismutase, total protein ubiquinitation, E214k, atrogin-1, FoxO1 and p65 were higher, while content of MyHC, creatine kinase, carbonic anhydrase-3, myogenin, and fast-twitch fibre size were decreased. Importantly, in nonwasted COPD patients, where MyHC was more oxidised than in controls, its content was preserved. Muscle inflammation and glutathione levels did not differ between patients and controls. In all patients, muscle structure abnormalities were increased, while muscle force and exercise capacity were reduced.

In severe COPD, while muscle oxidative stress increases regardless of their body composition, protein ubiquitination and loss of MyHC were enhanced only in patients exhibiting muscle atrophy. Oxidative stress does not seem to directly modulate muscle protein loss in these patients.
Exercise training reverses exertional oscillatory ventilation in heart failure patients
Authors: Zurek Marzena , Corrà Ugo , Piepoli Massimo F. , Binder Ronald K. , Saner Hugo , Schmid Jean-Paul
Published: March 2012

Exertional oscillatory ventilation (EOV) is an ominous prognostic sign in chronic heart failure (CHF), but little is known about the success of specific therapeutic interventions.

Our aim was to study the impact of an exercise training on exercise capacity and cardiopulmonary adaptation in stable CHF patients with left ventricular systolic dysfunction and EOV.

96 stable CHF patients with EOV were included in a retrospective analysis (52 trainingversus44 controls). EOV was defined as follows: 1) three or more oscillatory fluctuations in minute ventilation (V′E) during exercise; 2) regular oscillations; and 3) minimal average ventilation amplitude ≥5 L.

EOV disappeared in 37 (71.2%) out of 52 patients after training, but only in one (2.3%) out of 44 without training (p<0.001). The decrease of EOV amplitude correlated with changes in end-tidal carbon dioxide tension (r= -0.60, p<0.001) at the respiratory compensation point andV′E/carbon dioxide production (V′CO2) slope (r=0.50, p<0.001). Training significantly improved resting values of respiratory frequency (fR),V′E, tidal volume (VT) andV′E/V′CO2ratio. During exercise,V′EandVTreached significantly higher values at the peak, whilefRandV′E/V′CO2ratio were significantly lower at submaximal exercise. No change was noted in the control group.

Exercise training leads to a significant decrease of EOV and improves ventilatory efficiency in patients with stable CHF.