bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting the Cellular Signaling: BRAF Inhibition and Beyond for the Treatment of Metastatic Malignant Melanoma
Authors: Ades Felipe , Metzger-Filho Otto
Published: December 2011

Although advances in cytotoxic treatments have been obtained in several neoplasias, in metastatic melanoma there was no drug able to significantly change the natural history of the disease in the last 30 years. In the last decade, translational research identified important mechanisms in malignant transformation, invasion, and progression. Signaling pathways can be abnormally activated by oncogenes. The identification of oncogenic mutated kinases implicated in this process provides an opportunity for new target therapies. The melanoma dependence on BRAF-mutated kinase allowed the development of inhibitors that produced major responses in clinical trials. This is the beginning of a novel class of drugs in metastatic melanoma; the identification of the transduction signaling networking and other “druggable” kinases is in active research. In this paper, we discuss the ongoing research on cellular signaling inhibition, resistance mechanisms, and strategies to overcome treatment failure.
Synthesis, Characterization, and Evaluation of Boron-Doped Iron Oxides for the Photocatalytic Degradation of Atrazine under Visible Light
Authors: Hu Shan , Liu Guanglong , Zhu Duanwei , Chen Chao , Liao Shuijiao
Published: December 2011

Photocatalytic degradation of atrazine by boron-doped iron oxides under visible light irradiation was investigated. In this work, boron-doped goethite and hematite were successfully prepared by sol-gel method with trimethylborate as boron precursor. The powders were characterized by XRD, UV-vis diffuse reflectance spectra, and porosimetry analysis. The results showed that boron doping could influence the crystal structure, enlarge the BET surface area, improve light absorption ability, and narrow their band-gap energy. The photocatalytic activity of B-doped iron oxides was evaluated in the degradation of atrazine under the visible light irradiation, and B-doped iron oxides showed higher atrazine degradation rate than that of pristine iron oxides. Particularly, B-doped goethite exhibited better photocatalytic activity than B-doped hematite.
Comprehensive Predictive Biomarker Analysis for MEK Inhibitor GSK1120212
Authors: Jing Junping , Greshock Joel , Holbrook Joanna Dawn , Gilmartin Aidan , Zhang Xiping , McNeil Elizabeth , Conway Theresa , Moy Christopher , Laquerre Sylvie , Bachman Kurt , Wooster Richard , Degenhardt Yan
Published: December 2011

The MEK1 and MEK2 inhibitor GSK1120212 is currently in phase II/III clinical development. To identify predictive biomarkers, sensitivity to GSK1120212 was profiled for 218 solid tumor cell lines and 81 hematologic malignancy cell lines. For solid tumors, RAF/RAS mutation was a strong predictor of sensitivity. Among RAF/RAS mutant lines, co-occurring PIK3CA/PTEN mutations conferred a cytostatic response instead of a cytotoxic response for colon cancer cells that have the biggest representation of the comutations. Among KRAS mutant cell lines, transcriptomics analysis showed that cell lines with an expression pattern suggestive of epithelial-to-mesenchymal transition were less sensitive to GSK1120212. In addition, a proportion of cell lines from certain tissue types not known to carry frequent RAF/RAS mutations also seemed to be sensitive to GSK1120212. Among these were breast cancer cell lines, with triple negative breast cancer cell lines being more sensitive than cell lines from other breast cancer subtypes. We identified a single gene DUSP6, whose expression was associated with sensitivity to GSK1120212 and lack of expression associated with resistance irrelevant of RAF/RAS status. Among hematologic cell lines, acute myeloid leukemia and chronic myeloid leukemia cell lines were particularly sensitive. Overall, this comprehensive predictive biomarker analysis identified additional efficacy biomarkers for GSK1120212 in RAF/RAS mutant solid tumors and expanded the indication for GSK1120212 to patients who could benefit from this therapy despite the RAF/RAS wild-type status of their tumors. Mol Cancer Ther; 11(3); 720–9. ©2011 AACR.
An Epstein-Barr Virus-Associated Leukemic Lymphoma in a Patient Treated with Rabbit Antithymocyte Globulin and Cyclosporine for Hepatitis-Associated Aplastic Anemia
Authors: Ohata Kinya , Iwaki Noriko , Kotani Takeharu , Kondo Yukio , Yamazaki Hirohito , Nakao Shinji
Published: December 2011

Lymphoproliferative disorders (LPDs) are generally caused by uncontrolled B-cell proliferation induced by the Epstein-Barr virus (EBV) in the setting of impaired EBV-specific T-cell immunity, particularly when there is pharmacological immunosuppression including antithymocyte globulin. We herein present an unusual case of EBV associated with LPD (EBV-LPD) in which LPD occurred 3 weeks after the use of rabbit antithymocyte globulin administered for severe hepatitis-associated aplastic anemia; the patient died of fulminant leukemic lymphoma 5 days after the onset. We also review the pertinent literature on EBV-LPD after immunosuppressive therapy and document the efficacy of EBV viral load monitoring and the need for preemptive therapy.
Haemodynamic Impact of a Slower Pump Speed at Start of Continuous Renal Replacement Therapy in Critically Ill Adults with Acute Kidney Injury: A Prospective Before-and-After Study
Authors: Eastwood Glenn M. , Peck Leah , Young Helen , Bailey Michael , Reade Michael C. , Baldwin Ian , Bellomo Rinaldo
Published: December 2011

Background and Objective: Patients are at risk of haemodynamic instability when starting continuous renal replacement therapy (CRRT). Methods: We compared data for ‘routine-protocol’ pump speed increases of 50 ml/min over 1–4 min with ‘slower’ increases of 20–50 ml/min over 3–10 min to achieve an operating blood flow of 200 ml/min. Results: We studied 21 routine and 20 slower CRRT starts. ‘Routine protocol’ starts reached the target pump speed more quickly than the slower CRRT start (p < 0.05). Heart rate was higher in the routine group compared to the slower group at baseline (p < 0.01) and remained so throughout. There were no significant changes in central venous pressure or mean arterial pressure, and no episodes of hypotension or hypertension, in either group, or in the subset of 17 CRRT starts in vasopressor-dependent patients. Conclusion: We cannot recommend a slower pump speed start based on our findings, but advocate for close haemodynamic monitoring, as haemodynamic changes in individual patients cannot be predicted in advance.
Hyper-Heuristics with Low Level Parameter Adaptation
Authors: Ren Zhilei , Jiang He , Xuan Jifeng , Luo Zhongxuan
Published: December 2011

Recent years have witnessed the great success of hyper-heuristics applying to numerous real-world applications. Hyper-heuristics raise the generality of search methodologies by manipulating a set of low level heuristics (LLHs) to solve problems, and aim to automate the algorithm design process. However, those LLHs are usually parameterized, which may contradict the domain independent motivation of hyper-heuristics. In this paper, we show how to automatically maintain low level parameters (LLPs) using a hyper-heuristic with LLP adaptation (AD-HH), and exemplify the feasibility of AD-HH by adaptively maintaining the LLPs for two hyper-heuristic models. Furthermore, aiming at tackling the search space expansion due to the LLP adaptation, we apply a heuristic space reduction (SAR) mechanism to improve the AD-HH framework. The integration of the LLP adaptation and the SAR mechanism is able to explore the heuristic space more effectively and efficiently. To evaluate the performance of the proposed algorithms, we choose the p-median problem as a case study. The empirical results show that with the adaptation of the LLPs and the SAR mechanism, the proposed algorithms are able to achieve competitive results over the three heterogeneous classes of benchmark instances.
Incoming Solar and Infrared Radiation Derived from METEOSAT: Impact on the Modeled Land Water and Energy Budget over France
Authors: Carrer D. , Lafont S. , Roujean J.-L. , Calvet J.-C. , Meurey C. , Le Moigne P. , Trigo I. F.
Published: December 2011

The Land Surface Analysis Satellite Applications Facility (LSA SAF) project radiation fluxes, derived from the Meteosat Second Generation (MSG) geostationary satellite, were used in the Interactions between Soil, Biosphere, and Atmosphere (ISBA) land surface model (LSM), which is a component of the Surface Externalisée (SURFEX) modeling platform. The Système d’Analyze Fournissant des Renseignements Atmosphériques à la Neige (SAFRAN) atmospheric analysis provides high-resolution atmospheric variables used to drive LSMs over France. The impact of using the incoming solar and infrared radiation fluxes [downwelling surface shortwave (DSSF) and longwave (DSLF), respectively] from either SAFRAN or LSA SAF, in ISBA, was investigated over France for 2006. In situ observations from the Flux Network (FLUXNET) were used for the verification. Daily differences between SAFRAN and LSA SAF radiation fluxes averaged over the whole year 2006 were 3.75 and 2.61 W m−2 for DSSF and DSLF, respectively, representing 2.5% and 0.8% of their average values. The LSA SAF incoming solar radiation presented a better agreement with in situ measurements at six FLUXNET stations than the SAFRAN analysis. The bias and standard deviation of differences were reduced by almost 50%. The added value of the LSA SAF products was assessed with the simulated surface temperature, soil moisture, and the water and energy fluxes. The latter quantities were improved by the use of LSA SAF satellite estimates. As many areas lack a high-resolution meteorological analysis, the LSA SAF radiative products provide new and valuable information.
Estuarine Exchange Flow Quantified with Isohaline Coordinates: Contrasting Long and Short Estuaries
Authors: Chen Shih-Nan , Geyer W. Rockwell , Ralston David K. , Lerczak James A.
Published: December 2011

Isohaline coordinate analysis is used to compare the exchange flow in two contrasting estuaries, the long (with respect to tidal excursion) Hudson River and the short Merrimack River, using validated numerical models. The isohaline analysis averages fluxes in salinity space rather than in physical space, yielding the isohaline exchange flow that incorporates both subtidal and tidal fluxes and precisely satisfies the Knudsen relation. The isohaline analysis can be consistently applied to both subtidally and tidally dominated estuaries. In the Hudson, the isohaline exchange flow is similar to results from the Eulerian analysis, and the conventional estuarine theory can be used to quantify the salt transport based on scaling with the baroclinic pressure gradient. In the Merrimack, the isohaline exchange flow is much larger than the Eulerian quantity, indicating the dominance of tidal salt flux. The exchange flow does not scale with the baroclinic pressure gradient but rather with tidal volume flux. This tidal exchange is driven by tidal pumping due to the jet–sink flow at the mouth constriction, leading to a linear dependence of exchange flow on tidal volume flux. Finally, a tidal conversion parameter Qin/Qprism, measuring the fraction of tidal inflow Qprism that is converted into net exchange Qin, is proposed to characterize the exchange processes among different systems. It is found that the length scale ratio between tidal excursion and salinity intrusion provides a characteristic to distinguish estuarine regimes.
Simultaneous Velocity Ambiguity Resolution and Noise Suppression for Multifrequency Coherent Doppler Sonar
Authors: Dillon Jeremy , Zedel Len , Hay Alex E.
Published: December 2011

Coherent Doppler sonar is a useful tool for noninvasive measurement of ocean currents, sediment transport, and turbulence in coastal environments. Various methods have been proposed to separately address two of its inherent limitations: velocity ambiguity and measurement noise. However, in energetic turbulent flows, both factors may be present simultaneously. The presence of measurement noise complicates velocity ambiguity resolution, and conversely velocity ambiguity presents a challenge for existing noise suppression methods. A velocity estimator based on maximum a posteriori (MAP) estimation has been developed to resolve velocity ambiguity and suppress measurement noise simultaneously rather than separately. The estimator optimally combines measurements from multiple acoustic carrier frequencies and multiple transducers. Data fusion is achieved using a probabilistic approach, whereby measurements are combined numerically to derive a velocity likelihood function. The MAP velocity estimator is evaluated using a high-fidelity coherent Doppler sonar simulation of oscillating flow and data from a towing tank grid turbulence experiment where both velocity ambiguity and backscatter decorrelation were present. Time series and spectra from MAP velocity estimation are compared to those obtained with conventional Doppler signal processing. In addition to robustly resolving velocity ambiguity, the MAP velocity estimator is shown to reduce high-frequency noise in turbulence spectra.
Religion, jeunesse et modernité: Le camp d’été, nouvelle pratique rituelle du bouddhisme chinois
Authors: Zhe JI
Published: December 2011

La reconstruction religieuse en Chine contemporaine implique non seulement des adaptations stratégiques aux conditions socio-politiques locales, mais aussi des réponses novatrices aux défis modernes dans leur généralité, tels que le moindre taux de participation des jeunes aux rituels en raison de l’affirmation de l’autonomie et de la mobilité individuelles. Sur la base d’une étude de cas portant sur un camp d’été bouddhique, l’auteur analyse dans quelle mesure le camp constitue une nouvelle forme de mobilisation religieuse des jeunes. Au-delà des limites de la communauté habituelle et du calendrier traditionnel, le camp crée un contexte temporaire et ambivalent de pratique collective, dans lequel les frontières entre croyants et non-croyants, entre religieux et non-religieux deviennent flexibles, ce qui permet de mieux répondre aux besoins d’ouverture identitaire et d’expérimentation sociale de la jeunesse.
A robust adaptive control for micro-positioning of piezoelectric actuators with environment force estimation
Authors: Ghafarirad H , Rezaei SM , Zareinejad M , Hamdi M
Published: December 2011

Piezoelectric actuators are widely used for precise micro-positioning. In most applications, there is contact with the environment. Sensing external forces is a challenging problem in controlling mechanical systems, especially in micro scales. The external force could cause dual hysteresis non-linearity effects, which will disrupt the actuator positioning accuracy. Therefore, an effective controller should be designed to guarantee the trajectory tracking in the presence of external forces and perturbations. In this paper, a modified Prandtl–Ishlinskii operator and its inverse is utilized for both identification and real time compensation of the hysteresis effect. A variable structure controller is proposed for trajectory tracking of the actuator position. A sliding-based observer would estimate full states from the only measurable position trajectory. An adaptive perturbation estimation approach is proposed so that external forces can be separated from disturbances. The stability of the controller in the presence of estimated states and external forces is demonstrated analytically. The experimental results depict that the proposed approach achieves precise trajectory tracking and good external force estimation.
Global capitalism and twenty-first century fascism: a US case study
Authors: Robinson William I. , Barrera Mario
Published: December 2011

This seminal article analyses the current structural crisis and instability in an ever more polarised world in relation to earlier systemic crises that were resolved through fascism or through Fordist-Keynesian ‘class compromise’ (the 1930s) and the emergence of capitalist globalisation (the 1970s). The authors identify three basic responses to the crisis: popular insurgency from below; reformist stabilisation from above; and, a twenty-first century neo-fascism. Looking specifically at the US, they analyse political and economic developments that demonstrate fascistic characteristics. While no simple replication of the past, the emergence of a Christian Right since the mid-1980s, the growth of certain currents within the Tea Party movement, the sharp increase in violent hate groups, the spread of a vicious anti-immigrant movement, the psychopathology of white decline, sharp militarisation and pervasive policing give some indications of the rise of fascist tendencies. But what is crucial today is the sophistication of such a project, made possible by the ideological domination of media together with new surveillance and social control technologies that allow it to rely more on selective than generalised repression. In calling for a co-ordinated fightback, both in the US and beyond, the authors see the only viable solution to the crisis of global capitalism as a massive redistribution of wealth and power downward towards the poor majority of humanity, along the lines of a twenty-first century democratic socialism.
Facial telangiectasia: an unusual manifestation of neonatal lupus erythematosus
Authors: Guinovart RM , Vicente A , Rovira C , Suñol M , González-Enseñat MA
Published: December 2011

Neonatal lupus erythematosus (NLE) is an uncommon condition usually associated with maternal anti-Ro autoantibodies. The cutaneous lesions of NLE are usually transient, disappearing about six months after birth, but telangiectasia is a rare complication of NLE which persists. Telangiectasias are small focal red macules and papules created by abnormally prominent capillaries, venules, and arterioles and are a characteristic marker of connective tissue diseases. We report the case of an infant diagnosed with NLE presenting typical annular lesions, positive ANA and positive anti-Ro antibodies. By five months of age, both ANA and anti-Ro antibodies were negative and the annular cutaneous lesions had gradually faded, but small scattered focal red macules appeared on the face, especially in the peri-orbital area and scalp. The cutaneous lupus disappeared but the telangiectasia persisted. We would like to suggest that the diagnosis of NLE should be considered when cutaneous telangiectasias are observed in infants.
Investigation on the damage identification of bridges using distributed long-gauge dynamic macrostrain response under ambient excitation
Authors: Hong Wan , Wu Zhishen , Yang Caiqian , Wan Chunfeng , Wu Gang
Published: December 2011

In this study, an output-only method for extraction of modal macrostrain and damage identification of bridges under ambient excitation is presented. It is theoretically proved that the modal macrostrain within the gauge length of a long-gauge macrostrain sensor is uniquely determined by the peak value of the power spectral density (PSD) of dynamic macrostrain response. Then damage occurred within the gauge length of a sensor can be identified by the ratio change between the peak value of PSD of this sensor response and that of the reference sensor response. The damage extent has also been verified to have corresponding relationship with the ratio change. Numerical simulation was carried out to confirm the feasibility of the proposed method. Analysis results of the numerical simulation reveal that the maximum error of the identified modal macrostrain relative to that of the modal analysis is 3%. Results of simulation show that the proposed PSD-based method can not only accurately localize the damage but also assess the damage extent. The influence of several typical excitations on real bridges was also investigated that further proves the robustness of the method. It is worth mentioning that only the first-order mode is necessary for the method to identify damage. Finally, the proposed method is employed for condition assessment of a real bridge located in New Jersey, wherein 17 long-gauge macrostrain sensors with the gauge length of 1 m were distributedly arranged along the critical region of the girder. Analysis results of the field measurements further verify that the PSD-based method can be utilized to assess the damage state of structures under ambient excitation.
Order reduction of linear systems with an improved pole clustering
Authors: Komarasamy Ramesh , Albhonso Nirmalkumar , Gurusamy Gurusamy
Published: December 2011

A new model order reduction technique for the reduction of the linear time invariant system has been proposed in this paper. An improved clustering algorithm is employed in the proposed method to obtain the reduced order denominator polynomial. The reduced order numerator polynomial is obtained with a simple mathematical calculation as mentioned in the proposed scenario. The validity of the proposed method has been illustrated through some numerical examples. The improved clustering algorithm guaranteed the stability in the reduced model and also preserves the characteristics of the original system in the approximated one. The method is extended to the higher order multivariable system described by its matrix transfer function.
Experimental study on vertical performance of multidimensional earthquake isolation and mitigation devices for long-span reticulated structures
Authors: Xu Zhao-Dong , Tu Qing , Guo Yi-Feng
Published: December 2011

The earthquake excitation is a complicated multidimensional motion, which will cause the damage or even collapse of structures. Consequently, some measures to prevent structure failure must be taken under multidimensional excitations, especially for long-span reticulated structures and high-rise buildings. Many earthquake isolation or mitigation devices have been manufactured to reduce the horizontal dynamic responses of structures, but there are few reports concerning the device isolating and mitigating earthquake actions both in horizontal and vertical directions simultaneously. In this paper, a new multidimensional earthquake isolation and mitigation device for long-span reticulated structures is developed and tested under different cases. Effects of excitation frequency and amplitude on vertical properties of this device are studied. Then, the modified equivalent standard solid model is proposed to describe the vertical properties of the device. Experimental and numerical studies show that this device has good capability of energy dissipation in vertical direction.
Vibration isolation pad for medical purposes: modeling and simulation
Authors: Hanieh Ahmed Abu
Published: December 2011

This project aims at establishing new research about protecting sensitive human beings from vibration syndrome. The main application targeted here is the protection of patients undergoing the Magnetic Resonance Imaging test where noise and vibration can cause severe damage to the test results. Stability and accuracy are very important issues in this medical test. An active vibration isolation pad will be designed and manufactured in this research where the force of the vibrating human body is measured and compensated to be fed back to a linear piezoelectric actuator to isolate the disturbing source of vibrations from propagating into the patient’s body. This paper presents analytical and numerical models for the vibration isolation system where the Integral Force Feedback control technique is applied. The results prove high authority and robustness for this control technique especially on the first vibration mode.
The role of identity in disposal
Authors: Phillips Barbara J. , Sego Trina
Published: December 2011

This study uses depth interviews with mothers about their disposal of children’s possessions to craft a new understanding of the role of identity in disposal. Our study asks: How does identity influence the disposal process of ordinary possessions? A disposal identity continuum of keepers and discarders emerged from the data. This new understanding suggests that disposal involves decisions regarding the match of possession to mother, partner, child, and family identities. When disposal identities lead to conflict between the actors in the disposal decision, decision makers use coping strategies such as subterfuge, avoidance, forced choice, and training/discussion. In addition, the disposal process can lead to negative emotional outcomes such as ambivalence and guilt for both keepers and discarders.
Co-authoring tomorrow
Authors: Domegan Christine
Published: December 2011

Tomorrow’s marketing theory is best co-authored with its past, the history of marketing thought. The merits of this co-authoring are deeply rooted in the value this brings to marketing knowledge and the marketing discipline – conceptual, methodological, scientific and pedagogical value. The purpose of this contribution is to demonstrate the relationship between the history of marketing thought and the further development of marketing theory.
A comment on the relationship between the history of marketing thought and the development of marketing theory
Authors: Shaw Eric H.
Published: December 2011

This comment argues that the history of marketing thought and the development of marketing theory are intimately intertwined. The history of marketing thought is necessary for the development of marketing theory, and marketing theory is necessary for the advancement of marketing as a social science. Science matures as theoretical developments improve over time, contributing to the body of historical thought. As this thought–theory cycle continues to regenerate, the social science of marketing continues to progress.
Percival White (1887–1970)
Authors: Jones D.G. Brian , Tadajewski Mark
Published: December 2011

This paper outlines an intellectual biography of Percival White whose major contributions to marketing thought focused on market research and the application of scientific management to marketing. White published 20 books during his career, 11 of those dealing with marketing, including one of the earliest texts on market research. Like other pioneers in the marketing discipline, White’s legacy also includes major contributions to marketing practice. His company, Market Research Corporation of America, represented some of the best technical practices of the 1930s. Unlike many other pioneers in marketing whose education was in economics, White’s background was in industrial engineering. He considered himself a marketing engineer.
Low-rate wireless personal area networks applied to street lighting
Authors: Domingo-Perez F , Gil-de-Castro A , Flores-Arias JM , Bellido-Outeirino FJ , Moreno-Munoz A
Published: December 2011

This paper focuses on the development of an energy-efficient street lighting remote management system making use of low-rate wireless personal area networks and the digital addressable lighting interface (DALI) protocol to get the bidirectional communication necessary for checking lamp parameters like lamp status, current level, etc. Because of the fact that two-thirds of the installed street lighting systems use old and inefficient technologies, there exists a huge potential to renew street lighting and save energy consumption. The proposed system uses the DALI protocol in street lighting, increasing the maximum number of ballasts that can be controlled with DALI – originally it can only drive up to 64 ballasts. Some aspects of the wireless communication system and experimental measurements are presented and discussed.
A Comparison of Extraperitoneal and Intraperitoneal Approaches for Robotic Prostatectomy
Authors: Jacobs Bruce L. , Montgomery Jeffrey S. , Dunn Rodney L. , Weizer Alon Z. , Miller David C. , Wood David P. , Wolf J. Stuart , Zhang Yun , Wei John T. , Hollenbeck Brent K.
Published: December 2011

Objectives. This study compared oncologic and health-related quality-of-life outcomes among patients undergoing intraperitoneal or extraperitoneal robotic prostatectomy. Methods. Of 215 patients undergoing robotic prostatectomy, the approach was intraperitoneal in 48 and extraperitoneal in 167. Cancer control was evaluated using margin status. Recovery after surgery and functional health was assessed using the Convalescence and Recovery Evaluation and Expanded Prostate Cancer Index Composite questionnaires, respectively. Results. Positive surgical margin rates were similar between approaches (14% extraperitoneal, 10% intraperitoneal; P = .63). Functional outcomes were slightly improved for those with the extraperitoneal approach (ie, higher urinary irritation/obstruction scores at 3 months). The extraperitoneal group demonstrated higher activity (91.8 vs 83.3, P = .03) and cognitive scores (94.9 vs 91.7, P = .04) at 6 weeks as well as higher gastrointestinal scores at 2 weeks (94.2 vs 90.8, P = .05). Conclusions. These data support efforts to broaden the adoption of the extraperitoneal approach for robotic prostatectomy.
Objective Assessment of Laparoscopic Skills
Authors: Meneghetti Adam T. , Pachev George , Zheng Bin , Panton Ormond Neely , Qayumi Karim
Published: December 2011

Background. Assessment of surgical performance is often accomplished with traditional methods that often provide only subjective data. Trainees who perform well on a simulator in a controlled environment may not perform well in a real operating room environment with distractions. This project uses the ideas of dual-task methodology and applies them to the assessment of performance of laparoscopic surgical skills. The level of performance on distracting secondary tasks while trying to perform a primary task becomes an indirect but objective measure of the surgical skill of the trainee. Methods. Nine surgery residents and 6 experienced laparoscopic surgeons performed 3 primary tasks on a laparoscopic virtual reality simulator (camera position, grasping, and cholecystectomy) while being distracted by 3 secondary tasks (counting beeps, selective responses, and mental arithmetic). Completion time and error rates were recorded for each combination of tasks. Results. When performed separately, time to completion and error rates for primary and secondary tasks were similar for learners and experts. When performing the tasks simultaneously, learners had more errors than experts. Error rates increased for learners when distracting tasks became more difficult or required more attention. Expert surgeons maintained consistent error rates despite the increasing difficulty of task combinations. Conclusions. The use of dual-task methodology may help trainers to identify which surgical trainees require more preparation before entering the real operating room environment. Expert surgeons are capable of maintaining performance levels on a primary task in the face of distractions that may occur in the operating room.
Autocuidado: elementos para sus bases conceptuales
Authors: Arenas-Monreal Luz , Jasso-Arenas Jazmín , Campos-Navarro y Roberto
Published: December 2011

Resumen

Desde la antropología y las ciencias sociales el autocuidado se refiere a las distintas actividades de la vida cotidiana que son realizadas por las personas, familias y los grupos sociales para el cuidado de la salud, la prevención de enfermedades y limitación de daños. El objetivo de este manuscrito es aportar elementos teóricos para la comprensión del autocuidado en el marco de la promoción de la salud. Tomando como base el planteamiento de A. Giddens quien señala que las conductas se dividen en intencionales y deliberadas, se propone que el autocuidado se construye a partir de distintos elementos que contribuyen a que se estructuren hábitos a partir de dos ejes: i) acciones intencionales que efectúan las personas sin reflexión previa ni cuestionamientos y ii) acciones deliberadas en las que la reflexión y la experiencia de vivencias significativas provocan la incorporación de pautas de autocuidado que no se tenían previamente. Se señala que en las acciones de autocuidado tanto intencionales como deliberadas, ejercen una influencia fundamental los determinantes sociales y específicamente la clase social, la ocupación, el género, el grupo étnico, así como la familia, la edad, y las experiencias de enfermedad y muerte de personas cercanas. Se concluye que es necesario avanzar en la construcción teórica del autocuidado para ubicar este concepto dentro de una perspectiva social más amplia y no reducirlo al ámbito funcionalista y de responsabilidad individual.
Therapeutic strategy in unresectable metastatic colorectal cancer
Authors: Chibaudel Benoist , Tournigand Christophe , André Thierry , de Gramont Aimery
Published: December 2011

While surgery is the cornerstone treatment for early-stage colorectal cancer, chemotherapy is the first treatment option for metastatic disease when tumor lesions are frequently not fully resectable at presentation. Mortality from colon cancer has decreased over the past 30 years, but there is still a huge heterogeneity in survival rates that can be mainly explained by patient and tumor characteristics, host response factors, and treatment modalities. The management of unresectable metastatic colorectal cancer is a global treatment strategy, which applies several lines of therapy, salvage surgery, maintenance, and treatment-free intervals. The individualization of cancer treatment is based on the evaluation of prognostic factors for survival (serum lactate dehydrogenase level, performance status), and predictive factors for treatment efficacy [Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status]. The available treatment modalities for metastatic colorectal cancer are chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), anti-angiogenic agents (e.g. bevacizumab), and anti-epidermal growth factor agents (cetuximab, panitumumab). The increasing number of active compounds dictates the strategy of trials evaluating these treatments either in combination or sequentially. Alternative outcomes that can be measured earlier than overall survival are needed to shorten the duration and reduce the size and cost of clinical trials.
Avoiding Disclosure of Individually Identifiable Health Information
Authors: Prada Sergio I. , González-Martínez Claudia , Borton Joshua , Fernandes-Huessy Johannes , Holden Craig , Hair Elizabeth , Mulcahy and Tim
Published: December 2011

Achieving data and information dissemination without harming anyone is a central task of any entity in charge of collecting data. In this article, the authors examine the literature on data and statistical confidentiality. Rather than comparing the theoretical properties of specific methods, they emphasize the main themes that emerge from the ongoing discussion among scientists regarding how best to achieve the appropriate balance between data protection, data utility, and data dissemination. They cover the literature on de-identification and reidentification methods with emphasis on health care data. The authors also discuss the benefits and limitations for the most common access methods. Although there is abundant theoretical and empirical research, their review reveals lack of consensus on fundamental questions for empirical practice: How to assess disclosure risk, how to choose among disclosure methods, how to assess reidentification risk, and how to measure utility loss.
The response of early neural genes to FGF signaling or inhibition of BMP indicate the absence of a conserved neural induction module
Authors: Rogers Crystal D , Ferzli George S , Casey Elena S
Published: December 2011

Background

The molecular mechanism that initiates the formation of the vertebrate central nervous system has long been debated. Studies in Xenopus and mouse demonstrate that inhibition of BMP signaling is sufficient to induce neural tissue in explants or ES cells respectively, whereas studies in chick argue that instructive FGF signaling is also required for the expression of neural genes. Although additional signals may be involved in neural induction and patterning, here we focus on the roles of BMP inhibition and FGF8a.

Results

To address the question of necessity and sufficiency of BMP inhibition and FGF signaling, we compared the temporal expression of the five earliest genes expressed in the neuroectoderm and determined their requirements for induction at the onset of neural plate formation in Xenopus. Our results demonstrate that the onset and peak of expression of the genes vary and that they have different regulatory requirements and are therefore unlikely to share a conserved neural induction regulatory module. Even though all require inhibition of BMP for expression, some also require FGF signaling; expression of the early-onset pan-neural genes sox2 and foxd5α requires FGF signaling while other early genes, sox3, geminin and zicr1 are induced by BMP inhibition alone.

Conclusions

We demonstrate that BMP inhibition and FGF signaling induce neural genes independently of each other. Together our data indicate that although the spatiotemporal expression patterns of early neural genes are similar, the mechanisms involved in their expression are distinct and there are different signaling requirements for the expression of each gene.
The mosquito Aedes aegypti has a large genome size and high transposable element load but contains a low proportion of transposon-specific piRNAs
Authors: Arensburger Peter , Hice Robert H , Wright Jennifer A , Craig Nancy L , Atkinson Peter W
Published: December 2011

Background

The piRNA pathway has been shown in model organisms to be involved in silencing of transposons thereby providing genome stability. In D. melanogaster the majority of piRNAs map to these sequences. The medically important mosquito species Aedes aegypti has a large genome size, a high transposon load which includes Miniature Inverted repeat Transposable Elements (MITES) and an expansion of the piRNA biogenesis genes. Studies of transgenic lines of Ae. aegypti have indicated that introduced transposons are poorly remobilized and we sought to explore the basis of this. We wished to analyze the piRNA profile of Ae. aegypti and thereby determine if it is responsible for transposon silencing in this mosquito.

Results

Estimated piRNA sequence diversity was comparable between Ae. aegypti and D. melanogaster, but surprisingly only 19% of mosquito piRNAs mapped to transposons compared to 51% for D. melanogaster. Ae. aegypti piRNA clusters made up a larger percentage of the total genome than those of D. melanogaster but did not contain significantly higher percentages of transposon derived sequences than other regions of the genome. Ae. aegypti contains a number of protein coding genes that may be sources of piRNA biogenesis with two, traffic jam and maelstrom, implicated in this process in model organisms. Several genes of viral origin were also targeted by piRNAs. Examination of six mosquito libraries that had previously been transformed with transposon derived sequence revealed that new piRNA sequences had been generated to the transformed sequences, suggesting that they may have stimulated a transposon inactivation mechanism.

Conclusions

Ae. aegypti has a large piRNA complement that maps to transposons but primarily gene sequences, including many viral-derived sequences. This, together the more uniform distribution of piRNA clusters throughout its genome, suggest that some aspects of the piRNA system differ between Ae. aegypti and D. melanogaster.
Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells
Authors: Eskew Jeffery D , Sadikot Takrima , Morales Pedro , Duren Alicia , Dunwiddie Irene , Swink Megan , Zhang Xiaoying , Hembruff Stacey , Donnelly Alison , Rajewski Roger A , Blagg Brian SJ , Manjarrez Jacob R , Matts Robert L , Holzbeierlein Jeffrey M , Vielhauer George A
Published: December 2011

Background

The molecular chaperone, heat shock protein 90 (Hsp90) has been shown to be overexpressed in a number of cancers, including prostate cancer, making it an important target for drug discovery. Unfortunately, results with N-terminal inhibitors from initial clinical trials have been disappointing, as toxicity and resistance resulting from induction of the heat shock response (HSR) has led to both scheduling and administration concerns. Therefore, Hsp90 inhibitors that do not induce the heat shock response represent a promising new direction for the treatment of prostate cancer. Herein, the development of a C-terminal Hsp90 inhibitor, KU174, is described, which demonstrates anti-cancer activity in prostate cancer cells in the absence of a HSR and describe a novel approach to characterize Hsp90 inhibition in cancer cells.

Methods

PC3-MM2 and LNCaP-LN3 cells were used in both direct and indirect in vitro Hsp90 inhibition assays (DARTS, Surface Plasmon Resonance, co-immunoprecipitation, luciferase, Western blot, anti-proliferative, cytotoxicity and size exclusion chromatography) to characterize the effects of KU174 in prostate cancer cells. Pilot in vivo efficacy studies were also conducted with KU174 in PC3-MM2 xenograft studies.

Results

KU174 exhibits robust anti-proliferative and cytotoxic activity along with client protein degradation and disruption of Hsp90 native complexes without induction of a HSR. Furthermore, KU174 demonstrates direct binding to the Hsp90 protein and Hsp90 complexes in cancer cells. In addition, in pilot in-vivo proof-of-concept studies KU174 demonstrates efficacy at 75 mg/kg in a PC3-MM2 rat tumor model.

Conclusions

Overall, these findings suggest C-terminal Hsp90 inhibitors have potential as therapeutic agents for the treatment of prostate cancer.
Production in yeast of pseudotype virus-like particles harboring functionally active antibody fragments neutralizing the cytolytic activity of vaginolysin
Authors: Pleckaityte Milda , Zvirbliene Aurelija , Sezaite Indre , Gedvilaite Alma
Published: December 2011

Background

Recombinant antibodies can be produced in different formats and different expression systems. Single chain variable fragments (scFvs) represent an attractive alternative to full-length antibodies and they can be easily produced in bacteria or yeast. However, the scFvs exhibit monovalent antigen-binding properties and short serum half-lives. The stability and avidity of the scFvs can be improved by their multimerization or fusion with IgG Fc domain. The aim of the current study was to investigate the possibilities to produce in yeast high-affinity scFv-Fc proteins neutralizing the cytolytic activity of vaginolysin (VLY), the main virulence factor ofGardnerella vaginalis.

Results

The scFv protein derived from hybridoma cell line producing high-affinity neutralizing antibodies against VLY was fused with human IgG1 Fc domain. Four different variants of anti-VLY scFv-Fc fusion proteins were constructed and produced in yeastSaccharomyces cerevisiae. The non-tagged scFv-Fc and hexahistidine-tagged scFv-Fc proteins were found predominantly as insoluble aggregates and therefore were not suitable for further purification and activity testing. The addition of yeast α-factor signal sequence did not support secretion of anti-VLY scFv-Fc but increased the amount of its intracellular soluble form. However, the purified protein showed a weak VLY-neutralizing capability. In contrast, the fusion of anti-VLY scFv-Fc molecules with hamster polyomavirus-derived VP2 protein and its co-expression with VP1 protein resulted in an effective production of pseudotype virus-like particles (VLPs) that exhibited strong VLY-binding activity. Recombinant scFv-Fc molecules displayed on the surface of VLPs neutralized VLY-mediated lysis of human erythrocytes and HeLa cells with high potency comparable to that of full-length antibody.

Conclusions

Recombinant scFv-Fc proteins were expressed in yeast with low efficiency. New approach to display the scFv-Fc molecules on the surface of pseudotype VLPs was successful and allowed generation of multivalent scFv-Fc proteins with high VLY-neutralizing potency. Our study demonstrated for the first time that large recombinant antibody molecule fused with hamster polyomavirus VP2 protein and co-expressed with VP1 protein in the form of pseudotype VLPs was properly folded and exhibited strong antigen-binding activity. The current study broadens the potential of recombinant VLPs as a highly efficient carrier for functionally active complex proteins.
Granulocyte colony-stimulating factor affects the distribution and clonality of TRGV and TRDV repertoire of T cells and graft-versus-host disease
Authors: Xuan Li , Wu Xiuli , Zhang Yu , Fan Zhiping , Ling Yiwen , Huang Fen , Zhang Fuhua , Zhai Xiao , Liu Qifa
Published: December 2011

Background

The immune modulatory effect of granulocyte colony-stimulating factor (G-CSF) on T cells resulted in an unexpected low incidence of graft-versus-host disease (GVHD) in allogeneic peripheral blood stem cell transplantation (allo-PBSCT). Recent data indicated that gamma delta+T cells might participate in mediating graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect after allogeneic hematopoietic stem cell transplantation. However, whether G-CSF could influence the T cell receptors (TCR) of gamma delta+T cells (TRGVandTRDVrepertoire) remains unclear. To further characterize this feature, we compared the distribution and clonality ofTRGVandTRDVrepertoire of T cells before and after G-CSF mobilization and investigated the association between the changes of TCR repertoire and GVHD in patients undergoing G-CSF mobilized allo-PBSCT.

Methods

The complementarity-determining region 3 (CDR3) sizes of threeTRGVand eightTRDVsubfamily genes were analyzed in peripheral blood mononuclear cells (PBMCs) from 20 donors before and after G-CSF mobilization, using RT-PCR and genescan technique. To determine the expression levels ofTRGVsubfamily genes, we performed quantitative analysis ofTRGVI~III subfamilies by real-time PCR.

Results

The expression levels of threeTRGVsubfamilies were significantly decreased after G-CSF mobilization (P= 0.015, 0.009 and 0.006, respectively). The pattern ofTRGVsubfamily expression levels wasTRGVII >TRGVI >TRGVIII before mobilization, and changed toTRGVI >TRGVII >TRGVIII after G-CSF mobilization. The expression frequencies ofTRGVandTRDVsubfamilies changed at different levels after G-CSF mobilization. MostTRGVandTRDVsubfamilies revealed polyclonality from pre-G-CSF-mobilized and G-CSF-mobilized samples. Oligoclonality was detected inTRGVandTRDVsubfamilies in 3 donors before mobilization and in another 4 donors after G-CSF mobilization, distributed inTRGVII,TRDV1,TRDV3 andTRDV6, respectively. Significant positive association was observed between the invariable clonality ofTRDV1 gene repertoire after G-CSF mobilization and low incidence of GVHD in recipients (P= 0.015,OR= 0.047).

Conclusions

G-CSF mobilization not only influences the distribution and expression levels ofTRGVandTRDVrepertoire, but also changes the clonality of gamma delta+T cells. This alteration ofTRGVandTRDVrepertoire might play a role in mediating GVHD in G-CSF mobilized allo-PBSCT.