bluuebunny/crossref_metadata_2025_split huggingface dataset:
Responsiveness of the VISA-P scale for patellar tendinopathy in athletes
Authors: Hernandez-Sanchez Sergio , Hidalgo Ma Dolores , Gomez Antonia 
Published: September 2012

BackgroundPatient-reported outcome measures are increasingly used in sports medicine to assess results after treatment, but interpretability of change for many instruments remains unclear.ObjectiveTo define the minimum clinically important difference (MCID) for the Victorian Institute of Sport Assessment scale (VISA-P) in athletes with patellar tendinopathy (PT) who underwent conservative treatment.MethodsNinety-eight athletes with PT were enrolled in the study. Each participant completed the VISA-P at admission, after 1 week, and at the final visit. Athletes also assessed their clinical change at discharge on a 15-point Likert scale. We equated important change with a score of ≥3 (somewhat better). Receiver-operating characteristic (ROC) curve analysis and mean change score were used to determine MCID. Minimal detectable change was calculated. The effect of baseline scores on MCID and different criteria used to define important change were investigated. A Bayesian analysis was used to establish the posterior probability of reporting clinical changes related to MCID value.ResultsAthletes with PT who showed an absolute change greater than 13 points in the VISA-P score or 15.4–27% of relative change achieved a minimal important change in their clinical status. This value depended on baseline scores. The probability of a clinical change in a patient was 98% when this threshold was achieved and 45% when MCID was not achieved.ConclusionsDefinition of the MCID will enhance the interpretability of changes in the VISA-P score in the athletes with PT, but caution is required when these values are used.
Disseminating results to clinical trial participants: a qualitative review of patient understanding in a post-trial population
Authors: Darbyshire Julie Lorraine , Price Hermione Clare 
Published: September 2012

ObjectiveTo identify the most appropriate format for results dissemination to maximise understanding of trial results.DesignQualitative.SettingOf the original 58 4-T trial centres, 34 agreed to take part in this ancillary research.ParticipantsAll participants from these centres were eligible. All 343 participants were sent questionnaires.Primary and secondary outcome measuresThe low response rate meant that we were unable to make any firm conclusions about the patients' preferred method of dissemination; however, we were able to comment on the level of understanding demonstrated by the trial participants.ResultsAll 40 (12%) returned questionnaires were received from 15 centres. We received no questionnaires from over half of the centres. The questionnaires which were returned demonstrated broad satisfaction with the results letter, general enthusiasm for the trial and a variable level of understanding of the results; however, there was a high proportion of responders who were not clear on why the research was undertaken or what the results meant.ConclusionsThe low response rate may be related to delays during the trial set-up process suggesting that interest in a study quickly wanes for both patients and centres. From this we deduce that rapid dissemination of results is needed if it is to have any impact at all. The responders are likely to reflect a biased cohort who were both enthusiastic about the research and who had a good experience during their 3 years in the 4-T trial. It is perhaps not surprising therefore that the overview is positive. That this population was still not fully informed about the purpose of the research would seem to confirm a low level of understanding among the general public which we suggest should be addressed during the consent process.
Using ‘amenable mortality’ as indicator of healthcare effectiveness in international comparisons: results of a validation study
Authors: Mackenbach Johan P , Hoffmann Rasmus , Khoshaba Bernadette , Plug Iris , Rey Grégoire , Westerling Ragnar , Pärna Kersti , Jougla Eric , Alfonso José , Looman Caspar , McKee Martin 
Published: September 2012

Background and study aimsThere is widespread consensus on the need for better indicators of the effectiveness of healthcare. We carried out an analysis of the validity of amenable mortality as an indicator of the effectiveness of healthcare, focusing on the potential use in routine surveillance systems of between-country variations in rates of mortality. We assessed whether the introduction of specific healthcare innovations coincided with declines in mortality from potentially amenable causes in seven European countries. In this paper, we summarise the main results of this study and illustrate them for four conditions.Data and methodsWe identified 14 conditions for which considerable declines in mortality have been observed and for which there is reasonable evidence in the literature of the effectiveness of healthcare interventions to lower mortality. We determined the time at which these interventions were introduced and assessed whether the innovations coincided with favourable changes in the mortality trends from these conditions, measured using Poisson linear spline regression. All the evidence was then presented to a Delphi panel.Main resultsThe timing of innovation and favourable change in mortality trends coincided for only a few conditions. Other reasons for mortality decline are likely to include diffusion and improved quality of interventions and in incidence of diseases and their risk factors, but there is insufficient evidence to differentiate these at present. For most conditions, a Delphi panel could not reach consensus on the role of current mortality levels as measures of effectiveness of healthcare.Discussion and conclusionsImprovements in healthcare probably lowered mortality from many of the conditions that we studied but occurred in a much more diffuse way than we assumed in the study design. Quantification of the contribution of healthcare to mortality requires adequate data on timing of innovation and trends in diffusion and quality and in incidence of disease, none of which are currently available. Given these gaps in knowledge, between-country differences in levels of mortality from amenable conditions should not be used for routine surveillance of healthcare performance. The timing and pace of mortality decline from amenable conditions may provide better indicators of healthcare performance.
Improving outcome in severe trauma: trauma systems and initial management—intubation, ventilation and resuscitation
Authors: Harris Tim , Davenport Ross , Hurst Tom , Jones Jonathan 
Published: September 2012

Abstract
Severe trauma is an increasing global problem mainly affecting fit and healthy younger adults. Improvements in the entire pathway of trauma care have led to improvements in outcome. Development of a regional trauma system based around a trauma centre is associated with a 15–50% reduction in mortality. Trauma teams led by senior doctors provide better care. Although intuitively advantageous, the involvement of doctors in the pre-hospital care of trauma patients currently lacks clear evidence of benefit. Poor airway management is consistently identified as a cause of avoidable morbidity and mortality. Rapid sequence induction/intubation is frequently indicated but the ideal drugs have yet to be identified. The benefits of cricoid pressure are not clear cut. Dogmas in the management of pneumothoraces have been challenged: chest x-ray has a role in the diagnosis of tension pneumothoraces, needle aspiration may be ineffective, and small pneumothoraces can be managed conservatively. Identification of significant haemorrhage can be difficult and specific early resuscitation goals are not easily definable. A hypotensive approach may limit further bleeding but could worsen significant brain injury. The ideal initial resuscitation fluid remains controversial. In appropriately selected patients early aggressive blood product resuscitation is beneficial. Hypothermia can exacerbate bleeding and the benefit in traumatic brain injury is not adequately studied for firm recommendations.
Laboratory evaluation on the high temperature rheological properties of rubber asphalt: a preliminary study
Authors: Wang Hainian , You Zhanping , Goh Shu Wei , Hao Peiwen , Huang Xiaoming 
Published: September 2012

Crumb rubber is the recycled rubber particle obtained from mechanical shearing or grinding scrap tires into small particle sizes less than 6.3 mm (or approximately 1/4”). The rheological properties of asphalt binder have an important effect on the field performance of asphalt mixtures and the long-term serviceability of asphalt pavement. The objective of this research is to evaluate the high temperature rheological performance of rubber asphalt binder based on the complex shear modulus (|G*|) and the phase angle (δ) values using the dynamic shear rheometer. Five rubber asphalt dosages at 0, 10, 15, 20, and 25% by weight of asphalt (Superpave PG 64-22), respectively, were used to modify asphalt binder; and three rubber particle meshes, 20#, 30#, and 40#, were utilized in this research. The |G*| at various temperatures and frequencies were tested on each sample, including original and short-term aging binder using the rolling thin-film over. The master curves of |G*|/sin(δ) for each type of rubber asphalt was generated to investigate its rheological properties over a broad range of temperatures and frequencies. Based on the testing results, it was found that the addition of crumb rubber significantly increases the |G*| of asphalt binder, which is desirable to potentially improve the anti-rutting performance of asphalt mixtures. It was also found that the addition of 10% mesh crumb rubbers bumps up the high temperature grade of asphalt, from PG64 to PG76 in this case. The master curve using the |G*|/sin(δ) of rubber asphalt shows a substantial improvement in rutting resistant at each testing temperature and loading frequency. However, it was noteworthy that the rutting resistance enhancement of crumb rubber was affected by the percentage of rubber used, the rubber particle size and its aging condition.
Loss of Heterozygosity at Tumor Suppressor Genes Detectable on Fractionated Circulating Cell-Free Tumor DNA as Indicator of Breast Cancer Progression
Authors: Schwarzenbach Heidi , Eichelser Corinna , Kropidlowski Jolanthe , Janni Wolfgang , Rack Brigitte , Pantel Klaus 
Published: September 2012

Abstract
Purpose: LOH on circulating DNA may provide tumor-specific information on breast cancer. As identification of LOH on cell-free DNA is impeded by the prevalence of wild type DNA in blood of cancer patients, we fractionated plasma DNA, and determined the diagnostic and prognostic value of both fractions.
Experimental design: Our cohort of 388 patients with primary breast cancer before chemotherapy was selected from a multicenter study (SUCCESS). Postoperative plasma was fractionated in low- and high-molecular weight DNA by two different column systems. In both fractions, LOH was determined by a PCR-based microsatellite analysis using a panel of 8 polymorphic markers. Circulating tumor DNA in plasma from 30 patients after chemotherapy was additionally analyzed. The significance levels were adjusted for multiple comparisons.
Results: More patients (38%) had LOH at all markers in the fraction containing short DNA fragments than in the fraction containing the long DNA molecules (28%, P = 0.0001). In both fractions 32.85% of LOH were concordant. LOH at the markers D3S1605, D10S1765, D12S1725, D13S218, and D17S855 significantly correlated with tumor stage, tumor size, and lymph node metastasis, positive progesterone, and HER2 receptor status. Most importantly, LOH at D12S1725 mapping to cyclin D2 correlated with shorter overall survival (P = 0.004).
Conclusions: The improved detection of LOH on cell-free DNA provides important information on DNA losses of tumor suppressor genes TIG1, PTEN, cyclin D2, RB1, and BRCA1 in breast cancer. In particular, loss of the cyclin D2 gene might become an important prognostic marker easily detectable in the peripheral blood. Clin Cancer Res; 18(20); 5719–30. ©2012 AACR.
Targeting the Inhibitor of Apoptosis Proteins as a Novel Therapeutic Strategy in Medulloblastoma
Authors: Keating Joanna , Tsoli Maria , Hallahan Andrew R. , Ingram Wendy J. , Haber Michelle , Ziegler David S. 
Published: September 2012

Abstract
Medulloblastoma is the most common malignant brain tumor of childhood. Novel therapeutic strategies are urgently needed to overcome cytotoxic resistance. We hypothesized that antiapoptotic signals contribute to resistance and that treatment with proapoptotic agents could increase the efficacy of conventional therapies. A PCR array was used to assess the status of the apoptotic signaling pathway in medulloblastoma cells after treatment with cytotoxic chemotherapy. Treatment with cisplatin led to the upregulation of antiapoptotic signals, including inhibitor of apoptosis proteins (IAP), in medulloblastoma cells. We subsequently investigated the synergistic effect of a small-molecule IAP inhibitor, LBW242, in combination with cisplatin and/or radiotherapy in three human medulloblastoma cell lines and 5 short term primary patient medulloblastoma cultures. The addition of LBW242 to chemotherapy resulted in significantly increased antitumor activity with a similar effect observed in combination with radiotherapy. Measurement of caspase-8 and -9 activity indicated that the synergy resulted from induction of both the intrinsic and extrinsic apoptotic pathways. Apoptosis was confirmed by Annexin V staining and activation of caspases 3/7. Xenograft models were used to evaluate the mechanism of action and efficacy in vivo. The combination therapy significantly reduced the tumor burden in a medulloblastoma xenograft model and TUNEL analysis in a medulloblastoma orthograft confirmed in vivo induction of apoptosis. These findings support the strategy of targeting IAPs in combination with cytotoxic therapy as a novel treatment strategy for patients with medulloblastoma. Mol Cancer Ther; 11(12); 2654–63. ©2012 AACR.
Inhibiting Aurora Kinases Reduces Tumor Growth and Suppresses Tumor Recurrence after Chemotherapy in Patient-Derived Triple-Negative Breast Cancer Xenografts
Authors: Romanelli Angela , Clark Anderson , Assayag Franck , Chateau-Joubert Sophie , Poupon Marie-France , Servely Jean-Luc , Fontaine Jean-Jacques , Liu Xiaohong , Spooner Edward , Goodstal Samantha , de Cremoux Patricia , Bièche Ivan , Decaudin Didier , Marangoni Elisabetta 
Published: September 2012

Abstract
Triple-negative breast cancers (TNBC) have an aggressive phenotype with a relatively high rate of recurrence and poor overall survival. To date, there is no approved targeted therapy for TNBCs. Aurora kinases act as regulators of mammalian cell division. They are important for cell-cycle progression and are frequently overexpressed or mutated in human tumors, including breast cancer. In this study, we investigated the therapeutic potential of targeting Aurora kinases in preclinical models of human breast cancers using a pan-inhibitor of Aurora kinases, AS703569. In vitro, AS703569 was tested in 15 human breast cancer cell lines. TNBC cell lines were more sensitive to AS703569 than were other types of breast cancer cells. Inhibition of proliferation was associated with cell-cycle arrest, aneuploidy, and apoptosis. In vivo, AS703569 administered alone significantly inhibited tumor growth in seven of 11 patient-derived breast cancer xenografts. Treatment with AS703569 was associated with a decrease of phospho-histone H3 expression. Finally, AS703569 combined to doxorubicin–cyclophosphamide significantly inhibited in vivo tumor recurrence, suggesting that Aurora kinase inhibitors could be used both in monotherapy and in combination settings. In conclusion, these data indicate that targeting Aurora kinases could represent a new effective approach for TNBC treatment. Mol Cancer Ther; 11(12); 2693–703. ©2012 AACR.
RSK2Ser227 at N-Terminal Kinase Domain Is a Potential Therapeutic Target for Multiple Myeloma
Authors: Shimura Yuji , Kuroda Junya , Ri Masaki , Nagoshi Hisao , Yamamoto-Sugitani Mio , Kobayashi Tsutomu , Kiyota Miki , Nakayama Ryuko , Mizutani Shinsuke , Chinen Yoshiaki , Sakamoto Natsumi , Matsumoto Yosuke , Horiike Shigeo , Shiotsu Yukimasa , Iida Shinsuke , Taniwaki Masafumi 
Published: September 2012

Abstract
Multiple myeloma is an entity of cytogenetically and genetically heterogenous plasma cell neoplasms. Despite recent improvement in the treatment outcome of multiple myeloma by novel molecular-targeted chemotherapeutics, multiple myeloma remains incurable. The identification of a therapeutic target molecule in which various signaling for cell-survival converge is a core component for the development of new therapeutic strategies against multiple myeloma. RSK2 is an essential mediator of the ERK1/2 signaling pathway for cell survival and proliferation. In this study, we discovered that RSK2Ser227, which is located at the N-terminal kinase domain and is one site responsible for substrate phosphorylation, is activated through phosphorylation regardless of the type of cytogenetic abnormalities or upstream molecular signaling in all 12 multiple myeloma–derived cell lines examined and 6 of 9 patient-derived CD138-positive primary myeloma cells. The chemical inhibition of RSK2Ser227 by BI-D1870 or gene knockdown of RSK2 inhibits myeloma cell proliferation through apoptosis induction, and this anti-myeloma effect was accompanied by downregulation of c-MYC, cyclin D, p21WAF1/CIP1, and MCL1. RSK2Ser227 inhibition resulting from BI-D1870 treatment restored lenalidomide-induced direct cytotoxicity of myeloma cells from interleukin-6–mediated cell protection, showed no cross-resistance to bortezomib, and exerted additive/synergistic antiproliferative effects in conjunction with the mTOR, histone deacetylase, and BH3-mimicking BCL2/BCLXL inhibitors. These results suggest that RSK2Ser227 is a potential therapeutic target not only for newly diagnosed but also for patients with later phase multiple myeloma who are resistant or refractory to currently available anti-myeloma therapies. Mol Cancer Ther; 11(12); 2600–9. ©2012 AACR.
Targeting KRAS-Mutant Non–Small Cell Lung Cancer with the Hsp90 Inhibitor Ganetespib
Authors: Acquaviva Jaime , Smith Donald L. , Sang Jim , Friedland Julie C. , He Suqin , Sequeira Manuel , Zhang Chaohua , Wada Yumiko , Proia David A. 
Published: September 2012

AbstractMutant KRAS is a feature of more than 25% of non–small cell lung cancers (NSCLC) and represents one of the most prevalent oncogenic drivers in this disease. NSCLC tumors with oncogenic KRAS respond poorly to current therapies, necessitating the pursuit of new treatment strategies. Targeted inhibition of the molecular chaperone Hsp90 results in the coordinated blockade of multiple oncogenic signaling pathways in tumor cells and has thus emerged as an attractive avenue for therapeutic intervention in human malignancies. Here, we examined the activity of ganetespib, a small-molecule inhibitor of Hsp90 currently in clinical trials for NSCLCs in a panel of lung cancer cell lines harboring a diverse spectrum of KRAS mutations. In vitro, ganetespib was potently cytotoxic in all lines, with concomitant destabilization of KRAS signaling effectors. Combinations of low-dose ganetespib with MEK or PI3K/mTOR inhibitors resulted in superior cytotoxic activity than single agents alone in a subset of mutant KRAS cells, and the antitumor efficacy of ganetespib was potentiated by cotreatment with the PI3K/mTOR inhibitor BEZ235 in A549 xenografts in vivo. At the molecular level, ganetespib suppressed activating feedback signaling loops that occurred in response to MEK and PI3K/mTOR inhibition, although this activity was not the sole determinant of combinatorial benefit. In addition, ganetespib sensitized mutant KRAS NSCLC cells to standard-of-care chemotherapeutics of the antimitotic, topoisomerase inhibitor, and alkylating agent classes. Taken together, these data underscore the promise of ganetespib as a single-agent or combination treatment in KRAS-driven lung tumors. Mol Cancer Ther; 11(12); 2633–43. ©2012 AACR.
Low-Flow Mediated Constriction is Endothelium-Dependent
Authors: Dawson Ellen A. , Alkarmi Amr , Thijssen Dick H.J. , Rathore Sudhir , Marsman Diane E. , Cable N. Timothy , Wright D. Jay , Green Daniel J. 
Published: September 2012

Background—
Radial artery catheterization is associated with endothelial denudation and impaired vasodilator function, while postcatheterization exercise training may enhance artery function. The impact of catheterization and subsequent exercise training on low-flow mediated vasoconstriction (L-FMC) has not previously been studied. The aim of this study was to examine whether radial artery L-FMC is impaired by catheterization and consequent endothelial denudation. A further aim was to examine the effect of local handgrip exercise training on radial artery L-FMC and flow-mediated dilation (FMD) after transradial catheterization.

Methods and Results—

Thirty-two subjects undergoing transradial catheterization underwent assessment of L-FMC and FMD in the catheterized and contralateral radial artery before, and the day after, catheterization. A further 18 patients were recruited and randomly assigned to either a 6-week handgrip exercise training program (N=9) or a nonexercise control period (N=9). L-FMC was attenuated 1 day postcatheterization in the catheterized arm (−2.07±0.84 to 0.35±0.83), but unchanged in the noncatheterized arm (−0.93±0.86 to −0.90±0.92;
P
<0.05). In the training study, both FMD and L-FMC of the catheterized arm were preserved in the exercise group 7 weeks after catheterization (FMD-pre, 6.84±0.79; FMD-post, 6.85±1.16; L-FMC-pre, −2.14±1.42; L-FMC-post, −3.58±1.04%), but reduced in the control group (FMD-pre, 8.27±1.52; FMD-post, 4.66±0.70;
P
=0.06; L-FMC-pre, −3.26±1.19; L-FMC-post, −1.34±1.27%;
P
<0.05).

Conclusions—
Catheterization, and associated endothelial denudation, decreases L-FMC in the radial artery, suggesting that it is endothelium-dependent. Moreover, we demonstrate for the first time that exercise training has beneficial impacts on radial artery vasodilator and constrictor function.
From Recording to Intervention
Authors: Piedras Pablo 
Published: September 2012

The study of Argentine social and political documentaries from 1956 to 1974 allows one to trace the crisis and discrediting of democracy that began in 1930 and intensified after 1955 with the overthrow of Juan Domingo Perón. The documentaries show the decline of legitimacy of the opposing political forces, the radicalization of the political actors involved, and the configuration and affirmation of antagonistic social subjects. Toward the end of the 1960s, this process led to an imaginary of revolution and violence that energized documentary practices and forms. Un análisis del documental social y político de la Argentina desde 1956 a 1974 permite reconocer la crisis y desacreditación de la democracia que comienza en 1930 y se intensifica luego de 1955 con el derrocamiento de Juan Domingo Perón. Los documentales demuestran el decline de la legitimidad de fuerzas políticas opositoras, la radicalización de los actores políticos involucrados, y la configuración y afirmación de sujetos sociales antagónicos. A fines de 1960, este proceso condujo a la construcción de un imaginario de revolución y violencia que transformó las formas y las prácticas del cine documental.