bluuebunny/crossref_metadata_2025_split huggingface dataset:
Measurement of In Vivo BCR-ABL Kinase Inhibition to Monitor Imatinib-Induced Target Blockade and Predict Response in Chronic Myeloid Leukemia
Authors: White Deborah , Saunders Verity , Grigg Andrew , Arthur Chris , Filshie Robin , Leahy Michael F. , Lynch Kevin , To L. Bik , Hughes Timothy 
Published: September 2007

Purpose Intrinsic sensitivity to imatinib, based on measurement of inhibitory concentration 50% for imatinib, is variable in untreated patients with chronic myeloid leukemia (CML). This suggests that patient-tailored dosing may be more rational than a fixed dose for all. Dose optimization potentially could be based on accurate measurement of the level of BCR-ABL kinase inhibition achieved in vivo. Patients and Methods In vivo kinase inhibition was measured by calculating the reduction in protein (p) -Crkl level in mononuclear blood cells taken from 49 CML patients at weekly intervals after imatinib therapy was commenced. Results Greater than 50% inhibition (> 50% reduction in p-Crkl from baseline) was achieved by 21% of patients by days 7 to 14 (and maintained in all patients on days 21 to 28) and an additional 24% of patients achieved more than 50% inhibition by days 21 to 28. Thus, overall 45% of patients achieved more than 50% inhibition. All of these patients achieved major molecular responses by 24 months compared with 56% of the patients who failed to achieve 50% kinase inhibition (P < .001). Patients with less than 50% kinase inhibition were also more likely to have suboptimal responses. Conclusion In vivo BCR-ABL kinase inhibition can be assessed in the first month of imatinib therapy and may provide a valuable guide to optimization of dosage. The extent of BCR-ABL kinase inhibition is an excellent predictor of cytogenetic and molecular response. These observations suggest that dose adjustment based on in vivo measurements of drug-induced target inhibition could be applied in settings beyond imatinib and may be a more effective approach than using one dose for all patients in targeted anticancer therapy.
Treatment-Specific Risks of Second Malignancies and Cardiovascular Disease in 5-Year Survivors of Testicular Cancer
Authors: van den Belt-Dusebout Alexandra W. , de Wit Ronald , Gietema Jourik A. , Horenblas Simon , Louwman Marieke W.J. , Ribot Jacques G. , Hoekstra Harald J. , Ouwens Gabey M. , Aleman Berthe M.P. , van Leeuwen Flora E. 
Published: September 2007

Purpose To compare radiotherapy and chemotherapy effects on long-term risks of second malignant neoplasms (SMNs) and cardiovascular diseases (CVDs) in testicular cancer (TC) survivors. Patients and Methods In our nationwide cohort comprising 2,707 5-year TC survivors, incidences of SMNs and CVDs were compared with general-population rates by calculating standardized incidence ratios (SIRs) and absolute excess risks (AERs). Treatment effects on risks of SMN and CVD were quantified in multivariable Cox regression and competing risks analyses. Results After a median follow-up time of 17.6 years, 270 TC survivors developed SMNs. The SIR of SMN overall was 1.7 (95% CI, 1.5 to 1.9), with an AER of 32.3 excess occurrences per 10,000 person-years. SMN risk was 2.6-fold (95% CI, 1.7- to 4.0-fold) increased after subdiaphragmatic radiotherapy and 2.1-fold (95% CI, 1.4- to 3.1-fold) increased after chemotherapy, compared with surgery only. Subdiaphragmatic radiotherapy increased the risk of a major late complication (SMN or CVD) 1.8-fold (95% CI, 1.3- to 2.4-fold), chemotherapy increased the risk of a major late complication 1.9-fold (95% CI, 1.4- to 2.5-fold), and smoking increased the risk of a major late complication 1.7-fold (95% CI, 1.4- to 2.1-fold), compared with surgery only. The median survival time was 1.4 years after SMN and 4.7 years after CVD. Conclusion Radiotherapy and chemotherapy increased the risk of developing SMN or CVD to a similar extent as smoking. Subdiaphragmatic radiotherapy strongly increases the risk of SMNs but not of CVD, whereas chemotherapy increases the risks of both SMNs and CVDs. Prolonged follow-up after chemotherapy is needed to reliably compare the late complications of radiotherapy and chemotherapy after 20 years.
Global Histone Modifications Predict Prognosis of Resected Non–Small-Cell Lung Cancer
Authors: Barlési Fabrice , Giaccone Giuseppe , Gallegos-Ruiz Marielle I. , Loundou Anderson , Span Simone W. , Lefesvre Pierre , Kruyt Frank A.E. , Rodriguez Jose Antonio 
Published: September 2007

Purpose Epigenetic modifications may contribute to the development and progression of cancer. We investigated whether epigenetic changes involving multiple histones influence prognosis of non–small-cell lung cancer (NSCLC) patients. Patients and Methods We used immunohistochemistry to assess histone 3 lysine 4 dimethylation (H3K4diMe), and acetylation of histone 2A lysine 5 (H2AK5Ac), histone 2B lysine 12, histone 3 lysine 9 (H3K9Ac), and histone 4 lysine 8 in resected tumor samples of 138 NSCLC patients. Data were analyzed using a recursive partitioning analysis (RPA). Results The RPA classified the patients into seven distinct prognostic groups based on TNM stage (first node), histology, and histone modifications: H3K4diMe (< or ≥ 85% tumor cells), H3K9Ac (< or ≥ 68% tumor cells), and H2AK5Ac (< or ≥ 5% tumor cells). The seven groups were associated with significantly different disease-free (P < .0001) and overall survival (P < .0001). Interestingly, the four groups determined by stage I patients (below the first node) displayed dramatic differences in survival (median, 10 months in adenocarcinoma patients with H3K9Ac ≥ 68% v 147 months in nonadenocarcinoma patients with H3K4diMe ≥ 85%). A Cox model retained age and RPA groups as the sole independent factors significantly influencing overall survival. Conclusion The prognostic influence of epigenetic changes involving multiple histones, in particular H2A and H3, is greater in early NSCLC, and evaluation of these changes may help in selecting early-stage NSCLC patients for adjuvant treatment. Our observations provide a rationale for the use of a combination of standard chemotherapy with drugs interacting with histone modifications, such as histone deacetylase inhibitors.
Nuclear Receptor TLX Regulates Cell Cycle Progression in Neural Stem Cells of the Developing Brain
Authors: Li Wenwu , Sun Guoqiang , Yang Su , Qu Qiuhao , Nakashima Kinichi , Shi Yanhong 
Published: September 2007

AbstractTLX is an orphan nuclear receptor that is expressed exclusively in vertebrate forebrains. Although TLX is known to be expressed in embryonic brains, the mechanism by which it influences neural development remains largely unknown. We show here that TLX is expressed specifically in periventricular neural stem cells in embryonic brains. Significant thinning of neocortex was observed in embryonic d 14.5 TLX-null brains with reduced nestin labeling and decreased cell proliferation in the germinal zone. Cell cycle analysis revealed both prolonged cell cycles and increased cell cycle exit in TLX-null embryonic brains. Increased expression of a cyclin-dependent kinase inhibitor p21 and decreased expression of cyclin D1 provide a molecular basis for the deficiency of cell cycle progression in embryonic brains of TLX-null mice. Furthermore, transient knockdown of TLX by in utero electroporation led to precocious cell cycle exit and differentiation of neural stem cells followed by outward migration. Together these results indicate that TLX plays an important role in neural development by regulating cell cycle progression and exit of neural stem cells in the developing brain.
Prediction of human pharmacokinetics—gut-wall metabolism
Authors: Fagerholm Urban 
Published: September 2007

AbstractIntestinal mucosal cells operate with different metabolic and transport activity, and not all of them are involved in drug absorption and metabolism. The fraction of these cells involved is dependent on the absorption characteristics of compounds and is difficult to predict (it is probably small). The cells also appear comparably impermeable. This shows a limited applicability of microsome intrinsic clearance (CLint)-data for prediction of gut-wall metabolism, and the difficulty to predict the gut-wall CL (CLGW) and extraction ratio (EGW). The objectives of this review were to evaluate determinants and methods for prediction of first-pass and systemic EGW and CLGW in man, and if required and possible, develop new simple prediction methodology. Animal gut-wall metabolism data do not appear reliable for scaling to man. In general, the systemic CLGW is low compared with the hepatic CL. For a moderately extracted CYP3A4-substrate with high permeability, midazolam, the gut-wall/hepatic CL-ratio is only 1/35. This suggests (as a general rule) that systemic CLGW can be neglected when predicting the total CL. First-pass EGW could be of importance, especially for substrates of CYP3A4 and conjugating enzymes. For several reasons, including those presented above and that blood flow based models are not applicable in the absorptive direction, it seems poorly predicted with available methodology. Prediction errors are large (several-fold on average; maximum-15-fold). A new simple first-pass EGW-prediction method that compensates for regional and local differences in absorption and metabolic activity has been developed. It has been based on human cell in-vitro CLint and fractional absorption from the small intestine for reference (including verapamil) and test substances, and in-vivo first-pass EGW-data for reference substances. First-pass EGW-values for CYP3A4-substrates with various degrees of gastrointestinal uptake and CLint and a CYP2D6-substrate were well-predicted (negligible errors). More high quality in-vitro CLint- and in-vivo EGW-data are required for further validation of the method.
In-vitro controlled release of doxorubicin from silica xerogels
Authors: Prokopowicz Magdalena 
Published: September 2007

Abstract
This study aimed at the development of a novel silica xerogel matrix as a delivery tool for an anti-cancer drug. Doxorubicin was incorporated as a hydrochloride salt during hydrolysis and polycondensation of tetraethylorthosilicate (TEOS) in the sol-gel process. The effect of sol-gel synthesis parameters (drug concentration, size of the device and lyophilizing process) on the release rate of the drug were investigated. In addition, dissolution rate, as well as weight loss of silica xerogel, was evaluated. In general, both the lyophilizing process of xerogels and the increase in size of non-lyophilizing device significantly decrease both the rate of drug release and the rate of dissolution of matrix. The overall release process was found to be governed by diffusion control and simultaneous zero-order dissolution of the xerogel.
Is bicarbonate buffer suitable as a dissolution medium?
Authors: Boni Julia Elisabeth , Brickl Rolf Stefan , Dressman Jennifer 
Published: September 2007

Abstract
The objectives of this study were to compare two methods for the preparation of bicarbonate buffer, and to compare media prepared with bicarbonate buffer with commonly used biorelevant and pharmacopoeial media in terms of their suitability for dissolution testing. The various media were compared with regard to ease of preparation, robustness and reproducibility of composition. The dissolution of three formulations of a typical Biopharmaceutical Classification System Class II drug (BIXX) was compared in bicarbonate buffer, standard phosphate buffer, a biorelevant buffer (fasted-state simulating intestinal fluid, FaSSIF) and a modified FaSSIF prepared with bicarbonate buffer. The bicarbonate buffer used for dissolution testing was produced by supplying carbon dioxide to a saline solution (0.9% NaCl, to which 12 or 42 mmol NaOH had been added). The bicarbonate buffer had to be prepared in-situ, which proved to be time-consuming, and the pH stability of the bicarbonate buffer could only be maintained under constant CO2 supply. To minimize the mechanical stress caused by inflow and evaporation of gas, the carbon dioxide was supplied above the medium during the dissolution test. Despite taking these measures, use of bicarbonate buffer led to less reproducible dissolution results than the phosphate buffers commonly used to prepare compendial media and FaSSIF, with coefficient of variance values 1.5- to 5-times higher in bicarbonate buffer. It was concluded that although a bicarbonate buffer system would be physiologically relevant for the fasted state in the small intestine, its suitability for dissolution testing is restricted by lack of practicability and poor reproducibility of results.
3-[(aryl)(4-fluorobenzyloxy)methyl]piperidine derivatives: high-affinity ligands for the serotonin transporter
Authors: Nencetti Susanna , Demontis Gian Carlo , Mazzoni Maria Rosa , Betti Laura , Banti Irene , Rossello Armando , Lapucci Annalina 
Published: September 2007

Abstract
The structural requirements for high-affinity binding at the serotonin transporter (SERT) have been investigated through the preparation of some 3-[(aryl)(4-fluorobenzyloxy)methyl]piperidine derivatives. The affinity of synthesised piperidinic compounds (1–4) at the SERT was evaluated by displacement of [3H]-paroxetine binding. Derived inhibition constant (Ki) values were in the same order of magnitude as that of fluoxetine, ranging between 2 and 400 nm. To better define the profiles of these compounds as potential antidepressants, binding affinity for 5-HT1A receptors and α2-adrenoceptors was also investigated by competition experiments using [3H]8-hydroxy-2-(dipropylamino)tetralin ([3H]8-OH-DPAT) and [3H]rauwolscine as radiolabelled ligands, respectively. Inhibition data indicate that compounds 1–4 possess a very weak affinity for these receptors. The high affinity of compound 1 for SERT indicates that it is worth investigating further.
The responses of extrinsic fibroblasts infiltrating the devitalised patellar tendon to IL-1β are different from those of normal tendon fibroblasts
Authors: Tohyama H. , Yasuda K. , Uchida H. , Nishihira J. 
Published: September 2007

In order to clarify the role of cytokines in the remodelling of the grafted tendon for ligament reconstruction we compared the responses to interleukin (IL)-1β, platelet-derived growth factor (PDGF)-BB and transforming growth factor (TGF)-β1 of extrinsic fibroblasts infiltrating the frozen-thawed patellar tendon in rats with that of the normal tendon fibroblasts, in regard to the gene expression of matrix metalloproteinase (MMP)-13, using Northern blot analysis. We also examined, immunohistologically, the local expression of IL-1β, PDGF-BB, and TGF-β1 in fibroblasts infiltrating the frozen-thawed patellar tendon. Northern blot analysis showed that fibroblasts derived from the patellar tendon six weeks after the freeze-thaw procedure in situ showed less response to IL-1β than normal tendon fibroblasts with respect to MMP-13 mRNA gene expression. The immunohistological findings revealed that IL-1β was over-expressed in extrinsic fibroblasts which infiltrated the patellar tendon two and six weeks after the freeze-thaw procedure in situ, but neither PDGF-BB nor TGF-β1 was over-expressed in these extrinsic fibroblasts. Our findings indicated that IL-1β had a close relationship to matrix remodelling of the grafted tendon for ligament reconstruction, in addition to the commencement of inflammation during the tissue-healing process.
Pain relief and functional results after resection arthroplasty of the shoulder
Authors: Rispoli D. M. , Sperling J. W. , Athwal G. S. , Schleck C. D. , Cofield R. H. 
Published: September 2007

We have examined the relief from pain and the functional outcome in 18 patients who underwent resection arthroplasty of the shoulder as a salvage operation between 1988 and 2002. The indications included failed shoulder replacement in 17, with infection in 13, and chronic septic arthritis in one. The mean follow-up was 8.3 years (2.5 to 16.6). Two intra-operative fractures of the humerus occurred, both of which healed. The level of pain was significantly decreased (t-test, p < 0.001) but five patients continued to have moderate to severe pain. The mean active elevation was 70° (0° to 150°) postoperatively and represented an improvement from 39° (0° to 140°) (t-test, p = 0.003), but internal and external rotation were hardly changed. The mean number of positive answers on the 12-question Simple Shoulder Test was 3.1 (0 to 12) but the shoulder was generally comfortable when the arm was positioned at rest by the side. The mean post-operative American Shoulder and Elbow Surgeon’s score was 36 (8 to 73). Despite applying this procedure principally to failed shoulder replacements, the results were similar to those reported in the literature for patients after severe fracture-dislocation. Reduction of pain is possible in one half to two-thirds of patients. The outcome of this operation in providing relief from pain cannot be guaranteed, but the shoulder is usually comfortable at rest, albeit with profound functional limitations.
Implementing Strategy: the politics of healthcare commissioning
Authors: North Nancy 
Published: September 2007

English
The purchaser-provider division in the National Health Service was intended to enable informed purchasers – general practitioner (GP) fundholders and district health authorities (DHAs) – to improve the cost-efficiency and quality of healthcare provision. Competition, or the threat of it, would encourage compliance from hospital and community trusts which previously had been protected by routinely provided resources. Although much attention has been given to the performance of GP fund holders, rather less interest has been paid to the activities of DHAs, whose task is qualitatively and quantitatively different from that of our GP purchasers. Drawing on research undertaken over a 15-month period, this article analyses a DHA’s attempts to implement a purchasing strategy. It uncovers several factors contributing to the strategy’s slow progress and concludes that factors constrained the DHA’s ability to achieve strategic changes in an important service area.
Evaluating Quality in Mental Health Services: contexts and issues
Authors: Shaw Ian 
Published: September 2007

English
Quality in healthcare services is neither a simple nor an apolitical issue. Quality is a complex concept and how it is defined and measured has important consequences for services. This article explores some of the issues which arise when the notions of ‘quality’ and ‘mental health’ are discussed together. Mental health services contribute to the regulation and maintenance of social order. The article particularly focuses upon the changing role of service users in quality assurance methods and argues for a new approach.
Mental Health Policy: making gender and ethnicity visible
Authors: Busfied Joan 
Published: September 2007

English
The implications of two major twentieth century changes in mental health policy are explored in relation to gender and ethnicity. The most visible change has been a shift in the dominant focus of service provision away from the asylum towards a diverse range of services loosely defined as community care. This shift has been associated with a second change: the expansion of services dealing with less severe forms of mental disorder such as depression and anxiety – a terrain where women tend to be more heavily represented both as patients and as service providers. At the same time inpatient care is increasingly focused on those with severe problems, especially persons considered dangerous – a population where men and those from certain ethnic groups tend to be over-represented.
United States Mental Health Policy in the 1990s: an era of cost-effectiveness, research and consumerism
Authors: Salzer Mark S. 
Published: September 2007

English
This article reviews three forces that currently influence US mental health policy: cost-effectiveness, mental health services research and consumerism. Rising mental health care costs, managed care cost-containment strategies, and concerns about the quality of services all influence the emphasis on cost-effectiveness by mental health service policy makers. The emphasis on cost-effectiveness co-occurs within the larger zeitgeist of data-driven policy making. Appropriations for mental health services research are a major funding priority. Finally, the concerns and perspectives of mental health consumers are more frequently voiced and heard, and are influencing service delivery concepts and how services are evaluated.
Therapeutic Communities in Prisons
Authors: Rawlings Barbara 
Published: September 2007

English
This review of research into prison therapeutic communities (TCs) covers democratic TCs, which treat personality disorders, and hierachical TCs, which treat drug abusers. The article outlines the history and establishment of TCs in Britain, USA, Canada and Europe and also describes typical TC treatment regimes and examines research into treatment outcome. It highlights the fact that outcome research rests mainly on reconviction and recidivism figures, despite criticisms of these as measures. Research shows that TCs can reduce offending and a relationship between length of time in therapy and positive outcome as been a consistent finding. However, TCs are established sparingly in prisons and historically have been relatively short-lived.
Whose lives and whose learning? Whose narratives and whose writing? Taking the next research and literature steps with experts by experience
Authors: Preston-Shoot Michael 
Published: September 2007

English
This article reviews the barriers that impact on the involvement of ‘experts by experience’ in research and in publishing. It charts how their views are generally reported through others and how their roles are often limited to particular aspects of the research process. Drawing on work within several research and social work education projects, and journal editorship, the article also explores practices that contribute to further change in the relationships surrounding knowledge production and dissemination, extending the involvement of experts by experience and embedding it more securely in research practice and in academic and professional publishing.
Gradations of Researchers’ Obligation to Provide Ancillary Care for HIV/AIDS in Developing Countries
Authors: Richardson Henry S. 
Published: September 2007

Three principal factors affect the stringency of medical researchers’ obligation to provide antiretroviral treatment to participants in non-HIV/AIDS studies that are conducted in developing countries: (1) the centrality of HIV/AIDS to the study design, (2) the extent of the researcher–participant interaction, and (3) the cost relative to the study budget. I provide a basis for assessing the comparative stringency of the researchers’ obligation to provide this type of ancillary care. Practically, given the range of possible responses to study participants’ needs, calibrating the researcher’s responsibility to provide ancillary care is a useful step in ethical analysis. Theoretically, a gradation of obligation suggests how research ethics committees or institutional review boards can take multiple, potentially conflicting ethical factors into account without undertaking spurious efforts to quantify their importance.