bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrated analysis of preclinical data to support the design of the first in man study of LY2181308, a second generation antisense oligonucleotide
Authors: Callies Sophie , André Valérie , Patel Bharvin , Waters David , Francis Paul , Burgess Michael , Lahn Michael 
Published: October 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The plasma pharmacokinetics (PK) of second generation antisense oligonucleotides (ASOs) are fairly well understood with well conserved pharmacokinetic properties across species, moderate clearance and extensive volume of distribution. WHAT THIS STUDY ADDS • The tissue distribution and exposure and the pharmacodynamic (PD) or target inhibition following ASO administration are not yet well understood leading to still fairly empiric early clinical development strategies. This paper illustrates how preclinical PK and PD data were used to predict more accurately the ASO tissue exposure in humans and to support the early clinical development strategy.AIMS To predict the concentration and target inhibition profiles of the survivin inhibitor antisense oligonucleotide LY2181308 in humans.METHODS An indirect pharmacokinetic/pharmacodynamic (PK/PD) model was built to predict the inhibition of survivin mRNA and protein in humans following LY2181308 dosing. Plasma and tissue PK data from cynomolgus monkeys were analyzed by non‐linear mixed effect modelling techniques. Human PK parameters were predicted using allometric scaling. Assumptions about the pharmacodynamic parameters were made based upon the target and tumour growth inhibition data from mouse xenograft models. This enabled the prediction of the clinical PK/PD profiles.RESULTS Following a 750 mg dose, LY2181308 tumour concentrations ranging from 18.8 to 54 µg g−1 were predicted to lead to 50 to 90% target inhibition. In humans, LY2181308 tumour concentrations from 13.9 to 52.8 µg g−1 (n = 4, LY2181308 750 mg) were observed associated with a median survivin mRNA and protein inhibition of 20% ± 34 (SD) (n = 9) and 23% ± 63 (SD) (n = 10), respectively. The human PK parameters were adequately estimated: central Vd, 4.09 l (90% CI, 3.6, 4.95), distribution clearances, 2.54 (2.36, 2.71), 0.0608 (0.033, 0.6) and 1.67 (1.07, 2.00) l h−1, peripheral Vds, 25 900 (19 070, 37 200), 0.936 (0.745, 2.07) and 2.51 (1.01, 2.922) l, mean elimination clearance 23.1 l h−1 (5.6, 33.4) and mean terminal half‐life, 32.7 days (range 22–52 days).CONCLUSION The model reasonably predicted LY2181308 PK in humans. Overall, the integration of preclinical PK/PD data enabled to appropriately predict dose and dosing regimen of LY2181308 in humans with pharmacologically relevant survivin inhibition achieved at 750 mg.
Population pharmacokinetic model and Bayesian estimator for two tacrolimus formulations – twice daily Prograf® and once daily Advagraf®
Authors: Woillard Jean‐Baptiste , de Winter Brenda C. M. , Kamar Nassim , Marquet Pierre , Rostaing Lionel , Rousseau Annick 
Published: October 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Tacrolimus is an immunosuppressant agent, largely used in kidney transplantation, with a narrow therapeutic range.• Therapeutic drug monitoring of tacrolimus exposure improves the efficacy and toxicity of this drug.• Separated Bayesian estimators have been developed to estimate tacrolimus exposure following administration of Prograf® and the prolonged release formulation Advagraf®. WHAT THIS STUDY ADDS • A population model was developed to compare the pharmacokinetics of 32 patients treated with Prograf® and 41 treated with Advagraf®.• A mixture model and a model using formulation as covariates were developed to describe the bimodal distribution in the absorption rate following Advagraf® administration. Comparison of these two models showed that the nonmixture model was adequate.• A single Bayesian estimator was developed to estimate the exposure for both formulations, which is more suitable for clinical practice.AIM To investigate the differences in the pharmacokinetics of Prograf® and the prolonged release formulation Advagraf® and to develop a Bayesian estimator to estimate tacrolimus inter‐dose area under the curve (AUC) in renal transplant patients receiving either Prograf® or Advagraf®.METHODS Tacrolimus concentration–time profiles were collected, in adult renal transplant recipients, at weeks 1 and 2, and at months 1, 3 and 6 post‐transplantation from 32 Prograf® treated patients, and one profile was collected from 41 Advagraf® patients more than 12 months post‐transplantation. Population pharmacokinetic (popPK) parameters were estimated using nonmem®. In a second step, the popPK model was used to develop a single Bayesian estimator for the two tacrolimus formulations.RESULTS A two‐compartment model with Erlang absorption (n= 3) and first‐order elimination best described the data. In Advagraf® patients, a bimodal distribution was observed for the absorption rate constant (Ktr): one group with a Ktr similar to that of Prograf® treated patients and the other group with a slower absorption. A mixture model for Ktr was tested to describe this bimodal distribution. However, the data were best described by the nonmixture model including covariates (cytochrome P450 3A5, haematocrit and drug formulation). Using this model and tacrolimus concentrations measured at 0, 1 and 3 h post‐dose, the Bayesian estimator could estimate tacrolimus AUC accurately (bias = 0.1%) and with good precision (8.6%).CONCLUSIONS The single Bayesian estimator developed yields good predictive performance for estimation of individual tacrolimus inter‐dose AUC in Prograf® and Advagraf® treated patients and is suitable for clinical practice.
Equilibrative nucleoside transporter 1 genotype, cytidine deaminase activity and age predict gemcitabine plasma clearance in patients with solid tumours
Authors: Gusella Milena , Pasini Felice , Bolzonella Caterina , Meneghetti Silvia , Barile Carmen , Bononi Antonio , Toso Silvia , Menon Daniela , Crepaldi Giorgio , Modena Yasmina , Stievano Laura , Padrini Roberto 
Published: October 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Gemcitacine is taken up by the cell through various nucleoside transporters of either the concentrative (CNT) or equilibrative type (ENT) and is then transformed into the inactive metabolite, dFdU, by cytidine deaminase (CDA) and into the active metabolite, dFdCMP, by deoxycytidine kinase (dCK).• While the major contribution of CDA to gemcitabine elimination is well recognized no data about the role of CNT and ENT activities have yet been reported. Both nucleoside transporters exhibit genetic polymorphisms characterized by different expression levels or nucleoside affinity. WHAT THIS STUDY ADDS • The plasma clearance (CL) of gemcitabine has been determined following the standard 30 min infusion of 1000–1250 mg m−2. The in vivo CDA activity was measured as end of infusion metabolic ratio (MR = dFdU : gembitabine) and the variant hCNT‐1 and hENT‐1 alleles were genotyped.• Our results confirmed that gemcitabine CL is directly correlated with CDA activity and inversely correlated with age and, for the first time, show that patients heterozygous for the –706 G > C hENT‐1 mutation have a lower CL as compared with wild type patients.AIM Gemcitabine (GEM) enters normal and tumour cells via concentrative (CNT) and equilibrative nucleoside transporters (ENT) and is subsequently deaminated to the inactive difluorodeoxyurine (dFdU) by cytidine deaminase (CDA). The aim of our study was to ascertain whether the nucleoside transporter genotype and the CDA activity phenotype can predict total GEM plasma clearance.METHODS Forty‐seven patients received GEM 1000–1250 mg m−2 i.v. over 30 min. Plasma concentrations of GEM and dFdU were measured and individual pharmacokinetic profiles were determined. CDA activity was measured ex vivo in plasma samples. The two most common hENT1 and hCNT1 polymorphisms were determined from genomic DNA.RESULTS Multivariate analysis revealed that GEM plasma clearance (CL) was positively correlated with the end of infusion dFdU : GEM ratio (P < 0.0001), which is a marker of in vivo CDA activity. The ENT1 genotype characterized by high transport capacity (G/G) and age were inversely correlated with CL (P= 0.027 and 0.048, respectively). A strong correlation was found between end of infusion GEM concentration and area under the concentration–time curve from time 0 to infinity (AUC(0,∞)) (r2= 0.77).CONCLUSIONS Our results confirm the role of CDA and age on the interindividual variability of GEM CL and show the contribution of the hENT1 genotype for the first time.
Normal red blood cells partially decrease diepoxybutane‐induced chromosome breakage in cultured lymphocytes from Fanconi anaemia patients
Authors: Porto B. , Sousa R. , Malheiro I. , Gaspar J. , Rueff J. , Gonçalves C. , Barbot J. 
Published: October 2010

AbstractObjectives:  Fanconi anaemia (FA) is a cancer‐prone chromosome instability syndrome characterized by hypersensitivity to DNA cross‐linking agents, such as diepoxybutane (DEB). Previous studies have shown that normal red blood cells (RBC) can protect cultured lymphocytes against chromosomal breaks induced by DEB. The present study was designed to analyse influence of RBCs from normal individuals on frequency of DEB‐induced chromosome breaks in lymphocyte cultures from FA patients.Materials and methods:  A comparative study was performed between DEB‐induced chromosome breaks in cultures of FA lymphocytes with either autologous or heterologous RBCs. A further comparative study was carried out between whole blood cultures from FA patients performed on two occasions, before and 1 week after transfusion of RBCs.Results:  It was observed that normal RBCs compared to FA RBCs, partially reduced chromosome breaks in cultured FA lymphocytes. A significant reduction in DEB‐induced breaks was also observed in FA cultured lymphocytes obtained 1 week after transfusion of RBCs, in comparison to those observed in the same patients before RBC transfusion.Conclusions:  This study shows that DEB‐induced chromosome instability in FA lymphocytes is partially reduced by normal RBCs. This effect may have some clinical relevance in vivo, whenever FA patients receive a RBC transfusion.
Chromatin‐bound PCNA as S‐phase marker in mononuclear blood cells of patients with acute lymphoblastic leukaemia or multiple myeloma
Authors: Zölzer F. , Basu O. , Devi P. U. , Mohanty S. P. , Streffer C. 
Published: October 2010

AbstractObjectives:  Proliferating cell nuclear antigen (PCNA) has often been used as a marker to aid assessment of tumour growth fraction. This paper addresses the question of whether it can be used as an S‐phase marker, when the non‐chromatin‐bound form of the protein is removed by pepsin treatment.Materials and methods:  Cytofluorometric measurements were carried out after immunofluorescence staining of PCNA and counterstaining of DNA. S‐phase fraction was determined with the help of windows on PCNA versus DNA scattergrams, or mathematically from DNA histograms.Results:  S‐phase fractions obtained using the two methods correlated well, but did not always agree, exact discrepancies depending on the mathematical model used for histogram analysis.Conclusions:  Determination of S‐phase fractions with the help of PCNA immunofluorescence staining is possible, and probably more reliable than calculation of S‐fractions from DNA histograms. It thus offers an alternative to assays involving BrdU labelling in vivo.
Experimental analysis and modelling ofin vitroHUVECs proliferation in the presence of various types of drugs
Authors: Mancuso L. , Scanu M. , Pisu M. , Concas A. , Cao G. 
Published: October 2010

AbstractObjectives: This study focuses on experimental analysis and corresponding mathematical simulation ofin vitroHUVECs (human umbilical vein endothelial cells) proliferation in the presence of various types of drugs.Materials and methods: HUVECs, once seeded in Petri dishes, were expanded to confluence. Temporal profiles of total count obtained by classic haemocytometry and cell size distribution measured using an electronic Coulter counter, are quantitatively simulated by a suitable model based on the population balance approach. Influence of drugs on cell proliferation is also properly simulated by accounting for suitable kinetic equations.Results and discussion: The models’ parameters have been determined by comparison with experimental data related to cell population expansion and cell size distribution in the absence of drugs. Inhibition constant for each type of drug has been estimated by comparing the experimental data with model results concerning temporal profiles of total cell count. The reliability of the model and its predictive capability have been tested by simulating cell size distribution for experiments performed in the presence of drugs. The proposed model will be useful in interpreting effects of selected drugs on expansion of readily available human cells.
Ectosomes as modulators of inflammation and immunity
Authors: Sadallah S , Eken C , Schifferli J A 
Published: October 2010

SummaryVesicles released by cells have been described using various names, including exosomes, microparticles, microvesicles and ectosomes. Here we propose to differentiate clearly between ectosomes and exosomes according to their formation and release. Whereas exosomes are formed in multi-vesicular bodies, ectosomes are vesicles budding directly from the cell surface. Depending upon the proteins expressed, exosomes activate or inhibit the immune system. One of the major properties of exosomes released by antigen-presenting cells is to induce antigen-specific T cell activation. Thus, they have been used for tumour immunotherapy. By contrast, the major characteristics of ectosomes released by various cells, including tumour cells, polymorphonuclear leucocytes and erythrocytes, are the expression of phosphatidylserine and to have anti-inflammatory/immunosuppressive activities similarly to apoptotic cells.
Intercellular adhesion molecule-1 on synovial cells attenuated interleukin-6-induced inhibition of osteoclastogenesis induced by receptor activator for nuclear factor κB ligand
Authors: Suzuki M , Hashizume M , Yoshida H , Shiina M , Mihara M 
Published: October 2010

Summary
In a co-culture of osteoclast precursor cells and synovial cells, interleukin-6 (IL-6) induces osteoclast formation. In contrast, in a monoculture of osteoclast precursor cells, IL-6 directly suppresses receptor activator for nuclear factor κB ligand (RANKL)-induced differentiation of osteoclast precursor cells into osteoclasts. In the present study, we explored why the effect of IL-6 differed between the monoculture and the co-culture systems. In the monoculture, mouse osteoclast precursor cell line, RAW 264·7 (RAW) cells were cultured with soluble RANKL (sRANKL) for 24 h or 3 days. sRANKL increased both expression of osteoclastogenesis marker, tartrate-resistant acid phosphatase isoform 5b (TRAP5b) and nuclear factor of activated T cells cytoplasmic 1 (NFATc1), whereas the co-addition of IL-6 decreased them both in a dose-dependent manner. In the co-culture, RAW cells and human synovial cell line, SW982 cells were cultured with IL-6 + soluble IL-6 receptor (sIL-6R) for 3 days. TRAP5b and NFATc1 expression reduced by IL-6 was increased by the addition of SW982 cells in a manner dependent upon the number of added cells. IL-6 + sIL-6R treatment significantly induced RANKL production in SW982 cells, and anti-RANKL antibody inhibited IL-6 + sIL-6R-induced osteoclastogenesis. SW982 cells expressed high levels of ICAM-1 originally, and ICAM-1 expression was increased significantly by IL-6 + sIL-6R. Anti-ICAM-1 antibody suppressed IL-6-induced osteoclastogenesis. Finally, in the monoculture system, addition of sICAM-1 dose-dependently restored the expression of TRAP5b reduced by IL-6. Similar results were obtained when the formation of TRAP-positive multi-nuclear cells were examined using mouse bone marrow cells. In conclusion, IL-6 gave different results in the co-culture and monoculture systems because in the co-culture, ICAM-1 from the synovial cells restored osteoclastogenesis suppressed by IL-6.
Reduced levels of both circulating CD4+CD25+CD127low/neg and CD4+CD8neg invariant natural killer regulatory T cells in stable heart transplant recipients
Authors: Chen M , Mohtize M , Matteï M-F , Villemot J-P , Kohler C , Faure G C , Béné M C , De Carvalho Bittencourt M 
Published: October 2010

Summary
A cross-regulation between two regulatory T cell (Treg) subsets [CD4+CD25+ and invariant natural killer (NK) T – iNK T] has been described to be important for allograft tolerance induction. However, few studies have evaluated these cellular subsets in stable recipients as correlates of favourable clinical outcome after heart transplantation. Treg and iNK T cell levels were assayed by flow cytometry in peripheral blood samples from 44 heart transplant recipients at a 2-year interval in 38 patients, and related to clinical outcome. Multi-parameter flow cytometry used CD4/CD25/CD127 labelling to best identify Treg, and a standard CD3/CD4/CD8/Vα24/Vβ11 labelling strategy to appreciate the proportions of iNK T cells. Both subtypes of potentially tolerogenic cells were found to be decreased in stable heart transplant recipients, with similar or further decreased levels after 2 years. Interestingly, the patient who presented with several rejection-suggesting incidents over this period displayed a greater than twofold increase of both cell subsets. These results suggest that CD4+CD25+CD127low/neg Treg and iNK T cells could be involved in the local control of organ rejection, by modulating immune responses in situ, in clinically stable patients. The measurement of these cell subsets in peripheral blood could be useful for non-invasive monitoring of heart transplant recipients, especially in the growing context of tolerance-induction trials.
Utilizing spiral computerized tomography during the removal of a fractured endodontic instrument lying beyond the apical foramen
Authors: Wang H. , Ni L. , Yu C. , Shi L. , Qin R. 
Published: October 2010

Wang H, Ni L, Yu C, Shi L, Qin R. Utilizing spiral computerized tomography during the removal of a fractured endodontic instrument lying beyond the apical foramen. International Endodontic Journal, 43, 1143–1151, 2010.AbstractAim  To present a case that used spiral computerized tomography (CT) to locate and successfully remove a fractured endodontic instrument lying beyond the apical foramen using a surgical approach.Summary  The fracture of an endodontic instrument beyond the apical foramen is rare. In this case report, after an attempt to remove a fractured instrument failed, a multi‐slice spiral computerized tomography (MSCT) was used for diagnosis and treatment planning. The fractured segment was precisely located and found in the soft tissue and successfully removed by surgery. For the successful removal of a fractured endodontic instrument beyond the apical foramen, the following are necessary: (i) knowledge of the cause of fracture and how to plan treatment; (ii) determining the precise location of the fractured segment using CT; and 3) skilful operation.Key learning points

Fractured endodontic instruments might lie within the soft tissue.
Computerized tomography is an effective diagnostic aid for localizing the precise position of fractured instruments.
An evaluation of a mental health screening and referral pathway for community nursing care: nurses’ and general practitioners’ perspectives
Authors: Annells Merilyn , Allen Jacqui , Nunn Russell , Lang Lyn , Petrie Eileen , Clark Eileen , Robins Alan 
Published: October 2010

Aims and objectives.  To evaluate a feasible, best practice mental health screening and referral clinical pathway for generalist community nursing care of war veterans and war widow(er)s in Australia.Background.  War veterans commonly experience mental health difficulties and do not always receive required treatment, as can also occur for war widow(er)s. Whenever opportunity arises, such as during community nursing care, it is vital to identify mental health problems in a health promotion framework.Design.  A clinical pathway was developed by literature review and consultation and then trialled and evaluated using mixed methods – quantitative and qualitative.Methods.  Community nurses who trialled the pathway completed an evaluation survey and attended focus groups. General practitioners responded to an evaluation survey.Results.  Most nurses found the pathway clear and easy to understand but not always easy to use. They emphasised the need to establish trust and rapport with clients prior to implementing the pathway. It was sometimes difficult to ensure effective referral to general practitioners for clients who screened positive for a mental health problem. When referral was accomplished, general practitioners reported adequate and useful information was provided. Some general practitioners also commented on the difficulty of achieving effective communication between general practitioners and nurses.Conclusions.  Nurses and some general practitioners found the pathway useful for their practice. They offered several suggestions for improvement by simplifying the trialled pathway and accompanying guidelines and strategies to improve communication between nurses and general practitioners. This study adds understanding of how community nurses might productively screen for mental health difficulties.Relevance to clinical practice.  The trialled pathway, which was modified and refined following the study, is an evidence‐based resource for community nurses in Australia and similar contexts to guide practise and maximise holistic care for war veterans and war widow(er)s and possibly other client groups.
Validity and reliability of the ‘good perioperative nursing care scale’ for Turkish patients and nurses
Authors: Donmez Yelda Candan , Ozbayır Turkan 
Published: October 2010

Aim.  To test the validity and reliability of the Turkish version of Good Perioperative Nursing Care Scale for nurses and patients.Background.  The nursing care in operating departments has an important role in modern health care and therefore more research concerning perioperative care quality is needed and the development of a measurement tool is necessary.Design.  The study was designed as a cross‐sectional survey.Method.  The research population was 346 patients who had surgery and 159 operating room nurses who worked at 11 hospitals. The GPNCS contains 32 items. The items on the nurses’ form were changed as little as possible to create the form for patients to be able to directly compare them. To determine the tool’s language equivalency/adaptation of the questionnaire for both nurses and patients, the tool was translated into Turkish then retranslated, and a pilot study was conducted.Results.  The total scale’s total mean score and standard deviation for nurses was determined to be 113·23 (SD 2·13) and for patients was 128·23 (SD 1·27). To test the scale’s stability over time, a test‐retest was conducted and the results showed a strong confirmatory correlation.Conclusions.  The GPNCS was determined to be a tool that had indicators of being adequate, reliable and valid for the Turkish population.Relevance to clinical practice.  This study highlighted the importance of comparing the quality and effectiveness of nursing care in different operating departments. It is recommended that it be used to determine the quality of perioperative nursing care in Turkey.