bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oxygen removal during pathogen inactivation with riboflavin and UV light preserves protein function in plasma for transfusion
Authors: Feys H. B. , Van Aelst B. , Devreese K. , Devloo R. , Coene J. , Vandekerckhove P. , Compernolle V. 
Published: October 2013

Background and ObjectivePhotochemical pathogen inactivation technologies (PCT) for individual transfusion products act by inhibition of replication through irreversibly damaging nucleic acids. Concern on the collateral impact of PCT on the blood component's integrity has caused reluctance to introduce this technology in routine practice. This work aims to uncover the mechanism of damage to plasma constituents by riboflavin pathogen reduction technology (RF‐PRT).MethodsActivity and antigen of plasma components were determined following RF‐PRT in the presence or absence of dissolved molecular oxygen.ResultsEmploying ADAMTS13 as a sentinel molecule in plasma, our data show that its activity and antigen are reduced by 23 ± 8% and 29 ± 9% (n = 24), respectively, which corroborates with a mean decrease of 25% observed for other coagulation factors. Western blotting of ADAMTS13 shows decreased molecular integrity, with no obvious indication of additional proteolysis nor is riboflavin able to directly inhibit the enzyme. However, physical removal of dissolved oxygen prior to RF‐PRT protects ADAMTS13 as well as FVIII and fibrinogen from damage, indicating a direct role for reactive oxygen species. Redox dye measurements indicate that superoxide anions are specifically generated during RF‐PRT. Protein carbonyl content as a marker of disseminated irreversible biomolecular damage was significantly increased (3·1 ± 0·8 vs. 1·6 ± 0·5 nmol/mg protein) following RF‐PRT, but not in the absence of dissolved molecular oxygen (1·8 ± 0·4 nmol/mg).ConclusionsRF‐PRT of single plasma units generates reactive oxygen species that adversely affect biomolecular integrity of relevant plasma constituents, a side‐effect, which can be bypassed by applying hypoxic conditions during the pathogen inactivation process.
Allowing blood donation from men who had sex with men more than 5 years ago: a model to evaluate the impact on transfusion safety in Canada
Authors: Germain M. , Robillard P. , Delage G. , Goldman M. 
Published: October 2013

Canada now allows donations from men who had sex with men (MSM) if their last sexual contact with a man was more than 5 years ago. We modelled the impact of this policy on supply and safety. Approximately 4500 new donors will be added and assuming compliance to the new policy remains unchanged, the worst‐case scenario predicts the introduction of one HIV‐contaminated unit in the inventory every 1072 years. This change will entail negligible additional HIV risk to recipients. A five‐year deferral will also protect recipients against the theoretical concern that MSM may represent a group at higher risk of sexually transmitted, emerging blood borne pathogens.
Are Vancomycin Trough Concentrations Adequate for Optimal Dosing?
Authors: Neely Michael N. , Youn Gilmer , Jones Brenda , Jelliffe Roger W. , Drusano George L. , Rodvold Keith A. , Lodise Thomas P. 
Published: October 2013

ABSTRACT

The current vancomycin therapeutic guidelines recommend the use of only trough concentrations to manage the dosing of adults with
Staphylococcus aureus
infections. Both vancomycin efficacy and toxicity are likely to be related to the area under the plasma concentration-time curve (AUC). We assembled richly sampled vancomycin pharmacokinetic data from three studies comprising 47 adults with various levels of renal function. With Pmetrics, the nonparametric population modeling package for R, we compared AUCs estimated from models derived from trough-only and peak-trough depleted versions of the full data set and characterized the relationship between the vancomycin trough concentration and AUC. The trough-only and peak-trough depleted data sets underestimated the true AUCs compared to the full model by a mean (95% confidence interval) of 23% (11 to 33%;
P
= 0.0001) and 14% (7 to 19%;
P
< 0.0001), respectively. In contrast, using the full model as a Bayesian prior with trough-only data allowed 97% (93 to 102%;
P
= 0.23) accurate AUC estimation. On the basis of 5,000 profiles simulated from the full model, among adults with normal renal function and a therapeutic AUC of ≥400 mg · h/liter for an organism for which the vancomycin MIC is 1 mg/liter, approximately 60% are expected to have a trough concentration below the suggested minimum target of 15 mg/liter for serious infections, which could result in needlessly increased doses and a risk of toxicity. Our data indicate that adjustment of vancomycin doses on the basis of trough concentrations without a Bayesian tool results in poor achievement of maximally safe and effective drug exposures in plasma and that many adults can have an adequate vancomycin AUC with a trough concentration of <15 mg/liter.
Efficacy of an Experimental Azithromycin Cream for Prophylaxis of Tick-Transmitted Lyme Disease Spirochete Infection in a Murine Model
Authors: Piesman Joseph , Hojgaard Andrias , Ullmann Amy J. , Dolan Marc C. 
Published: October 2013

ABSTRACTAs an alternative to oral prophylaxis for the prevention of tick transmission ofBorrelia burgdorferi, we tested antibiotic cream prophylactic formulations in a murine model of spirochete infection. A 4% preparation of doxycycline cream afforded no protection, but a single application of 4% azithromycin cream was 100% protective when applied directly to the tick bite site at the time of tick removal. Indeed, the azithromycin cream was 100% effective when applied at up to 3 days after tick removal and protected 74% of mice exposed to tick bite when applied at up to 2 weeks after tick removal. Azithromycin cream was also protective when applied at a site distal to the tick bite site, suggesting that it was having a systemic effect in addition to a local transdermal effect. Mice that were protected from tick-transmitted infection did not seroconvert and did not infect larval ticks on xenodiagnosis. Azithromycin cream formulations appear to hold promise for Lyme disease prophylaxis.
Characterizing
In Vivo
Pharmacodynamics of Carbapenems against Acinetobacter baumannii in a Murine Thigh Infection Model To Support Breakpoint Determinations
Authors: MacVane Shawn H. , Crandon Jared L. , Nicolau David P. 
Published: October 2013

ABSTRACT

Pharmacodynamic profiling data of carbapenems for
Acinetobacter
spp. are sparse. This study aimed to determine the pharmacodynamic targets of carbapenems for
Acinetobacter baumannii
based on a range of percentages of the dosing interval in which free drug concentrations remained above the MIC (
f
T>MIC) in the neutropenic murine thigh infection model.
f
T>MIC values of 23.7%, 32.8%, and 47.5% resulted in stasis, 1-log reductions, and 2-log reductions in bacterial density after 24 h, respectively. The pharmacodynamic targets of carbapenems for
A. baumannii
demonstrated
in vivo
are similar to those of other Gram-negative bacteria.
Candida albicans Airway Exposure Primes the Lung Innate Immune Response against Pseudomonas aeruginosa Infection through Innate Lymphoid Cell Recruitment and Interleukin-22-Associated Mucosal Response
Authors: Mear Jean Baptiste , Gosset Philippe , Kipnis Eric , Faure Emmanuel , Dessein Rodrigue , Jawhara Samir , Fradin Chantal , Faure Karine , Poulain Daniel , Sendid Boualem , Guery Benoit 
Published: October 2013

ABSTRACTPseudomonas aeruginosaandCandida albicansare two pathogens frequently encountered in the intensive care unit microbial community. We have demonstrated thatC. albicansairway exposure protected againstP. aeruginosa-induced lung injury. The goal of the present study was to characterize the cellular and molecular mechanisms associated withC. albicans-induced protection. Airway exposure byC. albicansled to the recruitment and activation of natural killer cells, innate lymphoid cells (ILCs), macrophages, and dendritic cells. This recruitment was associated with the secretion of interleukin-22 (IL-22), whose neutralization abolishedC. albicans-induced protection. We identified, by flow cytometry, ILCs as the only cellular source of IL-22. Depletion of ILCs by anti-CD90.2 antibodies was associated with a decreased IL-22 secretion and impaired survival afterP. aeruginosachallenge. Our results demonstrate that the production of IL-22, mainly by ILCs, is a major and inducible step in protection againstP. aeruginosa-induced lung injury. This cytokine may represent a clinical target inPseudomonas aeruginosa-induced lung injury.
CSF xanthochromia analysis takes longer following centralisation of the laboratories testing samples - how can we improve the time to result?
Authors: Martin Sean , Page Melanie , Godber Ian , McGregor Calum 
Published: October 2013

AbstractLumbar puncture is an essential tool for excluding subarachnoid haemorrhage. In August 2012, the laboratory at which cerebrospinal fluid (CSF) is analysed for xanthochromia in Lanarkshire was centralised at Hairmyres (East Kilbride, UK). Prior to this, each of the three hospitals analysed their own specimens.We aim to assess whether or not the change in xanthochromia processing has resulted in diagnostic delay at Wishaw General Hospital in the assessment of CT negative possible subarachnoid haemorrhage. We subsequently assessed the impact of a strategy to minimise any delay, i.e. increasing laboratory processing hours.Patients undergoing CSF analysis for xanthochromia were identified directly from the laboratory database. Time of lumbar puncture, and time of xanthochromia results were obtained from the hospital's laboratory computer system. Data were analysed using a commercially available statistical software programme (Microsoft Excel). Audit was repeated after the change to a centralised laboratory, and again following the increased laboratory working hours.Mean time from lumbar puncture to availability of xanthochromia result was significantly longer following the laboratory change (20.8±3.5 hours post [n=35] vs. 12.5±3.0 pre, p=0.01 [n=17]). However, following a change in the laboratory's practice, there was no improvement (19.8±3.4 hours post practice change [n=35]), and this remained significantly longer when compared to the original laboratory set-up (p=0.025).The change in laboratory processing CSF samples for xanthochromia in Lanarkshire resulted in a significant delay in analysing the samples. Attempts by the laboratory to extend processing hours did not make any significant improvement, but having expanded our knowledge of the issues, further measures are now planned to minimise delays in the future.Centralisation of laboratory services for CSF analysis, whilst cheaper, may impact negatively on clinical care.
Warfarin Management Pathway: A clear and safe algorithm, from admission to discharge.
Authors: Hart-George Alice 
Published: October 2013

AbstractWarfarin is the most commonly prescribed anticoagulant in the UK and the one most frequently associated with both fatal medication errors and litigation claims [1]. Its life-threatening interactions and side effects are a concern for all doctors. Identifying and implementing solutions to achieve safer prescribing and monitoring is imperative to improve patient safety. The National Patient Safety Agency (NPSA) has outlined the major risks associated with anticoagulant therapy and sought to establish safer practice [1]. The monitoring of safety indicators has been highlighted as a solution. This quality improvement project (QIP) introduces a management algorithm for oral anticoagulant therapy in hospital patients, validated through a completed audit cycle. It was completed at one district general hospital (DGH) in England and involved all inpatient wards.Doctors and pharmacists were interviewed to assess their knowledge of the correct pathways for management of patients on warfarin. The number of errors on hospital warfarin charts was audited over three weeks. These results, coupled with senior haematological advice led to the production of an algorithm illustrating the gold-standard pathway for warfarin management from admission to discharge. It was emailed to all doctors in the Trust and a laminated copy attached to hospital Pneumatic Tube System (PTS) machines. The warfarin charts were re-audited over the following three weeks. The results showed a marked decrease in errors and incomplete anticoagulation referrals as well as a reduction in doctors’ anxiety around prescribing warfarin.
MET and AXL Inhibitor NPS-1034 Exerts Efficacy against Lung Cancer Cells Resistant to EGFR Kinase Inhibitors Because of MET or AXL Activation
Authors: Rho Jin Kyung , Choi Yun Jung , Kim Seon Ye , Kim Tae Won , Choi Eun Kyung , Yoon Seon-Joo , Park Bu Man , Park Eunhye , Bae Jong Hwan , Choi Chang-Min , Lee Jae Cheol 
Published: October 2013

Abstract
In non–small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations, acquired resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKI) can occur through a generation of bypass signals such as MET or AXL activation. In this study, we investigated the antitumor activity of NPS-1034, a newly developed drug that targets both MET and AXL, in NSCLC cells with acquired resistance to gefitinib or erlotinib (HCC827/GR and HCC827/ER, respectively). Characterization of H820 cells and evaluation of NPS-1034 efficacy in these cells were also performed. The resistance of HCC827/GR was mediated by MET activation, whereas AXL activation led to resistance in HCC827/ER. The combination of gefitinib or erlotinib with NPS-1034 synergistically inhibited cell proliferation and induced cell death in both resistant cell lines. Accordingly, suppression of Akt was noted only in the presence of treatment with both drugs. NPS-1034 was also effective in xenograft mouse models of HCC827/GR. Although the H820 cell line was reported previously to have T790M and MET amplification, we discovered that AXL was also activated in this cell line. There were no antitumor effects of siRNA or inhibitors specific for EGFR or MET, whereas combined treatment with AXL siRNA or NPS-1034 and EGFR-TKIs controlled H820 cells, suggesting that AXL is the main signal responsible for resistance. In addition, NPS-1034 inhibited cell proliferation as well as ROS1 activity in HCC78 cells with ROS1 rearrangement. Our results establish the efficacy of NPS-1034 in NSCLC cells rendered resistant to EGFR-TKIs because of MET or AXL activation or ROS1 rearrangement. Cancer Res; 74(1); 253–62. ©2013 AACR.
Outcomes of Breast Cancer in Brazil Related to Health Care Coverage: A Retrospective Cohort Study
Authors: Liedke Pedro E.R. , Finkelstein Dianne M. , Szymonifka Jackie , Barrios Carlos H. , Chavarri-Guerra Yanin , Bines José , Vasconcelos Cláudia , Simon Sérgio D. , Goss Paul E. 
Published: October 2013

AbstractBackground: Breast cancer is the most common malignancy in women in Brazil. Differences between patients with public versus private healthcare coverage about general characteristics, disease presentation, treatment of primary tumors, and clinical outcomes have not been fully investigated.Methods: A national, retrospective cohort of 3,142 patients drawn from a representative sample of Brazilian medical centers was selected. Clinical and demographic data and type of healthcare coverage were retrieved by chart review. Groups were compared using the χ2 test. The log-rank test was used for comparison of disease-free survival (DFS), postrelapse, and overall survival (OS). Multivariate Cox regression modeling with adjustment for patient characteristics and stage at diagnosis was performed. All P values are two sided.Results: Patients with public health coverage presented with more advanced disease at diagnosis (P &lt; 0.001). DFS and OS for patients presenting with stage 0–II disease did not differ according to the type of healthcare coverage, whereas a significant difference in outcomes was seen for stage III–IV patients (P = 0.002 and P = 0.008, respectively). In a Cox multivariate analysis, no association was found for the type of health coverage with either DFS or OS, but there was an association for postrelapse survival (P &lt; 0.001).Conclusion: In Brazil, patients with breast cancer with public health coverage present with more advanced disease, and this possibly explains worse DFS and OS when compared with those with private coverage.Impact: Earlier diagnosis and treatment of breast cancer could improve outcomes of women with public health coverage in Brazil. Cancer Epidemiol Biomarkers Prev; 23(1); 126–33. ©2013 AACR.
Comprehensive Biomarker Analysis and Final Efficacy Results of Sorafenib in the BATTLE Trial
Authors: Blumenschein George R. , Saintigny Pierre , Liu Suyu , Kim Edward S. , Tsao Anne S. , Herbst Roy S. , Alden Christine , Lee J. Jack , Tang Ximing , Stewart David J. , Kies Merrill S. , Fossella Frank V. , Tran Hai T. , Mao L. , Hicks Marshall E. , Erasmus Jeremy , Gupta Sanjay , Girard Luc , Peyton Michael , Diao Lixia , Wang Jing , Davis Suzanne E. , Minna John D. , Wistuba Ignacio , Hong Waun K. , Heymach John V. , Lippman Scott M. 
Published: October 2013

Abstract
Purpose: To report the clinical efficacy of sorafenib and to evaluate biomarkers associated with sorafenib clinical benefit in the BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) program.
Patients and Methods: Patients with previously treated non–small cell lung cancer (NSCLC) received sorafenib until progression or unacceptable toxicity. Eight-week disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were assessed. Prespecified biomarkers included K-RAS, EGFR, and B-RAF mutations, and EGFR gene copy number. Gene expression profiles from NSCLC cell lines and patient tumor biopsies with wild-type EGFR were used to develop a sorafenib sensitivity signature (SSS).
Results: A total of 105 patients were eligible and randomized to receive sorafenib. Among 98 patients evaluable for eight-week DCR, the observed DCR was 58.2%. The median PFS and OS were 2.83 [95% confidence interval (CI), 2.04–3.58] and 8.48 months (95% CI, 5.78–10.97), respectively. Eight-week DCR was higher in patients with wild-type EGFR than patients with EGFR mutation (P = 0.012), and in patients with EGFR gene copy number gain (FISH-positive) versus patients FISH-negative (P = 0.048). In wild-type EGFR tumors, the SSS was associated with improved PFS (median PFS 3.61 months in high SSS vs. 1.84 months in low SSS; P = 0.026) but not with eight-week DCR. Increased expression of fibroblast growth factor-1, NF-κB, and hypoxia pathways were identified potential drivers of sorafenib resistance.
Conclusion: Sorafenib demonstrates clinical activity in NSCLC, especially with wild-type EGFR. SSS was associated with improved PFS. These data identify subgroups that may derive clinical benefit from sorafenib and merit investigation in future trials. Clin Cancer Res; 19(24); 6967–75. ©2013 AACR.
Molecular Pathways: Transcription Factories and Chromosomal Translocations
Authors: Osborne Cameron S. 
Published: October 2013

Abstract
The mammalian nucleus is a highly complex structure that carries out a diverse range of functions such as DNA replication, cell division, RNA processing, and nuclear export/import. Many of these activities occur at discrete subcompartments that intersect with specific regions of the genome. Over the past few decades, evidence has accumulated to suggest that RNA transcription also occurs in specialized sites, called transcription factories, that may influence how the genome is organized. There may be certain efficiency benefits to cluster transcriptional activity in this way. However, the clustering of genes at transcription factories may have consequences for genome stability, and increase the susceptibility to recurrent chromosomal translocations that lead to cancer. The relationships between genome organization, transcription, and chromosomal translocation formation will have important implications in understanding the causes of therapy-related cancers. Clin Cancer Res; 20(2); 296–300. ©2013 AACR.
Anticipating the Clinical Use of Prognostic Gene Expression–Based Tests for Colon Cancer Stage II and III: Is Godot Finally Arriving?
Authors: Sveen Anita , Nesbakken Arild , Ågesen Trude H. , Guren Marianne G. , Tveit Kjell M. , Skotheim Rolf I. , Lothe Ragnhild A. 
Published: October 2013

Abstract
Purpose: According to current recommendations for adjuvant treatment, patients with colon cancer stage II are not routinely offered chemotherapy, unless considered to have a high risk of relapse based on specific clinicopathological parameters. Following these criteria, it is challenging to identify the subgroup of patients that will benefit the most from adjuvant treatment. Contrarily, patients with colon cancer stage III are routinely offered chemotherapy, but due to expected adverse effects and frailty, elderly patients are often excluded from standard protocols. Colon cancer is a disease of the elderly and accordingly, there is a large subgroup of patients for which guidelines for adjuvant treatment remain less clear. In these two clinical settings, improved risk stratification has great potential impact on patient care, anticipating that high-risk patients will benefit from chemotherapy. However, microsatellite instability is the only molecular prognostic marker recommended for clinical use.
Experimental Design: In this perspective, we provide an updated view on the status and clinical potential of the many proposed prognostic gene expression–based tests for colon cancer stage II and III.
Results: The main limitation for clinical implementation is lack of prospective validation. For patients with stage II, highly promising tests have been identified and clinical trials are ongoing. For elderly patients with stage III, the value of such tests has received less focus, but promising early results have been shown.
Conclusion: Although awaiting results from prospective trials, improved risk assessment for patients with stage II and III is likely to be achieved in the foreseeable future. Clin Cancer Res; 19(24); 6669–77. ©2013 AACR.