bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vitro
Activity of Ceftolozane-Tazobactam against Pseudomonas aeruginosa Isolates Obtained from Patients in Canadian Hospitals in the CANWARD Study, 2007 to 2012
Authors: Walkty A. , Karlowsky J. A. , Adam H. , Baxter M. , Lagacé-Wiens P. , Hoban D. J. , Zhanel G. G. 
Published: August 2013

ABSTRACT

The
in vitro
activity of ceftolozane in combination with tazobactam (fixed concentration of 4 μg/ml) was evaluated against 2,435
Pseudomonas aeruginosa
clinical isolates obtained from across Canada using Clinical and Laboratory Standards Institute broth microdilution methods. The MIC
50
and MIC
90
values for ceftolozane-tazobactam were 0.5 μg/ml and 1 μg/ml, respectively (a 32-fold-lower MIC
90
than that for ceftazidime). Eighty-nine percent (141/158) of multidrug-resistant isolates were inhibited by ≤8 μg/ml of ceftolozane-tazobactam.
Identification of a Human Monoclonal Antibody To Replace Equine Diphtheria Antitoxin for Treatment of Diphtheria Intoxication
Authors: Sevigny Leila M. , Booth Brian J. , Rowley Kirk J. , Leav Brett A. , Cheslock Peter S. , Garrity Kerry A. , Sloan Susan E. , Thomas William , Babcock Gregory J. , Wang Yang 
Published: August 2013

ABSTRACT

Diphtheria antitoxin (DAT) has been the cornerstone of the treatment of
Corynebacterium diphtheriae
infection for more than 100 years. Although the global incidence of diphtheria has declined steadily over the last quarter of the 20th century, the disease remains endemic in many parts of the world, and significant outbreaks still occur. DAT is an equine polyclonal antibody that is not commercially available in the United States and is in short supply globally. A safer, more readily available alternative to DAT would be desirable. In the current study, we obtained human monoclonal antibodies (hMAbs) directly from antibody-secreting cells in the circulation of immunized human volunteers. We isolated a panel of diverse hMAbs that recognized diphtheria toxoid, as well as a variety of recombinant protein fragments of diphtheria toxin. Forty-five unique hMAbs were tested for neutralization of diphtheria toxin in
in vitro
cytotoxicity assays with a 50% effective concentration of 0.65 ng/ml for the lead candidate hMAb, 315C4. In addition, 25 μg of 315C4 completely protected guinea pigs from intoxication in an
in vivo
lethality model, yielding an estimated relative potency of 64 IU/mg. In comparison, 1.6 IU of DAT was necessary for full protection from morbidity and mortality in this model. We further established that our lead candidate hMAb binds to the receptor-binding domain of diphtheria toxin and physically blocks the toxin from binding to the putative receptor, heparin-binding epidermal growth factor-like growth factor. The discovery of a specific and potent human neutralizing antibody against diphtheria toxin holds promise as a potential therapeutic.
The accuracy of alternative triage rules for identification of significant traumatic brain injury: a diagnostic cohort study
Authors: Fuller Gordon , Lawrence Thomas , Woodford Maralyn , Lecky Fiona 
Published: August 2013

IntroductionTraumatic brain injury (TBI) is a leading cause of death and disability in young adults. Reorganisation of trauma services with direct triage of suspected head injury patients to trauma centres may improve outcomes following TBI. This study aimed to determine the sensitivity of principal English triage tools for identifying significant TBI.MethodsWe performed a diagnostic cohort study using data prospectively collated from the Trauma Audit and Research Network database between 2005 and 2011. Adult head injury patients were retrospectively classified according to London Ambulance Service (LAS) and Head Injury Transportation Straight to Neurosurgery study (HITS-NS) triage criteria. Sensitivity and specificity were then calculated against a reference standard of significant TBI, comprising head region abbreviated injury score (AIS) ≥3 or neurosurgical operation.Results6559 patients were included in complete case analyses. The LAS and HITS-NS triage tools demonstrated sensitivities of 44.5% (95% CI 43.2 to 45.9) and 32.6% (95% CI 31.4 to 33.9), respectively, for identifying significant TBI patients. False negative significant TBI cases were relatively older, more likely to be female, more frequently secondary to low-level falls, and were less likely to have very severe AIS five or six head injuries, p<0.01.ConclusionsA considerable proportion of significant head injury patients may not be triaged directly to trauma centres. Investment is therefore necessary to improve the accuracy of existing triage rules and maintain expertise in TBI diagnosis and management in non-specialist emergency departments.
Postmortem serum tryptase levels in anaphylactic and non-anaphylactic deaths
Authors: McLean-Tooke Andrew , Goulding Mark , Bundell Christine , White Jodi , Hollingsworth Peter 
Published: August 2013

BackgroundThe postmortem diagnosis of anaphylaxis remains difficult due to the lack of specific biomarkers. Mast cell tryptase (MCT) levels are used as a marker of mast cell degranulation in living patients and elevated levels have also been described in postmortem serum samples in anaphylaxis-associated deaths, although elevated levels may also be seen in non-anaphylaxis-associated deaths.ObjectiveTo investigate the effects of cause of death, site of blood sampling, degree of sample haemolysis and the presence of opiates on postmortem MCT levels.MethodWe obtained sera from three collection sites from 189 non-suspicious coronial postmortems and aortic samples from 10 anaphylactic deaths to characterise postmortem MCT.ResultsMCT were elevated (>11.4 μg/L) in 57% of aortic samples, 58% of femoral samples and 30% of subclavian samples. In aortic samples, there were significantly higher levels of MCT in anaphylaxis-associated deaths compared with other causes of death. Aortic MCT levels >110 μg/L had a sensitivity of 80% and specificity of 92.1% for anaphylaxis-associated deaths. There was a significant correlation between MCT and degree of sample haemolysis but no correlation with the presence of opiates.ConclusionsModerately elevated MCT levels are common in postmortem sera. Aortic values >110 μg/L may support a diagnosis of anaphylaxis-associated death, although the diagnosis should not be based on this test alone. There was significant variation between sample sites and reference ranges for individual sample sites should be established.
Modelling the effects of low indoor temperatures on the lung function of children with asthma
Authors: Pierse Nevil , Arnold Richard , Keall Michael , Howden-Chapman Philippa , Crane Julian , Cunningham Malcolm ,   the Heating Housing and Health Study Group
Published: August 2013

IntroductionWhile many epidemiological studies have shown that low outdoor temperatures are associated with increased rates of hospitalisation and mortality (especially for respiratory or cardiovascular disease), very few studies have looked at the association between indoor temperatures and health. Such studies are clearly warranted, as people have greater exposure to the indoor environment than the outdoor environment.ObjectivesTo examine the relationship between various metrics of indoor temperature and lung function in children with asthma. Our specific research questions were: (1) In which room of the home is temperature most strongly associated with lung function? (2) Which exposure metric best describes the relationship between indoor temperature and lung function? (3) Over what lag/time period does indoor air temperature affect lung function most strongly?MethodsThe Heating Housing and Health Study was a randomised controlled trial that investigated the effect of installing heaters in the homes of children with asthma. This study collected measurements of lung function (daily) and indoor temperature (hourly). Lung function and indoor temperature were measured for 309 children over 12 049 child-days. Statistical models were fitted to identify the best measures and metrics.ResultsThe strongest association with lung function was found for the severity of exposure to low bedroom temperatures averaged over the preceding periods of 0–7 to 0–12 days. A 1°C increase in temperature was associated with an average increase of 0.010, 0.008, 10.06, 12.06, in our four measures of lung function (peak expiratory flow rate (PEFR) morning, PEFR evening, forced expiratory volume in 1 s (FEV1) morning and FEV1evening).ConclusionsIndoor temperatures have a small, but significant, association with short-term variations in the lung function of children with asthma.
Effect of Telmisartan or Losartan for Treatment of Nonalcoholic Fatty Liver Disease: Fatty Liver Protection Trial by Telmisartan or Losartan Study (FANTASY)
Authors: Hirata Takumi , Tomita Kengo , Kawai Toshihide , Yokoyama Hirokazu , Shimada Akira , Kikuchi Masahiro , Hirose Hiroshi , Ebinuma Hirotoshi , Irie Junichiro , Ojiro Keisuke , Oikawa Yoichi , Saito Hidetsugu , Itoh Hiroshi , Hibi Toshifumi 
Published: August 2013

Aim.This study compared the effects of telmisartan and losartan on nonalcoholic fatty liver disease (NAFLD) and biochemical markers of insulin resistance in hypertensive NAFLD patients with type 2 diabetes mellitus.Methods.This was a randomized, open-label, parallel-group comparison of therapy with telmisartan or losartan. Nineteen hypertensive NAFLD patients with type 2 diabetes were randomly assigned to receive telmisartan at a dose of 20 mg once a day (n=12) or losartan at a dose of 50 mg once a day (n=7) for 12 months. Body fat area as determined by CT scanning and hepatic fat content based on the liver-to-spleen (L/S) ratio, as well as several parameters of glycemic and lipid metabolism, were compared before and after 12 months.Results.The telmisartan group showed a significant decline in serum free fatty acid (FFA) level (from0.87±0.26to0.59±0.22 mEq/L (mean ± SD),P=0.005) and a significant increase in L/S ratio (P=0.049) evaluated by CT scan, while these parameters were not changed in the losartan group.Conclusion.Although there was no significant difference in improvement in liver enzymes with telmisartan and losartan treatment in hypertensive NAFLD patients with type 2 diabetes after 12 months, it is suggested that telmisartan may exert beneficial effects by improving fatty liver.Erratum to “Effect of Telmisartan or Losartan for Treatment of Nonalcoholic Fatty Liver Disease: Fatty Liver Protection Trial by Telmisartan or Losartan Study (FANTASY)”
Double Minute Chromosomes in Glioblastoma Multiforme Are Revealed by Precise Reconstruction of Oncogenic Amplicons
Authors: Sanborn J. Zachary , Salama Sofie R. , Grifford Mia , Brennan Cameron W. , Mikkelsen Tom , Jhanwar Suresh , Katzman Sol , Chin Lynda , Haussler David 
Published: August 2013

Abstract
DNA sequencing offers a powerful tool in oncology based on the precise definition of structural rearrangements and copy number in tumor genomes. Here, we describe the development of methods to compute copy number and detect structural variants to locally reconstruct highly rearranged regions of the tumor genome with high precision from standard, short-read, paired-end sequencing datasets. We find that circular assemblies are the most parsimonious explanation for a set of highly amplified tumor regions in a subset of glioblastoma multiforme samples sequenced by The Cancer Genome Atlas (TCGA) consortium, revealing evidence for double minute chromosomes in these tumors. Further, we find that some samples harbor multiple circular amplicons and, in some cases, further rearrangements occurred after the initial amplicon-generating event. Fluorescence in situ hybridization analysis offered an initial confirmation of the presence of double minute chromosomes. Gene content in these assemblies helps identify likely driver oncogenes for these amplicons. RNA-seq data available for one double minute chromosome offered additional support for our local tumor genome assemblies, and identified the birth of a novel exon made possible through rearranged sequences present in the double minute chromosomes. Our method was also useful for analysis of a larger set of glioblastoma multiforme tumors for which exome sequencing data are available, finding evidence for oncogenic double minute chromosomes in more than 20% of clinical specimens examined, a frequency consistent with previous estimates. Cancer Res; 73(19); 6036–45. ©2013 AACR.
Identification of Transcriptional Subgroups in EGFR-Mutated and EGFR/KRAS Wild-Type Lung Adenocarcinoma Reveals Gene Signatures Associated with Patient Outcome
Authors: Planck Maria , Isaksson Sofi , Veerla Srinivas , Staaf Johan 
Published: August 2013

Abstract
Purpose: In lung adenocarcinoma, EGFR and KRAS mutations dominate the mutational spectrum and have clear therapeutic implications. We sought to determine whether transcriptional subgroups of clinical relevance exist within EGFR-mutated, KRAS-mutated, or EGFR and KRAS wild-type (EGFRwt/KRASwt) adenocarcinomas.
Experimental Design: Gene expression profiles from 1,186 adenocarcinomas, including 215 EGFR-mutated, 84 KRAS-mutated, and 219 EGFRwt/KRASwt tumors, were assembled and divided into four discovery (n = 522) and four validation cohorts (n = 664). Subgroups within the mutation groups were identified by unsupervised consensus clustering, significance analysis of microarrays (SAM) analysis, and centroid classification across discovery cohorts. Genomic alterations in identified mutation subgroups were assessed by integration of genomic profiles for 158 cases with concurrent data. Multicohort expression subgroup predictors were built for each mutation group using the discovery cohorts, and validated in the four validation cohorts.
Results: Consensus clustering within the mutation groups identified reproducible transcriptional subgroups in EGFR-mutated and EGFRwt/KRASwt tumors, but not in KRAS-mutated tumors. Subgroups displayed differences in genomic alterations, clinicopathologic characteristics, and overall survival. Multicohort gene signatures derived from the mutation subgroups added independent prognostic information in their respective mutation group, for adenocarcinoma in general and stage I tumors specifically, irrespective of mutation status, when applied to the validation cohorts. Consistent with their worse clinical outcome, high-risk subgroups showed higher expression of proliferation-related genes, higher frequency of copy number alterations/amplifications, and association with a poorly differentiated tumor phenotype.
Conclusions: We identified transcriptional subgroups in EGFR-mutated and EGFRwt/KRASwt adenocarcinomas with significant differences in clinicopathologic characteristics and patient outcome, not limited to a mutation-specific setting. Clin Cancer Res; 19(18); 5116–26. ©2013 AACR.
HLA and Killer Immunoglobulin-like Receptor Genes as Outcome Predictors of Hepatitis C Virus–Related Hepatocellular Carcinoma
Authors: Cariani Elisabetta , Pilli Massimo , Zerbini Alessandro , Rota Cristina , Olivani Andrea , Zanelli Paola , Zanetti Adele , Trenti Tommaso , Ferrari Carlo , Missale Gabriele 
Published: August 2013

Abstract
Purpose: We evaluated the impact of the killer immunoglobulin-like receptors (KIR) of natural killer (NK) cells and of their HLA ligands over the clinical outcome of hepatitis C virus (HCV)–related hepatocellular carcinoma after curative treatment by either surgical resection or radiofrequency thermal ablation (RTA).
Experimental Design: Sixty-one consecutive patients with HCV-related hepatocellular carcinoma underwent KIR genotyping and HLA typing. A phenotypic/functional characterization of NK cells was carried out in patients with different KIR/KIR-ligand genotype.
Results: Activating KIR2DS5 was associated with significantly longer time to recurrence (TTR) and overall survival (OS; P &lt; 0.03 each). Homozygous HLA-C1 (P &lt; 0.02) and HLA-Bw4I80 (P &lt; 0.05) were expressed by patients with significantly better OS, whereas HLA-C2 (P &lt; 0.02) and HLA-Bw4T80 (P &lt; 0.01) were associated with a worse OS. Multivariate analysis identified as parameters independently related to TTR the type of treatment (surgical resection vs. RTA; P &lt; 0.03) and HLA-C1 (P &lt; 0.03), whereas only KIR2DS5 was an independent predictor of longer OS (P &lt; 0.05). Compound KIR2DL2-C1 and KIR3DS1-Bw4T80 genotypes were associated with better TTR (P &lt; 0.03) and worse OS (P = 0.02), respectively. A prevalent cytotoxic (CD56dim) NK phenotype was detected in patients with both longer TTR and OS. Cytotoxic capacity measured by upregulation of CD107a was significantly higher in subjects with HLA-C1 alone or combined with KIR2DL2/KIR2DL3.
Conclusions: These results support a central role of NK cells in the immune response against hepatocellular carcinoma, providing a strong rationale for therapeutic strategies enhancing NK response and for individualized posttreatment monitoring schemes. Clin Cancer Res; 19(19); 5465–73. ©2013 AACR.
Overcoming Platinum Resistance in Preclinical Models of Ovarian Cancer Using the Neddylation Inhibitor MLN4924
Authors: Jazaeri Amir A. , Shibata Etsuko , Park Jonghoon , Bryant Jennifer L. , Conaway Mark R. , Modesitt Susan C. , Smith Peter G. , Milhollen Michael A. , Berger Allison J. , Dutta Anindya 
Published: August 2013

Abstract
The nearly ubiquitous development of chemoresistant disease remains a major obstacle against improving outcomes for patients with ovarian cancer. In this investigation, we evaluated the preclinical activity of MLN4924, an investigational inhibitor of the NEDD8-activating enzyme, in ovarian cancer cells. Efficacy of MLN4924 both alone and in combination with platinum was assessed. Overall, single-agent MLN4924 exhibited moderate activity in ovarian cancer cell lines. However, the combination of MLN4924 with cisplatin or carboplatin produced synergistic effects in SKOV3 and ES2 cells, as well as in primary ovarian cancer cell lines established from high-grade serous, clear cell, and serous borderline ovarian tumors. The efficacy of cisplatin plus MLN4924 was also evident in several in vitro models of platinum-resistant ovarian cancer. Mechanistically, the combination of cisplatin and MLN4924 was not associated with DNA re-replication, altered platinum-DNA adduct formation, abrogation of FANCD2 monoubiquitination, or CHK1 phosphorylation. An siRNA screen was used to investigate the contribution of each member of the cullin RING ligase (CRL) family of E3 ubiquitin ligases, the best-characterized downstream mediators of MLN4924's biologic effects. Cisplatin-induced cytotoxicity was augmented by depletion of CUL3, and antagonized by siCUL1 in both ES2 and SKOV3 ovarian cancer cells. This investigation identifies inhibition of neddylation as a novel mechanism for overcoming platinum resistance in vitro, and provides a strong rationale for clinical investigations of platinum and MLN4924 combinations in ovarian cancer. Mol Cancer Ther; 12(10); 1958–67. ©2013 AACR.
A Urokinase Receptor–Derived Peptide Inhibiting VEGF-Dependent Directional Migration and Vascular Sprouting
Authors: Bifulco Katia , Longanesi-Cattani Immacolata , Liguori Eleonora , Arra Claudio , Rea Domenica , Masucci Maria Teresa , De Rosa Mario , Pavone Vincenzo , Stoppelli Maria Patrizia , Carriero Maria Vincenza 
Published: August 2013

Abstract
The receptor for the urokinase-type plasminogen activator (uPAR) is a widely recognized master regulator of cell migration, and uPAR88–92 is the minimal sequence required to induce cell motility. We previously showed that soluble forms of uPAR elicit angiogenic responses through their uPAR88–92 chemotactic sequence and that the synthetic peptide SRSRY exerts similar effects. By a drug design approach, based on the conformational analysis of the uPAR88–92 sequence, we developed peptides (pERERY, RERY, and RERF) that potently inhibit signaling triggered by uPAR88–92. In this study, we present evidence that these peptides are endowed also with a clear-cut antiangiogenic activity, although to different extents. The most active, RERF, prevents tube formation by human endothelial cells exposed to SRSRY. RERF also inhibits VEGF-triggered endothelial cell migration and cord-like formation in a dose-dependent manner, starting in the femtomolar range. RERF prevents F-actin polymerization, recruitment of αvβ3 integrin at focal adhesions, and αvβ3/VEGFR2 complex formation in endothelial cells exposed to VEGF. At molecular level, the inhibitory effect of RERF on VEGF signaling is shown by the decreased amount of phospho-FAK and phospho-Akt in VEGF-treated cells. In vivo, RERF prevents VEGF-dependent capillary sprouts originating from the host vessels that invaded angioreactors implanted in mice and neovascularization induced by subcorneal implantation of pellets containing VEGF in rabbits. Consistently, RERF reduced the growth and vascularization rate of tumors formed by HT1080 cells injected subcutaneously in the flanks of nude mice, indicating that RERF is a promising therapeutic agent for the control of diseases fuelled by excessive angiogenesis such as cancer. Mol Cancer Ther; 12(10); 1981–93. ©2013 AACR.
Characterization of a New Class of Androgen Receptor Antagonists with Potential Therapeutic Application in Advanced Prostate Cancer
Authors: Li Huifang , Hassona Mohamed D.H. , Lack Nathan A. , Axerio-Cilies Peter , Leblanc Eric , Tavassoli Peyman , Kanaan Natalia , Frewin Kate , Singh Kriti , Adomat Hans , Böhm Konrad J. , Prinz Helge , Guns Emma Tomlinson , Rennie Paul S. , Cherkasov Artem 
Published: August 2013

Abstract
The human androgen receptor plays a major role in the development and progression of prostate cancer and represents a well-established drug target. All clinically approved androgen receptor antagonists possess similar chemical structures and exhibit the same mode of action on the androgen receptor. Although initially effective, resistance to these androgen receptor antagonists usually develops and the cancer quickly progresses to castration-resistant and metastatic states. Yet even in these late-stage patients, the androgen receptor is critical for the progression of the disease. Thus, there is a continuing need for novel chemical classes of androgen receptor antagonists that could help overcome the problem of resistance. In this study, we implemented and used the synergetic combination of virtual and experimental screening to discover a number of new 10-benzylidene-10H-anthracen-9-ones that not only effectively inhibit androgen receptor transcriptional activity, but also induce almost complete degradation of the androgen receptor. Of these 10-benzylidene-10H-anthracen-9-one analogues, a lead compound (VPC-3033) was identified that showed strong androgen displacement potency, effectively inhibited androgen receptor transcriptional activity, and possesses a profound ability to cause degradation of androgen receptor. Notably, VPC-3033 exhibited significant activity against prostate cancer cells that have already developed resistance to the second-generation antiandrogen enzalutamide (formerly known as MDV3100). VPC-3033 also showed strong antiandrogen receptor activity in the LNCaP in vivo xenograft model. These results provide a foundation for the development of a new class of androgen receptor antagonists that can help address the problem of antiandrogen resistance in prostate cancer. Mol Cancer Ther; 12(11); 2425–35. ©2013 AACR.