bluuebunny/crossref_metadata_2025_split huggingface dataset:
DO WE HAVE A CONSENSUS TO APPLY MODEL-BASED AMINOGLYCOSIDE THERAPY: A REVIEW OF POPULATION PHARMACOKINETIC MODELS
Authors: Hao Guo-Xiang , Teng Sophie , Jacqz-Aigrain Evelyne , Zhao Wei 
Published: December 2015

Background and ObjectiveAminoglycosides remain the standard antibiotic therapy for Gram-negative infections in both adults and children. The pharmacokinetic modeling approach has been widely used to evaluate aminoglycosides therapy. The aim of the present study is to review the published population pharmacokinetic models of commonly used aminoglycosides (gentamycin, amikacin and tobramycin), in order to determine if there was a consensus to apply model-based personalized aminoglycoside therapy in routine clinical practice.MethodsThe bibliographic search was performed electronically using PubMed on 30th January 2015, following the search strategy: “((population Pharmacokinetics) OR (Pharmacokinetic modeling)) AND (gentamycin OR gentamicin OR amikacin OR tobramycin)”.ResultsA total of 49 articles were identified. Persistent variabilities exist in terms of structure model; typical pharmacokinetic parameters and identified covariates.ConclusionA pharmacokinetic meta-analysis is required to evaluate the study-related factors influencing the pharmacokinetics of aminoglycosides. A clinical evaluation of pharmacokinetic model of aminoglycosides is required to demonstrate its clinical utility.
USE OF FLUOROQUINOLONES IN HOSPITALIZED CHILDEN, PRELIMINARY REPORT OF A CHART REVIEW IN A BELGIAN UNIVERSITY CHILDREN'S HOSPITAL
Authors: Meesters Kevin , Bruyne Pauline De , Mauel Reiner , Walle Johan Vande 
Published: December 2015

According to international guidelines, fluoroquinolones (FQ) should only be prescribed to children when there is no alternative antibiotic. FQ resistance is a rapidly growing problem worldwide. We hypothesize that FQ are frequently prescribed off-label in children. To confirm this hypothesis, we analyzed FQ prescriptions for hospitalized children in a Belgian university hospital.MethodWe reviewed all prescriptions of FQ for children up to 17 years of age who were hospitalized at Universitair Ziekenhuis Brussel, a Belgian university children's hospital, in the period 2010–2013. Patient characteristics, indication for the FQ prescription and microbial cultures were obtained from the medical file. The study was approved by the institutional review board.ResultsAs we foresee to finish our data analysis by the end of April 2015, we present results of our interim analysis here. Until now, a total of 178 FQ prescriptions in 79 children were analyzed. The majority of children had major comorbidities such as childhood cancer, cystic fibrosis or inflammatory bowel disease. FQ prescription was based on a microbial culture in 15.4% of cases. Frequent indications for FQ prescription were Pseudomonas eradication in cystic fibrosis patients, long term antibiotic prophylaxis in neutropenic patients and wound infections. Prescribed daily doses and consumed daily doses varied widely, even for the same indication. Concomitant medications were common and included mainly other antibiotics, steroids and chemotherapeutics.ConclusionFQ were used as ‘reserve antibiotic,' and so on-label, in a minority of all FQ prescriptions for hospitalized children.
DESIGN OF A EUROPEAN SURVEY ON THE PHARMACOLOGICAL MANAGEMENT OF PAEDIATRIC HEART FAILURE
Authors: Díez Cristina Castro , Khalil Feras , Dalinghaus Michiel , Meulen Marijke van der , de Wildt Saskia , Jovanović Ida , Bajčetić Milica , Burch Michel , Male Christoph , Läer Stephanie 
Published: December 2015

BackgroundLittle evidence is presently available to help clinicians guide decisions when tackling the pharmacological management of paediatric heart failure (HF). As a consequence, therapeutic strategies are largely supported by adults' data extrapolation and own expertise. The variability in drug treatment routines across Europe is expected to be high. Nevertheless, there are no epidemiological data that describe the current situation.AimTo develop a survey in the context of the LENA project to characterise the different therapeutic strategies for the management of paediatric HF that are currently practiced across Europe with special focus in the use of Angiotensin Converting Enzyme Inhibitors (ACE-I).MethodsItems to be included in the survey were selected through a thorough literature review and expert group discussions. European hospitals providing paediatric cardiology care were identified using websites of European and national paediatric cardiology associations as well as the ones of congresses and conferences related to the field. Standard recommendations for survey design were followed. The study protocol was approved by a data protection officer and an ethics committee. Web-survey tool EvaSys® was used. The survey was pre- and pilot-tested by a group of experts. A statistical analysis plan for the later processing and analysis of the data to be obtained was elaborated.ResultsA Europe-wide web-based survey was started in January 2015. 203 clinicians were invited via e-mail to participate. The questionnaire consisted of 23 questions addressing different aspects of drug therapy for HF in children. Use patterns of ACE-I (dosage by age group, effectiveness and toxicity assessment, use according to HF aetiology) and drug therapy for dilated cardiomyopathy where explored. Participants' demographic characteristics were also asked.ConclusionsThe procedure followed for the survey development should assure the quality of the tool. The results of this survey will provide an overview of the clinical treatment routine of paediatric heart failure across Europe.The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA).The following authors will also be included in the later poster: Ingrid Klingmann (PHARMAPLEX BVBA, Germany), András Szatmári (GOTTSEGEN GYORGY ORSZAGOS KARDIOLOGIAI INTEZET, Hungary), László Ablonczy (GOTTSEGEN GYORGY ORSZAGOS KARDIOLOGIAI INTEZET, Hungary), Holger Schwender (HEINRICH-HEINE-UNIVERSITÄT DÜSSELDORF, GERMANY)
PHARMACEUTICAL CARE OF ADOLESCENTS WITH DIABETES MELLITUS TYPE 1: THE DIADEMA STUDY, A RANDOMIZED CONTROLLED TRIAL
Authors: Obarčanin Emina , Krueger Manfred , Mueller Petra , Nemitz Verena , Schwender Holger , Hasanbegović Sniježana , Kalajdzisalihovic Sena , Läer Stephanie 
Published: December 2015

BackgroundAdolescents with type 1 diabetes mellitus (T1DM) often show low adherence to complex insulin regimens, leading to poor glycemic control. The benefit of pharmaceutical care in adults with diabetes mellitus type 2 (T2DM) has been widely explored; however, evidence in adolescents with T1DM remains scarce.ObjectiveTo evaluate the impact of pharmaceutical care in adolescents with T1DM provided by a multidisciplinary team on multiple important clinical outcomes.SettingAt the outpatient Helios Paediatric Clinic and at the 12 regular community pharmacies of the study patients with 14 pharmacists in the Krefeld area, Germany, and at the University Pediatric Clinic with one pharmacist on-site in Sarajevo, Bosnia-Herzegovina.MethodsA randomized, controlled, prospective, multicenter study in 68 adolescents with T1DM. The intervention group received monthly structured pharmaceutical care delivered by pharmacists plus supplementary phone calls for 6 months. The control group received usual diabetic care. Data were collected at baseline and after 3 and 6 months. In addition, HbA1c was measured after 12 months.Main outcome measures The between-group difference in the change from baseline in glycosylated hemoglobin (HbA1c), the number of severe hypoglycemic events in both groups, and patient well-being in the intervention group.ResultsThe improvement from baseline in HbA1c was significantly greater in the intervention group than in the control group after 6 months (change from baseline −0.54 vs. +0.32%, p=0.0075), even after adjustment for country-specific variables (p=0.0078). However, the effect was more pronounced after only 3 months (−1.09 vs. +0.23%, p=0.00002). There was no significant between-group difference in the number of severe hypoglycemia events. After 6 months, the well-being according to the WHO-5 index in the intervention group increased significantly from 52.8% to 63.3%. After 12 months the mean total HbA1c remained significantly reduced in the intervention compared to the control group (8.6% vs. 9.5%, p=0.0184).ConclusionThe improved outcomes seen in this study provide new evidence that pharmaceutical care adds value to the management of T1DM in adolescents. However, the optimal methods of achieving sustained long-term improvements in this specific patient population require further study.
Resolution of incontinence using an artificial urethral sphincter in feline genitourinary dysplasia
Authors: Roundell Candice D G , Friend Edward James 
Published: December 2015

Limited information exists about surgical techniques to treat incontinence in cats. In this case, a four‐month‐old female entire domestic shorthair cat was presented with a history of severe urinary incontinence. Contrast studies supported a diagnosis of genitourinary and urethral dysplasia with urethral sphincter mechanism incompetence (USMI). The incontinence was unresponsive to medical treatment. At 10 months old, an artificial urethral sphincter (AUS) was surgically placed, restoring urinary continence completely. This case report demonstrates that an AUS—a technique previously described only for treatment in dogs with refractory incontinence—may be suitable for the management of refractory USMI in cats with congenital urinary incontinence. Also, in cases of persistent or recurrent incontinence, and at any time subsequent to the surgery, an increase in pressure around the urethra can be achieved, non‐invasively, by inflating the AUS's percutaneous occluder.
Late Cretaceous–Cenozoic tectonic transition from collision to transtension, Honduran Borderlands and Nicaraguan Rise, NW Caribbean Plate boundary
Authors: Sanchez Javier , Mann Paul , Emmet Peter A. 
Published: December 2015

Abstract
Northern Honduras and its offshore area include an active transtensional margin separating the Caribbean and North American plates. We use deep-penetration seismic-reflection lines combined with gravity and magnetic data to describe two distinct structural domains in the Honduran offshore area: (1) an approximately 120 km-wide Honduran Borderlands (HB) adjacent to the Cayman Trough characterized by narrow rift basins controlled by basement-involving normal faults subparallel to the margin; and (2) the Nicaraguan Rise (NR), characterized by small-displacement normal faulting and sag-type basins influenced by Paleocene–Eocene shelf sedimentation beneath an Oligocene–Recent, approximately 1–2 km-thick carbonate platform. Thinning of continental crust from 25–30 km beneath the NR to 6–8 km beneath the oceanic Cayman Trough is attributed to an Oligocene–Recent phase of transtension. Five tectonostratigraphic phases established in the HB and NR include: (1) a Late Cretaceous uplift in the north and south-dipping thrusting related to the collision in the south, between the Chortis continental block and arc and oceanic plateau rocks of the Caribbean; (2) Eocene sag basins in the NR and minor extension in the HB; two phases (3) and (4) of accelerated extension (transtension) across the subsidence mainly of the HB; and (5) Pliocene–Recent minor fault activity in the HB and a stable carbonate platform in the NR.
The Slottsmøya marine reptile
Lagerstätte
: depositional environments, taphonomy and diagenesis
Authors: Delsett Lene L. , Novis Linn K. , Roberts Aubrey J. , Koevoets Maayke J. , Hammer Øyvind , Druckenmiller Patrick S. , Hurum Jørn H. 
Published: December 2015

Abstract

The Late Jurassic Slottsmøya Member
Lagerstätte
on Spitsbergen offers a unique opportunity to study the relationships between vertebrate fossil preservation, invertebrate occurrences and depositional environment. In this study, 21 plesiosaurian and 17 ichthyosaur specimens are described with respect to articulation, landing mode, preservation, and possible predation and scavenging. The stratigraphic distribution of marine reptiles in the Slottsmøya Member is analysed, and a correlation between high total organic content, low oxygen levels, few benthic invertebrates and optimal reptile preservation is observed. A new model for 3D preservation of vertebrates in highly compacted organic shales is explained.

Supplementary material:

A taphonomic description of each marine reptile specimen is available at
https://doi.org/10.6084/m9.figshare.c.2133549
The Evolving Scale and Profile of Cancer Worldwide: Much Ado About Everything
Authors: Bray Freddie 
Published: December 2015

Abstract
Today, cancer is responsible for one in three premature deaths from noncommunicable diseases worldwide, and the number of annual cancer diagnoses will rise to well over 20 million by the year 2030. That cancer is of profound importance to future global health reflects both recent gains in human development as well as mortality transitions that are centuries old. Still, cancer is complex, and the extensive geographical and temporal heterogeneity alerts us to the need for targeted, local approaches to cancer control. The study of trends in specific cancer types remains essential in monitoring and evaluating such strategies and as a descriptive tool for hypothesizing possible contributory factors. Of greatest necessity is an expansion of the availability of high-quality data. To improve the limited cancer incidence data available in low- and middle-income countries (LMIC), the Global Initiative for Cancer Registry Development (http://gicr.iarc.fr) is an international partnership supporting countries to redraw the surveillance map. Cancer Epidemiol Biomarkers Prev; 25(1); 3–5. ©2015 AACR.
See related article by Torre et al., p. 16
CCR 20th Anniversary Commentary: Autologous T Cells—The Ultimate Personalized Drug for the Immunotherapy of Human Cancer
Authors: Rosenberg Steven A. 
Published: December 2015

Abstract
The article by Rosenberg and colleagues, which was published in the July 1, 2011, issue of Clinical Cancer Research, demonstrated the power of the adoptive transfer of autologous antitumor T cells to mediate the complete, durable, and likely curative regression of cancer in patients with heavily pretreated metastatic melanoma. It also provided a stimulus to the development of cell transfer approaches for other cancer types using both natural and genetically engineered lymphocytes. Clin Cancer Res; 21(24); 5409–11. ©2015 AACR.
See related article by Rosenberg et al., Clin Cancer Res 2011;17(13) July 1, 2011;4550–7
A Phase Ib/II Study of Afatinib in Combination with Nimotuzumab in Non–Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib
Authors: Lee Ji Yun , Sun Jong-Mu , Lim Sung Hee , Kim Hae Su , Yoo Kwai Han , Jung Ki Sun , Song Haa-Na , Ku Bo Mi , Koh Jiae , Bae Yeon-Hee , Lee Se-Hoon , Ahn Jin Seok , Park Keunchil , Ahn Myung-Ju 
Published: December 2015

Abstract
Purpose: In this phase Ib/II study, we aimed to assess the safety and efficacy of afatinib plus nimotuzumab (N) in advanced non–small cell lung cancer (NSCLC) patients with acquired resistance to gefitinib or erlotinib.
Experimental Design: In phase Ib stage, patients received afatinib (40 mg or 30 mg once daily) plus nimotuzumab (100 mg or 200 mg once weekly) for 28-day cycles to determine the recommended phase II dose (RPIID). The safety and efficacy of RPIID dose was evaluated in phase II stage.
Results: In total, 50 patients were enrolled (13 to phase Ib and 37 to phase II). In the first dose-finding cohort (afatinib 40 mg plus nimotuzumab 100 mg), one patient experienced dose-limiting toxicity (DLT) of grade 3 diarrhea and in the subsequent cohort (afatinib 40 mg plus nimotuzumab 200 mg), two DLTs (grade 3 diarrhea and grade 3 neutropenia) occurred in 2 of 6 patients. Accordingly, RPIID was determined as afatinib 40 mg plus nimotuzumab 100 mg. In 44 patients treated with RPIID, 7 (16%) patients had grade 3 toxicities; skin rash (7%), diarrhea (5%), acne (2%), and fatigue (2%). The overall response rate was 23% and the median duration of response was 4.3 months (range, 0.7–16.2 months). The median progression-free survival and overall survival were 4.0 months [95% confidence interval (CI), 2.3–5.7 months] and 11.7 months (95% CI, 9.4–14.0 months), respectively.
Conclusions: Combination treatment of afatinib and nimotuzumab demonstrated an acceptable safety profile and encouraging antitumor activity in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib. Larger phase III trial is warranted to confirm its efficacy and safety. Clin Cancer Res; 22(9); 2139–45. ©2015 AACR.
Expression and Function of Phosphodiesterase Type 5 in Human Breast Cancer Cell Lines and Tissues: Implications for Targeted Therapy
Authors: Catalano Stefania , Campana Antonella , Giordano Cinzia , Győrffy Balázs , Tarallo Roberta , Rinaldi Antonio , Bruno Giuseppina , Ferraro Aurora , Romeo Francesco , Lanzino Marilena , Naro Fabio , Bonofiglio Daniela , Andò Sebastiano , Barone Ines 
Published: December 2015

Abstract
Purpose: By catalyzing cGMP hydrolysis, phosphodiesterase (PDE) 5 is a critical regulator of its concentration and effects in different (patho)physiologic processes, including cancers. As PDE5 is a known druggable target, we investigated the clinical significance of its expression in breast cancer and the underlying mechanisms by which it may contribute to tumor progression.
Experimental Design: PDE5 expression was evaluated in seven breast cancer cell lines by RT-PCR and immunoblotting. To examine the impact of PDE5 on cancer phenotype, MCF-7 cells expressing lower levels of the enzyme were engineered to stably overexpress PDE5. Proliferation was evaluated by MTT assays, motility and invasion by wound-healing/transmigration/invasion assays, transcriptome-profiling by RNA-sequencing, and Rho GTPase signaling activation by GST-pulldown assays and immunoblotting. Clinical relevance was investigated by IHC on tissues and retrospective studies from METABRIC cohort.
Results: PDE5 is differentially expressed in each molecular subtype of both breast cancer cell lines and tissues, with higher levels representing a startling feature of HER2-positive and triple-negative breast cancers. A positive correlation was established between elevated PDE5 levels and cancers of high histologic grade. Higher PDE5 expression correlated with shorter patient survival in retrospective analyses. On molecular level, stable PDE5 overexpression in Luminal-A–like MCF-7 cells resulted in enhanced motility and invasion through Rho GTPase signaling activation. Treatment of PDE5-stable clones with selective ROCK or PDE5 inhibitors completely restored the less motile and weak invasive behavior of control vector cells.
Conclusions: PDE5 expression enhances breast cancer cell invasive potential, highlighting this enzyme as a novel prognostic candidate and an attractive target for future therapy in breast cancers. Clin Cancer Res; 22(9); 2271–82. ©2015 AACR.
A Novel Crizotinib-Resistant Solvent-Front Mutation Responsive to Cabozantinib Therapy in a Patient with ROS1-Rearranged Lung Cancer
Authors: Drilon Alexander , Somwar Romel , Wagner Jacob P. , Vellore Nadeem A. , Eide Christopher A. , Zabriskie Matthew S. , Arcila Maria E. , Hechtman Jaclyn F. , Wang Lu , Smith Roger S. , Kris Mark G. , Riely Gregory J. , Druker Brian J. , O'Hare Thomas , Ladanyi Marc , Davare Monika A. 
Published: December 2015

Abstract
Purpose: Rearranged ROS1 is a crizotinib-sensitive oncogenic driver in lung cancer. The development of acquired resistance, however, poses a serious clinical challenge. Consequently, experimental and clinical validation of resistance mechanisms and potential second-line therapies is essential.
Experimental Design: We report the discovery of a novel, solvent-front ROS1D2033N mutation in a patient with CD74-ROS1–rearranged lung adenocarcinoma and acquired resistance to crizotinib. Crizotinib resistance of CD74-ROS1D2033N was functionally evaluated using cell-based assays and structural modeling.
Results: In biochemical and cell-based assays, the CD74-ROS1D2033N mutant demonstrated significantly decreased sensitivity to crizotinib. Molecular dynamics simulation revealed compromised crizotinib binding due to drastic changes in the electrostatic interaction between the D2033 residue and crizotinib and reorientation of neighboring residues. In contrast, cabozantinib binding was unaffected by the D2033N substitution, and inhibitory potency against the mutant was retained. Notably, cabozantinib treatment resulted in a rapid clinical and near-complete radiographic response in this patient.
Conclusions: These results provide the first example of successful therapeutic intervention with targeted therapy to overcome crizotinib resistance in a ROS1-rearranged cancer. Clin Cancer Res; 22(10); 2351–8. ©2015 AACR.
DNA Alkylating Agent Protects Against Spontaneous Hepatocellular Carcinoma Regardless of O6-Methylguanine-DNA Methyltransferase Status
Authors: Herzig Maryanne C.S. , Zavadil Jessica A. , Street Karah , Hildreth Kim , Drinkwater Norman R. , Reddick Traci , Herbert Damon C. , Hanes Martha A. , McMahan C. Alex , Reddick Robert L. , Walter Christi A. 
Published: December 2015

Abstract
Hepatocellular carcinoma is increasingly important in the United States as the incidence rate rose over the last 30 years. C3HeB/FeJ mice serve as a unique model to study hepatocellular carcinoma tumorigenesis because they mimic human hepatocellular carcinoma with delayed onset, male gender bias, approximately 50% incidence, and susceptibility to tumorigenesis is mediated through multiple genetic loci. Because a human O6-methylguanine-DNA methyltransferase (hMGMT) transgene reduces spontaneous tumorigenesis in this model, we hypothesized that hMGMT would also protect from methylation-induced hepatocarcinogenesis. To test this hypothesis, wild-type and hMGMT transgenic C3HeB/FeJ male mice were treated with two monofunctional alkylating agents: diethylnitrosamine (DEN; 0.025 μmol/g body weight) on day 12 of life with evaluation for glucose-6-phosphatase-deficient (G6PD) foci at 16, 24, and 32 weeks or N-methyl-N-nitrosurea (MNU; 25 mg MNU/kg body weight) once monthly for 7 months starting at 3 months of age with evaluation for liver tumors at 12 to 15 months of age. No difference in abundance or size of G6PD foci was measured with DEN treatment. In contrast, it was unexpectedly found that MNU reduces liver tumor prevalence in wild-type and hMGMT transgenic mice despite increased tumor prevalence in other tissues. hMGMT and MNU protections were additive, suggesting that MNU protects through a different mechanism, perhaps through the cytotoxic N7-alkylguanine and N3-alkyladenine lesions which have low mutagenic potential compared with O6-alkylguanine lesions. Together, these results suggest that targeting the repair of cytotoxic lesions may be a good preventative for patients at high risk of developing hepatocellular carcinoma. Cancer Prev Res; 9(3); 245–52. ©2015 AACR.