bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expansion Cohorts in First-in-Human Solid Tumor Oncology Trials
Authors: Theoret Marc R. , Pai-Scherf Lee H. , Chuk Meredith K. , Prowell Tatiana M. , Balasubramaniam Sanjeeve , Kim Tamy , Kim Geoffrey , Kluetz Paul G. , Keegan Patricia , Pazdur Richard 
Published: October 2015

Abstract
In 1962, the passage of the Kefauver–Harris Amendment to the 1938 Food, Drug, and Cosmetic Act required that sponsors seeking approval of new drugs demonstrate the drug's efficacy, in addition to its safety, through a formal process that includes “adequate and well-controlled” clinical trials as the basis to support claims of effectiveness. As a result of this amendment, FDA formalized in regulation the definitions of various phases of clinical investigations (i.e., phase I, phase II, and phase III). The clinical drug development paradigm for anticancer drugs intended to support marketing approval has historically followed this “phased” approach with sequential, stand-alone trials, with an increasing number of patients exposed to an investigational drug with each trial in order to fulfill the objectives of that particular stage in development. Increasingly, it is the Office of Hematology and Oncology Products' experience that commercial sponsors of solid tumor oncology drug development programs are amending ongoing phase I trials to add expansion cohorts designed to evaluate study objectives typical of later-phase trials. For investigational anticancer drugs that demonstrate preliminary clinical evidence of substantial antitumor activity early in clinical testing, use of expansion cohorts as a component of the solid tumor oncology drug development pathway, with appropriate measures to mitigate the risks of this approach, may fit in well with the goals and concepts described by FDA's expedited programs for serious conditions.Clin Cancer Res; 21(20); 4545–51. ©2015 AACR.
See all articles in this CCR Focus section, “Innovations to Speed Drug Development.”
The Urgent Need for Clinical Research Reform to Permit Faster, Less Expensive Access to New Therapies for Lethal Diseases
Authors: Stewart David J. , Batist Gerald , Kantarjian Hagop M. , Bradford John-Peter , Schiller Joan H. , Kurzrock Razelle 
Published: October 2015

AbstractHigh costs of complying with drug development regulations slow progress and contribute to high drug prices and, hence, mounting health care costs. If it is exorbitantly expensive to bring new therapies to approval, fewer agents can be developed with available resources, impeding the emergence of urgently needed treatments and escalating prices by limiting competition. Excessive regulation produces numerous speed bumps on the road to drug authorization. Although an explosion of knowledge could fuel rapid advances, progress has been slowed worldwide by inefficient regulatory and clinical research systems that limit access to therapies that prolong life and relieve suffering. We must replace current compliance-centered regulation (appropriate for nonlethal diseases like acne) with “progress-centered regulation” in lethal diseases, where the overarching objective must be rapid, inexpensive development of effective new therapies. We need to (i) reduce expensive, time-consuming preclinical toxicology and pharmacology assessments, which add little value; (ii) revamp the clinical trial approval process to make it fast and efficient; (iii) permit immediate multiple-site trial activation when an eligible patient is identified (“just-in-time” activation); (iv) reduce the requirement for excessive, low-value documentation; (v) replace this excessive documentation with sensible postmarketing surveillance; (vi) develop pragmatic investigator accreditation; (vii) where it is to the benefit of the patient, permit investigators latitude in deviating from protocols, without requiring approved amendments; (viii) confirm the value of predictive biomarkers before requiring the high costs of IDE/CLIA compliance; and (ix) approve agents based on high phase I–II response rates in defined subpopulations, rather than mandating expensive, time-consuming phase III trials. Clin Cancer Res; 21(20); 4561–8. ©2015 AACR.See all articles in this CCR Focus section, “Innovations to Speed Drug Development.”
Clinical Application of Prognostic Gene Expression Signature in Fusion Gene–Negative Rhabdomyosarcoma: A Report from the Children's Oncology Group
Authors: Hingorani Pooja , Missiaglia Edoardo , Shipley Janet , Anderson James R. , Triche Timothy J. , Delorenzi Mauro , Gastier-Foster Julie , Wing Michele , Hawkins Douglas S. , Skapek Stephen X. 
Published: October 2015

Abstract
Purpose: Pediatric rhabdomyosarcoma (RMS) has two common histologic subtypes: embryonal (ERMS) and alveolar (ARMS). PAX–FOXO1 fusion gene status is a more reliable prognostic marker than alveolar histology, whereas fusion gene–negative (FN) ARMS patients are clinically similar to ERMS patients. A five-gene expression signature (MG5) previously identified two diverse risk groups within the fusion gene–negative RMS (FN-RMS) patients, but this has not been independently validated. The goal of this study was to test whether expression of the MG5 metagene, measured using a technical platform that can be applied to routine pathology material, would correlate with outcome in a new cohort of patients with FN-RMS.
Experimental Design: Cases were taken from the Children's Oncology Group (COG) D9803 study of children with intermediate-risk RMS, and gene expression profiling for the MG5 genes was performed using the nCounter assay. The MG5 score was correlated with clinical and pathologic characteristics as well as overall and event-free survival.
Results: MG5 standardized score showed no significant association with any of the available clinicopathologic variables. The MG5 signature score showed a significant correlation with overall (N = 57; HR, 7.3; 95% CI, 1.9–27.0; P = 0.003) and failure-free survival (N = 57; HR, 6.1; 95% CI, 1.9–19.7; P = 0.002).
Conclusions: This represents the first, validated molecular prognostic signature for children with FN-RMS who otherwise have intermediate-risk disease. The capacity to measure the expression of a small number of genes in routine pathology material and apply a simple mathematical formula to calculate the MG5 metagene score provides a clear path toward better risk stratification in future prospective clinical trials. Clin Cancer Res; 21(20); 4733–9. ©2015 AACR.
Advancing Clinical Trials to Streamline Drug Development
Authors: Bates Susan E. , Berry Donald A. , Balasubramaniam Sanjeeve , Bailey Stuart , LoRusso Patricia M. , Rubin Eric H. 
Published: October 2015

AbstractThe last decade in oncology has been marked by the identification of numerous new potential cancer targets and even more agents designed to inhibit them. The matrix of new targets, new agents, and the companion diagnostics required to identify the right patient for the right drug has created a major challenge for the clinical trial process. This has been compounded by the addition of new immunomodulators targeting the host immune system rather than the tumor. Recognizing the need for new approaches, industry, investigators, and regulators have responded to this challenge. New clinical trial designs are being evaluated to incorporate the genomic sequence data being obtained almost routinely after cancer diagnosis. New dose-finding approaches are being proposed to identify the maximum effective dose rather than the maximum tolerated dose. The FDA is involved in the drug approval process from points early in development and has accepted registration quality data from expansion cohorts in support of drug approval. Despite progress on several fronts, many challenges remain, including the lack of predictability of preclinical data for clinical results and phase II data for phase III results, an infrastructure that can be an obstacle to clinical trial development and implementation, and the increasing use of contracted clinical research organizations that limit a fit-for-purpose approach to clinical trial execution. Perhaps most challenging and important of all are the difficulties with clinical trial accrual that can prevent study completion. Both the innovations and the challenges highlight the important role of process in progress in clinical oncology. Clin Cancer Res; 21(20); 4527–35. ©2015 AACR.See all articles in this CCR Focus section, “Innovations to Speed Drug Development.”
PROS1 genotype phenotype relationships in a large cohort of adults with suspicion of inherited quantitative protein S deficiency
Authors: Plu-Bureau Genevieve , Horellou Marie Héléne , Rauch Antoine , Suchon Pierre , Alhenc-Gelas Martine ,   for the GEHT genetic thrombophilia group
Published: October 2015

SummaryInherited protein S deficiency (PSD) is an established risk factor for venous thromboembolism (VTE). However, data are conflicting concerning risk of VTE associated with decreased free PS level (FPS) and information on PROS1 genotype-phenotype relationship is sparse. In a retrospective cohort of 579 patients with inherited type I/III deficiency suspicion, PROS1 genotyping was performed and the effect of genotype on FPS and on VTE risk was investigated. We found 116 (including 65 novel) detrimental mutations (DM) in 222 (type I/III in 194, type II in 28), PS Heerlen in 74, possibly non DM in 38 and no mutation in 245 subjects. Among DMs, type I/IIIDMs only were found in subjects with FPS<30 %. Prevalence of type I/III DM decreased with increasing FPS level. Risk of VT associated with FPS level and genotype was studied in the 467 subjects with personal or family history of thrombosis. Only type I/IIIDM carriers presented with an increased risk of VTE [1.41 (95%CI (1.05–1.89)] compared to subjects with no mutation. Among the group of type I/IIIDM heterozygotes and subjects with no mutation, the optimal FPS cut-off point for identifying subjects at increased VTE risk was searched for. We found that only subjects with FPS<30% and type I/IIIDM presented with an increased risk [1.48 (95%CI 1.08–2.04)]. Our findings confirm the value of a cut-off FPS level for identifying subjects at increased VTE risk far below the lower limit of the normal range and suggest a place for PROS1 genotyping in PSD diagnosis strategy.
Improved coagulation and haemostasis in haemophilia with inhibitors by combinations of superFactor Va and Factor VIIa
Authors: Gale Andrew J. , Griffin John H. , Mosnier Laurent O. , Bhat Vikas , Drygalski Annette von 
Published: October 2015

SummaryBypassing inhibitors in haemophilia patients is limited to activated (a) Factor(F)VII products. We introduced “FVa activity augmentation” as another bypassing strategy and studied effects of an engineered FVa variant designated superFVa. Procoagulant and clot stabilising properties of superFVa and recombinant human (rh)FVIIa, either alone or in combination, were studied in thrombin generation and clot lysis assays in normal human plasma (NHP) with or without anti-FVIII inhibitors, in haemophilia plasma, and in FVIII-deficient mice or in wild-type mice with anti-FVIII inhibitors. SuperFVa was as effective as rhFVIIa to improve thrombin generation or clot lysis. Furthermore, procoagulant effects were significantly enhanced when these compounds were combined. RhFVIIa at 40 nM (a therapeutic concentration) improved thrombin generation mildly, but markedly improved thrombin generation when combined with a low concentration (e. g. 3 nM) of superFVa. In clot lysis studies, the concentration of rhFVIIa to normalise clot lysis times could be reduced by 100-fold (e. g. from 40 nM to 0.4 nM) when combined with a low concentration (0.37 nM) of superFVa. In haemostasis studies of FVIII-deficient mice, blood loss was dose-dependently reduced by either superFVa or rhFVIIa. SuperFVa (200 U/kg) corrected mean blood loss indistinguishably from rhFVIII. Blood loss correction by rhFVIIa was greatly improved when combined with superFVa. Similar blood loss correction results were observed for therapies in wild-type mice after infusion with anti-FVIII inhibitors. Thus, superFVa may be an effective procoagulant agent in the setting of haemophilia with inhibitors and it merits further evaluation for new bypassing strategies.Supplementary Material to this article is available online at www.thrombosis-online.com.
Dabigatran treatment simulation in patients undergoing maintenance haemodialysis
Authors: Kreuzer Joerg , Brueckmann Martina , Schulze Friedrich , Liesenfeld Karl-Heinz , Clemens Andreas 
Published: October 2015

SummaryPatients with atrial fibrillation requiring maintenance haemodialysis are at increased risk of ischaemic stroke and bleeds. Currently, vitamin K antagonists such as warfarin are predominantly used in these patients as limited data are available on the use of non-vitamin K oral anticoagulants, including dabigatran etexilate (dabigatran). Dabigatran is approximately 85 % renally eliminated, thus, its half-life is prolonged in renal impairment. This study simulated the dose-exposure relationship of dabigatran in patients undergoing haemodialysis. Dabigatran exposure was modelled at once- and twice-daily doses of 75 mg, 110 mg and 150 mg and at variations in non-renal clearance and dialysis settings. Resultant dose exposure (area under the curve [AUC]) was compared with values simulated from typical patients in the RE-LY® trial (based on a previously characterised pharmacometric model). In this simulation, all twice-daily dosages resulted in exposures above those simulated from typical RE-LY patients (1.5- to 3.3-fold increase in AUC) and thus may not be optimal for use in haemodialysis patients. However, dabigatran doses of 75 mg or 110 mg once daily produced exposures comparable to those simulated in typical RE-LY patients (-13.3 and +4.4 %, respectively). Of patient and dialysis variables, non-renal clearance had the highest impact on exposure (≤30.8 % change). These data could potentially inform dose selection in patients undergoing maintenance haemodialysis and the findings warrant investigation in future clinical trials.
O espelho invertido
Authors: Giannotti Marco 
Published: October 2015

O objetivo deste artigo é discutir de que modo a pintura dos imigrantes japoneses residentes no Brasil está de alguma maneira relacionada ao que o Japão produziu nos períodos moderno e contemporâneo. Ao longo de sua pesquisa, o autor constatava com espanto que a grande maioria dos japoneses não fazia ideia da importância cultural que possuem seus imigrantes para o contexto brasileiro. A conclusão primeira era a de que seria muito difícil estabelecer uma comparação direta entre os dois grupos sem levar em consideração um estilo internacional (americano e europeu), bem como a personalidade e o estilo dos artistas abordados.
Investigação e arte: enunciação e propósitos
Authors: Laranjo Francisco 
Published: October 2015

Pretendemos refletir sobre o que se depara ao artista enquanto criador e investigador, ao mesmo tempo em que olhamos o universo da criação e investigação contemporâneas nas instituições universitárias e museológicas. Uma abordagem ao que se pode entender por criação e investigação legitimadas, é ainda alvo de atenção.
Obra expandida: as vanguardas e o regime alográfico
Authors: Freitas Artur 
Published: October 2015

Este texto é um ensaio de interpretação a respeito do caráter “múltiplo” e “projetual” de determinadas obras de vanguarda a partir da “teoria dos regimes de imanência” de Nelson Goodman e Gérard Genette. Por hipótese, suporemos que a aceitação do chamado “regime alográfico” no âmbito das artes visuais tenha sido responsável, no contexto histórico das vanguardas, pelo surgimento de obras de arte “projetuais”.
Projection of Climate Change Influences on U.S. West Nile Virus Vectors
Authors: Brown Heidi E. , Young Alex , Lega Joceline , Andreadis Theodore G. , Schurich Jessica , Comrie Andrew 
Published: October 2015

Abstract
While estimates of the impact of climate change on health are necessary for health care planners and climate change policy makers, models to produce quantitative estimates remain scarce. This study describes a freely available dynamic simulation model parameterized for three West Nile virus vectors, which provides an effective tool for studying vectorborne disease risk due to climate change. The Dynamic Mosquito Simulation Model is parameterized with species-specific temperature-dependent development and mortality rates. Using downscaled daily weather data, this study estimates mosquito population dynamics under current and projected future climate scenarios for multiple locations across the country. Trends in mosquito abundance were variable by location; however, an extension of the vector activity periods, and by extension disease risk, was almost uniformly observed. Importantly, midsummer decreases in abundance may be offset by shorter extrinsic incubation periods, resulting in a greater proportion of infective mosquitoes. Quantitative descriptions of the effect of temperature on the virus and mosquito are critical to developing models of future disease risk.
Strategic Capabilities for Public Sector-led Innovation: Managing Knowledge Worker Deployment at and Quality Performance of Public R&D Laboratories in India
Authors: Roy Santanu , Mitra Jay 
Published: October 2015

We investigate critically the relationship between the knowledge, capabilities of research and development (R&D) personnel, the structure and functions of public R&D laboratories in India and their quality performance record. Our objective is to assess whether this relationship create conditions that are conducive to innovation in developing economy contexts. We draw on theories of R&D management, organisation learning, knowledge management and strategic capability to reflect on contextual complexities that arise as a result of the nature of knowledge-based resources of research organisations. We deploy correspondence analysis and use this method to explore the structure of multivariate relationships among the different laboratories in the analysis, showing how various functions impact on effective R&D management and quality performance measured in terms of patents, publications and citations. We find that strategic innovation practices are essential for supporting pilot plants, experimental field stations and in the engineering and design units. We generate a map of laboratories capturing the innovation continuum as distinguished by their in-built strength in basic research, engineering and design services or the working of pilot plants. The article has particular implications for public R&D management for innovation in a developing economy context where the public sector continues to play a significant role in economic development. It should assist with organising public R&D management for innovation in an emerging economy, a relatively under-researched area. It should also help R&D management practitioners to navigate their way effectively in delivering effective performance outcomes at a time of rapid economic change.
N-WASP is required for B-cell–mediated autoimmunity in Wiskott-Aldrich syndrome
Authors: Volpi Stefano , Santori Elettra , Abernethy Katrina , Mizui Masayuki , Dahlberg Carin I. M. , Recher Mike , Capuder Kelly , Csizmadia Eva , Ryan Douglas , Mathew Divij , Tsokos George C. , Snapper Scott , Westerberg Lisa S. , Thrasher Adrian J. , Candotti Fabio , Notarangelo Luigi D. 
Published: October 2015

Key PointsMice lacking both WASP and N-WASP in B lymphocytes have impaired response to T-cell-dependent antigens and defective B-cell activation. Deletion of N-WASP in B cells attenuates autoimmunity in WASP-deficient mice.
Molecular phylogenetics reveals convergent evolution in lower Congo River spiny eels
Authors: Alter S. Elizabeth , Brown Bianca , Stiassny Melanie L. J. 
Published: October 2015

AbstractBackgroundThe lower Congo River (LCR) is a region of exceptional species diversity and endemism in the Congo basin, including numerous species of spiny eels (genusMastacembelus). Four of these exhibit distinctive phenotypes characterized by greatly reduced optic globes deeply embedded into the head (cryptophthalmia) and reduced (or absent) melanin pigmentation, among other characteristics. A strikingly similar cryptophthalmic phenotype is also found in members of a number of unrelated fish families, strongly suggesting the possibility of convergent evolution. However, little is known about the evolutionary processes that shaped diversification in LCRMastacembelus, their biogeographic origins, or when colonization of the LCR occurred.MethodsWe sequenced mitochondrial and nuclear genes fromMastacembelusspecies collected in the lower Congo River, and compared them with other African species and Asian representatives as outgroups. We analyzed the sequence data using Maximum Likelihood and Bayesian phylogenetic inference.ResultsBayesian and Maximum Likelihood phylogenetic analyses, and Bayesian coalescent methods for species tree reconstruction, reveal that endemic LCR spiny eels derive from two independent origins, clearly demonstrating convergent evolution of the cryptophthalmic phenotype.Mastacembelus crassus,M. aviceps, andM. simbiform a clade, allied to species found in southern, eastern and central Africa. Unexpectedly,M. brichardiandbrachyrhinusfall within a clade otherwise endemic to Lake Tanganikya (LT) ca. 1500 km east of the LCR. Divergence dating suggests the ages of these two clades of LCR endemics differ markedly. The age of thecrassusgroup is estimated at ~4 Myr while colonization of the LCR by thebrichardi-brachyrhinusprogenitor was considerably more recent, dated at ~0.5 Myr.ConclusionsThe phylogenetic framework of spiny eels presented here, the first to include LCR species, demonstrates that cryptophthalmia and associated traits evolved at least twice inMastacembelus: once inM. brichardiand at least once in theM. crassusclade. Timing of diversification is broadly consistent with the onset of modern high-energy flow conditions in the LCR and with previous studies of endemic cichlids. The close genetic relationship betweenM. brichardiandM. brachyrhinusis particularly notable given the extreme difference in phenotype between these species, and additional work is needed to better understand the evolutionary history of diversification in this clade. The findings presented here demonstrate strong, multi-trait convergence in LCR spiny eels, suggesting that extreme selective pressures have shaped numerous phenotypic attributes of the endemic species of this region.