bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bortezomib‐based therapy for relapsed/refractory multiple myeloma in real‐world medical practice
Authors: Terpos Evangelos , Katodritou Eirini , de la Rubia Javier , Hungria Vania , Hulin Cyrille , Roussou Maria , Delforge Michel , Bries Greet , Stoppa Anne‐Marie , Aagesen Jesper , Sargin Deniz , Belch Andrew , Ahlberg Lucia , Diels Joris , Olie Robert A. , Robinson Don , Spencer Mike , Potamianou Anna , van de Velde Helgi , Dimopoulos Meletios A. 
Published: July 2018

AbstractObjectiveThe efficacy and safety of bortezomib‐based therapy for relapsed/refractory multiple myeloma (RRMM) in clinical trials may differ from the oncology practice experience. The electronic VELCADE® OBservational Study was designed to prospectively evaluate bortezomib for multiple myeloma (MM) in real‐world medical practice.MethodPatients scheduled to receive intravenous bortezomib for MM were eligible. The primary objective was to evaluate clinical outcomes, including response, time to response, time to next therapy, treatment‐free interval, progression‐free survival (PFS), and overall survival (OS). Secondary objectives included safety and healthcare resource utilization.ResultsIn total, 873 patients with a median of two therapy lines prior to initiating bortezomib were included. The overall response rate (≥partial response) was 69%, including 37% complete response/near‐complete response. Median time to response was 1.8 months, median time to next therapy was 9.7 months, and median treatment‐free interval was 7.9 months. After 22.6 months’ median follow‐up, median PFS was 12.0 months and median OS was 36.1 months. The most common adverse events (AEs) were neuropathy not otherwise specified (19%), diarrhea NOS, and thrombocytopenia (each 17%); 230 (26%) patients discontinued bortezomib due to AEs. Of 689 (79%) patients without baseline peripheral neuropathy (PN), the rate of new‐onset any‐grade PN increased to 51% (12% grade 3/4) by cycle 8. Overall, 244 (28%) patients were hospitalized, 372 (43%) attended an outpatient visit, and 341 (39%) underwent a diagnostic/therapeutic procedure during bortezomib treatment.ConclusionThese prospective real‐world data demonstrate the effectiveness and safety of bortezomib‐based therapy for RRMM and confirm high response rates and long OS for this population.
Secretion and fusion of biogeochemically active archaeal membrane vesicles
Authors: Johnson Tyler B. , Mach Collin , Grove Ryan , Kelly Robert , Van Cott Kevin , Blum Paul 
Published: July 2018

AbstractMicrobes belonging to the genus Metallosphaera oxidize sulfidic minerals. These organisms thrive at temperature extremes and are members of the archaeal phylum Crenarchaeota. Because they can employ a lithoautotrophic metabolism, energy availability likely limits their activity raising questions about how they conduct biogeochemical activity. Vesicles are membrane encapsulated structures produced by all biological lineages but using very different mechanisms. Across the Crenarchaeota, it has been proposed that a eukaryotic‐like Endosomal Sorting Complex Required for Transport system promotes formation of these structures but in response to unknown signals and for undefined purposes. To address such questions, Metallosphaera sedula vesicle formation and function were studied under lithoautotrophic conditions. Energy deprivation was evaluated and found to stimulate vesicle synthesis while energy excess repressed vesicle formation. Purified vesicles adhered rapidly to the primary copper ore, chalcopyrite, and formed compact monolayers. These vesicle monolayers catalyzed iron oxidation and solubilization of mineralized copper in a time‐dependent process. As these activities were membrane associated, their potential transfer by vesicle fusion to M. sedula cells was examined. Fluorophore‐loaded vesicles rapidly transferred fluorescence under environmentally relevant conditions. Vesicles from a related archaeal species were also capable of fusion; however, this process was species‐specific as vesicles from different species were incapable of fusion. In addition, vesicles produced by a copper‐resistant M. sedula cell line transferred copper extrusion capacity along with improved viability over mutant M. sedula cells lacking copper transport proteins. Membrane vesicles may therefore play a role in modulating energy‐related traits in geochemical environments by fusion‐mediated protein delivery.
Improvement in clinical outcomes and replacement factor VIII use in patients with haemophilia A after factor VIII pharmacokinetic‐guided prophylaxis based on Bayesian models with myPKFiT®
Authors: Mingot‐Castellano M. E. , Parra R. , Núñez R. , Martorell M. 
Published: July 2018

ObjectivesPatients with severe haemophilia A (HA) receive factor VIII (FVIII) replacement therapy as prophylaxis. myPKFiT®is an online medical application that allows authorized users to simulate dosing regimens with patient pharmacokinetic (PK) profiles based on only 2 blood samples. Our aim was to assess the impact of using this medical device in routine practice in terms of FVIII consumption and clinical outcomes.MethodsThirty‐six patients with severe HA on prophylaxis with Advate® were recruited in 3 centres in Spain. Annual bleeding rate (ABR), annual joint bleeding rate (AJBR) and annual FVIII consumption before and after adjustment were obtained using the patient’s clinical history (12 months before) and prospectively recorded data (12 months after), respectively. Adjustment was based on PK parameters provided by myPKFiT®, joint status and relative risk associated with physical activity and bleeding phenotype.ResultsABR and AJBR were significantly reduced after adjustment in the overall sample (−2.2 ± 1.3, P = .018 and −1.9 ± 1.2, P = .012, respectively) and in patients aged >15 years (−2.6 ± 1.4, P = .011 and −2.0 ± 1.2, P = .005, respectively). Adjustment had an effect on the individual FVIII consumption of most patients: annual amount was reduced in 18 cases and increased in 14. There was no significant effect on the mean amount (198 784 ± 110 387) compared to that used the year prior to myPKFiT®‐adjusted prophylaxis (199 466 ± 103 670; P = .737).DiscussionOur results suggest that PK‐guided prophylaxis using myPKFiT® improved clinical outcomes and optimized FVIII consumption in the study population. This personalized approach may reduce bleeding rates without significantly increasing the overall cost of FVIII therapy.
Clinical management of Anti‐TNF‐alpha‐induced psoriasis or psoriasiform lesions in inflammatory bowel disease patients: a systematic review
Authors: Melo Francisco J. , Magina Sofia 
Published: July 2018

AbstractTumor necrosis factor alpha inhibitors (anti‐TNF‐α) completely revolutionized the treatment of inflammatory bowel disease (IBD). However, anti‐TNF‐α‐induced cutaneous side effects have been increasingly reported in the literature. Particularly, psoriasis and the recently recognized psoriasiform lesions are of particular concern, as anti‐TNF‐α agents are also used in the treatment of psoriasis, seemingly reflecting an immunological paradox. The clinical management of these cutaneous lesions is particularly challenging, owing to the potential need of anti‐TNF‐α discontinuation and scarcity of other therapeutic options. Therefore, optimization of current topical and systemic therapies and incorporation of new therapeutic agents is of great interest. Our aim is to review data in the literature regarding the clinical management of these cutaneous lesions and provide a therapeutic algorithm, supported by our experience as a tertiary referral center for IBD. Although in older reports no distinction was made, anti‐TNF‐α‐induced psoriasiform lesions are not only more prevalent but also bear notable differences from classical psoriasis, possibly reflecting a different nosological entity. Onset of lesions has been related to periods of IBD remission, as supported by low levels of fecal calprotectin. Psoriasiform lesions can be adequately managed either by topical (glucocorticoids, calcineurin inhibitors, and antibiotics) or systemic (phototherapy, acitretin, glucocorticoids, and antibiotics) therapies and/or switch to other anti‐TNF‐α agents. Data referring to patients who were able to continue on the same IBD therapy ranged from 30.7 to 100%, reinforcing the importance of an adequate control of these lesions. The recently approved ustekinumab offers another step in the management of anti‐TNF‐α‐intolerant patients.
The information environment of the firm and the market valuation of R&D
Authors: Zhang Lu Y. , Toffanin Melissa 
Published: July 2018

AbstractWe examine whether firms’ information environment influences the market valuation of their hard‐to‐value knowledge assets: R&D capital. We find that a better information environment, as measured by greater analyst coverage, lower earnings forecast dispersion, and greater earnings forecasting accuracy, is associated with higher stock market valuation of firms’ R&D capital. We conduct additional analyses to rule out alternative explanations and test for the direction of causality. Our causal evidence suggests that analysts significantly reduce the information uncertainty surrounding firms’ R&D capital.
Perceptions, knowledge, and perceived barriers of Yemeni pharmacists and pharmacy technicians towards evidence‐based practice
Authors: Al‐Jamei Sayida , Abu Farha Rana , Zawiah Mohammed , Kadi Taha , Al‐Sonidar Afnan 
Published: July 2018

AbstractRational, aims, and objectiveThe aim of this study was to assess the knowledge and perception towards evidence‐based practice (EBP) and identify the perceived barriers to practicing EBP among Yemeni pharmacists and pharmacy technicians.MethodsA cross‐sectional survey study was carried out among 153 Yemeni pharmacists and pharmacy technicians who are working in hospitals or community pharmacies. This study took place between the 15th of August and the 8th of November 2017 using a self‐administered validated questionnaire. The study was approved by the ethics committee/scientific research center of Yemen University, Yemen (Reference number: ERC/2017/103).ResultsCompleted questionnaires were received from 153 (46.6% response rate). Most of the respondents showed a positive attitude towards EBP; however, their understanding of the basic terms used in EBP was poor (34.6%). The types of source that the respondent used in high percentage to make their decisions were own judgement and consulting the colleagues that can no longer be accurate and evidence based. The barriers to practicing EBP identified by most respondents were the limited access to EBP sources and lack of personal time.ConclusionThese results reveal strong support for EBP among pharmacists and pharmacy technicians in Yemen but only a minority indicated that they understood the technical terms of EBP. Training and continuing education programs on EBP and guidelines for pharmacists are strongly needed. These findings may help in planning the use and the application of EBP process in pharmacy practice.
Distribution and prevalence of T. bryosalmonae in Austria: A first survey of trout from rivers with a shrinking population
Authors: Lewisch Eva , Unfer Guenther , Pinter Kurt , Bechter Thomas , El‐Matbouli Mansour 
Published: July 2018

AbstractThe first evidence of proliferative kidney disease (PKD) in an Austrian river (the River Kamp) was documented in 2016, and no information on the PKD infection status of trout in other rivers was available. Since then, brown trout (Salmo trutta fario) and rainbow trout (Oncorhynchus mykiss) have been collected from rivers in Upper and Lower Austria for different diagnostic purposes. In this study, we summarize the recent findings of a first survey concerning the distribution of Tetracapsuloides bryosalmonae, the causative agent of proliferative kidney disease (PKD), from these samples. Between September 2015 and October 2017, a total of 280 brown trout and 39 rainbow trout were collected from 21 rivers in the provinces of Upper and Lower Austria. T. bryosalmonae was detected by PCR of kidney tissue in 17 of 21 sampled rivers and in 138 of 280 brown trout as well as in 11 of 39 rainbow trout. Pathological signs of PKD (e.g., hypertrophy of the kidney) were observed in 33 analysed brown trout and six rainbow trout samples. No correlations between fish infected by T. bryosalmonae and the parameters size and age class, condition factor, geological origin of the streams and distribution within the river course were found, while positively tested fish are significantly increased at sampling sites exceeding water temperatures of 15°C for median periods of 115 days. The prevalence within the affected streams or stream sections is highly variable, and in single rivers, infection rates of up to 90% are confirmed.
Betanodavirus infection in bath‐challenged Solea senegalensis juveniles: A comparative analysis of RGNNV, SJNNV and reassortant strains
Authors: Souto Sandra , Olveira José G. , Alonso M. Carmen , Dopazo Carlos P. , Bandín Isabel 
Published: July 2018

AbstractSenegalese sole has been shown to be highly susceptible to betanodavirus infection, although virulence differences were observed between strains. To study the mechanisms involved in these differences, we have analysed the replication in brain tissue of three strains with different genotypes during 15 days after bath infection. In addition, possible portals of entry for betanodavirus into sole were investigated. The reassortant RGNNV/SJNNV and the SJNNV strain reached the brain after 1 and 2 days postinfection, respectively. Although no RGNNV replication was detected until day 3–4 postinfection, at the end of the experiment this strain yielded the highest viral load; this is in accordance with previous studies in which sole infected with the reassortant showed more acute signs and earlier mortality than the RGNNV and SJNNV strains. Differences between strains were also observed in the possible portals of entry. Thus, whereas the reassortant strain could infect sole mainly through the skin or the oral route, and, to a minor extent, through the gills, the SJNNV strain seems to enter fish only through the gills and the RGNNV strain could use all tissues indistinctly. Taken together, all these results support the hypothesis that reassortment has improved betanodavirus infectivity for sole.
Phase equilibrium modelling and implications forP–Tdeterminations of medium‐temperature UHP eclogites, North Qaidam terrane, China
Authors: Hernández‐Uribe David , Mattinson Chris G. , Zhang Jianxin 
Published: July 2018

AbstractIn contrast to low‐Teclogites (garnet growth zoning preserved) or high‐Teclogites (garnet diffusionally homogenized at peak conditions), medium‐temperature eclogites pose additional challenges toP–Tdeterminations due to the partial preservation of garnet zoning. The Dulan area, in the southeastern part of North Qaidam ultrahigh‐pressure terrane, exposes minor eclogites hosted by ortho‐ and paragneisses. Four fresh, medium‐temperature eclogites contain the paragenesis Grt+Omp+Rt+Qz/Coe+Ph±Ky±Zo. In all samples, garnetXMgshows little zoning, suggesting diffusional modification, and precludes the use of pyrope+almandine+grossular isopleth intersections to determine aP–Tpath. However, in one sample, sharp zoning in grossular content suggests that grossular growth compositions are preserved. Since garnet pyrope+almandine compositions appear to be modified, we instead use the intersections of grossular and garnet volume isopleths to define a progradeP–Tpath. This approach yields a path from ~17 kbar and ~410°C to ~35 kbar and ~625°C with a gradient of ~5–9°C/km through the lawsonite stability field. PeakP–Tconditions determined from the intersection between Si pfu in phengite and Zr‐in‐rutile isopleths are ~26–33 kbar and ~625–700 °C for the four eclogites. These conditions are close to the limit of the lawsonite stability field, suggesting that fluid released from lawsonite breakdown may have promoted re‐equilibration at these conditions. These peak conditions are also in good agreement (within 3 kbar and 50°C) with garnet–omphacite–phengite (±kyanite) thermobarometry in three of the four samples. We regard the phengite–rutile constraints as more reliable, because they are less sensitive to uncertainties associated with ferric iron compared to conventional thermobarometry. Phase equilibrium modelling predicts that the retrograde assemblage of amphibole+zoisite formed at ~60 km. Infiltration of external fluids was likely required for the growth of these hydrous minerals. Based on the comparison ofP–Testimation methods applied in this study, we propose that the garnet grossular+volume isopleths can recover the progradeP–Tpath of medium‐temperature eclogites, and that the combination of phengite+rutile isopleths represents a more robust approach to constrain peakP–Tconditions.
High‐density lipoprotein mimetic peptide 4F mitigates amyloid‐β‐induced inhibition of apolipoprotein E secretion and lipidation in primary astrocytes and microglia
Authors: Chernick Dustin , Ortiz‐Valle Stephanie , Jeong Angela , Swaminathan Suresh K. , Kandimalla Karunya K. , Rebeck G. William , Li Ling 
Published: July 2018

AbstractThe apolipoprotein E (apoE) ε4 allele is the primary genetic risk factor for late‐onset Alzheimer's disease (AD). ApoE in the brain is produced primarily by astrocytes; once secreted from these cells, apoE binds lipids and forms high‐density lipoprotein (HDL)‐like particles. Accumulation of amyloid‐β protein (Aβ) in the brain is a key hallmark of AD, and is thought to initiate a pathogenic cascade leading to neurodegeneration and dementia. The level and lipidation state of apoE affect Aβ aggregation and clearance pathways. Elevated levels of plasma HDL are associated with lower risk and severity of AD; the underlying mechanisms, however, have not been fully elucidated. This study was designed to investigate the impact of an HDL mimetic peptide, 4F, on the secretion and lipidation of apoE. We found that 4F significantly increases apoE secretion and lipidation in primary human astrocytes as well as in primary mouse astrocytes and microglia. Aggregated Aβ inhibits glial apoE secretion and lipidation, causing accumulation of intracellular apoE, an effect that is counteracted by co‐treatment with 4F. Pharmacological and gene editing approaches show that 4F mediates its effects partially through the secretory pathway from the endoplasmic reticulum to the Golgi apparatus and requires the lipid transporter ATP‐binding cassette transporter A1. We conclude that the HDL mimetic peptide 4F promotes glial apoE secretion and lipidation and mitigates the detrimental effects of Aβ on proper cellular trafficking and functionality of apoE. These findings suggest that treatment with such an HDL mimetic peptide may provide therapeutic benefit in AD.
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Structure of monomeric full‐length ARC sheds light on molecular flexibility, protein interactions, and functional modalities
Authors: Hallin Erik I. , Eriksen Maria S. , Baryshnikov Sergei , Nikolaienko Oleksii , Grødem Sverre , Hosokawa Tomohisa , Hayashi Yasunori , Bramham Clive R. , Kursula Petri 
Published: July 2018

AbstractThe activity‐regulated cytoskeleton‐associated protein (ARC) is critical for long‐term synaptic plasticity and memory formation. Acting as a protein interaction hub, ARC regulates diverse signalling events in postsynaptic neurons. A protein interaction site is present in the ARC C‐terminal domain (CTD), a bilobar structure homologous to the retroviral Gag capsid domain. We hypothesized that detailed knowledge of the three‐dimensional molecular structure of monomeric full‐length ARC is crucial to understand its function; therefore, we set out to determine the structure of ARC to understand its various functional modalities. We purified recombinant ARC and analyzed its structure using small‐angle X‐ray scattering and synchrotron radiation circular dichroism spectroscopy. Monomeric full‐length ARC has a compact, closed structure, in which the oppositely charged N‐terminal domain (NTD) and CTD are juxtaposed, and the flexible linker between them is not extended. The modeled structure of ARC is supported by intramolecular live‐cell Förster resonance energy transfer imaging in rat hippocampal slices. Peptides from several postsynaptic proteins, including stargazin, bind to the N‐lobe, but not to the C‐lobe, of the bilobar CTD. This interaction does not induce large‐scale conformational changes in the CTD or flanking unfolded regions. The ARC NTD contains long helices, predicted to form an anti‐parallel coiled coil; binding of ARC to phospholipid membranes requires the NTD. Our data support a role for the ARC NTD in oligomerization as well as lipid membrane binding. The findings have important implications for the structural organization of ARC with respect to distinct functions, such as postsynaptic signal transduction and virus‐like capsid formation.Open PracticesOpen Science: This manuscript was awarded with the Open Materials Badge.For more information see: https://cos.io/our-services/open-science-badges/
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Adult neurogenesis and its role in brain injury and psychiatric diseases
Authors: Hayashi Yoshitaka , Jinnou Hideo , Sawamoto Kazunobu , Hitoshi Seiji 
Published: July 2018

AbstractIn the adult mammalian brain, neural stem cells (NSCs) reside in two neurogenic regions, the walls of the lateral ventricles, and the subgranular zone of the hippocampus, which generate new neurons for the olfactory bulb and dentate gyrus, respectively. These adult NSCs retain their self‐renewal ability and capacity to differentiate into neurons and glia as demonstrated by in vitro studies. However, their contribution to tissue repair in disease and injury is limited, lending credence to the claim by prominent neuropathologist Ramón y Cajal that ‘once development was ended, the founts of growth and regeneration of the axons and dendrites dried up irrevocably’. However, recent progress toward understanding the fundamental biology of adult NSCs and their role in pathological conditions has provided new insight into the potential therapeutic utility of endogenous NSCs. In this short review, we highlight two topics: the altered behavior of NSCs after brain damage and the dysfunction of NSCs and oligodendrocyte precursor cells, another type of undifferentiated cell in the adult brain, in mood affective disorders.
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