bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual inhibition of DNMTs and EZH2 can overcome both intrinsic and acquired resistance of myeloma cells to IMiDs in a cereblon‐independent manner
Authors: Dimopoulos Konstantinos , Søgaard Helbo Alexandra , Fibiger Munch‐Petersen Helga , Sjö Lene , Christensen Jesper , Sommer Kristensen Lasse , Asmar Fazila , Hermansen Niels Emil Ulrich , O'Connel Casey , Gimsing Peter , Liang Gangning , Grønbæk Kirsten 
Published: November 2017

Thalidomide and its derivatives, lenalidomide and pomalidomide (also known as IMiDs), have significantly changed the treatment landscape of multiple myeloma, and the recent discovery of cereblon (CRBN) as their direct biological target has led to a deeper understanding of their complex mechanism of action. In an effort to comprehend the precise mechanisms behind the development of IMiD resistance and examine whether it is potentially reversible, we established lenalidomide‐resistant (‐LR) and pomalidomide‐resistant (‐PR) human myeloma cell lines from two IMiD‐sensitive cell lines, OPM2 and NCI‐H929, by continuous culture in the presence of lenalidomide or pomalidomide for 4–6 months, until acquirement of stable resistance. By assessing genome‐wide DNA methylation and chromatin accessibility in these cell lines, we found that acquired IMiD resistance is associated with an increase in genome‐wide DNA methylation and an even greater reduction in chromatin accessibility. Transcriptome analysis confirmed that resistant cell lines are mainly characterized by a reduction in gene expression, identifying SMAD3 as a commonly downregulated gene in IMiD‐resistant cell lines. Moreover, we show that these changes are potentially reversible, as combination of 5‐azacytidine and EPZ‐6438 not only restored the observed accessibility changes and the expression of SMAD3, but also resensitized the resistant cells to both lenalidomide and pomalidomide. Interestingly, the resensitization process was independent of CRBN. Our data suggest that simultaneous inhibition of DNA methyl transferases and EZH2 leads to an extensive epigenetic reprogramming which allows myeloma cells to (re)gain sensitivity to IMiDs.
Melt Welding and Its Role in Fault Reactivation and Localization of Fracture Damage in Seismically Active Faults
Authors: Hayward Kathryn S. , Cox Stephen F. 
Published: November 2017

AbstractLow displacement fracture damage plays an important role in influencing the behavior and mechanical evolution of faults. Fracture damage zones influence slip behavior through changing near‐field stress orientations, altering fluid pathways and modifying fault structure. Here we use small displacement triaxial experiments to explore the development of fault zone damage, frictional lock‐up, and the generation of new faults using samples with preground faults, oriented in 5° increments between 25° and 65° relative to the shortening direction. With increasing reactivation angle, faults support higher peak normal stresses (104–845 MPa) and behavior transitions from stable sliding to stick slip. Frictional melting occurs on surfaces where stick slip is initiated, forming micron‐thick layers that locally weld asperity contacts. The extent of melt welding is correlated with normal stress and melt‐welded zones increase fault cohesion. Distribution of fracture damage adjacent to the fault is spatially correlated with melt‐welded zones and the corresponding concentrations of stress and elastic strain. In a process referred to as “adhesive wear,” fractures bypassing welded zones transfer melt‐adhered material from one side of the fault to the other, forming new geometric asperities. On faults with high reactivation angles (55°–60°) the increase in cohesive strength resulting from melt‐welded contacts drives fault lock‐up after an initial slip event; subsequent slip localizes on new, favorably oriented faults. Given their size, melt‐welded zones are likely to be short‐lived in nature but may play a significant and previously unrecognized role in the development of fault‐related damage.
Clouds, Circulation, and Climate Sensitivity in a Radiative‐Convective Equilibrium Channel Model
Authors: Cronin Timothy W. , Wing Allison A. 
Published: November 2017

AbstractTropical cloud and circulation changes are large sources of uncertainty in future climate change. This problem owes partly to the scale separation between large‐scale tropical dynamics (
km) and convective dynamics (
km), which generally requires parameterizing convection in models that resolve large‐scale dynamics, or parameterizing (or omitting) large‐scale dynamics in models that permit convection. Here we discuss simulations of radiative‐convective equilibrium (RCE) across a wide range of surface temperatures in long‐channel geometry—where the domain size and resolution marginally resolve both large‐scale dynamics and convection. Self‐aggregation of convection in these simulations spontaneously produces realistic dynamical regimes of large‐scale vertical motion. The circulation weakens with surface warming but changes in the degree of self‐aggregation depend on the metric that is used; there is no obvious trend in aggregation with warming. Surface warming causes an upward shift and decrease in area of high clouds, and a sharp decline in midlevel clouds, but no systematic trend in low cloud cover. We introduce a method for approximate radiative kernel feedback analysis in RCE, and apply it to both simulations in long‐channel geometry and in a smaller square domain. The kernel‐corrected cloud feedback is positive but its magnitude varies across temperatures. Compared to simulations that do not have aggregation, there is a more negative net feedback due to the effects of aggregation on relative humidity and cloud cover. These results are consistent with the hypothesis that self‐aggregation moderately reduces climate sensitivity.
Profiling Response to Tumor Necrosis Factor Inhibitor Treatment in Axial Spondyloarthritis
Authors: Alazmi Mansour , Sari Ismail , Krishnan Bharath , Inman Robert D. , Haroon Nigil 
Published: November 2017

ObjectiveLack of response to tumor necrosis factor inhibitor (TNFi) agents is not uncommon, encountered during the treatment of axial spondyloarthritis (SpA) patients, and it can be classified as primary lack of response (PLR) or secondary lack of response (SLR). The primary aim of this study was to evaluate factors associated with TNFi failure types and their characteristics in axial SpA.MethodsAdult axial SpA patients who were TNFi naive at the time of baseline evaluation and started receiving their first biologics for active axial disease were identified. Based on the clinical response to the first TNFi, patients were then stratified into 3 groups: PLR, SLR, and responders. Clinical, demographic, and laboratory data were collected and analyzed.ResultsThere was a total of 249 axial SpA patients in the study (70.7% male, mean ± SD age 37.3 ± 12.4 years), which included PLR (n = 62), SLR (n = 93), and responders (n = 94). PLR patients tended to be older, with a lower HLA–B27 rate, a higher percentage of nonresponder axial SpA patients, and a higher baseline Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score compared to SLR patients or responders. In multiple regression analysis, increasing age, negative HLA–B27, higher baseline BASDAI, and treatment with the soluble TNF receptor protein were the independent predictors of PLR.ConclusionPLR accounted for nearly 40% of the TNFi failures in axial SpA patients. Older age, negative HLA–B27, higher baseline disease activity, and treatment with soluble TNF receptors were the independent predictors of the primary nonresponse to TNFi.
Direct ortho‐Acyloxylation of Arenes and Alkenes by Cobalt Catalysis
Authors: Lin Cong , Chen Zhengkai , Liu Zhanxiang , Zhang Yuhong 
Published: November 2017

AbstractAn efficient protocol for the cobalt‐catalyzed acyloxylation of arenes and alkenes with the assistance of an 8‐aminoquinolyl auxiliary group is reported. In this transformation, benzoic acids, alkenyl acids, and aliphatic acids could be readily involved to afford structurally diverse esters. It is worth noting that the silver sulfate (Ag2SO4) oxidant is renewable and the directing group could be removed and recycled. The strategy represents the first successful example of transition metal‐catalyzed acyloxylation of alkenyl carboxamides C(sp2)−H bonds with carboxylic acids.magnified image
Accounting for measurement error in human life history trade‐offs using structural equation modeling
Authors: Helle Samuli 
Published: November 2017

AbstractObjectivesRevealing causal effects from correlative data is very challenging and a contemporary problem in human life history research owing to the lack of experimental approach. Problems with causal inference arising from measurement error in independent variables, whether related either to inaccurate measurement technique or validity of measurements, seem not well‐known in this field. The aim of this study is to show how structural equation modeling (SEM) with latent variables can be applied to account for measurement error in independent variables when the researcher has recorded several indicators of a hypothesized latent construct.MethodsAs a simple example of this approach, measurement error in lifetime allocation of resources to reproduction in Finnish preindustrial women is modelled in the context of the survival cost of reproduction. In humans, lifetime energetic resources allocated in reproduction are almost impossible to quantify with precision and, thus, typically used measures of lifetime reproductive effort (e.g., lifetime reproductive success and parity) are likely to be plagued by measurement error. These results are contrasted with those obtained from a traditional regression approach where the single best proxy of lifetime reproductive effort available in the data is used for inference.ResultsAs expected, the inability to account for measurement error in women's lifetime reproductive effort resulted in the underestimation of its underlying effect size on post‐reproductive survival.ConclusionsThis article emphasizes the advantages that the SEM framework can provide in handling measurement error via multiple‐indicator latent variables in human life history studies.
A localized pallidal physiomarker in cervical dystonia
Authors: Neumann Wolf‐Julian , Horn Andreas , Ewert Siobhan , Huebl Julius , Brücke Christof , Slentz Colleen , Schneider Gerd‐Helge , Kühn Andrea A. 
Published: November 2017

ObjectiveDeep brain stimulation (DBS) allows for direct recordings of neuronal activity from the human basal ganglia. In Parkinson's disease, a disease‐specific physiomarker was identified that is now used to investigate adaptive closed‐loop stimulation in first studies. In dystonia, such a physiomarker is missing.MethodsPallidal oscillations were recorded from 153 contact pairs in 27 patients. We investigated whether power amplitudes in theta and beta bands correlate with dystonic symptom severity across patients. We then projected theta power from each contact pair onto standard subcortical anatomy. In this way, we defined a theta hot spot on a group level and investigated whether proximity of the active DBS contacts to it correlated with clinical improvement.ResultsDystonic symptom severity significantly correlated with theta but not beta oscillatory amplitudes (ρ = 0.4, p = 0.009) and interhemispheric coherence (ρ = 0.5, p = 0.002). The sweet spot of theta activity localized to the posterior third of the internal pallidum and theta power correlated with proximity to this location (ρ = 0.23, p = 0.002), which coincided with 3 previously published coordinates describing optimal stimulation targets. Finally, motor improvement through pallidal long‐term DBS correlated with theta peak amplitude (ρ = 0.38, p = 0.018).InterpretationOur findings suggest that theta oscillations in the internal pallidum are robustly associated with dystonic symptoms in cervical dystonia and may be a useful biomarker for adaptive closed‐loop stimulation. Furthermore, theta oscillatory activity may have a predictive value for the clinical benefit after chronic DBS that could be used to improve intraoperative neurophysiological target mapping during electrode implantation. Ann Neurol 2017;82:912–924
Molecular Magnesium Hydrides
Authors: Mukherjee Debabrata , Okuda Jun 
Published: November 2017

AbstractSolid magnesium hydride [MgH2]∞ has been pursued as a potential hydrogen‐storage material. Organic chemists were rather interested in soluble magnesium hydride reagents from mid‐20th century. It was only in the last two decades that molecular magnesium hydride chemistry received a major boost from organometallic chemists with a series of structurally well‐characterized examples that continues to build a whole new class of compounds. More than 40 such species have been isolated, ranging from mononuclear terminal hydrides to large hydride clusters with more than 10 magnesium atoms. They provide not only insights into the structure and bonding of Mg−H motifs, but also serve as models for hydrogen‐storage materials. Some of them are also recognized to participate in catalytic transformations, such as hydroelementation. Herein, an overview of these molecular magnesium hydrides is given, focusing on their synthesis and structural characterization.
Preparation and characterization of graphene reinforced PA6 fiber
Authors: Tang Lian , Li Yiren , Chen Ye , Ji Peng , Wang Chaosheng , Wang Huaping , Huang Qing 
Published: November 2017

ABSTRACTHere, we report the successful preparation of PA6/GO composite fibers through in situ polymerization and the melting spinning method. The results suggest that graphene has induced only minor changes on the relative viscosity yet exhibits significant effects on the crystallization characteristics. The SEM images of the fibers have shown several expended borders as a consequence of graphene addition. The maximum strength of the composite fibers (5.3 cN/dtex) has been reached 0.05 wt % graphene added to the system; the draw ratio was equaled to 3.8. Compared to the neat PA6 fiber, the fibers with graphene displayed superior creep resistance features; the creep rate constant was 0.38 at a 0.05 graphene concentration, with a draw ratio of 3.5. The approach employed in this research paves the way towards PA6/graphene nanocomposites have been prepared through in situ polymerization using caprolactam and graphene oxide/water pulp as starting materials. In situ polymerization approach facilitated a superior interaction between PA6 and graphene. Compared to graphene oxide powder, the graphene oxide in water pulp has prevented the agglomeration when added to the caprolactam melt, leading to its enhanced dispersion within the system. PA6/graphene as‐spun fiber has been produced by the mean of melt‐spinning strategy using a melt‐spinning machine, obtaining products with different draw ratios after drawing at 120 °C. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018, 135, 45834.
Leaching studies on Novolac resin‐coated proppants‐performance, stability, product safety, and environmental health considerations
Authors: Horadam William , Venkat Narayanan , Tran Tuan , Bai Litao , Josyula Kanth , Mehta Vinay 
Published: November 2017

ABSTRACTUnderstanding the failure mechanisms of resin‐coated proppants under extreme environments facilitates the development of stronger proppants for superior long‐term performance in the oil and gas sector. In the current study, the leaching behavior of Novolac resin‐coated proppants (RCPs) and that of polyurethane (PU) based RCPs with aqueous media under different pH conditions and at elevated temperatures have been critically examined, to assess their chemical stability and integrity. Our study indicates that Novolac‐based RCPs are substantially more stable to leaching conditions at 250 °F compared to PU‐based RCPs. An in‐depth nuclear magnetic resonance analysis of the aqueous leachates from the RCP systems reveals that the averaged total levels of the leached components from the PU‐based RCPs is five‐ to sevenfold higher than those of the Novolac RCPs at the higher temperature. In addition, a critical examination of the Novolac RCPs from a product safety and environmental health viewpoint is accomplished by ultraviolet–visible spectrophotometric analysis of the aqueous leachates. The findings reveal that the concentrations of the phenolics, including free phenol, are lower than the detectable limits (<1 ppm) of the technique. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018, 135, 45845.
A rule of unity for human intestinal absorption 3: Application to pharmaceuticals
Authors: Patel Raj B. , Yalkowsky Samuel H. 
Published: November 2017

AbstractThe rule of unity is based on a simple absorption parameter, Π, that can accurately predict whether or not an orally administered drug will be well absorbed or poorly absorbed. The intrinsic aqueous solubility and octanol–water partition coefficient, along with the drug dose are used to calculate Π. We show that a single delineator value for Π exist that can distinguish whether a drug is likely to be well absorbed (FA ≥ 0.5) or poorly absorbed (FA < 0.5) at any specified dose. The model is shown to give 82.5% correct predictions for over 938 pharmaceuticals. The maximum well‐absorbed dose (i.e. the maximum dose that will be more than 50% absorbed) calculated using this model can be utilized as a guideline for drug design and synthesis.
Release kinetics of somatostatin from self‐assembled nanostructured hydrogels
Authors: Rai Uma , Thrimawithana Thilini R. , Dharmadana Durga , Valery Celine , Young Simon A. 
Published: November 2017

AbstractSomatostatin‐14 is a native neuropeptide with widespread functions in the body. Self‐assembly of somatostatin‐14 into amyloid‐like nanofibrils has been previously demonstrated in aqueous media. We here hypothesize that the somatostatin nanofibrils can form a stable depot that release monomers in a controlled manner. This study aims to investigate if somatostatin monomers are released from physical hydrogels formed in water and in the presence of electrolytes. The release kinetics of the somatostatin monomers is investigated for the first time. This is correlated with the rheological properties of the hydrogels formed. We demonstrate that at the concentrations tested, there is release of somatostatin monomers from the hydrogels following a novel hybrid model of zero‐order and first‐order release. In the presence of electrolytes, somatostatin hydrogels demonstrated higher elastic moduli (G′) which correlates to the narrower and higher density of nanofibrils observed with TEM. The presence of electrolytes resulted in a slower release of the somatostatin monomers and in a lower cumulative percentage released over 48 hrs. It is questionable that the concentrations released will be therapeutically effective. However, self‐assembled somatostatin hydrogels have the potential to act as a depot for ocular drug delivery.
Periprocedural transfusion in patients undergoing transfemoral transcatheter aortic valve implantation
Authors: Mayr N Patrick , Wiesner Gunther , Hapfelmeier Alexander , van der Starre Pieter , Husser Oliver , Bleiziffer Sabine , Schunkert Heribert , Lange Rüdiger , Tassani‐Prell Peter , Martin Klaus 
Published: November 2017

AbstractObjectivesThe aim of this investigation was to identify patient's characteristics and periprocedural variables related to periprocedural transfusion in transfemoral Transcatheter Aortic Valve Implantation (tf‐TAVI).BackgroundTransfusion of allogenic red‐blood cells (RBC) in tf‐TAVI and the number of transfused units has been linked to an increased 30‐day mortality. In line with the trend of minimization and cost‐effectiveness, transfusion should be avoided, wherever possible.MethodsBetween 2007 and 2015, 1,734 procedures were analyzed from our prospective registry for RBC‐transfusion. Multiple logistic regression analysis was used to identify the dependent variables.ResultsTransfusion was considered necessary in 14% (n = 243) of the patients. Female gender (OR [95% CI]) (1.680 [1.014‐2.783]) and preprocedural moderate (7.594 [4.404‐13.095]) and severe anemia (8.202 [0.900‐74.752]) according to WHO were the most important preprocedural variables. Periprocedural, pericardial effusion (12.109 [3.753‐39.063]), emergency extracorporeal circulation (54.5288 [6.178‐481.259]) and major vascular injury (2.647 [1.412‐4.962]) were related to transfusion. The same applies to moderate (4.255 [1.859‐9.740]) and severe anemia (31.567 [8.560‐116.416]) as well as periprocedural experience (0.072 [0.035‐0.149] – 0.141[0.079‐0.251], P < 0.001)ConclusionProcedural experience, serious adverse events, low pre‐ and periprocedural Hb levels and female gender were the main variables relating to transfusion. Even in experienced high‐volume centers, transfusion is still necessary in a considerable number of patients.
Thromboembolism after WATCHMANTM in a clopidogrel non‐responder: A case for concern?
Authors: Venkataraman Ganesh , Bliden Kevin P. , Tantry Udaya S. , Gurbel Paul A. 
Published: November 2017

AbstractAtrial fibrillation (AF) is associated with an increased risk of stroke and thromboembolism (TE). The WATCHMANTM left atrial appendage (LAA) closure device is indicated to reduce the risk of TE from the LAA in patients with non‐valvular AF. Here, we present a case of a patient with device‐related thrombus who suffered a TE event two months after WATCHMANTM LAA closure and two weeks after switching from aspirin plus warfarin to aspirin plus clopidogrel therapy. Laboratory investigation identified the patient to be hypercoagulable and to be a non‐responder to clopidogrel therapy. We discuss the potential role of platelet function testing to prevent device‐related thrombi.
Pushing boundaries: Implantation of the 34 mm Medtronic CoreValve in patients with a large aortic annulus
Authors: Elmously Adham , Worku Berhane , Wong S. Chiu , Salemi Arash 
Published: November 2017

AbstractThe relationship between adherence to the recommended CoreValve sizing parameters and clinical outcomes is not well known for the recently released 34 mm valve, which is currently the largest available transcatheter valve. There is a presumed temporal reduction in paravalvular regurgitation in patients who receive an in‐range valve, however, certain patients possess annular dimensions that are too large. We therefore describe two patients with annular dimensions larger than the manufacturer recommended range for the 34 mm CoreValve, who despite this underwent transcatheter aortic valve replacement with excellent clinical outcomes.