bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trajectories of health‐related quality of life during the natural history of dementia: a six‐wave longitudinal study
Authors: Yu Hongmei , Gao Caihong , Zhang Yanbo , He Runlian , Zhou Liye , Liang Ruifeng 
Published: July 2016

ObjectiveThe objective of this study was to explore profiles of quality of life (QoL) trajectories during the natural history of dementia and individual variations contributing to QoL trajectories.MethodsWe conducted a longitudinal community‐based study of 520 elderly people with mild cognitive impairment and 100 healthy people aged 60 years or over. We conducted six waves of assessment between October 2010 and May 2013 in Taiyuan, mainland China. Cognitively normal, mild cognitive impairment, global impairment, and Alzheimer's disease (AD) were defined as state 1, 2, 3, and 4, respectively. We assessed health‐related QoL (HRQoL) via the Quality of Life–Alzheimer's Disease (QoL–AD) Chinese version. We used the latent growth curve model (LGCM) to investigate change in HRQoL over time.ResultsLatent growth curve model analysis revealed a mean initial QoL level of 29.865 with substantial variation and a significant mean slope for the whole sample. Multigroup LGCM showed substantial variations across individuals in initial QoL levels for each cognitive state transition group. For the slope factor, we found significant changes and variations for the transition from state 2 to 3 and from state 3 to 4. We estimated mean QoL levels over six assessments based on intercept, slope, and factor loadings for the whole sample and the three cognitive state transition groups.ConclusionsA decline in subjective QoL is not inevitable during the natural history of dementia in community settings, and there is a degree of individual variation in QoL. Future studies should investigate the factors associated with individual variations in QoL trajectories in AD.
Mutant p53 and mTOR/PKM2 regulation in cancer cells
Authors: Dando Ilaria , Cordani Marco , Donadelli Massimo 
Published: July 2016

AbstractMutations of TP53 gene are the most common feature in aggressive malignant cells. In addition to the loss of the tumor suppressive role of wild‐type p53, hotspot mutant p53 isoforms display oncogenic proprieties notoriously referred as gain of functions (GOFs) which result in chemoresistance to therapies, genomic instability, aberrant deregulation of cell cycle progression, invasiveness and enhanced metastatic potential, and finally, in patient poor survival rate. The identification of novel functional oncogenic pathways regulated by mutant p53 represent and intriguing topic for emerging therapies against a broad spectrum of cancer types bearing mutant TP53 gene. Mammalian target of rapamycin (mTOR), as well as pyruvate kinase isoform M2 (PKM2) are master regulators of cancer growth, metabolism, and cell proliferation. Herein, we report that GOF mutant R175H and R273H p53 proteins trigger PKM2 phosphorylation on Tyr 105 through the involvement of mTOR signaling. Our data, together with the newly discovered connection between mutant p53 and mTOR stimulation, raise important implications for the potential therapeutic use of synthetic drugs inhibiting mTOR/PKM2 axis in cancer cells bearing mutant TP53 gene. We further hypothesize that mTOR/PKM2 pathway stimulation serves to sustain the oncogenic activity of mutant p53 through both the enhancement of chemoresistance and of aerobic glycolysis of cancer cells. © 2016 IUBMB Life, 68(9):722–726, 2016
More Power to OATP1B1: An Evaluation of Sample Size in Pharmacogenetic Studies Using a Rosuvastatin PBPK Model for Intestinal, Hepatic, and Renal Transporter‐Mediated Clearances
Authors: Emami Riedmaier Ariane , Burt Howard , Abduljalil Khaled , Neuhoff Sibylle 
Published: July 2016

AbstractRosuvastatin is a substrate of choice in clinical studies of organic anion‐transporting polypeptide (OATP)1B1‐ and OATP1B3‐associated drug interactions; thus, understanding the effect of OATP1B1 polymorphisms on the pharmacokinetics of rosuvastatin is crucial. Here, physiologically based pharmacokinetic (PBPK) modeling was coupled with a power calculation algorithm to evaluate the influence of sample size on the ability to detect an effect (80% power) of OATP1B1 phenotype on pharmacokinetics of rosuvastatin. Intestinal, hepatic, and renal transporters were mechanistically incorporated into a rosuvastatin PBPK model using permeability‐limited models for intestine, liver, and kidney, respectively, nested within a full PBPK model. Simulated plasma rosuvastatin concentrations in healthy volunteers were in agreement with previously reported clinical data. Power calculations were used to determine the influence of sample size on study power while accounting for OATP1B1 haplotype frequency and abundance in addition to its correlation with OATP1B3 abundance. It was determined that 10 poor‐transporter and 45 intermediate‐transporter individuals are required to achieve 80% power to discriminate the AUC0‐48h of rosuvastatin from that of the extensive‐transporter phenotype. This number was reduced to 7 poor‐transporter and 40 intermediate‐transporter individuals when the reported correlation between OATP1B1 and 1B3 abundance was taken into account. The current study represents the first example in which PBPK modeling in conjunction with power analysis has been used to investigate sample size in clinical studies of OATP1B1 polymorphisms. This approach highlights the influence of interindividual variability and correlation of transporter abundance on study power and should allow more informed decision making in pharmacogenomic study design.
Transporter‐Enzyme Interplay: Deconvoluting Effects of Hepatic Transporters and Enzymes on Drug Disposition Using Static and Dynamic Mechanistic Models
Authors: Varma Manthena V. , El‐Kattan Ayman F. 
Published: July 2016

AbstractA large body of evidence suggests hepatic uptake transporters, organic anion‐transporting polypeptides (OATPs), are of high clinical relevance in determining the pharmacokinetics of substrate drugs, based on which recent regulatory guidances to industry recommend appropriate assessment of investigational drugs for the potential drug interactions. We recently proposed an extended clearance classification system (ECCS) framework in which the systemic clearance of class 1B and 3B drugs is likely determined by hepatic uptake. The ECCS framework therefore predicts the possibility of drug‐drug interactions (DDIs) involving OATPs and the effects of genetic variants of SLCO1B1 early in the discovery and facilitates decision making in the candidate selection and progression. Although OATP‐mediated uptake is often the rate‐determining process in the hepatic clearance of substrate drugs, metabolic and/or biliary components also contribute to the overall hepatic disposition and, more importantly, to liver exposure. Clinical evidence suggests that alteration in biliary efflux transport or metabolic enzymes associated with genetic polymorphism leads to change in the pharmacodynamic response of statins, for which the pharmacological target resides in the liver. Perpetrator drugs may show inhibitory and/or induction effects on transporters and enzymes simultaneously. It is therefore important to adopt models that frame these multiple processes in a mechanistic sense for quantitative DDI predictions and to deconvolute the effects of individual processes on the plasma and hepatic exposure. In vitro data‐informed mechanistic static and physiologically based pharmacokinetic models are proven useful in rationalizing and predicting transporter‐mediated DDIs and the complex DDIs involving transporter‐enzyme interplay.
Evaluation and Quantitative Prediction of Renal Transporter‐Mediated Drug‐Drug Interactions
Authors: Feng Bo , Varma Manthena V. 
Published: July 2016

AbstractWith numerous drugs cleared renally, inhibition of uptake transporters localized on the basolateral membrane of renal proximal tubule cells, eg, organic anion transporters (OATs) and organic cation transporters (OCTs), may lead to clinically meaningful drug‐drug interactions (DDIs). Additionally, clinical evidence for the possible involvement of efflux transporters, such as P‐glycoprotein (P‐gp) and multidrug and toxin extrusion protein 1/2‐K (MATE1/2‐K), in the renal DDIs is emerging. Herein, we review recent progress regarding mechanistic understanding of transporter‐mediated renal DDIs as well as the quantitative predictability of renal DDIs using static and physiologically based pharmacokinetic (PBPK) models. Generally, clinical DDI data suggest that the magnitude of plasma exposure changes attributable to renal DDIs is less than 2‐fold, unlike the DDIs associated with inhibition of cytochrome P‐450s and/or hepatic uptake transporters. It is concluded that although there is a need for risk assessment early in drug development, current available data imply that safety concerns related to the renal DDIs are generally low. Nevertheless, consideration must be given to the therapeutic index of the victim drug and potential risk in a specific patient population (eg, renal impairment). Finally, in vitro transporter data and clinical pharmacokinetic parameters obtained from the first‐in‐human studies have proven useful in support of quantitative prediction of DDIs associated with inhibition of renal secretory transporters, OATs or OCTs.
Causes and Consequences of Variability in Drug Transporter Activity in Pediatric Drug Therapy
Authors: Rodieux Frédérique , Gotta Verena , Pfister Marc , van den Anker Johannes N. 
Published: July 2016

AbstractDrug transporters play a key role in mediating the uptake of endo‐ and exogenous substances into cells as well as their efflux. Therefore, variability in drug transporter activity can influence pharmaco‐ and toxicokinetics and be a determinant of drug safety and efficacy. In children, particularly in neonates and young infants, the contribution of tissue‐specific drug transporters to drug absorption, distribution, and excretion may differ from that in adults. In this review 5 major factors and their interdependence that may influence drug transporter activity in children are discussed: developmental differences, genetic polymorphisms, pediatric comorbidities, interacting comedication, and environmental factors. Even if data are sparse, altered drug transporter activity due to those factors have been associated with clinically relevant differences in drug disposition, efficacy, and safety in pediatric patients. Single nucleotide polymorphisms in drug transporter‐encoding genes were the most studied source of drug transporter variability in children. However, in the age group where drug transporter activity has been reported to differ from that in adults, namely neonates and young infants, hardly any studies have been performed. Longitudinal studies in this young population are required to investigate the age‐ and disease‐dependent genotype‐phenotype relationships and relevance of drug transporter drug‐drug interactions. Physiologically based pharmacokinetic modeling approaches can integrate drug‐ and patient‐specific parameters, including drug transporter ontogeny, and may further improve in silico predictions of pediatric‐specific pharmacokinetics.
Leaching of carbon and nitrogen from a sandy soil substrate: A comparison between suction plates and ion exchange resins
Authors: Willich Melanie , Buerkert Andreas 
Published: July 2016

AbstractTo determine boundary effects on leaching, we investigated (1) how filter materials affect the concentrations of dissolved organic carbon (DOC) and nitrate (NO3‐N) in soil percolates and (2) whether ion exchange resins and suction plates are equally suited to capture NO3‐N. DOC leaching was higher with PE suction plates and plate material did not affect NO3‐N leachate concentrations. Cumulative NO3‐N leaching was similar for glass suction plates and ion exchange resins.
Sonodegradation of cyanidin‐3‐glucosylrutinoside: degradation kinetic analysis and its impact on antioxidant capacity in vitro
Authors: Sun Jianxia , Li Xinghua , Lin Xinyu , Mei Zhouxiong , Li Yitao , Ding Lijun , Bai Weibin 
Published: July 2016

AbstractBACKGROUNDAs an alternative preservation method for thermal treatment, ultrasound comprises a novel non‐thermal processing technology that can significantly avoid undesirable nutritional changes. However, the recent literature indicates that anthocyanin degradation occurs when ultrasound is applied in juice at high amplitude parameters. Such work has mainly focussed on the effect of ultrasound on stability, the antioxidant capacity of cyanidin‐3‐glucosylrutinoside (Cy‐3‐glc‐rut) and the correlation between anthocyanin degradation and ·OH generation in a simulated system.RESULTSThe spectral intensities of Cy‐3‐glc‐rut at 518 and 282 nm decreased with increasing ultrasound power and treatment time. The degradation of Cy‐3‐glc‐rut was consistent with first‐order reaction kinetics (r2 > 0.9000) and there was a good linear correlation between anthocyanin degradation and hydroxyl radical formation induced by ultrasound (r2 = 0.9258). Moreover, a decrease in the antioxidant activity of Cy‐3‐glc‐rut after ultrasound evaluated by the 1,1‐diphenyl‐2‐picrylhydrazyl and ferric reducing antioxidant power methods was observed.CONCLUSIONOverall, the results of the present study show that ultrasound will accelerate the degradation of Cy‐3‐glc‐rut with the growth of power over time. © 2016 Society of Chemical Industry
Fate of Organic and Inorganic Nitrogen in Crusted and Non‐Crusted Kobresia Grasslands
Authors: Zhang Li , Unteregelsbacher Sebastian , Hafner Silke , Xu Xingliang , Schleuss Per‐Marten , Miehe Georg , Kuzyakov Yakov 
Published: July 2016

AbstractA widespread pattern of the Tibetan plateau is mosaics of grasslands of Cyperaceae and grasses with forbs, interspersed with patches covered by lichen crusts induced by overgrazing. However, the fate of inorganic and organic N in non‐crusted and crusted patches in Kobresia grasslands remains unknown. We reported on a field 15N‐labeling experiment in two contrasting patches to compare retention of organic and inorganic N over a period of 29 days. 15N as KNO3, (NH4)2SO4 or glycine was sprayed onto soil surface. Crusted patches decreased plant and soil N stocks. More 15N from three N forms was recovered in soil than plants in both patches 29 days after the labeling. In non‐crusted patches, 15N recovery by the living roots was about two times higher than in crusted ones, mainly because of higher root biomass. Microorganisms in non‐crusted patches were N‐limited because of more living roots and competed strongly for N with roots. Inorganic N input to non‐crusted patches could alleviate N limitation to plants and microorganisms, and leads to higher total 15N recovery (plant + soil) for inorganic N forms. Compared to non‐crusted patches, microorganisms in crusted patches were more C‐limited because of depletion of available C caused by less root exudation. Added glycine could activate microorganisms, together with the hydrophobicity of glycine and crusts, leading to higher 15N‐glycine than inorganic N. We conclude that overgrazing‐induced crusts in Kobresia grasslands changed the fate of inorganic and organic N, and lead to lower total recovery from inorganic N but higher from organic N. Copyright © 2016 John Wiley & Sons, Ltd.
Early‐ and late‐onset essential tremor patients represent clinically distinct subgroups
Authors: Hopfner Franziska , Ahlf Anjuli , Lorenz Delia , Klebe Stephan , Zeuner Kirsten E. , Kuhlenbäumer Gregor , Deuschl Günther 
Published: July 2016

ABSTRACTObjectiveEssential tremor is a very common disease defined by sparse clinical criteria. It is unlikely that essential tremor is an etiologically homogeneous disease. Stratifying broadly defined diseases using clinical characteristics has often aided the etiopathological understanding. Most studies of essential tremor show 2 distinct age at onset peaks: early and late. This study investigates phenotypical differences between early‐ and late‐onset essential tremor patients.MethodsWe studied a sample of 1137 tremor patients. Of these patients, 978 suffered from definite or probable essential tremor. All of the patients underwent the same standardized examination encompassing, among other items, drawing of the Archimedes spiral and assessment of the Fahn‐Tolosa‐Marin scale.ResultsTwo subgroups of early‐onset (≤ 24 years of age, n = 317) and late‐onset (≥ 46 years of age, n = 356) patients were selected based on the visual and mathematical analysis of the age‐at‐onset distribution. Tremor severity in both groups was comparable. Tremor progression measured as Archimedes spiral score and the Fahn‐Tolosa‐Marin subscales divided by the disease duration in 10‐year bins was significantly faster in late‐onset patients when compared with early‐onset patients. Early‐onset patients more frequently reported a positive family history and alcohol sensitivity of the tremor.ConclusionsThe age‐at‐onset distribution suggests a distinction between early‐ and late‐onset tremor. Early‐onset and late‐onset essential tremor differ in the progression rates and the frequencies of a positive family history and history of a positive effect of alcohol on tremor. © 2016 International Parkinson and Movement Disorder Society
Fakten und Trends: Chemiestudiengänge 2015
Authors: Schmitz Karin 
Published: July 2016

AbstractWie jedes Jahr hat die Gesellschaft Deutscher Chemiker auch 2015 umfangreiche statistische Daten zu den Chemiestudiengängen erhoben. Danach gab es erneut mehr Studienanfänger als im Vorjahr. Bei den Studienabschlüssen waren Master und Promotionen weiter ansteigend, während die Zahl der Bachelorabsolventen auf hohem Niveau blieb. Fast alle Bachelorabsolventen von Universitäten und über 60 Prozent von Fachhochschulen schlossen ein Masterstudium an. Rund 80 Prozent der Masterabsolventen von Universitäten und etwa 10 Prozent der Masterabsolventen von Fachhochschulen begannen eine Promotion. Für promovierte Absolventen blieb der Berufseinstieg schwieriger als für die Absolventen vergangener Jahre.
Current practices of obesity pharmacotherapy, bariatric surgery referral and coding for counselling by healthcare professionals
Authors: Petrin Christine , Kahan Scott , Turner M. , Gallagher C. , Dietz W. H. 
Published: July 2016

SummaryIntroductionRates of obesity pharmacotherapy use, bariatric surgery and intensive behavioural counselling have been extremely low.ObjectivesThe primary objective of this study was to survey healthcare provider beliefs, practice and knowledge regarding obesity management.MethodsPrimary care physicians (PCPs), OB‐GYN physicians and nurse practitioners (NPs) responded to a web‐based survey related to drug therapy practice, bariatric surgery referral and reimbursement coding practice.ResultsRates of reported use of obesity pharmacotherapy appear to be increasing among PCPs, which is likely related to the approval of four new obesity pharmacotherapy agents since 2012. Rates of pharmacotherapy use among OB‐GYNs and NPs appear much lower. Similarly, few PCPs are averse to recommending bariatric surgery, but aversion among OB‐GYNs and NPs is significantly higher.ConclusionTogether, these observations suggest that OB‐GYN and NP populations are important targets for education about obesity management. Very few PCPs, OB‐GYNs or NPs use behavioural counselling coding for obesity. Better understanding of why this benefit is not being fully used could inform outreach to improve counselling rates.
Ion channel blockers and glioblastoma risk and outcome: a nested case–control and retrospective cohort studies
Authors: Boursi Ben , Han Harry J , Haynes Kevin , Mamtani Ronac , Yang Yu‐Xiao 
Published: July 2016

AbstractPurposeMutations in ion channels are common among patients with glioblastoma multiforme (GBM) and promote cell migration and invasion. We sought to evaluate the association between the use of specific ion channel blockers such as digoxin, amiodarone, diltiazem and verapamil and GBM risk and survival.MethodsWe conducted a nested case–control study in a large primary care database from the UK. Cases were defined as all individuals with incident diagnosis of GBM during follow‐up. For each case, up to four controls were selected using incidence density sampling. The primary exposure of interest was active treatment with each of the four ion channel blockers. We used conditional logistic regression to estimate odds ratios and 95% confidence interval (CI) for the association between ion channel blocker use and GBM risk. We then performed a Cox regression analysis among those diagnosed with GBM in order to evaluate the association between use of ion channel blockers and overall survival. Both analyses were adjusted to common confounders.ResultsThe study included 1076 cases and 4253 matched controls. There was no statistically significant difference between cases and controls in cardiac and metabolic risk factors. There was no change in GBM risk in active users of ion channel blockers compared with non‐users. Among patients with GBM, active users of amiodarone had worse survival compared with never users with an HR of 4.41 (95%CI 1.95–9.96). There was no statistically significant change in survival among diltiazem, verapamil or digoxin users.ConclusionTreatment with specific ion channel blockers was not associated with the risk of GBM but was associated with worse survival in patients with GBM. Copyright © 2016 John Wiley & Sons, Ltd.
Theoretical investigation of the structures and spectroscopic properties of (H2O4)n (n = 1–4) clusters
Authors: Kim Hong‐Dal , Seo Hyun‐Il , Song Hui‐Seong , Kim Seung‐Joon 
Published: July 2016

AbstractDensity functional theory and ab initio calculations were performed to elucidate the hydrogen interactions in (H2O4)n (n = 1–4) clusters. The optimized geometries, binding energies, and harmonic vibrational frequencies were predicted at various levels of theory. The trans conformer of the H2O4 monomer was predicted to be the most stable structure at the CCSD(T)/aug‐cc‐pVTZ level of theory. The binding energies per H2O4 monomer increased in absolute value by 9.0, 10.1, and 11.8 kcal/mol from n = 2 to n = 4 at the MP2/cc‐pVTZ level of theory (after the zero‐point vibrational energy and basis set superposition error corrections). This result implies that the intermolecular hydrogen bonds were stronger in the long‐chain clusters, that is, the formation of the longer chain in the (H2O4)n clusters was more energetically favorable.
CP‐ABE with outsourced decryption and directionally hidden policy
Authors: Wang Zhiwei , Liu Wenyang 
Published: July 2016

AbstractCiphertext‐policy attribute‐based encryption (CP‐ABE) is a novel cryptographic primitive for access controlling. However, the existing CP‐ABE schemes are very inefficient as the decryptions involve many expensive pairing operations. Another drawback is that the access policy itself may disclose some privacies of the users. In certain applications, access structures also should be protected. In this work, we propose a notion of CP‐ABE with outsourced decryption and directionally hidden policy, which allows a semi‐trusted proxy in the cloud to help a user decrypt a ciphertext, but the proxy cannot learn the plaintext and the access policy. We construct a concrete scheme from Waters' CP‐ABE and prove its security, verifiability, and directionally hidden policy. Copyright © 2016 John Wiley & Sons, Ltd.