bluuebunny/crossref_metadata_2025 huggingface dataset:
Facile Silylation of Cyclitols Using Silyl Bis(triflates)
Authors: Topp Anke , Köckerling Martin , Reinke Helmut , Miethchen Ralf , Mamat Constantin
Published: January 2018

Novel silylated diols and polyols were prepared using a recently developed synthesis route with bifunctionalized silyl triflates. These silyl derivatives include two triflate functions, which allow a selective protection of two hydroxy groups. Moreover, the conformation of the silyl chain in the silane backbone led to exceptional UV properties.
Deacidification of Crude Hazelnut Oil Using Molecular Distillation – Multiobjective Optimization for Free Fatty Acids and Tocopherol
Authors: Altuntas Ayse H. , Ketenoglu Onur , Cetinbas Sena , Erdogdu Ferruh , Tekin Aziz
Published: January 2018

Hazelnut oil is a good source for its high oleic acid and tocopherol contents. Since tocopherols are beneficial compounds in human diet, preservation of tocopherols in oil plays a great role in refining process. The aim of this study is to determine the optimum molecular distillation conditions for deacidification of crude hazelnut oil at which free fatty acids (FFAs) are removed while tocopherols are preserved as much as possible. A short‐path distillation column is used with evaporation temperatures ranging from 110 to 190 °C and vacuums from 0.05 to 5 mmHg for deacidification. Multiobjective optimization is performed for minimizing tocopherol loss and maximizing FFA removal simultaneously. Results reveal that higher temperature and vacuums achieve more deacidification in residual oil. FFA content is reduced to 2.05% at 190 °C and 0.05 mmHg. On the other hand, tocopherol concentrations are considerably affected at this condition while they remain almost stable at other conditions. Optimized conditions for removal of FFAs and protecting of tocopherols in crude hazelnut oil are calculated as 188.65 °C and 0.14 mmHg. For verification, an additional distillation is carried out at the calculated conditions, and the results are found very close to that of optimized conditions.

Practical Applications: Physical refining or vacuum distillation process is a substitute to conventional refining which causes excessive neutral oil losses during neutralization. However, heat treatment for long periods of time may inevitably cause degradation of beneficial compounds such as tocopherols. For this purpose, this study focuses on optimizing molecular distillation conditions at which maximum tocopherol and minimum FFA could be obtained simultaneously. Outcomes would be useful for industrial physical refining plants dealing with optimum points for the same purpose.

Deacidification of crude hazelnut oil using molecular distillation – multiobjective optimization for tocopherol and FFA
Preparation and Optical and Electrochemical Properties of Phthalocyanines with Four or Eight Diphenylphosphino, Diphenylphosphoryl, and Diphenylthiophosphinyl Groups
Authors: Kimura Takeshi , Muraoka Hiroki , Nakajo Shiduko , Ogawa Satoshi , Yamamoto Satoshi , Kobayashi Nagao
Published: January 2018

Several phthalocyanines (Pcs), in which four or eight phosphines are directly linked to their periphery, have been prepared. The starting materials, 4‐(diphenylphosphino)‐5‐chlorophthalonitrile (2), 4,5‐bis(diphenylphosphino)phthalonitrile (3), and 4‐(diphenylphosphino)‐5‐(diphenylphosphoryl)‐phthalonitrile (4), were prepared by the reaction of 4,5‐dichlorophthalonitrile (1) and diphenyltrimethylsilylphosphine in toluene at 110 °C. Compound 2 was treated with Li in hexan‐1‐ol at 120 °C, to produce β‐tetrakis(diphenylphosphino)tetrachloroPc [Pc(PPh2)4Cl4, 11], while refluxing 3 in ethoxyethanol in the presence of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) yielded β‐octakis(diphenylphosphino)Pc [Pc(PPh2)8, 12]. The reactions of 11 with mCPBA or elemental sulfur produced β‐tetrakis(diphenylphosphoryl)tetrachloroPc [Pc(POPh2)4Cl4, 13] or β‐tetrakis(diphenylthiophosphinyl)tetrachloroPc [Pc(PSPh2)4Cl4, 15], respectively, whereas that of 12 with mCPBA or elemental sulfur afforded β‐octakis(diphenylphosphoryl)Pc [Pc(POPh2)8, 14] or β‐octakis(diphenylthiophosphinyl)Pc [Pc(PSPh2)8, 16], respectively. β‐Octakis(diphenylphosphino)‐α‐octafluorophthalocyaninato magnesium [Pc(PPh2)8F8Mg, 17] was prepared from tetrafluorophthalonitrile (6) in two‐step reactions. The structures of simplified model compounds 11a–16a were optimized using DFT methods with the Gaussian 09 program. The optimized structures were utilized to calculate the HOMO and LUMO orbital energies, and the electronic transitions in the absorption spectra by the TD‐DFT method.
A TBPB‐Mediated C‐3 Cycloalkylation and Formamidation of 4‐Arylcoumarin
Authors: Joychandra Singh Sarangthem , Ahmad Mir Bilal , Patel Bhisma K.
Published: January 2018

A tert‐butyl peroxybenzoate (TBPB) mediated cycloalkylation and formamidation efficiently took place at 120 °C in chlorobenzene or the corresponding formamide, respectively. The cycloalkylation required the addition of acetic acid, whereas the formamidation proceeded in its absence. This radical‐mediated process tolerated a broad scope of substrates and provided the products in moderate to good yields.
Isobutanol Synthesis from Syngas over Zn‐Cr Catalyst: Effect of Zn/Cr Element Ratio
Authors: Tian Shaopeng , Wu Yingquan , Li Kexuan , Xie Hongjuan , Ren Huaping , Zhao Yuzhen , Miao Zongcheng , Tan Yisheng
Published: January 2018

This report demonstrated the effect of Zn/Cr element ratio on Zn−Cr catalyst for isobutanol formation from the reaction of carbon monoxide hydrogenation. The catalysts of different Zn/Cr element ratios including 1 : 3, 1 : 1, 3 : 1 and 5 : 1 have been prepared by a facile coprecipitation approach and their activity evaluation of isobutanol formation by carbon monoxide hydrogenation were tested. The Zn1Cr1 catalyst of Zn/Cr element ratio being 1 : 1 presented outstanding activity for iso‐butanol formation from the carbon monoxide hydrogenation, carbon monoxide conversion and isobutanol selectivity reached to the maximum to ∼32 % and ∼24 %, respectively. Multi‐Characterization including TEM, XRD, BET, XAS, H2‐TPR, CO2‐TPD and XPS were proceed to investigate the physico‐chemical property of catalysts. The characterization results display that the Zn1Cr1 catalyst presents more nonstoichiometric Zn−Cr spinel and oxygen vacancies as well as more defects. The Zn1Cr1 catalyst also presents better properties of basicity, reducibility and BET surface area which are some other factors for better result of activity evaluation for isobutanol formation by carbon monoxide hydrogenation.
Are trans diagnostic models of eating disorders fit for purpose? A consideration of the evidence for food addiction
Authors: Treasure Janet , Leslie Monica , Chami Rayane , Fernández‐Aranda Fernando
Published: January 2018

Explanatory models for eating disorders have changed over time to account for changing clinical presentations. The transdiagnostic model evolved from the maintenance model, which provided the framework for cognitive behavioural therapy for bulimia nervosa. However, for many individuals (especially those at the extreme ends of the weight spectrum), this account does not fully fit. New evidence generated from research framed within the food addiction hypothesis is synthesized here into a model that can explain recurrent binge eating behaviour. New interventions that target core maintenance elements identified within the model may be useful additions to a complex model of treatment for eating disorders.
Spatial and temporal analysis of hillslope–channel coupling and implications for the longitudinal profile in a dryland basin
Authors: Michaelides Katerina , Hollings Rory , Singer Michael Bliss , Nichols Mary H. , Nearing Mark A.
Published: January 2018

The long‐term evolution of channel longitudinal profiles within drainage basins is partly determined by the relative balance of hillslope sediment supply to channels and the evacuation of channel sediment. However, the lack of theoretical understanding of the physical processes of hillslope–channel coupling makes it challenging to determine whether hillslope sediment supply or channel sediment evacuation dominates over different timescales and how this balance affects bed elevation locally along the longitudinal profile. In this paper, we develop a framework for inferring the relative dominance of hillslope sediment supply to the channel versus channel sediment evacuation, over a range of temporal and spatial scales. The framework combines distinct local flow distributions on hillslopes and in the channel with surface grain‐size distributions. We use these to compute local hydraulic stresses at various hillslope‐channel coupling locations within the Walnut Gulch Experimental Watershed (WGEW) in southeast Arizona, USA. These stresses are then assessed as a local net balance of geomorphic work between hillslopes and channel for a range of flow conditions generalizing decadal historical records. Our analysis reveals that, although the magnitude of hydraulic stress in the channel is consistently higher than that on hillslopes, the product of stress magnitude and frequency results in a close balance between hillslope supply and channel evacuation for the most frequent flows. Only at less frequent, high‐magnitude flows do channel hydraulic stresses exceed those on hillslopes, and channel evacuation dominates the net balance. This result suggests that WGEW exists mostly (~50% of the time) in an equilibrium condition of sediment balance between hillslopes and channels, which helps to explain the observed straight longitudinal profile. We illustrate how this balance can be upset by climate changes that differentially affect relative flow regimes on slopes and in channels. Such changes can push the long profile into a convex or concave condition. © 2018 The Authors. Earth Surface Processes and Landforms published by John Wiley & Sons Ltd.
Detrital zircon U–Pb ages of the Murui Formation in the Zhalantun area: Implications for the Early Cretaceous tectonic setting of the southern Great Xing'an Range, NE China
Authors: Han Xiaomeng , Zheng Changqing , Han Yubao , Xu Xuechun , Shi Lu , Xu Jiulei , Li Juan
Published: January 2018

This paper reports U–Pb ages of detrital zircons from a series of clastic and pyroclastic rocks from the Murui Formation in the southern Great Xing'an Range (GXR), NE China, with the aim of constraining the depositional age of this poorly dated unit. These data, combined with the petrographic and sedimentology characteristics of the rocks, are used to constrain the sediment sources and tectonic setting of the provenance and provide wider insight into the tectonic evolution of the southern GXR during the Late Mesozoic. Two lithic arkose samples have dominant age groups at 249–250, 159–160, 136–147, and 394–415 Ma, and 301–323, 278–288, 209–237, and 142–163 Ma, respectively. The U–Pb zircon data constrain the maximum depositional age of the Murui Formation to 136 ± 1 Ma, that is, the Early Cretaceous. A lithic–crystal tuff from the upper Murui Formation yielded zircons with a weighted mean U–Pb age of 136 ± 1 Ma (n = 47, mean square weighted deviation (MSWD) = 2.2), indicating that volcanic activity was contemporaneous with sedimentation of the Murui Formation. U–Pb dating of zircons from a pyromeride in the Baiyingaolao Formation that was erupted unconformably onto the Murui Formation yielded a peak age of ~120 Ma, which constrains the depositional age of the Murui Formation to 120–136 Ma. Further dating of detrital zircons shows a range of ages, indicating the various of sediment origins. The Late Jurassic to Early Cretaceous volcanic rocks in the GXR served as the principal detrital sources for the Murui Formation in the southern GXR. Grain size and modal analysis of the sediments shows that the depositional environment was a stable intracontinental fluvial setting, and the provenance of the detritus was most likely a magmatic arc. According to stratigraphic contact relations, the Baiyingaolao Formation is supposed to have obvious intervals with lower volcanic strata, which combined with disparities between the southern and northern GXR in terms of the duration of volcanism, magmatic events, and the depositional age of the Murui Formation. We can conclude that the restricted occurrence of the Early Cretaceous detritus between the earlier and later phases of volcanism suggests progressive exhumation of the southern GXR in the Early Cretaceous. These may relate to post‐orogenic extension related to oceanic subduction. The southern GXR remained a site of active sedimentation during the continental extension period across the whole of NE China in the Late Jurassic to Early Cretaceous.
Diagnosis of cognitive decline and dementia in rural areas — A scoping review
Authors: Barth Janina , Nickel Franziska , Kolominsky‐Rabas Peter L.
Published: January 2018

Objectives

Due to the demographic change, the global prevalence of dementia will continually rise. Barriers to diagnosis and care are still high. But timely diagnosis is associated with valuable benefits and can promote timely and optimal management. Receiving an early diagnosis is especially in rural areas a problem due to the limited access to assessments. Therefore, the aim of our scoping review is to investigate different interventions targeted at rural living elderly to screen and diagnose cognitive decline and dementia.

Methods

A scoping review was conducted in line with the framework of Arksey and O'Malley. The following databases were systematically searched: PubMed, PsycINFO, Cochrane Library, and ScienceDirect. The interventions were categorized in four main categories (interventions for general practitioners/institutions; online/mobile offers; telehealth applications; telephone‐based screenings).

Results

Thirty studies were included. The four categories show different scopes of application. Telehealth applications show that it is feasible and valid to diagnose dementia via videoconference. Assessments described in three other categories show that remotely used tools are appropriate to screen for mild cognitive impairment or cognitive decline, but are not valid to establish a dementia diagnosis.

Conclusions

Telehealth applications can appropriately be used to diagnose dementia. However, most of the studies included only small sample sizes and did not test the applications explicitly in rural or remote populations. Therefore, studies taking these limitations into account are needed. On top, only two RCTs are included in this review indicating that more high quality studies in this field are needed.
Test–retest reliability and longitudinal analysis of automated hippocampal subregion volumes in healthy ageing andAlzheimer's disease populations
Authors: Worker Amanda , Dima Danai , Combes Anna , Crum William R. , Streffer Johannes , Einstein Steven , Mehta Mitul A. , Barker Gareth J. , Williams Steve C. R. , O'daly Owen
Published: January 2018

The hippocampal formation is a complex brain structure that is important in cognitive processes such as memory, mood, reward processing and other executive functions. Histological and neuroimaging studies have implicated the hippocampal region in neuropsychiatric disorders as well as in neurodegenerative diseases. This highly plastic limbic region is made up of several subregions that are believed to have different functional roles. Therefore, there is a growing interest in imaging the subregions of the hippocampal formation rather than modelling the hippocampus as a homogenous structure, driving the development of new automated analysis tools. Consequently, there is a pressing need to understand the stability of the measures derived from these new techniques. In this study, an automated hippocampal subregion segmentation pipeline, released as a developmental version of Freesurfer (v6.0), was applied to T1‐weighted magnetic resonance imaging (MRI) scans of 22 healthy older participants, scanned on 3 separate occasions and a separate longitudinal dataset of 40 Alzheimer's disease (AD) patients. Test–retest reliability of hippocampal subregion volumes was assessed using the intra‐class correlation coefficient (ICC), percentage volume difference and percentage volume overlap (Dice). Sensitivity of the regional estimates to longitudinal change was estimated using linear mixed effects (LME) modelling. The results show that out of the 24 hippocampal subregions, 20 had ICC scores of 0.9 or higher in both samples; these regions include the molecular layer, granule cell layer of the dentate gyrus, CA1, CA3 and the subiculum (ICC > 0.9), whilst the hippocampal fissure and fimbria had lower ICC scores (0.73–0.88). Furthermore, LME analysis of the independent AD dataset demonstrated sensitivity to group and individual differences in the rate of volume change over time in several hippocampal subregions (CA1, molecular layer, CA3, hippocampal tail, fissure and presubiculum). These results indicate that this automated segmentation method provides a robust method with which to measure hippocampal subregions, and may be useful in tracking disease progression and measuring the effects of pharmacological intervention.
Endoscopic endonasal approach for sinonasal and anterior skull base malignancies in the elderly
Authors: Lepera Davide , Leone Federico , Volpi Luca , Bignami Maurizio , Karligkiotis Apostolos , Lambertoni Alessia , Pistochini Andrea , Accorona Remo , Nicolai Piero , Castelnuovo Paolo
Published: January 2018

Background

The purpose of this study was to report the outcomes of endoscopic transnasal resection for sinonasal and anterior skull‐base cancers in elderly patients.

Methods

A retrospective review was performed. The patients were divided into 2 groups, <70 years old and ≥70 years old and compared by univariate analysis. Prognostic factors were evaluated with a multivariate analysis. Survival rates were also calculated.

Results

Two hundred three elderly patients and 397 younger patients were enrolled in this study. The elderly patients reported lower survival rates than the younger patients. When melanoma and esthesioneuroblastoma were censored, the disease‐specific survival (DSS) and recurrence‐free survival (RFS) were similar. Complication rates were 17.5% without any statistical significance between the groups. Multivariate analysis revealed that histology, stage, surgical margins, and surgical approaches were independent predictors of survival in elderly patients.

Conclusion

The endoscopic transnasal approach reported low mortality and morbidity rates also in geriatric patients, and age itself is not to be considered as a contraindication.
Cardiorespiratory fitness is associated with enhanced hippocampal functional connectivity in healthy young adults
Authors: Stillman Chelsea M. , Uyar Fatma , Huang Haiqing , Grove George A. , Watt Jennifer C. , Wollam Mariegold E. , Erickson Kirk I.
Published: January 2018

Consistent associations have been found between higher cardiorespiratory fitness (CRF) and indices of enhanced brain health and function, including behavioral measures of cognition as well as neuroimaging indicators such as regional brain volume. Several studies have reported that higher CRF levels are associated with a larger hippocampus, yet associations between volume and memory or functional connectivity metrics remain poorly understood. Using a multi‐modal framework, we hierarchically examine the association between CRF and hippocampal volume and resting state functional connectivity (rsFC) in younger adults, as well as their relationship between with memory function. We conducted theoretically‐driven analyses with seeds in the anterior and posterior hippocampus, as well as control seeds in the caudate nucleus. We tested whether (1) hippocampal connectivity with prefrontal cortical regions was associated with CRF in an adult sample much younger than traditionally tested, (2) associations between CRF and rsFC remain significant after adjusting for volume, and (3) volume and rsFC are related to memory. We found that higher CRF levels were associated with larger anterior hippocampal volume and more positive rsFC of the anterior hippocampus to several regions including the prefrontal cortex. rsFC also accounted for significant variance in CRF, above and beyond volume. CRF can thus be independently linked to increased anterior hippocampal volume, as well as stronger hippocampal rsFC in a population much younger than those typically tested, suggesitng it is critical to maintainig multiple aspects of brain health.
Cognitive trajectories and spectrum of neuropathology in SuperAgers: The first 10 cases
Authors: Rogalski Emily , Gefen Tamar , Mao Qinwen , Connelly Maureen , Weintraub Sandra , Geula Changiz , Bigio Eileen H. , Mesulam M.‐Marsel
Published: January 2018

On average, memory capacity is significantly higher in populations of 50–60 year olds than in populations of 80 year olds. We define SuperAgers as individuals 80 or older whose episodic memory capacity is at least as good as that of cognitively average individuals in their 50s and 60s. SuperAgers therefore have memory capacity that is superior for age. Previous work showed that SuperAgers have greater cortical volumes and greater resistance to age‐related cortical atrophy than “cognitively average” individuals of the same age. Here we report on the cognitive, personality, and neuropathologic characteristics of the first 10 autopsy cases in the Northwestern SuperAging Program. During the follow‐up period, seven SuperAgers maintained episodic memory performance within or above the average range for 50–65 year‐old norms and all 10 SuperAgers maintained episodic memory scores within normal limits for their own age. Extraversion scores tended to be high on the NEO‐PI‐R measure of personality. The 10 autopsy specimens showed variable findings within the spectrum of Alzheimer pathology. The hippocampus and entorhinal cortex contained neurofibrillary degeneration mostly in the Braak II–III stages. However, even these limbic areas contained many healthy appearing neurons and the neocortex was generally free of neurofibrillary degeneration. In contrast, neocortical areas in at least five of the cases contained moderate to high densities of neuritic plaques. These findings need to be placed in context by comparing them to the neuropathology of cognitively average individuals of the same age. Future research on SuperAgers is likely to offer insights into factors that either prevent the emergence of involutional changes in the brain or that makes cognitive function more resistant to their consequences.
Near‐infrared photoimmunotherapy targeting EGFR—Shedding new light on glioblastoma treatment
Authors: Burley Thomas A. , Mączyńska Justyna , Shah Anant , Szopa Wojciech , Harrington Kevin J. , Boult Jessica K.R. , Mrozek‐Wilczkiewicz Anna , Vinci Maria , Bamber Jeffrey C. , Kaspera Wojciech , Kramer‐Marek Gabriela
Published: January 2018

Glioblastomas (GBMs) are high‐grade brain tumors, differentially driven by alterations (amplification, deletion or missense mutations) in the epidermal growth factor receptor (EGFR), that carry a poor prognosis of just 12–15 months following standard therapy. A combination of interventions targeting tumor‐specific cell surface regulators along with convergent downstream signaling pathways may enhance treatment efficacy. Against this background, we investigated a novel photoimmunotherapy approach combining the cytotoxicity of photodynamic therapy with the specificity of immunotherapy. An EGFR‐specific affibody (ZEGFR:03115) was conjugated to the phthalocyanine dye, IR700DX, which when excited with near‐infrared light produces a cytotoxic response. ZEGFR:03115–IR700DX EGFR‐specific binding was confirmed by flow cytometry and confocal microscopy. The conjugate showed effective targeting of EGFR positive GBM cells in the brain. The therapeutic potential of the conjugate was assessed both in vitro, in GBM cell lines and spheroids by the CellTiter‐Glo® assay, and in vivo using subcutaneous U87‐MGvIII xenografts. In addition, mice were imaged pre‐ and post‐PIT using the IVIS/Spectrum/CT to monitor treatment response. Binding of the conjugate correlated to the level of EGFR expression in GBM cell lines. The cell proliferation assay revealed a receptor‐dependent response between the tested cell lines. Inhibition of EGFRvIII+ve tumor growth was observed following administration of the immunoconjugate and irradiation. Importantly, this response was not seen in control tumors. In conclusion, the ZEGFR:03115–IR700DX showed specific uptake in vitro and enabled imaging of EGFR expression in the orthotopic brain tumor model. Moreover, the proof‐of‐concept in vivo PIT study demonstrated therapeutic efficacy of the conjugate in subcutaneous glioma xenografts.
Rare missense mutations in RECQL and POLG associate with inherited predisposition to breast cancer
Authors: Tervasmäki Anna , Mantere Tuomo , Hartikainen Jaana M. , Kauppila Saila , Lee Hang‐Mao , Koivuluoma Susanna , Grip Mervi , Karihtala Peeter , Jukkola‐Vuorinen Arja , Mannermaa Arto , Winqvist Robert , Pylkäs Katri
Published: January 2018

Several known breast cancer susceptibility genes with moderate‐to‐high risk alleles encode proteins involved in DNA damage response (DDR). As these explain less than half of the hereditary breast cancer cases, additional predisposing alleles are likely to be discovered. Many of the previous studies utilizing massive parallel sequencing have focused on the protein‐truncating variants, and the role of rare missense mutations has remained poorly addressed. To identify novel susceptibility factors, we have systematically analyzed the data from our parallel sequencing of 796 DDR genes in 189 Northern Finnish hereditary breast cancer patients for rare missense variants, predicted as deleterious. Thirty‐five variants were studied here for the disease association using Finnish breast cancer case (n = 492–2,035) and control (n = 277–1,539) cohorts. As a result, two missense variants in genes involved in DNA replication, RECQL p.I156M and POLG p.L392V, the former involving genomic and the latter mitochondrial DNA replication, showed significant association with risk of breast cancer. Rare RECQL p.I156M allele was observed in breast cancer cases only (6/1,946, 0.3%, p = 0.043), whereas POLG p.L392V was two times more frequent in breast cancer cases (53/2,238, 2.4%) compared to controls (18/1,539, 1.2%, OR = 2.1, 95% CI 1.2–3.5, p = 0.010). Based on the current genetic data, both RECQL p.I156M and POLG p.L392V represent novel breast cancer predisposing alleles.
Nitroxide Radicals with Cucurbit[n]urils and Other Cavitands
Authors: Ouari Olivier , Bardelang David
Published: January 2018

The interface of nitroxide radicals with cucurbit[n]urils (CB[n]) is covered in this review. Either used as spin probes, spin labels, or stoppers for paramagnetic rotaxanes, nitroxides offer new opportunities to investigate CB[n] and their inclusion complexes, especially thanks to EPR spectroscopy. On the other hand, CB[n] also offer interesting opportunities to modulate nitroxide properties such as protection or structuring. The multiple back and forth between the two well‐established areas where nitroxides bring information about CB[n], and CB[n] modulate nitroxide properties, have enabled to shed some light at this new interesting interface.
Winner of the society for biomaterials student award in the Ph.D. category for the annual meeting of the society for biomaterials, april 11–14, 2018, Atlanta, GA: Development of a bimodal, in situ crosslinking method to achieve multifactor release from electrospun gelatin
Authors: Kishan Alysha , Walker Taneidra , Sears Nick , Wilems Thomas , Cosgriff‐Hernandez Elizabeth
Published: January 2018

To better mimic native tissue microenvironments, current efforts have moved beyond single growth factor delivery to more complex multiple growth factor delivery with distinct release profiles. Electrospun gelatin, a widely investigated drug delivery vehicle, requires postprocessing crosslinking techniques that generate a mesh with uniform crosslinking density, limiting the ability to deliver multiple factors at different rates. Herein, we describe a method to independently control release of multiple factors from a single electrospun gelatin mesh. Two in situ crosslinking modalities, photocrosslinking of methacyrlated gelatin and reactive crosslinking of gelatin with a diisocyanate, are coelectrospun to generate distinct fiber populations with different crosslinking chemistry and density in a single mesh. The photocrosslinked gelatin‐methacrylate resulted in a relatively rapid release of a model protein (48 ± 12% at day 1, 96 ± 3% at day 10) due to diffusion of embedded protein from the crosslinked fibers. The reactive crosslinking system displayed a more sustained release (7 ± 5% at day 1, 33 ± 2% at day 10) that was attributed to the conjugation of protein to gelatin with the diisocyanate, requiring degradation of gelatin prior to diffusion out of the fibers. Both modalities displayed tunable release profiles. Subsequent release studies of a cospun mesh with two different crosslinked fiber populations confirmed that the cospun mesh displayed multifactor release with independent release profiles. Overall, this bimodal, in situ crosslinking approach enables the delivery of multiple factors with distinct release kinetics from a single mesh and is expected to have broad utility in tissue engineering. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1155–1164, 2018.
An N‐Ethyl‐N‐Nitrosourea (ENU) Mutagenized Mouse Model for Autosomal Dominant Nonsyndromic Kyphoscoliosis Due to Vertebral Fusion
Authors: Esapa Christopher T , Piret Sian E , Nesbit M Andrew , Thomas Gethin P , Coulton Leslie A , Gallagher Orla M , Simon Michelle M , Kumar Saumya , Mallon Ann‐Marie , Bellantuono Ilaria , Brown Matthew A , Croucher Peter I , Potter Paul K , Brown Steve DM , Cox Roger D , Thakker Rajesh V
Published: January 2018

Kyphosis and scoliosis are common spinal disorders that occur as part of complex syndromes or as nonsyndromic, idiopathic diseases. Familial and twin studies implicate genetic involvement, although the causative genes for idiopathic kyphoscoliosis remain to be identified. To facilitate these studies, we investigated progeny of mice treated with the chemical mutagen N‐ethyl‐N‐nitrosourea (ENU) and assessed them for morphological and radiographic abnormalities. This identified a mouse with kyphoscoliosis due to fused lumbar vertebrae, which was inherited as an autosomal dominant trait; the phenotype was designated as hereditary vertebral fusion (HVF) and the locus as Hvf. Micro–computed tomography (μCT) analysis confirmed the occurrence of nonsyndromic kyphoscoliosis due to fusion of lumbar vertebrae in HVF mice, consistent with a pattern of blocked vertebrae due to failure of segmentation. μCT scans also showed the lumbar vertebral column of HVF mice to have generalized disc narrowing, displacement with compression of the neural spine, and distorted transverse processes. Histology of lumbar vertebrae revealed HVF mice to have irregularly shaped vertebral bodies and displacement of intervertebral discs and ossification centers. Genetic mapping using a panel of single nucleotide polymorphic (SNP) loci arranged in chromosome sets and DNA samples from 23 HVF (eight males and 15 females) mice, localized Hvf to chromosome 4A3 and within a 5‐megabase (Mb) region containing nine protein coding genes, two processed transcripts, three microRNAs, five small nuclear RNAs, three large intergenic noncoding RNAs, and 24 pseudogenes. However, genome sequence analysis in this interval did not identify any abnormalities in the coding exons, or exon‐intron boundaries of any of these genes. Thus, our studies have established a mouse model for a monogenic form of nonsyndromic kyphoscoliosis due to fusion of lumbar vertebrae, and further identification of the underlying genetic defect will help elucidate the molecular mechanisms involved in kyphoscoliosis. © 2018 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research
Comorbidities Only Account for a Small Proportion of Excess Mortality After Fracture: A Record Linkage Study of Individual Fracture Types
Authors: Chen Weiwen , Simpson Judy M , March Lyn M , Blyth Fiona M , Bliuc Dana , Tran Thach , Nguyen Tuan V , Eisman John A , Center Jacqueline R
Published: January 2018

Nonhip, nonvertebral (NHNV) fractures constitute the majority of osteoporotic fractures, but few studies have examined the association between these fractures, comorbidity, and mortality. Our objective was to examine the relationship between individual nonhip, nonvertebral fractures, comorbidities, and mortality. The prospective population-based cohort of 267,043 subjects (45 and Up Study, Australia) had baseline questionnaires linked to hospital administrative and all-cause mortality data from 2006 to 2013. Associations between fracture and mortality were examined using multivariate, time-dependent Cox models, adjusted for age, prior fracture, body mass index, smoking, and comorbidities (cardiovascular disease, diabetes, stroke, thrombosis, and cancer), and survival function curves. Population attributable fraction was calculated for each level of risk exposure. During 1,490,651 person-years, women and men experienced 7571 and 4571 fractures and 7064 deaths and 11,078 deaths, respectively. In addition to hip and vertebral fractures, pelvis, humerus, clavicle, rib, proximal tibia/fibula, elbow and distal forearm fractures in both sexes, and ankle fractures in men were associated with increased multivariable-adjusted mortality hazard ratios ranging from 1.3 to 3.4. Comorbidity independently added to mortality such that a woman with a humeral fracture and 1 comorbidity had a similarly reduced 5-year survival as that of a woman with a hip fracture and no comorbidities. Population mortality attributable to any fracture without comorbidity was 9.2% in women and 5.3% in men. All proximal nonhip, nonvertebral fractures in women and men were associated with increased mortality risk. Coexistent comorbidities independently further increased mortality. Population attributable risk for mortality for fractures was similar to cardiovascular disease and diabetes, highlighting their importance and potential benefit for early intervention and treatment. © 2018 American Society for Bone and Mineral Research.
Association of Pre-ESRD Serum Calcium With Post-ESRD Mortality Among Incident ESRD Patients: A Cohort Study
Authors: Obi Yoshitsugu , Park Christina , Soohoo Melissa , Sumida Keiichi , Hamano Takayuki , Rhee Connie M , Kovesdy Csaba P , Kalantar-Zadeh Kamyar , Streja Elani
Published: January 2018

Albumin-corrected serum calcium (cSCa) decline at late stages of chronic kidney disease and rise after dialysis initiation. Although hypercalcemia is associated with higher mortality in end-stage renal disease (ESRD), there are scarce data on the impact of pre-ESRD cSCa on post-ESRD mortality. Therefore, we used a large national cohort of 21,826 US veterans who transitioned to dialysis in all US Department of Veterans Affairs health care facilities over 2009 to 2014 to examine the associations with all-cause and cause-specific post-ESRD mortality of (1) cSCa concentrations averaged over the last 6 months and (2) its rate of decline during the last 12 months before dialysis initiation. Mean concentrations and median rate of decline of cSCa were 9.3 ± 0.7 mg/dL and −0.15 (interquartile range −0.39 to 0.07) mg/dL/year, respectively. A total of 9596 patients died during the follow-up period (mean 1.9 years; total 41,541 patient-years) with an incidence rate of 23.1 per 100 patient-years. There was an independent linear association between higher cSCa with higher mortality (ptrend < 0.001). The mortality risk associated with cSCa ≥9.0 mg/dL was attenuated among active vitamin D users (pinteraction < 0.001). Patients with faster decline in cSCa showed lower mortality irrespective of baseline cSCa concentrations. These cSCa-mortality associations were stronger for noncardiovascular versus cardiovascular death. In conclusion, lower pre-ESRD cSCa and faster decline in cSCa were consistently and linearly associated with better post-ESRD survival among US veterans, especially for noncardiovascular death. Further studies are needed to determine if correcting hypocalcemia is beneficial or harmful and which intervention is preferred when indicated among patients transitioning to ESRD. © 2018 American Society for Bone and Mineral Research.
Population Pharmacokinetic Modeling of Guselkumab, a Human IgG1λ Monoclonal Antibody Targeting IL‐23, in Patients with Moderate to Severe Plaque Psoriasis
Authors: Yao Zhenling , Hu Chuanpu , Zhu Yaowei , Xu Zhenhua , Randazzo Bruce , Wasfi Yasmine , Chen Yang , Sharma Amarnath , Zhou Honghui
Published: January 2018

Psoriasis is a common inflammatory skin disorder that requires chronic treatment and is associated with multiple comorbidities. Guselkumab, a human immunoglobulin‐G1‐lambda monoclonal antibody, binds to interleukin‐23 with high specificity and affinity and is effective in treating moderate to severe plaque psoriasis. As part of the guselkumab psoriasis clinical trial program, using a confirmatory approach, a population pharmacokinetics (PopPK) model was established using 13 014 PK samples from 1454 guselkumab‐treated patients across 3 phase 2/3 trials. Observed serum guselkumab concentrations were adequately described by a 1‐compartment linear PK model with first‐order absorption and elimination. The final PK model was robust and stable, with apparent clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (ka) estimates of 0.516 L/day, 13.5 L, and 1.11 day‐1, respectively. A model‐derived elimination half‐life of 18.1 days indicated achievement of steady‐state serum guselkumab concentrations within 12–14 weeks. The primary covariate contributing to the observed PK variability was body weight, which accounted for only 28% (CL/F) and 32% (V/F) of the interindividual proportion of variance. Diabetes was identified to marginally reduce guselkumab exposure, owing to 12% higher CL/F in diabetic versus nondiabetic patients, but its contribution was not clinically relevant. None of the other covariates tested (eg, age, sex, ethnicity, immune response to guselkumab, or concomitant medications) had a clinically relevant effect on guselkumab exposure.
A novel synthesis of 6′′‐[18F]‐fluoromaltotriose as a PET tracer for imaging bacterial infection
Authors: Namavari Mohammad , Gowrishankar Gayatri , Srinivasan Ananth , Gambhir Sanjiv S. , Haywood Thomas , Beinat Corinne
Published: January 2018

The aim of this study was to develop a positron emission tomography (PET) tracer to visualize and monitor therapeutic response to bacterial infections. In our continued efforts to find maltose based PET tracers that can image bacterial infections, we have designed and prepared 6′′‐[18F]fluoromaltotriose as a second generation PET imaging tracer targeting the maltodextrin transporter of bacteria. We have developed methods to synthesize 6′′‐deoxy‐6′′‐[18F]fluoro‐α‐D‐glucopyranosyl‐(1‐4)‐O‐α‐D‐glucopyranosyl‐(1‐4)‐O‐D‐glucopyranose (6′′‐[18F]‐fluoromaltotriose) as a bacterial infection PET imaging agent. 6′′‐[18F]fluoromaltotriose was prepared from precursor, 2′′,3′′,4′′‐tri‐O‐acetyl‐6′′‐O‐nosyl‐α‐D‐glucopyranosyl‐(1‐4)‐O‐2′,3′,6′‐tri‐O‐acetyl‐α‐D‐glucopyranosyl‐(1‐4)‐1,2,3,6‐tetra‐O‐acetyl‐D‐glucopyranose (per‐O‐acetyl‐6′′‐O‐nosyl‐maltotriose 4). This method utilizes the reaction between precursor 4 and anhydrous [18F]KF/Kryptofix 2.2.2 in dimethylformamide (DMF) at 85°C for 10 minutes to yield per‐O‐acetyl‐6′′‐deoxy‐6‐′′ [18F]‐fluoromaltotriose (7). Successive acidic and basic hydrolysis of the acetyl protecting groups in 7 produced 6′′‐[18F]fluoromaltotriose (8). Also, cold 6′′‐ [19F]fluoromaltotriose was prepared from per‐O‐acetyl‐6′′‐hydroxymaltotriose via a diethylaminosulfur trifluoride reaction followed by a basic hydrolysis. A successful synthesis of 6′′‐[18F]‐fluoromaltotriose has been accomplished in 8 ± 1.2% radiochemical yield (decay corrected). Total synthesis time was 120 minutes. Serum stability of 6′′‐[18F]fluoromaltotriose at 37°C indicated that 6′′‐[18F]‐fluoromaltotriose remained intact up to 2 hours. In conclusion, we have successfully synthesized 6′′‐[18F]‐fluoromaltotriose via direct fluorination of an appropriate precursor of a protected maltotriose.
89Zr‐ImmunoPET companion diagnostics and their impact in clinical drug development
Authors: McKnight Brooke N. , Viola‐Villegas Nerissa T.
Published: January 2018

Therapeutic monoclonal antibodies have been used in cancer treatment for 30 years, with around 24 mAb and mAb:drug conjugates approved by the FDA to date. Despite their specificity, efficacy has remained limited, which, in part, derails nascent initiatives towards precision medicine. An image‐guided approach to reinforce treatment decisions using immune positron emission tomography (immunoPET) companion diagnostic is warranted. This review provides a general overview of current translational research using Zr‐89 immunoPET and opportunities for utilizing and harnessing this tool to its full potential. Patient case studies are cited to illustrate immunoPET probes as tools for profiling molecular signatures. Discussions on its utility in reinforcing clinical decisions as it relates to histopathological tumor assessment and standard diagnostic methods, and its potential as predictive biomarkers, are presented. We finally conclude with an overview of practical considerations to its utility in the clinic.
Electrochemical monitoring of aflatoxin M1 in milk samples using silver nanoparticles dispersed on α‐cyclodextrin‐GQDs nanocomposite
Authors: Shadjou Rana , Hasanzadeh Mohammad , Heidar‐poor Mohammad , Shadjou Nasrin
Published: January 2018

Aflatoxins are potential food pollutants produced by fungi. One of important toxins is aflatoxin M1 (AFM1). A great deal of concern is associated with AFM1 toxicity. In the present study, an innovative electrochemical interface for quantitation of AFM1 based on ternary signal amplification strategy was fabricated. In this work, silver nanoparticles was electrodeposited onto green and biocompatible nanocomposite containing α‐cyclodextrin as conductive matrix and graphene quantum dots as amplification element. Therefore, a multilayer film based on α‐cyclodextrin, graphene quantum dots, and silver nanoparticles was exploited to develop a highly sensitive electrochemical sensor for detection of AFM1. Fully electrochemical methodology was used to prepare a transducer on a glassy carbon electrode, which provided a high surface area toward sensitive detection of AFM1. The surface morphology of electrode surface was characterized by high‐resolution field emission scanning electron microscope. The proposed sensing platform provides a simple tool for AFM1 detection. Under optimized condition, the calibration curve for AFM1 concentration was linear in 0.015mM to 25mM with low limit of quantification of 2μM. The practical analytical utility of the modified electrode was illustrated by determination of AFM1 in unprocessed milk samples.
Cerebral blood volume mapping with ferumoxytol in dynamic susceptibility contrast perfusion MRI: Comparison to standard of care
Authors: Varallyay Csanad G. , Nesbit Eric , Horvath Andrea , Varallyay Peter , Fu Rongwei , Gahramanov Seymur , Muldoon Leslie L. , Li Xin , Rooney William D. , Neuwelt Edward A.
Published: January 2018

Background

Cerebral blood volume (CBV) mapping with a dynamic susceptibility contrast (DSC) perfusion technique has become a clinical tool in diagnosing and follow‐up of brain tumors. Ferumoxytol, a long‐circulating iron oxide nanoparticle, has been tested for CBV mapping, but the optimal dose has not been established.

Purpose

To compare ferumoxytol DSC of two different doses to standard of care gadoteridol by analyzing time–intensity curves and CBV maps in normal‐appearing brain regions.

Study Type

Retrospective.

Subjects

Fifty‐four patients with various brain disorders.

Field Strength/Sequence

3T MRI. DSC‐MRI was performed with 0.1 mmol/kg gadoteridol and 1 day later with ferumoxytol in doses of 1 or 2 mg/kg.

Assessment

Signal changes during first pass, relative CBV (rCBV) in normal‐appearing thalamus, putamen, and globus pallidus, and contrast‐to‐noise ratio (CNR) of the CBV maps were compared between gadoteridol and various doses of ferumoxytol using an automated method. To subjectively assess the quality of the CBV maps, two blinded readers also assessed visual conspicuity of the putamen.

Statistical Tests

Linear mixed effect model was used for statistical comparison.

Results

Compared to gadoteridol, 1 mg/kg ferumoxytol showed no difference in CNR (P = 0.6505), peak ΔR2*, and rCBV in the putamen (P = 0.2669, 0.0871) or in the thalamus (P = 0.517, 0.9787); 2 mg/kg ferumoxytol increased peak ΔR2* as well as the CNR (P < 0.0001), but also mildly increased rCBV in putamen and globus pallidus (P = 0.0005, 0.0012). Signal intensities during first pass remained highly above the noise level, with overlapping of 95% confidence intervals with noise only in 3 out of 162 tested regions. Compared to gadoteridol, the visual image quality showed mild improvement with 1 mg/kg (P = 0.02) and marked improvement with 2 mg/kg ferumoxytol (P < 0.0001).

Data Conclusion

1 mg/kg ferumoxytol provides similar imaging results to standard gadoteridol for DSC‐MRI, and 2 mg/kg has a benefit of increased CNR, but may also result in mildly increased rCBV values.

Level of Evidence: 3

Technical Efficacy: Stage 1

J. MAGN. RESON. IMAGING 2018;48:441–448.
Characterization of Adrenal Lesions on Unenhanced MRI Using Texture Analysis: A Machine‐Learning Approach
Authors: Romeo Valeria , Maurea Simone , Cuocolo Renato , Petretta Mario , Mainenti Pier Paolo , Verde Francesco , Coppola Milena , Dell'Aversana Serena , Brunetti Arturo
Published: January 2018

Background

Adrenal adenomas (AA) are the most common benign adrenal lesions, often characterized based on intralesional fat content as either lipid‐rich (LRA) or lipid‐poor (LPA). The differentiation of AA, particularly LPA, from nonadenoma adrenal lesions (NAL) may be challenging. Texture analysis (TA) can extract quantitative parameters from MR images. Machine learning is a technique for recognizing patterns that can be applied to medical images by identifying the best combination of TA features to create a predictive model for the diagnosis of interest.

Purpose/Hypothesis

To assess the diagnostic efficacy of TA‐derived parameters extracted from MR images in characterizing LRA, LPA, and NAL using a machine‐learning approach.

Study Type

Retrospective, observational study.

Population/Subjects/Phantom/Specimen/Animal Model

Sixty MR examinations, including 20 LRA, 20 LPA, and 20 NAL.

Field Strength/Sequence

Unenhanced T1‐weighted in‐phase (IP) and out‐of‐phase (OP) as well as T2‐weighted (T2‐w) MR images acquired at 3T.

Assessment

Adrenal lesions were manually segmented, placing a spherical volume of interest on IP, OP, and T2‐w images. Different selection methods were trained and tested using the J48 machine‐learning classifiers.

Statistical Tests

The feature selection method that obtained the highest diagnostic performance using the J48 classifier was identified; the diagnostic performance was also compared with that of a senior radiologist by means of McNemar's test.

Results

A total of 138 TA‐derived features were extracted; among these, four features were selected, extracted from the IP (Short_Run_High_Gray_Level_Emphasis), OP (Mean_Intensity and Maximum_3D_Diameter), and T2‐w (Standard_Deviation) images; the J48 classifier obtained a diagnostic accuracy of 80%. The expert radiologist obtained a diagnostic accuracy of 73%. McNemar's test did not show significant differences in terms of diagnostic performance between the J48 classifier and the expert radiologist.

Data Conclusion

Machine learning conducted on MR TA‐derived features is a potential tool to characterize adrenal lesions.

Level of Evidence: 4

Technical Efficacy: Stage 2

J. Magn. Reson. Imaging 2018.