bluuebunny/crossref_metadata_2025 huggingface dataset:
Immediate verbal recall and familial dementia risk: population-based study of over 4000 twins
Authors: Lindgren Noora , Kaprio Jaakko , Rinne Juha O , Vuoksimaa Eero
Published: October 2018

Objective

To investigate the effect of familial risk for dementia on verbal learning by comparing cognitively healthy twins who had demented co-twins with cognitively healthy twins who had cognitively healthy co-twins.

Methods

4367 twins aged ≥65 years including 1375 twin pairs (533 monozygotic (MZ), 823 dizygotic (DZ) and 19 unknown zygosity pairs) from a population-based Finnish Twin Cohort participated in a cross-sectional telephone assessment for dementia and in a single free recall trial of a 10-item word list.

Results

Cognitively healthy twins with demented co-twins (n=101 pairs) recalled less words than cognitively healthy twins with cognitively healthy co-twins (n=770 pairs) after adjusting for age, sex and education, B=− 0.44, 95%  CI (−0.73 to −0.14), p=0.003. The effect size was similar in MZ (n=31) twins (3.88 vs 4.29 words, B=−0.41, 95%  CI (−0.96 to 0.13)) and DZ (n=66) twins (3.70 vs 4.17 words, B=−0.47, 95%  CI (−0.84 to −0.10)). The heritability estimate of immediate recall (IR) was 0.37, 95%  CI (0.21 to 0.43).

Conclusions

The results demonstrate that familial risk for dementia is reflected in the IR performance of cognitively healthy older persons. The finding of poorer IR performance in non-affected siblings compared with the general population, together with substantial heritability of IR, supports IR as a useful endophenotype for molecular genetic studies of dementia.
Decreasing incidence of subarachnoid hemorrhage
Authors: Nicholson Patrick , O’Hare Alan , Power Sarah , Looby Seamus , Javadpour Mohsen , Thornton John , Brennan Paul
Published: October 2018

Objective

To determine the incidence and trends in subarachnoid hemorrhage in Ireland using data from a national database.

Materials and methods

We performed a retrospective nationwide query of the Irish Hospital In-patient Enquiry System (HIPE). This is a national database of all in-patient activity in acute public hospitals in Ireland. Each HIPE entry records one episode of in-patient care. The study period ranged from 1997 to 2015. Population data was obtained from the Irish Central Statistics Office, and the annual prevalence of smoking from the Irish National Tobacco Control Office. We were therefore able to calculate both crude annual acute subarachnoid hemorrhage (SAH) incidence rates, as well as population-standardized rates, and compared them with trends in the annual smoking rates.

Results

The mean number of SAH cases per year is 549, with 465 cases in 1997 and 517 in 2015 (range: 465–624). The absolute incidence of SAH, therefore, remained relatively stable. Due to population increases over time, the population-adjusted rate of SAH therefore decreased, from 126.9/million people/year in 1997 to 111.5/million people/year in 2015. Nationally, there was a decrease in smoking prevalence, from 31% in 1998 to 19.2% in 2015. There was a statistically significant correlation between decreasing smoking rates and decreasing population-adjusted incidence of SAH (P=<0.0001).

Conclusions

Our data suggests that the incidence of non-traumatic subarachnoid hemorrhage in our population appears to be decreasing, a decrease which is correlated with decreasing smoking rates. This provides important data both in terms of the epidemiology of SAH, as well as the possible role of public-health interventions in tackling both smoking and declining rates of SAH.
Impact of an increase in the inhaled corticosteroid dose on blood eosinophils in asthma
Authors: Lommatzsch Marek , Klein Maria , Stoll Paul , Virchow Johann Christian
Published: October 2018

Here, we report that increasing treatment with inhaled corticosteroids (ICS) in patients with not well-controlled asthma from a medium to a high dose results in a profound reduction of blood eosinophils (median fall in blood eosinophil concentrations from 560 to 320 cells/µL). Therefore, ‘normal values’ of blood eosinophils in patients with asthma need to be considered in view of the individual ICS doses of the patients. In addition, increases in the dose of ICS may result in blood eosinophil concentrations which would formally preclude treatment with biologics targeting the interleukin-5 pathway.
William Brian Singleton
Authors: Jones Bruce Vivash
Published: October 2018

A man of influence: founder of the British Small Animal Veterinary Association (BSAVA) and the World Small Animal Veterinary Association and president of the RCVS, BSAVA and the British Equine Veterinary Association.
Correlating tropical climate with survival of an Arctic-breeding, trans-equatorial migrant seabird
Authors: Fife Danielle T. , Davis Shanti E. , Robertson Gregory J. , Gilchrist H. Grant , Stenhouse Iain J. , Shutler Dave , Mallory Mark L.
Published: October 2018

Extreme climate can negatively affect survival through increased physiological demands or by reducing prey availability. This can have significant population-level consequences for organisms with low reproductive rates, such as seabirds. As an Arctic-breeding trans-equatorial migrant, Sabine’s gull (Xema sabini) is exposed to a profound variety of climate regimes during the year. Therefore, its annual survival may be affected by broad-scale teleconnection patterns that influence regional climate variability. We used Program MARK to estimate apparent survival and resighting probabilities from 2007 to 2013 for adult Sabine’s gulls breeding at a High Arctic colony. We then combined capture–mark–recapture data for the High Arctic colony with those previously published from a Low Arctic colony (1998–2002) to examine influences of climate variability on survival. Mean ± standard error apparent survival estimated for the High Arctic colony was 0.90 ± 0.03, similar to that previously reported for the Low Arctic colony. We found a negative relationship between survival and the Tropical/Northern Hemisphere pattern, an atmospheric mode that is associated with the Pacific jet stream. Our study suggests that although Sabine’s gull survival was generally high and relatively constant over time, adult mortality may increase during years of extreme climate events in regions far beyond their Arctic breeding grounds.
Serum ferritin level as an early indicator of metabolic dysregulation in young obese adults — a cross-sectional study
Authors: Hitha Harshitha , Gowda Damodara , Mirajkar Amrit
Published: October 2018

The aim of this study was to investigate the relationship between serum ferritin level and antioxidative status and metabolic dysregulation in young adult obese population. This cross-sectional study included 300 subjects of either sex, grouped as obese and non-obese subjects. The body mass index, total iron binding capacity, fasting blood glucose, superoxide dismutase activity, and levels of serum ferritin, iron, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, glutathione, and vitamin C were estimated. Analysis showed a significant alteration in all the parameters in obese adults. The correlation of ferritin level and body mass index showed a positive correlation (r = −0.81, p < 0.001, respectively) with levels of fasting blood glucose, superoxide dismutase, total cholesterol, low-density lipoprotein cholesterol, and triglyceride in obese individuals, whereas an insignificant correlation with vitamin C and glutathione level was observed in obese individuals. The significant positive correlation of ferritin level with the metabolic parameters and some antioxidative parameters in obese individuals signifies the development of metabolic disorders. Therefore, estimation of serum ferritin level will be an important early indicator for the risk of developing metabolic disorders in young adults.
Optical solitary waves and conservation laws to the (2 + 1)-dimensional hyperbolic nonlinear Schrödinger equation
Authors: Aliyu Aliyu Isa , Inc Mustafa , Yusuf Abdullahi , Baleanu Dumitru
Published: October 2018

This work studies the hyperbolic nonlinear Schrödinger equation (H-NLSE) in (2 + 1)-dimensions. The model describes the evolution of the elevation of water wave surface for slowly modulated wave trains in deep water in hydrodynamics, and also governs the propagation of electromagnetic fields in self-focusing and normally dispersive planar wave guides in optics. A class of gray and black optical solitary wave solutions of the H-NLSE are reported by adopting an appropriate solitary wave ansatz solution. Moreover, classification of conservation laws (Cls) to the H-NLSE is implemented using the multipliers approach. Some physical interpretations and analysis of the results obtained are also presented.
Schrödinger systems with quadratic interactions
Authors: Tian Rushun , Wang Zhi-Qiang , Zhao Leiga
Published: October 2018

In this paper, we consider the existence and multiplicity of nontrivial solutions to a quadratically coupled Schrödinger system [Formula: see text] where [Formula: see text], [Formula: see text] and [Formula: see text] are constants and [Formula: see text], [Formula: see text]. Such type of systems stem from applications in nonlinear optics, Bose–Einstein condensates and plasma physics. The existence (and nonexistence), multiplicity and asymptotic behavior of vector solutions of the system are established via variational methods. In particular, for multiplicity results we develop new techniques for treating variational problems with only partial symmetry for which the classical minimax machinery does not apply directly. For the above system, the variational formulation is only of even symmetry with respect to the first component [Formula: see text] but not with respect to [Formula: see text], and we prove that the number of vector solutions tends to infinity as [Formula: see text] tends to infinity.
Characterization of generalized Orlicz spaces
Authors: Ferreira Rita , Hästö Peter , Ribeiro Ana Margarida
Published: October 2018

The norm in classical Sobolev spaces can be expressed as a difference quotient. This expression can be used to generalize the space to the fractional smoothness case. Because the difference quotient is based on shifting the function, it cannot be used in generalized Orlicz spaces. In its place, we introduce a smoothed difference quotient and show that it can be used to characterize the generalized Orlicz–Sobolev space. Our results are new even in Orlicz spaces and variable exponent spaces.
Geometrically distinct solutions given by symmetries of variational problems with the O(N)-symmetry
Authors: Marzantowicz Wacław
Published: October 2018

For variational problems with [Formula: see text]-symmetry, the existence of several geometrically distinct solutions has been shown by use of group theoretic approach in the previous papers. It was done by a crafty choice of a family [Formula: see text] subgroups such that the fixed point subspaces [Formula: see text] of the action in a corresponding functional space are linearly independent, next restricting the problem to each [Formula: see text] and using the Palais symmetry principle. In this work, we give a thorough explanation of this approach showing a correspondence between the equivalence classes of such subgroups, partial orthogonal flags in [Formula: see text], and unordered partitions of the number [Formula: see text]. By showing that spaces of functions invariant with respect to different classes of groups are linearly independent, we prove that the amount of series of geometrically distinct solutions obtained in this way grows exponentially in [Formula: see text], in contrast to logarithmic, and linear growths of earlier papers.
Antipodes of monoidal decomposition spaces
Authors: Carlier Louis , Kock Joachim
Published: October 2018

We introduce a notion of antipode for monoidal (complete) decomposition spaces, inducing a notion of weak antipode for their incidence bialgebras. In the connected case, this recovers the usual notion of antipode in Hopf algebras. In the non-connected case, it expresses an inversion principle of more limited scope, but still sufficient to compute the Möbius function as [Formula: see text], just as in Hopf algebras. At the level of decomposition spaces, the weak antipode takes the form of a formal difference of linear endofunctors [Formula: see text], and it is a refinement of the general Möbius inversion construction of Gálvez–Kock–Tonks, but exploiting the monoidal structure.
Sensitivity and specificity of normalized truncated navicular height in assessment of static foot posture in children aged 6–12 years
Authors: Aboelnasr Emad A. , El-Talawy Hoda A. , Abdelazim Faten H. , Hegazy Fatma A.
Published: October 2018

Background: Normalized truncated navicular height (NTNH) is a non-invasive, easy to perform, and simple clinical measure of static foot posture. However, its sensitivity and specificity in evaluation of the static foot posture in children have not been investigated yet.

Objective: To investigate the intra-rater reliability, sensitivity, and specificity of NTNH in evaluation of the static foot posture in children using radiographic measure as a gold standard measure.

Methods: A cross-sectional study of a random sample of 300 school children aged 6–12 years old. Intra-rater reliability, minimal detectable change, sensitivity, and specificity of NTNH were investigated. NTNH as a clinical measure of static foot posture was calculated and compared to the radiographic measure and displayed on the receiver operating characteristic (ROC) curve.

Results: NTNH demonstrated an intra-rater reliability of [Formula: see text]. The sensitivity and specificity of NTNH were 88.1% and 99.5%, respectively. The optimal cutoff point for the diagnosis of flat foot using NTNH in children aged 6–12 years is NTNH [Formula: see text].

Conclusion: NTNH is a sensitive and specific measure of static foot posture in the children aged 6–12 years. It is recommended to be used as a screening measure of static foot posture in children as it is easy, simple to perform, and a non-invasive clinical measure.
Evaluating the influence of meteorite impact events on global potassium feldspar availability to the atmosphere since 600 Ma
Authors: Coldwell B. C. , Pankhurst M. J.
Published: October 2018

Potassium feldspar present in global mineral aerosol (<5%) plays a disproportionate role in modulating the microphysics of mixed-phase cloud. Via exceptional ice nucleation properties, it is capable of changing cloud properties and behaviour. Here we identify times of substantial and abrupt change in the global availability of potassium feldspar since 600 Ma. Normally, weathering and vegetation cover contribute to low availability, with clay dominating mineral aerosol. Periods of maximum availability are reasoned to follow the emplacement and remobilization of ejecta blankets from major meteorite impact events, before returning to background after some hundreds to thousands of years. We review the 44 largest confirmed craters and evaluate the potassium feldspar content of their target rocks, which range from
c.
0 to >30%. By combining crater size and tectonic reconstructions, we are able to provide a quantitative and self-consistent assessment of changes to global potassium feldspar availability. Considerable differences in potassium feldspar availability following meteorite impact events are revealed. Different impact events generated dust containing different amounts of potassium feldspar. Differing levels of influence upon climate are hypothesized, and should now be tested by looking at stratigraphic records of these events to reveal the sensitivity of climate to different dust mineralogy.

Supplementary material:
Figures showing palaeolatitude determinations using various methods and reconstruction models, and estimates of alkali feldspar abundance and distribution across contemporary continental landmasses for meteorite impact events are available at:
https://doi.org/10.6084/m9.figshare.c.4253312
Distributed Machine Learning on Smart-Gateway Network toward Real-Time Smart-Grid Energy Management with Behavior Cognition
Authors: Huang Hantao , Xu Hang , Cai Yuehua , Khalid Rai Suleman , Yu Hao
Published: October 2018

Real-time data analytics for smart-grid energy management is challenging with consideration of both occupant behavior profiles and energy profiles. This article proposes a distributed and networked machine-learning platform on smart-gateway-based smart-grid in residential buildings. It can analyze occupant behaviors, provide short-term load forecasting, and allocate renewable energy resources. First, occupant behavior profile is captured by real-time indoor positioning system with WiFi data analytics; and the energy profile is extracted by real-time meter system with electricity load data analytics. Then, the 24-hour occupant behavior profile and energy profile are fused with prediction using an online distributed machine-learning algorithm with real-time data update. Based on the forecasted occupant behavior profile and energy profile, solar energy source is allocated to reduce peak demand on the main electricity power-grid. The whole management flow can be operated on the distributed smart-gateway network with limited computational resources but with a supported general machine-learning engine. Experimental results on occupant behavior extraction show that the proposed algorithm can achieve 91.2% positioning accuracy within 3.64m. Moreover, 50× and 38× speed-up is obtained during data testing and training, respectively, when compared to traditional support vector machine (SVM) method. For short-term load forecasting, it is 14.83% more accurate when compared to SVM-based data analytics. Based on the predicted occupant behavior profile and energy profile, our proposed energy management system can achieve 19.66% more peak load reduction and 26.41% more cost saving as compared to the SVM-based method.
Seq3seq fingerprint
Authors: Zhang Xiaoyu , Wang Sheng , Zhu Feiyun , Xu Zheng , Wang Yuhong , Huang Junzhou
Published: October 2018

Observing the recent progress in Deep Learning, the employment of AI is surging to accelerate drug discovery and cut R&D costs in the last few years. However, the success of deep learning is attributed to large-scale clean high-quality labeled data, which is generally unavailable in drug discovery practices.

In this paper, we address this issue by proposing an end-to-end deep learning framework in a semi-supervised learning fashion. That is said, the proposed deep learning approach can utilize both labeled and unlabeled data. While labeled data is of very limited availability, the amount of available unlabeled data is generally huge. The proposed framework, named as
seq3seq fingerprint
, automatically learns a strong representation of each molecule in an unsupervised way from a huge training data pool containing a mixture of both unlabeled and labeled molecules. In the meantime, the representation is also adjusted to further help predictive tasks, e.g., acidity, alkalinity or solubility classification. The entire framework is trained end-to-end and simultaneously learn the representation and inference results. Extensive experiments support the superiority of the proposed framework.
Usability evaluation framework for domain-specific language
Authors: Poltronieri Ildevana , Zorzo Avelino Francisco , Bernardino Maicon , de Borba Campos Marcia
Published: October 2018

Software engineers are increasingly taking advantage of new methods to improve software quality. The use of languages developed for specific domains, which in the literature are known as Domain-Specific Languages (DSLs), has grown in the past years. Although several experimental studies that subjectively evaluate usability of these languages can be found in the literature, few of them have taken advantage of applying Human-Computer Interaction (HCI) techniques in those evaluations. Therefore, the main goals of this paper are to present a usability evaluation framework for DSLs, called Usa-DSL, and to show the evaluation of the framework through a Focus Group method. The evaluation was performed by seven specialists that discussed the framework usability and suggested some modifications of our initial proposal. The specialists recommendations were incorporated in the final framework presented in this paper.
Hot Potato Criminology: Ethnographers and the Shame of Poor People's Crimes
Authors: Katz Jack
Published: October 2018

When ethnographers study street crime, they anticipate that readers might shame them for shaming the poor. One common response is to compromise the quality of ethnographic data. Another is to pass righteous indignation away from the poor by arguing the causal significance of deindustrialization, class inequalities, racial prejudice, policing, colonialism, or hostility toward immigrants. Almost always, such arguments are gratuitous: The evidence for the structural and historical causes offered by ethnographers does not vary with the situational and biographical variations in behavior that make for high-quality ethnographic data. Nevertheless, if we read around the rhetorical practices that contemporary ethnographers of crime use to shift shame away from their subjects and themselves, we learn how street crime is produced through small criminogenic social circles. Considered as a set, recent ethnographies have significantly advanced knowledge about the social psychology of criminality, and they provide promising leads for improving the understanding of variations in crime patterns over time and across metropolitan spaces.
Government Policies for Counteracting Violent Extremism
Authors: LaFree Gary , Freilich Joshua D.
Published: October 2018

It took the 1995 bombing of the Murrah Federal Building in Oklahoma City and, more importantly, the four coordinated attacks of September 11, 2001, to produce substantial interest among criminologists in the empirical study of violent political extremism. In the past two decades, this situation has changed dramatically with research on political extremism now routinely appearing in major criminology outlets, theses and dissertations, and meetings of professional associations. In this review, we track these changes specifically as they relate to government policies on countering violent extremism. What we find is a burgeoning literature. In the past twenty years, we have moved rapidly toward developing a criminology of political extremism. But not surprisingly, given how recent the sustained interest in this area has been, we find research areas where data are weak or nonexistent, rigorous methods are lacking, and results are disconnected from theoretical frameworks. We have divided our review of government responses to violent political extremism along a continuum ranging from the most repressive to the most conciliatory. In general, the trajectory of research on governmental policies to counteract terrorism resembles the early years of criminology itself, characterized by an incredible amount of energy and imagination but at the same time struggling to produce strong empirical data, cutting-edge methods, and sophisticated theoretical explanations.
Methodological Challenges and Opportunities in Testing for Racial Discrimination in Policing
Authors: Neil Roland , Winship Christopher
Published: October 2018

A large body of empirical research exists that attempts to determine whether or not police discriminate on the basis of race. We investigate whether the methods used typically produce valid inferences. We find that they often most likely do not and that results may diverge from reality in either direction, indicating discrimination when it is not present or alternatively indicating a lack of discrimination when it is in fact present. The reason for this is that tests make assumptions about police behavior that are often implausible. Because of this, the simplest forms of benchmark and outcome tests should not be used, although the problem is more general. We discuss several possible ways to improve inferences about the absence or presence of discrimination, such as employing matching or weighting techniques and using novel, computationally intensive methods.
Nonreproductive Effects of Insect Parasitoids on Their Hosts
Authors: Abram Paul K. , Brodeur Jacques , Urbaneja Alberto , Tena Alejandro
Published: October 2018

The main modes of action of insect parasitoids are considered to be killing their hosts with egg laying followed by offspring development (reproductive mortality), and adults feeding on hosts directly (host feeding). However, parasitoids can also negatively affect their hosts in ways that do not contribute to current or future parasitoid reproduction (nonreproductive effects). Outcomes of nonreproductive effects for hosts can include death, altered behavior, altered reproduction, and altered development. On the basis of these outcomes and the variety of associated mechanisms, we categorize nonreproductive effects into ( a) nonconsumptive effects, ( b) mutilation, ( c) pseudoparasitism, ( d) immune defense costs, and ( e) aborted parasitism. These effects are widespread and can cause greater impacts on host populations than successful parasitism or host feeding. Nonreproductive effects constitute a hidden dimension of host–parasitoid trophic networks, with theoretical implications for community ecology as well as applied importance for the evaluation of ecosystem services provided by parasitoid biological control agents.
Fat Body Biology in the Last Decade
Authors: Li Sheng , Yu Xiaoqiang , Feng Qili
Published: October 2018

The insect fat body is analogous to vertebrate adipose tissue and liver. In this review, the new and exciting advancements made in fat body biology in the last decade are summarized. Controlled by hormonal and nutritional signals, insect fat body cells undergo mitosis during embryogenesis, endoreplication during the larval stages, and remodeling during metamorphosis and regulate reproduction in adults. Fat body tissues are major sites for nutrient storage, energy metabolism, innate immunity, and detoxification. Recent studies have revealed that the fat body plays a central role in the integration of hormonal and nutritional signals to regulate larval growth, body size, circadian clock, pupal diapause, longevity, feeding behavior, and courtship behavior, partially by releasing fat body signals to remotely control the brain. In addition, the fat body has emerged as a fascinating model for studying metabolic disorders and immune diseases. Potential future directions for fat body biology are also proposed herein.
Comparative gene array analyses of severe elastic fiber defects in late embryonic and newborn mouse aorta
Authors: Staiculescu Marius Catalin , Cocciolone Austin J. , Procknow Jesse D. , Kim Jungsil , Wagenseil Jessica E.
Published: October 2018

Elastic fibers provide reversible elasticity to the large arteries and are assembled during development when hemodynamic forces are increasing. Mutations in elastic fiber genes are associated with cardiovascular disease. Mice lacking expression of the elastic fiber genes elastin ( Eln−/−), fibulin-4 ( Efemp2−/−), or lysyl oxidase ( Lox−/−) die at birth with severe cardiovascular malformations. All three genetic knockout models have elastic fiber defects, aortic wall thickening, and arterial tortuosity. However, Eln−/−mice develop arterial stenoses, while Efemp2−/−and Lox−/−mice develop ascending aortic aneurysms. We performed comparative gene array analyses of these three genetic models for two vascular locations and developmental stages to determine differentially expressed genes and pathways that may explain the common and divergent phenotypes. We first examined arterial morphology and wall structure in newborn mice to confirm that the lack of elastin, fibulin-4, or lysyl oxidase expression provided the expected phenotypes. We then compared gene expression levels for each genetic model by three-way ANOVA for genotype, vascular location, and developmental stage. We found three genes upregulated by genotype in all three models, Col8a1, Igfbp2, and Thbs1, indicative of a common response to severe elastic fiber defects in developing mouse aorta. Genes that are differentially regulated by vascular location or developmental stage in all three models suggest mechanisms for location or stage-specific disease pathology. Comparison of signaling pathways enriched in all three models shows upregulation of integrins and matrix proteins involved in early wound healing, but not of mature matrix molecules such as elastic fiber proteins or fibrillar collagens.
Prognostic Value of Cancer Stem Cell Markers in Potentially Malignant Disorders of Oral Mucosa: A Meta-analysis
Authors: Saluja Tajindra Singh , Ali Murtaza , Mishra Prabhaker , Kumar Vijay , Singh Satyendra Kumar
Published: October 2018

Background:

Oral squamous cell carcinoma (OSCC) is usually preceded by clinically visible changes on oral mucosa categorized as oral potentially malignant disorders (OPMD). The progression of OPMD to OSCC is a multistep process that provides an opportunity for early cancer detection and interception. Recent research suggests that cancer stem cells (CSC) hold the key to unlocking effective strategies to curb initiation and growth of several malignant neoplasms, including OSCC. In this meta-analysis, we evaluated the efficacy of CSC markers CD133, podoplanin, ALDH1, and others in predicting risk of malignant transformation of OPMDs.

Methods:

The PubMed database was systematically reviewed for relevant articles. Quality of eligible studies was assessed as per reporting recommendations for tumor marker (REMARK) criteria. A total of 18 investigations from 12 studies evaluated clinical or prognostic significance of CSC markers in OPMDs. A reasonable number of patients (1,659) were included in this analysis.

Results:

Positive expression of CSC markers in OPMDs is significantly associated with progression to OSCC [risk ratio (RR), 3.31; 95% confidence interval (CI), 2.72–4.02]. Variability in CSC population makes it difficult to understand exact biology of OPMDs based on single CSC marker investigation.

Conclusions:

Identifying CSC population is a reliable prognostic indicator in OPMDs with or without dysplasia. Multi-marker panel investigation for CSCs in OPMDs may assist in curtailing new cases of oral cancer to a great extent.

Impact:

The study illustrates that evaluating CSC marker expression in OPMDs is a key tool in identifying high-risk cases to prevent development of OSCC.
Combined Blockade of Activating ERBB2 Mutations and ER Results in Synthetic Lethality of ER+/HER2 Mutant Breast Cancer
Authors: Croessmann Sarah , Formisano Luigi , Kinch Lisa N. , Gonzalez-Ericsson Paula I. , Sudhan Dhivya R. , Nagy Rebecca J. , Mathew Aju , Bernicker Eric H. , Cristofanilli Massimo , He Jie , Cutler Richard E. , Lalani Alshad S. , Miller Vincent A. , Lanman Richard B. , Grishin Nick V. , Arteaga Carlos L.
Published: October 2018

Purpose:

We examined the role of ERBB2-activating mutations in endocrine therapy resistance in estrogen receptor positive (ER+) breast cancer.

Experimental Design:

ERBB2 mutation frequency was determined from large genomic databases. Isogenic knock-in ERBB2 mutations in ER+ MCF7 cells and xenografts were used to investigate estrogen-independent growth. Structural analysis was used to determine the molecular interaction of HERL755S with HER3. Small molecules and siRNAs were used to inhibit PI3Kα, TORC1, and HER3.

Results:

Genomic data revealed a higher rate of ERBB2 mutations in metastatic versus primary ER+ tumors. MCF7 cells with isogenically incorporated ERBB2 kinase domain mutations exhibited resistance to estrogen deprivation and to fulvestrant both in vitro and in vivo, despite maintaining inhibition of ERα transcriptional activity. Addition of the irreversible HER2 tyrosine kinase inhibitor neratinib restored sensitivity to fulvestrant. HER2-mutant MCF7 cells expressed higher levels of p-HER3, p-AKT, and p-S6 than cells with wild-type HER2. Structural analysis of the HER2L755S variant implicated a more flexible active state, potentially allowing for enhanced dimerization with HER3. Treatment with a PI3Kα inhibitor, a TORC1 inhibitor or HER3 siRNA, but not a MEK inhibitor, restored sensitivity to fulvestrant and to estrogen deprivation. Inhibition of mutant HER2 or TORC1, when combined with fulvestrant, equipotently inhibited growth of MCF7/ERBB2V777L xenografts, suggesting a role for TORC1 in antiestrogen resistance induced by ERBB2 mutations.

Conclusions:

ERBB2 mutations hyperactivate the HER3/PI3K/AKT/mTOR axis, leading to antiestrogen resistance in ER+ breast cancer. Dual blockade of the HER2 and ER pathways is required for the treatment of ER+/HER2 mutant breast cancers.
Peripheral Stem Cell Apheresis is Feasible Post 131Iodine-Metaiodobenzylguanidine-Therapy in High-Risk Neuroblastoma, but Results in Delayed Platelet Reconstitution
Authors: Kraal Kathelijne C.J.M. , Timmerman Ilse , Kansen Hannah M. , van den Bos Cor , Zsiros Jozsef , van den Berg Henk , Somers Sebastiaan , Braakman Eric , Peek Annemarie M.L. , van Noesel Max M. , van der Schoot C. Ellen , Fiocco Marta , Caron Huib N. , Voermans Carlijn , Tytgat Godelieve A.M.
Published: October 2018

Purpose:

Targeted radiotherapy with 131iodine-meta-iodobenzylguanidine (131I-MIBG) is effective for neuroblastoma (NBL), although optimal scheduling during high-risk (HR) treatment is being investigated. We aimed to evaluate the feasibility of stem cell apheresis and study hematologic reconstitution after autologous stem cell transplantation (ASCT) in patients with HR-NBL treated with upfront 131I-MIBG-therapy.

Experimental Design:

In two prospective multicenter cohort studies, newly diagnosed patients with HR-NBL were treated with two courses of 131I-MIBG-therapy, followed by an HR-induction protocol. Hematopoietic stem and progenitor cell (e.g., CD34+ cell) harvest yield, required number of apheresis sessions, and time to neutrophil (>0.5 × 109/L) and platelet (>20 × 109/L) reconstitution after ASCT were analyzed and compared with “chemotherapy-only”–treated patients. Moreover, harvested CD34+ cells were functionally (viability and clonogenic capacity) and phenotypically (CD33, CD41, and CD62L) tested before cryopreservation (n = 44) and/or after thawing (n = 19).

Results:

Thirty-eight patients (47%) were treated with 131I-MIBG-therapy, 43 (53%) only with chemotherapy. Median cumulative 131I-MIBG dose/kg was 0.81 GBq (22.1 mCi). Median CD34+ cell harvest yield and apheresis days were comparable in both groups. Post ASCT, neutrophil recovery was similar (11 days vs. 10 days), whereas platelet recovery was delayed in 131I-MIBG- compared with chemotherapy-only–treated patients (29 days vs. 15 days, P = 0.037). Testing of harvested CD34+ cells revealed a reduced post-thaw viability in the 131I-MIBG-group. Moreover, the viable CD34+ population contained fewer cells expressing CD62L (L-selectin), a marker associated with rapid platelet recovery.

Conclusions:

Harvesting of CD34+ cells is feasible after 131I-MIBG. Platelet recovery after ASCT was delayed in 131I-MIBG-treated patients, possibly due to reinfusion of less viable and CD62L-expressing CD34+ cells, but without clinical complications. We provide evidence that peripheral stem cell apheresis is feasible after upfront 131I-MIBG-therapy in newly diagnosed patients with NBL. However, as the harvest of 131I-MIBG-treated patients contained lower viable CD34+ cell counts after thawing and platelet recovery after reinfusion was delayed, administration of 131I-MIBG after apheresis is preferred.
Return to Work in Patients with Hematological Cancers 1 Year after Treatment: A Prospective Longitudinal Study
Authors: Hartung Tim J. , Sautier Leon P. , Scherwath Angela , Sturm Kirsten , Kröger Nicolaus , Koch Uwe , Mehnert Anja
Published: October 2018

Background: Although hematological cancer survivors have a high risk of disability, data on work-related issues are scarce for this population. Methods: We investigated return to work (RTW) and work ability (Work Ability Index, WAI) in hematological cancer patients 6 months and 1 year after cancer treatment. We explored associations between baseline sociodemographic and medical characteristics and RTW as well as work ability at follow-up. Results: The participation rate was 42% (baseline n = 91, after 12 months n = 40 (44%)). 6 months after cancer treatment, 33% (95% confidence interval 21%-46%) of the remaining patients had returned to work. After 12 months, the RTW rate was 58% (42%-73%). Mean WAI sum score ± SD significantly increased from 18.5 ± 7.3 at baseline to 28.3 ± 8.3 after 12 months (p = 0.001). Patients with lymphoma (r = 0.31, p = 0.02) and patients who received radiation therapy (r = 0.29, p = 0.04) were significantly more likely to return to work. Work ability after 6 months was most strongly associated with higher education (r = 0.60, p < 0.01). Patients' subjective prognosis of gainful employment before cancer treatment predicted work ability after 6 (r = 0.62, p < 0.01) and 12 months (r = 0.51, p < 0.01). Conclusion: The chance of returning to work of hematological malignancy survivors is similar to that of other cancer patients.
Homocysteine Level in Children with Classic Congenital Adrenal Hyperplasia: Relationship to Carotid Intimal Wall Thickness and Left Ventricular Function
Authors: Metwalley Kotb Abbass , Farghaly Hekma Saad , Abdelhamid Abdelrahman
Published: October 2018

Background/Aims: Homocysteine is an important and independent risk factor for atherosclerotic diseases. The aim of this study was to evaluate serum levels of homocysteine in children with congenital adrenal hyperplasia (CAH) and their relation to carotid artery intima-media thickness (CA-IMT) and left ventricular (LV) function. Methods: This study included 36 children with classic CAH and 36 healthy children. All underwent anthropometric evaluation. Measurement of serum levels of total homocysteine was carried out. The LV mass (LVM) and function were assessed using conventional echocardiography. Duplex ultrasonography was used to measure CA-IMT. Results: Compared to the controls, the patients had higher homocysteine levels (p = 0.001), a thicker CA-IMT (p = 0.01), a higher LVM index (LVMI) (p = 0.001), and a prolonged mitral deceleration time (DcT) (p = 0.01). Abnormalities were marked in children who were uncontrolled on medical treatment. In multivariate analysis, homocysteine levels were significantly correlated with systolic (OR = 2.2; 95% CI: 1.10–1.18; p = 0.01) and diastolic blood pressures (OR = 2.9; 95% CI: 1.45–2.4; p = 0.01), atherogenic index (OR = 2.6; 95% CI: 1.33–2.89; p = 0.01), HOMA-IR (OR = 1.3; 95% CI: 1.04–1.34; p = 0.001), LVMI (OR = 2.6; 95% CI: 1.1–1.13; p = 0.001), mitral DcT (OR = 2.4; 95% CI: 1.15–2.05; p = 0.01), and CA-IMT (OR = 1.6; 95% CI: 1.16–1.57; p = 0.01). Conclusions: Serum total homocysteine was elevated in children with classic CAH, particularly in those with poor control on medical treatment, and it was correlated with CA-IMT, LVMI, and mitral DcT. Measurement of homocysteine in children with CAH may help to identify those at high risk of developing LV dysfunction and subclinical atherosclerosis.
The Osteogenic Potential of the Neural Crest Lineage May Contribute to Craniosynostosis
Authors: Doro Daniel , Liu Annie , Grigoriadis Agamemnon E. , Liu Karen J.
Published: October 2018

The craniofacial skeleton is formed from the neural crest and mesodermal lineages, both of which contribute mesenchymal precursors during formation of the skull bones. The large majority of cranial sutures also includes a proportion of neural crest-derived mesenchyme. While some studies have addressed the relative healing abilities of neural crest and mesodermal bone, relatively little attention has been paid to differences in intrinsic osteogenic potential. Here, we use mouse models to compare neural crest osteoblasts (from frontal bones or dura mater) to mesodermal osteoblasts (from parietal bones). Using in vitro culture approaches, we find that neural crest-derived osteoblasts readily generate bony nodules, while mesodermal osteoblasts do so less efficiently. Furthermore, we find that co-culture of neural crest-derived osteoblasts with mesodermal osteoblasts is sufficient to nucleate ossification centres. Altogether, this suggests that the intrinsic osteogenic abilities of neural crest-derived mesenchyme may be a primary driver behind craniosynostosis.
Genetically Determined Platelet Count and Risk of Cardiovascular Disease
Authors: Gill Dipender , Monori Grace , Georgakis Marios K. , Tzoulaki Ioanna , Laffan Mike
Published: October 2018

Objective—

Cardiovascular disease, including coronary artery disease (CAD) and ischemic stroke, is the leading cause of death worldwide. This Mendelian randomization study uses genetic variants as instruments to investigate whether there is a causal effect of genetically determined platelet count on CAD and ischemic stroke risk.

Approach and Results—

A genome-wide association study of 166 066 subjects was used to identify instruments and genetic association estimates for platelet count. Genetic association estimates for CAD and ischemic stroke were obtained from genome-wide association studies, including 60 801 CAD cases and 123 504 controls, and 60 341 ischemic stroke cases and 454 450 controls, respectively. The inverse-variance weighted meta-analysis of ratio method Mendelian randomization estimates was the main method used to obtain estimates for the causal effect of genetically determined platelet count on risk of cardiovascular outcomes. We found no significant Mendelian randomization effect of genetically determined platelet count on risk of CAD (odds ratio of CAD per SD unit increase in genetically determined platelet count, 1.01; 95% CI, 0.98–1.04;
P
=0.60). However, higher genetically determined platelet count was causally associated with an increased risk of ischemic stroke (odds ratio, 1.07; 95% CI, 1.04–1.11;
P
<1×10
−5
), including all major ischemic stroke subtypes. Similar results were obtained in sensitivity analyses more robust to the inclusion of pleiotropic genetic variants.

Conclusions—

This Mendelian randomization study found evidence that higher genetically determined platelet count is causally associated with higher risk of ischemic stroke.
Intravenous Heme Arginate Induces HO-1 (Heme Oxygenase-1) in the Human Heart
Authors: Andreas Martin , Oeser Claudia , Kainz Frieda-Maria , Shabanian Shiva , Aref Tandis , Bilban Martin , Messner Barbara , Heidtmann Julian , Laufer Guenther , Kocher Alfred , Wolzt Michael
Published: October 2018

Objective—

HO-1 (heme oxygenase-1) induction may prevent or reduce ischemia-reperfusion injury. We previously evaluated its in vivo induction after a single systemic administration of heme arginate in peripheral blood mononuclear cells. The current trial was designed to assess the pharmacological tissue induction of HO-1 in the human heart with heme arginate in vivo.

Approach and Results—

Patients planned for conventional aortic valve replacement received placebo (n=8), 1 mg/kg (n=7) or 3 mg/kg (n=9) heme arginate infused intravenously 24 hours before surgery. A biopsy of the right ventricle was performed directly before aortic cross-clamping and after cross-clamp release. In addition, the right atrial appendage was partially removed for analysis. HO-1 protein and mRNA concentrations were measured in tissue samples and in peripheral blood mononuclear cells before to and up to 72 hours after surgery. No study medication-related adverse events occurred. A strong, dose-dependent effect on myocardial HO-1 mRNA levels was observed (right ventricle: 7.9±5.0 versus 88.6±49.1 versus 203.6±148.7;
P
=0.002 and right atrium: 10.8±8.8 versus 229.8±173.1 versus 392.7±195.7;
P
=0.001). This was paralleled by a profound increase of HO-1 protein concentration in atrial tissue (8401±3889 versus 28 585±10 692 versus 29 022±8583;
P
<0.001). Surgery and heme arginate infusion significantly increased HO-1 mRNA concentration in peripheral blood mononuclear cells (
P
<0.001). HO-1 induction led to a significant increase of postoperative carboxyhemoglobin (1.7% versus 1.4%;
P
=0.041). No effect on plasma HO-1 protein levels could be detected.

Conclusions—

Myocardial HO-1 mRNA and protein can be dose-dependently induced by heme arginate. Protective effects of this therapeutic strategy should be evaluated in upcoming clinical trials.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT02314780.
Rotors Detected by Phase Analysis of Filtered, Epicardial Atrial Fibrillation Electrograms Colocalize With Regions of Conduction Block
Authors: Podziemski Piotr , Zeemering Stef , Kuklik Pawel , van Hunnik Arne , Maesen Bart , Maessen Jos , Crijns Harry J. , Verheule Sander , Schotten Ulrich
Published: October 2018

Background:

Several recent studies suggest rotors detected by phase mapping may act as main drivers of persistent atrial fibrillation. However, the electrophysiological nature of detected rotors remains unclear. We performed a direct, 1:1 comparison between phase and activation time mapping in high-density, epicardial, direct-contact mapping files of human atrial fibrillation.

Methods:

Thirty-eight unipolar electrogram files of 10 s duration were recorded in patients with atrial fibrillation (n=20 patients) using a 16×16 electrode array placed on the epicardial surface of the left atrial posterior wall or the right atrial free wall. Phase maps and isochrone wave maps were constructed for all recordings. For each detected phase singularity (PS) with a lifespan of >1 cycle length, the corresponding conduction pattern was investigated in the isochrone wave maps.

Results:

When using sinusoidal recomposition and Hilbert Transform, 138 PSs were detected. One hundred and four out of 138 PSs were detected within 1 electrode distance (1.5 mm) from a line of conduction block between nonrotating wavefronts detected by activation mapping. Far fewer rotating wavefronts were detected when rotating activity was identified based on wave mapping (18 out of 8219 detected waves). Fourteen out of these 18 cases were detected as PSs in phase mapping. Phase analysis of filtered electrograms produced by simulated wavefronts separated by conduction block also identified PSs on the line of conduction block.

Conclusions:

PSs identified by phase analysis of filtered epicardial electrograms colocalize with conduction block lines identified by activation mapping. Detection of PSs using phase analysis has a low specificity for identifying rotating wavefronts during human atrial fibrillation using activation mapping.