bluuebunny/crossref_metadata_2025 huggingface dataset:
Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load
Authors: Schuch Anita , Salimi Alizei Elahe , Heim Kathrin , Wieland Dominik , Kiraithe Michael Muthamia , Kemming Janine , Llewellyn-Lacey Sian , Sogukpinar Özlem , Ni Yi , Urban Stephan , Zimmermann Peter , Nassal Michael , Emmerich Florian , Price David A , Bengsch Bertram , Luxenburger Hendrik , Neumann-Haefelin Christoph , Hofmann Maike , Thimme Robert
Published: January 2019

Objective

A hallmark of chronic HBV (cHBV) infection is the presence of impaired HBV-specific CD8+ T cell responses. Functional T cell exhaustion induced by persistent antigen stimulation is considered a major mechanism underlying this impairment. However, due to their low frequencies in chronic infection, it is currently unknown whether HBV-specific CD8+ T cells targeting different epitopes are similarly impaired and share molecular profiles indicative of T cell exhaustion.

Design

By applying peptide-loaded MHC I tetramer-based enrichment, we could detect HBV-specific CD8+ T cells targeting epitopes in the HBV core and the polymerase proteins in the majority of 85 tested cHBV patients with low viral loads. Lower detection rates were obtained for envelope-specific CD8+ T cells. Subsequently, we performed phenotypic and functional in-depth analyses.

Results

HBV-specific CD8+ T cells are not terminally exhausted but rather exhibit a memory-like phenotype in patients with low viral load possibly reflecting weak ongoing cognate antigen recognition. Moreover, HBV-specific CD8+ T cells targeting core versus polymerase epitopes significantly differed in frequency, phenotype and function. In particular, in comparison with core-specific CD8+ T cells, a higher frequency of polymerase-specific CD8+ T cells expressed CD38, KLRG1 and Eomes accompanied by low T-bet expression and downregulated CD127 indicative of a more severe T cell exhaustion. In addition, polymerase-specific CD8+ T cells exhibited a reduced expansion capacity that was linked to a dysbalanced TCF1/BCL2 expression.

Conclusions

Overall, the molecular mechanisms underlying impaired T cell responses differ with respect to the targeted HBV antigens. These results have potential implications for immunotherapeutic approaches in HBV cure.
Minimally invasive endoscopic hematoma evacuation vs best medical management for spontaneous basal-ganglia intracerebral hemorrhage
Authors: Goyal Nitin , Tsivgoulis Georgios , Malhotra Konark , Katsanos Aristeidis H , Pandhi Abhi , Alsherbini Khalid A , Chang Jason J , Hoit Daniel , Alexandrov Andrei V , Elijovich Lucas , Fiorella David , Nickele Christopher , Arthur Adam S
Published: January 2019

Background

We conducted a case-control study to assess the relative safety and efficacy of minimally invasive endoscopic surgery (MIS) for clot evacuation in patients with basal-ganglia intracerebral hemorrhage (ICH).

Methods

We evaluated consecutive patients with acute basal-ganglia ICH at a single center over a 42-month period. Patients received either best medical management according to established guidelines (controls) or MIS (cases). The following outcomes were compared before and after propensity-score matching (PSM): in-hospital mortality; discharge National Institutes of Health Stroke Scale score; discharge disposition; and modified Rankin Scale scores at discharge and at 3 months.

Results

Among 224 ICH patients, 19 (8.5%) underwent MIS (mean age, 50.9±10.9; 26.3% female, median ICH volume, 40 (IQR, 25–51)). The interventional cohort was younger with higher ICH volume and stroke severity compared with the medically managed cohort. After PSM, 18 MIS patients were matched to 54 medically managed individuals. The two cohorts did not differ in any of the baseline characteristics. The median ICH volume at 24 hours was lower in the intervention group (40 cm3(IQR, 25–50) vs 15 cm3(IQR, 5–20); P<0.001). The two cohorts did not differ in any of the pre-specified outcomes measures except for in-hospital mortality, which was lower in the interventional cohort (28% vs 56%; P=0.041).

Conclusions

Minimally invasive endoscopic hematoma evacuation was associated with lower rates of in-hospital mortality in patients with spontaneous basal-ganglia ICH. These findings support a randomized controlled trial of MIS versus medical management for ICH.
Biomarkers and clinical outcomes in COPD: a systematic review and meta-analysis
Authors: Fermont Jilles M , Masconi Katya L , Jensen Magnus T , Ferrari Renata , Di Lorenzo Valéria A P , Marott Jacob M , Schuetz Philipp , Watz Henrik , Waschki Benjamin , Müllerova Hana , Polkey Michael I , Wilkinson Ian B , Wood Angela M
Published: January 2019

Background

Conventional measures to evaluate COPD may fail to capture systemic problems, particularly musculoskeletal weakness and cardiovascular disease. Identifying these manifestations and assessing their association with clinical outcomes (ie, mortality, exacerbation and COPD hospital admission) is of increasing clinical importance.

Objective

To assess associations between 6 min walk distance (6MWD), heart rate, fibrinogen, C reactive protein (CRP), white cell count (WCC), interleukins 6 and 8 (IL-6 and IL-8), tumour necrosis factor-alpha, quadriceps maximum voluntary contraction, sniff nasal inspiratory pressure, short physical performance battery, pulse wave velocity, carotid intima-media thickness and augmentation index and clinical outcomes in patients with stable COPD.

Methods

We systematically searched electronic databases (August 2018) and identified 61 studies, which were synthesised, including meta-analyses to estimate pooled HRs, following Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Results

Shorter 6MWD and elevated heart rate, fibrinogen, CRP and WCC were associated with higher risk of mortality. Pooled HRs were 0.80 (95% CI 0.73 to 0.89) per 50 m longer 6MWD, 1.10 (95% CI 1.02 to 1.18) per 10 bpm higher heart rate, 3.13 (95% CI 2.14 to 4.57) per twofold increase in fibrinogen, 1.17 (95% CI 1.06 to 1.28) per twofold increase in CRP and 2.07 (95% CI 1.29 to 3.31) per twofold increase in WCC. Shorter 6MWD and elevated fibrinogen and CRP were associated with exacerbation, and shorter 6MWD, higher heart rate, CRP and IL-6 were associated with hospitalisation. Few studies examined associations with musculoskeletal measures.

Conclusion

Findings suggest 6MWD, heart rate, CRP, fibrinogen and WCC are associated with clinical outcomes in patients with stable COPD. Use of musculoskeletal measures to assess outcomes in patients with COPD requires further investigation.

Trial registration number

CRD42016052075.
FKBP25 participates in DNA double-strand break repair
Authors: Dilworth David , Gong Fade , Miller Kyle , Nelson Christopher J.
Published: January 2019

FK506-binding proteins (FKBPs) alter the conformation of proteins via cis–trans isomerization of prolyl-peptide bonds. While this activity can be demonstrated in vitro, the intractability of detecting prolyl isomerization events in cells has limited our understanding of the biological processes regulated by FKBPs. Here we report that FKBP25 is an active participant in the repair of DNA double-strand breaks (DSBs). FKBP25 influences DSB repair pathway choice by promoting homologous recombination (HR) and suppressing single-strand annealing (SSA). Consistent with this observation, cells depleted of FKBP25 form fewer Rad51 repair foci in response to etoposide and ionizing radiation, and they are reliant on the SSA repair factor Rad52 for viability. We find that FKBP25’s catalytic activity is required for promoting DNA repair, which is the first description of a biological function for this enzyme activity. Consistent with the importance of the FKBP catalytic site in HR, rapamycin treatment also impairs homologous recombination, and this effect is at least in part independent of mTor. Taken together these results identify FKBP25 as a component of the DNA DSB repair pathway.
Limited impact of big fish mothers for population replenishment
Authors: Andersen Ken H. , Jacobsen Nis Sand , van Denderen P. Daniël
Published: January 2019

A recent meta-analysis by Barneche et al. (2018; Science, 360(6389): 642–645) shows that fish reproductive output scales hypergeometrically with female weight. This result challenges the common assumption that reproductive output is proportional to weight. The implication made is that current theory and practice severely underestimate the importance of larger females for population replenishment. Their example for cod (Gadus morhua) shows that current practice makes an error of 149%. By properly accounting for fish demography, we show that the error is maximally on the order of 10% and in most other fish stocks likely much less.
A workflow to minimize shadows in UAV-based orthomosaics
Authors: Rahman Mir Mustafizur , McDermid Gregory J. , Mckeeman Taylor , Lovitt Julie
Published: January 2019

Shadows from buildings, terrain, and other elevated features represent lost and (or) impaired data values that hinder the quality of optical images acquired under all but the most diffuse illumination conditions. This is particularly problematic in high-spatial-resolution imagery acquired from unmanned aerial vehicles (UAVs), which generally operate very close to the ground. However, the flexibility and low cost of re-deployment of the platform also presents opportunities, which we capitalize on in a new workflow designed to eliminate shadows from UAV-based orthomosaics. Our straightforward, three-step procedure relies on images acquired from two different UAV flights, where illumination conditions produce diverging shadow orientations: one before solar noon and another after. From this multi-temporal image stack, we first identify and then eliminate shadows from individual orthophoto components, then construct the final orthomosaic using a feature-matching strategy with the commercial software package Photoscan. The utility of our strategy is demonstrated over a treed-wetland study site in northwestern Alberta, Canada; a complex scene containing a wide variety of shadows, which our workflow effectively eliminated. While shadow-reduced orthomosaics are generally less useful for feature-identification tasks that rely on the shadow element of image interpretation, they create a superior foundation for most other image-processing routines, including classification and change-detection.
Study on the Geometrical Properties and Existence of Orbit Homoclinic to a Saddle Point in n-Dimensional Autonomous Vector Field with Polynomials
Authors: Xie Lingli
Published: January 2019

According to the theory of stable and unstable manifolds of an equilibrium point, we firstly find out some geometrical properties of orbits on the stable and unstable manifolds of a saddle point under some brief conditions of nonlinear terms composed of polynomials for [Formula: see text]-dimensional time continuous system. These properties show that the orbits on stable and unstable manifolds of the saddle point will stay on the corresponding stable and unstable subspaces in the [Formula: see text]-neighborhood of the saddle point. Furthermore, the necessary conditions of existence for orbit homoclinic to a saddle point are exposed. Some examples including homoclinic bifurcation are given to indicate the application of the results. Finally, the conclusions are presented.
Dynamic Analysis of a Delayed Fractional-Order SIR Model with Saturated Incidence and Treatment Functions
Authors: Wang Xinhe , Wang Zhen , Huang Xia , Li Yuxia
Published: January 2019

In this paper, a delayed fractional-order SIR (susceptible, infected, and removed) epidemic model with saturated incidence and treatment functions is presented. Firstly, the non-negativity and boundedness of solutions of the proposed model are proved. Next, some sufficient conditions are established to ensure the local asymptotic stability of the disease-free equilibrium point [Formula: see text] and the endemic equilibrium point [Formula: see text] for any delay. Meanwhile, global asymptotic stability of the endemic equilibrium point [Formula: see text] is investigated by constructing a suitable Lyapunov function. Some sufficient conditions are established for the global asymptotic stability of this endemic equilibrium point. Finally, some numerical simulations are illustrated to verify the correctness of the theoretical results.
A Simplified Method of Trend Removal to Determine Noise Observed During a Supercapacitor’s Discharging
Authors: Lentka Ł. , Smulko J.
Published: January 2019

In this paper, new method of trend removal is proposed. This is a simplified method based on Empirical Mode Decomposition (EMD). The method was applied for voltage time series observed during supercapacitor discharging process. It assured the determination of an additive noise component after subtracting the identified trend component. We analyzed voltage time series observed between the terminals of the supercapacitor when discharged by a loading resistance [Formula: see text]. The steps of the proposed method are presented in detail. The results are compared with the results obtained for polynomial approximation. Statistical parameters (kurtosis, skewness) of the histograms of the identified noise component were estimated to evaluate the quality of the proposed detrending method. The method was adjusted to the analyzed data by selecting a parameter of the applied envelope function of the EMD method. We conclude that the proposed method is faster and more efficient for detecting the additive noise component than the competitive polynomial approximation. The identified noise component may be used to evaluate the State of Health of tested supercapacitors and therefore requires fast algorithms with efficient detection.
Structural, electronic and magnetic properties of stoichiometric cobalt oxide clusters (CoO)nq (n=3−10,q=0,+1): A modified basin-hopping Monte Carlo algorithm with spin-polarized DFT
Authors: Daud Mohammad Noh
Published: January 2019

The structural, electronic and magnetic properties of the neutral and cationic cobalt oxide clusters (CoO)[Formula: see text] ([Formula: see text], [Formula: see text]) have been studied using a modified basin-hopping Monte Carlo (BHMC) algorithm refined by spin-polarized DFT. A systematic search of global minimum structures predicts new global minima of (CoO)[Formula: see text] and reproduced other minima that are in excellent agreement with previous works. For most low-spin and high-spin states, the structural transition from planar-like to compact structure occurs at (CoO)[Formula: see text], which is in contrast with the general notion that the structural changes at (CoO)[Formula: see text]. Supported by the results of the binding energy, second-order total energy difference, chemical hardness, chemical potential and HOMO-LUMO gap confirms the stability of (CoO)4. Results of the spin magnetic moments for the global minima show that (CoO)4 and (CoO)8 spin configurations exhibit a fully antiferromagnetic (AFM) ordering, while (CoO)9 spin displays the highest ferromagnetic (FM) ordering. Interestingly, elongation of Co–Co bond in (CoO)4 causes O being polarized by the neighboring Co atoms that accordingly follows the Goodenough-Kanamori-Anderson rule of FM super-exchange coupling for the Co-O-Co structural rearrangement to 90∘ ([Formula: see text] structure) in order to accommodate the spin magnetic ordering changes. This rearrangement is a result of the valence band being shifted away from the Fermi level to lower energy causing high population of the spin-up density of state and leading to the asymmetrical polarization of the whole (CoO)4 structure. As far as the dissociation energy surfaces are concerned, the first ever such surfaces are constructed corresponding to [Formula: see text], which identify a complete dissociation pathway linking the cationic and neutral clusters and finally confirm (CoO)[Formula: see text] as the most stable cluster compared to the rest.
Modeling the dynamics of black holes through balanced equations of motion
Authors: Gallo Emanuel , Moreschi Osvaldo M.
Published: January 2019

We present a general approach for the formulation of equations of motion for astrophysical compact objects in general relativistic theories. The objects are modeled as relativistic particles, which are assumed to be moving in a geometric background which in turn is asymptotically flat. The background can be affected by the compact object; so that our approach can be applied to binary systems; by concentrating on the main contributions coming from back reaction effects due to gravitational radiation.

Our premises are different from the traditional post-Newtonian and self-force approaches since we make strong use of the asymptotic properties of the self geometry of the particle; as is described below. In particular, we use a center of mass setting, and relativistic individual dynamical times for each object. We expect our model to complement the other approaches in different regimes.
Along-strike variations in thin-skinned thrusting style controlled by pre-existing basement structure in the easternmost Jura Mountains (Northern Switzerland)
Authors: Malz Alexander , Madritsch Herfried , Jordan Peter , Meier Beat , Kley Jonas
Published: January 2019

A detailed analysis of the Late Miocene Mandach Thrust, a key tectonic structure of the easternmost Jura Mountains (northern Alpine foreland), is presented providing insights into the modes of along-strike structural cover–basement interactions in a classical foreland setting. Our study builds on the construction, restoration and forward modelling of eight closely spaced cross-sections constrained by depth-migrated 2D seismics and geological maps. The results indicate predominantly thin-skinned thrust tectonics without significant inversion of underlying basement structures. However, inherited pre-thrusting normal faults exerted a strong control on the observed thrusting style, changing along-strike from a comparatively simple geometry to a complex, partly overthrust, partly reactivated normal fault. The observed variations relate to changes in the relief of the mechanical basement and the characteristics of pre-thrusting normal faults. The thrust's complexity is further increased by the local activation of secondary detachment horizons and possibly along-strike sedimentary facies changes within the thrust-faulted sedimentary sequence. The variations in thrusting style go along with subtle changes in shortening that may point towards as yet undetected transfer structures. As such, our structural analysis of the Mandach Thrust provides an improved understanding of the fault's kinematics and serves to highlight existing exploration uncertainties.
Sequential Feature Explanations for Anomaly Detection
Authors: Siddiqui Md Amran , Fern Alan , Dietterich Thomas G. , Wong Weng-Keen
Published: January 2019

In many applications, an anomaly detection system presents the most anomalous data instance to a human analyst, who then must determine whether the instance is truly of interest (e.g., a threat in a security setting). Unfortunately, most anomaly detectors provide no explanation about why an instance was considered anomalous, leaving the analyst with no guidance about where to begin the investigation. To address this issue, we study the problems of computing and evaluating sequential feature explanations (SFEs) for anomaly detectors. An SFE of an anomaly is a sequence of features, which are presented to the analyst one at a time (in order) until the information contained in the highlighted features is enough for the analyst to make a confident judgement about the anomaly. Since analyst effort is related to the amount of information that they consider in an investigation, an explanation’s quality is related to the number of features that must be revealed to attain confidence. In this article, we first formulate the problem of optimizing SFEs for a particular density-based anomaly detector. We then present both greedy algorithms and an optimal algorithm, based on branch-and-bound search, for optimizing SFEs. Finally, we provide a large scale quantitative evaluation of these algorithms using a novel framework for evaluating explanations. The results show that our algorithms are quite effective and that our best greedy algorithm is competitive with optimal solutions.
The Art of Getting Deep Neural Networks in Shape
Authors: Mammadli Rahim , Wolf Felix , Jannesari Ali
Published: January 2019

Training a deep neural network (DNN) involves selecting a set of hyperparameters that define the network topology and influence the accuracy of the resulting network. Often, the goal is to maximize prediction accuracy on a given dataset. However, non-functional requirements of the trained network -- such as inference speed, size, and energy consumption -- can be very important as well. In this article, we aim to automate the process of selecting an appropriate DNN topology that fulfills both functional and non-functional requirements of the application. Specifically, we focus on tuning two important hyperparameters, depth and width, which together define the shape of the resulting network and directly affect its accuracy, speed, size, and energy consumption. To reduce the time needed to search the design space, we train a fraction of DNNs and build a model to predict the performances of the remaining ones. We are able to produce tuned ResNets, which are up to 4.22 times faster than original depth-scaled ResNets on a batch of 128 images while matching their accuracy.
Dual-Page Checkpointing
Authors: Wu Song , Zhou Fang , Gao Xiang , Jin Hai , Ren Jinglei
Published: January 2019

Data persistence is necessary for many in-memory applications. However, the disk-based data persistence largely slows down in-memory applications. Emerging non-volatile memory (NVM) offers an opportunity to achieve in-memory data persistence at the DRAM-level performance. Nevertheless, NVM typically requires a software library to operate NVM data, which brings significant overhead.

This article demonstrates that a hardware-based high-frequency checkpointing mechanism can be used to achieve efficient in-memory data persistence on NVM. To maintain checkpoint consistency, traditional logging and copy-on-write techniques incur excessive NVM writes that impair both performance and endurance of NVM; recent work attempts to solve the issue but requires a large amount of metadata in the memory controller. Hence, we design a new
dual-page checkpointing
system, which achieves low metadata cost and eliminates most excessive NVM writes at the same time. It breaks the traditional trade-off between metadata space cost and extra data writes. Our solution outperforms the state-of-the-art NVM software libraries by 13.6× in throughput, and leads to 34% less NVM wear-out and 1.28× higher throughput than state-of-the-art hardware checkpointing solutions, according to our evaluation with OLTP, graph computing, and machine-learning workloads.
Blaze-Tasks
Authors: Pirkelbauer Peter , Wilson Amalee , Peterson Christina , Dechev Damian
Published: January 2019

Compared to threads, tasks are a more fine-grained alternative. The task parallel programming model offers benefits in terms of better performance portability and better load-balancing for problems that exhibit nonuniform workloads. A common scenario of task parallel programming is that a task is recursively decomposed into smaller sub-tasks. Depending on the problem domain, the number of created sub-tasks may be nonuniform, thereby creating potential for significant load imbalances in the system. Dynamic load-balancing mechanisms will distribute the tasks across available threads. The final result of a computation may be modeled as a reduction over the results of all sub-tasks.

This article describes a simple, yet effective prototype framework, Blaze-Tasks, for task scheduling and task reductions on shared memory architectures. The framework has been designed with lock-free techniques and generic programming principles in mind. Blaze-Tasks is implemented entirely in C++17 and is thus portable. To load-balance the computation, Blaze-Tasks uses task stealing. To manage contention on a task pool, the number of lock-free attempts to steal a task depends on the distance between thief and pool owner and the estimated number of tasks in a victim’s pool. This article evaluates the Blaze framework on Intel and IBM dual-socket systems using nine benchmarks and compares its performance with other task parallel frameworks. While Cilk outperforms Blaze on Intel on most benchmarks, the evaluation shows that Blaze is competitive with OpenMP and other library-based implementations. On IBM, the experiments show that Blaze outperforms other approaches on most benchmarks.
Metric Selection for GPU Kernel Classification
Authors: Shekofteh S.-Kazem , Noori Hamid , Naghibzadeh Mahmoud , Yazdi Hadi Sadoghi , Fröning Holger
Published: January 2019

Graphics Processing Units (GPUs) are vastly used for running massively parallel programs. GPU kernels exhibit different behavior at runtime and can usually be classified in a simple form as either “compute-bound” or “memory-bound.” Recent GPUs are capable of concurrently running multiple kernels, which raises the question of how to most appropriately schedule kernels to achieve higher performance. In particular, co-scheduling of compute-bound and memory-bound kernels seems promising. However, its benefits as well as drawbacks must be determined along with which kernels should be selected for a concurrent execution. Classifying kernels can be performed online by instrumentation based on performance counters. This work conducts a thorough analysis of the metrics collected from various benchmarks from Rodinia and CUDA SDK. The goal is to find the minimum number of effective metrics that enables online classification of kernels with a low overhead. This study employs a wrapper-based feature selection method based on the Fisher feature selection criterion. The results of experiments show that to classify kernels with a high accuracy, only three and five metrics are sufficient on a Kepler and a Pascal GPU, respectively. The proposed method is then utilized for a runtime scheduler. The results show an average speedup of 1.18× and 1.1× compared with a serial and a random scheduler, respectively.
Capillary-Dominated Fluid Displacement in Porous Media
Authors: Singh Kamaljit , Jung Michael , Brinkmann Martin , Seemann Ralf
Published: January 2019

Liquid invasion into a porous medium is a phenomenon of great importance in both nature and technology. Despite its enormous importance, there is a surprisingly sparse understanding of the processes occurring on the scale of individual pores and of how these processes determine the global invasion pattern. In particular, the exact influence of the wettability remains unclear besides the limiting cases of very small or very large contact angles of the invading fluid. Most quantitative pore-scale experiments and theoretical considerations have been conducted in effectively two-dimensional (2D) micromodels and Hele–Shaw geometries. Although these pioneering works helped to unravel some of the physical aspects of the displacement processes, the relevance of 2D models has not always been appreciated for natural porous media. With the availability of X-ray microtomography, 3D imaging has become a standard for exploring pore-scale processes in porous media. Applying advanced postprocessing routines and synchrotron microtomography, researchers can image even slow flow processes in real time and extract relevant material parameters like the contact angle from the interfaces in the pore space. These advances are expected to boost both theoretical and experimental understanding of pore-scale processes in natural porous media.
Dynamics of Flexible Fibers in Viscous Flows and Fluids
Authors: du Roure Olivia , Lindner Anke , Nazockdast Ehssan N. , Shelley Michael J.
Published: January 2019

The dynamics and deformations of immersed flexible fibers are at the heart of important industrial and biological processes, induce peculiar mechanical and transport properties in the fluids that contain them, and are the basis for novel methods of flow control. Here we focus on the low–Reynolds number regime where advances in studying these fiber–fluid systems have been especially rapid. On the experimental side, this is due to new methods of fiber synthesis, microfluidic flow control, and microscope-based tracking measurement techniques. Likewise, there have been continuous improvements in the specialized mathematical modeling and numerical methods needed to capture the interactions of slender flexible fibers with flows, boundaries, and each other.
The islet-expressed Lhx1 transcription factor interacts with Islet-1 and contributes to glucose homeostasis
Authors: Bethea Maigen , Liu Yanping , Wade Alexa K. , Mullen Rachel , Gupta Rajesh , Gelfanov Vasily , DiMarchi Richard , Bhatnagar Sushant , Behringer Richard , Habegger Kirk M. , Hunter Chad S.
Published: January 2019

The LIM-homeodomain (LIM-HD) transcription factor Islet-1 (Isl1) interacts with the LIM domain-binding protein 1 (Ldb1) coregulator to control expression of key pancreatic β-cell genes. However, Ldb1 also has Isl1-independent effects, supporting that another LIM-HD factor interacts with Ldb1 to impact β-cell development and/or function. LIM homeobox 1 (Lhx1) is an Isl1-related LIM-HD transcription factor that appears to be expressed in the developing mouse pancreas and in adult islets. However, roles for this factor in the pancreas are unknown. This study aimed to determine Lhx1 interactions and elucidate gene regulatory and physiological roles in the pancreas. Co-immunoprecipitation using β-cell extracts demonstrated an interaction between Lhx1 and Isl1, and thus we hypothesized that Lhx1 and Isl1 regulate similar target genes. To test this, we employed siRNA-mediated Lhx1 knockdown in β-cell lines and discovered reduced Glp1R mRNA. Chromatin immunoprecipitation revealed Lhx1 occupancy at a domain also known to be occupied by Isl1 and Ldb1. Through development of a pancreas-wide knockout mouse model ( Lhx1∆Panc), we demonstrate that aged Lhx1∆Pancmice have elevated fasting blood glucose levels, altered intraperitoneal and oral glucose tolerance, and significantly upregulated glucagon, somatostatin, pancreatic polypeptide, MafB, and Arx islet mRNAs. Additionally, Lhx1∆Pancmice exhibit significantly reduced Glp1R, an mRNA encoding the insulinotropic receptor for glucagon-like peptide 1 along with a concomitant dampened Glp1 response and mild glucose intolerance in mice challenged with oral glucose. These data are the first to reveal that the Lhx1 transcription factor contributes to normal glucose homeostasis and Glp1 responses.
Cosmological Implications of the Generalized Entropy Based Holographic Dark Energy Models in Dynamical Chern-Simons Modified Gravity
Authors: Younas M. , Jawad Abdul , Qummer Saba , Moradpour H. , Rani Shamaila
Published: January 2019

Recently, Tsallis, Rényi, and Sharma-Mittal entropies have widely been used to study the gravitational and cosmological setups. We consider a flat FRW universe with linear interaction between dark energy and dark matter. We discuss the dark energy models using Tsallis, Rényi, and Sharma-Mittal entropies in the framework of Chern-Simons modified gravity. We explore various cosmological parameters (equation of state parameter, squared sound of speed ) and cosmological plane (ωd-ωd′, where ωd′ is the evolutionary equation of state parameter). It is observed that the equation of state parameter gives quintessence-like nature of the universe in most of the cases. Also, the squared speed of sound shows stability of Tsallis and Rényi dark energy model but unstable behavior for Sharma-Mittal dark energy model. The ωd-ωd′ plane represents the thawing region for all dark energy models.
Sequential [18F]FDG-[18F]FMISO PET and Multiparametric MRI at 3T for Insights into Breast Cancer Heterogeneity and Correlation with Patient Outcomes: First Clinical Experience
Authors: Andrzejewski Piotr , Wengert Georg , Helbich Thomas H. , Magometschnigg Heinrich , Georg Dietmar , Hacker Marcus , Baltzer Pascal , Clauser Paola , Kapetas Panagiotis , Georg Petra , Wadsak Wolfgang , Pinker Katja
Published: January 2019

The aim of this study was to assess whether sequential multiparametric 18[F]fluoro-desoxy-glucose (18[F]FDG)/[18F]fluoromisonidazole ([18F]FMISO) PET-MRI in breast cancer patients is possible, facilitates information on tumor heterogeneity, and correlates with prognostic indicators. In this pilot study, IRB-approved, prospective study, nine patients with ten suspicious breast lesions (BIRADS 5) and subsequent breast cancer diagnosis underwent sequential combined [18F]FDG/[18F]FMISO PET-MRI. [18F]FDG was used to assess increased glycolysis, while [18F]FMISO was used to detect tumor hypoxia. MRI protocol included dynamic breast contrast-enhanced MRI (DCE-MRI) and diffusion-weighted imaging (DWI). Qualitative and quantitative multiparametric imaging findings were compared with pathological features (grading, proliferation, and receptor status) and clinical endpoints (recurrence/metastases and disease-specific death) using multiple correlation analysis. Histopathology was the standard of reference. There were several intermediate to strong correlations identified between quantitative bioimaging markers, histopathologic tumor characteristics, and clinical endpoints. Based on correlation analysis, multiparametric criteria provided independent information. The prognostic indicators proliferation rate, death, and presence/development of recurrence/metastasis correlated positively, whereas the prognostic indicator estrogen receptor status correlated negatively with PET parameters. The strongest correlations were found between disease-specific death and [18F]FDGmean (R=0.83, p<0.01) and between the presence/development of metastasis and [18F]FDGmax (R=0.79, p<0.01), respectively. This pilot study indicates that multiparametric [18F]FDG/[18F]FMISO PET-MRI might provide complementary quantitative prognostic information on breast tumors including clinical endpoints and thus might be used to tailor treatment for precision medicine in breast cancer.
Path Contribution Analysis of Vibration Transfer Path Systems
Authors: Zhao Wei , Zhang Yi-Min , Feng Wen-Zhou
Published: January 2019

To analyze the vibration characteristics of mechanical systems from the aspect of vibration transfer, two types of models for vibration transfer path systems were designed, which comprised three subsystems: excitation sources, transfer paths, and receivers. One type of model represented that the systems only sustained unidirectional force excitation, where the transfer paths remained free from the influence of mass parameters. The other type indicated that the systems were subjected to simultaneous excitations of forces and moments, with transfer paths without mass parameter. Because the transfer characteristics of vibration paths directly determine the output response behaviours of the systems, the analysis of path contributions to the vibration responses of system receivers is important in systemic vibration and noise reduction. In order to evaluate the path contributions quantitatively, the concepts of path transfer ratio (TR) and path insertion loss (IL) were introduced and the convenient formulae were derived based on the path transfer force analysis and the path disconnected method in this work. Thereby the measurement of path contributions to the receiver vibration responses within the frequency domain can be accomplished. Through numerical examples, the ideal calculation results were obtained. These conclusions further indicate that the path TR and path IL can be applied as evaluation indicators of path contributions for the vibration transfer path systems.
Interleukin-37: The Effect of Anti-Inflammatory Response in Human Coronary Artery Endothelial Cells
Authors: Yan Xianfeng , Xie Bin , Wu Guihai , Hu Jing , Wang Di , Cai Xiangna , Li Jilin
Published: January 2019

Interleukin-37 (IL-37) is unique in the IL-1 family since it broadly suppresses innate immunity and elevates in humans with inflammatory and autoimmune diseases. IL-37 shows definite groups and transcripts for human IL37 gene, but it is still not completely understood the effect and mechanisms of inflammatory response in endothelial cells. It is well accepted that endothelial dysfunction caused by inflammation is a key initiating event in atherosclerotic plaque formation, which leads to the occurrence and development of the cardiovascular adverse events in clinical since the inflammatory responses of endothelial cells could induce and enhance the deposition of extensive lipid and the formation of atherosclerotic plaque in the intima. Thus, it is essential to investigate the role and potential mechanisms in endothelial inflammatory response to prevent the formation and development of many cardiovascular diseases including atherosclerosis. So far, the recent studies have revealed that IL-37 is able to inhibit inflammatory response by suppressing the TLR2-NF-κB-ICAM-1 pathway intracellularly in human coronary artery endothelial cells (HCAECs). Further, the role of IL-37 may be related to the IL-18 pathway extracellularly and involved in the adhesion and transmigration of neutrophils in HCAECs.
Derechos humanos, nuevo ángulo de las relaciones laborales
Authors: Ljubetic Yerko
Published: January 2019

Esta columna aboga por la incorporación de la perspectiva de los derechos humanos en el desempeño de la actividad empresarial chilena y, en particular, en el ámbito de las relaciones laborales. Tras examinar cómo esta perspectiva ha sido definida por organismos internacionales, el autor subraya algunos desafíos pendientes para las empresas y el Estado chileno.
Frizzled-7 Is Required for Wnt Signaling in Gastric Tumors with and Without Apc Mutations
Authors: Flanagan Dustin J. , Barker Nick , Costanzo Natasha S. Di , Mason Elizabeth A. , Gurney Austin , Meniel Valerie S. , Koushyar Sarah , Austin Chloe R. , Ernst Matthias , Pearson Helen B. , Boussioutas Alex , Clevers Hans , Phesse Toby J. , Vincan Elizabeth
Published: January 2019

A subset of patients with gastric cancer have mutations in genes that participate in or regulate Wnt signaling at the level of ligand (Wnt) receptor (Fzd) binding. Moreover, increased Fzd expression is associated with poor clinical outcome. Despite these findings, there are no in vivo studies investigating the potential of targeting Wnt receptors for treating gastric cancer, and the specific Wnt receptor transmitting oncogenic Wnt signaling in gastric cancer is unknown. Here, we use inhibitors of Wnt/Fzd (OMP-18R5/vantictumab) and conditional gene deletion to test the therapeutic potential of targeting Wnt signaling in preclinical models of intestinal-type gastric cancer and ex vivo organoid cultures. Pharmacologic targeting of Fzd inhibited the growth of gastric adenomas in vivo. We identified Fzd7 to be the predominant Wnt receptor responsible for transmitting Wnt signaling in human gastric cancer cells and mouse models of gastric cancer, whereby Fzd7-deficient cells were retained in gastric adenomas but were unable to respond to Wnt signals and consequently failed to proliferate. Genetic deletion of Fzd7 or treatment with vantictumab was sufficient to inhibit the growth of gastric adenomas with or without mutations to Apc. Vantictumab is currently in phase Ib clinical trials for advanced pancreatic, lung, and breast cancer. Our data extend the scope of patients that may benefit from this therapeutic approach as we demonstrate that this drug will be effective in treating patients with gastric cancer regardless of APC mutation status.

Significance:

The Wnt receptor Fzd7 plays an essential role in gastric tumorigenesis irrespective of Apc mutation status, therefore targeting Wnt/Fzd7 may be of therapeutic benefit to patients with gastric cancer.
Urinary Biomarkers of Carcinogenic Exposure among Cigarette, Waterpipe, and Smokeless Tobacco Users and Never Users of Tobacco in the Golestan Cohort Study
Authors: Etemadi Arash , Poustchi Hossein , Chang Cindy M. , Blount Benjamin C. , Calafat Antonia M. , Wang Lanqing , De Jesus Victor R. , Pourshams Akram , Shakeri Ramin , Shiels Meredith S. , Inoue-Choi Maki , Ambrose Bridget K. , Christensen Carol H. , Wang Baoguang , Murphy Gwen , Ye Xiaoyun , Bhandari Deepak , Feng Jun , Xia Baoyun , Sosnoff Connie S. , Kamangar Farin , Brennan Paul , Boffetta Paolo , Dawsey Sanford M. , Abnet Christian C. , Malekzadeh Reza , Freedman Neal D.
Published: January 2019

Background:

How carcinogen exposure varies across users of different, particularly noncigarette, tobacco products remains poorly understood.

Methods:

We randomly selected 165 participants of the Golestan Cohort Study from northeastern Iran: 60 never users of any tobacco, 35 exclusive cigarette, 40 exclusive (78% daily) waterpipe, and 30 exclusive smokeless tobacco (nass) users. We measured concentrations of 39 biomarkers of exposure in 4 chemical classes in baseline urine samples: tobacco alkaloids, tobacco-specific nitrosamines (TSNA), polycyclic aromatic hydrocarbons (PAH), and volatile organic compounds (VOC). We also quantified the same biomarkers in a second urine sample, obtained 5 years later, among continuing cigarette smokers and never tobacco users.

Results:

Nass users had the highest concentrations of tobacco alkaloids. All tobacco users had elevated TSNA concentrations, which correlated with nicotine dose. In both cigarette and waterpipe smokers, PAH and VOC biomarkers were higher than never tobacco users and nass users, and highly correlated with nicotine dose. PAH biomarkers of phenanthrene and pyrene and two VOC metabolites (phenylmercapturic acid and phenylglyoxylic acid) were higher in waterpipe smokers than in all other groups. PAH biomarkers among Golestan never tobacco users were comparable to those in U.S. cigarette smokers. All biomarkers had moderate to good correlations over 5 years, particularly in continuing cigarette smokers.

Conclusions:

We observed two patterns of exposure biomarkers that differentiated the use of the combustible products (cigarettes and waterpipe) from the smokeless product. Environmental exposure from nontobacco sources appeared to contribute to the presence of high levels of PAH metabolites in the Golestan Cohort.

Impact:

Most of these biomarkers would be useful for exposure assessment in a longitudinal study.
Efficacy and Safety of the Biosimilar ABP 215 Compared with Bevacizumab in Patients with Advanced Nonsquamous Non–small Cell Lung Cancer (MAPLE): A Randomized, Double-blind, Phase III Study
Authors: Thatcher Nicholas , Goldschmidt Jerome H. , Thomas Michael , Schenker Michael , Pan Zhiying , Paz-Ares Rodriguez Luis , Breder Valery , Ostoros Gyula , Hanes Vladimir
Published: January 2019

Purpose:

This phase III study compared clinical efficacy and safety of the biosimilar ABP 215 with bevacizumab reference product (RP) in patients with advanced nonsquamous non–small cell lung cancer (NSCLC).

Patients and Methods:

Patients were randomized 1:1 to ABP 215 or bevacizumab 15 mg/kg every three weeks for 6 cycles. All patients received carboplatin and paclitaxel every three weeks for ≥4 and ≤6 cycles. The primary efficacy endpoint was risk ratio of objective response rate (ORR); clinical equivalence was confirmed if the 2-sided 90% confidence interval (CI) of the risk ratio was within the margin of 0.67 to 1.5. Secondary endpoints included risk difference of ORR, duration of response (DOR), progression-free survival (PFS), and overall survival (OS); pharmacokinetics, adverse events (AEs), and incidence of antidrug antibodies (ADAs) were monitored.

Results:

A total of 820 patients were screened; 642 were randomized to ABP 215 (n = 328) and bevacizumab (n = 314). Overall, 128 (39.0%) and 131 (41.7%) patients in the ABP 215 and bevacizumab groups, respectively, had objective responses [ORR risk ratio: 0.93 (90% CI, 0.80–1.09)]. In the ABP 215 and bevacizumab group, 308 (95.1%) and 289 (93.5%) patients, respectively, had at least 1 AE; 13 (4.0%) and 11 (3.6%) experienced a fatal AE. Anti-VEGF toxicity was low and comparable between treatment groups. At week 19, median trough serum drug concentration was 132 μg/mL (ABP 215 group) and 129 μg/mL (bevacizumab group). No patient tested positive for neutralizing antibodies.

Conclusions:

ABP 215 is similar to bevacizumab RP with respect to clinical efficacy, safety, immunogenicity, and pharmacokinetics. The totality of evidence supports clinical equivalence of ABP 215 and bevacizumab.
Genomic Landscape of Pancreatic Adenocarcinoma in Younger versus Older Patients: Does Age Matter?
Authors: Ben-Aharon Irit , Elkabets Moshe , Pelossof Raphael , Yu Kenneth H. , Iacubuzio-Donahue Christine A. , Leach Steven D. , Lowery Maeve A. , Goodman Karyn A. , O'Reilly Eileen M.
Published: January 2019

Purpose:

State-of-the-art genomic analyses of pancreatic adenocarcinoma (PDAC) have yielded insight into signaling pathways underlying carcinogenesis. PDAC is characterized by substantial genomic heterogeneity. We aimed to determine whether early-onset PDAC (EOPC; ≤55 years) displays a distinctive molecular landscape from average-age onset PDAC (AOPC; ≥70 years).

Experimental Design:

Three distinct datasets for PDAC were analyzed. In the first, patients undergoing treatment at Memorial Sloan Kettering (MSK) were consented for MSK-IMPACT next-generation sequencing. The second cohort analyzed was The Cancer Genome Atlas (TCGA) dataset for differences in somatic mutations, gene expression, and protein expression. The third dataset was an Australian cohort of PDAC. Clinical data were correlated with genomic analyses.

Results:

A total of 293 samples were analyzed, yielding 90 patients aged ≤55 years and 203 patients aged ≥70 years. Among the genes known to be associated with carcinogenesis, SMAD4 displayed higher mutation rates in younger patients. Comprehensive transcriptomic analysis of cellular pathways indicated that the TGFβ pathway has increased activation, and the expression levels of phospho-GSK3 were higher in EOPC. Survival outcomes revealed no differences between age groups.

Conclusions:

These exploratory analyses suggest that there may be somatic gene alterations within the population of patients with early-onset PDAC that involve unique cellular pathways compared with average-onset PDAC. Former studies imply these cellular pathways may play a role in smoking-related PDAC carcinogenesis. Larger genomic datasets are warranted for future evaluation to extend these observations.
Immune Exclusion-Wnt/CTNNB1 Class Predicts Resistance to Immunotherapies in HCC
Authors: Pinyol Roser , Sia Daniela , Llovet Josep M.
Published: January 2019

Next-generation sequencing has provided information on actionable targets and biomarkers of response in oncology. In hepatocellular carcinoma (HCC), Wnt/CTNNB1 mutations characterize the immune-excluded class (cold tumors) and might represent the biomarkers predicting resistance to immune checkpoint inhibitors. Large-scale validation of these data is needed to customize immunotherapy in advanced HCC.

See related article by Harding et al., p. 2116
Revision of three taxa of Ophiorrhiza (Rubiaceae) from China

Authors: WU LEI , LIU WEN-JIAN , NGUYEN KHANG SINH
Published: January 2019

Through field observations, recollections at known sites and research on specimens and relevant literature, Ophiorrhiza alatiflora H.S.Lo is re-instated; O. alatiflora H.S.Lo var. trichoneura H.S.Lo and O. aureolina H.S.Lo f. qiongyaensis H.S.Lo are reduced to the synonym of O. baviensis Drake and O. subpunicea Craib, respectively. The lectotype of Ophiorrhiza baviensis is here designated. In addition, the detailed description, colour photographs and conservation status of the three species are provided here.