bluuebunny/crossref_metadata_2025 huggingface dataset:
Wearable Physical Activity Tracking Systems for Older Adults—A Systematic Review
Authors: Vargemidis Dimitri , Gerling Kathrin , Spiel Katta , Abeele Vero Vanden , Geurts Luc
Published: September 2020

Physical activity (PA) positively impacts the quality of life of older adults, with technology as a promising factor in maintaining motivation. Within Computer Science and Engineering, research investigates how to track PA of older adults for various purposes. We present a systematic review of 204 papers and discuss wearable tracking systems according to their purpose, technological context, and target audience, as well as design and evaluation processes with particular attention to the meaningful involvement of older adults. Our results show that most systems focus on
supervising
older adults in the context of disease and frailty management. Only few systems focus on
supporting
older adults by promoting rehabilitation and respecting agency of older adults via self-monitoring PA, or encouraging PA to maintain healthy levels of activity. Moreover, systems are often narrowly limited to walking, although older adults may enjoy a broader range of activities. Likewise, the involvement of older adults in design processes is scarce, and their experience with a given technology is rarely considered relevant for evaluation. In sum, we contribute an overview of wearable technology for tracking older adults’ PA, contextualize our findings within recommendations provided by Sports and Rehabilitation Science, and illustrate opportunities for future work.
ECO
TLB
Authors: Maass Steffen , Kumar Mohan Kumar , Kim Taesoo , Krishna Tushar , Bhattacharjee Abhishek
Published: September 2020

We propose
ecoTLB
—software-based eventual translation lookaside buffer (TLB) coherence—which eliminates the overhead of the synchronous TLB shootdown mechanism in operating systems that use address space identifiers (ASIDs). With an eventual TLB coherence,
ecoTLB
improves the performance of
free
and
page swap
operations by removing the inter-processor interrupt (IPI) overheads incurred to invalidate TLB entries. We show that the TLB shootdown has implications for page swapping in particular in emerging, disaggregated data centers and demonstrate that
ecoTLB
can improve both the performance and the specific swapping policy decisions using
ecoTLB
’s asynchronous mechanism. We demonstrate that
ecoTLB
improves the performance of real-world applications, such as Memcached and Make, that perform page swapping using
Infiniswap
, a solution for next generation data centers that use disaggregated memory, by up to 17.2%. Moreover,
ecoTLB
improves the 99th percentile tail latency of Memcached by up to 70.8% due to its asynchronous scheme and improved policy decisions. Furthermore, we show that recent features to improve security in the Linux kernel, like kernel page table isolation (KPTI), can result in significant performance overheads on architectures without support for specific instructions to clear single entries in tagged TLBs, falling back to full TLB flushes. In this scenario,
ecoTLB
is able to recover the performance lost for supporting KPTI due to its asynchronous shootdown scheme and its support for tagged TLBs. Finally, we demonstrate that
ecoTLB
improves the performance of free operations by up to 59.1% on a 120-core machine and improves the performance of Apache on a 16-core machine by up to 13.7% compared to baseline Linux, and by up to 48.2% compared to ABIS, a recent state-of-the-art research prototype that reduces the number of IPIs.
Effective Loop Fusion in Polyhedral Compilation Using Fusion Conflict Graphs
Authors: Acharya Aravind , Bondhugula Uday , Cohen Albert
Published: September 2020

Polyhedral auto-transformation frameworks are known to find efficient loop transformations that maximize locality and parallelism and minimize synchronization. While complex loop transformations are routinely modeled in these frameworks, they tend to rely on ad hoc heuristics for loop fusion. Although there exist multiple loop fusion models with cost functions to maximize locality and parallelism, these models involve separate optimization steps rather than seamlessly integrating with other loop transformations like loop permutation, scaling, and shifting. Incorporating parallelism-preserving loop fusion heuristics into existing affine transformation frameworks like Pluto, LLVM-Polly, PPCG, and PoCC requires solving a large number of Integer Linear Programming formulations, which increase auto-transformation times significantly.

In this work, we incorporate polynomial time loop fusion heuristics into the
Pluto-lp-dfp
framework. We present a data structure called the
fusion conflict graph
(FCG), which enables us to efficiently model loop fusion in the presence of other affine loop transformations. We propose a clustering heuristic to group the vertices of the FCG, which further enables us to provide three different polynomial time greedy fusion heuristics, namely,
maximal fusion
,
typed fusion
, and
hybrid fusion
, while maintaining the compile time improvements of Pluto-lp-dfp over Pluto. Our experiments reveal that the hybrid fusion model, in conjunction with Pluto’s cost function, finds efficient transformations that outperform PoCC and Pluto by mean factors of 1.8× and 1.07×, respectively, with a maximum performance improvement of 14× over PoCC and 2.6× over Pluto.
OD-SGD
Authors: Xu Yemao , Dong Dezun , Zhao Yawei , Xu Weixia , Liao Xiangke
Published: September 2020

The training of modern deep learning neural network calls for large amounts of computation, which is often provided by GPUs or other specific accelerators. To scale out to achieve faster training speed, two update algorithms are mainly applied in the distributed training process, i.e., the Synchronous SGD algorithm (SSGD) and Asynchronous SGD algorithm (ASGD). SSGD obtains good convergence point while the training speed is slowed down by the synchronous barrier. ASGD has faster training speed but the convergence point is lower when compared to SSGD. To sufficiently utilize the advantages of SSGD and ASGD, we propose a novel technology named One-step Delay SGD (OD-SGD) to combine their strengths in the training process. Therefore, we can achieve similar convergence point and training speed as SSGD and ASGD separately.

To the best of our knowledge, we make the first attempt to combine the features of SSGD and ASGD to improve distributed training performance. Each iteration of OD-SGD contains a global update in the parameter server node and local updates in the worker nodes, the local update is introduced to update and compensate the delayed local weights. We evaluate our proposed algorithm on MNIST, CIFAR-10, and ImageNet datasets. Experimental results show that OD-SGD can obtain similar or even slightly better accuracy than SSGD, while its training speed is much faster, which even exceeds the training speed of ASGD.
Senselet
Authors: Nahrstedt Klara , Yang Zhe , Yu Tuo , Su Patrick , Kaufman Robert , Shan Ishan , Konstanty Steve , McCollum Mark , Dallesasse John
Published: September 2020

Semiconductor cleanrooms are used to fabricate devices with feature sizes that can be much smaller than a dust particle. Hence, any environmental deviations in temperature, or humidity around fabrication instruments may become the root cause of hundreds of transistors failing during the manufacturing. Furthermore, researchers work with dangerous chemicals in cleanrooms and violation of safety may lead to disastrous consequences. Therefore, we have developed an affordable, locally-controlled distributed sensing infrastructure, called SENSELET, for academic cleanrooms. It provides highly effective services for environment sensing around scientific instruments, sensory data collection and visualization, indoor localization, and instrument proximity detection for safety of researchers.
Scavenging Reactive Lipids to Prevent Oxidative Injury
Authors: May-Zhang Linda S. , Kirabo Annet , Huang Jiansheng , Linton MacRae F. , Davies Sean S. , Murray Katherine T.
Published: September 2020

Oxidative injury due to elevated levels of reactive oxygen species is implicated in cardiovascular diseases, Alzheimer's disease, lung and liver diseases, and many cancers. Antioxidant therapies have generally been ineffective at treating these diseases, potentially due to ineffective doses but also due to interference with critical host defense and signaling processes. Therefore, alternative strategies to prevent oxidative injury are needed. Elevated levels of reactive oxygen species induce lipid peroxidation, generating reactive lipid dicarbonyls. These lipid oxidation products may be the most salient mediators of oxidative injury, as they cause cellular and organ dysfunction by adducting to proteins, lipids, and DNA. Small-molecule compounds have been developed in the past decade to selectively and effectively scavenge these reactive lipid dicarbonyls. This review outlines evidence supporting the role of lipid dicarbonyls in disease pathogenesis, as well as preclinical data supporting the efficacy of novel dicarbonyl scavengers in treating or preventing disease.
E-cigarette constituents propylene glycol and vegetable glycerin decrease glucose uptake and its metabolism in airway epithelial cells in vitro
Authors: Woodall M. , Jacob J. , Kalsi K. K. , Schroeder V. , Davis E. , Kenyon B. , Khan I. , Garnett J. P. , Tarran R. , Baines D. L.
Published: September 2020

Electronic nicotine delivery systems, or e-cigarettes, utilize a liquid solution that normally contains propylene glycol (PG) and vegetable glycerin (VG) to generate vapor and act as a carrier for nicotine and flavorings. Evidence indicated these “carriers” reduced growth and survival of epithelial cells including those of the airway. We hypothesized that 3% PG or PG mixed with VG (3% PG/VG, 55:45) inhibited glucose uptake in human airway epithelial cells as a first step to reducing airway cell survival. Exposure of H441 or human bronchiolar epithelial cells (HBECs) to PG and PG/VG (30–60 min) inhibited glucose uptake and mitochondrial ATP synthesis. PG/VG inhibited glycolysis. PG/VG and mannitol reduced cell volume and height of air-liquid interface cultures. Mannitol, but not PG/VG, increased phosphorylation of p38 MAPK. PG/VG reduced transepithelial electrical resistance, which was associated with increased transepithelial solute permeability. PG/VG decreased fluorescence recovery after photobleaching of green fluorescent protein-linked glucose transporters GLUT1 and GLUT10, indicating that glucose transport function was compromised. Puffing PG/VG vapor onto the apical surface of primary HBECs for 10 min to mimic the effect of e-cigarette smoking also reduced glucose transport. In conclusion, short-term exposure to PG/VG, key components of e-cigarettes, decreased glucose transport and metabolism in airway cells. We propose that this was a result of PG/VG reduced cell volume and membrane fluidity, with further consequences on epithelial barrier function. Taking these results together, we suggest these factors contribute to reduced defensive properties of the epithelium. We propose that repeated/chronic exposure to these agents are likely to contribute to airway damage in e-cigarette users.
Spectral plasticity in monkey primary auditory cortex limits performance generalization in a temporal discrimination task
Authors: Beitel Ralph E. , Schreiner Christoph E. , Vollmer Maike
Published: September 2020

Monkeys’ ability to generalize amplitude-modulation discrimination to nontrained carriers was limited to one octave below and 0.6 octave above the trained carrier frequency. Asymmetric generalization was paralleled by sharpening in cortical spectral tuning and enhanced firing-rate contrast between rewarded and nonrewarded sinusoidally amplitude-modulated stimuli at carriers near the trained frequency. The spectral content of the training stimulus specified spectral and temporal plasticity that may provide a neural substrate for limitations in generalization of temporal discrimination learning.
Kv4 channel expression and kinetics in GABAergic and non-GABAergic rNST neurons
Authors: Chen Z. , Boxwell A. , Conte C. , Haas T. , Harley A. , Terman D. H. , Travers S. P. , Travers J. B.
Published: September 2020

Here, we demonstrate that the transient outward K+ current IA occurs in both GABAergic and non-GABAergic neurons via Kv4.3 channels in the rostral (gustatory) solitary nucleus. Although found in both cell types, IA is more prevalent in non-GABAergic cells; a larger conductance at more negative potentials leads to a greater impact on spike initiation compared with GABAergic neurons. An IA window current further suggests that IA can regulate excitatory afferent input to the nucleus.
Large-Scale and Refined Green Space Identification-Based Sustainable Urban Renewal Mode Assessment
Authors: Guo Rong , Song Xiaoya , Li Peiran , Wu Guangming , Guo Zhiling
Published: September 2020

Urban sustainable renewal has received extensive attention in a wide range of fields, including urban planning, urban management, energy management, and transportation. Given that environmental resource conservation is critical to urban sustainability renewal, this study highlighted the imbalance among green space, urban development, and transportation accessibility. Here, a novel node-place-green model is presented to measure sustainable urban development; meanwhile, deep learning is utilized to identify and extract the green space to measure the environmental index. Based on the generated node, place, and green value, urban developing status could be classified into nine modes for further analysis of transportation, urban function, and ecological construction. The experimental results of Harbin reveal the feasibility of the proposed method in providing specific guidelines for urban planning and policies on sustainable development.
Computing Edge Weights of Magic Labeling on Rooted Products of Graphs
Authors: Liu Jia-Bao , Afzal Hafiz Usman , Javaid Muhammad
Published: September 2020

Labeling of graphs with numbers is being explored nowadays due to its diverse range of applications in the fields of civil, software, electrical, and network engineering. For example, in network engineering, any systems interconnected in a network can be converted into a graph and specific numeric labels assigned to the converted graph under certain rules help us in the regulation of data traffic, connectivity, and bandwidth as well as in coding/decoding of signals. Especially, both antimagic and magic graphs serve as models for surveillance or security systems in urban planning. In 1998, Enomoto et al. introduced the notion of super a,0 edge-antimagic labeling of graphs. In this article, we shall compute super a,0 edge-antimagic labeling of the rooted product of Pn and the complete bipartite graph K2,m combined with the union of path, copies of paths, and the star. We shall also compute a super a,0 edge-antimagic labeling of rooted product of Pn with a special type of pancyclic graphs. The labeling provided here will also serve as super a′,2 edge-antimagic labeling of the aforesaid graphs. All the structures discussed in this article are planar. Moreover, our findings have also been illustrated with examples and summarized in the form of a table and 3D plots.
Investigation of the Effect of Magnification, Accelerating Voltage, and Working Distance on the 3D Digital Reconstruction Techniques
Authors: Bayazid Seyed Mahmoud , Brodusch Nicolas , Gauvin Raynald , Relucenti Michela
Published: September 2020

In this study, the effect of Scanning Electron Microscopy (SEM) parameters such as magnification (

M

), accelerating voltage (

V

), and working distance (WD) on the 3D digital reconstruction technique, as the first step of the quantitative characterization of fracture surfaces with SEM, was investigated. The 2D images were taken via a 4-Quadrant Backscattered Electron (4Q-BSE) detector. In this study, spherical particles of Ti-6Al-4V (15-45 μm) deposited on the silicon substrate were used. It was observed that the working distance has a significant influence on the 3D digital rebuilding method via SEM images. The results showed that the best range of the working distance for our system is 9 to 10 mm. It was shown that by increasing the magnification to 1000x, the 3D digital reconstruction results improved. However, there was no significant improvement by increasing the magnification beyond 1000x. In addition, results demonstrated that the lower the accelerating voltage, the higher the precision of the 3D reconstruction technique, as long as there are clean backscattered signals. The optimal condition was achieved when magnification, accelerating voltage, and working distance were chosen as 1000x, 3 kV, and 9 mm, respectively.
Protective Effects of Grape Seed Proanthocyanidins on the Kidneys of Diabetic Rats through the Nrf2 Signalling Pathway
Authors: Ding Yusong , Li Haiyan , Li Yang , Liu Dandan , Zhang Liyuan , Wang Tongling , Liu Tao , Ma Long
Published: September 2020

Background. Diabetic nephropathy (DN) is the most common cause of end‐stage renal failure. Grape seed proanthocyanidin extract (GSPE) is a powerful antioxidant that is believed to protect the kidney through antioxidant action. However, the underlying mechanism of GSPE protection against DN remains unclear. Objective. To explore if GSPE can improve DN by activating nuclear factor erythroid 2‐related factor 2 (Nrf2) antioxidant response element signalling and to clarify its possible mechanism. Materials and methods. Ten healthy Sprague‐Dawley rats were randomly selected as controls. Rats with streptozotocin‐induced diabetes were randomly divided into three groups (10 animals/group): type 2 diabetes mellitus (T2DM) group (untreated), L‐GSPE group (treated with 125‐mg/kg/day GSPE for 8 weeks), and H‐GSPE group (treated with 250 mg/kg/day GSPE for 8 weeks). Results. Renal histopathological results indicated limited pathological damage in GSPE‐treated groups. Compared with the T2DM group, the H‐GSPE group had significantly reduced kidney weight and renal index. Similarly, the levels of fasting blood glucose, serum creatinine, blood urea nitrogen, uric acid, urinary albumin, and renal malondialdehyde (p < 0.05) were also significantly decreased. In addition, GSPE significantly increased the levels of superoxide dismutase, total antioxidative capability, and glutathione (p < 0.05) as well as the protein levels of Nrf2, HO‐1, glutathione S‐transferase, and NAD (P)H quinone oxidoreductase 1 (p < 0.05). Conclusion. The results indicate that GSPE reduced renal damage in rats with diabetes by activating the Nrf2 signalling pathway, which consequently increased the antioxidant capacity of the tissue. Therefore, GSPE is a potential natural agent for the treatment of diabetic nephropathy.
Simple Quadratic Interpolation-Inspired Symbiosis Organisms Search Algorithm for Optimal Placement of Capacitors in Radial Distribution Networks with Different Loading Models
Authors: Nguyen Tri Phuoc , Nguyen Tuan Trong , Quang Trung Hieu , Vo Dieu Ngoc , Khooban Mohammad Hassan
Published: September 2020

This paper proposes a novel hybrid algorithm based on a combination of the simple quadratic interpolation and the symbiosis organisms search algorithm (SQI-SOS) for finding the optimal location and size of capacitors in radial distribution networks. The objective of the problem is to minimize the system operating cost so that the net yearly savings of the system are increased. The effectiveness of the SQI-SOS has been tested on 33-, 69-, and 119-bus radial distribution networks with different load models. The obtained results from the test system by the proposed SQI-SOS are compared with those from the conventional SOS and other mature optimization methods in the literature. The result comparison has shown that the proposed SQI-SOS algorithm can provide a better solution than the other methods. Accordingly, the proposed SQI-SOS can be a very effective and efficient method for dealing with the optimal capacitor placement problem in distribution networks.
A Mathematical Model for Nipah Virus Infection
Authors: Zewdie Assefa Denekew , Gakkhar Sunita
Published: September 2020

It has been reported that unprotected contact with the dead bodies of infected individuals is a plausible way of Nipah virus transmission. An SIRD model is proposed in this paper to investigate the impact of unprotected contact with dead bodies of infected individuals before burial or cremation and their disposal rate on the dynamics of Nipah virus infection. The model is analyzed, and the reproduction number is computed. It is established that the disease-free state is globally asymptotically stable when the reproduction number is less than unity and unstable if it is greater than unity. By using the central manifold theory, we observe that the endemic equilibrium is locally stable near to unity. It is concluded that minimizing unsafe contact with the infected dead body and/or burial or cremation as fast as possible contributes positively. Further, the numerical simulations for the given choice of data and initial conditions illustrate that the endemic state is stable and the disease persists in the community when the reproduction number is greater than one.
Identification of Circular RNA‐MicroRNA‐Messenger RNA Regulatory Network in Atrial Fibrillation by Integrated Analysis
Authors: Liu Tao , Zhang Guoru , Wang Yaling , Rao Mingyue , Zhang Yang , Guo Anjun , Wang Mei
Published: September 2020

Background. Circular RNA (circRNA) is a noncoding RNA that forms a closed‐loop structure, and its abnormal expression may cause disease. We aimed to find potential network for circRNA‐related competitive endogenous RNA (ceRNA) in atrial fibrillation (AF). Methods. The circRNA, miRNA, and mRNA expression profiles in the heart tissue from AF patients were retrieved from the Gene Expression Omnibus database and analyzed comprehensively. Differentially expressed circRNAs (DEcircRNAs), differentially expressed miRNAs (DEmiRNAs), and differentially expressed mRNAs (DEmRNAs) were identified, followed by the establishment of DEcircRNA‐DEmiRNA‐DEmRNA regulatory network. Functional annotation analysis of host gene of DEcircRNAs and DEmRNAs in ceRNA regulatory network was performed. In vitro experiment and electronic validation were used to validate the expression of DEcircRNAs, DEmiRNAs, and DEmRNAs. Results. A total of 1611 DEcircRNAs, 51 DEmiRNAs, and 1250 DEmRNAs were identified in AF. The DEcircRNA‐DEmiRNA‐DEmRNA network contained 62 circRNAs, 14 miRNAs, and 728 mRNAs. Among which, two ceRNA regulatory pairs of hsa‐circRNA‐100053‐hsa‐miR‐455‐5p‐TRPV1 and hsa‐circRNA‐005843‐hsa‐miR‐188‐5p‐SPON1 were identified. In addition, six miRNA‐mRNA regulatory pairs including hsa‐miR‐34c‐5p‐INMT, hsa‐miR‐1253‐DDIT4L, hsa‐miR‐508‐5p‐SMOC2, hsa‐miR‐943‐ACTA1, hsa‐miR‐338‐3p‐WIPI1, and hsa‐miR‐199a‐3p‐RAP1GAP2 were also obtained. MTOR was a significantly enriched signaling pathway of host gene of DEcircRNAs. In addition, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy were remarkably enriched signaling pathways of DEmRNAs in DEcircRNA‐DEmiRNA‐DEmRNA regulatory network. The expression validation of hsa‐circRNA‐402565, hsa‐miR‐34c‐5p, hsa‐miR‐188‐5p, SPON1, DDIT4L, SMOC2, and WIPI1 was consistent with the integrated analysis. Conclusion. We speculated that hsa‐circRNA‐100053‐hsa‐miR‐455‐5p‐TRPV1 and hsa‐circRNA‐005843‐hsa‐miR‐188‐5p‐SPON1 interaction pairs may be involved in AF.
Experimental Investigation of the Diagnosis of Angular Contact Ball Bearings Using Acoustic Emission Method and Empirical Mode Decomposition
Authors: Tabatabaei Ramtin , Aasi Aref , Jafari Seyed Mohammad , Ciulli Enrico
Published: September 2020

Early detection of angular contact bearings, one of the important subsets of rolling element bearings (REBs), is critical for applications of high accuracy and high speed performance. In this study, acoustic emission (AE) method was applied to an experimental case with defects on angular contact bearing. AE signals were collected by AE sensors in different operating conditions. Signal to noise ratio (SNR) was calculated by kurtosis to entropy ratio (KER), then acquired signals were denoised by empirical mode decomposition (EMD) method, and optimal intrinsic mode function (IMF) was selected by the proposed method. Finally, envelope spectrum was applied to the denoised signals, and frequencies of defects were obtained in different rotating speeds, loadings, and defect sizes. For the first time, a small defect with width of 0.3 mm and loading of 475 N was detected in early stage of 0.04 KHz. Moreover, a comparison between theoretical and extracted defect frequencies suggested that our method successfully detected localized defects in both inner and outer race. Our results show promise in detecting small size defects in REBs.
Corrigendum to “A Hypothesis: Hydrogen Sulfide Might Be Neuroprotective against Subarachnoid Hemorrhage Induced Brain Injury”
Authors: Yu Yong-Peng , Chi Xiang-Lin , Liu Li-Jun
Published: September 2020

Gases such as nitric oxide (NO) and carbon monoxide (CO) play important roles both in normal physiology and in disease. Recent studies have shown that hydrogen sulfide (H2S) protects neurons against oxidative stress and ischemia-reperfusion injury and attenuates lipopolysaccharides (LPS) induced neuroinflammation in microglia, exhibiting anti-inflammatory and antiapoptotic activities. The gas H2S is emerging as a novel regulator of important physiologic functions such as arterial diameter, blood flow, and leukocyte adhesion. It has been known that multiple factors, including oxidative stress, free radicals, and neuronal nitric oxide synthesis as well as abnormal inflammatory responses, are involved in the mechanism underlying the brain injury after subarachnoid hemorrhage (SAH). Based on the multiple physiologic functions of H2S, we speculate that it might be a promising, effective, and specific therapy for brain injury after SAH.
A Panoramic Sketch about the Robust Stability of Time-Delay Systems and Its Applications
Authors: Aguirre-Hernández Baltazar , Villafuerte-Segura Raúl , Luviano-Juárez Alberto , Loredo-Villalobos Carlos Arturo , Díaz-González Edgar Cristian
Published: September 2020

This paper presents a brief review on the current applications and perspectives on the stability of complex dynamical systems, with an emphasis on three main classes of systems such as delay-free systems, time-delay systems, and systems with uncertainties in its parameters, which lead to some criteria with necessary and/or sufficient conditions to determine stability and/or stabilization in the domains of frequency and time. Besides, criteria on robust stability and stability of nonlinear time-delay systems are presented, including some numerical approaches.
Local Targeting of NAD+ Salvage Pathway Alters the Immune Tumor Microenvironment and Enhances Checkpoint Immunotherapy in Glioblastoma
Authors: Li Ming , Kirtane Ameya R. , Kiyokawa Juri , Nagashima Hiroaki , Lopes Aaron , Tirmizi Zain A. , Lee Christine K. , Traverso Giovanni , Cahill Daniel P. , Wakimoto Hiroaki
Published: September 2020

The aggressive primary brain tumor glioblastoma (GBM) is characterized by aberrant metabolism that fuels its malignant phenotype. Diverse genetic subtypes of malignant glioma are sensitive to selective inhibition of the NAD+ salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT). However, the potential impact of NAD+ depletion on the brain tumor microenvironment has not been elaborated. In addition, systemic toxicity of NAMPT inhibition remains a significant concern. Here we show that microparticle-mediated intratumoral delivery of NAMPT inhibitor GMX1778 induces specific immunologic changes in the tumor microenvironment of murine GBM, characterized by upregulation of immune checkpoint PD-L1, recruitment of CD3+, CD4+, and CD8+ T cells, and reduction of M2-polarized immunosuppressive macrophages. NAD+ depletion and autophagy induced by NAMPT inhibitors mediated the upregulation of PD-L1 transcripts and cell surface protein levels in GBM cells. NAMPT inhibitor modulation of the tumor immune microenvironment was therefore combined with PD-1 checkpoint blockade in vivo, significantly increasing the survival of GBM-bearing animals. Thus, the therapeutic impacts of NAMPT inhibition extended beyond neoplastic cells, shaping surrounding immune effectors. Microparticle delivery and release of NAMPT inhibitor at the tumor site offers a safe and robust means to alter an immune tumor microenvironment that could potentiate checkpoint immunotherapy for glioblastoma.

Significance:

Microparticle-mediated local inhibition of NAMPT modulates the tumor immune microenvironment and acts cooperatively with anti-PD-1 checkpoint blockade, offering a combination immunotherapy strategy for the treatment of GBM.
Itacitinib (INCB039110), a JAK1 Inhibitor, Reduces Cytokines Associated with Cytokine Release Syndrome Induced by CAR T-cell Therapy
Authors: Huarte Eduardo , O'Connor Roddy S. , Peel Michael T. , Nunez-Cruz Selene , Leferovich John , Juvekar Ashish , Yang Yan-ou , Truong Lisa , Huang Taisheng , Naim Ahmad , Milone Michael C. , Smith Paul A.
Published: September 2020

Purpose:

T cells engineered to express a chimeric antigen receptor (CAR) are a promising cancer immunotherapy. Such targeted therapies have shown long-term relapse-free survival in patients with B-cell leukemia and lymphoma. However, cytokine release syndrome (CRS) represents a serious, potentially life-threatening side effect often associated with CAR T-cell therapy. CRS manifests as a rapid (hyper)immune reaction driven by excessive inflammatory cytokine release, including IFNγ and IL6.

Experimental Design:

Many cytokines implicated in CRS are known to signal through the JAK-STAT pathway. Here we study the effect of blocking JAK pathway signaling on CAR T-cell proliferation, antitumor activity, and cytokine levels in in vitro and in vivo models.

Results:

We report that itacitinib, a potent, selective JAK1 inhibitor, was able to significantly and dose-dependently reduce levels of multiple cytokines implicated in CRS in several in vitro and in vivo models. Importantly, we also report that at clinically relevant doses that mimic human JAK1 pharmacologic inhibition, itacitinib did not significantly inhibit proliferation or antitumor killing capacity of three different human CAR T-cell constructs (GD2, EGFR, and CD19). Finally, in an in vivo model, antitumor activity of CD19-CAR T cells adoptively transferred into CD19+ tumor-bearing immunodeficient animals was unabated by oral itacitinib treatment.

Conclusions:

Together, these data suggest that itacitinib has potential as a prophylactic agent for the prevention of CAR T cell–induced CRS, and a phase II clinical trial of itacitinib for prevention of CRS induced by CAR T-cell therapy has been initiated (NCT04071366).
Clinical and Genome-Wide Analysis of Multiple Severe Cisplatin-Induced Neurotoxicities in Adult-Onset Cancer Survivors
Authors: Trendowski Matthew R. , Wheeler Heather E. , El-Charif Omar , Feldman Darren R. , Hamilton Robert J. , Vaughn David J. , Fung Chunkit , Kollmannsberger Christian , Einhorn Lawrence H. , Travis Lois B. , Dolan M. Eileen
Published: September 2020

Purpose:

Cisplatin is a first-line chemotherapeutic for many cancers, but causes neurotoxicity including hearing loss, tinnitus, and peripheral sensory neuropathy. However, no study has comprehensively characterized risk factors for developing multiple (>1) severe neurotoxicities.

Experimental Design:

The relationship between multiple severe neurotoxicities and age, cumulative cisplatin dose, medical history, and lifestyle/behavioral factors was evaluated in 300 cisplatin-treated testicular cancer survivors using logistic regression. Case–control genome-wide association study (GWAS; cases, n = 104 and controls, n = 196) was also performed.

Results:

Age at clinical examination (P = 6.4 × 10−16) and cumulative cisplatin dose (P = 5.4 × 10−4) were positively associated with multiple severe neurotoxicity risk, as were high serum platinum levels (P = 0.02), tobacco use (ever smoker, P = 0.001 and current smoker, P = 0.002), and hypertension (P = 0.01) after adjustment for age and cumulative cisplatin dose. Individuals with multiple severe neurotoxicities were more likely to experience dizziness/vertigo (P = 0.01), Raynaud phenomenon (P = 3.7 × 10−9), and symptoms consistent with peripheral motor neuropathy (P = 4.3 × 10−14) after age and dose adjustment. These patients also reported poorer overall health (P = 2.7 × 10−5) and a greater use of psychotropic medications (P = 0.06). GWAS identified no genome-wide significant SNPs. Gene-based association analysis identified RGS17 (P = 3.9 × 10−5) and FAM20C (P = 5.5 × 10−5) as near genome-wide significant. Decreased FAM20C expression was associated with increased cisplatin sensitivity in tumor cell lines.

Conclusions:

Certain survivors are more susceptible to cisplatin-induced neurotoxicity, markedly increasing likelihood of developing numerous neuro-otological symptoms that affect quality of life. Genome-wide analysis identified genetic variation in FAM20C as a potentially important risk factor.
A Novel Bispecific Antibody with PD-L1–assisted OX40 Activation for Cancer Treatment
Authors: Kuang Zhihui , Pu Pu , Wu Min , Wu Zhihai , Wang Li , Li Yiming , Zhang Shaofei , Jing Hua , Wu Weiwei , Chen Bingliang , Liu Junjian
Published: September 2020

Immunotherapy using OX40 agonist antibodies shows great preclinical efficacy in mouse tumor models. But in a clinical setting, OX40 agonist antibody alone or in combination with checkpoint blockade exhibits only modest efficacy due to lack of sufficient activation. We hypothesized that the limited antitumor activity in patients may due to insufficient clustering of OX40 antibody in the tumor. To test this hypothesis, we generated a tetravalent programmed death ligand-1 (PD-L1)/OX40 BsAb by fusing two PD-L1 VHH fragments to the C-terminus of a nonblocking agonistic anti-OX40 antibody. The resulting BsAb had intact function of each parental antibody, including efficiently blocking PD1/PD-L1 interaction and inducing OX40 activation. In addition, this BsAb showed significantly enhanced potency in activation of OX40-expressing T cells when PD-L1–expressing tumor cells or dendrite cells were present, through PD-L1–mediated cross-linking of OX40. Moreover, the BsAb exhibited superior antitumor activities over the parental monospecific antibodies alone or in combination in multiple in vivo tumor models. These results demonstrated a great potential for further clinical development of the potent immunostimulatory PD-L1/OX40 bispecific antibody.
Prognostic Integrated Image-Based Immune and Molecular Profiling in Early-Stage Endometrial Cancer
Authors: Horeweg Nanda , de Bruyn Marco , Nout Remi A. , Stelloo Ellen , Kedzierska Katarzyna , León-Castillo Alicia , Plat Annechien , Mertz Kirsten D. , Osse Michelle , Jürgenliemk-Schulz Ina M. , Lutgens Ludy C.H.W. , Jobsen Jan J. , van der Steen-Banasik Elzbieta M. , Smit Vincent T. , Creutzberg Carien L. , Bosse Tjalling , Nijman Hans W. , Koelzer Viktor H. , Church David N.
Published: September 2020

Optimum risk stratification in early-stage endometrial cancer combines clinicopathologic factors and the molecular endometrial cancer classification defined by The Cancer Genome Atlas (TCGA). It is unclear whether analysis of intratumoral immune infiltrate improves this. We developed a machine-learning, image-based algorithm to quantify density of CD8+ and CD103+ immune cells in tumor epithelium and stroma in 695 stage I endometrioid endometrial cancers from the PORTEC-1 and -2 trials. The relationship between immune cell density and clinicopathologic/molecular factors was analyzed by hierarchical clustering and multiple regression. The prognostic value of immune infiltrate by cell type and location was analyzed by univariable and multivariable Cox regression, incorporating the molecular endometrial cancer classification. Tumor-infiltrating immune cell density varied substantially between cases, and more modestly by immune cell type and location. Clustering revealed three groups with high, intermediate, and low densities, with highly significant variation in the proportion of molecular endometrial cancer subgroups between them. Univariable analysis revealed intraepithelial CD8+ cell density as the strongest predictor of endometrial cancer recurrence; multivariable analysis confirmed this was independent of pathologic factors and molecular subgroup. Exploratory analysis suggested this association was not uniform across molecular subgroups, but greatest in tumors with mutant p53 and absent in DNA mismatch repair–deficient cancers. Thus, this work identified that quantification of intraepithelial CD8+ cells improved upon the prognostic utility of the molecular endometrial cancer classification in early-stage endometrial cancer.
Prevention and Treatment of Tumor Lysis Syndrome in the Era of Onco-Nephrology Progress
Authors: Matuszkiewicz-Rowinska Joanna , Malyszko Jolanta
Published: September 2020

Background: Tumor lysis syndrome (TLS) is an oncologic emergency due to a rapid break down of malignant cells usually induced by cytotoxic therapy, with hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and serious clinical consequences such as acute renal injury, cardiac arrhythmia, hypotension, and death. Rapidly expanding knowledge of cancer immune evasion mechanisms and host-tumor interactions has significantly changed our therapeutic strategies in hemato-oncology what resulted in the expanding spectrum of neoplasms with a risk of TLS. Summary: Since clinical TLS is a life-threatening condition, identifying patients with risk factors for TLS development and implementation of adequate preventive measures remains the most critical component of its medical management. In general, these consist of vigilant laboratory and clinical monitoring, vigorous IV hydration, urate-lowering therapy, avoidance of exogenous potassium, use of phosphate binders, and – in high-risk cases – considering cytoreduction before the start of the aggressive agent or a gradual escalation of its dose. Key Messages: In patients with a high risk of TLS, cytotoxic chemotherapy should be given in the facility with ready access to dialysis and a treatment plan discussed with the nephrology team. In the case of hyperkalemia, severe hyperphosphatemia or acidosis, and fluid overload unresponsive to diuretic therapy, the early renal replacement therapy (RRT) should be considered. One must remember that in TLS, the threshold for RRT initiation may be lower than in other clinical situations since the process of cell breakdown is ongoing, and rapid increases in serum electrolytes cannot be predicted.
Personalidade da Marca de Destinos e sua Relação com o Critério de Escolha dos Turistas Brasileiros
Authors: Silva Leonilde da Conceição , Costa Junior Lindemberg
Published: September 2020

Este estudo teve como objetivo identificar o critério de escolha de turistas brasileiros ao decidirem por um destino para passarem suas férias. Utilizou-se modelo capaz de mensurar a personalidade da marca de destinos turísticos. Adotou-se metodologia quantitativa, com caráter descritivo e corte transversal. Os dados foram coletados por meio do formulário eletrônico TypeForm. Obteve-se um total de 268 respostas de turistas brasileiros. Em relação ao critério de escolha de um destino turístico os dados confirmam a hipótese principal que em média os turistas brasileiros se consideram muito criteriosos ao escolher por um destino turístico. Evidencia-se que o brasileiro planeja previamente suas viagens, e que o mesmo ao buscar informações sobre destinos leva em consideração as experiências de amigos e conhecidos, bem como realiza pesquisas na internet. Essas fontes de informações são relevantes para a decisão do turista brasileiro. Sugere-se que o turista brasileiro procura por destinos hospitaleiros e que possuam atividades destinadas tanto para adultos como para as crianças. Não obstante, o destino turístico deve ser ousado e emocionante, proporcionando boas recordações para os envolvidos na viagem.
A mineralogia acessória do Amazonita Pegmatito Serra Branca: classificação de um pegmatito NYF na Província Borborema, Nordeste do Brasil
Authors: Souza Igor Manoel Belo de Albuquerque e , Barreto Sandra de Brito , Santos Glenda Lira , Araújo Neto José Ferreira de , Guimarães Ignez de Pinho
Published: September 2020

O campo pegmatítico de Vieirópolis é caracterizado pela ocorrência de pegmatitos com amazonita e/ou berilo. Esse campo contém pegmatitos do tipo NYF (Nb-Y-F) inseridos no Domínio Rio Grande do Norte (DRGN), fora do contexto da Província Pegmatítica do Seridó (PPS). O principal pegmatito desse campo, o Amazonita Pegmatito Serra Branca, destaca-se pela mineralização de megacristais de amazonita e por sua exploração como rocha ornamental de elevado valor econômico. Para caracterizar a paragênese e a química mineral das fases acessórias do Amazonita Pegmatito Serra Branca, além de elucidar a classificação e a natureza petrogenética desse pegmatito, foram utilizados dados de campo, petrográficos, difração de raios X  e química mineral. O Amazonita Pegmatito Serra Branca ocorre como dique tabular com aproximadamente 3 m de espessura, de direção NW-SE e caimento 45° WSW, caracterizado por apresentar uma zona composta por megacristais de amazonita e quartzo, e outra, por albita e quartzo sacaroidais. Apresenta vasta mineralogia acessória que compreende anglesita, biotita, bismutita, cerussita, columbita-(Mn), espessartina, helvina, fenaquita, fluorita, hematita, ilita, ilmenita, magnetita, montmorilonita, muscovita, piromorfita, pirocloro, rutilo e zircão. Destacando-se, também, atípicas mineralizações de sulfetos e a presença de beríliossilicatos reportados pioneiramente no contexto geológico da Província Borborema (PB). A paragênese mineral e a química dos minerais acessórios do Amazonita Pegmatito Serra Branca o classificam como pertence à família NYF da classe dos elementos raros, tipo da gadolinita, possivelmente associado a um magmatismo do tipo I.
Conflitos na relação entre Cirurgiões-dentistas e operadoras de Odontologia suplementar
Authors: Feitosa Larissa Barradas Lima , Santos Denise Ribeiro , Santos Rai Matheus Carvalho
Published: September 2020

Este artigo buscou levantar na literatura nacional os motivos pelos quais a relação entre as operadoras de planos de saúde e os cirurgiões-dentistas é conflituosa, traçando um histórico do mercado brasileiro na área, bem como o perfil do profissional deste segmento,  destacando as implicações observadas quanto à autonomia profissional, remuneração e satisfação com o trabalho, a fim de fomentar uma reflexão crítica na categoria quanto às relações de trabalho no âmbito da assistência odontológica suplementar. A análise realizada evidenciou que o sistema de saúde suplementar se desenvolveu por mais de trinta anos sem interferência governamental, culminando em um crescimento alarmante, desordenado e desregulado, influenciado pelo excesso de oferta de dentistas e redução de pacientes que pagam por serviços privados. Dessa forma, grande parcela dos profissionais que têm se associado a planos de saúde na expectativa de expansão dos seus serviços são submetidos às demandas das operadoras que limitam seu trabalho àquele menos oneroso, interferem no plano de tratamento e utilizam tabelas de preços desatualizadas para o pagamento de procedimentos clínicos, levando a uma percepção negativa e descontentamento em relação ao desempenho das operadoras. Concluiu-se que de fato a relação é conflituosa, atingindo o profissional em diversas esferas, não apenas econômicas como pessoais, e está associada à expansão do sistema suplementar. Sendo assim, a prática odontológica é afetada na sua essência, sem que medidas de controle e supervisão, tão necessárias, sejam implementadas para corrigir assimetrias nas relações corporativas e evitar condições precárias da profissão.
Autolesão não suicida na adolescência como fator de predisposição ao suicídio
Authors: Carmo Julia De Souza , Silveira Pedro Henrique Feldman Sznajderman , Vignardi Renan Gianecchini , Canicoba Gabriel Stecca , Mota Anna Carolina Macieira Feitosa , Miziara Carmen Silvia Molleis Galego , Miziara Ivan Dieb
Published: September 2020

A autolesão não suicida na adolescência é um evento frequente e está associada a tentativas subsequentes de suicídio ou ao suicídio completo, sugerindo que esse comportamento e aspectos psicológicos relacionados a ele possam estar na mesma trajetória de risco. As regras legais determinam a obrigação do médico notificar casos suspeitos ou confirmados de automutilação às autoridades de saúde. No entanto, não se trata apenas de cumprir com os requisitos legais; o médico deve estar ciente dessa possibilidade, conhecendo os mecanismos aplicados pelos adolescentes, sabendo os motivos que possam desencadear esse comportamento prejudicial e, consequentemente, adotar medidas preventivas eficazes. De maneira geral, os adolescentes relatam que a autolesão alivia o sentimento de angústia, culpa ou vergonha, sendo uma maneira de autopunição. Embora a autolesão não-suicida geralmente resulte em alívio momentâneo da angústia, frequentemente leva a consequências negativas a longo prazo. Este estudo narrativo teve como objetivo mostrar os principais tópicos relacionados a este grave e prevalente problema.
Dentinogenesis imperfecta type II
Authors: Vieira Heloisa Aparecida Orsini , Freitas Aldevina Campos de , Fernandes Regina Maura , Longo Daniele Lucca , Silva Raquel Assed Bezerra da , Daltoé Mariana De Oliveira , Queiroz Alexandra Mussolino de , Nelson Filho Paulo
Published: September 2020

Dentinogenesis imperfecta (DI) is a hereditary developmental disorder of dentin formation that can occur associated with osteogenesis imperfecta (type I), isolated (type II), or in a specific isolated resident group of Brandywine, in southern Maryland (type III). This work aims at reporting a clinical case of DI type II in childhood with a 34-year follow up. The child at issue was taken to the dental health service at a very young age, which favored an appropriate treatment, avoiding complications, and portending a favorable long-term prognosis, besides safeguarding the patient physical and mental well-being. The clinical aspects of this condition are teeth with short crowns and gray-brown coloration, and an altered consistency of affected dental elements. Radiographically, the teeth present bulbous crowns, cervical constriction, thin roots, and early obliteration of the root canal and pulp chambers due to excessive dentin production. Rehabilitation treatment included the use of stainless-steel crowns for reconstructing deciduous molars and composite resin restorations on the anterior deciduous teeth. As for permanent dentition, it consisted of aesthetic-functional rehabilitation using metal crowns on the first molars and ceramic crowns and facets on the anterior teeth. Endodontic, prosthetic and restorative treatment was performed on other posterior teeth. Preventive measures were instituted. DI may cause serious changes in dentin structure, affecting function and aesthetics in both dentitions. The sooner it is administered, the more promising the multidisciplinary dental treatment will be in promoting health and minimizing damage to affected individuals.