bluuebunny/crossref_metadata_2025 huggingface dataset:
CaffePresso
Authors: Hegde Gopalakrishna , Siddhartha  , Kapre Nachiket
Published: November 2017

Auto-tuning and parametric implementation of deep learning kernels allow off-the-shelf accelerator-based embedded platforms to deliver high-performance and energy-efficient mappings of the inference phase of lightweight neural networks. Low-complexity classifiers are characterized by operations on small image maps with two to three deep layers and few class labels. For these use cases, we consider a range of embedded systems with 20W power budgets such as the Xilinx ZC706 (FPGA), NVIDIA Jetson TX1 (GPU), TI Keystone II (DSP), and Adapteva Parallella (RISC+NoC). In CaffePresso, we combine auto-tuning of the implementation parameters, and platform-specific constraints deliver optimized solutions for each input ConvNet specification.
BubbleView
Authors: Kim Nam Wook , Bylinskii Zoya , Borkin Michelle A. , Gajos Krzysztof Z. , Oliva Aude , Durand Fredo , Pfister Hanspeter
Published: November 2017

In this article, we present BubbleView, an alternative methodology for eye tracking using discrete mouse clicks to measure which information people consciously choose to examine. BubbleView is a mouse-contingent, moving-window interface in which participants are presented with a series of blurred images and click to reveal “bubbles” -- small, circular areas of the image at original resolution, similar to having a confined area of focus like the eye fovea. Across 10 experiments with 28 different parameter combinations, we evaluated BubbleView on a variety of image types: information visualizations, natural images, static webpages, and graphic designs, and compared the clicks to eye fixations collected with eye-trackers in controlled lab settings. We found that BubbleView clicks can both (i) successfully approximate eye fixations on different images, and (ii) be used to rank image and design elements by importance. BubbleView is designed to collect clicks on static images, and works best for defined tasks such as describing the content of an information visualization or measuring image importance. BubbleView data is cleaner and more consistent than related methodologies that use continuous mouse movements. Our analyses validate the use of mouse-contingent, moving-window methodologies as approximating eye fixations for different image and task types.
Runtime Performance and Power Optimization of Parallel Disparity Estimation on Many-Core Platforms
Authors: Leech Charles , Kumar Charan , Acharyya Amit , Yang Sheng , Merrett Geoff V. , Al-Hashimi Bashir M.
Published: November 2017

This article investigates the use of many-core systems to execute the disparity estimation algorithm, used in stereo vision applications, as these systems can provide flexibility between performance scaling and power consumption. We present a learning-based runtime management approach that achieves a required performance threshold while minimizing power consumption through dynamic control of frequency and core allocation. Experimental results are obtained from a 61-core Intel Xeon Phi platform for the aforementioned investigation. The same performance can be achieved with an average reduction in power consumption of 27.8% and increased energy efficiency by 30.04% when compared to Dynamic Voltage and Frequency Scaling control alone without runtime management.
A Generalized Constraint Approach to Bilingual Dictionary Induction for Low-Resource Language Families
Authors: Nasution Arbi Haza , Murakami Yohei , Ishida Toru
Published: November 2017

The lack or absence of parallel and comparable corpora makes bilingual lexicon extraction a difficult task for low-resource languages. The pivot language and cognate recognition approaches have been proven useful for inducing bilingual lexicons for such languages. We propose constraint-based bilingual lexicon induction for closely related languages by extending constraints from the recent pivot-based induction technique and further enabling multiple symmetry assumption cycle to reach many more cognates in the transgraph. We further identify cognate synonyms to obtain many-to-many translation pairs. This article utilizes four datasets: one Austronesian low-resource language and three Indo-European high-resource languages. We use three constraint-based methods from our previous work, the Inverse Consultation method and translation pairs generated from Cartesian product of input dictionaries as baselines. We evaluate our result using the metrics of precision, recall, and F-score. Our customizable approach allows the user to conduct cross validation to predict the optimal hyperparameters (cognate threshold and cognate synonym threshold) with various combination of heuristics and number of symmetry assumption cycles to gain the highest F-score. Our proposed methods have statistically significant improvement of precision and F-score compared to our previous constraint-based methods. The results show that our method demonstrates the potential to complement other bilingual dictionary creation methods like word alignment models using parallel corpora for high-resource languages while well handling low-resource languages.
Ouroboros Wear Leveling for NVRAM Using Hierarchical Block Migration
Authors: Liu Qingyue , Varman Peter
Published: November 2017

Emerging nonvolatile RAM (NVRAM) technologies have a limit on the number of writes that can be made to any cell, similar to the erasure limits in NAND Flash. This motivates the need for wear leveling techniques to distribute the writes evenly among the cells. Unlike NAND Flash, cells in NVRAM can be rewritten without the need for erasing the entire containing block, avoiding the issues of space reclamation and garbage collection, motivating alternate approaches to the problem. In this article, we propose a hierarchical wear-leveling model called Ouroboros wear leveling. Ouroboros uses a two-level strategy whereby frequent low-cost intraregion wear leveling at small granularity is combined with interregion wear leveling at a larger time interval and granularity. Ouroboros is a hybrid migration scheme that exploits correct demand predictions in making better wear-leveling decisions while using randomization to avoid wear-leveling attacks by deterministic access patterns. We also propose a way to optimize wear-leveling parameter settings to meet a target smoothness level under limited time and space overhead constraints for different memory architectures and trace characteristics. Several experiments are performed on synthetically generated memory traces with special characteristics, two block-level storage traces, and two memory-line-level memory traces. The results show that Ouroboros wear leveling can distribute writes smoothly across the whole NVRAM with no more than 0.2% space overhead and 0.52% time overhead for a 512GB memory.
Autonomic regulation of the immune system in cardiovascular diseases
Authors: Abboud François M. , Singh Madhu V.
Published: November 2017

The autonomic nervous system is a powerful regulator of circulatory adjustments to acute hemodynamic stresses. Here we focus on new concepts that emphasize the chronic influence of the sympathetic and parasympathetic systems on cardiovascular pathology. The autonomic neurohumoral system can dramatically influence morbidity and mortality from cardiovascular disease through newly discovered influences on the innate and adaptive immune systems. Specifically, the end-organ damage in heart failure or hypertension may be worsened or alleviated by pro- or anti-inflammatory pathways of the immune system, respectively, that are activated through neurohumoral transmitters. These concepts provide a major new perspective on potentially life-saving therapeutic interventions in the deadliest of diseases.
Physiology undergraduate degree requirements in the U.S.
Authors: VanRyn Valerie S. , Poteracki James M. , Wehrwein Erica A.
Published: November 2017

Course-level learning objectives and core concepts for undergraduate physiology teaching exist. The next step is to consider how these resources fit into generalizable program-level guidelines for Bachelor of Science (BS) degrees in Physiology. In the absence of program-level guidelines for Physiology degree programs, we compiled a selective internal report to review degree requirements from 18 peer BS programs entitled “Physiology” in the United States (U.S.). There was a range of zero to three required semesters of math, physics, physics laboratory, general biology, biology laboratory, general chemistry, chemistry laboratory, organic chemistry, organic chemistry laboratory, biochemistry, biochemistry laboratory, anatomy, anatomy laboratory, core systems physiology, and physiology laboratory. Required upper division credits ranged from 11 to 31 and included system-specific, exercise and environmental, clinically relevant, pathology/disease-related, and basic science options. We hope that this information will be useful for all programs that consider themselves to be physiology, regardless of name. Reports such as this can serve as a starting point for collaboration among BS programs to improve physiology undergraduate education and best serve our students.
Effectiveness of interprofessional education in renal physiology curricula for health sciences graduate students
Authors: Harrison-Bernard Lisa M. , Naljayan Mihran V. , Eason Jane M. , Mercante Donald E. , Gunaldo Tina P.
Published: November 2017

The primary purpose of conducting an interprofessional education (IPE) experience during the renal physiology block of a graduate-level course was to provide basic science, physical therapy, and physician assistant graduate students with an opportunity to work as a team in the diagnosis, treatment, and collaborative care of a patient with acute kidney injury. The secondary purpose was to enhance the understanding of basic renal physiology principles with a patient case presentation of renal pathophysiology. The overall purpose was to assess the value of IPE integration within a basic science course by examining student perceptions and program evaluation. Graduate-level students operated in interprofessional teams while working through an acute kidney injury patient case. The following Interprofessional Education Collaborative subcompetencies were targeted: Roles/Responsibilities (RR) Behavioral Expectations (RR1, RR4) and Interprofessional Communication (CC) Behavioral Expectations (CC4). Clinical and IPE stimulus questions were discussed both within and between teams with assistance provided by faculty facilitators. Students were given a pre- and postsurvey to determine their knowledge of IPE. There were statistically significant increases from pre- to postsurvey scores for all six IPE questions for all students. Physical therapy and physician assistant students had a statistically significant increase in pre- to postsurvey scores, indicating a more favorable perception of their interprofessional competence for RR1, RR4, and CC4. No changes were noted in pre- to postsurvey scores for basic science graduate students. Incorporating planned IPE experiences into multidisciplinary health science courses represents an appropriate venue to have students learn and apply interprofessional competencies.
Low-protein diet-induced hyperphagia and adiposity are modulated through interactions involving thermoregulation, motor activity, and protein quality in mice
Authors: Blais Anne , Chaumontet Catherine , Azzout-Marniche Dalila , Piedcoq Julien , Fromentin Gilles , Gaudichon Claire , Tomé Daniel , Even Patrick C.
Published: November 2017

Low protein (LP)-containing diets can induce overeating in rodents and possibly in humans in an effort to meet protein requirement, but the effects on energy expenditure (EE) are unclear. The present study evaluated the changes induced by reducing dietary protein from 20% to 6%—using either soy protein or casein—on energy intake, body composition, and EE in mice housed at 22°C or at 30°C (thermal neutrality). LP feeding increased energy intake and adiposity, more in soy-fed than in casein-fed mice, but also increased EE, thus limiting fat accumulation. The increase in EE was due mainly to an increase in spontaneous motor activity related to EE and not to thermoregulation. However, the high cost of thermoregulation at 22°C and the subsequent heat exchanges between nonshivering thermogenesis, motor activity, and feeding induced large differences in adaptation between mice housed at 22°C and at 30°C.
Protecting Privacy in Shared Photos via Adversarial Examples Based Stealth
Authors: Liu Yujia , Zhang Weiming , Yu Nenghai
Published: November 2017

Online image sharing in social platforms can lead to undesired privacy disclosure. For example, some enterprises may detect these large volumes of uploaded images to do users’ in-depth preference analysis for commercial purposes. And their technology might be today’s most powerful learning model, deep neural network (DNN). To just elude these automatic DNN detectors without affecting visual quality of human eyes, we design and implement a novel Stealth algorithm, which makes the automatic detector blind to the existence of objects in an image, by crafting a kind of adversarial examples. It is just like all objects disappear after wearing an “invisible cloak” from the view of the detector. Then we evaluate the effectiveness of Stealth algorithm through our newly defined measurement, named privacy insurance. The results indicate that our scheme has considerable success rate to guarantee privacy compared with other methods, such as mosaic, blur, and noise. Better still, Stealth algorithm has the smallest impact on image visual quality. Meanwhile, we set a user adjustable parameter called cloak thickness for regulating the perturbation intensity. Furthermore, we find that the processed images have transferability property; that is, the adversarial images generated for one particular DNN will influence the others as well.
Neurolysis for Treatment of Infraorbital Neuropathy
Authors: Mahli Ahmet , Coskun Demet
Published: November 2017

Two patients, a woman aged 34 and a man aged 56, were included in the study. They reported the existence of pain in the areas of the infraorbital nerve, which, over the last four to five years, aggravated by the stimuli of eating, laughing, and being touched. 2 ml of 0.5% lidocaine was administered to these patients six times percutaneously. It was observed that the ease of pain lasted until the local anesthesia lost its effect, and the pain resumed its original intensity. Neurolysis with 0.5 ml of 50% ethanol was applied to the infraorbital nerve. This procedure was applied to the first patient twice and three times to the second. Thereafter, the patients were cured completely. For the treatment of idiopathic chronic infraorbital neuropathy, the neurolysis of the infraorbital nerve using 50% ethanol could be considered as an effective treatment alternative.
Analytic Approximation of Solutions of Parabolic Partial Differential Equations with Variable Coefficients
Authors: Kravchenko Vladislav V. , Otero Josafath A. , Torba Sergii M.
Published: November 2017

A complete family of solutions for the one-dimensional reaction-diffusion equation, uxx(x,t)-q(x)u(x,t)=ut(x,t), with a coefficient q depending on x is constructed. The solutions represent the images of the heat polynomials under the action of a transmutation operator. Their use allows one to obtain an explicit solution of the noncharacteristic Cauchy problem with sufficiently regular Cauchy data as well as to solve numerically initial boundary value problems. In the paper, the Dirichlet boundary conditions are considered; however, the proposed method can be easily extended onto other standard boundary conditions. The proposed numerical method is shown to reveal good accuracy.
Effect of Gas Flowrate on Nucleation Mechanism of MWCNTs for a Compound Catalyst
Authors: Shukrullah S. , Mohamed N. M. , Khan Y. , Naz M. Y. , Ghaffar A. , Ahmad I.
Published: November 2017

Activation of the catalyst particles during a CVD process can be anticipated from the carbon feeding rate. In this study, Fe2O3/Al2O3 catalyst was synthesized with uniformly dispersed iron over alumina support for onward production of multiwalled carbon nanotubes (MWCNTs) in a fluidized bed chemical CVD reactor. The effect of the ethylene flowrate on catalytic activity of the compound catalyst and morphology of the as-grown MWCNTs was also investigated in this study. The dispersed active phases of the catalyst and optimized gas flowrate helped in improving the tube morphology and prevented the aggregation of the as-grown MWCNTs. The flowrates, below 100 sccm, did not provide sufficient reactants to interact with the catalyst for production of defect-free CNT structures. Above 100 sccm, concentration of the carbon precursor did not show notable influence on decomposition rate of the gas molecules. The most promising results on growth and structural properties of MWCNTs were gained at ethylene flowrate of 100 sccm. At this flowrate, the ratio of G and D intensity peaks (IG/ID) was deliberated about 1.40, which indicates the growth of graphitic structures of MWCNTs.
Round Robin Tests to Determine Fiber Content of Carbon Fiber-Reinforced Thermoplastic Composites by Combustion and Thermogravimetry
Authors: Funabashi Masahiro , Ninomiya Fumi , Oishi Akihiro , Mizuno Wataru , Tahira Kimitaka , Tanaka Shogo , Kunioka Masao
Published: November 2017

To propose methods to determine the fiber content of carbon fiber-reinforced plastics (CFRP) for the International Organization for Standardization, the fiber contents of CFRP with polyamide-6 were measured using a combustion method based on ISO 14127 and a thermogravimetry method based on the modified ISO 9924-3 under a round robin test managed by the Polymer Subcommittee of the Industrial Technology Cooperative Promotion Committee in Japan. In the combustion method, the fiber contents of the CFRTP (~0.3 g) were determined by the mass of carbon fiber remaining after burning (ISO 14127). The fiber contents in weight of the CFRTP with 8, 9, or 10 plies were determined to be 55.720%, 61.088%, or 65.326%, respectively, by 17 research institutes. In the thermogravimetry method, the fiber contents of the CFRTP (~10 mg) were determined by the mass of carbon fiber remaining after heating it to 600°C in nitrogen gas using thermogravimetry apparatus (modified ISO 9924-3). The fiber contents of the CFRTP with 8, 9, or 10 plies were determined to be 56.908%, 61.579%, or 64.819%, respectively, by 8 research institutes. It was confirmed that thermogravimetry method was as accurate as the combustion method based on ISO 14127.
Feasibility of Residual Stress Nondestructive Estimation Using the Nonlinear Property of Critical Refraction Longitudinal Wave
Authors: Zhang Yu-Hua , Li Xin-Xin , Wang Xiang-Hong , Huang Zhen-Feng , Mao Han-Ling , Mao Han-Ying
Published: November 2017

Residual stress has significant influence on the performance of mechanical components, and the nondestructive estimation of residual stress is always a difficult problem. This study applies the relative nonlinear coefficient of critical refraction longitudinal (LCR) wave to nondestructively characterize the stress state of materials; the feasibility of residual stress estimation using the nonlinear property of LCR wave is verified. The nonlinear ultrasonic measurements based on LCR wave are conducted on components with known stress state to calculate the relative nonlinear coefficient. Experimental results indicate that the relative nonlinear coefficient monotonically increases with prestress and the increment of relative nonlinear coefficient is about 80%, while the wave velocity only decreases about 0.2%. The sensitivity of the relative nonlinear coefficient for stress is much higher than wave velocity. Furthermore, the dependence between the relative nonlinear coefficient and deformation state of components is found. The stress detection resolution based on the nonlinear property of LCR wave is 10 MPa, which has higher resolution than wave velocity. These results demonstrate that the nonlinear property of LCR wave is more suitable for stress characterization than wave velocity, and this quantitative information could be used for residual stress estimation.
Nonfragile Finite-Time Extended Dissipative Control for a Class of Uncertain Switched Neutral Systems
Authors: Gao Hui , Xia Jianwei , Zhuang Guangming , Wang Zhen , Sun Qun
Published: November 2017

This paper is concerned with finite-time extended dissipative analysis and nonfragile control for a class of uncertain switched neutral systems with time delay, and the controller is assumed to have either additive or multiplicative form. By employing the average dwell-time and linear matrix inequality technique, sufficient conditions for finite-time boundedness of the switched neutral system are provided. Then finite-time extended dissipative performance for the switched neutral system is addressed, where we can solve H∞, L2-L∞, Passivity, and (Q,S,R)-dissipativity performance in a unified framework based on the concept of extended dissipative. Furthermore, nonfragile state feedback controllers are proposed to guarantee that the closed-loop system is finite-time bounded with extended dissipative performance. Finally, numerical examples are given to demonstrate the effectiveness of the proposed method.
The Flavonoid Glabridin Induces OCT4 to Enhance Osteogenetic Potential in Mesenchymal Stem Cells
Authors: Heo June Seok , Lee Seung Gwan , Kim Hyun Ok
Published: November 2017

Mesenchymal stem cells (MSCs) are a promising tool for studying intractable diseases. Unfortunately, MSCs can easily undergo cellular senescence during in vitro expansion by losing stemness. The aim of this study was to improve the stemness and differentiation of MSCs by using glabridin, a natural flavonoid. Assessments of cell viability, cell proliferation, β-galactosidase activity, differentiation, and gene expression by reverse transcription PCR were subsequently performed in the absence or presence of glabridin. Glabridin enhanced the self-renewal capacity of MSCs, as indicated by the upregulation of the OCT4 gene. In addition, it resulted in an increase in the osteogenic differentiation potential by inducing the expression of osteogenesis-related genes such as DLX5 and RUNX2. We confirmed that glabridin improved the osteogenesis of MSCs with a significant elevation in the expression of OSTEOCALCIN and OSTEOPONTIN genes. Taken together, these results suggest that glabridin enhances osteogenic differentiation of MSCs with induction of the OCT4 gene; thus, glabridin could be useful for stem cell-based therapies.
Zinc Protects Oxidative Stress‐Induced RPE Death by Reducing Mitochondrial Damage and Preventing Lysosome Rupture
Authors: Rajapakse Dinusha , Curtis Tim , Chen Mei , Xu Heping
Published: November 2017

Zinc deficiency is known to increase the risk of the development of age‐related macular degeneration (AMD), although the underlying mechanism remains poorly defined. In this study, we investigated the effect of zinc on retinal pigment epithelium (RPE) survival and function under oxidative conditions. Zinc level was 5.4 μM in normal culture conditions (DMEM/F12 with 10% FCS) and 1.5 μM in serum‐free medium (DMEM/F12). Under serum‐free culture conditions, the treatment of RPE cells with oxidized photoreceptor outer segment (oxPOS) significantly increased intracellular ROS production, reduced ATP production, and promoted RPE death compared to oxPOS‐treated RPE under normal culture condition. Serum deprivation also reduced RPE phagocytosis of oxPOS and exacerbated oxidative insult‐induced cathepsin B release from lysosome, an indicator of lysosome rupture. The addition of zinc in the serum‐free culture system dose dependently reduced ROS production, recovered ATP production, and reduced oxidative stress‐ (oxPOS‐ or 4‐HNE) induced cell death. Zinc supplementation also reduced oxidative stress‐mediated cathepsin B release in RPE cells. Our results suggest that zinc deficiency sensitizes RPE cells to oxidative damage, and zinc supplementation protects RPE cells from oxidative stress‐induced death by improving mitochondrial function and preventing lysosome rupture.
Elevated Levels of Interferon-γ Are Associated with High Levels of Epstein-Barr Virus Reactivation in Patients with the Intestinal Type of Gastric Cancer
Authors: Cárdenas-Mondragón María G. , Torres Javier , Sánchez-Zauco Norma , Gómez-Delgado Alejandro , Camorlinga-Ponce Margarita , Maldonado-Bernal Carmen , Fuentes-Pananá Ezequiel M.
Published: November 2017

Background. The inflammatory response directed against Helicobacter pylori (HP) is believed to be one of the main triggers of the appearance of gastric lesions and their progression to gastric cancer (GC). Epstein-Barr virus (EBV) has been found responsible for about 10% of all GCs, but the inflammatory response has not been studied in GC patients with evidence of high levels of EBV reactivation. Objective. To determine the relationship between inflammation and antibodies against EBV reactivation antigens, HP, and the bacterium virulence factor CagA in patients with GC. Methods. 127 GC patients, 46 gastritis patients, and 197 healthy subjects were studied. IL-1β, IL-6, IL-8, IL-10, TNF-α, TGF-β, MCP-1, and IFN-γ levels were measured in serum or plasma and compared against the antibody titers of VCA-IgG, HP, and the HP virulence factor CagA. Statistical associations were estimated. Results. Significant ORs and positive trends were found between VCA-IgG and IFN-γ, specifically for patients with GC of intestinal type (OR: 6.4, 95% C.I. 1.2–35.4) (p<0.044). Conclusions. We confirmed a positive association between a marker of EBV reactivation and intestinal gastric cancer and present evidence of a correlation with elevated serum levels of IFN-γ, but not with the other cytokines.
Circularly Polarized Dielectric Resonator Antenna Arrays with Fractal Cross-Slot-Coupled DRA Elements
Authors: Lin Jia-Hong , Shen Wen-Hui , Shi Zhi-Dong , Zhong Shun-Shi
Published: November 2017

In the design of circularly polarized (CP) dielectric resonator antenna (DRA) arrays, the regular-shaped DRAs with simple feeding configurations are mostly used as array elements to make the design procedure more efficient. However, such array element DRA usually achieves only about 6% axial ratio (AR) bandwidth. In this paper, a CP DRA element coupled by a fractal cross-slot which can radiate efficiently and excite the rectangular DRA simultaneously is considered. By adjusting the dimensions of the fractal cross-slot properly, the resonances of the fractal cross-slot and the dielectric resonator can be merged to obtain a wider AR bandwidth. Based on the proposed fractal cross-slot-coupled CP DRA element, two different CP DRA arrays are designed: a wideband CP DRA array and a low-sidelobe-level (SLL) CP DRA array. The designed DRA arrays are fabricated and measured, and structures and performances of the arrays are presented and discussed.
Research on Gastroesophageal Reflux Disease Based on Dynamic Features of Ambulatory 24-Hour Esophageal pH Monitoring
Authors: Liu Shuang , Xu Minpeng , Yang Jiajia , Qi Hongzhi , He Feng , Zhao Xin , Zhou Peng , Zhang Lixin , Ming Dong
Published: November 2017

Ambulatory 24-hour esophageal pH monitoring has been considered as the gold standard for diagnosing gastroesophageal reflux disease (GERD), and in clinical application, static parameters are widely used, such as DeMeester score. However, a shortcoming of these static variables is their relatively high false negative rate and long recording time required. They may be falsely labeled as nonrefluxers and not appropriately treated. Therefore, it is necessary to seek more accurate and objective parameters to detect and quantify GERD. This paper first describes a new effort that investigated the feasibility of dynamic features of 24-hour pH recording. Wavelet energy, information entropy, and wavelet entropy were estimated for three groups (severe, mild-to-moderate, and normal). The results suggest that wavelet energy and entropy are physiologically meaningful since they differentiated patients with varying degrees of GERD.K-means clustering algorithm was employed to obtain the sensitivity and specificity of new parameters. It is obvious that information entropy goes with the highest sensitivity of 87.3% and wavelet energy has the highest specificity of 97.1%. This would allow a more accurate definition of the best indicators to detect and quantify GERD as well as provide an alternative insight into the early diagnosis of GERD.
Immunotherapy of Hepatocellular Carcinoma: Facts and Hopes
Authors: Iñarrairaegui Mercedes , Melero Ignacio , Sangro Bruno
Published: November 2017

Treatment of patients with hepatocellular carcinoma (HCC) in the advanced stage remains a great challenge, with very few drugs approved. After decades of failure of immune therapies, immune checkpoint inhibitors have emerged as potentially effective treatments for patients with HCC in the advanced stage. Immune checkpoints, including human cancer, cytotoxic T-lymphocyte protein 4 (CTLA-4), and programmed cell death protein 1 (PD-1), are surface proteins expressed in a variety of immune cells and mostly provide immunosuppressive signals. Monoclonal antibodies able to block these molecules have shown antitumor activity against a wide spectrum of human cancers. Clinical experience with checkpoint inhibitors in HCC includes early trials with the anti–CTLA-4 agent tremelimumab and a large phase II trial with the anti–PD-1 agent nivolumab. The latter has shown strong activity particularly as second-line therapy, both in terms of tumor response and patient survival. At least three topics should be the focus of future research: (i) the search for activity in patients at less-advanced stages, including the adjuvant treatment of patients with resectable or ablatable tumors; (ii) the enhanced efficacy of combination therapies, including particularly the combination with those targeted and locoregional therapies that may have a synergistic effect or act upon mechanisms of primary or acquired resistance to checkpoint inhibitors; and (iii) the identification of clinical features and serum or tissue biomarkers that would allow a better patient selection for individual treatments. Hopefully, ongoing trials will help to design better treatments in the future. Clin Cancer Res; 24(7); 1518–24. ©2017 AACR.
A Phase I Clinical Trial of the Poly(ADP-ribose) Polymerase Inhibitor Veliparib and Weekly Topotecan in Patients with Solid Tumors
Authors: Wahner Hendrickson Andrea E. , Menefee Michael E. , Hartmann Lynn C. , Long Harry J. , Northfelt Donald W. , Reid Joel M. , Boakye-Agyeman Felix , Kayode Olumide , Flatten Karen S. , Harrell Maria I. , Swisher Elizabeth M. , Poirier Guy G. , Satele Daniel , Allred Jake , Lensing Janet L. , Chen Alice , Ji Jiuping , Zang Yiping , Erlichman Charles , Haluska Paul , Kaufmann Scott H.
Published: November 2017

Purpose:

To determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of veliparib in combination with weekly topotecan in patients with solid tumors. Correlative studies were included to assess the impact of topotecan and veliparib on poly(ADP-ribose) levels in peripheral blood mononuclear cells, serum pharmacokinetics of both agents, and potential association of germline repair gene mutations with outcome.

Experimental Design:

Eligible patients had metastatic nonhematologic malignancies with measurable disease. Using a 3 + 3 design, patients were treated with veliparib orally twice daily on days 1–3, 8–10, and 15–17 and topotecan intravenously on days 2, 9, and 16 every 28 days. Tumor responses were assessed by RECIST.

Results:

Of 58 patients enrolled, 51 were evaluable for the primary endpoint. The MTD and RP2D was veliparib 300 mg twice daily on days 1–3, 8–10, and 15–17 along with topotecan 3 mg/m2 on days 2, 9, and 16 of a 28-day cycle. DLTs were grade 4 neutropenia lasting >5 days. The median number of cycles was 2 (1–26). The objective response rate was 10%, with 1 complete and 4 partial responses. Twenty-two patients (42%) had stable disease ranging from 4 to 26 cycles. Patients with germline BRCA1, BRCA2, or RAD51D mutations remained on study longer than those without homologous recombination repair (HRR) gene mutations (median 4 vs. 2 cycles).

Conclusions:

Weekly topotecan in combination with veliparib has a manageable safety profile and appears to warrant further investigation.
IMMU-140, a Novel SN-38 Antibody–Drug Conjugate Targeting HLA-DR, Mediates Dual Cytotoxic Effects in Hematologic Cancers and Malignant Melanoma
Authors: Cardillo Thomas M. , Govindan Serengulam V. , Zalath Maria B. , Rossi Diane L. , Wang Yang , Chang Chien-Hsing , Goldenberg David M.
Published: November 2017

HLA-DR is a member of the MHC class II antigen family expressed on hematologic and solid tumors. Antibodies directed against HLA-DR have demonstrated some clinical success, but toxicities limited development. IMMU-140 is an anti–HLA-DR antibody–drug conjugate composed of the active metabolite of irinotecan, SN-38, conjugated to a humanized anti–HLA-DR IgG4 antibody (IMMU-114); the IgG4 naked antibody is devoid of immune functions. Our aim was to determine if SN-38, the metabolite of a drug not commonly used in hematopoietic cancers, would be effective and safe when targeted to HLA-DR–expressing tumors. IMMU-140 had dual-therapeutic mechanisms, as evidenced by its retention of nonoverlapping anti–HLA-DR nonclassical apoptotic signaling and classical apoptosis mediated by its SN-38 payload. In seven human disease models [acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), acute myeloid leukemia (AML), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma (HL), and melanoma], IMMU-140 provided significant therapeutic efficacy compared with controls, in vitro, in 3D spheroid models, and in vivo. Except for MM and HL, IMMU-140 imparted significantly improved antitumor effects compared with parental IMMU-114. Even in intractable AML and ALL, where IMMU-114 only had modest antitumor effects, IMMU-140 therapy mediated >80% improvement in survival. Therapy was well tolerated, as demonstrated by no marked loss in body weight. Combined with doxorubicin, IMMU-140 produced significantly greater antitumor effects in HL than with monotherapy and without any added toxicity. The dual-therapeutic action of IMMU-140 resulted in promising therapeutic activity in a range of hematopoietic tumors and melanoma, and therefore warrants clinical development. Mol Cancer Ther; 17(1); 150–60. ©2017 AACR.
PARP1 Trapping and DNA Replication Stress Enhance Radiosensitization with Combined WEE1 and PARP Inhibitors
Authors: Parsels Leslie A. , Karnak David , Parsels Joshua D. , Zhang Qiang , Vélez-Padilla Jonathan , Reichert Zachery R. , Wahl Daniel R. , Maybaum Jonathan , O'Connor Mark J. , Lawrence Theodore S. , Morgan Meredith A.
Published: November 2017

KRAS mutations in non–small cell lung cancer (NSCLC) cause increased levels of DNA damage and replication stress, suggesting that inhibition of the DNA damage response (DDR) is a promising strategy for radiosensitization of NSCLC. This study investigates the ability of a WEE1 inhibitor (AZD1775) and a PARP inhibitor (olaparib) to radiosensitize KRAS-mutant NSCLC cells and tumors. In addition to inhibiting the DDR, these small-molecule inhibitors of WEE1 and PARP induce DNA replication stress via nucleotide exhaustion and PARP trapping, respectively. As monotherapy, AZD1775 or olaparib alone modestly radiosensitized a panel of KRAS-mutant NSCLC lines. The combination of agents, however, significantly increased radiosensitization. Furthermore, AZD1775-mediated radiosensitization was rescued by nucleotide repletion, suggesting a mechanism involving AZD1775-mediated replication stress. In contrast, radiosensitization by the combination of AZD1775 and olaparib was not rescued by nucleosides. Whereas both veliparib, a PARP inhibitor that does not efficiently trap PARP1 to chromatin, and PARP1 depletion radiosensitized NSCLC cells as effectively as olaparib, which does efficiently trap PARP, only olaparib potentiated AZD1775-mediated radiosensitization. Taken together, these mechanistic data demonstrate that although nucleotide depletion is sufficient for radiosensitization by WEE1 inhibition alone, and inhibition of PARP catalytic activity is sufficient for radiosensitization by olaparib alone, PARP1 trapping is required for enhanced radiosensitization by the combination of WEE1 and PARP inhibitors.

Implications: This study highlights DNA replication stress caused by nucleotide depletion and PARP1 trapping as an important mechanism of radiosensitization in KRAS-mutant tumors and supports further development of DNA replication as a therapeutic target. Mol Cancer Res; 16(2); 222–32. ©2017 AACR.
Adipose-Derived VEGF–mTOR Signaling Promotes Endometrial Hyperplasia and Cancer: Implications for Obese Women
Authors: Sahoo Subhransu S. , Lombard Janine M. , Ius Yvette , O'Sullivan Rachel , Wood Lisa G. , Nahar Pravin , Jaaback Kenneth , Tanwar Pradeep S.
Published: November 2017

Obesity is responsible for increased morbidity and mortality in endometrial cancer. Despite the positive correlation of body mass index (BMI) or obesity in endometrial carcinogenesis, the contribution of adipose tissue to the pathogenesis of endometrial hyperplasia and cancer is unclear. This study clarifies the role of adipocytes in the pathogenesis of endometrial cancer by demonstrating that adipocyte-conditioned medium (ACM) increases proliferation, migration, and survival of endometrial cancer cells compared with preadipocyte-conditioned medium (PACM). Comparative cytokine array analysis of ACM and PACM reveal upregulation of a group of cytokines belonging to the VEGF signaling pathway in ACM. VEGF protein expression is upregulated in visceral adipose tissue (VAT) in obese patients, which is correlated with increased tumor growth in an in vivo xenograft model. The increased tumor size is mechanistically associated with the activation of the PI3K/AKT/mTOR pathway, a downstream target of VEGF signaling, and its suppression decreased the growth-promoting effects of VAT on endometrial cancer cells. Similar to the human model systems, pathologic changes in endometrial cells in a hyperphagic obese mouse model are associated with increased body weight and hyperactive mTOR signaling. Analysis of human tissue specimens depicts increased in tumor vasculature and VEGF-mTOR activity in obese endometrial cancer patients compared with nonobese patients. Collectively, these results provide evidence that VEGF-mTOR signaling drives endometrial cell growth leading to hyperplasia and cancer.

Implications: Adipocyte-derived VEGF–mTOR signaling may be an attractive therapeutic target against endometrial cancer in obese women. Mol Cancer Res; 16(2); 309–21. ©2017 AACR.
Targeted Next-Generation Sequencing for Detecting MLL Gene Fusions in Leukemia
Authors: Afrin Sadia , Zhang Christine R.C. , Meyer Claus , Stinson Caedyn L. , Pham Thy , Bruxner Timothy J.C. , Venn Nicola C. , Trahair Toby N. , Sutton Rosemary , Marschalek Rolf , Fink J. Lynn , Moore Andrew S.
Published: November 2017

Mixed lineage leukemia (MLL) gene rearrangements characterize approximately 70% of infant and 10% of adult and therapy-related leukemia. Conventional clinical diagnostics, including cytogenetics and fluorescence in situ hybridization (FISH) fail to detect MLL translocation partner genes (TPG) in many patients. Long-distance inverse (LDI)-PCR, the “gold standard” technique that is used to characterize MLL breakpoints, is laborious and requires a large input of genomic DNA (gDNA). To overcome the limitations of current techniques, a targeted next-generation sequencing (NGS) approach that requires low RNA input was tested. Anchored multiplex PCR-based enrichment (AMP-E) was used to rapidly identify a broad range of MLL fusions in patient specimens. Libraries generated using Archer FusionPlex Heme and Myeloid panels were sequenced using the Illumina platform. Diagnostic specimens (n = 39) from pediatric leukemia patients were tested with AMP-E and validated by LDI-PCR. In concordance with LDI-PCR, the AMP-E method successfully identified TPGs without prior knowledge. AMP-E identified 10 different MLL fusions in the 39 samples. Only two specimens were discordant; AMP-E successfully identified a MLL-MLLT1 fusion where LDI-PCR had failed to determine the breakpoint, whereas a MLL-MLLT3 fusion was not detected by AMP-E due to low expression of the fusion transcript. Sensitivity assays demonstrated that AMP-E can detect MLL-AFF1 in MV4-11 cell dilutions of 10−7 and transcripts down to 0.005 copies/ng.

Implications: This study demonstrates a NGS methodology with improved sensitivity compared with current diagnostic methods for MLL-rearranged leukemia. Furthermore, this assay rapidly and reliably identifies MLL partner genes and patient-specific fusion sequences that could be used for monitoring minimal residual disease. Mol Cancer Res; 16(2); 279–85. ©2017 AACR.
CD137 (4-1BB) Costimulation Modifies DNA Methylation in CD8+ T Cell–Relevant Genes
Authors: Aznar M. Angela , Labiano Sara , Diaz-Lagares Angel , Molina Carmen , Garasa Saray , Azpilikueta Arantza , Etxeberria Iñaki , Sanchez-Paulete Alfonso R. , Korman Alan J. , Esteller Manel , Sandoval Juan , Melero Ignacio
Published: November 2017

CD137 (4-1BB) costimulation imprints long-term changes that instruct the ultimate behavior of T cells that have previously experienced CD137 ligation. Epigenetic changes could provide a suitable mechanism for these long-term consequences. Genome-wide DNA methylation arrays were carried out on human peripheral blood CD8+ T lymphocytes stimulated with agonist monoclonal antibody to CD137, including urelumab, which is in phase I/II clinical trials for cancer immunotherapy. Several genes showed consistent methylation patterns in response to CD137 costimulation, which were confirmed by pyrosequencing in a series of healthy donors. CD96, HHLA2, CCR5, CXCR5, and CCL5 were among the immune-related genes regulated by differential DNA methylation, leading to changes in mRNA and protein expression. These genes are also differentially methylated in naïve versus antigen-experienced CD8+ T cells. The transcription factor TCF1 and the microRNA miR-21 were regulated by DNA methylation upon CD137 costimulation. Such gene-expression regulatory factors can, in turn, broaden the effects of DNA methylation by controlling expression of their target genes. Overall, chromatin remodeling is postulated to leave CD137-costimulated T lymphocytes poised to differentially respond upon subsequent antigen recognition. Accordingly, CD137 connects costimulation during priming to genome-wide DNA methylation and chromatin reprogramming. Cancer Immunol Res; 6(1); 69–78. ©2017 AACR.
Gut Microbiota in Health and Disease
Authors: Yamashiro Yuichiro
Published: November 2017

Intestinal regulatory T (Treg) cells are critical to maintaining immune tolerance to dietary antigens and gut microbiota. This paper reviews several papers on this topic that were recently published by Japanese researchers. Specifically, Prof. K. Honda and his group have found that commensal microbiota capable of metabolizing butyrate induces the differentiation of colonic Treg cells. In a separate work, Prof. Y. Yokoyama and his group used a novel, culture-independent analytical method (the Yakult Intestinal Flora-Scan) for detection of bacteria in the bloodstream. Their work revealed that bacteremia in invasive surgery patients was ameliorated by synbiotic supplementation; similar results were reported in pediatric surgical cases by Dr. T. Okazaki and his group. This cutting-edge method may lead to the evolution of an altered disease concept; an example of this change is provided by the description of bacteremia in patients with type 2 diabetes, as reported by Dr. J. Sato and her group. In a similar work, Prof. Y. Yamashiro and his group found that infants born by cesarean (C)-section, who typically have gut dysbiosis, exhibit higher carriage of toxigenic Clostridium perfringens. The finding suggests that C-section-born infants may serve as a potential reservoir of this opportunistic pathogen. Another separate work by the laboratory of Dr. K. Yamashiro has revealed that gut dysbiosis is associated with altered metabolism and systemic inflammation in patients with ischemic stroke. These papers are consistent with a study by Prof. N. Sudo and his group, who have made significant progress in research on interaction among the microbiota, gut, and brain.
Incidence of Multiple Sclerosis in Germany: A Cohort Study Applying Different Case Definitions Based on Claims Data
Authors: Schmedt Niklas , Khil Laura , Berger Klaus , Riedel Oliver
Published: November 2017

Background: Data on the incidence of multiple sclerosis (MS) on the national level is scarce. We aimed to estimate the incidence of MS in Germany and to compare different MS case definitions based on claims data. Methods: We conducted a cohort study with the German Pharmacoepidemiological Research Database in 2012 and calculated age- and gender-standardized incidence rates (sIRs) for 3 case definitions. In addition, the effect of stepwise reduction of the look-back period without MS diagnosis on the incidence rate was evaluated. Results: Our cohort comprised 4,175,877 individuals. The first case definition based on ICD-10 diagnoses yielded an sIR of 21.8 (95% CI 20.2–23.5) per 100,000 person years, whereas the second and third case definitions with additional requirements for drug treatment and diagnostic tests resulted in lower sIRs of 10.1 (9.1–11.3) and 6.6 (5.8–7.6) respectively. We observed a higher incidence for shorter look-back periods. Conclusion: The incidence of MS in Germany might be substantially higher than suggested in earlier studies. In addition, our study highlights the importance of a look-back period of at least 36 months to identify incident MS cases based on claims data.
Risk Factor Analysis for AKI Including Laboratory Indicators: a Nationwide Multicenter Study of Hospitalized Patients
Authors: Nie Sasa , Feng Zhe , Tang Li , Wang Xiaolong , He Yani , Fang Jingai , Li Suhua , Yang Yibin , Mao Huijuan , Jiao Jundong , Liu Wenhu , Cao Ning , Wang Wenge , Sun Jifeng , Shao Fengmin , Li Wenge , He Qiang , Jiang Hongli , Lin Hongli , Fu Ping , Zhang Xinzhou , Liu Yinghong , Wu Yonggui , Xi ChunSheng , Liang Meng , Qu Zhijie , Zhu Jun , Wu Guangli , Zheng Yali , Na Yu , Li Ying , Li Wei , Cai Guangyan , Chen Xiangmei
Published: November 2017

Background/Aims: Risk factor studies for acute kidney injury (AKI) in China are lacking, especially those regarding non-traditional risk factors, such as laboratory indicators. Methods: All adult patients admitted to 38 tertiary and 22 secondary hospitals in China in any one month between July and December 2014 were surveyed. AKI patients were screened according to the Kidney Disease: Improving Global Outcomes’ definition of AKI. Logistic regression was used to analyze the risk factors for AKI, and Cox regression was used to analyze the risk of in-hospital mortality for AKI patients; additionally, a propensity score analysis was used to reconfirm the risk factors among laboratory indicators for mortality. Results: The morbidity of AKI was 0.97%. Independent risk factors for AKI were advancing age, male gender, hypertension, and chronic kidney disease. All-cause mortality was 16.5%. The predictors of mortality in AKI patients were advancing age, tumor, higher uric acid level and increases in Acute Physiologic Assessment and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores. The hazard ratio (HR) for mortality with uric acid levels > 9.1 mg/dl compared with ≤ 5.2 mg/dl was 1.78 (95% CI: 1.23 to 2.58) for the AKI patients as a group, and was 1.73 (95% CI: 1.24 to 2.42) for a propensity score-matched set. Conclusion: In addition to traditional risk factors, uric acid level is an independent predictor of all-cause mortality after AKI.