bluuebunny/crossref_metadata_2025 huggingface dataset:
Scale-Out vs Scale-Up
Authors: Azimi Reza , Fox Tyler , Gonzalez Wendy , Reda Sherief
Published: August 2018

ARM 64-bit processing has generated enthusiasm to develop ARM-based servers that are targeted for both data centers and supercomputers. In addition to the server-class components and hardware advancements, the ARM software environment has grown substantially over the past decade. Major development ecosystems and libraries have been ported and optimized to run on ARM, making ARM suitable for server-class workloads. There are two trends in available ARM SoCs: mobile-class ARM SoCs that rely on the heterogeneous integration of a mix of CPU cores, GPGPU streaming multiprocessors (SMs), and other accelerators, and the server-class SoCs that instead rely on integrating a larger number of CPU cores with no GPGPU support and a number of IO accelerators. For scaling the number of processing cores, there are two different paradigms: mobile-class SoCs that use scale-out architecture in the form of a cluster of simpler systems connected over a network, and server-class ARM SoCs that use the scale-up solution and leverage symmetric multiprocessing to pack a large number of cores on the chip. In this article, we present ScaleSoC cluster, which is a scale-out solution based on mobile class ARM SoCs. ScaleSoC leverages fast network connectivity and GPGPU acceleration to improve performance and energy efficiency compared to previous ARM scale-out clusters. We consider a wide range of modern server-class parallel workloads to study both scaling paradigms, including latency-sensitive transactional workloads, MPI-based CPU and GPGPU-accelerated scientific applications, and emerging artificial intelligence workloads. We study the performance and energy efficiency of ScaleSoC compared to server-class ARM SoCs and discrete GPGPUs in depth. We quantify the network overhead on the performance of ScaleSoC and show that packing a large number of ARM cores on a single chip does not necessarily guarantee better performance, due to the fact that shared resources, such as last-level cache, become performance bottlenecks. We characterize the GPGPU accelerated workloads and demonstrate that for applications that can leverage the better CPU-GPGPU balance of the ScaleSoC cluster, performance and energy efficiency improve compared to discrete GPGPUs.
A Survey on Game-Theoretic Approaches for Intrusion Detection and Response Optimization
Authors: Kiennert Christophe , Ismail Ziad , Debar Herve , Leneutre Jean
Published: August 2018

Intrusion Detection Systems (IDS) are key components for securing critical infrastructures, capable of detecting malicious activities on networks or hosts. However, the efficiency of an IDS depends primarily on both its configuration and its precision. The large amount of network traffic that needs to be analyzed, in addition to the increase in attacks’ sophistication, renders the optimization of intrusion detection an important requirement for infrastructure security, and a very active research subject. In the state of the art, a number of approaches have been proposed to improve the efficiency of intrusion detection and response systems. In this article, we review the works relying on decision-making techniques focused on game theory and Markov decision processes to analyze the interactions between the attacker and the defender, and classify them according to the type of the optimization problem they address. While these works provide valuable insights for decision-making, we discuss the limitations of these solutions as a whole, in particular regarding the hypotheses in the models and the validation methods. We also propose future research directions to improve the integration of game-theoretic approaches into IDS optimization techniques.
Entity-Based Query Recommendation for Long-Tail Queries
Authors: Huang Zhipeng , Cautis Bogdan , Cheng Reynold , Zheng Yudian , Mamoulis Nikos , Yan Jing
Published: August 2018

Query recommendation, which suggests related queries to search engine users, has attracted a lot of attention in recent years. Most of the existing solutions, which perform analysis of users’ search history (or
query logs
), are often insufficient for
long-tail queries
that rarely appear in query logs. To handle such queries, we study the use of
entities
found in queries to provide recommendations. Specifically, we extract entities from a query, and use these entities to explore new ones by consulting an information source. The discovered entities are then used to suggest new queries to the user. In this article, we examine two information sources: (1) a knowledge base (or KB), such as YAGO and Freebase; and (2) a click log, which contains the URLs accessed by a query user. We study how to use these sources to find new entities useful for query recommendation. We further study a hybrid framework that integrates different query recommendation methods effectively. As shown in the experiments, our proposed approaches provide better recommendations than existing solutions for long-tail queries. In addition, our query recommendation process takes less than 100ms to complete. Thus, our solution is suitable for providing online query recommendation services for search engines.
Property Testing of Joint Distributions using Conditional Samples
Authors: Bhattacharyya Rishiraj , Chakraborty Sourav
Published: August 2018

In this article, we consider the problem of testing properties of joint distributions under the Conditional Sampling framework. In the standard sampling model, sample complexity of testing properties of joint distributions are exponential in the dimension, resulting in inefficient algorithms for practical use. While recent results achieve efficient algorithms for product distributions with significantly smaller sample complexity, no efficient algorithm is expected when the marginals are not independent.

In this article, we initialize the study of conditional sampling in the multidimensional setting. We propose a subcube conditional sampling model where the tester can condition on a (adaptively) chosen subcube of the domain. Due to its simplicity, this model is potentially implementable in many practical applications, particularly when the distribution is a joint distribution over Σ

n

for some set Σ.

We present algorithms for various fundamental properties of distributions in the subcube-conditioning model and prove that the sample complexity is polynomial in the dimension
n
(and not exponential as in the traditional model). We present an algorithm for testing identity to a known distribution using Õ(
n
2
)-subcube-conditional samples, an algorithm for testing identity between two unknown distributions using Õ(
n
5
)-subcube-conditional samples and an algorithm for testing identity to a product distribution using Õ(
n
5
)-subcube-conditional samples.

The central concept of our technique involves an elegant chain rule, which can be proved using basic techniques of probability theory, yet it is powerful enough to avoid the curse of dimensionality.
Regulation of Division and Differentiation of Plant Stem Cells
Authors: Pierre-Jerome Edith , Drapek Colleen , Benfey Philip N.
Published: August 2018

A major challenge in developmental biology is unraveling the precise regulation of plant stem cell maintenance and the transition to a fully differentiated cell. In this review, we highlight major themes coordinating the acquisition of cell identity and subsequent differentiation in plants. Plant cells are immobile and establish position-dependent cell lineages that rely heavily on external cues. Central players are the hormones auxin and cytokinin, which balance cell division and differentiation during organogenesis. Transcription factors and miRNAs, many of which are mobile in plants, establish gene regulatory networks that communicate cell position and fate. Small peptide signaling also provides positional cues as new cell types emerge from stem cell division and progress through differentiation. These pathways recruit similar players for patterning different organs, emphasizing the modular nature of gene regulatory networks. Finally, we speculate on the outstanding questions in the field and discuss how they may be addressed by emerging technologies.
Corpus Phonetics
Authors: Liberman Mark Y.
Published: August 2018

Semiautomatic analysis of digital speech collections is transforming the science of phonetics. Convenient search and analysis of large published bodies of recordings, transcripts, metadata, and annotations—up to three or four orders of magnitude larger than a few decades ago—have created a trend towards “corpus phonetics,” whose benefits include greatly increased researcher productivity, better coverage of variation in speech patterns, and crucial support for reproducibility. The results of this work include insights into theoretical questions at all levels of linguistic analysis, along with applications in fields as diverse as psychology, medicine, and poetics, as well as within phonetics itself. Remaining challenges include still-limited access to the necessary skills and a lack of consistent standards. These changes coincide with the broader Open Data movement, but future solutions will also need to include more constrained forms of publication motivated by valid concerns for privacy, confidentiality, and intellectual property.
Deletion of the forminDiaph1protects from structural and functional abnormalities in the murine diabetic kidney
Authors: Manigrasso Michaele B. , Friedman Richard A. , Ramasamy Ravichandran , D’Agati Vivette , Schmidt Ann Marie
Published: August 2018

Diaphanous 1 (DIAPH1), a member of the formin family, binds to the cytoplasmic domain of the receptor for advanced glycation end products (RAGE) and is required for RAGE signal transduction. Experiments employing genetic overexpression or deletion of Ager (the gene encoding RAGE) or its pharmacological antagonism implicate RAGE in the pathogenesis of diabetes-associated nephropathy. We hypothesized that DIAPH1 contributes to pathological and functional derangements in the kidneys of diabetic mice. We show that DIAPH1 is expressed in the human and murine diabetic kidney, at least in part in the tubulointerstitium and glomerular epithelial cells or podocytes. To test the premise that DIAPH1 is linked to diabetes-associated derangements in the kidney, we rendered male mice globally devoid of Diaph1 ( Diaph1−/−) or wild-type controls (C57BL/6 background) diabetic with streptozotocin. Control mice received equal volumes of citrate buffer. After 6 mo of hyperglycemia, diabetic Diaph1−/−mice displayed significantly reduced mesangial sclerosis, podocyte effacement, glomerular basement thickening, and urinary albumin-to-creatinine ratio compared with diabetic mice expressing Diaph1. Analysis of whole kidney cortex revealed that deletion of Diaph1 in diabetic mice significantly reduced expression of genes linked to fibrosis and inflammation. In glomerular isolates, expression of two genes linked to podocyte stress, growth arrest-specific 1 ( Gas1) and cluster of differentiation 36 ( Cd36), was significantly attenuated in diabetic Diaph1−/−mice compared with controls, in parallel with significantly higher levels of nestin (Nes) mRNA, a podocyte marker. Collectively, these data implicate DIAPH1 in the pathogenesis of diabetes-associated nephropathy and suggest that the RAGE-DIAPH1 axis is a logical target for therapeutic intervention in this disorder.
Electrically stimulated acupuncture increases renal blood flow through exosome-carried miR-181
Authors: Klein Janet D. , Wang Xiaonan H.
Published: August 2018

Acupuncture with low-frequency electrical stimulation (Acu/LFES) can prevent muscle atrophy by increasing muscle protein anabolism in mouse models of chronic kidney disease. During the treatment of muscle wasting, we found that Acu/LFES on the gastrocnemius muscle of the leg enhances renal blood flow. We also found that Acu/LFES increases exosome abundance and alters exosome-associated microRNA expression in the circulation. When exosome secretion was blocked using GW4869, the Acu/LFES-induced increase in renal blood flow was limited. This provided evidence that the increased renal blood flow is exosome mediated. To identify how exosomes regulate renal blood flow, we performed microRNA deep sequencing in exosomes isolated from treated and untreated mouse serum and found that the 34 microRNAs are altered by Acu/LFES. In particular, miR-181d-5p is increased in the serum exosome of Acu/LFES-treated mice. In silico searching suggested that miR-181d-5p could target angiotensinogen. Using a luciferase reporter assay, we demonstrated that miR-181 directly inhibits angiotensinogen. When Acu/LFES-treated muscle was excised and incubated in culture medium, we found that the amount of exosomes and miR-181d-5p was increased in the medium providing evidence that Acu/LFES can increase miR-181 secretion. We conclude that Acu/LFES on leg hindlimb increases miR-181 in serum exosome leading to increased renal blood flow. This study provides important new insights about the mechanism(s) by which acupuncture may regulation of muscle-organ cross talk through exosome-derived microRNA.
Electrical stimulation of the pudendal nerve promotes neuroregeneration and functional recovery from stress urinary incontinence in a rat model
Authors: Jiang Hai-Hong , Song Qi-Xiang , Gill Bradley C. , Balog Brian M. , Juarez Raul , Cruz Yolanda , Damaser Margot S.
Published: August 2018

The pudendal nerve can be injured during vaginal delivery of children, and slowed pudendal nerve regeneration has been correlated with development of stress urinary incontinence (SUI). Simultaneous injury to the pudendal nerve and its target muscle, the external urethral sphincter (EUS), during delivery likely leads to slowed neuroregeneration. The goal of this study was to determine if repeat electrical stimulation of the pudendal nerve improves SUI recovery and promotes neuroregeneration in a dual muscle and nerve injury rat model of SUI. Rats received electrical stimulation or sham stimulation of the pudendal nerve twice weekly for up to 2 wk after injury. A separate cohort of rats received sham injury and sham stimulation. Expression of brain-derived neurotrophic factor (BDNF) and βII-tubulin expression in Onuf’s nucleus were measured 2, 7, and 14 days after injury. Urodynamics, leak point pressure (LPP), and EUS electromyography (EMG) were recorded 14 days after injury. Electrical stimulation significantly increased expression of BDNF at all time points and βII-tubulin 1 and 2 wk after injury. Two weeks after injury, LPP and EUS EMG during voiding and LPP testing were significantly decreased compared with sham-injured animals. Electrical stimulation significantly increased EUS activity during voiding, although LPP did not fully recover. Repeat pudendal nerve stimulation promotes neuromuscular continence mechanism recovery possibly via a neuroregenerative response through BDNF upregulation in the pudendal motoneurons in this model of SUI. Electrical stimulation of the pudendal nerve may therefore improve recovery after childbirth and ameliorate symptoms of SUI by promoting neuroregeneration after injury.
Long-latency reflexes for inter-effector coordination reflect a continuous state feedback controller
Authors: Crevecoeur Frederic , Kurtzer Isaac
Published: August 2018

Successful performance in many everyday tasks requires compensating unexpected mechanical disturbance to our limbs and body. The long-latency reflex plays an important role in this process because it is the fastest response to integrate sensory information across several effectors, like when linking the elbow and shoulder or the arm and body. Despite the dozens of studies on inter-effector long-latency reflexes, there has not been a comprehensive treatment of how these reveal the basic control organization that sets constraints on any candidate model of neural feedback control such as optimal feedback control. We considered three contrasting ways that controllers can be organized: multiple independent controllers vs. a multiple-input multiple-output (MIMO) controller, a continuous feedback controller vs. an intermittent feedback controller, and a direct MIMO controller vs. a state feedback controller. Following a primer on control theory and review of the relevant evidence, we conclude that continuous state feedback control best describes the organization of inter-effector coordination by the long-latency reflex.
Role of muscle spindle feedback in regulating muscle activity strength during walking at different speed in mice
Authors: Mayer William P. , Murray Andrew J. , Brenner-Morton Susan , Jessell Thomas M. , Tourtellotte Warren G. , Akay Turgay
Published: August 2018

Terrestrial animals increase their walking speed by increasing the activity of the extensor muscles. However, the mechanism underlying how this speed-dependent amplitude modulation is achieved remains obscure. Previous studies have shown that group Ib afferent feedback from Golgi tendon organs that signal force is one of the major regulators of the strength of muscle activity during walking in cats and humans. In contrast, the contribution of group Ia/II afferent feedback from muscle spindle stretch receptors that signal angular displacement of leg joints is unclear. Some studies indicate that group II afferent feedback may be important for amplitude regulation in humans, but the role of muscle spindle feedback in regulation of muscle activity strength in quadrupedal animals is very poorly understood. To examine the role of feedback from muscle spindles, we combined in vivo electrophysiology and motion analysis with mouse genetics and gene delivery with adeno-associated virus. We provide evidence that proprioceptive sensory feedback from muscle spindles is important for the regulation of the muscle activity strength and speed-dependent amplitude modulation. Furthermore, our data suggest that feedback from the muscle spindles of the ankle extensor muscles, the triceps surae, is the main source for this mechanism. In contrast, muscle spindle feedback from the knee extensor muscles, the quadriceps femoris, has no influence on speed-dependent amplitude modulation. We provide evidence that proprioceptive feedback from ankle extensor muscles is critical for regulating muscle activity strength as gait speed increases.

NEW & NOTEWORTHY Animals upregulate the activity of extensor muscles to increase their walking speed, but the mechanism behind this is not known. We show that this speed-dependent amplitude modulation requires proprioceptive sensory feedback from muscle spindles of ankle extensor muscle. In the absence of muscle spindle feedback, animals cannot walk at higher speeds as they can when muscle spindle feedback is present.
Edge orientation perception during active touch
Authors: Olczak Derek , Sukumar Vaishnavi , Pruszynski J. Andrew
Published: August 2018

Previous studies investigating the perceptual attributes of tactile edge orientation processing have applied their stimuli to an immobilized fingertip. Here we tested the perceptual attributes of edge orientation processing when participants actively touched the stimulus. Our participants moved their finger over two pairs of edges, one pair parallel and the other nonparallel to varying degrees, and were asked to identify which of the two pairs was nonparallel. In addition to the psychophysical estimates of edge orientation acuity, we measured the speed at which participants moved their finger and the forces they exerted when moving their finger over the stimulus. We report four main findings. First, edge orientation acuity during active touch averaged 12.4°, similar to that previously reported during passive touch. Second, on average, participants moved their finger over the stimuli at ~20 mm/s and exerted contact forces of ~0.3 N. Third, there was no clear relationship between how people moved their finger or how they pressed on the stimulus and their edge orientation acuity. Fourth, consistent with previous work testing tactile spatial acuity, we found a significant correlation between fingertip size and orientation acuity such that people with smaller fingertips tended to have better orientation acuity.

NEW & NOTEWORTHY Edge orientation acuity expressed by the motor system during manipulation is many times better than edge orientation acuity assessed in psychophysical studies where stimuli are applied to a passive fingertip. Here we show that this advantage is not because of movement per se because edge orientation acuity assessed in a psychophysical task, where participants actively move their finger over the stimuli, yields results similar to previous passive psychophysical studies.
Corticospinal correlates of fast and slow adaptive processes in motor learning
Authors: Sarwary Adjmal M. E. , Wischnewski Miles , Schutter Dennis J. L. G. , Selen Luc P. J. , Medendorp W. Pieter
Published: August 2018

Recent computational theories and behavioral observations suggest that motor learning is supported by multiple adaptation processes, operating on different timescales, but direct neural evidence is lacking. We tested this hypothesis by applying transcranial magnetic stimulation over motor cortex in 16 human subjects during a validated reach adaptation task. Motor-evoked potentials (MEPs) and cortical silent periods (CSPs) were recorded from the biceps brachii to assess modulations of corticospinal excitability as indices for corticospinal plasticity. Guided by a two-state adaptation model, we show that the MEP reflects an adaptive process that learns quickly but has poor retention, while the CSP correlates with a process that responds more slowly but retains information well. These results provide a physiological link between models of motor learning and distinct changes in corticospinal excitability. Our findings support the relationship between corticospinal gain modulations and the adaptive processes in motor learning.

NEW & NOTEWORTHY Computational theories and behavioral observations suggest that motor learning is supported by multiple adaptation processes, but direct neural evidence is lacking. We tested this hypothesis by applying transcranial magnetic stimulation over human motor cortex during a reach adaptation task. Guided by a two-state adaptation model, we show that the motor-evoked potential reflects a process that adapts and decays quickly, whereas the cortical silent period reflects slow adaptation and decay.
Decreased spontaneous electrical activity in neuronal networks exposed to radiofrequency 1,800 MHz signals
Authors: El Khoueiry Corinne , Moretti Daniela , Renom Rémy , Camera Francesca , Orlacchio Rosa , Garenne André , Poulletier De Gannes Florence , Poque-Haro Emmanuelle , Lagroye Isabelle , Veyret Bernard , Lewis Noëlle
Published: August 2018

The rapid development of wireless communications has raised questions about their potential health risks. So far, the only identified biological effects of radiofrequency fields (RF) are known to be caused by heating, but the issue of potential nonthermal biological effects, especially on the central nervous system (CNS), remains open. We previously reported a decrease in the firing and bursting rates of neuronal cultures exposed to a Global System for Mobile (GSM) RF field at 1,800 MHz for 3 min (Moretti D, Garenne A, Haro E, Poulleier de Gannes F, Lagroye I, Lévêque P, Veyret B, Lewis N. Bioelectromagnetics 34: 571-578, 2013). The aim of the present work was to assess the dose-response relationship for this effect and also to identify a potential differential response elicited by pulse-modulated GSM and continuous-wave (CW) RF fields. Spontaneous bursting activity of neuronal cultures from rat embryonic cortices was recorded using 60-electrode multielectrode arrays (MEAs). At 17–28 days in vitro, the neuronal cultures were subjected to 15-min RF exposures, at specific absorption rates (SAR) ranging from 0.01 to 9.2 W/kg. Both GSM and CW signals elicited a clear decrease in bursting rate during the RF exposure phase. This effect became more marked with increasing SAR and lasted even beyond the end of exposure for the highest SAR levels. Moreover, the amplitude of the effect was greater with the GSM signal. Altogether, our experimental findings provide evidence for dose-dependent effects of RF signals on the bursting rate of neuronal cultures and suggest that part of the mechanism is nonthermal.

NEW & NOTEWORTHY In this study, we investigated the effects of some radiofrequency (RF) exposure parameters on the electrical activity of neuronal cultures. We detected a clear decrease in bursting activity, dependent on exposure duration. The amplitude of this effect increased with the specific absorption rate (SAR) level and was greater with Global System for Mobile signal than with continuous-wave signal, at the same average SAR. Our experiment provides unique evidence of a decrease in electrical activity of cortical neuronal cultures during RF exposure.
Human spatial representation: what we cannot learn from the studies of rodent navigation
Authors: Zhao Mintao
Published: August 2018

Studies of human and rodent navigation often reveal a remarkable cross-species similarity between the cognitive and neural mechanisms of navigation. Such cross-species resemblance often overshadows some critical differences between how humans and nonhuman animals navigate. In this review, I propose that a navigation system requires both a storage system (i.e., representing spatial information) and a positioning system (i.e., sensing spatial information) to operate. I then argue that the way humans represent spatial information is different from that inferred from the cellular activity observed during rodent navigation. Such difference spans the whole hierarchy of spatial representation, from representing the structure of an environment to the representation of subregions of an environment, routes and paths, and the distance and direction relative to a goal location. These cross-species inconsistencies suggest that what we learn from rodent navigation does not always transfer to human navigation. Finally, I argue for closing the loop for the dominant, unidirectional animal-to-human approach in navigation research so that insights from behavioral studies of human navigation may also flow back to shed light on the cellular mechanisms of navigation for both humans and other mammals (i.e., a human-to-animal approach).
Tumor de células granulares de la mama. Presentación de un caso.
Authors: Villarroel Pérez Alejandra , Navarro Ortega M. Elena , Razmilic Valdés Dravna , Camus Appuhn Mauricio , Oddó Benavides David
Published: August 2018

El tumor de células granulares (TCG) es una neoplasia muy infrecuente y usualmente benigna,  que afecta preferentemente a la lengua. En sólo un 6% de los casos publicados ha sido primario de la mama. Desde el punto de vista clínico e imagenológico, se plantea el diagnóstico diferencial con un carcinoma mamario invasor. Por ende, el examen anatomopatológico de muestras por punción o quirúrgicas, es crucial para establecer el diagnóstico e intentar subclasificarlo para predecir su conducta biológica. Se presenta el caso de una mujer chilena de 54 años con un TCG de la mama izquierda.
Identificación de gatillantes de sistema de respuesta rápida en pacientes de unidades de baja complejidad de un hospital universitario.
Authors: Eymin Lago Gonzalo , Ortega González Francisco , Heredia Castro Ana , Yáñez Ferrada Tatina
Published: August 2018

Introducción: Las complicaciones graves de pacientes en unidades de baja complejidad habitualmente son precedidas por alteración en los signos vitales. Los equipos de respuesta rápida (ERR) atienden precozmente a pacientes con alteración de signos vitales que se relacionan con resultados adversos. Nuestro  objetivo es determinar la tasa  de gatillantes de ERR en pacientes hospitalizados en unidades de baja complejidad y su eventual relación con eventos adversos posteriores. Métodos: Observación de registros de una cohorte prospectiva de pacientes mayores de 18 años en unidades de baja complejidad de un hospital universitario. Resultados: Se encontraron gatillantes en 50 de 1144 pacientes (4,4%). La edad promedio fue de  58 años, y 58% fueron mujeres. Los gatillantes más frecuentes fueron: Hipotensión (40%), frecuencia respiratoria mayor a 25 por minuto (26%) y Saturación de oxígeno menor a 90% (24%). Presentaron eventos adversos mayores 6 pacientes (12%), 1 de ellos con desenlace fatal y los 6 fueron trasladados a unidad de mayor complejidad. No existió diferencia significativa entre quienes tuvieron 1 o 2 gatillantes en relación a eventos adversos mayores. Los 3 pacientes que presentaron compromiso de conciencia sufrieron eventos adversos mayores incluyendo la muerte de uno. Conclusión: Los gatillantes más frecuentes fueron hipotensión y taquipnea. La presencia de dos eventos gatillantes muestra una tendencia a un peor resultado, si bien no alcanza significancia estadística. Dado nuestra eventual tasa de activación de ERR si se justificaría la implementación de estos equipos en nuestro medio.
A Novel Microtubule Inhibitor Overcomes Multidrug Resistance in Tumors
Authors: Ning Nannan , Yu Yamei , Wu Min , Zhang Ruihong , Zhang Ting , Zhu Changjun , Huang Lei , Yun Cai-Hong , Benes Cyril H. , Zhang Jianming , Deng Xianming , Chen Qiang , Ren Ruibao
Published: August 2018

Microtubule inhibitors as chemotherapeutic drugs are widely used for cancer treatment. However, the development of multidrug resistance (MDR) in cancer is a major challenge for microtubule inhibitors in their clinical implementation. From a high-throughput drug screen using cells transformed by oncogenic RAS, we identify a lead heteroaryl amide compound that blocks cell proliferation. Analysis of the structure-activity relationship indicated that this series of scaffolds (exemplified by MP-HJ-1b) represents a potent inhibitor of tumor cell growth. MP-HJ-1b showed activities against a panel of more than 1,000 human cancer cell lines with a wide variety of tissue origins. This compound depolymerized microtubules and affected spindle formation. It also induced the spike-like conformation of microtubules in vitro and in vivo, which is different from typical microtubule modulators. Structural analysis revealed that this series of compounds bound the colchicine pocket at the intra-dimer interface, although mostly not overlapping with colchicine binding. MP-HJ-1b displayed favorable pharmacological properties for overcoming tumor MDR, both in vitro and in vivo. Taken together, our data reveal a novel scaffold represented by MP-HJ-1b that can be developed as a cancer therapeutic against tumors with MDR.

Significance: Paclitaxel is a widely used chemotherapeutic drug in patients with multiple types of cancer. However, resistance to paclitaxel is a challenge. This study describes a novel class of microtubule inhibitors with the ability to circumvent multidrug resistance across multiple tumor cell lines. Cancer Res; 78(20); 5949–57. ©2018 AACR.
Extracellular HMGA1 Promotes Tumor Invasion and Metastasis in Triple-Negative Breast Cancer
Authors: Méndez Olga , Peg Vicente , Salvans Cándida , Pujals Mireia , Fernández Yolanda , Abasolo Ibane , Pérez José , Matres Ana , Valeri Marta , Gregori Josep , Villarreal Laura , Schwartz Simó , Ramon y Cajal Santiago , Tabernero Josep , Cortés Javier , Arribas Joaquín , Villanueva Josep
Published: August 2018

Purpose:

The study of the cancer secretome suggests that a fraction of the intracellular proteome could play unanticipated roles in the extracellular space during tumorigenesis. A project aimed at investigating the invasive secretome led us to study the alternative extracellular function of the nuclear protein high mobility group A1 (HMGA1) in breast cancer invasion and metastasis.

Experimental Design:

Antibodies against HMGA1 were tested in signaling, adhesion, migration, invasion, and metastasis assays using breast cancer cell lines and xenograft models. Fluorescence microscopy was used to determine the subcellular localization of HMGA1 in cell lines, xenograft, and patient-derived xenograft models. A cohort of triple-negative breast cancer (TNBC) patients was used to study the correlation between subcellular localization of HMGA1 and the incidence of metastasis.

Results:

Our data show that treatment of invasive cells with HMGA1-blocking antibodies in the extracellular space impairs their migration and invasion abilities. We also prove that extracellular HMGA1 (eHMGA1) becomes a ligand for the Advanced glycosylation end product-specific receptor (RAGE), inducing pERK signaling and increasing migration and invasion. Using the cytoplasmic localization of HMGA1 as a surrogate marker of secretion, we showed that eHMGA1 correlates with the incidence of metastasis in a cohort of TNBC patients. Furthermore, we show that HMGA1 is enriched in the cytoplasm of tumor cells at the invasive front of primary tumors and in metastatic lesions in xenograft models.

Conclusions:

Our results strongly suggest that eHMGA1 could become a novel drug target in metastatic TNBC and a biomarker predicting the onset of distant metastasis.
Mutual Influence of ROS, pH, and CLIC1 Membrane Protein in the Regulation of G1–S Phase Progression in Human Glioblastoma Stem Cells
Authors: Peretti Marta , Raciti Federica Maddalena , Carlini Valentina , Verduci Ivan , Sertic Sarah , Barozzi Sara , Garré Massimiliano , Pattarozzi Alessandra , Daga Antonio , Barbieri Federica , Costa Alex , Florio Tullio , Mazzanti Michele
Published: August 2018

Glioblastoma (GB) is the most lethal, aggressive, and diffuse brain tumor. The main challenge for successful treatment is targeting the cancer stem cell (CSC) subpopulation responsible for tumor origin, progression, and recurrence. Chloride Intracellular Channel 1 (CLIC1), highly expressed in CSCs, is constitutively present in the plasma membrane where it is associated with chloride ion permeability. In vitro, CLIC1 inhibition leads to a significant arrest of GB CSCs in G1 phase of the cell cycle. Furthermore, CLIC1 knockdown impairs tumor growth in vivo. Here, we demonstrate that CLIC1 membrane localization and function is specific for GB CSCs. Mesenchymal stem cells (MSC) do not show CLIC1-associated chloride permeability, and inhibition of CLIC1 protein function has no influence on MSC cell-cycle progression. Investigation of the basic functions of GB CSCs reveals a constitutive state of oxidative stress and cytoplasmic alkalinization compared with MSCs. Both intracellular oxidation and cytoplasmic pH changes have been reported to affect CLIC1 membrane functional expression. We now report that in CSCs these three elements are temporally linked during CSC G1–S transition. Impeding CLIC1-mediated chloride current prevents both intracellular ROS accumulation and pH changes. CLIC1 membrane functional impairment results in GB CSCs resetting from an allostatic tumorigenic condition to a homeostatic steady state. In contrast, inhibiting NADPH oxidase and NHE1 proton pump results in cell death of both GB CSCs and MSCs. Our results show that CLIC1 membrane protein is crucial and specific for GB CSC proliferation, and is a promising pharmacologic target for successful brain tumor therapies. Mol Cancer Ther; 17(11); 2451–61. ©2018 AACR.
Four Circulating Long Non-Coding RNAs Act as Biomarkers for Predicting Cervical Cancer
Authors: Sun Wenping , Wang Liehong  , Zhao Dexiong  , Wang Pinhua  , Li Yongping  , Wang Shulin
Published: August 2018

Background/Aims: Circulation long non-coding RNAs (lncRNAs) have emerged recently as major players in tumor biology and might be applied for cancer diagnosis, prognosis, or potential therapeutic targets. In this study, we aimed to explore whether the circulation lncRNA could predict the tumorigenesis of surgical squamous cervical cancer (CC). Methods: In this study, we applied the lncRNA microarray to screen the potential biomarker for CC. Real-time quantitate polymerase chain reaction was conducted for further validation in a larger sample size. The multi-stage validation and risk score formula analysis were used to examine the sensitivity and specificity. Results: We discovered 4 lncRNAs including HOTAIR, PVT1, XLOC_000303, and AL592284.1, which were upregulated in CC comparing with the cancer-free controls. Further, the receiver operating characteristic curve (ROC) analysis by risk score formula revealed the combined 4 factors with a high diagnostic ability with the area under ROC curve value of 0.875 and 0.958 in training set and validation set respectively. We finally confirmed the stable detection of the 4 lncRNAs by 5 cycles of freezing and thawing. Conclusion: HOTAIR, PVT1, XLOC_000303, and AL592284.1 might be the potential biomarkers for predicting the tumorigenesis of CC in the future.
Diagnostic Yield of Computed Tomography-Guided Transthoracic Lung Biopsy in Diffuse Lung Diseases
Authors: Padrão Eva , Rodrigues Márcio , Guimarães Susana , Caetano Mota Patrícia , Melo Natália , Souto Moura Conceição , Morais António , Pereira José Miguel
Published: August 2018

Background: Accurate diagnosis is essential for successful management of diffuse lung disease (DLD). Histopathology may sometimes be necessary. Surgical lung biopsy, the gold standard, carries a risk of morbidity and mortality. Computed tomography (CT) guided transthoracic lung biopsy (CT-TLB) is a minimally invasive method for obtaining lung tissue. However, its diagnostic yield is unknown in DLD. Objective: To assess the diagnostic yield of CT-TLB in DLD according to the predominant high-resolution CT (HRCT) patterns. Methods: Between January 2009 and December 2016, we enrolled all consecutive adult patients with suspicion of DLD who underwent CT-guided transthoracic lung biopsy during the diagnostic work-up. All biopsies were performed by a senior interventional radiologist using CT fluoroscopy. Results: The study included 169 patients (50.3% men) with a mean (±SD) age of 58.3 ± 14 years. Consolidation was the predominant HRCT pattern. A definitive or probable diagnosis was made in 66.3%. The most frequent diagnosis was organizing pneumonia (36.2%). Diagnostic yield was higher when the predominant HRCT pattern was consolidation or nodular. The most common complication was pneumothorax (17.8%); other complications included mild hemoptysis (7.7%), hemothorax (1.2%), and death (0.59%). No acute exacerbation of the underlying condition was observed. Conclusions: CT-TLB proved to be accurate and safe for the diagnosis of DLD. The overall diagnostic yield of the procedure was 66.3%. Given its low complication rates, CT-TLB can be an option in patients whose respiratory function is seriously impaired and in those with substantial comorbidities, where more invasive procedures cannot be performed for reasons of safety.
Oral Immunotherapy Using Partially Hydrolyzed Formula for Cow’s Milk Protein Allergy: A Randomized, Controlled Trial
Authors: Inuo Chisato , Tanaka Kenichi , Suzuki Satoko , Nakajima Yoichi , Yamawaki Kazuo , Tsuge Ikuya , Urisu Atsuo , Kondo Yasuto
Published: August 2018

Background: Partially hydrolyzed cow’s milk protein-based formula (pHF) possesses low allergenicity. Here, we investigate the safety and efficacy of oral immunotherapy using pHF for children with cow’s milk protein allergy (CMPA). Objectives: A randomized, double-blind, controlled single-center trial was conducted to evaluate the efficacy and safety of pHF oral immunotherapy in children with CMPA. Methods: Participants were randomized into double-blind pHF-pHF and extensively hydrolyzed cow’s milk protein-based formula (eHF)-pHF groups. During this phase, the pHF-pHF group received pHF and the eHF-pHF group received eHF. During the open phase, all participants received pHF. The primary end point was a change in thresholds between baseline and the end of the first phase. Secondary end points were changes in thresholds between baseline and the end of the second phase, and casein-specific immunoglobulin (Ig)E, IgG4, and basophil activation. Results: Twenty-five children, aged 1–9 years, were randomized into pHF-pHF and eHF-pHF groups. The threshold between baseline and the end of the first phase was significantly elevated in the pHF-pHF group (p = 0.048), but not in the eHF-pHF group. The threshold between other phases did not change significantly in either group. There were significant decreases in casein-specific IgE antibody levels between baseline and the second phase in the eHF-pHF group (p = 0.014). No participants suffered systemic allergic reactions requiring adrenaline or systemic corticosteroids after receiving the formulas. Conclusions: The results of this trial suggest that, in children with CMPA, tolerance to cow’s milk might be safely enhanced by intake of pHF, relative to that of eHF.
Human Papillomavirus-Associated Invasive Condylomas in a Man with Immunosuppressive Comorbidities
Authors: Zeuschner Philip , Ueberdiek Stefan , Pryalukhin Alexey , Veith Christian , Saar Matthias , Smola Sigrun , Bohle Rainer Maria , Junker Kerstin , Stöckle Michael , Heinzelbecker Julia
Published: August 2018

Human papilloma virus (HPV) infections are one of the most common sexually transmitted diseases. We present the case of a 77-year-old Caucasian male with enormous genital warts of the penis, scrotum, groins and anus. Lesions were excised by electrosurgery. The histological examination revealed Condylomata gigantea as well as an invasive perianal squamous cell carcinoma. Mucosal “low-risk” HPV type 6 was detected. The patient had a history of an immunosuppressing disease. During the 4-year follow-up, multiple relapses occurred. Thus, particularly in immunosuppressed patients, early prophylactic HPV vaccination seems to be indicated for use in the prevention of HPV-associated mutilating and life-threatening disease. Vaccination should also protect from “low-risk” HPV.
Primary Intra-Arterial Chemotherapy for Retinoblastoma in the Intravitreal Chemotherapy Era: Five Years of Experience
Authors: Dalvin Lauren A. , Kumari Mamta , Essuman Vera Adobea , Shohelly Shipa Shormin , Ancona-Lezama David  , Lucio-Alvarez J. Antonio , Jabbour Pascal , Shields Carol L.
Published: August 2018

Purpose: To report our 5-year experience with intra-arterial chemotherapy (IAC) in the intravitreal chemotherapy (IvitC) era. Methods: Retrospective review of retinoblastoma treated with primary unilateral IAC in the IvitC era (2012–2017). Results: There were 34 eyes treated with IAC alone versus 20 eyes treated with IAC plus IvitC for vitreous seeds. IAC (IAC alone vs. IAC plus IvitC) consisted of melphalan (41 vs. 10%) or melphalan plus topotecan (59 vs. 90%, p = 0.03). IvitC consisted of melphalan (60%) or melphalan plus topotecan (40%). Tumor control and globe salvage were achieved in 100% of group B and C eyes without IvitC. Despite more extensive vitreous seeds in the IvitC group (p < 0.01), comparison of IAC alone versus IAC plus IvitC revealed no difference in tumor control for group D (88 vs. 69%, p = 0.36) or group E (67 vs. 100%, p = 0.25) and no difference in globe salvage for group D (88 vs. 69%, p = 0.36) or group E (58 vs. 57%, p = 0.39). Conclusions: IAC is effective as primary therapy for unilateral group B, C, D, and E retinoblastoma. IvitC is an important adjuvant therapy to achieve comparable globe salvage rates for group D and E eyes with persistent active vitreous seeds.
Racial/Ethnic Disparities in US Pediatric Growth Hormone Treatment
Authors: Grimberg Adda , Lindberg Anders , Wajnrajch Michael , Cucchiara Andrew J. , Camacho-Hübner Cecilia
Published: August 2018

Background/Aims: To compare racial/ethnic proportions of subjects receiving growth hormone (GH) treatment to the expected proportions, and secondarily, to assess racial/ethnic differences in subject characteristics at GH treatment initiation. Methods: Race/ethnicity-based expected frequencies of height <–2.25 SD were determined by applying relative risks for short stature, calculated from a regional population of 189,280 pediatric primary care patients, to US census data, and compared to racial/ethnic proportions of US subjects enrolled in the Pfizer International Growth Study (KIGS) using the χ2 test. Characteristics of white and black subjects at GH treatment initiation were presented as medians and compared by the Wilcoxon rank sum test (significant p < 0.01). Results: White subjects exceeded the expected frequency (63%) for all indications (83%) and each separately, ranging from 73% for congenital GH deficiency (GHD) to 85% for idiopathic short stature (p < 0.001). Compared to white subjects, black subjects treated for idiopathic GHD had greater height deficits relative both to the population (–2.97 vs. –2.56 SD) and to their mid-parental heights (–2.47 vs. –1.89 SD), lower stimulated GH peak levels (4.9 vs. 6.0 ng/mL), and lower birth weights (–0.86 vs. –0.48 SD). Black subjects with congenital GHD had lower stimulated GH peaks (2.1 vs. 3.2 ng/mL) and started GH treatment at younger ages (2.9 vs. 4.8 years), while those with acquired GHD had lower birth weights (–1.12 vs. –0.08 SD). Male predominance did not differ by race for any or all indications. Conclusion: Overrepresentation of white children among those receiving GH treatment in the US KIGS registry reflects racial/ethnic treatment biases, not just differences in growth rates.
Optimal Thermal Control with Sufficient Nutrition May Reduce the Incidence of Neonatal Jaundice by Preventing Body-Weight Loss Among Non-Low Birth Weight Infants Not Admitted to Neonatal Intensive Care Unit
Authors: Zaitsu Masayoshi , Yoshihara Tatsuya , Nakai Hiromitsu , Kubota Shiro
Published: August 2018

Background: Neonatal jaundice is strongly attributable to excess body-weight loss as a result of insufficient calorific intake. Objectives: To examine the incidence of neonatal jaundice (defined by use of phototherapy) and body-weight loss, as well as their association, among neonates under optimal thermal control with sufficient nutrition, a local protocol for temperature and nutritional regulation. Methods: We retrospectively identified a cohort of 10,544 neonates (birth weight ≥2,500 g) placed in thermo-controlled incubators for 2 h immediately after birth. Neonates were fed with 5% glucose solution 1 h after birth and breastfed every 3 h (with supplementary formula milk if applicable) according to basal maintenance expenditure. Total serum bilirubin levels at day 4 (peak level) were assessed. Phototherapy was performed on the basis of total serum bilirubin level ≥18 mg/dL. Risk ratio (RR) and 95% CI for the use of phototherapy against maximum body-weight loss were estimated using Poisson regression with robust variance. Results: Incidence of phototherapy use was low (0.3%) and the mean total serum bilirubin level was 8.5 mg/dL (SD 2.7 mg/dL), with a low mean maximum body-weight loss (1.9%) and low incidence of excess body-weight loss ≥7% (0.4%). Maximum body-weight loss was associated with risk of neonatal jaundice (RR 1.27; 95% CI 1.04–1.54), and became significant at approximately 4% of maximum body-weight loss. Conclusion: Optimal thermal control and sufficient nutrition may greatly reduce the incidence of neonatal jaundice by preventing neonatal body-weight loss.