bluuebunny/crossref_metadata_2025 huggingface dataset:
Enabling semantic technologies using multimedia ontology
Authors: Rinaldi Antonio M.
Published: March 2017

The new vision of the Web as a global intelligent repository needs advanced knowledge structure to manage complex data and services. From this perspective, the use of formal models to represent information on the web is a suitable way to allow the cooperation of users and services. This paper describes a general ontological approach to represent knowledge using multimedia data and linguistic properties to bridge the gap between the target semantic classes and the available low-level multimedia descriptors. We choose to implement our approach in a system to edit, manage and share multimedia ontology in the WEB. The system provides tools to add multimedia objects by means of user interaction. The multimedia features are automatically extracted using algorithms based on standard MPEG-7 descriptors.
Multilingual semantic dictionaries for natural language processing: The case of BabelNet
Authors: Bovi Claudio Delli , Navigli Roberto
Published: March 2017

Accurate semantic modeling lies at the very core of today’s Natural Language Processing (NLP). Getting a handle on the various phenomena that regulate the meaning of linguistic utterances can pave the way for solving many compelling and ambitious tasks in the field, from Machine Translation to Question Answering and Information Retrieval. A complete semantic model of language, however, needs first of all reliable building blocks. In the last two decades, research in lexical semantics (which focuses on the meaning of individual linguistic elements, i.e., words and expressions), has produced increasingly comprehensive and effective machine-readable dictionaries in multiple languages: like humans, NLP systems can now leverage these sources of lexical knowledge to discriminate among various senses of a given lexeme, thereby improving their performances on downstream tasks and applications. In this paper, we focus on the case study of BabelNet, a large multilingual encyclopedic dictionary and semantic network, to describe in detail how such knowledge resources are built, improved and exploited for crucial NLP tasks such as Word Sense Disambiguation, Entity Linking and Semantic Similarity.
A multimedia semantic framework for image understanding and retrieval
Authors: Penta Antonio
Published: March 2017

On the grounds, ontologies have been shown to be a powerful resource for the interpretation and translation of the terminological and semantic relationships within domains of interest but it is still unclear how they can be applied in the context of multimedia data. In this paper, we describe a framework which can capture and manage semantic information related to the multimedia data by modeling in the ontology their features. In particular, the proposed ontology-based framework is organized in the following way: at the lower levels, spatial objects, colors, shapes are represented, and semantic relationships can be established among them; at the higher levels, objects with semantic properties are put into relationship among themselves as well as with the corresponding low-level objects. On this basis, we have designed an ontological system particularly suitable for image retrieval. We have also taken into account the inherent uncertainty related to the representation and detection of multimedia properties in this complex domain. Along this work, we have provided examples from the image domain; moreover, since ontologies provide a semantic means for the semantic comparison of objects and relationships across different formats, the system is easily extensible to other, heterogeneous data sources.
Enriching semantic search with preference and quality scores
Authors: Missikoff Michele , Formica Anna , Pourabbas Elaheh , Taglino Francesco
Published: March 2017

This paper proposes an advanced searching method, aimed at improving Web Information Systems by adopting semantic technology solutions. In particular, it first illustrates the main solutions for semantic search and then proposes the semantic search method [Formula: see text] that represents an evolution of the original SemSim method. The latter is based on the annotation of the resources in a given search space by means of Ontology Feature Vectors ([Formula: see text]), built starting from a reference ontology. Analogously, a user request is expressed as a set of keywords (concepts) selected from the reference ontology, that represent the desired characteristics of the searched resources. Then, the searching method consists in extracting the resources having the [Formula: see text] that exhibit the highest conceptual similarity to the user request. The new method, [Formula: see text], improves the above mechanism by enriching the [Formula: see text] with scores. In the user request, a score (High, Medium, Low) is associated with a concept and indicates the preference (i.e., the priority) that the user assigns to the different concepts in searching for resources. In the resource annotation, the score indicates the level of quality of the concept used to characterize the resource. The [Formula: see text] method has been experimented and the results show that it outperforms the SemSim method and, therefore, also the most representative similarity methods proposed in the literature, as already shown in previous works of the authors.
Formation and Reciprocation of Dyadic Trust
Authors: Roy Atanu , Singhal Ayush , Srivastava Jaideep
Published: March 2017

This paper reports a detailed empirical study of interpersonal trust in a multi-relational online social network. This study addresses two main aspects of interpersonal trust: formation and reciprocation. Computational models developed, using multi-relational networks, for these processes provide interesting insights about online social interactions. Our findings for trust formation (initiation) indicate a strong role of lower familiarity interactions before trust(high familiarity relationship) is formed. Similarly, trust reciprocation is not automatic, but strongly depends on enough lower familiarity interactions. This study is the first quantification of the “scaffolding role” played by lower familiarity interactions, in formation of high familiarity relationships.
Cyber-Physical Social Networks
Authors: Weth Christian Von Der , Abdul Ashraf M. , Kankanhalli Mohan
Published: March 2017

In the offline world, getting to know new people is heavily influenced by people’s physical context, that is, their current geolocation. People meet in classes, bars, clubs, public transport, and so on. In contrast, first-generation online social networks such as Facebook or Google+ do not consider users’ context and thus mainly reflect real-world relationships (e.g., family, friends, colleagues). Location-based social networks, or second-generation social networks, such as Foursquare or Facebook Places, take the physical location of users into account to find new friends. However, with the increasing number and wide range of popular platforms and services on the Web, people spend a considerable time moving through the online worlds. In this article, we introduce cyber-physical social networks (CPSN) as the third generation of online social networks. Beside their physical locations, CPSN consider also users’
virtual locations
for connecting to new friends. In a nutshell, we regard a web page as a place where people can meet and interact. The intuition is that a web page is a good indicator for a user’s current interest, likings, or information needs. Moreover, we link virtual and physical locations, allowing for users to socialize across the online and offline world. Our main contributions focus on the two fundamental tasks of creating meaningful virtual locations as well as creating meaningful links between virtual and physical locations, where “meaningful” depends on the application scenario. To this end, we present OneSpace, our prototypical implementation of a cyber-physical social network. OneSpace provides a live and social recommendation service for touristic venues (e.g., hotels, restaurants, attractions). It allows mobile users close to a venue and web users browsing online content about the venue to connect and interact in an ad hoc manner. Connecting users based on their shared virtual and physical locations gives way to a plethora of novel use cases for social computing, as we will illustrate. We evaluate our proposed methods for constructing and linking locations and present the results of a first user study investigating the potential impact of cyber-physical social networks.
Coloring 3-Colorable Graphs with Less than
n
1/5
Colors
Authors: Kawarabayashi Ken-Ichi , Thorup Mikkel
Published: March 2017

We consider the problem of coloring a 3-colorable graph in polynomial time using as few colors as possible. We first present a new combinatorial algorithm using
Õ
(
n
4/11
) colors. This is the first combinatorial improvement since Blum’s
Õ
(
n
3/8
) bound from FOCS’90. Like Blum’s algorithm, our new algorithm composes immediately with recent semi-definite programming approaches, and improves the best bound for the polynomial time algorithm for the coloring of 3-colorable graphs from
O
(
n
0.2072
) colors by Chlamtac from FOCS’07 to
O
(
n
0.2049
) colors.

Next, we develop a new recursion tailored for combination with semi-definite approaches, bringing us further down to
O
(
n
0.19996
) colors.
Measurement Theory-Based Trust Management Framework for Online Social Communities
Authors: Ruan Yefeng , Zhang Ping , Alfantoukh Lina , Durresi Arjan
Published: March 2017

We propose a trust management framework based on measurement theory to infer indirect trust in online social communities using trust’s transitivity property. Inspired by the similarities between human trust and measurement, we propose a new trust metric, composed of impression and confidence, which captures both trust level and its certainty. Furthermore, based on error propagation theory, we propose a method to compute indirect confidence according to different trust transitivity and aggregation operators. We perform experiments on two real data sets, Epinions.com and Twitter, to validate our framework. Also, we show that inferring indirect trust can connect more pairs of users.
Computing the arts
Authors: Shein Esther
Published: March 2017

Artists can use software to create art, and some software creates art all on its own.
Certifying a file system using crash hoare logic
Authors: Chajed Tej , Chen Haogang , Chlipala Adam , Kaashoek M. Frans , Zeldovich Nickolai , Ziegler Daniel
Published: March 2017

FSCQ is the first file system with a machine-checkable proof that its implementation meets a specification, even in the presence of fail-stop crashes. FSCQ provably avoids bugs that have plagued previous file systems, such as performing disk writes without sufficient barriers or forgetting to zero out directory blocks. If a crash happens at an inopportune time, these bugs can lead to data loss. FSCQ's theorems prove that, under any sequence of crashes followed by reboots, FSCQ will recover its state correctly without losing data.

To state FSCQ's theorems, this paper introduces the Crash Hoare logic (CHL), which extends traditional Hoare logic with a crash condition, a recovery procedure, and logical address spaces for specifying disk states at different abstraction levels. CHL also reduces the proof effort for developers through proof automation. Using CHL, we developed, specified, and proved the correctness of the FSCQ file system. Although FSCQ's design is relatively simple, experiments with FSCQ as a user-level file system show that it is sufficient to run Unix applications with usable performance. FSCQ's specifications and proofs required significantly more work than the implementation, but the work was manageable even for a small team of a few researchers.
Online social networks and global women's empowerment
Authors: Buskens Ineke
Published: March 2017

Mediating social change or reinforcing male hegemony?
What it means to be an entrepreneur today
Authors: Strickler Yancey
Published: March 2017

In his keynote address before the fifth edition of the Tech Open Air conference in Berlin in 2016, Kickstarter's cofounder and CEO Yancey Strickler suggests the city's tech community faces "a very rare opportunity."
Nutrient sensing by absorptive and secretory progenies of small intestinal stem cells
Authors: Kishida Kunihiro , Pearce Sarah C. , Yu Shiyan , Gao Nan , Ferraris Ronaldo P.
Published: March 2017

Nutrient sensing triggers responses by the gut-brain axis modulating hormone release, feeding behavior and metabolism that become dysregulated in metabolic syndrome and some cancers. Except for absorptive enterocytes and secretory enteroendocrine cells, the ability of many intestinal cell types to sense nutrients is still unknown; hence we hypothesized that progenitor stem cells (intestinal stem cells, ISC) possess nutrient sensing ability inherited by progenies during differentiation. We directed via modulators of Wnt and Notch signaling differentiation of precursor mouse intestinal crypts into specialized organoids each containing ISC, enterocyte, goblet, or Paneth cells at relative proportions much higher than in situ as determined by mRNA expression and immunocytochemistry of cell type biomarkers. We identified nutrient sensing cell type(s) by increased expression of fructolytic genes in response to a fructose challenge. Organoids comprised primarily of enterocytes, Paneth, or goblet, but not ISC, cells responded specifically to fructose without affecting nonfructolytic genes. Sensing was independent of Wnt and Notch modulators and of glucose concentrations in the medium but required fructose absorption and metabolism. More mature enterocyte- and goblet-enriched organoids exhibited stronger fructose responses. Remarkably, enterocyte organoids, upon forced dedifferentiation to reacquire ISC characteristics, exhibited a markedly extended lifespan and retained fructose sensing ability, mimicking responses of some dedifferentiated cancer cells. Using an innovative approach, we discovered that nutrient sensing is likely repressed in progenitor ISCs then irreversibly derepressed during specification into sensing-competent absorptive or secretory lineages, the surprising capacity of Paneth and goblet cells to detect fructose, and the important role of differentiation in modulating nutrient sensing.

NEW & NOTEWORTHY Small intestinal stem cells differentiate into several cell types transiently populating the villi. We used specialized organoid cultures each comprised of a single cell type to demonstrate that 1) differentiation seems required for nutrient sensing, 2) secretory goblet and Paneth cells along with enterocytes sense fructose, suggesting that sensing is acquired after differentiation is triggered but before divergence between absorptive and secretory lineages, and 3) forcibly dedifferentiated enterocytes exhibit fructose sensing and lifespan extension.
Increased hypoxia-inducible factor-1α in striated muscle of tumor-bearing mice
Authors: Devine Raymond D. , Bicer Sabahattin , Reiser Peter J. , Wold Loren E.
Published: March 2017

Cancer cachexia is a progressive wasting disease resulting in significant effects on the quality of life and high mortality. Most studies on cancer cachexia have focused on skeletal muscle; however, the heart is now recognized as a major site of cachexia-related effects. To elucidate possible mechanisms, a proteomic study was performed on the left ventricles of colon-26 (C26) adenocarcinoma tumor-bearing mice. The results revealed several changes in proteins involved in metabolism. An integrated pathway analysis of the results revealed a common mediator in hypoxia-inducible factor-1α (HIF-1α). Work by other laboratories has shown that extensive metabolic restructuring in the C26 mouse model causes changes in gene expression that may be affected directly by HIF-1α, such as glucose metabolic genes. M-mode echocardiography showed progressive decline in heart function by day 19, exhibited by significantly decreased ejection fraction and fractional shortening, along with posterior wall thickness. Using Western blot analysis, we confirmed that HIF-1α is significantly upregulated in the heart, whereas there were no changes in its regulatory proteins, prolyl hydroxylase domain-containing protein 2 (PHD2) and von Hippel-Lindau protein (VHL). PHD2 requires both oxygen and iron as cofactors for the hydroxylation of HIF-1α, marking it for ubiquination via VHL and subsequent destruction by the proteasome complex. We examined venous blood gas values in the tumor-bearing mice and found significantly lower oxygen concentration compared with control animals in the third week after tumor inoculation. We also examined select skeletal muscles to determine whether they are similarly affected. In the diaphragm, extensor digitorum longus, and soleus, we found significantly increased HIF-1α in tumor-bearing mice, indicating a hypoxic response, not only in the heart, but also in skeletal muscle. These results indicate that HIF-1α may contribute, in part, to the metabolic changes that occur during cancer cachexia.

NEW & NOTEWORTHY We used proteomics and metadata analysis software to identify contributors to metabolic changes in striated muscle during cancer cachexia. We found increased expression of hypoxia-inducible factor-1α in the heart and skeletal muscle, suggesting a potential target for the therapeutic treatment of cancer cachexia.
Muscle length-dependent contribution of motoneuron Cav1.3 channels to force production in model slow motor unit
Authors: Kim Hojeong
Published: March 2017

Persistent inward current (PIC)-generating Cav1.3 channels in spinal motoneuron dendrites are thought to be actively recruited during normal behaviors. However, whether and how the activation of PIC channels influences force output of motor unit remains elusive. Here, building a physiologically realistic model of slow motor unit I demonstrated that force production induced by the PIC activation is much smaller for short than lengthened muscles during the regular firing of the motoneuron that transitions from the quiescent state by either a brief current pulse at the soma or a brief synaptic excitation at the dendrites. By contrast, the PIC-induced force potentiation was maximal for short muscles when the motoneuron switched from a stable low-frequency firing state to a stable high-frequency firing state by the current pulse at the soma. Under the synaptic excitation at the dendrites, however, the force could not be potentiated by the transitioning of the motoneuron from a low- to a high-frequency firing state due to the simultaneous onset of PIC at the dendrites and firing at the soma. The strong dependency of the input-output relationship of the motor unit on the neuromodulation and Ia afferent inputs for the PIC channels was further shown under static variations in muscle length. Taken together, these findings suggest that the PIC activation in the motoneuron dendrites may differentially affect the force production of the motor unit, depending not only on the firing state history of the motoneuron and the variation in muscle length but also on the mode of motor activity.

NEW & NOTEWORTHY Cav1.3 channels in motoneuron dendrites are actively involved during normal motor activities. To investigate the effects of the activation of motoneuron Cav1.3 channels on force production, a model motor unit was built based on best-available data. The simulation results suggest that force potentiation induced by Cav1.3 channel activation is strongly modulated not only by firing history of the motoneuron but also by length variation of the muscle as well as neuromodulation inputs from the brainstem.
The effects of short work vs. longer work periods within intermittent exercise on V̇o2pkinetics, muscle deoxygenation, and energy system contribution
Authors: McCrudden Michael C. , Keir Daniel A. , Belfry Glen R.
Published: March 2017

We examined the effects of inserting 3-s recovery periods during high-intensity cycling exercise at 25-s and 10-s intervals on pulmonary oxygen uptake (V̇o2p), muscle deoxygenation [deoxyhemoglobin (HHb)], their associated kinetics (τ), and energy system contributions. Eleven men (24 ± 3 yr) completed two trials of three cycling protocols: an 8-min continuous protocol (CONT) and two 8-min intermittent exercise protocols with work-to-rest periods of 25 s to 3 s (25INT) and 10 s to 3 s (10INT). Each protocol began with a step-transition from a 20-W baseline to a power output (PO) of 60% between lactate threshold and maximal V̇o2p(Δ60). This PO was maintained for 8 min in CONT, whereas 3-s periods of 20-W cycling were inserted every 10 s and 25 s after the transition to Δ60 in 10INT and 25INT, respectively. Breath-by-breath gas exchange measured by mass spectrometry and turbine and vastus lateralis [HHb] measured by near-infrared spectroscopy were recorded throughout. Arterialized-capillary lactate concentration ([Lac−]) was obtained before and 2 min postexercise. The τV̇o2pwas lowest ( P < 0.05) for 10INT (24 ± 4 s) and 25INT (23 ± 5 s) compared with CONT (28 ± 4 s), whereas HHb kinetics did not differ ( P > 0.05) between conditions. Postexercise [Lac−] was lowest ( P < 0.05) for 10INT (7.0 ± 1.7 mM), was higher for 25INT (10.3 ± 1.9 mM), and was greatest in CONT (14.3 ± 3.1 mM). Inserting 3-s recovery periods during heavy-intensity exercise speeded V̇o2pkinetics and reduced overall V̇o2p, suggesting an increased reliance on PCr-derived phosphorylation during the work period of INT compared with an identical PO performed continuously.

NEW & NOTEWORTHY We report novel observations on the effects of differing heavy-intensity work durations between 3-s recovery periods on pulmonary oxygen uptake (V̇o2p) kinetics, muscle deoxygenation, and energy system contributions. Relative to continuous exercise, V̇o2pkinetics are faster in intermittent exercise, and increased frequency of 3-s recovery periods improves microvascular O2delivery and reduces V̇o2pand arterialized-capillary lactate concentration. The metabolic burden of identical intensity work is altered when performed intermittently vs. continuously.
Differential Impact of Symptom Prevalence and Chronic Conditions on Quality of Life in Cancer Survivors and Non-Cancer Individuals: A Population Study
Authors: Huang I-Chan , Hudson Melissa M. , Robison Leslie L. , Krull Kevin R.
Published: March 2017

Background: To compare associations of symptom prevalence, chronic conditions, and health-related quality of life (HRQOL) between cancer survivors and non-cancer individuals using the U.S. National Health Interview Survey.

Methods: Study samples comprised 604 survivors and 6,166 non-cancer individuals. Symptoms included sensation abnormality, pain, fatigue, cognitive disturbance, depression, and anxiety. Physical and mental HRQOL was measured by the Patient-Reported Outcomes Measurement Information System.

Results: Compared with non-cancer individuals, survivors had higher prevalence in sensation abnormality (OR = 2.4; 95% CI = 1.9 to 3.0), pain (OR = 2.1; 95% CI = 1.7 to 2.6), fatigue (OR = 1.4; 95% CI = 1.1 to 1.8), and decremented physical HRQOL (difference = −3.7; 95% CI = −4.7 to −2.6). The prevalence of individual symptoms was significantly associated with decremented physical HRQOL [range = −5.9 (anxiety) to −8.9 (pain)] and mental HRQOL [range = −4.7 (sensation) to −8.4 (depression)]. The association between cancer experience and physical and mental HRQOL was chiefly explained by the prevalence of six symptoms and presence of chronic conditions. Pain (β = −4.0; 95% CI = −4.5 to −3.6) and ≥2 chronic conditions (β = −9.2; 95% CI = −10.2 to −8.2) significantly decremented physical HRQOL. Depression (β = −5.2; 95% CI = −5.8 to −4.6) and ≥2 chronic conditions (β = −3.3; 95% CI = −4.4 to −2.3) significantly decremented mental HRQOL.

Conclusions: Cancer survivors experience more symptom burden than non-cancer individuals, which is associated with more chronic conditions and impaired HRQOL.

Impacts: Interventions to manage symptom prevalence especially for older cancer survivors and survivors with more chronic conditions may improve their HRQOL outcomes. Cancer Epidemiol Biomarkers Prev; 26(7); 1124–32. ©2017 AACR.
Identification of a Novel SYK/c-MYC/MALAT1 Signaling Pathway and Its Potential Therapeutic Value in Ewing Sarcoma
Authors: Sun Haibo , Lin De-Chen , Cao Qi , Pang Brendan , Gae David D. , Lee Victor Kwan Min , Lim Huey Jin , Doan Ngan , Said Jonathan W. , Gery Sigal , Chow Marilynn , Mayakonda Anand , Forscher Charles , Tyner Jeffrey W. , Koeffler H. Phillip
Published: March 2017

Purpose: Ewing sarcoma (EWS) is a devastating soft tissue sarcoma affecting predominantly young individuals. Tyrosine kinases (TK) and associated pathways are continuously activated in many malignancies, including EWS; these enzymes provide candidate therapeutic targets.

Experimental Design: Two high-throughput screens (a siRNA library and a small-molecule inhibitor library) were performed in EWS cells to establish candidate targets. Spleen tyrosine kinase (SYK) phosphorylation was assessed in EWS patients and cell lines. SYK was inhibited by a variety of genetic and pharmacological approaches, and SYK-regulated pathways were investigated by cDNA microarrays. The transcriptional regulation of MALAT1 was examined by ChIP-qPCR, luciferase reporter, and qRT-PCR assays.

Results: SYK was identified as a candidate actionable target through both high-throughput screens. SYK was highly phosphorylated in the majority of EWS cells, and SYK inhibition by a variety of genetic and pharmacologic approaches markedly inhibited EWS cells both in vitro and in vivo. Ectopic expression of SYK rescued the cytotoxicity triggered by SYK-depletion associated with the reactivation of both AKT and c-MYC. A long noncoding RNA, MALAT1, was identified to be dependent on SYK-mediated signaling. Moreover, c-MYC, a SYK-promoted gene, bound to the promoter of MALAT1 and transcriptionally activated MALAT1, which further promoted the proliferation of EWS cells.

Conclusions: This study identifies a novel signaling involving SYK/c-MYC/MALAT1 as a promising therapeutic target for the treatment of EWS. Clin Cancer Res; 23(15); 4376–87. ©2017 AACR.
Lectin, Galactoside-Binding Soluble 3 Binding Protein Promotes 17-N-Allylamino-17-demethoxygeldanamycin Resistance through PI3K/Akt Pathway in Lung Cancer Cell Line
Authors: Woo Jong Kyu , Jang Jeong-Eun , Kang Ju-Hee , Seong Je Kyung , Yoon Yeo Sung , Kim Hyoung-Chin , Lee Sang-Jin , Oh Seung Hyun
Published: March 2017

Heat shock protein 90 (HSP90) stabilizing oncoproteins has been an attractive target in cancer therapy. 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG), an HSP90 inhibitor, was tested in phase II/III clinical trials, but due to lack of efficacy, clinical evaluation of 17-AAG has achieved limited success, which led to resistance to 17-AAG. However, the mechanism of 17-AAG resistance has not clearly been identified. Here, we identified LGALS3BP (Lectin, galactoside-binding soluble 3 binding protein), a secretory glycoprotein, as a 17-AAG resistance factor. In the clinical reports, it was suggested that LGALS3BP was associated with low survival rate, development of cancer progression, and enhancement of metastasis in human cancers. As we confirmed that the LGALS3BP level was increased in 17-AAG–resistant cells (H1299_17R) compared with that of the parental cell line (H1299_17P), knockdown of LGALS3BP expression increased sensitivity to 17-AAG in H1299_17R cells. Overexpression of LGALS3BP also augmented PI3K/Akt and ERK signaling pathways. Furthermore, we determined that the PI3K/Akt signaling pathway was involved in LGALS3BP-mediated 17-AAG resistance in vitro and in vivo, demonstrating that LGALS3BP mediates the resistance against 17-AAG through PI3K/Akt activation rather than ERK activation. These findings suggest that LGALS3BP would be a target to overcome resistance to 17-AAG in lung cancer. For example, the combination of 17-AAG and PI3K/Akt inhibitor would effectively suppress acquired resistance to 17-AAG. In conclusion, targeting of LGALS3BP-mediated–specific survival signaling pathway in resistant cells may provide a novel therapeutic model for the cancer therapy. Mol Cancer Ther; 16(7); 1355–65. ©2017 AACR.
PMP22 Regulates Self-Renewal and Chemoresistance of Gastric Cancer Cells
Authors: Cai Wangyu , Chen Gang , Luo Qicong , Liu Jun , Guo Xiaofeng , Zhang Tian , Ma Fei , Yuan Liang , Li Boan , Cai Jianchun
Published: March 2017

Cancer stem cells possess self-renewal and chemoresistance activities. However, the manner in which these features are maintained remains obscure. We sought to identify cell surface protein(s) that mark self-renewing and chemoresistant gastric cancer cells using the explorer antibody microarray. We identified PMP22, a target gene of the Wnt/β-catenin pathway, as the most upregulated cell surface protein in gastric cancer xenografts exposed to cisplatin (DDP). PMP22 expression was markedly upregulated in tumorspheric cells and declined with differentiation. Infecting gastric cancer cells with lentivirus expressing PMP22 shRNAs reduced proliferation, tumorsphere formation, and chemoresistance to cisplatin in vitro and in NOD/SCID mice. When combined with bortezomib, a PMP22 inhibitor, the chemotherapeutic sensitivity to cisplatin treatment was dramatically increased by inducing cell apoptosis in cultured cells and xenograft mouse models. Finally, mRNA expression levels of PMP22 were detected in 38 tumor specimens from patients who received six cycles of perioperative chemotherapy. A strong correlation between PMP22 level and tumor recurrence was revealed, thus showing a pivotal role of PMP22 in the clinical chemoresistance of gastric cancer. Our study is the first to show the role of PMP22 in gastric cancer stemness and chemoresistance and reveals a potential new target for the diagnosis and treatment of recurrent gastric cancer. Mol Cancer Ther; 16(6); 1187–98. ©2017 AACR.
Prospective Comprehensive Molecular Characterization of Lung Adenocarcinomas for Efficient Patient Matching to Approved and Emerging Therapies
Authors: Jordan Emmet J. , Kim Hyunjae R. , Arcila Maria E. , Barron David , Chakravarty Debyani , Gao JianJiong , Chang Matthew T. , Ni Andy , Kundra Ritika , Jonsson Philip , Jayakumaran Gowtham , Gao Sizhi Paul , Johnsen Hannah C. , Hanrahan Aphrothiti J. , Zehir Ahmet , Rekhtman Natasha , Ginsberg Michelle S. , Li Bob T. , Yu Helena A. , Paik Paul K. , Drilon Alexander , Hellmann Matthew D. , Reales Dalicia N. , Benayed Ryma , Rusch Valerie W. , Kris Mark G. , Chaft Jamie E. , Baselga José , Taylor Barry S. , Schultz Nikolaus , Rudin Charles M. , Hyman David M. , Berger Michael F. , Solit David B. , Ladanyi Marc , Riely Gregory J.
Published: March 2017

Tumor genetic testing is standard of care for patients with advanced lung adenocarcinoma, but the fraction of patients who derive clinical benefit remains undefined. Here, we report the experience of 860 patients with metastatic lung adenocarcinoma analyzed prospectively for mutations in >300 cancer-associated genes. Potentially actionable genetic events were stratified into one of four levels based upon published clinical or laboratory evidence that the mutation in question confers increased sensitivity to standard or investigational therapies. Overall, 37.1% (319/860) of patients received a matched therapy guided by their tumor molecular profile. Excluding alterations associated with standard-of-care therapy, 14.4% (69/478) received matched therapy, with a clinical benefit of 52%. Use of matched therapy was strongly influenced by the level of preexistent clinical evidence that the mutation identified predicts for drug response. Analysis of genes mutated significantly more often in tumors without known actionable mutations nominated STK11 and KEAP1 as possible targetable mitogenic drivers.

Significance: An increasing number of therapies that target molecular alterations required for tumor maintenance and progression have demonstrated clinical activity in patients with lung adenocarcinoma. The data reported here suggest that broader, early testing for molecular alterations that have not yet been recognized as standard-of-care predictive biomarkers of drug response could accelerate the development of targeted agents for rare mutational events and could result in improved clinical outcomes. Cancer Discov; 7(6); 596–609. ©2017 AACR.

See related commentary by Liu et al., p. 555.

This article is highlighted in the In This Issue feature, p. 539
Moderate-Grade Germinal Matrix Haemorrhage Activates Cell Division in the Neonatal Mouse Subventricular Zone
Authors: Dawes William J. , Zhang Xinyu , Fancy Stephen P.J. , Rowitch David , Marino Silvia
Published: March 2017

Precise temporal and spatial control of the neural stem/progenitor cells within the subventricular zone (SVZ) germinal matrix of the brain is important for normal development in the third trimester and the early postnatal period. The high metabolic demands of proliferating germinal matrix precursors, coupled with the flimsy structure of the germinal matrix cerebral vasculature, are thought to account for the high rates of haemorrhage in extremely- and very-low-birth-weight preterm infants. Germinal matrix haemorrhage can commonly extend to intraventricular haemorrhage (IVH). Because neural stem/progenitor cells are sensitive to microenvironmental cues from the ventricular, intermediate, and basal domains within the germinal matrix, haemorrhage has been postulated to impact neurological outcomes through aberration of normal neural stem/progenitor cell behaviour. We developed an animal model of neonatal germinal matrix haemorrhage using stereotactic injection of autologous blood into the mouse neonatal germinal matrix. Pathological analysis at 4 days postinjury showed high rates of intraventricular extension and ventricular dilatation but low rates of parenchymal disruption outside the germinal zone, recapitulating key features of human “Papile grade III” IVH. At 4 days postinjury we observed proliferation in the wall of the lateral ventricle with significantly increased numbers of transient amplifying cells within the SVZ and the corpus callosum. Analysis at 21 days postinjury revealed that cortical development was also affected, with increased neuronal and concomitant reduced oligodendroglial differentiation. At the molecular level, we showed downregulation of the expression of the transmembrane receptor Notch2 in CD133+ve cells of the SVZ, raising the possibility that the burst of precocious proliferation seen in our experimental mouse model and the skewed differentiation could be mediated by downregulation of the Notch pathway within the proximal/ventricular domain. These findings raise the possibility that Notch regulation plays a critical role in mediating the response of the neonatal SVZ to ischaemic and haemorrhagic insults.
Cytological Findings of Ascitic Fluid with a Malignant Ovarian Steroid Cell Tumor: A Case Report and Literature Review
Authors: Kosaka Nobuaki , Hasegawa Kiyoshi , Kiuchi Kaori , Ochiai Shoko , Nagai Tamiko , Machida Hiromi , Imai Yasuo , Fukasawa Ichio
Published: March 2017

Background: Ovarian steroid cell tumors (SCTs) are rare and usually benign, although 25-43% are reportedly malignant. The cytologic findings of these rare ovarian tumors have almost never been reported. Case: We report a rare case of a malignant ovarian SCT with peritoneal dissemination and malignant ascites in a 40-year-old woman. Her tumor was classified as stage IIB (pT2bNoM0) according to the FIGO (International Federation of Gynecology and Obstetrics) classification system, and she was treated with adjuvant chemotherapy following staging laparotomy. Cytology of the ascitic fluid revealed large, polygonal-to-round cells and multinucleated cells with atypia, appearing in clusters with slight overlapping or as isolated tumor cells. Numerous tumor cells had small central round or eccentric nuclei with conspicuous nucleoli, and a moderate-to-abundant amount of cytoplasm, varying from granular and eosinophilic to pale and multivacuolated (foamy), with cannibalism formations. The nuclear chromatin was fine and granular, with irregular distribution and nuclear-membrane thickening. Conclusion: These may be the first reported cytology results for ascites with a malignant SCT. Our patient's cytological ascitic findings, rather than the histopathologic features of the original and disseminated tumors, represent the malignant features of the tumor.
Idiopathic Pulmonary Fibrosis in Switzerland: Diagnosis and Treatment
Authors: Funke-Chambour Manuela , Azzola Andrea , Adler Dan , Barazzone-Argiroffo Constance , Benden Christian , Boehler Annette , Bridevaux Pierre-Olivier , Brutsche Martin , Clarenbach Christian F. , Hostettler Katrin , Kleiner-Finger Rebekka , Nicod Laurent P. , Soccal Paola M. , Tamm Michael , Geiser Thomas , Lazor Romain
Published: March 2017

Idiopathic pulmonary fibrosis (IPF) is a severe progressive and irreversible lung disease. Novel antifibrotic drugs that slow disease progression are now available. However, many issues regarding patient management remain unanswered, such as the choice between available drugs, their use in particular subgroups and clinical situations, time of treatment onset, termination, combination or switch, or nonpharmacologic management. To guide Swiss respiratory physicians in this evolving field still characterized by numerous areas of uncertainty, the Swiss Working Group for interstitial and rare lung diseases of the Swiss Respiratory Society provides a position paper on the diagnosis and treatment of IPF.
Effect of L-Carnitine Supplementation on Reverse Remodeling in Patients with Ischemic Heart Disease Undergoing Coronary Artery Bypass Grafting: A Randomized, Placebo-Controlled Trial
Authors: da Silva Guimarães Sheila , de Souza Cruz Wanise , da Silva Licinio , Maciel Gabrielle , Huguenin Ana Beatriz , de Carvalho Monicque , Costa Bárbara , da Silva Geisiane , da Costa Carlos , D'Ippolito João Alvaro , Colafranceschi Alexandre , Scalco Fernanda , Boaventura Gilson
Published: March 2017

During cardiac failure, cardiomyocytes have difficulty in using the substrates to produce energy. L-carnitine is a necessary nutrient for the transport of fatty acids that are required for generating energy. Coronary artery graft surgery reduces the plasma levels of L-carnitine and increases the oxidative stress. This study demonstrates the effect of L-carnitine supplementation on the reverse remodeling of patients undergoing coronary artery bypass graft. Patients with ischemic heart failure who underwent coronary graft surgery were randomized to group A - supplemented with L-carnitine or group B controls. Left ventricular ejection fraction, left ventricular systolic and diastolic diameters were assessed preoperatively, 60 and 180 days after surgery. Our study included 28 patients (26 [93.0%] males) with a mean age ± SD of 58.1 ± 10.5 years. The parameters for the evaluation of reverse remodeling did not improve after 60 and 180 days of coronary artery bypass grafting in comparison between groups (p > 0.05). Evaluation within the L-carnitine group showed a 37.1% increase in left ventricle ejection fraction (p = 0.002) and 14.3% (p = 0.006) and 3.3% (p > 0.05) reduction in systolic and diastolic diameters, respectively. L-carnitine supplementation at a dose of 50 mg/kg combined with artery bypass surgery did not demonstrate any additional benefit in reverse remodeling. However, evaluation within the L-carnitine group may indicate a clinical benefit of L-carnitine supplementation.
The Effect of Ineffective Esophageal Motility on Gastroesophageal Reflux Disease
Authors: Kasamatsu Shingo , Matsumura Tomoaki , Ohta Yuki , Hamanaka Shinsaku , Ishigami Hideaki , Taida Takashi , Okimoto Kenichiro , Saito Keiko , Maruoka Daisuke , Nakagawa Tomoo , Katsuno Tatsuro , Fujie Mai , Kikuchi Atsuko , Arai Makoto
Published: March 2017

Background/Aims: Ineffective esophageal motility (IEM) is the most common gastrointestinal motility disorder. Studies have reported that IEM is related to gastroesophageal reflux disease (GERD). However, the relationship between IEM and GERD remains uncertain. This study aims to clarify this relationship retrospectively. Methods: We analyzed 195 subjects who underwent high-resolution manometry between January 2011 and September 2016. Of these subjects, 72 had normal esophageal motility (NEM) and 26 had IEM. We investigated differences in the clinical characteristics, severity and duration of GERD symptoms, and comorbid extra-esophageal symptoms of the subjects. Comorbid extra-esophageal symptoms were assessed with the Gastrointestinal Symptom Rating Scale questionnaire. Investigation-defined GERD was diagnosed when erosive esophagitis or abnormal multichannel intraluminal impedance was present. Results: We found no significant difference in the prevalence of IEM between patients with and without GERD (37.5 and 21.1%, respectively; p = 0.174). There were no differences in age, gender, body mass index, presence of hiatal hernia, or duration of GERD between the groups. Compared to patients with NEM, those with IEM were significantly less likely to have comorbid extra-esophageal symptoms (p < 0.05). Conclusion: There is no association between IEM and GERD.
СИНТЕЗ ТА АНТИБАКТЕРІАЛЬНІ ВЛАСТИВОСТІ 4-АМІНОФЕНІЛСУЛЬФОНАМІДУ, ІММОБІЛІЗОВАНОГО НА ПОЛІМЕРНОМУ НОСІЇ
Authors: Toropin V. N. , Kremenchutskiy G. N. , Burmistrov K. S. , Shunkevich A. A. , Polikarpov A. P.
Published: March 2017

Мета роботи. У сучасних умовах іммобілізація лікарських засобів на полімерних носіях набуває все більшого значення, що пов’язане з вимогами до зменшення токсичності та пролонгації дії препаратів. Відома іммобілізація сульфаніламідних препаратів на стиромалі, метакрилатних полімерних матрицях, де фармакологічно активний сульфаніламід легко вивільняється з полімеру при застосуванні, в результаті кислотного гідролізу. Разом з тим спостерігається, що іммобілізовані сульфаніламіди, отримані на основі амінометильованого співполімеру стиролу з дивінілбензолом, незважаючи на стійкість до гідролізу, зберігають антибактеріальні властивості. З метою розширення прикладів ковалентної іммобілізації сульфаніламідів нами синтезовані 4-амінофенілсульфонаміди на гранульній і волокнистій формах співполімерів стиролу з дивінілбензолом через місткову групу SO2.Матеріали і методи. Як вихідну сировину використано макропористий гранульний співполімер стиролу з дивінілбензолом і сульфовані волокнисті форми прищепленого до поліпропіленової нитки співполімеру стиролу з дивінілбензолом. Сульфохлоруванням цих співполімерів отримано полімерні сульфохлориди, які використовували в реакції з 4-амінофенілсульфонамідом. Антибактеріальні властивості матеріалу досліджені за визначенням зон пригнічення росту тест-мікроорганізмів E.coli К-12 на поживному середовищі.Результати й обговорення. Будову синтезованих іммобілізованих 4-амінофенілсульфонамідів доведено методом ІЧ спектроскопії. Показано, що такі матеріали проявляють виражені антибактеріальні властивості щодо тест-культури мікроорганізмів E. coli К-12, незважаючи на їхню стійкість до гідролізу.Висновки. Зроблено припущення, що гідроліз матеріалів перебігає при специфічному ферментативному каталізі на поживному середовищі виділенням 4-амінофенілсульфонаміду.
Lipoprotein(a) and HIV
Authors: Enkhmaa Byambaa , Anuurad Erdembileg , Zhang Wei , Li Chin-Shang , Kaplan Robert , Lazar Jason , Merenstein Dan , Karim Roksana , Aouizerat Brad , Cohen Mardge , Butler Kenneth , Pahwa Savita , Ofotokun Igho , Adimora Adaora A. , Golub Elizabeth , Berglund Lars
Published: March 2017

Objective—

In the general population, lipoprotein(a) [Lp(a)] has been established as an independent causal risk factor for cardiovascular disease. Lp(a) levels are to a major extent regulated by a size polymorphism in the apolipoprotein(a) [apo(a)] gene. The roles of Lp(a)/apo(a) in human immunodeficiency virus (HIV)–related elevated cardiovascular disease risk remain unclear.

Approach and Results—

The associations between total plasma Lp(a) level, allele-specific apo(a) level, an Lp(a) level carried by individual apo(a) alleles, and common carotid artery intima–media thickness were assessed in 150 HIV-infected and 100 HIV-uninfected women in the WIHS (Women’s Interagency HIV Study). Linear regression analyses with and without adjustments were used. The cohort was young (mean age, ≈31 years), with the majority being Blacks (≈70%). The prevalence of a small size apo(a) (≤22 Kringle repeats) or a high Lp(a) level (≥30 mg/dL) was similar by HIV status. Total plasma Lp(a) level (
P
=0.029) and allele-specific apo(a) level carried by the smaller apo(a) sizes (
P
=0.022) were significantly associated with carotid artery intima–media thickness in the HIV-infected women only. After accounting for confounders (age, race, smoking, body mass index, blood pressure, hepatitis C virus coinfection, menopause, plasma lipids, treatment status, CD4
+
T cell count, and HIV/RNA viral load), the association remained significant for both Lp(a) (
P
=0.035) and allele-specific apo(a) level carried by the smaller apo(a) sizes (
P
=0.010) in the HIV-infected women. Notably, none of the other lipids/lipoproteins was associated with carotid artery intima–media thickness.

Conclusions—

Lp(a) and allele-specific apo(a) levels predict carotid artery intima–media thickness in HIV-infected young women. Further research is needed to identify underlying mechanisms of an increased Lp(a) atherogenicity in HIV infection.
Human MicroRNA-548p Decreases Hepatic Apolipoprotein B Secretion and Lipid Synthesis
Authors: Zhou Liye , Hussain M. Mahmood
Published: March 2017

Objective—

MicroRNAs (miRs) play important regulatory roles in lipid metabolism. Apolipoprotein B (ApoB), as the only essential scaffolding protein in the assembly of very-low-density lipoproteins, is a target to treat hyperlipidemia and atherosclerosis. We aimed to find out miRs that reduce apoB expression.

Approach and Results—

Bioinformatic analyses predicted that hsa-miR-548p can interact with apoB mRNA. MiR-548p or control miR was transfected in human and mouse liver cells to test its role in regulating apoB secretion and mRNA expression levels. Site-directed mutagenesis was used to identify the interacting site of miR-548p in human apoB 3′-untranslated region. Fatty acid oxidation and lipid syntheses were examined in miR-548p overexpressing cells to investigate its function in lipid metabolism. We observed that miR-548p significantly reduces apoB secretion from human hepatoma cells and primary hepatocytes. Mechanistic studies showed that miR-548p interacts with the 3′-untranslated region of human apoB mRNA to enhance post-transcriptional degradation. Bioinformatic algorithms suggested 2 potential binding sites of miR-548p on human apoB mRNA. Site-directed mutagenesis studies revealed that miR-548p targets site I involving both seed and supplementary sequences. MiR-548p had no effect on fatty acid oxidation but significantly decreased lipid synthesis in human hepatoma cells by reducing HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) and ACSL4 (Acyl-CoA synthetase long-chain family member 4) enzymes involved in cholesterol and fatty acid synthesis. In summary, miR-548p reduces lipoprotein production and lipid synthesis by reducing expression of different genes in human liver cells.

Conclusions—

These studies suggest that miR-548p regulates apoB secretion by targeting mRNA. It is likely that it could be useful in treating atherosclerosis, hyperlipidemia, and hepatosteatosis.