bluuebunny/crossref_metadata_2025 huggingface dataset:
Towards European harmonisation of contagious equine metritis diagnosis through interlaboratory trials
Authors: Petry Sandrine , Breuil Marie‐France , Duquesne Fabien , Laugier Claire
Published: April 2018

The performance of culture and PCR methods routinely used to diagnose contagious equine metritis (CEM) was evaluated and compared by two interlaboratory trials involving a total of 24 European laboratories, including 22 National Reference Laboratories for CEM. Samples were swab specimens artificially contaminated with bacteria present in the genital tract of Equidae, some with and some without Taylorella equigenitalis, the causative agent of CEM, and T asinigenitalis, responsible for possible misidentification as T equigenitalis. Throughout both interlaboratory trials, PCR performed better in terms of specificity and sensitivity than the culture method, supporting the assertion that PCR should be accepted for CEM diagnosis. However, the culture performance during the second interlaboratory trial was better than during the first one, suggesting that the expertise of participants improved. This reveals the advantage of regular interlaboratory trials to constantly improve the expertise of laboratories. It also shows the need to develop new culture media that are more selective and/or better geared to the metabolism of T equigenitalis in order to improve the bacteriological diagnosis of CEM.
Ameliorating effects of Sporidiobolus pararoseus extract on dyslipidemia in mice with high fat diet induced obesity
Authors: Du Chao , Ying Danyu , Guo Yahui , Cheng Yuliang , Han Mei , Zhang Weiguo , Qian He
Published: April 2018

The study investigated how an extract of Sporidiobolus pararoseus (S.p.) affects lipid metabolism in Kunming mice that were obese as a result of being fed a high-fat diet; the control group were administered Max EPA fish oil. Ten mice were randomly selected from a pool of 60 mice for the control group and the remaining 50 mice were fed with a high-fat diet to establish a dyslipidemia model. After 4 weeks, these 50 mice were randomly distributed among 5 groups: high-fat model group; Max EPA group; and 3 groups of mice fed different doses of S.p. extract (low dose, medium dose, and high dose). After 8 weeks, the mice were sacrificed and the relevant parameters were measured. Compared with the high-fat model group, the group administered the high dose of S.p. extract showed significantly decreased body mass and serum levels of total cholesterol, triglycerides, and low-density lipoprotein cholesterol, and increased levels of high-density lipoprotein cholesterol. The results from RT-PCR showed that the mRNA expression of sterol regulatory element-binding protein 1c, fatty acid synthesis enzyme, and acetyl-CoA carboxylase was lower in the groups supplemented with S.p. extract than in the high-fat model group, whereas the expression of carnitine palmitoyltransferase 1 was higher in the group supplemented with S.p. extract than in the high-fat model group. Our results suggest that taking S.p. extract could benefit patients with dyslipidemia. Therefore, S.p. extract should be developed as a dietary supplement to improve lipid metabolism in obese people.
Movement-based methods to infer parturition events in migratory ungulates
Authors: Cameron Matthew D. , Joly Kyle , Breed Greg A. , Parrett Lincoln S. , Kielland Knut
Published: April 2018

Long-distance migrations by ungulate species are a globally imperiled natural phenomenon and conservation of them requires monitoring population vital rates. Satellite telemetry tracking is widely used for understanding the spatial distribution and movement of animals, especially migratory animals in remote environments. Recently, analytical methods have been developed to infer parturition events from movement data in multiple species that calve in isolation, but to date such methods have not been tested on animals that both migrate and spatially aggregate during calving. We applied two movement-based methods developed to infer parturition in nonmigratory woodland caribou (Rangifer tarandus caribou (Gmelin, 1788)) to 241 reproductive seasons spanning 6 years of GPS data from migratory barren-ground caribou (Rangifer tarandus granti J.A. Allen, 1902). We compared results from both methods to data from aerial surveys of collared females during the calving period. We found that each movement-based method had ∼80% overall accuracy to identify calving events, with interannual variation ranging from 61% to 100%. When we considered instances when the two analytical methods agreed on parturition outcome, the accuracy increased to 89% with an annual range of 73%–100%. Using these methods, we identified marked interannual differences in peak calving dates and higher parturition rates than previously reported for this caribou herd. The successful application of these analyses to a migratory, gregarious ungulate suggests a broader applicability of the methodology.
IN-SITU DETECTION OF HEAVY METAL POLLUTION IN SEAWATER WITH DIAMOND COATED ELECTRODES
Authors: ZHAO BIN , LI JIA , YU XIANG , ZHANG JING , REN YI
Published: April 2018

Heavy metal pollution endangers seawater and there is urgent need for the development of effective detectors that can provide warning of heavy metal pollution. Anodic stripping voltammetry is applicable for the detection of heavy metal pollution in sea water, but it suffers from two problems that are associated with the mercury electrode used: one is insufficient sensitivity and the other is secondary pollution caused by toxic mercury. In this work, we employed boron-doped diamond electrode as an alternative to mercury electrode for the detection of heavy metals. The BDD electrode was fabricated and its electrochemical properties were ascertained. The results of this work showed that: (1) the electrode prepared has a wide electrochemical window (4.2 V) and low background current ([Formula: see text]A). (2) multiple heavy metals (Pb[Formula: see text], Cd[Formula: see text], Zn[Formula: see text] and Cu[Formula: see text]) in seawater samples are detected simultaneously with the optimized electrode, with high sensitivity and good repeatability. (3) the repeatability of the detection meets the values stipulated in the national standard. The detection period is less than 15[Formula: see text]min, and in situ monitoring of heavy metals in seawater can be achieved by automatic sampling and wireless data transmission.
Speech emotion recognition
Authors: Schuller Björn W.
Published: April 2018

Tracing 20 years of progress in making machines hear our emotions based on speech signal properties.
More than the code
Authors: Tenenberg Josh , Roth Wolff-Michael , Chinn Donald , Jornet Alfredo , Socha David , Walter Skip
Published: April 2018

A teacher and students coding together make explicit the unwritten rules of programming.
Enhanced Audit Strategies for Collaborative and Accountable Data Sharing in Social Networks
Authors: Bahri Leila , Carminati Barbara , Ferrari Elena , Bianco Andrea
Published: April 2018

Data sharing and access control management is one of the issues still hindering the development of decentralized online social networks (DOSNs), which are now gaining more research attention with the recent developments in P2P computing, such as the secure public ledger–based protocols (Blockchains) for monetary systems. In a previous work, we proposed an initial audit–based model for access control in DOSNs. In this article, we focus on enhancing the audit strategies and the privacy issues emerging from records kept for audit purposes. We propose enhanced audit and collaboration strategies, for which experimental results, on a real online social network graph with simulated sharing behavior, show an improvement in the detection rate of bad behavior of more than 50% compared to the basic model. We also provide an analysis of the related privacy issues and discuss possible privacy-preserving alternatives.
Dynamic Optimization of the Level of Operational Effectiveness of a CSOC Under Adverse Conditions
Authors: Shah Ankit , Ganesan Rajesh , Jajodia Sushil , Cam Hasan
Published: April 2018

The analysts at a cybersecurity operations center (CSOC) analyze the alerts that are generated by intrusion detection systems (IDSs). Under normal operating conditions, sufficient numbers of analysts are available to analyze the alert workload. For the purpose of this article, this means that the cybersecurity analysts in each shift can fully investigate each and every alert that is generated by the IDSs in a reasonable amount of time and perform their normal tasks in a shift. Normal tasks include analysis time, time to attend training programs, report writing time, personal break time, and time to update the signatures on new patterns in alerts as detected by the IDS. There are several disruptive factors that occur randomly and can adversely impact the normal operating condition of a CSOC, such as (1) higher alert generation rates from a few IDSs, (2) new alert patterns that decrease the throughput of the alert analysis process, and (3) analyst absenteeism. The impact of the preceding factors is that the alerts wait for a long duration before being analyzed, which impacts the level of operational effectiveness (LOE) of the CSOC. To return the CSOC to normal operating conditions, the manager of a CSOC can take several actions, such as increasing the alert analysis time spent by analysts in a shift by canceling a training program, spending some of his own time to assist the analysts in alert investigation, and calling upon the on-call analyst workforce to boost the service rate of alerts. However, additional resources are limited in quantity over a 14-day work cycle, and the CSOC manager must determine when and how much action to take in the face of uncertainty, which arises from both the intensity and the random occurrences of the disruptive factors. The preceding decision by the CSOC manager is nontrivial and is often made in an ad hoc manner using prior experiences. This work develops a reinforcement learning (RL) model for optimizing the LOE throughout the entire 14-day work cycle of a CSOC in the face of uncertainties due to disruptive events. Results indicate that the RL model is able to assist the CSOC manager with a decision support tool to make better decisions than current practices in determining when and how much resource to allocate when the LOE of a CSOC deviates from the normal operating condition.
Mining Significant Microblogs for Misinformation Identification
Authors: Liu Qiang , Yu Feng , Wu Shu , Wang Liang
Published: April 2018

With the rapid growth of social media, massive misinformation is also spreading widely on social media, e.g., Weibo and Twitter, and brings negative effects to human life. Today, automatic misinformation identification has drawn attention from academic and industrial communities. Whereas an event on social media usually consists of multiple microblogs, current methods are mainly constructed based on global statistical features. However, information on social media is full of noise, which should be alleviated. Moreover, most of the microblogs about an event have little contribution to the identification of misinformation, where useful information can be easily overwhelmed by useless information. Thus, it is important to mine significant microblogs for constructing a reliable misinformation identification method. In this article, we propose an attention-based approach for identification of misinformation (AIM). Based on the attention mechanism, AIM can select microblogs with the largest attention values for misinformation identification. The attention mechanism in AIM contains two parts: content attention and dynamic attention. Content attention is the calculated-based textual features of each microblog. Dynamic attention is related to the time interval between the posting time of a microblog and the beginning of the event. To evaluate AIM, we conduct a series of experiments on the Weibo and Twitter datasets, and the experimental results show that the proposed AIM model outperforms the state-of-the-art methods.
Learning a Multi-Concept Video Retrieval Model with Multiple Latent Variables
Authors: Mazaheri Amir , Gong Boqing , Shah Mubarak
Published: April 2018

Effective and efficient video retrieval has become a pressing need in the “big video” era. The objective of this work is to provide a principled model for computing the ranking scores of a video in response to one or more concepts, where the concepts could be directly supplied by users or inferred by the system from the user queries. Indeed, how to deal with multi-concept queries has become a central component in modern video retrieval systems that accept text queries. However, it has been long overlooked and simply implemented by weighted averaging of the corresponding concept detectors’ scores. Our approach, which can be considered as a latent ranking SVM, integrates the advantages of various recent works in text and image retrieval, such as choosing ranking over structured prediction, modeling inter-dependencies between querying concepts, and so on. Videos consist of shots, and we use latent variables to account for the mutually complementary cues within and across shots. Concept labels of shots are scarce and noisy. We introduce a simple and effective technique to make our model robust to outliers. Our approach gives superior performance when it is tested on not only the queries seen at training but also novel queries, some of which consist of more concepts than the queries used for training.
A Generic Approach to Video Buffer Modeling Using Discrete-Time Analysis
Authors: Burger Valentin , Zinner Thomas , Dinh-Xuan Lam , Wamser Florian , Tran-Gia Phuoc
Published: April 2018

The large share of traffic in the Internet generated by video streaming services puts high loads on access and aggregation networks, resulting in high costs for the content delivery infrastructure. To reduce the bandwidth consumed while maintaining a high playback quality, video players use policies that control and limit the buffer level by using thresholds for pausing and continuing the video download. This allows shaping the bandwidth consumed by video streams and limiting the traffic wasted in case of playback abortion. Especially in mobile scenarios, where the throughput can be highly variant, the buffer policy can have a high impact on the probability of interruptions during video playback. To find the optimal setting for the buffer policy in each network condition, the relationship between the parameters of the buffer policy, the network throughput dynamics, and the corresponding video playback behavior needs to be understood. To this end, we model the video buffer as GI/GI/1 queue with
pq
-policy using discrete-time analysis. By studying the stochastic properties of the buffer-level distribution, we are able to accurately evaluate the impact of network and video bitrate dynamics on the video playback quality based on the buffer policy. We find a fundamental relationship between the bandwidth variation and the expected interarrival time of segments, meaning that overproportionately more bandwidth is necessary to prevent stalling events for high bandwidth variation. The proposed model further allows to optimize the trade-off between the traffic wasted in case of video abortion and video streaming quality experienced by the user.
DeepProduct
Authors: Jiang Yu-Gang , Li Minjun , Wang Xi , Liu Wei , Hua Xian-Sheng
Published: April 2018

Features extracted by deep networks have been popular in many visual search tasks. This article studies deep network structures and training schemes for mobile visual search. The goal is to learn an effective yet portable feature representation that is suitable for bridging the domain gap between mobile user photos and (mostly) professionally taken product images while keeping the computational cost acceptable for mobile-based applications. The technical contributions are twofold. First, we propose an alternative of the contrastive loss popularly used for training deep Siamese networks, namely robust contrastive loss, where we relax the penalty on some positive and negative pairs to alleviate overfitting. Second, a simple multitask fine-tuning scheme is leveraged to train the network, which not only utilizes knowledge from the provided training photo pairs but also harnesses additional information from the large ImageNet dataset to regularize the fine-tuning process. Extensive experiments on challenging real-world datasets demonstrate that both the robust contrastive loss and the multitask fine-tuning scheme are effective, leading to very promising results with a time cost suitable for mobile product search scenarios.
Toward Personalized Activity Level Prediction in Community Question Answering Websites
Authors: Liu Zhenguang , Xia Yingjie , Liu Qi , He Qinming , Zhang Chao , Zimmermann Roger
Published: April 2018

Community Question Answering (CQA) websites have become valuable knowledge repositories. Millions of internet users resort to CQA websites to seek answers to their encountered questions. CQA websites provide information far beyond a search on a site such as Google due to (1) the plethora of high-quality answers, and (2) the capabilities to post new questions toward the communities of domain experts. While most research efforts have been made to identify experts or to preliminarily detect potential experts of CQA websites, there has been a remarkable shift toward investigating how to keep the engagement of experts. Experts are usually the major contributors of high-quality answers and questions of CQA websites. Consequently, keeping the expert communities active is vital to improving the lifespan of these websites. In this article, we present an algorithm termed PALP to predict the activity level of expert users of CQA websites. To the best of our knowledge, PALP is the first approach to address a personalized activity level prediction model for CQA websites. Furthermore, it takes into consideration user behavior change over time and focuses specifically on expert users. Extensive experiments on the Stack Overflow website demonstrate the competitiveness of PALP over existing methods.
Commenting on code, considering data's bottleneck
Authors: Torres Edwin , Saba Walid
Published: April 2018

The
Communications
Web site, http://cacm.acm.org, features more than a dozen bloggers in the BLOG@CACM community. In each issue of
Communications
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Edwin Torres considers the enduring value of code comments, while Walid Saba wonders if we have overreacted to the knowledge acquisition bottleneck.
Finding a healthier approach to managing medical data
Authors: Greengard Samuel
Published: April 2018

Researchers are exploring ways to put medical data to greater use while better protecting privacy.
Using functions for easier programming
Authors: Savage Neil
Published: April 2018

Functional programming languages automate many of the details underlying specific operations.
Free press
Authors: MacLeod Ken
Published: April 2018

From the intersection of computational science and technological speculation, with boundaries limited only by our ability to imagine what could be.

When all online news and comment can be digitally manipulated, some might recall a more trustworthy way to spread the word.
Internet freedom in West Africa
Authors: Brooks Richard R. , Yu Lu , Fu Yu , Hambolu Oluwakemi , Gaynard John , Owono Julie , Yepmou Archippe , Blanc Felix
Published: April 2018

The U.S. State Department's Internet Freedom agenda is being adapted to help them communicate without DNS and IP address filtering.
Is the law ready for driverless cars?
Authors: Calo Ryan
Published: April 2018

Yes, with one big exception.
The march into the black hole of complexity
Authors: Lawson Harold "Bud"
Published: April 2018

Addressing the root causes of rapidly increasing software complexity.
Phosphodiesterase 4B knockout prevents skeletal muscle atrophy in rats with burn injury
Authors: Balasubramaniam Ambikaipakan , Sheriff Sulaiman , Friend Lou Ann , James J. Howard
Published: April 2018

The phosphodiesterase 4 (PDE4)-cAMP pathway plays a predominant role in mediating skeletal muscle proteolysis in burn injury. The present investigations to determine the PDE4 isoform(s) involved in this action revealed that burn injury increased the expression of rat skeletal muscle PDE4B mRNA by sixfold but had little or no effect on expression of other PDE4 isoforms. These observations led us to study the effects of burn in PDE4B knockout (KO) rats. As reported by us previously, burn injury significantly increased extensor digitorum longus (EDL) muscle total and myofibrillar proteolysis in wild-type (WT) rats, but there were no significant effects on either total or myofibrillar protein breakdown in EDL muscle of PDE4B KO rats with burn injury. Moreover, burn injury increased PDE4 activity in the skeletal muscle of WT rats, but this was reduced by >80% in PDE4B KO rats. Also, burn injury decreased skeletal muscle cAMP concentration in WT rats but had no significant effects in the muscles of PDE4B KO rats. Incubation of the EDL muscle of burn-PDE4B KO rats with an inhibitor of the exchange factor directly activated by cAMP, but not with a protein kinase A inhibitor, eliminated the protective effects of PDE4B KO on EDL muscle proteolysis and increased muscle proteolysis to the same extent as in the EDL of burn-WT rats. These novel findings confirm a major role for PDE4B in skeletal muscle proteolysis in burn injury and suggest that an innovative therapy based on PDE4B-selective inhibitors could be developed to treat skeletal muscle cachexia in burn injury without the fear of causing emesis, which is associated with PDE4D inhibition.
Chronic kidney disease, uremic milieu, and its effects on gut bacterial microbiota dysbiosis
Authors: Chaves Lee D. , McSkimming Daniel I. , Bryniarski Mark A. , Honan Amanda M. , Abyad Sham , Thomas Shruthi A. , Wells Steven , Buck Michael , Sun Yijun , Genco Robert J. , Quigg Richard J. , Yacoub Rabi
Published: April 2018

Several lines of evidence suggest that gut bacterial microbiota is altered in patients with chronic kidney disease (CKD), though the mechanism of which this dysbiosis takes place is not well understood. Recent studies delineated changes in gut microbiota in both CKD patients and experimental animal models using microarray chips. We present 16S ribosomal RNA gene sequencing of both stool pellets and small bowel contents of C57BL/6J mice that underwent a remnant kidney model and establish that changes in microbiota take place in the early gastrointestinal tract. Increased intestinal urea concentration has been hypothesized as a leading contributor to dysbiotic changes in CKD. We show that urea transporters (UT)-A and UT-B mRNA are both expressed throughout the whole gastrointestinal tract. The noted increase in intestinal urea concentration appears to be independent of UTs’ expression. Urea supplementation in drinking water resulted in alteration in bacterial gut microbiota that is quite different than that seen in CKD. This indicates that increased intestinal urea concentration might not fully explain the CKD- associated dysbiosis.
Signals driving the adaptation of saccades that require spatial updating
Authors: Soetedjo Robijanto
Published: April 2018

Saccades adapt to persistent natural or artificially imposed dysmetrias. The characteristics and circuitry of saccade adaptation have been revealed using a visually guided task (VGT) where the vectors of the target step and the intended saccade command are the same. However, in real life, another saccade occasionally intervenes before the saccade to the target occurs. This necessitates an updating of the intended saccade to account for the intervening saccadic displacement, which dissociates the visual target signal and the intended saccade command. We determined whether the adaptation process is similar for VGT and updated saccades by studying the transfer of adaptation between them. The ultimate visual target was dissociated from the intended saccade command with double-step saccade tasks (DSTs) in which two targets are flashed sequentially at different locations while the monkey maintains fixation. The resulting saccades toward the first and second targets occur in the dark. The transfer of visually guided saccade adaptation to the second saccades of a DST and vice versa depended on the eccentricity of the second visual target, and not the second saccade command. If a target with the same eccentricity as the adapted target appears briefly during the intersaccadic interval of a DST, more adaptation transfers. Because a brief appearance of the visual target either before the first saccade or during the intersaccadic interval influences how much adaptation transfer the second saccade will express, the processing of adaptation and DST updating may overlap.

NEW & NOTEWORTHY Adaptation and the spatial updating of saccades are thought to be independent processes. When we dissociate the visual target and the intended saccade command, the transfer of visually guided saccade adaptation to the saccades of the double-step saccade tasks (DST) and vice versa is driven by a visual not motor error. The visual target has an effect until the second saccade of a DST occurs. Therefore, the processing of adaptation and the spatial updating of saccades may overlap.
Stable long-term BCI-enabled communication in ALS and locked-in syndrome using LFP signals
Authors: Milekovic Tomislav , Sarma Anish A. , Bacher Daniel , Simeral John D. , Saab Jad , Pandarinath Chethan , Sorice Brittany L. , Blabe Christine , Oakley Erin M. , Tringale Kathryn R. , Eskandar Emad , Cash Sydney S. , Henderson Jaimie M. , Shenoy Krishna V. , Donoghue John P. , Hochberg Leigh R.
Published: April 2018

Restoring communication for people with locked-in syndrome remains a challenging clinical problem without a reliable solution. Recent studies have shown that people with paralysis can use brain-computer interfaces (BCIs) based on intracortical spiking activity to efficiently type messages. However, due to neuronal signal instability, most intracortical BCIs have required frequent calibration and continuous assistance of skilled engineers to maintain performance. Here, an individual with locked-in syndrome due to brain stem stroke and an individual with tetraplegia secondary to amyotrophic lateral sclerosis (ALS) used a simple communication BCI based on intracortical local field potentials (LFPs) for 76 and 138 days, respectively, without recalibration and without significant loss of performance. BCI spelling rates of 3.07 and 6.88 correct characters/minute allowed the participants to type messages and write emails. Our results indicate that people with locked-in syndrome could soon use a slow but reliable LFP-based BCI for everyday communication without ongoing intervention from a technician or caregiver.

NEW & NOTEWORTHY This study demonstrates, for the first time, stable repeated use of an intracortical brain-computer interface by people with tetraplegia over up to four and a half months. The approach uses local field potentials (LFPs), signals that may be more stable than neuronal action potentials, to decode participants’ commands. Throughout the several months of evaluation, the decoder remained unchanged; thus no technical interventions were required to maintain consistent brain-computer interface operation.
Mechanisms of Acquired Resistance to Trastuzumab Emtansine in Breast Cancer Cells
Authors: Li Guangmin , Guo Jun , Shen Ben-Quan , Yadav Daniela Bumbaca , Sliwkowski Mark X. , Crocker Lisa M. , Lacap Jennifer A. , Phillips Gail D. Lewis
Published: April 2018

The receptor tyrosine kinase HER2 is overexpressed in approximately 20% of breast cancer, and its amplification is associated with reduced survival. Trastuzumab emtansine (Kadcyla, T-DM1), an antibody–drug conjugate that is comprised of trastuzumab covalently linked to the antimitotic agent DM1 through a stable linker, was designed to selectively deliver DM1 to HER2-overexpressing tumor cells. T-DM1 is approved for the treatment of patients with HER2-positive metastatic breast cancer following progression on trastuzumab and a taxane. Despite the improvement in clinical outcome, many patients who initially respond to T-DM1 treatment eventually develop progressive disease. The mechanisms that contribute to T-DM1 resistance are not fully understood. To this end, we developed T-DM1–resistant in vitro models to examine the mechanisms of acquired T-DM1 resistance. We demonstrate that decreased HER2 and upregulation of MDR1 contribute to T-DM1 resistance in KPL-4 T-DM1–resistant cells. In contrast, both loss of SLC46A3 and PTEN deficiency play a role in conferring resistance in BT-474M1 T-DM1–resistant cells. Our data suggest that these two cell lines acquire resistance through distinct mechanisms. Furthermore, we show that the KPL-4 T-DM1 resistance can be overcome by treatment with an inhibitor of MDR1, whereas a PI3K inhibitor can rescue PTEN loss–induced resistance in T-DM1–resistant BT-474M1 cells. Our results provide a rationale for developing therapeutic strategies to enhance T-DM1 clinical efficacy by combining T-DM1 and other inhibitors that target signaling transduction or resistance pathways. Mol Cancer Ther; 17(7); 1441–53. ©2018 AACR.
Selective Targeting and Eradication of LGR5+ Cancer Stem Cells Using RSPO-Conjugated Doxorubicin Liposomes
Authors: Cao Jing , Li Chong , Wei Xiaohui , Tu Meiqing , Zhang Yan , Xu Fengwei , Xu Yuhong
Published: April 2018

Cancer stem cells (CSC) that may account for only a small fraction of tumor mass were found to play crucial roles during tumor initiating, progression, and metastasis. However, they are usually difficult to be treated and notoriously resilient to drug eradication. In this study, we aimed at the Wnt signaling characteristic of CSCs and designed a liposomal drug delivery system to target CSCs. Liposomes decorated with RSPO1 on the surface were constructed for specific interactions with the Wnt pathway coreceptor LGR5. Doxorubicin carried by the RSPO1-liposomes was more effective at lower concentrations than the same drug loaded in PEG-liposomes. More importantly, we showed using a patient-derived xenograft tumor model where LGR5+ CSCs coexisted with LGR5− cells, the RSPO1-liposomes were able to access more CSC cells and deliver the drug specifically and efficiently. Such a focused effect in eradicating LGR5+ cells led to massive tumor tissue necrosis and growth inhibition even when only a fraction of the conventional drug dose was used. These data clearly demonstrated the advantages of CSC-targeted drug delivery and would support the development of such approaches as a new cancer treatment strategy. Mol Cancer Ther; 17(7); 1475–85. ©2018 AACR.
Improving the In Vivo Efficacy of an Anti-Tac (CD25) Immunotoxin by Pseudomonas Exotoxin A Domain II Engineering
Authors: Kaplan Gilad , Mazor Ronit , Lee Fred , Jang Youjin , Leshem Yasmin , Pastan Ira
Published: April 2018

Tac (CD25) is expressed on multiple hematologic malignancies and is a target for cancer therapies. LMB-2 is an extremely active anti-Tac recombinant immunotoxin composed of an Fv that binds to Tac and a 38-kDa fragment of Pseudomonas exotoxin A (PE38). Although LMB-2 has shown high cytotoxicity toward Tac-expressing cancer cells in clinical trials, its efficacy was hampered by the formation of anti-drug antibodies against the immunogenic bacterial toxin and by dose-limiting off-target toxicity. To reduce toxin immunogenicity and nonspecific toxicity, we introduced six point mutations into domain III that were previously shown to reduce T-cell immunogenicity and deleted domain II from the toxin, leaving only the 11aa furin cleavage site, which is required for cytotoxic activity. Although this strategy has been successfully implemented for mesothelin and CD22-targeting immunotoxins, we found that removal of domain II significantly lowered the cytotoxic activity of anti-Tac immunotoxins. To restore cytotoxic activity in the absence of PE domain II, we implemented a combined rational design and screening approach to isolate highly active domain II–deleted toxin variants. The domain II–deleted variant with the highest activity contained an engineered disulfide-bridged furin cleavage site designed to mimic its native conformation within domain II. We found that this approach restored 5-fold of the cytotoxic activity and dramatically improved the MTD. Both of these improvements led to significantly increased antitumor efficacy in vivo. We conclude that the next-generation anti-Tac immunotoxin is an improved candidate for targeting Tac-expressing malignancies. Mol Cancer Ther; 17(7); 1486–93. ©2018 AACR.
Allelic Polymorphisms of KIRs and HLAs Predict Favorable Responses to Tyrosine Kinase Inhibitors in CML
Authors: Ureshino Hiroshi , Shindo Takero , Kojima Hiroto , Kusunoki Yasushi , Miyazaki Yuki , Tanaka Hidenori , Saji Hiroh , Kawaguchi Atsushi , Kimura Shinya
Published: April 2018

Response to tyrosine kinase inhibitors (TKIs) is variable in chronic myeloid leukemia (CML), and elevated natural killer (NK) cells during TKI therapy are positively correlated with superior outcomes. NK cell function involves interactions of their killer immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I on target cells, and the avidity of KIR–HLA interactions depends on the combination of KIR and HLA alleles. We hypothesized that KIR and HLA polymorphisms may influence response to TKIs. KIR and HLA allele genotyping was performed by next-generation sequencing for 76 CML cases, and association with clinical outcome was analyzed. Second-generation TKIs as first-line therapy and patients' sex (female) were strongly associated with achievement of complete molecular response (CMR: MR4.0) after 2 years (P < 0.001 and P = 0.002, respectively). After adjustment for these two characteristics, several KIR alleles remained associated with achievement of MR4.0: KIR2DL4*005/011 or *008 (HR = 1.797, P = 0.032); KIR2DS4*003 or *007/010 (HR = 3.348, P < 0.001); KIR3DL1*005 (HR = 2.746, P = 0.003); and KIR3DL2*009 or *010 [HR = 1.980 (1.109–3.524), P = 0.021]. Strong linkage among these alleles exists, implying that they comprise favorable KIR allele haplotypes. Allelic polymorphisms of KIR3DL1 and HLA-B determine their differential avidity into strong/weak or no interaction. Patients carrying noninteracting KIR3DL1 and HLA-B allele pairs achieved better outcomes than those with strongly interacting pairs, and KIR3DL1*005 associated with a positive outcome among patients with weak-interacting pairs. Thus, KIR3DL1*005 and its associated haplotypes associated with superior TKI therapeutic effects. The combinations of these KIR and HLA alleles may correlate with potent NK cell immunity against CML. Cancer Immunol Res; 6(6); 745–54. ©2018 AACR.
Sustained Erythroid Response in a Patient with Myelofibrosis Receiving Concomitant Treatment with Ruxolitinib and Deferasirox
Authors: Piro Eugenio , Lentini Maria , Levato Luciano , Russo Antonio , Molica Stefano
Published: April 2018

Iron overload (IOL) due to transfusion-dependent anemia is a serious adverse effect in patients with myelofibrosis (MF). Recent studies have shown that the oral iron chelator deferasirox may prevent multiple organ damage due to IOL in MF. However, it is not clear whether deferasirox may contribute to revert transfusion-dependent anemia. Here, we present a patient with transfusion-dependent intermediate-2 MF according to the International Prognostic Scoring System treated with ruxolitinib in combination with deferasirox. In addition to a reduced serum ferritin level, the patient required less blood transfusions, ultimately resulting in long-lasting transfusion-free survival.
Prognostic Impact of DNA Repair Protein Expression in Non-Small Cell Lung Cancers Treated with Platinum-Based Chemotherapy and Subsequent Curative Lung Resection
Authors: Shin Junghoon , Lee Kyu Sang , Yoh Kyung Ah , Cho Hyun Jin , Choi Moon Ki , Kim Se Hyun , Kim Yu Jung , Chung Jin-Haeng , Cho Sukki , Kim Kwhanmien , Jheon Sanghoon , Yoon Ho Il , Lee Jae Ho , Lee Choon-Taek , Lee Jong Seok
Published: April 2018

Objective: Multimodal treatments that include preoperative platinum-based chemotherapy are fundamental to the treatment of advanced non-small cell lung cancer (NSCLC). This study aimed to investigate the predictive value of DNA repair protein expression in surgically resected NSCLCs in terms of prognosis and responses to platinum-containing chemotherapy. Methods: This retrospective study included 136 patients with NSCLC who were treated with preoperative platinum-based chemotherapy, followed by curative lung resection. ATM, RAD51, LKB1, H2AX, and SIRT1 expression levels were analyzed in resected tumor specimens via immunostaining and were used to classify patients and compare survival and responses to chemotherapy. Results: SIRT1 expression correlated significantly with improved responses to platinum-based chemotherapy (odds ratio, 2.28; p = 0.024), progression-free survival (hazard ratio [HR], 0.74; p = 0.036), overall survival (HR, 0.63; p = 0.006), and tumor-bearing survival (HR, 0.62; p = 0.014). After adjusting for clinical variables, the HR of SIRT1 expression remained significant for overall survival (HR, 0.59; p = 0.039) but not for progression-free survival (HR, 0.74; p = 0.183). No prognostic stratification was observed for the other 4 markers. Conclusion: Patients with SIRT1-expressing NSCLC had superior responses to chemotherapy and longer survival durations than those with SIRT1-negative cancer.
Clinical Features of Hereditary Angioedema in Korean Patients: A Nationwide Multicenter Study
Authors: Jung Jae-Woo , Suh Dong In , Park Hye Jung , Kim Sujeong , Kwon Hyouk Soo , Yang Min Suk , Park Chan Sun , Kim Joo-Hee , Kim Sae-Hoon , Lee Yong Won , Hur Gyu Young , Ye Young-Min , Kwon Yong Eun , Park Hye-Kyung , Kim Cheol Woo , Koh Young-Il , Park Jung Wong , Lee Jong-Myung , Min Kyung-Up , Wickner Paige , Kang Hye-Ryun
Published: April 2018

Background: Hereditary angioedema (HAE) is a genetically heterogeneous autosomal dominant disorder characterized by recurrent episodes of nonpruritic, nonpitting edema increasing after puberty. It can be fatal due to laryngeal or gastrointestinal (GI) involvement with varied and changing frequency of mortality according to studies published from the Western countries. Epidemiological and clinical data of HAE in Asian countries are sparse. We sought to examine the clinical characteristics of HAE patients in Korea. Methods: Patients diagnosed with HAE at 15 tertiary hospitals across the country until 2016 were retrospectively reviewed. Results: A total of 65 patients diagnosed with HAE by 2016 were identified. The prevalence of HAE was estimated at 1.3/1,000,000 in Korea. Of the 65 patients, 21 (32.3%) were males. A total of 90.8% patients had type I HAE, while the remaining 9.2% patients had type II HAE. The first symptom developed after 20 years in 73.8% of patients, with a mean age 28.4 ± 14.1 years. The age at diagnosis was 36.5 ± 15.8 years, with a mean time delay of 7.8 ± 10.5 years. While the face (82.3%) and extremities (upper 71.0%, lower 62.9%) were the most frequently involved, the GI tract was affected in 40.5% of Korean HAE patients. Prophylaxis was maintained in 62.5% of patients. There was no reported case of death from HAE so far. Conclusions: The clinical manifestation and severity of HAE may vary according to ethnicity. HAE is more infrequent and GI involvement is less likely in Korea compared with Western countries.
Single-Center, Prospective, Blinded Study Comparing the Efficacy and Compatibility of Efinaconazole 10% Solution in Treating Onychomycosis with and without Concurrent Nail Polish Use
Authors: Canavan Theresa N. , Bevans Stephanie L. , Cantrell Wendy C. , Wang Casey , Elewski Boni E.
Published: April 2018

Background: Topical efinaconazole 10% solution is a promising new treatment for distal lateral subungual onychomycosis (DLSO). However, it is unknown whether this treatment is both compatible and efficacious in individuals wearing toenail polish. Materials and Methods: We evaluated the efficacy and compatibility of efinaconazole 10% solution with concurrent nail polish use in treating DLSO over 52 weeks. Efficacy was assessed using the onychomycosis severity index (OSI) and by measuring nail growth and thickness, while compatibility with nail polish was evaluated with questionnaires. Results: Eleven patients completed the study; 6 wore nail polish regularly and 5 abstained from polish. The efficacy of efinaconazole was not diminished by concurrent nail polish use as measured by OSI, nail growth, and thickness. However, this treatment produced undesirable cosmetic changes to the quality of nail polish over time. Conclusions: While efinaconazole 10% solution is an effective treatment of DLSO in patients wearing nail polish, this treatment may diminish the quality of the polish. Further research and development is needed to enhance the compatibility of topical onychomycosis treatments with nail polish use.
Gastric Adenocarcinomas in Central Tunisia: Evolution Specificities through Two Decades and Relation with Helicobacter pylori
Authors: Elghali Mohamed Amine , Gouader Amine , Bouriga Rym , Mahjoub Mohamed , Jarrar Mohamed Salah , Ziadi Sonia , Mokni Moncef , Hamila Fahmi , Ltaeif Rached
Published: April 2018

Introduction: In developed countries, authors have reported variations over time in the seat and histological type of gastric adenocarcinomas, which were explained by Helicobacter pylori infection (HPI) incidence changes. In North-African countries and the Arabic world, epidemiological changes in gastric adenocarcinomas are still unknown. Our study aims to explore and to describe those changes in central Tunisia. Materials and Methods: This is a retrospective observational and descriptive study including 876 cases based on the National Central Tunisian Register of Cancers over a period of 21 years. Two groups were formed and compared (group A: 337 patients from 1995 to 2005; group B: 539 patients from 2006 to 2015). Results: HPI decreased from 32.6% in group A to 11.2% in group B (p < 0.05). Signet ring cell carcinomas increased in 2 decades from 14% in group A to 36% in group B (p < 0.05). Proximal cancers were 16.61% in group A and increased to 19.66% in group B (p = 0.3). Total gastrectomy rate was 10.4% in group A versus 23.2% in group B (p < 0.05). Conclusion: This study has shown a significant increase of signet ring cell carcinomas with a simultaneous decrease in HPI in the last decade in central Tunisia.
The Neutrophil to Lymphocyte Ratio May Predict Benefit from Chemotherapy in Lung Cancer
Authors: Liu Dan , Jin Jing , Zhang Li , Li Lei , Song Juan , Li Weimin
Published: April 2018

Background/Aims: The objectives of this study were to evaluate the impact of the neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) on overall survival (OS) and to explore the value of changes in the NLR and PLR with treatment as a response indicator. Methods: A total of 934 patients were eligible for retrospective analysis between 2008 and 2014. The pretreatment and post-treatment PLR and NLR in all patients were calculated based on complete blood counts. Univariate and multivariate Cox regression analyses were performed to determine the associations of the PLR and NLR with OS. Results: The pretreatment NLR and PLR were correlated with different disease status and response to chemotherapy. Patients with lower NLR and PLR had a significantly better complete response (CR) rate to chemotherapy versus those with a higher NLR and PLR (p< 0.001). The NLR and PLR were sustained in patients who obtained a CR compared with moderate or poor response patients. The lower NLR of pretreatment was independently associated with a favourable prognosis in whole patients with lung cancer (HR: 0.69, 95% CI, 0.55-0.85, p< 0.001). In the patients under control after chemotherapy, the NLR of post-chemotherapy had a greater impact on survival, and the low NLR level maintained during chemotherapy was identified a predictor for favourable survival. PLR was not an independent prognostic indicator in the whole cohort or any subgroups. Conclusion: Our results suggested that NLR was well-connected with outcomes and response to chemotherapy in patients with lung cancer. As a response indicator, NLR may predict benefit from chemotherapy and improve patient selection.
CircRNA-Cdr1as Exerts Anti-Oncogenic Functions in Bladder Cancer by Sponging MicroRNA-135a
Authors: Li Peng , Yang Xiao , Yuan Wenbo , Yang Chengdi , Zhang Xiaolei , Han Jie , Wang Jingzi , Deng Xiaheng , Yang Haiwei , Li Pengchao , Tao Jun , Lu Qiang , Gu Min
Published: April 2018

Background/Aims: CircRNAs regulate gene expression in different malignancies. However, the role of Cdr1as in the tumourigenesis of bladder cancer and its potential mechanisms remain unknown. Methods: qRT-PCR was used to detect Cdr1as and target miRNA expression in bladder cancer tissues and cell lines. Biological functional experiments were performed to detect the effects of Cdr1as on the biological behaviour of bladder cancer cells in vivo and in vitro. Bioinformatic analysis was utilised to predict potential miRNA target sites on Cdr1as. Ago2 RNA binding protein immunoprecipitation assay, RNA antisense purification assay, biotin pull down assay and RNA FISH were performed to detect the interaction between Cdr1as and target miRNAs. Western blot was used to determine the expression level of p21 in bladder cancer cells. Results: Cdr1as was significantly down-regulated in bladder cancer tissues compared with adjacent normal tissues. Overexpression of Cdr1as inhibited the proliferation, invasion and migration of bladder cancer cells in vitro and slowed down tumour growth in vivo. Cdr1as sponged multiple miRNAs in bladder cancer. Moreover, Cdr1as directly bound to miR-135a and inhibited its activity in bladder cancer. Conclusion: Cdr1as is down-regulated and sponges multiple miRNAs in bladder cancer. It exerts anti-oncogenic functions by sponging microRNA-135a.
Mitochondrial Perturbation Contributing to Cognitive Decline in Streptozotocin-Induced Type 1 Diabetic Rats
Authors: Zhou Yu , Lian Siheng , Zhang Jin , Lin Donghai , Huang Caihua , Liu Libin , Chen Zhou
Published: April 2018

Background/Aims: Mitochondrial perturbation is a well-established cause of cognitive decline, but as yet it is unclear how mitochondria-associated neuronal abnormalities in type 1 diabetic (T1DM) brain contribute to cognitive decline. Methods: The streptozotocin (STZ)-induced mouse model of T1DM was used. The Morris water maze test was applied to assess the effect of T1DM on learning and memory. We detected changes in mitochondrial morphology, function and dynamics. Furthermore, we employed metabolomic analysis to reveal the underlying mechanisms of mitochondrial perturbation which contribute to cognitive decline. Results: Our results show that T1DM impairs mitochondrial dynamics, morphology and function in neurons, associated with a decline in cognitive ability. Metabolomic analyses revealed that T1DM mainly affects metabolic pathways involved in mitochondrial energy failure and impairs the antioxidative system. Conclusion: These results lay the basis for understanding the underlying mitochondria-associated causes of T1DM-associated cognitive decline and may provide a potential treatment strategy for this condition in future.