bluuebunny/crossref_metadata_2025 huggingface dataset:
Live cumulative network meta-analysis: protocol for second-line treatments in advanced non-small-cell lung cancer with wild-type or unknown status for epidermal growth factor receptor
Authors: Créquit Perrine , Trinquart Ludovic , Ravaud Philippe
Published: August 2016

Introduction

Many second-line treatments for advanced non-small-cell lung cancer (NSCLC) have been assessed in randomised controlled trials, but which treatments work the best remains unclear. Novel treatments are being rapidly developed. We need a comprehensive up-to-date evidence synthesis of all these treatments. We present the protocol for a live cumulative network meta-analysis (NMA) to address this need.

Methods and analysis

We will consider trials of second-line treatments in patients with advanced NSCLC with wild-type or unknown epidermal growth factor receptor status. We will consider any single agent of cytotoxic chemotherapy, targeted therapy, combination of cytotoxic chemotherapy and targeted therapy and any combination of targeted therapies. The primary outcomes will be overall survival and progression-free survival. The live cumulative NMA will be initiated with a NMA and then iterations will be repeated at regular intervals to keep the NMA up-to-date over time. We have defined the update frequency as 4 months, based on an assessment of the pace of evidence production on this topic. Each iteration will consist of six methodological steps: adaptive search for treatments and trials, screening of reports and selection of trials, data extraction, assessment of risk of bias, update of the network of trials and synthesis, and dissemination. We will set up a research community in lung cancer, with different groups of contributors of different skills. We will distribute tasks through online crowdsourcing. This proof-of-concept study in second-line treatments of advanced NSCLC will allow one for assessing the feasibility of live cumulative NMA and opening the path for this new form of synthesis.

Ethics and dissemination

Ethical approval is not required because our study will not include confidential participant data and interventions. The description of all the steps and the results of this live cumulative NMA will be available online.

Trial registration number

CRD42015017592.
Venous thromboembolism in medical patients during hospitalisation and 3 months after hospitalisation: a prospective observational study
Authors: Khalafallah Alhossain A , Kirkby Brooke E , Wong Sophia , Foong Yi Chao , Ranjan Nishant , Luttrell James , Mathew Ronnie , Chilvers Charles M , Mauldon Emily , Sharp Colin , Hannan Terry
Published: August 2016

Objectives

This study was conducted to assess the incidence and risk factors for venous thromboembolism (VTE) in a cohort of medical patients both during the period of hospitalisation and following discharge.

Design

This was a prospective observational study to document the risk profile and incidence of VTE posthospitalisation among all medical patients admitted to our institution during the trial period.

Settings

Primary healthcare. Single tertiary referral centre, Tasmania, Australia.

Participants

A total of 986 patients admitted to the medical ward between January 2012 and September 2012 were included in the study with male to female ratio of 497:489. The mean age of patients was 68 years (range 17–112, SD 16).

Results

Overall, 54/986 patients (5.5%) had a VTE during the study period. Of these, 40/54 (74.1%) occurred during hospitalisation and 14/54 (25.9%) occurred following discharge. VTE risk factors revealed in multivariate analysis to be associated with a previous diagnosis of VTE (p<0.001, OR=6.63, 95% CI 3.3 to 13.36), the occurrence of surgery within the past 30 days (p<0.001, OR=2.52, 95% CI 1.33 to 4.79) and an admission diagnosis of pulmonary disease (p<0.01, OR 3.61, 95% CI 1.49 to 8.76). Mobility within 24 hours of admission was not associated with an increased risk. There was risk of VTE when the length of stay prolonged (p=0.046, OR=1.01, 95% CI 1.00 to 1.03), however it was not sustained with multivariate modelling. VTE-specific prophylaxis was used in 53% of the studied patients. Anticoagulation including antiplatelet agents were administered in 63% of patients who developed VTE.

Conclusions

This prospective observational study found that 5.5% of the studied patients developed VTE. Among those, 25.9% (14/54) of patients had a detected VTE posthospitalisation with this risk being increased if there was a history of VTE, recent surgery and pulmonary conditions. Thromboprophylaxis may be worth considering in these cohorts. Further study to confirm these findings are warranted.

Trial registration number

ACTRN12611001255976.
P Values: From Suggestion to Superstition
Authors: Concato John , Hartigan John A
Published: August 2016

A threshold probability value of ‘p≤0.05’ is commonly used in clinical investigations to indicate statistical significance. To allow clinicians to better understand evidence generated by research studies, this review defines the p value, summarizes the historical origins of the p value approach to hypothesis testing, describes various applications of p≤0.05 in the context of clinical research and discusses the emergence of p≤5×10−8 and other values as thresholds for genomic statistical analyses. Corresponding issues include a conceptual approach of evaluating whether data do not conform to a null hypothesis (ie, no exposure–outcome association). Importantly, and in the historical context of when p≤0.05 was first proposed, the 1-in-20 chance of a false-positive inference (ie, falsely concluding the existence of an exposure–outcome association) was offered only as a suggestion. In current usage, however, p≤0.05 is often misunderstood as a rigid threshold, sometimes with a misguided ‘win’ (p≤0.05) or ‘lose’ (p>0.05) approach. Also, in contemporary genomic studies, a threshold of p≤10−8 has been endorsed as a boundary for statistical significance when analyzing numerous genetic comparisons for each participant. A value of p≤0.05, or other thresholds, should not be employed reflexively to determine whether a clinical research investigation is trustworthy from a scientific perspective. Rather, and in parallel with conceptual issues of validity and generalizability, quantitative results should be interpreted using a combined assessment of strength of association, p values, CIs, and sample size.
Analysis of safety outcomes for radial versus femoral access for percutaneous coronary intervention from a large clinical registry
Authors: Dobies David R , Barber Kimberly R , Cohoon Amanda L
Published: August 2016

Objective

Using a multisite, contemporary registry of 58 862 percutaneous coronary intervention (PCI) procedures in a national healthcare system, the present study compared radial access with femoral access on safety and efficacy outcomes.

Methods

This is a real-world, large-scale, retrospective study using clinical data from a 137-hopsital System and reported to a multisite clinical registry. All patients undergoing a cardiac catheterisation procedure were included in this database. The primary end points were major bleeding and radiation exposure. Multivariate logistic regression modelling was used to compare access groups.

Results

Femoral access (n=55 729) accounted for 94.7% and radial access (n=3137) for 5.3%. There were fewer bleeding events in the radial group (n=28, 0.9%) than those in the femoral group (n=1234, 2.2%) in the unadjusted analysis. For patients receiving bivalirudin, bleeding occurred in 337 patients (1.6%), and there was no difference in rates between radial access (n=13, 1.1%) and femoral access (n=327, 1.7%) (OR=0.65, CI 0.40 to 1.22, p=0.19). The radial technique resulted in higher radiation exposure in each case, but particularly for procedures involving prior coronary artery bypass graft history and non-ST-elevated myocardial infarction patients. The mean fluoroscopy time among femoral access procedures was 15.68 min (SD=11.7) versus 19.86 min (SD=13.8) for radial access procedures (p<0.0001).

Conclusions

Radial access for PCI is associated with higher fluoroscopy times but not with less major bleeding when bivalirudin is used. Our analysis, combined with other study findings, suggest that the safest route for PCI may be the use of femoral access with bivalirudin.
Get the Diagnosis: an evidence-based medicine collaborative Wiki for diagnostic test accuracy
Authors: Hammer Mark M , Kohlberg Gavriel D
Published: August 2016

Background

Despite widespread calls for its use, there are challenges to the implementation of evidence-based medicine (EBM) in clinical practice.

Methods

In response to the challenges of finding timely, pertinent information on diagnostic test accuracy, we developed an online, crowd-sourced Wiki on diagnostic test accuracy called Get the Diagnosis (GTD, http://www.getthediagnosis.org).

Results

Since its launch in November 2008 till October 2015, GTD has accumulated information on 300 diagnoses, with 1617 total diagnostic entries. There are a total of 1097 unique diagnostic tests with a mean of 5.4 tests (range 0–38) per diagnosis. 73% of entries (1182 of 1617) have an associated sensitivity and specificity and 89% of entries (1432 of 1617) have associated peer-reviewed literature citations. Altogether, GTD contains 474 unique literature citations. For a sample of three diagnoses, the search precision (percentage of relevant results in the first 30 entries) in GTD was 100% as compared with a range of 13.3%–63.3% for PubMed and between 6.7% and 76.7% for Google Scholar.

Conclusion

GTD offers a fast, precise and efficient way to look up diagnostic test accuracy. On three selected examples, GTD had a greater precision rate compared with PubMed and Google Scholar in identifying diagnostic test information. GTD is a free resource that complements other currently available resources.
Development of a force–resultant model for spudcan footings on loose sand under combined loads
Authors: Cheng Ning , Cassidy Mark Jason
Published: August 2016

Spudcans are typical foundations used in shallow to moderate-depth water oil and gas fields to support jack-up drilling units. Understanding the behaviour of spudcans under combined loadings is crucial to the overall response of the jack-up structure. This paper presents the development of a strain-hardening plasticity model for a spudcan footing on loose sand. Most of the model components are developed from direct centrifuge observations. The centrifuge tests were performed at an acceleration of 100 times that of the Earth’s gravity on a model spudcan footing subjected to combined vertical, horizontal, and moment loads. All the experiments have been designed and conducted to allow the results to be interpreted with a strain-hardening plasticity framework. Combined loads were applied by using a novel apparatus, which enables independent vertical, horizontal, and rotational movements of the footing. Test results also revealed the existence of a three dimensional sliding surface that intersects with the conventional yield surface. This additional surface has been defined analytically. Retrospective simulation of the experimental data using the plasticity model confirms the model’s capability for use in predicting the behaviour of larger spudcan applications offshore.
Fossil species in Boehmerieae (Urticaceae) in Dominican and Mexican amber: a new genus (Ekrixanthera) and two new species with anemophilous pollination by explosive pollen release, and possible lepidopteran herbivory
Authors: Poinar George , Kevan Peter G. , Jackes Betsy R.
Published: August 2016

The first fossil flowers of Neotropical Urticaceae (Boehmerieae) are described from the Dominican Republic and Mexico as belonging to a new genus, Ekrixanthera. Ekrixanthera hispaniolae sp. nov. from Dominican amber has pentamerous staminate flowers on short pedicels with a pilose pistillode and heteromorphic pilose tepals: two are clavate and three linear. Ekrixanthera ehecatli sp. nov. has pentamerous staminate flowers lacking pedicels, a pistillode with greatly reduced pilosity, glabrous and heteromorphic tepals with two linear and three wedge-shaped with truncate tips. The presence or absence of a pedicel, heterotrophic condition of the tepals, and the presence or absence of pilosity of the pistillode and tepals separate the two species. Those characters, together with the pentamerous flowers separate both fossil species from extant genera. The floral structures indicate explosive pollen release and pollination by wind (anemophily). Pistillate flowers have not been found for this usually dioecious tribe. Lepidopteran herbivory is suggested by a damaged stipule in one specimen and a nymphalid butterfly (Vanessa-like) caterpillar that may have used Ekrixanthera as a food plant is illustrated. The fossils establish an early lineage of Boehmerieae with characteristic explosive pollen release and perhaps associated herbivorous insects in the West Indies and North America during the mid-Tertiary.
Post-column hydrogen–deuterium exchange technique to assist in the identification of small organic molecules by mass spectrometry
Authors: Eysseric Emmanuel , Bellerose Xavier , Lavoie Jean-Michel , Segura Pedro A.
Published: August 2016

To improve the certainty that a specific small organic molecule has been detected in a given sample by high-resolution mass spectrometry, other techniques that give conclusive evidence about the chemical structure of a compound like nuclear magnetic resonance or complementary information on its composition such as hydrogen–deuterium exchange (HDX) are often necessary. This study presents a systematic investigation that aims to improve the applicability of post-column HDX for those purposes. Key parameters like mobile-phase flow rates, volume percentage of H2O in the mobile phase, and D2O addition flow rates were optimized to provide an isotopic pattern that allows the accurate determination of the number of exchangeable hydrogen atoms in small organic molecules. A loop injection setup was used to emulate chromatographic conditions in the optimization process, and trimethoprim, a widely used anti-infective, was used as test compounds for the experiments. As expected, results showed that deuteration percentage decreased with a higher mobile-phase flow rate and increased with higher D2O flow rate. The post-column HDX technique was then validated with extracts of samples of river water and plants separated by liquid chromatography in hydrophilic interaction or reversed-phase modes. Mass spectra showed a completely visible isotopic pattern that allowed assessing correctly and unambiguously the number of exchangeable hydrogens in the compounds of interest. This study shows that post-column HDX can be used as a complementary technique to identify unknown small organic molecules in complex matrices. The current paper proposes an efficient, cost-effective, versatile technique of HDX that is helpful to assign a unique structure to a given high-resolution mass spectrometry signal.
Controlling the Human-Induced Longitudinal Vibrations of a Nielsen-Truss Footbridge Via the Modification of Its Natural Frequencies
Authors: Jiménez-Alonso Javier Fernando , Sáez Andrés
Published: August 2016

This paper describes a case-study where the human-induced vibrations of a footbridge have been controlled by means of the modification of its natural frequencies. The structure, a Nielsen variable depth truss, is located over a highway on the outskirts of Malaga (Spain), so that it was designed to withstand low pedestrian densities and its dynamic behavior was just analyzed according to Spanish standards at the date of construction. However, the presence of a nearby sports pavilion originated unexpected large pedestrian flows. This new service condition was not properly anticipated, leading to significant longitudinal vibration levels. To overcome this problem, experimental and numerical studies were carried out, with the aim of finding a low cost solution that yet maintained the footbridge aesthetic appearance. Following these studies, corrective measures that increased its stiffness were then adopted. Subsequently, experimental tests and a finite element model tuning were performed to obtain: (i) its modified modal parameters; and (ii) a more accurate estimation of its dynamic behavior under different pedestrian flows. Presently, the footbridge has been in service for more than four years, maintaining an adequate comfort level.
Analyzing Runtime and Size Complexity of Integer Programs
Authors: Brockschmidt Marc , Emmes Fabian , Falke Stephan , Fuhs Carsten , Giesl Jürgen
Published: August 2016

We present a modular approach to automatic complexity analysis of integer programs. Based on a novel alternation between finding symbolic time bounds for program parts and using these to infer bounds on the absolute values of program variables, we can restrict each analysis step to a small part of the program while maintaining a high level of precision. The bounds computed by our method are polynomial or exponential expressions that depend on the absolute values of input parameters.

We show how to extend our approach to arbitrary cost measures, allowing the use of our technique to find upper bounds for other expended resources, such as network requests or memory consumption. Our contributions are implemented in the open-source tool KoAT, and extensive experiments show the performance and power of our implementation in comparison with other tools.
Harmonic Segment-Based Semi-Partitioning Scheduling on Multi-Core Real-Time Systems
Authors: Hassan Hadeer A. , Salem Sameh A. , Mostafa Ahmed M. , Saad E. M.
Published: August 2016

Nowadays, the issue of scheduling multi-core real-time systems has become the focus of such research in industrial, biomedical, military, and other fields. As a consequence, a new semi-partitioning algorithm that uses a static Rate-Monotonic criterion to schedule real-time tasks on multi-core platforms is proposed. The improvement in the performance of real-time systems is achieved by exploitingthe fact that the utilization boundary of a task set increases to fully utilize the processors if the periods of tasks have harmonic nature among each other. Experimental results on randomly generated datasets and real-world datasets show that the proposed algorithm inevitably outperforms other competitive algorithms.
A Control-Theoretic Analysis of Low-Priority Congestion Control Reprioritization under AQM
Authors: Cicco Luca De , Gong Yixi , Rossi Dario , Leonardi Emilio
Published: August 2016

Recently, a negative interplay has been shown to arise when scheduling/Active Queue Management (AQM) techniques and low-priority congestion control protocols are used together; namely, AQM resets the relative level of priority among congestion control protocols. This work explores this issue by carrying out a control-theoretic analysis of the dynamical system to prove some fundamental properties that fully characterize the reprioritization phenomenon. In particular, (i) we provide the closed-form solution of the equilibrium in the open loop (i.e., fixing a target loss probability
p
); (ii) we provide a stability analysis and a characterization of the reprioritization phenomenon when closing the loop with AQM (i.e., that dynamically adjusts the system loss probability). Our results are important as the characterization of the reprioritization phenomenon is not only quantitatively accurate for the specific protocols and AQM considered but also qualitatively accurate for a broader range of congestion control protocol and AQM combinations. Finally, while we find a sufficient condition to avoid the reprioritization phenomenon, we also show, at the same time, such conditions to be likely impractical: Therefore, we propose a simple and practical system-level solution that is able to reinstate priorities among protocols.
An Efficient Technique of Application Mapping and Scheduling on Real-Time Multiprocessor Systems for Throughput Optimization
Authors: Liu Weichen , Xiao Chunhua
Published: August 2016

Multiprocessor systems are becoming ubiquitous in today’s embedded systems design. In this article, we address the problem of mapping an application represented by a Homogeneous Synchronous Dataflow (HSDF) graph onto a real-time multiprocessor platform with the objective of maximizing total throughput. We propose that the optimal solution to the problem is composed of three components: actor-to-processor mapping, retiming, and actor ordering on each processor. The entire problem is systematically modeled into a Boolean Satisfiability (SAT) problem such that the optimal solution can be guaranteed theoretically. In order to explore the vast solution space more efficiently, we develop a specific HSDF theory solver based on the special characteristics of the timed HSDF, and integrate it into the general search framework of the SAT solver. Two alternative integration methods based on branch-and-bound are presented to achieve early branch pruning in the search space; thus, the scalability is greatly improved. Extensive performance evaluation on synthetic examples and a case study on the realistic H.264 Video Decoder show that our approach provides as much as 76.9% throughput improvement, and is scalable to industry-sized applications.
When Game Becomes Life
Authors: Jia Adele Lu , Shen Siqi , Epema Dick H. J. , Iosup Alexandru
Published: August 2016

Online gaming franchises such as World of Tanks, Defense of the Ancients, and StarCraft have attracted hundreds of millions of users who, apart from playing the game, also socialize with each other through gaming and viewing gamecasts. As a form of User Generated Content (UGC), gamecasts play an important role in user entertainment and gamer education. They deserve the attention of both industrial partners and the academic communities, corresponding to the large amount of revenue involved and the interesting research problems associated with UGC sites and social networks. Although previous work has put much effort into analyzing general UGC sites such as YouTube, relatively little is known about the gamecast sharing sites. In this work, we provide the first comprehensive study of gamecast sharing sites, including commercial streaming-based sites such as Amazon’s Twitch.tv and community-maintained replay-based sites such as WoTreplays. We collect and share a novel dataset on WoTreplays that includes more than 380,000 game replays, shared by more than 60,000 creators with more than 1.9 million gamers. Together with an earlier published dataset on Twitch.tv, we investigate basic characteristics of gamecast sharing sites, and we analyze the activities of their creators and spectators. Among our results, we find that (i) WoTreplays and Twitch.tv are both fast-consumed repositories, with millions of gamecasts being uploaded, viewed, and soon forgotten; (ii) both the gamecasts and the creators exhibit highly skewed popularity, with a significant
heavy tail
phenomenon; and (iii) the upload and download preferences of creators and spectators are different: while the creators emphasize their individual skills, the spectators appreciate team-wise tactics. Our findings provide important knowledge for infrastructure and service improvement, for example, in the design of proper resource allocation mechanisms that consider future gamecasting and in the tuning of incentive policies that further help player retention.
Intra-component resource sharing on a virtual multiprocessor platform
Authors: Afshar Sara , Khalilzad Nima , Behnam Moris , Bril Reinder J. , Nolte Thomas
Published: August 2016

Component-based software development facilitates the development process of large and complex software systems. By the advent of multiprocessors, the independently developed components can be integrated on a multi-core platform to achieve an efficient use of system hardware and a decrease in system power consumption and costs. In this paper, we consider a virtual multiprocessor platform where each component can be dynamically allocated to any set of processors of the platform with a maximum concurrency level. Global-EDF is used for intra-component scheduling. The existing analysis for such systems have assumed that tasks are independent. In this paper, we enable intra-component resource sharing for this platform. We investigate using a spin-based resource sharing protocol with the accompanying analysis that extends the existing analysis for independent tasks. We briefly illustrate and evaluate our initial results with an example.
Optimizing the resource requirements of hierarchical scheduling systems
Authors: Kim Jin Hyun , Legay Axel , Traonouez Louis-Marie , Boudjadar Abdeldjalil , Nyman Ulrik , Larsen Kim G. , Lee Insup , Choi Jin-Young
Published: August 2016

Compositional reasoning on hierarchical scheduling systems is a well-founded formal method that can construct schedulable and optimal system configurations in a compositional way. However, a compositional framework formulates the resource requirement of a component, called an interface, by assuming that a resource is always supplied by the parent components in the most pessimistic way. For this reason, the component interface demands more resources than the amount of resources that are really sufficient to satisfy sub-components. We provide two new supply bound functions which provides tighter bounds on the resource requirements of individual components. The tighter bounds are calculated by using more information about the scheduling system.

We evaluate our new tighter bounds by using a model-based schedulability framework for hierarchical scheduling systems realized as Uppaal models. The timed models are checked using model checking tools Uppaal and Uppaal SMC, and we compare our results with the state of the art tool CARTS.
Toll-like receptor 4 mutation suppresses hyperhomocysteinemia-induced hypertension
Authors: Familtseva Anastasia , Chaturvedi Pankaj , Kalani Anuradha , Jeremic Nevena , Metreveli Naira , Kunkel George H. , Tyagi Suresh C.
Published: August 2016

Hyperhomocysteinemia (HHcy) has been observed to promote hypertension, but the mechanisms are unclear. Toll-like receptor 4 (TLR-4) is a cellular membrane protein that is ubiquitously expressed in all cell types of the vasculature. TLR-4 activation has been known to promote inflammation that has been associated with the pathogenesis of hypertension. In this study we hypothesize that HHcy induces hypertension by TLR-4 activation, which promotes inflammatory cytokine (IL-1β, IL-6, and TNF-α) upregulation and initiation of mitochondria-dependent apoptosis, leading to cell death and chronic vascular inflammation. To test this hypothesis, we used C57BL/6J (WT) mice, cystathionine β-synthase (CBS)-deficient (CBS+/−) mice with genetic mild HHcy, C3H/HeJ (C3H) mice with TLR-4 mutation, and mice with combined genetic HHcy and TLR-4 mutation (CBS+/−/C3H). Ultrasonography of the superior mesenteric artery (SMA) detected an increase in wall-to-lumen ratio, resistive index (RI), and pulsatility index (PI). Tail cuff blood pressure (BP) measurement revealed elevated BP in CBS+/− mice. RI, PI, and wall-to-lumen ratio of the SMA in CBS+/−/C3H mice were similar to the control group, and BP was significantly alleviated. TLR-4, IL-1β, IL-6, and TNF-α expression were upregulated in the SMA of CBS+/− mice and reduced in the SMA of CBS+/−/C3H mice. Molecules involved in the mitochondria-mediated cell death pathway (BAX, caspase-9, and caspase-3) were upregulated in CBS+/− mice and attenuated in CBS+/−/C3H mice. We conclude that HHcy promotes TLR-4-driven chronic vascular inflammation and mitochondria-mediated cell death, inducing hypertension. TLR-4 mutation attenuates vascular inflammation and cell death, which suppress hypertension.
Role of the sodium-dependent multivitamin transporter (SMVT) in the maintenance of intestinal mucosal integrity
Authors: Sabui Subrata , Bohl Jennifer Ann , Kapadia Rubina , Cogburn Kyle , Ghosal Abhisek , Lambrecht Nils W. , Said Hamid M.
Published: August 2016

Utilizing a conditional (intestinal-specific) knockout (cKO) mouse model, we have recently shown that the sodium-dependent multivitamin transporter (SMVT) ( SLC5A6) is the only biotin uptake system that operates in the gut and that its deletion leads to biotin deficiency. Unexpectedly, we also observed that all SMVT-cKO mice develop chronic active inflammation, especially in the cecum. Our aim here was to examine the role of SMVT in the maintenance of intestinal mucosal integrity [permeability and expression of tight junction (TJ) proteins]. Our results showed that knocking out the mouse intestinal SMVT is associated with a significant increase in gut permeability and with changes in the level of expression of TJ proteins. To determine whether these changes are related to the state of biotin deficiency that develops in SMVT-cKO mice, we induced (by dietary means) biotin deficiency in wild-type mice and examined its effect on the above-mentioned parameters. The results showed that dietary-induced biotin deficiency leads to a similar development of chronic active inflammation in the cecum with an increase in the level of expression of proinflammatory cytokines, as well as an increase in intestinal permeability and changes in the level of expression of TJ proteins. We also examined the effect of chronic biotin deficiency on permeability and expression of TJ proteins in confluent intestinal epithelial Caco-2 monolayers but observed no changes in these parameters. These results show that the intestinal SMVT plays an important role in the maintenance of normal mucosal integrity, most likely via its role in providing biotin to different cells of the gut mucosa.
Modeling age-related changes in muscle-tendon dynamics during cyclical contractions in the rat gastrocnemius
Authors: Danos Nicole , Holt Natalie C. , Sawicki Gregory S. , Azizi Emanuel
Published: August 2016

Efficient muscle-tendon performance during cyclical tasks is dependent on both active and passive mechanical tissue properties. Here we examine whether age-related changes in the properties of muscle-tendon units (MTUs) compromise their ability to do work and utilize elastic energy storage. We empirically quantified passive and active properties of the medial gastrocnemius muscle and material properties of the Achilles tendon in young (∼6 mo) and old (∼32 mo) rats. We then used these properties in computer simulations of a Hill-type muscle model operating in series with a Hookean spring. The modeled MTU was driven through sinusoidal length changes and activated at a phase that optimized muscle-tendon tuning to assess the relative contributions of active and passive elements to the force and work in each cycle. In physiologically realistic simulations where young and old MTUs started at similar passive forces and developed similar active forces, the capacity of old MTUs to store elastic energy and produce positive work was compromised. These results suggest that the observed increase in the metabolic cost of locomotion with aging may be in part due to the recruitment of additional muscles to compensate for the reduced work at the primary MTU. Furthermore, the age-related increases in passive stiffness coupled with a reduced active force capacity in the muscle can lead to shifts in the force-length and force-velocity operating range that may significantly impact mechanical and metabolic performance. Our study emphasizes the importance of the interplay between muscle and tendon mechanical properties in shaping MTU performance during cyclical contractions.
The Generation of Human Induced Pluripotent Stem Cells from Blood Cells: An Efficient Protocol Using Serial Plating of Reprogrammed Cells by Centrifugation
Authors: Kim Youngkyun , Rim Yeri Alice , Yi Hyoju , Park Narae , Park Sung-Hwan , Ju Ji Hyeon
Published: August 2016

Human induced pluripotent stem cells (hiPSCs) have demonstrated great potential for differentiation into diverse tissues. We report a straightforward and highly efficient method for the generation of iPSCs from PBMCs. By plating the cells serially to a newly coated plate by centrifugation, this protocol provides multiple healthy iPSC colonies even from a small number of PBMCs. The generated iPSCs expressed pluripotent markers and differentiated into all three germ layer lineages. The protocol can also be used with umbilical cord blood mononuclear cells (CBMCs). In this study, we present a simple and efficient protocol that improved the yield of iPSCs from floating cells such as PBMCs and CBMCs by serial plating and centrifugation.
Preparation and Characterization of Baicalein-Loaded Nanoliposomes for Antitumor Therapy
Authors: Li Kun , Zhang Haizhao , Gao Liming , Zhai Yue , Shi Ming , Li Jian , Xiu Chenlin , Cao Junli , Cheng Shaohui , Jiang Li , Di Hao
Published: August 2016

Baicalein (BAI) is a major constituent of Scutellaria baicalensis Georgi. Previous studies showed that BAI had obvious effects on U14 cervical tumor-bearing mice model and HeLa cells. However, the use of BAI is inconvenient and troublesome, due to its low oral bioavailability. The aim of this study was to develop baicalein-loaded nanoliposomes (BAI-LP) to improve its bioavailability. In this study, BAI-LP was prepared by thin film hydration method. The average size, polydispersity index (PDI), zeta potential and encapsulation efficiency (EE) of the BAI-LP were194.6±2.08 nm,0.17±0.025,-30.73±0.41 mV, and44.3±2.98%, respectively. Drug storage stability study showed no significant changes in these values after 4 weeks of storing at 4°C. Additionally, Sulforhodamine B (SRB) experimental results indicated that the BAI-LP could achieve better anti-tumor effects than free BAI. The results of the experiment demonstrated that BAI-LP had a better antitumor effect with a higher inhibition rate of66.34±15.33% than free BAI with a inhibition rate of41.89±10.50% by using U14 cervical tumor-bearing mice model. In conclusion, the study suggested that BAI-LP would serve as a potent delivery vehicle for BAI in future cancer therapy.
Full-Thickness Excision versus Shaving by Laparoscopy for Intestinal Deep Infiltrating Endometriosis: Rationale and Potential Treatment Options
Authors: Laganà Antonio Simone , Vitale Salvatore Giovanni , Trovato Maria Antonietta , Palmara Vittorio Italo , Rapisarda Agnese Maria Chiara , Granese Roberta , Sturlese Emanuele , De Dominici Rosanna , Alecci Stefano , Padula Francesco , Chiofalo Benito , Grasso Roberta , Cignini Pietro , D’Amico Paolo , Triolo Onofrio
Published: August 2016

Endometriosis is defined as the presence of endometrial mucosa (glands and stroma) abnormally implanted in locations other than the uterine cavity. Deep infiltrating endometriosis (DIE) is considered the most aggressive presentation of the disease, penetrating more than 5 mm in affected tissues, and it is reported in approximately 20% of all women with endometriosis. DIE can cause a complete distortion of the pelvic anatomy and it mainly involves uterosacral ligaments, bladder, rectovaginal septum, rectum, and rectosigmoid colon. This review describes the state of the art in laparoscopic approach for DIE with a special interest in intestinal involvement, according to recent literature findings. Our attention has been focused particularly on full-thickness excision versus shaving technique in deep endometriosis intestinal involvement. Particularly, the aim of this paper is clarifying from the clinical and methodological points of view the best surgical treatment of deep intestinal endometriosis, since there is no standard of care in the literature and in different surgical settings. Indeed, this review tries to suggest when it is advisable to manage the full-thickness excision or the shaving technique, also analyzing perioperative management, main complications, and surgical outcomes.
On the Theory of Multilinear Singular Operators with Rough Kernels on the Weighted Morrey Spaces
Authors: He Sha , Tao Xiangxing
Published: August 2016

We study some multilinear operators with rough kernels. For the multilinear fractional integral operatorsTΩ,αAand the multilinear fractional maximal integral operatorsMΩ,αA, we obtain their boundedness on weighted Morrey spaces with two weightsLp,κ(u,v)whenDγA∈Λ˙β  (|γ|=m-1)orDγA∈BMO  (|γ|=m-1). For the multilinear singular integral operatorsTΩAand the multilinear maximal singular integral operatorsMΩA, we show they are bounded on weighted Morrey spaces with two weightsLp,κ(u,v)ifDγA∈Λ˙β  (|γ|=m-1)and bounded on weighted Morrey spaces with one weightLp,κ(w)ifDγA∈BMO  (|γ|=m-1)form=1,2.
Unilateral Opening of Rat Blood-Brain Barrier Assisted by Diagnostic Ultrasound Targeted Microbubbles Destruction
Authors: Xu Yali , Cui Hai , Zhu Qiong , Hua Xing , Xia Hongmei , Tan Kaibin , Gao Yunhua , Zhao Jing , Liu Zheng
Published: August 2016

Objective. Blood-brain barrier (BBB) is a key obstacle that prevents the medication from blood to the brain. Microbubble-enhanced cavitation by focused ultrasound can open the BBB and proves to be valuable in the brain drug delivery. The study aimed to explore the feasibility, efficacy, and safety of unilateral opening of BBB using diagnostic ultrasound targeted microbubbles destruction in rats.Methods. A transtemporal bone irradiation of diagnostic ultrasound and intravenous injection of lipid-coated microbubbles were performed at unilateral hemisphere. Pathological changes were monitored. Evans Blue extravasation grades, extraction from brain tissue, and fluorescence optical density were quantified. Lanthanum nitrate was traced by transmission electron microscopy.Results. After diagnostic ultrasound mediated microbubbles destruction, Evans Blue extravasation and fluorescence integrated optical density were significantly higher in the irradiated hemisphere than the contralateral side (allp<0.01). Erythrocytes extravasations were demonstrated in the ultrasound-exposed hemisphere (4±1, grade 2) while being invisible in the control side. Lanthanum nitrate tracers leaked through interendothelial cleft and spread to the nerve fiber existed in the irradiation side.Conclusions. Transtemporal bone irradiation under DUS mediated microbubble destruction provides us with a more accessible, safer, and higher selective BBB opening approach in rats, which is advantageous in brain targeted drugs delivery.
Exploiting Product Related Review Features for Fake Review Detection
Authors: Sun Chengai , Du Qiaolin , Tian Gang
Published: August 2016

Product reviews are now widely used by individuals for making their decisions. However, due to the purpose of profit, reviewers game the system by posting fake reviews for promoting or demoting the target products. In the past few years, fake review detection has attracted significant attention from both the industrial organizations and academic communities. However, the issue remains to be a challenging problem due to lacking of labelling materials for supervised learning and evaluation. Current works made many attempts to address this problem from the angles of reviewer and review. However, there has been little discussion about the product related review features which is the main focus of our method. This paper proposes a novel convolutional neural network model to integrate the product related review features through a product word composition model. To reduce overfitting and high variance, a bagging model is introduced to bag the neural network model with two efficient classifiers. Experiments on the real-life Amazon review dataset demonstrate the effectiveness of the proposed approach.
Vector Solitons of a Coupled Schrödinger System with Variable Coefficients
Authors: Muñoz Grajales Juan Carlos
Published: August 2016

We show the existence of waveforms of finite-energy (vector solitons) for a coupled nonlinear Schrödinger system with inhomogeneous coefficients. Furthermore, some of these solutions are approximated using a Newton-type iteration, combined with a collocation-spectral strategy to discretize the corresponding soliton equations. Some numerical simulations concerned with analysis of a collision of two oncoming vector solitons of the system are also performed.
The Exponentiated Gumbel Type-2 Distribution: Properties and Application
Authors: Okorie I. E. , Akpanta A. C. , Ohakwe J.
Published: August 2016

We introduce a generalized version of the standard Gumble type-2 distribution. The new lifetime distribution is called the Exponentiated Gumbel (EG) type-2 distribution. The EG type-2 distribution has three nested submodels, namely, the Gumbel type-2 distribution, the Exponentiated Fréchet (EF) distribution, and the Fréchet distribution. Some statistical and reliability properties of the new distribution were given and the method of maximum likelihood estimates was proposed for estimating the model parameters. The usefulness and flexibility of the Exponentiated Gumbel (EG) type-2 distribution were illustrated with a real lifetime data set. Results based on the log-likelihood and information statistics values showed that the EG type-2 distribution provides a better fit to the data than the other competing distributions. Also, the consistency of the parameters of the new distribution was demonstrated through a simulation study. The EG type-2 distribution is therefore recommended for effective modelling of lifetime data.
Preserved Renal Function in Kidney Transplantation over a Thrombosed Aortobifemoral Bypass Graft: The Role of Retrograde Flow and Early Thrombolysis
Authors: Pampa-Saico Saúl , Jiménez-Alvaro Sara , Caravaca-Fontán Fernando , Fernández-Rodríguez Ana , Rivera-Gorrín Maite , Sánchez Juan , Chinchilla Antonio , Marcén Roberto
Published: August 2016

Aortobifemoral bypass (ABFB) thrombosis is not uncommon, and when the artery of a renal graft is implanted on a bypass the risk of graft loss is high. We report the case of a 48-year-old woman with a previous history of ABFB under antiplatelet therapy and a kidney allograft implanted on the vascular prosthesis, who presented with acute limb ischemia and severe renal impairment. Imaging techniques revealed a complete thrombosis of the proximal left arm of the ABFB. However, a faint retrograde flow over the graft was observed thanks to the recanalization of distal left bypass by collateral native arteries. This unusual situation not previously reported in a kidney transplant setting, together with an early diagnosis, allowed graft survival until an early local thrombolysis resolved the problem. Two years later, renal function remains normal.
Heme Oxygenase-1 Controls an HDAC4-miR-206 Pathway of Oxidative Stress in Rhabdomyosarcoma
Authors: Ciesla Maciej , Marona Paulina , Kozakowska Magdalena , Jez Mateusz , Seczynska Marta , Loboda Agnieszka , Bukowska-Strakova Karolina , Szade Agata , Walawender Magdalena , Kusior Magdalena , Stepniewski Jacek , Szade Krzysztof , Krist Bart , Yagensky Oleksandr , Urbanik Aleksandra , Kazanowska Bernarda , Dulak Jozef , Jozkowicz Alicja
Published: August 2016

Rhabdomyosarcoma (RMS) is an aggressive soft tissue cancer characterized by disturbed myogenic differentiation. Here we report a role for the oxidative stress response factor HO-1 in progression of RMS. We found that HO-1 was elevated and its effector target miR-206 decreased in RMS cell lines and clinical primary tumors of the more aggressive alveolar phenotype (aRMS). In embryonal RMS (eRMS), HO-1 expression was induced by Pax3/7-FoxO1, an aRMS hallmark oncogene, followed by a drop in miR-206 levels. Inhibition of HO-1 by tin protoporphyrin (SnPP) or siRNA downregulated Pax3/7-FoxO1 target genes and induced a myogenic program in RMS. These effects were not mediated by altered myoD expression; instead, cells with elevated HO-1 produced less reactive oxygen species, resulting in nuclear localization of HDAC4 and miR-206 repression. HO-1 inhibition by SnPP reduced growth and vascularization of RMS tumors in vivo accompanied by induction of miR-206. Effects of SnPP on miR-206 expression and RMS tumor growth were mimicked by pharmacologic inhibition of HDAC. Thus, HO-1 inhibition activates an miR-206–dependent myogenic program in RMS, offering a novel therapeutic strategy for treatment of this malignancy. Cancer Res; 76(19); 5707–18. ©2016 AACR.
Amplification of TLK2 Induces Genomic Instability via Impairing the G2–M Checkpoint
Authors: Kim Jin-Ah , Anurag Meenakshi , Veeraraghavan Jamunarani , Schiff Rachel , Li Kaiyi , Wang Xiao-Song
Published: August 2016

Managing aggressive breast cancers with enhanced chromosomal instability (CIN) is a significant challenge in clinics. Previously, we described that a cell cycle–associated kinase called Tousled-like kinase 2 (TLK2) is frequently deregulated by genomic amplifications in aggressive estrogen receptor–positive (ER+) breast cancers. In this study, it was discovered that TLK2 amplification and overexpression mechanistically impair Chk1/2-induced DNA damage checkpoint signaling, leading to a G2–M checkpoint defect, delayed DNA repair process, and increased CIN. In addition, TLK2 overexpression modestly sensitizes breast cancer cells to DNA-damaging agents, such as irradiation or doxorubicin. To our knowledge, this is the first report linking TLK2 function to CIN, in contrast to the function of its paralog TLK1 as a guardian of genome stability. This finding yields new insight into the deregulated DNA damage pathway and increased genomic instability in aggressive ER+ breast cancers.

Implications: Targeting TLK2 presents an attractive therapeutic strategy for the TLK2-amplified breast cancers that possess enhanced genomic instability and aggressiveness. Mol Cancer Res; 14(10); 920–7. ©2016 AACR.
Clinical Relevance of ASC-H Cytologies: Experience in a Single Tertiary Hospital
Authors: Díaz del Arco Cristina , Sanabria Montoro Mª Carmen , García López Dolores , Rodríguez Escudero Eva , Fernández Aceñero Mª Jesús
Published: August 2016

Objectives: To review the cases of atypical squamous cells (ASC), cannot exclude squamous intraepithelial lesion (ASC-H) diagnosed at a single institution and to discuss the interpretation challenges and clinical management of these cases. Study Design: The ASC-H cases diagnosed at our institution from 2006 to 2015 were studied retrospectively; of 159,000 Pap smears, there were 959 cases of ASC of undetermined significance (ASC-US) and 148 cases of ASC-H. We have reviewed the clinical records of the ASC-H cases, and data have been analyzed using SPSS 20.0. Results: Median age was 43.1 years; 49.6% of the patients had previous cervical cytologies, and 55.9% of them were negative. Following ASC-H diagnosis, another smear was obtained in 97.1% of the cases and in 67.6% a biopsy was performed. Biopsy revealed low-grade dysplasia in 18.8% of the cases, high-grade dysplasia in 27.8%, and infiltrating carcinoma in 2.3%. Patients with significant lesions in histology were younger than patients with negative results (p = 0.08). A diagnosis of ASC-H/squamous intraepithelial lesion in the repeated cytology had a sensitivity of 74.2%, specificity of 39.6%, positive predictive value of 44.8%, and negative predictive value of 70% for the diagnosis of dysplasia. Conclusions: ASC-H diagnosis is associated with a high incidence of histological high-grade lesions. A repeat cytology can aid in the selection of high-risk patients, but there may be false-negative results.