bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving the fault resilience of an H.264 decoder using static analysis methods
Authors: Schmoll Florian , Heinig Andreas , Marwedel Peter , Engel Michael
Published: December 2013

Fault tolerance rapidly evolves into one of the most significant design objectives for embedded systems due to reduced semiconductor structures and supply voltages. However, resource-constrained systems cannot afford traditional error correction for overhead and cost reasons. New methods are required to sustain acceptable service quality in case of errors while avoiding crashes.

We present a flexible fault-tolerance approach that is able to select correction actions depending on error semantics using application annotations and static analysis approaches. We verify the validity of our approach by analyzing the vulnerability and improving the reliability of an H.264 decoder using flexible error handling.
Predictable and configurable component-based scheduling in the C
omposite
OS
Authors: Parmer Gabriel , West Richard
Published: December 2013

This article presents the design of user-level scheduling hierarchies in the C
omposite
component-based system. The motivation for this is centered around the design of a system that is both dependable and predictable, and which is configurable to the needs of specific applications. Untrusted application developers can safely develop services and policies, that are isolated in protection domains outside the kernel. To ensure predictability, C
omposite
enforces timing control over user-space services. Moreover, it must provide a means by which asynchronous events, such as interrupts, are handled in a timely manner without jeopardizing the system. Towards this end, we describe the features of C
omposite
that allow user-defined scheduling policies to be composed for the purposes of combined interrupt and task management. A significant challenge arises from the need to synchronize access to shared data structures (e.g., scheduling queues), without allowing untrusted code to disable interrupts. Additionally, efficient upcall mechanisms are needed to deliver asynchronous event notifications in accordance with policy-specific priorities, without undue recourse to schedulers. We show how these issues are addressed in C
omposite
, by comparing several hierarchies of scheduling polices, to manage both tasks and the interrupts on which they depend. Studies show how it is possible to implement guaranteed differentiated services as part of the handling of I/O requests from a network device while diminishing livelock. Microbenchmarks indicate that the costs of implementing and invoking user-level schedulers in C
omposite
are on par with, or less than, those in other systems, with thread switches more than twice as fast as in Linux.
Software-based register file vulnerability reduction for embedded processors
Authors: Lee Jongeun , Shrivastava Aviral
Published: December 2013

Register File (RF) is extremely vulnerable to soft errors, and traditional redundancy based schemes to protect the RF are prohibitive not only because RF is often in the timing critical path of the processor, but also since it is one of the hottest blocks on the chip. Software approaches would be ideal in this case, but previous approaches based on instruction scheduling are only moderately effective due to local scope. In this article we present a compiler approach, based on interprocedural program analysis, to reduce the vulnerability of registers by temporarily writing live variables to protected memory. We formulate the problem as an integer linear programming problem and also present a very efficient heuristic algorithm. Further we present an iterative optimization method based on Kernighan-Lin's graph partitioning algorithm. Our experiments demonstrate that our proposed techniques can reduce the vulnerability of a RF by 33 ∼ 37% on average and up to 66%, with a small 2% increase in runtime. In addition, our overhead reduction optimization can effectively reduce the code size overhead, by more than 40% on average, to a mere 5 ∼ 6%, compared to highly optimized binaries.
Exact Learning Algorithms, Betting Games, and Circuit Lower Bounds
Authors: Harkins Ryan C. , Hitchcock John M.
Published: December 2013

This article extends and improves the work of Fortnow and Klivans [2009], who showed that if a circuit class C has an efficient learning algorithm in Angluin’s model of exact learning via equivalence and membership queries [Angluin 1988], then we have the lower bound EXP
NP
not C. We use entirely different techniques involving betting games [Buhrman et al. 2001] to remove the NP oracle and improve the lower bound to EXP not C. This shows that it is even more difficult to design a learning algorithm for C than the results of Fortnow and Klivans [2009] indicated. We also investigate the connection between betting games and natural proofs, and as a corollary the existence of strong pseudorandom generators.

Our results also yield further evidence that the class of Boolean circuits has no efficient exact learning algorithm. This is because our separation is strong in that it yields a natural proof [Razborov and Rudich 1997] against the class. From this we conclude that an exact learning algorithm for Boolean circuits would imply that strong pseudorandom generators do not exist, which contradicts widely believed conjectures from cryptography. As a corollary we obtain that if strong pseudorandom generators exist, then there is no exact learning algorithm for Boolean circuits.
Analyzing memory ownership patterns in C libraries
Authors: Ravitch Tristan , Liblit Ben
Published: December 2013

Programs written in multiple languages are known as
polyglot programs
. In part due to the proliferation of new and productive high-level programming languages, these programs are becoming more common in environments that must interoperate with existing systems. Polyglot programs must manage resource lifetimes across language boundaries. Resource lifetime management bugs can lead to leaks and crashes, which are more difficult to debug in polyglot programs than monoglot programs.

We present analyses to automatically infer the ownership semantics of C libraries. The results of these analyses can be used to generate bindings to C libraries that intelligently manage resources, to check the correctness of polyglot programs, and to document the interfaces of C libraries. While these analyses are unsound and incomplete, we demonstrate that they significantly reduce the manual annotation burden for a suite of fifteen open source libraries.
Pacman
Authors: Brock Jacob , Gu Xiaoming , Bao Bin , Ding Chen
Published: December 2013

As caches become larger and shared by an increasing number of cores, cache management is becoming more important. This paper explores collaborative caching, which uses software hints to influence hardware caching. Recent studies have shown that such collaboration between software and hardware can theoretically achieve optimal cache replacement on LRU-like cache.

This paper presents Pacman, a practical solution for collaborative caching in loop-based code. Pacman uses profiling to analyze patterns in an optimal caching policy in order to determine which data to cache and at what time. It then splits each loop into different parts at compile time. At run time, the loop boundary is adjusted to selectively store data that would be stored in an optimal policy. In this way, Pacman emulates the optimal policy wherever it can. Pacman requires a single bit at the load and store instructions. Some of the current hardware has partial support. This paper presents results using both simulated and real systems, and compares simulated results to related caching policies.
Characterization of Cellulose Microfibrils Obtained from Hemp
Authors: Šutka Anna , Kukle Silvija , Gravitis Janis , Grave Laima
Published: December 2013

Microfibrillated cellulose was extracted from hemp fibres using steam explosion pretreatment and high-intensity ultrasonic treatment (HIUS). The acquired results after steam explosion treatment and water and alkali treatments are discussed and interpreted by Fourier transform infrared spectroscopy (FTIR). Scanning electron microscopy (SEM) was used to examine the microstructure of hemp fibres before and after each treatment. A fibre size analyser was used to analyse the dimensions of the untreated and treated cellulose fibrils. SEM observations show that the sizes of the different treated fibrils have a diameter range of several micrometres, but after HIUS treatment fibres are separate from microfibrils, nanofibres, and their agglomerates.
Numerical Investigation on Heat and Flow Characteristics of Temperature-Sensitive Ferrofluid in a Square Cavity
Authors: Lee Moo-Yeon , Seo Jae-Hyeong
Published: December 2013

The objective of this paper is numerically to study the heat and flow characteristics of temperature-sensitive ferrofluid in the square cavity with and without the magnetic intensity. The numerical model was developed to predict the behavior of the ferrofluid using finite element method (FEM) and showed good agreement with the existing data within 5% at all Rayleigh number ranges from 103 to 106. Natural convection and heat transfer characteristics of the ferrofluids within the tested cavity were found to depend on both magnetic intensity and magnetic volume fractions of magnetite. In addition, the mean Nusselt numbers and mean velocity of the ferrofluid in a square cavity were increased with the rise of the magnetic intensities and increased by 23.2% and 143.7%, respectively, at both magnetic intensity of H = 10000 A/m and the elapsed time of t = 30000 seconds.
On the Behaviour of Singular Semigroups in Intermediate and Interpolation Spaces and Its Applications to Maximal Regularity for Degenerate Integro-Differential Evolution Equations
Authors: Favaron Alberto , Favini Angelo
Published: December 2013

For those semigroups, which may have power type singularities and whose generators are abstract multivalued linear operators, we characterize the behaviour with respect to a certain set of intermediate and interpolation spaces. The obtained results are then applied to provide maximal time regularity for the solutions to a wide class of degenerate integro- and non-integro-differential evolution equations in Banach spaces.
The Ethanol Extract ofOsmanthus fragransFlowers Reduces Oxidative Stress and Allergic Airway Inflammation in an Animal Model
Authors: Hung Chien-Ya , Huang Fu-Long , Shi Li-Shian , Ka Shuk-Man , Wang Jing-Yao , Tsai Yu-Cheng , Hung Tsung-Jen , Ye Yi-Ling
Published: December 2013

TheOsmanthus fragransflower, a popular herb in Eastern countries, contains several antioxidant compounds.Ben Cao Gang Mu, traditional Chinese medical literature, describes the usefulness of these flowers for phlegm and stasis reduction, arrest of dysentery with blood in the bowel, and stomachache and diarrhea treatment. However, modern evidence regarding the therapeutic efficacy of these flowers is limited. This study was aimed at assessing the antioxidative effects of the ethanol extract ofO. fragransflowers (OFE)in vivoand evaluating its antioxidant maintenance and therapeutic effect on an allergic airway inflammation in mice. After OFE’s oral administration to mice, the values obtained in the oxygen radical absorbance capacity assay as well as the glutathione concentration in the lungs and spleens of mice increased while thiobarbituric acid reactive substances decreased significantly, indicating OFE’s significantin vivoantioxidant activity. OFE was also therapeutically efficacious in a mouse model of ovalbumin-induced allergic airway inflammation. Orally administered OFE suppressed ovalbumin-specific IgE production and inflammatory cell infiltration in the lung. Moreover, the antioxidative state of the mice improved. Thus, our findings confirm the ability of theO. fragransflowers to reduce phlegm and suggest that OFE may be useful as an antiallergic agent.
Short-Term Effect of Pitavastatin Treatment on Glucose and Lipid Metabolism and Oxidative Stress in Fasting and Postprandial State Using a Test Meal in Japanese Men
Authors: Kakuda Hirokazu , Kobayashi Junji , Nakato Mio , Takekoshi Noboru
Published: December 2013

Introduction.The objective of this study was to clarify how pitavastatin affects glucose and lipid metabolism, renal function, and oxidative stress.Methods.Ten Japanese men (average age of 33.9 years) were orally administered 2 mg of pitavastatin for 4 weeks. Postprandial glucose, lipoprotein metabolism, and oxidative stress markers were evaluated at 0 and 4 weeks of pitavastatin treatment (2 mg once daily) with a test meal consisting of total calories: 460 kcal, carbohydrates: 56.5 g (226 kcal), protein: 18 g (72 kcal), lipids: 18 g (162 kcal), and NaCl: 1.6 g. Metabolic parameters were measured at 0, 60, and 120 minutes after test meal ingestion.Results.After administration of pitavastatin, serum total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, arachidonic acid, insulin, and adjusted urinary excretion of uric acid decreased, whereas creatinine clearance (CCr) and uric acid clearance (CUA) increased. And postprandial versus fasting urine 8-hydroxydeoxyguanosine remained unchanged, while postprandial versus fasting isoprostane decreased after pitavastatin treatment. Next, we compared postprandial glucose and lipid metabolism after test meal ingestion before and after pitavastatin administration. Incremental areas under the curve significantly decreased for triglycerides (P<0.05) and remnant-like particle cholesterol (P<0.01), while those for apolipoprotein E (apoE), glucose, insulin, and high-sensitivity C-reactive protein remained unchanged.Conclusion.Pitavastatin improves postprandial oxidative stress along with hyperlipidemia.
Development of Stability Indicating LC Method for the Estimation of Tolperisone in Bulk and Pharmaceutical Dosage Form
Authors: Chhalotiya U. K. , Bhatt K. K. , Shah D. A. , Baldania S. L. , Patel S. B.
Published: December 2013

A rapid, specific, and sensitive reverse phase high performance liquid chromatographic method has been developed and validated for analysis of tolperisone in both bulk and pharmaceutical dosage form. The HPLC method was performed with a reversed phase C18 SunFire column (250 mm × 4.6 mm i.d., 5 mm particle size), detection at 261 nm and a mixture of methanol, water and pH 7.5 adjusted by use of 1% solution of triethylamine (60 : 40) as mobile phase. The flow rate was 1.0 mL min−1 and effluents were monitored at 261 nm. The retention time of tolperisone was 4.8 min. Tolperisone was subjected to acid and alkali hydrolysis, chemical oxidation, wet hydrolysis, dry heat degradation, and sunlight degradation. The degraded product peaks were well resolved from the pure drug peak with significant difference in their retention time values. Stressed samples were assayed using developed LC method. The proposed method was validated with respect to linearity, accuracy, precision, and robustness. The method was successfully applied to the estimation of tolperisone in tablet dosage forms.
Assessment of the Quality of Life of Vulnerable Young Males with Severe Emotional and Behaviour Difficulties in a Residential Setting
Authors: Carroll D. , Duffy T. , Martin C. R.
Published: December 2013

Sixty‐four looked after and accommodated males aged 13–16 had an assessment of their quality of life using Paediatric Quality of Life Inventory (PedsQL) and Quality of Life in Care (QOLIC). The participants were from a Scottish residential centre for young people with severe emotional and behavioural difficulties. The total sample of 64 participants consists of two distinct groups: residential group (n = 33) and a secure care group (n = 31). Over 3 observations the aim of the study was to identify similarities and differences between the groups and to establish the sensitivity of the PedsQL and the PedsQL in care module (QOLIC) as a measurement instrument for Quality of Life (QoL) in adolescent males. Overall there was a nonsignificant increase in the quality of life of these young people at the centre as measured by PedsQL and QOLIC over 3 observations. No significant differences were detected in the quality of life scores between the two groups using the QOLIC.
Progression of Voice and Speech Impairment in the Course of Parkinson's Disease: A Longitudinal Study
Authors: Skodda S. , Grönheit W. , Mancinelli N. , Schlegel U.
Published: December 2013

Impairment of voice and speech occurs in the majority of patients in the course of Parkinson's disease (PD). The aim of the current study was to survey the changes of voice and speech performance in the individual patients over time. 80 patients with PD and 60 healthy speakers were tested and retested after at least 12 months (average time interval: 32.5 months). Participants had to read a given text which was digitally recorded as a source for the perceptual and acoustic analysis. Stage of the disease and global motor impairment were rated according to the accepted scales. As a result, abnormalities of voice and speech were already present in mildly affected patients and there were significant deteriorations of quality of voice and articulatory velocity and precision between baseline and followup examination which showed no correlation with the time interval between the visits. Summarized, voice, and speech performance were found to further deteriorate in the individual patient in the course of time although global motor impairment was widely stable which might be a hint for nondopaminergic mechanisms of progression of dysarthrophonia. Further investigations are warranted to get a better insight into the dynamics of the progression of voice and speech impairment in PD as a precondition for the development of therapeutic approaches.
Cardiorespiratory Dynamic Response to Mental Stress: A Multivariate Time-Frequency Analysis
Authors: Widjaja Devy , Orini Michele , Vlemincx Elke , Van Huffel Sabine
Published: December 2013

Mental stress is a growing problem in our society. In order to deal with this, it is important to understand the underlying stress mechanisms. In this study, we aim to determine how the cardiorespiratory interactions are affected by mental arithmetic stress and attention. We conduct cross time-frequency (TF) analyses to assess the cardiorespiratory coupling. In addition, we introduce partial TF spectra to separate variations in the RR interval series that are linearly related to respiration from RR interval variations (RRV) that are not related to respiration. The performance of partial spectra is evaluated in two simulation studies. Time-varying parameters, such as instantaneous powers and frequencies, are derived from the computed spectra. Statistical analysis is carried out continuously in time to evaluate the dynamic response to mental stress and attention. The results show an increased heart and respiratory rate during stress and attention, compared to a resting condition. Also a fast reduction in vagal activity is noted. The partial TF analysis reveals a faster reduction of RRV power related to (3 s) than unrelated to (30 s) respiration, demonstrating that the autonomic response to mental stress is driven by mechanisms characterized by different temporal scales.
Isolation of III-V/Ge Multijunction Solar Cells by Wet Etching
Authors: Turala A. , Jaouad A. , Masson D. P. , Fafard S. , Arès R. , Aimez V.
Published: December 2013

Microfabrication cycles of III-V multijunction solar cells include several technological steps and end with a wafer dicing step to separate individual cells. This step introduces damage at lateral facets of the junctions that act as charge trapping centers, potentially causing performance and reliability issues, which become even more important with today’s trend of cell size reduction. In this paper we propose a process of wet etching of microtrenches that allows electrical isolation of individual solar cells with no damage to the sidewalls. Etching with bromine-methanol, the solution that is typically used for nonselective etching of III-V compounds, results in the formation of unwanted holes on the semiconductor surfaces. We investigate the origin of holes formation and discuss methods to overcome this effect. We present an implementation of the isolation step into a solar cell fabrication process flow. This improved fabrication process opens the way for improved die strength, yield, and reliability.
Distributed Bayesian Inference for Consistent Labeling of Tracked Objects in Nonoverlapping Camera Networks
Authors: Wan Jiuqing , Liu Li
Published: December 2013

One of the fundamental requirements for visual surveillance using nonoverlapping camera networks is the correct labeling of tracked objects on each camera in a consistent way, in the sense that the observations of the same object at different cameras should be assigned with the same label. In this paper, we formulate this task as a Bayesian inference problem and propose a distributed inference framework in which the posterior distribution of labeling variable corresponding to each observation is calculated based solely on local information processing on each camera and mutual information exchanging between neighboring cameras. In our framework, the number of objects presenting in the monitored region does not need to be specified beforehand. Instead, it can be determined automatically on the fly. In addition, we make no assumption about the appearance distribution of a single object, but use “similarity” scores between appearance pairs as appearance likelihood for inference. To cope with the problem of missing detection, we consider an enlarged neighborhood of each camera during inference and use a mixture model to describe the higher order spatiotemporal constraints. Finally, we demonstrate the effectiveness of our method through experiments on an indoor office building dataset and an outdoor campus garden dataset.
Proactive Caching and Forwarding Schemes for Seamless Handover in IEEE WAVE Networks
Authors: Chung Young-uk , Lee Hyukjoon , Choi Yong-Hoon , Lee Chungwon
Published: December 2013

The IEEE Wireless Access for Vehicular Environment (WAVE) standard consists of the IEEE 802.11p and the IEEE 1609 specifications supporting fast link establishment as well as broadband data communication in vehicular environment. Although the standard has been widely accepted by industry as well as highway authorities in many countries to be used for the radio communication infrastructure of the next-generation Intelligent Transport System (ITS), it remains open for further enhancements such as seamless handover support. This paper presents two proactive caching and forwarding schemes for seamless handover in IEEE WAVE networks: one for straight highway sections and the other for crossroads and junctions. Practical and efficient handover procedures, based on the proposed schemes, are also presented. Specifically, an on-board unit (OBU) informs the old road-side unit (RSU) about its departure from the coverage area such that the old RSU can forward the buffered packets to candidate RSUs for proactive caching. In handover scenarios around crossroads and junctions, the IEEE 802.11f Move-notify message is used by the new RSU to request the rest of candidate RSUs to purge the cached packets in order to prevent the waste of radio resource. Simulation results show that the proposed schemes outperform conventional schemes.
Internal-Notched Flexure Test for Measurement of Mode II Delamination Resistance of Fibre-Reinforced Polymers
Authors: Fan Chengye , Jar P.-Y. Ben , Cheng J.-J. Roger
Published: December 2013

This paper introduces a new test, method, named internal-notched flexure (INF) test, that is designed to measure the critical energy release rate of fibre-reinforced polymers for delamination growth in shear mode (mode II). The INF test generates stable delamination growth, with a monotonic increase of load and displacement in a nearly linear fashion. Values of the mode II delamination toughness were deduced using experimental compliance fitting method. Good repeatability of the results was obtained. Compared with the end-notched flexure (ENF) test using the same material, the INF test yielded higher delamination resistance, possibly due to the bridging fibres found between fracture surfaces of the INF test specimens.
Fabrication of Orderly Copper Particle Arrays on a Multi‐Electrolyte‐Step Anodic Aluminum Oxide Template
Authors: Chen Chun-Ko , Chan Der-Sheng , Lee Cheng-Chung , Chen Sheng-Hui
Published: December 2013

A multi‐electrolyte‐step (MES) anodic aluminum oxide (AAO) method was used to achieve nanochannel arrays with good circularity and periodic structure. The nano‐channel array fabrication process included immersion in a phosphoric acid solution with a 120–150 bias voltage. Bowl‐shaped structures were then formed by removing the walls of the nano‐channel arrays. The nano‐channel arrays were grown from the bottom of the bowl structure in an oxalic solution using a 50 V bias voltage. A comparison of this new MES process with the one‐step and five‐step AAO process showed a 50% improvement in the circularity over the one‐step process. The standard deviation of the average period in the MES array was 25 nm which is less than that of one‐step process. This MES method also took 1/4 of the growing time of the five‐step process. The orderliness of the nano‐channel arrays for the five‐step and MES process was similar. Finally, Cu nanoparticle arrays with a 200 nm period were grown using an electroplating process inside the MES nano‐channel arrays on fluorine doped tin oxide glass. Stronger surface plasmon resonance absorption from 550 nm to 750 nm was achieved with the MES process than was possible with the one‐step process.
Antiproliferative and Apoptotic Effects of a Specific Antiprostate Stem Cell Single Chain Antibody on Human Prostate Cancer Cells
Authors: Nejatollahi Foroogh , Abdi Soghra , Asgharpour Mahdi
Published: December 2013

Prostate stem cell antigen (PSCA) is a highly glycosylated cell surface protein which is overexpressed in several malignancies including prostate, pancreas, and urinary bladder cancers. Tumor suppression has been reported by anti-PSCA antibody. Small and high affinity single chain antibodies (scFv) have been introduced as effective agents for cancer immunotargeting approaches. In the present study, we used a phage antibody display library of scFv and selected two antibodies against two immunodominant epitopes of PSCA by panning process. The reactivity of the scFvs for the corresponding epitopes was determined by phage ELISA. The binding specificity of antibodies to PSCA-expressing prostate cancer cell line, DU-145, was analyzed by flow cytometry. The antiproliferative and apoptotic induction effects were evaluated by MTT and Annexin-V assays, respectively. Results represented functional scFv C5-II which could bind specifically to DU-145 cells and significantly inhibited the proliferation of these cells (61%) with no effect on PSCA-negative cells. The antibody also induced apoptosis in the PSCA expressing cells. The percentage of the apoptotic cells after 24 hrs of exposure to 500 scFv/cell was 33.80%. These results demonstrate that the functional anti-PSCA scFv C5-II has the potential to be considered as a new agent for targeted therapy of prostate cancer.
A Genetic Mouse Model of Invasive Endometrial Cancer Driven by Concurrent Loss of Pten and Lkb1 Is Highly Responsive to mTOR Inhibition
Authors: Cheng Hailing , Liu Pixu , Zhang Fan , Xu Erbo , Symonds Lynn , Ohlson Carolynn E. , Bronson Roderick T. , Maira Sauveur-Michel , Di Tomaso Emmanuelle , Li Jane , Myers Andrea P. , Cantley Lewis C. , Mills Gordon B. , Zhao Jean J.
Published: December 2013

Signals from the tumor suppressors PTEN and LKB1 converge on mTOR to negatively regulate its function in cancer cells. Notably, both of these suppressors are attenuated in a significant fraction of human endometrial tumors. In this study, we generated a genetic mouse model of endometrial cancer driven by concomitant loss of these suppressors to gain pathophysiological insight into this disease. Dual loss of Pten and Lkb1 in the endometrial epithelium led to rapid development of advanced endometrioid endometrial tumors with 100% penetrance and short host survival. The tumors displayed dysregulated phosphatidylinositol 3-kinase (PI3K)/Akt and Lkb1/Ampk signaling with hyperactivation of mTOR signaling. Treatment with a dual PI3K/mTOR inhibitor, BEZ235, extended the time before tumor onset and prolonged overall survival. The PI3K inhibitor GDC-0941 used as a single agent reduced the growth rate of primary tumor implants in Pten/Lkb1-deficient mice, and the mTOR inhibitor RAD001 was unexpectedly as effective as BEZ235 in triggering tumor regression. In parallel, we also found that ectopic expression of LKB1 in PTEN/LKB1-deficient human endometrial cancer cells increased their sensitivity to PI3K inhibition. Together, our results demonstrated that Pten/Lkb1-deficient endometrial tumors rely strongly on deregulated mTOR signaling, and they provided evidence that LKB1 status may modulate the response of PTEN-deficient tumors to PI3K or mTOR inhibitors. Cancer Res; 74(1); 15–23. ©2013 AACR.
Colon Cancer Cells Escape 5FU Chemotherapy-Induced Cell Death by Entering Stemness and Quiescence Associated with the c-Yes/YAP Axis
Authors: Touil Yasmine , Igoudjil Wassila , Corvaisier Matthieu , Dessein Anne-Frédérique , Vandomme Jérôme , Monté Didier , Stechly Laurence , Skrypek Nicolas , Langlois Carole , Grard Georges , Millet Guillaume , Leteurtre Emmanuelle , Dumont Patrick , Truant Stéphanie , Pruvot François-René , Hebbar Mohamed , Fan Fan , Ellis Lee M. , Formstecher Pierre , Van Seuningen Isabelle , Gespach Christian , Polakowska Renata , Huet Guillemette
Published: December 2013

Purpose: Metastasis and drug resistance are the major limitations in the survival and management of patients with cancer. This study aimed to identify the mechanisms underlying HT29 colon cancer cell chemoresistance acquired after sequential exposure to 5-fluorouracil (5FU), a classical anticancer drug for treatment of epithelial solid tumors. We examined its clinical relevance in a cohort of patients with colon cancer with liver metastases after 5FU-based neoadjuvant chemotherapy and surgery.

Results: We show that a clonal 5F31 cell population, resistant to 1 μmol/L 5FU, express a typical cancer stem cell–like phenotype and enter into a reversible quiescent G0 state upon reexposure to higher 5FU concentrations. These quiescent cells overexpressed the tyrosine kinase c-Yes that became activated and membrane-associated upon 5FU exposure. This enhanced signaling pathway induced the dissociation of the Yes/YAP (Yes-associated protein) molecular complex and depleted nuclear YAP levels. Consistently, YES1 silencing decreased nuclear YAP accumulation and induced cellular quiescence in 5F31 cells cultured in 5FU-free medium. Importantly, YES1 and YAP transcript levels were higher in liver metastases of patients with colon cancer after 5FU-based neoadjuvant chemotherapy. Moreover, the YES1 and YAP transcript levels positively correlated with colon cancer relapse and shorter patient survival (P < 0.05 and P < 0.025, respectively).

Conclusions: We identified c-Yes and YAP as potential molecular targets to eradicate quiescent cancer cells and dormant micrometastases during 5FU chemotherapy and resistance and as predictive survival markers for colon cancer. Clin Cancer Res; 20(4); 837–46. ©2013 AACR.
p53/mdm2 Feedback Loop Sustains miR-221 Expression and Dictates the Response to Anticancer Treatments in Hepatocellular Carcinoma
Authors: Fornari Francesca , Milazzo Maddalena , Galassi Marzia , Callegari Elisa , Veronese Angelo , Miyaaki Hisamitsu , Sabbioni Silvia , Mantovani Vilma , Marasco Elena , Chieco Pasquale , Negrini Massimo , Bolondi Luigi , Gramantieri Laura
Published: December 2013

The overexpression of microRNA-221 (miR-221) is reported in several human cancers including hepatocellular carcinoma, and its targeting by tailored treatments has been proposed. The evidence supporting the role of miR-221 in cancer is growing and has been mainly focused on the discovery of miR-221 targets as well as on its possible therapeutic exploitations. However, the mechanism sustaining miR-221 aberrant expression remains to be elucidated. In this study, MDM2 (E3 ubiquitin-protein ligase homolog), a known p53 (TP53) modulator, is identified as a direct target of miR-221, and a feed-forward loop is described that sustains miR-221 aberrant expression. Interestingly, miR-221 can activate the p53/mdm2 axis by inhibiting MDM2 and, in turn, p53 activation contributes to miR-221 enhanced expression. Moreover, by modulating the p53 axis, miR-221 impacts cell-cycle progression and apoptotic response to doxorubicin in hepatocellular carcinoma–derived cell lines. Finally, CpG island methylation status was assessed as a causative event associated with miR-221 upregulation in hepatocellular carcinoma cells and primary tumor specimens. In hepatocellular carcinoma–derived cell lines, pharmacologically induced DNA hypomethylation potentiated a significant increase in miR-221 expression. These data were confirmed in clinical specimens of hepatocellular carcinoma in which elevated miR-221 expression was associated with the simultaneous presence of wild-type p53 and DNA hypomethylation.

Implications: These findings reveal a novel miR-221–sustained regulatory loop that determines a p53-context-specific response to doxorubicin treatment in hepatocellular carcinoma. Mol Cancer Res; 12(2); 203–16. ©2013 AACR.
A Systems Biology Approach to Personalizing Therapeutic Combinations
Authors: Kwong Lawrence N. , Heffernan Timothy P. , Chin Lynda
Published: December 2013

Summary: The identification of evidence-based, efficacious drug combinations for each cancer, among thousands of potential permutations, is a daunting task. In this perspective, we propose a systematic approach to defining such combinations by molecularly benchmarking a drug against a desired state of efficacy using model systems. Cancer Discov; 3(12); 1339–44. ©2013 AACR.
Clinical Efficacy of Autologous Plasma Therapy for Atopic Dermatitis
Authors: Cho Su-Mi , Kim Myoung-Eun , Kim Jin-Young , Park Jun-Chul , Nahm Dong-Ho
Published: December 2013

Background: The clinical efficacy of autologous blood therapy (ABT) in patients with atopic dermatitis (AD) was demonstrated by a randomized double-blind placebo-controlled study. To characterize the blood component mediating the therapeutic efficacy of ABT for AD, we evaluated the clinical efficacy of autologous plasma therapy (APT) and autologous high-molecular-weight plasma protein fraction therapy (AHPT) in patients with AD in this study. Methods: A total of 22 patients with recalcitrant AD were treated with 8 weekly intramuscular injections of either autologous plasma (n = 11) or autologous high-molecular-weight plasma protein fraction (n = 11) for 7 weeks. Results: The clinical severity score of AD (SCORAD value) of 11 patients who completed AHPT significantly decreased from 79.7 ± 17.0 (mean ± SD) at baseline to 65.8 ± 16.4 at 6 weeks and 60.1 ± 16.0 at 7 weeks (Wilcoxon signed-rank test, p < 0.05). There were no significant differences among the SCORAD values measured at baseline (74.2 ± 19.6), at 6 weeks (66.3 ± 23.6) and at 7 weeks (67.5 ± 20.8) in 10 patients who completed APT (p > 0.05). Conclusion: This result suggests that the blood component mediating the therapeutic efficacy of ABT in patients with AD might be present in the high-molecular-weight plasma protein fraction.
Earlier Onset and Poor Prognosis of Lung Cancer in Imprisoned Patients
Authors: Carbonnaux M. , Fossard G. , Amzallag E. , Piegay C. , Perot E. , Chossegros P. , Souquet P.J. , Couraud S.
Published: December 2013

Introduction: Prison inmates are known to be more exposed to various lung cancer risk factors, and some studies have shown that lung cancer is the most common cancer in prisoners. However, no study has particularly focused on lung cancer features in this population. Method: Charts of patients with lung cancer hospitalized in one of the French secured hospital units between 1997 and 2012 were reviewed. Data from this cohort were then compared to those of two large observational studies conducted in 2000 and 2010 (KBP studies). Results: Thirty-two cases were included. All were men. The mean age was 52.2 ± 11.5 years, which was significantly lower than in the KBP-2000 (64.4 years) and KBP-2010 (65.5 years; both p < 0.0001) studies. The percentage of current smokers was much higher in prisoners (87.1 vs. 52.2 and 49.2%, respectively; both p < 0.001). Ninety percent of prisoners presented with at least one comorbidity. Lung cancer clinical presentation did not differ between prisoners and the reference populations. The median overall survival was 5.8 months (range 0-15.1) for all stages and 4.7 months (range 2.8-6.6) for stage IIIB/IV. Conclusion: Although our study suffers from limitations, prisoners seem to develop lung cancer at a younger age and their prognosis is poor.
Soluble Tumor Necrosis Factor Receptors and Heart Failure Risk in Older Adults
Authors: Marti Catherine N. , Khan Hassan , Mann Douglas L. , Georgiopoulou Vasiliki V. , Bibbins-Domingo Kirsten , Harris Tamara , Koster Annemarie , Newman Anne , Kritchevsky Stephen B. , Kalogeropoulos Andreas P. , Butler Javed
Published: December 2013

Background—

Tumor necrosis factor (TNF) levels are associated with risk for heart failure (HF). The soluble TNF type 1 (sTNF-R1) and type 2 (sTNF-R2) receptors are elevated in patients with manifest HF, but whether they are associated with risk for incident HF is unclear.

Methods and Results—

Using Cox proportional hazard models, we examined the association between baseline levels of sTNF-R1 and sTNF-R2 with incident HF risk among 1285 participants of the Health, Aging, and Body Composition Study (age, 74.0±2.9 years; 51.4% women; 41.1% black). At baseline, median (interquartile range) of TNF, sTNF-R1, and sTNF-R2 levels was 3.14 (2.42–4.06), 1.46 (1.25–1.76), and 3.43 (2.95–4.02) ng/mL, respectively. During a median follow-up of 11.4 (6.9–11.7) years, 233 (18.1%) participants developed HF. In models controlling for other HF risk factors, TNF (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.02–1.61 per log
2
increase) and sTNF-R1 (HR, 1.68; 95% CI, 1.15–2.46 per log
2
increase), but not sTNF-R2 (HR, 1.15; 95% CI, 0.80–1.63 per log
2
increase), were associated with a higher risk for HF. These associations were consistent across whites and blacks (TNF, sTNF-R1, sTNF-R2; interaction
P
=0.531, 0.091, and 0.795, respectively) and in both sexes (TNF, sTNF-R1, sTNF-R2; interaction
P
=0.491, 0.672, and 0.999, respectively). TNF-R1 was associated with a higher risk for HF with preserved versus reduced ejection fraction (HR, 1.81; 95% CI, 1.03–3.18;
P
=0.038 for preserved versus HR, 0.90; 95% CI, 0.56–1.44;
P
=0.667 for reduced ejection fraction; interaction
P
=0.05).

Conclusions—

In older adults, elevated levels of sTNF-R1 are associated with increased risk for incident HF. However, addition of TNF-R1 to the previously validated Health ABC HF risk model did not demonstrate material improvement in net discrimination or reclassification.
TE-array—a high throughput tool to study transposon transcription
Authors: Gnanakkan Veena P , Jaffe Andrew E , Dai Lixin , Fu Jie , Wheelan Sarah J , Levitsky Hyam I , Boeke Jef D , Burns Kathleen H
Published: December 2013

Background

Although transposable element (TE) derived DNA accounts for more than half of mammalian genomes and initiates a significant proportion of RNA transcripts, high throughput methods are rarely leveraged specifically to detect expression from interspersed repeats.

Results

To characterize the contribution of transposons to mammalian transcriptomes, we developed a custom microarray platform with probes covering known human and mouse transposons in both sense and antisense orientations. We termed this platform the “TE-array” and profiled TE repeat expression in a panel of normal mouse tissues. Validation with nanoString®and RNAseq technologies demonstrated that TE-array is an effective method. Our data show that TE transcription occurs preferentially from the sense strand and is regulated in highly tissue-specific patterns.

Conclusions

Our results are consistent with the hypothesis that transposon RNAs frequently originate within genomic TE units and do not primarily accumulate as a consequence of random ‘read-through’ from gene promoters. Moreover, we find TE expression is highly dependent on the tissue context. This suggests that TE expression may be related to tissue-specific chromatin states or cellular phenotypes. We anticipate that TE-array will provide a scalable method to characterize transposable element RNAs.
Antibiotic resistance, virulence determinants and production of biogenic amines among enterococci from ovine, feline, canine, porcine and human milk
Authors: Jiménez Esther , Ladero Victor , Chico Irene , Maldonado-Barragán Antonio , López María , Martín Virginia , Fernández Leonides , Fernández María , Álvarez Miguel A , Torres Carmen , Rodríguez Juan M
Published: December 2013

Background

Recent studies have shown that mammalian milk represents a continuous supply of commensal bacteria, including enterococci. The objectives of this study were to evaluate the presence of enterococci in milk of different species and to screen them for several genetic and phenotypic traits of clinical significance among enterococci.

Results

Samples were obtained from, at least, nine porcine, canine, ovine, feline and human healthy hosts. Enterococci could be isolated, at a concentration of 1.00 × 102 -1.16 × 103 CFU/ml, from all the porcine samples and, also from 85, 50, 25 and 25% of the human, canine, feline and ovine ones, respectively. They were identified as Enterococcus faecalis, Enterococcus faecium, Enterococcus hirae, Enterococcus casseliflavus and Enterococcus durans. Among the 120 initial enterococcal isolates, 36 were selected on the basis of their different PFGE profiles and further characterized. MLST analysis revealed a wide diversity of STs among the E. faecalis and E. faecium strains, including some frequently associated to hospital infections and novel STs. All the E. faecalis strains possessed some of the potential virulence determinants (cad, ccf, cob, cpd, efaA

fs
, agg2, gelE, cylA, esp

fs
) assayed while the E. faecium ones only harboured the efaA

fm
gene. All the tested strains were susceptible to tigecycline, linezolid and vancomycin, and produced tyramine. Their susceptibility to the rest of the antimicrobials and their ability to produce other biogenic amines varied depending on the strain. Enterococci strains isolated from porcine samples showed the widest spectrum of antibiotic resistance.

Conclusions

Enterococci isolated from milk of different mammals showed a great genetic diversity. The wide distribution of virulence genes and/or antibiotic resistance among the E. faecalis and E. faecium isolates indicates that they can constitute a reservoir of such traits and a risk to animal and human health.
Thyroid volume, goiter prevalence, and selenium levels in an iodine-sufficient area: a cross-sectional study
Authors: Liu Yang , Huang Hui , Zeng Jing , Sun Chengjun
Published: December 2013

Background

Selenium (Se) is a necessary element for the biosynthesis of thyroid hormones. We investigated the relationship between selenium status, thyroid volume, and goiter in a cross-sectional study in an iodine-sufficient area.

Methods

We selected residents of Chengdu (over 18 years old and living in the city for more than 5 years) using a stratified cluster sampling technique. Fifteen hundred subjects were selected for the study, which involved a questionnaire survey, physical examination, thyroid ultrasound, serum thyroid function test, and determination of serum selenium level. Thyroid volume was calculated from the thickness, width, length, and a corrective factor for each lobe. Ultimately, 1,205 subjects completed the investigation and were included in our study. Additionally, 80 school-age children were selected to provide urine samples for urinary iodine analysis. We analyzed the data using appropriate nonparametric and parametric statistical tests.

Results

The median urinary iodine value was 184 μg/L in school-age children, indicating iodine sufficiency. The median serum selenium level of the 1,205 subjects was 52.63 (interquartile range [IQR] : 40.40-67.00) μg/L. The median thyroid volume was 9.93 (IQR: 7.71-12.57) mL; both log-transformed serum selenium and log-transformed thyroid volume were Gaussian distributions (P = .638 and P = .046, respectively). The prevalences of goiter and thyroid nodules were 8.8% and 18.6%. The prevalences of positive thyroid autoantibodies, thyroperoxidase autoantibodies and thyroglobulin autoantibodies were 16.7%, 12.0%, and 11.1%, respectively. In the general linear regression model, there were positive associations between serum selenium and age, and body mass index. We found no association between serum selenium and thyroid-stimulating hormone. In simple linear regression analyses, we found no association between thyroid volume and serum selenium. There were no significant differences in serum selenium between persons with or without goiter. Serum selenium was not a risk factor for goiter.

Conclusion

In our study population, serum selenium was neither associated with thyroid volume nor with goiter in an iodine-sufficient area. More studies should be conducted by following non-goitrous persons over time and monitoring their selenium status.
Psychometric properties of the World Health Organization quality of life assessment – brief in methadone patients: a validation study in northern Taiwan
Authors: Fu Tiffany Szu-Ting , Tuan Yung-Change , Yen Muh-Yong , Wu Wei-Hsin , Huang Chun-Wei , Chen Wei-Ti , Li Chiang-Shan R , Lee Tony Szu-Hsien
Published: December 2013

Background

Quality of life (QOL) is an important outcome measure in the treatment of heroin addiction. The Taiwan version of the World Health Organization Quality of Life assessment (WHOQOL-BREF [TW]) has been developed and studied in various groups, but not specifically in a population of injection drug users. The aim of this study was to analyze the psychometric properties of the WHOQOL-BREF (TW) in a sample of injection drug users undergoing methadone maintenance treatment.

Methods

A total of 553 participants were interviewed and completed the instrument. Item-response distributions, internal consistency, corrected item-domain correlation, criterion-related validity, and construct validity through confirmatory factor analysis were evaluated.

Results

The frequency distribution of the 4 domains of the WHOQOL-BREF (TW) showed no floor or ceiling effects. The instrument demonstrated adequate internal consistency (Cronbach’s alpha coefficients were higher than 0.7 across the 4 domains) and all items had acceptable correlation with the corresponding domain scores (r = 0.32-0.73). Correlations (p < 0.01) of the 4 domains with the 2 benchmark items assessing overall QOL and general health were supportive of criterion-related validity. Confirmatory factor analysis yielded marginal goodness-of-fit between the 4-domain model and the sample data.

Conclusions

The hypothesized WHOQOL-BREF measurement model was appropriate for the injection drug users after some adjustments. Despite different patterns found in the confirmatory factor analysis, the findings overall suggest that the WHOQOL-BREF (TW) is a reliable and valid measure of QOL among injection drug users and can be utilized in future treatment outcome studies. The factor structure provided by the study also helps to understand the QOL characteristics of the injection drug users in Taiwan. However, more research is needed to examine its test-retest reliability and sensitivity to changes due to treatment.