bluuebunny/crossref_metadata_2025 huggingface dataset:
OpenStream
Authors: Pop Antoniu , Cohen Albert
Published: January 2013

We present OpenStream, a data-flow extension of OpenMP to express dynamic dependent tasks. The language supports nested task creation, modular composition, variable and unbounded sets of producers/consumers, and first-class streams. These features, enabled by our original compilation flow, allow translating high-level parallel programming patterns, like dependences arising from StarSs' array regions, or universal low-level primitives like futures. In particular, these dynamic features can be embedded efficiently and naturally into an unmanaged imperative language, avoiding the complexity and overhead of a concurrent garbage collector. We demonstrate the performance advantages of a data-flow execution model compared to more restricted task and barrier models. We also demonstrate the efficiency of our compilation and runtime algorithms for the support of complex dependence patterns arising from StarSs benchmarks.
Delta-compressed caching for overcoming the write bandwidth limitation of hybrid main memory
Authors: Du Yu , Zhou Miao , Childers Bruce , Melhem Rami , Mossé Daniel
Published: January 2013

Limited PCM write bandwidth is a critical obstacle to achieve good performance from hybrid DRAM/PCM memory systems. The write bandwidth is severely restricted in PCM devices, which harms application performance. Indeed, as we show, it is more important to reduce PCM write traffic than to reduce PCM read latency for application performance. To reduce the number of PCM writes, we propose a DRAM cache organization that employs compression. A new delta compression technique for modified data is used to achieve a large compression ratio. Our approach can selectively and predictively apply compression to improve its efficiency and performance. Our approach is designed to facilitate adoption in existing main memory compression frameworks. We describe an instance of how to incorporate delta compression in IBM's MXT memory compression architecture when used for DRAM cache in a hybrid main memory. For fourteen representative memory-intensive workloads, on average, our delta compression technique reduces the number of PCM writes by 54.3%, and improves IPC performance by 24.4%.
Finding good optimization sequences covering program space
Authors: Purini Suresh , Jain Lakshya
Published: January 2013

The compiler optimizations we enable and the order in which we apply them on a program have a substantial impact on the program execution time. Compilers provide default optimization sequences which can give good program speedup. As the default sequences have to optimize programs with different characteristics, they embed in them multiple subsequences which can optimize different classes of programs. These multiple subsequences may falsely interact with each other and affect the potential program speedup achievable. Instead of searching for a single
universally
optimal sequence, we can construct a small set of
good sequences
such that for every program class there exists a near-optimal optimization sequence in the good sequences set. If we can construct such a good sequences set which covers all the program classes in the program space, then we can choose the best sequence for a program by trying all the sequences in the good sequences set. This approach completely circumvents the need to solve the program classification problem. Using a sequence set size of around 10 we got an average speedup up to 14% on PolyBench programs and up to 12% on MiBench programs. Our approach is quite different from either the iterative compilation or machine-learning-based prediction modeling techniques proposed in the literature so far. We use different training and test datasets for cross-validation as against the Leave-One-Out cross-validation technique.
A dynamic self-scheduling scheme for heterogeneous multiprocessor architectures
Authors: Belviranli Mehmet E. , Bhuyan Laxmi N. , Gupta Rajiv
Published: January 2013

Today's heterogeneous architectures bring together multiple general-purpose CPUs and multiple domain-specific GPUs and FPGAs to provide dramatic speedup for many applications. However, the challenge lies in utilizing these heterogeneous processors to optimize overall application performance by minimizing workload completion time. Operating system and application development for these systems is in their infancy.

In this article, we propose a new scheduling and workload balancing scheme, HDSS, for execution of loops having dependent or independent iterations on heterogeneous multiprocessor systems. The new algorithm dynamically learns the computational power of each processor during an adaptive phase and then schedules the remainder of the workload using a weighted self-scheduling scheme during the completion phase. Different from previous studies, our scheme uniquely considers the runtime effects of block sizes on the performance for heterogeneous multiprocessors. It finds the right trade-off between large and small block sizes to maintain balanced workload while keeping the accelerator utilization at maximum. Our algorithm does not require offline training or architecture-specific parameters.

We have evaluated our scheme on two different heterogeneous architectures: AMD 64-core Bulldozer system with nVidia Fermi C2050 GPU and Intel Xeon 32-core SGI Altix 4700 supercomputer with Xilinx Virtex 4 FPGAs. The experimental results show that our new scheduling algorithm can achieve performance improvements up to over 200% when compared to the closest existing load balancing scheme. Our algorithm also achieves full processor utilization with all processors completing at nearly the same time which is significantly better than alternative current approaches.
SCIN-cache
Authors: Negi Anurag , Titos-Gil Ruben
Published: January 2013

This article describes cache designs for efficiently supporting speculative techniques like transactional memory on chip multiprocessors with multithreaded cores. On-demand allocation and prompt freeing of speculative cache space in the design reduces the burden on nonspeculative execution. Quick access to both clean and speculative versions of data for multiple contexts provides flexibility and greater design freedom to HTM architects. Performance analysis shows the designs stand up well against other HTM design proposals, with potential performance gains in high contention applications with small transactions.
Variable projection methods for approximate GCD computations
Authors: Usevich Konstantin , Markovsky Ivan
Published: January 2013

This paper presents optimization methods and software for the approximate GCD problem of multiple univariate polynomials in the weighted 2-norm. Backward error minimization and Sylvester low-rank approximation formulations of the problem are solved by the variable projection method. Optimization methods are implemented in publicly available C++ software package with an interface to MATLAB. Results on computational complexity are presented.
Making alive register transfer level and transaction level modeling in Ada
Authors: Mahani Negin
Published: January 2013

Over the past 50 years, design of hardware has evolved from transistor level to register transfer level (RTL), and now to transaction level. Transaction Level Modeling (TLM) enhances simulation performance of today's complex digital systems and also provides the ability of early design space exploration. TLM divides a system into computation parts, i.e. processing elements, and communication parts, i.e. channels and sockets. The inherent concurrency of Ada along with its object oriented features gives it potentials for being used as a TLM language.

In this paper, we use a specialized form of Ada as a system description language, like the way SystemC is used for description of systems. We refer to our form of Ada as SystemAda and we use a public Ada compiler (Gnat) to evaluate system descriptions written in Ada. SystemAda is meant for modeling system behavior and structure at the transaction level and we consider possible approaches for extending Ada to meet these requirements. This paper discusses the specification of our proposed SystemAda, its hardware description style, its RTL link, and description of a TLM 1.0 channel using SystemAda.
Challenges and communities of medical informatics research
Authors: Hristidis Vagelis
Published: January 2013

This article discusses experiences and lessons learned from working on health informatics research as a computer scientist. In particular, I present challenges faced when conducting research on medical informatics, and explain some of the aspects that make medical data and systems unique. Then, I present the two broad research communities studying medical informatics problems. Finally, I offer advice on how to bridge the gap between these communities and increase their research productivity.
XLDB Asia 2012
Authors: Meng Xiaofeng , Wang Fusheng
Published: January 2013

The Extremely Large Databases (XLDB) series of conferences/ workshops have been held successfully six times in recent years. The First XLDB Conference at Asia (XLDB Asia) was held at Beijing, China on June 22-23, 2012. The conference attracted nearly 200 participants. XLDB takes a fresh format on the organization through invited talks, lightning talks and open discussions. Most invited speakers are also owners of real extremely large data from industries and scientific research, practitioners who are handling the real data, or DBMS researchers who are researching new solutions. Based on the enthusiastic embrace and positive feedbacks from participants, we believe the conference series will continue as a venue for the discussion on the management and analysis of extremely large data sets with increasing popularity.
Isolation and TLC Densitometric Quantification of Lysergol from the Seeds of Ipomoea muricata (Linn.) Jacq.
Authors: Patil Shrikant , Nivsarkar Manish , Anandajiwala Sheetal
Published: January 2013

Seeds of Ipomoea muricata, well known in Ayurveda for its purgative action, contains mainly indole alkaloids. Lysergol (major alkaloid) exhibits hypotensive, psychotropic, and uterus and intestine-stimulating properties. TLC fingerprint profile of I. muricata seeds was developed using chloroform : methanol (95 : 5 v/v) as the mobile phase. Plate was visualized under UV 254 nm and UV 366 nm and after derivatization with Van Urk reagent. Lysergol resolved at . Further, TLC-densitometric method was developed and validated for quantification of Lysergol avoiding derivatization step. Ethyl acetate :  methanol (7 : 3 v/v) was used as the mobile phase. Linear regression analysis data for the calibration curve showed a good linear relationship () in the concentration range from 20 ng to 140 ng, with respect to the peak area. The developed method was precise with RSD for intraday (range from 1.20 to 1.89) and interday (range from 1.39 to 1.92) for 60, 80, and 100 ng/spot of Lysergol. The instrumental precision was 0.67 (% RSD). The limit of detection and limit of quantification for Lysergol were 12 ng and 40 ng, respectively. The average percentage recovery was 99.68. The amount of Lysergol was found to be 0.23% w/w. To the best of our knowledge, this is the first report for the quantification of Lysergol from I. muricata seeds without derivatization.
Monitoring of Active Human Herpes Virus 6 Infection in Iranian Patients with Different Subtypes of Multiple Sclerosis
Authors: Ramroodi Nourollah , Sanadgol Nima , Ganjali Zohre , Niazi Abbas Ali , Sarabandi Vida , Moghtaderi Ali
Published: January 2013

Background. Recently, it has been suggested that human herpes virus 6 (HHV6) may play a role in the pathogenesis of multiple sclerosis (MS). Our purpose is to determine the incidence of reactivated HHV6 in MS patients.Methods. Viral sequence analyzed by qPCR in the peripheral blood mononuclear cells (PBMCs), serum, and saliva samples of different subtypes of MS patients (n=78) and healthy controls (n=123). HHV6 IgG and IgM antibody levels measured by ELISA technique in the plasma samples of both groups. Likewise, cerebrospinal fluid (CSF) samples of some MS patients (n=38) were analyzed for viral sequence.Results. Results demonstrate increased levels of anti-HHV6-IgG (78.2% versus 76.4% in controls;P=NS), and IgM (34.6% versus 6.5% in controls;P<0.05) in MS patients. Furthermore, RRMS and SPMS patients showed relatively higher anti-HHV6 IgG and IgM compared to PPMS (P<0.001). Moreover, load of cell-free viral DNA was higher in RRMS and SPMS patients and detected in 60.2% (47/78) of MS patients, compared with 14.6% (18/123) of healthy controls (P<0.001). Moreover, load of cell-free viral DNA was higher in RRMS and SPMS patients and detected in 60.2% (47/78) of MS patients, compared with 14.6% (18/123) of healthy controls (P<0.001).Conclusions. The results extend the observation of an increased frequency of systemic reactivated HHV6 infection in MS patients with developed stages of disease.
German Spent Nuclear Fuel Legacy: Characteristics and High-Level Waste Management Issues
Authors: Schwenk-Ferrero A.
Published: January 2013

Germany is phasing-out the utilization of nuclear energy until 2022. Currently, nine light water reactors of originally nineteen are still connected to the grid. All power plants generate high-level nuclear waste like spent uranium or mixed uranium-plutonium dioxide fuel which has to be properly managed. Moreover, vitrified high-level waste containing minor actinides, fission products, and traces of plutonium reprocessing loses produced by reprocessing facilities has to be disposed of. In the paper, the assessments of German spent fuel legacy (heavy metal content) and the nuclide composition of this inventory have been done. The methodology used applies advanced nuclear fuel cycle simulation techniques in order to reproduce the operation of the German nuclear power plants from 1969 till 2022. NFCSim code developed by LANL was adopted for this purpose. It was estimated that ~10,300 tonnes of unreprocessed nuclear spent fuel will be generated until the shut-down of the ultimate German reactor. This inventory will contain ~131 tonnes of plutonium, ~21 tonnes of minor actinides, and 440 tonnes of fission products. Apart from this, ca.215 tonnes of vitrified HLW will be present. As fission products and transuranium elements remain radioactive from 104to 106years, the characteristics of spent fuel legacy over this period are estimated, and their impacts on decay storage and final repository are discussed.
Tree Pruning for New Search Techniques in Computer Games
Authors: Greer Kieran
Published: January 2013

This paper proposes a new mechanism for pruning a search game tree in computer chess. The algorithm stores and then reuses chains or sequences of moves, built up from previous searches. These move sequences have a built-in forward-pruning mechanism that can radically reduce the search space. A typical search process might retrieve a move from a Transposition Table, where the decision of what move to retrieve would be based on the position itself. This algorithm stores move sequences based on what previous sequences were better, or caused cutoffs. The sequence is then returned based on the current move only. This is therefore position independent and could also be useful in games with imperfect information or uncertainty, where the whole situation is not known at any one time. Over a small set of tests, the algorithm was shown to clearly out perform Transposition Tables, both in terms of search reduction and game-play results. Finally, a completely new search process will be suggested for computer chess or games in general.
Quality Evaluation of Ayurvedic Crude DrugDaruharidra, Its Allied Species, and Commercial Samples from Herbal Drug Markets of India
Authors: Srivastava Sharad , Rawat A. K. S.
Published: January 2013

Berberis aristataknown as “Daruharidra” in Ayurveda is a versatile medicinal plant used singly or in combination with other medicinal plants for treating a variety of ailments like jaundice, enlargement of spleen, leprosy, rheumatism, fever, morning/evening sickness, snakebite, and so forth. A major bioactive marker of this genus is an alkaloid berberine, which is known for its activity against cholera, acute diarrhea, amoebiasis, and latent malaria and for the treatment of oriental sore caused byLeishmania tropica. Although the roots ofB. aristataare considered as the official drug (Ayurvedic Pharmacopoeia of India), the study revealed that different species ofBerberis,namely.B. asiatica,B. chitria,andB. lyciumare also used under the name ofDaruharidrain different parts of the country. Detailed physicochemical and phytochemical studies of subjects like total ash, acid insoluble ash, tannins, and total alkaloids were calculated from the shade dried powdered material according to the recommended procedures. Further, heavy metal studies and quantitative estimation of berberine through HPTLC have also been performed as per ICH guidelines. A detailed study of fourBerberisspecies, namelyB. aristata,B. asiatica,B. chitria,andB. lycium,which are implicated asDaruharidraand collected from wild and ten commercial samples procured from various important drug markets in India has been carried out, which may be useful to pharmaceutical industries for the authentication of the commercial samples and exploring the possibilities of using other species as a substitute ofB. aristata.
Sex-Biased Networks and Nodes of Sexually Antagonistic Conflict in Drosophila
Authors: Hansen Matthew E. B. , Kulathinal Rob J.
Published: January 2013

Sexual antagonism, or conflict, can occur when males and females harbor opposing reproductive strategies. The large fraction of sex-biased genes in genomes present considerable opportunities for conflict to occur, suggesting that sexual antagonism may potentially be a general phenomenon at the molecular level. Here, we employ a novel strategy to identify potential nodes of sexual conflict in Drosophila melanogaster by coupling male, female, and sex-unbiased networks derived from genome-wide expression data with available genetic and protein interaction data. We find that sex-biased networks comprise a large fraction (~1/3) of the total interaction network with the male network possessing nearly twice the number of nodes (genes) relative to the female network. However, there are far less edges or interaction partners among male relative to female subnetworks as seen in their power law distributions. We further identified 598 sex-unbiased genes that can act as indirect nodes of interlocus sexual conflict as well as 271 direct nodal pairs of potential conflict between male- and female-biased genes. The pervasiveness of such potentially conflicting nodes may explain the rapid evolution of sex-biased as well as non-sex-biased genes via this molecular mechanism of sexual selection even among taxa such as Drosophila that are nominally sexually dimorphic.
Advances in Optical and Magnetooptical Scatterometry of Periodically Ordered Nanostructured Arrays
Authors: Veis Martin , Antos Roman
Published: January 2013

We review recent advances in optical and magnetooptical (MO) scatterometry applied to periodically ordered nanostructures such as periodically patterned lines, wires, dots, or holes. The techniques are based on spectroscopic ellipsometry (SE), either in the basic or generalized modes, Mueller matrix polarimetry, and MO spectroscopy mainly based on MO Kerr effect measurements. We briefly present experimental setups, commonly used theoretical approaches, and experimental results obtained by SE and MO spectroscopic analyses of various samples. The reviewed analyses are mainly related to monitoring optical critical dimensions such as
the widths, depths, and periods of the patterned elements, their real shapes, and their line edge or linewidth roughness. We also discuss the advantages and disadvantages of the optical spectroscopic techniques compared to direct monitoring techniques.
L-Shaped-Sensor-Array-Based Localization and Tracking Method for 3D Maneuvering Target
Authors: Zhang Xing , Wang Xue
Published: January 2013

The localization and tracking technology for a three-dimensional target, which is a kernel problem in the military area, has received more and more attention. This paper proposes a closed-loop system to detect 3D maneuvering targets, including data acquisition, the direction of arrival (DOA) estimation, the triangle localization, and a trajectory prediction. This system firstly uses several L-shaped sensor arrays to sample the signals of maneuvering targets. Then the 2D ESPRIT algorithm and a maximum likelihood algorithm are introduced to achieve the positions of the spatial targets. Thirdly an autoregressive (AR) particle filter (PF) algorithm is realized to predict the locations in the next moment. Finally the localization process is directed by using the predicted positions to form a positive feedback closed loop. Experiment results show that this system can enhance the robustness and accuracy of the localization and tracking for three-dimensional maneuvering targets.
SPECT versus Planar Scintigraphy as a Clinical Aid in Evaluation of the Elderly with Knee Pain
Authors: Oron Amir , Arieli Izhar , Pritsch Tamir , Even-Sapir Einat , Halperin Nahum , Agar Gabriel
Published: January 2013

Chronic knee pain is a common complaint among the elderly and appears in 30%–40% of the population over the age of 65. This study was performed in order to evaluate correlation between clinical presentation of chronic knee pain and the imaging findings of SPECT and planar bone scintigraphy. Methods. We prospectively recruited 116 patients over the age of 50 who had neither knee surgery nor trauma. Patients were divided into symptomatic and asymptomatic groups. All patients were examined by an experienced orthopedic surgeon; on the same day imaging was performed. Statistical analysis was performed to correlate physical examination findings with planar scintigraphy and SPECT findings and blood pool images. Results. In symptomatic patients, planar scintigraphy correlated significantly () with the presence of excessive joint fluid, synovial condensation, and decrease in range of motion as measured in extension and flexion and patellar grinding test. SPECT findings correlated with all of the above tests as well as with medial and patellofemoral joint tenderness. Conclusions. We believe a finding of tenderness at the medial articular crease or of the patellofemoral compartment of the knee should be considered an indication for the use of SPECT scintigraphy rather than planar scintigraphy.
Plane-Based Sampling for Ray Casting Algorithm in Sequential Medical Images
Authors: Lin Lili , Chen Shengyong , Shao Yan , Gu Zichun
Published: January 2013

This paper proposes a plane-based sampling method to improve the traditional Ray Casting Algorithm (RCA) for the fast reconstruction of a three-dimensional biomedical model from sequential images. In the novel method, the optical properties of all sampling points depend on the intersection points when a ray travels through an equidistant parallel plan cluster of the volume dataset. The results show that the method improves the rendering speed at over three times compared with the conventional algorithm and the image quality is well guaranteed.
Comparison of Atrial Fibrillation in the Young versus That in the Elderly: A Review
Authors: Sankaranarayanan Rajiv , Kirkwood Graeme , Dibb Katharine , Garratt Clifford J.
Published: January 2013

The incidence and prevalence of atrial fibrillation (AF) are projected to increase significantly worldwide, imposing a significant burden on healthcare resources. The disease itself is extremely heterogeneous in its epidemiology, pathophysiology, and treatment options based on individual patient characteristics. Whilst ageing is well recognised to be an independent risk factor for the development of AF, this condition also affects the young in whom the condition is frequently symptomatic and troublesome. Traditional thinking suggests that the causal factors and pathogenesis of the condition in the young with structurally normal atria but electrophysiological “triggers” in the form of pulmonary vein ectopics leading to lone AF are in stark contrast to that in the elderly who have AF primarily due to an abnormal substrate consisting of fibrosed and dilated atria acting in concert with the pulmonary vein triggers. However, there can be exceptions to this rule as there is increasing evidence of structural and electrophysiological abnormalities in the atrial substrate in young patients with “lone AF,” as well as elderly patients who present with idiopathic AF. These reports seem to be blurring the distinction in the pathophysiology of so-called idiopathic lone AF in the young versus that in the elderly. Moreover with availability of improved and modern investigational and diagnostic techniques, novel causes of AF are being reported thereby seemingly consigning the diagnosis of “lone AF” to a rather mythical existence. We shall also elucidate in this paper the differences seen in the epidemiology, causes, pathogenesis, and clinical features of AF in the young versus that seen in the elderly, thereby requiring clearly defined management strategies to tackle this arrhythmia and its associated consequences.
Impurities Effect on Carbonate Reactive Crystallization for the Wastewater
Authors: Shimizu Y. , Hirasawa I.
Published: January 2013

Reactive crystallization designed to separate nickel or copper ion from effluents has been advanced for applying to actual industrial wastewater containing impurities. In the primary reaction of this method, metal sulfate solution reacts with sodium carbonate solution in a semibatch crystallizer. In the present study, during the process of nickel or copper ions incorporation, inhibitory effect on seed growth of impurities, like cobalt, manganese, zinc, and borate and phosphate ions, was investigated. Through the 8-hour reactive crystallization, obtained particles’ characters and metals removal efficient were examined. Considering analyses data on metal component ratio in produced crystals, metal ions initial uptake rate was found to be different by the kind of seeds and impurities. And the centrifugation was performed against obtained crystals aimed for examining target metal purity improvement. The results indicated that copper components can incorporate and remove other metal ions easily. In addition, when the anions are used as impurities, depending on the kind of anions, the effect of damaging the surface of seeds or producing many fine particles has been confirmed.
Therapeutic Efficacy of Bifunctional siRNA Combining TGF-β1 Silencing with RIG-I Activation in Pancreatic Cancer
Authors: Ellermeier Jonathan , Wei Jiwu , Duewell Peter , Hoves Sabine , Stieg Mareike R. , Adunka Tina , Noerenberg Daniel , Anders Hans-Joachim , Mayr Doris , Poeck Hendrik , Hartmann Gunther , Endres Stefan , Schnurr Max
Published: January 2013

Deregulated TGF-β signaling in pancreatic cancer promotes tumor growth, invasion, metastasis, and a potent immunosuppressive network. A strategy for disrupting this tumor-promoting pathway is silencing TGF-β by siRNA. By introducing a triphosphate group at the 5′ end of siRNA (ppp-siRNA), gene silencing can be combined with immune activation via the cytosolic helicase retinoic acid-inducible gene I (RIG-I), a ubiquitously expressed receptor recognizing viral RNA. We validated RIG-I as a therapeutic target by showing that activation of RIG-I in pancreatic carcinoma cells induced IRF-3 phosphorylation, production of type I IFN, the chemokine CXCL10, as well as caspase-9–mediated tumor cell apoptosis. Next, we generated a bifunctional ppp-siRNA that combines RIG-I activation with gene silencing of TGF-β1 (ppp-TGF-β) and studied its therapeutic efficacy in the orthotopic Panc02 mouse model of pancreatic cancer. Intravenous injection of ppp-TGF-β reduced systemic and tumor-associated TGF-β levels. In addition, it induced high levels of type I IFN and CXCL10 in serum and tumor tissue, systemic immune cell activation, and profound tumor cell apoptosis in vivo. Treatment of mice with established tumors with ppp-TGF-β significantly prolonged survival as compared with ppp-RNA or TGF-β siRNA alone. Furthermore, we observed the recruitment of activated CD8+ T cells to the tumor and a reduced frequency of CD11b+ Gr-1+ myeloid cells. Therapeutic efficacy was dependent on CD8+ T cells, whereas natural killer cells were dispensable. In conclusion, combing TGF-β gene silencing with RIG-I signaling confers potent antitumor efficacy against pancreatic cancer by breaking tumor-induced CD8+ T cell suppression. Cancer Res; 73(6); 1709–20. ©2013 AACR.
The Planar Cell Polarity Pathway Drives Pathogenesis of Chronic Lymphocytic Leukemia by the Regulation of B-Lymphocyte Migration
Authors: Kaucká Markéta , Plevová Karla , Pavlová Šárka , Janovská Pavlína , Mishra Archana , Verner Jan , Procházková Jiřina , Krejčí Pavel , Kotašková Jana , Ovesná Petra , Tichý Boris , Brychtová Yvona , Doubek Michael , Kozubík Alois , Mayer Jiří , Pospíšilová Šárka , Bryja Vítězslav
Published: January 2013

The planar cell polarity (PCP) pathway is a conserved pathway that regulates cell migration and polarity in various contexts. Here we show that key PCP pathway components such as Vangl2, Celsr1, Prickle1, FZD3, FZD7, Dvl2, Dvl3, and casein kinase 1 (CK1)-ϵ are upregulated in B lymphocytes of patients with chronic lymphocytic leukemia (CLL). Elevated levels of PCP proteins accumulate in advanced stages of the disease. Here, we show that PCP pathway is required for the migration and transendothelial invasion of CLL cells and that patients with high expression of PCP genes, FZD3, FZD7, and PRICKLE1, have a less favorable clinical prognosis. Our findings establish that the PCP pathway acts as an important regulator of CLL cell migration and invasion. PCP proteins represent an important class of molecules regulating pathogenic interaction of CLL cells with their microenvironment. Cancer Res; 73(5); 1491–501. ©2012 AACR.
Prooncogenic Factors miR-23b and miR-27b Are Regulated by Her2/Neu, EGF, and TNF-α in Breast Cancer
Authors: Jin Lianjin , Wessely Oliver , Marcusson Eric G. , Ivan Cristina , Calin George A. , Alahari Suresh K.
Published: January 2013

miRNAs (miR) are a critical class of small (21–25 nucleotides) noncoding endogenous RNAs implicated in gene expression regulation. We identified miR-23b and miR-27b as miRNAs that are highly upregulated in human breast cancer. We found that engineered knockdown of miR-23b and miR-27b substantially repressed breast cancer growth. Nischarin (NISCH) expression was augmented by knockdown of miR-23b as well as miR-27b. Notably, these miRNAs and Nischarin were inversely expressed in human breast cancers, underscoring their biologic relevance. We showed the clinical relevance of the expression of these miRNAs and showed that high expression of miR-23b and miR-27b correlates with poor outcome in breast cancer. Moreover, intraperitoneally delivered anti-miR-27b restored Nischarin expression and decreased tumor burden in a mouse xenograft model of human mammary tumor. Also, we report for the first time that HER2/neu (ERBB2), EGF, and TNF-α promote miR-23b/27b expression through the AKT/NF-κB signaling cascade. Nischarin was found to regulate miR-27b/23b expression through a feedback loop mechanism by suppressing NF-κB phosphorylation. Because anti-miR-27b compounds that suppress miR-27b inhibit tumor growth, the anti-miR-27b seems to be a good candidate for the development of new antitumor therapies. Cancer Res; 73(9); 2884–96. ©2013 AACR.
Diffuse Large B-cell Lymphoma in the Elderly: A Review of Potential Difficulties
Authors: Sarkozy Clémentine , Coiffier Bertrand
Published: January 2013

Half of patients with diffuse large B-cell lymphoma (DLBCL) are more than 65 years old. These elderly patients frequently have other diseases, some of them severe, which may alter their ability to receive standard curative therapy. However, these associated diseases are heterogeneous and only a few contraindicate chemotherapy treatments. We reviewed all potential difficulties, such as the evaluation of comorbidities, the heterogeneous functional status of this population, and the consequences of the aging process that might be associated with treating these patients, and now propose solutions. As standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy may cure the majority of patients, it must always be the first proposed option. With this approach, elderly patients with DLBCL treated with a curative intent can reach a complete remission and have a similar outcome as younger patients. Reduced dose intensity must be applied for very elderly patients or those unfit for full-dose anthracycline. The critical question for a physician is why these patients cannot be treated with the standard regimen, namely R-CHOP. Clin Cancer Res; 19(7); 1660–9. ©2013 AACR.
Antitumor Effect of SIRT1 Inhibition in Human HCC Tumor Models In Vitro and In Vivo
Authors: Portmann Simone , Fahrner René , Lechleiter Antje , Keogh Adrian , Overney Sarah , Laemmle Alexander , Mikami Kei , Montani Matteo , Tschan Mario P. , Candinas Daniel , Stroka Deborah
Published: January 2013

Sirtuins (SIRT1-7) are a highly conserved family of NAD+-dependent enzymes that control the activity of histone and nonhistone regulatory proteins. SIRT1 is purposed to promote longevity and to suppress the initiation of some cancers. Nevertheless, SIRT1 is reported to function as a tumor suppressor as well as an oncogenic protein. Our data show that compared with normal liver or surrounding tumor tissue, SIRT1 is strongly overexpressed in human hepatocellular carcinoma (HCC). In addition, human HCC cell lines (Hep3B, HepG2, HuH7, HLE, HLF, HepKK1, skHep1) were screened for the expression of the sirtuin family members and only SIRT1 was consistently overexpressed compared with normal hepatocytes. To determine its effect on HCC growth, SIRT1 activity was inhibited either with lentiviruses expressing short hairpin RNAs or with the small molecule inhibitor, cambinol. Knockdown or inhibition of SIRT1 activity had a cytostatic effect, characterized by an altered morphology, impaired proliferation, an increased expression of differentiation markers, and cellular senescence. In an orthotopic xenograft model, knockdown of SIRT1 resulted in 50% fewer animals developing tumors and cambinol treatment resulted in an overall lower tumor burden. Taken together, our data show that inhibition of SIRT1 in HCC cells impairs their proliferation in vitro and tumor formation in vivo. These data suggest that SIRT1 expression positively influences the growth of HCC and support further studies aimed to block its activity alone or in combination as a novel treatment strategy. Mol Cancer Ther; 12(4); 499–508. ©2013 AACR.
Novel Inhibitors of Rad6 Ubiquitin Conjugating Enzyme: Design, Synthesis, Identification, and Functional Characterization
Authors: Sanders Matthew A. , Brahemi Ghali , Nangia-Makker Pratima , Balan Vitaly , Morelli Matteo , Kothayer Hend , Westwell Andrew D. , Shekhar Malathy P.V.
Published: January 2013

Protein ubiquitination is important for cell signaling, DNA repair, and proteasomal degradation, and it is not surprising that alterations in ubiquitination occur frequently in cancer. Ubiquitin-conjugating enzymes (E2) mediate ubiquitination by selective interactions with ubiquitin-activating (E1) and ubiquitin ligase (E3) enzymes, and thus selective E2 small molecule inhibitor (SMI) will provide specificity unattainable with proteasome inhibitors. Here we describe synthesis and functional characterization of the first SMIs of human E2 Rad6B, a fundamental component of translesion synthesis DNA repair. A pharmacophore model for consensus E2 ubiquitin-binding sites was generated for virtual screening to identify E2 inhibitor candidates. Twelve triazine (TZ) analogs screened in silico by molecular docking to the Rad6B X-ray structure were verified by their effect on Rad6B ubiquitination of histone H2A. TZs #8 and 9 docked to the Rad6B catalytic site with highest complementarity. TZs #1, 2, 8, and 9 inhibited Rad6B-ubiquitin thioester formation and subsequent ubiquitin transfer to histone H2A. SMI #9 inhibition of Rad6 was selective as BCA2 ubiquitination by E2 UbcH5 was unaffected by SMI #9. SMI #9 more potently inhibited proliferation, colony formation, and migration than SMI #8, and induced MDA-MB-231 breast cancer cell G2–M arrest and apoptosis. Ubiquitination assays using Rad6 immunoprecipitated from SMI #8- or 9-treated cells confirmed inhibition of endogenous Rad6 activity. Consistent with our previous data showing Rad6B-mediated polyubiquitination stabilizes β-catenin, MDA-MB-231 treatment with SMIs #8 or 9 decreased β-catenin protein levels. Together these results describe identification of the first Rad6 SMIs. Mol Cancer Ther; 12(4); 373–83. ©2013 AACR.
Nuclear Expression of β-Catenin Promotes RB Stability and Resistance to TNF-Induced Apoptosis in Colon Cancer Cells
Authors: Han Jinbo , Soletti Rossana C. , Sadarangani Anil , Sridevi Priya , Ramirez Michael E. , Eckmann Lars , Borges Helena L. , Wang Jean Y.J.
Published: January 2013

Tumor necrosis factor (TNF)-α promotes tumor development under chronic inflammation. Because TNF also activates caspase-8, selective inhibition of TNF-induced extrinsic apoptosis would be required for inflammation-associated tumor growth. In a mouse model of inflammation-associated colon carcinogenesis, we found nuclear expression of β-catenin in tumors of wild-type, but not mutant, mice that were made resistant to TNF-induced apoptosis by a germline mutation blocking caspase cleavage of the retinoblastoma (RB) protein, despite similar frequencies of β-catenin exon-3 mutations in these two genetic backgrounds. TNF-induced apoptosis was also attenuated in human colon cancer cell lines with genetically activated β-catenin. However, we found that HCT116 cells, which contain an activated allele of β-catenin but do not express nuclear β-catenin, were sensitive to TNF-induced apoptosis. In HCT116 cells, TNF stimulated efficient RB cleavage that preceded chromatin condensation. In contrast, TNF did not induce RB cleavage in colon cancer cells expressing nuclear β-catenin and these cells could be sensitized to basal and/or TNF-induced apoptosis by the knockdown of β-catenin or RB. In the apoptosis-resistant colon cancer cells, knockdown of β-catenin led to a reduction in the RB protein without affecting RB mRNA. Furthermore, ectopic expression of the caspase-resistant, but not the wild-type, RB re-established resistance to TNF-induced caspase activation in colon cancer cells without β-catenin. Together, these results suggest that nuclear β-catenin–dependent RB stabilization suppresses TNF-induced apoptosis in caspase-8–positive colon cancer cells.

Visual Overview: http://mcr.aacrjournals.org/content/11/3/207/F1.large.jpg.

Mol Cancer Res; 11(3); 207–18. ©2012 AACR.
Polymorphisms near Interleukin 28B Gene Are Not Associated with Hepatitis B Virus Clearance, Hepatitis B e Antigen Clearance and Hepatocellular Carcinoma Occurrence
Authors: Lee Dong Hyeon , Cho Yuri , Seo Ji Yeon , Kwon Jung Hee , Cho Eun Ju , Jang Eun Sun , Kwak Min-Sun , Cheong Jae Youn , Cho Sung Won , Lee Jeong-Hoon , Yu Su Jong , Yoon Jung-Hwan , Lee Hyo-Suk , Kim Chung Yong , Shin Hyoung Doo , Kim Yoon Jun
Published: January 2013

Background: Polymorphisms near the IL28B gene have been proposed to be strongly associated with treatment response and the rate of spontaneous clearance of hepatitis C virus infection, and treatment response of hepatitis B virus (HBV) infection. In this study, we aimed to determine whether these polymorphisms could affect natural courses of HBV infection. Methods: Genetic variations were identified through direct DNA sequencing using TaqMan assay in 1,439 patients with past or present HBV infection. Subjects included 404 spontaneously recovered patients, 313 chronic hepatitis B (CHB) patients, 305 liver cirrhosis (LC) patients and 417 hepatocellular carcinoma (HCC) patients. Three polymorphisms near the IL28B gene, rs8099917T>G, rs12979860C>T and rs12980275A>G, were identified. Associations between these polymorphisms and HBV clearance, hepatitis B e antigen (HBeAg) clearance as well as HCC occurrence among patients were analyzed using logistic regression analyses adjusted for age and gender. Results: There were no significant associations between these polymorphisms and the HBV clearance both in CHB and LC groups. Similarly, these polymorphisms showed no significant associations with HBeAg clearance and the occurrence of HCC either. Discussion: No significant association was identified between polymorphisms near the IL28B gene and the natural courses of chronic HBV infection, including the HBV clearance and HCC occurrence.
Intravitreal Bevacizumab May Increase Diabetic Macular Edema in Eyes with Attached Posterior Vitreous
Authors: Ozsutcu Mustafa , Gulkilik Gokhan , Ayintap Emre , Altinisik Muhammed , Demirci Goktug , Aras Cengiz
Published: January 2013

Purpose: To report 2 eyes of a patient which developed vitreomacular traction (VMT)1 month after intravitreal bevacizumab (IVB) injection. Materials and Methods: A 45-year-old female with bilateral diffuse diabetic macular edema (DME) received bilateral IVB. Results: Her initial visual acuity (VA) was 0.15 and 0.2 in OD and OS, respectively. Central foveal thickness (CFT) was 568 and 662 µm in OD and OS, respectively, without any sign of VMT. Both eyes responded well initially but developed VMT at 1 month. This time, intravitreal triamcinolone (IVTA) injection was performed. One month after IVTA injection, VMT was released and CFT decreased to 163 and 181 µm in OD and OS, respectively. Six months after IVTA injection, CFT was 163 and 153 µm, and VA was 0.7 and 0.9 in OD and OS, respectively. Conclusion: In eyes with DME and attached posterior vitreous, VMT may develop after IVB injection and increase edema. IVTA injection might be an option to release VMT before considering vitrectomy.
Bitemporal Intractable Epilepsy: Could It Be Surgically Treatable?
Authors: Chkhenkeli Sozari A. , Šramka Miron , Rakviashvili Tamas N. , Lortkipanidze George S. , Magalashvili George E. , Bregvadze Eteri Sh. , Otarashvili Alexander , Gagoshidze Tamar Sh.
Published: January 2013

Background: The goal of this study is to retrieve the attention to the treatment opportunities for this cohort of intractable bitemporal epilepsy patients who in most cases are not considered optimal candidates for surgery. Objectives: The purpose of this study is to demonstrate that electrophysiologically guided precise surgeries on both temporal lobes can have a beneficial effect on seizures without additional cognitive decline. Methods: Twenty-one intractable bitemporal epilepsy patients [13 men, 8 women, mean age 21 years (range 6–43), mean duration of illness 17 years (range 3–31), frequency of seizures 6–55 per month] underwent stereotactic cryosurgery on both temporal lobes guided by chronic and intraoperative depth electrode studies. Results: Class I (‘free of disabling seizures’) outcome was achieved for 11/21 (52%), class II (‘rare seizures’) for 6/21 (29%), and class IV (‘no worthwhile improvement’) for 4/21 (19%) patients. No worsening of seizure or clinically significant cognitive or memory impairments were observed in this cohort of patients (follow-up 5–10 years). Conclusions: The minimally invasive precise surgeries on both temporal lobes confined to the removal/lesion of just the brain tissue that exhibited epileptic activity can have a beneficial effect on seizure frequency and severity without additional devastating declines in intelligence, learning and memory.
Effect of Subthalamic Nucleus or Globus Pallidus Interna Stimulation on Oculomotor Function in Patients with Parkinson’s Disease
Authors: Fridley Jared , Adams Gareth , Sun Ping , York Michelle , Atassi Farah , Lai Eugene , Simpson Richard , Viswanathan Ashwin , Yoshor Daniel
Published: January 2013

Background: Deep brain stimulation (DBS) of either the globus pallidus interna (GPi) or subthalamic nucleus (STN) is similarly effective for treating somatomotor manifestations of Parkinson’s disease (PD), but differences in how stimulation of each target affects oculomotor function are poorly understood. Objective: We sought to determine if stimulation of the STN, but not the GPi, affects oculomotor function in PD patients. Methods: Nineteen PD patients with DBS implants (8 bilateral GPi, 9 bilateral STN and 2 unilateral STN) were studied. Testing was performed with stimulation on, then off. Somatomotor function was tested using the Unified Parkinson’s Disease Rating Scale (UPDRS) motor exam. For oculomotor testing, patients performed pro- and antisaccade tasks while monitored with an infrared eye tracker. Saccadic latency, saccadic intrusions, and square-wave jerks (SWJs) were measured for each trial. Results: As expected, UPDRS motor scores improved with both GPi and STN stimulation. With GPi stimulation, there was no significant difference in oculomotor function with stimulation on or off. However, with STN stimulation on, there was a significant increase in the mean number of SWJs/s, as well as a significant decrease in latency for both pro- and antisaccade tasks. Conclusion: Stimulation of either GPi or STN had similar effects on somatomotor function, but only STN stimulation significantly altered oculomotor function.
Constant Face Pain in Typical Trigeminal Neuralgia and Response to Gamma Knife Radiosurgery
Authors: Brisman Ronald
Published: January 2013

Background/Aims: Constant pain, especially if prominent, is sometimes considered incompatible with a diagnosis of typical idiopathic trigeminal neuralgia. This study aims to clarify the frequency of patient-reported constant pain in patients with medically intractable, typical, idiopathic trigeminal neuralgia as diagnosed with standard clinical parameters and confirmed by the response to a modified McGill questionnaire, a ‘hold-still’ test that eliminated triggers and the response to Gamma Knife radiosurgery. Method: Forty consecutive patients with typical trigeminal neuralgia were given questionnaires prior to Gamma Knife radiosurgery. Those with constant pain were further tested by being advised to hold completely still for up to 3 min. Final pain relief was evaluated after Gamma Knife radiosurgery. Results: Twenty of forty patients indicated on a questionnaire that they had constant face pain. Pain decreased on the ‘hold-still’ test on all 12 patients who were tested. Following Gamma Knife radiosurgery, there was no significant difference in pain relief in those without or with constant pain. Conclusion: Patients with typical idiopathic trigeminal neuralgia frequently report that 50% or more of their pain is constant. This constant pain is markedly decreased if the patient holds completely still for a few minutes and does not affect the outcome of Gamma Knife radiosurgery.