bluuebunny/crossref_metadata_2025 huggingface dataset:
tinyFLP and tinyCAT: software for automatic peak selection and scoring of AFLP data tables
Authors: ARTHOFER W.
Published: July 2009

Amplified fragment length polymorphism (AFLP) is a well‐established method for DNA fingerprinting. In the last years, fragment separation gradually changed from using gel to capillary electrophoresis, resulting in large, digital data sets. Automatic scoring softwares available to date are proprietary and expensive. tinyFLP/tinyCAT is a compact, open‐source software for automatic scoring of AFLP data. It reads from PeakScanner© generated tables, optimizes the conversion of peak data into a binary allelic matrix and removes operator‐mediated ambiguities from the scoring process. The output is formatted for direct use in MrBayes and other phylogenetic applications.
NONDETERMINISTIC FINITE AUTOMATA — RECENT RESULTS ON THE DESCRIPTIONAL AND COMPUTATIONAL COMPLEXITY
Authors: HOLZER MARKUS , KUTRIB MARTIN
Published: July 2009

Nondeterministic finite automata (NFAs) were introduced in [68], where their equivalence to deterministic finite automata was shown. Over the last 50 years, a vast literature documenting the importance of finite automata as an enormously valuable concept has been developed. In the present paper, we tour a fragment of this literature. Mostly, we discuss recent developments relevant to NFAs related problems like, for example, (i) simulation of and by several types of finite automata, (ii) minimization and approximation, (iii) size estimation of minimal NFAs, and (iv) state complexity of language operations. We thus come across descriptional and computational complexity issues of nondeterministic finite automata. We do not prove these results but we merely draw attention to the big picture and some of the main ideas involved.
PATH DECOMPOSITION AND SEMILINEARITY OF PETRI NETS
Authors: YEN HSU-CHUN
Published: July 2009

Semilinearity plays a key role not only in formal languages but also in the study of Petri nets. Although the reachability set of a Petri net may not be semilinear in general, there are a wide variety of subclasses of Petri nets which enjoy having semilinear reachability sets. In this paper, we develop sufficient conditions for Petri nets under which semilinearity is guaranteed. Our approach, based on the idea of path decomposition, can be used for consolidating several existing semilinearity results as well as for deriving new results all under the same framework.
ANALYSIS OF BIT-SPLIT LANGUAGES FOR PACKET SCANNING AND EXPERIMENTS WITH WILDCARD MATCHING
Authors: DIXON RYAN , EĞECIOĞLU ÖMER , SHERWOOD TIMOTHY
Published: July 2009

Monitoring traffic payloads to detect the occurrence of suspicious patterns has proven to be a useful and necessary tool for network security. Bit-splitting breaks the problem of monitoring payloads to detect such patterns into several parallel components, each of which searches for a particular bit pattern. We analyze bit-splitting as applied to Aho-Corasick style string matching and present a formal treatment of bit-slicing to prove correctness and to provide bounds on the NFA to DFA conversion of the Aho-Corasick type machine used for bit-splitting. The problem can be viewed as the recovery of a special class of regular languages over product alphabets from a collection of homomorphic images. Furthermore, in an attempt to extend the flexibility and applicability of the original bit-splitting algorithm, we explore the expressiveness and limitations of bit-slicing with respect to wildcard matching applications.
N-WAY COMPOSITION OF WEIGHTED FINITE-STATE TRANSDUCERS
Authors: ALLAUZEN CYRIL , MOHRI MEHRYAR
Published: July 2009

Composition of weighted transducers is a fundamental algorithm used in many applications, including for computing complex edit-distances between automata, or string kernels in machine learning, or to combine different components of a speech recognition, speech synthesis, or information extraction system. We present a generalization of the composition of weighted transducers, n-way composition, which is dramatically faster in practice than the standard composition algorithm when combining more than two transducers. The worst-case complexity of our algorithm for composing three transducers T1, T2, and T3resulting in T, is O(|T|Qmin (d(T1)d(T3), d(T2)) + |T|E), where |·|Qdenotes the number of states, |·|Ethe number of transitions, and d(·) the maximum out-degree. As in regular composition, the use of perfect hashing requires a pre-processing step with linear-time expected complexity in the size of the input transducers. In many cases, this approach significantly improves on the complexity of standard composition. Our algorithm also leads to a dramatically faster composition in practice. Furthermore, standard composition can be obtained as a special case of our algorithm. We report the results of several experiments demonstrating this improvement. These theoretical and empirical improvements significantly enhance performance in the applications already mentioned.
DETERMINISTIC PUSHDOWN AUTOMATA AND UNARY LANGUAGES
Authors: PIGHIZZINI GIOVANNI
Published: July 2009

The simulation of deterministic pushdown automata defined over a one-letter alphabet by finite state automata is investigated from a descriptional complexity point of view. We show that each unary deterministic pushdown automaton of size s can be simulated by a deterministic finite automaton with a number of states that is exponential in s. We prove that this simulation is tight. Furthermore, its cost cannot be reduced even if it is performed by a two-way nondeterministic automaton. We also prove that there are unary languages for which deterministic pushdown automata cannot be exponentially more succinct than finite automata. In order to state this result, we investigate the conversion of deterministic pushdown automata into context-free grammars. We prove that in the unary case the number of variables in the resulting grammar is strictly smaller than the number of variables needed in the case of nonunary alphabets.
HYPER-MINIMIZATION IN O(n2)
Authors: BADR ANDREW
Published: July 2009

Two formal languages are f-equivalent if their symmetric difference L1 Δ L2 is a finite set — that is, if they differ on only finitely many words. The study of f -equivalent languages, and particularly the DFAs that accept them, was recently introduced [3]. First, we restate the fundamental results in this new area of research. Second, we introduce our main result, which is a faster algorithm for the natural minimization problem: given a starting DFA D, find the smallest (by number of states) DFA D′ such that L(D) and L(D′) are f -equivalent. Finally, we suggest a technique that combines this hyper-minimization with the well-studied notion of a deterministic finite cover automaton [2, 4, 5], or DFCA, thereby extending the applicability of DFCAs from finite to infinite regular languages.
INFLUENCE OF INFORMATION ON CROWD DISPERSION PROCESS
Authors: TIAN H. , XUE Y. , WEI Y.-F.
Published: July 2009

The influence of information on the pedestrian in crowd dispersion process is investigated under the open boundary condition on the square lattice by the use of the lattice gas model of biased random walkers without the back step. It is found that the jamming phenomenon occurs when the total entrance density is small in spite of influence of information. The mean velocity 〈v〉 ped of the walkers moving remains a constant via a small fluctuation for the small total entrance density, but for the large total entrance density, the 〈v〉 ped increases from 0 to 1. The mean velocity 〈v〉 inf of information spreading increases from 0 to 1, and then decreases to 0. The critical density decreases with increasing the size W of the system. When the size of the system is small, the platform appears because of asymmetry in propagation of information.
INCOMPRESSIBLE MRT LATTICE BOLTZMANN MODEL WITH EIGHT VELOCITIES IN 2D SPACE
Authors: DU RUI , SHI BAOCHANG
Published: July 2009

In this paper a two-dimensional-eight-velocity lattice Boltzmann model with multi-relaxation-time is proposed for incompressible flows, in which the equilibria in the momentum space are derived from an earlier incompressible lattice Boltzmann model with single relaxation time. Through the Chapman–Enskog expansion, the incompressible Navier–Stokes equations can be recovered. Numerical tests, including the steady Poiseuille flow, the double shear flow and the driven cavity flow, have been carried out to verify the present model. The numerical results agree well with the analytical solutions or the existing results, and it is found that the present model exhibits much better numerical stability than the single relaxation time model.
EFFECT OF MEMORY AND REINFORCEMENT ON THE PROPAGATION AND MORPHOLOGY OF FRACTURE IN A TWO-DIMENSIONAL MASS-SPRING SYSTEM
Authors: ESLETA GEORGE ALLAN , MONTEROLA CHRISTOPHER
Published: July 2009

We investigate the interplay of damage accumulation and structural reinforcement in the fatigue failure of a two-dimensional mass-spring system. Damage accumulation is captured in the model such that the damage of a spring at a certain time depends on its entire deformation history. Structural reinforcement, on the other hand, is implemented by increasing the breaking thresholds of the springs [Esleta and Monterola, Comp. Phys. Comm. 20081]. We demonstrate that consistent with known empirical laws, in the presence of memory, the lifetime tfof the system subjected to a stress amplitude σ0is a power law [Formula: see text]. As damage accumulation memory f0is incorporated into the system, the transition from non-power law (f0= 0, no memory) to power law distribution is observed. Preservation of the power law behavior (equal value of γ) is guaranteed even when the system's lifetime is prolonged through static reinforcement. Finally, our model demonstrates that strengthening the stress memory of spring elements leads to more scattered crack patterns, a result that agrees phenomenologically with existing experiments.
REVERSIBILITY OF A SYMMETRIC LINEAR CELLULAR AUTOMATA
Authors: DEL REY A. MARTÍN , SÁNCHEZ G. RODRÍGUEZ
Published: July 2009

The characterization of the size of the cellular space of a particular type of reversible symmetric linear cellular automata is introduced in this paper. Specifically, it is shown that those symmetric linear cellular with 2k + 1 cells, and whose transition matrix is a k-diagonal square band matrix with nonzero entries equal to 1 are reversible. Furthermore, in this case the inverse cellular automata are explicitly computed. Moreover, the reversibility condition is also studied for a general number of cells.
NUMERICAL SIMULATION OF THE SHS TEMPERATURE FIELDS OF Al-Ti-C SYSTEM BASED ON PLANE PROPAGATING PATTERN
Authors: YING GUOBING , WANG XIANG
Published: July 2009

Three-dimensional heat equations of Al - Ti - C system at the perfect state of self-propagating high-temperature synthesis (SHS) have been established according to the temperature distribution in the reactants, which may be disturbed by density, heat capacity, porosity, conductivity and radiance. Then the effective thermal conductivity and boundary conditions have been revised according to the practical condition. The heat equation of plane propagating pattern has been derived based on the assumption that the propagating pattern at the combustion front was plane pattern. Finally, the temperature distribution of different parts in the 50 Al -40 Ti -10% C (wt.%) preformed specimen was simulated by means of finite element method. Simulation results show that the central temperature of each cross-section is higher than that of other parts. It is due to the heat transfer of the preformed specimen's side face and the fact that each center part of the cross-section has a higher average temperature than other parts. The calculated value is in good agreement with the measured value, and the error is no more than 2%.
MODELING OF PARTICLE SIZE DISTRIBUTION (PSD) DURING THE AGEING PROCESS: A MODIFIED KWN MODEL
Authors: WU LINDA , FERGUSON W. GEORGE
Published: July 2009

During the process of precipitation hardening, the phase decompositions in supersaturated solid solution (SSS) are often initiated by nucleation, then proceed to particle growth and eventually ended by Ostwald coarsening. To produce a model that is valid over the full range of transformation, the competing processes of nucleation, growth and coarsening cannot be considered in isolation. A powerful method for dealing with concomitant nucleation, growth and coarsening has been developed by Kampmann and Wagner. In the present work, the standard Kampmann and Wagner numerical model (KWN model) has been extended and modified to determine the dynamics of particle size distribution (PSD) as well as the microstructure evolution. In the present model, the newly nucleated particles are added to the corresponding size classes using the Trapezoidal shape assumption in order to eliminate the problem of discontinuity. During the growth and coarsening, since phase separations start as an interface-controlled transformation and gradually shift towards diffusion control, the mixed-mode (or co-controlled) model, therefore, is used in the present work instead of the diffusion controlled rate used in the standard KWN. Finally, the model is applied to aluminium alloys under both isothermal and non-isothermal heat treatment conditions.
INVESTMENT CLIMATE ASSESSMENT IN INDONESIA, MALAYSIA, THE PHILIPPINES AND THAILAND: RESULTS FROM POOLING FIRM-LEVEL DATA
Authors: ESCRIBANO ALVARO , GUASCH J. LUIS , DE ORTE MANUEL , PENA JORGE
Published: July 2009

Investment Climate surveys (ICs) are a recent instrument used by the World Bank to identify key obstacles to country competitiveness and to guide policy reforms and government interventions in developing countries. In this paper, panel data from four ICs of four South East Asian (SEA) countries namely, Indonesia, Malaysia, The Philippines, and Thailand, are pooled to estimate total factor productivity (TFP) and allocative efficiency aspects of firms in each country, using variants of the Olley and Pakes (1996) productivity decomposition. Several economic performance results are disaggregated to obtain country-specific evaluation of the IC impacts. To establish priorities for policy reforms, the corresponding key IC results are organized in five categories: infrastructures, red tape, corruption and crime, finance and corporate governance, quality, innovation and labor skills, and other control variables.
ARE OECD MACROECONOMIC VARIABLES TREND STATIONARY? EVIDENCE FROM PANEL STATIONARITY TESTS ALLOWING FOR A STRUCTURAL BREAK AND CROSS-SECTIONAL DEPENDENCE
Authors: HADRI KADDOUR , RAO YAO
Published: July 2009

This article applies the panel stationarity test with a break proposed by Hadri and Rao (2008) to examine whether 14 macroeconomic variables of OECD countries can be best represented as random walk or stationary fluctuations around a deterministic trend. In contrast to previous studies, based essentially on visual inspection of the break type or just applying the most general break model, we use a model selection procedure based on BIC. We do this for each time series so that heterogeneous break models are allowed for in the panel. Our results suggest, overwhelmingly, that if we account for a structural break, cross-sectional dependence and choose the break models to be congruent with the data, then the null of stationarity cannot be rejected for all the 14 macroeconomic variables examined in this article. This is in sharp contrast with the results obtained by Hurlin (2004), using the same data but a different methodology.
AN ANALYSIS OF STRATEGIC BEHAVIOR IN eBAY AUCTIONS
Authors: GONZALEZ RAUL , HASKER KEVIN , SICKLES ROBIN C.
Published: July 2009

A relatively new type of panel data analysis is becoming more and more topical in the applied econometrics literature as auction mechanisms are being explored in more depth. The typical data utilized in such studies involves repeated measures of auction outcomes, where the variable of interest involves order statistics from the sample of bids from many bids on completed auctions for a particular commodity. This article presents structural estimates of bidding behavior in eBay computer monitor auctions. We exploit characteristics of such repeated measures to analyze the efficiency of private value auctions for a relatively homogeneous good, computer monitors sold on eBay. We discuss how outcomes of the auction mechanism can be analyzed and their equilibrium outcomes assessed and evaluate the consumer surplus that is generated from such auctions. Particular attention is given to the collection of the eBay data from data recovery protocols that monitor in real time and in relative detail, characteristics of a particular auction with heterogeneity controls for different types of monitors and for different reputation effects of the auctioneer. Among other findings, our results point to a rejection of the use of Jump Bidding (Avery, 1998) or "Snipe or War" bidding (Roth and Ockenfels, 2002). We also find that longer auctions only have a small effect on price and experienced auctioneers respond to this incentive.
SOCIAL CAPITAL FORMATION AND INTRA FAMILIAL CORRELATION: A SOCIAL PANEL PERSPECTIVE
Authors: HAUSER CHRISTOPH , PFAFFERMAYR MICHAEL , TAPPEINER GOTTFRIED , WALDE JANETTE
Published: July 2009

Social capital is widely regarded to constitute an important indicator for the economic performance of a society. This paper analyzes the impact of various socio-demographic characteristics on social capital. Proxy variables for social capital are obtained from a comprehensive principal components analysis exercise using survey data from the British Household Panel Survey (BHPS). The BHPS provides information on social and economic change at the individual and household levels in Britain and the UK with an annual survey of ca. 10,000 individuals from ca. 5,000 households. Based on the 13th wave of this database, we investigate the impact of exogenous qualities, individually acquired characteristics, and of the social environment using a spatial auto-regression framework. The results show that the formation of social capital can be modeled to a very high degree of statistical accuracy. The structural effect from the households contributes substantially to the social capital level of each household member. Thus, the social capital formation can be based equally on individual measures (such as education) and social contagion processes.
FERMIONS TUNNELING FROM BARDEEN–VAIDYA BLACK HOLE VIA GENERAL TORTOISE COORDINATE TRANSFORMATION
Authors: KAI LIN , SHUZHENG YANG
Published: July 2009

In this paper, we research on the scalar field particles and 1/2 spin fermions tunneling from the event horizon of Bardeen–Vaidya black hole by semiclassical method and general tortoise coordinate transformation, and obtain the Hawking temperature and tunneling rate near the event horizon.
CHAPLYGIN INFLATION IN LOOP QUANTUM COSMOLOGY
Authors: ZHANG XIN , ZHANG JINGFEI , CUI JINGLEI , ZHANG LI
Published: July 2009

In this paper we discuss the inflationary universe in the context of a Chaplygin gas equation of state within the framework of the effective theory of loop quantum cosmology. Under the slow-roll approximation, we calculate the primordial perturbations for this model. We give the general expressions of the scalar spectral index, its running, and the tensor-to-scalar ratio, etc. For the chaotic inflation with a quadratic potential, using the WMAP 5-year results, we determine the parameters of the Chaplygin inflation model in loop quantum cosmology. The results are consistent with the WMAP observations.
THE STEADY STATE CONFIGURATIONAL DISTRIBUTION DIFFUSION EQUATION OF THE STANDARD FENE DUMBBELL POLYMER MODEL: EXISTENCE AND UNIQUENESS OF SOLUTIONS FOR ARBITRARY VELOCITY GRADIENTS
Authors: CIUPERCA IONEL SORIN , PALADE LIVIU IULIAN
Published: July 2009

The configurational distribution function, solution of an evolution (diffusion) equation of the Fokker–Planck–Smoluchowski type, is (at least part of) the corner stone of polymer dynamics: it is the key to calculating the stress tensor components. This can be reckoned from Ref. 1, where a wealth of calculation details is presented regarding various polymer chain models and their ability to accurately predict viscoelastic flows. One of the simplest polymer chain idealization is the Bird and Warner's model of finitely extensible nonlinear elastic (FENE) chains. In this work we offer a proof that the steady state configurational distribution equation has unique solutions irrespective of the (outer) flow velocity gradients (i.e. for both slow and fast flows).
Recent Advances in Image-Guided Radiotherapy for Head and Neck Carcinoma
Authors: Nath Sameer K. , Simpson Daniel R. , Rose Brent S. , Sandhu Ajay P.
Published: July 2009

Radiotherapy has a well-established role in the management of head and neck cancers. Over the past decade, a variety of new imaging modalities have been incorporated into the radiotherapy planning and delivery process. These technologies are collectively referred to as image-guided radiotherapy and may lead to significant gains in tumor control and radiation side effect profiles. In the following review, these techniques as they are applied to head and neck cancer patients are described, and clinical studies analyzing their use in target delineation, patient positioning, and adaptive radiotherapy are highlighted. Finally, we conclude with a brief discussion of potential areas of further radiotherapy advancement.
Targeting the PI3K/AKT Pathway for the Treatment of Prostate Cancer
Authors: Sarker Debashis , Reid Alison H.M. , Yap Timothy A. , de Bono Johann S.
Published: July 2009

Despite recent advances in our understanding of the biological basis of prostate cancer, the management of the disease, especially in the castration-resistant phase, remains a significant challenge. Deregulation of the phosphatidylinositol 3-kinase pathway is increasingly implicated in prostate carcinogenesis. In this review, we detail the role of this pathway in the pathogenesis of prostate cancer and the rapidly evolving therapeutic implications of targeting it. In particular, we highlight the importance of the appropriate selection of agents and combinations, and the critical role of predictive and pharmocodynamic biomarkers.
2B4 (CD244) Signaling by Recombinant Antigen-specific Chimeric Receptors Costimulates Natural Killer Cell Activation to Leukemia and Neuroblastoma Cells
Authors: Altvater Bianca , Landmeier Silke , Pscherer Sibylle , Temme Jaane , Schweer Katharina , Kailayangiri Sareetha , Campana Dario , Juergens Heribert , Pule Martin , Rossig Claudia
Published: July 2009

Purpose: Novel natural killer (NK) cell–directed strategies in cancer immunotherapy aim at specifically modulating the balance between NK cell receptor signals toward tumor-specific activation. The signaling lymphocyte activation molecule–related receptor 2B4 (CD244) is an important regulator of NK cell activation. We investigated whether 2B4-enhanced activation signals can redirect the cytolytic function of human NK cells to NK cell–resistant and autologous leukemia and tumor targets.

Experimental Design: In vitro–stimulated NK cells from healthy donors and pediatric leukemia patients were gene modified with CD19 or GD2-specific chimeric receptors containing either the T-cell receptor ζ or 2B4 endodomain alone or combined.

Results: Chimeric 2B4 signaling alone failed to induce interleukin-2 receptor up-regulation and cytokine secretion but triggered a specific degranulation response. Integration of the 2B4 endodomain into T-cell receptor ζ chimeric receptors significantly enhanced all aspects of the NK cell activation response to antigen-expressing leukemia or neuroblastoma cells, including CD25 up-regulation, secretion of IFN-γ and tumor necrosis factor-α, release of cytolytic granules, and growth inhibition, and overcame NK cell resistance of autologous leukemia cells while maintaining antigen specificity.

Conclusion: These data indicate that the 2B4 receptor has a potent costimulatory effect in NK cells. Antigen-specific 2B4ζ-expressing NK cells may be a powerful new tool for adoptive immunotherapy of leukemia and other malignancies.
Cul3 overexpression depletes Nrf2 in breast cancer and is associated with sensitivity to carcinogens, to oxidative stress, and to chemotherapy
Authors: Loignon Martin , Miao Weimin , Hu Lianggao , Bier Andrew , Bismar Tarek A. , Scrivens P. James , Mann Koren , Basik Mark , Bouchard Amélie , Fiset Pierre O. , Batist Zachary , Batist Gerald
Published: July 2009

Nrf2 is the key transcription factor for cytoprotective gene programs. Nrf2 is normally maintained at very low concentrations by proteasomal degradation, through its interaction with the adapter protein Keap1 and the Cul3 E3 ligase. Increased Nrf2 concentration resulting from loss of function Keap1 mutations has been described in chemoresistant non–small cell lung cancer. Previous studies in breast cancer showed low levels of some Nrf2-regulated detoxification genes, but the mechanism has not been systematically examined. We found that half of the breast cancer cell lines examined have decreased concentration of Nrf2 compared with normal mammary epithelial cell lines, associated with variable but detectable levels in Keap1 levels, and consistently increased Cul3 mRNA and protein. Immunochemistry showed that 7 of 10 breast cancer specimens examined also have low Nrf2 levels and increased Cul3. Keap1 protein levels are variable. We found no C23Y mutation in Keap1 of any of the cell lines. Using siRNA, we silenced Cul3 in MCF-7 breast cancer cells, and microarray analysis reveals the induction of GCL, NQO1, AKR1C1, UGDH, and TXN by at least 2-fold. The Nrf2-regulated ABCC1 drug transporter was also found to be increased. These Cul3-silenced MCF7 cells are highly resistant to oxidative stress induced by H2O2, to the carcinogen benzo(a)pyrene, and to both Doxorubicin and Paclitaxel. This high Cul3/low Nrf2 signature may be key to cellular sensitivity to both chemical carcinogeneic stimuli as well as to cytotoxicity of commonly used chemotherapeutic drugs in established breast cancers. [Mol Cancer Ther 2009;8(8):2432–40]
Insulin-like growth factor-I receptor tyrosine kinase inhibitor cyclolignan picropodophyllin inhibits proliferation and induces apoptosis in multidrug resistant osteosarcoma cell lines
Authors: Duan Zhenfeng , Choy Edwin , Harmon David , Yang Cao , Ryu Keinosuke , Schwab Joseph , Mankin Henry , Hornicek Francis J.
Published: July 2009

Insulin-like growth factor-I receptor (IGF-IR) is an important mediator of tumor cell survival and shows prognostic significance in sarcoma. To explore potential therapeutic strategies for interrupting signaling through this pathway, we assessed the ability of cyclolignan picropodophyllin (PPP), a member of the cyclolignan family, to selectively inhibit the receptor tyrosine kinase activity of IGF-IR in several sarcoma cell line model systems. Of the diverse sarcoma subtypes studied, osteosarcoma cell lines were found to be particularly sensitive to IGF-IR inhibition, including several multidrug resistant osteosarcoma cell lines with documented resistance to various conventional anticancer drugs. PPP shows relatively little toxicity in human osteoblast cell lines when compared with osteosarcoma cell lines. These studies show that PPP significantly inhibits IGF-IR expression and activation in both chemotherapy-sensitive and chemotherapy-resistant osteosarcoma cell lines. This inhibition of the IGF-IR pathway correlates with suppression of proliferation of osteosarcoma cell lines and with apoptosis induction as measured by monitoring of poly(ADP-ribose) polymerase and its cleavage product and by quantitative measurement of apoptosis-associated CK18Asp396. Importantly, PPP increases the cytotoxic effects of doxorubicin in doxorubicin-resistant osteosarcoma cell lines U-2OSMR and KHOSMR. Furthermore, small interfering RNA down-regulation of IGF-IR expression in drug-resistant cell lines also caused resensitization to doxorubicin. Our data suggest that inhibition of IGF-IR with PPP offers a novel and selective therapeutic strategy for ostosarcoma, and at the same time, PPP is effective at reversing the drug-resistant phenotype in osteosarcoma cell lines. [Mol Cancer Ther 2009;8(8):2122–30]
Silibinin suppresses growth and induces apoptotic death of human colorectal carcinoma LoVo cells in culture and tumor xenograft
Authors: Kaur Manjinder , Velmurugan Balaiya , Tyagi Alpna , Deep Gagan , Katiyar Suchitra , Agarwal Chapla , Agarwal Rajesh
Published: July 2009

Colorectal cancer is one of the leading causes of cancer-related morbidity and mortality. The use of nontoxic phytochemicals in the prevention and intervention of colorectal cancer has been suggested as an alternative to chemotherapy. Here we assessed the anticancer efficacy of silibinin against advanced colorectal cancer LoVo cells both in vitro and in vivo. Our results showed that silibinin treatment strongly inhibits the growth of LoVo cells (P < 0.05-0.001) and induces apoptotic death (P < 0.01-0.001), which was associated with increased levels of cleaved caspases (3 and 9) and cleaved poly(ADP-ribose) polymerase. Additionally, silibinin caused a strong cell cycle arrest at G1 phase and a slight but significant G2-M-phase arrest at highest concentration (P < 0.01-0.001). Molecular analyses for cell cycle regulators showed that silibinin decreases the level of cyclins (D1, D3, A and B1) and cyclin-dependent kinases (1, 2, 4, and 6) and increases the level of cyclin-dependent kinase inhibitors (p21 and p27). Consistent with these results, silibinin treatment also decreased the phosphorylation of retinoblastoma protein at Ser780, Ser795, and Ser807/Ser811 sites without significantly affecting its total level. In animal studies, oral administration of silibinin for 6 weeks (at 100 and 200 mg/kg/d for 5 days/wk) significantly inhibited the growth of LoVo xenograft (P < 0.001) in athymic nude mice without any apparent toxicity. Analyses of xenograft tissue showed that silibinin treatment inhibits proliferation and increases apoptosis along with a strong increase in p27 levels but a decrease in retinoblastoma phosphorylation. Together, these results suggest the potential use of silibinin against advanced human colorectal cancer. [Mol Cancer Ther 2009;8(8):2366–74]
Bortezomib up-regulates activated signal transducer and activator of transcription-3 and synergizes with inhibitors of signal transducer and activator of transcription-3 to promote head and neck squamous cell carcinoma cell death
Authors: Li Changyou , Zang Yan , Sen Malabika , Leeman-Neill Rebecca J. , Man David SK. , Grandis Jennifer R. , Johnson Daniel E.
Published: July 2009

Head and neck squamous cell carcinomas (HNSCC) are commonly resistant to conventional chemotherapy drugs and exhibit overexpression of signal transducer and activator of transcription 3 (STAT3). STAT3 promotes both the proliferation and survival of HNSCC cells. Recent studies have shown that the proteasome inhibitor bortezomib shows cytotoxic activity against HNSCC in vitro and in vivo. We report that treatment of HNSCC cells with bortezomib led to up-regulation of total STAT3 protein and the phosphorylated/activated form of STAT3, as well as an increase in cellular STAT3 activity. This suggested that the ability of bortezomib to kill HNSCC cells may be blunted due to induction of STAT3, and inhibition of STAT3 may be a useful means for improving bortezomib efficacy. Indeed, forced expression of dominant-active STAT3 inhibited bortezomib-induced cell death, whereas expression of dominant-negative STAT3 served to enhance killing by this compound. In addition, specific inhibition of STAT3 with the use of a STAT3 decoy oligonucleotide resulted in enhancement of bortezomib-induced apoptosis signaling and loss of clonogenic survival. Cotreatment of HNSCC cells with bortezomib and guggulsterone, a naturally occurring compound known to inhibit STAT3 activation, led to synergistic activation of cell death and loss of clonogenic survival. In summary, these studies show that bortezomib induces the expression of active STAT3, a key growth- promoting protein in HNSCC cells. Furthermore, our findings suggest that the therapeutic activity of bortezomib against HNSCC may be markedly improved by cotreatment with molecular targeting agents against STAT3. [Mol Cancer Ther 2009;8(8):2211–20]
Identification of Gene Signatures and Molecular Markers for Human Lung Cancer Prognosis using anIn vitroLung Carcinogenesis System
Authors: Kadara Humam , Lacroix Ludovic , Behrens Carmen , Solis Luisa , Gu Xuemin , Lee J. Jack , Tahara Eiji , Lotan Dafna , Hong Waun Ki , Wistuba Ignacio I. , Lotan Reuben
Published: July 2009

Lung cancer continues to be a major deadly malignancy. The mortality of this disease could be reduced by improving the ability to predict cancer patients' survival. We hypothesized that genes differentially expressed among cells constituting an in vitro human lung carcinogenesis model consisting of normal, immortalized, transformed, and tumorigenic bronchial epithelial cells are relevant to the clinical outcome of non–small cell lung cancer (NSCLC). Multidimensional scaling, microarray, and functional pathways analyses of the transcriptomes of the above cells were done and combined with integrative genomics to incorporate the microarray data with published NSCLC data sets. Up-regulated (n = 301) and down-regulated genes (n = 358) displayed expression level variation across the in vitro model with progressive changes in cancer-related molecular functions. A subset of these genes (n = 584) separated lung adenocarcinoma clinical samples (n = 361) into two clusters with significant survival differences. Six genes, UBE2C, TPX2, MCM2, MCM6, FEN1, and SFN, selected by functional array analysis, were also effective in prognosis. The mRNA and protein levels of one these genes—UBE2C—were significantly up-regulated in NSCLC tissue relative to normal lung and increased progressively in lung lesions. Moreover, stage I NSCLC patients with positive UBE2C expression exhibited significantly poorer overall and progression-free survival than patients with negative expression. Our studies with this in vitro model have lead to the identification of a robust six-gene signature, which may be valuable for predicting the survival of lung adenocarcinoma patients. Moreover, one of those genes, UBE2C, seems to be a powerful biomarker for NSCLC survival prediction.
Profiles in Variation: Lung Carcinogenesis
Authors: Carbone David P.
Published: July 2009

This perspective on Kadara et al. (beginning on p. 702 in this issue of the journal) examines the critical development of genomic and proteomic signatures of lung cancer risk, prognosis, and sensitivity to chemoprevention or chemotherapy. The novel work of Kadara et al. represents the first demonstration that a molecular signature developed in a premalignancy model (in this case, cultured normal human bronchial epithelial cells and increasingly transformed derivative cells) is clinically relevant to invasive lung cancer.
Association between a Genetic Variant of the Alpha-7 Nicotinic Acetylcholine Receptor Subunit and Four Types of Dementia
Authors: Fehér Ágnes , Juhász Anna , Rimanóczy Ágnes , Csibri Éva , Kálmán János , Janka Zoltán
Published: July 2009

We tested the hypothesis whether the partially duplicated variant of α7 nicotinic acetylcholine receptor subunit gene (CHRFAM7A) 2-bp deletion (–2 bp) polymorphism and apolipoprotein E (ApoE) ε4 allele confer susceptibility to Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), Pick’s disease (PiD) and vascular dementia (VD). The study included 175 AD, 35 DLB patients, 38 PiD, 96 VD and 175 healthy control (HC) probands. The CHRFAM7A genotype without the –2 bp allele was significantly over-represented in AD (p = 0.011), DLB (p = 0.001) and PiD (p < 0.0001) compared to HC, but there were no statistical differences in VD (p = 0.407) compared to HC. We confirmed again that the ApoE ε4 allele is a risk factor for dementias. The –2 bp polymorphism of CHRFAM7A can be implicated in AD, DLB and PiD. However, it is unlikely that it plays an important role in the pathogenesis of VD.
Chronic Myelogenous Leukemia with the e6a2 BCR-ABL and Lacking Imatinib Response: Presentation of Two Cases
Authors: Vefring Hege K. , Gruber Franz X.E. , Wee Line , Hovland Randi , Hjorth-Hansen Henrik , Gedde Dahl Tobias , Meyer Peter
Published: July 2009

The BCR-ABL fusion gene represents the hallmark of chronic myelogenous leukemia (CML) and is derived from a translocation between chromosome 9 and 22. The majority of CML patients have a breakpoint in the major BCR region of the BCR gene giving rise to e13a2 or e14a2 BCR-ABL transcripts. Occasionally, other BCR breakpoints occur. The current report describes two e6a2 CML patients with imatinib treatment failure and unusual disease progression. One patient was Philadelphia chromosome positive and one was Philadelphia chromosome negative with an atypical BCR-ABL rearrangement, ins (22;9).
Human Monocyte Receptor Sites
Authors: Huber H. , Douglas S.D. , Huber C. , Goldberg L.S.
Published: July 2009

Incubation of human monocytes with red cells coated with secretory or myeloma IgA showed neither phagocytosis nor rosette formation. IgA proteins in the fluid phase did not inhibit monocyte receptors for ΓG1 and ΓG3. The findings indicate that IgA fails to demonstrate cytophilia.
Ultrastructure of 19S Antibody-Producing Cells from ALS, PHA and D2O-Treated Animals
Authors: Neher G.H. , Siegel B.V.
Published: July 2009

19S plaque-forming cells from anti-lymphocyte serum (ALS), phytohemagglutinin (PHA) and deuterium oxide (D2O) treated animals were examined with the electron microscope and compared to similar cells from untreated animals. The only differences between cells from control and immunologically depressed animals were an increase in the number of mitochondria per section of D2O cells, and a lower average maturation of ALS and PHA plaque-forming cells than corresponding control cells. All the ultrastructural features noted in control cells were seen in cells from each experimental group. Abnormal plasma cells were present in all groups suggesting that this is a distinct cell type.
Effects of Anti-Lymphocyte, Anti-Macrophage and Anti-Thymocyte Serum IgG on the Immune Response
Authors: Schell K. , Daniel K. , Blazkovec A.A.
Published: July 2009

The primary and secondary responses to SRBC in outbred guinea pigs were characterized using several parameters including enumeration of IgM and IgG PFC present in the spleen and humoral hemolysin and hemagglutinin levels. These parameters were used to study and compare the effects of three heterologous antiserum IgG preparations, namely, ALS, AMS and ATS on the immune response. That immune IgG in all cases failed to suppress either the primary or secondary response to SRBC was shown and these results are discussed in relationship to the findings of others.
Effects of Anti-Lymphocyte, Anti-Macrophage and Anti-Thymocyte Serum IgG on the Immune Response
Authors: Schell K. , Daniel K. , Blazkovec A.A.
Published: July 2009

The immune response of outbred guinea pigs injected with SRBC in Freund’s complete adjuvant was characterized using several parameters which included cutaneous hypersensitivity, humoral hemagglutinin levels, and the capacity of PE cells to migrate in vitro in the presence of specific antigen. Two of these parameters were used to assess the effects of heterologous antiserum IgG (ALS, AMS and ATS) on the immune response. ALS, ATS and, to a lesser extent, AMS were capable of significantly suppressing delayed-type but not immediate-type hypersensitivity or humoral antibody production.
Effects of Anti-Lymphocyte, Anti-Macrophage and Anti-Thymocyte Serum IgG on the Immune Response
Authors: Artis W. , Schell K. , Blazkovec A.A.
Published: July 2009

The effects of in vivo and in vitro treatment of immunocompetent cells with heterologous antiserum IgG were studied using the LPT technique and isogeneic strains of guinea pigs. Treatment of hypersensitive animals with ALS, AMS and ATS was shown to effect suppression of delayed-type cutaneous hypersensitivity to SRBC confirming the findings presented in the previous study. Treatment of normal isogeneic recipients with ALS, AMS and ATS likewise induced significant suppression of LPT reactions induced in these animals with cells from donors hypersensitized with SRBC. However, no suppression of LPT reactions was detectable using: (1) PE cells from hypersensitized donors treated with immune IgG and in which suppression was demonstrable prior to harvest of cells or (2) PE cells from hypersensitive donors treated in vitro with immune IgG prior to LPT. These findings suggest that the primary mechanism whereby heterologous anti-serum IgG induces suppression involves impairment of the capacity of cells to migrate.
Peripheral Lymphocyte Populations
Authors: Benezra D. , Gery I. , Davies A.M.
Published: July 2009

Blood lymphocytes from rabbits immunized against BSA were stimulated by this antigen in vitro and their response determined by the increase in uptake of 3HT. The rabbits were immunized with different doses of antigen in complete adjuvant or in saline solution and the lymphocytes, collected at intervals of 3 to 270 days were stimulated in vitro by concentrations of antigen, ranging from 10––2µg to 2 × 104µg/culture. Lymphocytes from rabbits immunized with 20 mg BSA in adjuvant showed a marked increase in sensitivity toward the antigen (up to 105-fold) when collected at intervals up to a month after immunization, while lymphocytes from rabbits immunized with 0.5 mg BSA in adjuvant reached a peak by day 16 and decreased thereafter. This increase was expressed by a decrease in the minimal dose of antigen needed to stimulate a significant response. The increase in sensitivity was faster and the levels of response were higher in rabbits immunized with 0.5 mg than with 20 mg. Lymphocytes collected at different intervals late after immunization with the above doses of antigen showed periodical changes in the levels of response with alternating high and low responses. Cells from animals immunized with 10 µg BSA in adjuvant, on the other hand, showed low levels of response and a diminished increase in sensitivity, compared to cells from the other 2 groups. Cells from rabbits injected with BSA in saline did not react to antigen in culture. This form of antigen was found also to induce a partial unresponsiveness as shown by decreased responses after subsequent challenge with antigen in adjuvant.
Studies on IgE Fragments Prepared by Papain Digestion
Authors: Ito Koji , Wicher K. , Arbesman C.E.
Published: July 2009

IgE (PS) myeloma protein was digested with papain for various lengths of time. After 1 h, several components of the IgE could already be demonstrated. After 3-11 h of digestion Fc, Fc′ fragments and a third component tentatively termed Fx were obtained. The Fc′ component showed partial identity with the Fc fragment, in the immunoelectrophoresis demonstrated faster mobility than the Fc fragment, had a molecular weight of approximately 58,000 and could not block passive sensitization of human skin by reaginic antibody. Thus far the Fx component was not obtained in a pure form. This component was demonstrated only in immunoelectrophoresis and had a slower mobility than the Fc and Fc′ fragments. For the time being it is not clear whether the Fx is a F(ab′)2 fragment or a part of it, or is a third component of the Fc fragment.
Loss of Macrophages from Peritoneal Exudates of Sensitized Rats After Injection of Streptococcal Antigens
Authors: Bültmann B. , Sodomann C.P. , Heymer B. , Haferkamp O. , Schmidt W.C.
Published: July 2009

Experiments are reported describing the macrophage disappearance phenomenon elicited by streptococcal cell wall antigens in rats sensitized with viable β-hemolytic streptococci emulsified in Freund’s complete adjuvant. Macrophage loss from peritoneal exudates of rats sensitized to group A streptococci was demonstrable after i.p. injection of Streptomyces albus enzyme- or formamide-extracted and not further purified group A antigens. No macrophage disappearance occurred when the same antigens were injected into non-sensitized animals or animals sensitized with streptococci of groups B, C, E or G. In contrast to the chemically extracted partially purified carbohydrate preparations, chromatographically purified C-carbohydrates did not induce macrophage loss. Data are presented which indicate that carbohydrate-mucopeptide complexes and possibly nucleic acid degradation products are responsible for the macrophage disappearance phenomena observed.
Non-Organ-Specific Cytoplasmic Antibodies Detected by Immunofluorescence
Authors: Doniach D. , Lindqvist H.L. , Berg P.A.
Published: July 2009

Appearances in the immunofluorescence test produced by mitochondrial antibodies associated with primary biliary cirrhosis (‘M’ fluorescence) are compared and contrasted with those of the cardiolipin fluorescent antibodies (‘CLF’) seen in patients with active secondary syphilis. The corresponding antigens are quite distinct but are both situated in the inner membrane of the mitochondria. A further structural connection between them is suggested by the selective staining with both antibodies of mitochondria engaged in high energy work and utilizing fatty acid pathways for energy production. Two other cytoplasmic autoantibodies are described. Both are thought to be of rare occurrence and could be absorbed-out with ribosomal subfractions of rat liver homogenates while mitochondria had no effect. The pathogenic role of all these non-organ-specific reactions is still unknown but they are thought to be stimulated by contact with viruses or other microorganisms.
Isolated Glomerular Basement Membrane as Antigen in Indirect Immunofluorescent Test for Identification of Circulating Rabbit Anti-Rat Glomerular-Basement Membrane Antibodies
Authors: de Almeida Dinah B. , de Franco M.F.
Published: July 2009

A new indirect immunofluorescent test for the identification of anti-glomerular basement membrane (GBM) antibodies, using as antigen isolated GBM, is described. Anti-rat kidney rabbit serum was the source of antibodies. The use of isolated GBM, the specific antigen, avoids the interference of antibodies against other kidney structures. Comparison of the proposed method with a similar test using kidney frozen sections as antigen indicates that the use of isolated GBM gives better and more accurate results.
A Search for High Molecular Impurities in Penicillin G
Authors: Ottens H. , de Haan E. , Sengers C.H.J.
Published: July 2009

A search for high molecular residues in penicillin G was carried out using several recently described methods. By the membrane filtration method the protein content of a large number of batches of penicillin G, 6-APA (chemically prepared), and ampicillin was determined. Significantly lower protein values were found for these compounds than for microbiologically produced 6-APA and the ampicillin made from it. Purified macromolecular complexes of penicillin gave protein values in the membrane filter method. Our results indicate that the protein content of most commercially available benzylpenicillins is negligible.
The Rapid Adjuvant Effect in the Acquisition of Delayed Hypersensitivity to Low Molecular Weight Sensitizers in the Guinea Pig
Authors: Maguire, jr. H.C. , Coghlan Patricia
Published: July 2009

Guinea pigs were substantially sensitized to the low molecular weight chemicals dinitrochlorobenzene (DNCB), paranitrosodimethylaniline (NDMA), Rhus extract and picric acid, by the injection of Freund’s complete adjuvant into a skin site primed several days previously with a borderline sensitizing concentration of the particular chemical. The adjuvant effect may occur in as little as two days. The skin site prepared with allergen need be present only during the early portion of the inductive phase of the hypersensitivity. It appears that enhancement takes place via a quantitative and/or qualitative stimulation of centrally-located clones of cells previously selected by antigen.