bluuebunny/crossref_metadata_2025 huggingface dataset:
Spectral characteristics of three styles of Croatian folk singing
Authors: Boersma Paul , Kovacic Gordana
Published: March 2006

This paper examines the differences between three Croatian folk singing styles, namely klapa, ojkanje, and tarankanje. In order to factor out singer-specific properties, each of the styles was performed by the same 12 professional male singers. The 36 performances were analyzed with a long-term average spectrum (LTAS) method from which direct effects of the pitch distribution were removed. After factoring out each singer’s average, the 36 pitch-corrected LTAS contours were reduced to a two-dimensional representation in two ways: (1) a principal-component analysis and (2) a graphical plot of spectral slope versus speaker’s formant strength. Both ways clearly separate the three styles. The spectrum of the klapa style turns out to be similar to that of speech. The ojkanje style is extremely loud and shows two spectral peaks: a sharp one tuned at twice the fundamental frequency and appropriate for long-distance communication on mountain slopes, and a broad one around 3.5kHz, reminiscent of a speaker’s formant. The tarankanje style has a very flat spectrum implemented by vocal pressedness and nasality, which is appropriate for blending into or imitating the timbral characteristics of the sopile folk instrument.
Muscular damage and intravascular haemolysis during an 18 hour subterranean exploration in a cave of 700 m depth
Authors: Stenner E , Gianoli E , Biasioli B , Piccinini C , Delbello G , Bussani A
Published: February 2006

Objective:To verify presence and severity of muscular and/or intravascular damage during a subterranean exploration of long duration.

Methods:We measured serum levels of creatine kinase (CK) and lactate dehydrogenase (LDH) as markers of muscular damage. We also measured haptoglobin as a marker of intravascular haemolysis, and platelets and leucocytes as markers of inflammation.

Results:We found in all the participants an increase in CK, LDH, and platelets and leucocytes (mainly due to neutrophilia and monocytosis), and a decrease in the level of haptoglobin and circulating lymphocytes.

Conclusions:The observed data suggest that continuous effort during long alpine subterranean explorations, environmental conditions, sleep deprivation, multiple impacts on rocks, and compression caused by bindings of the caving harness cause muscle damage, intravascular haemolysis, inflammation response, and immunological changes.
Prospective study of change in patellar tendon abnormality on imaging and pain over a volleyball season
Authors: Malliaras P , Cook J , Ptasznik R , Thomas S
Published: February 2006

Objective:Patellar tendon injury, defined by tendon abnormality (TA) on imaging and by pain, is common among volleyball players, but little is known about change in this injury over a volleyball season. Increased activity in the season compared with the off season may result in the development of TA and/or pain. This study investigated the behaviour of TA and pain over a competitive volleyball season.

Methods:Tendon abnormality and pain were measured in 101 volleyball players at the beginning and end of a season. Pain was measured with the single leg decline squat test, which loads the patellar tendon, and TA was detected with ultrasound imaging. Hours of weekly activity were measured and compared during the season and the off season. The proportion of tendons that underwent development and resolution in TA and/or pain over the season was investigated.

Results:Hours of weekly activity was greater during the season than in the off season. Most of the tendons investigated (66.3%) did not undergo a change in TA or pain over the season. Tendon abnormality and/or pain developed in 16.6% of tendons and resolved in 11.2%.

Conclusions:The tendons of volleyball players respond variably to the increased load over the season. Change in TA and pain does not appear to be entirely dependent upon load.
A 10 GB/S EQUALIZER WITH INTEGRATED CLOCK AND DATA RECOVERY FOR OPTICAL COMMUNICATION SYSTEMS
Authors: MCPHERSON D. S. , TRAN H. , POPESCU P.
Published: March 2006

A 10 Gb/s analog continuous-time equalizer with integrated clock and data recovery circuit is presented. It is designed to recover signals degraded by chromatic and polarization mode dispersion. The key components in the design are a feedforward equalizer and a decision feedback equalizer, the parameters of which are electronically adjustable. Both circuit blocks are fully described and characterized with emphasis on minimizing self-induced distortion and maximizing high-speed performance. In addition to the equalizer and the clock and data recovery, the circuit also includes an integrated automatic gain control. The circuit is implemented in a commercial 0.18 μm SiGe BiCMOS technology and consumes 900 mW. The capacity of the equalizer to mitigate signal impairments is demonstrated using three electrically generated channels.
RECENT PROGRESS IN 40- TO 100-GBIT/S-CLASS OPTICAL COMMUNICATIONS ICS USING INP-BASED HBT TECHNOLOGIES
Authors: ISHII Kiyoshi , NOSAKA Hideyuki , SANO Kimikazu , IDA Minoru , KURISHIMA Kenji , SHIBATA Tsugumichi , ENOKI Takatomo
Published: March 2006

This paper describes our InP-based heterojunction bipolar transistor (HBT) technologies and circuit design techniques for small-scale-integration (SSI) and medium-scale-integration (MSI) circuits for 40- to 100-Gbit/s-class optical communications systems. The circuits include a sub-4-ps emitter-coupled logic (ECL) gate, 100-Gbit/s selector circuit, 90-Gbit/s decision circuit, 50-Gbit/s 4:1 multiplexer (MUX) and 1:4 demultiplexer (DEMUX) ICs, aver-40-Gbit/s 16:1 MUX IC, and 40-Gbit/s full-clock-rate DEMUX with a clock and data recovery (CDR) circuit. This paper demonstrates that InP-based HBT technologies and our circuit design techniques are attractive for fabricating ultrahigh-speed SSI circuits with data rates approaching 100 Gbit/s and low-power MSI circuits with data rates of over 40 Gbit/s.
40 Gb/s TDM SYSTEM TRANSCEIVER PROTOTYPE IN InP HBT TECHNOLOGY
Authors: KRISHNAMURTHY KARTHIKEYAN , XU JIAN , SHOU XIAOQIANG , VETURY RAMAKRISHNA , JAGANATHAN SHRINIVASAN , LIU YET-ZEN , PULLELA RAJA , YU RUAI , RODWELL MARK J. W.
Published: March 2006

A time-division-multiplexing (TDM) system transceiver with 4–channel 10 Gb/s interfaces to achieve 40 Gb/s non-return to zero (NRZ) transmission is presented. The front-end components are implemented in an indium phosphide double hetero-junction bipolar transistor (InP DHBT) technology. They include a 4:1 multiplexer with a voltage controlled oscillator and clock multiplication unit, modulator drivers for electro-absorption and differential lithium-niobate modulators, trans-impedance amplifier, limiting amplifier and 1:4 demultiplexer with clock and data recovery circuit. The transceiver was used to teat optical transmission over a 2.26 km link with a 40 Gb/s, 231-1 pseudo-random bit sequence (PRBS) data. The transmitter achieves better than 12.9 dB extinction ratio, 1 ps added root mean square (RMS) jitter and 4 dBm output power. Without any optical amplification the receiver achieves -9.1 dBm back to back sensitivity at a bit error rate (BER) of 10-12 and a high dynamic range of 12.5 dBm.
TWO-LOOP EULER–HEISENBERG EFFECTIVE ACTIONS FROM CHARGED OPEN STRINGS
Authors: MAGNEA LORENZO , RUSSO RODOLFO , SCIUTO STEFANO
Published: February 2006

We present the multiloop partition function of open bosonic string theory in the presence of a constant gauge field strength, and discuss its low-energy limit. The result is written in terms of twisted determinants and differentials on higher-genus Riemann surfaces, for which we provide an explicit representation in the Schottky parametrization. In the field theory limit, we recover from the string formula the two-loop Euler–Heisenberg effective action for adjoint scalars minimally coupled to the background gauge field.
GENERALIZED SECOND-ORDER TWO-DIMENSIONAL SYSTEMS: COMPUTING THE TRANSFER FUNCTION
Authors: ANTONIOU GEORGE E. , MICHAEL MARINOS T.
Published: February 2006

In this paper, the discrete Fourier transform is used to determine the coefficients of a transfer function of a new generalized two-dimensional system of second-order: Ex(i1 + 2, i2 + 2) = A0x(i1 + 1, i2 + 1) + A1x(i1 + 1, i2) + A2x(i1, i2 + 1). The algorithm is straightforward and has been implemented using the software package Matlab™. A step-by-step example illustrating the application of the algorithm is presented.
NEUTRONS FLUX DISTRIBUTIONS OF THE Pu-Be SOURCE AND ITS SIMULATION BY THE MCNP-4B CODE
Authors: FAGHIHI F. , MEHDIZADEH S. , HADAD K.
Published: March 2006

Neutron Fluence rate of a low intense Pu-Be source is measured by Neutron Activation Analysis (NAA) of 197 Au foils. Also, the neutron fluence rate distribution versus energy is calculated using the MCNP-4B code based on ENDF/B-V library. Theoretical simulation as well as our experimental performance are a new experience for Iranians to make reliability with the code for further researches. In our theoretical investigation, an isotropic Pu-Be source with cylindrical volume distribution is simulated and relative neutron fluence rate versus energy is calculated using MCNP-4B code. Variation of the fast and also thermal neutrons fluence rate, which are measured by NAA method and MCNP code, are compared.
A REVIEW OF EINSTEIN'S THEORY OF SPECIAL RELATIVITY
Authors: MOTT GERALD
Published: March 2006

Using only the descriptions and the results of the 'thought experiment' contained in Einstein's seminal 1905 paper, proofs are offered which show that the transformation equations of Einstein's special relativity apply only to the joint use in his experiment of point sources of light and point reflectors. Further, it is shown that two different special relativities could have been invented by Einstein and, because they possess differing space and time contraction factors, they cannot co-exist and, therefore, both must be discarded.
DESCRIPTION LOGICS OVER LATTICES
Authors: STRACCIA UMBERTO
Published: March 2006

It is generally accepted that knowledge based systems would be smarter if they could manage uncertainty and/or imprecision. In this paper we extend Description Logics, well-known logics for managing structured knowledge, allowing to express that a sentence is not just true or false, but true to some degree, which is taken from a certainty lattice.
FUZZY SET BASED PROTOCOLS FOR PROCESS QUALITY CONTROL
Authors: DELGADO M. , OLAVARRIETA P. , VERGARA P.
Published: March 2006

Industrial process quality control has as yet been carried out using Shewhart's classic charts and control charts with probabilistic limits, using sampling statistics for average and deviation [Formula: see text] and [Formula: see text], respectively, or Cp and Cpk, derived from them, in order to determine whether the process is precise or imprecise. Although these statistics has been formulated using crisp mathematics, their use returns statements about "quality control" which are full of vagueness (for example, the aforementioned idea of precise or imprecise processes). For this reason, it seems both natural and interesting to introduce tools from Fuzzy Sets Theory for the formulation of quality control models.

Fuzzy Sets shall be used to study process quality capability and to generate a bilateral simultaneous control for the central tendency and a unilateral one for variability. We shall define linguistic rules in order to perform this control and membership functions for the sample control mean and deviation, [Formula: see text] and ŝ.
THE ADOMIAN DECOMPOSITION METHOD APPLIED TO THE FUZZY SYSTEM OF FREDHOLM INTEGRAL EQUATIONS OF THE SECOND KIND
Authors: ABBASBANDY S. , ALLAHVIRANLOO T.
Published: March 2006

In this work, the Adomian decomposition(AD) method is applied to the Fuzzy system of linear Fredholm integral equations of the second kind(FFIE). First the crisp Fredholm integral equation is solved by AD method and then the crisp solution is fuzzified by extension principle. The proposed algorithm is illustrated by solving a numerical example.
YET ANOTHER FUZZY MODEL FOR LINEAR LOGIC
Authors: SYROPOULOS APOSTOLOS
Published: March 2006

The construction of a new categorical fuzzy model for linear logic is presented. The construction is based on a general poset-valued model. Since the resulting categories are not identical to existing categories of all fuzzy sets, we investigate the relationship between the two categories. We conclude with very brief comments regarding the usefulness of this work.
A MULTI CULTURE PERCEPTION OF THE ENTREPRENEURIAL LIFESTYLE
Authors: BENJAMIN MARTZ W. M. , BISCACCIANTI ALESSANDRO , NEIL THOMAS C. , WILLIAMS ROBERT J.
Published: March 2006

Business schools around the world offer courses and even complete degrees emphasizing entrepreneurship. However, the perception of an entrepreneur differs across cultures. This paper presents results from a set of 900 questionnaires collected over two years in three countries: United States; United Kingdom and France. The analysis found support for the basic conjecture that the perception of entrepreneurship differs between countries; the US students perceived the entrepreneurship lifestyle as a better lifestyle than did students from the France or the UK.

Historically, the area of entrepreneurship is suggested as a key factor for a successful business environment. Business schools around the world offer courses and even complete degrees emphasizing entrepreneurship. However, the perception of an entrepreneur differs across cultures. The entrepreneurial lifestyle is perceived, rewarded, acknowledged, etc. differently across cultures based upon cultural norms. This paper presents results from a set of data collected over two years in three countries: United States; United Kingdom and France. The analysis of over 900 questionnaires found support for the basic conjecture that the perception of entrepreneurship differs between countries and in the direction predicted by the TEA report; the US students perceived the entrepreneurship lifestyle better than did students from the France or the UK. The final section of the paper is highlights the cross-cultural differences found and offers some ideas on why they occur.
A FUZZY RELIABILITY ANALYSIS BASED ON THE TRANSFORMATION BETWEEN DISCRETE FUZZY VARIABLES AND DISCRETE RANDOM VARIABLES
Authors: DONG YUGE , WANG AINAN
Published: March 2006

When fuzzy information is taken into consideration in design, it is difficult to analyze the reliability of machine parts because we usually must deal with random information and fuzzy information simultaneously. Therefore, in order to make it easy to analyze fuzzy reliability, this paper proposes the transformation between discrete fuzzy random variable and discrete random variable based on a fuzzy reliability analysis when one of the stress and strength is a discrete fuzzy variable and the other is a discrete random variable. The transformation idea put forwards in this paper can be extended to continuous case, and can also be used in the fuzzy reliability analysis of repairable system.
ON USING SOFT COMPUTING TECHNIQUES IN SOFTWARE RELIABILITY ENGINEERING
Authors: MADSEN HENRIK , THYREGOD POUL , BURTSCHY BERNARD , ALBEANU GRIGORE , POPENTIU FLORIN
Published: March 2006

Previous investigations have shown the importance of evaluating computer performances and predicting the system reliability. This paper considers soft computing techniques in order to be used for software fault diagnosis, reliability optimization and for time series prediction during the software reliability analysis. It is shown that the study of the data collections during a software project development can be done within a soft computing framework.
Inhibitory Synaptic Transmission Governs Inspiratory Motoneuron Synchronization
Authors: Sebe Joy Y. , van Brederode Johannes F. , Berger Albert J.
Published: March 2006

Neurons within the intact respiratory network produce bursts of action potentials that cause inspiration or expiration. Within inspiratory bursts, activity is synchronized on a shorter timescale to generate clusters of action potentials that occur in a set frequency range and are called synchronous oscillations. We investigated how GABA and glycine modulate synchronous oscillations and respiratory rhythm during postnatal development. We recorded inspiratory activity from hypoglossal nerves using the in vitro rhythmically active mouse medullary slice preparation from P0–P11 mice. Average oscillation frequency increased with postnatal development, from 17 ± 12 Hz in P0–P6 mice ( n = 15) to 38 ± 7 Hz in P7–P11 mice ( n = 37) ( P < 0.0001). Bath application of GABAA and GlyR antagonists significantly reduced oscillation power in neonates (P0–P6) and juveniles (P7–P10) and increased peak integrated activity in both age groups. To test whether elevating slice excitability is sufficient to reduce oscillation power, Substance P was bath applied alone. Substance P, although increasing peak integrated activity, had no significant effect on oscillation power. Prolonging the time course of GABAergic synaptic currents with zolpidem decreased the median oscillation frequency in P9–P10 mouse slices. These data demonstrate that oscillation frequency increases with postnatal development and that both GABAergic and glycinergic transmission contribute to synchronization of activity. Further, the time course of synaptic GABAergic currents is a determinant of oscillation frequency.
Ischemic and nephrotoxic acute renal failure are distinguished by their broad transcriptomic responses
Authors: Yuen Peter S. T. , Jo Sang-Kyung , Holly Mikaela K. , Hu Xuzhen , Star Robert A.
Published: March 2006

Acute renal failure (ARF) has a high morbidity and mortality. In animal ARF models, effective treatments must be administered before or shortly after the insult, limiting their clinical potential. We used microarrays to identify early biomarkers that distinguish ischemic from nephrotoxic ARF or biomarkers that detect both injury types. We compared rat kidney transcriptomes at 2 and 8 h after ischemia/reperfusion and after mercuric chloride. Quality control and statistical analyses were necessary to normalize microarrays from different lots, eliminate outliers, and exclude unaltered genes. Principal component analysis revealed distinct ischemic and nephrotoxic trajectories and clear array groupings. Therefore, we used supervised analysis, t-tests, and fold changes to compile gene lists for each group, exclusive or nonexclusive, alone or in combination. There was little network connectivity, even in the largest group. Some microarray-identified genes were validated by TaqMan assay, ruling out artifacts. Western blotting confirmed that heme oxygenase-1 (HO-1) and activating transcription factor-3 (ATF3) proteins were upregulated; however, unexpectedly, their localization changed within the kidney. HO-1 staining shifted from cortical (early) to outer stripe of the outer medulla (late), primarily in detaching cells, after mercuric chloride but not ischemia/reperfusion. ATF3 staining was similar, but with additional early transient expression in the outer stripe after ischemia/reperfusion. We conclude that microarray-identified genes must be evaluated not only for protein levels but also for anatomical distribution among different zones, nephron segments, or cell types. Although protein detection reagents are limited, microarray data lay a rich foundation to explore biomarkers, therapeutics, and the pathophysiology of ARF.
Gene expression profiling reveals the profound upregulation of hypoxia-responsive genes in primary human astrocytes
Authors: Mense S. M. , Sengupta A. , Zhou M. , Lan C. , Bentsman G. , Volsky D. J. , Zhang L.
Published: March 2006

Oxygen is vital for the development and survival of mammals. In response to hypoxia, the brain initiates numerous adaptive responses at the organ level as well as at the molecular and cellular levels, including the alteration of gene expression. Astrocytes play critical roles in the proper functioning of the brain; thus the manner in which astrocytes respond to hypoxia is likely important in determining the outcome of brain hypoxia. Here, we used microarray gene expression profiling and data-analysis algorithms to identify and analyze hypoxia-responsive genes in primary human astrocytes. We also compared gene expression patterns in astrocytes with those in human HeLa cells and pulmonary artery endothelial cells (ECs). Remarkably, in astrocytes, five times as many genes were induced as suppressed, whereas in HeLa and pulmonary ECs, as many as or more genes were suppressed than induced. More genes encoding hypoxia-inducible functions, such as glycolytic enzymes and angiogenic growth factors, were strongly induced in astrocytes compared with HeLa cells. Furthermore, gene ontology and computational algorithms revealed that many target genes of the EGF and insulin signaling pathways and the transcriptional regulators Myc, Jun, and p53 were selectively altered by hypoxia in astrocytes. Indeed, Western blot analysis confirmed that two major signal transducers mediating insulin and EGF action, Akt and MEK1/2, were activated by hypoxia in astrocytes. These results provide a global view of the signaling and regulatory network mediating oxygen regulation in human astrocytes.
Fibulins 3 and 5 Antagonize Tumor Angiogenesis In vivo
Authors: Albig Allan R. , Neil Jason R. , Schiemann William P.
Published: March 2006

Lethal tumor growth and progression cannot occur without angiogenesis, which facilitates cancer cell proliferation, survival, and dissemination. Fibulins (FBLN) 5 and 3 are widely expressed extracellular matrix proteins that regulate cell proliferation in a context-specific manner. Reduced FBLN-5 expression has been associated with cancer formation and progression in humans, whereas its constitutive expression antagonizes endothelial cell angiogenic sprouting in vitro. Thus, FBLN-5 may suppress tumorigenesis by preventing tumor angiogenesis. FBLN-3 is homologous to FBLN-5 and expressed in endothelial cells, yet its role in tumorigenesis and angiogenesis is unknown. We find FBLN-3 expression to be altered in some human tumors and that its constitutive expression in endothelial cells inhibited their proliferation, invasion, and angiogenic sprouting, as well as their response to vascular endothelial growth factor as measured by p38 mitogen-activated protein kinase activation. In endothelial cells, both FBLNs (a) reduced angiogenic sprouting stimulated by basic fibroblast growth factor (bFGF); (b) inhibited matrix metalloproteinase expression and activity; and (c) stimulated tissue inhibitor of metalloproteinase expression. More importantly, both FBLNs prevented angiogenesis and vessel infiltration into bFGF-supplemented Matrigel plugs implanted in genetically normal mice, as well as decreased the growth and blood vessel density in tumors produced by MCA102 fibrosarcoma cells implanted s.c. into syngeneic mice. Our findings establish FBLN-3 and FBLN-5 as novel angiostatic agents capable of reducing tumor angiogenesis and, consequently, tumor growth in vivo and suggest that these angiostatic activities may one day be exploited to combat tumor angiogenesis and metastasis in cancer patients. (Cancer Res 2006; 66(5): 2621-9)
Antiangiogenic Therapy Decreases Integrin Expression in Normalized Tumor Blood Vessels
Authors: Yao Virginia J. , Ozawa Michael G. , Varner Amanda S. , Kasman Ian M. , Chanthery Yvan H. , Pasqualini Renata , Arap Wadih , McDonald Donald M.
Published: March 2006

Tumor blood vessels normalized by antiangiogenic therapy may provide improved delivery of chemotherapeutic agents during a window of time but it is unknown how protein expression in tumor vascular endothelial cells changes. We evaluated the distribution of RGD-4C phage, which binds αvβ3, αvβ5, and α5β1 integrins on tumor blood vessels before and after antiangiogenic therapy. Unlike the control phage, fd-tet, RGD-4C phage homed to vascular endothelial cells in spontaneous tumors in RIP-Tag2 transgenic mice in a dose-dependent fashion. The distribution of phage was similar to αvβ3 and α5β1 integrin expression. Blood vessels that survived treatment with AG-013736, a small molecule inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors, had only 4% as much binding of RGD-4C phage compared with vessels in untreated tumors. Cellular distribution of RGD-4C phage in surviving tumor vessels matched the α5β1 integrin expression. The reduction in integrin expression on tumor vessels after antiangiogenic therapy raises the possibility that integrin-targeted delivery of diagnostics or therapeutics may be compromised. Efficacious delivery of drugs may benefit from identification by in vivo phage display of targeting peptides that bind to tumor blood vessels normalized by antiangiogenic agents. (Cancer Res 2006; 66(5): 2639-49)
Cyclin D1 Is Transcriptionally Regulated by and Required for Transformation by Activated Signal Transducer and Activator of Transcription 3
Authors: Leslie Kenneth , Lang Cynthia , Devgan Geeta , Azare Janeen , Berishaj Marjan , Gerald William , Kim Young Bae , Paz Keren , Darnell James E. , Albanese Christopher , Sakamaki Toshiyuki , Pestell Richard , Bromberg Jacqueline
Published: March 2006

Signal transducers and activators of transcription 3 (STAT3) is a transcription factor that is aberrantly activated in many cancer cells. Constitutively activated STAT3 is oncogenic, presumably as a consequence of the genes that it differentially regulates. Activated STAT3 correlated with elevated cyclin D1 protein in primary breast tumors and breast cancer–derived cell lines. Cyclin D1 mRNA levels were increased in primary rat-, mouse-, and human-derived cell lines expressing either the oncogenic variant of STAT3 (STAT3-C) or vSrc, which constitutively phosphorylates STAT3. Mutagenesis of STAT3 binding sites within the cyclin D1 promoter and chromatin immunoprecipitation studies showed an association between STAT3 and the transcriptional regulation of the human cyclin D1 gene. Introduction of STAT3-C and vSrc into immortalized cyclin D1−/− and cyclin D1−/+ fibroblasts led to anchorage-independent growth of only cyclin D1−/+ cells. Furthermore, knockdown of cyclin D1 in breast carcinoma cells led to a reduction in anchorage-independent growth. Phosphorylation of the retinoblastoma (Rb) protein [a target of the cyclin D1/cyclin-dependent kinase 4/6 (cdk4/6) holoenzyme] was delayed in the cyclin D1−/− cells relative to cyclin D1−/+ cells. The E7 oncogene, whose activity includes degradation of Rb and dissociation of Rb from E2F, did not confer anchorage-independent growth to the cyclin D1−/− cells but, in conjunction with vSrc, resulted in robust growth in soft agar. These results suggest both a cdk-dependent and cdk-independent role for cyclin D1 in modulating transformation by different oncogenes. (Cancer Res 2006; 66(5): 2544-52)
A Novel Mechanism for Integrin-Mediated Ras Activation in Breast Carcinoma Cells: The α6β4 Integrin Regulates ErbB2 Translation and Transactivates Epidermal Growth Factor Receptor/ErbB2 Signaling
Authors: Yoon Sang-Oh , Shin Sejeong , Lipscomb Elizabeth A.
Published: March 2006

ErbB2 (HER2, Neu) and Ras play key roles in tumor invasion and metastasis. We identified a novel mechanism by which integrin α6β4 regulates ErbB2 expression, Ras activation, and the invasion of breast carcinoma cells. Here we show that integrin α6β4 regulates Ras activity especially in serum-depleted condition. Down-regulation of β4 integrin by β4 short hairpin RNA (shRNA) decreased Ras activity and carcinoma invasion whereas reexpression of this integrin restored Ras activity. ErbB2, a binding partner of epidermal growth factor receptor (EGFR), and EGFR modulated Ras activity, and integrin α6β4 regulated phospho-EGFR level without affecting EGFR expression. We also found that integrin α6β4 is involved in ErbB2 expression. Depletion of β4 by shRNA reduced ErbB2 protein level without affecting ErbB2 mRNA level and reexpression of β4 increased ErbB2 protein level. Reduction of eukaryotic initiation factor 4E, a rate-limiting factor for cap-dependent translation, decreased ErbB2 protein level, and β4 shRNA cells exhibited a shift in ErbB2 mRNA to light polysomes compared with control cells. These results show that integrin α6β4 regulates ErbB2 through translational control. In summary, we propose a novel mechanism for ErbB2 up-regulation and Ras activation in serum-depleted breast cancer cells; integrin α6β4 regulates the expression of ErbB2 and the subsequent phosphorylation of EGFR and activation of Ras. These findings provide a mechanism that substantiates the reported role of α6β4 in carcinoma invasion. (Cancer Res 2006; 66(5): 2732-9)
Role of the Tumor Suppressor RASSF1A in Mst1-Mediated Apoptosis
Authors: Oh Hyun Jung , Lee Kyung-Kwon , Song Su Jung , Jin Mi Sun , Song Min Sup , Lee Joo Hyun , Im Chang Rak , Lee Jie-Oh , Yonehara Shin , Lim Dae-Sik
Published: March 2006

Mammalian sterile 20–like kinase 1 (Mst1) is activated by both caspase-mediated cleavage and phosphorylation in response to apoptotic stimuli, including Fas ligation. Here, we examined the possible role of the tumor suppressor RASSF1A in Mst1 activation and Mst1-mediated apoptosis induced by death receptor signaling. Immunoprecipitation and immunofluorescence analyses revealed that Mst1 was associated with RASSF1A in cultured mammalian cells, with both proteins colocalizing to microtubules throughout the cell cycle. Whereas purified recombinant RASSF1A inhibited the kinase activity of purified recombinant Mst1 in vitro, overexpression of RASSF1A increased the kinase activity of Mst1 in intact cells, suggesting that regulation of Mst1 by RASSF1A in vivo involves more than the simple association of the two proteins. Both the activation of Mst1 and the incidence of apoptosis induced by Fas ligation were markedly reduced in cells depleted of RASSF1A by RNA interference and were increased by restoration of RASSF1A expression in RASSF1A-deficient cells. Moreover, the stimulatory effect of RASSF1A overexpression on Fas-induced apoptosis was inhibited by depletion of Mst1. These findings indicate that RASSF1A facilitates Mst1 activation and thereby promotes apoptosis induced by death receptor signaling. (Cancer Res 2006; 66(5): 2562-9)
Renal Cyst Development in Mice with Conditional Inactivation of the von Hippel-Lindau Tumor Suppressor
Authors: Rankin Erinn B. , Tomaszewski John E. , Haase Volker H.
Published: March 2006

Inactivation of the von Hippel-Lindau tumor suppressor, pVHL, is associated with both hereditary and sporadic renal cysts and renal cell carcinoma, which are commonly thought to arise from the renal proximal tubule. pVHL regulates the protein stability of hypoxia-inducible factor (HIF)-α subunits and loss of pVHL function leads to HIF stabilization. The role of HIF in the development of VHL-associated renal lesions remains to be determined. To investigate the functional consequences of pVHL inactivation and the role of HIF signaling in renal epithelial cells, we used the phosphoenolpyruvate carboxykinase (PEPCK) promoter to generate transgenic mice in which Cre-recombinase is expressed in the renal proximal tubule and in hepatocytes. We found that conditional inactivation of VHL in PEPCK-Cre mutants resulted in renal cyst development that was associated with increased erythropoietin levels and polycythemia. Increased expression of the HIF target gene erythropoietin was limited to the liver, whereas expression of carbonic anhydrase 9 and multidrug resistance gene 1 was up-regulated in the renal cortex of mutant mice. Inactivation of the HIF-α binding partner, arylhydrocarbon receptor nuclear translocator (Arnt), but not Hif-1α, suppressed the development of renal cysts. Here, we present the first mouse model of VHL-associated renal disease that will provide a basis for further genetic studies to define the molecular events that are required for the progression of VHL-associated renal cysts to clear cell renal cell carcinoma. (Cancer Res 2006; 66(5): 2576-83)
XRCC1 Genotype and Breast Cancer: Functional Studies and Epidemiologic Data Show Interactions between XRCC1 Codon 280 His and Smoking
Authors: Pachkowski Brian F. , Winkel Scott , Kubota Yoshiko , Swenberg James A. , Millikan Robert C. , Nakamura Jun
Published: March 2006

Tobacco smoke produces oxidative and alkylative DNA damage that necessitates repair by base excision repair coordinated by X-ray cross-complementing gene 1 (XRCC1). We investigated whether polymorphisms in XRCC1 alter DNA repair capacity and modify breast cancer risk associated with smoking. To show the functionality of the 280His variant, we evaluated single-strand break (SSB) repair capacity of isogenic Chinese hamster ovary cells expressing human forms of XRCC1 after exposure to hydrogen peroxide (H2O2), methyl methanesulfonate (MMS), or camptothecin by monitoring NAD(P)H. We used data from the Carolina Breast Cancer Study (CBCS), a population-based, case-control study that included 2,077 cases (786 African Americans and 1,281 Whites) and 1,818 controls (681 African Americans and 1,137 Whites), to examine associations among XRCC1 codon 194, 280, and 399 genotypes, breast cancer, and smoking. Odds ratios and 95% confidence intervals (95% CI) were calculated by unconditional logistic regression. Only cells expressing the 280His protein accumulated SSB, indicated by NAD(P)H depletion, from both H2O2 and MMS exposures. In the CBCS, positive associations were observed between breast cancer and smoking dose for participants with XRCC1 codon 194 Arg/Arg (Ptrend = 0.046), 399 Arg/Arg (Ptrend = 0.012), and 280 His/His or His/Arg (Ptrend = 0.047) genotypes. The 280His allele was in strong linkage disequilibrium with 194Arg (Lewontin's D′ = 1.0) and 399Arg (D′ = 1.0). These data suggest that less common, functional polymorphisms may lie within common haplotypes and drive gene-environment interactions. (Cancer Res 2006; 66(5): 2860-8)
Targeting Multiple Signaling Pathways by Green Tea Polyphenol (−)-Epigallocatechin-3-Gallate
Authors: Khan Naghma , Afaq Farrukh , Saleem Mohammad , Ahmad Nihal , Mukhtar Hasan
Published: March 2006

Cell signaling pathways, responsible for maintaining a balance between cell proliferation and death, have emerged as rational targets for the management of cancer. Emerging data amassed from various laboratories around the world suggests that green tea, particularly its major polyphenolic constituent (−)-epigallocatechin-3-gallate (EGCG), possesses remarkable cancer chemopreventive and therapeutic potential against various cancer sites in animal tumor bioassay systems and in some human epidemiologic studies. EGCG has been shown to modulate multiple signal transduction pathways in a fashion that controls the unwanted proliferation of cells, thereby imparting strong cancer chemopreventive as well as therapeutic effects. This review discusses the modulations of important signaling events by EGCG and their implications in cancer management.(Cancer Res 2006;66(5):2500–5)
Fibrinogen γ Overexpression in Pancreatic Cancer Identified by Large-scale Proteomic Analysis of Serum Samples
Authors: Bloomston Mark , Zhou Jeff X. , Rosemurgy Alexander S. , Frankel Wendy , Muro-Cacho Carlos A. , Yeatman Timothy J.
Published: March 2006

Detection of serum markers for pancreatic cancer has been elusive. Although CA 19-9 is most commonly used, its sensitivity and specificity are modest. We used large-scale proteomics to identify potential serum markers for pancreatic cancer. Samples were analyzed using high-resolution two-dimensional gel electrophoresis to identify differentially expressed proteins in 32 normal and 30 pancreatic cancer patients. Up to 1,744 protein spots were resolved for each serum sample. Candidate proteins were identified using mass spectrometry. ANOVA was used to identify proteins that could discriminate cancer from normal sera. Serum fibrinogen level was also measured using enzymatic assay. Immunohistochemistry was used to detect fibrinogen in resected pancreatic cancers. One hundred fifty-four proteins were commonly overexpressed in all pancreatic cancers. Nine protein spots (four with identifications by mass spectrometry) could effectively separate cancer from normal controls using cross-validation. These proteins successfully discriminated all pancreatic cancer samples (30 of 30) and 94% of normal (30 of 32) samples. Prominent among these candidates was fibrinogen γ, which was subsequently confirmed to be overexpressed in pancreatic cancer sera by enzymatic analysis (54.1 ± 64.1 versus 0.0 ± 0.0 mg/dL, P < 0.05) and tissue by immunohistochemistry (67% versus 29%, P < 0.05) relative to normal pancreas. Proteomic analysis combining two-dimensional gel electrophoresis and mass spectrometry successfully identified 154 potential serum markers for pancreatic cancer. Of these, fibrinogen γ, a protein associated with the hypercoagulable state of pancreatic cancer, discriminated cancer from normal sera. Fibrinogen is a potential tumor marker in pancreatic cancer. (Cancer Res 2006; 66(5): 2592-9)
A Prospective Study of Hemoglobin A1c Concentrations and Risk of Breast Cancer in Women
Authors: Lin Jennifer , Ridker Paul M. , Rifai Nader , Lee I-Min , Manson JoAnn E. , Buring Julie E. , Zhang Shumin M.
Published: March 2006

Impaired glucose metabolism and hyperinsulinemia have been hypothesized to increase breast cancer risk. However, findings from observational studies relating blood concentrations of hyperinsulinemia markers to breast cancer risk have been inconsistent. We prospectively evaluated whether hemoglobin A1c (HbA1c) concentrations predict breast cancer risk in a large female cohort. We included 27,110 female participants of the Women's Health Study who were, at baseline, free of cancer and had usable blood specimens as well as sufficient information on potential risk factors for breast cancer. Relative risks (RR) and 95% confidence intervals (95% CI) were estimated from Cox proportional hazards regression models. All Ps were two sided. During an average of 10 years of follow-up, 790 incident cases of invasive breast cancer were confirmed. Higher baseline HbA1c levels were not associated with an increased risk of breast cancer. The multivariate RR for the highest relative to the lowest quintile of HbA1c levels was 0.87 (95% CI, 0.69-1.10; Ptrend = 0.22). Higher HbA1c levels were also not associated with an increased risk of breast cancer according to alternative clinical cutoff points for HbA1c or in the analyses stratified by body mass index or according to certain tumor characteristics. However, a weakly inverse association was noted among postmenopausal women, especially among those who had never used hormone therapy. There was also a weakly inverse association between HbA1c levels and estrogen receptor–negative breast tumors. These data suggest that higher HbA1c concentrations do not seem to increase risk of breast cancer among apparently healthy women. (Cancer Res 2006; 66(5): 2869-75)
Increased Expression of Genes Converting Adrenal Androgens to Testosterone in Androgen-Independent Prostate Cancer
Authors: Stanbrough Michael , Bubley Glenn J. , Ross Kenneth , Golub Todd R. , Rubin Mark A. , Penning Trevor M. , Febbo Phillip G. , Balk Steven P.
Published: March 2006

Androgen receptor (AR) plays a central role in prostate cancer, and most patients respond to androgen deprivation therapies, but they invariably relapse with a more aggressive prostate cancer that has been termed hormone refractory or androgen independent. To identify proteins that mediate this tumor progression, gene expression in 33 androgen-independent prostate cancer bone marrow metastases versus 22 laser capture–microdissected primary prostate cancers was compared using Affymetrix oligonucleotide microarrays. Multiple genes associated with aggressive behavior were increased in the androgen-independent metastatic tumors (MMP9, CKS2, LRRC15, WNT5A, EZH2, E2F3, SDC1, SKP2, and BIRC5), whereas a candidate tumor suppressor gene (KLF6) was decreased. Consistent with castrate androgen levels, androgen-regulated genes were reduced 2- to 3-fold in the androgen-independent tumors. Nonetheless, they were still major transcripts in these tumors, indicating that there was partial reactivation of AR transcriptional activity. This was associated with increased expression of AR (5.8-fold) and multiple genes mediating androgen metabolism (HSD3B2, AKR1C3, SRD5A1, AKR1C2, AKR1C1, and UGT2B15). The increase in aldo-keto reductase family 1, member C3 (AKR1C3), the prostatic enzyme that reduces adrenal androstenedione to testosterone, was confirmed by real-time reverse transcription-PCR and immunohistochemistry. These results indicate that enhanced intracellular conversion of adrenal androgens to testosterone and dihydrotestosterone is a mechanism by which prostate cancer cells adapt to androgen deprivation and suggest new therapeutic targets. (Cancer Res 2006; 66(5): 2815-25)
Genetic Polymorphisms in Alcoholic Pancreatitis
Authors: Whitcomb David C.
Published: February 2006

Background: Chronic, excessive alcohol consumption is clearly associated with acute and chronic pancreatitis. However, both clinical and laboratory studies demonstrate that alcohol consumption alone does not directly cause alcoholic chronic pancreatitis. Growing evidence suggests that environmental and possibly genetic cofactors must also be present to overcome the redundant mechanisms protecting the pancreas from pancreatitis and facilitating complete recovery. Methods: The SAPE hypothesis model was used to organize potential triggering factors, susceptibility factors and disease-modifying factors based on insights from animal studies. A systematic review of genetic studies on alcoholic pancreatitis was conducted and the results were analyzed in the context of animal studies. Results: To date, no major genetic cofactors for susceptibility or progression have been identified in ∼90% of cases of human alcoholic chronic pancreatitis. Mutations have been identified in the pancreatic secretory trypsin inhibitor gene (SPINK1) in about 8% of cases, and an excess in cystic fibrosis transmembrane conductance inhibitor (CFTR) gene variants have been reported, but the details of the complex genetics with CFTR have not been clarified. None of the polymorphisms in alcohol-metabolizing genes or detoxifying genes appear to explain pancreatic susceptibility. Conclusions: New, adequately powered genetic studies are needed. Several major genetic epidemiology studies are underway in both Europe and the United States to help determine why only a subset of alcoholics develop alcoholic chronic pancreatitis.
Lethal Giant Puzzle of Lgl
Authors: Vasioukhin Valeri
Published: March 2006

Cell polarity is one of the most basic properties of all normal cells and loss of polarity is a hallmark of cancer. While multiple proteins have been implicated in the maintenance of cell polarity, the functionally related neoplastic tumor suppressors Lethal giant larvae (Lgl), Scribble and Disks large comprise a unique group of molecules that are not only involved in the maintenance of cell polarity, but also in the regulation of cell proliferation and cancer. Lgl is the first identified member of this group. Loss of Lgl leads to massive tissue disorganization, tumor-like growth and lethal phenotypes in both Drosophila and mice. Lgl mutant cells display disruption of cell polarity, failure of asymmetric cell division, deregulation of Notch signaling and loss of proper cell fate determination. Lgl is a critical downstream target of the Par6/aPKC cell polarity complex; however, the functional role of Lgl itself and, specifically, the mechanisms of Lgl function in cell polarity and regulation of cell proliferation remain enigmatic. This minireview summarizes available information and discusses potential mechanisms of Lgl function.
Distinct Functions of Human Numb Isoforms Revealed by Misexpression in the Neural Stem Cell Lineage in the Drosophila Larval Brain
Authors: Toriya Masako , Tokunaga Akinori , Sawamoto Kazunobu , Nakao Keiko , Okano Hideyuki
Published: March 2006

Mammalian Numb (mNumb) has multiple functions and plays important roles in the regulation of neural development, including maintenance of neural progenitor cells and promotion of neuronal differentiation in the central nervous system (CNS). However, the molecular bases underlying the distinct functions of Numb have not yet been elucidated. mNumb, which has four splicing isoforms, can be divided into two types based on the presence or absence of an amino acid insert in the proline-rich region (PRR) in the C-terminus. It has been proposed that the distinct functions of mNumb may be attributable to these two different types of isoforms. In this study, we used the outer optic anlage (OOA) of the Drosophila larval brain as an assay system to analyze the functions of these two types of isoforms in the neural stem cells, since the proliferation pattern of neuroepithelial (NE) stem cells in the OOA closely resembles that of the vertebrate neural stem/progenitor cells. They divide to expand the progenitor cell pool during early neurogenesis and to produce neural precursors/neurons during late neurogenesis. Clonal analysis in the OOA allows one to discriminate between the NE stem cells, which divide symmetrically to expand the progenitor pool, and the postembryonic neuroblasts (pNBs), which divide asymmetrically to produce neural precursors (ganglion mother cells), each of which divides once to produce two neurons. We found that in the OOA, the human Numb isoform with a long PRR domain (hNumb-PRRL), which is mainly expressed during early neurogenesis in the mouse CNS, promotes proliferation of both NE cells and pNBs without affecting neuronal differentiation, while the other type of hNumb isoform with a short PRR domain (hNumb-PRRS), which is expressed throughout neurogenesis in the mouse embryonic CNS, inhibits proliferation of the stem cells and promotes neuronal differentiation. We also found that hNumb-PRRS, a functional homologue of Drosophila Numb, more strongly decreases the amount of nuclear Notch than hNumb-PRRL, and could antagonize Notch functions probably through endocytic degradation, suggesting that the two distinct types of hNumb isoforms could contribute to different phases of neurogenesis in the mouse embryonic CNS.
Specificity of Cognitive Deficits in Bipolar Disorder versus Schizophrenia
Authors: Daban Claire , Martinez-Aran Anabel , Torrent Carla , Tabarés-Seisdedos Rafael , Balanzá-Martínez Vicent , Salazar-Fraile Jose , Selva-Vera Gabriel , Vieta Eduard
Published: March 2006

Background: More and more epidemiological, genetic and neuroimaging studies show similarities between bipolar disorder (BD) and schizophrenia (SZ). Cognitive functions are known to be highly impaired in SZ and are increasingly studied in BD. When both populations are compared, the conclusions appear to be contradictory. The purpose of this review is to help define the profile of cognitive deficits in BD and in SZ. Methods: A systematic review of the literature of neuropsychological studies comparing BD and SZ was made, beginning in January 1990 and ending in January 2005. Thirty-eight studies met the required quality criteria and were included in this review. Results: Bipolar patients exhibit extensive cognitive abnormalities with a pattern of deficits that is not unique to this disease. However, when compared to schizophrenic patients, bipolar patients demonstrate a lesser degree of deficits, particularly concerning premorbid and current intelligence quotient and perhaps attention, verbal memory and executive functions. When looking into effect sizes, there seem to be different profiles even in studies finding no significant differences. Conclusions: The neuropsychological differences reported between both groups could be due to the presence of psychotic features, to environmental factors (stressful events, duration of the disease and number of hospitalisations) and could also be related to differences during the neurodevelopmental phase. Further studies should confirm whether these results are truly related to different neurobiological backgrounds.