bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms of neonatal increase in glomerular filtration rate
Authors: Turner Anita J. , Brown Russell D. , Carlström Mattias , Gibson Karen J. , Persson A. Erik G.
Published: July 2008

To investigate the mechanisms responsible for the neonatal increase in glomerular filtration rate (GFR), renal function studies (whole kidney and micropuncture) were carried out in anesthesized fetal sheep (133–140 days gestation; term = 150 days) and lambs (12–18 days). Fetuses were delivered and placed in a water bath (39.5°C), keeping the umbilical cord moist and intact. Lambs were studied on a thermostatically controlled heating pad. Animals were prepared for either blood flow studies or micropuncture measurements. Expected differences in blood composition and cardiovascular and renal function were observed between fetuses and lambs, and values obtained for most variables were similar to those measured in chronically catheterized unanesthetized animals. Fetal GFR was much lower than that of lambs (0.20 vs. 0.62 ml·min−1·g kidney−1, P < 0.001). Free-flow, stop-flow, and net filtration pressures (NFP) were lower in the fetuses than the lambs (NFP 20.8 vs. 23.8 mmHg, P < 0.001), as was the calculated ultrafiltration coefficient (0.014 vs. 0.022 ml·min−1·g−1·mmHg−1, P < 0.001). Thus, we conclude that rises in both net filtration pressure and the ultrafiltration coefficient contribute to the large increase in GFR between fetal life and ∼2 wk after birth.
Linoleic acid increases chorda tympani nerve responses to and behavioral preferences for monosodium glutamate by male and female rats
Authors: Stratford Jennifer M. , Curtis Kathleen S. , Contreras Robert J.
Published: July 2008

Previous studies suggest that the chorda tympani nerve (CT) is important in transmitting fat taste information to the central nervous system. However, the contribution of the CT in this process may depend upon the presence of other taste stimuli and/or differ in males and females. Accordingly, the present study investigated the role of the CT in free fatty acid taste processing by examining electrophysiological activity of the CT in response to the free fatty acid linoleic acid (LA), as well as by measuring behavioral responses to LA-taste mixtures. We recorded whole nerve responses from the CT in response to lingual application of LA with or without monosodium glutamate (MSG) in anesthetized male and female rats. In addition, we examined preferences for MSG + LA taste mixtures in behavioral tests. Although lingual application of LA alone did not produce CT whole nerve responses, coapplication of LA and MSG elicited greater CT responses than did MSG alone. These findings were paralleled by greater preferences for MSG + LA taste mixtures than for MSG alone. In both cases, the effect was particularly pronounced in male rats. Thus LA enhances CT activity and behavioral responses to LA + MSG taste mixtures, although there are sex differences in the effects. These results suggest that CT input is important in mediating behavioral responses to fat taste, but the effects depend upon other taste stimuli and differ in males and females.
Interstitial cells of Cajal in the urethra are cGMP-mediated targets of nitrergic neurotransmission
Authors: García-Pascual Ángeles , Sancho María , Costa Gonzalo , Triguero Domingo
Published: July 2008

While interstitial cells of Cajal (ICC) in the urethra respond to nitric oxide (NO) donors by increasing cGMP, it remains unclear whether urethral ICC are functionally innervated by nitrergic nerves. We have addressed this issue in the rat and sheep urethra, where cGMP production and relaxation were compared in preparations subjected to electrical field stimulation (EFS; 2 Hz, 4 min) of nitrergic nerves or to exogenous S-nitroso-l-cysteine (SNC; 0.1 mM, 4 min). Upon EFS, cGMP immunoreactivity (cGMP-ir) was observed in both smooth muscle cells (SMC) and in spindle-shaped cells that contained c-kit and vimentin, features of ICC. Similarly, cGMP-ir was preferentially, but inconsistently, found in ICC of the outer muscle layer on exposure to SNC. We found separate functional groups of ICC within the urethra. Thus only ICC present in the muscle layers (ICC-M) but not those in the serosa (ICC-SR) and lamina propia (ICC-LP) seem to be specifically influenced by activation of neuronal NO synthase (nNOS). Thus the increase in cGMP-ir in the ICC-M induced by EFS was prevented by Nω-nitro-l-arginine and ODQ. Urethral ICC did not express nNOS, although they were closely associated with nitrergic nerves. cGMP-ir was also present in the urothelium (in the rat but not in the sheep) and the vascular endothelium but not in neural structures, such as the nerve trunks and nerve terminals. Together, these results suggest a model of parallel innervation in which both SMC and ICC-M are effectors of nerve-released NO in the urethra.
Upregulation of vascular endothelial growth factor isoform VEGF-164 and receptors (VEGFR-2, Npn-1, and Npn-2) in rats with cyclophosphamide-induced cystitis
Authors: Cheppudira Bopaiah P. , Girard Beatrice M. , Malley Susan E. , Schutz Kristin C. , May Victor , Vizzard Margaret A.
Published: July 2008

Regulation of the VEGF-VEGF receptor system was examined in the urinary bladder after acute (2–48 h) and chronic (10 days) cyclophosphamide (CYP)-induced cystitis. ELISAs demonstrated significant ( P ≤ 0.01) upregulation of VEGF in whole urinary bladder with acute and chronic CYP-induced cystitis; however, the magnitude of increase was greater after acute (2–4 h) cystitis. Immunohistochemistry for VEGF immunoreactivity revealed a significant ( P ≤ 0.05) increase in VEGF immunoreactivity in the urothelium, suburothelial vasculature, and detrusor smooth muscle with acute (4 and 48 h) CYP treatment. RT-PCR identified the isoform VEGF-164, the VEGF receptor VEGFR-2, and the VEGF co-receptors neuropilin (Npn)-1 and Npn-2 in the urinary bladder. Quantitative PCR demonstrated upregulation of VEGF-164 transcript with acute and chronic CYP-induced cystitis, but VEGFR-2, Npn-1, and Npn-2 transcripts were upregulated ( P ≤ 0.01) in whole bladder only with chronic CYP-induced cystitis. Additional studies demonstrated regulation of VEGF transcript expression in the urinary bladder by nerve growth factor (NGF) in a novel line of NGF-overexpressing mice. These studies demonstrated that urinary bladder inflammation and NGF regulate the VEGF-VEGF receptor system in the urinary bladder. Functional role(s) for the VEGF-VEGF receptor system in urinary bladder inflammation remain to be determined.
Pitch Representations in the Auditory Nerve: Two Concurrent Complex Tones
Authors: Larsen Erik , Cedolin Leonardo , Delgutte Bertrand
Published: July 2008

Pitch differences between concurrent sounds are important cues used in auditory scene analysis and also play a major role in music perception. To investigate the neural codes underlying these perceptual abilities, we recorded from single fibers in the cat auditory nerve in response to two concurrent harmonic complex tones with missing fundamentals and equal-amplitude harmonics. We investigated the efficacy of rate-place and interspike-interval codes to represent both pitches of the two tones, which had fundamental frequency (F0) ratios of 15/14 or 11/9. We relied on the principle of scaling invariance in cochlear mechanics to infer the spatiotemporal response patterns to a given stimulus from a series of measurements made in a single fiber as a function of F0. Templates created by a peripheral auditory model were used to estimate the F0s of double complex tones from the inferred distribution of firing rate along the tonotopic axis. This rate-place representation was accurate for F0s ≳900 Hz. Surprisingly, rate-based F0 estimates were accurate even when the two-tone mixture contained no resolved harmonics, so long as some harmonics were resolved prior to mixing. We also extended methods used previously for single complex tones to estimate the F0s of concurrent complex tones from interspike-interval distributions pooled over the tonotopic axis. The interval-based representation was accurate for F0s ≲900 Hz, where the two-tone mixture contained no resolved harmonics. Together, the rate-place and interval-based representations allow accurate pitch perception for concurrent sounds over the entire range of human voice and cat vocalizations.
Graded Size Sensitivity of Object-Exemplar–Evoked Activity Patterns Within Human LOC Subregions
Authors: Eger Evelyn , Kell Christian A. , Kleinschmidt Andreas
Published: July 2008

A central issue for understanding visual object recognition is how the cortical hierarchy represents incoming sensory information and transforms it across successive processing stages. The format of object representation in the human brain has thus far mostly been studied using adaptation paradigms because the neuronal layout of object selectivities was thought to be beyond the resolution of conventional functional MRI (fMRI). Recently, however, multivariate pattern recognition succeeded in discriminating fMRI responses of object-selective cortex to different object exemplars within a given category. Here, we use increased spatial fMRI resolution to explore size sensitivity and tolerance to size change of response patterns evoked by object exemplars across a range of three sizes. Results from Support Vector Classification on responses of the human lateral occipital complex (LOC) show that discrimination of size (for a given object) and discrimination of objects across changes in size depended on the amount of size difference. Even across the largest amount of size change, accuracy for generalization was still significant in LOC, whereas the same comparison was at chance performance in early visual (calcarine) cortex. Analyzing subregions, we further found an anterior-posterior gradient in the degree of size sensitivity and size generalization within the posterior-dorsal and anterior-ventral parts of LOC. These results speak against fully size-invariant representation of object information in human LOC and are hence congruent with findings in monkeys showing object identity and size information in population activity of inferotemporal cortex. Moreover, these results provide evidence for a fine-grained functional heterogeneity within human LOC beyond the commonly used LO/fusiform subdivision.
Gaze Behavior When Reaching to Remembered Targets
Authors: Flanagan J. Randall , Terao Yasuo , Johansson Roland S.
Published: July 2008

People naturally direct their gaze to visible hand movement goals. Doing so improves reach accuracy through use of signals related to gaze position and visual feedback of the hand. Here, we studied where people naturally look when acting on remembered target locations. Four targets were presented on a screen, in peripheral vision, while participants fixed a central cross (encoding phase). Four seconds later, participants used a pen to mark the remembered locations while free to look wherever they wished (recall phase). Visual references, including the screen and the cross, were present throughout. During recall, participants neither looked at the marked locations nor prevented eye movements. Instead, gaze behavior was erratic and was comprised of gaze shifts loosely coupled in time and space with hand movements. To examine whether eye and hand movements during encoding affected gaze behavior during recall, in additional encoding conditions, participants marked the visible targets with either free gaze or with central cross fixation or just looked at the targets. All encoding conditions yielded similar erratic gaze behavior during recall. Furthermore, encoding mode did not influence recall performance, suggesting that participants, during recall, did not exploit sensorimotor memories related to hand and gaze movements during encoding. Finally, we recorded a similar lose coupling between hand and eye movements during an object manipulation task performed in darkness after participants had viewed the task environment. We conclude that acting on remembered versus visible targets can engage fundamentally different control strategies, with gaze largely decoupled from movement goals during memory-guided actions.
Neural Modulation by Regularity and Passage of Time
Authors: Correa Ángel , Nobre Anna C.
Published: July 2008

The current study tested whether multiple rhythms could flexibly induce temporal expectations (temporal orienting) and whether these expectations interact with temporal expectations associated with the passage of time (foreperiod effects). A visual stimulus that moved following a regular rhythm was temporarily occluded for a variable duration (occlusion foreperiod). The task involved making a speeded perceptual discrimination about the target stimulus that reappeared after the occlusion. Temporal-orienting effects were measured by comparing performance and event-related potentials on conditions in which the timing for target reappearance was predictable (valid) versus unpredictable (invalid) according to the rhythm. Foreperiod effects were measured by comparing conditions in which the target was occluded for progressively longer periods of time (short, medium, and long foreperiods) and hence were increasingly predictable. The results showed strong interactions between temporal orienting and foreperiod effects during the facilitation of behavior and neural activity associated with late perceptual and response selection processes. Temporal orienting attenuated the N2 amplitude and decreased the P3 latency only at short foreperiods. Temporal preparation related to foreperiod effects abolished temporal orienting effects at medium and long foreperiods. Likewise, foreperiod effects attenuated the N1 and N2 amplitudes and decreased the P3 latency only in the invalid orienting condition as preparation related to temporal orienting abolished foreperiod effects in the valid condition. This high degree of neural overlap between the effects of temporal orienting driven by rhythms and foreperiod effects associated with the passage of time suggests the involvement of a common mechanism for temporal preparation.
Short-Term Synaptic Depression and Recovery at the Mature Mammalian Endbulb of Held Synapse in Mice
Authors: Wang Yong , Manis Paul B.
Published: July 2008

The endbulb of Held synapses between the auditory nerve fibers (ANF) and cochlear nucleus bushy neurons convey fine temporal information embedded in the incoming acoustic signal. The dynamics of synaptic depression and recovery is a key in regulating synaptic transmission at the endbulb synapse. We studied short-term synaptic depression and recovery in mature (P22-38) CBA mice with stimulation rates that were comparable to sound-driven activities recorded in vivo. Synaptic depression in mature mice is less severe (∼40% at 100 Hz) than reported for immature animals and the depression is predominately due to depletion of releasable vesicles. Recovery from depression depends on the rate of activity and accumulation of intracellular Ca2+ at the presynaptic terminal. With a regular stimulus train at 100 Hz in 2 mM external [Ca2+], the recovery from depletion was slow (τslow, ∼2 s). In contrast, a fast (τfast, ∼25 ms), Ca2+-dependent recovery followed by a slower recovery (τslow, ∼2 s) was seen when stimulus rates or external [Ca2+] increased. In normal [Ca2+], recovery from a 100-Hz Poisson-like train is rapid, suggesting that Poisson-like trains produce a higher internal [Ca2+] than regular trains. Moreover, the fast recovery was slowed by approximately twofold in the presence of calmidazolium, a Ca2+/calmodulin inhibitor. Our results suggest that endbulb synapses from high spontaneous firing rate auditory nerve fibers normally operate in a depressed state. The accelerated synaptic recovery during high rates of activity is likely to ensure that reliable synaptic transmission can be achieved at the endbulb synapse.
Resistance to diet-induced obesity in mice with a single substituted chromosome
Authors: Buchner David A. , Burrage Lindsay C. , Hill Annie E. , Yazbek Soha N. , O'Brien William E. , Croniger Colleen M. , Nadeau Joseph H.
Published: July 2008

Obesity and its comorbidities are taking an increasing toll on human health. Key pathways that were identified with single gene variants in humans and model organisms have led to improved understanding and treatment of rare cases of human obesity. However, similar progress remains elusive for the more common multifactorial cases of metabolic dysfunction and disease. A survey of mouse chromosome substitution strains (CSSs) provided insight into the complex genetic control of diet-induced obesity and related conditions. We now report a survey of 60 traits related to obesity and metabolic syndrome in mice with a single substituted chromosome as well as selected traits measured in congenic strains derived from the substituted strain. We found that each strain that was resistant to diet-induced obesity had a distinct phenotype that uniquely modeled different combinations of traits related to metabolic disease. For example, the chromosome 6 CSS remained insulin resistant in the absence of obesity, demonstrating an atypical relationship between body weight and insulin resistance. These results provide insights into the genetic control of constant components of this mouse model of diet-induced metabolic disease as well as phenotypes that vary depending on genetic background. A better understanding of these genotype-phenotype relationships may enable a more individualized diagnosis and treatment of obesity and the metabolic syndrome.
Importance and Limits of Ischemia in Renal Partial Surgery: Experimental and Clinical Research
Authors: Secin Fernando P.
Published: July 2008

Introduction. The objective is to determine the clinical and experimental evidences of the renal responses to warm and cold ischemia, kidney tolerability, and available practical techniques of protecting the kidney during nephron-sparing surgery.Materials and methods. Review of the English and non-English literature using MEDLINE, MD Consult, and urology textbooks.Results and discussion. There are three main mechanisms of ischemic renal injury, including persistent vasoconstriction with an abnormal endothelial cell compensatory response, tubular obstruction with backflow of urine, and reperfusion injury. Controversy persists on the maximal kidney tolerability to warm ischemia (WI), which can be influenced by surgical technique, patient age, presence of collateral vascularization, indemnity of the arterial bed, and so forth.Conclusions. When WI time is expected to exceed from 20 to 30 minutes, especially in patients whose baseline medical characteristics put them at potentially higher, though unproven, risks of ischemic damage, local renal hypothermia should be used.
Determination of Differential Enthalpy and Isotherm by Adsorption Calorimetry
Authors: Garcia-Cuello V. , Moreno-Piraján J. C. , Giraldo-Gutiérrez L. , Sapag K. , Zgrablich G.
Published: July 2008

An adsorption microcalorimeter for the simultaneous determination of the differential heat of adsorption and the adsorption isotherm for gas-solid systems are designed, built, and tested. For this purpose, a Calvet heat-conducting microcalorimeter is developed and is connected to a gas volumetric unit built in stainless steel to record adsorption isotherms. The microcalorimeter is electrically calibrated to establish its sensitivity and reproducibility, obtaining K=154.34±0.23 WV−1. The adsorption microcalorimeter is used to obtain adsorption isotherms and the corresponding differential heats for the adsorption of CO2 on a reference solid, such as a NaZSM-5 type zeolite. Results for the behavior of this system are compared with those obtained with commercial equipment and with other studies in the literature.
Starlike and Convex Properties for Hypergeometric Functions
Authors: Kwon Oh Sang , Cho Nak Eun
Published: July 2008

The purpose of the present paper is to give some characterizations for a (Gaussian)
hypergeometric function to be in various subclasses of starlike and convex functions.
We also consider an integral operator related to the hypergeometric function.
PPAR Ligands as Potential Modifiers of Breast Carcinoma Outcomes
Authors: Baranova Ancha
Published: July 2008

Chemically synthesized ligands for nuclear receptors of the PPAR family modulate a number of physiological functions, particularly insulin resistance in the context of energy homeostasis and the metabolic syndrome. Additionally, these compounds may treat or prevent the development of many secondary consequences of the metabolic syndrome. Many PPAR agonists are also known to influence the proliferation and apoptosis of breast carcinoma cells though the experiments were carried out at suprapharmacological doses of PPAR ligands. It is possible that the breast epithelium of diabetics exposed to PPAR agonists will experience perturbation of the corresponding signaling pathway. Consequently, these patients′ lifetime breast carcinoma risks could be modified, as their breast lesion incidence or the rates of the conversion of these lesions to carcinomas might vary upward or downward. PPAR activating treatment may also influence the progression of existing, undiagnosed invasive lesions. In this review, we attempt to summarize the possible influence of chemical PPAR ligands on the molecular pathways involved in the initiation and progression of breast carcinoma, with a major emphasis on PPARγ agonists thiazolidinediones (TZDs).
Titanium Dioxide‐Based 64∘ YX LiNbO3 Surface Acoustic Wave Hydrogen Gas Sensors
Authors: Sadek A. Z. , Buso D. , Martucci A. , Mulvaney P. , Wlodarski W. , Kalantar-zadeh K.
Published: July 2008

Amorphous titanium dioxide (TiO2) and gold (Au) doped TiO2‐based surface acoustic wave (SAW) sensors have been investigated as hydrogen gas detectors. The nanocrystal‐doped TiO2 films were synthesized through a sol‐gel route, mixing a Ti‐butoxide‐based solution with diluted colloidal gold nanoparticles. The films were deposited via spin coating onto 64∘ YX LiNbO3 SAW transducers in a helium atmosphere. The SAW gas sensors were operated at various temperatures between 150 and 310∘C. It was found that gold doping on TiO2 increased the device sensitivity and reduced the optimum operating temperature.
Mitochondria, PPARs, and Cancer: Is Receptor‐Independent Action of PPAR Agonists a Key?
Authors: Scatena Roberto , Bottoni Patrizia , Giardina Bruno
Published: July 2008

Before the discovery of peroxisome proliferator activated receptors (PPARs), it was well known that certain drugs considered as classical PPAR‐alpha agonists induced hepatocarcinoma or peroxisome proliferation in rodents. These drugs were derivatives of fibric acid, and they included clofibrate, bezafibrate, and fenofibrate. However, such toxicity has never been observed in human patients treated with these hypolipidemic drugs. Thiazolidinediones are a new class of PPAR activators showing greater specificity for the γ isoform of PPARs. These drugs are used as insulin sensitizers in the treatment of type II diabetes. In addition, they have been shown to induce cell differentiation or apoptosis in various experimental models of cancer. PPAR‐α ligands have also been shown to induce cancer cell differentiation and, paradoxically, PPAR‐γ drug activators have been reported to act as carcinogens. The confusing picture that emerges from these data is further complicated by the series of intriguing side effects observed following administration of pharmacological PPAR ligands (rhabdomyolysis, liver and heart toxicity, anemia, leucopenia). These side effects cannot be easily explained by simple interactions between the drug and nuclear receptors. Rather, these side effects seem to indicate that the ligands have biological activity independent of the nuclear receptors. Considering the emerging role of mitochondria in cancer and the potential metabolic connections between this organelle and PPAR physiology, characterization of the reciprocal influences is fundamental not only for a better understanding of cancer biology, but also for more defined pharmacotoxicological profiles of drugs that modulate PPARs.
High‐Level Development of Multiserver Online Games
Authors: Glinka Frank , Ploss Alexander , Gorlatch Sergei , Müller-Iden Jens
Published: July 2008

Multiplayer online
games with support for high user numbers must
provide mechanisms to support an increasing
amount of players by using additional resources.
This paper provides a comprehensive analysis of
the practically proven multiserver distribution
mechanisms, zoning, instancing, and replication,
and the tasks for the game developer implied by
them. We propose a novel, high‐level development
approach which integrates the three distribution
mechanisms seamlessly in today′s online
games. As a possible base for this high‐level
approach, we describe the real‐time framework
(RTF) middleware system which liberates the
developer from low‐level tasks and allows him to
stay at high level of design abstraction. We
explain how RTF supports the implementation of
single‐server online games and how RTF allows to
incorporate the three multiserver distribution
mechanisms during the development process.
Finally, we describe briefly how RTF provides
manageability and maintenance functionality for
online games in a grid context with dynamic
resource allocation scenarios.
Cryoablation for Small Renal Masses
Authors: Dominguez-Escrig J. L. , Sahadevan K. , Johnson P.
Published: July 2008

Advances in imaging techniques (CT and MRI) and widespread use of imaging especially ultrasound scanning have resulted in a dramatic increase in the detection of small renal masses. While open partial nephrectomy is still the reference standard for the management of these small renal masses, its associated morbidity has encouraged clinicians to exploit the advancements in minimally invasive ablative techniques. The last decade has seen the rapid development of laparoscopic partial nephrectomy and novel ablative techniques such as, radiofrequency ablation (RFA), high-intensity focused ultrasound (HIFU), and cryoablation (CA). In particular, CA for small renal masses has gained popularity as it combines nephron-sparing surgery with a minimally invasive approach. Studies with up to 5-year followup have shown an overall and cancer-specific 5-year survival of 82% and 100%, respectively. This manuscript will focus on the principles and clinical applications of cryoablation of small renal masses, with detailed review of relevant literature.
About the Properties of a Modified Generalized Beverton‐Holt Equation in Ecology Models
Authors: De La Sen M.
Published: July 2008

This paper is devoted to the study of a generalized modified version of the well‐known Beverton‐Holt equation in ecology. The proposed model describes the population evolution of some species in a certain habitat driven by six parametrical sequences, namely, the intrinsic growth rate (associated with the reproduction capability), the degree of sympathy of the species with the habitat (described by a so‐called environment carrying capacity), a penalty term to deal with overpopulation levels, the harvesting (fishing or hunting) regulatory quota, or related to use of pesticides when fighting damaging plagues, and the independent consumption which basically quantifies predation. The independent consumption is considered as a part of a more general additive disturbance which also potentially includes another extra additive disturbance term which might be attributed to net migration from or to the habitat or modeling measuring errors. Both potential contributions are included for generalization purposes in the proposed modified generalized Beverton‐Holt equation. The properties of stability and boundedness of the solution sequences, equilibrium points of the stationary model, and the existence of oscillatory solution sequences are investigated. A numerical example for a population of aphids is investigated with the theoretical tools developed in the paper.
Expression and Hydroxylamine Cleavage of Thymosin Alpha 1 Concatemer
Authors: Zhou Liang , Lai Zong-Teng , Lu Min-Kan , Gong Xing-Guo , Xie Yi
Published: July 2008

Human thymosin alpha 1 (Tα1) is an important peptide in the development and senescence of immunological competence in human, and many studies have reported the expression of this peptide. In this study, we designed and synthesized the Tα1 gene according to the E. coli codon usage preference and constructed a 6×Tα1 concatemer. The latter was inserted into an E. coli expression vector pET‐22b (+), and transformed into E. coli BL21 (DE3). After induction with IPTG, the concatemer protein was successfully expressed in E. coli then cleaved by hydroxylamine to release the Tα1 monomer. Gly‐SDS‐PAGE and mass spectrometry confirmed that the recombinant protein was cleaved as intended. The bioactivity of the Tα1 monomer was analyzed by lymphocyte proliferation and by mitochondrial activity in two different tumor cell lines. This study provides a description of the preparation of a bioactive Tα1, which may prove useful in future biomedical research.
RELAP5/MOD3.3 Code Validation with Plant Abnormal Event
Authors: Prošek Andrej , Mavko Borut
Published: July 2008

Measured plant data from various abnormal events are of great importance for code validation. The purpose of the study was to validate the RELAP5/MOD3.3 Patch 03 computer code with the abnormal event which occurred at Krško Nuclear Power Plant (NPP) on April 10, 2005. The event analyzed was a malfunction, which occurred during a power reduction sequence when regular periodic testing of the turbine valves was performed. Unexpected turbine valve closing caused safety injection signal, followed by reactor trip. The RELAP5 input model delivered by Krško NPP was used. In short term, the calculation agrees very well with the plant measured data. In the long term, this is also true when operator actions and special plant systems are modeled. In the opposite, the transient would progress quite differently. Finally, the calculated data may be supplemental to plant measured data when the information is missing or the measurement is questionable.
Reflection Band Control of Inverse Opal Film with Photoresponse Properties of Push-Pull Type Azobenzene LC Polymers
Authors: Kim Sunnam , Shiozawa Takahiro , Moritsugu Masaki , Ogata Tomonari , Nonaka Takamasa , Kurihara Seiji
Published: July 2008

DcAz2Mc and DR1Mc molecules having push-pull type of azobenzene groups are synthesized, and their photo-orientational behaviors are investigated in the polymer system. In order to understand the relationship between a molecular structure and its physical properties, electronic structure calculation is computationally carried out. Regarding to their photo response properties, the copolymers ofpoly(DcAz2Mc-co-M6PBMe) andpoly(DR1Mc-co-M6PBMe) are infiltrated into inverse opal films, and Bragg reflection shifts are observed under photostimuli. When the linearly polarized light is irradiated, Bragg reflection bands are shifted to the longer wavelength region as reflective index increases.
Cyclin D1b Is Aberrantly Regulated in Response to Therapeutic Challenge and Promotes Resistance to Estrogen Antagonists
Authors: Wang Ying , Dean Jeffry L. , Millar Ewan K.A. , Tran Thai Hong , McNeil Catriona M. , Burd Craig J. , Henshall Susan M. , Utama Fransiscus E. , Witkiewicz Agnieszka , Rui Hallgeir , Sutherland Robert L. , Knudsen Karen E. , Knudsen Erik S.
Published: July 2008

Cyclin D1 is a key mediator of cell cycle progression that is aberrantly regulated in multiple cancers, especially in breast cancers. A number of studies have indicated that a polymorphism in a splice donor site in the cyclin D1 gene is associated with alternative splicing and the production of the alternative cyclin D1b transcript. Furthermore, this polymorphism is selectively associated with disease outcomes. However, relatively little is known regarding the protein product of the alternatively spliced message, cyclin D1b. Using antibodies specific for cyclin D1b, it was found that this protein is readily detectable in a number of cancer cell lines and primary breast cancers. Whereas cyclin D1b interacts with cyclin-dependent kinase 4 (CDK4), it is relatively inefficient at mediating RB phosphorylation and cell cycle progression in model systems due to the lack of exon 5 of cyclin D1–encoded sequences. However, cyclin D1b protein levels are not significantly attenuated by DNA damage or antiestrogen treatment, indicating that the protein may have significant effect on the response to such therapeutic modalities. Whereas enforced expression of cyclin D1b was not sufficient to abrogate DNA damage checkpoint responses, it did efficiently overcome cell cycle arrest mediated by antiestrogen therapeutics. This action of cyclin D1b was not associated with effects on estrogen receptor activity, but was rather dependent on functional association with CDK4. Combined, these studies indicate that the cyclin D1b protein is aberrantly regulated and could contribute to therapeutic failure in the context of ER-positive breast cancer. [Cancer Res 2008;68(14):5628–38]
Hsp90 Inhibition Suppresses Mutant EGFR-T790M Signaling and Overcomes Kinase Inhibitor Resistance
Authors: Shimamura Takeshi , Li Danan , Ji Hongbin , Haringsma Henry J. , Liniker Elizabeth , Borgman Christa L. , Lowell April M. , Minami Yuko , McNamara Kate , Perera Samanthi A. , Zaghlul Sara , Thomas Roman K. , Greulich Heidi , Kobayashi Susumu , Chirieac Lucian R. , Padera Robert F. , Kubo Shigeto , Takahashi Masaya , Tenen Daniel G. , Meyerson Matthew , Wong Kwok-Kin , Shapiro Geoffrey I.
Published: July 2008

The epidermal growth factor receptor (EGFR) secondary kinase domain T790M non–small cell lung cancer (NSCLC) mutation enhances receptor catalytic activity and confers resistance to the reversible tyrosine kinase inhibitors gefitinib and erlotinib. Currently, irreversible inhibitors represent the primary approach in clinical use to circumvent resistance. We show that higher concentrations of the irreversible EGFR inhibitor CL-387,785 are required to inhibit EGFR phosphorylation in T790M-expressing cells compared with EGFR mutant NSCLC cells without T790M. Additionally, CL-387,785 does not fully suppress phosphorylation of other activated receptor tyrosine kinases (RTK) in T790M-expressing cells. These deficiencies result in residual Akt and mammalian target of rapamycin (mTOR) activities. Full suppression of EGFR-mediated signaling in T790M-expressing cells requires the combination of CL-387,785 and rapamycin. In contrast, Hsp90 inhibition overcomes these limitations in vitro and depletes cells of EGFR, other RTKs, and phospho-Akt and inhibits mTOR signaling whether or not T790M is present. EGFR-T790M–expressing cells rendered resistant to CL-387,785 by a kinase switch mechanism retain sensitivity to Hsp90 inhibition. Finally, Hsp90 inhibition causes regression in murine lung adenocarcinomas driven by mutant EGFR (L858R) with or without T790M. However, efficacy in the L858R-T790M model requires a more intense treatment schedule and responses were transient. Nonetheless, these findings suggest that Hsp90 inhibitors may be effective in T790M-expressing cells and offer an alternative therapeutic strategy for this subset of lung cancers. [Cancer Res 2008;68(14):5827–38]
A Special Linker between Macrophage and Hematopoietic Malignant Cells: Membrane Form of Macrophage Colony-Stimulating Factor
Authors: Wang Lin , Zheng Guo-Guang , Ma Cui-Hua , Lin Yong-Min , Zhang Hai-Yan , Ma Yuan-Yuan , Chong Jing-Hui , Wu Ke-Fu
Published: July 2008

The membrane form of macrophage colony–stimulating factor (mM-CSF) is an alternative splicing variant of this cytokine. Although its high expression was detected in hematopoietic malignancies, its physiologic and pathologic roles in hematopoietic system have not been established. In this report, stable transfectant clones expressing mM-CSF (Namalwa-M and Ramos-M) were obtained, which showed reduced proliferation potential in vitro. Moreover, the in vivo study showed that Namalwa-M and Ramos-M exhibited enhanced oncogenicity in tumor size in nude mice model, which could be inhibited by M-CSF monoclonal antibody. A remarkable increase in infiltrating macrophage and the vessel densities was found in tumor tissues formed by lymphoma cell lines that stably expressed mM-CSF, which suggested the involvement of macrophages in this process. The in vitro results using coculture system showed that macrophages could promote Namalwa-M and Ramos-M proliferation and activate extracellular signal-regulated kinase/mitogen-activated protein kinase signal pathway. In addition, the expression of murine origin vascular endothelial growth factor, basic fibroblast growth factor, and hepatocyte growth factor was elevated in Namalwa-M formed tumor tissues. These results suggested that mM-CSF should be a positive regulator in the development of hematopoietic malignancies by abnormally activating infiltrating macrophages, which in turn promote the malignant development. Thus, mM-CSF may be a critical linker between macrophages and malignant cells in the development of hematopoietic malignancies. [Cancer Res 2008;68(14):5639–47]
Regulatory T Cell–Resistant CD8+ T Cells Induced by Glucocorticoid-Induced Tumor Necrosis Factor Receptor Signaling
Authors: Nishikawa Hiroyoshi , Kato Takuma , Hirayama Michiko , Orito Yuki , Sato Eiichi , Harada Naozumi , Gnjatic Sacha , Old Lloyd J. , Shiku Hiroshi
Published: July 2008

We previously found that a Salmonella typhimurium vector engineered to secrete soluble tumor antigen induces CD4+ T cells resistant to CD4+CD25+ regulatory T cells (Treg) and that glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR) signal is involved in the development of this resistance. In this study, we address the potential of incorporating GITR ligand (GITRL) as a way to augment the immunogenicity of cancer vaccines. BALB/c mice were immunized by gene gun with plasmids encoding the mutated extracellular signal-regulated kinase 2 (mERK) with or without plasmids encoding mouse GITRL. Coadministration with GITRL during primary and secondary immunization enhanced the induction of mERK-specific CD8+ T cells. Antibody depletion and minigene analysis suggested that GITRL directly activated CTL epitope-specific CD8+ T cells independently of CD4+ T cells. Immunization with plasmids encoding a CTL epitope and GITRL resulted in strong tumor inhibition in a CD8+ T cell–dependent manner. Furthermore, CTL epitope-specific CD8+ T cells induced by immunization with plasmids encoding CTL epitope coadministered with GITRL were refractory to suppression by CD4+CD25+ Tregs compared with CD8+ T cells induced without GITR signaling. We propose that coadministration of GITR signaling agents with tumor antigens constitutes a promising novel strategy for cancer vaccine development. [Cancer Res 2008;68(14):5948–54]
SerpinB2 Protection of Retinoblastoma Protein from Calpain Enhances Tumor Cell Survival
Authors: Tonnetti Laura , Netzel-Arnett Sarah , Darnell Grant A. , Hayes Tamara , Buzza Marguerite S. , Anglin Ian E. , Suhrbier Andreas , Antalis Toni M.
Published: July 2008

The tumor suppressor retinoblastoma protein (Rb) plays a pivotal role in the regulation of cell proliferation and sensitivity to apoptosis through binding to E2F transcription factors. Loss of Rb in response to genotoxic stress or inflammatory cytokines can enhance cell death, in part, by eliminating Rb-mediated repression of proapoptotic gene transcription. Here we show that calpain cleavage of Rb facilitates Rb loss by proteasome degradation and that this may occur during tumor necrosis factor α–induced apoptosis. The cytoprotective, Rb-binding protein SerpinB2 (plasminogen activator inhibitor type 2) protects Rb from calpain cleavage, increasing Rb levels and enhancing cell survival. Chromatin immunoprecipitation assays show that the increased Rb levels selectively enhance Rb repression of proapoptotic gene transcription. This cytoprotective role of SerpinB2 is illustrated by reduced susceptibility of SerpinB2-deficient mice to multistage skin carcinogenesis, where Rb-dependent cell proliferation competes with apoptosis during initiation of papilloma development. These data identify SerpinB2 as a cell survival factor that modulates Rb repression of proapoptotic signal transduction and define a new posttranslational mechanism for selective regulation of the intracellular levels of Rb. [Cancer Res 2008;68(14):5648–57]
Clinical and Biological Significance of Tissue Transglutaminase in Ovarian Carcinoma
Authors: Hwang Jee Young , Mangala Lingegowda S. , Fok Jansina Y. , Lin Yvonne G. , Merritt William M. , Spannuth Whitney A. , Nick Alpa M. , Fiterman Derek J. , Vivas-Mejia Pablo E. , Deavers Michael T. , Coleman Robert L. , Lopez-Berestein Gabriel , Mehta Kapil , Sood Anil K.
Published: July 2008

Tissue type transglutaminase (TG2) is a unique multifunctional protein that plays a role in many steps in the cancer metastatic cascade. Here, we examined the clinical (n = 93 epithelial ovarian cancers) and biological (in vitro adhesion, invasion, and survival and in vivo therapeutic targeting) significance of TG2 in ovarian cancer. The overexpression of TG2 was associated with significantly worse overall patient survival in both univariate and multivariate analyses. Transfection of TG2 into SKOV3ip1 cells promoted attachment and spreading on fibronectin-coated surfaces and increased the in vitro invasive potential of these cells. Conversely, TG2 silencing with small interfering RNA (siRNA) of HeyA8 cells significantly decreased the invasive potential of the cells and also increased docetaxel-induced cell death. In vivo therapy experiments using chemotherapy-sensitive (HeyA8) and chemotherapy-resistant (HeyA8-MDR and RMG2) models showed significant antitumor activity both with TG2 siRNA-1,2-dioleoyl-sn-glycero-3-phosphatidylcholine alone and in combination with docetaxel chemotherapy. This antitumor activity was related to decreased proliferation and angiogenesis and increased tumor cell apoptosis in vivo. Taken together, these findings indicate that TG2 overexpression is an adverse prognostic factor in ovarian carcinoma and TG2 targeting may be an attractive therapeutic approach. [Cancer Res 2008;68(14):5849–58]
Tripartite Motif Protein 32 Facilitates Cell Growth and Migration via Degradation of Abl-Interactor 2
Authors: Kano Satoshi , Miyajima Naoto , Fukuda Satoshi , Hatakeyama Shigetsugu
Published: July 2008

Tripartite motif protein 32 (TRIM32) mRNA has been reported to be highly expressed in human head and neck squamous cell carcinoma, but the involvement of TRIM32 in carcinogenesis has not been fully elucidated. In this study, we found by using yeast two-hybrid screening that TRIM32 binds to Abl-interactor 2 (Abi2), which is known as a tumor suppressor and a cell migration inhibitor, and we showed that TRIM32 mediates the ubiquitination of Abi2. Overexpression of TRIM32 promoted degradation of Abi2, resulting in enhancement of cell growth, transforming activity, and cell motility, whereas a dominant-negative mutant of TRIM32 lacking the RING domain inhibited the degradation of Abi2. In addition, we found that TRIM32 suppresses apoptosis induced by cis-diamminedichloroplatinum (II) in HEp2 cell lines. These findings suggest that TRIM32 is a novel oncogene that promotes tumor growth, metastasis, and resistance to anticancer drugs. [Cancer Res 2008;68(14):5572–80]
The Side Population of Ovarian Cancer Cells Is a Primary Target of IFN-α Antitumor Effects
Authors: Moserle Lidia , Indraccolo Stefano , Ghisi Margherita , Frasson Chiara , Fortunato Elena , Canevari Silvana , Miotti Silvia , Tosello Valeria , Zamarchi Rita , Corradin Alberto , Minuzzo Sonia , Rossi Elisabetta , Basso Giuseppe , Amadori Alberto
Published: July 2008

The side population (SP), recently identified in several normal tissues and in a variety of tumors based on its ability to extrude some fluorescent dyes, may comprise cells endowed with stem cell features. In this study, we investigated the presence of SP in epithelial ovarian cancer and found it in 9 of 27 primary tumor samples analyzed, as well as in 4 of 6 cultures from xenotransplants. SP cells from one xenograft bearing a large SP fraction were characterized in detail. SP cells had higher proliferation rates, were much less apoptotic compared with non-SP cells, and generated tumors more rapidly than non-SP cells. We also investigated the effects of IFN-α, a cytokine that has widely been used to treat solid tumors, on epithelial ovarian cancer cells and observed that IFN-α exerted marked antiproliferative and proapoptotic effects on primary cultures containing high numbers of SP cells. In vitro, IFN-α treatment invariably caused a dramatic reduction in SP size in tumor cell lines of different origins; moreover, IFN-α treatment of purified SP cells was associated with a distinctive change in their transcriptional profile. Gene therapy with human IFN-α resulted in regression of established tumors bearing a large SP fraction, which was not observed when tumors bearing low SP levels were treated. These findings could have relevant clinical implications because they imply that tumors bearing large SP numbers, albeit rare, could be sensitive to IFN-α treatment. [Cancer Res 2008;68(14):5658–68]
Cell Competition and Its Possible Relation to Cancer
Authors: Baker Nicholas E. , Li Wei
Published: July 2008

Cell competition can occur when cells of different genotypes share the same developing compartment, with one genotype displacing the other as a result of a proliferative advantage. Studies of cell competition in Drosophila have identified an active process of cell assassination and corpse engulfment, and also roles for Myc and the Warts/Hippo tumor suppressor pathway. Here, we discuss the possible relevance of cell competition to cancer. [Cancer Res 2008;68(14):5505–7]
Identification of c-Cbl as a New Ligase for Insulin-like Growth Factor-I Receptor with Distinct Roles from Mdm2 in Receptor Ubiquitination and Endocytosis
Authors: Sehat Bita , Andersson Sandra , Girnita Leonard , Larsson Olle
Published: July 2008

The insulin-like growth factor receptor (IGF-IR) plays several pivotal roles in cancer. Although most studies on the function of the IGF-IR have been attributed to kinase-dependent signaling, recent findings by our group and others have implicated biological roles mediated by ubiquitination of the receptor. As previously reported, the E3 ligases Mdm2 and Nedd4 mediate IGF-IR ubiquitination. Here we show that c-Cbl is a novel E3 ligase for IGF-IR. On ligand stimulation, both Mdm2 and c-Cbl associate with IGF-IR and mediate receptor polyubiquitination. Whereas Mdm2 catalyzed lysine 63 (K63) chain ubiquitination, c-Cbl modified IGF-IR through K48 chains. Mdm2-mediated ubiquitination occurred when cells were stimulated with a low concentration (5 ng/mL) of IGF-I, whereas c-Cbl required high concentrations (50–100 ng/mL). Mdm2-ubiquitinated IGF-IR was internalized through the clathrin endocytic pathway whereas c-Cbl–ubiquitinated receptors were endocytosed via the caveolin route. Taken together, our results show that c-Cbl constitutes a new ligase responsible for the ubiquitination of IGF-IR and that it complements the action of Mdm2 on ubiquitin lysine residue specificity, responsiveness to IGF-I, and type of endocytic pathway used. The actions and interactions of Mdm2 and c-Cbl in the ubiquitination and endocytosis of IGF-IR may have implications in cancer. In addition, identification and functional characterization of new E3 ligases are important in itself because therapeutic targeting of substrate-specific E3 ligases is likely to represent a critical strategy in future cancer treatment. [Cancer Res 2008;68(14):5669–77]