bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute Hormonal Responses to a Single Bout of Heavy Resistance Exercise in Trained Power Lifters and Untrained Men
Authors: Kraemer William J. , Fleck Steven J. , Maresh Carl M. , Ratamess Nicholas A. , Gordon Scott E. , Goetz Kenneth L. , Harman Everett A. , Frykman Peter N. , Volek Jeff S. , Mazzetti Scott A. , Fry Andrew C. , Marchitelli Louis J. , Patton John F.
Published: June 2009

The purpose of this study was to investigate the acute responses of both stress and fluid regulatory hormones to a single bout of resistance exercise in both trained and untrained men. Seven competitive power lifters (PL) and 12 untrained subjects (UT) performed one set of the leg press exercise to exhaustion at 80% of their respective one-repetition maximum. Blood samples were obtained twice prior to exercise (at P1 and P2), immediately postexercise (IP), and at 5 minutes postexercise (5PE). Compared to P1 and P2, plasma epinephrine, norepinephrine, dopamine, atrial peptide, osmolality, and blood lactic acid increased significantly (p < 0.05) at IP. Plasma epinephrine, norepinephrine, atrial peptide, and blood lactic acid concentrations remained elevated at 5PE compared to P1 and P2. Plasma renin activity and angiotensin II were significantly elevated at 5PE compared to P1, P2, and IP, and this increase was significantly greater in PL compared to UT at 5PE. These data indicate that an acute bout of resistance exercise dramatically affects secretion of stress and fluid regulatory hormones. Key words: catecholamines, atrial peptide, arginine vasopressin, aldosterone, renin, angiotensin II
Weight Relapsers, Maintainers, and Controls: Metabolic and Behavioural Differences
Authors: Ball Geoff D.C. , Gingras Jacqui R. , Fimrite Andrea , Villetard Karen , Kayman Susan , Mccargar Linda J.
Published: June 2009

The present investigation was undertaken to describe selected factors associated with the maintenance of body weight in three groups of women: relapsers (regained weight after losing weight), maintainers (maintained weight loss), and controls (weight stable). The following physiological variables were also assessed: resting energy expenditure (REE), serum glucose, insulin, leptin, triiodothyronine (T3), and body composition. As well, participants completed the interviewer-administered Weight Maintenance Questionnaire (WMQ). Overall, relapsers were older and heavier than maintainers and controls. As well, BMI, sum-of-four skinfolds, waist and arm circumference, serum leptin, and insulin levels were significantly greater for relapsers than for maintainers and controls. There were no differences between maintainers and controls in any of the parameters measured. Although relapsers revealed a history of weight cycling, the weight loss strategies and exercise habits of maintainers and relapsers did not differ. The data suggest that the higher body mass and fat mass in relapsers may explain the physiological differences between relapsers and maintainers. Key words: energy metabolism, obesity, weight loss, weight maintenance
The Optimal Joint Angle for Adductor Pollicis Force Production in Men and Women
Authors: Ditor David , Hicks Audrey
Published: June 2009

The purpose of this study was to determine the joint angle that allows for the greatest MVC and evoked twitch forces from the adductor pollicis (AP), and also whether there is a gender difference in either the above forces or the optimum thumb angle. Ten men (25.2 yrs) and 10 women (27.6 yrs) participated. The nondominant hand was placed palm-down with the thumb fixed at four angles of abduction (55, 70, 85, 100°). Male MVC forces were significantly greater than female, and there was no significant effect of joint angle on MVC force in either gender. For the evoked twitch, men were significantly stronger than women when tested at the 100 and 85° angles, and a significant effect was found for joint angle such that the lowest twitch force occurred at 55°. Men also tended to have a greater rate of force development than women (p = 0.07). These data suggest that studies using the AP muscle in stimulated and voluntary paradigms should use a thumb angle between 70 and 100° of abduction, or approximately 85°, and that the same angle can be used for both men and women. Key words: evoked twitch, MVC, gender, EMG, rate of force development
ANALYSIS OF COMPLEMENTS IN MULTI-EXPONENTIATION ALGORITHMS USING SIGNED DIGIT REPRESENTATIONS
Authors: HEUBERGER CLEMENS , PRODINGER HELMUT
Published: June 2009

Wu, Lou, Lai and Chang proposed a multi-exponentiation algorithm using binary complements and the non-adjacent form. The purpose of this paper is to give a precise asymptotic analysis of the expected costs of this algorithm. It turns out that the complement operation does not have significant influence on the performance of the algorithm.
SUCCESSFUL ELEMENTARY GENE ASSEMBLY STRATEGIES
Authors: ROGOJIN VLADIMIR
Published: June 2009

We study elementary gene assembly in ciliates. During sexual reproduction, broken and shuffled gene segments in micronuclei get assembled into contiguous macronuclear genes. We consider here a restricted version of the intramolecular model (called elementary), where at most one gene segment is involved at a time (either inverted, or translocated). Not all gene patterns may be assembled by elementary operations, and not all assembly strategies are successful. For a given gene pattern, we characterize in this paper all successful translocation-only elementary assemblies. We also estimate the number of such assemblies. We solve the problem in terms of graphs and permutations.
PROPOSAL OF A SEMIFORMAL MODEL OF ANONYMOUS COMMUNICATION
Authors: ŠPROJCAR JOSEF
Published: June 2009

We present a semiformal model of anonymous communication with several participants performing several anonymous actions on several messages, e.g. in digital pseudosignatures. The goal is to design a model having enough expressive power to model simple as well as very complex anonymous communication patterns.

Our model concentrates on anonymity of a sender, a receiver, and on the relationship anonymity. However, the model is easy to adopt to other types of anonymity. A special anonymous channel formalism is introduced and extensively explored in this paper. The formalism builds on the top of so-called estimation procedure which takes knowledge of the adversary and processes it to find anonymous participants. Some other, already published, models of anonymity, e.g. the model of Hughes and Shmatikov or of Halpern and O'Neill, are compatible with our model – they could be used as building blocks together with (or instead of) our estimation procedure. Therefore, the tools developed for those models can be easily adapted to be used with our model.

We use protocol runs and an observational equivalence on the runs which is induced by adversary's knowledge. This is a well developed area of the theoretical computer science and many tools developed therein can be adapted to work with our model. Our model is also open to many additional features, e.g. the possibility to include probability distributions on anonymity sets.
RADIATIVE DECAYS OF PSEUDOSCALAR (P) AND VECTOR (V) MESONS AND THE PROCESSES e+e- → ηρ(ω) AND e+e- → ϕη(η')
Authors: BYSTRITSKIY YU. M. , KURAEV E. A. , SEČANSKÝ M. , VOLKOV M. K.
Published: June 2009

Radiative decays of pseudoscalar and vector mesons are calculated in the frames of chiral Nambu–Jona-Lasinio (NJL) model. We use triangle quark loops of anomalous type. During the evaluation of this loop integrals we used two methods. In the first method we neglect the dependence of external momenta. In that case we reproduce the Wess–Zumino–Witten terms of effective chiral meson Lagrangian. In the second method we take into account the momenta dependence of loop integrals omitting their imaginary part. This enables us to take into account quark confinement. The application of both methods are in qualitative agreement with each other and with experimental data. The second method allows us to describe the electron–positron annihilation with production pseudoscalar and vector mesons in center-of-mass energy range from 1 to 5 GeV. Comparisons with the recent experimental data are presented.
SOLUTIONS OF THE SCHRÖDINGER–POISSON PROBLEM CONCENTRATING ON SPHERES, PART I: NECESSARY CONDITIONS
Authors: IANNI ISABELLA , VAIRA GIUSI
Published: June 2009

In this paper we study a coupled nonlinear Schrödinger–Poisson problem with radial functions. This system has been introduced as a model describing standing waves for the nonlinear Schrödinger equations in the presence of the electrostatic field.

We provide necessary conditions for concentration on sphere for the solutions of this kind of problem extending the results already known.
Searches for Fractionally Charged Particles
Authors: Perl Martin L. , Lee Eric R. , Loomba Dinesh
Published: June 2009

Since the initial measurements of the electron charge were made a century ago, experimenters have faced the persistent question of the existence of elementary particles with charges that are fractional multiples of the electron charge. In this review, we discuss the results of recent searches for these fractionally charged particles.
Peroxisome proliferator-activated receptor-γ agonist improves skeletal muscle insulin signaling in the pregestational intrauterine growth-restricted rat offspring
Authors: Oak Shilpa , Tran Cang , Castillo Maria-Olivia , Thamotharan Shanthie , Thamotharan Manikkavasagar , Devaskar Sherin U.
Published: June 2009

The effect of early intervention with a peroxisome proliferator-activated receptor-γ (PPARγ) agonist on skeletal muscle GLUT4 translocation and insulin signaling was examined in intrauterine (IUGR) and postnatal (PNGR) growth-restricted pregestational female rat offspring. Rosiglitazone [11 μmol/day provided from postnatal day (PN)21 to PN60] improved skeletal muscle insulin sensitivity and GLUT4 translocation in prenatal nutrient restriction [50% calories from embryonic day (e)11 to e21; IUGR] with (IUGR+PNGR) and without (IUGR) postnatal nutrient restriction (50% calories from PN1 to PN21; PNGR) similar to that of control (ad libitum feeds throughout; Con) ( n = 6 each). This was accomplished by diminished basal and improved insulin-responsive GLUT4 association with the plasma membrane in IUGR, IUGR+PNGR, and PNGR mimicking that in Con ( P < 0.005). While no change in p85-phosphatidylinositol 3-kinase (PI3-K) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was observed, a decrease in protein tyrosine phosphatase 1B (PTP1B; P < 0.0002) and SH2-containing protein tyrosine phosphatase 2 (SHP2; P < 0.05) contributing to the rosiglitazone-induced insulin sensitivity was seen only in IUGR+PNGR. In contrast, an increase in phosphorylated 5′-adenosine monophosphate kinase (pAMPK; P < 0.04) and insulin responsiveness of phosphorylated phosphoinositide-dependent protein kinase-1 (pPDK1; P < 0.05), pAkt ( P < 0.01), and particularly pPKCζ ( P < 0.0001) and its corresponding enzyme activity ( P < 0.005) were observed in all four experimental groups. We conclude that early introduction of PPARγ agonist improved skeletal muscle activation of AMPK and insulin signaling, resulting in insulin-independent AMPK and insulin-responsive GLUT4 association with plasma membranes in IUGR, IUGR+PNGR, and PNGR adult offspring, similar to that of Con. These findings support a role for insulin sensitizers in preventing the subsequent development of gestational or type 2 diabetes mellitus in intrauterine and postnatal growth-restricted offspring.
Bile high-mobility group box 1 contributes to gut barrier dysfunction in experimental endotoxemia
Authors: Yang Runkuan , Miki Keita , Oksala Niku , Nakao Atsunori , Lindgren Leena , Killeen Meaghan E. , Mennander Ari , Fink Mitchell P. , Tenhunen Jyrki
Published: June 2009

Lipopolysaccharide (LPS) is an important factor in sepsis. LPS given by intraperitoneal injection induces intestinal hyperpermeability and bacterial translocation in animals and stimulates hepatic Kupffer cells to release TNF-α into the bile. This study aims to test the hypothesis that in response to LPS stimulation, hepatic Kupffer cells and extrahepatic macrophages release a large amount of the inflammatory cytokine high-mobility group box 1 (HMGB1) into the bile and that bile containing HMGB1 contributes to gut barrier dysfunction in experimental endotoxemia. To test this, rat common bile ducts were catheterized and bile flow rate was monitored before and during the LPS administration. Eight hours after LPS challenge, anti-HMGB1 neutralizing antibody or nonimmune (sham) IgG was injected into the duodenal lumen of endotoxemic rats; normal mice were also gavaged with normal or endotoxemic rat bile (bile collected from LPS-treated rats). We found that after LPS challenge, the bile flow rate in rats was significantly decreased at the 4- to 12-h time points, TNF-α concentration in the bile was markedly elevated at the 3- to 4-h time points, and bile HMGB1 levels were significantly increased at the 8- to 12-h time points. Duodenal injection with anti-HMGB1 antibody reversed LPS-induced gut barrier dysfunction in rats. In addition, feeding endotoxemic rat bile to normal mice significantly increased both mucosal permeability and bacterial translocation. The increase in permeability and bacterial translocation was reversible following removal of HMGB1 from the endotoxemic rat bile. These findings document that bile HMGB1 mediates gut barrier dysfunction in experimental endotoxemia.
Low-frequency electroacupuncture and physical exercise decrease high muscle sympathetic nerve activity in polycystic ovary syndrome
Authors: Stener-Victorin Elisabet , Jedel Elizabeth , Janson Per Olof , Sverrisdottir Yrsa Bergmann
Published: June 2009

We have recently shown that polycystic ovary syndrome (PCOS) is associated with high muscle sympathetic nerve activity (MSNA). Animal studies support the concept that low-frequency electroacupuncture (EA) and physical exercise, via stimulation of ergoreceptors and somatic afferents in the muscles, may modulate the activity of the sympathetic nervous system. The aim of the present study was to investigate the effect of these interventions on sympathetic nerve activity in women with PCOS. In a randomized controlled trial, 20 women with PCOS were randomly allocated to one of three groups: low-frequency EA ( n = 9), physical exercise ( n = 5), or untreated control ( n = 6) during 16 wk. Direct recordings of multiunit efferent postganglionic MSNA in a muscle fascicle of the peroneal nerve before and following 16 wk of treatment. Biometric, hemodynamic, endocrine, and metabolic parameters were measured. Low-frequency EA ( P = 0.036) and physical exercise ( P = 0.030) decreased MSNA burst frequency compared with the untreated control group. The low-frequency EA group reduced sagittal diameter ( P = 0.001), while the physical exercise group reduced body weight ( P = 0.004) and body mass index ( P = 0.004) compared with the untreated control group. Sagittal diameter was related to MSNA burst frequency ( Rs = 0.58, P < 0.005) in the EA group. No correlation was found for body mass index and MSNA in the exercise group. There were no differences between the groups in hemodynamic, endocrine, and metabolic variables. For the first time we demonstrate that low-frequency EA and physical exercise lowers high sympathetic nerve activity in women with PCOS. Thus, treatment with low-frequency EA or physical exercise with the aim to reduce MSNA may be of importance for women with PCOS.
Overtrained horses alter their resting pulsatile growth hormone secretion
Authors: de Graaf-Roelfsema E. , Veldhuis P. P. , Keizer H. A. , van Ginneken M. M. E. , van Dam K. G. , Johnson M. L. , Barneveld A. , Menheere P. P. C. A. , van Breda E. , Wijnberg I. D. , van der Kolk J. H.
Published: June 2009

The influence of intensified and reduced training on nocturnal growth hormone (GH) secretion and elimination dynamics was studied in young (1.5 yr) Standardbred geldings to detect potential markers indicative for early overtraining. Ten horses trained on a treadmill for 32 wk in age-, breed-, and gender-matched fixed pairs. Training was divided into four phases (4, 18, 6, and 4 wk, respectively): 1) habituation to high-speed treadmill trotting, 2) normal training, in which speed and duration of training sessions were gradually increased, 3) in this phase, the horses were divided into 2 groups: control (C) and intensified trained (IT) group. In IT, training intensity, duration, and frequency were further increased, whereas in control these remained unaltered, and 4) reduced training (RT). At the end of phases 2, 3, and 4, blood was sampled overnight every 5 min for 8 h for assessment of GH secretory dynamics using pulse detection, deconvolution analysis, and approximate entropy (ApEn). Intensified training induced overtraining (performance decreased by 19% compared with C), which was associated with an increase in concentration peaks number (3.6 vs. 2.0, respectively), a smaller peak secretion pattern with a prolonged half-life (15.2 vs. 7.3 min, respectively), and an increased ApEn (0.89 vs. 0.49, respectively). RT did not lead to full recovery for the overtrained horses. The increased irregularity of nocturnal GH pulsatility pattern is indicative of a loss of coordinated control of GH regulation. Longer phases of somatostatin withdrawal are hypothesized to be the underlying mechanism for the observed changes in GH pulsatility pattern.
Global Behavior of the Max‐Type Difference Equationxn+1= max {1/xn,An/xn−1}
Authors: Sun Taixiang , Qin Bin , Xi Hongjian , Han Caihong
Published: June 2009

We study global behavior of the following max‐type difference equationxn+1= max {1/xn,An/xn−1},n= 0, 1, …, where is a sequence of positive real numbers with 0 ≤ inf An≤ sup An< 1. The special case when is a periodic sequence with periodkandAn∈ (0, 1) for everyn≥ 0 has been completely investigated by Y. Chen. Here we extend his results to the general case.
Modified Iterative Algorithms for Nonexpansive Mappings
Authors: Yao Yonghong , Noor Muhammad Aslam , Mohyud-Din Syed Tauseef
Published: June 2009

Let H be a real Hilbert space, let S, T be two nonexpansive mappings such that F(S)∩F(T) ≠ ∅, let f be a contractive mapping, and let A be a strongly positive linear bounded operator on H. In this paper, we suggest and consider the strong converegence analysis of a new two‐step iterative algorithms for finding the approximate solution of two nonexpansive mappings as xn+1 = βnxn + (1 − βn)Syn, yn = αnγf(xn) + (I − αnA)Txn, n ≥ 0 is a real number and {αn}, {βn} are two sequences in (0, 1) satisfying the following
control conditions:
(C1) lim n→∞ αn = 0, (C3) 0 < lim inf n→∞ βn≤lim sup n→∞ βn < 1, then ∥xn+1 − xn∥ → 0. We also discuss several special cases of this iterative algorithm.
Discriminant Analysis of Zero Recovery for China's NPL
Authors: Tang Yue , Chen Hao , Wang Bo , Chen Muzi , Chen Min , Yang Xiaoguang
Published: June 2009

Classification of whether recovery of non-performing loans (NPL) is zero or positive is not only important in management of non-performing loans, but also is essential for estimating recovery rate and implementing the new Basel Capital Accord. Based on the largest database of NPL's recovering information in China, this paper tries to establish discriminant models to predict the loan with zero recovery. We first use Step-wise discrimination method to select variables; then give an in-depth analysis on why the selected variables are important factors influencing whether a loan is zero or positive recovery rate. Using the selected variables, we establish two-type discriminant models to classify the NPLs. Empirical results show that both models achieve high prediction accuracy, and the characteristics of obligors are the most important factors in determining whether a NPL is positively recovered or zero recovered.
Inhibition of Transforming Growth Factor-β–Mediated Immunosuppression in Tumor-Draining Lymph Nodes Augments Antitumor Responses by Various Immunologic Cell Types
Authors: Fujita Takuya , Teramoto Koji , Ozaki Yoshitomo , Hanaoka Jun , Tezuka Noriaki , Itoh Yasushi , Asai Tohru , Fujino Shozo , Kontani Keiichi , Ogasawara Kazumasa
Published: June 2009

Tumor-draining lymph nodes (DLN) are the most important priming sites for generation of antitumor immune responses. They are also the location where an immunosuppressive cytokine, transforming growth factor-β (TGF-β), plays a critical role in suppressing these antitumor immune responses. We focused on TGF-β–mediated immunosuppression in DLNs and examined whether local inhibition of TGF-β augmented antitumor immune responses systemically in tumor-bearing mice models. For inhibition of TGF-β–mediated immunosuppression in DLNs, C57BL/6 mice subcutaneously bearing E.G7 tumors were administered plasmid DNA encoding the extracellular domain of TGF-β type II receptor fused to the human IgG heavy chain (TGFR DNA) i.m. near the established tumor. In DLNs, inhibition of TGF-β suppressed the proliferation of regulatory T cells and increased the number of tumor antigen-specific CD4+ or CD8+ cells producing IFN-γ. Enhancement of antitumor immune responses in DLNs were associated with augmented tumor antigen-specific cytotoxic and natural killer activity in spleen as well as elevated levels of tumor-specific antibody in sera. The growth of the established metastatic as well as primary tumors was effectively suppressed via augmented antitumor immune responses. Inhibition of TGF-β–mediated immunosuppression in DLNs is significantly associated with augmented antitumor responses by various immunocompetent cell types. This animal model provides a novel rationale for molecular cancer therapeutics targeting TGF-β. [Cancer Res 2009;69(12):5142–50]
Notch Activation Induces Akt Signaling via an Autocrine Loop to Prevent Apoptosis in Breast Epithelial Cells
Authors: Meurette Olivier , Stylianou Spyros , Rock Rebecca , Collu Giovanna M. , Gilmore Andrew P. , Brennan Keith
Published: June 2009

The Notch pathway is aberrantly activated in a wide range of cancers, including breast carcinoma, and is required to maintain the transformed phenotype of many of these tumors. Notch signaling contributes to the transformed phenotype, in part, by preventing apoptosis in response to many different stimuli. However, it is unclear how Notch activation can lead to a general suppression of apoptosis. We show here that Notch signaling induced an autocrine signaling loop that activates Akt in breast epithelial cells. This activation of Akt was necessary for Notch-induced protection against apoptosis in the nontransformed breast epithelial cell line MCF10A. Moreover, inhibiting Notch signaling in breast cancer cells induced a decrease in Akt activity and an increase in sensitivity to apoptosis. Finally, the inhibition of ASK1 by Akt was responsible for the protection from apoptosis induced by DNA damage, as it prevented c-Jun NH2-terminal kinase-mediated phosphorylation and activation of p53. [Cancer Res 2009;69(12):5015–22]
In vitro and In vivo Activity of Novel Small-Molecule Inhibitors Targeting the Pleckstrin Homology Domain of Protein Kinase B/AKT
Authors: Moses Sylvestor A. , Ali M. Ahad , Zuohe Song , Du-Cuny Lei , Zhou Li Li , Lemos Robert , Ihle Nathan , Skillman A. Geoffrey , Zhang Shuxing , Mash Eugene A. , Powis Garth , Meuillet Emmanuelle J.
Published: June 2009

The phosphatidylinositol 3-kinase/AKT signaling pathway plays a critical role in activating survival and antiapoptotic pathways within cancer cells. Several studies have shown that this pathway is constitutively activated in many different cancer types. The goal of this study was to discover novel compounds that bind to the pleckstrin homology (PH) domain of AKT, thereby inhibiting AKT activation. Using proprietary docking software, 22 potential PH domain inhibitors were identified. Surface plasmon resonance spectroscopy was used to measure the binding of the compounds to the expressed PH domain of AKT followed by an in vitro activity screen in Panc-1 and MiaPaCa-2 pancreatic cancer cell lines. We identified a novel chemical scaffold in several of the compounds that binds selectively to the PH domain of AKT, inducing a decrease in AKT activation and causing apoptosis at low micromolar concentrations. Structural modifications of the scaffold led to compounds with enhanced inhibitory activity in cells. One compound, 4-dodecyl-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide, inhibited AKT and its downstream targets in cells as well as in pancreatic cancer cell xenografts in immunocompromised mice; it also exhibited good antitumor activity. In summary, a pharmacophore for PH domain inhibitors targeting AKT function was developed. Computer-aided modeling, synthesis, and testing produced novel AKT PH domain inhibitors that exhibit promising preclinical properties. [Cancer Res 2009;69(12):5073–81]
Cathepsin D and Eukaryotic Translation Elongation Factor 1 as Promising Markers of Cellular Senescence
Authors: Byun Hae-Ok , Han Na-Kyung , Lee Hae-June , Kim Ki-Bum , Ko Young-Gyu , Yoon Gyesoon , Lee Yun-Sil , Hong Seok-Il , Lee Jae-Seon
Published: June 2009

Induction of premature senescence may be a promising strategy for cancer treatment. However, biomarkers for senescent cancer cells are lacking. To identify such biomarkers, we performed comparative proteomic analysis of MCF7 human breast cancer cells undergoing cellular senescence in response to ionizing radiation (IR). IR-induced senescence was associated with up-regulation of cathepsin D (CD) and down-regulation of eukaryotic translation elongation factor 1β2 (eEF1B2), as confirmed by Western blot. The other elongation factor, eukaryotic translation elongation factor 1α1 (eEF1A1), was also down-regulated. IR-induced senescence was associated with similar changes of CD and eEF1 (eEF1A1 and eEF1B2) levels in the HCT116 colon cancer cell line and the H460 lung cancer cell line. Up-regulation of CD and down-regulation of eEF1 seemed to be specific to senescence, as they were observed during cellular senescence induced by hydrogen peroxide or anticancer drugs (camptothecin, etoposide, or 50 ng doxorubicin) but not during apoptosis induced by Taxol or 10 μg doxorubicin or autophagy induced by tamoxifen. The same alterations in CD and eEF1A1 levels were observed during replicative senescence and Ras oncogene-induced senescence. Transient cell cycle arrest did not alter levels of eEF1 or CD. Chemical inhibition of CD (pepstatin A) and small interfering RNA–mediated knockdown of CD and eEF1 revealed that these factors participate in cell proliferation. Finally, the senescence-associated alteration in CD and eEF1 levels observed in cell lines was also observed in IR-exposed xenografted tumors. These findings show that CD and eEF1 are promising markers for the detection of cellular senescence induced by a variety of treatments. [Cancer Res 2009;69(11):4638–47]
Analysis of Gene Expression Profiles of Microdissected Cell Populations Indicates that Testicular CarcinomaIn situIs an Arrested Gonocyte
Authors: Sonne Si Brask , Almstrup Kristian , Dalgaard Marlene , Juncker Agnieszka Sierakowska , Edsgard Daniel , Ruban Ludmila , Harrison Neil J. , Schwager Christian , Abdollahi Amir , Huber Peter E. , Brunak Søren , Gjerdrum Lise Mette , Moore Harry D. , Andrews Peter W. , Skakkebaek Niels E. , Meyts Ewa Rajpert-De , Leffers Henrik
Published: June 2009

Testicular germ cell cancers in young adult men derive from a precursor lesion called carcinoma in situ (CIS) of the testis. CIS cells were suggested to arise from primordial germ cells or gonocytes. However, direct studies on purified samples of CIS cells are lacking. To overcome this problem, we performed laser microdissection of CIS cells. Highly enriched cell populations were obtained and subjected to gene expression analysis. The expression profile of CIS cells was compared with microdissected gonocytes, oogonia, and cultured embryonic stem cells with and without genomic aberrations. Three samples of each tissue type were used for the analyses. Unique expression patterns for these developmentally very related cell types revealed that CIS cells were very similar to gonocytes because only five genes distinguished these two cell types. We did not find indications that CIS was derived from a meiotic cell, and the similarity to embryonic stem cells was modest compared with gonocytes. Thus, we provide new evidence that the molecular phenotype of CIS cells is similar to that of gonocytes. Our data are in line with the idea that CIS cells may be gonocytes that survived in the postnatal testis. We speculate that disturbed development of somatic cells in the fetal testis may play a role in allowing undifferentiated cells to survive in the postnatal testes. The further development of CIS into invasive germ cell tumors may depend on signals from their postpubertal niche of somatic cells, including hormones and growth factors from Leydig and Sertoli cells. [Cancer Res 2009;69(12):5241–50]
Androgen Receptor Expression in Prostate Cancer Cells Is Suppressed by Activation of Epidermal Growth Factor Receptor and ErbB2
Authors: Cai Changmeng , Portnoy David C. , Wang Hongyun , Jiang Xinnong , Chen Shaoyong , Balk Steven P.
Published: June 2009

Prostate cancers (PCa) that relapse after androgen deprivation therapies [castration-resistant PCa (CRPC)] express high levels of androgen receptor (AR) and androgen-regulated genes, and evidence from several groups indicates that ErbB family receptor tyrosine kinases [epidermal growth factor (EGF) receptor (EGFR) and ErbB2] may contribute to enhancing this AR activity. We found that activation of these kinases with EGF and heregulin-β1 rapidly (within 8 hours) decreased expression of endogenous AR and androgen-regulated PSA in LNCaP PCa cells. AR expression was similarly decreased in LAPC4 and C4-2 cells, but not in the CWR22Rv1 PCa cell line. The rapid decrease in AR was not due to increased AR protein degradation and was not blocked by phosphatidylinositol 3-kinase (LY294002) or MEK (UO126) inhibitors. Significantly, AR mRNA levels in LNCaP cells were markedly decreased by EGF and heregulin-β1, and experiments with actinomycin D to block new mRNA synthesis showed that AR mRNA degradation was increased. AR mRNA levels were still markedly decreased by EGF and heregulin-β1 in LNCaP cells adapted to growth in androgen-depleted medium, although AR protein levels did not decline due to increased AR protein stability. These findings show that EGFR and ErbB2 can negatively regulate AR mRNA and may provide an approach to suppress AR expression in CRPC. [Cancer Res 2009;69(12):5202–9]
PUMA Suppresses Intestinal Tumorigenesis in Mice
Authors: Qiu Wei , Carson-Walter Eleanor B. , Kuan Shih Fan , Zhang Lin , Yu Jian
Published: June 2009

Defective apoptosis contributes to tumorigenesis, although the critical molecular targets remain to be fully characterized. PUMA, a BH3-only protein essential for p53-dependent apoptosis, has been shown to suppress lymphomagenesis. In this study, we investigated the role of PUMA in intestinal tumorigenesis using two animal models. In the azoxymethane (AOM)/dextran sulfate sodium salt model, PUMA deficiency increased the multiplicity and size of colon tumors but reduced the frequency of β-catenin hotspot mutations. The absence of PUMA led to a significantly elevated incidence of precursor lesions induced by AOM. AOM was found to induce p53-dependent PUMA expression and PUMA-dependent apoptosis in the colonic crypts and stem cell compartment. Furthermore, PUMA deficiency significantly enhanced the formation of spontaneous macroadenomas and microadenomas in the distal small intestine and colon of APCMin/+ mice. These results show an essential role of PUMA-mediated apoptosis in suppressing intestinal tumorigenesis in mice. [Cancer Res 2009;69(12):4999–5006]
Extracellular Engagement of α6 Integrin Inhibited Urokinase-Type Plasminogen Activator–Mediated Cleavage and Delayed Human Prostate Bone Metastasis
Authors: Ports Michael O. , Nagle Ray B. , Pond Gerald D. , Cress Anne E.
Published: June 2009

Expression of α6 integrin, a laminin receptor, on tumor cell surfaces is associated with reduced patient survival and increased metastasis in a variety of tumors. In prostate cancer, tumor extracapsular escape occurs in part via laminin-coated nerves and vascular dissemination, resulting in clinically significant bone metastases. We previously identified a novel form of α6 integrin, called α6p, generated by urokinase-type plasminogen activator-dependent cleavage of the laminin-binding domain from the tumor cell surface. Cleavage increased laminin-dependent migration. Currently, we used the known conformation sensitivity of integrin function to determine if engagement of the extracellular domain inhibited integrin cleavage and the extravasation step of metastasis. We show that α6 integrin was present on prostate carcinoma escaping the gland via nerves. Both endogenous and inducible levels of α6p were inhibited by engaging the extracellular domain of α6 with monoclonal antibody J8H. J8H inhibited tumor cell invasion through Matrigel. A severe combined immunodeficient mouse model of extravasation and bone metastasis produced detectable, progressive osteolytic lesions within 3 weeks of intracardiac injections. Injection of tumor cells, pretreated with J8H, delayed the appearance of metastases. Validation of the α6 cleavage effect on extravasation was confirmed through a genetic approach using tumor cells transfected with uncleavable α6 integrin. Uncleavable α6 integrin significantly delayed the onset and progression of osseous metastases out to six weeks post-injection. The results suggest that α6 integrin cleavage permits extravasation of human prostate cancer cells from circulation to bone and can be manipulated to prevent metastasis. [Cancer Res 2009;69(12):5007–14]
Epithelial Phenotype Confers Resistance of Ovarian Cancer Cells to Oncolytic Adenoviruses
Authors: Strauss Robert , Sova Pavel , Liu Ying , Li Zong Yi , Tuve Sebastian , Pritchard David , Brinkkoetter Paul , Möller Thomas , Wildner Oliver , Pesonen Sari , Hemminki Akseli , Urban Nicole , Drescher Charles , Lieber André
Published: June 2009

We studied the susceptibility of primary ovarian cancer cells to oncolytic adenoviruses. Using gene expression profiling of cancer cells either resistant or susceptible to viral oncolysis, we discovered that the epithelial phenotype of ovarian cancer represents a barrier to infection by commonly used oncolytic adenoviruses targeted to coxsackie-adenovirus receptor or CD46. Specifically, we found that these adenovirus receptors were trapped in tight junctions and not accessible for virus binding. Accessibility to viral receptors was critically linked to depolarization and the loss of tight and adherens junctions, both hallmarks of epithelial-to-mesenchymal transition (EMT). We showed that specific, thus far little-explored adenovirus serotypes (Ad3, Ad7, Ad11, and Ad14) that use receptor(s) other than coxsackie-adenovirus receptor and CD46 were able to trigger EMT in epithelial ovarian cancer cells and cause efficient oncolysis. Our studies on ovarian cancer cultures and xenografts also revealed several interesting cancer cell biology features. Tumors in situ as well as tumor xenografts in mice mostly contained epithelial cells and cells that were in a hybrid stage where they expressed both epithelial and mesenchymal markers (epithelial/mesenchymal cells). These epithelial/mesenchymal cells are the only xenograft-derived cells that can be cultured and with passaging undergo EMT and differentiate into mesenchymal cells. Our study provides a venue for improved virotherapy of cancer as well as new insights into cancer cell biology. [Cancer Res 2009;69(12):5115–25]
Direct Targeting of the Mucin 1 Oncoprotein Blocks Survival and Tumorigenicity of Human Breast Carcinoma Cells
Authors: Raina Deepak , Ahmad Rehan , Joshi Maya Datt , Yin Li , Wu Zekui , Kawano Takeshi , Vasir Baldev , Avigan David , Kharbanda Surender , Kufe Donald
Published: June 2009

The mucin 1 (MUC1) oncoprotein is aberrantly overexpressed by ∼90% of human breast cancers. However, there are no effective agents that directly inhibit MUC1 and induce death of breast cancer cells. We have synthesized a MUC1 inhibitor (called GO-201) that binds to the MUC1 cytoplasmic domain and blocks the formation of MUC1 oligomers in cells. GO-201, and not an altered version, attenuates targeting of MUC1 to the nucleus of human breast cancer cells, disrupts redox balance, and activates the DNA damage response. GO-201 also arrests growth and induces necrotic death. By contrast, the MUC1 inhibitor has no effect on cells null for MUC1 expression or nonmalignant mammary epithelial cells. Administration of GO-201 to nude mice bearing human breast tumor xenografts was associated with loss of tumorigenicity and extensive necrosis, which results in prolonged regression of tumor growth. These findings show that targeting the MUC1 oncoprotein is effective in inducing death of human breast cancer cells in vitro and in tumor models. [Cancer Res 2009;69(12):5133–41]
Reciprocal Effects of STAT5 and STAT3 in Breast Cancer
Authors: Walker Sarah R. , Nelson Erik A. , Zou Lihua , Chaudhury Mousumi , Signoretti Sabina , Richardson Andrea , Frank David A.
Published: June 2009

Breast cancer is often associated with inappropriate activation of transcription factors involved in normal mammary development. Two related transcription factors, signal transducer and activator of transcription (STAT) 5 and STAT3, play important and distinct roles in mammary development and both can be activated in breast cancer. However, the relative contribution of these STATs to mammary tumorigenesis is unknown. We have found that primary human breast tumors displaying activation of both STATs are more differentiated than those with STAT3 activation alone and display more favorable prognostic characteristics. To understand this difference, we have analyzed the effect of these STATs on gene regulation and phenotype of mammary carcinoma cells. STAT5 and STAT3 mediate opposing effects on several key target genes, with STAT5 exerting a dominant role. Using a model system of paired breast cancer cell lines, we found that coactivation of STAT5 and STAT3 leads to decreased proliferation and increased sensitivity to the chemotherapeutic drugs paclitaxel and vinorelbine compared with cells that have only STAT3 activation. Thus, STAT5 can modify the effects of STAT3 from the level of gene expression to cellular phenotype and analysis of the activation state of both STAT5 and STAT3 may provide important diagnostic and prognostic information in breast cancer. (Mol Cancer Res 2009;7(6):966–76)
Results of a Minimally Invasive Surgical Pulmonary Vein Isolation and Ganglionic Plexi Ablation for Atrial Fibrillation
Authors: Han Frederick T. , Kasirajan Vigneshwar , Kowalski Marcin , Kiser Robert , Wolfe Luke , Kalahasty Gautham , Shepard Richard K. , Wood Mark A. , Ellenbogen Kenneth A.
Published: June 2009

Background—

The Cox Maze procedure for treatment of medically refractory atrial fibrillation (AF) is limited by its complexity and requirement for cardiopulmonary bypass. Long-term follow-up and success using criteria established by the Heart Rhythm Society/European Heart Rhythm Association/European Cardiac Arrhythmia Society consensus statement have not been reported for surgical AF ablation. We describe the results of using a thorascopic approach and radiofrequency energy to perform bilateral pulmonary vein isolation and left atrial ganglionic plexi ablation for treatment of AF.

Methods and Results—

Forty-five (33 paroxysmal; 12 persistent) consecutive patients underwent thorascopic bilateral radiofrequency pulmonary vein isolation, ganglionic plexi ablation, ligament of Marshall ablation, and left atrial appendage exclusion by a single surgeon. Forty-three patients were prospectively followed without antiarrhythmic drugs for a minimum of 1 year with a 30-day continuous event monitor or pacemaker interrogation at 6 and 12 months. Failure was defined as any atrial tachyarrhythmia of >30 seconds’ duration occurring >90 days after surgery. Mean follow-up was 516�181 days (202 to 858 days). Twenty-eight (65%) patients had no atrial tachyarrhythmia >30 seconds by 1 year, and 15 (35%) patients had atrial tachyarrhythmia recurrences by 1 year. Eight of 15 patients with recurrent AF had catheter ablation resulting in elimination and/or reduction of AF episodes in 7 of 8 patients. Four of 15 patients had AF elimination or reduction with antiarrhythmic drugs alone. Three patients did not benefit from surgery and received rate control only. There were no deaths; 1 phrenic nerve injury and 2 pleural effusions were the only major complications.

Conclusions—

The single procedure success at 1-year follow-up for surgical pulmonary vein isolation and ganglionic plexi ablation is 65%. Atrial tachyarrhythmia recurrences after surgery are usually responsive to catheter ablation and/or antiarrhythmic drugs.
Tropical Storm Development from African Easterly Waves in the Eastern Atlantic: A Comparison of Two Successive Waves Using a Regional Model as Part of NASA AMMA 2006
Authors: Vizy Edward K. , Cook Kerry H.
Published: June 2009

Two successive African easterly waves (AEWs) from August 2006 are analyzed utilizing observational data, the European Centre for Medium-Range Weather Forecasts reanalysis, and output from the National Center for Atmospheric Research–National Oceanic and Atmospheric Administration Weather Research and Forecasting model (WRF) to understand why the first wave does not develop over the eastern Atlantic while the second wave does. The first AEW eventually forms Hurricane Ernesto over the Caribbean Sea, but genesis does not occur over the eastern Atlantic. The second wave, although weaker than the first over land, leaves the West African coast and quickly intensifies into Tropical Storm Debby west of the Cape Verde islands. This study shows that the environmental conditions associated with the first AEW’s passage inhibited development. These conditions include strong low- and midtropospheric vertical wind shear owing to a stronger than normal African easterly jet, lower than normal relative humidity, and increased atmospheric stability. All of these are characteristics of an intensification of the Saharan air layer (SAL), or SAL outbreak, over the eastern Atlantic. The environmental conditions were more favorable for genesis 2½ days later when the second wave left the African coast. Additionally, a strong low-level southwesterly surge develops over the eastern North Atlantic in the wake of the passage of the first wave. This westerly surge is associated with an enhancement of the low-level westerly flow, low-level cyclonic vorticity, large-scale low-level wind convergence, and vertical motion conducive for development over the region. While the initial westerly surge is likely associated with the passage of the first wave, over time (i.e., by 1600 UTC 20 August 2006) the development of the second wave becomes influential in maintaining the low-level westerly surge. Although SAL outbreaks are also associated with the addition of dust, the different cyclogenesis histories of the two systems are simulated without including dust in the regional model.
Modeling Mesoscale Cellular Structures and Drizzle in Marine Stratocumulus. Part II: The Microphysics and Dynamics of the Boundary Region between Open and Closed Cells
Authors: Wang Hailong , Feingold Graham
Published: June 2009

This is the second of two companion papers on modeling of mesoscale cellular structures and drizzle in marine stratocumulus. In the first, aerosol–cloud–precipitation interactions and dynamical feedbacks were investigated to study the formation and evolution of open and closed cellular structures separately. In this paper, coexisting open and closed cells and how they influence one another are examined in a model domain of 180 × 60 × 1.5 km3. Simulations show that gradients in aerosol at the open–closed-cell boundary cause gradients in precipitation that generate a mesoscale circulation. The circulation promotes precipitation in the polluted closed cells but suppresses it in open cells by transporting water vapor to the closed-cell regime and carrying drier air and aerosol back to the open cells. The strength of this circulation depends on the contrast in precipitation under clean and polluted conditions at the boundary. Ship plumes emitted into clean, precipitating regions, simulated as a special case of a clean–polluted boundary, develop a similar circulation. Drizzle in the ship track is first suppressed by the increase in aerosol particles but later recovers and becomes even stronger because the local circulation enhances liquid water path owing to the convergence of water vapor from the region adjacent to the track. This circulation modifies the transport and mixing of ship plumes and enhances their dispersal. Finally, results show that whereas ship emissions do increase cloud albedo in regions of open cells, even the addition of very large aerosol concentrations cannot transform an open cellular structure to a closed one, for the case considered.
How Much Do Tropical Cyclones Affect Seasonal and Interannual Rainfall Variability over the Western North Pacific?
Authors: Kubota Hisayuki , Wang Bin
Published: June 2009

The authors investigate the effects of tropical cyclones (TCs) on seasonal and interannual rainfall variability over the western North Pacific (WNP) by using rainfall data at 22 stations. The TC-induced rainfall at each station is estimated by using station data when a TC is located within the influential radius (1000 km) from the station. The spatial–temporal variability of the proportion of TC rainfall is examined primarily along the east–west island chain near 10°N (between 7° and 13°N) and the north–south island chain near 125°E (between 120° and 130°E).

Along 10°N the seasonality of total rainfall is mainly determined by non-TC rainfall that is influenced by the WNP monsoon trough. The proportion of the TC rain is relatively low. During the high TC season from July to December, TC rainfall accounts for 30% of the total rainfall in Guam, 15%–23% in Koror and Yap, and less than 10% at other stations. In contrast, along 125°E where the WNP subtropical high is located, the TC rainfall accounts for 50%–60% of the total rainfall between 18° and 26°N during the peak TC season from July to October. In Hualien of Taiwan, TC rainfall exceeds 60% of the total rainfall.

The interannual variability of the TC rainfall and total rainfall is primarily modulated by El Niño–Southern Oscillation (ENSO). Along 10°N, the ratio of TC rainfall versus total rainfall is higher than the climatology during developing and mature phases of El Niño (from March to the following January), whereas the ratio is below the climatology during the decaying phase of El Niño. The opposite is true for La Niña, except that the impact of La Niña is shorter in duration. Furthermore, in summer of El Niño developing years, the total seasonal rainfall increases primarily because of the increase of TC rainfall. In the ensuing autumn, an anticyclonic anomaly develops over the Philippine Sea and TC rainfall shifts eastward; as a result, the total rainfall over the Philippines and Taiwan decreases. The total rainfall to the east of 140°E, however, changes little, because the westward passage of TCs enhances TC rainfall, which offsets the decrease of non-TC rainfall. Along the meridional island chain between 120° and 130°E, the total rainfall anomaly is affected by ENSO starting from the autumn to the following spring, and the variation in TC rainfall dominates the total rainfall variation only in autumn (August–November) of ENSO years.

The results from this study suggest that in the tropical WNP and subtropical East Asian monsoon regions (east of 120°E), the seasonal and interannual variations of rainfall are controlled by changes in nonlocal circulations. These changes outside the monsoon domain may substantially affect summer monsoon rainfall by changing TC genesis and tracks.