bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapamycin prevents mesenteric neo‐angiogenesis and reduces splanchnic blood flow in portal hypertensive mice
Authors: Geerts Anja M. , Vanheule Eline , Van Vlierberghe Hans , Leybaert Luc , Van Steenkiste Christophe , De Vos Martine , Colle Isabelle 
Published: June 2008

Aim:  Increased angiogenesis in the mesenteric microvasculature of portal hypertensive animals may contribute to the development of splanchnic vasodilation associated with portal hypertension (PHT). Experimental data suggest that rapamycin may reduce angiogenesis and tumour growth by inhibiting the vascular endothelial growth factor (VEGF) pathway. This study determines whether rapamycin can prevent the neoangiogenesis in the mesentery of portal hypertensive mice and may influence the splanchnic vasodilation.Methods:  PHT was induced by partial portal vein ligation (PPVL). PPVL and Sham mice were treated daily with rapamycin or placebo for 2 weeks. Protein expressions of VEGF, CD 31, Akt and p70S6 kinase (mTOR signalling pathway) were evaluated. Mesenteric blood flow (MBF) was measured by a perivascular flow probe.Results:  Increased mesenteric angiogenesis and VEGF protein levels were observed in PPVLplacebo mice compared to Shamplacebo mice. Rapamycin treatment caused significant reduction in CD 31 positive endothelial cells and VEGF protein in the PPVLrapamycine group compared to the PPVLplacebo group, to levels comparable with Shamplacebo and Shamrapamycine groups. MBF was significantly higher in PPVLplacebo mice compared to the Shamplacebo mice. Rapamycin decreased significantly the MBF in PPVLrapamycine mice compared to PPVLplacebo mice. Phospo‐Akt and p70S6 kinase protein levels were increased in the mesenteric tissue of PPVLplacebo mice compared to Shamplacebo mice, which were also prevented by treatment with rapamycin.Conclusions:  An increased VEGF dependent neo‐angiogenesis is present in the mesentery of portal hypertensive mice. Rapamycin prevents angiogenesis in the mesenteric tissue and decreases the mesenteric blood flow in portal hypertensive mice, at least in part through an anti‐VEGF activity and influence on the mTOR signalling pathway.
Association between changes in body composition and the increasing prevalence of fatty liver in Japanese men
Authors: Imamura Yasushi , Uto Hirofumi , Oketani Makoto , Hiramine Yasunari , Hosoyamada Kaori , Sho Yukihiko , Hiwaki Takuya , Baba Yoshirou , Tahara Kenji , Kubozono Osamu , Kusano Ken , Tsubouchi Hirohito 
Published: June 2008

Aim:  Prevalence of fatty liver is increasing. In this study, to elucidate the factor that contributes most to recent increases in prevalence of fatty liver, we determined the independent predictors for the onset of fatty liver and compared these predictors between 2000 and 2005.Methods:  Japanese persons, aged 30–74 years, who participated in regular health checks at Kagoshima Kouseiren Medical Health Care Center (10 336 persons in 2000 and 11 011 persons in 2005) were enrolled in the study. Diagnosis of fatty liver was performed by ultrasonography. Body fat percentage (BFP) was determined using a bipedal bioimpedance instrument.Results:  The prevalence of fatty liver has increased between 2000 and 2005 in men (33.3 vs 38.5% in 2000 vs 2005, respectively, P < 0.0001), but not in women (21.3 vs 21.0%, P = 0.8101). Logistic regression analysis revealed that both body mass index (BMI) and BFP are independent predictors of fatty liver in both men and women. BMI did not change in either men (23.4 ± 2.9 vs 23.8 ± 3.0 kg/m2, P = 0.0528) or women (22.8 ± 3.1 vs 22.8 ± 3.3 kg/m2, P = 0.9862) during the survey period. In contrast, BFP increased in men (20.6 ± 4.7 vs 22.3 ± 5.0 kg/m2, P = 0.0003), but not in women (27.4 ± 5.5 vs 28.4 ± 5.9 kg/m2, P = 0.3993). There was no significant change in triglycerides and glucose levels.Conclusion:  These results suggest that altered body composition, particularly increased BFP without an increase in BMI, has developed in men and is strongly associated with the increasing prevalence of fatty live amongst Japanese men.
Cooling strategies improve intermittent sprint performance in the heat of athletes with tetraplegia
Authors: Webborn N , Price M J , Castle P , Goosey-Tolfrey V L 
Published: June 2008

BackgroundPrecooling has been shown to enhance performance in repeated sprint exercise in able-bodied subjects in a hot environment. Spinal cord injury causes thermoregulatory impairment with a detrimental effect on performance. This study assessed whether cooling strategies before and during exercise in the heat enhances sprint performance in athletes with tetraplegia.MethodsEight male athletes with tetraplegia performed intermittent arm crank exercise in the heat (32.0°C (0.1°C); humidity, 50% (0.1%)) for a maximum of 60 min or until exhaustion. Trials involved a no-cooling control (CON), precooling (PRE) or cooling during exercise (DUR). Each intermittent sprint protocol consisted of varied periods of passive rest, maximal sprinting and active recovery.ResultsBoth PRE and DUR cooling strategies improved the ability of the athletes to repeatedly perform high-intensity sprints, with times to exhaustion (TTE), whereas during the CON trial, athletes demonstrated a reduction in the total number of sprints and TTE (47.2 (10.8), 52.8 (5.8) and 36.2 (9.6) min for CON, PRE and DUR, respectively). Core temperature was significantly higher for CON (37.3°C (0.3°C)) when compared with both PRE and DUR (36.5°C (0.6°C) and 37.0°C (0.5°C), respectively, p<0.01). Ratings of perceived exertion and thermal sensation upon exhaustion or completion were not different.ConclusionsAthletes with tetraplegia should use a precooling or during-exercise cooling strategy specific to the characteristics of their sport when exercising in hot conditions.
Does exercise training during pregnancy affect gestational age? A randomised controlled trial
Authors: Barakat R , Stirling J R , Lucia A 
Published: June 2008

Background:Some controversy exists over the possibility that exercise during pregnancy might increase the risk of preterm delivery.Objective:This study aimed to determine the possiblecause–effectrelationship between regular exercise performed during the second and third trimesters of pregnancy by previously sedentary, healthy gravidae and gestational age at the moment of delivery.Methods:Caucasian (Spanish) women with singleton gestation were assigned to either a training (n = 72) or a control (n = 70) group. The supervised training programme focused mainly onverylight resistance and toning exercises and included ∼80 sessions (three times/week, 35 min/session from weeks 12–13 to weeks 38–39 of pregnancy).Results:No significant differences were found (p>0.05) between the groups in those maternal characteristics (age, smoking habits, number of hours standing or prior parity history) that could potentially influence gestational age. The mean gestational age did not differ (p = 0.745) between the training (39 weeks,3 days (SD 1 day)) and the control group (39 weeks,4 days (SD 1 day)).Conclusions:Previously sedentary, healthy gravidae with singleton gestation can safely engage in moderate, supervised exercise programmes until the end of gestation as this would not affect gestational age.
Fair stateless model checking
Authors: Musuvathi Madanlal , Qadeer Shaz 
Published: June 2008

Stateless model checking is a useful state-space exploration technique for systematically testing complex real-world software. Existing stateless model checkers are limited to the verification of safety properties on terminating programs. However, realistic concurrent programs are nonterminating, a property that significantly reduces the efficacy of stateless model checking in testing them. Moreover, existing stateless model checkers are unable to verify that a nonterminating program satisfies the important liveness property of livelock-freedom, a property that requires the program to make continuous progress for any input.
To address these shortcomings, this paper argues for incorporating a fair scheduler in stateless exploration. The key contribution of this paper is an explicit scheduler that is (strongly) fair and at the same time sufficiently nondeterministic to guarantee full coverage of safety properties.We have implemented the fair scheduler in the CHESS model checker. We show through theoretical arguments and empirical evaluation that our algorithm satisfies two important properties: 1) it visits all states of a finite-state program achieving state coverage at a faster rate than existing techniques, and 2) it finds all livelocks in a finite-state program. Before this work, nonterminating programs had to be manually modified in order to apply CHESS to them. The addition of fairness has allowed CHESS to be effectively applied to real-world nonterminating programs without any modification. For example, we have successfully booted the Singularity operating system under the control of CHESS.
Kaposi's Sarcoma–Associated Herpesvirus Confers a Survival Advantage to Endothelial Cells
Authors: Wang Ling , Damania Blossom 
Published: June 2008

Abstract
Kaposi's sarcoma–associated herpesvirus (KSHV) is associated with three different human malignancies, including Kaposi's sarcoma (KS), primary effusion lymphoma, and multicentric Castleman's disease. The KS lesion is of endothelial cell in origin and is highly dependent on autocrine and paracrine factors for survival and growth. In this study, we show that KSHV infection of endothelial cells induces the activation of the prosurvival phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin pathway. KSHV infection of endothelial cells augmented cell survival in the presence of apoptotic inducers, including etoposide and staurosporine, and under conditions of serum deprivation. We found that KSHV infection of endothelial cells also increased the ability of these cells to form an in vitro tubular network under conditions of stress and growth factor deprivation. Finally, we show that the nuclear factor-κB and PI3K pathways are also required for endothelial tubular network formation. Collectively, these results suggest that KSHV infection of endothelial cells modulates cell signaling pathways and induces cell survival and angiogenesis, thereby contributing to the pathogenesis induced by KSHV. [Cancer Res 2008;68(12):4640–8]
Stopping Treatment Can Reverse Acquired Resistance to Letrozole
Authors: Sabnis Gauri J. , Macedo Luciana F. , Goloubeva Olga , Schayowitz Adam , Brodie Angela M.H. 
Published: June 2008

Abstract
Using the intratumoral aromatase xenograft model, we have observed that despite long-lasting growth inhibition, tumors eventually begin to grow during continued letrozole treatment. In cells isolated from these long-term letrozole-treated tumors (LTLT-Ca), estrogen receptor-α (ERα) levels were decreased, whereas signaling proteins in the mitogen-activated protein kinase cascade were up-regulated along with human epidermal growth factor receptor 2 (Her-2). In the current study, we evaluated the effect of discontinuing letrozole treatment on the growth of letrozole-resistant cells and tumors. The cells formed tumors equally well in the absence or presence of letrozole and had similar growth rates. After treatment was discontinued for 6 weeks, letrozole was administered again. Marked tumor regression was observed with this second course of letrozole treatment. Similarly, in MCF-7Ca xenografts, a 6-week break in letrozole treatment prolonged the responsiveness of the tumors to letrozole. To understand the mechanisms of this effect, LTLT-Ca cells were cultured in the absence of letrozole for 16 weeks. The resulting cell line (RLT-Ca) exhibited properties similar to MCF-7Ca cells. The cell growth was inhibited by letrozole and stimulated by estradiol. The expression of phosphorylated mitogen-activated protein kinase (MAPK) was reduced and ERα and aromatase levels increased compared with LTLT-Ca cells and were similar to levels in MCF-7Ca cells. These results indicate that discontinuing treatment can reverse letrozole resistance. This could be a beneficial strategy to prolong responsiveness to aromatase inhibitors for patients with breast cancer. [Cancer Res 2008;68(12):4518–24]
Suppression of Colorectal Oncogenesis by Selenium-Enriched Milk Proteins: Apoptosis and K-ras Mutations
Authors: Hu Ying , McIntosh Graeme H. , Le Leu Richard K. , Woodman Richard , Young Graeme P. 
Published: June 2008

Abstract
The chemical form and bioavailability of dietary selenium may influence its protectiveness against colorectal cancer. Selenium is readily incorporated into milk proteins by feeding cows with selenized-yeast. This study examined whether a dairy source of organic selenium (as milk proteins) is more effective than a yeast source at inhibiting oncogenesis in carcinogen-treated mice and whether it regulates the homeostatic response to carcinogen-induced DNA damage. Dietary interventions are as follows: selenium-enriched milk protein isolate (Tatura-Bio Se; 0.5 or 1 ppm selenium) or milk protein control and selenized-yeast (Sel-Plex; 1 or 4 ppm selenium) with casein or casein alone as control. After 4 weeks on diet, mice received a single azoxymethane (10 mg/kg) injection to induce mutations and were killed 6 hours later. Measures were as follows: plasma selenium, cell proliferation, and acute apoptotic response to azoxymethane (AARGC). Separate groups of mice on the same diets were given 4 weekly azoxymethane (15 mg/kg) injections to induce oncogenesis. Mice were killed 6 or 30 weeks after the last azoxymethane injection. Measures were as follows: aberrant crypt foci (ACF), cancers, and K-ras mutations. Dairy-selenium at 1 ppm significantly suppressed ACF and cancers, whereas yeast-selenium at an equivalent selenium intake had no effect. Dairy-selenium significantly increased plasma selenium levels and AARGC, and reduced cell proliferation and frequency of K-ras mutations in ACF relative to an equivalent dose of selenium from yeast. Selenium-enriched milk protein isolate is superior to selenized-yeast in terms of its bioavailability and capacity to suppress oncogenesis. Suppression may be a consequence of enhanced apoptotic deletion of azoxymethane-induced DNA lesions and the subsequent reduction in frequency of K-ras mutations. [Cancer Res 2008;68(12):4936–44]
Protein Phosphatase 2A and Rapamycin Regulate the Nuclear Localization and Activity of the Transcription Factor GLI3
Authors: Krauß Sybille , Foerster John , Schneider Rainer , Schweiger Susann 
Published: June 2008

Abstract
Gain-of-function alterations to the sonic hedgehog (SHH) signaling cascade have been found in a wide range of tumors. Three SHH effectors, GLI1, GLI2, and GLI3, regulate transcription of diverse genes involved in cell growth and cell proliferation. Here, we show that protein phosphatase 2A (PP2A), its regulatory subunit, α4, and rapamycin, an inhibitor of the mammalian target of rapamycin kinase complex 1 (mTORC1), regulate the nuclear localization and transcriptional activity of GLI3. An increase in PP2A activity or treatment with rapamycin leads to cytosolic retention of GLI3 and, consequently, reduced transcription of the GLI3 target gene and cell cycle regulator, cyclin D1. Conversely, inhibition of PP2A results in increased expression of cyclin D1. In summary, our findings reveal the existence of a hitherto unrecognized molecular cross-talk between the oncogenic SHH pathway and the tumor suppressor PP2A and suggest a novel mechanism underlying the anticancerogenic effects of rapamycin. [Cancer Res 2008;68(12):4658–65]
Thrombin Up-regulates Cathepsin D which Enhances Angiogenesis, Growth, and Metastasis
Authors: Hu Liang , Roth Jennifer M. , Brooks Peter , Luty Joanna , Karpatkin Simon 
Published: June 2008

Abstract
Cathepsin D (CD) up-regulation has been associated with human malignancy and poor prognosis. Thrombin up-regulated CD mRNA and protein in eight tumor cell lines as well as in human umbilical vascular endothelial cells (HUVEC). Thrombin increased the secretion of CD by 3- to 8-fold and enhanced chemotaxis (∼2-fold) in 4T1 murine mammary CA cells, which was completely inhibited with the knockdown of CD. Secreted 4T1 CD induced neoangiogenesis by 2.4-fold on a chick chorioallantoic membrane, which was blocked in CD-KD cells. The addition of pure CD (2 ng) to the chick chorioallantoic membrane increased angiogenesis by 2.1-fold, which was completely inhibited by Pepstatin A (Pep A). CD enhanced human HUVEC chemotaxis and Matrigel tube formation by 2-fold, which was then blocked by Pep A. CD enhanced HUVEC matrix metalloproteinase 9 (MMP-9) activity by ∼2-fold, which was completely inhibited by Pep A as well as a generic MMP inhibitor, GM6001. The injection of CD-KD 4T1 cells into syngeneic mice inhibited tumor growth by 3- to 4-fold compared with empty vector (EV) cells. Hirudin, a specific thrombin inhibitor, inhibited the growth of wild-type and EV cells by 2- to 3-fold, compatible with thrombin up-regulation of CD. CD and thrombin also contributed to spontaneous pulmonary metastasis; 4-fold nodule inhibition with CD versus EV and 4.6-fold inhibition with hirudin versus EV (P &lt; 0.02). Thus, thrombin-induced CD contributes to the malignant phenotype by inducing tumor cell migration, nodule growth, metastasis, and angiogenesis. CD-induced angiogenesis requires the proteolytic activation of MMP-9. [Cancer Res 2008;68(12):4666–73]
BIBF 1120: Triple Angiokinase Inhibitor with Sustained Receptor Blockade and Good Antitumor Efficacy
Authors: Hilberg Frank , Roth Gerald J. , Krssak Martin , Kautschitsch Susanna , Sommergruber Wolfgang , Tontsch-Grunt Ulrike , Garin-Chesa Pilar , Bader Gerd , Zoephel Andreas , Quant Jens , Heckel Armin , Rettig Wolfgang J. 
Published: June 2008

Abstract
Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a novel treatment modality in oncology. Preclinical findings suggest that long-term clinical outcomes may improve with blockade of additional proangiogenic receptor tyrosine kinases: platelet-derived growth factor receptors (PDGFR) and fibroblast growth factor receptors (FGFR). BIBF 1120 is an indolinone derivative potently blocking VEGF receptor (VEGFR), PDGFR and FGFR kinase activity in enzymatic assays (IC50, 20–100 nmol/L). BIBF 1120 inhibits mitogen-activated protein kinase and Akt signaling pathways in three cell types contributing to angiogenesis, endothelial cells, pericytes, and smooth muscle cells, resulting in inhibition of cell proliferation (EC50, 10–80 nmol/L) and apoptosis. In all tumor models tested thus far, including human tumor xenografts growing in nude mice and a syngeneic rat tumor model, BIBF 1120 is highly active at well-tolerated doses (25–100 mg/kg daily p.o.), as measured by magnetic resonance imaging of tumor perfusion after 3 days, reducing vessel density and vessel integrity after 5 days, and inducing profound growth inhibition. A distinct pharmacodynamic feature of BIBF 1120 in cell culture is sustained pathway inhibition (up to 32 hours after 1-hour treatment), suggesting slow receptor off-kinetics. Although BIBF 1120 is rapidly metabolized in vivo by methylester cleavage, resulting in a short mean residence time, once daily oral dosing is fully efficacious in xenograft models. These distinctive pharmacokinetic and pharmacodynamic properties may help explain clinical observations with BIBF 1120, currently entering phase III clinical development. [Cancer Res 2008;68(12):4774–82]
The Novel Polyamine Analogue CGC-11093 Enhances the Antimyeloma Activity of Bortezomib
Authors: Carew Jennifer S. , Nawrocki Steffan T. , Reddy Venudhar K. , Bush Dorothy , Rehg Jerold E. , Goodwin Andrew , Houghton Janet A. , Casero Robert A. , Marton Laurence J. , Cleveland John L. 
Published: June 2008

Abstract
Multiple myeloma (MM) is an incurable plasma cell malignancy. The recent successes of the proteasome inhibitor bortezomib in MM therapy have prompted investigations of its efficacy in combination with other anticancer agents. Polyamines play important roles in regulating tumor cell proliferation and angiogenesis and represent an important therapeutic target. CGC-11093 is a novel polyamine analogue that has completed a phase I clinical trial for the treatment of cancer. Here, we report that CGC-11093 selectively augments the in vitro and in vivo antimyeloma activity of bortezomib. Specifically, the combination of CGC-11093 and bortezomib compromised MM viability and clonogenic survival, and increased drug-induced apoptosis over that achieved by either single agent. Xenografts of MM tumors treated with this combination had marked increases in phospho-c-Jun-NH2-kinase (JNK)-positive cells and apoptosis, and corresponding reductions in tumor burden, tumor vasculature, and the expression of proliferating cell nuclear antigen and the proangiogenic cytokine vascular endothelial growth factor. Furthermore, inhibition of JNK with a pharmacologic inhibitor or by selective knockdown blunted the efficacy of CGC-11093 and bortezomib. Therefore, CGC-11093 enhances the anticancer activity of bortezomib by augmenting JNK-mediated apoptosis and blocking angiogenesis. These findings support the study of the use of the combination of bortezomib and CGC-11093 in MM patients that fail to respond to frontline therapy. [Cancer Res 2008;68(12):4783–90]
A Notch1 Ectodomain Construct Inhibits Endothelial Notch Signaling, Tumor Growth, and Angiogenesis
Authors: Funahashi Yasuhiro , Hernandez Sonia L. , Das Indranil , Ahn Audrey , Huang Jianzhong , Vorontchikhina Marina , Sharma Anshula , Kanamaru Emi , Borisenko Valeriya , DeSilva Dinuka M. , Suzuki Akihiko , Wang Xing , Shawber Carrie J. , Kandel Jessica J. , Yamashiro Darrell J. , Kitajewski Jan 
Published: June 2008

AbstractNotch signaling is required for vascular development and tumor angiogenesis. Although inhibition of the Notch ligand Delta-like 4 can restrict tumor growth and disrupt neovasculature, the effect of inhibiting Notch receptor function on angiogenesis has yet to be defined. In this study, we generated a soluble form of the Notch1 receptor (Notch1 decoy) and assessed its effect on angiogenesis in vitro and in vivo. Notch1 decoy expression reduced signaling stimulated by the binding of three distinct Notch ligands to Notch1 and inhibited morphogenesis of endothelial cells overexpressing Notch4. Thus, Notch1 decoy functioned as an antagonist of ligand-dependent Notch signaling. In mice, Notch1 decoy also inhibited vascular endothelial growth factor–induced angiogenesis in skin, establishing a role for Notch receptor function in this process. We tested the effects of Notch1 decoy on tumor angiogenesis using two models: mouse mammary Mm5MT cells overexpressing fibroblast growth factor 4 (Mm5MT-FGF4) and NGP human neuroblastoma cells. Exogenously expressed FGF4 induced Notch ligand expression in Mm5MT cells and xenografts. Notch1 decoy expression did not affect tumorigenicity of Mm5MT-FGF4 cells in vitro but restricted Mm5MT-FGF4 xenograft growth in mice while markedly impairing neoangiogenesis. Similarly, Notch1 decoy expression did not affect NGP cells in vitro but disrupted vessels and decreased tumor viability in vivo. These results strongly suggest that Notch receptor signaling is required for tumor neoangiogenesis and provides a new target for tumor therapy. [Cancer Res 2008;68(12):4727–35]