bluuebunny/crossref_metadata_2025_split huggingface dataset:
GSK1070916, a potent Aurora B/C kinase inhibitor with broad antitumor activity in tissue culture cells and human tumor xenograft models
Authors: Hardwicke Mary Ann , Oleykowski Catherine A. , Plant Ramona , Wang Jamin , Liao Qiaoyin , Moss Katherine , Newlander Ken , Adams Jerry L. , Dhanak Dashyant , Yang Jingsong , Lai Zhihong , Sutton David , Patrick Denis 
Published: July 2009

Abstract
The protein kinases, Aurora A, B, and C have critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. GSK1070916, is a novel ATP competitive inhibitor that is highly potent and selective for Aurora B/C kinases. Human tumor cells treated with GSK1070916 show dose-dependent inhibition of phosphorylation on serine 10 of Histone H3, a substrate specific for Aurora B kinase. Moreover, GSK1070916 inhibits the proliferation of tumor cells with EC50 values of &lt;10 nmol/L in over 100 cell lines spanning a broad range of tumor types. Although GSK1070916 has potent activity against proliferating cells, a dramatic shift in potency is observed in primary, nondividing, normal human vein endothelial cells, consistent with the proposed mechanism. We further determined that treated cells do not arrest in mitosis but instead fail to divide and become polyploid, ultimately leading to apoptosis. GSK1070916 shows dose-dependent inhibition of phosphorylation of an Aurora B–specific substrate in mice and consistent with its broad cellular activity, has antitumor effects in 10 human tumor xenograft models including breast, colon, lung, and two leukemia models. These results show that GSK1070916 is a potent Aurora B/C kinase inhibitor that has the potential for antitumor activity in a wide range of human cancers. [Mol Cancer Ther 2009;8(7):1808–17]
Folate-mediated intracellular drug delivery increases the anticancer efficacy of nanoparticulate formulation of arsenic trioxide
Authors: Chen Haimei , Ahn Richard , Van den Bossche Jeroen , Thompson David H. , O'Halloran Thomas V. 
Published: July 2009

AbstractArsenic trioxide (As2O3) is a frontline drug for treatment of acute promyelocytic leukemia and is in clinical trials for treatment of other malignancies, including multiple myeloma; however, efforts to expand clinical utility to solid tumors have been limited by toxicity. Nanoparticulate forms of As2O3 encapsulated in 100-nm-scale, folate-targeted liposomes have been developed to lower systematic toxicity and provide a platform for targeting this agent. The resultant arsenic “nanobins” are stable under physiologic conditions but undergo triggered drug release when the pH is lowered to endosomal/lysosomal levels. Cellular uptake and antitumor efficacy of these arsenic liposomes have been evaluated in folate receptor (FR)–positive human nasopharyngeal (KB) and cervix (HeLa) cells, as well as FR-negative human breast (MCF-7) tumor cells through confocal microscopy, inductively coupled plasma mass spectroscopy, and cytotoxicity studies. Uptake of folate-targeted liposomal arsenic by KB cells was three to six times higher than that of free As2O3 or nontargeted liposomal arsenic; the enhanced uptake occurs through folate-mediated endocytosis, leading to a 28-fold increase in cytotoxicity. In contrast, tumor cells with lower FR density on the surface (HeLa and MCF-7) showed much less uptake of the folate-targeted drug and lower efficacy. In cocultures of KB and MCF-7 cells, the folate-targeted arsenic liposomes were exclusively internalized by KB cells, showing high targeting specificity. Our studies further indicate that folate-targeted delivery of As2O3 with coencapsulated nickel(II) ions (as a nontoxic adjuvant) potentiates the As2O3 efficacy in relatively insensitive solid tumor–derived cells and holds the promise of improving drug therapeutic index. [Mol Cancer Ther 2009;8(7):1955–63]
Inhibition of vascular endothelial growth factor reduces angiogenesis and modulates immune cell infiltration of orthotopic breast cancer xenografts
Authors: Roland Christina L. , Dineen Sean P. , Lynn Kristi D. , Sullivan Laura A. , Dellinger Michael T. , Sadegh Leila , Sullivan James P. , Shames David S. , Brekken Rolf A. 
Published: July 2009

Abstract
Vascular endothelial growth factor (VEGF) is a primary stimulant of angiogenesis and is a macrophage chemotactic protein. Inhibition of VEGF is beneficial in combination with chemotherapy for some breast cancer patients. However, the mechanism by which inhibition of VEGF affects tumor growth seems to involve more than its effect on endothelial cells. In general, increased immune cell infiltration into breast tumors confers a worse prognosis. We have shown previously that 2C3, a mouse monoclonal antibody that prevents VEGF from binding to VEGF receptor 2 (VEGFR2), decreases tumor growth, angiogenesis, and macrophage infiltration into pancreatic tumors and therefore hypothesized that r84, a fully human IgG that phenocopies 2C3, would similarly affect breast tumor growth and immune cell infiltration. In this study, we show that anti-VEGF therapy with bevacizumab, 2C3, or r84 inhibits the growth of established orthotopic MDA-MB-231 breast tumors in severe combined immunodeficiency (SCID) mice, reduces tumor microvessel density, limits the infiltration of tumor-associated macrophages, but is associated with elevated numbers of tumor-associated neutrophils. In addition, we found that treatment with r84 reduced the number of CD11b+Gr1+ double-positive cells in the tumor compared with tumors from control-treated animals. These results show that selective inhibition of VEGFR2 with an anti-VEGF antibody is sufficient for effective blockade of the protumorigenic activity of VEGF in breast cancer xenografts. These findings further define the complex molecular interactions in the tumor microenvironment and provide a translational tool that may be relevant to the treatment of breast cancer. [Mol Cancer Ther 2009;8(7):1761–71]
An Erythropoietin Autocrine/Paracrine Axis Modulates the Growth and Survival of Human Prostate Cancer Cells
Authors: Jeong Jee-Yeong , Hoxhaj Gerta , Socha Amanda L. , Sytkowski Arthur J. , Feldman Laurie 
Published: July 2009

Abstract
Erythropoietin receptors have been identified on a variety of cancer-derived cell lines and primary cancer cells, including those of prostate cancer. The functional status of these extrahematopoietic erythropoietin receptors remains a matter of some dispute. The publication of several important clinical trials suggesting a direct effect of erythropoietin on the growth and survival of primary tumors adds further importance to the question of whether erythropoietin receptors on cancer cells are functional. We have reported previously that human prostate cancer cell lines and primary prostate cancer cells express functional erythropoietin receptors that respond to exogenous erythropoietin by increased cell proliferation and STAT5 phosphorylation. We now show that prostate cancer cell lines express both the EPO gene and the biologically active erythropoietin. The coexpression of functional receptor and biologically active ligand in the cells has led us to hypothesize an autocrine/paracrine mechanism, driven by endogenous erythropoietin, which may modulate the growth and progression of prostate cancer. To test our hypothesis, we have knocked down, independently, erythropoietin receptor and erythropoietin on prostate cancer cells by transfection with short hairpin RNAs. Erythropoietin receptor knockdown cells grow significantly more slowly than their erythropoietin receptor-bearing counterparts in monolayer culture, produce fewer, smaller colonies in soft agar, and do not exhibit erythropoietin-induced signaling. Erythropoietin knockdown cells exhibit dramatically slower rates of growth, which could be restored by transfecting the cells with a murine erythropoietin gene. Taken together, our data suggest that the coordinated regulation of a functional erythropoietin/erythropoietin receptor axis in prostate cancer cells may be integral to the growth and progression of prostate cancer. (Mol Cancer Res 2009;7(7):OF1–8) (Mol Cancer Res 2009;7(7):1150–7)
Vascular Caveolin Deficiency Supports the Angiogenic Effects of Nitrite, a Major End Product of Nitric Oxide Metabolism in Tumors
Authors: Frérart Françoise , Lobysheva Irina , Gallez Bernard , Dessy Chantal , Feron Olivier 
Published: July 2009

AbstractThe biological status of nitrite recently evolved from an inactive end product of nitric oxide (NO) metabolism to a major intravascular and tissue storage of NO. Several enzymes and proteins may indeed work as nitrite reductases. The endothelial NO synthase (eNOS) is proposed to be one of them, particularly when oxygen is lacking. Here, we examined whether the lack of caveolin, a scaffold protein known to limit eNOS activity under basal conditions and to be down-regulated in tumor vessels, could favor the reconversion of nitrite into NO and thereby promote angiogenesis. We found that nitrite-rich serum from caveolin-deficient mice and exogenous nitrite exert proangiogenic effects on aortic explants cultured in a three-dimensional collagen matrix. We identified a higher intrinsic capacity of caveolin-deficient vessels and endothelial cells to convert nitrite into bioactive NO. These effects did occur under moderate hypoxia and were abolished on exposure to a NO scavenger. Evidence for eNOS acting as a nitrite reductase derived from the failure to reproduce the proangiogenic effects of nitrite on eNOS-deficient aorta rings and endothelial cells. Finally, in a mouse tumor model, we documented the higher nitrite content in hypoxic tumors and identified inducible NO synthase as the major source of nitrite. Altogether, these data identify the lack of caveolin observed in the tumor vasculature as a favorable ground for nitrite-driven formation of endothelial tubes in the hypoxic tumor microenvironment. This work also strengthens the therapeutic value of the modulation of caveolin expression to interfere with tumor angiogenesis. (Mol Cancer Res 2009;7(7):1056–63)
Muscarinic effects and foetal cardiovascular and hormonal responses in utero
Authors: Jianli Zheng  , Weili Yang  , Li Cao  , Shigang Li  , Yuying Zhang  , Zhen Wan  , Caiping Mao  
Published: July 2009

Introduction. Cholinergic mechanisms play an important role in the control of hormonal and vascular regulation. However, in utero development of cholinergic regulation in the foetal hormonal systems is not clearly understood.This study investigated foetal hormonal and cardiovascular responses following application of the muscarinic antagonist atropine.Materials and methods. Chronically prepared near-term ovine foetuses (control and experimental: n=5, each group) were used.After 4—5 days’ surgical recovery, conscious ewes and their foetuses were tested in vivo.Results. In response to intravenous atropine, foetal systolic, diastolic, and mean arterial pressure, as well as heart rate, increased immediately. Inhibition of muscarinic systems in the circulation caused a reduction of plasma angiotensin II levels, while angiotensin I in the circulation remained unchanged in the foetus. In addition, foetal plasma aldosterone levels were significantly increased following blockade of the cholinergic receptor, while other hormones, including arginine vasopressin, adrenocorticotrophic hormone, and atrial natriuretic peptide, were not changed in foetal blood under the same condition.Conclusions. The results suggest that foetal automatic systems, not those hormonal factors tested, play a major role in cholinergic mechanisms mediating cardiovascular control. Furthermore, the data provide new information on how muscarinic inhibition affects renin-angiotensin system and adrenal cortex functions. Key words: aldosterone, angiotensin-converting enzyme, autonomic regulation, foetus
Efficient Calculation of Statistical Moments for Structural Health Monitoring
Authors: Choi Myoungkeun , Sweetman Bert 
Published: July 2009

Wireless networks of smart sensors with computations distributed over multiple sensor packages have shown considerable promise in providing low-cost structural health monitoring. In these networks, microprocessors are typically embedded in individual smart sensor packages. The efficiency of embedded computational algorithms is of critical importance because the size, cost, and power requirements of the sensor arrays are central concerns. Here, very efficient methodologies are presented to compute statistical moments of a measured response time-history. These moments: the mean, standard deviation, skewness, and kurtosis are often used to characterize a measured irregular response. Two alternative approaches are presented, each of which can save substantial computer memory requirements and CPU time in certain applications. The first approach reconsiders the computational benefits of computing statistical moments by separating the data into bins and then computing the moments from the geometry of the resulting histogram, which effectively becomes a one-pass algorithm for higher moments. One benefit is that the statistical moment calculations can be carried out to arbitrary accuracy such that the computations can be tuned to the precision of the sensor hardware. The second approach is a new analytical methodology to combine statistical moments from individual segments of a time-history such that the resulting overall moments are those of the complete time-history. This methodology could be used to allow for parallel computation of statistical moments with subsequent combination of those moments, or for combination of statistical moments computed at sequential times. A worked example is presented comparing two implementations of the new methodologies with conventional calculations in monitoring the global performance of an offshore tension leg platform. Accuracy, efficiency, and storage requirements of the calculation methods are compared with those of conventional methods. The results show that substantial CPU and memory savings can be attained with no loss in accuracy and that more dramatic savings can be attained if a slight reduction in accuracy is acceptable.
Gata1 expression driven by the alternative HS2 enhancer in the spleen rescues the hematopoietic failure induced by the hypomorphic Gata1low mutation
Authors: Migliaccio Anna Rita , Martelli Fabrizio , Verrucci Maria , Sanchez Massimo , Valeri Mauro , Migliaccio Giovanni , Vannucchi Alessandro Maria , Zingariello Maria , Di Baldassarre Angela , Ghinassi Barbara , Rana Rosa Alba , van Hensbergen Yvette , Fibbe Willem E. 
Published: July 2009

Abstract
Rigorously defined reconstitution assays developed in recent years have allowed recognition of the delicate relationship that exists between hematopoietic stem cells and their niches. This balance ensures that hematopoiesis occurs in the marrow under steady-state conditions. However, during development, recovery from hematopoietic stress and in myeloproliferative disorders, hematopoiesis occurs in extramedullary sites whose microenvironments are still poorly defined. The hypomorphic Gata1low mutation deletes the regulatory sequences of the gene necessary for its expression in hematopoietic cells generated in the marrow. By analyzing the mechanism that rescues hematopoiesis in mice carrying this mutation, we provide evidence that extramedullary microenvironments sustain maturation of stem cells that would be otherwise incapable of maturing in the marrow.
A lower risk of recurrent venous thrombosis in women compared with men is explained by sex-specific risk factors at time of first venous thrombosis in thrombophilic families
Authors: Lijfering Willem M. , Veeger Nic J. G. M. , Middeldorp Saskia , Hamulyák Karly , Prins Martin H. , Büller Harry R. , van der Meer Jan 
Published: July 2009

Abstract
Why men appear to have an increased risk of recurrent venous thrombosis compared with women is unknown. In a cohort study of families with thrombophilia, lifetime risk of recurrent venous thrombosis was assessed in men and women (n = 816). Adjusted relative risk of recurrence was 1.6 (95% CI, 1.3-2.0) in men compared with women. Women were younger at time of their first event (mean, 34 years vs 44 years; P < .001) and at time of recurrence (40 years vs 48 years, P < .001). After excluding provoked first and recurrent venous thrombosis, adjusted relative risk was 1.2 (95% CI, 0.8-1.7), although mean age at recurrence was comparable in men and women (50 years vs 49 years, P = .595). In women with a hormonal first event, median interval between first event and recurrence was 10.4 years versus 2.7 years in men (P < .001). This difference was not observed when only unprovoked events were considered (P = .938). The difference in lifetime risk of recurrent venous thrombosis between men and women in thrombophilic families can be explained by a younger age of women at time of first venous thrombosis due to hormonal risk factors, and a longer interval between a provoked first episode of venous thrombosis and recurrence in women.
Epigenetic regulation of the alternatively activated macrophage phenotype
Authors: Ishii Makoto , Wen Haitao , Corsa Callie A. S. , Liu Tianju , Coelho Ana L. , Allen Ronald M. , Carson William F. , Cavassani Karen A. , Li Xiangzhi , Lukacs Nicholas W. , Hogaboam Cory M. , Dou Yali , Kunkel Steven L. 
Published: July 2009

AbstractAlternatively activated (M2) macrophages play critical roles in diverse chronic diseases, including parasite infections, cancer, and allergic responses. However, little is known about the acquisition and maintenance of their phenotype. We report that M2-macrophage marker genes are epigenetically regulated by reciprocal changes in histone H3 lysine-4 (H3K4) and histone H3 lysine-27 (H3K27) methylation; and the latter methylation marks are removed by the H3K27 demethylase Jumonji domain containing 3 (Jmjd3). We found that continuous interleukin-4 (IL-4) treatment leads to decreased H3K27 methylation, at the promoter of M2 marker genes, and a concomitant increase in Jmjd3 expression. Furthermore, we demonstrate that IL-4–dependent Jmjd3 expression is mediated by STAT6, a major transcription factor of IL-4–mediated signaling. After IL-4 stimulation, activated STAT6 is increased and binds to consensus sites at the Jmjd3 promoter. Increased Jmjd3 contributes to the decrease of H3K27 dimethylation and trimethylation (H3K27me2/3) marks as well as the transcriptional activation of specific M2 marker genes. The decrease in H3K27me2/3 and increase in Jmjd3 recruitment were confirmed by in vivo studies using a Schistosoma mansoni egg–challenged mouse model, a well-studied system known to support an M2 phenotype. Collectively, these data indicate that chromatin remodeling is mechanistically important in the acquisition of the M2-macrophage phenotype.
Prognostic relevance of Wnt-inhibitory factor-1 (WIF1) and Dickkopf-3 (DKK3) promoter methylation in human breast cancer
Authors: Veeck Jürgen , Wild Peter J , Fuchs Thomas , Schüffler Peter J , Hartmann Arndt , Knüchel Ruth , Dahl Edgar 
Published: July 2009

Abstract

Background
Secreted Wnt signaling antagonists have recently been described as frequent targets of epigenetic inactivation in human tumor entities. Since gene silencing of certain Wnt antagonists was found to be correlated with adverse patient survival in cancer, we aimed at investigating a potential prognostic impact of the two Wnt antagonizing molecules WIF1 and DKK3 in breast cancer, which are frequently silenced by promoter methylation in this disease.

Methods

WIF1 and DKK3 promoter methylation were assessed by methylation-specific PCR with bisulfite-converted DNA from 19 normal breast tissues and 150 primary breast carcinomas. Promoter methylation was interpreted in a qualitative, binary fashion. Statistical evaluations included two-sided Fisher's exact tests, univariate log-rank tests of Kaplan-Meier curves as well as multivariate Cox regression analyses.

Results

WIF1 and DKK3 promoter methylation were detected in 63.3% (95/150) and 61.3% (92/150) of breast carcinoma samples, respectively. In normal breast tissues, WIF1 methylation was present in 0% (0/19) and DKK3 methylation in 5.3% (1/19) of samples. In breast carcinomas, WIF1 methylation was significantly associated with methylation of DKK3 (p = 0.009). Methylation of either gene was not associated with clinicopathological parameters, except for DKK3 methylation being associated with patient age (p = 0.007). In univariate analysis, WIF1 methylation was not associated with clinical patient outcome. In contrast, DKK3 methylation was a prognostic factor in patient overall survival (OS) and disease-free survival (DFS). Estimated OS rates after 10 years were 54% for patients with DKK3-methylated tumors, in contrast to patients without DKK3 methylation in the tumor, who had a favorable 97% OS after 10 years (p < 0.001). Likewise, DFS at 10 years for patients harboring DKK3 methylation in the tumor was 58%, compared with 78% for patients with unmethylated DKK3 (p = 0.037). Multivariate analyses revealed that DKK3 methylation was an independent prognostic factor predicting poor OS (hazard ratio (HR): 14.4; 95% confidence interval (CI): 1.9–111.6; p = 0.011), and short DFS (HR: 2.5; 95% CI: 1.0–6.0; p = 0.047) in breast cancer.

Conclusion
Although the Wnt antagonist genes WIF1 and DKK3 show a very similar frequency of promoter methylation in human breast cancer, only DKK3 methylation proves as a novel prognostic marker potentially useful in the clinical management of this disease.
Developing a scalable model of recombinant protein yield from Pichia pastoris: the influence of culture conditions, biomass and induction regime
Authors: Holmes William J , Darby Richard AJ , Wilks Martin DB , Smith Rodney , Bill Roslyn M 
Published: July 2009

Abstract

Background
The optimisation and scale-up of process conditions leading to high yields of recombinant proteins is an enduring bottleneck in the post-genomic sciences. Typical experiments rely on varying selected parameters through repeated rounds of trial-and-error optimisation. To rationalise this, several groups have recently adopted the 'design of experiments' (DoE) approach frequently used in industry. Studies have focused on parameters such as medium composition, nutrient feed rates and induction of expression in shake flasks or bioreactors, as well as oxygen transfer rates in micro-well plates. In this study we wanted to generate a predictive model that described small-scale screens and to test its scalability to bioreactors.

Results
Here we demonstrate how the use of a DoE approach in a multi-well mini-bioreactor permitted the rapid establishment of high yielding production phase conditions that could be transferred to a 7 L bioreactor. Using green fluorescent protein secreted from Pichia pastoris, we derived a predictive model of protein yield as a function of the three most commonly-varied process parameters: temperature, pH and the percentage of dissolved oxygen in the culture medium. Importantly, when yield was normalised to culture volume and density, the model was scalable from mL to L working volumes. By increasing pre-induction biomass accumulation, model-predicted yields were further improved. Yield improvement was most significant, however, on varying the fed-batch induction regime to minimise methanol accumulation so that the productivity of the culture increased throughout the whole induction period. These findings suggest the importance of matching the rate of protein production with the host metabolism.

Conclusion
We demonstrate how a rational, stepwise approach to recombinant protein production screens can reduce process development time.