bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sequencing and modular analysis of the hybrid non-ribosomal peptide synthase – polyketide synthase gene cluster from the marine sponge Hymeniacidon perleve-associated bacterium Pseudoalteromonas sp. strain NJ631
Authors: Zhu Peng , Zheng Yanling , You Yurong , Yan Xiaojun , Shao Jianzhong 
Published: April 2009

In the present study, we sought to confirm a putative non-ribosomal peptide synthase (NRPS) – polyketide synthase (PKS) gene cluster in marine sponge–associated bacterium with cytotoxic activity and elucidate the gene’s structural information. The genomic library of the marine sponge Hymeniacidon perleve –associated bacterium Pseudoalteromonas sp. strain NJ631 was constructed using a pCC1FOS fosmid. Positive clones that covered the whole gene cluster region of hybrid NRPS–PKS were selected for shotgun sequencing. The results obtained from BlastX and open reading frame (ORF) analysis indicated that there are 3 big ORFs, NJA1, NJA2, and NJA3, that encoded proteins with similarities to amino acid adenylation, β-ketoacyl synthase, and non-ribosomal peptide synthase, respectively, from different organisms. The results gave us a clue that there could be PKS or NRPS modules in the 3 ORFs. Further analysis demonstrated 3 ORFs encoding 2 NRPS modules, 1 PKS module, and 3 NRPS modules. Using the specificity-conferring selection rule, the substrate specificity of 4 adenylation (A) domains (A2, A3, A4, and A5) were successfully predicted, and the amino acids of the substrate specificity were glutamic acid – glutamine, serine, d-serine, and Aeo (2-amino-9,10-epoxy-8-oxodecanoic acid), respectively.
Development of a LUX real-time PCR for the detection and quantification of human herpesvirus 7
Authors: Bergallo Massimiliano , Costa Cristina , Terlizzi Maria Elena , Sidoti Francesca , Margio Samuela , Astegiano Sara , Ponti Renata , Cavallo Rossana 
Published: April 2009

Human herpesvirus 7 is a highly seroprevalent β-herpesvirus that, following primary infection, remains latent in CD4+ T cells and determines a persistent rather than a latent infection in various tissues and organs, including the lung and skin. This paper describes the development of an in-house light upon extension real-time PCR assay for quantification of human herpesvirus 7 DNA in clinical samples. The efficiency, sensitivity, specificity, inter- and intra-assay variability, and dynamic range have been determined. Subsequently, the assay has been validated by evaluating the human herpesvirus 7 load in bronchoalveolar lavages and skin specimens, chosen as 2 persistency sites, from healthy and pathological individuals. The real-time PCR assay developed in this study could be a useful tool to detect and quantify human herpesvirus 7 DNA in different clinical specimens to elucidate its epidemiological and pathogenic roles.
Effects of β-adrenergic receptor blockers on cardiac function: a comparative study in male versus female ratsThis article is one of a selection of papers from the NATO Advanced Research Workshop on Translational Knowledge for Heart Health (published in part 2 of a 2-part Special Issue).
Authors: Tuncay Erkan , Seymen Ali Aytac , Sam Pinar , Gurdal Hakan , Turan Belma 
Published: April 2009

In heart disease, differences exist between women and men with respect to the impact of risk factors, symptoms, and therapeutic responses. The use of β-adrenergic receptor blockers is now well established in the treatment of mild and moderate systolic heart failure. Although there are significant differences among agents, their clinical effects are predictable. To address the question of sex disparities in the heart, however, we investigated the effect of treatment with the nonselective β-blockers timolol and propranolol on mechanical and electrical function of heart preparations from male and female rats. We examined the long-term effects of intragastric treatment with timolol (5 mg/kg per day) or propranolol (25 mg/kg per day) for 7 months on the hemodynamic and intracellular action potential parameters of the heart. Chronic administration of timolol but not propranolol produced a significant increase in the baseline activity of the left ventricular developed pressure (LVDP) in both male and female rats with no significant effect on the left ventricular end-diastolic pressure. Timolol or propranolol treatment of male rats and timolol but not propranolol treatment of female rats induced significant shortening in the repolarization phases of action potentials recorded from left ventricular papillary muscle strips of the hearts. The responses of LVDP to β-adrenergic stimulation were similar in timolol- or propranolol-treated or untreated male rats. On the other hand, timolol treatment markedly increased, and propranolol treatment significantly decreased, the responses of increase in LVDP in female rats. Our results suggest that although treatment with β-blockers for 7 months confirmed the role of the β-adrenergic pathway in heart function, there are marked differences in the effects of individual β-blockers on heart physiology. Sex differences should be taken into consideration when using β-blockers during experimental studies and clinical therapy.
Habitat, movements, and behaviour of overwintering Blanding’s turtles (Emydoidea blandingii) in Nova Scotia
Authors: Newton Erica J. , Herman Thomas B. 
Published: April 2009

The overwintering ecology of a disjunct population complex of Blanding’s turtles ( Emydoidea blandingii (Holbrook, 1838)) in southwestern Nova Scotia was studied from January 2005 to April 2006. Sites were visited biweekly. We recorded structural characteristics and dissolved oxygen (DO), pH, and water and substrate temperatures in 7 overwintering sites containing at least 46 turtles and 7 paired “control sites”. Twenty-five adult turtles were radio-tracked to record locations and movements. Median winter temperature ranged from 0.8 to 8.6 °C in the organic substrate and from 0.3 to 7.6 °C in the water column. In overwintering sites, median DO ranged from 2.8 to 11.3 mg/L and median pH ranged from 4.6 to 5.5. Blanding’s turtles can tolerate submergence under ice for at least 3 months in severely hypoxic conditions. Movement was positively correlated with water temperature. Although some moderate movements were made during winter, 90% were less than 5 m. Movement to overwintering sites (September to mid-November) was gradual, but departure (late March to April) was rapid. Physical characteristics and environmental variables varied dramatically among overwintering sites, and no consistent patterns were observed between overwintering and control sites. We suggest that Blanding’s turtles return to communal sites year after year because of site fidelity and mating opportunities.
Operational semantics for multi-language programs
Authors: Matthews Jacob , Findler Robert Bruce 
Published: April 2009

Interoperability is big business, a fact to which .NET, the JVM, and COM can attest. Language designers are well aware of this, and they are designing programming languages that reflect it—for instance, SML.NET, F#, Mondrian, and Scala all treat interoperability as a central design feature. Still, current multi-language research tends not to focus on the semantics of these features, but only on how to implement them efficiently. In this article, we attempt to rectify that by giving a technique for specifying the operational semantics of a multi-language system as a composition of the models of its constituent languages. Our technique abstracts away the low-level details of interoperability like garbage collection and representation coherence, and lets us focus on semantic properties like type-safety, equivalence, and termination behavior. In doing so it allows us to adapt standard theoretical techniques such as subject-reduction, logical relations, and operational equivalence for use on multi-language systems. Generally speaking, our proofs of properties in a multi-language context are mutually referential versions of their single language counterparts.We demonstrate our technique with a series of strategies for embedding a Scheme-like language into an ML-like language. We start by connecting very simple languages with a very simple strategy, and work our way up to languages that interact in sophisticated ways and have sophisticated features such as polymorphism and effects. Along the way, we prove relevant results such as type-soundness and termination for each system we present using adaptations of standard techniques.Beyond giving simple expressive models, our studies have uncovered several interesting facts about interoperability. For example, higher-order function contracts naturally emerge as the glue to ensure that interoperating languages respect each other's type systems. Our models also predict that the embedding strategy where foreign values are opaque is as expressive as the embedding strategy where foreign values are translated to corresponding values in the other language, and we were able to experimentally verify this behavior using PLT Scheme's foreign function interface.
Preferential Induction of EphB4 over EphB2 and Its Implication in Colorectal Cancer Progression
Authors: Kumar S. Ram , Scehnet Jeffrey S. , Ley Eric J. , Singh Jasbir , Krasnoperov Valery , Liu Ren , Manchanda Parmeet K. , Ladner Robert D. , Hawes Debra , Weaver Fred A. , Beart Robert W. , Singh Gagandeep , Nguyen Cu , Kahn Michael , Gill Parkash S. 
Published: April 2009

Abstract
The receptor tyrosine kinase EphB2 is expressed by colon progenitor cells; however, only 39% of colorectal tumors express EphB2 and expression levels decline with disease progression. Conversely, EphB4 is absent in normal colon but is expressed in all 102 colorectal cancer specimens analyzed, and its expression level correlates with higher tumor stage and grade. Both EphB4 and EphB2 are regulated by the Wnt pathway, the activation of which is critically required for the progression of colorectal cancer. Differential usage of transcriptional coactivator cyclic AMP-responsive element binding protein–binding protein (CBP) over p300 by the Wnt/β-catenin pathway is known to suppress differentiation and increase proliferation. We show that the β-catenin-CBP complex induces EphB4 and represses EphB2, in contrast to the β-catenin-p300 complex. Gain of EphB4 provides survival advantage to tumor cells and resistance to innate tumor necrosis factor-related apoptosis-inducing ligand–mediated cell death. Knockdown of EphB4 inhibits tumor growth and metastases. Our work is the first to show that EphB4 is preferentially induced in colorectal cancer, in contrast to EphB2, whereby tumor cells acquire a survival advantage. [Cancer Res 2009;69(9):3736–45]
Treatment-Dependent Androgen Receptor Mutations in Prostate Cancer Exploit Multiple Mechanisms to Evade Therapy
Authors: Steinkamp Mara P. , O'Mahony Orla A. , Brogley Michele , Rehman Haniya , LaPensee Elizabeth W. , Dhanasekaran Saravana , Hofer Matthias D. , Kuefer Rainer , Chinnaiyan Arul , Rubin Mark A. , Pienta Kenneth J. , Robins Diane M. 
Published: April 2009

AbstractMutations in the androgen receptor (AR) that enable activation by antiandrogens occur in hormone-refractory prostate cancer, suggesting that mutant ARs are selected by treatment. To validate this hypothesis, we compared AR variants in metastases obtained by rapid autopsy of patients treated with flutamide or bicalutamide, or by excision of lymph node metastases from hormone-naïve patients. AR mutations occurred at low levels in all specimens, reflecting genetic heterogeneity of prostate cancer. Base changes recurring in multiple samples or multiple times per sample were considered putative selected mutations. Of 26 recurring missense mutations, most in the NH2-terminal domain (NTD) occurred in multiple tumors, whereas those in the ligand binding domain (LBD) were case specific. Hormone-naïve tumors had few recurring mutations and none in the LBD. Several AR variants were assessed for mechanisms that might underlie treatment resistance. Selection was evident for the promiscuous receptor AR-V716M, which dominated three metastases from one flutamide-treated patient. For the inactive cytoplasmically restricted splice variant AR23, coexpression with AR enhanced ligand response, supporting a decoy function. A novel NTD mutation, W435L, in a motif involved in intramolecular interaction influenced promoter-selective, cell-dependent transactivation. AR-E255K, mutated in a domain that interacts with an E3 ubiquitin ligase, led to increased protein stability and nuclear localization in the absence of ligand. Thus, treatment with antiandrogens selects for gain-of-function AR mutations with altered stability, promoter preference, or ligand specificity. These processes reveal multiple targets for effective therapies regardless of AR mutation. [Cancer Res 2009;69(10):4434–42]
Interleukin-15 Enhances Proteasomal Degradation of Bid in Normal Lymphocytes: Implications for Large Granular Lymphocyte Leukemias
Authors: Hodge Deborah L. , Yang Jun , Buschman Matthew D. , Schaughency Paul M. , Dang Hong , Bere William , Yang Yili , Savan Ram , Subleski Jeff J. , Yin Xiao-Ming , Loughran Thomas P. , Young Howard A. 
Published: April 2009

Abstract
Large granular lymphocyte (LGL) leukemia is a clonal proliferative disease of T and natural killer (NK) cells. Interleukin (IL)-15 is important for the development and progression of LGL leukemia and is a survival factor for normal NK and T memory cells. IL-15 alters expression of Bcl-2 family members, Bcl-2, Bcl-XL, Bim, Noxa, and Mcl-1; however, effects on Bid have not been shown. Using an adoptive transfer model, we show that NK cells from Bid-deficient mice survive longer than cells from wild-type control mice when transferred into IL-15-null mice. In normal human NK cells, IL-15 significantly reduces Bid accumulation. Decreases in Bid are not due to alterations in RNA accumulation but result from increased proteasomal degradation. IL-15 up-regulates the E3 ligase HDM2 and we find that HDM2 directly interacts with Bid. HDM2 suppression by short hairpin RNA increases Bid accumulation lending further support for HDM2 involvement in Bid degradation. In primary leukemic LGLs, Bid levels are low but are reversed with bortezomib treatment with subsequent increases in LGL apoptosis. Overall, these data provide a novel molecular mechanism for IL-15 control of Bid that potentially links this cytokine to leukemogenesis through targeted proteasome degradation of Bid and offers the possibility that proteasome inhibitors may aid in the treatment of LGL leukemia. [Cancer Res 2009;69(9):3986–94]
Prediction of Drug Response in Breast Cancer Using Integrative Experimental/Computational Modeling
Authors: Frieboes Hermann B. , Edgerton Mary E. , Fruehauf John P. , Rose Felicity R.A.J. , Worrall Lisa K. , Gatenby Robert A. , Ferrari Mauro , Cristini Vittorio 
Published: April 2009

Abstract
Nearly 30% of women with early-stage breast cancer develop recurrent disease attributed to resistance to systemic therapy. Prevailing models of chemotherapy failure describe three resistant phenotypes: cells with alterations in transmembrane drug transport, increased detoxification and repair pathways, and alterations leading to failure of apoptosis. Proliferative activity correlates with tumor sensitivity. Cell-cycle status, controlling proliferation, depends on local concentration of oxygen and nutrients. Although physiologic resistance due to diffusion gradients of these substances and drugs is a recognized phenomenon, it has been difficult to quantify its role with any accuracy that can be exploited clinically. We implement a mathematical model of tumor drug response that hypothesizes specific functional relationships linking tumor growth and regression to the underlying phenotype. The model incorporates the effects of local drug, oxygen, and nutrient concentrations within the three-dimensional tumor volume, and includes the experimentally observed resistant phenotypes of individual cells. We conclude that this integrative method, tightly coupling computational modeling with biological data, enhances the value of knowledge gained from current pharmacokinetic measurements, and, further, that such an approach could predict resistance based on specific tumor properties and thus improve treatment outcome. [Cancer Res 2009;69(10):4484–92]
Major Findings By extracting mathematical model parameter values for drug and nutrient delivery from monolayer (one-dimensional) experiments and using the functional relationships to compute drug delivery in MCF-7 spheroid (three-dimensional) experiments, we use the model to quantify the diffusion barrier effect, which alone can result in poor response to chemotherapy both from diminished drug delivery and from lack of nutrients required to maintain proliferative conditions.
PIK3CAandPIK3CBInhibition Produce Synthetic Lethality when Combined with Estrogen Deprivation in Estrogen Receptor–Positive Breast Cancer
Authors: Crowder Robert J. , Phommaly Chanpheng , Tao Yu , Hoog Jeremy , Luo Jingqin , Perou Charles M. , Parker Joel S. , Miller Melinda A. , Huntsman David G. , Lin Li , Snider Jacqueline , Davies Sherri R. , Olson John A. , Watson Mark A. , Saporita Anthony , Weber Jason D. , Ellis Matthew J. 
Published: April 2009

AbstractSeveral phosphoinositide 3-kinase (PI3K) catalytic subunit inhibitors are currently in clinical trial. We therefore sought to examine relationships between pharmacologic inhibition and somatic mutations in PI3K catalytic subunits in estrogen receptor (ER)–positive breast cancer, in which these mutations are particularly common. RNA interference (RNAi) was used to determine the effect of selective inhibition of PI3K catalytic subunits, p110α and p110β, in ER+ breast cancer cells harboring either mutation (PIK3CA) or gene amplification (PIK3CB). p110α RNAi inhibited growth and promoted apoptosis in all tested ER+ breast cancer cells under estrogen deprived-conditions, whereas p110β RNAi only affected cells harboring PIK3CB amplification. Moreover, dual p110α/p110β inhibition potentiated these effects. In addition, treatment with the clinical-grade PI3K catalytic subunit inhibitor BEZ235 also promoted apoptosis in ER+ breast cancer cells. Importantly, estradiol suppressed apoptosis induced by both gene knockdowns and BEZ235 treatment. Our results suggest that PI3K inhibitors should target both p110α and p110β catalytic subunits, whether wild-type or mutant, and be combined with endocrine therapy for maximal efficacy when treating ER+ breast cancer. [Cancer Res 2009;69(9):3955–62]
Analysis of Recently Identified Prostate Cancer Susceptibility Loci in a Population-based Study: Associations with Family History and Clinical Features
Authors: FitzGerald Liesel M. , Kwon Erika M. , Koopmeiners Joseph S. , Salinas Claudia A. , Stanford Janet L. , Ostrander Elaine A. 
Published: April 2009

Abstract
Purpose: Two recent genome-wide association studies have highlighted several single nucleotide polymorphisms (SNPs) purported to be associated with prostate cancer risk. We investigated the significance of these SNPs in a population-based study of Caucasian men, testing the effects of each SNP in relation to family history of prostate cancer and the clinicopathologic features of the disease.
Experimental Design: We genotyped 13 SNPs in 1,308 prostate cancer patients and 1,267 unaffected controls frequency matched to cases by five-year age groups. The association of each SNP with disease risk stratified by family history of prostate cancer and clinicopathologic features of the disease was calculated with the use of logistic and polytomous regression.
Results: These results confirm the importance of multiple, previously reported SNPs in relation to prostate cancer susceptibility; 11 of the 13 SNPs were significantly associated with risk of developing prostate cancer. However, none of the SNP associations were of comparable magnitude with that associated with having a first-degree family history of the disease. Risk estimates associated with SNPs rs4242382 and rs2735839 varied by family history, whereas risk estimates for rs10993994 and rs5945619 varied by Gleason score.
Conclusions: Our results confirm that several recently identified SNPs are associated with prostate cancer risk; however, the variant alleles only confer a low to moderate relative risk of disease and are generally not associated with more aggressive disease features.
Dynamic Contrast-Enhanced Magnetic Resonance Imaging Identifies a Subgroup of Patients with Asymptomatic Monoclonal Plasma Cell Disease and Pathologic Microcirculation
Authors: Hillengass Jens , Zechmann Christian , Bäuerle Tobias , Wagner-Gund Barbara , Heiss Christiane , Benner Axel , Ho Anthony , Neben Kai , Hose Dirk , Kauczor Hans-Ulrich , Goldschmidt Hartmut , Delorme Stefan , Moehler Thomas 
Published: April 2009

Abstract
Purpose: The aim of our study was to investigate whether dynamic contrast–enhanced magnetic resonance imaging (DCE-MRI) allows visualization of changes in microcirculation between healthy controls on the one side and early/advanced stages of plasma cell disease on the other.
Experimental Design: We examined a group of 222 individuals consisting of 60 patients with monoclonal gammopathy of undetermined significance (MGUS), 65 patients with asymptomatic multiple myeloma (aMM), 75 patients with newly diagnosed symptomatic MM (sMM), and 22 healthy controls with DCE-MRI of the lumbar spine.
Results: A continuous increase in microcirculation parameters amplitude A and exchange rate constant kep reflecting vascular volume and permeability, respectively, was detected from normal controls over MGUS and aMM to sMM. For A and kep, significant differences were found between controls and aMM (P = 0.03 and P = 0.004, respectively) as well as controls and sMM (P = 0.001 and P &lt; 0.001, respectively). Although diffuse microcirculation patterns were found in healthy controls as well as MGUS and MM, a pattern with focal hotspots was exclusively detected in 42.6% of sMM and in 3 MGUS and 3 aMM patients. MGUS and aMM patients with increased microcirculation patterns showed significantly higher bone marrow plasmocytosis compared with patients with a low microcirculation pattern.
Conclusions: Our investigations substantiate the concept of an angiogenic switch from early plasma cell disorders to sMM. Pathologic DCE-MRI findings correlate with adverse prognostic factors and DCE-MRI identifies a distinct group of patients with increased microcirculation parameters in aMM and MGUS patients.