bluuebunny/crossref_metadata_2025 huggingface dataset:
MFG-E8/Lactadherin Promotes Tumor Growth in an Angiogenesis-Dependent Transgenic Mouse Model of Multistage Carcinogenesis
Authors: Neutzner Melanie , Lopez Theresa , Feng Xu , Bergmann-Leitner Elke S. , Leitner Wolfgang W. , Udey Mark C.
Published: July 2007

The relevance of angiogenesis in tumor biology and as a therapeutic target is well established. MFG-E8 (also termed lactadherin) and developmental endothelial locus 1 (Del1) constitute a two-gene family of αvβ3/β5 ligands that regulate angiogenesis. After detecting MFG-E8 mRNA in murine tumor cell lines, we sought to determine if MFG-E8 influenced tumorigenesis in Rip1-Tag2 transgenic mice, a cancer model in which angiogenesis is critical. MFG-E8 mRNA and protein were increased in angiogenic islets and tumors in Rip1-Tag2 mice compared with normal pancreas. Frequencies of angiogenic islets and tumor burdens were decreased in MFG-E8–deficient Rip1-Tag2 mice compared with those in control Rip1-Tag2 mice. Invasive carcinomas were modestly underrepresented in MFG-E8–deficient mice, but tumor frequencies and survivals were comparable in these two strains. Absence of MFG-E8 also led to decreases in tumor vascular permeability without obvious changes in vascular morphology. Decreased proliferation was noted in angiogenic islets and increases in apoptotic cells were detected in islets and tumors. Compensatory increases in mRNA encoding proangiogenic proteins, including FGF2, in angiogenic islets, and Del1, in angiogenic islets and tumors, were also detected in MFG-E8–deficient mice. MFG-E8 and its homologue Del1 may represent relevant targets in cancer and other diseases in which angiogenesis is prominent. [Cancer Res 2007;67(14):6777–84]
Therapeutic Vaccination against Murine Lymphoma by Intratumoral Injection of Recombinant Fowlpox Virus Encoding CD40 Ligand
Authors: Liu Aichun , Guardino Alice , Chinsangaram Lek , Goldstein Matthew J. , Panicali Dennis , Levy Ronald
Published: July 2007

The interaction between CD40 ligand (CD40L, CD154) and its receptor CD40 on antigen-presenting cells is essential for the initiation of cell-mediated and humoral immune responses. Malignant B cells also express CD40 and respond to CD40L by enhancing expression of costimulatory molecules. In this study, we investigated the therapeutic antitumor effect of intratumoral administration of recombinant fowlpox virus encoding murine CD40L (rF-mCD40L) in a murine B-cell lymphoma model. BALB/c mice with established s.c. and widely metastatic A20 lymphoma tumors were treated with intratumoral injections of rF-mCD40L together with systemic chemotherapy. This combined chemoimmunotherapy resulted in complete tumor regression and long-term survival of the mice. Some tumor cells in the injected sites expressed the CD40L transgene and had increased expression of the CD80 and CD86 costimulatory molecules. The therapeutic effect was dependent on CD8 but not on CD4 T cells. Moreover, there was a requirement that the recombinant CD40L virus be injected directly into the tumor, as opposed to peritumoral or distant sites. Thus, rF-mCD40L injected directly into the tumor microenvironment enhances the immunogenicity of tumor B cells. The results support future plans for intratumoral injection of rF-mCD40L in patients with lymphoma. [Cancer Res 2007;67(14):7037–44]
Nongenomic β Estrogen Receptors Enhance β1 Adrenergic Signaling Induced by the Nicotine-Derived Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone in Human Small Airway Epithelial Cells
Authors: Majidi Mourad , Al-Wadei Hussein A. , Takahashi Takashi , Schuller Hildegard M.
Published: July 2007

Women are at higher risk for the development of lung adenocarcinoma than men; however, the mechanisms responsible for this are poorly understood. In lung adenocarcinoma cells, the estrogen receptor β (ERβ) is the predominating form. We found that 17β-estradiol enhanced proliferation of the putative cells of origin of lung adenocarcinoma, small airway epithelial cells (HPLD1), in response to the nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Reverse-phase protein microarrays combined with Western blotting revealed that NNK induced phosphorylation of ERβ, an effect that involved stimulation of the adrenergic receptors β1 (β1AR). In transiently transfected cells, β1AR coprecipitated with ERβ, which increased with NNK treatment. ERβ enhanced NNK-induced cyclic AMP accumulation as well as Gαi-mediated mitogen-activated protein kinase/extracellular signal–regulated kinase (ERK) 1/2 activation. Coexpression of β1AR and ERβ activated NNK-mediated ERK1/2 cooperatively. ERβ gene knockdown, as well as coexpression of the dominant negative Ras and Raf, reduced stimulation of ERK1/2 by NNK. Whereas NNK phosphorylated Akt at Thr308 and Ser473, ERβ had no effect on this activity. Luciferase reporter assays showed that, in response to NNK, ERβ stimulated transcription of serum responsive element (SRE) but had a very small effect on the activity of estrogen responsive element (ERE). Together, the phosphorylation of ERβ, the dependence on Gαi proteins, the activation of ERK1/2, and the preferential targeting of SRE over the classic ERE pathway support a role for nongenomic ERβ in the development of smoking-associated lung cancer. This novel cooperation between β1AR and ERβ signaling may contribute to the prominence of lung adenocarcinoma in women. [Cancer Res 2007;67(14):6863–71]
Small Interfering RNA–Directed Reversal of Urokinase Plasminogen Activator Demethylation Inhibits Prostate Tumor Growth and Metastasis
Authors: Pulukuri Sai Murali Krishna , Rao Jasti S.
Published: July 2007

Recent studies have shown that small interfering RNA (siRNA) silences genes at the transcriptional level in human cells. However, the therapeutic potential of siRNA-mediated transcriptional gene silencing remains unclear. Here, we show that siRNA targeted to the urokinase plasminogen activator (uPA) promoter induced epigenetic transcriptional silencing in human prostate cancer cells. This silencing resulted in a dramatic reduction of tumor cell invasion and angiogenesis in vitro. Furthermore, the results from a bioluminescence tumor/metastasis model showed that the silencing of uPA significantly inhibits prostate tumor growth and the incidence of lung metastasis. Our findings represent a potentially powerful new approach to not only epigenetic silencing of metastasis or growth-promoting genes as a cancer therapy, but also as a means to shed light on how aberrant de novo methylation during cancer progression might be targeted to specific sequences. [Cancer Res 2007;67(14):6637–46]
Histone Deacetylase Inhibitors Enhance Lexatumumab-Induced Apoptosis via a p21Cip1-Dependent Decrease in Survivin Levels
Authors: Nawrocki Steffan T. , Carew Jennifer S. , Douglas Leslie , Cleveland John L. , Humphreys Robin , Houghton Janet A.
Published: July 2007

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in malignant cells by binding to the death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). Several agents that therapeutically exploit this phenomenon are being developed. We investigated the anticancer activity of two novel, highly specific agonistic monoclonal antibodies to TRAIL-R1 (mapatumumab, HGS-ETR1) and TRAIL-R2 (lexatumumab, HGS-ETR2) in colon cancer cell lines. Our analyses revealed that colon cancer cells display significantly higher surface expressions of TRAIL-R2 than TRAIL-R1, and are more sensitive to lexatumumab-induced apoptosis. The proapoptotic effects of lexatumumab in TRAIL-resistant HCT8 and HT29 cells were dramatically augmented by the histone deacetylase inhibitors trichostatin A or suberoylanilide hydroxamic acid. The presence of p21, but not p53, was critical for the synergy between lexatumumab and histone deacetylase inhibitors. The absence of p21 did not interfere with the formation of the death-inducing signaling complex by lexatumumab, suggesting the involvement of other apoptotic and/or cell cycle regulators. Indeed, treatment with suberoylanilide hydroxamic acid greatly reduced the expression of the inhibitor of apoptosis protein survivin and cdc2 activity in HCT116 p21+/+ cells but not in the HCT116 p21−/− cells. Inhibition of cdc2 activity with flavopiridol decreased survivin expression and sensitized the p21-deficient cells to lexatumumab-induced apoptosis. Similarly, small interfering RNA–mediated knockdown of survivin also enhanced lexatumumab-mediated cell death. Therefore, survivin expression plays a key role in lexatumumab resistance, and reducing survivin expression by inhibiting cdc2 activity is a promising strategy to enhance the anticancer activity of lexatumumab. [Cancer Res 2007;67(14):6987–94]
Fascin, a Novel Target of β-Catenin-TCF Signaling, Is Expressed at the Invasive Front of Human Colon Cancer
Authors: Vignjevic Danijela , Schoumacher Marie , Gavert Nancy , Janssen Klaus-Peter , Jih Gloria , Laé Marick , Louvard Daniel , Ben-Ze'ev Avri , Robine Sylvie
Published: July 2007

Cancer cells become metastatic by acquiring a motile and invasive phenotype. This step requires remodeling of the actin cytoskeleton and the expression of exploratory, sensory organelles known as filopodia. Aberrant β-catenin-TCF target gene activation plays a major role in colorectal cancer development. We identified fascin1, a key component of filopodia, as a target of β-catenin-TCF signaling in colorectal cancer cells. Fascin1 mRNA and protein expression were increased in primary cancers in a stage-dependent manner. Fascin1 was exclusively localized at the invasive front of tumors also displaying nuclear β-catenin. Forced expression of fascin1 in colorectal cancer cells increased their migration and invasion in cell cultures and caused cell dissemination and metastasis in vivo, whereas suppression of fascin1 expression by small interfering RNA reduces cell invasion. Although expression of fascin1 in primary tumors correlated with the presence of metastases, fascin1 was not expressed in metastases. Our studies show that fascin1 expression is tightly regulated during development of colon cancer metastases and is a novel target of β-catenin-TCF signaling. We propose that transient up-regulation of fascin1 in colorectal cancer promotes the acquisition of migratory and invasive phenotypes that lead to metastasis. Moreover, the expression of fascin1 is down-regulated when tumor cells reach their metastatic destination where migration ceases and proliferation is enhanced. Although metastasis to vital organs is often the cause of mortality, only limited success has been attained in developing effective therapeutics against metastatic disease. We propose that genes involved in cell migration and invasion, such as fascin1, could serve as novel targets for metastasis prevention. [Cancer Res 2007;67(14):6844–53]
Prostatic Acid Phosphatase Is Not a Prostate Specific Target
Authors: Quintero Ileana B. , Araujo César L. , Pulkka Anitta E. , Wirkkala Riikka S. , Herrala Annakaisa M. , Eskelinen Eeva-Liisa , Jokitalo Eija , Hellström Pekka A. , Tuominen Hannu J. , Hirvikoski Pasi P. , Vihko Pirkko T.
Published: July 2007

Prostatic acid phosphatase (PAP) is currently evaluated as a target for vaccine immunotherapy of prostate cancer. This is based on the previous knowledge about secretory PAP and its high prostatic expression. We describe a novel PAP spliced variant mRNA encoding a type I transmembrane (TM) protein with the extracellular NH2-terminal phosphatase activity and the COOH-terminal lysosomal targeting signal (YxxΦ). TM-PAP is widely expressed in nonprostatic tissues like brain, kidney, liver, lung, muscle, placenta, salivary gland, spleen, thyroid, and thymus. TM-PAP is also expressed in fibroblast, Schwann, and LNCaP cells, but not in PC-3 cells. In well-differentiated human prostate cancer tissue specimens, the expression of secretory PAP, but not TM-PAP, is significantly decreased. TM-PAP is localized in the plasma membrane-endosomal-lysosomal pathway and is colocalized with the lipid raft marker flotillin-1. No cytosolic PAP is detected. We conclude that the wide expression of TM-PAP in, for instance, neuronal and muscle tissues must be taken into account in the design of PAP-based immunotherapy approaches. [Cancer Res 2007;67(14):6549–54]
Mineralocorticoid Escape by the Kidney But Not the Heart in Experimental Asymptomatic Left Ventricular Dysfunction
Authors: Costello-Boerrigter Lisa C. , Boerrigter Guido , Harty Gail J. , Cataliotti Alessandro , Redfield Margaret M. , Burnett John C.
Published: July 2007

Unlike healthy subjects, overt congestive heart failure cannot “escape” the sodium- and water-retaining actions of mineralocorticoid excess. It is undefined whether escape occurs in asymptomatic left ventricular dysfunction (ALVD), which is characterized by preserved sodium homeostasis, natriuretic peptide activation, and normal circulating aldosterone. We hypothesized that, in ALVD, mineralocorticoid excess with exogenous deoxycorticosterone acetate (DOCA) would overwhelm renal compensatory mechanisms, resulting in sodium and water retention, and promote renal and cardiac collagen deposition. ALVD was induced in 2 groups (N=5 each) of dogs by tachypacing at 180 bpm. Urine was collected daily and blood drawn at baseline and days 2, 5, 8, and 11. One group served as control (ALVD), and the other received DOCA (ALVD+DOCA) starting at day 2 of pacing. Urine flow and sodium excretion were unchanged in the ALVD group. In ALVD+DOCA, urine flow and sodium excretion decreased on the first 2 days DOCA was given but normalized starting day 4. Urine flow and urinary cGMP excretion increased in ALVD+DOCA after DOCA escape. Plasma atrial natriuretic peptide, B-type natriuretic peptide, and cGMP increased equally in both groups. There were no differences in cardiorenal and hemodynamic parameters in an acute study on day 11. Although renal collagen area fraction was similar, left ventricular collagen area fraction in ALVD+DOCA was significantly higher than in ALVD (3.3±0.4% versus 2.0±0.2%;
P
=0.012). We conclude that ALVD can escape the sodium- and water-retaining effects of mineralocorticoid excess. Despite renal escape, increased left ventricular collagen deposition suggests that the heart but not the kidney failed to escape the tissue effects of DOCA.
Reporting a Potential Pandemic
Authors: Dudo Anthony D. , Dahlstrom Michael F. , Brossard Dominique
Published: July 2007

While quality mediated information does not guarantee accurate public risk perceptions, it provides the public with the means to construct informed risk assessments. This study analyzed four major U.S. newspapers to assess the quality of coverage related to risks posed by avian flu. “Quality of coverage” was examined with a five-dimension conceptualization that included measures of risk magnitude, self-efficacy, risk comparisons, sensationalism, and thematic and episodic framing. Findings revealed that coverage was dominated by episodic frames, exhibited high sensationalism, and contained minimal information promoting self-efficacy. Conversely, coverage exhibited high quality in terms of risk magnitude and risk comparison information.
Incidence of Antiheparin−Platelet Factor 4 Antibodies and Heparin-Induced Thrombocytopenia in Turkish Patients Undergoing Cardiac Surgery
Authors: Demir Muzaffer , Duran Enver , Yigitbasi Omer , Vural Ozden , Kurum Turhan , Yuksel Mahmut , Turgut Burhan , Walenga Jeanine M. , Fareed Jawed
Published: July 2007

The frequency of antiheparin−platelet factor 4 antibodies by means of antigenic and functional assays (14 C-serotonin release assay and citrated plasma platelet aggregation) was determined in 115 Turkish patients undergoing cardiac surgery. Blood samples were taken immediately before surgery and on days 5 and 10 ± 2. Platelet counts were recorded and thrombotic events were determined by clinical methods. Antibody generation measured by enzyme-linked immunosorbent assay before surgery (n = 44) and on days 5 (n = 44) and 10 (n = 115) was 15.9%, 34.1%, and 65.2%, respectively. Positive samples from functional assays were 4.4% on day 0 and 7.0% on day 10. All positive samples had been negative on day 0. A high frequency of antiheparin−platelet factor 4 antibody generation and a low frequency of clinical heparin-induced thrombocytopenia were determined in these patients. These results obtained for Turkish patients are similar to those of other studies of heparin-induced thrombocytopenia.
Themed Review: Nonpharmacologic Approaches to Osteoarthritis
Authors: Katz Warren A.
Published: July 2007

Osteoarthritis is the most common form of arthritis, occurring primarily in the older population. Pain, stiffness, and disability are the major complaints of the disease, which are best treated with pharmacologic and nonpharmacologic measures. The goals of therapy are pain relief, maintenance of function, and correction of deformities whenever possible to restore lost function. Nonpharmacologic treatments enhance the role of medicinal therapy in the management of chronic osteoarthritic pain. They help to improve overall lifestyle, build self-reliance, and instill a sense of control over the pain, which in turn may improve pharmacologic compliance. Nonpharmacologic therapy improves outcomes of total joint replacement and some other types of joint surgery. Options include patient as well as caregiver education, physical medical and rehabilitation, weight reduction, sleep hygiene, surgery, and psychosocial intervention. Alternative or complementary medicine, also referred to as integrative medicine, has become quite popular among many patients. Their effectiveness is not to be ignored, but for the most part, scientific evidence is sparse or missing. Clearly, in most patients, symptomatic osteoarthritis can be improved through a comprehensive, multidisciplinary approach.
State of the Art Reviews: Measurement of Physical Activity in Children and Adolescents
Authors: Trost Stewart G.
Published: July 2007

To date, a wide range of methods has been used to measure physical activity in children and adolescents. These include self-report methods such as questionnaires, activity logs, and diaries as well as objective measures of physical activity such as direct observation, doubly labeled water, heart rate monitoring, accelerometers, and pedometers. The purpose of this review is to overview the methods currently being used to measure physical activity in children and adolescents. For each measurement approach, new developments and/or innovations are identified and discussed. Particular attention is given to the use of accelerometers and the calibration of accelerometer output to units of energy expenditure to developing children.
Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis
Authors: Akin Cem , Scott Linda M. , Kocabas Can N. , Kushnir-Sukhov Nataliya , Brittain Erica , Noel Pierre , Metcalfe Dean D.
Published: July 2007

Idiopathic anaphylaxis remains a perplexing disorder in which existing prophylactic therapy is inadequate. In this prospective study, we sought to determine whether patients with idiopathic anaphylaxis might have evidence for a clonal disorder of mast cells related to mastocytosis and for which novel targeted therapies might be considered. We report 12 patients with “idiopathic” anaphylaxis who did not exhibit either urticaria pigmentosa or the characteristic bone marrow biopsy finding of multifocal mast-cell aggregates observed in systemic mastocytosis. Of these 12 patients, 5 had evidence of 1 or more minor criteria for mastocytosis. C-KIT mutational analysis was positive for the 816D>V activating mutation in 3 of 3 patients in CD25+ bone marrow cells where the analysis was performed. These results demonstrate the presence of an aberrant mast-cell population carrying clonal markers in a subset of patients diagnosed with “idiopathic” anaphylaxis, who may respond to inhibitors targeting mutated C-KIT. This intramural clinical trial was conducted in 2003 and 2004 and was registered at http://clinicalcenter.nih.gov with a study number 03-I-0010. Since the study is now closed, it is no longer available online.
The Shc-binding site of the βc subunit of the GM-CSF/IL-3/IL-5 receptors is a negative regulator of hematopoiesis
Authors: Ramshaw Hayley S. , Guthridge Mark A. , Stomski Frank C. , Barry Emma F. , Ooms Lisa , Mitchell Christina A. , Begley C. Glenn , Lopez Angel F.
Published: July 2007

Tyrosine and serine phosphorylation of the common β chain (βc) of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 receptors is widely viewed as a general mechanism that provides positive inputs by coupling the receptor to signaling pathways that stimulate several cellular functions. We show here that despite the known action of Tyr577 in βc to recruit Shc–PI-3 kinase (PI3K) pathway members, Tyr577 plays, surprisingly, a negative regulatory role in cell function, and that this is mediated, at least in part, through the uncoupling of SH2-containing inositol 5′-phosphatase (SHIP) from βc. Fetal liver cells from βc/βIL-3−/− mice expressing human GM-CSF receptor α chain and βc Tyr577Phe mutant showed enhanced colony formation and expansion of progenitor cells in response to GM-CSF. Dissection of these activities revealed that basal survival was increased, as well as cytokine-stimulated proliferation. As expected, the recruitment and activation of Shc was abolished, but interestingly, Gab-2 and Akt phosphorylation increased. Significantly, the activation of PI3K was enhanced and prolonged, accompanied by loss of SHIP activity. These results reveal a previously unrecognized negative signaling role for Tyr577 in βc and demonstrate that uncoupling Shc from cytokine receptors enhances PI3K signaling as well as survival and proliferation.
The EIPeptiDi tool: enhancing peptide discovery in ICAT-based LC MS/MS experiments
Authors: Cannataro Mario , Cuda Giovanni , Gaspari Marco , Greco Sergio , Tradigo Giuseppe , Veltri Pierangelo
Published: July 2007

Background

Isotope-coded affinity tags (ICAT) is a method for quantitative proteomics based on differential isotopic labeling, sample digestion and mass spectrometry (MS). The method allows the identification and relative quantification of proteins present in two samples and consists of the following phases. First, cysteine residues are either labeled using the ICAT Light or ICAT Heavy reagent (having identical chemical properties but different masses). Then, after whole sample digestion, the labeled peptides are captured selectively using the biotin tag contained in both ICAT reagents. Finally, the simplified peptide mixture is analyzed by nanoscale liquid chromatography-tandem mass spectrometry (LC-MS/MS). Nevertheless, the ICAT LC-MS/MS method still suffers from insufficient sample-to-sample reproducibility on peptide identification. In particular, the number and the type of peptides identified in different experiments can vary considerably and, thus, the statistical (comparative) analysis of sample sets is very challenging. Low information overlap at the peptide and, consequently, at the protein level, is very detrimental in situations where the number of samples to be analyzed is high.

Results

We designed a method for improving the data processing and peptide identification in sample sets subjected to ICAT labeling and LC-MS/MS analysis, based on cross validating MS/MS results. Such a method has been implemented in a tool, called EIPeptiDi, which boosts the ICAT data analysis software improving peptide identification throughout the input data set. Heavy/Light (H/L) pairs quantified but not identified by the MS/MS routine, are assigned to peptide sequences identified in other samples, by using similarity criteria based on chromatographic retention time and Heavy/Light mass attributes. EIPeptiDi significantly improves the number of identified peptides per sample, proving that the proposed method has a considerable impact on the protein identification process and, consequently, on the amount of potentially critical information in clinical studies. The EIPeptiDi tool is available at http://bioingegneria.unicz.it/~veltri/projects/eipeptidi/ with a demo data set.

Conclusion

EIPeptiDi significantly increases the number of peptides identified and quantified in analyzed samples, thus reducing the number of unassigned H/L pairs and allowing a better comparative analysis of sample data sets.
Expression profiling in vivo demonstrates rapid changes in lung microRNA levels following lipopolysaccharide-induced inflammation but not in the anti-inflammatory action of glucocorticoids
Authors: Moschos Sterghios A , Williams Andrew E , Perry Mark M , Birrell Mark A , Belvisi Maria G , Lindsay Mark A
Published: July 2007

Background

At present, nothing is known of the role of miRNAs in the immune response in vivo despite the fact that inflammation is thought to underlie multiple acute and chronic diseases. In these circumstances, patients are commonly treated with corticosteroids such as dexamethasone.

Results

To address this question, we have examined the differential expression of 104 miRNAs using real-time PCR during the innate immune response in mouse lung following exposure to aerosilised lipopolysaccharide (LPS). Following challenge, we observed rapid and transient increase in both the mean (4.3-fold) and individual levels of miRNA expression (46 miRNAs) which peaked at 3 hrs. Crucially, this increase was correlated with a reduction in the expression of tumour necrosis factor (TNF)-α, keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-2, suggesting a potential role for miRNAs in the regulation of inflammatory cytokine production. Examination of the individual miRNA expression profiles showed time dependent increases in miR-21, -25, -27b, -100, 140, -142-3p, -181c, 187, -194, -214, -223 and -224. Corticosteroid studies showed that pre-treatment with dexamethasone at concentrations that inhibited TNF-α production, had no effect either alone or upon the LPS-induced miRNA expression profile.

Conclusion

We have shown that the LPS-induced innate immune response is associated with widespread, rapid and transient increases in miRNA expression in the mouse lung and we speculate that these changes might be involved in the regulation of the inflammatory response. In contrast, the lack of effect of dexamethasone in either control or challenged animals implies that the actions of glucocorticoids per se are not mediated through changes in miRNAs expression and that LPS-induced increases in miRNA expression are not mediated via classical inflammatory transcription factors.
Semantic, syntactic, and phonological processing of written words in adult developmental dyslexic readers: an event-related brain potential study
Authors: Rüsseler Jascha , Becker Petra , Johannes Sönke , Münte Thomas F
Published: July 2007

Background

The present study used event-related brain potentials to investigate semantic, phonological and syntactic processes in adult German dyslexic and normal readers in a word reading task. Pairs of German words were presented one word at a time. Subjects had to perform a semantic judgment task (house – window; are they semantically related?), a rhyme judgment task (house – mouse; do they rhyme?) and a gender judgment task (das – Haus [the – house]; is the gender correct? [in German, house has a neutral gender: das Haus]).

Results

Normal readers responded faster compared to dyslexic readers in all three tasks. Onset latencies of the N400 component were delayed in dyslexic readers in the rhyme judgment and in the gender judgment task, but not in the semantic judgment task. N400 and the anterior negativity peak amplitudes did not differ between the two groups. However, the N400 persisted longer in the dyslexic group in the rhyme judgment and in the semantic judgment tasks.

Conclusion

These findings indicate that dyslexics are phonologically impaired (delayed N400 in the rhyme judgment task) but that they also have difficulties in other, non-phonological aspects of reading (longer response times, longer persistence of the N400). Specifically, semantic and syntactic integration seem to require more effort for dyslexic readers and take longer irrespective of the reading task that has to be performed.
Enzymatic engineering of the porcine genome with transposons and recombinases
Authors: Clark Karl J , Carlson Daniel F , Foster Linda K , Kong Byung-Whi , Foster Douglas N , Fahrenkrug Scott C
Published: July 2007

Background

Swine is an important agricultural commodity and biomedical model. Manipulation of the pig genome provides opportunity to improve production efficiency, enhance disease resistance, and add value to swine products. Genetic engineering can also expand the utility of pigs for modeling human disease, developing clinical treatment methodologies, or donating tissues for xenotransplantation. Realizing the full potential of pig genetic engineering requires translation of the complete repertoire of genetic tools currently employed in smaller model organisms to practical use in pigs.

Results

Application of transposon and recombinase technologies for manipulation of the swine genome requires characterization of their activity in pig cells. We tested four transposon systems- Sleeping Beauty, Tol2, piggyBac, and Passport in cultured porcine cells. Transposons increased the efficiency of DNA integration up to 28-fold above background and provided for precise delivery of 1 to 15 transgenes per cell. Both Cre and Flp recombinase were functional in pig cells as measured by their ability to remove a positive-negative selection cassette from 16 independent clones and over 20 independent genomic locations. We also demonstrated a Cre-dependent genetic switch capable of eliminating an intervening positive-negative selection cassette and activating GFP expression from episomal and genome-resident transposons.

Conclusion

We have demonstrated for the first time that transposons and recombinases are capable of mobilizing DNA into and out of the porcine genome in a precise and efficient manner. This study provides the basis for developing transposon and recombinase based tools for genetic engineering of the swine genome.
A novel real-time ultrasonic method for prion protein detection using plasminogen as a capture molecule
Authors: Negredo Carmen , Monks Eoin , Sweeney Torres
Published: July 2007

Background

High resolution ultrasonography (HR-US) can monitor the molecular changes and biochemical interactions between proteins in real-time. The aim of this study was to use HR-US to characterize the real-time interactions between plasminogen coated beads and PrPSc and to determine if this approach could be applied to the identification of animals affected by prion diseases. Plasminogen, immobilized to beads, was used as a capturing tool for PrPSc in brain homogenates from scrapie affected sheep and the binding reaction was monitored in real-time in an ultrasonic cell.

Results

Changes in the ultrasonic parameters suggested that three processes occurred during the incubation: binding, protein-protein network formation and precipitation and that these processes occurred in a concentration dependent manner. Conversely, when homogenates from normal sheep were similarly examined, no evidence for the occurrence of these processes was found indicating the specificity of the interaction between the plasminogen coated beads and PrPSc.

Conclusion

These results indicate firstly, that the plasminogen coated beads binded selectively to PrPSc and secondly, that a HR-US system can discriminate between scrapie affected and non-affected samples and thus has potential as a tool for the rapid diagnosis for prion diseases. This approach has the significant advantage of not requiring a proteinase K pre-digestion step, which is routinely used in current PrPSc detection assays.
Transcriptional response of P. pastoris in fed-batch cultivations to Rhizopus oryzae lipase production reveals UPR induction
Authors: Resina David , Bollók Mónika , Khatri Narendar K , Valero Francisco , Neubauer Peter , Ferrer Pau
Published: July 2007

Background

The analysis of transcriptional levels of the genes involved in protein synthesis and secretion is a key factor to understand the host organism's responses to recombinant protein production, as well as their interaction with the cultivation conditions. Novel techniques such as the sandwich hybridization allow monitoring quantitatively the dynamic changes of specific RNAs. In this study, the transcriptional levels of some genes related to the unfolded protein response (UPR) and central metabolism of Pichia pastoris were analysed during batch and fed-batch cultivations using an X-33-derived strain expressing a Rhizopus oryzae lipase under control of the formaldehyde dehydrogenase promoter (FLD1), namely the alcohol oxidase gene AOX1, the formaldehyde dehydrogenase FLD1, the protein disulfide isomerase PDI, the KAR2 gene coding for the BiP chaperone, the 26S rRNA and the R. oryzae lipase gene ROL.

Results

The transcriptional levels of the selected set of genes were first analysed in P. pastoris cells growing in shake flask cultures containing different carbon and nitrogen sources combinations, glycerol + ammonium, methanol + methylamine and sorbitol + methylamine. The transcriptional levels of the AOX1 and FLD1 genes were coherent with the known regulatory mechanism of C1 substrates in P. pastoris, whereas ROL induction lead to the up-regulation of KAR2 and PDI transcriptional levels, thus suggesting that ROL overexpression triggers the UPR. This was further confirmed in fed-batch cultivations performed at different growth rates. Transcriptional levels of the analysed set of genes were generally higher at higher growth rates. Nevertheless, when ROL was overexpressed in a strain having the UPR constitutively activated, significantly lower relative induction levels of these marker genes were detected.

Conclusion

The bead-based sandwich hybridization assay has shown its potential as a reliable instrument for quantification of specific mRNA species in P. pastoris cells grown in fed-batch cultures. As a proof-of-principle, the influence of the carbon and nitrogen sources, the specific growth rate, as well as the ROL overexpression on the transcriptional levels of a reduced set of bioprocess-relevant genes has been quantitatively studied, revealing that ROL overexpression and secretion seems to trigger the UPR in P. pastoris, resulting in a physiological bottleneck for the production process.
A comparative study on the efficacy of artesunate plus sulphadoxine/pyrimethamine versus artemether-lumefantrine in eastern Sudan
Authors: Mukhtar Ebtihal A , Gadalla Nahla B , El-zaki Salah-Eldin G , Mukhtar Izdihar , Mansour Fathi A , Babiker Ahmed , El-Sayed Badria B
Published: July 2007

Background

A combination of artesunate (AS) plus sulphadoxine/pyrimethamine (SP) as first-line and artemether-lumefantrine (AL) as second-line treatment are currently recommended against uncomplicatedP. falciparuminfection in Sudan. However, there is limited information on the efficacy of ACTs in the country and only one report of PCR-corrected results for AS/SP only.

Methods

The WHO protocol for the assessment of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria was employed. Artesunate plus sulphadoxine/pyrimethamine (AS/SP) was compared to artemether-lumefantrine (AL) in a 28-day follow up. Samples that were classified as early treatment failure (ETF), late treatment failure (LCF) or late parasitological failure (LPF) were genotyped formsp-1andmsp-2genes to differentiate recrudescence from reinfection.

Results

A total of 178 patients were screened and 160 met the enrolment criteria and were recruited to the study of which 157 (98.1%) completed the follow up and had an analysed treatment outcome. On the AS/SP arm, three (0.038%) patients were lost during the follow-up, two on day 1 and one on day 7, and 77 (96.3) completed the study, while all 80 (100%) patients completed the follow up in the AL arm. In the per protocol analysis for AS/SP the treatment outcome for patients who completed the follow-up were as follows: adequate clinical and parasitological response (ACPR); 84.4% ETF; 1.3%, LCF; 3.9%, (LPF); 10.4%. For the AL arm the out come was as follows, ACPR; 90%, ETF; 0%, LCF; 6.3% and LPF; 3.8%. However, when PCR-corrected, 6.5% (5/77) of patients treated with AS/SP maintained parasites from their primary infection, while (7/80) in the AL group maintained their initial parasite genotype. Therefore, PCR-corrected efficacy was 93.5% in the AS/SP treated group and for AL it was 91.3%.

Conclusion

Both AS/SP and AL are highly effective for the treatment of uncomplicated falciparum malaria in eastern Sudan. However, AS/SP appears to have a slightly higher efficacy than AL, this may be due to patient compliance with the repeated dose rather than drug efficacy.
Influence of spacer length on heparin coupling efficiency and fibrinogen adsorption of modified titanium surfaces
Authors: Tebbe David , Thull Roger , Gbureck Uwe
Published: July 2007

Background

Chemical bonding of the drug onto surfaces by means of spacer molecules is accompanied with a reduction of the biological activity of the drug due to a constricted mobility since normally only short spacer molecule like aminopropyltrimethoxysilane (APMS) are used for drug coupling. This work aimed to study covalent attachment of heparin to titanium(oxide) surfaces by varying the length of the silane coupling agent, which should affect the biological potency of the drug due to a higher mobility with longer spacer chains.

Methods

Covalent attachment of heparin to titanium metal and TiO2 powder was carried out using the coupling agents 3-(Trimethoxysilyl)-propylamine (APMS), N- [3-(Trimethoxysilyl)propyl]ethylenediamine (Diamino-APMS) and N
1- [3-(Trimethoxy-silyl)-propyl]diethylenetriamine (Triamino-APMS). The amount of bound coupling agent and heparin was quantified photometrically by the ninhydrin reaction and the tolidine-blue test. The biological potency of heparin was determined photometrically by the chromogenic substrate Chromozym TH and fibrinogen adsorption to the modified surfaces was researched using the QCM-D (Quartz Crystal Microbalance with Dissipation Monitoring) technique.

Results

Zeta-potential measurements confirmed the successful coupling reaction; the potential of the unmodified anatase surface (approx. -26 mV) shifted into the positive range (> + 40 mV) after silanisation. Binding of heparin results in a strongly negatively charged surface with zeta-potentials of approx. -39 mV. The retaining biological activity of heparin was highest for the spacer molecule Triamino-APMS. QCM-D measurements showed a lower viscosity for adsorbed fibrinogen films on heparinised surfaces by means of Triamino-APMS.

Conclusion

The remaining activity of heparin was found to be highest for the covalent attachment with Triamino-APMS as coupling agent due to the long chain of this spacer molecule and therefore the highest mobility of the drug. Furthermore, the adsorption of fibrinogen on the differently heparinised surfaces in real time demonstrated that with longer spacer chains the ΔD/Δf ratios became higher, which is also associated with better biocompatible properties of the substrates in contact with a biosystem.
Lola regulates Drosophila olfactory projection neuron identity and targeting specificity
Authors: Spletter Maria Lynn , Liu Jian , Liu Justin , Su Helen , Giniger Edward , Komiyama Takaki , Quake Stephen , Luo Liqun
Published: July 2007

Background

Precise connections of neural circuits can be specified by genetic programming. In the Drosophila olfactory system, projection neurons (PNs) send dendrites to single glomeruli in the antenna lobe (AL) based upon lineage and birth order and send axons with stereotyped terminations to higher olfactory centers. These decisions are likely specified by a PN-intrinsic transcriptional code that regulates the expression of cell-surface molecules to instruct wiring specificity.

Results

We find that the loss of longitudinals lacking (lola), which encodes a BTB-Zn-finger transcription factor with 20 predicted splice isoforms, results in wiring defects in both axons and dendrites of all lineages of PNs. RNA in situ hybridization and quantitative RT-PCR suggest that most if not all lola isoforms are expressed in all PNs, but different isoforms are expressed at widely varying levels. Overexpression of individual lola isoforms fails to rescue the lola null phenotypes and causes additional phenotypes. Loss of lola also results in ectopic expression of Gal4 drivers in multiple cell types and in the loss of transcription factor gene lim1 expression in ventral PNs.

Conclusion

Our results indicate that lola is required for wiring of axons and dendrites of most PN classes, and suggest a need for its molecular diversity. Expression pattern changes of Gal4 drivers in lola-/- clones imply that lola normally represses the expression of these regulatory elements in a subset of the cells surrounding the AL. We propose that Lola functions as a general transcription factor that regulates the expression of multiple genes ultimately controlling PN identity and wiring specificity.
The effect of psychosocial factors on breast cancer outcome: a systematic review
Authors: Falagas Matthew E , Zarkadoulia Effie A , Ioannidou Eleni N , Peppas George , Christodoulou Christos , Rafailidis Petros I
Published: July 2007

Introduction

We sought to review the available evidence regarding the effect of psychosocial factors on the survival of breast cancer patients.

Methods

We systematically searched the PubMed and PsycINFO databases to identify relevant studies.

Results

We identified 31 studies examining the association of various psychosocial parameters with overall breast cancer survival/disease free survival and 6 studies examining whether psychological intervention influences the disease outcome. Of the 31 studies summarized in this overview, 25 (80.6%) showed a statistically significant association between at least one psychosocial variable and disease outcome. Parameters associated with better breast cancer prognosis are social support, marriage, and minimizing and denial, while depression and constraint of emotions are associated with decreased breast cancer survival; however, the role of these factors has not been verified in all studies.

Conclusion

Most of the studies show a significant relationship between psychosocial factors and survival, but the actual psychosocial variables related to survival are not consistently measured across studies and the findings for many of the psychosocial variables with survival/recurrence are not consistent across studies. Thus, more research is warranted regarding the role of social support, marriage, minimizing and denial, depression and constraint of emotions on breast cancer survival.
Back to the Future? Diabetes, Hiv, and the Boundaries of Public Health
Authors: Fairchild Amy L. , Alkon Ava
Published: July 2007

The control of infectious diseases has traditionally fallen to public health and the clinical care of chronic diseases to private medicine. In New York City, however, the Department of Health and Mental Hygiene (DOHMH) has recently sought to expand its responsibilities in the oversight and management of chronic-disease care. In December 2005, in an effort to control epidemic rates of diabetes, the DOHMH began implementing a bold new plan for increased disease surveillance through electronic, laboratory-based reporting of A1C test results (a robust measure of blood-sugar levels). The controversy A1C reporting produced was relatively contained, but when Dr. Thomas Frieden, New York City health commissioner, called for the state to begin tracking viral loads and drug resistance among patients with HIV, both the medical community and a wider public took notice and have started to grapple with the meaning of expanded surveillance. In the context of the past century of medical surveillance in America, we analyze the current debates, focusing first on diabetes and then HIV. We identify the points of contention that arise from the city's proposed blend of public health surveillance, disease management, and quality improvement and suggest an approach to balancing the measures' perils and promises.
A new fatigue test procedure for die-casting tool materials
Authors: Norwood A J , Dickens P M , Soar R C , Harris R A
Published: July 2007

The objective of this research was to investigate a new test procedure for simulating the temperatures in die casting so that materials can be evaluated as tool materials for the high-pressure die casting of aluminium. Other procedures have been used for evaluating the thermal fatigue performance of tool materials, but these tests do not reproduce all the conditions found in production environments. A new test method has been established that enables the thermal fatigue resistance of materials to be identified. The test is robust, reliable, and versatile and has a large operating temperature range (25–1200°C), and the cycle times and dwell times are adjustable. The results have shown a similar number of cycles to induce the same level of fatigue cracking as in actual die-casting tools. The performance of different materials can be compared, and an approximate fatigue life for high-pressure die-casting tools can be determined.
Water Soluble Single-walled Carbon Nanotubes Using Inclusion Complex of Cyclodextrin with an Adamantane Derivative
Authors: Ogoshi Tomoki , Yamagishi Tada-aki , Nakamoto Yoshiaki , Harada Akira
Published: July 2007

Single-walled carbon nanotubes (SWNTs) were soluble in aqueous media by using host–guest complex between sodium adamantanecarboxylate (AdCNa) and β-cyclodextrin (β-CD), while SWNTs were insoluble with AdCNa or β-CD.
Synthesis and Helical Structure of Oligo(quinoline-2,3-diyl)s
Authors: Suginome Michinori , Noguchi Hiroyoshi , Murakami Masahiro
Published: July 2007

Oligo(quinoline-2,3-diyl)s having a terminal bromo group were synthesized by the Suzuki–Miyaura coupling of 5,8-disubstituted 2-bromoquinolin-3-ylboronic acid derivatives, and their helical structures were elucidated by a single-crystal X-ray analysis of the hexamer, UV measurements, and induction of a non-racemic helical sense by introduction of a chiral end group.
Enantioselective Recognition of Calix[5]arene-based Artificial Receptor Bearing Chiral Macrocycle for Chiral Ethyltrimethylammonium Salts
Authors: Haino Takeharu , Fukuoka Hiroyuki , Katayama Masakazu , Fukazawa Yoshimasa
Published: July 2007

Calix[5]arene-based artificial receptor 1 capped with chiral macrocycle 4 was synthesized and showed strong binding toward ethyltrimethylammonium salts via cation/π and hydrogen-bonding interactions. The calix[5]arene cavity provided the dissymmetric guest-binding environment in which chiral guests 6–14 were encapsulated in an enantioselective fashion.
Creativity as a Determinant of Thinking Style in Police Investigations
Authors: Dean Geoff , Fahsing Ivar Andre , Gottschalk Petter
Published: July 2007

This paper is concerned with how police detectives experience, understand, and think about the process of doing serious and complex criminal investigations. Imagination and creativity are considered inevitably essential components of this process. Investigative thinking by detectives is classified into four styles: method, challenge, skill and risk style. Some of these styles are expected to require more creativity than other styles. Our research proposition suggests that more creative detectives apply higher investigative thinking styles. Support for this proposition was found in empirical evidence collected among police investigators in Norway, as both the skill style and risk style were significantly related to the extent of creativity.