bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dll4 activation of Notch signaling reduces tumor vascularity and inhibits tumor growth
Authors: Segarra Marta , Williams Cassin Kimmel , Sierra Maria de la Luz , Bernardo Marcelino , McCormick Peter J. , Maric Dragan , Regino Celeste , Choyke Peter , Tosato Giovanna 
Published: June 2008

AbstractGene targeting experiments have shown that Delta-like 4 (Dll4) is a vascular-specific Notch ligand critical to normal vascular development. Recent studies have demonstrated that inhibition of Dll4/Notch signaling in tumor-bearing mice resulted in excessive, yet nonproductive tumor neovascularization and unexpectedly reduced tumor growth. Because nonfunctional blood vessels have the potential to normalize, we explored the alternative approach of stimulating Notch signaling in the tumor vasculature to inhibit tumor growth. Here we show that retrovirus-induced over-expression of Dll4 in tumor cells activates Notch signaling in cocultured endothelial cells and limits vascular endothelial growth factor (VEGF)–induced endothelial cell growth. Tumors produced in mice by injection of human and murine tumor cells transduced with Dll4 were significantly smaller, less vascularized and more hypoxic than controls, and displayed evidence of Notch activation. In addition, tumor blood perfusion was reduced as documented by vascular imaging. These results demonstrate that Notch activation in the tumor microenvironment reduces tumor neovascularization and blood perfusion, and suggest that Dll4-induced Notch activation may represent an effective therapeutic approach for the treatment of solid tumors.
Histopathology of experimentally induced asthma in a murine model of sickle cell disease
Authors: Nandedkar Sandhya D. , Feroah Thomas R. , Hutchins William , Weihrauch Dorothee , Konduri Kameswari S. , Wang Jingli , Strunk Robert C. , DeBaun Michael R. , Hillery Cheryl A. , Pritchard Kirkwood A. 
Published: June 2008

Abstract
Asthma is a comorbid condition associated with increased rates of pain, acute chest syndrome, and premature death in human sickle cell disease (SCD). We developed an experimental asthma model in SCD and control mice expressing either normal human or murine hemoglobin to determine its effect on mortality and lung pathology. To induce lung inflammation, experimental mice were sensitized to ovalbumin (OVA) by subcutaneous OVA implantation (Sen), allowed 2 weeks to recover, and then divided into 2 groups, each receiving over a subsequent 10-day period the same dosage of aerosolized OVA but 2 different levels of exposure: 15 minutes (LoSen) and 30 minutes (HiSen). During recovery, 10% of SCD mice died compared with no deaths in control mice. An additional 30% of HiSen SCD mice died during aerosolization compared with 10% in LoSen SCD. Histologic indices of lung inflammation (eg, eosinophil recruitment, airway and vessel wall thickening, and immunoreactive TGFβ and fsp-1) and bronchial alveolar lavage fluid eosinophil peroxidase activity differentially increased in sensitized mice compared with unsensitized mice. Our findings indicate SCD mice with experimentally induced asthma are more susceptible to death and pulmonary inflammation compared with control mice, suggesting that asthma contributes significantly to morbidity and mortality in SCD.
Biochemical characterization and cellular imaging of a novel, membrane permeable fluorescent cAMP analog
Authors: Moll Daniela , Prinz Anke , Brendel Cornelia M , Berrera Marco , Guske Katrin , Zaccolo Manuela , Genieser Hans-Gottfried , Herberg Friedrich W 
Published: June 2008

Abstract

Background
A novel fluorescent cAMP analog (8-[Pharos-575]- adenosine-3', 5'-cyclic monophosphate) was characterized with respect to its spectral properties, its ability to bind to and activate three main isoenzymes of the cAMP-dependent protein kinase (PKA-Iα, PKA-IIα, PKA-IIβ) in vitro, its stability towards phosphodiesterase and its ability to permeate into cultured eukaryotic cells using resonance energy transfer based indicators, and conventional fluorescence imaging.

Results
The Pharos fluorophore is characterized by a Stokes shift of 42 nm with an absorption maximum at 575 nm and the emission peaking at 617 nm. The quantum yield is 30%. Incubation of the compound to RIIα and RIIβ subunits increases the amplitude of excitation and absorption maxima significantly; no major change was observed with RIα. In vitro binding of the compound to RIα subunit and activation of the PKA-Iα holoenzyme was essentially equivalent to cAMP; RII subunits bound the fluorescent analog up to ten times less efficiently, resulting in about two times reduced apparent activation constants of the holoenzymes compared to cAMP. The cellular uptake of the fluorescent analog was investigated by cAMP indicators. It was estimated that about 7 μM of the fluorescent cAMP analog is available to the indicator after one hour of incubation and that about 600 μM of the compound had to be added to intact cells to half-maximally dissociate a PKA type IIα sensor.

Conclusion
The novel analog combines good membrane permeability- comparable to 8-Br-cAMP – with superior spectral properties of a modern, red-shifted fluorophore. GFP-tagged regulatory subunits of PKA and the analog co-localized. Furthermore, it is a potent, PDE-resistant activator of PKA-I and -II, suitable for in vitro applications and spatial distribution evaluations in living cells.
Automated discovery and phylogenetic analysis of new toxin-antitoxin systems
Authors: Guglielmini Julien , Szpirer Cédric , Milinkovitch Michel C 
Published: June 2008

Abstract

Background
Although often viewed as elements "at the service of" bacteria, plasmids exhibit replication and maintenance mechanisms that make them purely "selfish DNA" candidates. Toxin-antitoxin (TA) systems are a spectacular example of such mechanisms: a gene coding for a cytotoxic stable protein is preceded by a gene coding for an unstable antitoxin. The toxin being more stable than the antitoxin, absence of the operon causes a reduction of the amount of the latter relative to the amount of the former. Thus, a cell exhibiting a TA system on a plasmid is 'condemned' either not to loose it or to die.

Results
Different TA systems have been described and classified in several families, according to similarity and functional parameters. However, given the small size and large divergence among TA system sequences, it is likely that many TA systems are not annotated as such in the rapidly accumulating NCBI database. To detect these putative TA systems, we developed an algorithm that searches public databases on the basis of predefined similarity and TA-specific structural constraints. This approach, using a single starting query sequence for each of the ParE, Doc, and VapC families, and two starting sequences for the MazF/CcdB family, identified over 1,500 putative TA systems. These groups of sequences were analyzed phylogenetically for a better classification and understanding of TA systems evolution.

Conclusion
The phylogenetic distributions of the newly uncovered TA systems are very different within the investigated families. The resulting phylogenetic trees are available for browsing and searching through a java program available at http://ueg.ulb.ac.be/tiq/.
Depression and anxiety in relation to catechol-O-methyltransferase Val158Met genotype in the general population: The Nord-Trøndelag Health Study (HUNT)
Authors: Bækken Petter M , Skorpen Frank , Stordal Eystein , Zwart John-Anker , Hagen Knut 
Published: June 2008

Abstract

Background
The catechol-O-methyltransferase (COMT) gene contains a functional polymorphism, Val158Met, which has been linked to anxiety and depression, but previous results are not conclusive. The aim of the present study was to examine the relationship between the Val158Met COMT gene polymorphism and anxiety and depression measured by the Hospital Anxiety and Depression Scale (HADS) in the general adult population.

Methods
In the Nord-Trøndelag Health Study (HUNT) the association between the Val158Met polymorphism and anxiety and depression was evaluated in a random sample of 5531 individuals. Two different cut off scores (≥ 8 and ≥ 11) were used to identify cases with anxiety (HADS-A) and depression (HADS-D), whereas controls had HADS-A <8 and HADS-D <8.

Results
The COMT genotype distribution was similar between controls and individuals in the groups with anxiety and depression using cut-off scores of ≥ 8. When utilizing the alternative cut-off score HADS-D ≥ 11, Met/Met genotype and Met allele were less common among men with depression compared to the controls (genotype: p = 0.017, allele: p = 0.006). In the multivariate analysis, adjusting for age and heart disease, depression (HADS-D ≥ 11) was less likely among men with the Met/Met genotype than among men with the Val/Val genotype (OR = 0.37, 95% CI = 0.18–0.76).

Conclusion
In this population-based study, no clear association between the Val158Met polymorphism and depression and anxiety was revealed. The Met/Met genotype was less likely among men with depression defined as HADS-D ≥ 11, but this may be an incidental finding.
Proteomic profiling of urine for the detection of colon cancer
Authors: Ward Douglas G , Nyangoma Stephen , Joy Howard , Hamilton Emma , Wei Wenbin , Tselepis Chris , Steven Neil , Wakelam Michael JO , Johnson Philip J , Ismail Tariq , Martin Ashley 
Published: June 2008

AbstractBackgroundColorectal cancer is the second most common cause of cancer related death in the developed world. To date, no blood or stool biomarkers with both high sensitivity and specificity for potentially curable early stage disease have been validated for clinical use. SELDI and MALDI profiling are being used increasingly to search for biomarkers in both blood and urine. Both techniques provide information predominantly on the low molecular weight proteome (<15 kDa). There have been several reports that colorectal cancer is associated with changes in the serum proteome that are detectable by SELDI and we hypothesised that proteomic changes would also be detectable in urine.ResultsWe collected urine from 67 patients with colorectal cancer and 72 non-cancer control subjects, diluted to a constant protein concentration and generated MALDI and SELDI spectra. The intensities of 19 peaks differed significantly between cancer and non-cancer patients by both t-tests and after adjusting for confounders using multiple linear regressions. Logistic regression classifiers based on peak intensities identified colorectal cancer with up to 78% sensitivity at 87% specificity. We identified and independently quantified 3 of the discriminatory peaks using synthetic stable isotope peptides (an 1885 Da fragment of fibrinogen and hepcidin-20) or ELISA (β2-microglobulin).ConclusionChanges in the urine proteome may aid in the early detection of colorectal cancer.
Intraoperative frozen section assessment of sentinel lymph nodes in the operative management of women with symptomatic breast cancer
Authors: Ali Rohanna , Hanly Ann M , Naughton Peter , Castineira Constantino F , Landers Rob , Cahill Ronan A , Watson R Gordon 
Published: June 2008

Abstract

Background
Maximisation of the potential of sentinel lymph node biopsy as a minimally invasive method of axillary staging requires sensitive intraoperative pathological analysis so that rates of re-operation for lymphatic metastases are minimised. The aim of this study was to describe the test parameters of the frozen section evaluation of sentinel node biopsy for breast cancer compared to the gold standard of standard permanent pathological evaluation at our institution.

Methods
The accuracy of intraoperative frozen section (FS) of sentinel nodes was determined in 94 consecutive women undergoing surgery for clinically node negative, invasive breast cancer (37:T1 disease; 43:T2; 14:T3). Definitive evidence of lymphatic spread on FS indicated immediate level II axillary clearance while sentinel node "negativity" on intraoperative testing led to the operation being curtailed to allow formal H&E analysis of the remaining sentinel nodal tissue.

Results
Intraoperative FS correctly predicted axillary involvement in 23/30 patients with lymphatic metastases (76% sensitivity rate) permitting definitive surgery to be completed at the index operation in 87 women (93%) overall. All SN found involved on FS were confirmed as harbouring tumour cells on subsequent formal specimen examination (100% specificity and positive predictive value) with 16 patients having additional non-sentinel nodes found also to contain tumour. Negative Predictive Values were highest in women with T1 tumours (97%) and lessened with more local advancement of disease (T2 rates: 86%; T3: 75%). Of those with falsely negative FS, three had only micrometastatic disease.

Conclusion
Intraoperative FS reliably evaluates the status of the sentinel node allowing most women complete their surgery in a single stage. Thus SN can be offered with increased confidence to those less likely to have negative axillae hence expanding the population of potential beneficiaries.
Glucose metabolism in lymphocytes is a regulated process with significant effects on immune cell function and survival
Authors: MacIver Nancie J , Jacobs Sarah R , Wieman Heather L , Wofford Jessica A , Coloff Jonathan L , Rathmell Jeffrey C 
Published: June 2008

AbstractLymphocytes require glucose uptake and metabolism for normal survival and function. The signals that regulate the expression and localization of glucose transporter 1 (Glut1) to allow glucose uptake in T cells are now beginning to be understood. Resting T cells require extracellular signals, such as cytokines, hormones, and growth factors, or low-level TCR stimulation to take up adequate glucose to maintain housekeeping functions. In the absence of extrinsic signals, resting T cells internalize and degrade Glut1 and cannot maintain viability. Activated T cells have dramatically increased metabolic requirements to support the energy and biosynthetic needs necessary for growth, proliferation, and effector function. In particular, glucose metabolism and aerobic glycolysis fuel this demand. Therefore, activation of T cells causes a large increase in Glut1 expression and surface localization. If glucose uptake is limited, glycolytic flux decreases to a level that no longer sustains viability, and proapoptotic Bcl-2 family members become activated, promoting cell death. However, excessive glucose uptake can promote hyperactive immune responses and possible immune pathology. Tight regulation of glucose uptake is required to maintain immune homeostasis, and understanding of these metabolic pathways may lead to therapeutic strategies to target some forms of cancer or autoimmunity.
Differential turnover rates of monocyte-derived cells in varied ocular tissue microenvironments
Authors: Kezic Jelena , McMenamin Paul G 
Published: June 2008

AbstractMonocytes of bone marrow (BM) origin are circulating precursors that replenish dendritic cells and macrophage populations in peripheral tissues during homeostasis. The eye provides a unique range of varying tissue microenvironments in which to compare the different turnover rates of monocyte-derived cells. This was investigated in the present study using radiation chimeras, whereby BM from Cx3cr1+/gfp mice was used to rescue myeloablated wild-type (WT) BALB/c mice (conventional chimeras). The use of Cx3cr1+/gfp mice as BM donors allowed the clear visualization of newly recruited monocyte-derived cells. Following BM reconstitution, mice were killed at 2, 4, 6, and 8 weeks, and wholemount ocular tissues were processed for immunohistochemistry and confocal microscopy. “Reverse” chimeras (WT into Cx3cr1+/gfp) were also created to act as a further method of cross-referencing cell turnover rates. In conventional chimeras, Cx3cr1+/gfp cells began repopulating the uveal tract (iris, ciliary body, choroid) 2 weeks post-transplantation with close to complete replenishment by 8 weeks. By contrast, the earliest recruitment of Cx3cr1+/gfp cells into the host retina occurred at 4 weeks. In reverse chimeras, a steady accumulation of host Cx3cr1+/gfp macrophages in the subretinal space of Cx3cr1+/gfp adult mice suggests that these cells arise from long-term resident microglia and not newly recruited WT donor cells. In summary, chimeric mouse models, in which lineage-specific cells carry a fluorescent reporter, have been used in the present study to visualize the turnover of monocyte-derived cells in different tissue compartments of the eye. These data provide valuable insights into differential monocyte turnover rates within a single complex organ.
Ethical Exception: Capital Punishment in the Figure of Sovereignty
Authors: Thurschwell Adam 
Published: June 2008

Capital punishment has been analyzed in recent Anglo-American jurisprudence as a problem of moral rather than political philosophy—as a question of when, if ever, the heinousness of a crime justifies the imposition of death as a matter of retributive justice; when, if ever, the deterrent consequences of a sentence of death will outweigh the punishment's deleterious consequences from a utilitarian perspective; and so on. Yet, even the most cursory examination of the cultural, legal, and political roles of capital punishment as it is actually institutionalized (or not institutionalized) and practiced (or not practiced) around the world today demonstrates that this theoretical orientation gets it precisely backward—the most fundamental issues are neither individual nor moral but the profoundly political ones of the constitution and exercise of state sovereignty.
Beginning with Michel Foucault's discussion of capital punishment (which forms one part of his analysis of the nature of political sovereignty) and some recent work by U.S. legal academics that echoes Foucault's discussion (not always consciously), this essay attempts to show how such a shift from the moral perspective to a political-philosophical perspective might be effected and to demonstrate both the theoretical-explanatory and prescriptive-practical benefits of such a change in viewpoint.
Crystal Structure of Boryllithium with Two THF Molecules and DFT Analysis of Its Property as a Boryl Anion
Authors: Yamashita Makoto , Suzuki Yuta , Segawa Yasutomo , Nozaki Kyoko 
Published: June 2008

Abstract
The second crystal structure of boryllithium 2 with two coordinating THF solvent molecules was obtained. The 11B NMR chemical shift of a THF solution, made by dissolving single crystals of 2·(THF)2 in THF-d8, significantly and reversibly changed depending on temperature (from 20 to −100 °C). The calculated 11B chemical shift by GIAO method was close to two experimental values. The character of the sp2 lone pair on the boron center in opt-2·(THF)2 was shown to be similar to those in the calculated free phenyl anion and boryl anion. AIM analyses for opt-2·(THF)2 suggested that the B–Li bond of boryllithium is polarized, similar to the C–Li bond of alkyllithium.
Does HbA1C predict isolated impaired fasting glycaemia in the oral glucose tolerance test in subjects with impaired fasting glycaemia?
Authors: Likhari Taruna , Aulakh T S , Singh Baldev M , Gama R 
Published: June 2008

Background To assess the usefulness of erythrocyte glycated haemoglobin (HbA1C) as a screening tool to identify those subjects with impaired fasting glycaemia (IFG) who do not have impaired glucose tolerance (IGT) or diabetes mellitus (DM) on a 75 g oral glucose tolerance test (OGTT). Design and methods All subjects undergoing an OGTT had HbA1C measured at baseline. Receiver operator characteristics analysis was used to identify optimal HbA1C cut-off values for diagnosing and excluding IGT and DM. Results We studied 140 subjects (69 women) with IFG (fasting capillary plasma glucose between 6.1–6.9 mmol/L). Using World Health Organisation criteria, 27 had isolated IFG, 56 had IGT and 57 had DM. HbA1C was higher ( P < 0.001) in patients with DM (6.8 ± 0.93%) when compared with those with IGT (6.3 ± 0.68%) and isolated IFG (6.2 ± 0.30%), but HbA1C was similar in those with IGT and isolated IFG. There was no HbA1C cut-off value differentiating isolated IFG from IGT or DM. None of the subjects with isolated IFG had HbA1C concentration of >6.8%, but 76% and 54% subjects with IGT and DM, respectively, had HbA1C of ≤6.8%. Conclusions HbA1C measurement is of limited value in differentiating isolated IFG, IGT and DM in subjects with IFG. It cannot be used to identify which subjects with IFG do not require an OGTT.
2007 Guideline Update for Unstable Angina/Non–ST-Segment Elevation Myocardial Infarction: Focus on Antiplatelet and Anticoagulant Therapies
Authors: Coons James C , Battistone Sarah 
Published: June 2008

Objective: To summarize key changes in the 2007 American College of Cardiology/American Heart Association (ACC/AHA) guideline recommendations for pharmacologic therapy as they relate to antiplatelets and anticoagulants, and to evaluate the evidence from several landmark trials that was used to support the guideline updates for these agents. Data Sources: Literature was accessed through MEDLINE (1950–January 2008) using the search terms acute coronary syndromes, unstable angina (UA), non–ST-segment elevation myocardial infarction (NSTEMI), antiplatelet, and anticoagulant. All papers were cross-referenced to identify additional studies, Study Selection and Data Extraction: ACC/AHA guidelines, relevant original research articles, and review articles were evaluated. Studies with more than 1000 patients were the focus of the review. Data Synthesis: UA and NSTEMI are the most common presentations of acute coronary syndrome. The recently updated ACC/AHA guidelines for management of this condition were based on significant advances in pharmacotherapy including expanded use of drug-eluting stents, pretreatment with Clopidogrel, and newer anticoagulants such as bivalirudin and fondaparinux. Landmark trials have been published that describe advances in the use of antiplatelets and anticoagulants. According to the guidelines, unfractionated heparin (UFH) and enoxaparin are preferred options for both invasive and conservative management. Enoxaparin was noninferior to UFH for invasive management in the SYNERGY trial, although it was associated with a higher incidence of bleeding. Other alternatives for an invasive strategy per the guidelines include bivalirudin and fondaparinux. Bivalirudin (alone or with glycoprotein [GPJ llb/llla inhibitor) was compared with heparin plus GP llb/llla inhibitor in the ACUfTY trial of patients undergoing early invasive management. The bivalirudin groups were noninferior to standard of care, although bivalirudin alone was associated with less bleeding. Fondaparinux was found to be noninferior to enoxaparin and was associated with fewer bleeding events in the OASIS-5 study of patients who were not treated with an early invasive approach. Accordingly, the guidelines list fondaparinux as an alternative for a conservative strategy or in patients at increased risk of bleeding. Conclusions: Clinicians should be familiar with the updated 2007 ACC/AHA guidelines and the clinical trial evidence that serves as the basis for these recommendations. It is paramount for institutions to outline a preferred and consistent treatment approach. These decisions should Involve a review of established efficacy, bleeding risk, need for anticoagulant reversal, costs, and clinician familiarity with different treatment regimens.