bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selenium sensitizes MCF-7 breast cancer cells to doxorubicin-induced apoptosis through modulation of phospho-Akt and its downstream substrates
Authors: Li Song , Zhou Yunfei , Wang Ruiwen , Zhang Haitao , Dong Yan , Ip Clement 
Published: March 2007

Abstract
Doxorubicin is an effective drug against breast cancer. However, the favorable therapeutic response to doxorubicin is often associated with severe toxicity. The present research was aimed at developing a strategy of increasing doxorubicin sensitivity so that lower doses may be used without compromising efficacy. The MCF-7 human breast cancer cell line currently in use in our laboratory did not respond to doxorubicin cell killing during a 24-h treatment period. By combining doxorubicin with selenium, we were successful in producing a brisk enhancement of apoptosis. We examined the effects of these two agents on Akt activation and found that selenium was capable of depressing doxorubicin-induced Akt phosphorylation. Several lines of evidence converged to support the notion that this effect is important in mediating the synergy between selenium and doxorubicin. Selenium was no longer able to sensitize cells to doxorubicin under a condition in which Akt was constitutively activated. Increased Akt phosphorylation following treatment with doxorubicin was accompanied by increased phosphorylation of glycogen synthase kinase 3β (GSK3β) and FOXO3A, which are substrates of Akt (both GSK3β and FOXO3A lose their proapoptotic activities when they are phosphorylated). Selenium reduced the abundance of phospho-GSK3β induced by doxorubicin, whereas chemical inhibition of GSK3β activity muted the apoptotic response to the selenium/doxorubicin combination. Additional experiments showed that selenium increased the transactivation activity of FOXO3A, as evidenced by a reporter gene assay, as well as by the elevated expression of Bim (a target gene of FOXO3A). The functional significance of Bim was confirmed by the observation that RNA interference of Bim markedly reduced the potency of selenium/doxorubicin to induce apoptosis. [Mol Cancer Ther 2007;6(3):OF1–8
Adiponectin Cardioprotection After Myocardial Ischemia/Reperfusion Involves the Reduction of Oxidative/Nitrative Stress
Authors: Tao Ling , Gao Erhe , Jiao Xiangying , Yuan Yuexing , Li Shuzhuang , Christopher Theodore A. , Lopez Bernard L. , Koch Walter , Chan Lawrence , Goldstein Barry J. , Ma Xin L. 
Published: March 2007

Background—Several clinical studies have demonstrated that levels of adiponectin are significantly reduced in patients with type 2 diabetes and that adiponectin levels are inversely related to the risk of myocardial ischemia. The present study was designed to determine the mechanism by which adiponectin exerts its protective effects against myocardial ischemia/reperfusion.Methods and Results—Adiponectin−/−or wild-type mice were subjected to 30 minutes of myocardial ischemia followed by 3 hours or 24 hours (infarct size and cardiac function) of reperfusion. Myocardial infarct size and apoptosis, production of peroxynitrite, nitric oxide (NO) and superoxide, and inducible NO synthase (iNOS) and gp91phoxprotein expression were compared. Myocardial apoptosis and infarct size were markedly enhanced in adiponectin−/−mice (P<0.01). Formation of NO, superoxide, and their cytotoxic reaction product, peroxynitrite, were all significantly higher in cardiac tissue obtained from adiponectin−/−than from wild-type mice (P<0.01). Moreover, myocardial ischemia/reperfusion–induced iNOS and gp91phoxprotein expression was further enhanced, but endothelial NOS phosphorylation was reduced in cardiac tissue from adiponectin−/−mice. Administration of the globular domain of adiponectin 10 minutes before reperfusion reduced myocardial ischemia/reperfusion–induced iNOS/gp91phoxprotein expression, decreased NO/superoxide production, blocked peroxynitrite formation, and reversed proapoptotic and infarct-enlargement effects observed in adiponectin−/−mice.Conclusion—The present study demonstrates that adiponectin is a natural molecule that protects hearts from ischemia/reperfusion injury by inhibition of iNOS and nicotinamide adenine dinucleotide phosphate-oxidase protein expression and resultant oxidative/nitrative stress.
Direct Myocardial Effects of Levosimendan in Humans With Left Ventricular Dysfunction
Authors: Givertz Michael M. , Andreou Costa , Conrad Chester H. , Colucci Wilson S. 
Published: March 2007

Background—Enthusiasm for the development of Ca2+sensitizers as inotropic agents for heart failure has been tempered by reports of impaired relaxation. Levosimendan, which increases myofilament Ca2+sensitivity via Ca2+-dependent binding to troponin C, exerts positive inotropic and lusitropic effects in failing human myocardium in vitro. We sought to determine the direct effects of levosimendan on failing human myocardium in vivo, and in particular whether levosimendan exerts heart rate–dependent effects on systolic or diastolic function.Methods and Results—Ten patients with left ventricular dysfunction caused by nonischemic dilated cardiomyopathy (mean left ventricular ejection fraction, 27±2%) were instrumented with an infusion catheter in the left main coronary artery, a high-fidelity micromanometer-tipped catheter in the left ventricle, and a bipolar pacing wire in the right atrium. Inotropic (peak +dP/dt) and lusitropic (Tau) responses were assessed during continuous intracoronary drug infusion in sinus rhythm followed by atrial pacing at 20, 40, and 60 beats per minute above the sinus rate. Under control conditions (intracoronary 5% dextrose in water), atrial-pacing tachycardia decreased Tau by 13% (P<0.05), but did not increase +dP/dt. Intracoronary levosimendan (3.75 and 12.5 μg/min for 15 minutes each) increased +dP/dt dose-dependently and decreased Tau over a range of heart rates, but did not alter the slope of the force-frequency or relaxation-frequency relationship.Conclusions—Myocardial calcium sensitization with levosimendan exerts mild inotropic and lusitropic effects in humans with left ventricular dysfunction, but does not alter the force-frequency or relaxation-frequency relationship.
TLR3 ligand stimulates fully functional memory CD8+ T cells in the absence of CD4+ T-cell help
Authors: Hervas-Stubbs Sandra , Olivier Aurélie , Boisgerault Florence , Thieblemont Nathalie , Leclerc Claude 
Published: March 2007

AbstractWe investigated whether Toll-like receptor ligands (TLR-Ls) can bypass the requirement for CD4+ T-cell help in the induction of fully efficient memory CD8+ T cells (cytotoxic T lymphocytes [CTLs]). “Helpless” CTLs were induced by a synthetic CD8+ T-cell epitope administered with TLR3-L and TLR9-L, but not with TLR2/6-L, TLR4-L, or TLR7-L. The up-regulation of MHC-I and costimulatory molecules by dendritic cells following TLR stimulation was not sufficient for the priming of “helpless” CTLs, which depended essentially on the induction of a strong IFN-α/β response. The “helpless” CTLs induced by TLR-Ls differentiated into fully functional memory CTLs able to proliferate as well as their “helped” counterparts upon challenge, in the absence of CD4+ T-cell help.
Structural and evolutionary bioinformatics of the SPOUT superfamily of methyltransferases
Authors: Tkaczuk Karolina L , Dunin-Horkawicz Stanislaw , Purta Elzbieta , Bujnicki Janusz M 
Published: March 2007

Abstract

Background
SPOUT methyltransferases (MTases) are a large class of S-adenosyl-L-methionine-dependent enzymes that exhibit an unusual alpha/beta fold with a very deep topological knot. In 2001, when no crystal structures were available for any of these proteins, Anantharaman, Koonin, and Aravind identified homology between SpoU and TrmD MTases and defined the SPOUT superfamily. Since then, multiple crystal structures of knotted MTases have been solved and numerous new homologous sequences appeared in the databases. However, no comprehensive comparative analysis of these proteins has been carried out to classify them based on structural and evolutionary criteria and to guide functional predictions.

Results
We carried out extensive searches of databases of protein structures and sequences to collect all members of previously identified SPOUT MTases, and to identify previously unknown homologs. Based on sequence clustering, characterization of domain architecture, structure predictions and sequence/structure comparisons, we re-defined families within the SPOUT superfamily and predicted putative active sites and biochemical functions for the so far uncharacterized members. We have also delineated the common core of SPOUT MTases and inferred a multiple sequence alignment for the conserved knot region, from which we calculated the phylogenetic tree of the superfamily. We have also studied phylogenetic distribution of different families, and used this information to infer the evolutionary history of the SPOUT superfamily.

Conclusion
We present the first phylogenetic tree of the SPOUT superfamily since it was defined, together with a new scheme for its classification, and discussion about conservation of sequence and structure in different families, and their functional implications. We identified four protein families as new members of the SPOUT superfamily. Three of these families are functionally uncharacterized (COG1772, COG1901, and COG4080), and one (COG1756 represented by Nep1p) has been already implicated in RNA metabolism, but its biochemical function has been unknown. Based on the inference of orthologous and paralogous relationships between all SPOUT families we propose that the Last Universal Common Ancestor (LUCA) of all extant organisms contained at least three SPOUT members, ancestors of contemporary RNA MTases that carry out m1G, m3U, and 2'O-ribose methylation, respectively. In this work we also speculate on the origin of the knot and propose possible 'unknotted' ancestors. The results of our analysis provide a comprehensive 'roadmap' for experimental characterization of SPOUT MTases and interpretation of functional studies in the light of sequence-structure relationships.
An efficient grid layout algorithm for biological networks utilizing various biological attributes
Authors: Kojima Kaname , Nagasaki Masao , Jeong Euna , Kato Mitsuru , Miyano Satoru 
Published: March 2007

Abstract

Background
Clearly visualized biopathways provide a great help in understanding biological systems. However, manual drawing of large-scale biopathways is time consuming. We proposed a grid layout algorithm that can handle gene-regulatory networks and signal transduction pathways by considering edge-edge crossing, node-edge crossing, distance measure between nodes, and subcellular localization information from Gene Ontology. Consequently, the layout algorithm succeeded in drastically reducing these crossings in the apoptosis model. However, for larger-scale networks, we encountered three problems: (i) the initial layout is often very far from any local optimum because nodes are initially placed at random, (ii) from a biological viewpoint, human layouts still exceed automatic layouts in understanding because except subcellular localization, it does not fully utilize biological information of pathways, and (iii) it employs a local search strategy in which the neighborhood is obtained by moving one node at each step, and automatic layouts suggest that simultaneous movements of multiple nodes are necessary for better layouts, while such extension may face worsening the time complexity.

Results
We propose a new grid layout algorithm. To address problem (i), we devised a new force-directed algorithm whose output is suitable as the initial layout. For (ii), we considered that an appropriate alignment of nodes having the same biological attribute is one of the most important factors of the comprehension, and we defined a new score function that gives an advantage to such configurations. For solving problem (iii), we developed a search strategy that considers swapping nodes as well as moving a node, while keeping the order of the time complexity. Though a naïve implementation increases by one order, the time complexity, we solved this difficulty by devising a method that caches differences between scores of a layout and its possible updates.

Conclusion
Layouts of the new grid layout algorithm are compared with that of the previous algorithm and human layout in an endothelial cell model, three times as large as the apoptosis model. The total cost of the result from the new grid layout algorithm is similar to that of the human layout. In addition, its convergence time is drastically reduced (40% reduction).
Investigating the cost-effectiveness of videotelephone based support for newly diagnosed paediatric oncology patients and their families: design of a randomised controlled trial
Authors: Bensink Mark , Wootton Richard , Irving Helen , Hallahan Andrew , Theodoros Deborah , Russell Trevor , Scuffham Paul , Barnett Adrian G 
Published: March 2007

Abstract
Background
Providing ongoing family centred support is an integral part of childhood cancer care. For families living in regional and remote areas, opportunities to receive specialist support are limited by the availability of health care professionals and accessibility, which is often reduced due to distance, time, cost and transport. The primary aim of this work is to investigate the cost-effectiveness of videotelephony to support regional and remote families returning home for the first time with a child newly diagnosed with cancer

Methods/design
We will recruit 162 paediatric oncology patients and their families to a single centre randomised controlled trial. Patients from regional and remote areas, classified by Accessibility/Remoteness Index of Australia (ARIA+) greater than 0.2, will be randomised to a videotelephone support intervention or a usual support control group. Metropolitan families (ARIA+ ≤ 0.2) will be recruited as an additional usual support control group. Families allocated to the videotelephone support intervention will have access to usual support plus education, communication, counselling and monitoring with specialist multidisciplinary team members via a videotelephone service for a 12-week period following first discharge home. Families in the usual support control group will receive standard care i.e., specialist multidisciplinary team members provide support either face-to-face during inpatient stays, outpatient clinic visits or home visits, or via telephone for families who live far away from the hospital. The primary outcome measure is parental health related quality of life as measured using the Medical Outcome Survey (MOS) Short Form SF-12 measured at baseline, 4 weeks, 8 weeks and 12 weeks. The secondary outcome measures are: parental informational and emotional support; parental perceived stress, parent reported patient quality of life and parent reported sibling quality of life, parental satisfaction with care, cost of providing improved support, health care utilisation and financial burden for families.

Discussion
This investigation will establish the feasibility, acceptability and cost-effectiveness of using videotelephony to improve the clinical and psychosocial support provided to regional and remote paediatric oncology patients and their families.
A family practice breastfeeding education pilot program: an observational, descriptive study
Authors: Betzold Christine M , Laughlin Kathleen M , Shi Carol 
Published: March 2007

Abstract

Background
The United States Preventive Services Task Force found that effective interventions for extending breastfeeding duration are generally begun during the prenatal period, provide ongoing support for patients and combine information with face-to-face guidance. A 2001 literature review had similar findings but also found that employing a lactation consultant in the clinical setting may increase breastfeeding duration rates. Thus, a program was developed at a family practice office that employed a lactation consultant and followed the American Academy of Pediatrics' "Ten Steps to Support Parents' Choice to Breastfeed Their Baby."

Methods
The program distributed handouts at each prenatal and well-child visit (up to one year). Using questionnaires, a small audit project evaluated the program's impact on breastfeeding goals, duration, in-hospital exclusivity and maternal perception of success. Mothers completed goal surveys at baseline and post-intervention, usually while waiting for prenatal clinic visits. Duration was assessed by surveys completed during well-infant visits, postal mailings or telephone interviews at breastfeeding cessation, 6 months and 1 year. The outcomes measured were increases in goals, maternal perception of success, duration and in-hospital exclusivity.

Results
Participants included 33 women: 48% had a bachelor's or master's degree, 61% were non-Hispanic white, and 67% reported incomes of US$75,000 or higher. At baseline 5/31 planned to exclusively breastfeed for 4–6 months and 5/33 planned to breastfeed for 6–12 months. Post-intervention there was a 200% increase (15/31) in the exclusively breastfeeding 4–6 month group and a 160% increase (13/33) in the 6–12 month duration group. Actual in-hospital exclusivity rates were 61%, 6-month duration rates were 73%, and 12-month rates were 33%. Over 75% of mothers reported feeling successful.

Conclusion
This small pilot educational program may have significant impacts on breastfeeding goals. Setting and meeting goals may increase duration and in-hospital exclusivity rates as well as enhance maternal self-perception and empowerment due to succeeding at their breastfeeding goals and/or experiencing a fulfilling breastfeeding relationship.
Dissociation between the translocation and the activation of Akt in fMLP-stimulated human neutrophils—effect of prostaglandin E2
Authors: Burelout Chantal , Naccache Paul H , Bourgoin Sylvain G 
Published: March 2007

AbstractPGE2 and other cAMP-elevating agents are known to down-regulate most functions stimulated by fMLP in human polymorphonuclear neutrophils. We reported previously that the inhibitory potential of PGE2 resides in its capacity to suppress fMLP-stimulated PI-3Kγ activation via the PGE2 receptor EP2 and hence, to decrease phosphatidylinositol 3,4,5-triphosphate [PI(3,4,5)P3] formation. Akt activity is stimulated by fMLP through phosphorylation on threonine 308 (Thr308) and serine 473 (Ser473) by 3-phosphoinositide-dependent kinase 1 (PDK1) and MAPK-AP kinase (APK)-APK-2 (MAPKAPK-2), respectively, in a PI-3K-dependent manner. Despite the suppression of fMLP-induced PI-3Kγ activation observed in the presence of PGE2, we show that Akt is fully phosphorylated on Thr308 and Ser473. However, fMLP-induced Akt translocation is decreased markedly in this context. PGE2 does not affect the phosphorylation of MAPKAPK-2 but decreases the translocation of PDK1 induced by fMLP. Other cAMP-elevating agents such as adenosine (Ado) similarly block the fMLP-induced PI-3Kγ activation process but do not inhibit Akt phosphorylation. However, Akt activity stimulated by fMLP is down-regulated slightly by agonists that elevate cAMP levels. Whereas protein kinase A is not involved in the maintenance of Akt phosphorylation, it is required for the inhibition of Akt translocation by PGE2. Moreover, inhibition of fMLP-stimulated PI-3Kδ activity by the selective inhibitor IC87114 only partially affects the late phase of Akt phosphorylation in the presence of PGE2. Taken together, these results suggest that cAMP-elevating agents, such as PGE2 or Ado, are able to induce an alternative mechanism of Akt activation by fMLP in which the translocation of Akt to PI(3,4,5)P3-enriched membranes is not required prior to its phosphorylation.
Eosinophils develop in distinct stages and are recruited to peripheral sites by alternatively activated macrophages
Authors: Voehringer David , van Rooijen N , Locksley Richard M 
Published: March 2007

AbstractEosinophils are associated with allergic diseases and helminth infections. Development of these cells and recruitment to peripheral tissues are only partially understood. Distinct stages of eosinophil development in fetal liver, bone marrow, and blood could be identified using IL-4 reporter mice and mAb against FIRE, Siglec-F, and CCR3. Immature eosinophils were present in the fetal liver and could reconstitute the eosinophil compartment in irradiated recipient mice. In adult mice, eosinophil maturation proceeded from CCR3− to CCR3+ cells in the bone marrow and was accompanied with changes in the transcriptional profile. Eosinophils appeared as activated cells in lung, thymus, lymph nodes, and Peyer’s patches but remained in a resting state in bone marrow, blood, and spleen. Mixed bone marrow chimeras revealed that recruitment to lung and peritoneum was dependent on Stat6 expression in noneosinophils. Alternatively activated macrophages contributed substantially to tissue recruitment of eosinophils, providing a novel basis for development of therapeutic approaches to lower tissue eosinophilia.
Cannabidiol, unlike synthetic cannabinoids, triggers activation of RBL-2H3 mast cells
Authors: Del Giudice Elda , Rinaldi Luciano , Passarotto Marzia , Facchinetti Fabrizio , D’Arrigo Antonello , Guiotto Adriano , Carbonare Maurizio Dalle , Battistin Leontino , Leon Alberta 
Published: March 2007

AbstractCannabidiol (CBD), a prominent psychoinactive component of cannabis with negligible affinity for known cannabinoid receptors, exerts numerous pharmacological actions, including anti-inflammatory and immunosuppressive effects, the underlying mechanisms of which remain unclear. In the current study, we questioned whether CBD modulates activation of mast cells, key players in inflammation. By using the rat basophilic leukemia mast cell line (RBL-2H3), we demonstrate that CBD (3–10 μM) augments β-hexosaminidase release, a marker of cell activation, from antigen-stimulated and unstimulated cells via a mechanism, which is not mediated by Gi/Go protein-coupled receptors but rather is associated with a robust rise in intracellular calcium ([Ca2+]i) levels sensitive to clotrimazole and nitrendipine (10–30 μM). This action, although mimicked by Δ9-tetrahydrocannabinol (THC), is opposite to that inhibitory, exerted by the synthetic cannabinoids WIN 55,212-2 and CP 55,940. Moreover, the vanilloid capsaicin, a full agonist of transient receptor potential channel VR1, did not affect [Ca2+]ilevels in the RBL-2H3 cells, thus excluding the involvement of this receptor in the CBD-mediated effects. Together, these results support existence of yet-to-be identified sites of interaction, i.e., receptors and/or ion channels associated with Ca2+ influx of natural cannabinoids such as CBD and THC, the identification of which has the potential to provide for novel strategies and agents of therapeutic interest.