bluuebunny/crossref_metadata_2025 huggingface dataset:
Gun Felons and Gun Regulation
Authors: Unnithan N. Prabha , Pogrebin Mark , Stretesky Paul B. , Venor Gerry
Published: January 2008

Many states have recently adopted “shall-issue” gun laws making it is easier for applicants to receive permits for carrying concealed weapons. The policy shift is based on assumptions regarding criminal behavior and positive consequences of the change (e.g., reducing crime). Because Colorado had enacted a shall-issue law recently, the authors interviewed a sample of violent offenders there regarding their views on this policy change. Although some supported the new law, the majority were opposed. Reasons inmates viewed the law positively include arguments that it would deter crime and help protect people. Reasons inmates viewed the law negatively focused mostly on increased crime while also mentioning other objections such as more gang members (especially those without previous felony convictions) possessing guns, and the possible negative interaction of more guns and alcohol/drug use and mental states. The behavioral and policy implications of the findings are discussed.
Crime Prevention and the Science of Where People Are
Authors: Andresen Martin A. , Jenion Greg W.
Published: January 2008

Crime prevention initiatives are often conceptualized working at primary-secondary-tertiary (PST) levels. Primary prevention efforts address the underlying social, economic, and physical environmental conditions that generate crime; secondary prevention efforts focus on people, places, and social conditions that are at high risk of crime; whereas tertiary prevention efforts are directed toward already existing and specific crime problems. This article discusses the uses of the ambient population (a 24-hr average estimate of the population present in a spatial area) to better inform crime prevention initiatives within the PST framework. Though the results indicate the ambient population has utility for all three levels of crime prevention, the most immediate use is in tertiary prevention to better understand the nature of areas with a current crime problem. This information is not available from the resident (or census) population because the resident population indicates where people sleep, not where they are.
The Relationship Between Selection Processes of Public Trustees and State Higher Education Performance
Authors: Minor James T.
Published: January 2008

Theoretically, higher education professionals agree that public trusteeship matters, yet little attention is given to the influence trustees have on the performance of public higher education. This study examines the relationship between selection and appointment processes and state higher education performance. Findings show that top-performing states use appointment processes that use restrictions, requisite qualifications, and methods to scrutinize the appropriateness of potential candidates. There is no evidence of clear qualifications or scrutiny among the bottom-performing states.
Bikunin suppresses expression of pro-inflammatory cytokines induced by lipopolysaccharide in neutrophils
Authors: Kanayama Seiji , Yamada Yoshihiko , Onogi Akira , Shigetomi Hiroshi , Ueda Sachiyo , Tsuji Yoriko , Haruta Shoji , Kawaguchi Ryuji , Yoshida Shozo , Sakata Mariko , Sado Toshiyuki , Kitanaka Takashi , Oi Hidekazu , Yagyu Tatsuo , Kobayashi Hiroshi
Published: January 2008

Activated neutrophils contribute to the development of preterm delivery. Because of its ability to suppress inflammation, bikunin, a Kunitz-type protease inhibitor, is currently in clinical trials. To investigate the molecular mechanism of this inhibition, we analyzed the effect of bikunin on pro-inflammatory cytokine production and nuclear factor-kappaB (NF-κB) activation in mouse neutrophils stimulated by lipopolysaccharide (LPS), an inflammatory inducer. Here, we show that bikunin: (i) blocks LPS-induced secretion of pro-inflammatory cytokines, including TNF-α and IL-1β, in a dose-dependent manner; (ii) has an inhibitory effect on cytokine production at a concentration of 0.2 µM, reaching 65% inhibition at the highest doses of bikunin tested (5 µM); (iii) has the suppressive capacity of ERK1/2 and p38 signaling pathways; and (iv) inhibited sequentially the LPS-induced phosphorylation of IκB-α, degradation of IκB-α, and nuclear translocation of NF-κB. When the MAPK data are analyzed, a significant decrease in phosphorylation is not seen at 0.2 µM bikunin but is at 1.0 µM dosing. Bikunin can inhibit LPS-induced neutrophil activation and cytokine release, although it is unlikely that it works primarily through the inhibition of MAPK phosphorylation. These data suggest that such effects are important in vivo and play a major contributory role in abrogation of neutrophil-mediated inflammatory responses, such as preterm delivery.
Low-dose steroid alters in vivo endotoxin-induced systemic inflammation but does not influence autonomic dysfunction
Authors: Alvarez Sonia M. , Katsamanis Karavidas Maria , Coyle Susette M. , Lu Shou-En , Macor Marie , Oikawa Leo O. , Lehrer Paul M. , Calvano Steve E. , Lowry Stephen F.
Published: January 2008

Severe injury and infection are associated with autonomic dysfunction. Diminished heart rate variability (HRV) is also observed as a component of autonomic dysfunction and is induced by endotoxin administration to healthy subjects. It is established that low-dose glucocorticoid administration diminishes the systemic inflammatory manifestations of endotoxinemia but the influence of this anti-inflammatory intervention on overall autonomic dysfunction and HRV responses to endotoxin is unknown. This study was designed to assess the influence of a low-dose hydrocortisone infusion upon endotoxin-elicited systemic inflammatory responses including phenotypic features, cytokine production, and parameters of HRV. Of 19 subjects studied, nine received a continuous infusion of hydrocortisone (3 µg/kg/min continuously over 6 h) prior to intravenous administration of Escherichia coli endotoxin (2 ng/kg, CC-RE, Lot #2) while 10 healthy subjects received only the endotoxin after a 6-h period of saline control infusion. Serial determinations of vital signs, heart rate variability assessments, and cytokine levels were obtained over the subsequent 24 h. Prior cortisol infusion diminished the peak TNF-α ( P < 0.01) and IL-6 ( P < 0.0001) responses after endotoxin challenge, as compared to saline infusion controls and diminished the peak core temperature response to endotoxin ( P < 0.01). In contrast to the influence of cortisol on the above parameters of systemic inflammation, the significant endotoxin-induced decreases in HRV time and frequency domains were not influenced by prior hydrocortisone treatment. Hence, alterations in autonomic dysfunction occur despite hydrocortisone attenuation of other traditional systemic manifestations of endotoxinemia. The maintenance or restoration of autonomic balance is not influenced by glucocorticoid administration.
Coming to Terms: A Case Study of Hospice Collaboration Challenges
Authors: Pietroburgo Julie , Bush Richard
Published: January 2008

Recent research has focused on the growing phenomenon of mergers, collaborations, and alliances among nonprofit organizations and what makes such arrangements work. Examination of failed collaborative efforts is perhaps just as instructive. This case study examines recent attempts at collaboration between 2 nonprofit hospice organizations. The study finds that despite compelling reasons for and significant commonalities on which to base collaboration, the organizations were initially unable to forge any ongoing and substantive collaborative arrangement because of insurmountable cultural factors and past history. Furthermore, without imminent external pressures to collaborate, these organizations had insufficient motivation to attempt to move beyond their differences. The case also reviews the changed circumstances and factors that later facilitated partnering attempts.
Mean Maternal Second-Trimester Hemoglobin Concentration and Outcome of Pregnancy: A Population-Based Study
Authors: von Tempelhoff Georg-Friedrich , Heilmann Lothar , Rudig Lothar , Pollow Kunhard , Hommel Gerhard , Koscielny Jürgen
Published: January 2008

Both anemia and the lack of physiological maternal plasma volume expansion during the second trimester are associated with higher maternal morbidity and poor fetal outcome. Mean hemoglobin levels between the 14th and 30th gestational weeks were calculated in 4985 consecutive pregnant women and were correlated with outcome data of pregnancy. It was found that 9.4% of participants (n = 3959) had normal pregnancy outcome. Mean maternal hemoglobin levels were significantly lower in women with a normal pregnancy (11.96 ± 0.94 g/dL) compared with women who had adverse outcome events (preeclampsia, n = 423, 12.5 ± 1.0 g/dL, P < .0001; early birth, n = 464, 12.2 ± 1.01 g/dL, P < .0001; low birth weight newborn, n = 473, 12.2 ± 1.10 g/dL, P < .0001; intrauterine growth retardation, n = 250, 12.2 ± 1.0 g/dL, P < .0001). The risk for any adverse outcome event was lowest with a mean hemoglobin between 11.0 and 12.0 g/dL (odds ratio, 0.625; 95% confidence interval, 0.43-0.89) and highest between 13.0 and 15.0 g/dL (odds ratio, 2.24; 95% confidence interval, 1.54-3.31). In this population-based study from a community in Western Germany, impaired plasma volume expansion was an independent risk factor for the development of an adverse outcome of pregnancy.
Elected Versus Appointed School District Officials
Authors: Hoover Gary A.
Published: January 2008

This article explores the differences in student performance outcomes when school officials are either elected or appointed to their posts. If appointed officials are insulated by at least one level of bureaucracy, they might be more inclined to implement unpopular policies to impact student performance. Findings indicate that there are no differences in student performance when the school superintendent or the school board is appointed rather than elected. It is found that there is a slight positive difference in outcomes when the superintendent is elected as opposed to when the school board is elected.
The Effects of Earnings Inequality on State Social Spending in the United States
Authors: Schwabish Jonathan A.
Published: January 2008

States provide a variety of goods and services to their citizens, ranging from police protection to highway construction to education and health services. This study is concerned with how earnings inequality has affected such spending at the state level in the United States between 1977 and 2005. The results show that for every 1 percent increase in the 9050 percentile ratio of earnings, social spending on non-health and non-education goods and services increases by approximately 0.231 percent, or about $615 per person. A similar 1 percent increase in the 5010 percentile ratio of earnings is associated with a smaller 0.042 percent rise in spending, or $112 per person. A one percent increase in overall inequality, as measured by the Gini coefficient, is associated with a rise in social spending of about 0.255 percent, or $680 per person. The model is robust to a variety of sensitivity tests and generally shows that increases in inequality in both the upper- and lower-tail of the earnings distribution serve to increase social spending.
Agonistic Struggle
Authors: Grant Barbara M.
Published: January 2008

Hegel's master and slave is a significant archetype for graduate research supervision. The master—slave relation vividly exemplifies the hierarchical bond that ties supervisor and student together. Such a confronting view of supervision provides a counterbalance to contemporary emphases on equality between supervisor and student. In what follows, I use Zali Gurevitch's interpretation (`Dialectical dialogue', 2001, British Journal of Sociology) of Hegel's master and slave ( Phenomenology of Spirit, 1807) to analyse an extract of supervision dialogue between a supervisor and a Masters student in the Humanities. My analysis shows the mundaneness of the master—slave relation in action. This mundaneness derives from supervision's institutional underpinnings and contributes to the relative invisibility of the master—slave relation as an influential dynamic. In closing, I argue that this investigation usefully draws our attention to the third player in supervision, the thesis, and that master—slave dynamics may have both disturbing and helpful effects for supervisor and student.
The Resistance to Teaching
Authors: Varsos George
Published: January 2008

This article focuses on the figure of the university teacher of literature, viewed as an agent that possesses knowledge and transmits it via its oral word. The approach is historical and theoretical. The first part examines how different types of teaching are linked to different phases of the development of the university institution, from the formation of its modern idea in the 19th century to the drastic changes it is undergoing today. Particular attention is given to the idea of national culture as it connects to the modern functions of written language. The second part examines how literature as a domain of teachable knowledge emerges and develops within the modern university institution. It discusses, in particular, how teaching practices today can be affected by the epistemological ramifications of the demise of the cultural authority that modernity had invested in literature.
'Great Expectations'
Authors: Kormos Judit , Csizér Kata , Menyhárt Adrienn , Török Dóra
Published: January 2008

In this article we investigate what characterizes the language learning motivation of Hungarian English language students in terms of Dörnyei and Ottó's process model of motivation ( Motivation in Action, 1998). We used a mixed-method research design, in which qualitative interviews conducted with 20 students were supplemented with questionnaire data gained from 100 participants in order to have a better understanding of the apparent discrepancy between students' and society's expectations of teaching English Language at tertiary level and the present educational system in Hungary. The ambivalent nature of English language students' motivational profile was found to reflect this situation. The interview data revealed that the respondents had very favourable motivational characteristics but they did not invest sufficient energy in maintaining and improving their language competence. This is explained with reference to a low level of learner autonomy primarily caused by teacher-centered instruction.
Social Perception Deficits, Cognitive Distortions, and Empathy Deficits in Sex Offenders
Authors: Blake Emily , Gannon Theresa
Published: January 2008

This literature review examines the differences between sex offenders and nonoffenders with regard to social perception skills, cognitive distortions, and empathy skills in order to investigate sex offenders' cognition. The literature on cognitive distortions is discussed, with reference to the confusion surrounding its definition, and the debate between cognitive distortions as offense-supportive beliefs or justifications is examined. In terms of social perception, particular reference is made to sex offenders' misinterpretations of women's social cues and the source of this deficit. The authors discuss possibilities for this deficit, including offense-supportive beliefs that are driven by underlying implicit theories or schemata held by offenders. The concept of empathy and its relation to both social perception skills and cognitive distortions is discussed, and the integration of these factors is represented in a new model.
Review of Research On Child Maltreatment and Violence in Youth
Authors: Maas Carl , Herrenkohl Todd I. , Sousa Cynthia
Published: January 2008

This review addresses research regarding associations between child maltreatment and youth violence perpetration. The authors explore current findings on the direct effects of child maltreatment on later youth violence and possible gender and ethnic differences. They examine differences in the prediction of adolescent violence as a function of duration and timing of maltreatment. Results provide compelling evidence linking child maltreatment and later youth violence, although some research is inconclusive once demographics and other competing predictors are considered. Overall, physical abuse is perhaps the most consistent predictor of youth violence, patterned by an increased risk for children exposed to severe, compounded maltreatment. However, findings indicate that lesser severe forms of abuse can increase the risk of later violence for some youth. Limitations of current research include relatively few prospective, studies on the abuse-violence link; a general lack of specificity in definitions of key variables; and inconsistency in data analysis methods.
The Girl Who Ate Her House—Pica as an Obsessive-Compulsive Disorder
Authors: Baheretibeb Yonas , Law Samuel , Pain Clare
Published: January 2008

This report concerns the interesting clinical phenomenology of a 17-year-old Ethiopian female student with a long-standing history of ingesting nonnutritive materials. She was initially non-selective, but later began more exclusively consuming mud obtained from a wall in front of her house. She suffered from a feeding and eating disorder known as pica. Currently, there is no clearly established etiology for pica. This patient's particular psychopathology—recurrent, unwanted, intrusive images and thoughts of the mud wall and of eating the mud; feelings of distress and anxiousness that were not relieved unless she consumed mud; and significant effects on her daily life from her uncontrollable need to return home to eat mud from her wall—suggests an ego-dystonic, obsessive thought-distress-consumption-relief pattern that is consistent with obsessive-compulsive disorder. This case may contribute to the etiological understanding that some forms of pica may be part of the obsessive-compulsive spectrum disorders.
The Use of In Vivo Desensitization for the Treatment of a Specific Phobia of Earthworms
Authors: Buchanan Jeffrey A. , Houlihan Daniel
Published: January 2008

Graduated in vivo desensitization was used to treat an intense fear of earthworms in a female college student. The participant reported intense physiological anxiety and avoidance behavior in situations where worms could be encountered. Treatment outcome was measured using a behavioral avoidance test (BAT) and the State-Trait Anxiety Inventory (STAI). Exposure therapy sessions required the client to confront a variety of anxiety-producing situations arranged in a hierarchy. Results indicated that at posttreatment the client was able to complete the BAT and was able to complete the fear hierarchy. State anxiety scores as measured by the STAI declined by 50% from pretreatment to posttreatment. In addition, the client reported little subjective anxiety and no avoidance of situations where worms might be present at posttreatment. The client maintained all posttreatment gains at 1-, 5-, and 8-month follow-ups.
Hematopoietic cytokines
Authors: Metcalf Donald
Published: January 2008

The production of hematopoietic cells is under the tight control of a group of hematopoietic cytokines. Each cytokine has multiple actions mediated by receptors whose cytoplasmic domains contain specialized regions initiating the various responses—survival, proliferation, differentiation commitment, maturation, and functional activation. Individual cytokines can be lineage specific or can regulate cells in multiple lineages, and for some cell types, such as stem cells or megakaryocyte progenitors, the simultaneous action of multiple cytokines is required for proliferative responses. The same cytokines control basal and emergency hematopoietic cell proliferation. Three cytokines, erythropoietin, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor, have now been in routine clinical use to stimulate cell production and in total have been used in the management of many millions of patients. In this little review, discussion will be restricted to those cytokines well established as influencing the production of hematopoietic cells and will exclude newer candidate regulators and those active on lymphoid cells. As requested, this account will describe the cytokines in a historical manner, using a sequential format of discovery, understanding, validation, and puzzlement, a sequence that reflects the evolving views on these cytokines over the past 50 years.
BCR-ABL1 mediates up-regulation of Fyn in chronic myelogenous leukemia
Authors: Ban Kechen , Gao Yin , Amin Hesham M. , Howard Adrienne , Miller Claudia , Lin Quan , Leng Xiaohong , Munsell Mark , Bar-Eli Menashe , Arlinghaus Ralph B. , Chandra Joya
Published: January 2008

Chronic myelogenous leukemia (CML) invariably progresses to blast crisis, which represents the most proliferative phase of the disease. The BCR-ABL1 oncogene stimulates growth and survival pathways by phosphorylating numerous substrates, including various Src family members. Here we describe up-regulation, in contrast to activation, of the ubiquitously expressed Src kinase, Fyn, by BCR-ABL1. In a tissue microarray, Fyn expression was significantly increased in CML blast crisis compared with chronic phase. Cells overexpressing BCR-ABL1 in vitro and in vivo display an up-regulation of Fyn protein and mRNA. Knockdown of Fyn with shRNA slows leukemia cell growth, inhibits clonogenicity, and leads to increased sensitivity to imatinib, indicating that Fyn mediates CML cell proliferation. In severe combined immunodeficient (SCID) mice injected with Fyn shRNA–expressing cells, myeloid-derived cell numbers dropped by 50% and death from leukemia was delayed. Taken together, these results encourage the development of therapies targeting Fyn expression.
IL-21 mediates apoptosis through up-regulation of the BH3 family member BIM and enhances both direct and antibody-dependent cellular cytotoxicity in primary chronic lymphocytic leukemia cells in vitro
Authors: Gowda Aruna , Roda Julie , Hussain Syed-Rehan A. , Ramanunni Asha , Joshi Trupti , Schmidt Susan , Zhang Xiaoli , Lehman Amy , Jarjoura David , Carson William E. , Kindsvogel Wayne , Cheney Carolyn , Caligiuri Michael A. , Tridandapani Susheela , Muthusamy Natarajan , Byrd John C.
Published: January 2008

Interleukin-21 (IL-21) is a recently identified γ-chain receptor cytokine family member that promotes B-cell apoptosis as well as activation of innate immune system. Based on this, we hypothesized that IL-21 might enhance the apoptosis induced by fludarabine and rituximab and also play a role in augmenting immune-mediated clearance of the chronic lymphocytic leukemia (CLL) cells. Our studies demonstrate that the majority of CLL patients have surface IL-21 receptor-α, and its expression correlates with apoptosis, tyrosine phosphorylation of STAT1, and up-regulation of the proapoptotic BH3 domain protein BIM. IL-21–induced BIM up-regulation is critical for apoptosis because inhibition of BIM expression using small interfering RNA prevented IL-21–induced apoptosis. IL-21 treatment of CLL cells but not normal T cells with fludarabine or rituximab additively enhanced the direct cytotoxic effect of these therapies. In addition to its proapoptotic effect, IL-21 promoted STAT1 and STAT5 phosphorylation in natural killer cells with concurrent enhanced antibody-dependent cellular cytotoxicity against rituximab-coated CLL cells in vitro. These data provide justification for combination studies of IL-21 with fludarabine and rituximab in CLL and suggest that BIM up-regulation might serve as relevant pharmacodynamic end point to measure biologic effect of this cytokine in vivo.
The effects of dasatinib on IgE receptor–dependent activation and histamine release in human basophils
Authors: Kneidinger Michael , Schmidt Uwe , Rix Uwe , Gleixner Karoline V. , Vales Anja , Baumgartner Christian , Lupinek Christian , Weghofer Margit , Bennett Keiryn L. , Herrmann Harald , Schebesta Alexandra , Thomas Wayne R. , Vrtala Susanne , Valenta Rudolf , Lee Francis Y. , Ellmeier Wilfried , Superti-Furga Giulio , Valent Peter
Published: January 2008

Dasatinib is a multitargeted drug that blocks several tyrosine kinases. Apart from its well-known antileukemic activity, the drug has attracted attention because of potential immunosuppressive and anti-inflammatory effects. We report that dasatinib at 1 μM completely blocks anti-IgE–induced histamine release in blood basophils in healthy donors, and allergen-induced release of histamine in sensitized individuals. In addition, dasatinib inhibited FcϵRI-mediated release of IL-4 and IgE-mediated up-regulation of CD13, CD63, CD164, and CD203c in basophils. The effects of dasatinib were dose-dependent (IC50: 50-500 nM) and specific for FcϵRI activation in that the drug failed to inhibit C5a-induced or Ca-ionophore–induced histamine release. Interestingly, at lower concentrations, dasatinib even promoted FcϵRI-dependent histamine release in basophils in allergic subjects. In consecutive studies, dasatinib was found to interact with and block several FcϵRI downstream targets in basophils, in-cluding Btk. Correspondingly, FcϵRI-mediated histamine secretion in basophils was markedly reduced in Btk knockout mice and in a patient with Btk deficiency. However, the remaining “low-level” mediator secretion in Btk-deficient cells was fully blocked down again by 1 μM dasatinib. Together, these data suggest that dasatinib inhibits FcϵRI-mediated activation of basophils through multiple signaling molecules including Btk. Dasatinib may be an interesting agent for immunologic disorders involving Btk-dependent responses or/and FcϵRI activation of basophils.
Unraveling the immune response during AIHA
Authors: Avent Neil D.
Published: January 2008

In this issue of Blood, Ward and colleagues make some novel fundamental observations on the nature of the immune response during autoimmune hemolytic anemia (AIHA). They show a key role for T regulatory cells (Tregs) in the pathogenesis of this autoimmune disease.
Megakaryocyte and platelet biology: getting your FAKs straight
Authors: Italiano Joseph E.
Published: January 2008

In this issue of Blood, Hitchcock and colleagues show that the nonreceptor tyrosine kinase FAK plays a critical role in regulating megakaryocyte maturation and platelet function in vivo.
SMM: toward better predictors of progression
Authors: Bladé Joan , Rosiñol Laura
Published: January 2008

In this issue of Blood, Dispenzieri and colleagues report that the serum immunoglobulin free light chain (FLC) ratio is an independent predictor for progression in patients with smoldering multiple myeloma.
Oral iron chelation: new drug, old rules
Authors: Nathan David G.
Published: January 2008

The dose and schedule of an iron chelator, whether given parenterally or orally, is variable and depends on the rate of iron loading.
Clara cell adhesion and migration to extracellular matrix
Authors: Atkinson Jeffrey J , Adair-Kirk Tracy L , Kelley Diane G , deMello Daphne , Senior Robert M
Published: January 2008

Background

Clara cells are the epithelial progenitor cell of the small airways, a location known to be important in many lung disorders. Although migration of alveolar type II and bronchiolar ciliated epithelial cells has been examined, the migratory response of Clara cells has received little attention.

Methods

Using a modification of existing procedures for Clara cell isolation, we examined mouse Clara cells and a mouse Clara-like cell line (C22) for adhesion to and migration toward matrix substrate gradients, to establish the nature and integrin dependence of migration in Clara cells.

Results

We observed that Clara cells adhere preferentially to fibronectin (Fn) and type I collagen (Col I) similar to previous reports. Migration of Clara cells can be directed by a fixed gradient of matrix substrates (haptotaxis). Migration of the C22 cell line was similar to the Clara cells so integrin dependence of migration was evaluated with this cell line. As determined by competition with an RGD containing-peptide, migration of C22 cells toward Fn and laminin (Lm) 511 (formerly laminin 10) was significantly RGD integrin dependent, but migration toward Col I was RGD integrin independent, suggesting that Clara cells utilize different receptors for these different matrices.

Conclusion

Thus, Clara cells resemble alveolar type II and bronchiolar ciliated epithelial cells by showing integrin mediated pro-migratory changes to extracellular matrix components that are present in tissues after injury.
EST2uni: an open, parallel tool for automated EST analysis and database creation, with a data mining web interface and microarray expression data integration
Authors: Forment Javier , Gilabert Francisco , Robles Antonio , Conejero Vicente , Nuez Fernando , Blanca Jose M
Published: January 2008

Background

Expressed sequence tag (EST) collections are composed of a high number of single-pass, redundant, partial sequences, which need to be processed, clustered, and annotated to remove low-quality and vector regions, eliminate redundancy and sequencing errors, and provide biologically relevant information. In order to provide a suitable way of performing the different steps in the analysis of the ESTs, flexible computation pipelines adapted to the local needs of specific EST projects have to be developed. Furthermore, EST collections must be stored in highly structured relational databases available to researchers through user-friendly interfaces which allow efficient and complex data mining, thus offering maximum capabilities for their full exploitation.

Results

We have created EST2uni, an integrated, highly-configurable EST analysis pipeline and data mining software package that automates the pre-processing, clustering, annotation, database creation, and data mining of EST collections. The pipeline uses standard EST analysis tools and the software has a modular design to facilitate the addition of new analytical methods and their configuration. Currently implemented analyses include functional and structural annotation, SNP and microsatellite discovery, integration of previously known genetic marker data and gene expression results, and assistance in cDNA microarray design. It can be run in parallel in a PC cluster in order to reduce the time necessary for the analysis. It also creates a web site linked to the database, showing collection statistics, with complex query capabilities and tools for data mining and retrieval.

Conclusion

The software package presented here provides an efficient and complete bioinformatics tool for the management of EST collections which is very easy to adapt to the local needs of different EST projects. The code is freely available under the GPL license and can be obtained at http://bioinf.comav.upv.es/est2uni. This site also provides detailed instructions for installation and configuration of the software package. The code is under active development to incorporate new analyses, methods, and algorithms as they are released by the bioinformatics community.
Different subcellular localizations and functions of Arabidopsis myosin VIII
Authors: Golomb Lior , Abu-Abied Mohamad , Belausov Eduard , Sadot Einat
Published: January 2008

Background

Myosins are actin-activated ATPases that use energy to generate force and move along actin filaments, dragging with their tails different cargos. Plant myosins belong to the group of unconventional myosins and Arabidopsis myosin VIII gene family contains four members: ATM1, ATM2, myosin VIIIA and myosin VIIIB.

Results

In transgenic plants expressing GFP fusions with ATM1 (IQ-tail truncation, lacking the head domain), fluorescence was differentially distributed: while in epidermis cells at the root cap GFP-ATM1 equally distributed all over the cell, in epidermal cells right above this region it accumulated in dots. Further up, in cells of the elongation zone, GFP-ATM1 was preferentially positioned at the sides of transversal cell walls. Interestingly, the punctate pattern was insensitive to brefeldin A (BFA) while in some cells closer to the root cap, ATM1 was found in BFA bodies. With the use of different markers and transient expression in Nicotiana benthamiana leaves, it was found that myosin VIII co-localized to the plasmodesmata and ER, colocalized with internalized FM4-64, and partially overlapped with the endosomal markers ARA6, and rarely with ARA7 and FYVE. Motility of ARA6 labeled organelles was inhibited whenever associated with truncated ATM1 but motility of FYVE labeled organelles was inhibited only when associated with large excess of ATM1. Furthermore, GFP-ATM1 and RFP-ATM2 (IQ-tail domain) co-localized to the same spots on the plasma membrane, indicating a specific composition at these sites for myosin binding.

Conclusion

Taken together, our data suggest that myosin VIII functions differently in different root cells and can be involved in different steps of endocytosis, BFA-sensitive and insensitive pathways, ER tethering and plasmodesmatal activity.
Risk factors for house-entry by malaria vectors in a rural town and satellite villages in The Gambia
Authors: Kirby Matthew J , Green Clare , Milligan Paul M , Sismanidis Charalambos , Jasseh Momadou , Conway David J , Lindsay Steven W
Published: January 2008

Background

In the pre-intervention year of a randomized controlled trial investigating the protective effects of house screening against malaria-transmitting vectors, a multi-factorial risk factor analysis study was used to identify factors that influence mosquito house entry.

Methods

Mosquitoes were sampled using CDC light traps in 976 houses, each on one night, in Farafenni town and surrounding villages during the malaria-transmission season in The Gambia. Catches from individual houses were both (a) left unadjusted and (b) adjusted relative to the number of mosquitoes caught in four sentinel houses that were operated nightly throughout the period, to allow for night-to-night variation. Houses were characterized by location, architecture, human occupancy and their mosquito control activities, and the number and type of domestic animals within the compound.

Results

106,536 mosquitoes were caught, of which 55% were Anopheles gambiae sensu lato, the major malaria vectors in the region. There were seven fold higher numbers of An. gambiae s.l. in the villages (geometric mean per trap night = 43.7, 95% confidence intervals, CIs = 39.5–48.4) than in Farafenni town (6.3, 5.7–7.2) and significant variation between residential blocks (p < 0.001). A negative binomial multivariate model performed equally well using unadjusted or adjusted trap data. Using the unadjusted data the presence of nuisance mosquitoes was reduced if the house was located in the town (odds ratio, OR = 0.11, 95% CIs = 0.09–0.13), the eaves were closed (OR = 0.71, 0.60–0.85), a horse was tethered near the house (OR = 0.77, 0.73–0.82), and churai, a local incense, was burned in the room at night (OR = 0.56, 0.47–0.66). Mosquito numbers increased per additional person in the house (OR = 1.04, 1.02–1.06) or trapping room (OR = 1.19, 1.13–1.25) and when the walls were made of mud blocks compared with concrete (OR = 1.44, 1.10–1.87).

Conclusion

This study demonstrates that the risk of malaria transmission is greatest in rural areas, where large numbers of people sleep in houses made of mud blocks, where the eaves are open, horses are not tethered nearby and where churai is not burnt at night. These factors need to be considered in the design and analysis of intervention studies designed to reduce malaria transmission in The Gambia and other parts of sub-Saharan Africa.
Should tumor VEGF expression influence decisions on combining low-dose chemotherapy with antiangiogenic therapy? Preclinical modeling in ovarian cancer
Authors: Holtz David O , Krafty Robert T , Mohamed-Hadley Alisha , Zhang Lin , Alagkiozidis Ioannis , Leiby Benjamin , Guo Wensheng , Gimotty Phyllis A , Coukos George
Published: January 2008

Because of its low toxicity, low-dose (LD) chemotherapy is ideally suited for combination with antiangiogenic drugs. We investigated the impact of tumor vascular endothelial growth factor A (VEGF-A) expression on the efficacy of LD paclitaxel chemotherapy and its interactions with the tyrosine kinase inhibitor SU5416 in the ID8 and ID8-Vegf models of ovarian cancer. Functional linear models using weighted penalized least squares were utilized to identify interactions between Vegf, LD paclitaxel and antiangiogenic therapy. LD paclitaxel yielded additive effects with antiangiogenic therapy against tumors with low Vegf expression, while it exhibited antagonism to antiangiogenic therapy in tumors with high Vegf expression. This is the first preclinical study that models interactions of LD paclitaxel chemotherapy with antiangiogenic therapy and tumor VEGF expression and offers important lessons for the rational design of clinical trials.
The ubiquitin E3 ligase activity of BRCA1 and its biological functions
Authors: Wu Wenwen , Koike Ayaka , Takeshita Takashi , Ohta Tomohiko
Published: January 2008

The basal-like breast cancer, a new category of breast cancer associated with poor prognosis and possibly unique chemosensitivity, is a current topic in the breast cancer field. Evidence from multiple sources strongly indicate that impairment of BRCA1 pathways is responsible for this phenotype, implying the importance of BRCA1 not only in familial breast cancers but also in sporadic cancers. BRCA1 acts as a hub protein that coordinates a diverse range of cellular pathways to maintain genomic stability. BRCA1 participates in multiple cellular supercomplexes to execute its tasks and, in most of the complexes, BRCA1 exists as a RING heterodimer with BARD1 to provide ubiquitin E3 ligase activity that is required for its tumor suppressor function. It was revealed recently that the BRCA1 RING finger is capable of catalyzing multiple types of ubiquitination depending upon the interacting E2, the ubiquitin carrier protein. BRCA1 may catalyze distinct ubiquitination on different substrates as the situation demands. On the other hand, in response to DNA double-strand breaks where BRCA1 plays its major role for homologous recombination repair, recent evidence showed that ubiquitination is a critical step to recruit BRCA1 to the damaged site through UIM (ubiquitin interacting motif) containing protein RAP80. Thus, ubiquitin and BRCA1 likely affect each other in many ways to perform cellular functions. Elucidation of this mechanism in relation to cell survival is now much anticipated because it could be a key to predict chemosensitivity of basal-like breast cancer.
Comparing two strategies of dynamic intensity modulated radiation therapy (dIMRT) with 3-dimensional conformal radiation therapy (3DCRT) in the hypofractionated treatment of high-risk prostate cancer
Authors: Yuen Jasper , Rodrigues George , Trenka Kristina , Coad Terry , Yartsev Slav , D'Souza David , Lock Michael , Bauman Glenn
Published: January 2008

Background

To compare two strategies of dynamic intensity modulated radiation therapy (dIMRT) with 3-dimensional conformal radiation therapy (3DCRT) in the setting of hypofractionated high-risk prostate cancer treatment.

Methods

3DCRT and dIMRT/Helical Tomotherapy(HT) planning with 10 CT datasets was undertaken to deliver 68 Gy in 25 fractions (prostate) and simultaneously delivering 45 Gy in 25 fractions (pelvic lymph node targets) in a single phase. The paradigms of pelvic vessel targeting (iliac vessels with margin are used to target pelvic nodes) and conformal normal tissue avoidance (treated soft tissues of the pelvis while limiting dose to identified pelvic critical structures) were assessed compared to 3DCRT controls. Both dIMRT/HT and 3DCRT solutions were compared to each other using repeated measures ANOVA and post-hoc paired t-tests.

Results

When compared to conformal pelvic vessel targeting, conformal normal tissue avoidance delivered more homogenous PTV delivery (2/2 t-test comparisons; p < 0.001), similar nodal coverage (8/8 t-test comparisons; p = ns), higher and more homogenous pelvic tissue dose (6/6 t-test comparisons; p < 0.03), at the cost of slightly higher critical structure dose (Ddose, 1–3 Gy over 5/10 dose points; p < 0.03). The dIMRT/HT approaches were superior to 3DCRT in sparing organs at risk (22/24 t-test comparisons; p < 0.05).

Conclusion

dIMRT/HT nodal and pelvic targeting is superior to 3DCRT in dose delivery and critical structure sparing in the setting of hypofractionation for high-risk prostate cancer. The pelvic targeting paradigm is a potential solution to deliver highly conformal pelvic radiation treatment in the setting of nodal location uncertainty in prostate cancer and other pelvic malignancies.
Cytogenetic analysis of HER1/EGFR, HER2, HER3 and HER4 in 278 breast cancer patients
Authors: Sassen Andrea , Rochon Justine , Wild Peter , Hartmann Arndt , Hofstaedter Ferdinand , Schwarz Stephan , Brockhoff Gero
Published: January 2008

Introduction

The HER (human EGFR related) family of receptor tyrosine kinases (HER1/EGFR (epidermal growth factor receptor)/c-erbB1, HER2/c-erbB2, HER3/c-erbB3 and HER4/c-erbB4) shares a high degree of structural and functional homology. It constitutes a complex network, coupling various extracellular ligands to intracellular signal transduction pathways resulting in receptor interaction and cross-activation. The most famous family member is HER2, which is a target in Herceptin™ therapy in metastatic status and also in adjuvant therapy of breast cancer in the event of dysregulation as a result of gene amplification and resulting protein overexpression. The HER2-related HER receptors have been shown to interact directly with HER2 receptors and thereby mutually affect their activity and subsequent malignant growth potential. However, the clinical outcome with regard to total HER receptor state remains largely unknown.

Methods

We investigated HER1–HER4, at both the DNA and the protein level, using fluorescence in situ hybridisation (FISH) probes targeted to all four receptor loci and also immunohistochemistry in tissue microarrays derived from 278 breast cancer patients.

Results

We retrospectively found HER3 gene amplification with a univariate negative impact on disease-free survival (hazard ratio 2.35, 95% confidence interval 1.08 to 5.11, p = 0.031), whereas HER4 amplification showed a positive trend in overall and disease-free survival. Protein expression revealed no additional information.

Conclusion

Overall, the simultaneous quantification of HER3 and HER4 receptor genes by means of FISH might enable the rendering of a more precise stratification of breast cancer patients by providing additional prognostic information. The continuation of explorative and prospective studies on all HER receptors will be required for an evaluation of their potential use for specific therapeutic targeting with respect to individualised therapy.
Horizontal gene transfer and the evolution of transcriptional regulation in Escherichia coli
Authors: Price Morgan N , Dehal Paramvir S , Arkin Adam P
Published: January 2008

Background

Most bacterial genes were acquired by horizontal gene transfer from other bacteria instead of being inherited by continuous vertical descent from an ancient ancestor. To understand how the regulation of these acquired genes evolved, we examined the evolutionary histories of transcription factors and of regulatory interactions from the model bacterium Escherichia coli K12.

Results

Although most transcription factors have paralogs, these usually arose by horizontal gene transfer rather than by duplication within the E. coli lineage, as previously believed. In general, most neighbor regulators - regulators that are adjacent to genes that they regulate - were acquired by horizontal gene transfer, whereas most global regulators evolved vertically within the γ-Proteobacteria. Neighbor regulators were often acquired together with the adjacent operon that they regulate, and so the proximity might be maintained by repeated transfers (like 'selfish operons'). Many of the as yet uncharacterized (putative) regulators have also been acquired together with adjacent genes, and so we predict that these are neighbor regulators as well. When we analyzed the histories of regulatory interactions, we found that the evolution of regulation by duplication was rare, and surprisingly, many of the regulatory interactions that are shared between paralogs result from convergent evolution. Another surprise was that horizontally transferred genes are more likely than other genes to be regulated by multiple regulators, and most of this complex regulation probably evolved after the transfer.

Conclusion

Our findings highlight the rapid evolution of niche-specific gene regulation in bacteria.
Tumor Angiogenic and Hypoxic Profiles Predict Radiographic Response and Survival in Malignant Astrocytoma Patients Treated With Bevacizumab and Irinotecan
Authors: Sathornsumetee Sith , Cao Yiting , Marcello Jennifer E. , Herndon James E. , McLendon Roger E. , Desjardins Annick , Friedman Henry S. , Dewhirst Mark W. , Vredenburgh James J. , Rich Jeremy N.
Published: January 2008

Purpose

The combination of a vascular endothelial growth factor (VEGF) –neutralizing antibody, bevacizumab, and irinotecan is associated with high radiographic response rates and improved survival outcomes in patients with recurrent malignant gliomas. The aim of these retrospective studies was to evaluate tumor vascularity and expression of components of the VEGF pathway and hypoxic responses as predictive markers for radiographic response and survival benefit from the bevacizumab and irinotecan therapy.

Patients and Methods

In a phase II trial, 60 patients with recurrent malignant astrocytomas were treated with bevacizumab and irinotecan. Tumor specimens collected at the time of diagnosis were available for further pathologic studies in 45 patients (75%). VEGF, VEGF receptor-2, CD31, hypoxia-inducible carbonic anhydrase 9 (CA9), and hypoxia-inducible factor-2α were semiquantitatively assessed by immunohistochemistry. Radiographic response and survival outcomes were correlated with these angiogenic and hypoxic markers.

Results

Of 45 patients, 27 patients had glioblastoma multiforme, and 18 patients had anaplastic astrocytoma. Twenty-six patients (58%) had at least partial radiographic response. High VEGF expression was associated with increased likelihood of radiographic response (P = .024) but not survival benefit. Survival analysis revealed that high CA9 expression was associated with poor survival outcome (P = .016).

Conclusion

In this patient cohort, tumor expression levels of VEGF, the molecular target of bevacizumab, were associated with radiographic response, and the upstream promoter of angiogenesis, hypoxia, determined survival outcome, as measured from treatment initiation. Validation in a larger clinical trial is warranted.
The Politics of Medical Inflation
Authors: Marmor Theodore R. , Wittman Donald A. , Heagy Thomas C.
Published: January 2008

This paper discusses the politics of anti-inflationary policy in the medical care sector. We first clarify the issue by distinguishing between four different conceptions commonly used when discussing medical inflation. We then present some of the standard solutions to these problems suggested by economists. In the main part of the paper, we analyze the response of the government. We show that the underlying causes for failure in the economic market are likely to exist in the political market as well. In particular, the public good aspect of anti-inflationary policy fails to provide a strong incentive for the consumers of medical care. In contrast, the providers have very powerful incentives in the political market because the benefits of governmental action in this sector greatly affect them. Providers exert great pressure to prevent government policies aimed at reducing medical care expenditures. We present evidence and theory to explicate which sets of circumstances are most conducive to governmental action. We show that the most effective anti-inflationary programs in medical financing are least likely to be implemented and that a dispersed, pluralistic financing structure reduces the government's incentive to curb inflation.