bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer
Authors: Kimmelman Alec C. , Hezel Aram F. , Aguirre Andrew J. , Zheng Hongwu , Paik Ji-hye , Ying Haoqiang , Chu Gerald C. , Zhang Jean X. , Sahin Ergun , Yeo Giminna , Ponugoti Aditya , Nabioullin Roustem , Deroo Scott , Yang Shenghong , Wang Xiaoxu , McGrath John P. , Protopopova Marina , Ivanova Elena , Zhang Jianhua , Feng Bin , Tsao Ming S. , Redston Mark , Protopopov Alexei , Xiao Yonghong , Futreal P. Andrew , Hahn William C. , Klimstra David S. , Chin Lynda , DePinho Ronald A.
Published: December 2008

Pancreas ductal adenocarcinoma (PDAC) is a highly lethal cancer that typically presents as advanced, unresectable disease. This invasive tendency, coupled with intrinsic resistance to standard therapies and genome instability, are major contributors to poor long-term survival. The genetic elements governing the invasive propensity of PDAC have not been well elucidated. Here, in the course of validating resident genes in highly recurrent and focal amplifications in PDAC, we have identified Rio Kinase 3 (RIOK3) as an amplified gene that alters cytoskeletal architecture as well as promotes pancreatic ductal cell migration and invasion. We determined that RIOK3 promotes its invasive activities through activation of the small G protein, Rac. This genomic and functional link to Rac signaling prompted a genome wide survey of other components of the Rho family network, revealing p21 Activated Kinase 4 (PAK4) as another amplified gene in PDAC tumors and cell lines. Like RIOK3, PAK4 promotes pancreas ductal cell motility and invasion. Together, the genomic and functional profiles establish the Rho family GTP-binding proteins as integral to the hallmark invasive nature of this lethal disease.
Voltage-dependent K
+
channel gating and voltage sensor toxin sensitivity depend on the mechanical state of the lipid membrane
Authors: Schmidt Daniel , MacKinnon Roderick
Published: December 2008

Voltage-dependent K
+
(Kv) channels underlie action potentials through gating conformational changes that are driven by membrane voltage. In this study of the paddle chimera Kv channel, we demonstrate that the rate of channel opening, the voltage dependence of the open probability, and the maximum achievable open probability depend on the lipid membrane environment. The activity of the voltage sensor toxin VsTx1, which interferes with voltage-dependent gating by partitioning into the membrane and binding to the channel, also depends on the membrane. Membrane environmental factors that influence channel function are divisible into two general categories: lipid compositional and mechanical state. The mechanical state can have a surprisingly large effect on the function of a voltage-dependent K
+
channel, including its pharmacological interaction with voltage sensor toxins. The dependence of VSTx1 activity on the mechanical state of the membrane leads us to hypothesize that voltage sensor toxins exert their effect by perturbing the interaction forces that exist between the channel and the membrane.
Beyond disciplinarity: humanities and supercomplexity
Authors: Parker Jan
Published: December 2008

The 'New Humanities' has called for new ways of engaging with Humanities texts; the European Science Foundation is just one major research funder to demand that the Humanities contribute to interdisciplinary collaborations. Meanwhile, traditionally trained disciplinary academics have
resisted bringing traditional texts into interdisciplinary courses as 'dumbing down the curriculum'. This article analyses briefly the different epistemological, narratological and disciplinary genres in one text: Herodotus' Histories or Enquiries. It concludes that Humanities
study must include such texts, not only as disciplinary but also as supra-disciplinary exemplary ways of knowing. It sketches a New Humanities curriculum based on such a text that could fit the twenty-first century student to live in a super-complex, multi-paradigmatic and radically interdisciplinary
world.
Widening participation; widening capability
Authors: Walker Melanie
Published: December 2008

This paper proposes that widening participation in higher education might distinctively be conceptualised beyond economically driven human capital outcomes, as a matter of widening capability. Specifically, the paper proposes forming the capability of students to become and to be 'strong
evaluators', able to make reflexive and informed choices about what makes a good life for each of them. Evaluating equality and justice in higher education, and specifically the case of 'widening participation', is then greatly advanced by considering the conceptual tools provided by Amartya
Sen's capability approach. The paper therefore elaborates on Sen's ideas and demonstrates their applicability in relation to widening participation student voices gathered in research interviews. Important though Sen's ideas are, there are barriers that stand in the way of taking up these
ideas educationally. While three such barriers are acknowledged in the paper, four resources of possibility for recovering widening participation as capability formation from neoliberal and other forms of instrumentalism are also sketched.
Using Community-Based Prevention Marketing to Improve Farm Worker Safety
Authors: Monaghan Paul F. , Bryant Carol A. , Baldwin Julie A. , Zhu Yiliang , Ibrahimou Boubakari , Lind Jason D. , Contreras Ricardo B. , Tovar Antonio , Moreno Tirso , Mcdermott Robert J.
Published: December 2008

Community-based prevention marketing (CBPM) combines a powerful planning framework, social marketing, with community organization principles to design behavior change programs. In southwest Florida, a coalition comprised of citrus workers and their employers, health providers, and academic researchers is using CBPM to identify occupational health issues among agricultural laborers, conduct community-based participatory research, and design culturally appropriate interventions. This article describes how this coalition was able to apply CBPM successfully to develop and implement an occupational safety program to prevent eye injuries among migrant farm workers. Lessons learned from this project and implications for designing and disseminating occupational safety programs for other agricultural workers are discussed.
A Case Study in Applied Social Marketing: Developing an Occupational Safety and Health Product
Authors: Scott Douglas F.
Published: December 2008

This case study provides an example of how social marketing was applied to meet the needs of business customers. Federal regulations require that all companies develop a written program to track hazardous chemicals at their sites. The HazComWriter, created by the National Institute for Occupational Safety and Health (NIOSH), is a software tool designed to help companies prepare their required Hazard Communications (HazCom) written plan and list all hazardous chemicals at the company's worksite. The social marketing goal was to provide a product for small- to medium-sized companies to use for federal HazCom rule compliance. The HazComWriter is a direct NIOSH response to customer and stakeholder needs (including the Mine Safety and Health Administration, the mining community, and Occupational Safety and Health Administration-regulated companies).
Use of Health Communication and Social Marketing Principles in Planning Occupational Safety and Health Interventions
Authors: Sublet Virginia H. , Lum Max R.
Published: December 2008

This study reviewed health communication and social marketing designs used in occupational safety and health interventions over the last 15 years in the United States. After an extensive literature review, 50 studies were identified that self-reported use of health communication and/or social marketing principles and practices to design occupational safety interventions. Nineteen of these studies were selected for analysis based on the following factors: the inclusion of a behavioral theory, strong study design, an intervention was conducted, and an evaluation was completed. Results indicated that all of the interventions met the criteria to be classified as a health communication intervention, but none met the complete criteria to be considered a true social marketing intervention. Limitations in the evaluation designs made it difficult to assess the impact of these interventions; however, results suggest that health communication principles have been applied widely, while social marketing techniques are poorly understood and underutilized in planning occupational safety programs.
Use of Occupational Ethnography and Social Marketing Strategies to Develop a Safety Awareness Campaign for Coal Miners
Authors: Cullen Elaine T. , Matthews Lori N. H. , Teske Theodore D.
Published: December 2008

Underground mining, like many high-risk industries, is facing a crisis in the near future. This industry has traditionally relied on a master–apprentice relationship to train new workers, but experienced miners are retiring in large numbers, leaving few“masters” to properly train their replacements. With a recent resurgence in mining, many new miners are entering the workforce each day. The rise in the number of inexperienced workers has implications for worker safety in an industry in which one mistake can blow up the entire workplace. The explosion in the Darby Mine in May 2006 that killed five miners illustrates what can happen in hazardous environments such as underground mines.

The Health Communications Team at the National Institute for Occupational Safety and Health Spokane Research Laboratory was asked to address this problem by developing new training and safety awareness materials to promote safe flame cutting and welding practices. This article describes how occupational ethnographic techniques provided insights needed for“new product development.” The result of this work was a national initiative to raise awareness and to protect underground coal miners from the dangers of flame cutting and welding in an environment filled with solid fuel and methane (natural gas). Although this project was initially designed for the mining industry, the approach and lessons learned are applicable to any high-risk industry and should be of interest to other social marketing or occupational safety and health professionals.
Evaluating Tractor Safety Messages: A Concept Development Project
Authors: Sorensen Julie A. , May John , O'Hara Patrick , Ostby Ronne , Lehman Thomas , Viebrock Stacey , Emmelin Maria
Published: December 2008

This article describes a formative strategy for developing effective tractor safety messages aimed at small crop and livestock farmers in New York. This population accounts for the highest proportion of tractors lacking rollover protective structures (ROPS), which reduce the risk of overturn injury or death. To encourage ROPS installation on unprotected tractors, persuasive messages were developed to be used as part of a social marketing intervention. The message development process involved evaluating concepts in small group discussions (triads) with the target audience. Participants were asked to review and provide feedback on 15 concepts, select two favorites, and discuss influential message channels. Results indicate that messages should address existing concerns for family safety or a permanently disabling injury and should realistically depict the lives of participants. Messages featuring financial incentives must clearly state the cost to the farmer. Although the data from the pilot test of intervention components has not yet been analyzed, data from the program hotline indicates concept development messages and rebates generated a greater demand for ROPS than generic messages and rebates. In conclusion, by employing the target population in the message development process it was possible to increase the efficacy of ROPS social marketing messages.
Computationally feasible estimation of haplotype frequencies from pooled DNA with and without Hardy–Weinberg equilibrium
Authors: Kuk Anthony Y. C. , Zhang Han , Yang Yaning
Published: December 2008

Motivation: Pooling large number of DNA samples is a common practice in association study, especially for initial screening. However, the use of expectation-maximization (EM)-type algorithms in estimating haplotype distributions for even moderate pool sizes is hampered by the computational complexity involved. A novel constrained EM algorithm called PoooL has been proposed recently to bypass the difficulty via the use of asymptotic normality of the pooled allele frequencies. The resulting estimates are, however, not maximum likelihood estimates and hence not optimal. Furthermore, the assumption of Hardy–Weinberg equilibrium (HWE) made may not be realistic in practice.

Methods: Rather than carrying out constrained maximization as in PoooL, we revert to the usual EM algorithm but make it computationally feasible by using normal approximations. The resulting algorithm is much simpler to implement than PoooL because there is no need to invoke sophisticated iterative scaling methods as in PoooL. We also develop an estimating equation analogue of the EM algorithm for the case of Hardy–Weinberg disequilibrium (HWD) by conditioning on the haplotypes of both chromosomes of the same individual. Incorporated into the method is a way of estimating the inbreeding coefficient by relating it to overdispersion.

Results: Simulation study assuming HWE shows that our simplified implementation of the EM algorithm leads to estimates with substantially smaller SDs than PoooL estimates. Further simulations show that ignoring HWD will induce biases in the estimates. Our extended method with estimation of inbreeding coefficient incorporated is able to reduce the bias leading to estimates with substantially smaller mean square errors. We also present results to suggest that our method can cope with a certain degree of locus-specific inbreeding as well as additional overdispersion not caused by inbreeding.

Availability:  http://staff.ustc.edu.cn/∼ynyang/aem-aes

Contact:  stakuka@nus.edu.sg; ynyang@ustc.edu.cn
Gene expression trends and protein features effectively complement each other in gene function prediction
Authors: Wabnik Krzysztof , Hvidsten Torgeir R. , Kedzierska Anna , Van Leene Jelle , De Jaeger Geert , Beemster Gerrit T. S. , Komorowski Jan , Kuiper Martin T. R.
Published: December 2008

Motivation: Genome-scale ‘omics’ data constitute a potentially rich source of information about biological systems and their function. There is a plethora of tools and methods available to mine omics data. However, the diversity and complexity of different omics data types is a stumbling block for multi-data integration, hence there is a dire need for additional methods to exploit potential synergy from integrated orthogonal data. Rough Sets provide an efficient means to use complex information in classification approaches. Here, we set out to explore the possibilities of Rough Sets to incorporate diverse information sources in a functional classification of unknown genes.

Results: We explored the use of Rough Sets for a novel data integration strategy where gene expression data, protein features and Gene Ontology (GO) annotations were combined to describe general and biologically relevant patterns represented by If-Then rules. The descriptive rules were used to predict the function of unknown genes in Arabidopsis thaliana and Schizosaccharomyces pombe. The If-Then rule models showed success rates of up to 0.89 (discriminative and predictive power for both modeled organisms); whereas, models built solely of one data type (protein features or gene expression data) yielded success rates varying from 0.68 to 0.78. Our models were applied to generate classifications for many unknown genes, of which a sizeable number were confirmed either by PubMed literature reports or electronically interfered annotations. Finally, we studied cell cycle protein–protein interactions derived from both tandem affinity purification experiments and in silico experiments in the BioGRID interactome database and found strong experimental evidence for the predictions generated by our models. The results show that our approach can be used to build very robust models that create synergy from integrating gene expression data and protein features.

Availability: The Rough Set-based method is implemented in the Rosetta toolkit kernel version 1.0.1 available at: http://rosetta.lcb.uu.se/

Contact:  kuiper@nt.ntnu.no; krwab@psb.ugent.be

Supplementary information:  Supplementary data are available at Bioinformatics online.
The management of artisanal fishing within the Marine Protected Area of the Port-Cros National Park (northwest Mediterranean Sea): a success story?
Authors: Cadiou Gwenaël , Boudouresque Charles F. , Bonhomme Patrick , Le Diréach Laurence
Published: December 2008

Cadiou, G., Boudouresque, C. F., Bonhomme, P., and Le Diréach, L. 2009. The management of artisanal fishing within the Marine Protected Area of the Port-Cros National Park (northwest Mediterranean Sea): a success story? – ICES Journal of Marine Science, 66: 41–49. The Port-Cros National Park, France (northwest Mediterranean Sea), established in 1963, is a Marine Protected Area (MPA) where, unlike no-take areas, artisanal fishing has been permitted (except trawling), owing to social and economic pressures. Nevertheless, restrictions on artisanal fishing have increased through a fishing charter (1999). In the meantime, recreational fishing was progressively banned, which has helped as a management tool to make the restrictions on artisanal fishing acceptable in social terms. Monitoring of the artisanal fishing (2000–2005) reveals the stability of the fishing fleet (9–13 vessels); of the fishing effort [number of fishing sets per day between 3.4 (±2.1) and 6.9 (±3.4) in spring, and 3.0 (±1.7) and 5.2 (±2.7) in summer]; and of yields [catch per unit effort between 1.27 (±0.72) and 1.68 (±1.44) kg 100 m of net−1 d−1]. Furthermore, based on an analysis of available data, artisanal fishing does not jeopardize the conservation objectives of the MPA, so that, from 1963 to date, the issue has changed from “What can be done to ban commercial fishing?” to “Is there any reason to ban commercial fishing?”.
Exploring the early origins of the synapse by comparative genomics
Authors: Kosik Kenneth S
Published: December 2008

One set of evolutionary features that has received less attention than the evolution of genes or species is the evolution of cellular machines, the self-contained structures in cells with dedicated functions. Here I suggest that domain expansion through shuffling, duplication, and changes in protein expression level are critical drivers in the evolution of cellular machines. Once established, evolutionary change in these cellular machines tends to occur by paralogy or expansion and modification of the existing core genes. A comparative genomics approach to one cellular machine—the post-synaptic complex—provided preliminary validation of these views. A comparative genomics approach to the entire cellulome may reveal the diversity of cellular machines and their inter-relationships.
Revisiting the cognitive buffer hypothesis for the evolution of large brains
Authors: Sol Daniel
Published: December 2008

Why have some animals evolved large brains despite substantial energetic and developmental costs? A classic answer is that a large brain facilitates the construction of behavioural responses to unusual, novel or complex socioecological challenges. This buffer effect should increase survival rates and favour a longer reproductive life, thereby compensating for the costs of delayed reproduction. Although still limited, evidence in birds and mammals is accumulating that a large brain facilitates the construction of novel and altered behavioural patterns and that this ability helps dealing with new ecological challenges more successfully, supporting the cognitive-buffer interpretation of the evolution of large brains.
Characterization of theArabidopsisNitrate Transporter NRT1.6 Reveals a Role of Nitrate in Early Embryo Development
Authors: Almagro Anabel , Lin Shan Hua , Tsay Yi Fang
Published: December 2008

This study of the Arabidopsis thaliana nitrate transporter NRT1.6 indicated that nitrate is important for early embryo development. Functional analysis of cDNA-injected Xenopus laevis oocytes showed that NRT1.6 is a low-affinity nitrate transporter and does not transport dipeptides. RT-PCR, in situ hybridization, and β-glucuronidase reporter gene analysis showed that expression of NRT1.6 is only detectable in reproductive tissue (the vascular tissue of the silique and funiculus) and that expression increases immediately after pollination, suggesting that NRT1.6 is involved in delivering nitrate from maternal tissue to the developing embryo. In nrt1.6 mutants, the amount of nitrate accumulated in mature seeds was reduced and the seed abortion rate increased. In the mutants, abnormalities (i.e., excessive cell division and loss of turgidity), were found mainly in the suspensor cells at the one- or two-cell stages of embryo development. The phenotype of the nrt1.6 mutants revealed a novel role of nitrate in early embryo development. Interestingly, the seed abortion rate of the mutant was reduced when grown under N-deficient conditions, suggesting that nitrate requirements in early embryo development can be modulated in response to external nitrogen changes.
Truncation of a Protein Disulfide Isomerase, PDIL2-1, Delays Embryo Sac Maturation and Disrupts Pollen Tube Guidance inArabidopsis thaliana
Authors: Wang Huanzhong , Boavida Leonor C. , Ron Mily , McCormick Sheila
Published: December 2008

Pollen tubes must navigate through different female tissues to deliver sperm to the embryo sac for fertilization. Protein disulfide isomerases play important roles in the maturation of secreted or plasma membrane proteins. Here, we show that certain T-DNA insertions in Arabidopsis thaliana PDIL2-1, a protein disulfide isomerase (PDI), have reduced seed set, due to delays in embryo sac maturation. Reciprocal crosses indicate that these mutations acted sporophytically, and aniline blue staining and scanning electron microscopy showed that funicular and micropylar pollen tube guidance were disrupted. A PDIL2-1-yellow fluorescent protein fusion was mainly localized in the endoplasmic reticulum and was expressed in all tissues examined. In ovules, expression in integument tissues was much higher in the micropylar region in later developmental stages, but there was no expression in embryo sacs. We show that reduced seed set occurred when another copy of full-length PDIL2-1 or when enzymatically active truncated versions were expressed, but not when an enzymatically inactive version was expressed, indicating that these T-DNA insertion lines are gain-of-function mutants. Our results suggest that these truncated versions of PDIL2-1 function in sporophytic tissues to affect ovule structure and impede embryo sac development, thereby disrupting pollen tube guidance.
Morphometric changes associated with the reproductive cycle and behaviour of the intertidal‐nesting, male plainfin midshipmanPorichthys notatus
Authors: Sisneros J. A. , Alderks P. W. , Leon K. , Sniffen B.
Published: December 2008

Morphometric changes in body condition, liver, sonic muscle and gonadal development associated with the annual reproductive cycle and behaviour of the intertidal‐nesting male plainfin midshipmanPorichthys notatuswere investigated. Body condition of type I males rapidly increased during the pre‐nesting (PN) period, peaked at the beginning of the summer nesting cycle and then gradually declined to lowest levels during the non‐reproductive (NR) period. The gonado‐somatic index of type I males peaked during PN and then declined during the summer nesting cycle to lowest levels at the end of the nest cycle and during NR. Indices of sonic muscle and liver of type I males were lowest during NR, gradually increased during PN and then peaked during the summer nesting cycle. Results indicate that body condition and fecundity of type I males were positively correlated with body mass at the end of the nest cycle. These findings as they relate to the annual reproductive cycle and behaviour of the type I maleP. notatusare discussed.
Variable gene family usage of protective and non‐protective anti‐Vibrio cholerae O1 LPS antibody heavy chains
Authors: Wade Terri K. , Wade William F.
Published: December 2008

Vibrio cholerae causes cholera, an enteric disease of humans that is a worldwide problem. The O1 serogroup of Vibrio cholerae contains two predominant serotypes (Inaba and Ogawa) of LPS, a proven protective antigen for humans and experimental animals. We generated B‐cell hybridomas from mice immunized with either: (i) two doses of purified Inaba LPS; (ii) two doses of an Inaba hexasaccharide conjugate (terminal six perosamine bound to a protein carrier), (iii) four doses of purified Inaba LPS; or (iv) a low dose of purified Inaba LPS followed by a booster with the Inaba conjugate. We showed previously that the first and third immunization protocols induce vibriocidal antibodies, as does the fourth; the second protocol induces antibodies that bind Inaba and Ogawa LPS but are not vibriocidal. Anti‐LPS mAbs derived from hybridomas resulting from each immunization protocol were characterized for binding to Inaba and Ogawa LPS, their vibriocidal or protective capacity, and the variable heavy chain family they expressed. LPS immunogens selected different LPS‐specific B cells expressing six different Vh chain families. Protective and non‐protective mAbs could express variable regions from the same family. One mAb was specific for Inaba LPS, the other mAbs were cross‐reactive with both LPS serotypes. Sequence comparison suggests that the pairing of a specific light chain, somatic mutation, or the specific VDJ recombination can modulate the protective capacity of mAbs that express a common variable heavy chain family member.
Analysis of severe acute respiratory syndrome coronavirus structural proteins in virus‐like particle assembly
Authors: Nakauchi Mina , Kariwa Hiroaki , Kon Yasuhiro , Yoshii Kentaro , Maeda Akihiko , Takashima Ikuo
Published: December 2008

SARS‐CoV has four major structural proteins: the N, S, M, and E proteins. To investigate the mechanism of SARS‐CoV assembly, we cloned the genes encoding these four proteins into the eukaryotic expression vector pCAGGS and transfected them into 293T cells. When all four expression vectors were co‐transfected VLP formed, as confirmed using electron microscopy. Using a rabbit polyclonal antibody specific to the N protein, N‐protein‐containing particles similar in size to the VLP were also observed by immunoelectron microscopy, indicating that the VLP contained the N protein. Co‐immunoprecipitation analyses demonstrated an interaction between the N and M proteins, suggesting that N protein binds directly to M protein to be incorporated into VLP.
A WT1 protein‐derived, naturally processed 16‐mer peptide, WT1332, is a promiscuous helper peptide for induction of WT1‐specific Th1‐type CD4+ T cells
Authors: Fujiki Fumihiro , Oka Yoshihiro , Kawakatsu Mai , Tsuboi Akihiro , Nakajima Hiroko , Elisseeva Olga A. , Harada Yukie , Li Zheyu , Tatsumi Naoko , Kamino Eriko , Shirakata Toshiaki , Nishida Sumiyuki , Taniguchi Yuki , Kawase Ichiro , Oji Yusuke , Sugiyama Haruo
Published: December 2008

The Wilms' tumor gene WT1 is overexpressed in various tumors, and the WT1 protein has been demonstrated to be an attractive target antigen for cancer immunotherapy. A WT1 protein‐derived 16‐mer peptide, WT1332 (KRYFKLSHLQMHSRKH), which was naturally generated through processing in cells and could elicit Th1‐type CD4+ helper T cell responses with an HLA‐DRB1*0405‐restriction has previously been identified by us. In the present study, it has been demonstrated that WT1332 can induce WT1332‐specific CD4+ T cell responses with the restriction of not only HLA‐DRB1*0405 but also HLA‐DRB1*1501, ‐DRB1*1502, or ‐DPB1*0901. These HLA class II‐restricted WT1332‐specific CD4+ T cell lines produced IFN‐γ but neither IL‐4 nor IL‐10 with WT1332 stimulation, thus showing a Th1‐type cytokine profile. Furthermore, HLA‐DRB1*1501 or ‐DRB1*1502‐restricted WT1332‐specific CD4+ T cell lines responded to WT1‐expressing transformed cells in an HLA‐DRB1‐restricted manner, which is consistent with our previous finding that WT1332 is a naturally processed peptide. These results indicate that the natural peptide, WT1332, is a promiscuous WT1‐specific helper epitope. WT1332 is expected to apply to cancer patients with various types of HLA class II as a WT1‐specific helper peptide in combination with HLA class I‐restricted WT1 peptides.
A comparative study of bone marrow and peripheral blood CD34+ myeloblasts in acute myeloid leukaemia
Authors: Cheung Alice M. S. , Chow Howard C. H. , Liang Raymond , Leung Anskar Y. H.
Published: December 2008

To examine the differences between primitive bone marrow (BM) and peripheral blood (PB) myeloblasts in acute myeloid leukaemia (AML), we compared CD34+ myeloblasts of paired BM and PB samples from 14 AML patients in terms of surface phenotype, homing and engraftment in a xenogeneic transplantation model, and gene expression, based on microarray studies and quantitative polymerase chain reaction. While there was no significant difference in surface phenotypes between these two populations, in vivo assay showed significantly better homing potential of PB CD34+ cells than BM CD34+ cells. Significant correlation between homing and engraftment in AML samples was also noted. In addition, gene expression profiling of CD34+ cells from five paired BM and PB leukaemic samples showed that genes involved in G‐protein and prostaglandin signalling, chemotaxis and stress response, cell proliferation and apoptosis were down‐regulated in PB CD34+ myeloblasts. These data suggested that circulating primitive myeloblasts in AML are functionally different from those residing in the marrow compartment, and such differences may be partly regulated by the BM microenvironment.
Longitudinal follow up of elevated pulmonary artery pressures in children with sickle cell disease
Authors: Pashankar Farzana D. , Carbonella Judith , Bazzy‐Asaad Alia , Friedman Alan
Published: December 2008

Elevated pulmonary artery pressures (PAP) occur in approximately 30% of children with sickle cell disease. In adults, pulmonary hypertension is significantly associated with mortality. There are no data on the long term significance in children. Nineteen children with SS/Sß0 thalassaemia had elevated PAP, defined as tricuspid regurgitant jet velocity (TRV) ≥2·5 m/s on screening echocardiograms. They were prospectively followed for 23 months (range 19–31 months). Patients with initial TRV ≥ 3 or TRV ≥ 2·5 m/s on repeat echocardiogram had cardiopulmonary evaluation and were offered treatment with hydroxyurea. Associated conditions like asthma and obstructive sleep apnea were treated. 18/19 patients had follow‐up echocardiograms. These showed normalization of TRV in 8 patients. Risk factors associated with persistent elevation were higher TRV on initial echocardiogram (P = 0·01), lower haemoglobin (P = 0·003) and lower oxygen saturation (P = 0·03). Five patients with persistently elevated PAP were treated with hydroxyurea. Mean right ventricular pressure dropped from 40·16 to 29·26 (P = 0·017) after 3–6 months and to 23·6 mmHg (P = 0·002) after 9–12 months on treatment. In conclusion (i) At borderline elevation of TRV there is intrapatient variability and echocardiograms should be repeated for confirmation. (ii) Elevated PAP are reversible in children with early detection and treatment with hydroxyurea.
Primary tumour diameter as a risk factor for advanced disease features of differentiated thyroid carcinoma
Authors: Verburg Frederik A. , Mäder Uwe , Luster Markus , Reiners Christoph
Published: December 2008

Objective  To study the relationship between primary tumour size and the risk of advanced disease features (multifocal or locally invasive disease, lymph‐node or distant metastases) in differentiated thyroid carcinoma (DTC).

Design  A retrospective chart review study.

Patients  The study sample comprised 935 papillary (PTC) and 291 follicular thyroid carcinoma (FTC) patients treated in our hospital from 1978 to 2007.

Measurements  Kaplan–Meier analyses and log‐rank tests were performed to calculate tumour size‐adjusted cumulative risk of advanced disease features.

Results  Accounting for primary tumour diameter, there were no significant differences in cumulative risks of multifocal carcinoma (P = 0·12) or distant metastases (P = 0·49) between PTC and FTC. PTC showed higher cumulative risks of local invasion (P < 0·0001) or lymph‐node metastases (P < 0·0001). The cumulative risk of tumour multifocality increased 5%/cm of primary tumour diameter. The cumulative risk of local invasion or lymph‐node metastases in PTC and of distant metastases in DTC increased exponentially at a threshold tumour diameter of 10 mm. In FTC, lymph‐node metastases are associated almost exclusively with primary tumours showing extrathyroidal growth.

Conclusions  Starting with a 1 cm primary tumour diameter, increasing tumour size is associated with an exponentially increasing risk of local invasion or lymph‐node or distant metastases of DTC. The current classification of carcinomas < 2 cm as T1 is therefore questionable.
Does preterm birth influence the response to growth hormone treatment in short, small for gestational age children?
Authors: De Kort Sandra W. K. , Willemsen Ruben H. , Van Der Kaay Danielle C. M. , Duivenvoorden Hugo J. , Hokken‐Koelega Anita C. S.
Published: December 2008

Objective  To investigate whether prematurity has an independent influence on the response to GH treatment in short, small for gestational age (SGA) children.

Design  A longitudinal 3‐year GH study.

Patients  A total of 392 prepubertal non‐GH‐deficient, short SGA children, comprising 138 preterm (< 36 weeks) and 254 term (≥ 36 weeks) children.

Measurements  Height, weight, head circumference, skinfolds and serum IGF‐I and IGFBP‐3 levels were measured before start of GH treatment and after 6 months, 1, 2 and 3 years of treatment.

Results  Preterm short SGA children were significantly lighter and shorter at birth after correction for gestational age than term short SGA children (P < 0·001). At start of GH treatment, preterm children were significantly shorter than term children when height was corrected for target height (TH). Preterm children were also significantly leaner as shown by a lower body mass index (BMI) standard deviation score (SDS) and a lower sum of four skinfolds SDS. Prematurity had no influence on childhood IGF‐I and IGFBP‐3 levels. The response to GH treatment was similar for preterm and term SGA children.

Conclusions  Within a population of short SGA children, prematurity is associated with a smaller size for gestational age and a shorter height corrected for TH and leaner phenotype in childhood. The response to GH treatment is similar for preterm and term short SGA children.
Enhanced proatherogenic inflammation after recombinant human TSH administration in patients monitored for thyroid cancer remnant
Authors: Desideri Giovambattista , Bocale Raffaella , Milardi Domenico , Ghiadoni Lorenzo , Grassi Davide , Necozione Stefano , Taddei Stefano , Di Orio Ferdinando , Pontecorvi Alfredo , Ferri Claudio
Published: December 2008

Objective  To evaluate the effect of recombinant human TSH (rhTSH) on biomarkers of vascular endothelial cell and platelet activation in patients monitored for thyroid carcinoma remnant.

Methods  Circulating levels of soluble(s) intercellular adhesion molecule (sICAM)‐1 and sE‐selectin, as indices of vascular endothelial cell activation, of sP‐selectin and sCD40 ligand (sCD40L), as indices of platelet activation, and of 8‐iso‐prostaglandin F2α (8‐iso‐PGF2α), as an index of lipid peroxidation, were evaluated in 20 patients (16 females, 48·0 ± 13·6 years) at baseline and after intramuscular rhTSH injection (0·9 mg/day on two consecutive days).

Results  At baseline, serum TSH values were below normal whereas free T3 and free T4 were within the normal range. After rhTSH injection, serum TSH increased significantly but free T3 and free T4 remained unchanged. Concomitantly, plasma sICAM‐1 concentrations increased significantly (from 155·9 ± 39·1 to 183·6 ± 38·1 ng/ml, P < 0·03), as did those of sE‐selectin (from 74·8 ± 15·4 to 91·4 ± 12·2 ng/ml, P < 0·0006), sP‐selectin (from 56·4 ± 13·7 to 72·2 ± 14·9 ng/ml, P < 0·002), sCD40L (from 2·1 ± 0·9 to 2·8 ± 1·1 ng/ml, P < 0·03) and total 8‐iso‐PGF2α(from 238·5 ± 47·0 to 307·8 ± 41·2 pg/l, P < 0·0001). Changes in circulating levels of sCD40L were directly correlated with changes in levels of plasma total 8‐iso‐PGF2α (r = 0·523, P < 0·02) and sP‐selectin (r = 0·480, P < 0·03).

Conclusions  Supraphysiological concentrations of rhTSH might exert proatherogenic effects by promoting activation of vascular endothelial cells and platelets probably through enhanced oxidative stress.
Higher serum TSH in thyroid cancer patients occurs independent of age and correlates with extrathyroidal extension
Authors: Haymart Megan R. , Glinberg Simone L. , Liu Jing , Sippel Rebecca S. , Jaume Juan C. , Chen Herbert
Published: December 2008

Background  It has previously been shown that higher serum TSH is associated with increased thyroid cancer incidence and advanced‐stage disease. In the healthy adult population, mean TSH increases with age. As age over 45 years is a known prognostic indicator for thyroid cancer, it is important to know whether higher TSH in patients with thyroid cancer occurs independent of age.

Objective  To determine the relationship between higher TSH, cancer and age.

Design  A retrospective cohort study.

Patients and methods  A total of 1361 patients underwent thyroid surgery between May 1994 and December 2007 at a single institution. Of these patients, 954 had pathological data, preoperative TSH and complete surgical history available. Data were analysed in relation to age and TSH.

Results  Mean TSH was significantly higher in cancer patients regardless of age < 45 years or ≥ 45 years (P = 0·046 and P = 0·027, respectively). When examining age groups < 20, 20–44, 45–59 and ≥ 60 years, there was a trend of rising mean TSH with age. Despite the rise in the benign subgroups, mean TSH was consistently higher in those with cancer vs. those without. On multivariate analysis, higher TSH was independently associated with cancer (P = 0·039) and pathological features of Hashimoto's thyroiditis (P = 0·001) but not with age (P = 0·557). On multivariate analysis of high‐risk features associated with poor prognosis, there was a significant association between higher TSH and extrathyroidal extension (P = 0·002), whereas there was no clear relationship with age, tumour size > 4 cm, and distant metastases.

Conclusion  Independent of age, thyroid cancer incidence correlates with higher TSH. Higher TSH is associated with extrathyroidal extension of disease.
Lipids, lipid modifying agents and cardiovascular risk: a review of the evidence
Authors: Preiss David , Sattar Naveed
Published: December 2008

It is well‐established that serum total‐cholesterol, LDL‐cholesterol, low HDL‐cholesterol and calculated indices such as total cholesterol : HDL‐cholesterol ratio or less commonly used indices such as non‐HDL cholesterol are strongly predictive of cardiovascular events. Serum triglycerides, by contrast, are only modestly associated with coronary heart disease (CHD) in multivariate analysis and incorporation of triglycerides into prediction algorithms is therefore unlikely to improve their prediction capability. Meta‐analysis of studies including > 90 000 subjects has provided robust evidence that statins reduce important clinical end‐points. These included a 12% fall in all‐cause mortality, 19% fall in CHD mortality and 23% fall in CHD mortality or myocardial infarction. Furthermore there are high quality data showing additional benefit of intensive statin therapy over standard statin therapy for secondary prevention of cardiovascular disease. However, meta‐analysis of 10 fibrate trials has shown inconsistent evidence of vascular benefit and non‐cardiovascular mortality has been slightly but consistently elevated in most fibrate trials and in meta‐analysis. The general use of fibrates for cardiovascular risk reduction can therefore not be supported at present. Other second line agents such as bile acid sequestrants, nicotinic acid and omega‐3 fatty acid supplements have been evaluated in a few randomized controlled studies in which cardiovascular benefit has been found but clearly further data are required to properly establish their use in clinical practice. Ongoing studies such as ACCORD, IMPROVE‐IT, ASCEND, ORIGIN and HPS2‐THRIVE should assist in answering outstanding questions over the next 5 years.
E‐cadherin prolongs the moment for interaction between intestinal stem cell and its progenitor cell to ensure Notch signaling in adult Drosophila midgut
Authors: Maeda Kousuke , Takemura Masahiko , Umemori Makoto , Adachi‐Yamada Takashi
Published: December 2008

Intestinal stem cells (ISCs) are required for maintenance of the proper cell composition in the adult intestine. To ensure permanent recruitment of newly differentiated cells, the ISC undergoes asymmetric cell division that generates an ISC itself and a progenitor cell. In the Drosophila midgut, cell fate for the absorptive cell is determined by Notch (N) signal in the progenitor cells that receive a ligand Delta (Dl) produced by the ISCs. Although most of the ISCs and progenitor cells are distantly located, they should retain their attachment when N is activated because the Dl–N interaction requires cell adhesion. Furthermore, N cannot be activated before completion of cell division. Thus, the moment after cell division and before cell separation should be prolonged for certain N activation, although the mechanism for this remains unclear. Here, we demonstrate that E‐cadherin (E‐cad) is required for stable attachment between the two cells. When E‐cad does not function, N is not activated and cell differentiation is attenuated. We also show that the ISC tumor by N inactivation is assisted by a defect in E‐cad down‐regulation. These findings reveal one of the normal N functions used to inhibit tumorigenesis through lowering of E‐cad for proper midgut cell turnover.
Characterization of the promoter region of the human PARG gene and its response to PU.1 during differentiation of HL‐60 cells
Authors: Uchiumi Fumiaki , Sakakibara Gakushi , Sato Junko , Tanuma Sei‐ichi
Published: December 2008

The metabolism of poly(ADP‐ribose) plays important roles in the nuclear function of mammalian cells. Previously, we analyzed expression of the poly(ADP‐ribose) glycohydrolase (PARG) gene during HL‐60 cell differentiation and found that expression was greatly reduced by 4 h after 12‐O‐tetradecanoyl‐phorbol‐13‐acetate (TPA) treatment and returned to the initial level within 20 h. In the present study, a 2.1‐kb fragment of the 5′‐flanking (promoter) region of the human PARG gene was isolated from the HL‐60 genome by polymerase chain reaction and ligated into a luciferase‐expression vector, pGL3, to generate the pPARG‐Luc#2 reporter plasmid. Deletion analysis revealed that a 75‐nt sequence is required for basal promoter activity and TPA responsiveness. Mutations in this 75‐nt sequence reduced promoter activity and the TPA response of HL‐60 cells. TFSEARCH analysis revealed that Ets family binding motifs are located in the 75‐nt sequence. Chromatin immunoprecipitation assay, electrophoretic mobility shift assay and competition analysis indicated that PU.1 (Spi‐1) binds to the 75‐nt sequence. Moreover, co‐transfection of HL‐60 cells with a PU.1 expression plasmid and pPARG‐Luc indicated that PU.1 down‐regulate the PARG promoter. These results suggest that PARG gene expression is modulated by PU.1 during TPA‐induced differentiation of HL‐60 cells.
Evaluation of trap capture in a geographically closed population of brown treesnakes on Guam
Authors: Tyrrell Claudine L. , Christy Michelle T. , Rodda Gordon H. , Yackel Adams Amy A. , Ellingson Aaron R. , Savidge Julie A. , Dean‐Bradley Kathy , Bischof Richard
Published: December 2008

Open population mark–recapture analysis of unbounded populations accommodates some types of closure violations (e.g. emigration, immigration). In contrast, closed population analysis of such populations readily allows estimation of capture heterogeneity and behavioural response, but requires crucial assumptions about closure (e.g. no permanent emigration) that are suspect and rarely tested empirically.

In 2003, we erected a double‐sided barrier to prevent movement of snakes in or out of a 5‐ha semi‐forested study site in northern Guam. This geographically closed population of >100 snakes was monitored using a series of transects for visual searches and a 13 × 13 trapping array, with the aim of marking all snakes within the site. Forty‐five marked snakes were also supplemented into the resident population to quantify the efficacy of our sampling methods. We used the programmarkto analyse trap captures (101 occasions), referenced to census data from visual surveys, and quantified heterogeneity, behavioural response, and size bias in trappability. Analytical inclusion of untrapped individuals greatly improved precision in the estimation of some covariate effects.

A novel discovery was that trap captures for individual snakes consisted of asynchronous bouts of high capture probability lasting about 7 days (ephemeral behavioural effect). There was modest behavioural response (trap happiness) and significant latent (unexplained) heterogeneity, with small influences on capture success of date, gender, residency status (translocated or not), and body condition.

Trapping was shown to be an effective tool for eradicating large brown treesnakesBoiga irregularis(>900 mm snout‐vent length, SVL).

Synthesis and applications.Mark–recapture modelling is commonly used by ecological managers to estimate populations. However, existing models involve making assumptions about either closure violations or response to capture. Physical closure of our population on a landscape scale allowed us to determine the relative importance of covariates influencing capture probability (body size, trappability periods, and latent heterogeneity). This information was used to develop models in which different segments of the population could be assigned different probabilities of capture, and suggests that modelling of open populations should incorporate easily measured, but potentially overlooked, parameters such as body size or condition.