Identification of novel prognostic markers in cervical intraepithelial neoplasia using LDMAS (LOH Data Management and Analysis Software).

BACKGROUND: Detection of Loss of Heterozygosity (LOH) is one of the most common molecular applications in the study of human diseases, in particular cancer. The technique is commonly used to examine whether a known tumour suppressor gene is inactivated or to map unknown tumour suppressor gene(s). However, with the increasing number of samples analysed using different software, no tool is currently available to integrate and facilitate the extensive and efficient data retrieval and analyses, such as correlation of LOH data with various clinical data sets. RESULTS: An algorithm to identify prognostic disease markers is devised and implemented as novel software called LDMAS. LDMAS is a software suite designed for data retrieval, management and integrated analysis of the clinico-pathological data and molecular results from independent databases. LDMAS is used in stratification of disease stages according to clinical stage or histological features and correlation of various clinico-pathological features with molecular findings to obtain relevant prognostic markers such as those used in predicting the outcome of cervical intraepithelial neoplasia (CIN). This approach lead to the identification of novel prognostic cervical cancer markers and extraction of useful clinical information such as correlation of Human Papilloma Virus (HPV) status with CIN lesions. CONCLUSIONS: A novel software called LDMAS is implemented and used to extract and identify prognostic disease markers. The software is used to successfully identify 4 novel prognostic markers that can be used to predict the outcome of CIN. LDMAS provides an essential platform for the extraction of useful information from large amount of data generated by LOH studies. LDMAS provides three unique and novel features for LOH analysis: (1) automatic extraction of relevant data from patient records and reports (2) correlation of LOH data with clinico-pathological data and (3) storage of complex data in flexible format. The first feature automates the creation of database of clinically relevant information from huge amount of data, the second feature extracts useful biomedical information such as prognostic markers in CIN and the third feature simplifies the statistical analyses of the data and allows non-statisticians to carry out the analysis. Additionally, LDMAS can be used to extract clinically useful markers from other diseases and interface to high throughput genotyping analysis software such as GDAS used to generate LOH data from Affymetrix GeneChip Mapping arrays.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

An analysis of GAVI, the Global Fund and World Bank support for human resources for health in developing countries

Shortages, geographic imbalances and poor performance of health workers pose major challenges for improving health service delivery in developing countries. In response, multilateral agencies have increasingly recognized the need to invest in human resources for health (HRH) to assist countries in achieving their health system goals. In this paper we analyse the HRH-related activities of three agencies: the Global Alliance for Vaccines and Immunisation (GAVI); the Global Fund for Aids, Tuberculosis, and Malaria (the Global Fund); and the World Bank. First, we reviewed the type of HRH-related activities that are eligible for financing within each agency. Second, we reviewed the HRH-related activities that each agency is actually financing. Third, we reviewed the literature to understand the impact that GAVI, Global Fund and World Bank investments in HRH have had on the health workforce in developing countries. Our analysis found that by far the most common activity supported across all agencies is short-term, in-service training. There is relatively little investment in expanding pre-service training capacity, despite large health worker shortages in developing countries. We also found that the majority of GAVI and the Global Fund grants finance health worker remuneration, largely through supplemental allowances, with little information available on how payment rates are determined, how the potential negative consequences are mitigated, and how payments are to be sustained at the end of the grant period. Based on the analysis, we argue there is an opportunity for improved co-ordination between the three agencies at the country level in supporting HRH-related activities. Existing initiatives, such as the International Health Partnership and the Health Systems Funding Platform, could present viable and timely vehicles for the three agencies to implement this improved co-ordinatio

An evaluation of the stimulants and impediments to innovation within PFI/PPP projects

This paper identifies the theoretical stimulants and impediments associated with the implementation of PFI/PPP (Private Finance Initiative/Public Private Partnership) projects. A current defect of this procurement approach is the unintentional constraint upon the innovations incorporated into the development of PFI projects. A critical evaluation of the published literature has been utilized to synthesize a theoretical model. The paper proposes a theoretical model for the identification of potential innovation stimulants and impediments within this type of procurement. This theoretical model is then utilised to evaluate four previously completed PFI projects. These project case-studies have been examined in detail. The evaluation demonstrates how ineffective current procedures are. The application of this model before project letting could eliminate unintentional constraints and stimulate improved innovation within the process. The implementation of the model could improve the successful delivery of innovation within the entire PFI/PPP procurement process

Molecular Pathogenesis of MALT lymphoma

The original dissertation included a number or articles which were excluded from the digital file for copyright reasons. This is a list of the articles:1) Hamoudi RA, Appert A, Ye H, Ruskone-Fourmestraux A, Streubel B, Chott A, Raderer M, Gong L, Wlodarska I, De Wolf-Peeters C, MacLennan KA, de Leval L, Isaacson PG, & Du MQ. Differential expression of NF-kappaB target genes in MALT lymphoma with and without chromosome translocation: insights into molecular mechanism. Leukemia. 2010 Aug;24(8):1487-1497 http://www.ncbi.nlm.nih.gov/pubmed/205206402) Ye H, Gong L, Liu H, Hamoudi RA, Shirali S, Ho L, Chott A, Streubel B, Siebert R, Gesk S, Martin-Subero JI, Radford JA, Banerjee S, Nicholson AG, Ranaldi R, Remstein ED, Gao Z, Zheng J, Isaacson PG, Dogan A & Du MQ. MALT lymphoma with t(14;18)(q32;q21)/IGH-MALT1 is characterized by strong cytoplasmic MALT1 and BCL10 expression. J Pathol. 2005 Feb;205(3):293-301. http://www.ncbi.nlm.nih.gov/pubmed/156824433) Liu H, Hamoudi RA, Ye H, Ruskone-Fourmestraux A, Dogan A, Isaacson PG & Du MQ. t(11;18)(q21;q21) of mucosa-associated lymphoid tissue lymphoma results from illegitimate non-homologous end joining following double strand breaks. Br J Haematol. 2004 May;125(3):318-329. http://www.ncbi.nlm.nih.gov/pubmed/150864124) Liu H, Ye H, Ruskone-Fourmestraux A, De Jong D, Pileri S, Thiede C, Lavergne A, Boot H, Caletti G, Wündisch T, Molina T, Taal BG, Elena S, Thomas T, Zinzani PL, Neubauer A, Stolte M, Hamoudi RA, Dogan A, Isaacson PG & Du MQ. T(11;18) is a marker for all stage gastric MALT lymphomas that will not respond to H. pylori eradication. Gastroenterology. 2002 May;122(5):1286-1294. http://www.ncbi.nlm.nih.gov/pubmed?term=119845155) Liu H, Ye H, Dogan A, Ranaldi R, Hamoudi RA, Bearzi I, Isaacson PG & Du MQ. T(11;18)(q21;q21) is associated with advanced mucosa-associated lymphoid tissue lymphoma that expresses nuclear BCL10. Blood. 2001 Aug 15;98(4):1182-1187. http://www.ncbi.nlm.nih.gov/pubmed?term=114934686) Liu H, Ruskon-Fourmestraux A, Lavergne-Slove A, Ye H, Molina T, Bouhnik Y, Hamoudi RA, Diss TC, Dogan A, Megraud F, Rambaud JC, Du MQ & Isaacson PG. Resistance of t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to Helicobacter pylori eradication therapy. Lancet. 2001 Jan 6;357(9249):39-40. http://www.ncbi.nlm.nih.gov/pubmed?term=11197361Mucosa associated lymphoid tissue (MALT) lymphoma is characterized by t(11;18)(q21;q21)/API2-MALT1, t(1;14)(p22;q32)/BCL10-IGH and t(14;18)(q32;q21)/IGH-MALT1, which commonly activate the NF-κB pathway. Gastric MALT lymphomas harbouring such translocation do not respond to Helicobacter pylori eradication, while those without translocation can be cured by antibiotics. To understand the molecular mechanism of MALT lymphoma with and without chromosome translocation, 24 cases (15 translocation-positive and 9 translocation-negative) of MALT lymphomas together with 7 follicular lymphomas and 7 mantle cell lymphomas were analysed by Affymetrix gene expression microarray platform. Unsupervised clustering showed that cases of MALT lymphoma were clustered as a single branch. However, within the MALT lymphoma group, translocation-positive cases were intermingled with translocation-negative cases. Gene set enrichment analysis (GSEA) of the NF-κB target genes and 4394 additional gene sets covering various cellular pathways, biological processes and molecular functions showed that translocation-positive MALT lymphomas were characterized by an enhanced expression of NF-κB target genes, particularly TLR6, CCR2, CD69 and BCL2, while translocation-negative cases were featured by active inflammatory and immune responses, such as IL8, CD86, CD28 and ICOS. Separate analyses of the genes differentially expressed between translocation-positive and negative cases and measurement of gene ontology term in these differentially expressed genes by hypergeometric test reinforced the above findings by GSEA. The differential expression of these NF-κB target genes between MALT lymphoma with and without translocation was confirmed by quantitative RT-PCR and immunohistochemistry or Western blot. Expression of TLR6, in the presence of TLR2, enhanced both API2-MALT1 and BCL10 mediated NF-κB activation in vitro. In addition, there was cooperation between expression of BCL10, MALT1 or API2-MALT1, and stimulation of the antigen receptor or CD40 or TLR in NF-κB activation as shown by both reporter assay and IκBα degradation. Interestingly, expression of BCL10 but not API2-MALT1 and MALT1, in the presence of LPS stimulation, also triggered IκBβ degradation, suggesting activation of different NF-κB dimers between these oncogenic products. Study by co-immunoprecipitation showed that BCL10 directly interacts with MALT1. Sub-cellular localisation experiments in BJAB B-cells, showed that BCL10 localisation was affected by MALT1. When BCL10 was over-expressed, the protein was predominantly expressed in the nuclei, but when MALT1 was over-expressed, BCL10 was mainly localised in the cytoplasm. When both BCL10 and MALT1 were over-expressed, BCL10 was expressed in the cytoplasm in the early hours when the protein level was low, but in both the cytoplasm and nuclei after 9 hours when the protein level was high. Over-expression of API2-MALT1 did not shown any apparent effect on BCL10 sub-cellular localisation in vitro. Finally, comparison of MALT lymphoma expression microarray with other lymphomas showed lactoferrin to be highly expressed in MALT lymphoma. This was confirmed by qRT-PCR, showing lactoferrin to be significantly over-expressed in MALT lymphoma compared to FL and MCL. Thus lactoferrin may be a potential marker for MALT lymphoma

Comparing research investment to United Kingdom institutions and published outputs for tuberculosis, HIV and malaria: A systematic analysis across 1997-2013

Background: The "Unfinished Agenda" of infectious diseases is of great importance to policymakers and research funding agencies that require ongoing research evidence on their effective management. Journal publications help effectively share and disseminate research results to inform policy and practice. We assess research investments to United Kingdom institutions in HIV, tuberculosis and malaria, and analyse these by numbers of publications and citations and by disease and type of science. Methods: Information on infection-related research investments awarded to United Kingdom institutions across 1997-2010 were sourced from funding agencies and individually categorised by disease and type of science. Publications were sourced from the Scopus database via keyword searches and filtered to include only publications relating to human disease and containing a United Kingdom-based first and/or last author. Data were matched by disease and type of science categories. Investment (United Kingdom pounds) and publications were compared to generate an 'investment per publication' metric; similarly, an 'investment per citation' metric was also developed as a measure of the usefulness of research. Results: Total research investment for all three diseases was £1.4 billion, and was greatest for HIV (£651.4 million), followed by malaria (£518.7 million) and tuberculosis (£239.1 million). There were 17,271 included publications, with 9,322 for HIV, 4,451 for malaria, and 3,498 for tuberculosis. HIV publications received the most citations (254,949), followed by malaria (148,559) and tuberculosis (100,244). According to UK pound per publication, tuberculosis (£50,691) appeared the most productive for investment, compared to HIV (£61,971) and malaria (£94,483). By type of science, public health research was most productive for HIV (£27,296) and tuberculosis (£22,273), while phase I-III trials were most productive for malaria (£60,491). According to UK pound per citation, tuberculosis (£1,797) was the most productive area for investment, compared to HIV (£2,265) and malaria (£2,834). Public health research was the most productive type of science for HIV (£2,265) and tuberculosis (£1,797), whereas phase I-III trials were most productive for malaria (£1,713). Conclusions: When comparing total publications and citations with research investment to United Kingdom institutions, tuberculosis research appears to perform best in terms of efficiency. There were more public health-related publications and citations for HIV and tuberculosis than other types of science. These findings demonstrate the diversity of research funding and outputs, and provide new evidence to inform research investment strategies for policymakers, funders, academic institutions, and healthcare organizations.Infectious Disease Research Networ

Global funding trends for malaria research in sub-Saharan Africa: a systematic analysis

Background Total domestic and international funding for malaria is inadequate to achieve WHO global targets in burden reduction by 2030. We describe the trends of investments in malaria-related research in sub-Saharan Africa and compare investment with national disease burden to identify areas of funding strength and potentially neglected populations. We also considered funding for malaria control. Methods Research funding data related to malaria for 1997–2013 were sourced from existing datasets, from 13 major public and philanthropic global health funders, and from funding databases. Investments (reported in US$) were considered by geographical area and compared with data on parasite prevalence and populations at risk in sub- Saharan Africa. 45 sub-Saharan African countries were ranked by amount of research funding received. Findings We found 333 research awards totalling US$814·4 million. Public health research covered $308·1 million (37·8$275·2 million (33·8%). Tanzania ($107·8 million [13·2$97·9 million [12·0%]), and Kenya ($92·9 million [11·4%]) received the highest sum of research investment and the most research awards. Malawi, Tanzania, and Uganda remained highly ranked after adjusting for national gross domestic product. Countries with a reasonably high malaria burden that received little research investment or funding for malaria control included Central African Republic (ranked 40th) and Sierra Leone (ranked 35th). Congo (Brazzaville) and Guinea had reasonably high malaria mortality, yet Congo (Brazzaville) ranked 38th and Guinea ranked 25th, thus receiving little investment. Interpretation Some countries receive reasonably large investments in malaria-related research (Tanzania, Kenya, Uganda), whereas others receive little or no investments (Sierra Leone, Central African Republic). Research investments are typically highest in countries where funding for malaria control is also high. Investment strategies should consider more equitable research and operational investments across countries to include currently neglected and susceptible populations

A formação da competência intercultural entre os alunos no processo de ensino do inglés

In the international level for modern journalist a linguistic and a cultural component have become increasingly important. In addition to knowledge in the professional field, future teacher needs to possess cultural, sociocultural knowledge and skills of intercultural communication. Nowadays this problem is widely discussed due to the active growth of theoretical and practical interest in issues of intercultural communication. The introduction of a two-level education system (bachelor's and master's degrees) in Russia entails a considerable number of changes, including creating courses of a foreign language. These programs must be compiled in accordance with the new federal state standards the main demand of which is to increase the level of intercultural competence of students in the process of teaching a foreign language at a university.This article touches upon an experiment on the formation of intercultural competence of students. The different technologies as: projects, discussions, brainstorming, and roles games were used for the formation of the intercultural competence. The results of the experiment proved the effectiveness of competence-based approach in the formation of intercultural competence of future journalist.El artículo trata del subsistema ontológico de los fundamentos filosóficos de la imagen correspondiente del mundo, definiendo la comprensión típica del mundo como una unidad en una variedad de propiedades y relaciones típicas de un período histórico particular sobre la base de la interpretación filosófica apropiada de categorías tales como la materia, el movimiento, el espacio y el tiempo, necesario y accidental, posible y real, y otras categorías, atraídos por el patrimonio filosófico clásico y las enseñanzas filosóficas no clásicas. El autor señala que un evento importante en el desarrollo del enfoque sistémico fue la publicación por Immanuel Kant en 1755 de la obra "Universal Natural History and Theory of the Sky". El artículo describe el logro fundamental que es el desarrollo de la llamada "física del surgimiento" que lee para expresar el principio ("De lo existente a lo emergente") de tal manera: el paradigma evolutivo se expande y se eleva al rango de la base de todos los procesos que ingresan según la segunda ley de la termodinámica. Se establece que el holismo moderno sintetiza el evolucionismo, llevado a la idea del autodesarrollo, con un enfoque sistémico, en el que la "zona de responsabilidad" no solo es aislada sino abierta los sistemas complejos caen en. Se afirma el apoyo de la nanotecnología y el tetraedro NBI 'en su conjunto, es decir, la iniciativa NBIC, también es un complejo de autoorganización y sistema de autodesarrollo.No nível internacional para o jornalista moderno, um componente linguístico e cultural tornou-se cada vez mais importante. Além do conhecimento no campo profissional, o futuro professor deve possuir habilidades de comunicação cultural, sociocultural e intercultural. Atualmente, este problema é amplamente debatido devido ao crescimento ativo do interesse teórico e prático em questões de comunicação intercultural. A introdução de um sistema de ensino de dois níveis (bacharel e mestrado) na Rússia envolve um número considerável de mudanças, incluindo a criação de cursos em uma língua estrangeira. Estes programas devem ser compilados de acordo com as novas normas federais do estado cuja principal demanda é aumentar o nível de competência intercultural dos estudantes no processo de ensino de uma língua estrangeira em uma universidade.Este artigo aborda um experimento sobre a formação da competência intercultural dos estudantes. As diferentes tecnologias, tais como: projetos, discussões, brainstorming e role plays foram utilizados para a formação da competência intercultural. Os resultados do experimento demonstraram a eficácia da abordagem baseada em competências na formação da competência intercultural do futuro jornalista