Artificial Immune Systems - Models, algorithms and applications

Copyright © 2010 Academic Research Publishing Agency.This article has been made available through the Brunel Open Access Publishing Fund.Artificial Immune Systems (AIS) are computational paradigms that belong to the computational intelligence family and are inspired by the biological immune system. During the past decade, they have attracted a lot of interest from researchers aiming to develop immune-based models and techniques to solve complex computational or engineering problems. This work presents a survey of existing AIS models and algorithms with a focus on the last five years.This article is available through the Brunel Open Access Publishing Fun

Artificial immune systems based committee machine for classification application

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.A new adaptive learning Artificial Immune System (AIS) based committee machine is developed in this thesis. The new proposed approach efficiently tackles the general problem of clustering high-dimensional data. In addition, it helps on deriving useful decision and results related to other application domains such classification and prediction. Artificial Immune System (AIS) is a branch of computational intelligence field inspired by the biological immune system, and has gained increasing interest among researchers in the development of immune-based models and techniques to solve diverse complex computational or engineering problems. This work presents some applications of AIS techniques to health problems, and a thorough survey of existing AIS models and algorithms. The main focus of this research is devoted to building an ensemble model integrating different AIS techniques (i.e. Artificial Immune Networks, Clonal Selection, and Negative Selection) for classification applications to achieve better classification results. A new AIS-based ensemble architecture with adaptive learning features is proposed by integrating different learning and adaptation techniques to overcome individual limitations and to achieve synergetic effects through the combination of these techniques. Various techniques related to the design and enhancements of the new adaptive learning architecture are studied, including a neuro-fuzzy based detector and an optimizer using particle swarm optimization method to achieve enhanced classification performance. An evaluation study was conducted to show the performance of the new proposed adaptive learning ensemble and to compare it to alternative combining techniques. Several experiments are presented using different medical datasets for the classification problem and findings and outcomes are discussed. The new adaptive learning architecture improves the accuracy of the ensemble. Moreover, there is an improvement over the existing aggregation techniques. The outcomes, assumptions and limitations of the proposed methods with its implications for further research in this area draw this research to its conclusion

Mass cytometry analysis of the tumour-immune landscape: The role of Axl receptor kinase

Postponed access: the file will be accessible after 2020-11-20Cancer is one of the leading causes of death in Norway (2016) and worldwide. Despite the advent of new immunotherapies, malignant cancer demonstrates an intrinsic plasticity and is able to evade, adapt and suppress the immune system. An important driver for this malignant phenotype is the epithelial-to-mesenchymal transition (EMT) program, characteristic of stem cells. Previous research showed a link between the AXL receptor tyrosine kinase (Axl) and EMT. The Axl receptor is further involved in immune suppression and could therefore serve as a potential target in immunotherapy and in combination with other cancer treatments. Chemotherapeutic treatment also shows evidence of immune involvement, and the immune system plays a vital role in all forms of cancer treatment. In this study, we evaluated current immunotherapy in combination the Axl kinase inhibitor, bemcentinib. Using single cell mass cytometry we conducted 30 parameter mapping of the immune system in an experimental murine tumour model. The data was analysed using dimensionality reduction and unsupervised clustering. By studying how the immune landscape changes during tumour development and immunotherapy treatment, important insightsinto how the immune system responds to tumour development and treatment was measured and a new treatment regime was evaluated.Masteroppgave i nanovitenskapMAMN-NANONANO39

Molecular mechanisms of Tea1 cortical anchoring in Schizosaccharomyces pombe

Establishment and maintenacne of a polarized axis is essential for all organisms. Cells can either change their shape in response to extracellular cues or maintain a stable polarity axis via landmarks defined in relation to internal cues. In the fission yeast Schizosaccharomyces pombe,microtubules regulate cortical cell polarity together with the landmark protein Tea1. Tea1 is transported to cell tips on microtubule plus-­‐ends and deposited upon microtubule contact with the membrane. Although Tea1 has been shown to interact with several binding-­partners, Tea1 anchoring at the cell tip depends mostly on the membrane-­associated protein, Mod5. Tea1 and Mod5 accumulate in clusters at the cell tip in a mutually dependent manner. I used a combination of live-­‐cell imaging, FRAP (Fluorescence Recovery After Photobleaching) and computational modeling to dissect the dynamics of the Tea1-­‐Mod5 interaction. I have shown that although Tea1 is stably associated with the cell tip, Mod5 is mobile within the cell tip. I proposed a model in which Tea1 is stable at the cell tip due to self-­‐polymerization and association in the form of a cluster-­‐network. In the model, the role of Mod5 in the cluster-­‐network is to facilitate the formation of Tea1-­‐Tea1 interactions. Moreover, in the model, Mod5 is restricted to the cell tip due to iterative binding to and release from the Tea1 cluster-­‐network. The properties of the proposed Tea1 cluster-­‐ network might contribute to the behavior of Tea1 as a polarity landmark. I hypothesized that Tea1 transfer from the microtubules to the cell tip was regulated by phosphorylation. Tea1 phosphorylated residues were mapped using mass spectroscopy (MS), and identified to be mostly enriched within a central region of the protein. Using a combination of mutagenic analysis and live-­‐cell imaging I demonstrate that Tea1 phosphorylation might be required for its dissociation from the cluster-­‐network at the cell tip. This suggests that Tea1 interactions within the cluster network are phospho-­‐regulated by one of the several tip-­‐localized kinases. It has been shown in other organisms and in this thesis that comparison among MS samples requires quantitative MS methodologies. Thus, I developed a robust SILAC (Stable Isotope Labeling in Cell Culture) method to perform quantitative MS in S. pombe. As a proof-­‐of-­‐principle of the method I performed a proteome-­‐wide comparison between the late G2 and the G1/S transition of the cell cycle. The cell cycle proteome-­‐wide analysis not only quantified variation in expression levels of cell cycle regulated proteins but also identified novel cell cycle regulated proteins.It has been previously shown that Tea1, Tea3 and Mod5 can interact simultaneously, with each pair interacting independently of the third protein. I describe here a Mod5 mutagenic analysis screen designed to separate Tea1 and Tea3 binding site on Mod5. The Mod5-­‐mutants obtained from this analysis indicate that the Tea3-­‐Mod5 interaction may play a role in cell polarity establishment. Moreover, although Tea3 is non-­‐essential for the cluster-­‐network formation, Tea3 might be important for its compaction, which may be particularly important during de novo formation of cell polarity

Helicobacter pylori and its Association with Gastric and Oesophageal Carcinomas

Helicobacter pylori is one of the most common infections in man. The infection is often acquired during childhood and usually results in a chronic life-long inflammation in the gastric mucosa. The aim of our studies was to investigate the association between H. pylori seropositivity and the development of gastric and oesophageal carcinomas. Nested case-control studies were performed in the Malmö Preventive Medicine cohort consisting of 32,906 subjects. Tumour cases were identified by the Swedish National Cancer Registry. H. pylori infection was identified serologically by an in-house ELISA and a commercial Western blot method, Helicoblot 2.1. The more virulent H. pylori cagA-positive strain was identified by the CagA band in Helicoblot 2.1. We found that H. pylori seropositivity was associated with a higher risk of non-cardia gastric adenocarcinoma. H. pylori seropositivity was a risk factor for non-cardia gastric adenocarcinoma among both smoking and non-smoking subjects. CagA seropositivity was a risk factor for non-cardia gastric adenocarcinoma in the H. pylori seropositive subgroup. The size of our material did not allow the estimation of the association between H. pylori seropositivity and oesophageal adenocarcinoma or oesophageal squamous cell carcinoma, however, there was an inverse tendency associated with oesophageal squamous cell carcinoma. The Helicoblot 2.1 CagA band was evaluated in subjects with no known gastric or oesophageal malignancy. The CagA band had a bimodal peak intensity distribution. The changes in seroprevalence with year of birth suggested that CagA seropositivity was false-positive in a major proportion of H. pylori seronegative subjects when identified by Helicoblot 2.1

ANALYSIS AND SIMULATION OF TANDEM MASS SPECTROMETRY DATA

This dissertation focuses on improvements to data analysis in mass spectrometry-based proteomics, which is the study of an organism’s full complement of proteins. One of the biggest surprises from the Human Genome Project was the relatively small number of genes (~20,000) encoded in our DNA. Since genes code for proteins, scientists expected more genes would be necessary to produce a diverse set of proteins to cover the many functions that support the complexity of life. Thus, there is intense interest in studying proteomics, including post-translational modifications (how proteins change after translation from their genes), and their interactions (e.g. proteins binding together to form complex molecular machines) to fill the void in molecular diversity. The goal of mass spectrometry in proteomics is to determine the abundance and amino acid sequence of every protein in a biological sample. A mass spectrometer can determine mass/charge ratios and abundance for fragments of short peptides (which are subsequences of a protein); sequencing algorithms determine which peptides are most likely to have generated the fragmentation patterns observed in the mass spectrum, and protein identity is inferred from the peptides. My work improves the computational tools for mass spectrometry by removing limitations on present algorithms, simulating mass spectroscopy instruments to facilitate algorithm development, and creating algorithms that approximate isotope distributions, deconvolve chimeric spectra, and predict protein-protein interactions. While most sequencing algorithms attempt to identify a single peptide per mass spectrum, multiple peptides are often fragmented together. Here, I present a method to deconvolve these chimeric mass spectra into their individual peptide components by examining the isotopic distributions of their fragments. First, I derived the equation to calculate the theoretical isotope distribution of a peptide fragment. Next, for cases where elemental compositions are not known, I developed methods to approximate the isotope distributions. Ultimately, I created a non-negative least squares model that deconvolved chimeric spectra and increased peptide-spectrum-matches by 15-30%. To improve the operation of mass spectrometer instruments, I developed software that simulates liquid chromatography-mass spectrometry data and the subsequent execution of custom data acquisition algorithms. The software provides an opportunity for researchers to test, refine, and evaluate novel algorithms prior to implementation on a mass spectrometer. Finally, I created a logistic regression classifier for predicting protein-protein interactions defined by affinity purification and mass spectrometry (APMS). The classifier increased the area under the receiver operating characteristic curve by 16% compared to previous methods. Furthermore, I created a web application to facilitate APMS data scoring within the scientific community.Doctor of Philosoph

Contribution to the evaluation of clinical prognostic factors in canine lymphoma

Non-Hodgkin Lymphoma (NHL) is the most common hematopoietic cancer in dogs, from which up to 50% of the cases are diffuse large B-cell lymphomas (DLBCL). The etiology, like in humans, is believed to be multifactorial. To the date, the best response rate and best survival times are offered by a combination therapy including cyclophosphamide, vincristine, doxorubicin and prednisolone, known by the acronym of CHOP. Infectious agents, namely vector-borne agents (VBA), can induce chronic B cell stimulation and immune deregulation permitting lymphomagenesis. Also, there are several reports in literature associating NHL with VBA, namely from the genus Borrelia and Leishmania mimicking or co-existing with hematopoietic malignancies either in humans or dogs. Vector-borne agents can induce haematological and clinical changes in hosts that, when existing in cancer patients, can either mislead the interpretation of clinical signs or interfere with recognized prognostic markers, namely blood cell populations. Prognosis, after quality of life, is determinant in veterinary oncology to further proceed with a treatment. Short survival times and therapy response rates determine the option for a non standard-of-care treatment or, lately, animal euthanasia without treatment. Consequently, easy to perform, “bench-to-bedside” widely available and cost-effective prognostic markers are fundamental to obtain client financial compliance and support treatment planning and disease outcome. Obtaining serological results on vector-borne agents or haematological information trough a total blood cell count and biochemical parameters are widely available and cost effective either by an “in-house” laboratory or trough commercial laboratories. Having in mind the existing published literature on human medicine regarding haematological parameters as prognostic indicators in lymphoma and the scarse information on the veterinary field, we aimed to: 1) investigate the prevalence of infection by four vector-borne agents (Leishmania infantum, Ehrlichia canis, Anaplasma phagocytophilum and Bartonella henselae), its potential role in lymphomagenesis and its possible association with the tumour subtype and with the haematological alterations present in dogs with lymphoma and, 2) determine the prognostic value of dogs’ sex, neutered status, clinical stage, presence of anaemia, presence of neutrophilia, presence of thrombocytopenia and the ratios lymphocyte-to-monocyte (LMR), neutrophil-tolymphocyte (NLR), platelet-to-lymphocyte (PLR) and platelet-to-neutrophil (PNR) in canine DLBCL that were naïve for treatment, fully staged and received chemotherapy with a 19 week-CHOP protocol. All dogs tested negative for B. henselae, A. phagocytophilum and E. canis by both serology and molecular detection. Regarding L. infantum, 8,2% of the dogs had a positive serologic result. Leishmania infantum DNA was detected in two samples of diffuse large B-cell lymphoma (DLBCL). These results show an increased, but not significant, seropositivity (8,2%, p=0,201) and molecular detection (3,3%, p=0,166), for L. infantum in dogs with lymphoma, when compared to matched historic controls in the same geographical area. In the second study, PNR showed to be an independent prognostic marker (p≤0,001) for TTPR at 180 and 365 days. Dogs with a PNR above 0,032 were more likely to progress before 180 days (sensitivity 46,5%, specificity 87,5%, p=0,004). On univariate analysis, NLR showed a prognostic significance for LSSR at 180 (p=0,006) and 365 days (p=0,009). A baseline NLR value below 7,45 was positively associated with survival at 180 days (sensitivity of 52%, specificity of 85.3%, p=0.025). The presence of substage b, was associated with early lymphoma progression and decreased survival at 180 days (p =0.031). Anaemia significantly reduced LSSR at 365 days (p=0,028). Although it was not possible to identify, in the first study, any significant association between canine lymphoma and the studied VBA, it was of extreme importance for the discussion of the second study on the possible effects on peripheral blood cell dynamics caused by the CBVD studied. Further studies, following dogs trough their CVBD disease evolution, are worthwhile and may help clarify a possible role of these agents in lymphomagenesis. This is the first study evaluating PLR and PNR in canine DLBCL and demonstrates that PNR could be a predictor of early lymphoma progression. Since peripheral blood cell composition can be affected by several non-oncological causes, the development of larger multicenter studies with homogeneous inclusion criteria could help to better determine the true predictive values of blood cell ratios in dogs suffering from DLBCL treated with CHOP chemotherapy.O linfoma é o tumor hematopoiético mais frequente no cão com uma incidência estimada entre 13 a 114 casos por 100.000 cães em risco. A poliquimioterapia, através da utilização de um protocolo composto pelos fármacos Ciclofosfamida, Hydroxidaurorrubicina (Doxorrubicina), Oncovin® (Vincristina) e Prednisolona, designado pelo acrónimo de “CHOP”, permite obter uma taxa de remissão e tempo médio de sobrevida global de cerca de 94% e 12 meses, respectivamente. O linfoma difuso de células B grandes (LDCBG) pode constituir até cerca de 50% dos casos totais de linfoma non-hodgkin (LNH) na espécie canina e é reconhecido como o modelo natural para o mesmo tipo de neoplasia no Homem. A aplicação do esquema de classificação da Organização Mundial da Saúde nas entidades de linfoma canino (LC) é recente na medicina veterinária. A maioria dos estudos clínicos realizados no LC para avaliação da resposta à terapêutica, assim como a determinação de factores de prognóstico realizados nas últimas três décadas, sofrem de limitações significativas. Os resultados desses estudos, foram obtidos através da inclusão de diversos subtipos e graus histológicos de linfoma, assim como, da utilização de metodologias de diagnóstico, estadiamento e terapêutica variáveis. Estas limitações comprometem, ainda hoje, a avaliação da eficácia do tratamento e colocam em questão a fiabilidade de diversos factores de prognóstico descritos para o LC. Na medicina humana e veterinária existem estudos que demonstram que a localização geográfica, a demografia, os fatores sócio-económicos dos doentes e as diferenças na distribuição de subtipos de linfoma podem interferir na resposta à terapêutica e na determinação do prognóstico. Em Portugal, existe um número muito reduzido de estudos sobre o LNH no cão. Que seja do conhecimento do autor, não existem trabalhos avaliando os aspectos clínicos, nomeadamente, no que diz respeito à resposta à terapia ou prognóstico. A infecção por agentes infecciosos transmitidos por vectores (AITV), nomeadamente dos géneros Ehrlichia e Leishmania, aparece pontualmente na literatura associada a tumores hematopoiéticos nos cães. Estes agentes infecciosos promovem uma resposta inflamatória crónica do hospedeiro, que causa uma importante desregulação imunológica, contribuindo para o processo de carcinogénese, nomeadamente, para a linfomagénese ou progressão tumoral. As manifestações clínicas das infecções AITV nos cães estão associadas a um amplo espectro de anomalias clínicas e laboratoriais. A presença de adenomegalia, hepato-esplenomegalia, síndromes imunomediados (uveíte, glomerulonefrite, poliartrite, etc.), anemia, alterações no número e tipo de leucócitos circulantes ou trombocitopénia estão entre as mais frequentes. Num cão que sofra de linfoma e que esteja, também, infectado por um ou mais destes agentes infecciosos, a interpretação adequada dos sinais clínicos e das alterações dos valores laboratoriais torna-se complexa, impedindo uma correcta diferenciação do que é devido à infecção, ao linfoma ou a ambos. Qualquer inferência de uma possível ausência de resposta à terapêutica oncológica instituída, assim como a determinação da presença de indicadores prognósticos específicos do linfoma torna-se difícil ou, mesmo, impossível. Tal como em medicina humana, na medicina veterinária a obtenção de informação diagnóstica e/ou prognóstica num conceito “bench-to-bedside” é de extrema importância. A confirmação serológica ou molecular de infecção por AITV é, actualmente, rápida e está amplamente disponível. A presença de laboratórios comerciais de patologia clínica veterinária ou a disponibilização nos hospitais e clínicas veterinárias de equipamentos de hematologia com tecnologia avançada permitem, ainda, obter rapidamente um hemograma com alto nível de fiabilidade nas contagens diferenciais das populações celulares. Na oncologia clínica humana e, posteriormente, na veterinária os valores obtidos no momento do diagnóstico, através da contagem diferencial de alguns componentes celulares do sangue periférico (neutrófilos, linfócitos, monócitos, e plaquetas), bem como os rácios neutrófilos-linfócitos (NLR), linfócitos-monócitos (LMR), demonstraram ter valor prognóstico ao reflectir as interfaces inflamatórias intra-neoplásica e doente-tumor no LDCBG. Tendo em consideração a literatura publicada em medicina humana sobre o valor prognóstico da composição celular e dos rácios NLR e LMR, obtidos a partir do sangue periférico no momento do diagnóstico do LDCBG, e a escassa ou contraditória informação nesse domínio na área veterinária, foram objetivos do presente trabalho: 1) investigar a prevalência de infecção por quatro agentes transmitidos por vectores (Leishmania infantum, Ehrlichia canis, Anaplasma phagocytophilum e Bartonella henselae), o seu potencial papel na linfomagénese e a sua eventual associação com o subtipo do tumor e com as alterações hematológicas presentes em cães diagnosticados com linfoma e 2) determinar o valor prognóstico dos parâmetros sexo, estado fértil, estádio clínico do linfoma, presença de anemia, presença de neutrofilia, presença de trombocitopénia, NLR, LMR e dois rácios adicionais, nunca descritos- plaquetas-linfócitos e plaquetas-neutrófilosem cães com LDCBG em estádio III/IV tratados com um protocolo CHOP de 19 semanas. Relativamente ao primeiro estudo, foi avaliada pela primeira vez (em Portugal e na Europa) a associação entre a infecção por quatro agentes transmitidos por vectores (Leishmania infantum, Ehrlichia canis, Anaplasma phagocytophilum e Bartonella henselae) em cães com linfoma. A presença de anticorpos (IgG) assim como a detecção molecular de Bartonella henselae, Ehrlichia canis e Anaplasma phagocytophilum foram negativas em todas as amostras de cães com linfoma estudadas. Para Leishmania infantum a taxa de seropositividade e de detecção molecular foi de, respectivamente, 8,2% e 3,3%. Estes valores não se mostraram significativamente diferentes quando comparados com os controlos históricos de cães com o mesmo estilo de vida e da mesma região geográfica: 7,9% (p = 0,201) e 1,2%, (p = 0,166), respectivamente. Dos 8,2% de cães seropositivos para Leishmania infantum, 60% tinham diagnóstico de LDCBG. Os 40% restantes desenvolveram formas de linfoma indolentes (Manto e de Pequenas células). Relativamente às alterações hematológicas nos cães seropositivos para Leishmania infantum (n=5), apenas um cão, portador de linfoma de pequenas células B, não apresentou qualquer alteração hematológica. A presença de anemia leve foi observada em dois cães, um deles com trombocitopénia concomitante. Verificou-se, ainda, a presença de monocitopénia e linfopénia moderadas em dois cães diferentes. Todas as alterações do sangue periférico observadas nestes cães foram leves e não associadas ao tipo de linfoma, título serológico ou positividade molecular para Leishmania infantum. No presente estudo não foi possível diferenciar se essas alterações hematológicas estão relacionadas com o linfoma e/ou com a infecção por Leishmania infantum. Provavelmente, as alterações dos hemogramas dos cães com linfoma e com leishmaniose devem-se à ação de ambas as doenças e resposta inflamatória associada, quer na produção, quer na cinética dos elementos celulares sanguíneos, ao nível da medula óssea e do sangue periférico. Os cães com leishmaniose, quando comparados com a população geral do estudo, apresentaram um Tempo para a Progressão (TPP) e uma Sobrevivência Específica para o Linfoma (SEL) mais curtos, 90 vs. 120 e 184 vs. 206 dias, respectivamente. Devido ao número muito pequeno de cães positivos, não foi possível obter qualquer conclusão significativa sobre a associação dos tipos específicos de linfoma e o impacto nas anomalias das células do sangue periférico, assim como a sua possível implicação na linfomagénese. Relativamente ao segundo objectivo, foram avaliados o valor prognóstico dos parâmetros sexo, estado fértil, estádio clínico, presença de anemia, presença de neutrofilia, presença de trombocitopénia, NLR, LMR e os rácios plaquetas-linfócitos (PLR) e plaquetasneutrófilos (PNL) relativamente ao TPP e SEL. Foram, ainda, calculados para dois marcos temporais específicos (6 e 12 meses) a Taxa do Tempo de Progressão (TTPP) e Taxa de Sobrevivência Especifica do Linfoma (TSEL). Estes segundos cálculos permitem uma compreensão mais clara da evolução do TPP e do SEL. O PNR revelou-se um marcador prognóstico independente (p ≤ 0,001) para a TTPP aos 180 e 365 dias. Os cães com PNR acima de 0,032 apresentaram maior probabilidade de progressão do linfoma antes de 180 dias (sensibilidade 46,5%, especificidade 87,5%, p = 0,004). O NLR mostrou uma significância prognóstica para a TSEL aos 180 (p = 0,006) e 365 dias (p = 0,009). Um valor de NLR ao diagnóstico abaixo de 7,45 mostrou estar associado positivamente a uma maior probabilidade de sobrevida aos 180 dias (sensibilidade de 52%, especificidade de 85,3%, p = 0,025). Relativamente à análise de outros factores de prognóstico anteriormente validados, no presente estudo a presença do sub-estádio b, demonstrou contribuir para a progressão precoce do linfoma e diminuição da sobrevida aos 180 dias (p = 0,031). Nos cães com anemia, designadamente com concentrações de hemoglobina inferiores a 11 g/dL, a TSEL aos 365 dias foi significativamente inferior aos cães com valores de concentração de hemoglobina normais (p = 0,028). No presente estudo, os cães com linfoma na região metropolitana de Lisboa apresentaram, para os agentes infecciosos estudados, a mesma seroprevalência e taxa de detecção molecular que os controlos históricos da mesma zona geográfica e com o mesmo estilo de vida. Este primeiro estudo foi de extrema importância para permitir compreender a magnitude da infecção pelos quatro AITV estudados nos cães com linfoma e o eventual impacto no subtipo morfológico, alterações hematológicas e possível contribuição para a linfomagénese. Os presentes resultados não revalidaram factores de prognóstico anteriormente descritos para o linfoma multicêntrico no cão, como o género, o estado fértil e, no caso particular do LDCBG, o LMR, a neutrofilia e trombocitopénia ao diagnóstico. O rácio neutrófilo-linfócito demostrou valor prognóstico na sobrevida total, como anteriormente descrito. Este é o primeiro estudo a realizar a avaliação dos factores PLR e PNR em cães com LDCBG e a demonstrar que o PNR ao diagnóstico, tem um valor predictivo da progressão precoce do linfoma. Uma vez que a composição celular do sangue periférico pode ser afetada por várias causas não oncológicas, inflamatórias ou infecciosas, será importante continuar o desenvolvimento de estudos prospectivos multicêntricos com critérios de inclusão homogéneos e com um número significativo de doentes, de forma a determinar a verdadeira associação entre os AITV e a dinâmica da composição celular periférica, nos cães com LDCBG tratados com CHOP. O presente estudo adiciona dados inovadores e importantes para melhor compreender a epidemiologia do linfoma canino e, particularmente, o espectro prognóstico do LDCBG. Os indicadores de prognóstico aqui descritos estão amplamente acessíveis, são de rápida obtenção e baixo custo, permitindo uma abordagem “bench-to-bedside” na estratificação de risco dos pacientes e, consequentemente, o desenvolvimento de abordagens terapêuticas personalizadas. Uma janela para a suposta contribuição de Leishmania infantum para a linfomagénese permanece aberta e constitui um ávido assunto de pesquisa que merece ser continuado

The C3b Receptor (CR1) on Human Blood Cells

The C3b receptor (CR1) was first isolated from human erythrocyte membranes in 1979 and shown to be a large single chain polypeptide glycoprotein with a molecular weight of 205,000 daltons. CR1 isolated from erythrocyte membranes has been shown in vitro to possess cofactor activity for the I mediated cleavage of C3b to iC3b and C4b to iC4b. It also plays a role in the prevention of lysis of bystander erythrocytes by its ability to cause the decay dissociation of C4b2a3b and C3bBb formed on these cells. In addition erythrocyte CR1 in vivo is thought to play a role in the transport of opsonised immune complexes from the circulation to the reticulo enclothrlial system where they can be removed. On unstimulated phagocytic cells the primary function of CR1 is the binding of complexes opsonised with C3 and C4 degradation while on stimulated phagocytes CR1 is able to directly mediate the phagocytosis of opsonised particles. CR1 may play a role in the regulation of B lymphocyte function and on kidney podocytes CR1 may serve to prevent complement activation on the basement membrane of the glomerulus