Significance of chemokine receptor expression in aggressive NK cell leukemia

ArticleLEUKEMIA. 19(7): 1169-1174 (2005)journal articl

Deciphering the role of Epstein-Barr virus in the pathogenesis of T and NK cell lymphoproliferations

Epstein-Barr virus (EBV) is a highly successful herpesvirus, colonizing more than 90% of the adult human population worldwide, although it is also associated with various malignant diseases. Primary infection is usually clinically silent, and subsequent establishment of latency in the memory B lymphocyte compartment allows persistence of the virus in the infected host for life. EBV is so markedly B-lymphotropic when exposed to human lymphocytes in vitro that the association of EBV with rare but distinct types of T and NK cell lymphoproliferations was quite unexpected. Whilst relatively rare, these EBV-associated T and NK lymphoproliferations can be therapeutically challenging and prognosis for the majority of patients is dismal. In this review, we summarize the current knowledge on the role of EBV in the pathogenesis of these tumours, and the implications for treatment. \ud \u

Aggressive NK-Cell Leukemia

Aggressive NK cell leukemia (ANKL) is a rare malignant lymphoproliferative disorder of mature NK cells closely associated with Epstein-Barr virus (EBV) and more common in East Asia than in other areas. Significant variations exist in the morphology of ANKL tumor cells, from typical large granular lymphocyte morphology to highly atypical features with basophilic cytoplasm containing azurophilc granules. The main involved sites are hepatosplenic lesions, bone marrow and peripheral blood, and nasal or skin lesions are infrequent. A fever and liver dysfunction with an often rapidly progressive course are the main clinical symptoms, including hemophagocytic syndrome and disseminated intravascular coagulation. Although the outcome had been dismal for decades, with a median survival of less than three months, the introduction of combined chemotherapy including L-asparaginase and allogeneic hematopoietic cell transplantation has helped achieve a complete response and potential cure for some patients. With the advent of next-generation sequencing technologies, molecular alterations of ANKL have been elucidated, and dysfunctions in several signaling pathways, including the JAK/STAT pathway, have been identified. Novel target approaches to managing these abnormalities might help improve the prognosis of patients with ANKL

Isolamento, caracterização e viabilidade tecnológica de bifidobactérias de origem humana com atividade potencialmente probiótica

Tese(doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Agrárias, Programa de Pós-Graduação em Ciência dos Alimentos, Florianópolis, 2009.Probióticos são suplementos alimentares microbianos vivos que, quando ingeridos, apresentam efeitos benéficos para o hospedeiro, promovendo o equilíbrio microbiano intestinal. São comercializados de diferentes formas, sendo que a mais popular e acessível no Brasil são os leites fermentados. A seleção de cepas baseadas em atitudes tecnológicas é um aspecto crítico do desenvolvimento de um alimento funcional probiótico. As bactérias probióticas devem exibir resistência aos processos tecnológicos usados na preparação do veículo. O presente trabalho teve por objetivo verificar a viabilidade tecnológica de bifidobactérias probióticas de origem fecal humana, a fim de auxiliar na escolha do veículo para a aplicação destas bactérias. As bifidobactérias foram isoladas de fezes de recém-nascidos, identificadas por meio de PCR e ARDRA e caracterizadas quanto a sua atividade probiótica, onde mostraram-se resistentes ao suco gástrico e à bile. Posteriormente foram testadas frente aos ingredientes (leite de vaca, extrato de soja e soro de queijo), na presença das bactérias do iogurte e de aditivos alimentares permitidos pela legislação vigente, verificando desta forma, o seu potencial para o uso na indústria de laticínios. As bifidobactérias isoladas apresentaram resistência a valores baixos de pH, mantendo-se viáveis e dentro dos padrões aceitáveis (106 UFC/mL), bem como apresentaram crescimento ao serem expostas ao oxigênio, indicando serem aerotolerantes. Entre os aditivos pesquisados, foram observadas pequena atividade inibitória do crescimento somente quando avaliadas na presença de NaCl e dos conservantes nisina, lisozima e sorbato de potássio, com diminuição da viabilidade das cepas isoladas, porém estatisticamente, não houve diferença significativa entre o controle e as amostras avaliadas na presença dos aditivos.Probiotics are live microbial food supplements which when ingested, have beneficial effects for the host by stimulating the intestinal microbial balance. Are marketed in different ways, and the most popular and accessible in Brazil are the fermented milk. The selection of strains based on technology attitudes is a critical aspect of developing a probiotic functional food. The probiotic bacteria should exhibit resistance to technological processes used in the preparation of the vehicle. This study aimed to verify the technological feasibility of bifidobacteria probiotic of human fecal origin, to assist in the choice of vehicle for the application of these bacteria. The bifidobacteria were isolated from feces of newborn babies, identified by PCR and ARDRA and characterized its activity in probiotics, which were resistant to gastric juice and bile. Were subsequently tested against the ingredients (cow's milk, soymilk and cheese whey) in the presence of bacteria in yogurt and food additives permitted by law, verifying thus the potential for use in the dairy industry. The bifidobacteria isolated showed resistance to low pH values, remaining viable and within acceptable standards (106 CFU / mL), and showed growth when exposed to oxygen, indicating they are aerotolerance. Among the additives studied, were some of the growth inhibitory activity only when measured in the presence of NaCl of preservatives nisin, lysozyme and potassium sorbate, with decreased viability of the strains

IKAROS and LEUKEMIA

Acute lymphoblastic leukemia (ALL) is characterized by an accumulation of immature lymphoid cells in the bone marrow and is the most common cancer type in children. It is an immunophenotypically, morphologically, clinically, and genetically heterogeneous disorder that comprises several distinct subtypes. Proper classification is important because determining the correct subtype plays a vital role for prognostication and treatment strategy. During the last decades, the use of polychemotherapy and implementation of risk stratification based on the presence of certain acquired genetic changes in pediatric B-cell precursor (BCP) ALL have increased the overall survival rates substantially; they are now approaching 90%. This notwithstanding, 20% of patients still relapse and only half of these survive. A considerable proportion of all relapses lacks the high risk-stratifying genetic changes included in most current ALL treatment protocols. Hence, it is important to identify novel genetic features associated with treatment failure to ensure proper therapy intensity and to detect genes and pathways that in the future can be targeted by specific drugs. To identify relapse-associated genetic aberrations in pediatric BCP ALL, single nucleotide polymorphism array analyses were performed on uniformly treated patients accrued between 1992 and 2011 from the Lund and Linköping University Hospitals (Article I). In the 191 successfully analyzed cases, deletions of IKZF1 (∆IKZF1) and SPRED1 were shown to be associated with a poor prognosis, with ∆IKZF1 being an independent risk factor for relapse. To ascertain whether ∆IKZF1 is an independent risk factor also in the context of minimal residual disease (MRD) findings, an extended cohort including all 334 Swedish pediatric BCP ALL cases with known IKZF1 status was investigated (Article II). That study confirmed that ∆IKZF1 confers a poor prognosis, revealed that such deletions are particularly common in cases with uninformative cytogenetics, and showed that the prognostic impact of ∆IKZF1 is independent of MRD stratification. However, coexisting genetic changes may play a role in modifying the pathogenetic and/or clinical impact of ∆IKZF1. Therefore, ∆IKZF1-positive cases were investigated further in Article III in order to identify additional, recurrent changes. Furthermore, targeted deep sequencing of all IKZF1 exons in 140 BCP ALL cases was performed, identifying sequence mutations (mutIKZF1) in 5.7%. Of the mutIKZF1-positive cases, one-fourth also harbored ∆IKZF1. In total, 35 cases with IKZF1 abnormalities (abnIKZF1), comprising ∆IKZF1 and/or mutIKZF1, could be analyzed with regard to other genetic anomalies. These analyses showed that CRLF2 rearrangements, caused by deletions of the pseudoautosomal region 1 (PAR1), and JAK2 mutations were significantly overrepresented in abnIKZF1-positive cases and that the presence of PAR1 deletions conferred a poor prognostic impact. Thus, in order to ascertain correctly the clinical ramifications of abnIKZF1 in pediatric BCP ALL, PAR1 deletions should possibly also be screened for

Pathogenesis of the \u3cem\u3eHelicobacter\u3c/em\u3e Induced Mucosal Disease: A Dissertation

Helicobacter pylori causes chronic gastritis, peptic ulceration and gastric cancer. This bacterium is one of the most prevalent in the world, but affects mostly the populations with a lower socioeconomical status. While it causes gastric and duodenal ulcers in only 20% of infected patients, less then 1% will develop gastric adenocarcinoma. In fact, H. pylori is the most important risk factor in developing gastric cancer. Epidemiological studies have shown that 80% of gastric cancer patients are H. pylori positive. The outcome of the infection with this bacterium depends on bacterial factors, diet, genetic background of the host, and coinfection with other microorganisms. The most important cofactor in H. pylori induced disease is the host immune response, even though the exact mechanism of how the bacterium is causing disease is unknown. The structural complexity of Helicobacter bacteria makes us believe that different bacterial factors interact with different components of the innate immunity. However, as a whole bacterium it may need mainly the TLR2 receptor to trigger an immune response. The type of adaptive immunity developed in response to Helicobacter is crucial in determining the consequences of infection. It is now known for decades that a susceptible host will follow the infection with a strong Th1 immune response. IFNγ, IL-12, IL-1β and TNF-α are the key components of a strong adaptive Th1 response. This is further supported by our work, where deficient T-bet (a master regulator for Th1 response) mice were protected against gastric cancer, despite maintaining an infection at similar levels to wild type mice. On the other hand, a host that is resistant to Helicobacter develops an infection that is followed by a Th2 response sparing the mucosa from severe inflammation. Human studies looking at single nucleotide polymorphism of cytokines, like IL-1β, IL-10 and TNF-α have clearly demonstrated how genotypes that result in high levels of IL-1β and TNF-α, but low IL-10 expression may confer a 50-fold higher risk in developing gastric cancer. The outcome of Helicobacter infection clearly relies on the immune response and genetic background, however the coinfection of the host with other pathogens should not be ignored as this may result in modulation of the adaptive immunity. In studying this, we took advantage of the Balb/C mice that are known to be protected against Helicobacter induced inflammation by mounting a strong Th2 polarization. We were able to switch their adaptive immunity to Th1 by coinfected them with a T. gondii infection (a well known Th1 infection in mice). The dual infected mice developed severe gastritis, parietal cell loss and metaplastic changes. These experiments have clearly shown how unrelated pathogens may interact and result in different clinical outcomes of the infected host. A strong immune response that results in severe inflammation will also cause a cascade of apoptotic changes in the mucosa. A strict balance between proliferation and apoptosis is needed, as its disruption may result in uncontrolled proliferation, transformation and metaplasia. The Fas Ag pathway is the leading cause of apoptosis in the Helicobacter-induced inflammation. One mechanism for escaping Fas mediating apoptosis is upregulation of MHCII receptor. Fas Ag and MHCII receptor interaction inhibits Fas mediated apoptosis by an impairment of the Fas Ag receptor aggregation when stimulated by Fas ligand. Because H. pylori infection is associated with an upregulation of the MHCII levels on gastric epithelial cells, this indeed may be one mechanism by which cells escape apoptosis. The link between chronic inflammation and cancer is well known since the past century. Helicobacter infection is a prime example how a chronic inflammatory state is causing uncontrolled cell proliferation that results in cancer. The cell biology of “cancer” is regarded not as an accumulation of cells that divide without any control, but rather as an organ formed of cancer stem cells, tumor stromal support cells, myofibroblasts and endothelial cells, which function as a group. The properties of the cancer stem cells are to self-renew and differentiate into tumor cells thus maintaining the tumor grow, emphasizing that a striking similarity exists between cancer stem cells and tissue stem cells. We looked into what role would BMDCs play in chronic inflammation that causes cancer. Using the mouse model of Helicobacter induced adenocarcinoma we discovered that gastric cancer originates from a mesenchymal stem cell coming from bone marrow. We believe that chronic inflammation, in our case of the stomach, sets up the perfect stage for bone marrow stem cells to migrate to the stomach where they are exposed to inflammatory stimuli and transform into cancer stem cells. One of the mechanism by which the MSC migrate to the inflammation site is the CXCR4/SDF-1 axis. Our work sheds new light on Helicobacter induced gastric cancer pathogenesis. I hope that our findings will promote the development of new therapies in the fight against this deadly disease

Coronary effects of endothelins

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