T cell depleted haploidentical transplantation: positive selection

Interest in mismatched transplantation arises from the fact that a suitable one-haplotype mismatched donor is immediately available for virtually all patients, particularly for those who urgently need an allogenic transplant. Work on one haplotype-mismatched transplants has been proceeding for over 20 years all over the world and novel transplant techniques have been developed. Some centres have focused on the conditioning regimens and post transplant immune suppression; others have concentrated on manipulating the graft which may be a megadose of extensively T celldepleted or unmanipulated progenitor cells. Excellent engraftment rates are associated with a very low incidence of acute and chronic GVHD and regimen-related mortality even in patients who are over 50 years old. Overall, event-free survival and transplant-related mortality compare favourably with reports on transplants from sources of stem cells other than the matched sibling

Back to the Future: Mismatched Unrelated Donor, Haploidentical Related Donor, or Unrelated Umbilical Cord Blood Transplantation?

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Intercâmbio cultural de jovens e as práticas protetivas como fator de proteção ao consumo de álcool: desafios para a psicopedagogia institucional

O presente estudo teve o objetivo de analisar as práticas familiares das famílias anfitriãs de um programa de intercâmbio de jovens para melhor compreensão do consumo de álcool pelos intercambiários na perspectiva da psicologia institucional. Foram levantas questões relacionadas ao consumo: qual seria a influência da família no consumo ou não do álcool pelo intercambiário, quais os fatores de proteção mais assertivos na dinâmica familiar para evitar o consumo de álcool pelo jovem e qual a percepção da família relacionada a esse uso. Aplicando questionário qualitativo no estudo de caso e palestra de orientação relativas ás práticas familiares foi verificado que: os participantes não consideram que a família influencia ou não o consumo de álcool, que o fator de proteção mais assertivo para evitar o consumo pelo jovem é a comunicação entre os pais e o adolescente e que os participantes da pesquisa relacionam práticas de comportamentos assertivos como fatores de proteção e risco, porém não percebem que o consumo poderia ser influenciado por eles. Durante a pesquisa fundamentada a partir dos autores Marinho-Araújo (2014), Rosa (2013), Miranda (2013), Hannum (2013), Lev Semenovitch Vygotsky (2000), Brito (2013), Ramos (2002) e Bossa (2011) foi constatado ainda que as famílias participantes da pesquisa não consideram o álcool um tipo de droga e não se percebem como influenciadores no consumo da substância

O atual padrão das intervenções internacionais de proteção humana : atores, cenários e instrumentos de ação

Tese (doutorado)—Universidade de Brasília, Instituto de Relações Internacionais, Programa de Pós-Graduação em Relações Internacionais, 2018.Uma característica marcante das relações internacionais no período Pós-Guerra Fria tem sido a crescente disposição por parte dos membros da comunidade internacional a usar a força armada para conter violações massivas de direitos humanos em cenários de conflito armado e crise humanitária. Trata-se das intervenções internacionais de proteção humana, conceito utilizado para descrever o uso de forças armadas estrangeiras para conter tais violações com base em normas internacionais de proteção humana e na aprovação da comunidade internacional. A partir dos anos 2010, tais intervenções formam um padrão de ocorrência, definido por um arcabouço jurídico-normativo que as legitimam, atores dispostos e capazes a conduzi-las, cenários de ocorrência específicos e conformação operacional própria. Esse é o objeto de estudo deste trabalho, sendo seu objetivo a determinação desse padrão de acordo com seus atores, cenários e meios de condução, analisando-o a partir das normas internacionais de proteção humana e das regras do Sistema Nações Unidas.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).A marked characteristic of international relations in the post-Cold War period has been the growing willingness by the members of the international community to use armed force to contain massive human rights violations in armed conflict and humanitarian crisis scenarios. These are the international intervention for human protection, concept used to describe the use of foreign armed forces to contain such violations based in international norms of human protection and on the approval of the international community. Starting in the 2010s, these interventions form a pattern of occurrence, defined by a legal-normative framework, players willing and able to undertake them, specific occurrence scenarios and operation design of their own. This is the object of study of this work, being the determination of this pattern according to its players, scenarios and means of analyzed from the international norms of human protection and the Unites Nations System’s rule its objective

As políticas europeias de segurança e defesa e a intervenção na Líbia

Dissertação (mestrado)—Universidade de Brasília, Instituto de Relações Internacionais, Programa de Pós-Graduação em Relações Internacionais, 2013.A intervenção na crise líbia de 2011, ainda que tenha sido legitimada em bases humanitárias, foi motivada, em grande parte, por preocupações de segurança dos Estados europeus membros da União Europeia e da Organização do Tratado do Atlântico Norte. A análise dessa intervenção revela, portanto, muito acerca das políticas europeias de segurança e defesa e do atual quadro das intervenções internacionais de proteção humana. O propósito deste trabalho é demonstrar a existência interesses estratégicos e motivações não humanitárias por trás da deflagração da referida intervenção. Para alcançá-lo, são apresentadas análises das políticas europeias de segurança e defesa no período Pós-Guerra Fria e do atual quadro das intervenções internacionais, aos se seguem o estudo de caso e a avaliação da intervenção na Líbia. A conjunção de tais análises permite concluir que a intervenção na Líbia ocorreu principalmente devido às preocupações de segurança e interesses estratégicos de países europeus, os quais utilizaram as normas internacionais de proteção humana para justificar e legitimar a ocorrência da intervenção. ______________________________________________________________________________ ABSTRACTThe 2011 intervention on the Libyan crisis, although it has been legitimized on humanitarian grounds, was motivated in large by security concerns of European states members of the European Union and of the North Atlantic Treaty Organization. The analysis of that intervention thus reveals much about the European security and defense policies and the current framework of international intervention for human protection. The purpose of this work is to demonstrate the existence of strategic interests and non-humanitarian motivations behind the outbreak of that intervention. To achieve it, it is presented analyzes of the European security and defense policies in the post-Cold War period and the current framework of international interventions, followed by the case study and the evaluation of the intervention in Libya. The conjunction of these analyzes shows that the intervention in Libya occurred primarily due to security concerns and strategic interests of European countries, which used international norms of human protection to justify and legitimize the occurrence of the intervention

Host defense pathways against fungi : the basis for vaccines and immunotherapy

Fungal vaccines have long been a goal in the fields of immunology and microbiology to counter the high mortality and morbidity rates owing to fungal diseases, particularly in immunocompromised patients. However, the design of effective vaccination formulations for durable protection to the different fungi has lagged behind due to the important differences among fungi and their biology and our limited understanding of the complex host–pathogen interactions and immune responses. Overcoming these challenges is expected to contribute to improved vaccination strategies aimed at personalized efficacy across distinct target patient populations. This likely requires the integration of multifaceted approaches encompassing advanced immunology, systems biology, immunogenetics, and bioinformatics in the fields of fungal and host biology and their reciprocal interactions.The studies were supported by the Specific Targeted Research Project “ALLFUN” (FP7-HEALTH-2009-260338) and the Fondazione per la Ricerca sulla Fibrosi Cistica (FFC#21/2010, with the contribution of Francesca Guadagnin, Coca Cola Light® Tribute to Fashion and Delegazione FFC di Belluno). Agostinho Carvalho and Cristina Cunha were financially supported by fellowships from Fundação para a Ciência e Tecnologia, Portugal (contracts SFRH/BPD/46292/2008 and SFRH/BD/65962/2009, respectively)

Current evidence of antifungal prophylaxis and therapy in pediatric patients

Invasive fungal infections (IFI) are an important complication in pediatric haematological and oncological patients who undergo intensive chemotherapy for leukemia, solid tumour at advanced stage or relapsed, and hematopoietic stem cell transplantation. The incidence of IFI is lower than bacterial infection but mortality rate remains high. This review is designed to help paediatric oncologists in choosing the appropriate anti-fungal strategy and agents for prophylaxis, empirical, pre-emptive and specific therapy on the basis of published evidence

Immunogenetic profiling to predict risk of invasive fungal diseases : where are we now?

Invasive fungal diseases remain nowadays life-threatening conditions affecting multiple clinical settings. The onset of these diseases is dependent on numerous factors, of which the "immunocompromised" phenotype of the patients is the more often acknowledged. However, and despite comparable immune dysfunction, not all patients are ultimately susceptible to disease, suggesting that additional risk factors, likely of genetic nature, may also be important. In the last years, genetic variants in several immune-related genes have also been proposed as major determinants of the susceptibility pattern of high-risk patients to invasive fungal diseases. Altogether, these findings highlighted the crucial significance of the individual genetic make-up in defining susceptibility to infection, providing a compelling rationale for the introduction of the immunogenetic profile as a risk prediction measure that may ultimately help to guide clinicians in the use of prophylaxis and preemptive fungal therapy in high-risk patients.Ricerca sulla Fibrosi Cistica (Project number FFC#21/2010)Fundação para a Ciência e a Tecnologia (FCT) SFRH/BD/65962/2009, SFRH/BPD/46292/200

PROTEASOME INHIBITORS MODULATE OSTEOCYTE DEATH AND AUTOPHAGY IN MULTIPLE MYELOMA.

Background: Cell death and autophagy are the main cellular processes involved in the regulation of bone remodeling by osteocytes. Recently we have demonstrated that an increased osteocyte death is involved in multiple myeloma (MM)-induced osteolysis through the upregulation of osteoclast recruitment. Aims: Because proteasome inhibitors including Bortezomib (BOR) are known to be able to target osteoblasts in this study we have investigated the potential effect of these drugs on osteocytes and their cell death and autophagy. Methods: Firstly the effect of the proteasome inhibitors BOR and MG262 on osteocyte viability was evaluated in vitro in murine osteocytic cell line MLO-Y4 and in the human pre-osteocytic one HOB-01. Both cell lines were co-coltured for 48 hours in the presence or absence of the human myeloma cell lines (HMCLs) RPMI8226 and JJN3, placed in a transwell insert in the presence or the absence of BOR or MG262. Moreover the effect of proteasome inhibitors on dexamethasone (DEX)-induced MLO-Y4 death, obtained at high doses (10-5-10-6M), was checked in combination with PTH(1-34). To evaluate the presence of autophagy and apoptosis in osteocytes, we checked the expression of both autophagic marker LC3 and apoptotic marker APAF-1 by confocal microscopy in the co-colture system with MLO-Y4 and RPMI-8226. Finally we performed a retrospective histological evaluation on bone biopsies of a cohort of 31 newly diagnosis MM underwent to different treatments including BOR-based regimen. Bone biopsies were obtained at the diagnosis and after an average time of 12 months of treatment. Osteocyte viability was evaluated in a total of 500 lacunae per histological sections. Results: The in vitro treatment with BOR or MG262 significantly blunted MLO-Y4 and HOB-01 cell death. Similarly, DEXinduced MLO-Y4 death was reduced by proteasome inhibitors. Interestingly, we found that both proteasome inhibitors potentiated the PTH (1-34) short-term effects on DEX-induced osteocyte death. Prevalence of autophagic cell death compared to apoptosis was observed in this system. In line with these data, we showed that neither the HMCLs nor treatment with DEX increase the apoptotic death and caspase 3 activation in both MLO-Y4 and HOB-01 cell lines. BOR treatment increased the basal level of LC3 indicating a pro-survival and protective function of autophagy against the BOR-induce stress. On the contrary, when the cells undergo to a stronger stress such as in the presence of HMCLs or by treatment with high dose of DEX we found that both proteasome inhibitors blocked autophagic cell death in osteocytes. In the in vivo study we found a significant increase of the number of viable osteocytes in MM patients treated with BOR-based regimen as compared to those treated without BOR (% median increase: +6% vs. +1.30%; p=0.017). Patients treated with BOR alone showed the highest increase of osteocyte viability, as compared to those either treated without BOR (+11.6% vs. +1.3%, p=0.0019) or treated with BOR plus DEX (+11.6% vs. +4.4%, p=0.01). On the other hand, any significant difference was not observed in patients treated with Thalidomide (THAL) or Immunomodulatory drugs (IMiDs) than in those untreated with these drugs (p= 0.7). A multiple regression non-parametric analysis showed that BOR had a significant positive impact on osteocyte viability (p=0.042) whereas THAL/IMiDs as well as Zoledronic acid (ZOL) treatments have not (p=0.2). BOR also counterbalanced the negative effect of DEX treatment (p=0.035). Summary/Conclusion: Our data suggest that proteasome inhibitors blunted osteocyte cell death induced by MM cells and DEX through the modulation of the autophagy and potentiated the effect of PTH. Overall our in vitro and in vivo data support the use of BOR to improve bone integrity in MM patients

Jack of all trades: thymosin α1 and its pleiotropy

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