Abstract Transplantation of stem cells derived from donors with CCR5Δ32 homozygous genotype is a potential strategy to achieve both the control of malignant hematological disease as well as sustained remission of the HIV infection, and researchers in different countries are looking for CCR5Δ32 homozygous donors to replicate such a ‘double-target’ strategy. We determined the frequency of the CCR5Δ32 variant in a sample of 1,398 bone marrow donors from Rio Grande do Sul State, Brazil. This study also evaluated whether HLA-A, HLA-B and HLA-DRB1 genotypes are homogeneously distributed between CCR5Δ32 carriers and non-carriers in a population characterized by a significant genetic admixture. The CCR5Δ32 allele frequency was 7.4% (CI0.95 6.4-8.4%), and the frequency of the Δ32/Δ32 homozygous genotype was 0.72% (CI0.95 0.34-1.31%). In general, HLA genotypes are homogeneously distributed between CCR5Δ32 carriers and non-carriers. Considering the large number of bone marrow donors in Brazil and the high CCR5Δ32 allele frequency observed in our study, our results clearly indicate the existence of a considerable amount of potential CCR5Δ32 homozygous bone marrow donors in southern Brazil, suggesting that an active search for these donors is not only feasible but an attractive and promising strategy towards effective HIV infection control and treatment. CCRΔ CCR Δ CCR5Δ3 ‘doubletarget doubletarget ‘double target double ‘double-target 1398 1 398 1,39 State HLAA, HLAA A, A HLA-A HLAB B HLADRB1 HLADRB DRB1 DRB HLA-DRB noncarriers non admixture 74 7 4 7.4 CI0.95 CI095 CI CI0 95 (CI0.9 6.48.4%, 6484 6.4 8.4% , 6 8 6.4-8.4%) Δ32Δ32 ΔΔ Δ32 Δ32/Δ3 072 0 72 0.72 0.341.31%. 034131 0.34 1.31% . 34 31 0.34-1.31%) general noncarriers. carriers. treatment CCR5Δ 139 39 1,3 7. CI0.9 CI09 9 (CI0. 48 6.48.4% 648 64 6. 84 8.4 6.4-8.4% Δ32Δ3 Δ3 Δ32/Δ 07 0.7 341 0.341.31% 03413 034 0.3 131 1.31 3 0.34-1.31% 13 1, CI0. (CI0 6.48.4 8. 6.4-8.4 Δ32Δ 0. 0.341.31 0341 03 1.3 0.34-1.31 (CI 6.48. 6.4-8. 0.341.3 1. 0.34-1.3 6.48 6.4-8 0.341. 0.34-1. 6.4- 0.341 0.34-1 0.34-

Abstract Prostate cancer (PCA) is the second most common type of cancer in the world. Nevertheless, diagnosis is still based on nonspecific methods, or invasive methods which makes clinical decision and diagnosis difficult, generating risk of both underdiagnosis and overdiagnosis. Given the high prevalence, morbidity and mortality of PCA, new strategies are needed for its diagnosis. A review of the literature on available biomarkers for PCA was performed, using the following terms: prostate cancer AND marker OR biomarker. The search was carried out in Pubmed, Science Direct, Web of Science and Clinical Trial. A total of 35 articles were used, and PHI (Prostate Health Index) and the 4Kscore tests were identified as the best well-established serum markers. These tests are based on the evaluation of expression levels of several molecules. For analysis of urine samples, Progensa, ExoDXProstate, and Mi Prostate Score Urine Test are available. All these tests have the potential to help diagnosis, avoiding unnecessary biopsies, but they are used only in association with digital rectal examination and PSA level data. The search for biomarkers that can help in the diagnosis and therapeutic management of PCA is still in its initial phase, requiring more efforts for an effective clinical application. (PCA world Nevertheless difficult overdiagnosis prevalence performed terms biomarker Pubmed Direct Trial 3 Index Kscore wellestablished well established markers molecules samples Progensa ExoDXProstate biopsies data phase application

Abstract The transmission of pathogens from wild animals to humans is called “zoonotic spillover”. Most human infectious diseases (60-75%) are derived from pathogens that originally circulated in non-human animal species. This demonstrates that spillover has a fundamental role in the emergence of new human infectious diseases. Understanding the factors that facilitate the transmission of pathogens from wild animals to humans is essential to establish strategies focused on the reduction of the frequency of spillover events. In this context, this article describes the basic aspects of zoonotic spillover and the main factors involved in spillover events, considering the role of the inter-species interactions, phylogenetic distance between host species, environmental drivers, and specific characteristics of the pathogens, animals, and humans. As an example, the factors involved in the emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic are discussed, indicating what can be learned from this public health emergency, and what can be applied to the Brazilian scenario. Finally, this article discusses actions to prevent or reduce the frequency of zoonotic spillover events.

Abstract The ongoing COVID-19 pandemic has caught the attention of the global community and rekindled the debate about our ability to prevent and manage outbreaks, epidemics, and pandemics. Many alternatives are suggested to address these urgent issues. Some of them are quite interesting, but with little practical application in the short or medium term. To realistically control infectious diseases, human, animal, and environmental factors need to be considered together, based on the One Health perspective. In this article, we highlight the most effective initiatives for the control and prevention of infectious diseases: vaccination; environmental sanitation; vector control; social programs that encourage a reduction in the population growth; control of urbanization; safe sex stimulation; testing; treatment of sexually and vertically transmitted infections; promotion of personal hygiene practices; food safety and proper nutrition; reduction of the human contact with wildlife and livestock; reduction of social inequalities; infectious disease surveillance; and biodiversity preservation. Subsequently, this article highlights the impacts of human genetics on susceptibility to infections and disease progression, using the SARS-CoV-2 infection as a study model. Finally, actions focused on mitigation of outbreaks and epidemics and the importance of conservation of ecosystems and translational ecology as public health strategies are also discussed.

Abstract Inflammation and angiogenesis are linked to the development of cancer since both can support the establishment of a tumor-prone microenvironment. The CCR5 is a major regulatory molecule involved in inflammation. The CD34 molecule is commonly described as a hematopoietic stem cell marker, and CD34+ cells are involved in the regulation of distinct physiological processes, including angiogenesis. CCR5 participates in the development of various types of cancer, and recently, a reduced CCR5 expression was associated with low CD34+ cell counts in human cord blood. A naturally occurring genetic variant of the CCR5 gene, the so-called CCR5Δ32 polymorphism, consists of a 32 base-pair deletion in the DNA, interfering in the CCR5 protein levels on the cell surface. When in homozygosis, this variant leads to a total absence of CCR5 expression on the cell surface. In heterozygous individuals, CCR5 surface levels are reduced. Based on these key findings, we hypothesize that a functional interaction can connect CCR5 and CD34 molecules (giving rise to a “CCR5-CD34 axis”). According to this, a CCR5-CD34 interaction can potentially support the development of different types of cancer. Consequently, the lack of CCR5 in association with reduced CD34+ cell counts could indicate a protective factor against the development of cancer. It is required to characterize in detail the functional relationship between CCR5 and CD34 proteins, as well as the real influence of both molecules on the susceptibility and development of cancer at population level. If our hypothesis is confirmed, the CCR5-CD34 axis may be a potential target in the development of anti-cancer therapies.

Abstract Emerging infectious diseases are a global threat. In countries like Brazil, where biodiversity is high and public health conditions in terms of infrastructure and medical care are often precarious, emerging diseases are particularly worrisome. The lack of monitoring strategies to identify pathogens with the potential to cause outbreaks or epidemics is another problem in Brazil and other developing countries. In this article, we present the history of the Sabiá virus (SABV), a pathogen that was described in the 1990s in Brazil. Several aspects of the biology and ecology of the SABV remain unknown. The SABV has the potential to cause hemorrhagic fever in humans. To date, four cases of human infections have been reported worldwide; two were naturally acquired (both in Brazil), whereas the other two were linked to occupational exposure in the laboratory environment (one in Brazil and one in the USA). In this review, we summarize the basic biological and ecological characteristics of the SABV. This is the first work to gather all available data on the historical aspects involving the cases of SABV infection along with an update on its characteristic features.

INTRODUÇÃO: Estudos têm relatado um aumento da expressão das células natural killer (NK) no sangue periférico de pacientes com esclerose sistêmica (ES). Essas células fazem parte da imunidade inata, reconhecendo células infectadas por meio dos receptores killer immunoglobulin-like receptor (KIR), que apresentam acentuado polimorfismo. Um novo modelo foi proposto prevendo a atividade das células NK, avaliando o excesso de ativação (EA), excesso de inibição (EI) ou se a célula está funcionalmente em equilíbrio (balance, B) (neutra). OBJETIVO: Avaliar a atividade das células NK em pacientes com ES e comparar com grupo-controle. MÉTODO: Cento e dez pacientes com ES e 115 controles foram estudados. Foi aplicado um novo modelo que prevê a atividade das células NK. Para esse método, considerou-se cada célula com seu respectivo ligante KIR/HLA-C e Bw4. A nomenclatura utilizada foi EA, EI e B. RESULTADOS: Nossos resultados mostraram que 63,5% dos controles saudáveis apresentavam o fenótipo KIR caracterizado por EI, em comparação com 39,1% dos pacientes com ES (P = 0,001). Considerando-se somente indivíduos com presença de KIR2DL2 (KIR2DL2+), encontramos 34,7% de EI em controles sadios e 10,9% em pacientes com ES (P < 0,001). CONCLUSÃO: Em nosso estudo, o modelo que prevê a ação das células NK mostrou que controles sadios têm maior frequência de EI quando comparados a pacientes com ES, sugerindo um efeito protetor do EI contra o desenvolvimento da ES. Outros estudos, porém, devem ser realizados para confirmar nossos dados.

INTRODUCTION: Previous studies have shown an increased expression of natural killer (NK) cells in the peripheral blood of patients with systemic sclerosis (SSc). NK cells are part of innate immunity, recognizing infected cells through killer immunoglobulin-like receptors (KIR), which show marked polymorphism. A novel model has been proposed predicting the activity of NK cells, evaluating whether there is excessive activation (EA), excessive inhibition (EI) or balance (B) (neutral). OBJECTIVE: To evaluate the activity of NK cells in patients with SSc and compare it with that of a control group. METHOD: This study comprised 110 patients with SSc and 115 healthy controls. A novel model that predicts the activity of NK cells was used. For that, cells with their respective KIR/HLA-C and Bw4 ligands were considered. The activity of NK cells was defined as EA, EI, or B. RESULTS: Our results showed that 63.5% of healthy controls had the KIR phenotype characterized by EI, as compared with 39.1% of the patients with SSc (P = 0.001). Considering only KIR2DL2-positive individuals, 34.7% of EI was found in healthy controls and 10.9% in patients with SSc (P < 0.001). CONCLUSION: In our study, the model that predicts the action of NK cells showed that healthy controls have higher frequency of EI as compared with SSc patients, suggesting a protective effect of the EI profile against the development of SSc. These results suggest a potential role of NK cells in the pathogenesis of SSc, but further studies should be conducted to confirm our data.

O antígeno leucocitário humano G (HLA-G) é uma molécula não clássica de complexo principal de histocompatibilidade (MHC) de classe I, caracterizada por baixo polimorfismo em sua região codificadora, um padrão de distribuição tecidual limitado em condições fisiológicas e expressão por meio de isoformas solúveis e acopladas à superfície de membranas por meio de splicing alternativo. O HLA-G é bastante conhecido por estar envolvido na indução e na manutenção da tolerância entre o sistema imunológico materno e o feto semialogênico ao nível da interface fetoplacentária. Além disso, diversos estudos apontam para um papel imunorregulatório mais amplo dessa molécula. Neste contexto, a expressão de HLA-G em doenças inflamatórias e reumatológicas é uma área relativamente recente de pesquisa. Os primeiros estudos descreveram a expressão de HLA-G em várias miopatias inflamatórias, dermatite atópica e psoríase cutânea. Com base nos achados de que o HLA-G poderia desviar respostas T helper para o tipo Th2, foi levantada a hipótese de que o HLA-G seria uma molécula protetora nas respostas inflamatórias. Neste artigo, revisamos os potenciais papéis da molécula HLA-G no sistema imunológico e em diversas doenças reumatológicas, tais como lúpus eritematoso sistêmico, artrite reumatoide, esclerose sistêmica e outras

Human leukocyte antigen G (HLA-G) is a non-classic class I major histocompatibility complex (MHC) molecule characterized by low polymorphism in its coding region, a limited tissue distribution pattern in physiologic conditions, and expression through soluble isoforms and isoforms bound to surface membranes through alternative splicing. HLA-G is fairly known since it is involved in induction and maintenance of tolerance between the maternal immunologic system and the semi-allogeneic fetus at the level of the fetal-placental interface. Besides, several studies have indicated a wider immunoregulatory role of this molecule. In this context, the expression of HLA-G in inflammatory and rheumatologic diseases is a relatively recent research area. The first studies described the expression of HLA-G in several inflammatory myopathies, atopic dermatitis, and cutaneous psoriasis. Based on the findings that HLA-G could divert T helper responses to the Th2 type, it was hypothesized that HLA-G would be a protective molecule in inflammatory responses. In this article, we review the potential roles of the HLA-G molecule in the immune system and in several rheumatologic diseases, such as systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, and others

HLA-G is a non-classical HLA (Human Leukocyte Antigen) molecule characterized by limited tissue distribution under normal physiological conditions and low variability at both DNA and protein levels. Several studies suggest that HLA-G could play a role, as an immunoregulatory molecule, in situations as diverse as transplantation, cancer, viral infections and inflammatory diseases. A total of 237 individuals from 21 South American tribes speaking nine different linguistic families were studied in relation to the 14 bp insertion/deletion polymorphism at the HLA-G gene. A consistent (seven in nine) excess of heterozygosity in samples classified by language was obtained. Our data supply evidences for balancing selection acting at the HLA-G 14 bp INDEL region. Enhanced fetal survival in a pathogen-rich environment may account for these findings.

The multidrug resistance (MDR) phenotype is associated with the expression of P-glycoprotein (Pgp), coded by the multigenic mdr family. Mice present the isoforms mdr1 and mdr3, which are responsible for multidrug resistance, and mdr2, that is involved in the transport of phospholipids. mdr1 expression has more recently been associated also with the secretion of steroid hormones. This work presents an RT-PCR analysis of the expression of mdr isoforms, in several organs of mice during different phases of the estrous cycle. Additionally, females were ovariectomized, submitted to different hormone treatments, and their uterus was analyzed for the expression of mdr isoforms. The results show that in the adrenal gland and ovaries mdr1 is the main isoform during proestrus, and that progesterone or a combination of progesterone and estrogen induce the expression of all mdr isoforms in the uterus of ovariectomized females. We suggest that the functions of mdr1 and mdr3 are overlapping, that mdr3 may be the more efficient isoform in the detoxification function, and that mdr1 may be more closely related to the secretion of steroid hormones.