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1.
Epigenomics ; 12(1): 69-80, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31833405

RESUMO

Despite remarkable improvements in survival of childhood acute lymphoblastic leukemia (ALL), nonresponding or relapsing patients still represent one of the most frequent causes of death by disease in children. Accurate patient risk stratification based on genetic markers could increases survival rates. miRNAs can represent novel candidates with diagnostic, predictive and prognostic potential; however, many groups investigated their involvement with contradictory results. Aim: To clarify the role of miRNAs as biomarkers through a systematic review. Results: From a revision of 45 manuscripts, we found that miR-128 and miR-181 overexpression could represent markers for ALL diagnosis and underexpression of miR-708 and miR-99a could be markers for bad prognosis. Conclusion: These signatures could refine classification and risk stratification of patients and improve ALL outcome.

2.
Front Immunol ; 9: 1709, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30083165

RESUMO

The ability of the CD300a inhibitory receptor to modulate immune cell functions and its involvement in the pathogenesis of many diseases has aroused a great interest in this molecule. Within human CD4+ T lymphocytes from healthy donors, the inhibitory receptor CD300a is differentially expressed among different T helper subsets. However, there are no data about the expression and regulation of CD300a receptor on CD4+ T cells from human immunodeficiency virus (HIV)-1-infected patients. The objective of this study was to investigate the expression of CD300a on CD4+ T cells from HIV-infected patients on suppressive combined antiretroviral therapy (cART) and cART naïve patients. Our results have demonstrated that the expression levels of this inhibitory receptor were higher on CD4+ T cells from HIV-1 infected subjects compared with healthy donors, and that cART did not reverse the altered expression of CD300a receptor in these patients. We have observed an increase of CD300a expression on both PD1+CD4+ and CD38+CD4+ T cells from HIV-1 infected people. Interestingly, a triple positive (CD300a+PD1+CD38+) subset was expanded in naïve HIV-1 infected patients, while it was very rare in healthy donors and patients on cART. Finally, we found a negative correlation of CD300a expression on CD4+ T lymphocytes and some markers associated with HIV-1 disease progression. Thus, our results show that HIV-1 infection has an impact in the regulation of CD300a inhibitory receptor expression levels, and further studies will shed light into the role of this cell surface receptor in the pathogenesis of HIV infection.

3.
Pharmacogenomics ; 19(4): 361-373, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29469670

RESUMO

Childhood acute lymphoblastic leukemia survival rates have increased remarkably during last decades due, in part, to intensive treatment protocols. However, therapy resistance and toxicity are still two important barriers to survival. In this context, pharmacoepigenetics arises as a tool to identify new predictive markers, required to guide clinicians on risk stratification and dose individualization. The present study reviews current evidence about miRNA implication on childhood acute lymphoblastic leukemia therapy resistance and toxicity. A total of 12 studies analyzing differential miRNA expression in relation to drug resistance and six studies exploring the association between miRNAs-related SNPs and drug-induced toxicities were identified. We pointed out to miR-125b together with miR-99a and/or miR-100 overexpression as markers of vincristine resistance and rs2114358 in mir-1206 as mucositis marker as the most promising results.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , MicroRNAs/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Animais , Humanos , Farmacogenética/métodos , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Taxa de Sobrevida
4.
J Microbiol Immunol Infect ; 51(4): 465-472, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28655573

RESUMO

BACKGROUND: Sepsis is a life-threatening illness with a challenging diagnosis. Current serum biomarkers are not sensitive enough for diagnosis. With the aim of finding proteins associated with sepsis, serum protein profile was compared between patients and healthy donors and serum classical inflammatory proteins were analyzed in both groups. METHODS: Serum protein profiles were characterized by two-dimensional electrophoresis (2DE). Identification of the proteins was carried out by mass spectrophotometry and their validation was performed by Enzyme-Linked-ImmunoSorbent Assay (ELISA) in a cohort of 85 patients and 67 healthy donors. Seven classical inflammatory proteins were analyzed in the same cohort by ELISA: interleukin-2 receptor α-chain (sCD25), scavenger receptor cysteine-rich-type-1 (sCD163), tumor-necrosis factor receptor superfamily-member-6 (sFas), hemeoxigenase-1 decycling (HO-1), interleukin-6 (IL-6), interleukin-18 (IL-18) and intercellular adhesion-molecule-1 (sICAM-1). RESULTS: After 2DE, 20 significantly differently expressed spots were identified by mass spectrometry analysis, revealing deregulation of six different proteins upon sepsis and 50% were validated by ELISA: Antithrombin-III (AT-III), Clusterin (CLUS) and Serum amyloid A-1 (SAA-1). Serum concentration of AT-III and CLUS was significantly lower in patients' serum, whereas SAA-1 showed higher values in septic patients. Serum concentration of the seven inflammatory proteins was significantly increased in septic patients. Functional analysis of the ten deregulated proteins revealed an enrichment of proteins related mainly to the activation of the immune response. CONCLUSION: We have identified a panel of ten potential sepsis marker proteins biologically connected and validated in a large number of patients, whose analysis could be considered as a complementary tool for the diagnosis of sepsis.


Assuntos
Biomarcadores/sangue , Proteínas Sanguíneas/análise , Sepse/diagnóstico , Estudos de Coortes , Eletroforese em Gel Bidimensional , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade
5.
Sci Rep ; 6: 32693, 2016 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-27595670

RESUMO

Neonates are more susceptible to infections than adults. This susceptibility is thought to reflect neonates' qualitative and quantitative defects in the adaptive and innate immune responses. Differential expression of cell surface receptors may result in altered thresholds of neonatal immune cell activation. We determined whether the expression and function of the lipid-binding CD300 family of receptors are different on neonatal immune cells compared to adult immune cells. A multiparametric flow cytometry analysis was performed to determine the expression of CD300 receptors on adult peripheral blood mononuclear cells and neonatal cord blood mononuclear cells. The expression of the CD300a inhibitory receptor was significantly reduced on cells from the newborn adaptive immune system, and neonatal antigen presenting cells exhibited a different CD300 receptors expression pattern. We also found differential LPS-mediated regulation of CD300 receptors expression on adult monocytes compared to cord blood monocytes, and that CD300c and CD300e-mediated activation was quantitatively different in neonatal monocytes. This is the first complete study examining the expression of CD300 receptors on human neonatal immune cells compared with adult immune cells. Significant differences in the expression and function of CD300 receptors may help to explain the peculiarities and distinctness of the neonatal immune responses.


Assuntos
Monócitos/metabolismo , Receptores Imunológicos/metabolismo , Adulto , Humanos , Imunofenotipagem , Recém-Nascido , Monócitos/imunologia , Receptores Imunológicos/imunologia
6.
Hum Immunol ; 73(7): 720-5, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22537750

RESUMO

Polymorphic Alu insertions from the MHC class I region were analyzed in 215 autochthonous Basques from Guipuzcoa and Navarre provinces, with the aim of contributing new MHC Alu data in European ancestry populations. We also seek to assess both the genetic position of native Basques among worldwide samples and the efficiency of the MHC Alu elements as ancestry informative markers (AIMs). According to the MDS and AMOVA results, worldwide populations included in the comparative analyses were grouped in three major clusters defined by genetic ancestry (Africans, Asians and Europeans). The δ values (differences in weighted allele frequencies) among ancestry groups indicated that Alu elements within the alpha-block (AluHF, AluHJ and AluHG) showed an adequate resolving power to discriminate appropriately between some of the major ancestry groups. Alpha block Alu were also revealing of the exceptionality of Basques, as they allowed for the detection of genetic heterogeneity even between Basques and the other Iberian collection considered in the analysis (Valencia). Thus, analysis of the Alu loci within the alpha-block may represent a reliable, informative and cost-effective method to explore the ancestry, geographic origins and demographic history of human populations, which can be very helpful for studies into epidemiological, forensic or evolutionary perspectives.


Assuntos
Cromossomos Humanos Par 6/metabolismo , Grupo com Ancestrais do Continente Europeu , Elementos Alu/genética , Cromossomos Humanos Par 6/genética , Frequência do Gene , Genes MHC Classe I/genética , Marcadores Genéticos , Humanos , Filogenia , Espanha
7.
Am J Hum Biol ; 23(6): 790-5, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21957018

RESUMO

OBJECTIVES: The Amazon basin is inhabited by some of the most isolated human groups worldwide. Among them, the Waorani tribe is one of the most interesting Native American populations from the anthropological perspective. This study reports a genetic characterization of the Waorani based on autosomal genetic loci. METHODS: We analyzed 12 polymorphic Alu insertions in 36 Waorani individuals from different communal longhouses settled in the Yasuní National Park. RESULTS: The most notable finding was the strikingly reduced genetic diversity detected in the Waorani, corroborated by the existence of four monomorphic loci (ACE, APO, FXIIIB, and HS4.65), and of other four Alu markers that were very close to the fixation for the presence (PV92 and D1) or the absence (A25 and HS4.32) of the insertion. Furthermore, results of the centroid analysis supported the notion of the Waorani being one of the Amerindian groups less impacted by gene flow processes. CONCLUSIONS: The prolonged isolation of the Waorani community, in conjunction with a historically low effective population size and high inbreeding levels, have resulted in the drastic reduction of their genetic diversity, because of the effects of severe genetic drift. Recurrent population bottlenecks most likely determined by certain deep-rooted sociocultural practices of the Waorani (characterized by violence, internal quarrels, and revenge killings until recent times) are likely responsible for this pattern of diversity. The findings of this study illustrate how sociocultural factors can shape the gene pool of human populations.


Assuntos
Elementos Alu , Frequência do Gene , Índios Sul-Americanos/genética , Polimorfismo Genético , Equador , Feminino , Fluxo Gênico , Deriva Genética , Humanos , Masculino
8.
Am J Hum Biol ; 23(2): 177-84, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21319246

RESUMO

OBJECTIVES: We seek to evaluate the influence of a diverse and rugged physical environment on the genetic background of human populations. METHODS: We analyzed eight polymorphic Alu insertions in 226 individuals from Jujuy province (Argentina), which is composed of several regions with well-defined geographical features and marked contrasts between them associated with differences in altitude (range: 700-3300 m). This regional division was used to assess the spatial variation of the Alu diversity. RESULTS: Deviations from Hardy-Weinberg Equilibrium expectations resulting from heterozygous deficit were found for FXIIIB and PV92 in the highest subpopulations. Several Alu elements showed genetic heterogeneity between the highest region (La Puna) and the lowest regions (Valle and Selva). Similarly, a decreasing trend of the average heterozygosity according to altitude was found. Both the centroid method and the admixture analysis unveiled a gene flow above the average in lowland populations, indicating a higher proportion of foreign genes introduced by immigrants of European and African ancestry. Furthermore, several Alu frequency clines fitting the orientation of the altitude gradient were detected. CONCLUSIONS: Our study reveals a spatial patterning of the Alu diversity in Jujuy, most likely determined by disparities in landscape and environmental features between the different subregions. Differences in the physical environment would have drastically reduced the homogenizing effects of the gene flow and would have promoted genetic drift episodes in the highest subpopulations. Microevolutionary processes detected in Jujuy have played an important role in the shaping of the gene pool of the populations from this sub-Andean zone from Argentina.


Assuntos
Altitude , Elementos Alu , Evolução Biológica , Argentina , Interpretação Estatística de Dados , Meio Ambiente , Fluxo Gênico , Frequência do Gene , Humanos , Polimorfismo Genético
9.
Ann Hum Biol ; 37(4): 488-500, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20113181

RESUMO

AIM: This work was intended to gain insights into the admixture processes occurring in Latin American populations by examining the genetic profiles of two ethnic groups from Antioquia (Colombia). SUBJECTS AND METHODS: To analyse the genetic variability, eight Alu insertions were typed in 64 Afro-Colombians and a reference group of 34 Hispanics (Mestizos). Admixture proportions were estimated using the Weighted Least Squares and the Gene Identity methods. The usefulness of the Alu elements as Ancestry Informative Markers (AIMs) was evaluated through differences in weighted allelic frequencies (delta values) and by hierarchical analysis of the molecular variance (AMOVA). RESULTS: The Afro-Colombian gene pool was largely determined by the African component (88.5-88.8%), but the most prominent feature was the null contribution of European genes. Mestizos were characterized by a major European component (60.0-63.8%) and a comparatively low proportion of Amerindian (19.2-20.7%) and African (17.0-19.3%) genes. Five of the Alu loci examined (ACE, APO, FXIIIB, PV92 and TPA25) showed an adequate resolving power to differentiate between continental groups, as indicated by delta values and AMOVA results. CONCLUSIONS: The peculiarity of the Afro-Colombian gene pool seems to be associated with intense genetic drift episodes that occurred in isolated communities founded by small groups of runaway slaves. ACE, APO, FXIIIB, PV92 and TPA25 could be efficiently utilized in studies dealing with demographic history and biogeographical ancestry in human populations.


Assuntos
Elementos Alu/genética , Grupos Étnicos/genética , Pool Gênico , África/etnologia , Análise por Conglomerados , Colômbia/etnologia , Frequência do Gene/genética , Variação Genética , Geografia , Humanos , Modelos Genéticos , Mutagênese Insercional
10.
Med Hypotheses ; 74(6): 989-92, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20110149

RESUMO

The diffusion of the cattle pastoralism across Europe during the Neolithic period was probably accompanied by the emergence and spread of diverse contagious diseases that were unknown in the Paleolithic and that would have affected the frequency of genes directly or indirectly associated with differential susceptibility and/or resistance to infectious pathogens. We therefore propose that the high frequency of the CFTR gene, and in particular, the common Delta F508 allele mutation in current European and European-derived populations might be a consequence of the impact of selective pressures generated by the transmission of pathogenic agents from domesticated animals, mainly bovine cattle, to the man. Intestinal infectious diseases were probably a major health problem for Neolithic peoples. In such a context, a gene mutation that conferred an increased resistance to the diseases caused by pathogens transmitted by dairy cattle would have constituted a definite selective advantage, particularly in those human groups where cow's milk became an essential component of the diet. This selective advantage would be determined by an increased resistance to Cl(-)-secreting diarrheas of those individuals carrying a single copy of the Delta F508 CFTR mutation (heterozygote resistance). This hypothesis is supported by the strong association between the geography of the diffusion of cattle pastoralism (assessed indirectly by the lactase persistence distribution), the geographic distribution of a sizeable number of HLA alleles (as indicative of potential selective pressures generated by epidemic mortality) and the geographic distribution of the most common mutation causing cystic fibrosis (Delta F508). The systematic interaction of humans with infectious pathogens would have begun in northern Europe, among the carriers of the Funnel Beaker Culture, the first farmers of the North European plain, moving progressively to the south with the dissemination of the cattle pastoralism. This gradual exposure to epidemic mortality among populations located further and further south in Europe as cattle pastoralism expanded could have generated differences in CFTR gene frequencies, thereby shaping the latitudinal frequency gradients observed in present-day European populations.


Assuntos
Evolução Biológica , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/história , Mutação , Animais , Bovinos , Doenças Transmissíveis/genética , Doenças Transmissíveis/história , Fibrose Cística/genética , Fibrose Cística/história , Vetores de Doenças , Europa (Continente) , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Heterozigoto , História Antiga , Humanos , Masculino , Modelos Genéticos , Seleção Genética , Deleção de Sequência
11.
Am J Hum Biol ; 18(4): 532-9, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16788906

RESUMO

In this work, seven multiallelic short-tandem repeat (STR) loci from the nonrecombining region of the human Y-chromosome (DYS19, DYS389 I, DYS389 II, DYS390, DYS391, DYS392, and DYS393) were typed in a sample of residents in the Basque Country (RBAS). In all, 40 different Y-STR haplotypic combinations were identified, resulting in a value of haplotypic diversity of 0.979. Y-STR data compiled from previous works were used for studying Y-chromosome diversity in the Iberian Peninsula and for assessing the effects of migratory movements on the genetic background of the population living currently in territories traditionally occupied by native (autochthonous) Basques. An analysis of the spatial distribution of allelic frequencies of the Y-STRs revealed a geographic pattern characterized by variation gradients (frequency clines) oriented for the most part in the direction southwest-northeast. Accordingly, a neighbor-joining analysis showed a relative polarization between populations located in the northeast and center of the Iberian Peninsula, and the rest of the samples considered. The study sample (RBAS) occupied an intermediate position in the population tree between the autochthonous Basques (BASQ) and the remaining samples. Interestingly, the RBAS collection only showed genetic heterogeneity with that of native Basques (PhiST = 0.013, P < 0.05). Estimates of admixture proportions in the gene pool of RBAS indicated a high level of hybridization with Basque (56%) and non-Basque (44%) genes, which could explain the genetic differentiation observed between BASQ and RBAS.


Assuntos
Cromossomos Humanos Y/genética , Fluxo Gênico/genética , Genética Populacional , Sequências de Repetição em Tandem/genética , Emigração e Imigração , Haplótipos/genética , Humanos , Masculino , Portugal/etnologia , Espanha/etnologia
12.
J Hum Genet ; 50(8): 403-14, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16133660

RESUMO

Genomic diversity based on 13 short tandem repeat (STR) loci (D3S1358, vWA, FGA, D8S1179, D21S11, D18S51, D5S818, D13S317, D7S820, D16S539, TH01, TPOX, and CSF1PO) is reported for the first time in Basques from the provinces of Guipúzcoa and Navarre (Spain). STR data from previous studies on Basques from Alava and Vizcaya provinces were also examined using hierarchal analysis of molecular variance (AMOVA) and genetic admixture estimations to ascertain whether the Basques are genetically heterogeneous. To assess the genetic position of Basques in a broader geographic context, we conducted phylogenetic analyses based on F(ST) genetic distances [neighbor-joining trees and multidimensional scaling (MDS)] using data compiled in previous publications. The genetic profile of the Basque groups revealed distinctive regional partitioning of short tandem repeat (STR) diversity. Consistent with the above, native Basques clearly segregated from other populations from Europe (including Spain), North Africa, and the Middle East. The main line of genetic discontinuity inferred from the spatial variability of the microsatellite diversity in Basques significantly overlapped the geographic distribution of the Basque language. The genetic heterogeneity among native Basque groups correlates with the peculiar geography of peopling and marital structure in rural Basque zones and with language boundaries resulting from the uneven impact of Romance languages in the different Basque territories.


Assuntos
Genética Populacional , Repetições de Microssatélites/genética , DNA/sangue , Frequência do Gene , Heterogeneidade Genética , Geografia , Humanos , Linguagem , Filogenia , Reação em Cadeia da Polimerase , Espanha
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