285 research outputs found
G-CSF does not worsen toxicities and efficacy of CAR-T cells in refractory/relapsed B-cell lymphoma
No full textthis is at our knowledge the largest real life observation concerning the use of G-CSF in R/R DLBCL patients treated with CAR-T. We observed that administering G-CSF from D5 as prophylaxis in neutropenic patients did not increase the risk of experiencing severe CRS, nor ICANS. G-CSF administration seemed not to interfere with CAR-T expansion kinetics and it was safe also in preserving CAR-T antilymphoma activity, with no impact on the quality of responses and outcomes. For these reasons, routine G-CSF administration seems to be safely considerable in the context of CAR-T treatment for R/R DLBCL
Robotized FSW – Evolution of forces and torque with nonlinear welds
No full textThe main purpose of the article is to study the evolution of the welding forces and torque with non-straight welding path. The main studies performed on forces and torque are usually done on plane straight welding path when the processing parameter are developed. As industrializing robotized FSW, the robot structure deformation under FSW load depends on the forces generated on the tool. Thus, in order to compensate the robot deformation automatically through the control, statistical model giving the welding forces and torque as function of the process parameters is established. This article deals with the study of the forces and torque generated as welding circular and semi-circular welds. The effect of the welding direction (i.e. position of advancing and retreating side) is also analyzed. The objective is to determine if the statistical model giving the welding forces and torque as function of the process parameters developed on straight line can be applied for welding different weld path geometries
Evolutionary systematics and biogeography of endemic gerbils (Rodentia, Muridae) from Morocco : an integrative approach
No full textNdiaye, A., Ba, K., Aniskin, V., Benazzou, T., Chevret, P., Konecny, A., Sembene, M., Tatard, C., Kergoat, G.J. & Granjon, L. (2011). Evolutionary systematics and biogeography of endemic gerbils (Rodentia, Muridae) from Morocco: an integrative approach. Zoologica Scripta, 41, 1128. Gerbils of the genus Gerbillus represent an important part of small mammal diversity in arid regions of North Africa, but their taxonomy and evolutionary systematics and biogeography are still poorly known. Based on the recent collection of a series of gerbils in southern Morocco, including at the type localities of three endemic species, we gathered morphological, chromosomal and molecular data on a number of specimens that we compared with other available results. These data provide new insights into the geographical distribution of the endemic species known to date and suggest that an additional and previously undetected species may exist within this area. Multivariate analyses of morphometrical skull data validated the criteria used in the description of some of these species, while confirming the morphological similarity of a set of medium to large-sized species with hairy feet that can be considered sibling species. Karyotypes were useful for the specific assignation of a number of specimens. Molecular phylogenetics and divergence time estimates allow us to draw the first picture of the evolutionary relationships between endemic Gerbillus species from Morocco and related species of North Africa, and to estimate their respective timing of diversification. Most of the lineage emergence events took place during the Pleistocene, a period characterised by a global aridification of North Africa, but more importantly by important climatic and eustatic variations that may have played a role in species differentiation and subsequent expansion. This integrative approach proved to be essential in such species group including morphologically similar species. It also enables to propose testable hypotheses as to possible scenarios of emergence and evolution of these species along the western margin of the Sahara desert
Epigenetic modulation of hTERT expression in cutaneous T-cell lymphomas
No full textLes lymphomes T-cutanés (CTCL) sont des tumeurs télomérase-positives exprimant hTERT, dans lesquelles ni l'amplification, ni les réarrangements, ni les mutations hotspots du promoteur peuvent expliquer la ré-expression du gène. Comme le promoteur de hTERT est riche en CpG, nous avons étudié la contribution des mécanismes épigénétiques dans sa ré-expression, puisqu’aucune étude à ce jour n’a été rapporté dans les CTCL. Nous avons analysé le statut de méthylation du promoteur de hTERT dans des lignées cellulaires, des cellules de patients ainsi que dans des cellules issues de donneurs sains. Nous avons également étudié la présence sur le promoteur de hTERT des histones H3K27ac et H3K27me3. Les analyses de méthylation spécifiques des cellules CTCL ont révélé un profil de méthylation caractéristique limité aux cellules tumorales, englobant une région distale hyperméthylée de -650 pb à -150 pb et une région proximale hypométhylée de -150 pb à + 150 pb, à partir du TSS. Ce double profil de méthylation observé sur le promoteur de hTERT est identique à celui observé dans d’autres types de tumeurs. La région distale hyperméthylée identifiée dans les cellules tumorales CTCL correspond à la région nommée récemment « région TERT oncogénique hyperméthylée » (THOR) et qui est rapportée associée à la réactivation de la télomérase dans les tumeurs, mais jusqu'à présent non rapportée dans les lymphomes. Nous avons évalué l'effet sur THOR de deux inhibiteurs d’histone désacétylases (HDACi), la romidepsine et le vorinostat, tous deux approuvés pour le traitement des CTCL ainsi que d'un inhibiteur de l'ADN méthyltransférase (DNMTi) 5-azacytidine, non approuvé pour les CTCL. Nos résultats obtenus à partir d’une cohorte limitée semblent suggérer, que la 5-azacytidine ne provoque pas la déméthylation de la région hyperméthylée du promoteur de hTERT alors que ce traitement s’accompagne d’une diminution de l’expression de hTERT et, fonctionnellement d’une baisse des capacités clonogènes des cellules. La romidepsine et le vorinostat modifient peu les marques d'histones H3K27ac et H3K27me3 présentes au niveau du promoteur hTERT. En conclusion, les résultats obtenus dans les cellules CTCL comparées à ceux de cellules saines confirment que la méthylation du promoteur de hTERT dans les cellules tumorales est particulière et spécifique à ces cellules, faisant de cette méthylation un biomarqueur de la cellule tumorale. De plus, ils révèlent que la méthylation du promoteur hTERT est relativement stable même sous la pression de thérapies épigénétiques, suggérant que la régulation de hTERT par ces thérapies s’opère en priorité de manière indirecte.Cutaneous T-lymphomas (CTCL) are telomerase-positive tumors expressing hTERT, in which neither amplification, nor rearrangement, nor promoter hotspot mutations can explain the re-expression of the gene. As the hTERT promoter is rich in CpG, we investigated the contribution of epigenetic mechanisms in its re-expression, since no studies to date have been reported in CTCL. We analyzed the methylation status of the hTERT promoter in cell lines, patients’ cells and in cells from healthy donors. We also studied the presence, on the hTERT promoter, of histones H3K27ac and H3K27me3. Methylation analyzes in CTCL cells revealed a characteristic methylation profile specific to tumor cells, encompassing a distal hypermethylated region from -650 bp to -150 bp and a proximal hypomethylated region from -150 bp to +150 bp, relatively to the TSS. This dual methylation profile on hTERT promoter is identical to the profile seen in other types of tumors. The hypermethylated distal region identified in CTCL tumor cells corresponds to the region recently named “TERT hypermethylated oncogenic region” (THOR) and which is reported to be associated with telomerase reactivation in several tumors, but so far not reported in lymphomas. We evaluated the effect on THOR of two histone deacetylases inhibitors (HDACi), romidepsin and vorinostat, both approved for the treatment of CTCL as well as a DNA methyltransferase inhibitor (DNMTi) 5- azacytidine, not approved for CTCL. Our results, obtained from a limited cohort, seem to suggest that 5-azacytidine does not cause a demethylation of the hypermethylated region on hTERT promoter, while this treatment is accompanied by a decrease in the expression of hTERT and, functionally with a decrease in the clonogenic capacities of tumor cells. Romidepsin and vorinostat can slightly modify the H3K27ac and H3K27me3 histone marks present on hTERT promoter. In conclusion, the results obtained in CTCL cells compared with those of healthy cells confirm that hTERT promoter methylation is specific to CTCL cells, making this methylation a biomarker of tumor cells. Furthermore, they reveal that the methylation of hTERT promoter is relatively stable even under the pressure of epigenetic therapies, suggesting that the regulation of hTERT by these therapies can happen indirectly
Análise dos polimorfismos dos transcritos da translocação T(15;17)(Q22;Q21) na leucemia promielocítica aguda
No full textTCC(graduação) - Universidade Federal de Santa Catarina. Centro de Ciências Biológicas. Biologia.As leucemias agudas (LAs) constituem um grupo de neoplasias malignas caracterizado pela proliferação descontrolada de células hematopoiéticas na medula óssea e nos tecidos linfóides. As LAs podem estar relacionadas a anormalidades genéticas, como é o caso da leucemia promielocítica aguda (LPA) caracterizada pela presença de rearranjos cromossômicos envolvendo o gene da Leucemia Promielocítica (PML) e o gene Receptor Alfa do Ácido Retinóico (RARα), a translocação t(15;17)(q22;q21). O gene híbrido PML-RARα, presente em 90% dos casos, codifica uma proteína de fusão essencial para a patogênese da doença. Conforme o ponto de quebra do gene PML, no cromossomo 15, os transcritos bcr1, bcr2 e bcr3 podem ser formados. A correlação entre essas isoformas e os parâmetros clínicos ainda é controversa. O objetivo deste estudo foi determinar a frequência dos subtipos transcricionais PML-RARα em um grupo de 16 pacientes portadores de LPA com a translocação t(15;17)(q22;q21), atendidos no Serviço de Hematologia do HU-UFSC e avaliar a associação desses subtipos com diferentes parâmetros clínicos e laboratoriais, como leucometria, idade, LDH, percentual de blastos, expressão imunofenotípica dos marcadores CD34 e CD2 e presença da mutação FLT3-DIT. O método utilizado foi o RT-PCR. Os resultados mostraram uma maior freqüência das isoformas bcr1 e bcr2 e uma associação entre o aumento da contagem de leucócitos e o transcrito bcr2 (P = 0,019). Não houve nenhuma associação estatisticamente significativa entre os subtipos moleculares e a idade, LDH e porcentagem de blastos. Esses resultados sugerem a importância de analisar a expressão dos transcritos para o diagnóstico e prognóstico, assim como para a terapia individualizada.Acute leukemias (LAs) are a group of malignant neoplasms characterized by the uncontrolled proliferation of hematopoietic cells in the bone marrow and lymphoid tissues. The LAs may be related to genetic abnormalities, such as acute promyelocytic leukemia (APL) characterized by the presence of rearrangements involving the promyelocytic leukemia gene (PML) and retinoic acid receptor (RARα) gene, the translocation t(15;17)(q22;q21) . The hybrid gene PML–RARα, present in 90% of cases, encodes a fusion protein essential to the pathogenesis of the disease. Depending of the PML’s gene breakpoint in chromosome 15, the transcript subtypes bcr1, bcr2 and bcr3 may be formed. The correlation between these isoforms and clinical parameters is still controversial. The objective of this study was to determine the frequencies of the PML–RARa transcripts in a series of 16 APL patients with translocation t(15;17)(q22;q21) treated at the Hematology Service of HU-UFSC and to evaluate the association of these subtypes to different parameters, like white blood cell (WBC) count, age, LDH, percentage of blasts, expression of immunophenotypic markers CD34 and CD2 and presence of the FLT3-DIT mutation. The method used was RT-PCR. The results showed a higher frequency of the bcr1 and bcr2 isoforms and an association between increased WBC count and bcr2 transcript (P=0,019). No significant statistical association was found between molecular subtypes and age, LDH and percentage of blasts. In conclusion, these data suggest the importance to analyze the expression of transcripts for diagnosis and prognosis, as well as for the therapy individualized
Characterization of hot bonding of bi-metal C45/25CrMo4 by plane strain compression test
No full textTime Profile of Time-Dependent Area Under the ROC Curve for Survival Data
No full textIn the setting of survival analysis, the time-dependent area under the receiver operating characteristic curve (AUC) has been proposed as a discrimination measure of interest. In contrast with the diagnostic setting, the definitions of time-dependent sensitivity and specificity are required. This paper evaluates the time-dependent profile of the resulting AUC(t), which has not been previously assessed. We show that, even when the effect of a binary biomarker on the hazard rate is constant, the value of AUC(t) varies over time according to the prevalence of the marker. The Time-profile of the continuous biomarker is illustrated with numerical integration, and data on several prognostic factors in AML are examined
Detecció i incidència d'anomalies cromosòmiques en espermatozoides humans
No full textConsultable des del TDXTítol obtingut de la portada digitalitzadaLes tècniques d'hibridació in situ fluorescent aplicades sobre nuclis d'espermatozoides humans prèviament descondensats permeten la seva caracterització citogenètica i, en conseqüència, determinar el risc de transmissió d'una anomalia cromosòmica a la descendència. Hem aplicat aquesta metodologia en espermatozoides procedents d'individus control, per tal de determinar la incidència basal d'anomalies en la població general, així com en individus que per les seves particularitats, sospitem que poden presentar una incidència d'anomalies cromosòmiques superior a la població control. L'anàlisi dels resultats ha posat de manifest que els mecanismes que originen gàmetes amb aneuploïdies afecten preferentment a alguns cromosomes, concretament el cromosoma 21 i els cromosomes sexuals. Els pares d'individus amb la síndrome de Down d'origen patern presenten un increment significatiu d'aneuploïdies pel cromosoma 21. En individus portadors d'anomalies cromosòmiques estructurals, la proporció dels genotips resultants de cada tipus de segregació no s'ajusta a la proporció 1:1 esperada, suggerint l'existència de punts de control al llarg de la meiosi que eliminen selectivament cèl·lules germinals en funció del seu contingut cromosòmic. Per algunes reorganitzacions, el risc de transmissió d'una anomalia cromosòmica a la descendència es pot veure incrementat per la presència d'efectes intercromosòmics. En individus amb la síndrome de Klinefelter, els nostres resultats confirmen la incapacitat de la línia cel·lular 47,XXY d'iniciar la meiosi. L'increment d'espermatozoides portadors d'anomalies numèriques pels cromosomes sexuals es podria explicar pel desenvolupament de la meiosi en un ambient testicular anormal, conduint a un increment de segregacions errònies de les cèl·lules diploides 46,XY presents al teixit testicular. En individus amb cariotip 47,XYY, algunes cèl·lules amb aquesta dotació cromosòmica tenen la capacitat d'iniciar la meiosi. Les dades en aquests individus suggereixen l'existència d'un bloqueig de les cèl·lules aneuploides en l'estadi d'espermatòcit primari, secundari o en l'estadi d'espermàtide, donant lloc a una eliminació continuada de les cèl·lules anormals al llarg de l'espermatogènesi. Les avantatges que presenten les tècniques d'hibridació in situ fluorescent per a l'estudi citogenètic de l'espermatozoide humà ha permès la seva incorporació com a eina de diagnòstic genètic en individus de risc. Tenint en compte que la majoria d'aquests individus presenten problemes de fertilitat, l'anàlisi del contingut cromosòmic dels espermatozoides permet determinar, per a cada cas en particular, el risc potencial de transmissió a la descendència. Aquesta informació pot ser utilitzada per establir el programa de reproducció assistida més adequat a les característiques de cada cas.Fluorescent in situ hybridization methodology allows analyzing the chromosome content of spermatozoa. With the analysis of the gametes, it is possible to determine the real risk of transmission of a chromosome abnormality to the offspring. We have used this methodology in the cytogenetic study of human spermatozoa obtained from two types of men; control men, in order to determine the basal incidence of chromosome anomalies in the normal population, and high risk men, that is, patients that for different reasons, we suspect the presence of a increased incidence of chromosome anomalies. Our results underline that the biological mechanisms which are behind of the non-disjunction phenomenon affected much more some chromosomes than others. The fathers of Down syndrome children of paternal origin showed a significant increased of 21 aneuploidies, suggesting that these patients had an increase risk of transmission of a chromosomal abnormality to the offspring. In carriers of structural reorganizations, the proportion of the expected genotypes in each type of segregation differs of the 1:1 proportion. This result suggests the presence of meiotic checkpoint along meiosis eliminating selectively those cells with chromosome anomalies. In some types of reorganizations, the risk of transmission to the offspring could also be increased for the presence of interchromosomal effects. In Klinefelter patients, our results underline the inability of the 47,XXY cell line to initiate the meiotic process. The abnormal sex chromosome constitution found in spermatozoa could be attributed to segregation errors in XY cells placed in a compromised testicular environment. In 47,XYY patients, although some aneuploid cells are meiotically competent, it seems that there is a continuous elimination of chromosomal abnormal germ cells along spermatogenesis, parallel to an increase in the percentage of normal cells. Altogether, the data underline the importance of incorporating the screening of aneuploidies in sperm in the genetic screening of affected patients, in order to determine the real risk of transmission of a numerical chromosome abnormality to the offspring. Obviously, the only thing that is obtained after sperm FISH studies is information, but this information could be very useful to the affected couple, to help them and the medical team, to choose among different possibilities of assisted reproduction methodologie
Inter- and intra-specific gene-density-correlated radial chromosome territory arrangements are conserved in Old World monkeys
No full textRecently it has been shown that the gene-density correlated radial distribution of human 18 and 19 homologous chromosome territories (CTs) is conserved in higher primates in spite of chromosomal rearrangements that occurred during evolution. However, these observations were limited to apes and New World monkey species. In order to provide further evidence for the evolutionary conservation of gene-density-correlated CT arrangements, we extended our previous study to Old World monkeys. They comprise the remaining species group to be analyzed in order to obtain a comprehensive overview of the nuclear topology of human 18 and 19 homologous CTs in higher primates. In the present study we investigated four lymphoblastoid cell lines from three species of Old World monkeys by three-dimensional fluorescence in situ hybridization (3D-FISH): two individuals of Japanese macaque ( Macaca fuscata), crab-eating macaque ( Macaca fascicularis), and an interspecies hybrid individual between African green monkey (Cercopithecus aethiops) and Patas monkey ( Erythrocebus patas). Our data demonstrate that gene-poor human 18 homologous CTs are located preferentially close to the nuclear periphery, whereas gene-dense human 19 homologous CTs are oriented towards the nuclear center in all cell lines analyzed. The gene-density-correlated positioning of human 18 and 19 homologous CTs is evolutionarily conserved throughout all major higher primate lineages, despite chromosomal inversions, fusions, fissions or reciprocal translocations that occurred in the course of evolution in these species. This remarkable preservation of a gene-density-correlated chromatin arrangement gives further support for a functionally relevant higher-order chromatin architecture. Copyright (C) 2005 S. Karger AG, Basel
L'épigénétique comme modulateur de l'expression de hTERT dans les lymphomes T cutanés
No full textCutaneous T-lymphomas (CTCL) are telomerase-positive tumors expressing hTERT, in which neither amplification, nor rearrangement, nor promoter hotspot mutations can explain the re-expression of the gene. As the hTERT promoter is rich in CpG, we investigated the contribution of epigenetic mechanisms in its re-expression, since no studies to date have been reported in CTCL. We analyzed the methylation status of the hTERT promoter in cell lines, patients’ cells and in cells from healthy donors. We also studied the presence, on the hTERT promoter, of histones H3K27ac and H3K27me3. Methylation analyzes in CTCL cells revealed a characteristic methylation profile specific to tumor cells, encompassing a distal hypermethylated region from -650 bp to -150 bp and a proximal hypomethylated region from -150 bp to +150 bp, relatively to the TSS. This dual methylation profile on hTERT promoter is identical to the profile seen in other types of tumors. The hypermethylated distal region identified in CTCL tumor cells corresponds to the region recently named “TERT hypermethylated oncogenic region” (THOR) and which is reported to be associated with telomerase reactivation in several tumors, but so far not reported in lymphomas. We evaluated the effect on THOR of two histone deacetylases inhibitors (HDACi), romidepsin and vorinostat, both approved for the treatment of CTCL as well as a DNA methyltransferase inhibitor (DNMTi) 5- azacytidine, not approved for CTCL. Our results, obtained from a limited cohort, seem to suggest that 5-azacytidine does not cause a demethylation of the hypermethylated region on hTERT promoter, while this treatment is accompanied by a decrease in the expression of hTERT and, functionally with a decrease in the clonogenic capacities of tumor cells. Romidepsin and vorinostat can slightly modify the H3K27ac and H3K27me3 histone marks present on hTERT promoter. In conclusion, the results obtained in CTCL cells compared with those of healthy cells confirm that hTERT promoter methylation is specific to CTCL cells, making this methylation a biomarker of tumor cells. Furthermore, they reveal that the methylation of hTERT promoter is relatively stable even under the pressure of epigenetic therapies, suggesting that the regulation of hTERT by these therapies can happen indirectly.Les lymphomes T-cutanés (CTCL) sont des tumeurs télomérase-positives exprimant hTERT, dans lesquelles ni l'amplification, ni les réarrangements, ni les mutations hotspots du promoteur peuvent expliquer la ré-expression du gène. Comme le promoteur de hTERT est riche en CpG, nous avons étudié la contribution des mécanismes épigénétiques dans sa ré-expression, puisqu’aucune étude à ce jour n’a été rapporté dans les CTCL. Nous avons analysé le statut de méthylation du promoteur de hTERT dans des lignées cellulaires, des cellules de patients ainsi que dans des cellules issues de donneurs sains. Nous avons également étudié la présence sur le promoteur de hTERT des histones H3K27ac et H3K27me3. Les analyses de méthylation spécifiques des cellules CTCL ont révélé un profil de méthylation caractéristique limité aux cellules tumorales, englobant une région distale hyperméthylée de -650 pb à -150 pb et une région proximale hypométhylée de -150 pb à + 150 pb, à partir du TSS. Ce double profil de méthylation observé sur le promoteur de hTERT est identique à celui observé dans d’autres types de tumeurs. La région distale hyperméthylée identifiée dans les cellules tumorales CTCL correspond à la région nommée récemment « région TERT oncogénique hyperméthylée » (THOR) et qui est rapportée associée à la réactivation de la télomérase dans les tumeurs, mais jusqu'à présent non rapportée dans les lymphomes. Nous avons évalué l'effet sur THOR de deux inhibiteurs d’histone désacétylases (HDACi), la romidepsine et le vorinostat, tous deux approuvés pour le traitement des CTCL ainsi que d'un inhibiteur de l'ADN méthyltransférase (DNMTi) 5-azacytidine, non approuvé pour les CTCL. Nos résultats obtenus à partir d’une cohorte limitée semblent suggérer, que la 5-azacytidine ne provoque pas la déméthylation de la région hyperméthylée du promoteur de hTERT alors que ce traitement s’accompagne d’une diminution de l’expression de hTERT et, fonctionnellement d’une baisse des capacités clonogènes des cellules. La romidepsine et le vorinostat modifient peu les marques d'histones H3K27ac et H3K27me3 présentes au niveau du promoteur hTERT. En conclusion, les résultats obtenus dans les cellules CTCL comparées à ceux de cellules saines confirment que la méthylation du promoteur de hTERT dans les cellules tumorales est particulière et spécifique à ces cellules, faisant de cette méthylation un biomarqueur de la cellule tumorale. De plus, ils révèlent que la méthylation du promoteur hTERT est relativement stable même sous la pression de thérapies épigénétiques, suggérant que la régulation de hTERT par ces thérapies s’opère en priorité de manière indirecte
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