RESUMO
Mono-n-hexyl phthalate (MnHexP) is a primary metabolite of di-n-hexyl phthalate (DnHexP) and other mixed side-chain phthalates that was recently detected in urine samples from adults and children in Germany. DnHexP is classified as toxic for reproduction category 1B in Annex VI of Regulation (EC) 1272/2008 and listed in Annex XIV of the European chemical legislation REACH; thereby, its use requires an authorisation. Health-based guidance values for DnHexP are lacking and a full-scale risk assessment has not been carried out under REACH. The detection of MnHexP in urine samples raises questions about the sources of exposure and concerns of consumer safety. Here, we propose the calculation of a provisional oral tolerable daily intake value (TDI) of 63 µg/kg body weight/day for DnHexP and compare it to intake levels corresponding to levels of MnHexP found in urine. The resulting mean intake levels correspond to less than 0.2% of the TDI, and maximum levels to less than 5%. The TDI was derived by means of an approximate probabilistic analysis using the credible interval from benchmark dose modelling of published ex vivo data on reduced foetal testosterone production in rats. Thus, for the dose associated to a 20% reduction in testosterone production, a lower and upper credible interval of 14.9 and 30.0 mg/kg bw/day, respectively, was used. This is considered a conservative approach, since apical developmental endpoints (e.g. changed anogenital distance) were only observed at higher doses. In addition, we modelled various scenarios of the exposure to the precursor substance DnHexP from different consumer products, taking measured contamination levels into account, and estimated systemic exposure doses. Of the modelled scenarios including the application of sunscreen (as a lotion or pump spray), the use of lip balm, and the wearing of plastic sandals, and considering conservative assumptions, the use of DnHexP-contaminated sunscreen was highlighted as a major contributing factor. A hypothetical calculation using conservative assumptions for the latter resulted in a margin of safety in relation to the lower credible interval of 3267 and 1007 for adults and young children, respectively. Most importantly, it was found that only a fraction of the TDI is reached in all studied exposure scenarios. Thus, with regard to the reported DnHexP exposure, a health risk can be considered very unlikely.
RESUMO
BACKGROUND: A 75 year old patient presenting with mucocutaneous bleeding was diagnosed with acquired thrombasthenia. The diagnosis was based on lack of platelet aggregation with adenosine diphosphate (ADP), arachidonic acid and collagen, and normal aggregation induced by ristocetin. OBJECTIVE: To study the mechanism of platelet function inhibition in a patient with acquired thrombasthenia. METHODS: Aggregation assays of platelets from the patient and healthy controls were performed. In addition, anti-glycoprotein (GP) IIbIIIa antibodies bindingto normal in the presence or absence of the patient's serum was by flow cytometry. RESULTS: Aggregation of normal platelets in the presence of patient's plasma was inhibited four- and 2.5-fold in the presence of ADP and arachidonic acid respectively, while collagen-induced aggregation was completely abolished. Ristocetin-induced aggregation was normal. The patient's serum inhibited binding of commercial anti-glycoprotein IIbIIIa antibodies to normal platelets twofold by flow cytometry. Treatment with anti-CD20 monoclonal antibody (rituximab) normalized the patient's platelet aggregation. CONCLUSIONS: These results suggest that the patient developed inhibitory anti-GPIIbIIIa autoantibodies that caused acquired thrombasthenia.
Assuntos
Autoanticorpos/análise , Transtornos Plaquetários , Agregação Plaquetária , Testes de Função Plaquetária/métodos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/imunologia , Difosfato de Adenosina , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Ácido Araquidônico , Transtornos Plaquetários/diagnóstico , Transtornos Plaquetários/etiologia , Transtornos Plaquetários/imunologia , Colágeno , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Agregação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/imunologia , Indução de Remissão , Ristocetina , Rituximab , Resultado do TratamentoRESUMO
BACKGROUND: People experiencing homelessness are vulnerable to SARS-CoV-2 infection and its consequences. We aimed to understand the perspectives of people experiencing homelessness, and of the health care and shelter workers who cared for them, during the COVID-19 pandemic. METHODS: We conducted an interpretivist qualitative study in Toronto, Canada, from December 2020 to June 2021. Participants were people experiencing homelessness who received SARS-CoV-2 testing, health care workers and homeless shelter staff. We recruited participants via email, telephone or recruitment flyers. Using individual interviews conducted via telephone or video call, we explored the experiences of people who were homeless during the pandemic, their interaction with shelter and health care settings, and related system challenges. We analyzed the data using reflexive thematic analysis. RESULTS: Among 26 participants were 11 men experiencing homelessness (aged 28-68 yr), 9 health care workers (aged 33-59 yr), 4 health care leaders (aged 37-60 yr) and 2 shelter managers (aged 47-57 yr). We generated 3 main themes: navigating the unknown, wherein participants grappled with evolving public health guidelines that did not adequately account for homeless individuals; confronting placelessness, as people experiencing homelessness often had nowhere to go owing to public closures and lack of isolation options; and struggling with powerlessness, since people experiencing homelessness lacked agency in their placelessness, and health care and shelter workers lacked control in the care they could provide. INTERPRETATION: Reduced shelter capacity, public closures and lack of isolation options during the COVID-19 pandemic exacerbated the displacement of people experiencing homelessness and led to moral distress among providers. Planning for future pandemics must account for the unique needs of those experiencing homelessness.
Assuntos
COVID-19 , Pessoas Mal Alojadas , COVID-19/epidemiologia , Teste para COVID-19 , Humanos , Masculino , Pandemias , SARS-CoV-2RESUMO
Among those visiting a testing centre in Toronto, ON, between March and April 2020, people experiencing homelessness (n = 214) were more likely to test positive for COVID-19 compared with those not experiencing homelessness (n = 1,836) even after adjustment for age, sex and medical co-morbidity (15.4% vs. 6.7%, p < 0.001; odds ratio [OR] 2.41, 95% confidence interval [CI: 1.51, 3.76], p < 0.001).
Assuntos
COVID-19 , Pessoas Mal Alojadas , COVID-19/epidemiologia , Estudos Transversais , Humanos , Razão de Chances , Problemas SociaisRESUMO
BACKGROUND: It is unclear what the best strategy is for detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among residents of homeless shelters and what individual factors are associated with testing positive for the virus. We sought to evaluate factors associated with testing positive for SARS-CoV-2 among residents of homeless shelters and to evaluate positivity rates in shelters where testing was conducted in response to coronavirus disease 2019 (COVID-19) outbreaks or for surveillance. METHODS: We conducted a retrospective chart audit to obtain repeated cross-sectional data from outreach testing done at homeless shelters between Apr. 1 and July 31, 2020, in Toronto, Ontario, Canada. We compared the SARS-CoV-2 positivity rate for shelters where testing was conducted because of an outbreak (at least 1 known case) with those tested for surveillance (no known cases). A patient-level analysis evaluated differences in demographic, health and behavioural characteristics of residents who did and did not test positive for SARS-CoV-2 at shelters with at least 2 positive cases. RESULTS: One thousand nasopharyngeal swabs were done on 872 unique residents at 20 shelter locations. Among the 504 tests done in outbreak settings, 69 (14%) were positive for SARS-CoV-2 and 1 (0.2%) was indeterminate. Among the 496 tests done for surveillance, 11 (2%) were positive and none were indeterminate. Shelter residents who tested positive for SARS-CoV-2 were significantly less likely to have a health insurance card (54% v. 72%, p = 0.03) or to have visited another shelter in the last 14 days (0% v. 18%, p < 0.01). There was no association between SARS-CoV-2 positivity and medical history or symptoms. INTERPRETATION: Our findings support testing of asymptomatic shelter residents for SARS-CoV-2 when a positive case is identified at the same shelter. Surveillance testing when there are no known positive cases may detect outbreaks, but further research should identify efficient strategies given scarce testing resources.
Assuntos
Teste para COVID-19/estatística & dados numéricos , COVID-19/diagnóstico , Pessoas Mal Alojadas/estatística & dados numéricos , SARS-CoV-2/genética , Adolescente , Adulto , Idoso , COVID-19/epidemiologia , COVID-19/transmissão , COVID-19/virologia , Criança , Pré-Escolar , Estudos Transversais , Surtos de Doenças/estatística & dados numéricos , Etnicidade/estatística & dados numéricos , Feminino , Humanos , Lactente , Recém-Nascido , Seguro Saúde/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Ontário/epidemiologia , Estudos Retrospectivos , SARS-CoV-2/isolamento & purificação , Adulto JovemRESUMO
Although mitosis is a general physiologic process, cancer cells are unusually sensitive to mitotic inhibitors. Therefore, there is an interest in the identification of novel mitotic inhibitors. Here, we report the novel discovery of the SIL gene as a regulator of mitotic entry and cell survival. The SIL gene was cloned from leukemia-associated chromosomal translocation. It encodes a cytosolic protein with an unknown function and no homology to known proteins. Previously, we observed an increased expression of SIL in multiple cancers that correlated with the expression of mitotic spindle checkpoint genes and with increased metastatic potential. Here, we show that SIL is important for the transition from the G(2) to the M phases of the cell cycle. Inducible knockdown of SIL in cancer cells in vitro delayed entrance into mitosis, decreased activation of the CDK1 (CDC2)-cyclin B complex, and induced apoptosis in a p53-independent manner. SIL is also essential for the growth of tumor explants in mice. Thus, SIL is required for mitotic entry and cancer cell survival. Because increased expression of SIL has been noted in multiple types of cancers and correlates with metastatic spread, it may be a suitable target for novel anticancer therapy.
Assuntos
Neoplasias do Colo/patologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Mitose/genética , Animais , Apoptose/genética , Processos de Crescimento Celular/genética , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Neoplasias do Colo/genética , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , RNA Interferente Pequeno/genética , Transplante HeterólogoRESUMO
Allogeneic stem cell transplantation remains the standard treatment for resistant advanced chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Relapse is the major cause of treatment failure in both diseases. Post-allo-SCT administration of TKIs could potentially reduce relapse rates, but concerns regarding their effect on immune reconstitution have been raised. We aimed to assess immune functions of 12 advanced CML and Ph+ ALL patients who received post-allo-SCT nilotinib. Lymphocyte subpopulations and their functional activities including T-cell response to mitogens, NK cytotoxic activity and thymic function, determined by quantification of the T cell receptor (TCR) excision circles (TREC) and TCR repertoire, were evaluated at several time points, including pre-nilotib-post-allo-SCT, and up to 365 days on nilotinib treatment. NK cells were the first to recover post allo-SCT. Concomitant to nilotinib administration, total lymphocyte counts and subpopulations gradually increased. CD8 T cells were rapidly reconstituted and continued to increase until day 180 post SCT, while CD4 T cells counts were low until 180-270 days post nilotinib treatment. T-cell response to mitogenic stimulation was not inhibited by nilotinib administration. Thymic activity, measured by TREC copies and surface membrane expression of 24 different TCR Vß families, was evident in all patients at the end of follow-up after allo-SCT and nilotinib treatment. Finally, nilotinib did not inhibit NK cytotoxic activity. In conclusion, administration of nilotinib post allo-SCT, in attempt to reduce relapse rates or progression of Ph+ ALL and CML, did not jeopardize immune reconstitution or function following transplantation.
Assuntos
Antineoplásicos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Reconstituição Imune , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Subpopulações de Linfócitos/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Pirimidinas/uso terapêutico , Adulto , DNA Circular , Feminino , Seguimentos , Genes Codificadores dos Receptores de Linfócitos T/genética , Doença Enxerto-Hospedeiro/imunologia , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Contagem de Linfócitos , Subpopulações de Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Tirosina Quinases/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Timo/efeitos dos fármacos , Timo/metabolismo , Transplante Homólogo/efeitos adversos , Adulto JovemRESUMO
By using a genome-wide N-ethyl-N-nitrosourea (ENU)-induced dominant mutagenesis screen in mice, a founder with low bone mineral density (BMD) was identified. Mapping and sequencing revealed a T to C transition in a splice donor of the collagen alpha1 type I (Col1a1) gene, resulting in the skipping of exon 9 and a predicted 18-amino acid deletion within the N-terminal region of the triple helical domain of Col1a1. Col1a1(Jrt) /+ mice were smaller in size, had lower BMD associated with decreased bone volume/tissue volume (BV/TV) and reduced trabecular number, and furthermore exhibited mechanically weak, brittle, fracture-prone bones, a hallmark of osteogenesis imperfecta (OI). Several markers of osteoblast differentiation were upregulated in mutant bone, and histomorphometry showed that the proportion of trabecular bone surfaces covered by activated osteoblasts (Ob.S/BS and N.Ob/BS) was elevated, but bone surfaces undergoing resorption (Oc.S/BS and N.Oc/BS) were not. The number of bone marrow stromal osteoprogenitors (CFU-ALP) was unaffected, but mineralization was decreased in cultures from young Col1a1(Jrt) /+ versus +/+ mice. Total collagen and type I collagen content of matrices deposited by Col1a1(Jrt) /+ dermal fibroblasts in culture was â¼40% and 30%, respectively, that of +/+ cells, suggesting that mutant collagen chains exerted a dominant negative effect on type I collagen biosynthesis. Mutant collagen fibrils were also markedly smaller in diameter than +/+ fibrils in bone, tendon, and extracellular matrices deposited by dermal fibroblasts in vitro. Col1a1(Jrt) /+ mice also exhibited traits associated with Ehlers-Danlos syndrome (EDS): Their skin had reduced tensile properties, tail tendon appeared more frayed, and a third of the young adult mice had noticeable curvature of the spine. Col1a1(Jrt) /+ is the first reported model of combined OI/EDS and will be useful for exploring aspects of OI and EDS pathophysiology and treatment.
Assuntos
Modelos Animais de Doenças , Síndrome de Ehlers-Danlos/complicações , Osteogênese Imperfeita/complicações , Absorciometria de Fóton , Processamento Alternativo/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Matriz Óssea/patologia , Remodelação Óssea , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Osso e Ossos/ultraestrutura , Calcificação Fisiológica , Colágeno Tipo I/química , Colágeno Tipo I/genética , Colágeno Tipo I/ultraestrutura , Cadeia alfa 1 do Colágeno Tipo I , Síndrome de Ehlers-Danlos/fisiopatologia , Fêmur/patologia , Masculino , Camundongos , Dados de Sequência Molecular , Mutação/genética , Osteogênese Imperfeita/fisiopatologia , Estrutura Terciária de Proteína , Células Estromais/metabolismo , Células Estromais/patologiaRESUMO
Factor XIII is a plasma transglutaminase that participates in the final stage of the coagulation cascade. Thrombin-activated FXIII (FXIIIa) catalyzes the formation of covalent crosslinks between gamma-glutamyl and epsilon-lysyl residues on fibrin molecules to yield the mature clot. In addition to its role in hemostasis, FXIIIa was previously shown by us to stimulate endothelial cells to exhibit pro-angiogenic activity. In this work, we studied the effect of FXIIIa on other cells that participate in angiogenesis and tissue repair, such as monocytes and fibroblasts. FXIIIa significantly enhanced migration and proliferation, and inhibited apoptosis of monocytes and fibroblasts. Similar to our previous observations with endothelial cells, the stimulating effect of FXIIIa on monocytes and fibroblasts was elicited via its binding to alpha (v)beta (3) integrin leading to cJun upregulation and TSP-1 downregulation. Since monocytes and fibroblasts are essential components of the tissue repair process, the results of this study, together with the proangiogenic activity of FXIIIa, further substantiate a significant role of FXIII in tissue repair.
Assuntos
Fator XIII/farmacologia , Fibroblastos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Apoptose , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Fibroblastos/fisiologia , Humanos , Monócitos/fisiologia , Proteínas Proto-Oncogênicas c-jun/metabolismo , Trombospondina 1/metabolismoRESUMO
The alpha1beta1 integrin, very late antigen (VLA)-1, characterizes collagen adherent interferon (IFN) gamma producing memory T cells in inflamed synovium. We now report that the mean percentage of VLA-1+ T cells is significantly lower among peripheral blood mononuclear cells of rheumatoid patients responsive to antitumor necrosis factor (TNF) alpha therapy than of those with active disease not receiving therapy. Neutralization of TNFalpha during in vitro polyclonal activation of VLA-1- T cells reduced differentiation to expression of VLA-1 and inhibited secretion of IFNgamma, but did not affect integrin expression on in vivo differentiated VLA-1+ T cells. Moreover, synovial fluids of patients relapsing during and after therapy were enriched in VLA-1+ T cells and lines derived from VLA-1+ T cells in peripheral blood of treated patients retained collagen binding and secreted IFN gamma. Thus, whereas therapy decreases VLA-1+ T cells in rheumatoid arthritis patients, a subset is resistant and contributes to residual and recurring inflammation.
Assuntos
Artrite Reumatoide/imunologia , Integrina alfa1/biossíntese , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Idoso , Anticorpos Bloqueadores/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Artrite Reumatoide/terapia , Linhagem Celular , Regulação para Baixo/imunologia , Feminino , Humanos , Infliximab , Integrina alfa1/fisiologia , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Recidiva , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
The consecutive fragmentation of ionized trimethyl vanadate(V), OV(OCH3)3 (1), is examined by experiment and theory. After an elimination of formaldehyde from the molecular ion 1+, subsequent dissociations proceed via losses of first H2 and then two molecules of formaldehyde to finally yield the VOH+ cation; these redox reactions involve the V(II)/V(IV) manifold. At elevated energies, expulsion of CH3O* from 1+ can efficiently compete to afford OV(OCH3)2+, a formal V(V) compound, from which subsequent losses of H2 and two units of CH2O lead to bare VO+, thereby exploring the V(III)/V(V) redox manifold. Experiments using complementary mass spectrometric techniques, i.e., neutralization-reionization experiments and ion/molecule reactions, in conjunction with extensive computational studies provide deep insight into the ion structures and the relative energetics of these dissociation reactions. In particular, a quantitative energetic scheme is obtained that ranges from neutral OV(OCH3)3 all the way down to the quasi-terminal fragment ions VOH+ and VO+, respectively.
RESUMO
A series of mixed alkoxyalkoxo chloro complexes of vanadium(V), [VOCl2(OCH2CH2OR)]2 (R = Me, Et, iPr, Bz), [VOCl2(OCMe2CH2OMe)]2 and [VOCl2(OCH2(cyclo-C4H7O)]2, were synthesised and characterised. The title compounds can be obtained either from VOCl3 and the alkoxyalcohols by HCl elimination or from the corresponding lithium alkoxides and VOCl3 by salt metathesis reaction. X-Ray diffraction studies revealed the title compounds to be dimers with chloride bridging ligands and intramolecular ether coordination. Electrochemical results obtained by cyclic voltammetry indicate irreversible, reductive behaviour. The interactions of the title compounds with oxygen, nitrogen and phosphorus donor ligands were examined. Phosphorus and nitrogen donors lead to reduction products whereas tetrahydrofuran coordinates to the vanadium(V) centre by breaking the chloride bridge. All tetrahydrofuran complexes, [VOCl2(OCH2CH2OR)(thf)] (R = Me, Et, iPr) and [VOCl2(OCMe2CH2OMe)(thf)], have been characterised by single-crystal X-ray diffraction. The solid-state structures of these complexes show that they consist of six-coordinate monomers. Reaction of [VOCl2(OCH2CH(2)OMe)]2 with Me3SiCH2MgCl gave [VO(CH2SiMe3)3], which has been structurally characterised. The compounds were tested as catalysts for epoxidation and polymerisation reactions. They convert unfunctionalised olefins into the corresponding epoxides with moderate activity. They are good pre-catalysts for the polymerisation of ethene and oligomerise 1-hexene.
Assuntos
Cloretos/química , Compostos Organometálicos , Óxidos/química , Vanádio/química , Catálise , Cristalografia por Raios X , Eletroquímica , Ligantes , Modelos Moleculares , Conformação Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/químicaRESUMO
Interactions of the TNF-related cell surface ligand CD70 with its receptor CD27 provide a costimulatory signal in B and T cell activation. Functional CD70-CD27 interactions could contribute to lymphoma and leukemia progression. This possibility was studied using DNA microarrays on a unique case of low-grade lymphoma/leukemia characterized by recurrent cycles of acute leukemic phase alternating with spontaneous remission. Upon induction of the acute phase expression of CD70 and CD27 in the leukemic cells increased 38- and 25-fold, respectively. Coexpression of membrane CD70 and CD27 on the leukemic (CD5+CD19+) cells was maximal 2-3 days following initiation of the attack. Soluble CD27 in the patient's serum was elevated during remission and further increased in the attack. Functional tests showed that neither anti-CD70 nor anti-CD27 Abs affect the rate of apoptosis. However, the anti-CD70 Ab specifically enhanced proliferation of the remission phase leukemic cells, whereas proliferation of the acute-phase counterparts that express higher level of membrane CD70 was unaffected. Hence, in this lymphoma/leukemia, membrane CD70 is presented on the leukemic cells in a responsive state during the remission and a nonresponsive state during the attack. Presumably, CD70 in its responsive state provides a costimulatory receptor for initiating the next acute phase while its nonresponsive state enables the remission.
Assuntos
Antígenos CD/metabolismo , Leucemia/imunologia , Leucemia/patologia , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/patologia , Proteínas de Membrana/metabolismo , Fatores de Necrose Tumoral/metabolismo , Antígenos CD/genética , Apoptose , Sequência de Bases , Ligante CD27 , Membrana Celular/imunologia , Proliferação de Células , DNA de Neoplasias/genética , Perfilação da Expressão Gênica , Humanos , Leucemia/genética , Ligantes , Linfoma não Hodgkin/genética , Proteínas de Membrana/genética , Recidiva , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/sangue , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Fatores de Necrose Tumoral/genéticaAssuntos
Aberrações Cromossômicas , Leucemia Mielomonocítica Crônica/complicações , Mielofibrose Primária/complicações , Trombocitemia Essencial/complicações , Adulto , Exame de Medula Óssea , Análise Citogenética , Humanos , Leucemia Mielomonocítica Crônica/genética , Mielofibrose Primária/genética , Trombocitemia Essencial/genéticaRESUMO
The Ph1 chromosome has rarely been reported in T-lineage acute lymphoblastic leukemia (T-ALL), and the clinical relevance of this translocation in T-ALL is currently unknown. In chronic myelogenous leukemia (CML) some data indicate derivation of T-cells from the leukemic clone and only a few cases of T-derived blastic crisis have been reported and quite often disputed. Particularly in cases identified initially in blastic crisis it may be difficult to distinguish those from Ph1-positive T-ALL. We herein report 2 patients who presented with a clinical picture of Ph1-positive T-ALL and who raised a differential diagnosis from T-cell blastic crisis of CML. We review the literature and suggest clinical and laboratory features that can help in the diagnosis. According to our literature review, 23 cases of Ph1-positive T-ALL and 44 cases of T-cell blastic crisis of CML, including ours, were reported. Some major differences between the two entities could help in establishing a diagnosis of Ph1-positive T-cell blastic crisis of CML vs. Ph1-positive T-ALL: Male sex and younger age was more predominant in T-ALL. While in most cases of CML blastic crisis there was a history of CML there was no such history in the T-ALL cases. Medullary involvement with lymphoblastic leukemia was present in all cases of T-ALL but only in about half of the cases of CML blastic crisis. None of the CML-blastic crisis cases tested by RT-PCR showed the minor breakpoint transcript, while 2 cases with T-ALL had the minor breakpoint transcript and 1 had both transcripts. Combined morphologic and FISH analysis can help to distinguish between the two entities and was applied in one of our cases. Although both entities carry a severe prognosis, differentiating between them might have clinical relevance, especially in the imatinib era.
Assuntos
Crise Blástica/patologia , Linhagem da Célula , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia-Linfoma de Células T do Adulto/patologia , Cromossomo Filadélfia , Crise Blástica/genética , Linhagem da Célula/genética , Diagnóstico Diferencial , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia-Linfoma de Células T do Adulto/genética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Translocação Genética/genéticaRESUMO
Affymetrix human Hu133A oligonucleotide arrays were used to study the expression profile of CD133+ cord blood (CB) and peripheral blood (PB) using CD133 cell-surface marker. An unsupervised hierarchical clustering of 14,025 valid probe sets showed a clear distinction between the CD133+ cells representing the hematopoietic stem cell (HSC) population and CD133-differentiated cells. Two hundred forty-four genes were found to be upregulated by at least twofold in the CD133-positive cells of both CB and PB compared with the CD133-negative cells. These genes represent the hematopoietic "stemness," whereas the 218 and 304 upregulated genes exclusively in PB and CB, respectively, represent tissue specificity. Some of the stemness genes were also common to HSC genes found to be upregulated in several recently published studies. Among these common stemness genes, we identified several groups of genes that have an important role in hematopoiesis: growth factor receptors, transcription factors, genes that have an important role in development, and genes involved in cell growth. Sixteen selected stemness genes are known to be mutated or abnormally regulated in acute leukemias. It can be suggested that key hematopoietic stemness machinery genes may lead to abnormal proliferation and leukemia upon mutation or change of their expression.
Assuntos
Regulação Neoplásica da Expressão Gênica , Hematopoese/genética , Células-Tronco Hematopoéticas/citologia , Leucemia/genética , Mutação , Antígeno AC133 , Adulto , Antígenos CD/análise , Sangue Fetal , Perfilação da Expressão Gênica , Glicoproteínas/análise , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Recém-Nascido , Análise de Sequência com Séries de Oligonucleotídeos , Peptídeos/análise , Receptores de Fatores de Crescimento/genética , Fatores de Transcrição/genética , Cordão UmbilicalRESUMO
BACKGROUND: Circulating microparticles are markers of cell activation associated with various prothrombotic states. As hypoxia due to uteroplacental thrombosis is considered to be one of the causes of pregnancy loss, microparticles may be associated with pregnancy loss, in addition to, or as part of, other procoagulant states such as antiphospholipid syndrome or hereditary thrombophilias. The objective of this study was to examine the prevalence of circulating microparticles in women with recurrent pregnancy loss. METHODS: A total of 96 women with recurrent pregnancy losses were enrolled in a case-control study and compared with 90 parous women. Microparticles were measured by flow cytometry using fluorescent anti-CD51/CD31 antibodies. RESULTS: Microparticle levels >2 SD above the mean of controls (57,700/ml) were detected in 12 out of 96 women with recurrent miscarriages (12.5%), compared with two of the 90 control women (2.2%), P<0.008. The titre of microparticles did not correlate with age, number of pregnancy losses, primary secondary or tertiary aborters status, or with pregnancy losses in the 1st or 2nd trimesters. CONCLUSIONS: A proportion of women with pregnancy loss have elevated endothelial microparticles suggesting that endothelial damage or activation might be associated with the pathogenesis of pregnancy loss.