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2.
Leukemia ; 27(11): 2196-9, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23558524

RESUMO

Recent studies have revealed recurrent mutations of the NOTCH1, SF3B1 and BIRC3 genes in chronic lymphocytic leukemia (CLL), especially among aggressive, chemorefractory cases. Nevertheless, it is currently unknown whether their presence may differ in subsets of patients carrying stereotyped B-cell receptors and also exhibiting distinct prognoses. Here, we analyzed the mutation status of NOTCH1, SF3B1 and BIRC3 in three subsets with particularly poor prognosis, that is, subset #1, #2 and #8, aiming to explore links between genetic aberrations and immune signaling. A remarkably higher frequency of SF3B1 mutations was revealed in subset #2 (44%) versus subset #1 and #8 (4.6% and 0%, respectively; P<0.001). In contrast, the frequency of NOTCH1 mutations in subset #2 was only 8%, lower than the frequency observed in either subset #1 or #8 (19% and 14%, respectively; P=0.04 for subset #1 versus #2). No associations were found for BIRC3 mutations that overall were rare. The apparent non-random association of certain mutations with stereotyped CLL subsets alludes to subset-biased acquisition of genomic aberrations, perhaps consistent with particular antigen/antibody interactions. These novel findings assist in unraveling specific mechanisms underlying clinical aggressiveness in poor-prognostic stereotyped subsets, with far-reaching implications for understanding their clonal evolution and implementing biologically oriented therapy.


Assuntos
Biomarcadores Tumorais/genética , Proteínas Inibidoras de Apoptose/genética , Leucemia Linfocítica Crônica de Células B/classificação , Leucemia Linfocítica Crônica de Células B/genética , Mutação/genética , Fosfoproteínas/genética , Receptor Notch1/genética , Ribonucleoproteína Nuclear Pequena U2/genética , Proteína 3 com Repetições IAP de Baculovírus , Estudos de Coortes , DNA de Neoplasias/genética , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Reação em Cadeia da Polimerase , Prognóstico , Fatores de Processamento de RNA , Taxa de Sobrevida , Ubiquitina-Proteína Ligases
3.
Leukemia ; 27(1): 150-8, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22922567

RESUMO

In chronic lymphocytic leukemia (CLL), the microenvironment influences gene expression patterns; however, knowledge is limited regarding the extent to which methylation changes with time and exposure to specific microenvironments. Using high-resolution 450K arrays, we provide the most comprehensive DNA methylation study of CLL to date, analyzing paired diagnostic/follow-up samples from IGHV-mutated/untreated and IGHV-unmutated/treated patients (n=36) and patient-matched peripheral blood and lymph node samples (n=20). On an unprecedented scale, we revealed 2239 differentially methylated CpG sites between IGHV-mutated and unmutated patients, with the majority of sites positioned outside annotated CpG islands. Intriguingly, CLL prognostic genes (for example, CLLU1, LPL, ZAP70 and NOTCH1), epigenetic regulator (for example, HDAC9, HDAC4 and DNMT3B), B-cell signaling (for example, IBTK) and numerous TGF-ß and NF-κB/TNF pathway genes were alternatively methylated between subgroups. Contrary, DNA methylation over time was deemed rather stable with few recurrent changes noted within subgroups. Although a larger number of non-recurrent changes were identified among IGHV-unmutated relative to mutated cases over time, these equated to a low global change. Similarly, few changes were identified between compartment cases. Altogether, we reveal CLL subgroups to display unique methylation profiles and unveil methylation as relatively stable over time and similar within different CLL compartments, implying aberrant methylation as an early leukemogenic event.


Assuntos
Biomarcadores Tumorais/genética , Proliferação de Células , Ilhas de CpG/genética , Metilação de DNA , Perfilação da Expressão Gênica , Leucemia Linfocítica Crônica de Células B/genética , Idoso , Linfócitos B/patologia , Estudos de Casos e Controles , Estudos de Coortes , DNA de Neoplasias/genética , Progressão da Doença , Feminino , Estudo de Associação Genômica Ampla , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico
6.
J Virol ; 72(10): 8338-43, 1998 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9733880

RESUMO

During EBV infection, lytic DNA replication activates late gene expression in trans via an uncharacterized pathway. In this study, we mapped the target of this regulatory cascade to a variant TATA box (TATTAAA) and the 3' flanking region within the core promoter of the BcLF1 gene. The inherent late activity of this core promoter is, surprisingly, disrupted by a heterologous enhancer, suggesting that late gene expression is regulated through core promoter sequences located in a transcriptionally inert environment.


Assuntos
Herpesvirus Humano 4/fisiologia , TATA Box , Linfócitos B/virologia , Sequência de Bases , Primers do DNA , Regulação Viral da Expressão Gênica , Herpesvirus Humano 4/genética , Humanos , Mutagênese , Regiões Promotoras Genéticas , Deleção de Sequência
8.
Am J Health Syst Pharm ; 52(19 Suppl 4): S24-6, 1995 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-8846243

RESUMO

Cautions in the interpretation and application of pharmacoeconomic data are discussed. Cost containment is driving outcomes research and can cause pharmacoeconomic study methods to be manipulated to support preordained conclusions. The usual tactic is to adopt a narrow perspective in assessing benefits and costs. For example, many calculations ignore financial and physical pain borne by the patient. Before the results of any pharmacoeconomic analysis are embraced, the perspective adopted should be carefully examined. Each provider must look at a product or service from all relevant angles and in the context of its own standards. Although outcomes research may indeed make it possible to provide high-quality care for less money in the long term, in the short term these studies are devoted largely to the goal of spending less, even if some patients may suffer. In such circumstances, legal issues unavoidably arise. Principal among them is tort liability, the risk of being deemed negligent either in providing care or in obtaining informed consent. Any topic pressing enough to be included in outcomes research agendas and debates is going to require decisions that consider (1) the positions of national medical specialty societies, (2) the relevant catchment area or other defining cohort, (3) the specific institution, and (4) the professionals practicing in that institution. The inhouse professional who disagrees with rationing can become a credible whistle blower, and the judiciary may go to extraordinary lengths to empower patients, even without whistle blowers. Complete honesty in obtaining informed consent can help avoid legal actions. Pharmacoeconomic research can be useful in describing value for money spent. It is important to remember, however, that perspective matters in any analysis and that honesty is vital in policymaking and in sharing information with patients.


Assuntos
Interpretação Estatística de Dados , Farmacoeconomia , Avaliação de Resultados em Cuidados de Saúde , Farmacoeconomia/estatística & dados numéricos , Humanos
14.
Radiol Manage ; 16(2): 22-5, 1994.
Artigo em Inglês | MEDLINE | ID: mdl-10134487

RESUMO

Current healthcare reform proposals (especially the Clinton administration's Health Security Act) are daunting in their detail, scope and possible effect on radiology--daunting, but crucial for understanding the immediate future of the profession. Ms. Cahill reveals some of the most important proposed changes, the context within which they are framed and their implications.


Assuntos
Reforma dos Serviços de Saúde/legislação & jurisprudência , Seguro Saúde/legislação & jurisprudência , Controle de Custos/legislação & jurisprudência , Reforma dos Serviços de Saúde/economia , Mão de Obra em Saúde , Legislação Médica , Política , Atenção Primária à Saúde/legislação & jurisprudência , Qualidade da Assistência à Saúde/legislação & jurisprudência , Radiologia/economia , Radiologia/legislação & jurisprudência , Especialização , Estados Unidos
20.
Immunology ; 52(2): 341-7, 1984 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-6429037

RESUMO

Fluorescein isothiocyanate (FITC) has been used to study lymphocyte migration in sheep. After being labelled in vitro with FITC, lymphocytes migrated from blood into lymph at the same rate and with the same recovery as lymphocytes labelled with with the radioisotope 51chromium. The in vivo labelling of mesenteric lymph nodes (MLN) with FITC resulted in high numbers of labelled lymphocytes appearing in prescapular lymph. However, the appearance of the FITC-labelled lymphocytes in the prescapular lymph could be prevented by cannulating the main intestinal lymph duct prior to the in vivo labelling procedure. It was concluded that lymphocytes labelled in vivo within the MLN required an intact lymphatic system to reach the blood circulation and did not enter the venous circulation directly from the MLN.


Assuntos
Linfonodos/citologia , Linfa/citologia , Linfócitos/fisiologia , Animais , Movimento Celular , Feminino , Fluoresceína-5-Isotiocianato , Fluoresceínas , Mesentério , Ovinos , Tiocianatos , Fatores de Tempo
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