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1.
Cancers (Basel) ; 12(2)2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32085520

RESUMO

The biology and clinical impact of bone marrow (BM) infiltration in patients with diffuse large B-cell lymphoma (DLBCL) remains unclear in the rituximab era. We retrospectively analyzed 232 patients diagnosed with DLBCL at our center between 1999 and 2014. Concordant-presence of large cells similar to those of the lymph node biopsy- and discordant-infiltration by small cells forming lymphoid aggregates, lacking cytological atypia-BM infiltration was defined by histological criteria and further characterized by flow cytometry (FCM). Cell of origin (COO) was determined using Hans' algorithm. For the clonal relationship between tumor and discordant BM, the VDJH rearrangement was analyzed. Survival analyses were restricted to 189 patients treated with rituximab and chemotherapy. Thirty-six (16%) had concordant, and 37 (16%) discordant BM infiltration. FCM described different indolent lymphomas among discordant cases, clonally related with DLBCL in 10/13 available samples. Median follow-up was 58 months. 5-year-progression-free survival (PFS) for non-infiltrated, discordant and concordant groups was 68%, 65% and 30%, respectively (p < 0.001). Combining COO and BM infiltration, patients with discordant BM and non-germinal center B-cell COO also had decreased 5-year-PFS (41.9%). In multivariate analysis, concordant BM had an independent effect on PFS (HR 2.5, p = 0.01). Five-year cumulative incidence of central nervous system (CNS) relapse was 21%, 4% and 1% in concordant, discordant and non-infiltrated groups, respectively (p < 0.001). In conclusion, concordant BM infiltration represents a subset with poor prognosis, whereas the prognostic impact of discordant BM infiltration could be limited to non-CGB cases.

2.
Nat Commun ; 10(1): 5563, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31804490

RESUMO

The prerequisite to prevent childhood B-cell acute lymphoblastic leukemia (B-ALL) is to decipher its etiology. The current model suggests that infection triggers B-ALL development through induction of activation-induced cytidine deaminase (AID; also known as AICDA) in precursor B-cells. This evidence has been largely acquired through the use of ex vivo functional studies. However, whether this mechanism governs native non-transplant B-ALL development is unknown. Here we show that, surprisingly, AID genetic deletion does not affect B-ALL development in Pax5-haploinsufficient mice prone to B-ALL upon natural infection exposure. We next test the effect of premature AID expression from earliest pro-B-cell stages in B-cell transformation. The generation of AID off-target mutagenic activity in precursor B-cells does not promote B-ALL. Likewise, known drivers of human B-ALL are not preferentially targeted by AID. Overall these results suggest that infections promote B-ALL through AID-independent mechanisms, providing evidence for a new model of childhood B-ALL development.

3.
Blood Cancer J ; 9(7): 52, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31209206

RESUMO

Follicular lymphoma (FL) is a heterogeneous disease whose pathogenesis remains partially unknown. Around 20% of FL patients experience early progression or treatment-refractory disease and 2-3% of patients per year experience histological transformation (HT) into a more aggressive lymphoma (tFL). Here, we evaluate the immunoglobulin heavy chain variable (IGHV) gene usage and mutational status in 187 FL cases to assess its impact on clinical outcome and histological transformation. The IGHV gene repertoire was remarkably biased in FL. The IGHV4-34 (14%), IGHV3-23 (14%), IGHV3-48 (10%), IGHV3-30 (9%) and IGHV3-21 (7%) genes accounted for more than half of the whole cohort. IGHV3-48 was overrepresented in cases of tFL (19%) compared with non-transformed FL at 5 years (5%, P = 0.05). Patients with the IGHV3-48 gene were significantly more likely to have had HT after 10 years than those who used other genes (71% vs. 25%, P < 0.05), irrespective of the therapy they received. Moreover, IGHV3-30 was also overrepresented in cases of FL (9%) and tFL (13%) compared with diffuse large B-cell lymphoma in which it was nearly absent. In conclusion, our results indicate a role for antigen selection in the development of FL, while the use of IGHV3-48 could help predict histological transformation.

4.
Nature ; 568(7753): 557-560, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30971822

RESUMO

The cell cycle is a tightly regulated process that is controlled by the conserved cyclin-dependent kinase (CDK)-cyclin protein complex1. However, control of the G0-to-G1 transition is not completely understood. Here we demonstrate that p38 MAPK gamma (p38γ) acts as a CDK-like kinase and thus cooperates with CDKs, regulating entry into the cell cycle. p38γ shares high sequence homology, inhibition sensitivity and substrate specificity with CDK family members. In mouse hepatocytes, p38γ induces proliferation after partial hepatectomy by promoting the phosphorylation of retinoblastoma tumour suppressor protein at known CDK target residues. Lack of p38γ or treatment with the p38γ inhibitor pirfenidone protects against the chemically induced formation of liver tumours. Furthermore, biopsies of human hepatocellular carcinoma show high expression of p38γ, suggesting that p38γ could be a therapeutic target in the treatment of this disease.


Assuntos
Carcinogênese/patologia , Ciclo Celular , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Fígado/enzimologia , Fígado/patologia , Proteína Quinase 12 Ativada por Mitógeno/metabolismo , Idoso , Animais , Carcinogênese/efeitos dos fármacos , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/metabolismo , Feminino , Hepatócitos/citologia , Hepatócitos/patologia , Humanos , Fígado/cirurgia , Neoplasias Hepáticas/induzido quimicamente , Masculino , Camundongos , Pessoa de Meia-Idade , Proteína Quinase 12 Ativada por Mitógeno/antagonistas & inibidores , Fosforilação , Piridonas/farmacologia , Proteína do Retinoblastoma/química , Proteína do Retinoblastoma/metabolismo , Homologia de Sequência , Especificidade por Substrato
5.
Blood ; 133(22): 2401-2412, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-30975638

RESUMO

Refractory or relapsed diffuse large B-cell lymphoma (DLBCL) often associates with the activated B-cell-like (ABC) subtype and genetic alterations that drive constitutive NF-κB activation and impair B-cell terminal differentiation. Here, we show that DNA damage response by p53 is a central mechanism suppressing the pathogenic cooperation of IKK2ca-enforced canonical NF-κB and impaired differentiation resulting from Blimp1 loss in ABC-DLBCL lymphomagenesis. We provide evidences that the interplay between these genetic alterations and the tumor microenvironment select for additional molecular addictions that promote lymphoma progression, including aberrant coexpression of FOXP1 and the B-cell mutagenic enzyme activation-induced deaminase, and immune evasion through major histocompatibility complex class II downregulation, PD-L1 upregulation, and T-cell exhaustion. Consistently, PD-1 blockade cooperated with anti-CD20-mediated B-cell cytotoxicity, promoting extended T-cell reactivation and antitumor specificity that improved long-term overall survival in mice. Our data support a pathogenic cooperation among NF-κB-driven prosurvival, genetic instability, and immune evasion mechanisms in DLBCL and provide preclinical proof of concept for including PD-1/PD-L1 blockade in combinatorial immunotherapy for ABC-DLBCL.


Assuntos
Linfócitos B/imunologia , Antígeno B7-H1/imunologia , Regulação Neoplásica da Expressão Gênica , Ativação Linfocitária , Linfoma Difuso de Grandes Células B/imunologia , Receptor de Morte Celular Programada 1/imunologia , Evasão Tumoral , Proteína Supressora de Tumor p53/imunologia , Animais , Linfócitos B/patologia , Antígeno B7-H1/genética , Feminino , Humanos , Imunoterapia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Masculino , Camundongos , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/genética , Linfócitos T/imunologia , Linfócitos T/patologia , Proteína Supressora de Tumor p53/genética
8.
Rev Esp Salud Publica ; 922018 Sep 05.
Artigo em Espanhol | MEDLINE | ID: mdl-30178781

RESUMO

OBJECTIVE: Obesity is one of the main pandemics of the 21st century and the 5th risk factor for death in the world. Every year more than 2.8 million people die due to this disease. This study aims to demonstrate the effectiveness of physical activity breaks programs to improve health in elementary school students, reducing their body fat percentage and BMI and increasing their physical condition. METHODS: The physical activity breaks program called Móvete 15 was developed in Curros Enríquez School from Celanova (Galicia-Spain), during 2016-17 school year. This consisted in interrupting the daily school day for 15 minutes to perform physical activity of moderate and vigorous intensity. A pretest-posttest study design was proposed, using descriptive statistical techniques (frequencies and statistics) and inferential techniques (t-Student, ANOVA, Marginal Homogeneity) on anthropometric variables (Fat, BMI) and physical condition (Eurofit test) as health indicators. RESULTS: The programme Móvete 15 achieved significant improvements (p < 0.05) in the participants' health, manifested in the reduction of the average percentage of fat, -1.33% (0.49 kg); and in the increase of physical condition, with improvements in speed-coordination (-1.45 seconds/circuit) and aerobic resistance (+1.46 phases). CONCLUSIONS: Móvete 15 is an appropriate program to improve physical condition and health in elementary school students.


Assuntos
Terapia por Exercício/métodos , Promoção da Saúde/métodos , Obesidade Pediátrica/terapia , Aptidão Física , Criança , Feminino , Humanos , Masculino , Obesidade Pediátrica/fisiopatologia , Instituições Acadêmicas , Espanha , Resultado do Tratamento
9.
EMBO J ; 37(14)2018 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-29880602

RESUMO

The impact of LMO2 expression on cell lineage decisions during T-cell leukemogenesis remains largely elusive. Using genetic lineage tracing, we have explored the potential of LMO2 in dictating a T-cell malignant phenotype. We first initiated LMO2 expression in hematopoietic stem/progenitor cells and maintained its expression in all hematopoietic cells. These mice develop exclusively aggressive human-like T-ALL In order to uncover a potential exclusive reprogramming effect of LMO2 in murine hematopoietic stem/progenitor cells, we next showed that transient LMO2 expression is sufficient for oncogenic function and induction of T-ALL The resulting T-ALLs lacked LMO2 and its target-gene expression, and histologically, transcriptionally, and genetically similar to human LMO2-driven T-ALL We next found that during T-ALL development, secondary genomic alterations take place within the thymus. However, the permissiveness for development of T-ALL seems to be associated with wider windows of differentiation than previously appreciated. Restricted Cre-mediated activation of Lmo2 at different stages of B-cell development induces systematically and unexpectedly T-ALL that closely resembled those of their natural counterparts. Together, these results provide a novel paradigm for the generation of tumor T cells through reprogramming in vivo and could be relevant to improve the response of T-ALL to current therapies.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinogênese , Transformação Celular Neoplásica , Proteínas com Domínio LIM/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Células-Tronco Hematopoéticas/fisiologia , Histocitoquímica , Camundongos , Timo/patologia
10.
PLoS One ; 13(6): e0198789, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29920526

RESUMO

The CXCR4/CXCL12 axis has been extensively associated with different types of cancer correlating with higher aggressiveness and metastasis. In diffuse large B-cell lymphoma (DLBCL), the expression of the chemokine receptor CXCR4 is involved in the dissemination of malignant B cells and is a marker of poor prognosis. CXCR7 is a chemokine receptor that binds to the same ligand as CXCR4 and regulates de CXCR4-CXCL12 axis. These findings together with the report of CXCR7 prognostic value in several tumor types, led us to evaluate the expression of CXCR7 in diffuse large B-cell lymphoma biopsies. Here, we describe that CXCR7 receptor is an independent prognostic factor that associates with good clinical outcome. Moreover, the expression of CXCR7 associates with increased survival in CXCR4+ but not in CXCR4- DLBCL patients. Thus, the combined immunohistochemical evaluation of both CXCR7 and CXCR4 expression in DLBCL biopsies may improve their prognostic value as single markers. Finally, we show that CXCR7 overexpression in vitro is able to diminish DLBCL cell survival and increase their sensitivity to antitumor drugs. Hence, further studies on the CXCR7 receptor may establish its role in DLBCL and the molecular mechanisms that modulate CXCR4 activity.


Assuntos
Regulação Neoplásica da Expressão Gênica , Linfoma Difuso de Grandes Células B/genética , Proteínas de Neoplasias/biossíntese , Receptores CXCR4/análise , Receptores CXCR/biossíntese , Adulto , Idoso , Biomarcadores Tumorais , Biópsia , Linhagem Celular Tumoral , Quimiocina CXCL12/fisiologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiologia , Prognóstico , Modelos de Riscos Proporcionais , Receptores CXCR/genética , Receptores CXCR/fisiologia
11.
Cancer Res ; 78(10): 2669-2679, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29490943

RESUMO

Preleukemic clones carrying BCR-ABLp190 oncogenic lesions are found in neonatal cord blood, where the majority of preleukemic carriers do not convert into precursor B-cell acute lymphoblastic leukemia (pB-ALL). However, the critical question of how these preleukemic cells transform into pB-ALL remains undefined. Here, we model a BCR-ABLp190 preleukemic state and show that limiting BCR-ABLp190 expression to hematopoietic stem/progenitor cells (HS/PC) in mice (Sca1-BCR-ABLp190) causes pB-ALL at low penetrance, which resembles the human disease. pB-ALL blast cells were BCR-ABL-negative and transcriptionally similar to pro-B/pre-B cells, suggesting disease onset upon reduced Pax5 functionality. Consistent with this, double Sca1-BCR-ABLp190+Pax5+/- mice developed pB-ALL with shorter latencies, 90% incidence, and accumulation of genomic alterations in the remaining wild-type Pax5 allele. Mechanistically, the Pax5-deficient leukemic pro-B cells exhibited a metabolic switch toward increased glucose utilization and energy metabolism. Transcriptome analysis revealed that metabolic genes (IDH1, G6PC3, GAPDH, PGK1, MYC, ENO1, ACO1) were upregulated in Pax5-deficient leukemic cells, and a similar metabolic signature could be observed in human leukemia. Our studies unveil the first in vivo evidence that the combination between Sca1-BCR-ABLp190 and metabolic reprogramming imposed by reduced Pax5 expression is sufficient for pB-ALL development. These findings might help to prevent conversion of BCR-ABLp190 preleukemic cells.Significance: Loss of Pax5 drives metabolic reprogramming, which together with Sca1-restricted BCR-ABL expression enables leukemic transformation. Cancer Res; 78(10); 2669-79. ©2018 AACR.


Assuntos
Proteínas de Fusão bcr-abl/metabolismo , Regulação Leucêmica da Expressão Gênica/genética , Fator de Transcrição PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Animais , Linfócitos B/metabolismo , Linhagem Celular , Metabolismo Energético/genética , Proteínas de Fusão bcr-abl/genética , Glucose/metabolismo , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Fator de Transcrição PAX5/metabolismo , Pré-Leucemia/patologia
12.
Rev. esp. salud pública ; 92: 0-0, 2018. tab
Artigo em Espanhol | IBECS | ID: ibc-177561

RESUMO

Fundamentos: La obesidad es una de las principales pandemias del siglo XXI y el 5º factor de riesgo de muerte en el mundo. Cada año mueren más de 2,8 millones de personas a causa de esta enfermedad. Este estudio pretendió demostrar la eficacia de los programas de descansos activos para mejorar la salud en estudiantes de Educación Primaria, reduciendo su porcentaje de grasa e IMC; así como, incrementando su condición física. Métodos: Se implantó el programa de descansos activos Móvete 15 en el Colegio Curros Enríquez de Celanova (Galicia-España), durante el periodo 2016-17. Este consistió en interrumpir la jornada escolar diaria por 15 minutos para realizar actividad física de intensidad media-alta. Se planteó un diseño de estudio pretest-posttest; empleándose técnicas estadísticas descriptivas (frecuencias y estadísticos) e inferenciales (t-Student, ANOVA, Homogeneidad Marginal) sobre variables antropométricas (Grasa, IMC) y de condición física (test Eurofit) como indicadores de salud. Resultados: Móvete 15 logró mejoras significativas (p < 0,05) en la salud de los participantes, manifestadas en la reducción del porcentaje medio de grasa, -1,33% (0,49 kg); y en el aumento de la condición física, con mejoras en velocidad-coordinación (-1,45 segundos/circuito) y resistencia aeróbica (+1,46 fases)


Background: Obesity is one of the main pandemics of the 21st century and the 5th risk factor for death in the world. Every year more than 2.8 million people die due to this disease. This study aims to demonstrate the effectiveness of physical activity breaks programs to improve health in elementary school students, reducing their body fat percentage and BMI and increasing their physical condition. Methods: The physical activity breaks program called Móvete 15 was developed in Curros Enríquez School from Celanova (Galicia-Spain), during 2016-17 school year. This consisted in interrupting the daily school day for 15 minutes to perform physical activity of moderate and vigorous intensity. A pretest-posttest study design was proposed, using descriptive statistical techniques (frequencies and statistics) and inferential techniques (t-Student, ANOVA, Marginal Homogeneity) on anthropometric variables (Fat, BMI) and physical condition (Eurofit test) as health indicators. Results: The programme Móvete 15 achieved significant improvements (p < 0.05) in the participants' health, manifested in the reduction of the average percentage of fat, -1.33% (0.49 kg); and in the increase of physical condition, with improvements in speed-coordination (-1.45 seconds/circuit) and aerobic resistance (+1.46 phases)


Assuntos
Humanos , Nível de Saúde , Aptidão Física/fisiologia , Obesidade Pediátrica/terapia , Sobrepeso/terapia , Terapia por Exercício/métodos , Estudantes/estatística & dados numéricos , Programas de Redução de Peso/organização & administração , Avaliação de Eficácia-Efetividade de Intervenções , Condicionamento Físico Humano/estatística & dados numéricos , Antropometria/métodos , Pesos e Medidas Corporais/estatística & dados numéricos
14.
Rev Chil Pediatr ; 88(4): 529-533, 2017.
Artigo em Espanhol | MEDLINE | ID: mdl-28898323

RESUMO

INTRODUCTION: Pontocerebellar hypoplasia (PCH) is a reduction of the size of the cerebellum and pons secondary to an alteration in its development, and can be caused by neurodegenerative diseases of genetic origin, of which there are known 10 subtypes (PCH 1-10), cortical malformations, metabolic and genetic diseases. OBJECTIVE: To present the case of a child with microcephaly, PCH and West syndrome, in which the genetic study allowed to make the diagnosis of a deletion on chromosome X. CASE REPORT: This is a female infant of 7-month at diagnosis, without family or obstetric history of interest, head circumference at birth -1.5 standard deviations (SD). She had little weight and growth in head circumference progression. In addition, physical examination revealed no fixating gaze, hypotonia with preserved deep tendon reflexes. Progressively developed refractary seizures. Brainsteam Auditory Evoked Potential demonstrated involvement of pontomesencefphalic ways and neuroimaging Pontocerebellar hypoplasia. The genetic study (aCGH) showed heterozygous deletion on the X chromosome, affecting the CASK gene. CONCLUSIONS: Given the wide differential diagnosis proposed at the PCH, new cytogenetic techniques have improved the classification of HPC and in some cases establish their etiology, so in these cases can provide appropriate genetic counseling to families.


Assuntos
Doenças Cerebelares/diagnóstico , Doenças Cerebelares/genética , Deleção de Genes , Guanilato Quinases/genética , Doenças Cerebelares/complicações , Pré-Escolar , Feminino , Marcadores Genéticos , Humanos , Lactente , Microcefalia/diagnóstico , Microcefalia/etiologia , Espasmos Infantis/diagnóstico , Espasmos Infantis/etiologia
15.
Rev Fac Cien Med Univ Nac Cordoba ; 74(2): 150-161, 2017.
Artigo em Espanhol | MEDLINE | ID: mdl-28657533

RESUMO

Refractive errors are caused by a decoupling of the power of convergence of the eye lens, the cornea and lens, which make the rays reaching the eye to focus and generate an image, and the retina, which is the biological photosensitive screen where the image will be transformed into a nerve impulse. These defects include myopia, hyperopia and astigmatism. Presbyopia can also be considered a refractive defect, but of special features, since only affects near vision in patients older than 40 years. By altering the quality of the focused image on the most sensitive area of the retina (the macula), they decrease visual acuity. For their management several options exist, from the use of glasses and contact lenses to surgical correction (refractive surgery). The incidence of certain refractive errors (myopia specifically) has increased in recent decades, some environmental factors related to it have been identified. Some medical management measures have shown a positive effect in controlling its onset and progression.


Assuntos
Erros de Refração , Progressão da Doença , Óculos/história , História Antiga , História Medieval , Humanos , Erros de Refração/história , Erros de Refração/fisiopatologia , Erros de Refração/reabilitação , Erros de Refração/terapia , Percepção Visual
16.
Cancer Res ; 77(16): 4365-4377, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28630052

RESUMO

ETV6-RUNX1 is associated with the most common subtype of childhood leukemia. As few ETV6-RUNX1 carriers develop precursor B-cell acute lymphocytic leukemia (pB-ALL), the underlying genetic basis for development of full-blown leukemia remains to be identified, but the appearance of leukemia cases in time-space clusters keeps infection as a potential causal factor. Here, we present in vivo genetic evidence mechanistically connecting preleukemic ETV6-RUNX1 expression in hematopoetic stem cells/precursor cells (HSC/PC) and postnatal infections for human-like pB-ALL. In our model, ETV6-RUNX1 conferred a low risk of developing pB-ALL after exposure to common pathogens, corroborating the low incidence observed in humans. Murine preleukemic ETV6-RUNX1 pro/preB cells showed high Rag1/2 expression, known for human ETV6-RUNX1 pB-ALL. Murine and human ETV6-RUNX1 pB-ALL revealed recurrent genomic alterations, with a relevant proportion affecting genes of the lysine demethylase (KDM) family. KDM5C loss of function resulted in increased levels of H3K4me3, which coprecipitated with RAG2 in a human cell line model, laying the molecular basis for recombination activity. We conclude that alterations of KDM family members represent a disease-driving mechanism and an explanation for RAG off-target cleavage observed in humans. Our results explain the genetic basis for clonal evolution of an ETV6-RUNX1 preleukemic clone to pB-ALL after infection exposure and offer the possibility of novel therapeutic approaches. Cancer Res; 77(16); 4365-77. ©2017 AACR.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Histona Desmetilases/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/microbiologia , Animais , Subunidade alfa 2 de Fator de Ligação ao Core/biossíntese , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Modelos Animais de Doenças , Células-Tronco Hematopoéticas , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Proteínas de Fusão Oncogênica/biossíntese , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética
17.
Rev. méd. Chile ; 145(6): 747-754, June 2017. tab
Artigo em Espanhol | LILACS-Express | ID: biblio-902540

RESUMO

Background: Spiritual issues are an important dimension of health care, but seldom addressed by professionals. Thus, a scale that assesses the presence and intensity of seven spiritual symptoms was developed. Aim: To validate the instrument in palliative care settings. Material and Methods: The spiritual symptoms scale was applied to 103 patients, aged 59 ± 17 years (58% women), admitted to hospice care in two centers located in Santiago. The reproducibility of the scale was evaluated in 33 patients and its internal consistency and liability in 70. Results: The Fleiss Kappa to assess reproducibility was 0.82 and the analysis of variance had a p of 0.94. Cronbach alpha to assess internal consistency was 0.74. Conclusions: The scale renders similar results when applied by different evaluators and has a good liability. Therefore, it can be a reliable instrument to assess spiritual symptoms in palliative care settings. Further studies would be needed to verify its utility in other settings.

18.
Medicine (Baltimore) ; 96(19): e6846, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28489772

RESUMO

RATIONALE: Primary lymphomas of the uterine cervix are a rare disease. They are often misdiagnosed because of their rarity and because they can be easily confused with a squamous cell carcinoma of the cervix, as they are usually presented as exophytic mass with vaginal bleeding as their most common symptoms. Nevertheless, considering that both the prognosis and the treatment are completely different between them, differential diagnosis should be taken into account. PATIENT CONCERNS: A case of a 51-year-old woman with a primary diffuse large B-cell lymphoma of the cervix is presented. DIAGNOSES: Diagnosis of this tumor was a challenge for pathologists and clinicians, as four biopsies were needed to achieve a final diagnosis. INTERVENTIONS: Patient was successfully treated with combined Rituximab and chemotherapy (R-CHOP) alone. OUTCOMES: Complete remission, confirmed through biopsy, was reached after six courses of chemotherapy. At 2-years follow up, patient is alive and free of disease. LESSONS: Considering that the prognosis and treatment of primary malignant lymphoma of the cervix are completely different than that of the squamous cell carcinoma, awareness of this disease should be considered in the differential diagnosis.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Rituximab/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Colo do Útero/diagnóstico por imagem , Colo do Útero/efeitos dos fármacos , Colo do Útero/patologia , Ciclofosfamida/uso terapêutico , Diagnóstico Diferencial , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/patologia , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/patologia , Vincristina/uso terapêutico
19.
Blood ; 129(19): 2645-2656, 2017 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-28288979

RESUMO

CREBBP is targeted by inactivating mutations in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Here, we provide evidence from transgenic mouse models that Crebbp deletion results in deficits in B-cell development and can cooperate with Bcl2 overexpression to promote B-cell lymphoma. Through transcriptional and epigenetic profiling of these B cells, we found that Crebbp inactivation was associated with broad transcriptional alterations, but no changes in the patterns of histone acetylation at the proximal regulatory regions of these genes. However, B cells with Crebbp inactivation showed high expression of Myc and patterns of altered histone acetylation that were localized to intragenic regions, enriched for Myc DNA binding motifs, and showed Myc binding. Through the analysis of CREBBP mutations from a large cohort of primary human FL and DLBCL, we show a significant difference in the spectrum of CREBBP mutations in these 2 diseases, with higher frequencies of nonsense/frameshift mutations in DLBCL compared with FL. Together, our data therefore provide important links between Crebbp inactivation and Bcl2 dependence and show a role for Crebbp inactivation in the induction of Myc expression. We suggest this may parallel the role of CREBBP frameshift/nonsense mutations in DLBCL that result in loss of the protein, but may contrast the role of missense mutations in the lysine acetyltransferase domain that are more frequently observed in FL and yield an inactive protein.


Assuntos
Linfócitos B/patologia , Proteína de Ligação a CREB/genética , Regulação Neoplásica da Expressão Gênica , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Animais , Epigênese Genética , Deleção de Genes , Humanos , Linfoma Folicular/genética , Camundongos , Camundongos Transgênicos , Mutação
20.
Leuk Lymphoma ; 58(5): 1144-1152, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27733075

RESUMO

Prognostic factors in Hodgkin lymphoma (HL) still fail to accurately identify high-risk patients. Tumor microenvironment in HL is a current focus of research for risk definition but few studies have focused on infiltrating lymphocytes. Here, we analyzed the number of tumor infiltrating lymphocytes by flow cytometry in diagnostic biopsies from 96 HL homogeneously treated patients with ABVD with or without radiotherapy. Most lymph node cells were lymphocytes (90 ± 17), with a median T/B/NK distribution of 74%/26%/0.7%, and CD4+ T-cell predominance. The amount of CD19+ B cells, and NK cells did not show association with disease features. However, high numbers of CD8+ and CD4+ cells were associated with better and poorer outcomes, respectively. Patients with ≥15% cytotoxic CD8+ cells among the total cell population had a longer 10-year freedom from treatment failure (FFTF) (93% vs. 73%, p=.04). In turn, cases with ≥75% of CD4+ infiltrating cells showed a significantly decreased FFTF (73% vs. 96%, p=.021). Consequently, CD4/CD8 ratio ≥5 associated with a poorer 10-year FFTF (69.5% vs. 94%, p=.02). This deleterious effect was particularly prominent in advanced disease (n = 58, p=.01). In multivariate analysis, a CD4/CD8 ratio ≥5 was the only independent variable to predict for treatment failure (HR = 4.5, 95% confidence interval, 1.2-16.8). In conclusion, our study shows that high CD4+ and low CD8+ T-cells infiltrates of tumor specimens associate with poor prognosis in HL patients, and CD4/CD8 ratio might be potentially useful for tailoring therapy.


Assuntos
Doença de Hodgkin/imunologia , Doença de Hodgkin/mortalidade , Linfonodos/imunologia , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/imunologia , Subpopulações de Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Bleomicina/efeitos adversos , Bleomicina/uso terapêutico , Relação CD4-CD8 , Criança , Dacarbazina/efeitos adversos , Dacarbazina/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Imunofenotipagem , Estimativa de Kaplan-Meier , Linfonodos/metabolismo , Linfonodos/patologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fenótipo , Prognóstico , Curva ROC , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Resultado do Tratamento , Vimblastina/efeitos adversos , Vimblastina/uso terapêutico , Adulto Jovem
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