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1.
ESMO Open ; 6(5): 100279, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34607284

RESUMO

BACKGROUND: KRAS is mutated in ∼30% of non-small-cell lung cancer (NSCLC) but it has also been identified as one of the mechanisms underlying resistance to tyrosine kinase inhibitors (TKIs) in EGFR-positive NSCLC patients. Novel KRAS inhibitors targeting KRAS p.G12C mutation have been developed recently with promising results. The proportion of EGFR-positive NSCLC tumours harbouring the KRAS p.G12C mutation upon disease progression is completely unexplored. MATERIALS AND METHODS: Plasma samples from 512 EGFR-positive advanced NSCLC patients progressing on a first first-line treatment with a TKI were collected. The presence of KRAS p.G12C mutation was assessed by digital PCR. RESULTS: Overall, KRAS p.G12C mutation was detected in 1.17% of the samples (n = 6). In two of these cases, we could confirm that the KRAS p.G12C mutation was not present in the pre-treatment plasma samples, supporting its role as an acquired resistance mutation. According to our data, KRASG12C patients showed similar clinicopathological characteristics to those of the rest of the study cohort and no statistically significant associations between any clinical features and the presence of the mutation were found. However, two out of six KRASG12C tumours harboured less common EGFR driver mutations (p.G719X/p.L861Q). All KRASG12C patients tested negative for the presence of p.T790M resistance mutation. CONCLUSIONS: The KRAS p.G12C mutation is detected in 1% of EGFR-positive NSCLC patients who progress on a first line with a TKI. All KRASG12C patients were negative for the presence of the p.T790M mutation and they did not show any distinctive clinical feature.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética
2.
J Invest Surg ; 33(1): 8-14, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29764253

RESUMO

Purpose: Evaluate the efficacy of hydroxytyrosol in the local treatment of inflammatory colitis. Currently, the existing treatments for inflammatory bowel diseases does not cure the disease and it is associated with high rates of side effects and complications. Hydroxytyrosol is a phenyl-ethyl-alcohol derived from the hydrolysis of oleuropein and present in olive oil, previous studies have demonstrated the anti-inflammatory effect of dietary hydroxytyrosol supplement, with no toxicity. Materials & Methods: Colitis has been induced by using Trinitrobenzene Sulfonic Acid at 40 rats. They were divided into four groups randomly: 10 rats without treatment; 10 rats with pectin/alginate mixture; 10 rats treated with pectin/alginate + olive oil; 10 rats treated with pectin/alginate + olive oil + hydroxytyrosol. Animals were sacrificed 10 days after induction of trinitrobenzene sulfonic acid, receiving 5 days of continuous treatment. Samples of the rectal area were studied and observed under a microscope to determine the damage by Hunter scoring modified, assessing inflammatory infiltration, number of intestinal walls involved, damage to the mucosal architecture, and edema. Results: When the rectum was analyzed in a global way, nonsignificant differences were observed; however, when performing an individualized analysis, statistically significant differences in the inflammatory infiltrate are present in the samples, which were evaluated using the ANOVA and Student-T statistics. Conclusions: Local treatment with the natural antioxidant hydroxytyrosol combined with pectin/alginate and olive oil of inflammatory bowel disease has been shown to be effective against inflammatory infiltration of TNBS-induced colitis.


Assuntos
Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Colite/tratamento farmacológico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Álcool Feniletílico/análogos & derivados , Alginatos/administração & dosagem , Alginatos/efeitos adversos , Animais , Anti-Inflamatórios/efeitos adversos , Antioxidantes/efeitos adversos , Colite/induzido quimicamente , Colite/patologia , Modelos Animais de Doenças , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Enema , Estudos de Viabilidade , Feminino , Humanos , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Azeite de Oliva/administração & dosagem , Azeite de Oliva/efeitos adversos , Pectinas/administração & dosagem , Pectinas/efeitos adversos , Álcool Feniletílico/administração & dosagem , Álcool Feniletílico/efeitos adversos , Ratos , Ratos Wistar , Reto/efeitos dos fármacos , Reto/imunologia , Reto/patologia , Ácido Trinitrobenzenossulfônico/toxicidade
3.
Rev. am. med. respir ; 18(1): 61-64, mar. 2018. ilus
Artigo em Espanhol | LILACS | ID: biblio-897308

RESUMO

La neumoconiosis constituye un grupo de enfermedades asociadas con la exposición e inhalación de polvo mineral, de partículas inorgánicas, sílice, berilio, carbón, cobalto, talco, etc. La exposición al polvo de sílice se asocia no sólo con silicosis, sino también con enfermedad pulmonar obstructiva crónica, cáncer de pulmón, insuficiencia renal y riesgo aumentado de tuberculosis pulmonar y enfermedades autoinmunes. Está bien establecida la asociación entre el contacto con el sílice por vía inhalatoria y enfermedades autoinmunes, particularmente en el contexto de una exposición intensa. La exposición al sílice se ha vinculado con un incremento de la síntesis de anticuerpos y complejos inmunes, aún sin la presencia de características clínicas de enfermedad autoinmune. El riesgo de desarrollar esclerosis sistémica, artritis reumatoidea, lupus eritematoso sistémico, dermatomiositis / polimiositis y anticuerpos anticitoplasmáticos del neutrófilo (ANCA) positivos (vasculitis) esta descripto en varios estudios. En paciente que trabajan en canteras con escasas medidas de prevención el desarrollo de silicosis ha llegado ser tan severo que ha requerido trasplante pulmonar; sobre esta base se recomienda seguirlos con un perfil inmunológico como control o estar atentos a otras manifestaciones de autoinmunidad. La esclerosis sistémica es una enfermedad autoinmune definida como un desorden generalizado de la microvasculatura y del tejido conectivo, con engrosamiento y obliteración de los vasos arteriales de piel, pulmón, tracto gastrointestinal, corazón y riñones. Su etiología es desconocida pero probablemente concurren factores endógenos y exógenos. Entre los factores exógenos, la exposición ocupacional juega un rol importante como causa potencial, incluyendo el polvo de sílice, cloruro de vinilo, resina epoxi, bleomicina, hidrocarburos aromáticos, aceites. Excepto el s-lice todos los otros agentes producen cambios reversibles una vez suspendido el contacto con el agente. El polvo de sílice y su inhalación es un factor de riesgo bien reconocido de esclerosis sistémica. Las partículas de cristal de sílice (cuarzo) que miden menos de un micrometro son las más patogénicas ya que al ser inertes pueden permanecer por tiempo indeterminado en el tejido. El antecedente de exposición al polvo de sílice y esclerosis sistémica se conoce como Síndrome de Erasmus.


Assuntos
Pneumoconiose , Silicose , Dióxido de Silício
4.
Bone Marrow Transplant ; 52(8): 1138-1143, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28346415

RESUMO

For patients with AML, the best alternative donor remains to be defined. We analyze outcomes of patients who underwent myeloablative umbilical cord blood or haploidentical hemopoietic stem cell transplantation (HSCT) in Spain. Fifty-one patients underwent single umbilical cord blood transplantation supported by a third party donor (Haplo-Cord) between 1999 and 2012, and 36 patients received an haploidentical HSCT with post-transplant cyclophosphamide (PTCY-haplo) between 2012 and 2014 in GETH centers. The Haplo-Cord cohort included a higher proportion of patients with high disease risk index and use of TBI in the conditioning regimen, and hematopoietic cell transplantation-age Comorbidity Age Index was higher in PTCY-haplo patients. Cumulative incidence of neutrophil engraftment was 97% in the Haplo-Cord and 100% in the PTCY-haplo group, achieved in a median of 12 and 17 days, respectively (P=0.01). Grade II-IV acute GvHD rate was significantly higher in the PTCY-haplo group (9.8% vs 29%, P=0.02) as well as chronic GvHD rates (20% vs 38%, P=0.03). With a median follow-up of 61 months for the Haplo-Cord group and 26 months for the PTCY-haplo cohort, overall survival at 2 years was 55% and 59% (P=0.66), event-free survival was 45% vs 56% (P=0.46), relapse rate was 27% vs 21% (P=0.79), and non-relapse mortality was 17% vs 23% (P=0.54), respectively. In this multicenter experience, Haplo-Cord and PTCY-haplo HSCT offer valid alternatives for patients with AML. Neutrophil engraftment was faster in the Haplo-Cord cohort, with similar survival rates, with higher GvHD rates after haploidentical HSCT.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Ciclofosfamida/uso terapêutico , Leucemia Mieloide Aguda/terapia , Transplante Haploidêntico/métodos , Adolescente , Adulto , Idoso , Transplante de Células-Tronco de Sangue do Cordão Umbilical/mortalidade , Intervalo Livre de Doença , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Condicionamento Pré-Transplante/métodos , Transplante Haploidêntico/mortalidade , Adulto Jovem
5.
Exp Gerontol ; 92: 46-51, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28315394

RESUMO

A side effect of increased life expectancy is a surge in sequelae of diseases and injuries, which in turn increase the duration of life with disability among the elderly. The aim of this study was to ascertain the physical activity and nutritional parameters that better predict cardiovascular risk in a cohort of older women. A cross-sectional study was designed including 65 women able to independently perform basic activities of daily life. Data collection included anthropometric measurement, blood pressure measurement, blood analytics, objectively measurement of physical activity, and dietary assessment. We were able to generate models that explain the relationship between physical activity, diet, and these health measurement parameters. We observed that the combination of moderate physical activity and a diet including protein-rich foods as nuts, dairy, and eggs were better predictors associated with favorable changes in risk factors for cardiovascular disease than age.


Assuntos
Envelhecimento/fisiologia , Doenças Cardiovasculares/epidemiologia , Dieta , Exercício Físico , Idoso , Antropometria , Pressão Sanguínea , Estudos Transversais , Feminino , Humanos , Vida Independente , Modelos Lineares , Modelos Logísticos , Fatores de Risco , Espanha
6.
Clin Transl Oncol ; 19(4): 409-418, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27778302

RESUMO

The potential role of the mitochondrial genome has recently attracted interest because of its high mutation frequency in tumors. Different aspects of mtDNA make it relevant for cancer's biology, such as it encodes a limited but essential number of genes for OXPHOS biogenesis, it is particularly susceptible to mutations, and its copy number can vary. Moreover, most ROS in mitochondria are produced by the electron transport chain. These characteristics place the mtDNA in the center of multiple signaling pathways, known as mitochondrial retrograde signaling, which modifies numerous key processes in cancer. Cybrid studies support that mtDNA mutations are relevant and exert their effect through a modification of OXPHOS function and ROS production. However, there is still much controversy regarding the clinical relevance of mtDNA mutations. New studies should focus more on OXPHOS dysfunction associated with a specific mutational signature rather than the presence of mutations in the mtDNA.


Assuntos
DNA Mitocondrial/genética , Mitocôndrias/genética , Mutação/genética , Neoplasias/genética , Neoplasias/patologia , Humanos
7.
Bone Marrow Transplant ; 51(7): 961-6, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26950372

RESUMO

The safety and efficacy of a 4-day myeloablative conditioning (MAC) regimen consisting of Bu 3.2 mg/kg and fludarabine 40 mg/m(2)/day for HLA-identical sibling allogeneic hematopoietic cell transplantation (HCT) in myeloid malignancies was investigated in 133 patients (median age, 47 years; range 19-74 years) with de novo AML (60%), secondary AML (20%) or myelodysplastic syndrome (20%). All patients engrafted. Hepatic veno-occlusive disease occurred in five patients (4%), and severe toxicities, mostly mucositis, occurred in twenty-three (17%) patients. The non-relapse mortality (NRM) at 100 days was 1.5%. The incidences of acute GVHD grade 2-4 and grade 3-4 were 32 and 13%, respectively. At a median follow-up of 38 months, the cumulative incidence of chronic GVHD was 67%. The relapse incidence was 30% (27 and 31%, respectively, in patients with early- and late-stage disease), and the overall NRM was 15%. The actuarial 4-year disease-free survival (DFS) and overall survival (OS) were 54 and 62%, respectively. Patients aged <50 years had better outcomes compared with older patients (DFS 64 vs 42%, P=0.006; OS 73 vs 47%, P<0.001, respectively).


Assuntos
Bussulfano/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Agonistas Mieloablativos/toxicidade , Síndromes Mielodisplásicas/terapia , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Adulto , Idoso , Bussulfano/toxicidade , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Hepatopatia Veno-Oclusiva/induzido quimicamente , Hepatopatia Veno-Oclusiva/etiologia , Histocompatibilidade/imunologia , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/mortalidade , Pessoa de Meia-Idade , Mucosite/induzido quimicamente , Mucosite/etiologia , Agonistas Mieloablativos/uso terapêutico , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/mortalidade , Recidiva , Análise de Sobrevida , Condicionamento Pré-Transplante/mortalidade , Vidarabina/administração & dosagem , Vidarabina/toxicidade , Adulto Jovem
9.
Transpl Infect Dis ; 17(5): 761-7, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26250790

RESUMO

BACKGROUND: It is well known that both acute and chronic graft-versus-host disease (GVHD) are associated with invasive fungal disease (IFD). Because the galactomannan antigen diagnostic test has low specificity and sensitivity outside of the neutropenic period, many institutions use posaconazole or voriconazole for IFD prophylaxis during GVHD treatment. Moreover, several factors, mainly hepatic impairment, can limit the use of extended spectrum azoles, both in prophylaxis or treatment. METHODS: We retrospectively analyzed 25 patients with allogeneic hematopoietic stem cell transplantation (HSCT) and GVHD - grade III-IV acute GHVD (n = 15), progressive chronic GVHD (n = 7), and "overlap" GVHD (n = 3) - who received intravenous anidulafungin (200 mg on day 1, followed by 100 mg once daily). If necessary, anidulafungin treatment was followed by oral administration of 200 mg voriconazole twice a day or 200 mg posaconazole 3 times daily until patients were considered not at risk for IFD. RESULTS: Twenty-one patients (85%) received anidulafungin as prophylaxis and 5 patients (15%) received it as treatment. Median duration of intravenous anidulafungin administration was 8 days (range 6-17). Seven patients (28%) presented mild adverse effects, with no significant interactions with calcineurin inhibitors. Sequentially, 4 patients received voriconazole and 6 posaconazole. Two patients (8%) developed IFD after anidulafungin withdrawal: 1 with Candida albicans and the other with Mucor, 8 and 5 days after withdrawal, respectively. CONCLUSIONS: Our results are of interest owing to the absence of data in the literature on anidulafungin use in HSCT patients with GVHD, and suggest that anidulafungin, because of its spectrum, pharmacological profile, low toxicity, and absence of interactions with immunosuppressants, could be a drug of choice in this setting.


Assuntos
Antifúngicos/uso terapêutico , Equinocandinas/uso terapêutico , Doença Enxerto-Hospedeiro/complicações , Transplante de Células-Tronco Hematopoéticas , Micoses/prevenção & controle , Administração Oral , Adulto , Anidulafungina , Esquema de Medicação , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Micoses/tratamento farmacológico , Micoses/etiologia , Micoses/imunologia , Estudos Retrospectivos , Transplante Homólogo , Resultado do Tratamento
12.
Blood Cancer J ; 5: e316, 2015 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-26024286

RESUMO

Although several new therapeutic approaches have improved outcomes in the treatment of hematologic malignancies, unmet need persists in acute myeloid leukemia (AML), multiple myeloma (MM) and non-Hodgkin's lymphoma. Here we describe the proteomic identification of a novel cancer target, SAIL (Surface Antigen In Leukemia), whose expression is observed in AML, MM, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). While SAIL is widely expressed in CLL, AML, MM, DLBCL and FL patient samples, expression in cancer cell lines is mostly limited to cells of AML origin. We evaluated the antitumor activity of anti-SAIL monoclonal antibodies, 7-1C and 67-7A, conjugated to monomethyl auristatin F. Following internalization, anti-SAIL antibody-drug conjugates (ADCs) exhibited subnanomolar IC50 values against AML cell lines in vitro. In pharmacology studies employing AML cell line xenografts, anti-SAIL ADCs resulted in significant tumor growth inhibition. The restricted expression profile of this target in normal tissues, the high prevalence in different types of hematologic cancers and the observed preclinical activity support the clinical development of SAIL-targeted ADCs.


Assuntos
Aminobenzoatos/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Antígenos de Neoplasias/imunologia , Antineoplásicos/administração & dosagem , Neoplasias Hematológicas/tratamento farmacológico , Imunoterapia/métodos , Oligopeptídeos/administração & dosagem , Animais , Cromatografia Líquida , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Hibridização In Situ , Camundongos , Camundongos SCID , Espectrometria de Massas em Tandem , Análise Serial de Tecidos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Bone Marrow Transplant ; 49(9): 1170-5, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24978140

RESUMO

This retrospective analysis compared two regimens of fludarabine combined with i.v. BU 6.4 mg/kg (FB2) or BU 12.8 mg/kg (FB4) for allografting of AML in first CR. A total of 437 patients (median age: 50 years) were administered FB2 (n = 225, 51%) or FB4 (n = 212, 49%). Median follow-up time was 28 months. Use of FB2 resulted in a longer time to neutrophil engraftment (17 vs 15 days, P < 0.0001) but no difference in incidence of grade II-IV acute (P = 0.54) or chronic GVHD (P = 0.51). In patients < 50 years of age, FB2 was associated with a higher 2-year cumulative incidence of relapse (33 ± 6% vs 20 ± 4%, P = 0.04), but there was no difference in 2-year leukemia-free survival (LFS) (P = 0.45), OS (P = 0.53) or non-relapse mortality (P = 0.17). In recipients ⩾ 50 years of age, FB2 resulted in better 2-year LFS (63 ± 4% vs 42 ± 7%, P = 0.02) and OS (68 ± 4% vs 45 ± 7%, P = 0.006); a lower 2-year non-relapse mortality, albeit not statistically significant (15 ± 3% vs 29 ± 6%, P = 0.06), was observed with FB2. FB2 is an effective and well-tolerated regimen in patients ⩾ 50 years of age and does not compromise survival when used in patients <50 years undergoing allogeneic transplantation for AML in first CR.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Bussulfano/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Administração Intravenosa , Adulto , Idoso , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Homólogo , Adulto Jovem
14.
Rev. med. vet. zoot ; 59(3): 165-175, jul.-dic. 2012. tab
Artigo em Espanhol | LILACS-Express | LILACS | ID: lil-677519

RESUMO

Se evaluó el efecto de un sistema de alimentación integrado por dietas formuladas con recursos alternativos orgánicos y diferentes niveles de fertilización orgánica sobre parámetros zootécnicos en peces de consumo cultivados en estanques de tierra. Se utilizaron 1.324 juveniles de Tilapia nilótica (Oreochromis niloticus) cuyo peso inicial promedio fue de 161,9 ± 7,0 g, solo machos sexados manualmente, sin reversión hormonal. Se empleó un diseño completamente al azar con tres tratamientos y tres repeticiones, distribuidos en 9 estanques de tierra (200 m² cada uno), cultivados bajo las normas de Naturland (2007, 2008, 2011) para la acuicultura orgánica. Durante 180 días se suministraron dietas (levante: 27% PB y 4.120 cal/g EB; finalización: 21% PB y 4.200 cal/g EB) formuladas con recursos provenientes de producción agrícola orgánica certificada. Se implementaron tres variables: un control sin fertilizante y dos diferentes niveles de fertilización con gallinaza orgánica (T1: Abonamiento intensivo con 5 g/m²/día; T2: Abonamiento periódico con 14 g/m²/semana y T3: Sin abonamiento). Se evaluó el efecto de los tratamientos sobre parámetros productivos: ganancia diaria de peso, conversión alimenticia aparente, tasa de crecimiento específico, rendimiento en filete, índices viscerosomático, hepatosomático y de grasa visceral, relación de eficiencia proteica, valor productivo de proteína y eficiencia de retención de energía. No se encontraron diferencias significativas en las variables evaluadas (p>0.05). Los resultados indican la posibilidad de implementar un sistema de alimentación orgánico como alternativa productiva que logra parámetros productivos que se aproximan a lo reportado para explotaciones convencionales de tilapia y con el potencial de posicionar un producto final en eco-mercados diferenciales siendo sustentable en su obtención.


It was evaluated the effect of a feeding system that included formulated diets with organic alternative resources and different levels of organic fertilization on animal production evaluation parameters in fish farmed in earthen ponds. 1,324 juvenile Nile tilapia (Oreochromis niloticus) with initial weight of 161.9 ± 7.0 g, male manually sexed without hormonal reversal were used. It was used a completely randomized design with three treatments and three replicates, randomly distributed in 9 earthen ponds of 200 m² each. The husbandry management was under the Naturland standards for organic aquaculture. During 180 days fish were fed diets (growth: 27% CP and 4,120 cal/g GE; finish: 21% CP and 4,200 cal/g GE) formulated using resources from certified organic agricultural production. Were handled without fertilizer control and two different levels of organic chicken manure fertilization (T1: intensive fertilization with 5g/m²/day; T2: periodically fertilization with 14g/m²/week and T3: no fertilization). The effect of treatments was evaluated on: daily weight gain, apparent feed conversion, specific growth rate, fillet yield, viscerosomatic, hepatosomatic and visceral fat index, protein efficiency ratio, protein production value and energy retention efficiency. There were not significant differences in the variables evaluated (p<0,05). Results obtained suggest that it is possible to implement an organic feeding system to be a productive alternative that able to maintain production parameters approximate to that reported to conventional production, with potential to position the final product markets to be sustainable differential extraction.

16.
Med Chem ; 4(3): 278-92, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18473921

RESUMO

As microbes use many mechanisms for avoiding immunological pressure, new strategies must be developed to bypass the immunological code of silence of conserved, functionally-important amino acid sequences, such as those involved in high activity binding peptides' (HABPs) attaching to their host cells. Hundreds of experiments in large numbers of Aotus monkeys revealed that this immunological code of silence could be broken by shifting the polarity of some critical host cell binding residues in these HABPs by substituting F for R and vice versa, Y<-->W, L<-->H, I<-->N, P<-->D, M<-->K or E, C<-->T, V<-->N or S; there are special rules for A, G and S. (1)H-nuclear magnetic resonance of these modified, immunogenic, protection-inducing HABPs and molecular modelling revealed that such modifications induced appropriate fitting into specific HLA-DRbeta1 Pockets, suggesting the presence of new pockets and a haplotype- and allele-specific conscious TCR. A highly immunogenic and protection-inducing anti-malarial vaccine can thus be produced.


Assuntos
Antígeno HLA-DR1/química , Peptídeos/química , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Aotidae , Sequência Conservada , Vacinas Antimaláricas/imunologia , Malária Falciparum/imunologia , Malária Falciparum/prevenção & controle , Modelos Moleculares , Dados de Sequência Molecular , Peptídeos/imunologia , Plasmodium falciparum/imunologia , Ligação Proteica , Receptores de Antígenos de Linfócitos T/química , Relação Estrutura-Atividade , Vacinas de Subunidades Antigênicas/imunologia
17.
Cytogenet Genome Res ; 122(3-4): 281-91, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-19188697

RESUMO

The Alternative Lengthening of Telomeres (ALT) mechanism is utilised by approximately 10% of human tumours and a higher proportion of some types of sarcomas. ALT+ cell lines and tumours show heterogeneous telomere length, extra-chromosomal circular and linear telomeric DNA, ALT associated promyelocytic bodies (APBs), a high frequency of post-replication exchanges in telomeres (designated as telomere-sister chromatid exchanges, T-SCE) and high instability at a GC-rich minisatellite, MS32 (D1S8). It is clear that there is a link between the minisatellite instability and the mechanism that underpins ALT, however currently the nature of this relationship is uncertain. Single molecule analysis of telomeric DNA from ALT+ cell lines and tumours has revealed complex telomere mutations that have not been seen in cell lines or tumours that express telomerase. These complex telomere mutations cannot be explained by T-SCE but must arise by another inter-molecular process. The break-induced replication (BIR) model that may explain the observed high frequency of T-SCE and the presence of complex telomere mutations is reviewed.


Assuntos
Neoplasias/genética , Telomerase/genética , Telomerase/metabolismo , Processamento Alternativo , Linhagem Celular , DNA/genética , DNA Fúngico/genética , DNA de Neoplasias/genética , Instabilidade Genômica , Humanos , Mutação , Neoplasias/enzimologia , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Recombinação Genética , Saccharomyces cerevisiae/enzimologia , Sarcoma/enzimologia , Sarcoma/genética , Telômero/genética , Telômero/ultraestrutura
18.
Int J Gynecol Cancer ; 15(5): 762-9, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16174221

RESUMO

The objective of this study was to analyze prognostic factors and epidemiologic data in young women with invasive epithelial cancer (YWEOC). Forty consecutive cases were selected from our database, treated according to current standards. A control group with older patients (>40 years) was created using concurrent cohort technique (n= 114). Median follow-up was 95 months in YWEOC and 84 months in elder patients. They were grouped by FIGO stages, histologic type, and tumor grade. Oncologic family history was compared in both cohorts. Survival was calculated using Kaplan-Meier curves. Chi-square, log rank test, uni- and multivariate analyses were used for statistical comparison. Family history was obtained in 25 of 40 of YWEOC, and 7 had first-line relatives with hematologic tumors, while this was observed in 1 of 80 of the elder patients (OR 9.8; 1.2-74.7). Due to these findings, a <40-years control healthy group selected from the gynecology office was rated and when compared with YWEOC, statistically significant differences were observed (OR 39.2; 4.5-338). Tumors were more differentiated, compared to the elder group (G(1): 68% vs 7%, P < 0.0001); stage I was more frequent (70% vs 19%, P < 0.0001) as well as mucinous and endometroid histologic types (P < 0.03). Survival was higher among younger patients (81% vs 35%, P < 0.0001) and decreased by decade, especially after 41 years. In advanced cases, optimal cytoreduction was more frequently performed, and survival was significantly higher. Multivariate analysis revealed that the only independent prognostic factor was residual disease in both groups. Age is not an independent prognostic factor for ovarian cancer but it has a different biologic behavior. An interesting association with hematologic tumors was observed, suggesting another pathway for ovarian cancer oncogenesis.


Assuntos
Neoplasias Ovarianas/cirurgia , Adulto , Idoso , Envelhecimento , Feminino , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/patologia , Prognóstico , Taxa de Sobrevida
19.
Avian Dis ; 49(4): 592-600, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16405006

RESUMO

Three hundred day-old Japanese quail (Coturnix coturnix japonica) were divided into two groups with 150 quail in each group. One group was maintained on quail mash alone, while Fusarium moniliforme culture material was added to quail mash in the second group from day 5 of age and was supplied at a rate of 150 ppm fumonisin B1 (FB1)/kg mash. At day 21, each group was further subdivided into two groups, yielding four groups with 75 birds apiece, which served as the control (group CX), the Salmonella Gallinarum alone group (group CS), the FB1 alone group (group FX), and the group fed FB1 and infected with Salmonella Gallinarum (group FS). An oral challenge with Salmonella Gallinarum organisms (2 x 10(4) colony-forming units/ml) was given to groups CS and FS at 21 days of age. Three quail each were necropsied on day 21 (0 day interval) from groups CX and FX only. At subsequent intervals (i.e., 1, 2, 3, 5, 7, 10, 14, and 21 days postinfection [DPI]), three quail were euthanatized from all four groups (CX, CS, FX, and FS). The gross and microscopic lesions were recorded in both mortality and euthanatized birds at the above intervals. The ultrastructural studies were done at 5 DPI. Mild to moderate hepatomegaly and pale discoloration of liver were observed in group FX, while congestion, hemorrhages, necrosis, and mild to severe hepatomegaly were the predominant gross lesions in both infected groups (CS and FS). The gross lesions in quail inoculated with Salmonella Gallinarum alone (group CS) generally developed slowly, appeared more widely scattered, and involved comparatively less surface area in contrast to the rapidly progressive and frequently confluent lesions in the combination group (FS), especially in the first 5 days of infection. Mild to marked hepatocellular swelling, multifocal hepatic necrosis, and hepatocellular and bile duct hyperplasia were the characteristic microscopic changes in the FX group. Microscopic lesions in quail of group CS comprised congestion, vacuolar changes, and focal necrosis in early stages, followed by granulomatous lesions at later intervals. Similar but more severe lesions were observed in the combination group (FS). Based on transmission electron microscopy, the maximum effect of FB1 toxicity was observed on mitochondria and endoplasmic reticulum. In general, the mitochondriae showed diverse form and structure, some of which appeared to lose their intact outer membrane, and the mitochondrial cristae were disoriented. The deformity in the cisternae structure of rough endoplasmic reticulum, with their rearrangement into round or tubular forms either bearing granular surface or leading to accumulation of smooth endoplasmic reticulum, was evident only in groups FX and FS. We conclude that the continuous presence of fumonisins in the diets of young quail might increase their susceptibility to or the severity of Salmonella Gallinarum infection.


Assuntos
Coturnix/microbiologia , Fumonisinas/toxicidade , Fusarium/patogenicidade , Micoses/veterinária , Doenças das Aves Domésticas/etiologia , Salmonelose Animal/etiologia , Salmonella/patogenicidade , Animais , Fígado/patologia , Microscopia Eletrônica , Micoses/etiologia , Micoses/microbiologia , Micoses/patologia , Doenças das Aves Domésticas/microbiologia , Doenças das Aves Domésticas/patologia , Salmonella/isolamento & purificação , Salmonelose Animal/microbiologia , Salmonelose Animal/patologia
20.
Rev. Fac. Med. (Caracas) ; 28(2): 187-189, 2005.
Artigo em Espanhol | LILACS | ID: lil-422043

RESUMO

El diagnóstico de síndrome de presunta histoplasmosis ocular se basa en criterios clínicos, descritos típicamente con la tétrada: escaras atróficas coriorretinianas, atrofia peripapilar, maculopatía serohemorrágica y ausencia de inflamación anterior y vítrea. Presentamos el caso de una mujer sana de 43 años, que acude a consulta por metamorfopsias en ambos ojos, mayor en el ojo derecho. En la evaluación de fondo de ojo se aprecia una zona de desprendimiento sero-hemorrágico paramacular compatible con membrana neovascular que se confirma con angiofluoresceingrafía en ojo izquierdo, asociado a múltiples lesiones atróficas corioretinianas ecuatoriales y atrofia peripapilar sin signos de vitreítis en ambos ojos


Assuntos
Adulto , Humanos , Feminino , Infecções Oculares Fúngicas , Histoplasmose , Oftalmologia , Venezuela
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