RESUMO
Lynch syndrome (LS) is the main hereditary colorectal cancer syndrome. There have been few reports regarding the clinical and molecular characteristics of LS patients in Latin America; this is particularly true in the Mexican population, where no information is available. The present study aims to describe the clinical and molecular spectrum of variants in a cohort of patients diagnosed with LS in Mexico. We present a retrospective analysis of 412 patients with suspected LS, whose main site of cancer diagnosis was the colon (58.25%), followed by the endometrium (18.93%). Next-generation sequencing analysis, with an extensive multigene panel, showed that 27.1% (112/414) had a variant in one of the genes of the mismatch repair pathway (MMR); 30.4% (126/414) had a variant in non-MMR genes such as CHEK2, APC, MUTYH, BRCA1, and BRCA2; and 42.5% (176/414) had no genetic variants. Most of the variants were found in MLH1. Pathogenic variants (PVs) in MMR genes were identified in 65.7% (96/146) of the total PVs, and 34.24% (45/146) were in non-MMR genes. Molecular and clinical characterization of patients with LS in specific populations allowed personalized follow-up, with the option for targeted treatment with immune checkpoint inhibitors and the development of public health policies. Moreover, such characterization allows for family cascade testing and consequent prevention strategies.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Inibidores de Checkpoint Imunológico , México/epidemiologia , Proteína 2 Homóloga a MutS/genética , Estudos RetrospectivosRESUMO
Abstract Background: Patients with familial erythrocytosis type 2 have no increased risk of von Hippel-Lindau-associated tumors, although mutations in the VHL gene cause both pathologies. Case report: We present a case of a compound heterozygote patient with von Hippel-Lindau disease and familial erythrocytosis type 2. One of the mutations found in our patient, c.416C>G (p.Ser139Cys) of the VHL gene, has not been previously reported. This case is the second one reported where von Hippel-Lindau disease and familial erythrocytosis type 2 coexist in the same individual. Conclusions: Despite the low frequency of familial erythrocytosis type 2 in patients with von Hippel-Lindau disease, the possibility of this diagnosis should be considered to avoid unnecessary invasive studies to explain the polyglobulia in these patients and guarantee an adequate follow-up and vigilance of both diseases.
Resumen Introducción: Los pacientes con eritrocitosis familiar tipo 2 no muestran un riesgo incrementado de desarrollar tumores asociados con la enfermedad de von Hippel-Lindau, a pesar de que ambas afecciones están causadas por variantes patogénicas en el gen VHL. Caso clínico: Se presenta el caso de un paciente heterocigoto compuesto con enfermedad de von Hippel-Lindau y eritrocitosis familiar tipo 2. Una de las variantes patogénicas en el paciente, VHL c.416C>G (p.Ser139Cys), no ha sido previamente reportada. Este es el segundo reporte de caso en que la enfermedad de von Hippel-Lindau y la eritrocitosis familiar tipo 2 coexisten en el mismo individuo. Conclusiones: A pesar de la baja frecuencia de la eritrocitosis familiar tipo 2 en pacientes con enfermedad de von Hippel-Lindau, la posibilidad del diagnóstico debe considerarse con el fin de evitar estudios invasivos innecesarios para explicar la presencia de poliglobulia en estos pacientes y para garantizar un adecuado seguimiento y una correcta vigilancia de ambas enfermedades.
RESUMO
BACKGROUND: Patients with familial erythrocytosis type 2 have no increased risk of von Hippel-Lindau-associated tumors, although mutations in the VHL gene cause both pathologies. CASE REPORT: We present a case of a compound heterozygote patient with von Hippel-Lindau disease and familial erythrocytosis type 2. One of the mutations found in our patient, c.416C>G (p.Ser139Cys) of the VHL gene, has not been previously reported. This case is the second one reported where von Hippel-Lindau disease and familial erythrocytosis type 2 coexist in the same individual. CONCLUSIONS: Despite the low frequency of familial erythrocytosis type 2 in patients with von Hippel-Lindau disease, the possibility of this diagnosis should be considered to avoid unnecessary invasive studies to explain the polyglobulia in these patients and guarantee an adequate follow-up and vigilance of both diseases.
Assuntos
Policitemia , Doença de von Hippel-Lindau , Criança , Humanos , Mutação , Policitemia/congênito , Policitemia/diagnóstico , Policitemia/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Doença de von Hippel-Lindau/diagnóstico , Doença de von Hippel-Lindau/genéticaRESUMO
The deletion of exons 9 to 12 of BRCA1 (9-12 del BRCA1) is considered a founder mutation in the Mexican population. We evaluate the usefulness of the target detection of 9-12 del BRCA1 as the first molecular diagnostic strategy in patients with Hereditary Breast and Ovarian Cancer (HBOC). We performed the genetic assessment of 637 patients with suspected HBOC. The region corresponding to the breakpoints for the 9-12 del BRCA1 was amplified by polymerase chain reaction (PCR). An analysis of the clinical data of the carriers and non-carriers was done, searching for characteristics that correlated with the deletion. The 9-12 del BRCA1 was detected in 5% of patients with suspected HBOC (30/637). In patients diagnosed with ovarian cancer, 13 of 30 were 9-12 del BRCA1 carriers, which represents 43%. We found a significant association between the 9-12 del BRCA1 carriers with triple negative breast cancer and high-grade papillary serous ovarian cancer. We concluded that the detection of the 9-12 del BRCA1 is useful as a first molecular diagnostic strategy in the Mexican population. In particular, it shortens the gap in genetic assessment in patients with triple negative breast cancer and ovarian cancer.
Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa , Neoplasias Ovarianas/genética , Adulto , Neoplasias da Mama/diagnóstico , Éxons/genética , Saúde da Família , Feminino , Efeito Fundador , Testes Genéticos , Humanos , México , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico , Deleção de Sequência , Adulto JovemRESUMO
Introduction: Since the beginning of the epidemic, human immunodeficiency virus (HIV) has taken more than 36 million lives. Objective: To determine the antiretroviral drug prescription patterns in a population of individuals with HIV infection in Colombia. Materials and methods: Cross-sectional study analyzing the profiles of patients treated with antiretroviral drugs between April 1st and September 30th, 2015. The sociodemographic, pharmacological, and comorbidity variables were identified. Individuals with a positive diagnosis of HIV of all ages and both genders were included. Results: We found 641 patients with a mean age of 39.0±17 years who were predominantly male (60.2%). The most used medications were lamivudine-zidovudine (51.6%), lopinavir-ritonavir (36%) and efavirenz (24.5%). The combination of lamivudine-zidovudine plus lopinavir-ritonavir was the most prescribed regimen (29.5%), but a total of 80 different regimens was identified. Being an adult between the ages of 45-64 years (OR=2.25; 95%CI 1.367-3.713) was associated with a greater probability of receiving 4 or more antiretrovirals. A total of 267 (41.6%) patients used at least one comedication (range: 1-18 drugs), especially anti-ulcer (57.3%), lipid-lowering (28.8%) and anti-hypertensive (28.5%) drugs. Conclusions: Patients undergoing antiretroviral treatment are receiving medications with elevated intrinsic values at the recommended doses and present comorbidities associated with chronic agerelated conditions. However, these patients receive a great variety of regimens that are not included in the clinical practice guidelines.
Introducción. La infección por HIV es una pandemia que actualmente se controla con el tratamiento farmacológico, el cual, además, prolonga la expectativa de vida del paciente. Objetivo. Determinar los patrones de prescripción de fármacos antirretrovirales en una población de personas afiliadas al régimen contributivo del Sistema General de Seguridad Social en Salud de Colombia, durante el 2015. Materiales y métodos. Se hizo un estudio de corte transversal para analizar la formulación de fármacos antirretrovirales en pacientes tratados con estos entre el 1° de abril y el 30 septiembre del 2015. Se determinaron las variables sociodemográficas, farmacológicas y las comorbilidades, y el análisis estadístico se hizo mediante SPSS™, versión 23.0. Resultados. Se hallaron 641 pacientes, la mayoría (60,2 %) hombres, con una edad media de 39,0±17 años. Los medicamentos más empleados fueron lamivudina-zidovudina (51,6 %), lopinavirritonavir (36 %) y efavirenz (24,5 %). La asociación lamivudina-zidovudina más lopinavir-ritonavir fue el esquema más prescrito (29,5 %), pero se encontraron 80 esquemas diferentes. El ser un adulto entre 45 y 64 años (odds ratio=2,25; IC95% 1,367-3,713; p=0,001) se asoció con una mayor probabilidad de recibir cuatro o más antirretrovirales. Del total de pacientes, 267 (41,6 %) recibían más de un medicamento simultáneamente (rango: 1-18 fármacos), especialmente fármacos contra las úlceras (57,3 %), hipolipemiantes (28,8 %) y antihipertensivos (28,5 %). Conclusiones. Los pacientes en tratamiento antirretroviral están recibiendo medicamentos de elevado valor intrínseco en las dosis recomendadas, y presentan las mismas comorbilidades asociadas con las condiciones crónicas relacionadas con la edad. Además, reciben una gran variedad de esquemas que no se encuentran incluidos en las guías de práctica clínica.
Assuntos
Prescrições de Medicamentos , Terapia Antirretroviral de Alta Atividade , Síndrome da Imunodeficiência Adquirida , FarmacoepidemiologiaRESUMO
INTRODUCTION: Since the beginning of the epidemic, human immunodeficiency virus (HIV) has taken more than 36 million lives. OBJECTIVE: To determine the antiretroviral drug prescription patterns in a population of individuals with HIV infection in Colombia. MATERIALS AND METHODS: Cross-sectional study analyzing the profiles of patients treated with antiretroviral drugs between April 1st and September 30th, 2015. The sociodemographic, pharmacological, and comorbidity variables were identified. Individuals with a positive diagnosis of HIV of all ages and both genders were included. RESULTS: We found 641 patients with a mean age of 39.0±17 years who were predominantly male (60.2%). The most used medications were lamivudine-zidovudine (51.6%), lopinavir-ritonavir (36%) and efavirenz (24.5%). The combination of lamivudine-zidovudine plus lopinavir-ritonavir was the most prescribed regimen (29.5%), but a total of 80 different regimens was identified. Being an adult between the ages of 45-64 years (OR=2.25; 95%CI 1.367-3.713) was associated with a greater probabilityof receiving 4 or more antiretrovirals. A total of 267 (41.6%) patients used at least one comedication (range: 1-18 drugs), especially anti-ulcer (57.3%), lipid-lowering (28.8%) and anti-hypertensive (28.5%) drugs. CONCLUSIONS: Patients undergoing antiretroviral treatment are receiving medications with elevated intrinsic values at the recommended doses and present comorbidities associated with chronic agerelated conditions. However, these patients receive a great variety of regimens that are not included in the clinical practice guidelines.
Introducción. La infección por HIV es una pandemia que actualmente se controla con el tratamiento farmacológico, el cual, además, prolonga la expectativa de vida del paciente. Objetivo. Determinar los patrones de prescripción de fármacos antirretrovirales en una población de personas afiliadas al régimen contributivo del Sistema General de Seguridad Social en Salud de Colombia, durante el 2015. Materiales y métodos. Se hizo un estudio de corte transversal para analizar la formulación de fármacos antirretrovirales en pacientes tratados con estos entre el 1° de abril y el 30 septiembre del 2015. Se determinaron las variables sociodemográficas, farmacológicas y las comorbilidades, y el análisis estadístico se hizo mediante SPSS™, versión 23.0. Resultados. Se hallaron 641 pacientes, la mayoría (60,2 %) hombres, con una edad media de 39,0±17 años. Los medicamentos más empleados fueron lamivudina-zidovudina (51,6 %), lopinavirritonavir (36 %) y efavirenz (24,5 %). La asociación lamivudina-zidovudina más lopinavir-ritonavir fue el esquema más prescrito (29,5 %), pero se encontraron 80 esquemas diferentes. El ser un adulto entre 45 y 64 años (odds ratio=2,25; IC95% 1,367-3,713; p=0,001) se asoció con una mayor probabilidad de recibir cuatro o más antirretrovirales. Del total de pacientes, 267 (41,6 %) recibían más de un medicamento simultáneamente (rango: 1-18 fármacos), especialmente fármacos contra las úlceras (57,3 %), hipolipemiantes (28,8 %) y antihipertensivos (28,5 %). Conclusiones. Los pacientes en tratamiento antirretroviral están recibiendo medicamentos de elevado valor intrínseco en las dosis recomendadas, y presentan las mismas comorbilidades asociadas con las condiciones crónicas relacionadas con la edad. Además, reciben una gran variedad de esquemas que no se encuentran incluidos en las guías de práctica clínica.
Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Protocolos Clínicos , Colômbia , Estudos Transversais , Prescrições de Medicamentos/estatística & dados numéricos , Uso de Medicamentos/estatística & dados numéricos , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Bacterial meningitis is an important cause of infectious neurological morbidity and mortality. Its incidence has decreased with the introduction of vaccination programmes against preventable agents. However, low-income and middle-income countries with poor access to health care still have a significant burden of the disease. Thus, the relationship between the Gini coefficient and H. influenzae and M. tuberculosis meningitis incidence in Colombia, during 2008-2011, was assessed. In this ecological study, the Gini coefficient was obtained from the Colombian Department of Statistics, incidence rates were calculated (cases/1,000,000 pop) and linear regressions were performed using the Gini coefficient, to assess the relationship between the latter and the incidence of meningitis. It was observed that when inequality increases in the Colombian departments, the incidence of meningitis also increases, with a significant association in the models (p<0.01) for both M. tuberculosis (r²=0.2382; p<0.001) and H. influenzae (r²=0.2509; p<0.001). This research suggests that high Gini coefficient values influence the incidence of Mycobacterium tuberculosis and Haemophilus influenzae meningitis, showing that social inequality is critical to disease occurrence. Early detection, supervised treatment, vaccination coverage, access to health care are efficient control strategies.
Assuntos
Haemophilus influenzae/isolamento & purificação , Disparidades em Assistência à Saúde/estatística & dados numéricos , Meningite por Haemophilus/complicações , Mycobacterium tuberculosis/isolamento & purificação , Fatores Socioeconômicos , Tuberculose Meníngea/complicações , Algoritmos , Colômbia/epidemiologia , Países em Desenvolvimento , Humanos , Interpretação de Imagem Assistida por Computador , Incidência , Meningite por Haemophilus/diagnóstico , Meningite por Haemophilus/epidemiologia , Meningite por Haemophilus/microbiologia , Modelos Estatísticos , Pobreza , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Risco , Tuberculose Meníngea/diagnóstico , Tuberculose Meníngea/epidemiologia , Tuberculose Meníngea/microbiologiaRESUMO
ABQ-48 (3-amino-7-benzylbenzimidazo[3,2-a]quinolinium chloride) and NBQ-48 (3-nitro-7-benzylbenzimidaw[3,2-a] quinolinium chloride) are un-natural alkaloids containing a planar heteroaromatic systems characterized by quaternized nitrogen fused to benzothiazole nucleus. Both compounds are structurally related to naturally occurring substances such as elliptine (from Ochrosia), and berberine (from Berberis). Previous in vitro studies have shown these agents to control tumor-cell proliferation indicating that both BQS are active but especially ABQ-48 at a 1 OuM dose with over 80% control of the proliferation of multiple cancer cell lines from various etiologies including colon, melanoma, CNS and ovarian cells. Mechanism of action studies have also been conducted however this is the first approach to evaluate immune modulatory activity of these novel BQS. Immune-based therapy is an increasing field in which scientists identify how the immunomodulatory activity of known and newly discovered compounds elicits an immune response that could be used against diseases. In this study, our main objective was to apply an in vitro model to show the immunomodulatory effects of ABQ-48 and NBQ-48 by analyzing the cytokine profile resulting after extracted murine spleen cells were treated with both BQS using a fluorescence-based multiplex ELISA approach. Screened cytokines included: G-CSF, GM-CSF, IL-1a, IL-2, IL-3, IL-5, IL-6, IL-7, IL-10, IL-12p70, IL-13, IL-15, IL-17, IL-21, IL-23, IFN-γ, and TNF-α. Our study results show ABQ 48 and NBQ-48 to stimulate the release of G-CSF, IL-2, IL-6, and, IFN-γ when mouse splenocytes are incubated with serial dilutions of these agents. Our finding opens new possibilities of potentially using ABQ-48 and NBQ-48 as immunomodulatory agents; with intend to activate the immune system such as the production of neutrophils against cancer or reducing chemotherapy side effects.
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BACKGROUND: The current live vaccinia virus vaccine used in the prevention of smallpox is contraindicated for millions of immune-compromised individuals. Although vaccination with the current smallpox vaccine produces protective immunity, it might result in mild to serious health complications for some vaccinees. Thus, there is a critical need for the production of a safe virus-free vaccine against smallpox that is available to everyone. For that reason, we investigated the impact of imiquimod and resiquimod (Toll-like receptors agonists), and the codon-usage optimization of the vaccinia virus A27L gene in the enhancement of the immune response, with intent of producing a safe, virus-free DNA vaccine coding for the A27 vaccinia virus protein. METHODS: We analyzed the cellular-immune response by measuring the IFN-γ production of splenocytes by ELISPOT, the humoral-immune responses measuring total IgG and IgG2a/IgG1 ratios by ELISA, and the TH1 and TH2 cytokine profiles by ELISA, in mice immunized with our vaccine formulation. RESULTS: The proposed vaccine formulation enhanced the A27L vaccine-mediated production of IFN-γ on mouse spleens, and increased the humoral immunity with a TH1-biased response. Also, our vaccine induced a TH1 cytokine milieu, which is important against viral infections. CONCLUSION: These results support the efforts to find a new mechanism to enhance an immune response against smallpox, through the implementation of a safe, virus-free DNA vaccination platform.
Assuntos
Fatores Imunológicos/administração & dosagem , Vacina Antivariólica/imunologia , Varíola/imunologia , Vírus da Varíola/imunologia , Adjuvantes Imunológicos , Animais , Anticorpos Antivirais/imunologia , Antígenos Virais/genética , Antígenos Virais/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , ELISPOT , Mapeamento de Epitopos , Feminino , Imunidade Celular , Imunidade Humoral , Isotipos de Imunoglobulinas/imunologia , Camundongos , Varíola/metabolismo , Varíola/prevenção & controle , Vacina Antivariólica/genética , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologiaRESUMO
Partial immune restoration may be obtained with highly active antiretroviral therapy (HAART), but specific anti-HIV-1 immune responses do not appear to improve substantially. We have demonstrated that a soluble factor(s) induced by a mixture of inactivated influenza and bacterial vaccines called polyantigenic immunomodulator (PAI), possesses strong immunoregulatory and anti-HIV-1 activities. In the present study, we show that culture fluids from both PAI-stimulated peripheral blood mononuclear cells (PBMC) and CD8+ T-cells of HIV-1 infected patients were able to suppress HIV-1 replication in an MHC-unrestricted fashion. The PAI-induced antiviral activity was eliminated when culture fluids were pre-heated at 100°C for 10 min. and it is associated with induction of IFN-γ, MIP-1α, MIP-1ß, and RANTES production, but inhibition of IL-10. Furthermore, this induction is dependent on the immunological status (CD4:CD8 ratio) of the HIV-1 infected patient. Taken together, our results suggest that the MHC-unrestricted HIV-1 suppression that is induced by culture fluids from PAI-stimulated PBMC may result from the stimulation of immune cell subpopulations to produce a heat-labile antiviral soluble factor(s), which in turn modulate cytokine and ß-chemokine production. The identification of this PAI-induced soluble factor(s) may have major therapeutic potential.