MicroRNA-7 Regulates Migration and Chemoresistance in Non-Hodgkin Lymphoma Cells Through Regulation of KLF4 and YY1.

The discovery and description of the role of microRNAs has become very important, specifically due to their participation in the regulation of proteins and transcription factors involved in the development of cancer. microRNA-7 (miR-7) has been described as a negative regulator of several proteins involved in cancer, such as YY1 and KLF4. We have recently reported that YY1 and KLF4 play a role in non-Hodgkin lymphoma (NHL) and that the expression of KLF4 is regulated by YY1. Therefore, in this study we analyzed the role of miR-7 in NHL through the negative regulation of YY1 and KLF4. qRT-PCR showed that there is an inverse expression of miR-7 in relation to the expression of YY1 and KLF4 in B-NHL cell lines. The possible regulation of YY1 and KLF4 by miR-7 was analyzed using the constitutive expression or inhibition of miR-7, as well as using reporter plasmids containing the 3 'UTR region of YY1 or KLF4. The role of miR-7 in NHL, through the negative regulation of YY1 and KLF4 was determined by chemoresistance and migration assays. We corroborated our results in cell lines, in a TMA from NHL patients including DLBCL and follicular lymphoma subtypes, in where we analyzed miR-7 by ISH and YY1 and KLF4 using IHC. All tumors expressing miR-7 showed a negative correlation with YY1 and KLF4 expression. In addition, expression of miR-7 was analyzed using the GEO Database; miR-7 downregulated expression was associated with pour overall-survival. Our results show for the first time that miR-7 is implicate in the cell migration and chemoresistance in NHL, through the negative regulation of YY1 and KLF4. That also support the evidence that YY1 and KLF4 can be a potential therapeutic target in NHL.

Regulation of Krüppel-Like Factor 4 (KLF4) expression through the transcription factor Yin-Yang 1 (YY1) in non-Hodgkin B-cell lymphoma.

Krüppel-Like Factor 4 (KLF4) is a member of the KLF transcription factor family, and evidence suggests that KLF4 is either an oncogene or a tumor suppressor. The regulatory mechanism underlying KLF4 expression in cancer, and specifically in lymphoma, is still not understood. Bioinformatics analysis revealed two YY1 putative binding sites in the KLF4 promoter region (-950 bp and -105 bp). Here, the potential regulation of KLF4 by YY1 in NHL was analyzed. Mutation of the putative YY1 binding sites in a previously reported system containing the KLF4 promoter region and CHIP analysis confirmed that these binding sites are important for KLF4 regulation. B-NHL cell lines showed that both KLF4 and YY1 are co-expressed, and transfection with siRNA-YY1 resulted in significant inhibition of KLF4. The clinical implications of YY1 in the transcriptional regulation of KLF4 were investigated by IHC in a TMA with 43 samples of subtypes DLBCL and FL, and all tumor tissues expressing YY1 demonstrated a correlation with KLF4 expression, which was consistent with bioinformatics analyses in several databases. Our findings demonstrated that KLF4 can be transcriptionally regulated by YY1 in B-NHL, and a correlation between YY1 expression and KLF4 was found in clinical samples. Hence, both YY1 and KLF4 may be possible therapeutic biomarkers of NHL.

Ingesta de macro y micronutrientes y su relación con el estado nutricional de adultos mayores activos de la ciudad de Chillán (Chile) / Relationship between macronutrient and micronutrient intake and nutritional status of active older adults in Chillán, Chile

Introducción. La participación social de adultos mayores constituye un elemento protector de la salud que promueve un adecuado estado nutricional mediante una ingesta apropiada de nutrientes, favoreciendo un envejecimiento exitoso. Material y métodos. Estudio analítico, de corte transversal. La muestra estuvo constituida por 118 adultos mayores. El consumo alimentario se midió con una encuesta recordatoria de 24h. El estado nutricional se evaluó mediante el índice de masa corporal. La información se analizó con estadística descriptiva uni y bivariada. Para comparar se utilizaron las pruebas estadísticas de Mann-Whitney y Kolmogorov-Smirnov, dada la no distribución normal de la respuesta. Se usó un nivel de significación α=0,05. Resultados. El 55% de las mujeres y el 61% de los hombres presentaron un estado nutricional normal. La ingesta calórica y de macronutrientes se encontró dentro de los rangos recomendados. Solo la ingesta de calorías fue diferente por estado nutricional en hombres y mujeres (p<0,05). Los micronutrientes presentaron diferencias significativas respecto al estado nutricional, desagregado por sexo y edad, en la mayoría de las vitaminas y los minerales (p<0,01). El grupo de 75-90 años cumple con la recomendación de ingesta en todos los casos. Conclusiones. La participación activa en grupos organizados de la comunidad, la escolaridad de los adultos mayores y el alto nivel de ingresos serían factores clave para explicar el buen estado nutricional del grupo, lo que sería un buen indicador de envejecimiento saludable (AU)

Introduction. Social participation by older adults is a health-protective element that promotes a normal nutritional status through the intake of appropriate nutrients that favour successful aging. Material and methods. A cross-sectional analytical study was performed on a sample of 118 older adults. Food intake was measured using a 24-h recall questionnaire. The body mass index was used to evaluate the nutritional status. The information was analysed using uni- and bivariate descriptive statistics. Given the abnormal distribution of the responses, the Mann-Whitney and Kolgomorov-Smirnov statistical test were used to compare data at the significance level α=0.05. Results. More than half (55%) of the women and 61% of men had a normal nutritional status. The calories and macronutrient intake were within the recommended ranges and unrelated to the nutritional status (P>.05). The micronutrients showed significant differences in relation to the nutritional status, broken down by gender and age, in the majority of vitamins and minerals. (P>.01). The group between 75-90 years old accomplished the recommended dietary allowance in every case. Conclusions. The active participation in organised community groups, the educational level of the older adults, and higher income, could be key factors to explain the good nutritional status of the group, and appears to be a good indicator of healthy aging (AU)

[Relationship between macronutrient and micronutrient intake and nutritional status of active older adults in Chillán, Chile]. / Ingesta de macro y micronutrientes y su relación con el estado nutricional de adultos mayores activos de la ciudad de Chillán (Chile).

INTRODUCTION: Social participation by older adults is a health-protective element that promotes a normal nutritional status through the intake of appropriate nutrients that favour successful aging. MATERIAL AND METHODS: A cross-sectional analytical study was performed on a sample of 118 older adults. Food intake was measured using a 24-h recall questionnaire. The body mass index was used to evaluate the nutritional status. The information was analysed using uni- and bivariate descriptive statistics. Given the abnormal distribution of the responses, the Mann-Whitney and Kolgomorov-Smirnov statistical test were used to compare data at the significance level α=0.05. RESULTS: More than half (55%) of the women and 61% of men had a normal nutritional status. The calories and macronutrient intake were within the recommended ranges and unrelated to the nutritional status (P>.05). The micronutrients showed significant differences in relation to the nutritional status, broken down by gender and age, in the majority of vitamins and minerals. (P>.01). The group between 75-90 years old accomplished the recommended dietary allowance in every case. CONCLUSIONS: The active participation in organised community groups, the educational level of the older adults, and higher income, could be key factors to explain the good nutritional status of the group, and appears to be a good indicator of healthy aging.

The role of surgery in primary gastric lymphoma: results of a controlled clinical trial.

OBJECTIVE: We began a controlled clinical trial to assess efficacy and toxicity of surgery (S), surgery + radiotherapy (SRT), surgery + chemotherapy (SCT), and chemotherapy (CT) in the treatment of primary gastric diffuse large cell lymphoma in early stages: IE and II1. SUMMARY BACKGROUND DATA: Management of primary gastric lymphoma remains controversial. No controlled clinical trials have evaluated the different therapeutic schedules, and prognostic factors have not been identified in a uniform population. PATIENTS AND METHODS: Five hundred eighty-nine patients were randomized to be treated with S (148 patients), SR (138 patients), SCT (153 patients), and CT (150 patients). Radiotherapy was delivered at doses of 40 Gy; chemotherapy was CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) at standard doses. International Prognostic Index (IPI) and modified IPI (MIPI) were assessed to determine outcome. RESULTS: Complete response rates were similar in the 4 arms. Actuarial curves at 10 years of event-free survival (EFS) were as follows: S: 28% (95% confidence interval [CI], 22% to 41%); SRT: 23% (95% CI, 16% to 29%); that were statistically significant when compared with SCT: 82% (95% CI, 73% to 89%); and CT: 92% (95% CI, 84% to 99%) (P < 0.001). Actuarial curves at 10 years showed that overall survivals (OS) were as follows: S: 54% (95% CI, 46% to 64%); SRT: 53% (95% CI, 45% to 68%); that were statistically significant to SCT: 91% (95% CI, 85% to 99%); CT: 96% (95% CI, 90% to 103%)(P < 0.001). Late toxicity was more frequent and severe in patients who undergoing surgery. IPI and MIPI were not useful in determining outcome and multivariate analysis failed to identify other prognostic factors. CONCLUSION: In patients with primary gastric diffuse large cell lymphoma and aggressive histology, diffuse large cell lymphoma in early stage SCT achieved good results, but surgery was associated with some cases of lethal complications. Thus it appears that CT should be considered the treatment of choice in this patient setting. Current clinical classifications of risk are not useful in defining treatment.

Lack of prognostic factors in follicular lymphoma.

We performed a retrospective analysis of prognostic factors in patients with stage III and IV and high-tumor burden follicular lymphoma (FL) treated with uniform schedules and with a long term follow-up. Eight-hundred and ten patients treated with intensive, anthracycline-based, chemotherapy and adjuvant radiotherapy to sites of initial bulky nodal disease were the basis of this analysis. Age >60 years, presence of B symptoms, bulky disease, >2 extranodal sites involved, high levels of LDH and the presence of serous effusions all identified as worse prognostic factors in univariate analysis were subject to multivariate analysis. Three factors remained significant: age >60 years old, presence of B symptoms and >2 extranodal sites involved and these were found to influence overall survival (OS) and progression-free survival (PFS). We developed a score system and only two groups (score 0 and 1 and score 2 and 3) showed statistical significance in OS. When the International Prognostic Index was applied to these patients, no statistical differences were observed in OS and PFS between the four groups. Comparison of our results with multiple previous studies showed a lack of uniform prognostic factors and adequate prognostic classification could not be performed. In conclusion, it is mandatory for multicentric international clinical analysis to define prognostic factors and search for a clinical classification, as in diffuse large B cell lymphoma, so as to define groups of FL for more aggressive or conservative therapy.