Dinámica del proceso de desarrollo y crecimiento a edades de inicio puberal normales, temprana en niñas y tardía en niños.

Objetivos: 1) Describir las características del crecimiento y desarrollo puberal en niñas yniños con diferentes edades de inicio puberal, incluyendo dos situaciones clínicasfrecuentes: la pubertad avanzada en niñas y la pubertad diferida en niños. 2) Describir losefectos del tratamiento farmacológico con análogos de la GnRH de la pubertad avanzada enrelación con un grupo control. 3) Describir los efectos del tratamiento farmacológico contestosterona de la pubertad diferida en relación con un grupo control.Material y métodos: Proyecto que consta de tres estudios, en los que los niños fueronestudiados hasta el momento de adquisición de su talla final. 1) Estudio longitudinalobservacional y prospectivo realizado en 116 niñas y 135 niños, con inicio puberal entre los10-13 y 11-14 años respectivamente, agrupados según la edad de inicio puberal. 2) Ensayoclínico controlado no aleatorio de intervención en niñas con pubertad avanzada (16pertenecientes al grupo tratado y 16 al grupo control) y 3) Ensayo clínico controlado noaleatorio de intervención en niños con pubertad diferida (17 tratados y 15 del grupocontrol). En los tres estudios, se realizaron mediciones antropométricas (peso, talla, plieguesdel tejido adiposo subcutáneo y perímetro braquial) y se evaluó la maduración puberalmediante los estadios de Tanner. Se procedió al cálculo del IMC, área muscular del brazo,suma de cuatro pliegues, talla diana, la duración puberal y el incremento puberal en talla.En varones también se determinó el índice del volumen testicular, y en niñas el tiempohasta la menarquia. En los estudios 2) y 3) se realizaron: valoración de la edad ósea,determinaciones hormonales y alguna exploración complementaria.Resultados y conclusiones: 1) Tanto en las niñas como en los niños con diferente edad deinicio puberal, el proceso biológico de crecimiento y desarrollo puberal, consiguecompensar las diferencias en talla observadas entre los diferentes ritmos madurativos alinicio puberal, incrementado la duración puberal, el incremento puberal en talla y en el casode las niñas el tiempo hasta la menarquia cuando la edad de inicio puberal es temprana.Todos los grupos alcanzan tallas finales similares. 2) El tratamiento con análogos de lapubertad avanzada, ejerce efectos a corto plazo clínicamente verificables, pero no modificala relación entre duración e intensidad del crecimiento puberal, ni tampoco tiene efectos alargo plazo sobre la talla final. 3) El tratamiento con testosterona de la pubertad diferida,ejerce efectos a corto plazo y permite alcanzar una talla final de acuerdo al potencialgenético sin afectar de forma negativa el eje gonadal. 4) En las niñas con pubertad avanzaday en los niños con pubertad diferida, al estudiar el proceso biológico del crecimiento ydesarrollo puberal, se observan dinámicas similares a las descritas en las niñas con iniciopuberal entre los 10-13 años y en los niños con inicio entre los 11-14 años, respectivamente.Las tallas finales, en niñas y niños son similares en todos los grupos de edad en cada sexo,por lo que dichos mecanismos compensatorios son efectivos en estas dos situacionesclínicas al límite de la normalidad.Objectives: 1) To describe the characteristics of growth and pubertal development in girlsand boys with different ages of pubertal onset, including two frecuent clinical situations:advanced puberty in girls and delayed puberty in boys, 2) To describe the GnRH analoguestreatment effects in girls with advanced puberty, compared with a control group; 3) Todescribe the testosterone treatment effects in boys with delayed puberty compared with acontrol group.Patients and Methods: This project is composed of three studies, where children werestudied since the onset of puberty until the moment of attaintment of their final height. 1) Alongitudinal observational and prospective study, in 116 girls and 135 boys, with pubertalonset at 10-13 and 11-14 years of age respectively, grouped by age of pubertal onset. 2)Non-randomized clinical study in girls with advanced puberty (16 treated LHRH analogueduring 1 year and 16 control subjects) and 3) Non-randomized clinical study in boyswith delayed puberty (17 treated with testosterone during 6 months and 15 controlsubjects).In all the studies, we carried out anthropometric measurements (weight, height, skinfoldthicknesses and arm circumference) and we assessed pubertal maturation by means ofTanner stages. We calculated the body mass index, muscular area of the arm, the targetheight, the pubertal height growth (gain in height from the puberty onset up to the finalheight) and the pubertal duration (time in years from the puberty onset up to the age atwhich final height is attained). In boys, we analyzed the testicular volume and in girlsthe age of menarche. In the studies 2) and 3) we assessed the bone age and somehormonal analyses.Results and conclusions: 1) Both in girls and boys with different age of pubertal onset, thedifferent dynamics of development and pubertal growth, lead to attain similar finalheights.This is due to a compensation between a smaller height at pubertal onset in the earlymaturers, with a longer pubertal duration, greater pubertal growth and longer time betweenonset and menarche. 2) Treatment with LHRH analogue delayed the menarche age, led toan involution in secondary sexual characteristics and a temporary decrease in growth rate,and delayed skeletal maturation. However, pubertal duration, pubertal height growth andfinal heights were similar in both groups.3) Treatment with testosterone leads to the startof puberty, but without stopping the maturation of the hypothalamic-pituitary axis,allowing a normal testicular evolution. The final heights were similar in both groups. 4)Girls with advanced puberty and boys with delayed puberty present a dynamics ofgrowth and pubertal development which are similar of those presented by the girls andboys with puberal onset at normal ages. The attained final heights were similar in all theage groups

The significance of PIWI family expression in human lung embryogenesis and non-small cell lung cancer

The expression of Piwi-interacting RNAs, small RNAs that bind to PIWI proteins, was until recently believed to be limited to germinal stem cells. We have studied the expression of PIWI genes during human lung embryogenesis and in paired tumor and normal tissue prospectively collected from 71 resected non-small-cell lung cancer patients. The mRNA expression analysis showed that PIWIL1 was highly expressed in 7-week embryos and downregulated during the subsequent weeks of development. PIWIL1 was expressed in 11 of the tumor samples but in none of the normal tissue samples. These results were validated by immunohistochemistry, showing faint cytoplasmic reactivity in the PIWIL1-positive samples. Interestingly, the patients expressing PIWIL1 had a shorter time to relapse (TTR) (p = 0.006) and overall survival (OS) (p = 0.0076) than those without PIWIL1 expression. PIWIL2 and 4 were downregulated in tumor tissue in comparison to the normal tissue (p < 0.001) and the patients with lower levels of PIWIL4 had shorter TTR (p = 0.048) and OS (p = 0.033). In the multivariate analysis, PIWIL1 expression emerged as an independent prognostic marker. Using 5-Aza-dC treatment and bisulfite sequencing, we observed that PIWIL1 expression could be regulated in part by methylation. Finally, an in silico study identified a stem-cell expression signature associated with PIWIL1 expression

The significance of PIWI family expression in human lung embryogenesis and non-small cell lung cancer

The expression of Piwi-interacting RNAs, small RNAs that bind to PIWI proteins, was until recently believed to be limited to germinal stem cells. We have studied the expression of PIWI genes during human lung embryogenesis and in paired tumor and normal tissue prospectively collected from 71 resected non-small-cell lung cancer patients. The mRNA expression analysis showed that PIWIL1 was highly expressed in 7-week embryos and downregulated during the subsequent weeks of development. PIWIL1 was expressed in 11 of the tumor samples but in none of the normal tissue samples. These results were validated by immunohistochemistry, showing faint cytoplasmic reactivity in the PIWIL1-positive samples. Interestingly, the patients expressing PIWIL1 had a shorter time to relapse (TTR) (p = 0.006) and overall survival (OS) (p = 0.0076) than those without PIWIL1 expression. PIWIL2 and 4 were downregulated in tumor tissue in comparison to the normal tissue (p < 0.001) and the patients with lower levels of PIWIL4 had shorter TTR (p = 0.048) and OS (p = 0.033). In the multivariate analysis, PIWIL1 expression emerged as an independent prognostic marker. Using 5-Aza-dC treatment and bisulfite sequencing, we observed that PIWIL1 expression could be regulated in part by methylation. Finally, an in silico study identified a stem-cell expression signature associated with PIWIL1 expression