Lithium chloride antileukemic activity in acute promyelocytic leukemia is GSK-3 and MEK/ERK dependent.

We recently identified that the MEK/ERK1/2 pathway synergized with retinoic acid (RA) to restore both transcriptional activity and RA-induced differentiation in RA-resistant acute promyelocytic leukemia (APL) cells. To target the MEK/ERK pathway, we identified glycogen synthase kinase-3ß (GSK-3ß) inhibitors including lithium chloride (LiCl) as activators of this pathway in APL cells. Using NB4 (RA-sensitive) and UF-1 (RA-resistant) APL cell lines, we observed that LiCl as well as synthetic GSK-3ß inhibitors decreased proliferation, induced apoptosis and restored, in RA-resistant cells, the expression of RA target genes and the RA-induced differentiation. Inhibition of the MEK/ERK1/2 pathway abolished these effects. These results were corroborated in primary APL patient cells and translated in vivo using an APL preclinical mouse model in which LiCl given alone was as efficient as RA in increasing survival of leukemic mice compared with untreated mice. When LiCl was combined with RA, we observed a significant survival advantage compared with mice treated by RA alone. In this work, we demonstrate that LiCl, a well-tolerated agent in humans, has antileukemic activity in APL and that it has the potential to restore RA-induced transcriptional activation and differentiation in RA-resistant APL cells in an MEK/ERK-dependent manner.

Intervención fisioterápica con vendaje neuromuscular en pacientes con cervicalgia mecánica. Un estudio piloto / Physiotherapy intervention with kinesio taping in patients suffering chronic neck pain. A pilot study

Objetivo: Comprobar si el vendaje neuromuscular mejora la eficacia del tratamiento fisioterápico más comúnmente utilizado y con mejores resultados demostrados en pacientes con cervicalgia mecánica. Material y método Se realizó un estudio prospectivo, tomándose una muestra de 10 pacientes con cervicalgia mecánica. Se asignó aleatoriamente a 5 pacientes al grupo control, con el fin de recibir tratamiento fisioterápico y 5 pacientes al grupo experimental, a los que se les aplicó el mismo tratamiento fisioterápico y el vendaje neuromuscular. Medidas Un evaluador a quien no se le informó de la asignación de los pacientes, recopiló datos de la intensidad del dolor en el cuello y en el brazo antes y después de la intervención con la escala analógica visual, de la movilidad del cuello y de la movilidad de la articulación del hombro con un goniómetro universal. Además se les administró la escala SF-36 y el cuestionario de dolor cervical. Resultados Los 10 pacientes finalizaron el estudio. En la comparación del grado de mejoría entre uno y otro procedimiento resultó que hubo una mejora significativa en la flexión del cuello en los sujetos del grupo experimental con respecto al grupo control (p<0,05). Lo mismo ocurrió con la extensión del cuello (p<0,02), la inclinación del cuello (p<0,05) y la rotación interna del hombro (p<0,01).Además, en el cuestionario de calidad de vida (SF-36), resultó estadísticamente significativa la mejora del estado de salud mental en el grupo experimental con respecto al grupo control, con una p<0,05. Conclusiones El vendaje neuromuscular ha mejorado la eficacia del tratamiento convencional de la cervicalgia mecánica (AU)

Objective: The main aim was to verify if the Kinesio Taping improves the efficacy of conventional treatments in those subjects who have chronic neck pain. Material and method: A prospective study using a sample of 10 patients with chronic neck pain was carried out. Five patients were randomly allocated to the control group in order to receive conventional physiotherapy. The remaining 5 were allotted to the experimental group in which conventional physiotherapy and neuromusclar kinesio taping were applied. Measures: Data was collected by an evaluator blinded to the treatment allocation of the patients on the intensity of the neck and arm pain before and after the intervention with the analogue visual scale, on the neck mobility and shoulder joint mobility using a universal goniometer. Moreover, the subjects were administered the SF-36 scale and the cervical pain questionnaire. Results: The 10 patients completed the study. When both procedures were compared for grade of improvement, it was found that there was a significant improvement in neck flexion of the experimental group compared to the control group (P<.05). The same was found with neck extension (P<.02), lateral tilt of the neck (P<.05) and the shoulder internal rotation (P<.01).In addition, mental health status was significantly improved according to the quality of life questionnaire (SF-36) in the experimental group compared to the control one (P<.05).Conclusions: Kinesio Taping has improved the efficiency of conventional chronic neck pain treatment (AU)

[Effect of mitomycin C on corneal regrowth after laser-assisted sub-epithelial keratectomy (LASEK)]. / Efecto de la mitomicina C en el engrosamiento corneal tras queratectomía subepitelial con láser excimer (LASEK).

PURPOSE: To study the effect of mitomycin C (MMC) on the corneal regrowth after laser-assisted sub-epithelial keratectomy (LASEK). METHODS: We performed a prospective, controlled, observer-masked study of 64 consecutive eyes scheduled to undergo LASEK to correct their myopia. The patients were divided into two age-matched groups, with group 1 including 32 eyes in which the ablation depth was ≤ 50 µm and received no MMC. Group 2 consisted of 32 eyes in which the ablation depth exceeded 50 µm and were treated with intra-operative 0.02% MMC for 30 seconds over the ablated zone. A masked observer measured the central corneal thickness (CCT) 1 and 3 months after surgery. We compared the change in CCT between both groups up to 3 months after surgery. RESULTS: The mean patient age was 31.5 years (SD 4.6) and 31.6 (SD 8.7) years in groups 1 and 2, respectively (P=.9). Group 1 showed a mean CCT of 444.0 (SD 41.3) µm one month after surgery and 450.3 (SD 43.5) µm three months after surgery (P=.04). CCT in group 2 was 399.7 (SD 31.2) µm and 407.9 (SD 32.6) µm one and three months after surgery, respectively (P=.006). The difference in the CCT increases between both groups was not statistically significant (P=.6). CONCLUSIONS: A single intraoperative application of 0.02% MMC for 30 seconds did not seem to cause a substantial change in the post-surgical corneal thickening expected after LASEK.

Efecto de la mitomicina C en el engrosamiento corneal tras queratectomía subepitelial con láser excimer (LASEK) / Effect of mitomycin C on corneal regrowth after laser-assisted sub-epithelial keratectomy (LASEK)

ObjetivoEstudiar el efecto de la mitomicina C (MMC) en el engrosamiento corneal tras queratectomía subepitelial con láser excimer (LASEK).MétodosRealizamos un estudio prospectivo, controlado, enmascarado de 64 ojos consecutivos operados con LASEK para corregir su miopía. Separamos dos grupos empatados por edad. Los 32 ojos en los que la profundidad de ablación era ≤ 50 micras (μm) fueron incluidos en el grupo 1 y no recibieron MMC. Los 32 ojos en los que la profundidad de ablación era > 50μm se incluyeron en el grupo 2 y recibieron MMC al 0,02% durante 30 seg. sobre el lecho ablacionado. Un observador enmascarado midió el grosor corneal central (GCC) al mes y tres meses tras la cirugía. Se comparó el cambio en el GCC postoperatorio entre los dos grupos.ResultadosLa media de edad era de 31,5 (DE 4,6) años y 31,6 (DE 8,7) años en los grupos 1 y 2 respectivamente (p=0,9). En el grupo 1, la media del GCC era 444,0 (DE 41,3) μm al mes y 450,3 (DE 43,5) μm a los tres meses (p=0,04). El GCC en el grupo 2 era 399,7 (DE 31,2) μm al mes y 407,9 (DE 32,6) μm tres meses tras la cirugía (p=0,006). La diferencia entre los incrementos de GCC entre los dos grupos no fue estadísticamente significativa (p=0,6).ConclusionesUna única aplicación intraoperatoria de MMC al 0,02% durante 30 seg. no parece causar un cambio sustancial en el incremento del grosor corneal postoperatorio observado tras LASEK(AU)

PurposeTo study the effect of mitomycin C (MMC) on the corneal regrowth after laser-assisted sub-epithelial keratectomy (LASEK).MethodsWe performed a prospective, controlled, observer-masked study of 64 consecutive eyes scheduled to undergo LASEK to correct their myopia. The patients were divided into two age-matched groups, with group 1 including 32 eyes in which the ablation depth was ≤ 50μm and received no MMC. Group 2 consisted of 32 eyes in which the ablation depth exceeded 50μm and were treated with intra-operative 0.02% MMC for 30seconds over the ablated zone. A masked observer measured the central corneal thickness (CCT) 1 and 3 months after surgery. We compared the change in CCT between both groups up to 3 months after surgery.ResultsThe mean patient age was 31.5 years (SD 4.6) and 31.6 (SD 8.7) years in groups 1 and 2, respectively (P=.9). Group 1 showed a mean CCT of 444.0 (SD 41.3) μm one month after surgery and 450.3 (SD 43.5) μm three months after surgery (P=.04). CCT in group 2 was 399.7 (SD 31.2) μm and 407.9 (SD 32.6) μm one and three months after surgery, respectively (P=.006). The difference in the CCT increases between both groups was not statistically significant (P=.6).ConclusionsA single intraoperative application of 0.02% MMC for 30seconds did not seem to cause a substantial change in the post-surgical corneal thickening expected after LASEK(AU)

New role for granulocyte colony-stimulating factor-induced extracellular signal-regulated kinase 1/2 in histone modification and retinoic acid receptor α recruitment to gene promoters: relevance to acute promyelocytic leukemia cell differentiation.

The induction of the granulocytic differentiation of leukemic cells by all-trans retinoic acid (RA) has been a major breakthrough in terms of survival for acute promyelocytic leukemia (APL) patients. Here we highlight the synergism and the underlying novel mechanism between RA and the granulocyte colony-stimulating factor (G-CSF) to restore differentiation of RA-refractory APL blasts. First, we show that in RA-refractory APL cells (UF-1 cell line), PML-RA receptor alpha (RARα) is not released from target promoters in response to RA, resulting in the maintenance of chromatin repression. Consequently, RARα cannot be recruited, and the RA target genes are not activated. We then deciphered how the combination of G-CSF and RA successfully restored the activation of RA target genes to levels achieved in RA-sensitive APL cells. We demonstrate that G-CSF restores RARα recruitment to target gene promoters through the activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and the subsequent derepression of chromatin. Thus, combinatorial activation of cytokines and RARs potentiates transcriptional activity through epigenetic modifications induced by specific signaling pathways.