ABSTRACT
The hypercalcemic effects of the hormone 1α,25-dihydroxyvitamin D3 (calcitriol) and most of known vitamin D metabolites and analogs call for the development of non secosteroidal vitamin D receptor (VDR) ligands as new selective and noncalcemic agonists for treatment of hyperproliferative diseases. We report on the in silico design and stereoselective synthesis of six lithocholic acid derivatives as well as on the calcemic activity of a potent LCA derivative and its crystallographic structure in complex with zVDR LBD. The low calcemic activity of this compound in comparison with the native hormone makes it of potential therapeutic value. Structure-function relationships provide the basis for the development of even more potent and selective lithocholic acid-based VDR ligands.
Subject(s)
Lithocholic Acid/pharmacology , Receptors, Calcitriol/agonists , Dose-Response Relationship, Drug , Humans , Lithocholic Acid/chemical synthesis , Lithocholic Acid/chemistry , Molecular Structure , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Objetivo: Analizar la secuencia de difusión en resonancia magnética (RM) y los valores del coeficiente de difusión aparente (ADC) en cáncer de mama según subtipos moleculares y parámetros histológicos de agresividad en pacientes que acudieron al Centro Clínico de Estereotáxia (CECLINES), Caracas, Venezuela, durante el período diciembre de 2010- diciembre de 2016. Pacientes y métodos: Estudio retrospectivo, observacional, descriptivo y transversal con muestra de 152 pacientes, edad promedio 56 años, que cumplieron criterios de inclusión: género femenino, cualquier edad con diagnóstico de cáncer de mama primario realizado por biopsia percutánea, información inmunohistoquímica y anatomía patológica intrainstitucional, resultados de RM con descripción de la secuencia de difusión (valores b 0 y 1000) y valor ADC. Resultados: El comportamiento de la difusión mediante RM y valores ADC no mostró diferencias significativas al estudiarlos por grado histológico, subtipo molecular ni positividad o negatividad de receptores hormonales. Se observaron diferencias estadísticamente significativas entre valores ADC en lesiones con Ki-67 ≤ 14 % de 0,808 mm²/seg y lesiones con Ki-67 > 14 % de 0,762 mm²/seg. El punto de corte para ADC-tumoral 0,78 mm²/seg mostró una proporción estadísticamente significativa entre los grupos según índice de proliferación, en el que Ki-67 > 14 % se asoció más a valores ADC-tumoral ≤ 0,78 mm²/seg y Ki-67 ≤14 % a valores ADC-tumoral > 0,78 mm²/seg. Conclusiones: Valores ADC y comportamiento de difusión no permiten diferenciar lesiones en resonancia por subtipos moleculares, identificar grado histológico tumoral ni estatus de receptores hormonales; sin embargo, bajos valores de ADC se correlacionan adecuadamente con alto índice de Ki-67.
Objective: To analyse diffusion sequence in magnetic resonance (MRI) and apparent diffusion coefficient (ADC) values in breast cancer according to molecular subtypes and histological parameters of aggressiveness in patients who attended the Clinical Center of Stereotaxy (CECLINES), Caracas-Venezuela between December 2010 - December 2016. Patients and methods: A retrospective, observational, descriptive and crosssectionalstudy including 152 patients with an average age of 56 years who met inclusion criteria: female gender, any age group with primary breast cancer diagnosis by percutaneous biopsy, intra-institutional immunohistochemical and anatomical pathology information, MRI results describing diffusion sequence (values b 0 and 1000) and ADC value. Results: The diffusion behavior by means of MRI and ADC values did not show significant differences when studying them by histologic grade, molecular subtype or hormone receptor-positivity or negativity. Statistically significant differences were found between ADC values in lesions with Ki-67 ≤14% of 0.808 mm² /s and lesions with Ki-67> 14% of 0.762 mm² /s. The cut-off point for tumor ADC of 0.78 mm² /s showed a statistically significant proportion between groups according to proliferation index in which Ki-67> 14% was more associated with tumor ADC values ≤0.78 mm² /s and Ki -67 ≤14% with tumor ADC values > 0.78 mm² /s. Conclusions: ADC values and diffusion behavior do not allow to differentiate lesions on resonance by molecular subtypes, nor to identify histologic tumor grade or hormone receptorstatus; however, low ADC values correlate adequately with high Ki67 index.
Subject(s)
Humans , Breast Neoplasms , Magnetic Resonance Imaging , DiffusionABSTRACT
OBJECTIVES: The objective was to determine the effect of myofascial techniques on the modulation of physiologic and psychologic variables. DESIGN: Forty-one (41) healthy male volunteers were randomly assigned to an experimental or control group. INTERVENTIONS: The experimental group underwent 3 manual therapy modalities: suboccipital muscle technique, compression of fourth intracranial ventricle, and deep cervical fascia technique. The control group remained in a resting position for the same time period under the same environmental conditions. OUTCOME MEASURES: Temperature, heart rate, and systolic and diastolic blood pressure (BP) were measured before, during, and after the intervention. State and trait anxiety levels and depression level were evaluated before and after the intervention. RESULTS: Repeated-measures analysis of variance revealed a significant time x groups interaction [F = 4.7(1,40); p = 0.036] for state anxiety. There were no significant time x group interaction effects for depression [F = 0.33(1,40); p = 0.57] or trait anxiety [F = 3.76(1,40), p = 0.060]. Among physiologic parameters, a significant time x group interaction was found for systolic BP [F = 2.86(6,240); p = 0.033] and heart rate [F = 2.89(6,240); p = 0.036]. CONCLUSIONS: Psychologic modulation is observed after application of manual therapy techniques, with a decrease in state anxiety in the experimental group. Heart rate and systolic BP were modulated during the course of myofascial induction techniques. All of these effects were observed up to 20 minutes after the therapy.
