Phase I study of peposertib and avelumab with or without palliative radiotherapy in patients with advanced solid tumors.

INTRODUCTION: We report results from a phase I, three-part, dose-escalation study of peposertib, a DNA-dependent protein kinase inhibitor, in combination with avelumab, an immune checkpoint inhibitor, with or without radiotherapy in patients with advanced solid tumors. MATERIALS AND METHODS: Peposertib 100-400 mg twice daily (b.i.d.) or 100-250 mg once daily (q.d.) was administered in combination with avelumab 800 mg every 2 weeks in Part A or avelumab plus radiotherapy (3 Gy/fraction × 10 days) in Part B. Part FE assessed the effect of food on the pharmacokinetics of peposertib plus avelumab. The primary endpoint in Parts A and B was dose-limiting toxicity (DLT). Secondary endpoints were safety, best overall response per RECIST version 1.1, and pharmacokinetics. The recommended phase II dose (RP2D) and maximum tolerated dose (MTD) were determined in Parts A and B. RESULTS: In Part A, peposertib doses administered were 100 mg (n = 4), 200 mg (n = 11), 250 mg (n = 4), 300 mg (n = 6), and 400 mg (n = 4) b.i.d. Of DLT-evaluable patients, one each had DLT at the 250-mg and 300-mg dose levels and three had DLT at the 400-mg b.i.d. dose level. In Part B, peposertib doses administered were 100 mg (n = 3), 150 mg (n = 3), 200 mg (n = 4), and 250 mg (n = 9) q.d.; no DLT was reported in evaluable patients. Peposertib 200 mg b.i.d. plus avelumab and peposertib 250 mg q.d. plus avelumab and radiotherapy were declared as the RP2D/MTD. No objective responses were observed in Part A or B; one patient had a partial response in Part FE. Peposertib exposure was generally dose proportional. CONCLUSIONS: Peposertib doses up to 200 mg b.i.d. in combination with avelumab and up to 250 mg q.d. in combination with avelumab and radiotherapy were tolerable in patients with advanced solid tumors; however, antitumor activity was limited. GOV IDENTIFIER: NCT03724890.

Cerebrospinal fluid: postmortem biochemical study.

UNLABELLED: Postmortem phenomena can change and alter biochemical components in body fluids such as blood and as cerebrospinal fluid (CSF). AIMS OF THE STUDY WERE: (a) to analyse urea, glucose, potassium, chloride, protein, creatinine, calcium, alkaline phosphatase and cortisol in CSF fluid and (b) to compare results between two age groups, between groups with or without mental or degenerative neurological illness and between a group reported as dying from natural causes and a group that had a violent death. MATERIALS AND METHODS: The study was carried out in Hospitalet de Llobregat (Barcelona) of 55 corpses. Samples were obtained following section of the corpus callosus, through the lateral ventricles and frozen to -80 degrees C until processed. RESULTS: Significant differences were found in urea levels between the two age groups, in protein between natural and violent death groups and in alkaline phosphatase between the two age groups and between the natural and violent death group. Cortisol levels revealed significant difference between the two age groups and is those supplying natural and violent death. CONCLUSIONS: The study indicates to the need for further studies designed to include groups with defined diagnose of mental or degenerative disorders as well as different age groups.

Androgen-induced neurite outgrowth is mediated by neuritin in motor neurones.

In the brain, the spinal cord motor neurones express the highest levels of the androgen receptor (AR). Experimental data have suggested that neurite outgrowth in these neurones may be regulated by testosterone or its derivative 5alpha-dihydrotestosterone (DHT), formed by the 5alpha-reductase type 2 enzyme. In this study we have produced and characterized a model of immortalized motor neuronal cells expressing the mouse AR (mAR) [neuroblastoma-spinal cord (NSC) 34/mAR] and analysed the role of androgens in motor neurones. Androgens either activated or repressed several genes; one has been identified as the mouse neuritin, a protein responsible for neurite elongation. Real-time PCR analysis has shown that the neuritin gene is expressed in the basal condition in immortalized motor neurones and is selectively up-regulated by androgens in NSC34/mAR cells; the DHT effect is counteracted by the anti-androgen Casodex. Moreover, DHT induced neurite outgrowth in NSC34/mAR, while testosterone was less effective and its action was counteracted by the 5alpha-reductase type 2 enzyme inhibitor finasteride. Finally, the androgenic effect on neurite outgrowth was abolished by silencing neuritin with siRNA. Therefore, the trophic effects of androgens in motor neurones may be explained by the androgenic regulation of neuritin, a protein linked to neurone development, elongation and regeneration.

Androgen 5-alpha-reductase type 2 is highly expressed and active in rat spinal cord motor neurones.

Spinal cord motoneurones express high levels of androgen receptor. However, in responsive tissue, the effects of testosterone is often mediated by the more potent androgenic derivative 5-alpha-dihydrotestosterone (DHT). This compound is formed in androgen target cells by the enzyme 5-alpha-reductase. Two isoforms of the 5-alpha-reductase, with limited degree of homology, have been cloned, type 1 and type 2. The low affinity-constitutive type 1 isoenzyme is widely distributed in the body; the high affinity-androgen regulated 5-alpha-reductase type 2 is confined to androgen-dependent structures and shows a peculiar pH optimum at acidic values. We have previously shown that high levels of 5-alpha-reductase activity are detectable in rat spinal cord. Here, using reverse transcriptase-polymerase chain reaction, we show that both isoforms are expressed in the whole spinal cord of the rat. The enzymatic pH optimum measured in immortalized spinal cord motoneurones (NSC34) is typical of the type 2 isoenzyme. Using in situ hybridization technique, we found that 5-alpha-reductase type 2 is confined to the motoneuronal cells of the anterior horns of the rat spinal cord, the cells that also are known to express high levels of androgen receptor. Because of the close association of androgen receptor and 5-alpha alpha-reductase type 2, motoneuronal cells should be considered as target cells for androgens.

Evolución de la infecciónpor virus de la hepatitis B en un Centro Penitenciario de Jóvenes: 1987-98. Vacunación / Evolution of viral hepatitis B infection in a young persons detention centre: 1987-1998. Vaccination

Objetivos: La evaluación del programa de vacunación contra la hepatitis B en una prisión. Población y Métodos: La población objeto fueron los reclusos que ingresaron en la prisión durante 1987-98.El procedimiento consistió en: a) Información individualizada de programa.b) Extracción sanguínea y determinación de marcadores serológicos. Los reclusos anti-HBc fueron calificados como susceptibles de infección por VHB.c) Vacunación con vacuna Engerix B® 20 microgramos, se aplicó la pauta estándar hasta 1990 (meses 0, 1 y 6). A partir de 1991 se aplicó la pauta rápida (0, 1, 2 y 12 meses).d) Determinación de marcadores serológicos para conocer la tasa de seroconversión postvacunal. Resultados: Se practicó serología prevacunal a 3.762 internos, de los cuales el 67 por ciento eran susceptibles del VHB. El 33 por ciento restante tenía marcadores que indicaban infección previa por el VHB. De estos últimos el 11 por ciento presentaron también posividad para HBsAg. A lo largo del periodo se observó un continuo descenso en la tasa de infección. En 1987 la tasa de ya expuestos al VHB era del 57,3 por ciento descendiendo progresivamente hasta un 10,9 por ciento en 1998.Adherencia vacunal del periodo 87-90: recibieron 1ª dosis el 76,9 por ciento, 2ª dosis el 49,7 por ciento y 3ª dosis el 32,4 por ciento. Adherencia vacunal del periodo 91-98: recibieron 1ª dosis el 64,5 por ciento, 2ª dosis el 48,8 por ciento, 3ª dosis el 40,7 por ciento y 4ª dosis el 25,8 por ciento. Discusión: 1. Dada la continua disminución en la tasa de anti-HBc, cabe plantearse un estudio de coste-beneficio para conocer la eficacia de continuar realizando marcadores serologicos prevacunales.2. El hecho de que comience a llegar al Centro población que ha sido objeto de campañas vacunales en la adolescencia plantea la conveniencia de estudiar anti-Hbs, a fin de evitar vacunaciones innecesarias. (AU)

Programa de mantenimiento con metadona (PMM) en prisión: cambios sociológicos y sanitarios / Methadone maintenance treatment in prision: social and health changes

Introducción: Los PMM ayudan al drogodependiente que no ha tenido éxito en programas libres de drogas a adoptar una conducta social adecuada, disminuir los problemas legales y mejorar la salud. Objetivos: Valorar los beneficios del tratamiento con metadona en heroinómanos, en comparación con las circunstancias anteriores a su inclusión en el programa. Valorar el consumo simultáneo de otras drogas y el consumo de metadona ilegal. Pacientes y Métodos: Se diseñó un estudio pre-experimental con un solo grupo pre-post intervención. Se realizó una única entrevista y se recogió información sobre el estado de los sujetos antes y después de recibir el tratamiento. La muestra fue de 62 internos del Centro Penitenciario de Brians (Barcelona). Las variables a considerar fueron . trabajo, nivel socioeconómico, autoestima y autocontrol, problemática legal, tratamiento psiquiátrico, intentos de suicidio, hábito de compartir jeringuillas, prostitución, hetero y auto-agresividad e historia de drogadicción. El tratamiento estadístico aplicado fue comparación de proporciones para variables categóricas, test de Mc Nemar y Test de Friedman para variables ordinales. Resultados: Durante la inclusión en el programa mejoraron de forma significativa las variables consideradas y disminuyó el consumo de cocaína y cannabis, aumentó el consumo de alcohol, nicotina, benzodiacepinas y drogas de diseño. Discusión: Se comparan los resultados con otros estudios. En conclusión los PMM representan una estrategia terapéutica válida dentro y fuera de centros penitenciarios. Constituyen una alternativa eficaz para la consecución de objetivos de salud, disminuyen conductas de riesgo para VIH y otras patologías asociadas y modifican positivamente aspectos legales y sociales (AU)

Pericardial fluid postmortem: Comparative study of natural and violent deaths.

Thanatochemistry is an increasingly important ancillary procedure in forensic practice. Alterations are known to take place in biochemical components during the postmortem period, particularly in the blood, and both research results and their interpretation have been the object of some controversy. For that reason, emphasis has been placed on the examination of fluids that are neither altered nor contaminated as rapidly as blood after death. This study tested the hypothesis that pericardial fluid (PF) may be a suitable medium for biochemical analysis in corpses. The study sought to determine concentrations of urea, creatinine, glucose, creatinine kinase 2, proteins, calcium, sodium, and potassium, in the pericardial fluid of corpses. The study sample was divided into two groups, natural deaths and violent deaths. Intergroup results were compared, using Mann-Whitney's U test for paired data. No significant differences were obtained between the natural death and violent death groups for the parameters studied, with the exception of urea (p < .05). Further studies are required to compare these results and create the possibility for new conclusions.

Synthesis of novel 6-amido-6-deoxy-l-galactose derivatives as sialyl Lewis X mimetics.

The synthesis and biological potency of several sialyl Lewis X (SLe(x)) mimetics is described. These mimics incorporate all of the critical functional groups present in SLe(x) necessary for binding to E-selectin. L-Galactose is used to mimic the naturally occurring L-fucose residue in SLe(x) due to the identical arrangement of the 2-, 3-, and 4-hydroxyl groups. Several synthetically and enzymatically prepared amino acids were used to mimic the D-galactose residue. Because of the variability incorporated in the synthesis of these amino acids the spatial requirements necessary for efficient binding were investigated. A carboxylate bearing side chain was introduced as a sialic acid mimic and the chain length was varied to maximize biological activity. By investigating the optimal arrangement of these two factors mimics were produced which were up twofold more active than SLe(x).