Nanobody-mediated SPECT/CT imaging reveals the spatiotemporal expression of programmed death-ligand 1 in response to a CD8+ T cell and iNKT cell activating mRNA vaccine.

Rationale: Although promising responses are obtained in patients treated with immune checkpoint inhibitors targeting programmed death ligand 1 (PD-L1) and its receptor programmed death-1 (PD-1), only a fraction of patients benefits from this immunotherapy. Cancer vaccination may be an effective approach to improve the response to immune checkpoint inhibitors anti-PD-L1/PD-1 therapy. However, there is a lack of research on the dynamics of PD-L1 expression in response to cancer vaccination. Methods: We performed non-invasive whole-body imaging to visualize PD-L1 expression at different timepoints after vaccination of melanoma-bearing mice. Mice bearing ovalbumin (OVA) expressing B16 tumors were i.v. injected with the Galsome mRNA vaccine: OVA encoding mRNA lipoplexes co-encapsulating a low or a high dose of the atypical adjuvant α-galactosylceramide (αGC) to activate invariant natural killer T (iNKT) cells. Serial non-invasive whole-body immune imaging was performed using a technetium-99m (99mTc)-labeled anti-PD-L1 nanobody, single-photon emission computerized tomography (SPECT) and X-ray computed tomography (CT) images were quantified. Additionally, cellular expression of PD-L1 was evaluated with flow cytometry. Results: SPECT/CT-imaging showed a rapid and systemic upregulation of PD-L1 after vaccination. PD-L1 expression could not be correlated to the αGC-dose, although we observed a dose-dependent iNKT cell activation. Dynamics of PD-L1 expression were organ-dependent and most pronounced in lungs and liver, organs to which the vaccine was distributed. PD-L1 expression in lungs increased immediately after vaccination and gradually decreased over time, whereas in liver, vaccination-induced PD-L1 upregulation was short-lived. Flow cytometric analysis of these organs further showed myeloid cells as well as non-immune cells with elevated PD-L1 expression in response to vaccination. SPECT/CT imaging of the tumor demonstrated that the expression of PD-L1 remained stable over time and was overall not affected by vaccination although flow cytometric analysis at the cellular level demonstrated changes in PD-L1 expression in various immune cell populations following vaccination. Conclusion: Repeated non-invasive whole-body imaging using 99mTc-labeled anti-PD-L1 nanobodies allows to document the dynamic nature of PD-L1 expression upon vaccination. Galsome vaccination rapidly induced systemic upregulation of PD-L1 expression with the most pronounced upregulation in lungs and liver while flow cytometry analysis showed upregulation of PD-L1 in the tumor microenvironment. This study shows that imaging using nanobodies may be useful for monitoring vaccine-mediated PD-L1 modulation in patients and could provide a rationale for combination therapy. To the best of our knowledge, this is the first report that visualizes PD-L1 expression upon cancer vaccination.

Calcifediol (25OH Vitamin D3) Deficiency: A Risk Factor from Early to Old Age.

Vitamin D deficiency is the main cause of nutritional rickets in children and osteomalacia in adults. There is consensus that nutritional access to vitamin D can be estimated by measuring serum concentrations of 25OHD and vitamin D deficiency can thus be considered as calcifediol deficiency. However, the threshold for vitamin D/calcifediol sufficiency remains a matter of debate. Vitamin D/calcifediol deficiency has been associated with musculoskeletal effects but also multiple adverse extra-skeletal consequences. If these consequences improve or if they can be treated with vitamin D supplementation is still unclear. Observational studies suggest a higher infection risk in people with low calcifediol levels. There is also a consistent association between serum calcifediol and cardiovascular events and deaths, but large-scale, long-term intervention studies did not show any benefit on cardiovascular outcomes from supplementation, at least not in subjects without clear vitamin D deficiency. Cancer risk also did not change with vitamin D treatment, although there are some data that higher serum calcifediol is associated with longer survival in cancer patients. In pregnant women, vitamin D supplementation decreases the risk of pre-eclampsia, gestational diabetes mellitus, and low birth weight. Although preclinical studies showed that the vitamin D endocrine system plays a role in certain neural cells as well as brain structure and function, there is no evidence to support a beneficial effect of vitamin D in neurodegenerative diseases. Vitamin D supplementation may marginally affect overall mortality risk especially in elderly subjects with low serum calcifediol concentrations.

Integrative demographic study of the Iberian painted frog (Discoglossus galganoi): inter-annual variation in the effective to census population size ratio, with insights on mating system and breeding success.

In the face of worldwide amphibian declines, integrative studies combining individual-based information and genetic data represent a powerful approach to produce robust, reliable, and comparable assessments of demographic dynamics. The Iberian painted frog (Discoglossus galganoi) is endemic to Spain and Portugal and shows decreasing population trends across its range, but few studies have attempted to estimate census sizes or assess genetic diversity in wild populations, and little is known about their reproductive biology. We applied an integrative approach based on the combination of capture-mark-recapture data and multilocus genotypes to monitor a breeding population of D. galganoi in central Spain during two consecutive breeding seasons, focusing on the estimation of demographic parameters and their temporal variation. Specifically, we estimated the number of adults (Na ), the effective population size (Ne ), and the effective number of breeders (Nb ), as well as survival and migration rates. We documented a >50% decrease in the estimated number of adults of both sexes between the breeding seasons of 2018 and 2019, probably associated with reduced rainfall in the latter. Estimates of Nb and the Nb /Na ratio were low in both seasons, with a 20-30% decrease in Nb and a 47% increase in the Nb /Na ratio in 2019. Based on the reconstruction of pedigrees from larval and adult genotypes, we provide the first genetic evidence of polygamy in males and females of D. galganoi and the first estimates of breeding success in the species.

II Consenso Colombiano para el Manejo de la Osteoporosis Posmenopáusica / Second Colombian Consensus on the Management of Post-menopausal Osteoporosis: 2017 Update

Resumen La Asociación Colombiana de Osteoporosis y Metabolismo Mineral se reunió a principios de 2017 para actualizar el Consenso Colombiano de Osteoporosis, elaborado por primera vez en 2005, un paso que se consideró necesario en vista del subdiagnóstico de esta enfermedad, el impacto esperado del envejecimiento poblacional y los cambios en el tratamiento farmacológico que ha habido desde entonces. Se seleccionó un equipo técnico con especialistas de múltiples áreas y amplia trayectoria, repartidos en 4 grupos de trabajo: definición y epidemiología, diagnóstico, tratamiento farmacológico y medidas no farmacológicas. Luego de una revisión de la literatura científica, en reuniones de trabajo se generaron las definiciones y recomendaciones que se resumen en este documento.

Abstract The Colombian Osteoporosis and Mineral Metabolism Association met in early 2017 to update the Colombian Consensus on Osteoporosis. This was first issued in 2005, and is seen as a necessary step in view of the underdiagnosed status of this disease, and the expected impact of population ageing. A technical team was formed with specialists with long experience across multiple disciplines, who were assigned to four working groups: definitions and epidemiology, diagnosis, pharmacological treatment, and non-pharmacological treatment. After a scientific literature review and a series of meetings, the definitions and recommendations are summarised in this article.

Glucose detection in human sweat using an electronic nose.

In the last years attempts to develop a non-invasive glucose system based on the glucose levels in sweat have been studied. In this paper, 32 metal oxide semiconductor (MOS) sensors operating at different temperatures have been used to develop a multisensor olfactory system that allows to study the glucose levels in sweat. In order to develop repeatable experiments, artificial sweat at different glucose concentrations were developed in the laboratory. The obtained results suggest high viability of the approach. Although, the sensitivity of the sensors system needs to be improved.