Folate-Targeted Polymeric Nanoparticle Formulation of Docetaxel Is an Effective Molecularly Targeted Radiosensitizer with Efficacy Dependent on the Timing of Radiotherapy

Nanoparticle (NP) chemotherapeutics hold great potential as radiosensitizers. Their unique properties, such as preferential accumulation in tumors and their ability to target tumors through molecular targeting ligands, are ideally suited for radiosensitization. We aimed to develop a molecularly targeted nanoparticle formulation of docetaxel (Dtxl) and evaluate its property as a radiosensitizer. Using a biodegradable and biocompatible lipid-polymer NP platform and folate as a molecular targeting ligand, we engineered a folate-targeted nanoparticle (FT-NP) formulation of Dtxl. These NPs have sizes of 72±4 nm and surface charges of −42±8 mV. Using folate receptor over-expressing KB cells and folate receptor low HTB-43 cells, we showed folate-mediated intracellular uptake of NPs. In vitro radiosensitization studies initially showed FT-NP is less effective than Dtxl as a radiosensitizer. However, the radiosensitization efficacy is dependent on the timing of radiotherapy. In vitro radiosensitization conducted with irradiation given at the optimal time (24 hours) showed FT-NP Dtxl is as effective as Dtxl. When FT-NP Dtxl is compared to Dtxl and non-targeted nanoparticle (NT-NP) Dtxl in vivo, FT-NP was found to be significantly more effective than Dtxl or NT-NP Dtxl as a radiosensitizer. We also confirmed that radiosensitization is dependent on timing of irradiation in vivo. In summary, FT-NP Dtxl is an effective radiosensitizer in folate-receptor over-expressing tumor cells. Time of irradiation is critical in achieving maximal efficacy with this nanoparticle platform. To the best of our knowledge, our report is the first to demonstrate the potential of molecularly targeted NPs as a promising new class of radiosensitizers

Protection from ultraviolet damage and photocarcinogenesis by vitamin d compounds

© Springer Nature Switzerland AG 2020. Exposure of skin cells to UV radiation results in DNA damage, which if inadequately repaired, may cause mutations. UV-induced DNA damage and reactive oxygen and nitrogen species also cause local and systemic suppression of the adaptive immune system. Together, these changes underpin the development of skin tumours. The hormone derived from vitamin D, calcitriol (1,25-dihydroxyvitamin D3) and other related compounds, working via the vitamin D receptor and at least in part through endoplasmic reticulum protein 57 (ERp57), reduce cyclobutane pyrimidine dimers and oxidative DNA damage in keratinocytes and other skin cell types after UV. Calcitriol and related compounds enhance DNA repair in keratinocytes, in part through decreased reactive oxygen species, increased p53 expression and/or activation, increased repair proteins and increased energy availability in the cell when calcitriol is present after UV exposure. There is mitochondrial damage in keratinocytes after UV. In the presence of calcitriol, but not vehicle, glycolysis is increased after UV, along with increased energy-conserving autophagy and changes consistent with enhanced mitophagy. Reduced DNA damage and reduced ROS/RNS should help reduce UV-induced immune suppression. Reduced UV immune suppression is observed after topical treatment with calcitriol and related compounds in hairless mice. These protective effects of calcitriol and related compounds presumably contribute to the observed reduction in skin tumour formation in mice after chronic exposure to UV followed by topical post-irradiation treatment with calcitriol and some, though not all, related compounds

Illuminating the life of GPCRs

The investigation of biological systems highly depends on the possibilities that allow scientists to visualize and quantify biomolecules and their related activities in real-time and non-invasively. G-protein coupled receptors represent a family of very dynamic and highly regulated transmembrane proteins that are involved in various important physiological processes. Since their localization is not confined to the cell surface they have been a very attractive "moving target" and the understanding of their intracellular pathways as well as the identified protein-protein-interactions has had implications for therapeutic interventions. Recent and ongoing advances in both the establishment of a variety of labeling methods and the improvement of measuring and analyzing instrumentation, have made fluorescence techniques to an indispensable tool for GPCR imaging. The illumination of their complex life cycle, which includes receptor biosynthesis, membrane targeting, ligand binding, signaling, internalization, recycling and degradation, will provide new insights into the relationship between spatial receptor distribution and function. This review covers the existing technologies to track GPCRs in living cells. Fluorescent ligands, antibodies, auto-fluorescent proteins as well as the evolving technologies for chemical labeling with peptide- and protein-tags are described and their major applications concerning the GPCR life cycle are presented

FTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals.

FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177,330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity

Análisis de las Estrategias Metodológicas implementadas por el docente en el desarrollo del proceso de enseñanza- aprendizaje en la disciplina de Geografía e Historia de Nicaragua y su Didáctica en los alumnos/as de Primer año “B” del turno regular de Formación Inicial Docente en la Escuela Normal Central de Managua Alesio Blandón Juárez durante el I semestre del Curso Escolar 2016

El presente trabajo de investigación tiene como finalidad analizar la efectividad que tienen las Estrategias Metodológicas implementadas por el docente en el desarrollo del proceso de enseñanza- aprendizaje en la disciplina de Geografía de Nicaragua y su Didáctica en los alumnos/as de Primer año “B” del turno regular de Formación Inicial Docente en la Escuela Normal Central de Managua Alesio Blandón Juárez durante el I semestre del Curso Escolar 2016. Dicho trabajo de investigación tiene un enfoque naturista o cualitativo, es una vía de transformación social, a través de la cual el ser humano descubre la realidad que le rodea, determina los medios y procedimientos para actuar sobre ella y transformarla de acuerdo a una intensión social. Los procesos de investigación cualitativa, tienen como finalidad primordial la generación y construcción de conocimientos que contribuyen al desarrollo social y personal de cada uno de los miembros de una comunidad. La fase de recolección de los datos de la investigación desarrollada, se realizó de dos formas: una información que se recogió mediante la observación directa del comportamiento de los informantes claves y una información que se obtuvo mediante la interrogación de algunos informantes claves. Para ello, primeramente el investigador realizo una inmersión en el campo de trabajo, con el propósito de identificar los lugares adecuados para recoger y producir la información necesaria y requerid

Upper limits from the LIGO and TAMA detectors on the rate of gravitational-wave bursts

We report on the first joint search for gravitational waves by the TAMA and LIGO collaborations. We looked for millisecond-duration unmodelled gravitational-wave bursts in 473 hr of coincident data collected during early 2003. No candidate signals were found. We set an upper limit of 0.12 events per day on the rate of detectable gravitational-wave bursts, at 90% confidence level. From simulations, we estimate that our detector network was sensitive to bursts with root-sum-square strain amplitude above approximately 1-3×10 in the frequency band 700-2000 Hz. We describe the details of this collaborative search, with particular emphasis on its advantages and disadvantages compared to searches by LIGO and TAMA separately using the same data. Benefits include a lower background and longer observation time, at some cost in sensitivity and bandwidth. We also demonstrate techniques for performing coincidence searches with a heterogeneous network of detectors with different noise spectra and orientations. These techniques include using coordinated signal injections to estimate the network sensitivity, and tuning the analysis to maximize the sensitivity and the livetime, subject to constraints on the background