Photodynamic Therapy (PDT) relies on the use of non-toxic photosensitizers that are locally and selectively activated by light to induce cell death or apoptosis through reactive oxygen species ...generation. The conjugation of porphyrinoids with sugars that target cancer is increasingly viewed as an effective way to increase the selectivity of PDT. To date, in vitro PDT efficacy is mostly screened using two-dimensional monolayer cultures. Compared to monolayer cultures, three-dimensional spheroid cultures have unique spatial distributions of nutrients, metabolites, oxygen and signalling molecules; therefore better mimic in vivo conditions. We obtained 0.05 mm3 spheroids with four different human tumor cell lines (HCT-116, MCF-7, UM-UC-3 and HeLa) with appropriate sizes for screening PDT agents. We observed that detachment from monolayer culture and growth as tumor spheroids was accompanied by changes in glucose metabolism, endogenous ROS levels, galectin-1 and glucose transporter GLUT1 protein levels. We compared the phototoxic responses of a porphyrin conjugated with four glucose molecules (PorGlu4) in monolayer and spheroid cultures. The uptake and phototoxicity of PorGlu4 is highly dependent on the monolayer versus spheroid model used and on the different levels of GLUT1 protein expressed by these in vitro platforms. This study demonstrates that HCT-116, MCF-7, UM-UC-3 and HeLa spheroids afford a more rational platform for the screening of new glycosylated-photosensitizers compared to monolayer cultures of these cancer cells.
Three phthalocyanines (Pcs) conjugated with α-, β- and γ-cyclodextrins (CDs) were prepared and their application as photosensitizer (PS) agents was assessed by photophysical, photochemical and in ...vitro photobiological studies. The photoactivity of Pc-α-CD and Pc-γ-CD ensures their potential as PDT drugs against UM-UC-3 human bladder cancer cells.
Introduction
Rheumatoid arthritis (RA) is a common systemic autoimmune disease of unknown cause, characterized by a chronic, symmetric, and progressive inflammatory polyarthritis. One of the most ...deleterious effects induced by the chronic inflammation of RA is bone loss. During the last 15 years, the better knowledge of the cytokine network involved in RA allowed the development of potent inhibitors of the inflammatory process classified as biological DMARDs. These new drugs are very effective in the inhibition of inflammation, but there are only few studies regarding their role in bone protection. The principal aim of this review was to show the evidence of the principal biologic therapies and bone loss in RA, focusing on their effects on bone mineral density, bone turnover markers, and fragility fractures.
Methods
Using the PICOST methodology, two coauthors (PC, LM-S) conducted the search using the following MESH terms: rheumatoid arthritis, osteoporosis, clinical trials, TNF- antagonists, infliximab, adalimumab, etanercept, certolizumab, golimumab, IL-6 antagonists, IL-1 antagonists, abatacept, tocilizumab, rituximab, bone mineral density, bone markers, and fractures. The search was conducted electronically and manually from the following databases: Medline and Science Direct. The search period included articles from 2003 to 2015. The selection included only original adult human research written in English. Titles were retrieved and the same two authors independently selected the relevant studies for a full text. The retrieved selected studies were also reviewed completing the search for relevant articles. The first search included 904 titles from which 253 titles were selected. The agreement on the selection among researchers resulted in a Kappa statistic of 0.95 (p < 0.000). Only 248 abstracts evaluated were included in the acronym PICOST. The final selection included only 28 studies, derived from the systematic search. Additionally, a manual search in the bibliography of the selected articles was made and included into the text and into the section of “small molecules of new agents.”
Conclusion
Treatment with biologic drugs is associated with the decrease in bone loss. Studies with anti-TNF blocking agents show preservation or increase in spine and hip BMD and also a better profile of bone markers. Most of these studies were performed with infliximab. Only three epidemiological studies analyzed the effect on fractures after anti-TNF blocking agent’s treatment. IL-6 blocking agents also showed improvement in localized bone loss not seen with anti-TNF agents. There are a few studies with rituximab and abatacept. Although several studies reported favorable actions of biologic therapies on bone protection, there are still unmet needs for studies regarding their actions on the risk of bone fractures.
The objective of this study was to analyse the dynamics of spatial dispersion of the coronavirus disease 2019 (COVID-19) in Brazil by correlating them to socioeconomic indicators. This is an ...ecological study of COVID-19 cases and deaths between 26 February and 31 July 2020. All Brazilian counties were used as units of analysis. The incidence, mortality, Bayesian incidence and mortality rates, global and local Moran indices were calculated. A geographic weighted regression analysis was conducted to assess the relationship between incidence and mortality due to COVID-19 and socioeconomic indicators (independent variables). There were confirmed 2 662 485 cases of COVID-19 reported in Brazil from February to July 2020 with higher rates of incidence in the north and northeast. The Moran global index of incidence rate (0.50, P = 0.01) and mortality (0.45 with P = 0.01) indicate a positive spatial autocorrelation with high standards in the north, northeast and in the largest urban centres between cities in the southeast region. In the same period, there were 92 475 deaths from COVID-19, with higher mortality rates in the northern states of Brazil, mainly Amazonas, Pará and Amapá. The results show that there is a geospatial correlation of COVID-19 in large urban centres and regions with the lowest human development index in the country. In the geographic weighted regression, it was possible to identify that the percentage of people living in residences with density higher than 2 per dormitory, the municipality human development index (MHDI) and the social vulnerability index were the indicators that most contributed to explaining incidence, social development index and the municipality human development index contributed the most to the mortality model. We hope that the findings will contribute to reorienting public health responses to combat COVID-19 in Brazil, the new epicentre of the disease in South America, as well as in other countries that have similar epidemiological and health characteristics to those in Brazil.
This work reports the synthesis and characterization of mesoporous silica nanoparticles (MSNs) functionalized with tridecafluorooctyltriethoxysilane (F13) and their in situ incorporation onto cotton ...textiles. The hybrid MSNs and the functional textiles were prepared by a one-pot co-condensation methodology between tetraethylorthosilicate (TEOS) and F13, with hexadecyltrimethylammonium chloride (CTAC) as the template and triethanolamine as the base. The influence of the F13 to TEOS molar ratio (1:10, 1:5 and 1:3) on the nanoparticle morphology, porosity, degree of functionalization, and hydro/oleophobic properties is discussed. The hybrid nanosilicas presented high colloidal stability and were spherical and monodispersed with average particle size of ∼45 nm. They also showed high surface areas, large pore volumes, and a wormhole-type mesoporous structure. The increase in the organosilane proportion during the co-condensation process led to a more radially branched wormhole-like mesoporosity, a decrease in the surface area, pore volume, and amount of surface silanol groups, and an enrichment of the surface with fluorocarbon moieties. These changes imparted hydrophobic and oleophobic properties to the materials, especially to that containing the highest F13 loading. Cotton textiles were coated with the F13-MSNs through an efficient and less time-consuming route. The combination between surface roughness and mesoporosity imparted by the MSNs, and the low surface energy provided by the organosilane resulted in superhydrophobic functional textiles. Moreover, the textile with the highest loading of fluorocarbon groups was superamphiphobic.
The LUX-ZEPLIN experiment is a dark matter detector centered on a dual-phase xenon time projection chamber operating at the Sanford Underground Research Facility in Lead, South Dakota, USA. This ...Letter reports results from LUX-ZEPLIN's first search for weakly interacting massive particles (WIMPs) with an exposure of 60 live days using a fiducial mass of 5.5 t. A profile-likelihood ratio analysis shows the data to be consistent with a background-only hypothesis, setting new limits on spin-independent WIMP-nucleon, spin-dependent WIMP-neutron, and spin-dependent WIMP-proton cross sections for WIMP masses above 9 GeV/c^{2}. The most stringent limit is set for spin-independent scattering at 36 GeV/c^{2}, rejecting cross sections above 9.2×10^{-48} cm at the 90% confidence level.
Numerous pharmacogenetic clinical guidelines and recommendations have been published, but barriers have hindered the clinical implementation of pharmacogenetics. The Translational Pharmacogenetics ...Program (TPP) of the National Institutes of Health (NIH) Pharmacogenomics Research Network was established in 2011 to catalog and contribute to the development of pharmacogenetic implementations at eight US healthcare systems, with the goal to disseminate real‐world solutions for the barriers to clinical pharmacogenetic implementation. The TPP collected and normalized pharmacogenetic implementation metrics through June 2015, including gene–drug pairs implemented, interpretations of alleles and diplotypes, numbers of tests performed and actionable results, and workflow diagrams. TPP participant institutions developed diverse solutions to overcome many barriers, but the use of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provided some consistency among the institutions. The TPP also collected some pharmacogenetic implementation outcomes (scientific, educational, financial, and informatics), which may inform healthcare systems seeking to implement their own pharmacogenetic testing programs.
The efficacy of vitamin D3 supplementation in coronavirus disease 2019 (COVID-19) remains unclear.
To investigate the effect of a single high dose of vitamin D3 on hospital length of stay in patients ...with COVID-19.
This was a multicenter, double-blind, randomized, placebo-controlled trial conducted in 2 sites in Sao Paulo, Brazil. The study included 240 hospitalized patients with COVID-19 who were moderately to severely ill at the time of enrollment from June 2, 2020, to August 27, 2020. The final follow-up was on October 7, 2020.
Patients were randomly assigned to receive a single oral dose of 200 000 IU of vitamin D3 (n = 120) or placebo (n = 120).
The primary outcome was length of stay, defined as the time from the date of randomization to hospital discharge. Prespecified secondary outcomes included mortality during hospitalization; the number of patients admitted to the intensive care unit; the number of patients who required mechanical ventilation and the duration of mechanical ventilation; and serum levels of 25-hydroxyvitamin D, total calcium, creatinine, and C-reactive protein.
Of 240 randomized patients, 237 were included in the primary analysis (mean SD age, 56.2 14.4 years; 104 43.9% women; mean SD baseline 25-hydroxyvitamin D level, 20.9 9.2 ng/mL). Median (interquartile range) length of stay was not significantly different between the vitamin D3 (7.0 4.0-10.0 days) and placebo groups (7.0 5.0-13.0 days) (log-rank P = .59; unadjusted hazard ratio for hospital discharge, 1.07 95% CI, 0.82-1.39; P = .62). The difference between the vitamin D3 group and the placebo group was not significant for in-hospital mortality (7.6% vs 5.1%; difference, 2.5% 95% CI, -4.1% to 9.2%; P = .43), admission to the intensive care unit (16.0% vs 21.2%; difference, -5.2% 95% CI, -15.1% to 4.7%; P = .30), or need for mechanical ventilation (7.6% vs 14.4%; difference, -6.8% 95% CI, -15.1% to 1.2%; P = .09). Mean serum levels of 25-hydroxyvitamin D significantly increased after a single dose of vitamin D3 vs placebo (44.4 ng/mL vs 19.8 ng/mL; difference, 24.1 ng/mL 95% CI, 19.5-28.7; P < .001). There were no adverse events, but an episode of vomiting was associated with the intervention.
Among hospitalized patients with COVID-19, a single high dose of vitamin D3, compared with placebo, did not significantly reduce hospital length of stay. The findings do not support the use of a high dose of vitamin D3 for treatment of moderate to severe COVID-19.
ClinicalTrials.gov Identifier: NCT04449718.
Chagas disease is caused by Trypanosoma cruzi, a protozoan parasite that has a heterogeneous population composed of a pool of strains with distinct characteristics, including variable levels of ...virulence. In previous work, transcriptome analyses of parasite genes after infection of human foreskin fibroblasts (HFF) with virulent (CL Brener) and non-virulent (CL-14) clones derived from the CL strain, revealed a reduced expression of genes encoding parasite surface proteins in CL-14 compared to CL Brener during the final steps of the intracellular differentiation from amastigotes to trypomastigotes. Here we analyzed changes in the expression of host genes during in vitro infection of HFF cells with the CL Brener and CL-14 strains by analyzing total RNA extracted from cells at 60 and 96 hours post-infection (hpi) with each strain, as well as from uninfected cells. Similar transcriptome profiles were observed at 60 hpi with both strains compared to uninfected samples. However, at 96 hpi, significant differences in the number and expression levels of several genes, particularly those involved with immune response and cytoskeleton organization, were observed. Further analyses confirmed the difference in the chemokine/cytokine signaling involved with the recruitment and activation of immune cells such as neutrophils upon T. cruzi infection. These findings suggest that infection with the virulent CL Brener strain induces a more robust inflammatory response when compared with the non-virulent CL-14 strain. Importantly, the RNA-Seq data also exposed an unexplored role of fibroblasts as sentinel cells that may act by recruiting neutrophils to the initial site of infection. This role for fibroblasts in the regulation of the inflammatory response during infection by T. cruzi was corroborated by measurements of levels of different chemokines/cytokines during in vitro infection and in plasma from Chagas disease patients as well as by neutrophil activation and migration assays.
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