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Despite being the most prevalent and lethal type of adult brain cancer, glioblastoma (GBM) remains intractable. Promising anti-GBM nanoparticle (NP) systems have been developed to improve the anti-cancer performance of difficult-to-deliver therapeutics, with particular emphasis on tumor targeting strategies. However, current disease modeling toolboxes lack close-to-native in vitro models that emulate GBM microenvironment and bioarchitecture, thus partially hindering translation due to poorly predicted clinical responses. Herein, human GBM heterotypic multicellular tumor microtissues (MCTMs) are generated through high-throughput 3D modeling of U-251 MG tumor cells, tissue differentiated macrophages isolated from peripheral monocytes, and brain microvascular primary endothelial cells. GBM MCTMs mimicked tumor spatial organization, extracellular matrix production and necrosis areas. The bioactivity of a model drug, docetaxel (DTX), and of tumor-targeted DTX-loaded polymeric NPs with a surface L-Histidine moiety (H-NPs), were assessed in the MCTMs. MCTMs cell uptake and anti-proliferative effect was 8- and 3-times higher for H-NPs, respectively, compared to the non-targeted NPs and to free DTX. H-NPs provided a decrease of MCTMs anti-inflammatory M2-macrophages, while increasing their pro-inflammatory M1 counterparts. Moreover, H-NPs showed a particular biomolecular signature through reduced secretion of an array of medium cytokines (IFN-γ, IL-1β, IL-1Ra, IL-6, IL-8, TGF-β). Overall, MCTMs provide an in vitro biomimetic model to recapitulate key cellular and structural features of GBM and improve in vivo drug response predictability, fostering future clinical translation of anti-GBM nano-therapeutic strategies.

Skin cancer is one of the most common types of cancer, and its incidence continues to increase. It is divided into two main categories, melanoma and non-melanoma. Treatments include surgery, radiation therapy, and chemotherapy. The relatively high mortality in melanoma and the existing recurrence rates, both for melanoma and non-melanoma, create the need for studying and developing new approaches for skin cancer management. Recent studies have focused on immunotherapy, photodynamic therapy, photothermal therapy, and photoimmunotherapy. Photoimmunotherapy has gained much attention due to its excellent potential outcomes. It combines the advantages of photodynamic and/or photothermal therapy with a systemic immune response, making it ideal for metastatic cancer. This review critically discusses different new nanomaterials’ properties and mechanisms of action for skin cancer photoimmunotherapy and the main results obtained in the field.

Objective: To compare brain metabolism using [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) in total thyroidectomy patients during hypothyroidism (levothyroxine withdrawal) or under recombinant human thyroid-stimulating hormone (rhTSH) against levothyroxine intake. Methods: A total of 12 patients were randomly divided into two groups. One group underwent the first [18F]FDG PET/CT brain scan after levothyroxine withdrawal (hypothyroidism condition) and repeated the scan 6 months later during regular levothyroxine intake (replacement condition). The other group underwent the first [18F]FDG PET/CT scan after receiving an rhTSH injection and maintained regular levothyroxine intake (rhTSH condition), and repeated the scan 7 months later during regular levothyroxine intake without rhTSH administration. The intra-group regional brain metabolisms were compared. Results: Under the hypothyroidism condition, brain metabolism was significantly reduced, namely in the bilateral pre-frontal, temporal, anterior cingulate, and primary motor cortices, insula, and striatum (uncorrected voxelwise p < 0.005); No significant differences were found between the rhTSH and replacement conditions. Conclusion: rhTSH administration could be a better option than levothyroxine withdrawal for 131I treatment, serum thyroglobulin measurement, or radioiodine scanning for patient follow-up.

Chitosan (Ch) has recently been used in different studies as a vaccine adjuvant with an ability to modulate the tumor microenvironment (TME). This systematic review aims to elucidate the added value of using Ch-based therapies for immunotherapeutic strategies in cancer treatment, through the exploration of different Ch-based formulations, their capacity to modulate immune cells in vitro and in vivo, and their translational potential for clinical settings. A systematic review was conducted on PubMed, following both inclusion and exclusion steps. Original articles which focused on the immunomodulatory role of Ch-based formulations in the TME were included, as well as its usage as a delivery vehicle for other immunomodulatory molecules. This review illustrates the added value of Ch-based systems to reshape the TME, through the modulation of immune cells using different Ch formulations, namely solutions, films, gels, microneedles and nanoparticles. Generally, Ch-based formulations increase the recruitment and proliferation of cells associated with pro-inflammatory abilities and decrease cells which exert anti-inflammatory activities. These effects correlated with a decreased tumor weight, reduced metastases, reversion of the immunosuppressive TME and increased survival in vivo. Overall, Ch-based formulations present the potential for immunotherapy in cancer. Nevertheless, clinical translation remains challenging, since the majority of the studies use Ch in formulations with other components, implicating that some of the observed effects could result from the combination of the individual effects. More studies on the use of different Ch-based formulations, complementary to standardization and disclosure of the Ch properties used are required to improve the immunomodulatory effects of Ch-based formulations in cancer.

Matrix complexity of fruit juices and their low antimony level requires sensitive, cost-effective instruments, time-consuming and error-prone sample pretreatment methods. Therefore, a flow-batch procedure (HG-FBA-AFS) was developed for the fast and sensitive determination of total inorganic Sb in grape juice samples by hydride generation atomic fluorescence spectrometry. The sample pretreatment, pre-reduction and stibine formation steps run through the mixing chamber. The HCl and NaBH

The objective was to quantify thyroid cancer incidence and mortality trends in Portugal. The number of thyroid cancer cases and incidence rates were retrieved from the Regional Cancer Registries for the period 1989–2011. The number of deaths and mortality rates were obtained from the WHO cancer mortality database (1988–2003 and 2007–2012) and Statistics Portugal (2004–2006; 1988–2012 by region). Joinpoint regression of the standardized incidence and mortality rates was performed. A significant, rapid and continued increase in incidence was observed for both sexes in each of the Regional Cancer Registries, with annual per cent changes (APCs) ranging between 2 and 9. Incidence in Portuguese women is higher than estimates for the world and Europe. Mortality decreased for women (APC: −1.5), with the greatest decrease in the North, and increased marginally for men (APC: +0.2), with a greater increase in the South. The significant increases in incidence in Portugal are predominantly because of the increase in incidence among women from the North. These trends, combined with an overall low mortality and high 5-year relative survival, raise concerns on the extent to which overdiagnosis may be taking place. Further research is needed, quantifying the importance of the most likely determinants of these trends as well as the extent and potentially deleterious effects of overdiagnosis and overtreatment in the Portuguese setting. This work was supported by the Grupo de Estudos da Tiróide da Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo (GET – SPEDM) and the Epidemiology Research Unit, Institute of Public Health, University of Porto (UID/DTP/047507/2013).

Embryonic stem (ES)-derived neural stem/progenitor cells (ES-NSPCs) constitute a promising cell source for application in cell therapies for the treatment of central nervous system disorders. In this study, a rotary orbital hydrodynamic culture system was applied to single-cell suspensions of ES-NSPCs, to obtain homogeneously-sized ES-NSPC cellular aggregates (neurospheres). Hydrodynamic culture allowed the formation of ES-NSPC neurospheres with a narrower size distribution than statically cultured neurospheres, increasing orbital speeds leading to smaller-sized neurospheres and higher neurosphere yield. Neurospheres formed under hydrodynamic conditions (72 h at 55 rpm) showed higher cell compaction and comparable percentages of viable, dead, apoptotic and proliferative cells. Further characterization of cellular aggregates provided new insights into the effect of hydrodynamic shear on ES-NSPC behaviour. Rotary neurospheres exhibited reduced protein levels of N-cadherin and β-catenin, and higher deposition of laminin (without impacting fibronectin deposition), matrix metalloproteinase-2 (MMP-2) activity and percentage of neuronal cells. In line with the increased MMP-2 activity levels found, hydrodynamically-cultured neurospheres showed higher outward migration on laminin. Moreover, when cultured in a 3D fibrin hydrogel, rotary neurospheres generated an increased percentage of neuronal cells. In conclusion, the application of a constant orbital speed to single-cell suspensions of ES-NSPCs, besides allowing the formation of homogeneously-sized neurospheres, promoted ES-NSPC differentiation and outward migration, possibly by influencing the expression of cell-cell adhesion molecules and the secretion of proteases/extracellular matrix proteins. These findings are important when establishing the culture conditions needed to obtain uniformly-sized ES-NSPC aggregates, either for use in regenerative therapies or in in vitro platforms for biomaterial development or pharmacological screening. Copyright © 2016 John WileySons, Ltd.

In an attempt to improve the efficacy of neural stem/progenitor cell (NSPC) based therapies, fibrin hydrogels are being explored to provide a favourable microenvironment for cell survival and differentiation following transplantation. In the present work, the ability of fibrin to support the survival, proliferation, and neuronal differentiation of NSPCs derived from embryonic stem (ES) cells under monolayer culture was explored. Single mouse ES-NSPCs were cultured within fibrin (fibrinogen concentration: 6 mg/ml) under neuronal differentiation conditions up to 14 days. The ES-NSPCs retained high cell viability and proliferated within small-sized spheroids. Neuronal differentiation was confirmed by an increase in the levels of βIII-tubulin and NF200 over time. At day 14, cell-matrix constructs mainly comprised NSPCs and neurons (46.5% βIII-tubulin

Bacillus Calmette-Guérin (BCG) immunotherapy is the gold standard treatment for superficial bladder tumors with intermediate/high risk of recurrence or progression. However, approximately 30% of patients fail to respond to the treatment. Effective BCG therapy needs precise activation of the type 1 helper cells immune pathway. Tumor-associated macrophages (TAMs) often assume an immunoregulatory M2 phenotype and may directly interfere with the BCG-induced antitumor immune response. Thus, we aim to clarify the influence of TAMs, in particular of the M2 phenotype in stroma and tumor areas, in BCG treatment outcome.The study included 99 patients with bladder cancer treated with BCG. Tumors resected before treatment were evaluated using immunohistochemistry for CD68 and CD163 antigens, which identify a lineage macrophage marker and a M2-polarized specific cell surface receptor, respectively. CD68(+) and CD163(+) macrophages were evaluated within the stroma and tumor areas, and high density of infiltrating cells spots were selected for counting. Hypoxia, an event known to modulate macrophage phenotype, was also assessed through hypoxia induced factor (HIF)-1α expression.Patients in whom BCG failed had high stroma-predominant CD163(+) macrophage counts (high stroma but low tumor CD163(+) macrophages counts) when compared with the ones with a successful treatment (71% vs. 47%, P = 0.017). Furthermore, patients presenting this phenotype showed decreased recurrence-free survival (log rank, P = 0.008) and a clear 2-fold increased risk of BCG treatment failure was observed in univariate analysis (hazard ratio = 2.343; 95% CI: 1.197-4.587; P = 0.013). Even when adjusted for potential confounders, such as age and therapeutic scheme, multivariate analysis revealed 2.6-fold increased risk of recurrence (hazard ratio = 2.627; 95% CI: 1.340-5.150; P = 0.005). High stroma-predominant CD163(+) macrophage counts were also associated with low expression of HIF-1α in tumor areas, whereas high counts of CD163(+) in the tumor presented high expression of HIF-1α in tumor nests.TAMs evaluation using CD163 is a good indicator of BCG treatment failure. Moreover, elevated infiltration of CD163(+) macrophages, predominantly in stroma areas but not in the tumor, may be a useful indicator of BCG treatment outcome, possibly owing to its immunosuppressive phenotype.

The development of scaffolds that combine the delivery of drugs with the physical support provided by electrospun fibres holds great potential in the field of nerve regeneration. Here it is proposed the incorporation of ibuprofen, a well-known non-steroidal anti-inflammatory drug, in electrospun fibres of the statistical copolymer poly(trimethylene carbonate-co-ε-caprolactone) [P(TMC-CL)] to serve as a drug delivery system to enhance axonal regeneration in the context of a spinal cord lesion, by limiting the inflammatory response. P(TMC-CL) fibres were electrospun from mixtures of dichloromethane (DCM) and dimethylformamide (DMF). The solvent mixture applied influenced fibre morphology, as well as mean fibre diameter, which decreased as the DMF content in solution increased. Ibuprofen-loaded fibres were prepared from P(TMC-CL) solutions containing 5% ibuprofen (w/w of polymer). Increasing drug content to 10% led to jet instability, resulting in the formation of a less homogeneous fibrous mesh. Under the optimized conditions, drug-loading efficiency was above 80%. Confocal Raman mapping showed no preferential distribution of ibuprofen in P(TMC-CL) fibres. Under physiological conditions ibuprofen was released in 24 h. The release process being diffusion-dependent for fibres prepared from DCM solutions, in contrast to fibres prepared from DCM-DMF mixtures where burst release occurred. The biological activity of the drug released was demonstrated using human-derived macrophages. The release of prostaglandin E2 to the cell culture medium was reduced when cells were incubated with ibuprofen-loaded P(TMC-CL) fibres, confirming the biological significance of the drug delivery strategy presented. Overall, this study constitutes an important contribution to the design of a P(TMC-CL)-based nerve conduit with anti-inflammatory properties.

Based on criteria of mathematical simplicity and consistency with empirical market data, a stochastic volatility model is constructed, the volatility process being driven by fractional noise. Price return statistics and asymptotic behavior are derived from the model and compared with data. Deviations from Black-Scholes and a new option pricing formula are also obtained.