Anaplastic thyroid cancer: how far can we go?

Globally, thyroid cancer accounts for 2 % of all cancer diagnoses, and can be classified as well-differentiated or undifferentiated. Currently, differentiated thyroid carcinomas have good prognoses, and can be treated with a combination of therapies, including surgical thyroidectomy, radioactive iodine therapy and hormone-based therapy. On the other hand, anaplastic thyroid carcinoma, a subtype of undifferentiated thyroid carcinoma characterized by the loss of thyroid-like phenotype and function, does not respond to either radioactive iodine or hormone therapies. In most cases, anaplastic thyroid carcinomas are diagnosed in later stages of the disease, deeming them inoperable, and showing poor response rates to systemic chemotherapy. Recently, treatment courses using multiple-target agents are being explored and clinical trials have shown very promising results, such as overall survival rates, progression-free survival and tumor shrinkage. This review is focused on thyroid carcinomas, with particular focus on anaplastic thyroid carcinoma, exploring its undifferentiated nature. Special interest will be given to the treatment approaches currently available and respective obstacles or drawbacks. Our purpose is to contribute to understand why this malignancy presents low responsiveness to current treatments, while overviewing novel therapies and clinical trials.This research was funded by Fundação para a Ciência e a Tecnologia (FCT) through the Project Reference UID/DTP/04138/2019.info:eu-repo/semantics/publishedVersio

Anaplastic thyroid cancer: How far can we go?

This research was funded by Fundacao para a Ciencia e a Tecnologia (FCT) through the Project Reference UID/DTP/04138/2019.Globally, thyroid cancer accounts for 2 % of all cancer diagnoses, and can be classified as well-differentiated or undifferentiated. Currently, differentiated thyroid carcinomas have good prognoses, and can be treated with a combination of therapies, including surgical thyroidectomy, radioactive iodine therapy and hormone-based ther-apy. On the other hand, anaplastic thyroid carcinoma, a subtype of undifferentiated thyroid carcinoma character-ized by the loss of thyroid-like phenotype and function, does not respond to either radioactive iodine or hormone therapies. In most cases, anaplastic thyroid carcinomas are diagnosed in later stages of the disease, deeming them inoperable, and showing poor response rates to systemic chemotherapy. Recently, treatment courses using multi-ple-target agents are being explored and clinical trials have shown very promising results, such as overall survival rates, progression-free survival and tumor shrinkage. This review is focused on thyroid carcinomas, with particular focus on anaplastic thyroid carcinoma, exploring its undifferentiated nature. Special interest will be given to the treatment approaches currently available and respective obstacles or drawbacks. Our purpose is to contribute to understand why this malignancy presents low responsiveness to current treatments, while overviewing novel therapies and clinical trials.publishersversionpublishe

Skin Tissue Models

Skin Tissue Models provides a translational link for biomedical researchers on the interdisciplinary approaches to skin regeneration. As the skin is the largest organ in the body, engineered substitutes have critical medical application to patients with disease and injury - from burn wounds and surgical scars, to vitiligo, psoriasis and even plastic surgery. This volume offers readers preliminary description of the normal structure and function of mammalian skin, exposure to clinical problems and disease, coverage of potential therapeutic molecules and testing, skin substitutes, models as study platforms of skin biology and emerging technologies. The editors have created a table of contents which frames the relevance of skin tissue models for researchers as platforms to study skin biology and therapeutic approaches for different skin diseases, for clinicians as tissue substitutes, and for cosmetic and pharmaceutical industries as alternative test substrates that can replace animal models. Offers descriptions of the normal structure/function of mammalian skin, exposure to clinical problems, and more Presents coverage of skin diseases (cancer, genodermatoses, vitiligo and psoriasis) that extends to clinical requirements and skin diseases in vitro models Addresses legal requirements and ethical concerns in drugs and cosmetics in vitro testing Edited and authored by internationally renowned group of researchers, presenting the broadest coverage possible. © 2018 Elsevier Inc. All rights reserved.(undefined)info:eu-repo/semantics/publishedVersio

Pre-selection of fibroblasts subsets prompt prevascularization of tissue engineered skin analogues

The papillary and reticular dermis harbors phenotypically distinct fibroblasts, whose functions such as maintenance of skin's microvasculature are also distinct. Thus, we hypothesized that pre-selection of the subpopulations of fibroblasts would benefit the generation of skin tissue engineered (TE) constructs, promoting their prevascularization in vitro. We first isolated papillary and reticular fibroblasts using fluorescence-activated cell sorting and studied the effect of their secretome and extracellular matrix (ECM) on human dermal microvascular endothelial cell (hDMEC) organization. Subsequently, we developed a bilayered 3D polymeric structure with distinct layer-associated features to house the subpopulations of fibroblasts, to generate a skin analogue. Both papillary and reticular fibroblasts were able to stimulate capillary-like network formation in a Matrigel assay. However, the secretome of the two subpopulations was substantially different, being enriched in VEGF, IGF-1, and Angio-1 in the case of papillary fibroblasts and in HGF and FGF-2 for the reticular subset. In addition, the fibroblast subpopulations deposited varied levels of ECM proteins, more collagen I and laminin was produced by the reticular subset, but these differences did not impact hDMEC organization. Vessel-like structures with lumens were observed earlier in the 3D skin analogue prepared with the sorted fibroblasts, although ECM deposition was not affected by the cell's pre-selection. Moreover, a more differentiated epidermal layer was obtained in the skin analogue formed by the sorted fibroblasts, confirming that its whole structure was not affected. Overall, we provide evidence that pre-selection of papillary and reticular fibroblasts is relevant for promoting the in vitro prevascularization of skin TE constructs.The authors would like to acknowledge the financial support from the Consolidator Grant “ECM_INK” (ERC-2016- COG-726061), to the FSE/POCH (Fundo Social Europeu através do Programa Operacional do Capital Humano) under the scope of the PD/169/2013, NORTE-08-5369-FSE-000037 (H.R. M.)

Interfollicular epidermal stem-like cells for the recreation of the hair follicle epithelial compartment

Background Hair follicle (HF) development and growth are dependent on epithelial-mesenchymal interactions (EMIs). Dermal papilla (DP) cells are recognized as the key inductive mesenchymal player, but the ideal source of receptive keratinocytes for human HF regeneration is yet to be defined. We herein investigated whether human interfollicular epidermal keratinocytes with stem-like features (EpSlKCs), characterized by a α6bri/CD71dimexpression, can replace human hair follicular keratinocytes (HHFKCs) for the recreation of the HF epithelium and respective EMIs. Methods The α6bri/CD71dim cellular fraction was selected from the whole interfollicular keratinocyte population through fluorescence-activated cell sorting and directly compared with follicular keratinocytes in terms of their proliferative capacity and phenotype. The crosstalk with DP cells was studied in an indirect co-culture system, and EpSlKC hair forming capacity tested in a hair reconstitution assay when combined with DP cells. Results EpSlKCs exhibited a phenotypic profile similar to follicular keratinocytes and were capable of increasing DP cell proliferation and, for short co-culture times, the number of alkaline phosphatase-active cells, suggesting an improvement of their inductivity. Moreover, the recreation of immature HFs and sebaceous glands was observed after EpSlKC and DP cell co-grafting in nude mice. Conclusions Our results suggest that EpSlKCs are akin to follicular keratinocytes and can crosstalk with DP cells, contributing to HF morphogenesis in vivo, thus representing an attractive epithelial cell source for hair regeneration strategies.This study was supported by the FCT/MCTES (Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia, e Ensino Superior) through the PD/59/2013, PD/BD/113800/2015 (C.M. Abreu), CEECIND/00695/2017 (M.T. Cerqueira), IF/00347/2015 (R. P. Pirraco), and IF/00945/2014 (A.P. Marques) grants

Dermal extracellular matrix extracts for wound healing: a pleiotropic trigger

Apresentação efetuada no "Tissue Engineering and Regenerative Medicine International Society (TERMIS) European Chapter Meeting" , em Manchester, Reino Unido, 2023INTRODUCTION: Extracellular matrix (ECM) role is defined by direct cell‐ECM interactions and biomechanics and also by its capacity to store biochemical cues that are vital in tissue's repair. With this in mind, an in‐house method was devised to obtain extracts comprised of structural ECM components (strECM) and enriched in soluble ECM‐derived factors (sECM). Herein we hypothesised that each ECM fraction may trigger different biological functions in multiple cell types, objectively confering them therapeutic and biomimetic potential. METHODS: To prove the concept, we used human dermal fibroblasts (hdFBs) to obtain the ECM extracts, prepared by fractioning cultured cells' own ECM. Extracts were analysed by mass spectrometry to obtain a proteomic profile and then regarding their in vitro functionality. Human dermal endothelial cells (hDMECs), keratinocytes (hKCs) and dFBs, were used to confirm the features identified by the proteomic profiling. The effect of the extracts over cell adhesion (focal adhesion formation) was analysed. A Matrigel assay was used to evaluate a potential angiogenic effect of the extracts. Moreover, hKCs migration and ability to differentiate and form a stratified epidermis was assessed. Finally, matrix (Collagen, elastin, GAGs) deposition by hdFBs and metalloproteinases (MMP 1, 2, 9)secretion and activity were measured. RESULTS: Proteomic analysis revealed that strECM and sECM complement each other, preserving the native ECM protein profile. The GO accessions linked to each fraction allowed pinpointing the specific cues provided by either of them. strECM was mainly comprised of components that were able to promote cell adhesion and spatial organization. On the other hand sECM proteomic profile revealed factors that play a role in wound healing such as angiogenesis, ECM remodeling and re‐epithelialization. A dose‐dependent response was observed regarding the formation of tubular structures in the angiogenic assay. The presence of sECM leads to a significant increase in the migration and proliferative ability (Ki67) of hKCs while maintaining their phenotype. Finally, sECM led to enhanced collagen, elastin and GAGs deposition by hDFbs while increasing the expression of MMPs. DISCUSSION & CONCLUSIONS: Our results validate the hypothesis that each ECM fraction effectively triggers different biological functions in multiple cell types. Overall the presence of sECM boosted the major cellular mechanisms that lead to successful wound healing, while strECM provides cues for cellular adhesion and organization. This study supports the use of ECM extracts as a wound healing enhancer, which might aid in the development of future therapies or improve the biomimicry of ECM‐based 3D tissue models

Semipermeable capsules wrapping a multifunctional and self-regulated co-culture microenvironment for osteogenic differentiation

A new concept of semipermeable reservoirs containing co-cultures of cells and supporting microparticles is presented, inspired by the multi-phenotypic cellular environment of bone. Based on the deconstruction of the â stem cell nicheâ , the developed capsules are designed to drive a self-regulated osteogenesis. PLLA microparticles functionalized with collagen I, and a co-culture of adipose stem (ASCs) and endothelial (ECs) cells are immobilized in spherical liquified capsules. The capsules are coated with multilayers of poly(L-lysine), alginate, and chitosan nano-assembled through layer-by-layer. Capsules encapsulating ASCs alone or in a co-culture with ECs are cultured in endothelial medium with or without osteogenic differentiation factors. Results show that osteogenesis is enhanced by the co-encapsulation, which occurs even in the absence of differentiation factors. These findings are supported by an increased ALP activity and matrix mineralization, osteopontin detection, and the up regulation of BMP-2, RUNX2 and BSP. The liquified co-capsules also act as a VEGF and BMP-2 cytokines release system. The proposed liquified capsules might be a valuable injectable self-regulated system for bone regeneration employing highly translational cell sources.The authors acknowledge the financial support by the Portuguese Foundation for Science and Technology (FCT) through the Ph.D. (SFRH/BD/69529/2010-Clara R. Correia) and the Post-doc grants (SFRH/BPD/96611/2013- Mariana T. Cerqueira), and the funding of RL3-TECT-NORTE-01-0124-FEDER-000020 for Rogério P. Pirraco. This work was also supported by European Research Council grant agreement ERC-2014-ADG-669858 for project ATLAS

Indicadores como aliados na gestão do centro cirúrgico / Indicators As Allies In The Surgical Center Management

A utilização de Indicadores de Qualidade como ferramenta de gestão do Centro Cirúrgico possibilita o monitoramento das práticas envolvidas, podendo serem elas assistenciais ou processuais. A presente pesquisa objetivou esclarecer o que são Indicadores de Qualidade com ênfase no Centro Cirúrgico, definindo como é feita a seleção e de que forma os mesmos podem ser utilizados na gestão. A metodologia utilizou revisão bibliográfica exploratória e concluiu que Indicadores são aliados importantes para a gestão, sendo possível selecionar os melhores e quais os indispensáveis. Dentro da classificação de estrutura, processos e resultados temos os principais como sendo: Taxa de infecção, Taxa de cancelamento cirúrgico, Quantitativo de cirurgias realizadas, Tempo de troca de sala, Taxa de atraso do início das primeiras cirurgias do dia. Portanto monitorar os resultados e apresentá-los à todas as equipes envolvidas nos processos trará conscientização e melhoria na performance desse importante Setor de um Hospital

Mineralogical and geochemical characterization of gold mining tailings and their potential to generate acid mine drainage (Minas Gerais, Brazil)

For more than 30 years, sulfide gold ores were treated in metallurgic plants located in Nova Lima, Minas Gerais, Brazil, and accumulated in the Cocoruto tailings dam. Both flotation and leaching tailings from a deactivated circuit, as well as roasted and leaching tailings from an ongoing plant, were studied for their acid mine drainage potential and elements’ mobility. Detailed characterization of both tailings types indicates the presence of fine-grain size material hosting substantial amounts of sulfides that exhibit distinct geochemical and mineralogical characteristics. The samples from the ongoing plant show high grades of Fe in the form of oxides, cyanide, and sulfates. Differently, samples from the old circuit shave higher average concentrations of Al (0.88%), Ca (2.4%), Mg (0.96%), and Mn (0.17%), present as silicates and carbonates. These samples also show relics of preserved sulfides, such as pyrite and pyrrhotite. Concentrations of Zn, Cu, Au, and As are higher in the tailings of the ongoing circuit, while Cr and Hg stand out in the tailings of the deactivated circuit. Although the obtained results show that the sulfide wastes do not tend to generate acid mine drainage, leaching tests indicate the possibility of mobilization of toxic elements, namely As and Mn in the old circuit, and Sb, As, Fe, Ni, and Se in the tailings of the plant that still works. This work highlights the need for proper management and control of tailing dams even in alkaline drainage environments such as the one of the Cocoruto dam. Furthermore, strong knowledge of the tailings’ dynamics in terms of geochemistry and mineralogy would be pivotal to support long-term decisions on wastes management and disposal.This work was funded by FCT—Fundação para a Ciência e a Tecnologia through projects UIDB/04683/2020 e UIDP/04683/2020 and Nano-MINENV 029259 (PTDC/CTA-AMB/29259/2017, and by AngloGold Ashanti Brazil

Sludge retention time impacts on polyhydroxyalkanoate productivity in uncoupled storage/growth processes

SFRH/BD/104767/2014 program ( GA 773375 ) UIDP/04378/2020 UIDB/04378/2020The process involving mixed microbial cultures (MMCs) and waste-based substrates emerged as an alternative solution to reduce the market price of polyhydroxyalkanoates (PHAs). The selection of an efficient MMC that displays a significant PHA accumulation potential and a high growth rate is considered a key factor for the MMC PHA production feasibility. This study used a pilot plant to investigate the dynamics of growth vs storage in a mixed culture fed with fermented fruit waste under uncoupled carbon and nitrogen feeding. Varying sludge retention times (SRTs) (2 and 4 d) and organic loading rates (OLRs) (from 2.6 to 14.5 gCOD.L−1.d−1) were imposed for this purpose. Results showed that, regardless of the OLR imposed, cultures selected at lower SRT grew faster and more efficiently using stored PHA. However, they had inferior specific storage rates and accumulation capacity, resulting in lower PHA productivity. Additionally, the polymer storage yield was independent of the SRT, and was directly linked with the abundance of putative PHA-storers in the MMC. The high PHA productivity (4.6 ± 0.3 g.L−1.d−1) obtained for the culture selected at 4 d of SRT was 80% above that obtained for the lower SRT tested, underlining the importance of achieving a good balance between culture growth and accumulation capacity to increase the viability of the PHA-producing process from wastes.publishersversionpublishe