Shape-Versatile Fixed Cellular Materials for Multiple Target Immunomodulation.

Therapeutic cells are usually administered as living agents, despite the risks of undesired cell migration and acquisition of unpredictable phenotypes. Additionally, most cell-based therapies rely on the administration of single cells, often associated with rapid in vivo clearance. 3D cellular materials may be useful to prolong the effect of cellular therapies and offer the possibility of creating structural volumetric constructs. Here, the manufacturing of shape-versatile fixed cell-based materials with immunomodulatory properties is reported. Living cell aggregates with different shapes (spheres and centimeter-long fibers) are fixed using a method compatible with maintenance of structural integrity, robustness, and flexibility of 3D constructs. The biological properties of living cells can be modulated before fixation, rendering an in vitro anti-inflammatory effect toward human macrophages, in line with a decreased activation of the nuclear factor kappa B (NF-κB) pathway that preponderantly correlated with the surface area of the materials. These findings are further corroborated in vivo in mouse skin wounds. Contact with fixed materials also reduces the proliferation of activated primary T lymphocytes, while promoting regulatory populations. The fixation of cellular constructs is proposed as a versatile phenotypic stabilization method that can be easily implemented to prepare immunomodulatory materials with therapeutic potential.

Encapsulated Mesenchymal Stromal Cells as Cyclic Providers of Immunomodulatory Secretomes: A Living on-Demand Delivery System.

The stimulation of mesenchymal stromal cells (MSCs) with inflammatory molecules is often used to boost their therapeutic effect. Prolonged exposure to inflammatory molecules has been explored to improve their action because MSCs therapies seem to be improved transiently with such stimuli. However, the possibility of cyclically stimulating MSCs to recover their optimized therapeutic potential is still to be elucidated, although the efficacy of cell-based therapies may be dependent on the ability to readapt to the relapse pathological conditions. Here, the response of MSCs, encapsulated in alginate hydrogels and cultured for 22 d, is explored using three different regimes: single, continuous, and intermittent stimulation with IFNγ. Exposure to IFNγ leads to a decrease in the secretion of IL-10, which is cyclically countered by IFNγ weaning. Conditioned media collected at different stages of pulsatile stimulation show an immunomodulatory potential toward macrophages, which directly correlates with IL-10 concentration in media. To understand whether the correlation between cyclic stimulation of MSCs and other biological actions can be observed, the effect on endothelial cells is studied, showcasing an overall modest influence on tube formation. Overall, the results describe the response of encapsulated MSCs to unusual pulsatile simulation regimens, exploring encapsulated MSCs as a living on-demand release system of tailored secretomes with recoverable immunomodulatory action.

Validity and reproducibility of a whole-room indirect calorimeter for the estimation of VO2 , VCO2 , and resting metabolic rate.

Whole-room indirect calorimeters (WRICs) provide accurate instruments for the measurement of respiratory exchange, energy expenditure, and macronutrient oxidation. Here, we aimed to determine the validity and reproducibility of a 7500 L WRIC for the measurement of ventilation rates and resting metabolic rate (RMR). Technical validation was performed with propane combustion tests (n = 10) whereas biological reproducibility was tested in healthy subjects (13 women, 6 men, mean ± SD age 39.6 ± 15.3) in two 60 min measurements separated by 24 h. Subjects followed a run-in protocol prior to measurements. The coefficient of variation (CV) and intraclass correlation coefficient (ICC) were calculated for ventilation rates of O2 (VO2), CO2 (VCO2), the respiratory quotient (RQ; VCO2/VO2), and RMR. Technical validation showed good validity with CVs ranging from 0.67% for VO2 to 1.00% for energy expenditure. For biological reproducibility, CVs were 2.89% for VO2 ; 2.67% for VCO2 ; 1.95% for RQ; and 2.68% for RMR. With the exception of RQ (74%), ICCs were excellent for VO2 (94%), VCO2 (96%) and RMR (95%). Excluding participants that deviated from the run-in protocol did not alter results. In conclusion, the 7500 L WRIC is technically valid and reproducible for ventilation rates and RMR.

Comprehensive Genomic Profiling of Cell-Free Circulating Tumor DNA Detects Response to Ribociclib Plus Letrozole in a Patient with Metastatic Breast Cancer.

Analysis of cell-free circulating tumor DNA obtained by liquid biopsy is a non-invasive approach that may provide clinically actionable information when conventional tissue biopsy is inaccessible or infeasible. Here, we followed a patient with hormone receptor-positive and human epidermal growth factor receptor (HER) 2-negative breast cancer who developed bone metastases seven years after mastectomy. We analyzed circulating cell-free DNA (cfDNA) extracted from plasma using high-depth massively parallel sequencing targeting 468 cancer-associated genes, and we identified a clonal hotspot missense mutation in the PIK3CA gene (3:178952085, A > G, H1047R) and amplification of the CCND1 gene. Whole-exome sequencing revealed that both alterations were present in the primary tumor. After treatment with ribociclib plus letrozole, the genetic abnormalities were no longer detected in cfDNA. These results underscore the clinical utility of combining liquid biopsy and comprehensive genomic profiling to monitor treatment response in patients with metastasized breast cancer.

Engineering Strategies for Allogeneic Solid Tissue Acceptance.

Advances in allogeneic transplantation of solid organs and tissues depend on our understanding of mechanisms that mediate the prevention of graft rejection. For the past decades, clinical practice has established guidelines to prevent allograft rejection, which mostly rely on the intake of nontargeted immunosuppressants as the gold standard. However, such lifelong regimens have been reported to trigger severe morbidities and commonly fail in preventing late allograft loss. In this review, the biology of allogeneic rejection and self-tolerance is analyzed, as well as the mechanisms of cellular-based therapeutics driving suppression and/or tolerance. Bioinspired engineering strategies that take advantage of cells, biomaterials, or combinations thereof to prevent allograft rejection are addressed, as well as biological mechanisms that drive their efficacy.

Atitudes dos estudantes de enfermagem perante a morte e os cuidados em fim de vida / Nursing students' attitudes towards death and end-of-life care / Actitudes de los estudiantes de Enfermería ante la muerte y los cuidados al final de la vida

Resumo Enquadramento: As vivências pessoais e em ensino clínico influenciam o modo como os estudantes de enfermagem lidam com a morte. Objetivo: Avaliar as atitudes dos estudantes de enfermagem perante a morte e os cuidados em fim de vida. Metodologia: Estudo descritivo. Os dados foram recolhidos através de um questionário online. Participaram 158 estudantes do curso de licenciatura em Enfermagem. Os dados quantitativos foram analisados com recurso ao programa IBM SPSS Statistics. Foram realizadas análises estatísticas descritivas e exploratórias dos dados através de testes paramétricos e não paramétricos. Resultados: Os estudantes evidenciam maior proximidade com atitudes de neutralidade, medo e aproximação perante a morte e menos proximidade com atitudes de evitamento e escape. Relativamente aos cuidados em fim de vida, os estudantes que já realizaram ensino clínico apresentam atitudes positivas. Conclusão: É importante utilizar metodologias de ensino/aprendizagem que permitam ao estudante expor as suas experiências com a morte e com os cuidados em fim de vida em ensino clínico.

Abstract Background: Personal and clinical experiences influence how nursing students cope with death. Objective: To assess nursing students' attitudes towards death and end-of-life care. Methods: Descriptive study. Data were collected through an online questionnaire. The sample consisted of 158 undergraduate nursing students. Quantitative data were analyzed using IBM SPSS Statistics software. Descriptive statistics and exploratory data analysis were performed through parametric and non-parametric tests. Results: Students tend more to attitudes of neutral acceptance, fear of death, and approach acceptance and less to attitudes of avoidance and escape. Regarding end-of-life care, students who had already completed clinical training showed positive attitudes. Conclusion: Teaching and learning methodologies should be used to allow students to expose their experiences with death and end-of-life care in clinical training.

Resumen Marco contextual: Las experiencias personales y en la enseñanza clínica influyen en el modo en que los estudiantes de enfermería se enfrentan a la muerte. Objetivo: Evaluar las actitudes de los estudiantes de Enfermería hacia la muerte y los cuidados al final de la vida. Metodología: Estudio descriptivo. Los datos se recogieron mediante un cuestionario en línea. Participaron un total de 158 estudiantes de la licenciatura de Enfermería. Los datos cuantitativos se analizaron con el programa IBM SPSS Statistics. Se realizaron análisis estadísticos descriptivos y exploratorios de los datos mediante pruebas paramétricas y no paramétricas. Resultados: Los estudiantes mostraron una mayor proximidad a las actitudes de neutralidad, miedo y cercanía hacia la muerte, y una menor proximidad a las actitudes de evitación y huida. Con respecto a los cuidados al final de la vida, los estudiantes que ya han realizado la enseñanza clínica tienen actitudes positivas. Conclusión: Es importante utilizar metodologías de enseñanza/aprendizaje que permitan a los estudiantes exponer sus experiencias con la muerte y los cuidados al final de la vida en la enseñanza clínica.

Recent advances in the design of implantable insulin secreting heterocellular islet organoids.

Islet transplantation has proved one of the most remarkable transmissions from an experimental curiosity into a routine clinical application for the treatment of type I diabetes (T1D). Current efforts for taking this technology one-step further are now focusing on overcoming islet donor shortage, engraftment, prolonged islet availability, post-transplant vascularization, and coming up with new strategies to eliminate lifelong immunosuppression. To this end, insulin secreting 3D cell clusters composed of different types of cells, also referred as heterocellular islet organoids, spheroids, or pseudoislets, have been engineered to overcome the challenges encountered by the current islet transplantation protocols. ß-cells or native islets are accompanied by helper cells, also referred to as accessory cells, to generate a cell cluster that is not only able to accurately secrete insulin in response to glucose, but also superior in terms of other key features (e.g. maintaining a vasculature, longer durability in vivo and not necessitating immunosuppression after transplantation). Over the past decade, numerous 3D cell culture techniques have been integrated to create an engineered heterocellular islet organoid that addresses current obstacles. Here, we first discuss the different cell types used to prepare heterocellular organoids for islet transplantation and their contribution to the organoids design. We then introduce various cell culture techniques that are incorporated to prepare a fully functional and insulin secreting organoids with select features. Finally, we discuss the challenges and present a future outlook for improving clinical outcomes of islet transplantation.

One-Step Rapid Fabrication of Cell-Only Living Fibers.

Cellular aggregates are used as relevant regenerative building blocks, tissue models, and cell delivery platforms. Biomaterial-free structures are often assembled either as 2D cell sheets or spherical microaggregates, both incompatible with free-form deposition, and dependent on challenging processes for macroscale 3D upscaling. The continuous and elongated nature of fiber-shaped materials enables their deposition in unrestricted multiple directions. Cellular fiber fabrication has often required exogenously provided support proteins and/or the use of biomaterial-based sacrificial templates. Here, the rapid (<24 h) assembly of fiberoids is reported: living centimeter-long scaffold-free fibers of cells produced in the absence of exogenous materials or supplements. Adipose-derived mesenchymal stem cell fiberoids can be easily modulated into complex multidimensional geometries and show tissue-invasive properties while keeping the secretion of trophic factors. Proangiogenic properties studied on a chick chorioallantoic membrane in an ovo model are observed for heterotypic fiberoids containing endothelial cells. These micro-to-macrotissues may find application as morphogenic therapeutic and tissue-mimetic building blocks, with the ability to integrate 3D and 4D full biological materials.

Nanotechnology-based siRNA delivery strategies for metastatic colorectal cancer therapy.

Colorectal cancer (CRC) is the second most common cause of cancer-related death in the world, mainly due to distant metastases events. The metastatic CRC (mCRC) stages are resistant to the therapeutic recommended. Therefore, it urges the development of more efficient strategies to impair the disease. Small interfering RNA (siRNA) is a well-known silencing tool with impact on targeted cancer therapy, even though in vivo challenges difficult its clinical application. Here, multiple solutions to overcome the extracellular and intracellular barriers encountered by intravenous delivery of siRNA are discussed. Moreover, it is emphasized the association of siRNA with nanoparticles to enable the long-term release and to counteract the toxicity issues of siRNA. Particular attention is paid on the potential of poly(lactic-co-glycolic acid) (PLGA) nanoparticles for systemic siRNA delivery in mCRC. Despite of being less used so far due to technological difficulties, multiple strategies to successfully encapsulate siRNA into PLGA nanocarriers are summarized.

Impact of CEA-targeting Nanoparticles for Drug Delivery in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common causes of cancer-related death in the world, mainly owing to distant metastasis events. Developing targeted strategies to treat and follow individuals in more developed stages is needed. The carcinoembryonic antigen (CEA) is a cell surface-overexpressed glycoprotein in most CRC patients, and the evaluation of its serum levels is recommended in the clinic. These reasons motivated the production of CEA-targeted nanotechnologies for monitorization of CRC progression, but only a few centers have reported their use for drug delivery. The cellular internalization of CEA-linked nanosystems occurs by the natural recycling of the CEA itself, enabling longer retention and sustained release of the cargo. The functionalization of nanoparticles with lower affinity ligands for CEA is possibly the best choice to avoid their binding to the soluble CEA. Here, we also highlight the use of nanoparticles made of poly(lactic-co-glycolic acid) (PLGA) polymer, a well known material, owing to its biocompatibility and low toxicity. This work offers support to the contribution of antibody fragment-functionalized nanoparticles as promising high affinity molecules to decorate nanosystems. The linkers and conjugation chemistries chosen for ligand-nanoparticle coupling will be addressed herein as an elements essential to the modulation of nanosystem features. This review, to our knowledge, is the first that focuses on CEA-targeted nanotechnologies to serve colorectal cancer therapy and monitorization.

Organization and implementation of a cardio-oncology program. / Organização e implementação de uma consulta de cardio-oncologia.

Considerable advances in cancer therapies in recent decades have reshaped the prognosis of cancer patients. There are now estimated to be over 20 million cancer survivors in the USA and Europe, numbers unimaginable a few years ago. However, this increase in survival, along with the aging of the patient population, has been accompanied by a rise in adverse cardiovascular effects, particularly when there is a previous history of heart disease. The incidence of cardiotoxicity continues to grow, which can compromise the effectiveness of cancer therapy. Cardiotoxicity associated with conventional therapies, especially anthracyclines and radiation, is well known, and usually leads to left ventricular dysfunction. However, heart failure represents only a fraction of the cardiotoxicity associated with newer therapies, which have diverse cardiovascular effects. There are few guidelines for early detection, prevention and treatment of cardiotoxicity of cancer treatments, and no well-established tools for screening these patients. Echocardiography is the method of choice for assessment of patients before, during and after cancer treatment. It therefore makes sense to adopt a multidisciplinary approach to these patients, involving cardiologists, oncologists and radiotherapists, collaborating in the development of new training modules, and performing clinical and translational research in a cardio-oncology program. Cardio-oncology is a new frontier in medicine and has emerged as a new medical subspecialty that concentrates knowledge, understanding, training and treatment of cardiovascular comorbidities, risks and complications in patients with cancer in a comprehensive approach to the patient rather than to the disease.

Evaluation of four commonly used normalizer genes for the study of decidual gene expression.

Reverse transcription quantitative PCR (RT-qPCR) gene expression results must be normalized using stably expressed genes to correct for technical variation. We evaluated the expression of four widely used normalizers (RNA18S, GAPDH, TBP, and YWHAZ) across 59 decidual tissue samples collected by vacuum suction from preeclamptic and normotensive pregnancies. RNA18S and GAPDH were not suitable as normalizers, while YWHAZ and TBP were stably expressed across the study groups.

The prognostic role of RANK SNP rs34945627 in breast cancer patients with bone metastases.

Receptor activator of NF-kB (RANK) pathway regulates bone remodeling and is involved in breast cancer (BC) progression. Genetic polymorphisms affecting RANK-ligand (RANKL) and osteoprotegerin (OPG) have been previously associated with BC risk and bone metastasis (BM)-free survival, respectively. In this study we conducted a retrospective analysis of the association of five missense RANK SNPs with clinical characteristics and outcomes in BC patients with BM. SNP rs34945627 had an allelic frequency of 12.5% in BC patients, compared to 1.2% in the control group (P = 0.005). SNP rs34945627 was not associated with any clinicopathological characteristics, but patients presenting SNP rs34945627 had decreased disease-free survival (DFS) (log-rank P = 0.039, adjusted HR 2.29, 95% CI 1.04-5.08, P = 0.041), and overall survival (OS) (log-rank P = 0.019, adjusted HR 4.32, 95% CI 1.55-12.04, P = 0.005). No differences were observed regarding bone disease-free survival (log-rank P = 0.190, adjusted HR 1.68, 95% CI 0.78-3.66, P = 0.187), time to first skeletal-related event (log-rank P = 0.753, adjusted HR 1.28, 95% CI 1.42-3.84; P = 0.665), or time to bone progression (log-rank P = 0.618, adjusted HR 0.511, 95% CI 0.17-1.51; P = 0.233). Our analysis shows that RANK SNP rs34945627 has a high allelic frequency in patients with BC and BM, and is associated with decreased DFS and OS.

Prevention of Nausea and Vomiting in Patients Undergoing Oral Anticancer Therapies for Solid Tumors.

Chemotherapy-induced nausea and vomiting (CINV) is still a common and debilitating side effect despite recent advances in its prevention and treatment. The intrinsic emetogenicity of chemotherapy agents allowed grouping into four risk groups (high, moderate, low, and minimal risk of emetogenicity). The prevention of acute and delayed CINV for intravenous agents and one day regimens is well studied, although, there are few data about management of CINV induced by oral cytotoxic agents and targeted therapies, usually administered in extended regimens of daily oral use. Until now treatment of nausea and vomiting caused by oral antineoplastic agents remains largely empirical. The level of evidence of prophylactic antiemetics recommended for these agents is low. There are differences in the classification of emetogenic potential of oral antineoplastic agents between the international guidelines and different recommendations for prophylactic antiemetic regimens. Herein we review the evidence for antiemetic regimens for the most used oral antineoplastic agents for solid tumors and propose antiemetic regimens for high to moderate risk and low to minimal risk of emetogenicity.

Peer support for people with mental illness / Suporte interpares na doença mental

Background Peer support is a mutual aid system based on the belief that someone who faced/overcome adversity can provide support, encouragement and guidance to those who experience similar situations. Objective: To conduct a systematic review that describes this concept and characterizes peer supporters, its practice and efficacy. Method: Research on ISI Web of Science, EBSCO Psychology and Behavioral Sciences Collection and Medline databases (from 2001 to December 2013) was conducted using as keywords “mental illness”, “mental health”, “psychiatric disability”, “mental health services”, combined with “peer support”, “mutual support”, “self-help groups”, “consumers as providers”, “peer-run services”, “peer-run programs” and “social support”. Results: We found 1,566 articles and the application of both the exclusion (studies with children, teenagers and elderly people; disease in comorbidity; peer support associated to physical illnesses or family members/caregivers) and the inclusion criteria (full text scientific papers, peer support or similar groups directed for schizophrenia, depression, bipolar or psychotic disorders) lead to 165 documents, where 22 were excluded due to repetition and 31 to incomplete text. We analyzed 112 documents, identifying as main peer support categories: characterization, peer supporter, practices and efficacy. Discussion Despite an increasing interest about this topic, there is no consensus, suggesting realizing more studies...

Contexto: O suporte interpares é um sistema de ajuda mútua baseado na crença de que alguém que enfrentou/superou adversidades pode oferecer apoio, encorajamento e orientação a outros que enfrentam situações similares. Objetivo: Realizar uma revisão sistemática que caracterize o suporte interpares como prática, analise a sua eficácia e caracterize os pares prestadores de suporte interpares. Método: Pesquisa nas bases de dados ISI Web of Science, EBSCO Psychology and Behavioral Sciences Collection e Medline (2001 a dezembro de 2013), utilizando as palavras-chave “mental illness”, “mental health”, “psychiatric disability”, “mental health services”, combinadas com “peer support”, “mutual support”, “self-help groups”, “consumers as providers”, “peer-run services”, “peer-run programs” e “social support”. Resultados: Encontraram-se 1.566 artigos e foram aplicados os critérios de exclusão (artigos com crianças, adolescentes e idosos; doença mental em comorbidade; suporte interpares em doenças físicas ou familiares/cuidadores) e de inclusão (revistas científicas com texto integral disponível; suporte interpares ou grupos similares dirigidos a esquizofrenia, depressão, transtorno bipolar e outras perturbações psicóticas), resultando em 165 documentos. Excluíram-se 22 por repetição e 31 por texto incompleto, resultando em 112, os quais se identificaram como principais categorias do suporte interpares: caracterização, prestador de suporte, práticas e eficácia. Conclusão: Existe interesse crescente pelo tema, embora alguns domínios não sejam consensuais, sugerindo necessidade de mais estudos...

The Treatment of Liver Metastases in Patients with Neuroendocrine Tumors in 2012.

Neuroendocrine tumors (NETs) comprise a heterogeneous group of tumors that form a distinct entity. Approximately 75-80% of patients present with liver metastases at the time of their diagnosis, and 20%-25% will develop these lesions in the course of their disease. The presence of secondary deposits in the liver significantly increases the morbidity and mortality in these patients. The only potentially curative treatment is the surgical resection of the primary tumor and hepatic lesions. However, only 10% of patients presents under ideal conditions for that approach. Several techniques aimed at localized liver lesions have been applied also with interesting results in terms of survival and symptom control. The same has been demonstrated with new systemic therapies (target therapies). However, these are still under study, in order to define their true role in the management of these patients. This paper intends to address, in a general way, the various treatment options in patients with liver metastases from neuroendocrine tumors.

Análise da função diastólica pelo Doppler tecidual em pacientes com doença renal crônica de origem hipertensiva / Analysis of the diastolic function through the tecidual Doppler in patients with chronic renal illness of hipertensiv origin

Objetivo: Avaliar alterações precoces da função diastólica pelo Doppler Tecidual(DT) em pacientes com doença renal crônica (DRC), de origem hipertensiva e que não estejam em terapia renal de substituição pela hemodiálise (TRS), medindo-se as velocidades dos seguimentos miocárdicos, no ânulo mitral, e comparando com a avaliação convencional pelo Doppler pulsado do fluxo transmitral. Os resultados foram comparados em indivíduos com hipertensão arterial sistêmica (HAS) sem DRC. Métodos: Estudo transversal e observacional, incluindo 32 pacientes. Foram divididos 02 grupos: HAS sem DRC (grupo controle - Grupo 1) e HAS com DRC (Grupo 2). Em todos, foi realizado ecocardiograma completo (M-mode, 2D, Doppler e Doppler tecidual). Foram analisadas a relação E/E' e a velocidade de E' em ambos os grupos, entre outras variáveis. Resultados: O Grupo 2, quando avaliado pelas variáveis convencionais, apresentou diferença na velocidade de onda E' ao Doppler tecidual, no septo lateral, em comparação com o Grupo 1(8,78 mais ou menos 2,90 x 10,19 mais ou menos 2,37, p<0,05). Houve correlação significativa (p<0,001) no Grupo 2, entre as velocidades da...