Pediatric Drug Development: Reviewing Challenges and Opportunities by Tracking Innovative Therapies.

The paradigm of pediatric drug development has been evolving in a "carrot-and-stick"-based tactic to address population-specific issues. However, the off-label prescription of adult medicines to pediatric patients remains a feature of clinical practice, which may compromise the age-appropriate evaluation of treatments. Therefore, the United States and the European Pediatric Formulation Initiative have recommended applying nanotechnology-based delivery systems to tackle some of these challenges, particularly applying inorganic, polymeric, and lipid-based nanoparticles. Connected with these, advanced therapy medicinal products (ATMPs) have also been highlighted, with optimistic perspectives for the pediatric population. Despite the results achieved using these innovative therapies, a workforce that congregates pediatric patients and/or caregivers, healthcare stakeholders, drug developers, and physicians continues to be of utmost relevance to promote standardized guidelines for pediatric drug development, enabling a fast lab-to-clinical translation. Therefore, taking into consideration the significance of this topic, this work aims to compile the current landscape of pediatric drug development by (1) outlining the historic regulatory panorama, (2) summarizing the challenges in the development of pediatric drug formulation, and (3) delineating the advantages/disadvantages of using innovative approaches, such as nanomedicines and ATMPs in pediatrics. Moreover, some attention will be given to the role of pharmaceutical technologists and developers in conceiving pediatric medicines.

Monocytes in the Characterization of Pain in Palliative Patients with Severe Dementia-A Pilot Study.

In assessing and managing pain, when obtaining a self-report is impossible, therapeutic decision-making becomes more challenging. This study aimed to investigate whether monocytes and some membrane monocyte proteins, identified as a cluster of differentiation (CD), could be potential non-invasive peripheral biomarkers in identifying and characterizing pain in patients with severe dementia. We used 53 blood samples from non-oncological palliative patients, 44 patients with pain (38 of whom had dementia) and 0 without pain or dementia (controls). We evaluated the levels of monocytes and their subtypes, including classic, intermediate, and non-classic, and characterized the levels of specific phenotypic markers, namely CD11c, CD86, CD163, and CD206. We found that the relative concentrations of monocytes, particularly the percentage of classic monocytes, may be a helpful pain biomarker. Furthermore, the CD11c expression levels were significantly higher in patients with mixed pain, while CD163 and CD206 expression levels were significantly higher in patients with nociceptive pain. These findings suggest that the levels of monocytes, particularly the classic subtype, and their phenotype markers CD11c, CD163, and CD206 could serve as pain biomarkers in patients with severe dementia.

The Debate between the Human Microbiota and Immune System in Treating Aerodigestive and Digestive Tract Cancers: A Review.

The human microbiota comprises a group of microorganisms co-existing in the human body. Unbalanced microbiota homeostasis may impact metabolic and immune system regulation, shrinking the edge between health and disease. Recently, the microbiota has been considered a prominent extrinsic/intrinsic element of cancer development and a promising milestone in the modulation of conventional cancer treatments. Particularly, the oral cavity represents a yin-and-yang target site for microorganisms that can promote human health or contribute to oral cancer development, such as Fusobacterium nucleatum. Moreover, Helicobacter pylori has also been implicated in esophageal and stomach cancers, and decreased butyrate-producing bacteria, such as Lachnospiraceae spp. and Ruminococcaceae, have demonstrated a protective role in the development of colorectal cancer. Interestingly, prebiotics, e.g., polyphenols, probiotics (Faecalibacterium, Bifidobacterium, Lactobacillus, and Burkholderia), postbiotics (inosine, butyrate, and propionate), and innovative nanomedicines can modulate antitumor immunity, circumventing resistance to conventional treatments and could complement existing therapies. Therefore, this manuscript delivers a holistic perspective on the interaction between human microbiota and cancer development and treatment, particularly in aerodigestive and digestive cancers, focusing on applying prebiotics, probiotics, and nanomedicines to overcome some challenges in treating cancer.

Platelet Membrane Proteins as Pain Biomarkers in Patients with Severe Dementia.

Pain is one of the most frequent health problems, and its evaluation and therapeutic approach largely depend on patient self-report. When it is not possible to obtain a self-report, the therapeutic decision becomes more difficult and limited. This study aims to evaluate whether some membrane platelet proteins could be of value in pain characterization. To achieve this goal, we used 53 blood samples obtained from palliative patients, 44 with non-oncological pain and nine without pain. We observed in patients with pain a decrease in the percentage of platelets expressing CD36, CD49f, and CD61 and in the expression levels of CD49f and CD61 when compared with patients without pain. Besides that, an increase in the percentage of platelets expressing CD62p was observed in patients with pain. These results suggest that the levels of these platelet cluster differentiations (CDs) could have some value as pain biomarkers objectively since they are not dependent on the patient's participation. Likewise, CD40 seems to have some importance as a biomarker of moderate and/or severe pain. The identification of pain biomarkers such as CD40, CD49f, CD62p and CD61 can lead to an adjustment of the therapeutic strategy, contributing to a faster and more adequate control of pain and reduction in patient-associated suffering.

Opioids and constipation therapy in the last week of life: Their impact on patients, caregivers, and the location of death.

The use of opioids to control pain at the end of life may cause constipation, a symptom that can negatively influence the well-being of patients and caregivers. The main aim of this study was to evaluate the impact of constipation on symptomatic control and patients' overall quality of life at this stage. A particular focus was placed on opioids. We also intended to investigate whether constipation and caregiver fatigue is related to the place of death (hospital vs home). The approach of 121 patients followed in 2021 in their last week of life by a home team specialized in palliative care was analyzed in an observational, retrospective, non-interventional study. The patients were followed up for an average of 39.7 days. A total of 82.6% wished to die at home, which occurred in 74% of the cases. The constipation prevention protocol reduced constipation by 55.1%. It seems that morphine is more related with constipation and tapentadol seems to reduce constipation induced by opioids. Patients tended to die in hospitals when their caregivers were exhausted; however, it was not possible to determine a cutoff point using the Zarit scale, which was used to assess caregiver burden. Constipation in the last week of life does not seem to influence the well-being of patients or their caregivers significantly and the individualization of intensive treatment of constipation is needed. Different opioids have different probabilities of causing adverse effects such as constipation. Future special support mechanisms can be created and activated for the most tired caregivers to avoid exhaustion and promote death at home, if that is the patient's will.

Novel Non-Viral Vectors Based on Pluronic® F68PEI with Application in Oncology Field.

Copolymers composed of low-molecular-weight polyethylenimine (PEI) and amphiphilic Pluronics® are safe and efficient non-viral vectors for pDNA transfection. A variety of Pluronic® properties provides a base for tailoring transfection efficacy in combination with the unique biological activity of this polymer group. In this study, we describe the preparation of new copolymers based on hydrophilic Pluronic® F68 and PEI (F68PEI). F68PEI polyplexes obtained by doping with free F68 (1:2 and 1:5 w/w) allowed for fine-tuning of physicochemical properties and transfection activity, demonstrating improved in vitro transfection of the human bone osteosarcoma epithelial (U2OS) and oral squamous cell carcinoma (SCC-9) cells when compared to the parent formulation, F68PEI. Although all tested systems condensed pDNA at varying polymer/DNA charge ratios (N/P, 5/1−100/1), the addition of free F68 (1:5 w/w) resulted in the formation of smaller polyplexes (<200 nm). Analysis of polyplex properties by transmission electron microscopy and dynamic light scattering revealed varied polyplex morphology. Transfection potential was also found to be cell-dependent and significantly higher in SCC-9 cells compared to the control bPEI25k cells, as especially evident at higher N/P ratios (>25). The observed selectivity towards transfection of SSC-9 cells might represent a base for further optimization of a cell-specific transfection vehicle.

"Dignity as a Small Candle Flame That Doesn't Go Out!": An Interpretative Phenomenological Study with Patients Living with Advanced Chronic Obstructive Pulmonary Disease.

Long-term illness, such as chronic obstructive pulmonary disease (COPD), can expose people to existential suffering that threatens their dignity. This qualitative study explored the lived experiences of patients with advanced COPD in relation to dignity. An interpretative phenomenological approach based on lifeworld existentials was conducted to explore and understand the world of the lived experience. Twenty individuals with advanced COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stages III and IV) were selected using a purposive sampling strategy. In-depth interviews were used to collect data, which were then analysed using Van Manen's phenomenology of practice. The existential experience of dignity was understood, in essence, as "a small candle flame that doesn't go out!". Four intertwined constituents illuminated the phenomenon: "Lived body-balancing between sick body and willingness to continue"; "Lived relations-balancing between self-control and belongingness"; "Lived Time-balancing between past, present and a limited future"; and "Lived space-balancing between safe places and non-compassionate places". This study explains how existential life phenomena are experienced during the final phases of the COPD trajectory and provides ethical awareness of how dignity is lived. More research is needed to investigate innovative approaches to manage complex care in advanced COPD, in order to assist patients in discovering their inner resources to develop and promote dignity.

Apoptosis and (in) Pain-Potential Clinical Implications.

The deregulation of apoptosis is involved in the development of several pathologies, and recent evidence suggests that apoptosis may be involved in chronic pain, namely in neuropathic pain. Neuropathic pain is a chronic pain state caused by primary damage or dysfunction of the nervous system; however, the details of the molecular mechanisms have not yet been fully elucidated. Recently, it was found that nerve endings contain transient receptor potential (TRP) channels that sense and detect signals released by injured tissues and respond to these damage signals. TRP channels are similar to the voltage-gated potassium channels or nucleotide-gated channels that participate in calcium and magnesium homeostasis. TRP channels allowing calcium to penetrate into nerve terminals can activate apoptosis, leading to nerve terminal destruction. Further, some TRPs are activated by acid and reactive oxygen species (ROS). ROS are mainly produced in the mitochondrial respiratory chain, and an increase in ROS production and/or a decrease in the antioxidant network may induce oxidative stress (OS). Depending on the OS levels, they can promote cellular proliferation and/or cell degeneration or death. Previous studies have indicated that proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), play an important role in the peripheral mediation of neuropathic pain. This article aims to perform a review of the involvement of apoptosis in pain, particularly the role of OS and neuroinflammation, and the clinical relevance of this knowledge. The potential discovery of new biomarkers and therapeutic targets can result in the development of more effective and targeted drugs to treat chronic pain, namely neuropathic pain. Highlights: Oxidative stress and neuroinflammation can activate cell signaling pathways that can lead to nerve terminal destruction by apoptosis. These could constitute potential new pain biomarkers and targets for therapy in neuropathic pain.

Where Is Nano Today and Where Is It Headed? A Review of Nanomedicine and the Dilemma of Nanotoxicology.

Worldwide nanotechnology development and application have fueled many scientific advances, but technophilic expectations and technophobic demands must be counterbalanced in parallel. Some of the burning issues today are the following: (1) Where is nano today? (2) How good are the communication and investment networks between academia/research and governments? (3) Is there any spotlight application for nanotechnology? Nanomedicine is a particular arm of nanotechnology within the healthcare landscape, focused on diagnosis, treatment, and monitoring of emerging (such as coronavirus disease 2019, COVID-19) and contemporary (including diabetes, cardiovascular diseases, neurodegenerative disorders, and cancer) diseases. However, it may only represent the bright side of the coin. In fact, in the recent past, the concept of nanotoxicology has emerged to address the dark shadows of nanomedicine. The nanomedicine field requires more nanotoxicological studies to identify undesirable effects and guarantee safety. Here, we provide an overall perspective on nanomedicine and nanotoxicology as central pieces of the giant puzzle of nanotechnology. First, the impact of nanotechnology on education and research is highlighted, followed by market trends and scientific output tendencies. In the next section, the nanomedicine and nanotoxicology dilemma is addressed through the interplay of in silico, in vitro, and in vivo models with the support of omics and microfluidic approaches. Lastly, a reflection on the regulatory issues and clinical trials is provided. Finally, some conclusions and future perspectives are proposed for a clearer and safer translation of nanomedicines from the bench to the bedside.

Prescription trends at the end of life in a palliative care unit: observational study.

BACKGROUND: Symptomatic control is essential in palliative care, particularly in end-of-life, in which the pathophysiological changes that characterize this last phase of life strengthen the need to carry out an early therapeutic review. Hence, we aim to evaluate the prescribing pattern at a palliative care unit at two different time points: on admission and the day of the patient's death. METHODS: Quantitative, analytic, longitudinal, retrospective and observational study. Participants were adult patients who were admitted and died in a palliative care unit, in Portugal. Sociodemographic, clinical and pharmacological data were collected, including frequencies and routes of administration of schedule prescribed drugs and rescue drugs, from the day of admission until the day of death. RESULTS: 115 patients were included with an average age of 70.0 ± 12.9 years old, 53.9 were male, mostly referred by the Hospital Palliative Care Support Teams. The most common pathology was cancer, mainly in advanced stage. On admission, the median scheduled prescription was seven and "as needed" was three drugs. On the day of death, a decrease of prescriptions was observed. Opioids were always the most prescribed drugs. Near death, there was a higher tendency to prescribe butylscopolamine, midazolam, diazepam and levomepromazine. The most frequent route of drug administration was oral on admission and subcutaneous on the day of death. CONCLUSIONS: Polypharmacy is a reality in palliative care despite specialist palliative care teams. A reduction of prescribed drugs was verified, essentially due less comorbidity-oriented drugs. Further studies are required to analyse the importance of Hospital Palliative Care Support Teams.

Non-steroidal anti-inflammatory drugs (NSAIDs), pain and aging: Adjusting prescription to patient features.

A narrative review of papers published from January 2011 to December 2021, after a literature search in selected databases using the terms "pharmacokinetics", "ibuprofen", "diclofenac", "acemetacin", "naproxen", "etodolac" and "etoricoxib" was performed. From 828 articles identified, only eight met the inclusion criteria. Selective COX-2 inhibitors are associated with higher cardiovascular risk, while non-selective COX inhibitors are associated with higher gastrointestinal risk. NSAIDs with lower renal excretion with phase 2 metabolism are less likely to induce adverse effects and drug-drug interactions. Patients with frequent NSAID use needs, such as elderly patients and patients with cardiovascular disease or impaired renal function, will benefit from lower renal excretion (e.g. acemethacin, diclofenac, and etodolac) (level of evidence 3). Polymedicated patients, elderly patients, and patients with chronic alcohol abuse will be at a lower risk for adverse effects with NSAIDs that undergo phase 2 liver biotransformation, namely, acemethacin and diclofenac (level of evidence 3). Young patients, patients dealing with acute pain, or with active and/or chronic symptomatic gastritis, selective COX-2 inhibitors (celecoxib or etoricoxib) may be a better option (level of evidence 2). Knowing the individual characteristics of the patients, combined with knowledge on basic pharmacology, offers greater safety and better adherence to therapy. PERSPECTIVE: Although there are several NSAIDs options to treat pain, physicians usually take special care to its prescription regarding cardiovascular and gastrointestinal side effects, despite the age of the patient. In this paper, based on the best evidence, the authors present a review of the safest NSAIDs to use in the elderly.

The Portuguese Performance Assessment of Self-Care Skills Measure: Validity and Reliability.

Performance Assessment of Self-Care Skills (PASS) is a performance-based scale developed in the United States. Because of cultural differences, a Portuguese version was developed, then validated in the Portuguese population and tested ensuring reliability. The objective of this study was to create and test psychometric properties of a Portuguese version of PASS. A linguistic validation on older adults with physical/cognitive disabilities enabled us to validate P-PASS. Some original tasks were changed. Data were analyzed by PASS constructs (independence-safety adequacy), age, and gender. Construct validity (known-group analyses, factor analyses), with 98 individuals yielded excellent results. Reliability between two observers for 30 participants yielded almost perfect agreement for all three constructs. Independence scores were highest, followed by safety and adequacy. Men presented greater independence, as well as participants <60 years. We obtained results comparable with the original version. Conclusion. P-PASS is valid and reliable for the Portuguese population, enabling effective assessment of function and measurement of health outcomes.

[Knowledge of Palliative Care Among Medical Students of the University of Coimbra]. / Conhecimento sobre Cuidados Paliativos em Estudantes de Medicina da Universidade de Coimbra.

INTRODUCTION: The need for palliative care is increasing. Future doctors must be prepared for this, so it is essential to develop skills during their undergraduate studies. The aim of this study was to evaluate the knowledge of medical students at the Faculty of Medicine of the University of Coimbra regarding palliative care. MATERIAL AND METHODS: An observational and cross-sectional study was performed through the application of a questionnaire answered by fifth year medical students. The collected data were analyzed using IBM® SPSS® Statistics, version 20 for Windows®. RESULTS: All 186 students surveyed were aware of what palliative care is and recognized its importance. From the total, 52.7% of students reported they knew what an informal caregiver is and 96.8% disagreed that palliative care is only provided at the end of life; 88.2% have never had any training on how to deal with palliative care patients. Only 57.5% of students reported that they had been trained to communicate 'bad news', but 70.4% assumed that they were not able to communicate such bad news. On the other hand, 89.8% reported their inability to take care of palliative patients and 98.4% admitted that they needed more training in this area. DISCUSSION: With the increasing number of patients who require palliative care, there is the need to investigate whether medical students are being adequately prepared to care for these patients and assess their knowledge level in this context. CONCLUSION: Fifth-year medical students know what palliative care is and consider it important. However, they do not feel adequately trained and ready to take care of patients who need palliative care. It is essential to reflect on how physicians should be trained and to reconsider the medical syllabus, given the present lack of undergraduate medical training in palliative care.

Introdução: Cada vez mais doentes necessitam de cuidados paliativos. Os futuros médicos têm de estar preparados para esta realidade, pelo que é fundamental que desenvolvam competências ao longo do curso. Este estudo teve como objetivo avaliar o conhecimento sobre cuidados paliativos em estudantes de Medicina da Faculdade de Medicina da Universidade de Coimbra.Material e Métodos: Foi realizado um estudo observacional e transversal, através da aplicação de um questionário a estudantes de Medicina, do quinto ano. Os dados recolhidos foram analisados no IBM® SPSS® Statistics, versão 20 para Windows®.Resultados: Todos os 186 estudantes inquiridos mostraram saber o que são cuidados paliativos e reconheceram a sua importância. Do total, 52,7% afirmaram saber o que é um cuidador informal e 96,8% discordaram que a prestação de cuidados paliativos apenas acontece em fim de vida; 88,2% não receberam formação para lidar com doentes terminais ou dependentes de cuidados permanentes. Somente 57,5% dizem ter recebido formação para comunicar 'más notícias', mas 70,4% assumiram que não eram capazes de o fazer. Por outro lado, 89,8% revelaram não se sentir capacitados para cuidarem de doentes em cuidados paliativos e 98,4% manifestaram necessidade de mais formação nesta área.Discussão: Com o número crescente de doentes a precisar de cuidados paliativos surge a necessidade de investigar se os estudantes de medicina estão a ser adequadamente preparados para cuidarem destes doentes e avaliar o seu grau de conhecimento no âmbito dos cuidados paliativos.Conclusão: Os estudantes do quinto ano de Medicina sabem o que são cuidados paliativos e consideram-nos importantes. No entanto, não se sentem adequadamente preparados para cuidarem de doentes que precisam destes cuidados. É essencial refletir sobre como deverão ser formados os médicos e ponderar o plano de estudos do ensino médico, dada a falta de formação dos estudantes de medicina em cuidados paliativos.

Implementation of the Humanitude Care Methodology: contribution to the quality of health care.

OBJECTIVE: to evaluate the contribution of the implementation of the Humanitude Care Methodology to the quality of health care in a Continuing Care Unit. METHOD: an action-research study with a non-probability convenience sampling, involving 34 health professionals from one unit in Portugal. Data was collected through a questionnaire and an observation worksheet for the Structured Sequence of Humanitude Care Procedures. We used data content analysis with the Statistical Package for Social Science, version 17.0. RESULTS: health professionals demonstrated difficulties to provide care for people who are agitated, confused, disoriented, aggressive and who refuse care, and to communicate with patients who do not communicate verbally. The professionals valued the accomplishment of the stages of the observation worksheet. There were discrepancies between the perception of accomplishment and the actual practice. Throughout the implementation of the methodology, there was an increase in the practical application of the procedures, with positive repercussion for the patients and for the professionals. CONCLUSION: the results allowed to perceive the contribution of the process of implementation of the methodology, through the positive transformations in health care delivery.

Implementation of the Humanitude Care Methodology: contribution to the quality of health care / Implementação da Metodologia de Cuidado Humanitude: contribuição para a qualidade da assistência à saúde / Implementación de la Metodología de Cuidado Humanitud: contribución a la calidad de la asistencia a la salud

ABSTRACT Objective: to evaluate the contribution of the implementation of the Humanitude Care Methodology to the quality of health care in a Continuing Care Unit. Method: an action-research study with a non-probability convenience sampling, involving 34 health professionals from one unit in Portugal. Data was collected through a questionnaire and an observation worksheet for the Structured Sequence of Humanitude Care Procedures. We used data content analysis with the Statistical Package for Social Science, version 17.0. Results: health professionals demonstrated difficulties to provide care for people who are agitated, confused, disoriented, aggressive and who refuse care, and to communicate with patients who do not communicate verbally. The professionals valued the accomplishment of the stages of the observation worksheet. There were discrepancies between the perception of accomplishment and the actual practice. Throughout the implementation of the methodology, there was an increase in the practical application of the procedures, with positive repercussion for the patients and for the professionals. Conclusion: the results allowed to perceive the contribution of the process of implementation of the methodology, through the positive transformations in health care delivery.

RESUMO Objetivo: avaliar a contribuição da implementação da Metodologia de Cuidado Humanitude para a qualidade da assistência à saúde em uma Unidade de Cuidados Continuados. Método: estudo de investigação-ação, que utilizou processo de amostragem não probabilística por conveniência, envolvendo 34 profissionais de saúde de uma unidade, em Portugal. A coleta de dados foi realizada por meio de questionário e planilha de observação de Sequência Estruturada de Procedimentos Cuidativos Humanitude. Utilizou-se análise de conteúdo dos dados e tratamento com Statistical Package for Social Science, versão 17.0. Resultados: os profissionais de saúde manifestaram dificuldades na prestação de cuidados de pessoas agitadas, confusas, desorientadas, agressivas e que recusavam os cuidados e, ainda, na comunicação com pacientes que não se expressavam verbalmente. Os profissionais valorizaram a realização das etapas da planilha de observação e verificaram discrepâncias entre a percepção de realização e a prática realmente efetivada. Ao longo da implementação da metodologia, observou-se aumento da aplicação prática dos procedimentos, repercutindo em ganhos para as pessoas cuidadas e para os profissionais. Conclusões: os resultados permitiram perceber a contribuição do processo de implementação da metodologia na transformação positiva da prestação de cuidados de saúde.

RESUMEN Objetivo: evaluar la contribución de la implementación de la Metodología de Cuidado Humanitud para la calidad de la asistencia a la salud en una Unidad de Cuidados Continuos. Método: estudio de investigación y acción, mediante un proceso de muestreo no probabilístico por conveniencia, con la participación de 34 profesionales de la salud, desde una unidad, en Portugal. Recolección de datos realizada por medio de un cuestionario y una ficha de observación de Secuencia Estructurada de Procedimientos Cuidadativos Humanitud. Utilizado análisis de contenido de los datos y tratamiento con Statistical Package for Social Science, versión 17.0. Resultados: los profesionales de la salud manifestaron dificultades en la prestación de cuidados de personas agitadas, confusas, desorientadas, agresivas y que rechazan los cuidados y aún, de comunicarse con pacientes que no se comunican verbalmente. Los profesionales valoraron la realización de las etapas de la ficha de observación y verificaron discrepancias entre la percepción de realización y la práctica, realmente, efectiva. A lo largo de la implementación de la metodología, se observó un aumento de la aplicación práctica de los procedimientos, repercutiendo en beneficios para las personas cuidadas y para los profesionales. Conclusiones: los resultados permitieron percibir la contribución del proceso de implementación de la metodología, en la transformación positiva de la prestación de atención de salud.

Epithelial-mesenchymal transition and microRNAs: Challenges and future perspectives in oral cancer.

BACKGROUND: Head and neck cancer is the sixth most common cancer worldwide, with oral squamous cell carcinoma (OSCC) being the most representative type. OSCC is a public health problem with high morbidity and poor survival rate. Epithelial-mesenchymal transition is emerging as a hallmark in OSCC. METHODS: In this study, we described the role of microRNAs in epithelial-mesenchymal transition regulation in OSCC based on a PubMed search using articles published in English between January 1, 2010, and January 31, 2018. RESULTS: MicroRNA's regulatory networks seem to be a hallmark of epithelial-mesenchymal transition in OSCC pathophysiology becoming a growing challenge to design new studies and strategies from biology to clinical applications. CONCLUSION: Therefore, we propose that targeting therapies to epithelial-mesenchymal transition-type cells, namely, coordinating microRNAs and/or hydrophobic drugs, such as conventional therapy, could be a promising strategy to improve the outcomes of patients with OSCC.

[Measuring Instruments of the Quality of Life Pediatric Palliative Care]. / Instrumentos de Medição da Qualidade de Vida em Idade Pediátrica em Cuidados Paliativos.

INTRODUCTION: Palliative care is closely linked to the concept of quality of life. In this work we will focus our interest on the need to assess quality of life in oncologic paediatric palliative care. OBJECTIVE: To describe/compare instruments for measuring quality of life in Oncologic paediatric palliative care. MATERIAL AND METHODS: A literature review of the sever a instruments for measuring quality of life of children under palliative care, in English and Portuguese, between 2000 and 2013, was carried out in the recognized databases for this purpose. RESULTS: We found fifteen measuring instruments: 10 of them were generic and 5 specific. For each instrument the country of origin, the target age group, fill manner, number of evaluated dimensions, description of dimensions, and number of questions, psychometric properties and validation for the Portuguese language were identified. DISCUSSION: There has been a growing concern in measuring quality of life in pediatric age. Most measuring instruments were designed, in the United States, after 1994, coinciding with the World Health Organization definition of quality of life. As regards to age, most of the instruments were developed for children aged eight or more years old and there is no one to be answered only by the child. We can see that the majority of measuring instruments, namely the most current, seeking to involve the child in evaluating his/her own health related quality of life through auto-population (n = 10). However, there is still a substantial dependence on parents for the measurement of health related quality of life of their children, despite studies demonstrates differences between the child and parents, on perception of health related quality of life. But, since many children are not able to provide data on health related quality of life either due to their age or because they are ill or with functional incapacity, the only possibility to get information about the health related quality of life of these children is to appeal to parents, who are asked to reflect on the lack of their child, or teenager. Thus full completion by parents of some measuring instruments may be justified. In Pediatrics measuring instruments of health related quality of life are multidimensional, often intended to measure the subjective point of view in relation to the impact of the disease and the treatment have on the physical, psychological and social well-being. Thus, the wide range of dimensions, the differences in number of dimensions and the number of questions between the various instruments tend to reflect the different stages of psychomotor development of the target population. CONCLUSION: The most commonly measure dimensions were physical ability, emotional/psychological impact, social and at school impact, followed by pain and discomfort and activity level. The majority of instruments are designed for children aged over 8 years. A large number of the questionnaires are self-completion questionnaires. Others can be completed by parents. Most of the instruments tested their internal coherence (n = 9) and, in a small number, the test-retest reproducibility (n = 7) and agreement among observers(n = 2). Most of the questionnaires reported their content validity (n = 10) and construct validity (n = 9), few have examined the validity of criterion (n = 2). Considering the examined instruments, six questionnaires are validated for the Portuguese population (five generic and one specific for oncologic disease).

Introdução: Os cuidados paliativos estão intimamente ligados ao conceito de qualidade de vida. Neste trabalho, focaremos a nossa atenção na necessidade de avaliar a qualidade de vida em cuidados paliativos pediátricos oncológicos.Objetivo: Descrever/comparar os instrumentos de medição da qualidade de vida em cuidados paliativos pediátricos oncológicos. Material e Métodos: Pesquisa da bibliográfica dos vários instrumentos de medição da qualidade de vida das crianças em cuidados paliativos, em inglês e português, entre 2000 e 2013, nas bases de dados reconhecidas para este efeito. Resultados: Encontraram-se quinze instrumentos de medição: 10 genéricos e cinco específicos. Identificou-se, para cada instrumento de medição, país de origem, faixa etária para que se encontra direcionado, modalidade de preenchimento, número de dimensões avaliadas, descrição das dimensões, número de perguntas, propriedades psicométricas e validação para português. Discussão: Verifica-se que tem havido uma crescente preocupação em medir a qualidade de vida em idade pediátrica e que a maioria dos instrumentos de medição foi desenhada, nos Estados Unidos, após 1994, coincidindo temporalmente com a definição de qualidade de vida da Organização Mundial de Saúde. Relativamente à faixa etária, a maioria dos instrumentos foi desenvolvida para crianças com idade igual ou superior a oito anos não existindo nenhum para ser respondido apenas pela criança. Podemos verificar que a maioria dos instrumentos de medição, sobretudo os mais atuais, procuram envolver a criança na avaliação da sua própria qualidadede vida relacionada com a saúde através do autopreenchimento (n = 10). Porém, há ainda uma dependência substancial dos pais para a medição da qualidade de vida relacionada com a saúde dos seus filhos, apesar dos estudos que demonstram diferenças na perceção de qualidade de vida relacionada com a saúde entre a criança e os pais. Mas como muitas crianças não têm capacidade de fornecer dados sobre a sua qualidade de vida relacionada com a saúde, quer devido à idade quer porque estão doentes ou com incapacidade funcional, a única possibilidade de obter informação sobre a qualidade de vida relacionada com a saúde destas criançasé o recurso aos pais, a quem é pedido que reflitam sobre a perceção da sua criança, ou adolescente, podendo, assim, justificar-se o preenchimento integral pelos pais de alguns instrumentos de medição. Os instrumentos de medição de qualidade de vida relacionada com a saúde em pediatria são geralmente multidimensionais, destinados a medir o ponto de vista subjetivo em relação ao impacto que a doença e o tratamento têm sobre o bem-estar físico, psicológico e social. Assim, a grande variedade de dimensões, as diferenças no número de dimensões e no número de perguntas entre os diversos instrumentos tendem a refletir os diferentes estádios de desenvolvimento psicomotor da população-alvo. Conclusão: As dimensões mais comummente medidas foram a capacidade física, impacto emocional/psicológico, impacto social e na escola, seguidas da dor e desconforto e nível de atividade. A maioria dos instrumentos é desenvolvida para crianças com idade igual/superior a oito anos. Grande parte dos questionários é de autopreenchimento. Outros podem ser preenchidos/respondidos pelos pais. A maioria dos instrumentos testaram a sua coerência interna (n = 9) e, em menor número, a reprodutibilidade teste-reteste (n = 7) e concordância entre observadores (n = 2). A maioria dos questionários relatou a sua validade de conteúdo (n = 10) e validade de construção (n = 9), poucos analisaram a validade de critério (n = 2). Dos instrumentos analisados, seis questionários estão validados para a população portuguesa (cinco genéricos e um específico de doença oncológica).

Farnesyltransferase inhibitors: molecular evidence of therapeutic efficacy in acute lymphoblastic leukemia through cyclin D1 inhibition.

BACKGROUND: Farnesyltransferase inhibitors have the ability to interfere with various intracellular pathways, reducing cell survival and proliferation. They have become an attractive tool for cancer therapy, namely acute leukemias. In this work, we have studied the efficacy of α-hydroxyfarnesylphosphonic acid (α-HFPA) in CEM (acute T-cell lymphoblastic leukemia) in culture. MATERIALS AND METHODS: CEM cells were incubated with α-HFPA at different concentrations; viability and proliferation studies were performed using the trypan blue exclusion assay and cell morphological analysis. Expression of lamin A/C, cyclin D1 and BAD were analyzed by flow cytometry. RESULTS: Our results show that α-HFPA significantly decreases Farnesyltransferase activity, reduces cell proliferation and induces cell death through apoptosis in CEM cells, which is correlated with a reduction of cyclin D1 levels. CONCLUSION: This study suggests that α-HFPA blocks the cell cycle and induces cell death through apoptosis in CEM cells and may be a therapeutic approach in ALL.

[Experimental models in oncology: contribution of cell culture on understanding the biology of cancer]. / Modelos experimentais em oncologia: O contributo da cultura de células para o conhecimento da biologia do cancro.

In the beginning of the 20th century, tissue culture was started with the aim of studying the behaviour of animal cells in normal and stress conditions. The cell study at molecular level depends on their capacity of growing and how they can be manipulated in laboratory. In vitro cell culture allows us the possibility of studying biological key processes, such as growth, differentiation and cell death, and also to do genetic manipulations essential to the knowledge of structure and genes function. Human stem cells culture provides strategies to circumvent other models' deficiencies. It seems that cancer stem cells remain quiescent until activation by appropriated micro-environmental stimulation. Several studies reveal that different cancer types could be due to stem cell malignant transformations. Removal of these cells is essential to the development of more effective cancer therapies for advanced disease. On the other hand, dendritic cells modified in culture may be used as a therapeutic vaccine in order to induce tumour withdraw.

CD26/DPPIV expression and 8-azaguanine response in T-acute lymphoblastic leukaemia cell lines in culture.

Dipeptidyl peptidase IV, a cell membrane surface protease also known as CD26 (CD26/DPPIV), is known to play multiple functions in human organism, where it is largely expressed, for instance, in the development of human cancer and metastasis as well as in chemotherapy response. The objective of this work was to study the CD26 membrane expression and DPPIV activity in T-acute leukaemia cell lines (CEM and MOLT3) in culture, in order to observe the modification of its expression under the 8-azaguanine treatment. Cell line samples were incubated, some without different azaguanine concentration and others with, ranging from 10 to 100muM. Cell surface CD26 expression has been identified by flow cytometry and DPPIV activity, in cultured medium, was fluorimetrically measured. Results we have observed showed that 8-azaguanine induced a decrease in cell viability in a dose, time and cell type dependent manner with MOLT3 cells being the most sensitive to 8-azaguanine citotoxic effects (24h IC50: +/-10muM) when compared with CEM cells (24h IC50: +/-100muM). In the same experimental conditions, MOLT3 cell treated with 8-azaguanine shows an increase in CD26 expression (MIF) compared with that of CEM cell submitted to the same conditions (65.4+/-1.3 versus 18.7+/-1.7). DPPIV activity in culture medium supernatant of CEM versus MOLT3 controls cells (1.91+/-0.43 versus 2.06+/-0.50) and of CEM versus MOLT3 treated cells (2.10+/-0.16 versus 1.89+/-0.04) did not show a significant difference. These preliminary results suggest that 8-azaguanine stimulates CD26 expression which may be related to cellular sensitivity to 8-azaguanine.