RESUMO
Breast cancer is the most prevalent type of cancer in women worldwide. Within breast tumors, the basal-like subtype has the worst prognosis, prompting the need for new tools to understand, detect, and treat these tumors. Certain germline-restricted genes show aberrant expression in tumors and are known as Cancer/Testis genes; their misexpression has diagnostic and therapeutic applications. Here we designed a new bioinformatic approach to examine Cancer/Testis gene misexpression in breast tumors. We identify several new markers in Luminal and HER-2 positive tumors, some of which predict response to chemotherapy. We then use machine learning to identify the two Cancer/Testis genes most associated with basal-like breast tumors: HORMAD1 and CT83. We show that these genes are expressed by tumor cells and not by the microenvironment, and that they are not expressed by normal breast progenitors; in other words, their activation occurs de novo. We find these genes are epigenetically repressed by DNA methylation, and that their activation upon DNA demethylation is irreversible, providing a memory of past epigenetic disturbances. Simultaneous expression of both genes in breast cells in vitro has a synergistic effect that increases stemness and activates a transcriptional profile also observed in double-positive tumors. Therefore, we reveal a functional cooperation between Cancer/Testis genes in basal breast tumors; these findings have consequences for the understanding, diagnosis, and therapy of the breast tumors with the worst outcomes.
Assuntos
Neoplasias da Mama , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Biologia Computacional/métodos , Metilação de DNA , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Masculino , Epigênese GenéticaRESUMO
Histórico -O tratamento de pacientes com lombalgia crônica (LC) em muitos países, incluindo o Brasil, é um grande desafio no nível de atendimento primário e especializado. Além disso, as informações sobre epidemiologia e tratamento de pacientes com LC são escassas. O objetivo principal desta revisão semi-sistemática foi a construção de evidências locais sobre a prevalência e o padrão de tratamento da LC. Métodos: Esta revisão semi-sistemática utilizou Medline, Embase e Biosis via plataforma Ovid e recursos adicionais (Google, Google Scholar, Banco de dados de incidência e prevalência, Organização Mundial da Saúde, Ministério da Saúde do Brasil e informações anedóticas de especialistas locais) para identificar literatura relevante entre 2002 e 2020 para mapear a jornada do paciente. Artigos de texto completos e originais do Brasil em inglês contendo dados sobre pontos de contato predefinidos na jornada do paciente (conscientização, triagem, diagnóstico, tratamento, adesão e controle) foram selecionados. Os dados foram obtidos usando uma média simples ou ponderada, conforme aplicável para os componentes da jornada do paciente. Resultados: De 297 registros, incluindo os fornecidos por especialistas locais, oito estudos foram incluídos para análise. A conscientização da LC e da LC-NeP foi de 30,4% e 12%, respetivamente. De acordo com estudos publicados, a adesão e o controle dos sintomas dos pacientes foram estimados com percentual semelhante de 38% e 18%, respetivamente para a LC e a LC-NeP. A prevalência de LC-NeP (3,6%) foi menor que a de LC (20,6%). Com exceção de uma porcentagem comparável da população tratada, para LC (39,1%) e LC-NeP (38%), a porcentagem de pontos de contato restantes foi maior no caso de LC do que no LC-NeP, o que implicava uma melhora no trajeto do paciente para a LC. Conclusão: O estudo destaca a necessidade de melhorar os resultados dos pacientes em nível nacional, medindo esses pontos de contato da jornada do paciente. O resultado deste estudo baseado em evidências é importante para preencher a lacuna de conhecimento do paciente com LC. Portanto, recomenda-se garantir a educação médica contínua, a conscientização do paciente e a restruturação do sistema de saúde brasileiro, ao mesmo tempo em que adota novas práticas sobre o gerenciamento da dor. [au]
Background: Managing patients with chronic low back pain (CLBP) in many countries, including Brazil, is a major challenge at the primary and specialty care level. Moreover, the information about epidemiology and patient management with CLBP is sparse. The primary objective of this semi-systematic review was to build local evidence about the prevalence and management pattern of CLBP. Methods: This semi-systematic review used Medline, Embase, and Biosis via Ovid the platform and additional resources (Google, Google Scholar, Incidence and Prevalence Database, World Health Organization, Brazilian Ministry of Health, and anecdotal information from local experts) to identify relevant literature between 20022020 to map the patient journey. Original full-text articles from Brazil in English containing data on pre-defined patient journey touchpoints (awareness, screening, diagnosis, treatment, adherence, and control) were screened. Data were synthesized using a simple or weighted mean, as applicable for patient journey components. Results. Of 297 records including those provided by local experts, eight studies were included for analysis. Awareness of CLBP and CLBP-NeP was 30.4% and 12%, respectively. According to published studies, adherence and symptoms control of patients was estimated with a similar percentage of 38% and 18%, respectively for CLBP and CLBP-NeP. CLBP-NeP prevalence (3.6%) was lower than that of CLBP (20.6%). Except for a comparable percentage of the treated population, for CLBP (39.1%) and CLBP-NeP (38%), the percentage of remaining touchpoints are higher in the case of CLBP than in CLBP-NeP, implying an improved patient journey for CLBP. Conclusion: The study highlights the usefulness to improve patient outcomes at the national level by measuring these mapping patient journey touchpoints. The outcome of this evidence-based study was fruitful to bridges the know-do gap in CLBP patients. Therefore, it is recommended to ensure continuing medical education, patient awareness, and health system preparedness while embracing the emerging insights on pain management. [au]
RESUMO
ABSTRACT BACKGROUND AND OBJECTIVES: Neuropathic pain is present in 37 to 55% of cases of low back pain. Neuropathic pain is associated with more intense pain, more severe comorbidities and worse quality of life. In addition, costs are 67% higher when compared to other etiologies. The purpose of this article is to review this issue that has significant impact on quality of life. CONTENTS: Pain radiating to the lower limb may be radicular or referred pain. Radiation paths of lumbar roots and myofascial trigger points may be very similar, as the root of L5 and gluteus minimus trigger point. Thus, it is essential to use a tool for neuropathic pain assessment, such as: Douleur neuropathique 4 questionnaire, Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale e painDETECT. Clinical history and physical evaluation should formulate diagnostic hypotheses, which should be confirmed with complementary tests when necessary. Guidelines for the treatment of neuropathic pain consider as the first line drugs: anticonvulsants (gabapentin and pregabalin), tricyclic antidepressants (amitriptyline, imipramine, clomipramine and nortriptyline), selective serotonin and norepinephrine reuptake inhibitor (duloxetine and venlafaxine). Second line drugs are: 5% lidocaine patches in localized neuropathic pain and opioids. Surgical treatment of lumbar radiculopathy should be indicated when there is limited or low efficacy of multimodal conservative treatment. CONCLUSION: In low back pain, diagnosis of neuropathic component is critical. Multimodal treatment is imperative, as well as other strategies to rehabilitate and improve the patient's quality of life.
RESUMO JUSTIFICATIVA E OBJETIVOS A dor neuropática está presente em 37 a 55% dos casos de lombociatalgia, a dor neuropática está relacionada com dor mais intensa, comorbidades mais graves e piora da qualidade de vida. Além disso, os custos são 67% maiores quando comparada a outras etiologias. O objetivo deste artigo foi fazer uma revisão sobre este tema que causa impacto importante na qualidade de vida dos pacientes. CONTEÚDO A dor irradiada para o membro inferior pode ser de origem radicular ou referida. Os trajetos de irradiação para o membro inferior de raízes lombares e de pontos-gatilhos miofasciais podem ser muito parecidos, como a raiz L5 e ponto-gatilho do glúteo mínimo. Assim, é essencial a utilização de um instrumento para avaliação da dor neuropática, como: Douleur neuropathique 4 questionnaire, Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale e Pain DETECT. Os dados da anamnese e do exame físico devem formular hipóteses diagnósticas, que devem ser confirmadas com os exames complementares quando necessário. As diretrizes para o tratamento da dor neuropática consideram como primeira linha: anticonvulsivantes (gabapentina e pregabalina), antidepressivos tricíclicos (amitriptilina, imipramina, clomipramina e nortriptilina), inibidores seletivos da receptação de serotonina e de noradrenalina (duloxetina e venlafaxina). As medicações de segunda linha são: emplastros de lidocaína a 5% em dor neuropática localizada e os opioides. O tratamento cirúrgico da radiculopatia lombar deve ser indicado quando existir limitação ou baixa eficácia no tratamento conservador multimodal. CONCLUSÃO Na lombalgia o diagnóstico do componente neuropático é fundamental. O tratamento multimodal é imperativo, assim como outras estratégias para reabilitar e melhorar a qualidade de vida do paciente.
RESUMO
Pain is an unpleasant, sensitive and emotional experience associated with or described in terms of tissue lesion, and may be acute or chronic. It may also be classified as nociceptive, neuropathic or psychogenic. Nociceptive pain involves the transformation of environmental stimuli into action potentials carried to the central nervous system, where they are modulated and integrated up to final interpretation in the cerebral cortex. Neuropathic pain may arise as a consequence of the direct lesion of axons, or of an increase in the production of neurotrophic factors. Chronic pain is always associated with anxiety and some degree of depression. Drug therapy should be selected according to its efficacy; nonetheless, the professional should also consider the tolerability and adverse effects that may occur, for example, in elderly individuals. It is necessary to emphasize the safety-considering the possibility of drug interactions-and define the posology to promote better adherence. However, the treatment of neuropathic pain should not be limited to the use of analgesic drugs, which are just one among several options enabling patients to participate in bio-psycho-social rehabilitation programs.