ABSTRACT
Target-protein degradation is an emerging field in drug discovery and development. In particular, the substrate-receptor proteins of the cullin-ubiquitin ligase system play a key role in selective protein degradation, which is an essential component of the anti-myeloma activity of immunomodulatory drugs (IMiDs), such as lenalidomide. Here, we demonstrate that a series of anticancer sulfonamides NSC 719239 (E7820), indisulam, and NSC 339004 (chloroquinoxaline sulfonamide, CQS) induce proteasomal degradation of the U2AF-related splicing factor coactivator of activating protein-1 and estrogen receptors (CAPERα) via CRL4DCAF15 mediated ubiquitination in human cancer cell lines. Both CRISPR-Cas9-based knockout of DCAF15 and a single amino acid substitution of CAPERα conferred resistance against sulfonamide-induced CAPERα degradation and cell-growth inhibition. Thus, these sulfonamides represent selective chemical probes for disrupting CAPERα function and designate DCAFs as promising drug targets for promoting selective protein degradation in cancer therapy.
Subject(s)
Indoles/pharmacology , Nuclear Proteins/metabolism , RNA Splicing , RNA-Binding Proteins/metabolism , Sulfonamides/metabolism , Antineoplastic Agents/pharmacology , Gene Knockdown Techniques , Humans , Nuclear Proteins/chemistry , Nuclear Proteins/genetics , Proteolysis/drug effects , RNA-Binding Proteins/chemistry , RNA-Binding Proteins/genetics , Sulfonamides/pharmacologyABSTRACT
Pancreatic cancer, the fourth leading cause of cancer death in the United States, has a negative prognosis because metastasis occurs before symptoms manifest. Leiodermatolide, a polyketide macrolide with antimitotic activity isolated from a deep water sponge of the genus Leiodermatium, exhibits potent and selective cytotoxicity toward the pancreatic cancer cell lines AsPC-1, PANC-1, BxPC-3, and MIA PaCa-2, and potent cytotoxicity against skin, breast and colon cancer cell lines. Induction of apoptosis by leiodermatolide was confirmed in the AsPC-1, BxPC-3 and MIA PaCa-2 cells. Leiodermatolide induces cell cycle arrest but has no effects on in vitro polymerization or depolymerization of tubulin alone, while it enhances polymerization of tubulin containing microtubule associated proteins (MAPs). Observations through confocal microscopy show that leiodermatolide, at low concentrations, causes minimal effects on polymerization or depolymerization of the microtubule network in interphase cells, but disruption of spindle formation in mitotic cells. At higher concentrations, depolymerization of the microtubule network is observed. Visualization of the growing microtubule in HeLa cells expressing GFP-tagged plus end binding protein EB-1 showed that leiodermatolide stopped the polymerization of tubulin. These results suggest that leiodermatolide may affect tubulin dynamics without directly interacting with tubulin and hint at a unique mechanism of action. In a mouse model of metastatic pancreatic cancer, leiodermatolide exhibited significant tumor reduction when compared to gemcitabine and controls. The antitumor activities of leiodermatolide, as well as the proven utility of antimitotic compounds against cancer, make leiodermatolide an interesting compound with potential chemotherapeutic effects that may merit further research.
Subject(s)
Antineoplastic Agents/administration & dosage , Macrolides/administration & dosage , Microtubules/drug effects , Pancreatic Neoplasms/drug therapy , Tubulin Modulators/administration & dosage , Animals , Antineoplastic Agents/pharmacology , Apoptosis , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Gene Expression Regulation, Neoplastic/drug effects , HeLa Cells , Humans , Macrolides/pharmacology , Mice , Microtubule-Associated Proteins/metabolism , Neoplasm Metastasis , Pancreatic Neoplasms/metabolism , Tubulin Modulators/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
A 68-year-old woman presented dizziness whenever she put her finger into the right ear and also complained of water-streaming tinnitus, which indicated she would have been suffering from perilymph fistula. An exploratory tympanotomy was conducted. Leakage of perilymph from the round window was suspected, although the cochlin-tomoprotein (CTP) results were negative. After the procedure, the patient's finger-induced dizziness, tinnitus, and vertigo spells disappeared completely. However, her dizzy symptom did not improve. The patient also complained of general fatigue, weight loss, and insomnia, which led us to suspect comorbid depression. Antidepressants and vestibular rehabilitation treatment resulted in a significant improvement in her dizziness. Although it is not apparent whether the patient had a perilymph fistula, this case demonstrates the importance of evaluating not only physical symptoms but also psychological comorbidity, especially when the physical symptoms are intractable despite treatment.
Subject(s)
Aged , Female , Humans , Antidepressive Agents , Comorbidity , Depression , Dizziness , Ear , Fatigue , Fingers , Fistula , Perilymph , Rehabilitation , Sleep Initiation and Maintenance Disorders , Tinnitus , Vertigo , Weight LossABSTRACT
OBJECTIVE: To demonstrate the utilization of a clinical improvement program in stable coronary artery disease patients to increase the evidence-proven treatment utilization, and to describe the ongoing clinical practice and lifestyle change counseling. METHODS: Cross-sectional study followed by a longitudinal component in which the tools utilization to improve clinical practice was assessed by means of additional cross-sectional data collection. 710 consecutive patients were included (Phase 1). After tools implementation, within 6 months period, 705 patients were included (Phase 2) for comparative analysis. Randomly, 318 patients from Phase 1 were selected, 6-12 months after the first evaluation (Phase 3). RESULTS: Phase 1 to Phase 2: there were improvement on smoking cessation (P=0.019), dyslipidemia (P<0.001), hypertension and physical activity (P<0.001). There was significant difference on angiotensin converting enzyme inhibitors - ACEI (67.2% vs. 56.8%, P<0.001); angiotensin II receptor blockers - ARB II (25.4% vs. 32.9%, P=0.002) and beta-blocker (88.7% vs. 91.9%, P=0.047). Phase 1 to Phase 3: there was both weight (P=0.044), and blood pressure reduction (P<0.001). There was statistical significant difference on ACEI (64.8% vs. 61.6%, P=0.011) and ARB II (27.0% vs. 31.3%, P=0.035). CONCLUSION: There was no significant change on the evidence-based pharmacological treatment utilization between pre and post-intervention phases; there was significant improvement concerning smoking and physical activity in phase 2; substantial improvement on blood pressure levels in both comparisons (Phase 1 to 2 and Phase 1 to 3). The inclusion of a case-manager for the process management was crucial for program efficacy. Comprehensive programs for clinical practice should be pursued for longer follow-up period.
Subject(s)
Coronary Disease/prevention & control , Guideline Adherence , Life Style , Secondary Prevention/methods , Adult , Aged , Aged, 80 and over , Cardiovascular Agents/therapeutic use , Coronary Disease/etiology , Cross-Sectional Studies , Dyslipidemias/therapy , Female , Humans , Hypertension/drug therapy , Male , Middle Aged , Reproducibility of Results , Risk Factors , Smoking Cessation , Time Factors , Treatment OutcomeABSTRACT
OBJETIVO: Demonstrar a eficácia de um programa de otimização da prática clínica em pacientes com doença arterial coronária para prescrição de medicamentos e documentar a prática clínica vigente quanto aos medicamentos e medidas para a mudança do estilo de vida. MÉTODOS: Estudo de corte transversal, seguido de componente longitudinal. Foram incluídos 710 pacientes consecutivos (Fase 1). Após aplicação de ferramentas para melhoria da prática clínica, foram incluídos, após seis meses, 705 pacientes com coleta dos mesmos dados (Fase 2). Foram selecionados aleatoriamente, a partir do primeiro grupo, 318 prontuários para comparação desses mesmos pacientes (Fase 3). RESULTADOS: Comparação entre as Fases 1 e 2: melhora em relação a tabagismo (P=0,019), dislipidemia (P<0,001), hipertensão arterial e atividade física regular (P<0,001). Diferença significativa para inibidores da enzima de conversão da angiotensina - IECA (67,2% vs. 56,8%, P<0,001); antagonistas do receptor da angiotensina II - ARA II (25,4% vs. 32,9%, P=0,002) e betabloqueador (88,7% vs. 91,9%, P=0,047). Comparação entre as Fases 1 e 3: houve redução do peso (P=0,044) e pressão arterial (P<0,001). Em relação à prescrição de medicamentos recomendados, diferença para IECA (64,8% vs. 61,6%, P=0,011) e ARA II (27,0% vs. 31,3%, P=0,035). CONCLUSÃO: Não houve mudança significativa na utilização de medicamentos; entretanto, observou-se melhora significativa em relação ao tabagismo e atividade física na Fase 2; melhora substancial nos níveis de pressão arterial, na comparação tanto entre as Fases 1 e 2 como entre as Fases 1 e 3. A inclusão de enfermeiro treinado para gerenciar o processo foi fundamental. Programas abrangentes de melhoria de qualidade assistencial, provavelmente, devem ser continuados por período de seguimento maior.
OBJECTIVE: To demonstrate the utilization of a clinical improvement program in stable coronary artery disease patients to increase the evidence-proven treatment utilization, and to describe the ongoing clinical practice and lifestyle change counseling. METHODS: Cross-sectional study followed by a longitudinal component in which the tools utilization to improve clinical practice was assessed by means of additional cross-sectional data collection. 710 consecutive patients were included (Phase 1). After tools implementation, within 6 months period, 705 patients were included (Phase 2) for comparative analysis. Randomly, 318 patients from Phase 1 were selected, 6-12 months after the first evaluation (Phase 3). RESULTS: Phase 1 to Phase 2: there were improvement on smoking cessation (P=0.019), dyslipidemia (P<0.001), hypertension and physical activity (P<0.001). There was significant difference on angiotensin converting enzyme inhibitors - ACEI (67.2% vs. 56.8%, P<0.001); angiotensin II receptor blockers - ARB II (25.4% vs. 32.9%, P=0.002) and beta-blocker (88.7% vs. 91.9%, P=0.047). Phase 1 to Phase 3: there was both weight (P=0.044), and blood pressure reduction (P<0.001). There was statistical significant difference on ACEI (64.8% vs. 61.6%, P=0.011) and ARB II (27.0% vs. 31.3%, P=0.035). CONCLUSION: There was no significant change on the evidence-based pharmacological treatment utilization between pre and post-intervention phases; there was significant improvement concerning smoking and physical activity in phase 2; substantial improvement on blood pressure levels in both comparisons (Phase 1 to 2 and Phase 1 to 3). The inclusion of a case-manager for the process management was crucial for program efficacy. Comprehensive programs for clinical practice should be pursued for longer follow-up period.
Subject(s)
Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Coronary Disease/prevention & control , Guideline Adherence , Life Style , Secondary Prevention/methods , Cardiovascular Agents/therapeutic use , Coronary Disease/etiology , Cross-Sectional Studies , Dyslipidemias/therapy , Hypertension/drug therapy , Reproducibility of Results , Risk Factors , Smoking Cessation , Time Factors , Treatment OutcomeABSTRACT
As diretrizes sobre a doença arterial coronária e das evidências científicas de que o tratamento medicamentoso otimizado acrescido de intervenção sobre os fatores de risco e a melhoria do estilo de vida reduzem eventos cardiovasculares fatais não-fatais, essa terapêutica de prevenção secundária continua a ser subutilizada na prática clínica. Métodos: Estudo de corte transversal para documentar a prática clínica vigente, seguido de componente longitudinal em que a utilização das ferramentas para a otimização da prática clínica foi avaliada por meio de novo corte transversal, com nova coleta de dados. Foram identificados retrospectivamente através dos prontuários, 710 pacientes consecutivos portadores de doença arterial coronária (Fase 1). Após a aplicação das ferramentas, foram incluídos 705 pacientes consecutivosatendidos no serviço com a coleta dos mesmos dados, para a análisecomparativa. Além disso, foram selecionados do primeiro grupo, de formaaleatória, 318 prontuários de seis a doze meses após a primeira avaliação,VII para a coleta dos mesmos dados, que foram comparados com asinformações iniciais destes mesmos pacientes. (Fase 3). Res: comparação entre Fase 1 e Fase 2: as características demográficas eram comparáveis entre os dois grupos. Quanto aos fatores de risco, houve melhora com diferença significativa para o tabagismo, dislipidemia, hipertensão arterial e atividade física regular . Comparação entre Fase 1 e Fase 3: os dados demográficos foram semelhantes, assim como as características clínicas, com exceção da doença arterial periférica obstrutiva: 31 pacientes (9,7%) e 42 (13,3%), p=0,007. Quanto às medidas de exame físico, houve redução significativa do peso, p=0,044, pressão arterial sistólica e diastólica, p<0,001. Em relação à prescrição de medicamentos recomendados, houve diferença para IECA (64,8% versus 61,6%, p=0,011) e ARA II (27,0% versus 31,3%, p=0,035
Subject(s)
Humans , Heart Diseases , Heart Diseases/nursing , Risk Factors , Secondary PreventionABSTRACT
Introdução: apesar das recomendações de todas as diretrizes sobre a doença arterial coronária e das evidências científicas de que o tratamento medicamentoso otimizado acrescido de intervenção sobre os fatores de risco e a melhoria do estilo de vida reduzem eventos cardiovasculares fatais não-fatais, essa terapêutica de prevenção secundária continua a ser subutilizada na prática clínica.
Subject(s)
Coronary Disease/prevention & control , Risk Factors , Practice Guidelines as TopicABSTRACT
As diretrizes sobre a doença arterial coronária e das evidências científicas de que o tratamento medicamentoso otimizado acrescido de intervenção sobre os fatores de risco e a melhoria do estilo de vida reduzem eventos cardiovasculares fatais não-fatais, essa terapêutica de prevenção secundária continua a ser subutilizada na prática clínica. Métodos: Estudo de corte transversal para documentar a prática clínica vigente, seguido de componente longitudinal em que a utilização das ferramentas para a otimização da prática clínica foi avaliada por meio de novo corte transversal, com nova coleta de dados. Foram identificados retrospectivamente através dos prontuários, 710 pacientes consecutivos portadores de doença arterial coronária (Fase 1). Após a aplicação das ferramentas, foram incluídos 705 pacientes consecutivosatendidos no serviço com a coleta dos mesmos dados, para a análisecomparativa. Além disso, foram selecionados do primeiro grupo, de formaaleatória, 318 prontuários de seis a doze meses após a primeira avaliação,VII para a coleta dos mesmos dados, que foram comparados com asinformações iniciais destes mesmos pacientes. (Fase 3). Res: comparação entre Fase 1 e Fase 2: as características demográficas eram comparáveis entre os dois grupos. Quanto aos fatores de risco, houve melhora com diferença significativa para o tabagismo, dislipidemia, hipertensão arterial e atividade física regular . Comparação entre Fase 1 e Fase 3: os dados demográficos foram semelhantes, assim como as características clínicas, com exceção da doença arterial periférica obstrutiva: 31 pacientes (9,7%) e 42 (13,3%), p=0,007. Quanto às medidas de exame físico, houve redução significativa do peso, p=0,044, pressão arterial sistólica e diastólica, p<0,001. Em relação à prescrição de medicamentos recomendados, houve diferença para IECA (64,8% versus 61,6%, p=0,011) e ARA II (27,0% versus 31,3%, p=0,035...
Subject(s)
Humans , Heart Diseases/nursing , Heart Diseases , Risk Factors , Secondary PreventionABSTRACT
OBJECTIVE: Transoral approach from the anterior direction is necessary if an upper spinal tumor is too big to extirpate via the posterior approach alone. To obtain a good anterior view of the surgical field, the mandible, tongue, and soft palate have to be split, and we developed a criterion to select the surgical strategy. STUDY DESIGN: We indicated a decision-making process of splitting techniques and indications with actual cases and review of literatures. RESULT: Tumors were located from the level of C1 to the lower part of C3. Computerized tomography and magnetic resonance imaging were important to decide approaches. The orthopedic surgical team invited oral and maxillofacial surgeons team to assist in all transoral anterior approach cases. CONCLUSIONS: Vertical splitting of the mandible, incising the skin of the mental region, and splitting the middle of the tongue were combined according to the position of the spinal tumor.
Subject(s)
Mandible/surgery , Spinal Neoplasms/surgery , Surgical Procedures, Operative/methods , Adult , Aged , Female , Humans , MaleABSTRACT
A doença das atérias coronárias de etiologia aterosclerótica assume importância induscutível em razão de elevada prevalência e mortalidade nos países desenvolvidos e em desenvolvimento. O correto diagnóstico da doença coronária na mulher constitui inquestionável desafio aos cardiologistas, o que levou ao surgimento, nas duas últimas décadas, de extenso conhecimento relacionado às diferenças da doença coronária entre homens e mulheres. Este artigo trata das peculiaridades da cardiopatia isquêmica na mulher, sob a óptica da doença coronária obstrutiva e não-obstrutiva, com especial ênfase nas alterações do território microvascular, em razão da grande quantidade de publicações recentes sobre o tema. A primeira parte do artigo trata da doença coronária obstrutiva, cujas características epidemiológicas, fisiopatológicas, de apresentação clínica e de diagnóstico complementar são examinadas, seguidas das melhores evidências relacionadas ao tratamento. A segunda parte do artigo é dedicada à doença microvascular coronária ou, como recentemente recomendado, doença coronária não-obstrutiva, que assume importância essencial na medida em que cerca de 50 por cento das mulheres sintomáticas submetidas a cinecoronariografia não têm lesões significativas, mas, ao contrário do que se pensava, de que teriam bom prognóstico, são vulneráveis a eventos cardíacos e mortalidade, conforme demosntrado pelo estudo WISE.
Atherosclerotic coronary disease is an extremely important pathology due to its high prevalence and mortality in developed and developing countries. The accurate diagnosis of coronary disease in women is a challenge for cardiologists and has led to the development of extensive knowledge on the understanding of the differences of coronary disease between men and women in the last few decades. This paper discusses the particularities of obstructive and non-obstructive ischemic heart disease in women, with special emphasis on the abnormalities of the microvascular territory, due to the large amount of recent publications on this topic. The first part of the manuscript discusses obstructive coronary disease, whose epidemiologic and pathophysiology characteristics, clinical presentation and complementary diagnosis are evaluated and supported by the best evidences related to the treatment. The second part of the manuscript is dedicated to coronary microvascular disease, or, as recently recommended, non-obstructive coronary disease, which becomes extremely important since about 50% of symptomatic women undergoing coronary scintigraphy do not have significant lesions, and are vulnerable to cardiac events and mortality, in contrast to former beliefs that they had a good prognosis, as shown by the WISE study.
