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2.
Nat Commun ; 11(1): 4615, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934241

RESUMO

Integration of the unique advantages of the fields of drug discovery and drug delivery is invaluable for the advancement of drug development. Here we propose a self-delivering one-component new-chemical-entity nanomedicine (ONN) strategy to improve cancer therapy through incorporation of the self-assembly principle into drug design. A lysosomotropic detergent (MSDH) and an autophagy inhibitor (Lys05) are hybridised to develop bisaminoquinoline derivatives that can intrinsically form nanoassemblies. The selected BAQ12 and BAQ13 ONNs are highly effective in inducing lysosomal disruption, lysosomal dysfunction and autophagy blockade and exhibit 30-fold higher antiproliferative activity than hydroxychloroquine used in clinical trials. These single-drug nanoparticles demonstrate excellent pharmacokinetic and toxicological profiles and dramatic antitumour efficacy in vivo. In addition, they are able to encapsulate and deliver additional drugs to tumour sites and are thus promising agents for autophagy inhibition-based combination therapy. Given their transdisciplinary advantages, these BAQ ONNs have enormous potential to improve cancer therapy.


Assuntos
Aminoquinolinas/química , Antineoplásicos/química , Sistemas de Liberação de Medicamentos/métodos , Lisossomos/efeitos dos fármacos , Nanomedicina/métodos , Neoplasias/tratamento farmacológico , Aminoquinolinas/administração & dosagem , Aminoquinolinas/farmacocinética , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Composição de Medicamentos , Sistemas de Liberação de Medicamentos/instrumentação , Humanos , Nanomedicina/instrumentação , Nanopartículas/química , Neoplasias/fisiopatologia , Ratos , Ratos Sprague-Dawley
3.
Medicine (Baltimore) ; 99(32): e21575, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769903

RESUMO

BACKGROUND: Recent studies showed that Macrophage migration inhibitory factor (MIF) is overexpressed and closely associated with prognosis in cancer patients. The present study was systematically evaluated the prognostic significance of MIF expression in cancer patients. METHODS: PubMed, Cochrane library and Scopus were searched for eligible studies up to January 2020. Pooled hazard ratio with confidence interval (CI) was determined to assess the relationship between MIF expression and survival in cancer patients. RESULTS: A total of 8 studies comprising 847 cancer patients were included in this meta-analysis. For overall survival, the pooled hazard ratio was 2.23 (95% CI 1.67-2.99, P < .001). For disease-free survival, the pooled hazard ratio was 2.24 (95% CI 1.69-2.96, P < .001). The results suggested that high expression of MIF was significantly related to poor overall survival and disease-free survival in cancer patients. CONCLUSION: MIF expression could be a valuable prognostic factor in cancer patients.


Assuntos
Fatores Inibidores da Migração de Macrófagos/análise , Neoplasias/sangue , Prognóstico , Distribuição de Qui-Quadrado , Expressão Gênica/fisiologia , Humanos , Oxirredutases Intramoleculares/análise , Oxirredutases Intramoleculares/sangue , Oxirredutases Intramoleculares/fisiologia , Fatores Inibidores da Migração de Macrófagos/sangue , Fatores Inibidores da Migração de Macrófagos/fisiologia , Neoplasias/fisiopatologia
4.
PLoS One ; 15(8): e0237837, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822434

RESUMO

INTRODUCTION: Cancer, the most stressful event a person may experience often triggers depression. Depression among these groups of people, in turn, affects chemotherapy adherence, length of hospitalization, quality of life and cancer treatment outcome. Even though the problem is enormous studies that address it are limited. Therefore this study was conducted to determine the prevalence of depression and associated factors among cancer patients on chemotherapy in Felege-Hiwot referral hospital and University of Gondar referral hospital, Northwest Ethiopia. METHODS: An institution-based cross-sectional study was conducted from April to May 2019. A total of 302 cancer patients on chemotherapy were included. Depression was assessed using the patient health questionnaire (PHQ-9). Binary logistic regression was used to select variables and determine Crude Odds Ratio (COR). Variables with P value < 0.2 were entered into multivariable logistic regression. Adjusted Odds Ratio (AOR) with 95% confidence intervals for variables with P-value < 0.05 was estimated to show factors affecting depression among cancer patients. The fitness of the model was checked by using the Hosmer-Lemeshow goodness-of-fit test. RESULTS: The prevalence of depression among cancer patients on chemotherapy was 70.86% (95% CI: 65.38, 75.92). Educational status of college and above (AOR = 0.1, 95% CI: 0.02, 0.43), Jobless (AOR = 0.15, 95% CI: 0.04, 0.58), Underweight(AOR = 2.39, 95% CI: 1.10, 5.19)chemotherapy duration ≥ 6 months or more (AOR = 2.36, 95% CI: 1.16, 4.79) were notably associated with depression. CONCLUSION: The burden of depression among cancer patients in this study was high. We recommend concerned bodies working to curve the problem to intervene based on the identified risk factors. Improving educational status, reducing work stress and maintaining normal weight would reduce depression.


Assuntos
Depressão/epidemiologia , Neoplasias/tratamento farmacológico , Neoplasias/psicologia , Adulto , Estudos Transversais , Demografia , Depressão/etiologia , Depressão/fisiopatologia , Progressão da Doença , Tratamento Farmacológico/psicologia , Escolaridade , Etiópia/epidemiologia , Feminino , Hospitais Universitários , Humanos , Modelos Logísticos , Masculino , Neoplasias/fisiopatologia , Razão de Chances , Prevalência , Qualidade de Vida , Fatores de Risco , Inquéritos e Questionários , Magreza/fisiopatologia , Magreza/psicologia , Desemprego/psicologia
5.
Hum Cell ; 33(4): 938-945, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32852669

RESUMO

Cancer tissue comprises not only cancer cells, but also several types of non-cancerous cells, such as cancer-associated fibroblasts. These fibroblasts directly and/or indirectly communicate with the cancer cells and other types of stromal cells, to create a specific tumor microenvironment. Cytotoxic chemotherapy plays a central role in treating cancer; however, tumor re-progression (recurrence) is a significant problem for cancer patients. Cytotoxic anticancer drugs act on fibroblasts as well as cancer cells and, after chemotherapy, all surviving cells are in contact with one another in the local environment. Therefore, an understanding of the molecular interactions between surviving cancer cells and fibroblasts is necessary to prevent tumor re-progression and to sustain the effect of cytotoxic agents. After chemotherapy, the number of fibroblasts may increase, some of which are identifiable as tumor-promoting. In this review, we discuss the significance of cancer-associated fibroblasts in tumor re-progression after chemotherapy, and the potential value of targeting them to enhance clinical outcomes.


Assuntos
Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/patologia , Recidiva Local de Neoplasia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Microambiente Tumoral , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Humanos , Neoplasias/fisiopatologia , Células Estromais , Microambiente Tumoral/efeitos dos fármacos
6.
Artigo em Inglês | MEDLINE | ID: mdl-32751331

RESUMO

The purpose of this study was to analyze and understand the mechanisms of physical activity obstructions in hospitalized cancer patients by investigating their physical activity levels, previous exercise experience levels, and exercise recognition. A survey was conducted for 194 hospitalized cancer patients using a questionnaire. In addition, we performed exploratory factor analysis, frequency analysis, reliability analysis, and hierarchical multiple regression analysis, using SPSS Statistics for Windows, Ver. 23.0. The results were as follows: (1) The physical activity level of the previous exercise participation experience (EPE) group had a greater effect on physical activity obstructions compared with the non-experience (NE) group. (2) The results for the effects of exercise recognition on the physical activity level and physical activity obstructions indicated that exercise recognition in the two groups increased the relative effects on physical activity obstructions in all variables except for the physical obstructions of the EPE group. Consequently, the physical activity level, exercise experience level, and exercise recognition in those patients were confirmed to be the major factors affecting their physical activity obstruction. Therefore, in this study, we provided quantitative data required for establishing healing environments based on motion.


Assuntos
Exercício Físico , Pacientes Internados , Neoplasias , Humanos , Neoplasias/fisiopatologia , Reprodutibilidade dos Testes , Inquéritos e Questionários
7.
Proc Natl Acad Sci U S A ; 117(28): 16391-16400, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32601196

RESUMO

Master splicing regulator MBNL1 shapes large transcriptomic changes that drive cellular differentiation during development. Here we demonstrate that MBNL1 is a suppressor of tumor dedifferentiation. We surveyed MBNL1 expression in matched tumor/normal pairs across The Cancer Genome Atlas and found that MBNL1 was down-regulated in several common cancers. Down-regulation of MBNL1 predicted poor overall survival in breast, lung, and stomach adenocarcinomas and increased relapse and distant metastasis in triple-negative breast cancer. Down-regulation of MBNL1 led to increased tumorigenic and stem/progenitor-like properties in vitro and in vivo. A discrete set of alternative splicing events (ASEs) are shared between MBNL1-low cancers and embryonic stem cells including a MAP2K7∆exon2 splice variant that leads to increased stem/progenitor-like properties via JNK activation. Accordingly, JNK inhibition is capable of reversing MAP2K7∆exon2-driven tumor dedifferentiation in MBNL1-low cancer cells. Our work elucidates an alternative-splicing mechanism that drives tumor dedifferentiation and identifies biomarkers that predict enhanced susceptibility to JNK inhibition.


Assuntos
MAP Quinase Quinase 4/metabolismo , MAP Quinase Quinase 7/genética , MAP Quinase Quinase 7/metabolismo , Neoplasias/metabolismo , Proteínas de Ligação a RNA/metabolismo , Diferenciação Celular , Humanos , MAP Quinase Quinase 4/genética , Neoplasias/genética , Neoplasias/fisiopatologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Processamento de RNA , Proteínas de Ligação a RNA/genética
8.
Nat Commun ; 11(1): 3586, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32681075

RESUMO

Aberrant expression of receptor tyrosine kinase AXL is linked to metastasis. AXL can be activated by its ligand GAS6 or by other kinases, but the signaling pathways conferring its metastatic activity are unknown. Here, we define the AXL-regulated phosphoproteome in breast cancer cells. We reveal that AXL stimulates the phosphorylation of a network of focal adhesion (FA) proteins, culminating in faster FA disassembly. Mechanistically, AXL phosphorylates NEDD9, leading to its binding to CRKII which in turn associates with and orchestrates the phosphorylation of the pseudo-kinase PEAK1. We find that PEAK1 is in complex with the tyrosine kinase CSK to mediate the phosphorylation of PAXILLIN. Uncoupling of PEAK1 from AXL signaling decreases metastasis in vivo, but not tumor growth. Our results uncover a contribution of AXL signaling to FA dynamics, reveal a long sought-after mechanism underlying AXL metastatic activity, and identify PEAK1 as a therapeutic target in AXL positive tumors.


Assuntos
Movimento Celular , Adesões Focais/metabolismo , Neoplasias/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linhagem Celular Tumoral , Adesões Focais/genética , Humanos , Invasividade Neoplásica , Neoplasias/genética , Neoplasias/fisiopatologia , Paxilina/genética , Paxilina/metabolismo , Fosforilação , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Transdução de Sinais
9.
Infect Dis Poverty ; 9(1): 82, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32616030

RESUMO

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the outbreak of pneumonia in Wuhan. The virus is highly infectious. Patients with cancer might be susceptible to the viral infection because of the immunosuppressive state cause by therapies on tumors. CASE PRESENTATION: We present the clinical features of four cancer patients who were infected with SARS-CoV-2 in late January of 2020 in our hospital. Cases 1 and 3 were diagnosed as mild and common type of coronavirus disease 2019 (COVID-2019) and survived from the viral infection. They acquired SARS-CoV-2 infection during their staying in hospital under radiotherapy and surgery of the tumors. Cases 2 and 4 suffered from severe type of COVID-19, and Case 2 was dead owning to the advanced age, uncontrolled chronic B cell lymphocytic leukemia and many other underlying diseases. The immunosuppressive state induced by liver transplantation and anti-rejection therapy might contribute to the severity of COVID-19 in Case 4, who suffered from hepatitis B related hepatocellular carcinoma. However, Case 4 was recovered from COVID-19 after a combination therapy against virus, bacteria and fungi, and also respiratory support. Nearly all patients showed a decrease in lymphocytes including total CD3+ T cells, B cells, and natural killer cells after infection of the virus. CONCLUSIONS: The severity of COVID-19 might be influenced by immune system state and underlying diseases in cancer patients. And the treatment of SARS-CoV-2 infection in cancer patients is challenged by the immunosuppressive state of these patients under chemotherapy or surgery.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Neoplasias/complicações , Pandemias , Pneumonia Viral , Adulto , Idoso , China , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/fisiopatologia , Evolução Fatal , Feminino , Humanos , Hospedeiro Imunocomprometido , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias/fisiopatologia , Neoplasias/terapia , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/fisiopatologia , Radiografia Torácica
10.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 49(1): 107-112, 2020 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-32621421

RESUMO

Neutrophil extracellular traps(NET)is neutrophil-derived extracellular fiber web-like structure, composed of DNA scaffold studded with various active proteins. In addition to its bactericidal effect, NET is closely related to various diseases including immune disease, thrombosis and tumor. Recently, lots of researches have shown that NET is highly expressed in a variety of tumors, tumor cells and microenvironment can promote NET formation, whereas NET participates in tumor progression as well, and is closely related to tumor proliferation, metastasis and thrombosis, which provides new clinical thinking in tumor diagnosis as well as treatment indeed. This review will focus on the research progress of NET and tumor, meanwhile make a prospect for its clinical application value.


Assuntos
Armadilhas Extracelulares , Neoplasias , Microambiente Tumoral , Armadilhas Extracelulares/genética , Humanos , Neoplasias/fisiopatologia , Neutrófilos/patologia
11.
Mol Cell ; 78(6): 1045-1054, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32516599

RESUMO

Cell death, or, more specifically, cell suicide, is a process of fundamental importance to human health. Throughout our lives, over a million cells are produced every second. When organismal growth has stopped, to balance cell division, a similar number of cells must be removed. This is achieved by activation of molecular mechanisms that have evolved so that cells can destroy themselves. The first clues regarding the nature of one of these mechanisms came from studying genes associated with cancer, in particular the gene for BCL-2. Subsequent studies revealed that mutations or other defects that inhibit cell death allow cells to accumulate, prevent removal of cells with damaged DNA, and increase the resistance of malignant cells to chemotherapy. Knowledge of this mechanism has allowed development of drugs that kill cancer cells by directly activating the cell death machinery and by synergizing with conventional chemotherapy as well as targeted agents to achieve improved outcomes for cancer patients.


Assuntos
Morte Celular/fisiologia , Neoplasias/genética , Neoplasias/terapia , Apoptose/genética , Morte Celular/genética , Dano ao DNA/genética , Humanos , Neoplasias/fisiopatologia
12.
PLoS One ; 15(6): e0234507, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32526771

RESUMO

INTRODUCTION: Maximal oxygen uptake ([Formula: see text]) is a measure of cardiorespiratory fitness often used to monitor changes in fitness during and after treatment in cancer patients. There is, however, limited knowledge in how criteria verifying [Formula: see text] work for patients newly diagnosed with cancer. Therefore, the aim of this study was to describe the prevalence of fulfillment of typical criteria verifying [Formula: see text] and to investigate the associations between the criteria and the test leader's evaluation whether a test was performed "to exhaustion". An additional aim was to establish new cut-points within the associated criteria. METHODS: From the Phys-Can randomized controlled trial, 535 patients (59 ±12 years) newly diagnosed with breast (79%), prostate (17%) or colorectal cancer (4%) performed an incremental [Formula: see text] test on a treadmill. The test was performed before starting (neo-)adjuvant treatment and an exercise intervention. Fulfillment of different cut-points within typical criteria verifying [Formula: see text] was described. The dependent key variables included in the initial bivariate analysis were achievement of a [Formula: see text] plateau, peak values for maximal heart rate, respiratory exchange ratio (RER), the patients' rating of perceived exertion on Borg's scale6-20 and peak breathing frequency (fR). A receiver operating characteristic analysis was performed to establish cut-points for variables associated with the test leader's evaluation. Last, a cross-validation of the cut-points found in the receiver operating characteristic analysis was performed on a comparable sample of cancer patients (n = 80). RESULTS: The criteria RERpeak (<0.001), Borg's RPE (<0.001) and fR peak (p = 0.018) were associated with the test leader's evaluation of whether a test was defined as "to exhaustion". The cut-points that best predicted the test leader's evaluation were RER ≥ 1.14, RPE ≥ 18 and fR ≥ 40. Maximal heart rate and [Formula: see text] plateau was not associated with the test leader's evaluation. CONCLUSION: We recommend a focus on RER (in the range between ≥1.1 and ≥1.15) and RPE (≥17 or ≥18) in addition to the test leader's evaluation. Additionally, a fR peak of ≥40 breaths/min may be a cut-point to help the test leader evaluate the degree of exhaustion. However, more research is needed to verify our findings, and to investigate how these criteria will work within a population that are undergoing or finished with cancer treatment.


Assuntos
Aptidão Cardiorrespiratória/fisiologia , Teste de Esforço/métodos , Terapia por Exercício , Neoplasias/reabilitação , Oxigênio/análise , Idoso , Estudos de Coortes , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Neoplasias/fisiopatologia , Oxigênio/metabolismo , Consumo de Oxigênio , Esforço Físico/fisiologia , Curva ROC , Valores de Referência , Resultado do Tratamento
13.
Nat Rev Cancer ; 20(7): 398-411, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32488200

RESUMO

The success of targeted therapies and immunotherapies has created optimism that cancers may be curable. However, not all patients respond, drug resistance is common and many patients relapse owing to dormant cancer cells. These rare and elusive cells can disseminate early and hide in specialized niches in distant organs before being reactivated to cause disease relapse after successful treatment of the primary tumour. Despite their importance, we are yet to leverage knowledge generated from experimental models and translate the potential of targeting dormant cancer cells to prevent disease relapse in the clinic. This is due, at least in part, to the lack of adherence to consensus definitions by researchers, limited models that faithfully recapitulate this stage of metastatic spread and an absence of interdisciplinary approaches. However, the application of new high-resolution, single-cell technologies is starting to revolutionize the field and transcend classical reductionist models of studying individual cell types or genes in isolation to provide a global view of the complex underlying cellular ecosystem and transcriptional landscape that controls dormancy. In this Perspective, we synthesize some of these recent advances to describe the hallmarks of cancer cell dormancy and how the dormant cancer cell life cycle offers opportunities to target not only the cancer but also its environment to achieve a durable cure for seemingly incurable cancers.


Assuntos
Ciclo Celular/fisiologia , Transformação Celular Neoplásica/metabolismo , Metástase Neoplásica/fisiopatologia , Microambiente Tumoral/fisiologia , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/fisiologia , Ciclo Celular/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Microambiente Celular/efeitos dos fármacos , Microambiente Celular/fisiologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Terapia de Alvo Molecular/métodos , Metástase Neoplásica/terapia , Neoplasias/tratamento farmacológico , Neoplasias/fisiopatologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/fisiologia , Microambiente Tumoral/efeitos dos fármacos
14.
Hum Cell ; 33(4): 930-937, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32507979

RESUMO

The tumor microenvironment (TME) plays a crucial role in tumor progression, therapeutic response, and patient outcomes. TME includes immune cells, blood and lymphatic vessels, and so on. There are anti-cancer and pro-cancer immune cells. In general, infiltration of anti-cancer immune cells, such as cytotoxic T cells (CTLs), is associated with a favorable patient prognosis. In contrast, infiltration of pro-cancer immune cells, such as regulatory T cells (Tregs), tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), is associated with a worse prognosis. However, some immune cells, which play an ambivalent role in cancer immunity, have demonstrated contradictory impacts on patient prognosis. Blood and lymphatic vessels play crucial roles in TME not only as delivery and draining systems of fluid and molecules, but also allowing cancer cells access to systematic circulation to metastasize. Angiogenesis promotes cancer aggressiveness and is associated with a worse prognosis. Its targeted therapy shows a benefit in some cancers, however, because the target can vary by caner type, a benefit of anti-angiogenesis therapy is limited in the current standard of care. Lymphangiogenesis plays a role in lymph node metastasis, thus, it is associated with a poor prognosis in some cancers. To study TME, the mouse model is one of the most commonly used tools. The choice of appropriate mouse model depends on the hypothesis being tested and the scientific question being asked. Here, we review recent studies that investigated the clinical relevance of TME components and introduce mouse models to study TME.


Assuntos
Modelos Animais de Doenças , Vasos Linfáticos/fisiopatologia , Neoplasias/irrigação sanguínea , Neoplasias/imunologia , Microambiente Tumoral , Animais , Progressão da Doença , Humanos , Vasos Linfáticos/patologia , Macrófagos/imunologia , Camundongos , Neoplasias/patologia , Neoplasias/fisiopatologia , Neovascularização Patológica , Prognóstico , Linfócitos T Reguladores/imunologia
15.
Pharmacol Ther ; 213: 107579, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32442437

RESUMO

Ubiquitin Proteasome System (UPS) is an adaptable and finely tuned system that sustains proteostasis network under a large variety of physiopathological conditions. Its dysregulation is often associated with the onset and progression of human diseases; hence, UPS modulation has emerged as a promising new avenue for the development of treatments of several relevant pathologies, such as cancer and neurodegeneration. The clinical interest in proteasome inhibition has considerably increased after the FDA approval in 2003 of bortezomib for relapsed/refractory multiple myeloma, which is now used in the front-line setting. Thereafter, two other proteasome inhibitors (carfilzomib and ixazomib), designed to overcome resistance to bortezomib, have been approved for treatment-experienced patients, and a variety of novel inhibitors are currently under preclinical and clinical investigation not only for haematological malignancies but also for solid tumours. However, since UPS collapse leads to toxic misfolded proteins accumulation, proteasome is attracting even more interest as a target for the care of neurodegenerative diseases, which are sustained by UPS impairment. Thus, conceptually, proteasome activation represents an innovative and largely unexplored target for drug development. According to a multidisciplinary approach, spanning from chemistry, biochemistry, molecular biology to pharmacology, this review will summarize the most recent available literature regarding different aspects of proteasome biology, focusing on structure, function and regulation of proteasome in physiological and pathological processes, mostly cancer and neurodegenerative diseases, connecting biochemical features and clinical studies of proteasome targeting drugs.


Assuntos
Neoplasias/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Ubiquitina/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Resistência a Medicamentos/fisiologia , Fator de Transcrição E2F4/metabolismo , Holoenzimas , Humanos , Gotículas Lipídicas/metabolismo , Chaperonas Moleculares/metabolismo , Proteínas Musculares/metabolismo , NF-kappa B/metabolismo , Neoplasias/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Inibidores de Proteassoma/uso terapêutico , Proteostase/fisiologia , Proteína Supressora de Tumor p53/metabolismo
16.
Pediatr Blood Cancer ; 67(7): e28339, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32386117

RESUMO

BACKGROUND: Physical activity and aerobic fitness are modifiable risk factors for cardiovascular disease (CVD) after childhood cancer. How survivors engage in physical activity remains unclear, potentially increasing CVD risk. We assessed survivors' physical activity levels, barriers and enablers, fitness, and identified predictors of fitness and physical activity stage of change. METHODS: Childhood cancer survivors (CCS; 8-18 years old) ≥1 year post-treatment were assessed for aerobic fitness (6-min walk test), used to extrapolate VO2max , and body composition (InBody 570). Survivors self-reported physical activity to determine stage of change (Patient-Centered Assessment and Counselling for Exercise). Physical activity and fitness were compared with guidelines and CVD-risk cut-points (VO2max  < 42 mL/kg/min: males; VO2max  < 35 mL/kg/min: females). Multiple regression and mediator-moderator analysis were used to identify fitness predictors and stage of change. RESULTS: One hundred two survivors (12.8 ± 3.3 years) participated (46% acute lymphoblastic leukaemia). Forty percent of males (VO2max  = 43.3 ± 6.3 mL/kg/min) and 28% of females (VO2max  = 36.5 ± 5.9 mL/kg/min) were in the CVD-risk category, while 25% met physical activity guidelines. Most prevalent physical activity barriers were fatigue (52%), preferring television instead of exercise (38%), and lacking time (34%). Predictive factors for reduced fitness included being older, female, higher waist-to-height ratio, higher screen time, and moderated by lower physical activity (r2  = 0.91, P < .001). Survivors with higher physical activity stage of change were male, lower body fat percentage, lower screen time, and lived with both parents (r = 0.42, P = .003). CONCLUSION: Aerobic fitness and physical activity of CCS is low compared with population norms, potentially increasing CVD risk. Addressing physical activity barriers and enablers, including reducing screen time, could promote regular physical activity, reducing CVD risk.


Assuntos
Sobreviventes de Câncer/psicologia , Exercício Físico , Fadiga/fisiopatologia , Força Muscular , Neoplasias/reabilitação , Qualidade de Vida , Adolescente , Sobreviventes de Câncer/estatística & dados numéricos , Criança , Estudos Transversais , Feminino , Seguimentos , Humanos , Masculino , Neoplasias/fisiopatologia , Neoplasias/psicologia , Prognóstico , Fatores de Risco
17.
Nat Commun ; 11(1): 2517, 2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32433464

RESUMO

Alterations in non-driver genes represent an emerging class of potential therapeutic targets in cancer. Hundreds to thousands of non-driver genes undergo loss of heterozygosity (LOH) events per tumor, generating discrete differences between tumor and normal cells. Here we interrogate LOH of polymorphisms in essential genes as a novel class of therapeutic targets. We hypothesized that monoallelic inactivation of the allele retained in tumors can selectively kill cancer cells but not somatic cells, which retain both alleles. We identified 5664 variants in 1278 essential genes that undergo LOH in cancer and evaluated the potential for each to be targeted using allele-specific gene-editing, RNAi, or small-molecule approaches. We further show that allele-specific inactivation of either of two essential genes (PRIM1 and EXOSC8) reduces growth of cells harboring that allele, while cells harboring the non-targeted allele remain intact. We conclude that LOH of essential genes represents a rich class of non-driver cancer vulnerabilities.


Assuntos
Genes Essenciais , Perda de Heterozigosidade , Neoplasias/genética , Alelos , Proliferação de Células , DNA Primase/genética , Complexo Multienzimático de Ribonucleases do Exossomo/genética , Humanos , Modelos Genéticos , Neoplasias/fisiopatologia , Proteínas de Ligação a RNA/genética
18.
Cancer Discov ; 10(7): 916-921, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32444466

RESUMO

The mapping of SARS-CoV-2 human protein-protein interactions by Gordon and colleagues revealed druggable targets that are hijacked by the virus. Here, we highlight several oncogenic pathways identified at the host-virus interface of SARS-CoV-2 to enable cancer biologists to apply their knowledge for rapid drug repurposing to treat COVID-19, and help inform the response to potential long-term complications of the disease.


Assuntos
Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Ciclo Celular , Infecções por Coronavirus/genética , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/fisiopatologia , Dano ao DNA , Epigenômica , Humanos , Proteínas de Neoplasias/efeitos dos fármacos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/metabolismo , Pneumonia Viral/fisiopatologia , Biossíntese de Proteínas
19.
Croat Med J ; 61(2): 159-166, 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32378382

RESUMO

Health can be defined as a harmony, or homeostasis, of the activities of thousands of different proteins, whereas aging and diseases result from their disharmony manifested at the levels of cells and tissues. Such disharmony is caused primarily by dysfunction and toxicity of misfolded proteins damaged by oxidation. This is an overview of key data that inspired new concepts allowing interpretation and integration of the scientific literature on aging and age-related diseases. These concepts suggest strategies for prevention and attenuation of age-related degenerative and malignant diseases mimicking the life of super-centenarians.


Assuntos
Envelhecimento/fisiologia , Neoplasias , Doenças Neurodegenerativas , Proteínas , Idoso , Dano ao DNA , Humanos , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Oxirredução , Redobramento de Proteína , Proteínas/química , Proteínas/metabolismo , Proteólise
20.
Adv Exp Med Biol ; 1194: 457, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468562

RESUMO

Cancer research has yielded tremendous gains over the last two decades with remarkable results addressing this worldwide major public health problem. Continuous technological developments and persistent research has led to significant progress in targeted therapies. This paper focuses on the study of mathematical models that describe in the most optimal way the development of malignant tumours induced in experimental animals of a particular species following chemical carcinogenesis with a complete carcinogen factor known as 3,4-benzopyrene. The purpose of this work is to study the phenomenon of chemical carcinogenesis, inhibition and growth of malignant tumours.


Assuntos
Carcinogênese , Simulação por Computador , Modelos Biológicos , Neoplasias , Animais , Carcinogênese/patologia , Carcinógenos , Modelos Animais de Doenças , Neoplasias/induzido quimicamente , Neoplasias/fisiopatologia , Neoplasias/prevenção & controle
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