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1.
Anticancer Res ; 41(10): 4969-4977, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593444

RESUMO

BACKGROUND/AIM: To identify the best of three isatin-based scaffolds in terms of anticancer activity. MATERIALS AND METHODS: Synthesis of isatin-based scaffolds was performed through a reaction to form Schiff bases. In silico analyses consisted of a target prediction with the Swiss Target Prediction tool and a molecular docking by AutoDock Vina. Anticancer activity and cytotoxicity were determined using the WST1 viability assay. RESULTS: Three scaffolds (IA, IB, and IC) were synthesized and confirmed with good reaction yields. The Swiss Target Prediction tool showed a trend towards kinases. Molecular docking assays demonstrated higher affinity of IC towards CDK2. Anticancer activity assays identified IC as the most active against the cancer cell lines. Cytotoxicity results in non-cancer cells suggested a lack of selectivity. CONCLUSION: The scaffold IC was identified as the best in terms of anticancer activity and these effects may be due to inhibition of CDK2, as evidenced by molecular docking.


Assuntos
Antineoplásicos/farmacologia , Quinase 2 Dependente de Ciclina/metabolismo , Isatina/farmacologia , Simulação de Acoplamento Molecular/métodos , Neoplasias/tratamento farmacológico , Bases de Schiff/química , Antineoplásicos/química , Apoptose , Proliferação de Células , Humanos , Isatina/química , Neoplasias/metabolismo , Neoplasias/patologia , Relação Estrutura-Atividade , Células Tumorais Cultivadas
2.
Anticancer Res ; 41(10): 5001-5006, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593448

RESUMO

BACKGROUND/AIM: To describe clinical features, radiotherapy (RT), and symptom outcomes in cancer patients with cranial nerve palsies associated with clival metastases. PATIENTS AND METHODS: This is a retrospective review of patients with primary metastatic cancers who developed clival metastases and received RT (2000-2020). RESULTS: Of the 44 patients with primary cancers (manly breast, prostate and multiple myeloma cancers) and distal clival metastases, 32 patients (73%) also had cervical spine metastases. Of the 23 RT-treated patients, 65% and 35% received clivus only and whole brain RT, respectively. Post-RT symptom improvement was observed in patients with diplopia (5/6; 83%), headache (8/10; 80%), chin numbness (2/4; 50%), blurry vision (2/5; 40%), lateral gaze deficit (2/6; 33%), and tongue deviation (1/4; 25%). CONCLUSION: Early detection and cranial nerve examination, in addition to RT treatment, should be considered in patients with breast, prostate, and multiple myeloma cancers, who developed cervical spine metastases.


Assuntos
Fossa Craniana Posterior/patologia , Neoplasias/patologia , Neoplasias da Base do Crânio/secundário , Avaliação de Sintomas/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Fossa Craniana Posterior/efeitos da radiação , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/radioterapia , Prognóstico , Estudos Retrospectivos , Neoplasias da Base do Crânio/radioterapia , Taxa de Sobrevida
3.
Anticancer Res ; 41(10): 5107-5116, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593461

RESUMO

BACKGROUND/AIM: We evaluated local control and toxicity in patients receiving radiotherapy associated with immune check point inhibitors and analyzed which oligometastatic disease setting benefits the most from local ablation in terms of advantage in overall survival. PATIENTS AND METHODS: We retrospectively identified 60 oligoprogressive patients treated with a PD-1 inhibitor in association with radiotherapy on the site of progression (119 lesions). RESULTS: After a median follow-up of 11.7 months (range=1-39 months), we observed complete response (CR) in 45/119, partial response (RP) in 42/119, and stable disease (SD) in 30/119 patients. Nine radionecrotic events occurred. Two patients experienced grade 3 toxicities and 32 patients reported grade 2 toxicities. The number of radiologically evident metastatic organs in patients who received concomitant PD-1 inhibitors and radiotherapy showed a significant increase in survival (respectively, 73% after 12 months and 47% after 24 months) in patients with 0-3 metastatic organs compared to those with more than 3 organ sites involved (p<0.0001). CONCLUSION: Radiotherapy associated with PD-1 inhibitors is overall safe and efficacious. Patients eligible for intensification of local treatments should have less or equal to 3 metastatic organ sites.


Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Recidiva Local de Neoplasia/mortalidade , Neoplasias/mortalidade , Radiocirurgia/mortalidade , Terapia Combinada , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Metástase Neoplásica , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Neoplasias/patologia , Neoplasias/terapia , Prognóstico , Hipofracionamento da Dose de Radiação , Estudos Retrospectivos , Taxa de Sobrevida , Testes de Toxicidade
5.
Nat Commun ; 12(1): 5330, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504093

RESUMO

Most autosomal genes are thought to be expressed from both alleles, with some notable exceptions, including imprinted genes and genes showing random monoallelic expression (RME). The extent and nature of RME has been the subject of debate. Here we investigate the expression of several candidate RME genes in F1 hybrid mouse cells before and after differentiation, to define how they become persistently, monoallelically expressed. Clonal monoallelic expression is not present in embryonic stem cells, but we observe high frequencies of monoallelism in neuronal progenitor cells by assessing expression status in more than 200 clones. We uncover unforeseen modes of allelic expression that appear to be gene-specific and epigenetically regulated. This non-canonical allelic regulation has important implications for development and disease, including autosomal dominant disorders and opens up therapeutic perspectives.


Assuntos
Alelos , Desequilíbrio Alélico , Epigênese Genética , Doenças Musculares/genética , Células-Tronco Neurais/metabolismo , Doenças Neurodegenerativas/genética , Hidrolases Anidrido Ácido/genética , Hidrolases Anidrido Ácido/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Diferenciação Celular , Quimera , Células Clonais , Metilação de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Feminino , Dosagem de Genes , Frequência do Gene , Loci Gênicos , Impressão Genômica , Masculino , Camundongos , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Células-Tronco Neurais/patologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Osteoporose/genética , Osteoporose/metabolismo , Osteoporose/patologia , Receptores de Ácido Caínico/genética , Receptores de Ácido Caínico/metabolismo
6.
Nat Commun ; 12(1): 5311, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493724

RESUMO

Although some effective therapies have been available for cancer, it still poses a great threat to human health and life due to its drug resistance and low response in patients. Here, we develop a ferroptosis-based therapy by combining iron nanoparticles and cancer-specific gene interference. The expression of two iron metabolic genes (FPN and LCN2) was selectively knocked down in cancer cells by Cas13a or microRNA controlled by a NF-κB-specific promoter. Cells were simultaneously treated by iron nanoparticles. As a result, a significant ferroptosis was induced in a wide variety of cancer cells. However, the same treatment had little effect on normal cells. By transferring genes with adeno-associated virus and iron nanoparticles, the significant tumor growth inhibition and durable cure were obtained in mice with the therapy. In this work, we thus show a cancer therapy based on gene interference-enhanced ferroptosis.


Assuntos
Proteínas de Transporte de Cátions/antagonistas & inibidores , Ferroptose/genética , Ferro/metabolismo , Lipocalina-2/antagonistas & inibidores , Neoplasias/terapia , Interferência de RNA , Espécies Reativas de Oxigênio/agonistas , Animais , Proteínas Associadas a CRISPR/genética , Proteínas Associadas a CRISPR/metabolismo , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Linhagem Celular Tumoral , Dependovirus/genética , Dependovirus/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Lipocalina-2/genética , Lipocalina-2/metabolismo , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Nanopartículas/administração & dosagem , Nanopartículas/química , Neoplasias/genética , Neoplasias/mortalidade , Neoplasias/patologia , Regiões Promotoras Genéticas , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Baço/metabolismo , Baço/patologia , Análise de Sobrevida , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Photochem Photobiol B ; 223: 112294, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34500215

RESUMO

Photo-induced cytotoxicity and antitumor activity of a series of dual function agents for photodynamic therapy (PDT) and fluorescent imaging based on bacteriochlorin photosensitizer conjugated with various naphthalimide fluorophores was studied in vitro using murine tumor cells of S37 sarcoma and in vivo on mice bearing murine S37 sarcoma. Upon irradiation at the absorption maximum of the photosensitizer, the activity of conjugates was as high as in the case of individual bacteriochlorin, while an additional excitation of the naphthalimide fragment led to an increase in the PDT efficacy due to resonance energy transfer from the fluorophore to photosensitizer. The fluorescence contrast and specific cytotoxic activity measurements indicate that the conjugate of bacteriochlorin with 3,4-dimethoxestyrene-substituted naphthalimide is the most promising agent for the application as theranostic in PDT.


Assuntos
Naftalimidas/química , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/química , Animais , Linhagem Celular Tumoral , Lasers , Camundongos , Naftalimidas/metabolismo , Neoplasias/diagnóstico , Neoplasias/patologia , Imagem Óptica , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/metabolismo , Distribuição Tecidual , Transplante Homólogo
8.
Br J Radiol ; 94(1126): 20201350, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34520673

RESUMO

OBJECTIVES: To evaluate the impact of fully automatic motion correction by data-driven respiratory gating (DDG) on positron emission tomography (PET) image quality, lesion detection and patient management. MATERIALS AND METHODS: A total of 149 patients undergoing PET/CT for cancer (re-)staging were retrospectively included. Patients underwent a PET/CT on a digital detector scanner and for every patient a PET data set where DDG was enabled (PETDDG) and as well as where DDG was not enabled (PETnonDDG) was reconstructed. All PET data sets were evaluated by two readers which rated the general image quality, motion effects and organ contours. Further, both readers reviewed all scans on a case-by-case basis and evaluated the impact of PETDDG on additional apparent lesion, change of report, and change of management. RESULTS: In 85% (n = 126) of the patients, at least one bed position was acquired using DDG, resulting in mean scan time increase of 4:37 min per patient in the whole study cohort (n = 149). General image quality was not rated differently for PETnonDDG and PETDDG images (p = 1.000) while motion effects (i.e. indicating general blurring) was rated significantly lower in PETDDG images and organ contours, including liver and spleen, were rated significantly sharper using PETDDG as compared to PETnonDDG (all p < 0.001). In 27% of patients, PETDDG resulted in a change of the report and in a total of 12 cases (8%), PETDDG resulted in a change of further clinical management. CONCLUSION: Deviceless DDG provided reliable fully automatic motion correction in clinical routine and increased lesion detectability and changed management in a considerable number of patients. ADVANCES IN KNOWLEDGE: DDG enables PET/CT with respiratory gating to be used routinely in clinical practice without external gating equipment needed.


Assuntos
Neoplasias/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Técnicas de Imagem de Sincronização Respiratória/métodos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Movimento (Física) , Estadiamento de Neoplasias , Neoplasias/patologia , Neoplasias/terapia , Estudos Retrospectivos
9.
Nat Commun ; 12(1): 5285, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489442

RESUMO

The mammalian DNA methylome is formed by two antagonizing processes, methylation by DNA methyltransferases (DNMT) and demethylation by ten-eleven translocation (TET) dioxygenases. Although the dynamics of either methylation or demethylation have been intensively studied in the past decade, the direct effects of their interaction on gene expression remain elusive. Here, we quantify the concurrence of DNA methylation and demethylation by the percentage of unmethylated CpGs within a partially methylated read from bisulfite sequencing. After verifying 'methylation concurrence' by its strong association with the co-localization of DNMT and TET enzymes, we observe that methylation concurrence is strongly correlated with gene expression. Notably, elevated methylation concurrence in tumors is associated with the repression of 40~60% of tumor suppressor genes, which cannot be explained by promoter hypermethylation alone. Furthermore, methylation concurrence can be used to stratify large undermethylated regions with negligible differences in average methylation into two subgroups with distinct chromatin accessibility and gene regulation patterns. Together, methylation concurrence represents a unique methylation metric important for transcription regulation and is distinct from conventional metrics, such as average methylation and methylation variation.


Assuntos
Metilação de DNA , Metilases de Modificação do DNA/genética , Proteínas de Ligação a DNA/genética , Epigênese Genética , Genoma , Neoplasias/genética , Proteínas Proto-Oncogênicas/genética , Transcrição Genética , Animais , Cromatina/química , Cromatina/metabolismo , Ilhas de CpG , DNA/genética , DNA/metabolismo , Metilases de Modificação do DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Ontologia Genética , Histonas/genética , Histonas/metabolismo , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Camundongos , Anotação de Sequência Molecular , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Proto-Oncogênicas/metabolismo , Linfócitos T/citologia , Linfócitos T/metabolismo
10.
Ann Surg ; 274(4): e315-e319, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34506325

RESUMO

OBJECTIVE: To determine how Medicare Advantage (MA) health plan networks impact access to high-volume hospitals for cancer surgery. BACKGROUND: Cancer surgery at high-volume hospitals is associated with better short- and long-term outcomes. In the United States, health insurance is a major detriment to seeking care at high-volume hospitals. A third of older (>65 years) Americans are enrolled in privatized MA health plans. The impact of MA plan networks on access to high-volume surgery hospitals is unknown. METHODS: We analyzed in-network hospitals for MA plans offered in Los Angeles county during open enrollment of 2015. For the purposes of this analysis, MA network data from provider directories were linked to hospital volume data from California Office of Statewide Health Planning and Development. Volume thresholds were based on published literature. RESULTS: A total of 34 MA plans enrolled 554,754 beneficiaries in Los Angeles county during 2014 open enrollment for coverage starting in 2015 (MA penetration ∼43%). The proportion of MA plans that included high-volume cancer surgery hospital varied by the type of cancer surgery. While most plans (>71%) included at least one high-volume hospital for colon, rectum, lung, and stomach; 59% to 82% of MA plans did not include any high-volume hospitals for liver, esophagus, or pancreatic surgery. A significant proportion of beneficiaries in MA plans did not have access to high-volume hospitals for esophagus (93%), stomach (44%), liver (39%), or pancreas (70%) surgery. In contrast, nearly all MA beneficiaries had access to at least one high-volume hospital for lung (93%), colon (100%), or rectal (100%) surgery. Overall, Centers for Medicare & Medicaid Services plan rating or plan popularity were not correlated with access to high-volume hospital (P > 0.05). CONCLUSIONS: The study identifies lack of high-volume hospital coverage in MA health plans as a major detriment in regionalization of cancer surgery impacting at least a third of older Americans.


Assuntos
Acesso aos Serviços de Saúde/organização & administração , Hospitais com Alto Volume de Atendimentos/estatística & dados numéricos , Medicare Part C/organização & administração , Neoplasias/cirurgia , Procedimentos Cirúrgicos Operatórios/estatística & dados numéricos , Idoso , Utilização de Instalações e Serviços , Feminino , Humanos , Masculino , Neoplasias/epidemiologia , Neoplasias/patologia , Utilização de Procedimentos e Técnicas , Estudos Retrospectivos , Estados Unidos
11.
Life Sci ; 284: 119942, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34506835

RESUMO

Cancer is one of the major causes of death in the world and its global burden is expected to continue increasing. In several types of cancers, reactive oxygen species (ROS) have been extensively linked to carcinogenesis and cancer progression. However, studies have reported conflicting evidence regarding the role of ROS in cancer, mostly dependent on the cancer type or the step of the tumorigenic process. We review recent studies describing diverse aspects of the interplay of ROS with cancer in the different stages of cancer progression, with a special focus on their role in carcinogenesis, their importance for cancer cell signaling and their relationship to the most prevalent cancer risk factors.


Assuntos
Carcinogênese/metabolismo , Progressão da Doença , Neoplasias/metabolismo , Neoplasias/patologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Animais , Carcinogênese/patologia , Humanos , Fatores de Risco
12.
Nat Biotechnol ; 39(9): 1141-1150, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504346

RESUMO

Clinical applications of precision oncology require accurate tests that can distinguish true cancer-specific mutations from errors introduced at each step of next-generation sequencing (NGS). To date, no bulk sequencing study has addressed the effects of cross-site reproducibility, nor the biological, technical and computational factors that influence variant identification. Here we report a systematic interrogation of somatic mutations in paired tumor-normal cell lines to identify factors affecting detection reproducibility and accuracy at six different centers. Using whole-genome sequencing (WGS) and whole-exome sequencing (WES), we evaluated the reproducibility of different sample types with varying input amount and tumor purity, and multiple library construction protocols, followed by processing with nine bioinformatics pipelines. We found that read coverage and callers affected both WGS and WES reproducibility, but WES performance was influenced by insert fragment size, genomic copy content and the global imbalance score (GIV; G > T/C > A). Finally, taking into account library preparation protocol, tumor content, read coverage and bioinformatics processes concomitantly, we recommend actionable practices to improve the reproducibility and accuracy of NGS experiments for cancer mutation detection.


Assuntos
Benchmarking , Neoplasias/genética , Análise de Sequência de DNA/normas , Sequenciamento Completo do Exoma/normas , Sequenciamento Completo do Genoma/normas , Linhagem Celular , Linhagem Celular Tumoral , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mutação , Neoplasias/patologia , Reprodutibilidade dos Testes
13.
Nat Commun ; 12(1): 5505, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535668

RESUMO

Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8+ T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients.


Assuntos
Proteína DEAD-box 58/metabolismo , Imunidade Inata , Inflamação/patologia , Sistema de Sinalização das MAP Quinases , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptores Imunológicos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citocinas/metabolismo , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Evasão da Resposta Imune/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Fator Regulador 1 de Interferon/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/patologia , Oncogenes , Transdução de Sinais/efeitos dos fármacos
14.
Curr Issues Mol Biol ; 43(2): 767-781, 2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34449532

RESUMO

KIN (Kin17) protein is overexpressed in a number of cancerous cell lines, and is therefore considered a possible cancer biomarker. It is a well-conserved protein across eukaryotes and is ubiquitously expressed in all cell types studied, suggesting an important role in the maintenance of basic cellular function which is yet to be well determined. Early studies on KIN suggested that this nuclear protein plays a role in cellular mechanisms such as DNA replication and/or repair; however, its association with chromatin depends on its methylation state. In order to provide a better understanding of the cellular role of this protein, we investigated its interactome by proximity-dependent biotin identification coupled to mass spectrometry (BioID-MS), used for identification of protein-protein interactions. Our analyses detected interaction with a novel set of proteins and reinforced previous observations linking KIN to factors involved in RNA processing, notably pre-mRNA splicing and ribosome biogenesis. However, little evidence supports that this protein is directly coupled to DNA replication and/or repair processes, as previously suggested. Furthermore, a novel interaction was observed with PRMT7 (protein arginine methyltransferase 7) and we demonstrated that KIN is modified by this enzyme. This interactome analysis indicates that KIN is associated with several cell metabolism functions, and shows for the first time an association with ribosome biogenesis, suggesting that KIN is likely a moonlight protein.


Assuntos
Cromatina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neoplasias/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas de Ligação a RNA/metabolismo , Ribossomos/metabolismo , Células Cultivadas , Humanos , Neoplasias/genética , Neoplasias/patologia , Proteínas Nucleares/metabolismo , Mapas de Interação de Proteínas , Splicing de RNA
15.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445354

RESUMO

PURPOSE: A major issue in radiotherapy is the relative resistance of hypoxic cells to radiation. Historic approaches to this problem include the use of oxygen mimetic compounds to sensitize tumour cells, which were unsuccessful. This review looks at modern approaches aimed at increasing the efficacy of targeting and radiosensitizing hypoxic tumour microenvironments relative to normal tissues and asks the question of whether non-targeted effects in radiobiology may provide a new "target". Novel techniques involve the integration of recent technological advancements such as nanotechnology, cell manipulation, and medical imaging. Particularly, the major areas of research discussed in this review include tumour hypoxia imaging through PET imaging to guide carbogen breathing, gold nanoparticles, macrophage-mediated drug delivery systems used for hypoxia-activate prodrugs, and autophagy inhibitors. Furthermore, this review outlines several features of these methods, including the mechanisms of action to induce radiosensitization, the increased accuracy in targeting hypoxic tumour microenvironments relative to normal tissue, preclinical/clinical trials, and future considerations. CONCLUSIONS: This review suggests that the four novel tumour hypoxia therapeutics demonstrate compelling evidence that these techniques can serve as powerful tools to increase targeting efficacy and radiosensitizing hypoxic tumour microenvironments relative to normal tissue. Each technique uses a different way to manipulate the therapeutic ratio, which we have labelled "oxygenate, target, use, and digest". In addition, by focusing on emerging non-targeted and out-of-field effects, new umbrella targets are identified, which instead of sensitizing hypoxic cells, seek to reduce the radiosensitivity of normal tissues.


Assuntos
Terapia de Alvo Molecular/métodos , Neoplasias/terapia , Hipóxia Tumoral/fisiologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Morte Celular , Humanos , Terapia de Alvo Molecular/tendências , Neoplasias/patologia , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Terapias em Estudo/métodos , Terapias em Estudo/tendências
16.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445629

RESUMO

General cancer-targeted ligands that can deliver drugs to cells have been given considerable attention. In this paper, a high-affinity DNA aptamer (HG1) generally binding to human tumor cells was evolved by cell-SELEX, and was further optimized to have 35 deoxynucleotides (HG1-9). Aptamer HG1-9 could be taken up by live cells, and its target protein on a cell was identified to be human transferrin receptor (TfR). As a man-made ligand of TfR, aptamer HG1-9 was demonstrated to bind at the same site of human TfR as transferrin with comparable binding affinity, and was proved to cross the epithelium barrier through transferrin receptor-mediated transcytosis. These results suggest that aptamer HG1-9 holds potential as a promising ligand to develop general cancer-targeted diagnostics and therapeutics.


Assuntos
Aptâmeros de Nucleotídeos/metabolismo , Neoplasias/metabolismo , Receptores da Transferrina/metabolismo , Técnica de Seleção de Aptâmeros/métodos , Aptâmeros de Nucleotídeos/química , Humanos , Ligantes , Neoplasias/patologia , Transcitose , Células Tumorais Cultivadas
17.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445633

RESUMO

Caspases, a family of cysteine-aspartic proteases, have an established role as critical components in the activation and initiation of apoptosis. Alongside this a variety of non-apoptotic caspase functions in proliferation, differentiation, cellular plasticity and cell migration have been reported. The activity level and context are important factors in determining caspase function. As a consequence of their critical role in apoptosis and beyond, caspases are uniquely situated to have pathological roles, including in cancer. Altered caspase function is a common trait in a variety of cancers, with apoptotic evasion defined as a "hallmark of cancer". However, the role that caspases play in cancer is much more complex, acting both to prevent and to promote tumourigenesis. This review focuses on the major findings in Drosophila on the dual role of caspases in tumourigenesis. This has major implications for cancer treatments, including chemotherapy and radiotherapy, with the activation of apoptosis being the end goal. However, such treatments may inadvertently have adverse effects on promoting tumour progression and acerbating the cancer. A comprehensive understanding of the dual role of caspases will aid in the development of successful cancer therapeutic approaches.


Assuntos
Apoptose , Carcinogênese , Caspases/metabolismo , Neoplasias/patologia , Animais , Drosophila , Humanos , Neoplasias/enzimologia , Neoplasias/etiologia , Neoplasias/prevenção & controle
18.
Nat Commun ; 12(1): 5041, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413299

RESUMO

In vivo reprogramming provokes a wide range of cell fate conversion. Here, we discover that in vivo induction of higher levels of OSKM in mouse somatic cells leads to increased expression of primordial germ cell (PGC)-related genes and provokes genome-wide erasure of genomic imprinting, which takes place exclusively in PGCs. Moreover, the in vivo OSKM reprogramming results in development of cancer that resembles human germ cell tumors. Like a subgroup of germ cell tumors, propagated tumor cells can differentiate into trophoblasts. Moreover, these tumor cells give rise to induced pluripotent stem cells (iPSCs) with expanded differentiation potential into trophoblasts. Remarkably, the tumor-derived iPSCs are able to contribute to non-neoplastic somatic cells in adult mice. Mechanistically, DMRT1, which is expressed in PGCs, drives the reprogramming and propagation of the tumor cells in vivo. Furthermore, the DMRT1-related epigenetic landscape is associated with trophoblast competence of the reprogrammed cells and provides a therapeutic target for germ cell tumors. These results reveal an unappreciated route for somatic cell reprogramming and underscore the impact of reprogramming in development of germ cell tumors.


Assuntos
Células-Tronco Pluripotentes Induzidas/patologia , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias/patologia , Fatores de Transcrição/metabolismo , Animais , Animais Geneticamente Modificados , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Células Cultivadas , Reprogramação Celular/fisiologia , Epigênese Genética , Feminino , Impressão Genômica , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/metabolismo , Fatores de Transcrição/genética
19.
Biomed Res Int ; 2021: 9800488, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34458371

RESUMO

Immune checkpoint inhibitors (ICIs) have been increasingly used in the treatment of various types of tumors with favorable results. But these treatments also led to a variety of immune-related adverse events (irAEs). Neurological irAEs such as Guillain-Barré Syndrome are rare and may have serious consequences once they occur. A systematic literature search was performed in PubMed and Embase for all case reports of GBS associated with ICIs published in English reporting on human beings from 1990 up to date. A total of 30 case reports (total patients = 33) were used for final analysis. The included cases were from 11 countries, covering 10 tumor types, with melanoma accounting for the largest number. The mean age was 62.2 ± 11.1 years old, and males were dominant (male: 26 and female: 7). The median time of initial symptoms was 8.2 weeks after the 1st dose of ICIs. The most common manifestations of GBS associated with ICIs were weakness, hyporeflexia or areflexia, and paresthesia in order. The GBS subtypes suggested by electrophysiological results were acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), and Miller Fisher syndrome (MFS). The protein level of CSF in patients with GBS related to ICIs was 180.68 ± 152.51 mg/dl. Immediate termination of ICIs followed by intravenous immunoglobulin was the preferred treatment option. 72.7% of patients recovered or had residual mild dysfunction after treatment. Elderly male patients with melanoma were most likely to develop ICI-related GBS. The specific neurological symptoms, CSF analysis, and electrophysiological examination were important means of diagnosis.


Assuntos
Síndrome de Guillain-Barré/induzido quimicamente , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias/tratamento farmacológico , Polineuropatias/etiologia , Fenômenos Eletrofisiológicos , Síndrome de Guillain-Barré/imunologia , Síndrome de Guillain-Barré/fisiopatologia , Humanos , Inibidores de Checkpoint Imunológico/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Neoplasias/metabolismo , Neoplasias/patologia , Farmacovigilância , Polineuropatias/patologia , Resultado do Tratamento
20.
Biomolecules ; 11(8)2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34439786

RESUMO

The global increase in cancer mortality and economic losses necessitates the cautious quest for therapeutic agents with compensatory advantages over conventional therapies. Anticancer peptides (ACPs) are a subset of host defense peptides, also known as antimicrobial peptides, which have emerged as therapeutic and diagnostic candidates due to several compensatory advantages over the non-specificity of the current treatment regimens. This review aimed to highlight the ravaging incidence of cancer, the use of ACPs in cancer treatment with their mechanisms, ACP discovery and delivery methods, and the limitations for their use. This would create awareness for identifying more ACPs with better specificity, accuracy and sensitivity towards the disease. It would also promote their efficacious utilization in biotechnology, medical sciences and molecular biology to ease the severity of the disease and enable the patients living with these conditions to develop an accommodating lifestyle.


Assuntos
Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Antineoplásicos/uso terapêutico , Membrana Celular/efeitos dos fármacos , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Sequência de Aminoácidos , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Membrana Celular/química , Membrana Celular/metabolismo , Descoberta de Drogas/métodos , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia
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