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1.
Anticancer Res ; 41(1): 517-526, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33419851

RESUMO

AIM: The evaluation of the prognostic role of nuclear pseudoinclusions (NPIs) and nuclear grooves (NGs) in UM. PATIENTS AND METHODS: We examined the presence of NPIs and NGs in hematoxylin and eosin-stained tissue sections from 164 removed eyeballs with uveal melanoma (UM) and analyzed statistical relationships with clinical and pathological parameters and the long-term survival rate. RESULTS: We observed NPIs in 38% and NG in 21% of all UM. The presence of NPIs was significantly positively correlated with epithelioid type, marked pleomorphism, and the presence of multinucleated giant cells, macro-nucleoli and multiple nucleoli. Patients with UM with NPIs had a significantly reduced overall survival rate (p<0.0001). The presence of NGs was significantly inversely correlated with marked pleomorphism, and the presence of multinucleated giant cells, macro-nucleoli and multiple nucleoli. Kaplan-Meier analysis demonstrated significantly better overall (p<0.01) and disease-free (p<0.05) survival rates for patients with NGs. CONCLUSION: The obtained results suggest that the presence of NGs in UM is associated with a better prognosis, as opposed to the presence of NPIs, which means the prognosis is worse.


Assuntos
Biomarcadores Tumorais , Núcleo Celular/patologia , Corpos de Inclusão Intranuclear/patologia , Melanoma/mortalidade , Melanoma/patologia , Neoplasias Uveais/mortalidade , Neoplasias Uveais/patologia , Idoso , Feminino , Histocitoquímica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico
2.
J Clin Pathol ; 74(3): 137-140, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33441390

RESUMO

TLE 1 is the human homologue belonging to a family of four genes and is located on chromosome 9q21. It consists of 19 exons. Although it does not bind directly to DNA, it acts as a repressor of several signalling pathways via transcription factors. TLE1 protein has several physiological roles in embryogenesis, haematopoiesis, general differentiation, and both neuronal and eye development. Much attention was focused on its expression in the tumour cell nuclei of synovial sarcoma (SS). However, several other soft tissue tumours that do and do not share morphological similarity with SS also display nuclear immunoreactivity for TLE1; hence, caution in interpretation is advocated.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas Correpressoras/genética , Sarcoma Sinovial/genética , Sarcoma Sinovial/metabolismo , Neoplasias de Tecidos Moles/metabolismo , Núcleo Celular/patologia , Proteínas Correpressoras/metabolismo , Humanos , Imuno-Histoquímica , Oncogenes/genética , Neoplasias de Tecidos Moles/patologia
3.
Jpn J Clin Oncol ; 51(3): 434-443, 2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33420502

RESUMO

OBJECTIVE: The Japan Clinical Oncology Group 1505 trial is a single-arm multicentre prospective study that examined the possibility of non-surgical follow-up with endocrine therapy for patients with low-grade ductal carcinoma in situ. In that study, the eligible criteria included histopathological findings comprising low to intermediate nuclear grade and absence of comedo necrosis, and cases were entered according to the local histopathological diagnosis. Nuclear grade is largely based on the Consensus Conference criteria (1997), whereas comedo necrosis is judged according to the Rosen's criteria (2017). The purpose of this study was to standardize and examine the interobserver agreement levels of these histopathological criteria amongst the participating pathologists. METHODS: We held slide conferences, where photomicrographs of haematoxylin-eosin-stained slides from 68 patients with ductal carcinoma in situ were presented using PowerPoint. The nuclear grade and comedo necrosis statuses individually judged by the pathologists were analysed using κ statistics. RESULTS: In the first and second sessions, where 22 cases each were presented, the interobserver agreement levels of nuclear grade whether low/intermediate grade or high grade were moderate amongst 29 and 24 participating pathologists, respectively (κ = 0.595 and 0.519, respectively). In the third session where 24 cases were presented, interobserver agreement levels of comedo necrosis or non-comedo necrosis were substantial amongst 25 participating pathologists (κ = 0.753). CONCLUSION: Although the concordance rates in nuclear grade or comedo necrosis were not high in a few of the cases, we believe that these results could provide a rationale for employing the present criteria of nuclear grade and comedo necrosis in the clinical study of ductal carcinoma in situ.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Núcleo Celular/patologia , Oncologia , Carcinoma in Situ/patologia , Feminino , Humanos , Japão , Necrose , Variações Dependentes do Observador , Estudos Prospectivos , Reprodutibilidade dos Testes
4.
Int J Nanomedicine ; 15: 8383-8400, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33149582

RESUMO

Purpose: Cancer tissue-specific and nuclei-targeted drug delivery is ideal for the delivery of chemotherapy. However, it has only been achieved in in vitro studies mainly due to low efficiency in vivo. In this study, we aimed to establish an efficient dual-targeted system that targets liver cancer tissue as well as the nuclei of cancer cells in vivo. Methods: We first synthesized TAT peptide (TATp)-mesoporous silica nanoparticle (MSN) complex (TATp-MSN) and generated liposomes that carried liver cancer-specific aptamer TLS11a (TLS11a-LB). We then generated the drug TLS11a-LB@TATp-MSN/doxorubicin (DOX) by mixing TLS11a-LB and DOX-loaded TATp-MSN. After physical and chemical characterization of the nanoparticles, DOX release from these formulations was evaluated at pH 5.0 and 7.4. Furthermore, we also evaluated nuclear localization and cytotoxicity of the drug in H22 cells in vitro and investigated the liver cancer targeting and antitumor activities of the nano-drug in vivo using a H22 tumor-bearing mice model. Results: TLS11a-LB@TATp-MSN/DOX and its controls were confirmed as nano-drugs (<100 nm) using transmission electron microscopy (TEM). The DOX release rate of TLS11a-LB@TATp-MSN/DOX was significantly faster at pH 5.0 than at pH 7.4. TLS11a-LB@TATp-MSN/DOX effectively targeted the nuclei of H22 cells and released DOX with a higher efficiency than that of the control groups. In addition, TLS11a-LB@TATp-MSN/DOX exhibited slight cytotoxicity, but not significantly more than controls. In vivo studies showed that TLS11a-LB@TATp-MSN accumulated in subcutaneous H22 tumors in the right axilla of BALB/c mice, reaching peak levels at 48 h after intravenous injection, respectively, and demonstrated that TLS11a-LB@TATp-MSN/DOX group enhanced tumor treatment efficacy while reducing systemic side effects. Conclusion: TLS11a-LB@TATp-MSN/DOX can efficiently deliver DOX to the nuclei of liver cancer cells by dual targeting liver cancer tissue and the nuclei of the cancer cells in mice. Thus, it is a promising nano-drug for the treatment of liver cancer.


Assuntos
Núcleo Celular/patologia , Portadores de Fármacos/química , Neoplasias Hepáticas/patologia , Nanopartículas/química , Dióxido de Silício/química , Animais , Antineoplásicos/uso terapêutico , Aptâmeros de Peptídeos/química , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Neoplasias Hepáticas/tratamento farmacológico , Camundongos Endogâmicos BALB C , Nanopartículas/ultraestrutura , Porosidade , Produtos do Gene tat do Vírus da Imunodeficiência Humana/química
5.
Nat Commun ; 11(1): 4305, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855391

RESUMO

Oligomeric assemblies of tau and the RNA-binding proteins (RBPs) Musashi (MSI) are reported in Alzheimer's disease (AD). However, the role of MSI and tau interaction in their aggregation process and its effects are nor clearly known in neurodegenerative diseases. Here, we investigated the expression and cellular localization of MSI1 and MSI2 in the brains tissues of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) as well as in the wild-type mice and tau knock-out and P301L tau mouse models. We observed that formation of pathologically relevant protein inclusions was driven by the aberrant interactions between MSI and tau in the nuclei associated with age-dependent extracellular depositions of tau/MSI complexes. Furthermore, tau and MSI interactions induced impairment of nuclear/cytoplasm transport, chromatin remodeling and nuclear lamina formation. Our findings provide mechanistic insight for pathological accumulation of MSI/tau aggregates providing a potential basis for therapeutic interventions in neurodegenerative proteinopathies.


Assuntos
Núcleo Celular/patologia , Proteínas do Tecido Nervoso/metabolismo , Doenças Neurodegenerativas/patologia , Proteínas de Ligação a RNA/metabolismo , Proteínas tau/metabolismo , Transporte Ativo do Núcleo Celular , Idoso , Idoso de 80 Anos ou mais , Animais , Núcleo Celular/metabolismo , Montagem e Desmontagem da Cromatina , Citoplasma/metabolismo , Modelos Animais de Doenças , Feminino , Lobo Frontal/citologia , Lobo Frontal/patologia , Células HEK293 , Humanos , Corpos de Inclusão/patologia , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Agregados Proteicos , Ligação Proteica , Proteínas tau/genética
6.
Platelets ; 31(8): 1085-1089, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-32857624

RESUMO

Coronavirus disease 2019 (COVID-19) is a global public health emergency with many clinical facets, and new knowledge about its pathogenetic mechanisms is deemed necessary; among these, there are certainly coagulation disorders. In the history of medicine, autopsies and tissue sampling have played a fundamental role in order to understand the pathogenesis of emerging diseases, including infectious ones; compared to the past, histopathology can be now expanded by innovative techniques and modern technologies. For the first time in worldwide literature, we provide a detailed postmortem and biopsy report on the marked increase, up to 1 order of magnitude, of naked megakaryocyte nuclei in the bone marrow and lungs from serious COVID-19 patients. Most likely related to high interleukin-6 serum levels stimulating megakaryocytopoiesis, this phenomenon concurs to explain well the pulmonary abnormal immunothrombosis in these critically ill patients, all without molecular or electron microscopy signs of megakaryocyte infection.


Assuntos
Betacoronavirus/patogenicidade , Medula Óssea/patologia , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/patologia , Coagulação Intravascular Disseminada/patologia , Pulmão/patologia , Pneumonia Viral/patologia , Trombose/patologia , Adulto , Idoso , Autopsia , Betacoronavirus/imunologia , Medula Óssea/imunologia , Medula Óssea/virologia , Núcleo Celular/imunologia , Núcleo Celular/patologia , Núcleo Celular/virologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Estado Terminal , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/complicações , Coagulação Intravascular Disseminada/imunologia , Coagulação Intravascular Disseminada/virologia , Evolução Fatal , Interações Hospedeiro-Patógeno/imunologia , Humanos , Interleucina-6/biossíntese , Interleucina-6/imunologia , Pulmão/imunologia , Pulmão/virologia , Masculino , Megacariócitos/imunologia , Megacariócitos/patologia , Megacariócitos/virologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Índice de Gravidade de Doença , Trombopoese/imunologia , Trombose/complicações , Trombose/imunologia , Trombose/virologia
7.
Medicine (Baltimore) ; 99(34): e21841, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846831

RESUMO

RATIONALE: Ovarian microcystic stromal tumor is a relatively rare tumor type, which is characterized by morphology with microcyst structure, solid cellular areas, and hyalinized fibrous stroma. The most reported tumors were stage I with good prognosis. PATIENT CONCERNS: We report a case of a 33-year-old woman with primary ovarian microcystic stromal tumor with significant bizarre nuclei. We describe the clinical, histopathological, and immunohistochemical findings and review the English literatures. So far, as we know, the patient presented here is a rare case of ovarian microcystic stromal tumor with prominent bizarre nuclei accounting for about 50% of the tumor cells. DIAGNOSES: She was diagnosed with ovarian microcystic stromal tumor with significant bizarre nuclei. INTERVENTIONS: The right ovarian tumor was resected laparoscopically on October 19, 2018. OUTCOMES: Up to now, the patient is free of disease at 19 months of follow-up. LESSONS: This is a rare case of ovarian microcystic stromal tumor with obvious bizarre nuclei. This report will contribute to expand the morphological spectrum of ovarian microcystic stromal tumor.


Assuntos
Núcleo Celular/patologia , Neoplasias Ovarianas/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/cirurgia , beta Catenina/metabolismo , Adulto , Assistência ao Convalescente , Biomarcadores Tumorais/metabolismo , Núcleo Celular/metabolismo , Núcleo Celular/ultraestrutura , Feminino , Humanos , Imuno-Histoquímica/métodos , Laparoscopia/métodos , Resultado do Tratamento
8.
Am J Surg Pathol ; 44(8): 1082-1091, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32604170

RESUMO

Some recent reports suggested that many Sertoli cell tumors, not otherwise specified (SCTs-NOS) of the testis were analogs of the solid pseudopapillary neoplasm (SPN) of the pancreas. One of the most relied on pieces of information for this assertion was the shared occurrence in both neoplasms of exon 3 mutations of the CTNNB1 gene, which was reflected by nuclear ß-catenin expression. We, therefore, compared the morphologic and immunohistochemical features of 18 SCTs-NOS with strong, diffuse nuclear ß-catenin expression with 16 SPNs that also showed such positivity. Although there were clear similarities in the light microscopic features of these neoplasms, there were also significant differences that included, in SCT-NOS and SPN, respectively: hollow tubules (53% vs. 0%), sheet-like growth (44% vs. 94%), circumscription (79% vs. 25%), corded or trabecular patterns (81% vs. 31%), formation of papillae or pseudopapillae (24% vs. 69%), growth in nests or clusters (94% vs. 50%), perivascular pseudorosettes (13% vs. 56%), and rhabdoid cytology (6% vs. 50%). Commonly shared morphologic features included signet-ring cells, pale or foamy cytoplasm, myxoid stroma, cyst formation, perivascular hyalinization, and globular or band-like basement membrane deposits. On immunohistochemical study, sex cord markers were frequently positive in SCTs-NOS (steroidogenic factor-1-94%; FOXL2-87%; SOX9-69%; calretinin-60%; Wilms tumor-1-38%; inhibin-29%) whereas all of these markers were negative in the SPNs. We conclude that even though SCT-NOS and SPN share some morphologic features and nuclear immunoreactivity for ß-catenin, there remain differences, both morphologically and immunohistochemically, between these neoplasms to the degree that SCT-NOS should not be equated with pancreatic SPN.


Assuntos
Biomarcadores Tumorais/análise , Núcleo Celular/química , Imuno-Histoquímica , Neoplasias Pancreáticas/química , Tumor de Células de Sertoli/química , Neoplasias Testiculares/química , beta Catenina/análise , Biópsia , Núcleo Celular/patologia , Humanos , Masculino , Neoplasias Pancreáticas/classificação , Neoplasias Pancreáticas/patologia , Valor Preditivo dos Testes , Tumor de Células de Sertoli/classificação , Tumor de Células de Sertoli/patologia , Neoplasias Testiculares/classificação , Neoplasias Testiculares/patologia
9.
Nat Cell Biol ; 22(7): 856-867, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32601372

RESUMO

The ESCRT-III membrane fission machinery maintains the integrity of the nuclear envelope. Although primary nuclei resealing takes minutes, micronuclear envelope ruptures seem to be irreversible. Instead, micronuclear ruptures result in catastrophic membrane collapse and are associated with chromosome fragmentation and chromothripsis, complex chromosome rearrangements thought to be a major driving force in cancer development. Here we use a combination of live microscopy and electron tomography, as well as computer simulations, to uncover the mechanism underlying micronuclear collapse. We show that, due to their small size, micronuclei inherently lack the capacity of primary nuclei to restrict the accumulation of CHMP7-LEMD2, a compartmentalization sensor that detects loss of nuclear integrity. This causes unrestrained ESCRT-III accumulation, which drives extensive membrane deformation, DNA damage and chromosome fragmentation. Thus, the nuclear-integrity surveillance machinery is a double-edged sword, as its sensitivity ensures rapid repair at primary nuclei while causing unrestrained activity at ruptured micronuclei, with catastrophic consequences for genome stability.


Assuntos
Núcleo Celular/patologia , Cromatina/metabolismo , Aberrações Cromossômicas , Dano ao DNA , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Instabilidade Genômica , Proteínas de Membrana/metabolismo , Proteínas Nucleares/metabolismo , Núcleo Celular/genética , Núcleo Celular/metabolismo , Cromatina/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Células HeLa , Humanos
10.
Acta Cytol ; 64(6): 511-519, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32570234

RESUMO

BACKGROUND: For more than a century, diagnostic pathologists have used morphologic abnormalities of the nucleus as essential diagnostic features to distinguish benign from malignant cells. These features include nuclear enlargement and increased nuclear-to-cytoplasmic ratio, nuclear membrane irregularities, hyperchromasia, and abnormal chromatin distribution. As our knowledge about the genetic and epigenetic abnormalities of cancer cells has increased in recent decades, the pathophysiologic mechanisms that underlie these morphologic abnormalities remain incompletely understood. SUMMARY: This review attempts to summarize biologic abnormalities in malignant cells related to these morphologic changes. The molecular anatomy of the nuclear envelope in normal and malignant cells is discussed as well as regulation of nuclear size and shape, regulation of signal transduction pathways by molecules of the nuclear envelope, chromatin distribution, and the effects of HPV infection on dysplastic cells in the uterine cervix. Key Message: Causes of morphologic nuclear abnormalities in malignant cells are likely multifactorial. They probably include mutations, dysregulation of signal transduction pathways, abnormal gene expression patterns, alterations of nuclear envelope proteins and chromatin, and aneuploidy.


Assuntos
Núcleo Celular/patologia , Cromatina/patologia , Citoplasma/patologia , Neoplasias/patologia , Humanos , Neoplasias/genética , Membrana Nuclear/patologia , Transdução de Sinais/fisiologia
11.
Sci Data ; 7(1): 185, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32561748

RESUMO

The distribution and appearance of nuclei are essential markers for the diagnosis and study of cancer. Despite the importance of nuclear morphology, there is a lack of large scale, accurate, publicly accessible nucleus segmentation data. To address this, we developed an analysis pipeline that segments nuclei in whole slide tissue images from multiple cancer types with a quality control process. We have generated nucleus segmentation results in 5,060 Whole Slide Tissue images from 10 cancer types in The Cancer Genome Atlas. One key component of our work is that we carried out a multi-level quality control process (WSI-level and image patch-level), to evaluate the quality of our segmentation results. The image patch-level quality control used manual segmentation ground truth data from 1,356 sampled image patches. The datasets we publish in this work consist of roughly 5 billion quality controlled nuclei from more than 5,060 TCGA WSIs from 10 different TCGA cancer types and 1,356 manually segmented TCGA image patches from the same 10 cancer types plus additional 4 cancer types.


Assuntos
Núcleo Celular/patologia , Técnicas Histológicas , Processamento de Imagem Assistida por Computador , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Amarelo de Eosina-(YS) , Hematoxilina , Humanos
12.
Nat Commun ; 11(1): 3231, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32591511

RESUMO

Genomic instability (GI) predisposes cells to malignant transformation, however the molecular mechanisms that allow for the propagation of cells with a high degree of genomic instability remain unclear. Here we report that miR-181a is able to transform fallopian tube secretory epithelial cells through the inhibition of RB1 and stimulator-of-interferon-genes (STING) to propagate cells with a high degree of GI. MiR-181a targeting of RB1 leads to profound nuclear defects and GI generating aberrant cytoplasmic DNA, however simultaneous miR-181a mediated inhibition of STING allows cells to bypass interferon mediated cell death. We also found that high miR-181a is associated with decreased IFNγ response and lymphocyte infiltration in patient tumors. DNA oncoviruses are the only known inhibitors of STING that allow for cellular transformation, thus, our findings are the first to identify a miRNA that can downregulate STING expression to suppress activation of intrinsic interferon signaling. This study introduces miR-181a as a putative biomarker and identifies the miR-181a-STING axis as a promising target for therapeutic exploitation.


Assuntos
Carcinogênese/genética , Transformação Celular Neoplásica/genética , Imunidade Inata/genética , MicroRNAs/metabolismo , Transdução de Sinais , Animais , Linhagem Celular Tumoral , Núcleo Celular/patologia , Transformação Celular Neoplásica/patologia , Citocinese , Dano ao DNA , Células Epiteliais/patologia , Tubas Uterinas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Instabilidade Genômica , Células HEK293 , Humanos , Interferons/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , MicroRNAs/genética , Mitose , Gradação de Tumores , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo
13.
Nat Cell Biol ; 22(7): 828-841, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32541879

RESUMO

Mutations in chromatin-modifying complexes and metabolic enzymes commonly underlie complex human developmental syndromes affecting multiple organs. A major challenge is to determine how disease-causing genetic lesions cause deregulation of homeostasis in unique cell types. Here we show that neural-specific depletion of three members of the non-specific lethal (NSL) chromatin complex-Mof, Kansl2 or Kansl3-unexpectedly leads to severe vascular defects and brain haemorrhaging. Deregulation of the epigenetic landscape induced by the loss of the NSL complex in neural cells causes widespread metabolic defects, including an accumulation of free long-chain fatty acids (LCFAs). Free LCFAs induce a Toll-like receptor 4 (TLR4)-NFκB-dependent pro-inflammatory signalling cascade in neighbouring vascular pericytes that is rescued by TLR4 inhibition. Pericytes display functional changes in response to LCFA-induced activation that result in vascular breakdown. Our work establishes that neurovascular function is determined by the neural metabolic environment.


Assuntos
Núcleo Celular/patologia , Cromatina/metabolismo , Histona Acetiltransferases/fisiologia , Inflamação/patologia , Neovascularização Patológica/patologia , Neurônios/patologia , Pericitos/patologia , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Núcleo Celular/metabolismo , Cromatina/genética , Ácidos Graxos/metabolismo , Feminino , Feto/citologia , Feto/metabolismo , Humanos , Inflamação/metabolismo , Masculino , Metaboloma , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neovascularização Patológica/metabolismo , Neurônios/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Pericitos/metabolismo
14.
PLoS Genet ; 16(5): e1008754, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32365093

RESUMO

FSHD is characterized by the misexpression of DUX4 in skeletal muscle. Although DUX4 upregulation is thought to be the pathogenic cause of FSHD, DUX4 is lowly expressed in patient samples, and analysis of the consequences of DUX4 expression has largely relied on artificial overexpression. To better understand the native expression profile of DUX4 and its targets, we performed bulk RNA-seq on a 6-day differentiation time-course in primary FSHD2 patient myoblasts. We identify a set of 54 genes upregulated in FSHD2 cells, termed FSHD-induced genes. Using single-cell and single-nucleus RNA-seq on myoblasts and differentiated myotubes, respectively, we captured, for the first time, DUX4 expressed at the single-nucleus level in a native state. We identified two populations of FSHD myotube nuclei based on low or high enrichment of DUX4 and FSHD-induced genes ("FSHD-Lo" and "FSHD Hi", respectively). FSHD-Hi myotube nuclei coexpress multiple DUX4 target genes including DUXA, LEUTX and ZSCAN4, and also upregulate cell cycle-related genes with significant enrichment of E2F target genes and p53 signaling activation. We found more FSHD-Hi nuclei than DUX4-positive nuclei, and confirmed with in situ RNA/protein detection that DUX4 transcribed in only one or two nuclei is sufficient for DUX4 protein to activate target genes across multiple nuclei within the same myotube. DUXA (the DUX4 paralog) is more widely expressed than DUX4, and depletion of DUXA suppressed the expression of LEUTX and ZSCAN4 in late, but not early, differentiation. The results suggest that the DUXA can take over the role of DUX4 to maintain target gene expression. These results provide a possible explanation as to why it is easier to detect DUX4 target genes than DUX4 itself in patient cells and raise the possibility of a self-sustaining network of gene dysregulation triggered by the limited DUX4 expression.


Assuntos
Núcleo Celular/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Distrofia Muscular Facioescapuloumeral , RNA-Seq/métodos , Análise de Célula Única/métodos , Estudos de Casos e Controles , Diferenciação Celular , Núcleo Celular/química , Núcleo Celular/classificação , Núcleo Celular/patologia , Células Cultivadas , Regulação da Expressão Gênica , Células HEK293 , Humanos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Fibras Musculares Esqueléticas/patologia , Fibras Musculares Esqueléticas/fisiologia , Fibras Musculares Esqueléticas/ultraestrutura , Distrofia Muscular Facioescapuloumeral/genética , Distrofia Muscular Facioescapuloumeral/metabolismo , Distrofia Muscular Facioescapuloumeral/patologia , Mioblastos/metabolismo , Mioblastos/fisiologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Sequenciamento Completo do Exoma
15.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(1): 73-78, 2020 Jan 30.
Artigo em Chinês | MEDLINE | ID: mdl-32376550

RESUMO

OBJECTIVE: To investigate the association of chromosomal polymorphisms with multinucleated embryos in infertile couples undergoing in vitro fertilization-intracytoplasmic sperm injection (IVF-ICSI). METHODS: This retrospective case-control study was conducted among 1145 infertile couples undergoing their first IVF/ICSI cycles. According to their karyotype, the couples were divided into chromosomal polymorphism group and control group, and the former group was divided into 3 subgroups: inversion group, D and G genome polymorphic group and 1, 9, and 16 qh+group. The blastomere multinucleation rate, clinical pregnancy rate and live birth rate were compared between the groups. RESULTS: Of the total of 1145 couples, 139 (6.10%) had chromosomal polymorphisms at least in one partner. No significant differences were found in female age, BMI, basal FSH level, total gonadotropin dose, E2 level on day of HCG, number of oocytes retrieved, fertilization rate, top quality embryo rate, clinical pregnancy rate or live birth rate among the groups (P > 0.05). The multinuclear rate of the embryos in couples with pericentric inversion of chromosomes 1, 9, and Y chromosomes and those with D and G genome polymorphisms were 8.23% and 4.65%, respectively, significantly higher than that in the control group (2.69%; P < 0.05); the multinuclear rate of the embryos was 2.77% in 1, 9, and 16 qh+ group, similar with that in the control group (P > 0.05). CONCLUSIONS: Infertile couples with pericentric inversion of chromosomes 1, 9, and Y chromosomes and in those with D and G genome polymorphism are at higher risks of blastomere multinucleation in IVF- ICSI cycles; 1, 9, and 16 qh + polymorphisms do not increase the rate of blastomere multinucleation of the embryos.


Assuntos
Blastômeros , Núcleo Celular/patologia , Aberrações Cromossômicas , Injeções de Esperma Intracitoplásmicas , Estudos de Casos e Controles , Inversão Cromossômica , Desenvolvimento Embrionário , Feminino , Fertilização In Vitro , Humanos , Cariótipo , Masculino , Gravidez , Taxa de Gravidez , Estudos Retrospectivos
16.
Sci Rep ; 10(1): 6707, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317728

RESUMO

The nucleus is fundamentally composed by lamina and nuclear membranes that enclose the chromatin, nucleoskeletal components and suspending nucleoplasm. The functional connections of this network integrate external stimuli into cell signals, including physical forces to mechanical responses of the nucleus. Canonically, the morphological characteristics of the nucleus, as shape and size, have served for pathologists to stratify and diagnose cancer patients; however, novel biophysical techniques must exploit physical parameters to improve cancer diagnosis. By using multiple particle tracking (MPT) technique on chromatin granules, we designed a SURF (Speeded Up Robust Features)-based algorithm to study the mechanical properties of isolated nuclei and in living cells. We have determined the apparent shear stiffness, viscosity and optical density of the nucleus, and how the chromatin structure influences on these biophysical values. Moreover, we used our MPT-SURF analysis to study the apparent mechanical properties of isolated nuclei from patients of acute lymphoblastic leukemia. We found that leukemia cells exhibited mechanical differences compared to normal lymphocytes. Interestingly, isolated nuclei from high-risk leukemia cells showed increased viscosity than their counterparts from normal lymphocytes, whilst nuclei from relapsed-patient's cells presented higher density than those from normal lymphocytes or standard- and high-risk leukemia cells. Taken together, here we presented how MPT-SURF analysis of nuclear chromatin granules defines nuclear mechanical phenotypic features, which might be clinically relevant.


Assuntos
Núcleo Celular/patologia , Leucemia/patologia , Algoritmos , Cromatina/metabolismo , Elasticidade , Humanos , Células Jurkat , Pressão Osmótica , Fenótipo , Reologia , Viscosidade
18.
DNA Cell Biol ; 39(8): 1410-1420, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32315547

RESUMO

Mitochondria play an important role in numerous processes, including energy generation, regulating ion homeostasis, and cell signaling. Mitochondria are also the main source of reactive oxygen species (ROS). Due to the oxidative environment within mitochondria, the macromolecules therein, for example, mtDNA, proteins, and lipids are more susceptible to sustaining damage. During aging, mitochondrial functions decline, partly as a result of an accumulation of mtDNA mutations, decreased mtDNA copy number and protein expression, and a reduction in oxidative capacity. The aim of this study was to summarize the knowledge on DNA oxidative damage in aging and age-related neurodegenerative diseases. It has been hypothesized that various ROS may play an important role not only in physiological senescence but also in the development of neurodegenerative diseases, for example, Alzheimer's disease and Parkinson's disease. Thus, mitochondria seem to be a potential target of novel treatments for neurodegenerative diseases.


Assuntos
Envelhecimento/genética , Núcleo Celular/genética , Mitocôndrias/genética , Estresse Oxidativo/genética , Núcleo Celular/patologia , Dano ao DNA/genética , DNA Mitocondrial/genética , Humanos , Mitocôndrias/patologia , Espécies Reativas de Oxigênio/metabolismo
20.
Tissue Cell ; 63: 101322, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32223950

RESUMO

Despite profound knowledge of the incidence of oral cancers and a large body of research beyond it, it continues to beat diagnosis and treatment management. Post physical observation by clinicians, a biopsy is a gold standard for accurate detection of any abnormalities. Towards the application of artificial intelligence as an aid to diagnosis, automated cell nuclei segmentation is the most essential step for the recognition of the cancer cells. In this study, we have extracted the shape, texture and color features from the histopathological images collected indigenously from regional hospitals. A dataset of 42 whole slide slices was used to automatically segment and generate a cell level dataset of 720 nuclei. Next, different classifiers were applied for classification purposes. 99.4 % accuracy using Decision Tree Classifier, 100 % accuracy using both SVM and Logistic regression and 100 % accuracy using SVM, Logistic regression and Linear Discriminant were acquired for shape, textural and color features respectively. The in-depth analysis showed SVM and Linear Discriminant classifier gave the best result for texture and color features respectively. The achieved result can be effectively converted to software as an assistant diagnostic tool.


Assuntos
Carcinoma de Células Escamosas/patologia , Núcleo Celular/ultraestrutura , Processamento de Imagem Assistida por Computador , Neoplasias Bucais/patologia , Inteligência Artificial , Biópsia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/ultraestrutura , Núcleo Celular/patologia , Conjuntos de Dados como Assunto , Feminino , Humanos , Masculino , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/diagnóstico por imagem , Neoplasias Bucais/ultraestrutura
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