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1.
Biomed Mater ; 17(1)2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34736242

RESUMO

This study aims to construct a composite system of the tri-block polyethylene glycol injectable hydrogel (3B-PEG IH) and neural epithelial growth factor-like protein 1 (Nell-1), and to analyze its therapeutic effect on temporomandibular joint osteoarthritis (TMJOA). Sol-gel transition temperature was measured via inverting test. The viscoelastic modulus curves was measured by rheometer. Degradation and controlled release profiles of 3B-PEG IH were drawnin vitro.In vivogel retention and biocompatibility were completed subcutaneously on the back of rats. After primary chondrocytes were extracted and identified, the cell viability in 3B-PEG IH was measured. Evaluation of gene expression in hydrogel was performed by real-time polymerase chain reaction. TMJOA rabbits were established by intra-articular injection of type II collagenase. Six weeks after composite systems being injected, gross morphological score, micro-CT, histological staining and grading were evaluated. The rusults showed that different types of 3B-PEG IH all reached a stable gel state at 37 °C and could support the three-dimensional growth of chondrocytes, but poly(lactide-co-caprolactone)-block-poly(ethyleneglycol)-block-poly(lactide-co-caprolactone) (PLCL-PEG-PLCL) hydrogel had a wider gelation temperature range and better hydrolytic stability for about 4 weeks. Its controlled release curve is closest to the zero-order release kinetics.In vitro, PLCL-PEG-PLCL/Nell-1 could promote the chondrogenic expression and reduce the inflammatory expression.In vivo, TMJOA rabbits were mainly characterized by the disorder of cartilage structure and the destruction of subchondral bone. However, PLCL-PEG-PLCL/Nell-1 could reverse the destruction of the subchondral trabecula, restore the fibrous and proliferative layers of the surface, and reduce the irregular hyperplasia of fibrocartilage layer. In conclusion, by comparing the properties of different 3B-PEG IH, 20 wt% PLCL-PEG-PLCL hydrogel was selected as the most appropriate material. PLCL-PEG-PLCL/Nell-1 composite could reverse osteochondral damage caused by TMJOA, Nfatc1-Runx3 signaling pathway may play a role in it. This study may provide a novel, minimally-invasive therapeutic strategy for the clinical treatment of TMJOA.

2.
SAGE Open Med Case Rep ; 9: 2050313X211054268, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34691476

RESUMO

Cryptococcosis is a rare complication of sarcoidosis, especially when it grows in lungs. It may escape from being diagnosed because of low prevalence and non-specific radiological presentation. Hereby, we reported an unusual case of pulmonary cryptococcosis secondary to the long-term use of glucocorticoids to treat sarcoidosis which can be misdiagnosed as progression of sarcoidosis due to the similar radiological presentation. After targeted therapy with fluconazole for 5 months, her chest computed tomography rescan revealed resolution of the pulmonary lesions.

4.
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
5.
Biomed Res Int ; 2021: 9978651, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34307684

RESUMO

Temporomandibular joint osteoarthritis (TMJOA) is characterized by chronic inflammatory degradation of mandibular condylar cartilage (MCC). Studies have found a positive correlation between inflammation and cyclooxygenase- (COX-) 2 in OA pathology. NF-κB is a crucial transcription factor of inflammatory and immune responses in the cause of TMJOA pathology. Resveratrol (RES) plays a critical role in antioxidation and anti-inflammation. But, studies on the effects of RES on TMJOA are very limited. So, the purpose of this study is to investigate the antioxidant and protective effects of RES against MCC degradation through downregulating COX-2/NF-κB expression. In vitro studies, the MCC cells were divided into three groups: the NC group, OA group, and RES group. The optimum dose of RES (10 µM) was determined. The TMJOA model of mice was created by injection of collagenase. And mice were injected with RES (100 µg/10 µl) 3 times one week for 4 weeks in the RES group. The expressions of COX-2, P65, MMP1, MMP13, COL2, and ACAN were measured by RT-PCR. Morphological changes of MCC were studied with HE staining. The results showed that inflammation could induce MCC degradation in vitro and vivo, while RES could reverse the degradation. Meanwhile, RES could downregulate COX-2/NF-κB/MMP expression and increase cartilage markers in vitro and vivo studies. The results indicated that RES treatment had antioxidant effects against chondrocyte apoptosis by downregulating the COX-2/NF-κB pathway in created TMJOA.


Assuntos
Antioxidantes/farmacologia , Apoptose , Condrócitos/patologia , Ciclo-Oxigenase 2/metabolismo , NF-kappa B/metabolismo , Osteoartrite/patologia , Substâncias Protetoras/farmacologia , Resveratrol/envenenamento , Articulação Temporomandibular/patologia , Animais , Apoptose/efeitos dos fármacos , Cartilagem Articular/patologia , Condrócitos/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Modelos Animais de Doenças , Feminino , Interleucina-1beta/farmacologia , Mandíbula/patologia , Camundongos Endogâmicos C57BL , Resveratrol/farmacologia
6.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 50(2): 212-221, 2021 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-34137227

RESUMO

Temporomandibular joint osteoarthritis (TMJOA) is mainly manifested as perforation of temporomandibular joint disc (TMJD) and destruction of condylar osteochondral complex (COCC). In recent years, tissue engineering technology has become one of the effective strategies in repairing this damage. With the development of scaffold material technology, composite scaffolds have become an important means to optimize the performance of scaffolds with the combined advantages of natural materials and synthetic materials. The gelling method with the minimally invasive concept can greatly solve the problems of surgical trauma and material anastomosis, which is beneficial to the clinical transformation of temporomandibular joint tissue engineering. Extracellular matrix scaffolds technology can solve the problem of scaffold source and maximize the simulation of the extracellular environment, which provides an important means for the transformation of temporo joint tissue engineering to animal level. Due to the limitation of the source and amplification of costal chondrocytes, the use of mesenchymal stem cells from different sources has been widely used for temporomandibular joint tissue engineering. The fibrochondral stem cells isolated from surface layer of articular cartilage may provide one more suitable cell source. Transforming growth factor ß superfamily, due to its osteochondrogenesis activity has been widely used in tissue engineering, and platelet-rich derivative as a convenient preparation of compound biological factor, gradually get used in temporomandibular joint tissue engineering. With the deepening of research on extracellular microenvironment and mechanical stimulation, mesenchymal stem cells, exosomes and stress stimulation are increasingly being used to regulate the extracellular microenvironment. In the future, the combination of complex bioactive factors and certain stress stimulation may become a trend in the temporomandibular joint tissue engineering research. In this article, the progress on tissue engineering in repairing COCC and TMJD, especially in scaffold materials, seed cells and bioactive factors, are reviewed, so as to provide information for future research design and clinical intervention.


Assuntos
Células-Tronco Mesenquimais , Engenharia Tecidual , Animais , Articulação Temporomandibular/cirurgia , Disco da Articulação Temporomandibular/cirurgia , Tecidos Suporte
7.
Front Med (Lausanne) ; 8: 656194, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33855039

RESUMO

Background: Talaromycosis is a serious fungal infection which is rare in immunocompetent people. Since its clinical manifestations lack specificity, it is easy to escape diagnosis or be misdiagnosed leading to high mortality and poor prognosis. It is necessary to be alert to the disease when broad-spectrum antibiotics do not work well in immunocompetent patients. Case Presentation: A 79-year-old man was admitted to our Infectious Diseases Department for recurrent fever and cough. Before admission he has been treated with piperacillin-tazobactam, moxifloxacin followed by antituberculous agents in other hospitals while his symptoms were not thoroughly eased. During the first hospitalization in another hospital, he has been ordered a series of examination including radionuclide whole body bone imaging, transbronchial needle aspiration for subcarinal nodes. However, the results were negative showing no neoplasm. After being admitted to our hospital, he underwent various routine examinations. The initial diagnosis was bacterial pneumonia, and he was given meropenem injection and tigecycline injection successively, but there were no improvement of symptoms and inflammatory indicators. In the end, the main pathogen Talaromyces marneffei was confirmed using Metagenomic Next-Generation Sequencing (mNGS), and his clinical symptoms gradually relieved after targeted antifungal treatment using voriconazole. Conclusion: When empirical anti-infective treatment is ineffective, it is necessary to consider the possibility of opportunistic fungal infections on immunocompetent patients. mNGS, as a new generation of pathogenic testing methods, can often detect pathogenic bacteria faster than traditional methods, providing important help for clinical decision-making.

8.
Nat Commun ; 12(1): 400, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33452255

RESUMO

Promoter DNA methylation is a well-established mechanism of transcription repression, though its global correlation with gene expression is weak. This weak correlation can be attributed to the failure of current methylation quantification methods to consider the heterogeneity among sequenced bulk cells. Here, we introduce Cell Heterogeneity-Adjusted cLonal Methylation (CHALM) as a methylation quantification method. CHALM improves understanding of the functional consequences of DNA methylation, including its correlations with gene expression and H3K4me3. When applied to different methylation datasets, the CHALM method enables detection of differentially methylated genes that exhibit distinct biological functions supporting underlying mechanisms.


Assuntos
Metilação de DNA , Epigênese Genética , Epigenômica/métodos , Regiões Promotoras Genéticas/genética , Sequenciamento de Cromatina por Imunoprecipitação , Ilhas de CpG/genética , Conjuntos de Dados como Assunto , Aprendizado Profundo , Histonas , Humanos , RNA-Seq
9.
Sci Adv ; 6(51)2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33328229

RESUMO

Circadian gene expression driven by transcription activators CLOCK and BMAL1 is intimately associated with dynamic chromatin remodeling. However, how cellular metabolism directs circadian chromatin remodeling is virtually unexplored. We report that the S-adenosylhomocysteine (SAH) hydrolyzing enzyme adenosylhomocysteinase (AHCY) cyclically associates to CLOCK-BMAL1 at chromatin sites and promotes circadian transcriptional activity. SAH is a potent feedback inhibitor of S-adenosylmethionine (SAM)-dependent methyltransferases, and timely hydrolysis of SAH by AHCY is critical to sustain methylation reactions. We show that AHCY is essential for cyclic H3K4 trimethylation, genome-wide recruitment of BMAL1 to chromatin, and subsequent circadian transcription. Depletion or targeted pharmacological inhibition of AHCY in mammalian cells markedly decreases the amplitude of circadian gene expression. In mice, pharmacological inhibition of AHCY in the hypothalamus alters circadian locomotor activity and rhythmic transcription within the suprachiasmatic nucleus. These results reveal a previously unappreciated connection between cellular metabolism, chromatin dynamics, and circadian regulation.

10.
J Int Med Res ; 48(9): 300060520952256, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32910698

RESUMO

Since the outbreak of coronavirus disease 2019 (COVID-19) in December 2019, an epidemic has spread rapidly worldwide. COVID-19 is caused by the highly infectious severe acute respiratory syndrome coronavirus-2. A 42-year-old woman presented to hospital who was suffering from epigastric discomfort and dyspepsia for the past 5 days. Before the onset of symptoms, she was healthy, and had no travel history to Wuhan or contact with laboratory-confirmed COVID-19 cases. An examination showed chronic superficial gastritis with erosion and esophagitis. Enhanced magnetic resonance imaging of the abdomen showed a lesion in the right lower lobe of the lungs. Chest computed tomography showed multiple ground-glass opacity in the lungs. Reverse transcription-polymerase chain reaction was negative for severe acute respiratory syndrome coronavirus-2. There was no improvement after antibiotic treatment. Polymerase chain reaction performed 2 days later was positive and she was diagnosed with COVID-19. After several days of antiviral and symptomatic treatments, her symptoms improved and she was discharged. None of the medical staff were infected. Clinical manifestations of COVID-19 are nonspecific, making differentiating it from other diseases difficult. This case shows the sequence in which symptoms developed in a patient with COVID-19 with gastrointestinal symptoms as initial manifestations.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/complicações , Gastroenteropatias/diagnóstico , Gastroenteropatias/virologia , Pneumonia Viral/complicações , Adulto , COVID-19 , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Feminino , Gastroenteropatias/patologia , Humanos , Pandemias , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Prognóstico , SARS-CoV-2
11.
Infect Dis (Lond) ; 52(12): 891-901, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32735163

RESUMO

BACKGROUND: No data is available about in-flight transmission of SARS-CoV-2. Here, we report an in-flight transmission cluster of COVID-19 and describe the clinical characteristics of these patients. METHODS: After a flight, laboratory-confirmed COVID-19 was reported in 12 patients. Ten patients were admitted to the designated hospital. Data was collected from 25th January to 28th February 2020. Clinical information was retrospectively collected. RESULTS: All patients were passengers, and none were flight attendants. The median age was 33 years, and 70% were females. None was admitted to intensive care unit, and no patients died up to 28th February. The median incubation period was 3.0 days and time from onset of illness to hospital admission was 2 days. The most common symptom was fever. Two patients were asymptomatic and had normal chest CT scan during hospital stay. On admission, initial RT-PCR was positive in 9 patients, and initial chest CT was positive in half of the patients. The median lung 'total severity score' of chest CT was 6. 'Crazy-paving' pattern, pleural effusion, and ground-glass nodules were seen. CONCLUSION: There is potential for COVID-19 transmission in aeroplanes, but the symptoms were mild in our patients. Passengers and attendants must be protected during flights.


Assuntos
Aeronaves , Infecções por Coronavirus/transmissão , Pneumonia Viral/transmissão , Adulto , Betacoronavirus/isolamento & purificação , COVID-19 , China/epidemiologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Feminino , Febre/diagnóstico , Febre/virologia , Humanos , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/terapia , Pneumonia Viral/virologia , Estudos Retrospectivos , SARS-CoV-2 , Tomografia Computadorizada por Raios X , Resultado do Tratamento
12.
Artigo em Inglês | MEDLINE | ID: mdl-32548104

RESUMO

Background: Grafting of biomaterial in alveolar defect facilitates bone healing and orthodontic treatment. BMP2-functionalized biomimetic calcium phosphate (BioCaP) graft had shown excellent bone defect healing potential in many preclinical studies. In this study, we aimed to investigate the influence of BioCaP graft on surgical alveolar bone defect healing during orthodontic tooth movement (OTM) in beagle dogs. Methods: Nine Beagle dogs were randomly assigned to three groups: control, deproteinized bovine bone (DBB), and BioCaP. The maxillary second premolars were protracted into the defects of the extracted maxillary first premolar for 8 weeks. The rate of OTM, alveolar remodeling and bone defect healing were evaluated by histology, histomorphometry, and cone beam computed tomography (CBCT) imaging. Periodontal probing depth was analyzed. Gingival cervicular fluid was collected at week 4 and 8, and the IL-1ß level was measured by ELISA. Results: The histological sections of the bone defect showed more newly formed bone in the BioCaP group. The percentage of new bone formation in the BioCaP group was 1.61-, and 1.25-fold higher compared to the control and DBB group, respectively. After 8 weeks of OTM, the resorption rate of BioCaP was 1.42-fold higher compared to DBB. The root resorption index in the DBB group was 1.87-, and 1.39-fold higher compared to the control and BioCaP group, respectively. CBCT images showed 1.92-, and 1.36-fold higher bone mineral density in the BioCaP group compared to the control and DBB group, respectively. There was no significant difference in OTM among the three groups. The distance between the enamel cementum and the crest of the alveolar ridge in the control group was 1.45-, and 1.69-fold higher compared to DBB and BioCaP group, respectively. Periodontal probing depth at week 8 was reduced in the BioCaP group compared to the control. IL-1ß concentration in the gingival cervicular fluid was significantly lower in the BioCaP group compared to the control group at week 4 and 8. Conclusion: BioCaP graft robustly promoted bone regeneration and alveolar bone defect healing without affecting OTM. BioCaP graft caused less alveolar bone recession and root resorption of traction tooth with favorable periodontal attachment level indicating that BioCaP as a bioactive and functional bone filling material for alveolar bone defects during orthodontic treatment.

13.
JCO Clin Cancer Inform ; 4: 567-582, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32598180

RESUMO

PURPOSE: Methods for depth normalization have been assessed primarily with simulated data or cell-line-mixture data. There is a pressing need for benchmark data enabling a more realistic and objective assessment, especially in the context of small RNA sequencing. METHODS: We collected a unique pair of microRNA sequencing data sets for the same set of tumor samples; one data set was collected with and the other without uniform handling and balanced design. The former provided a benchmark for evaluating evidence of differential expression and the latter served as a test bed for normalization. Next, we developed a data perturbation algorithm to simulate additional data set pairs. Last, we assembled a set of computational tools to visualize and quantify the assessment. RESULTS: We validated the quality of the benchmark data and showed the need for normalization of the test data. For illustration, we applied the data and tools to assess the performance of 9 existing normalization methods. Among them, trimmed mean of M-values was a better scaling method, whereas the median and the upper quartiles were consistently the worst performers; one variation of remove unwanted variation had the best chance of capturing true positives but at the cost of increased false positives. In general, these methods were, at best, moderately helpful when the level of differential expression was extensive and asymmetric. CONCLUSION: Our study (1) provides the much-needed benchmark data and computational tools for assessing depth normalization, (2) shows the dependence of normalization performance on the underlying pattern of differential expression, and (3) calls for continued research efforts to develop more effective normalization methods.


Assuntos
Algoritmos , Benchmarking , Humanos , Análise de Sequência de RNA
14.
Nat Cell Biol ; 22(4): 476-486, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32231310

RESUMO

SLC7A11-mediated cystine uptake is critical for maintaining redox balance and cell survival. Here we show that this comes at a significant cost for cancer cells with high levels of SLC7A11. Actively importing cystine is potentially toxic due to its low solubility, forcing cancer cells with high levels of SLC7A11 (SLC7A11high) to constitutively reduce cystine to the more soluble cysteine. This presents a significant drain on the cellular NADPH pool and renders such cells dependent on the pentose phosphate pathway. Limiting glucose supply to SLC7A11high cancer cells results in marked accumulation of intracellular cystine, redox system collapse and rapid cell death, which can be rescued by treatments that prevent disulfide accumulation. We further show that inhibitors of glucose transporters selectively kill SLC7A11high cancer cells and suppress SLC7A11high tumour growth. Our results identify a coupling between SLC7A11-associated cystine metabolism and the pentose phosphate pathway, and uncover an accompanying metabolic vulnerability for therapeutic targeting in SLC7A11high cancers.


Assuntos
Sistema y+ de Transporte de Aminoácidos/genética , Carcinoma de Células Renais/genética , Cistina/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/genética , Via de Pentose Fosfato/genética , Sistema y+ de Transporte de Aminoácidos/antagonistas & inibidores , Sistema y+ de Transporte de Aminoácidos/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Dissulfetos/metabolismo , Fármacos Gastrointestinais/farmacologia , Glucose/deficiência , Transportador de Glucose Tipo 1/antagonistas & inibidores , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 3/antagonistas & inibidores , Transportador de Glucose Tipo 3/genética , Transportador de Glucose Tipo 3/metabolismo , Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/metabolismo , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Camundongos , Camundongos Nus , Fosfogluconato Desidrogenase/genética , Fosfogluconato Desidrogenase/metabolismo , Pirazóis/farmacologia , Quinolinas/farmacologia , Estresse Fisiológico , Sulfassalazina/farmacologia , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Cancer Res ; 80(11): 2243-2256, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32273282

RESUMO

Epigenetic regulation of gene transcription has been shown to coordinate with nutrient availability, yet the mechanisms underlying this coordination remain incompletely understood. Here, we show that glucose starvation suppresses histone 2A K119 monoubiquitination (H2Aub), a histone modification that correlates with gene repression. Glucose starvation suppressed H2Aub levels independently of energy stress-mediated AMP-activated protein kinase activation and possibly through NADPH depletion and subsequent inhibition of BMI1, an integral component of polycomb-repressive complex 1 (PRC1) that catalyzes H2Aub on chromatin. Integrated transcriptomic and epigenomic analyses linked glucose starvation-mediated H2Aub repression to the activation of genes involved in the endoplasmic reticulum (ER) stress response. We further showed that this epigenetic mechanism has a role in glucose starvation-induced cell death and that pharmacologic inhibition of glucose transporter 1 and PRC1 synergistically promoted ER stress and suppressed tumor growth in vivo. Together, these results reveal a hitherto unrecognized epigenetic mechanism coupling glucose availability to the ER stress response. SIGNIFICANCE: These findings link glucose deprivation and H2A ubiquitination to regulation of the ER stress response in tumor growth and demonstrate pharmacologic susceptibility to inhibition of polycomb and glucose transporters.


Assuntos
Estresse do Retículo Endoplasmático/genética , Glucose/metabolismo , Histonas/genética , Histonas/metabolismo , Neoplasias Renais/genética , Neoplasias Pulmonares/genética , Animais , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Morte Celular/fisiologia , Linhagem Celular Tumoral , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Glucose/administração & dosagem , Glucose/deficiência , Transportador de Glucose Tipo 1/antagonistas & inibidores , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Células HEK293 , Xenoenxertos , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Fosforilação , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Ubiquitinação
16.
Cancer Cell ; 37(3): 387-402.e7, 2020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32142667

RESUMO

We report that neurofibromin, a tumor suppressor and Ras-GAP (GTPase-activating protein), is also an estrogen receptor-α (ER) transcriptional co-repressor through leucine/isoleucine-rich motifs that are functionally independent of GAP activity. GAP activity, in turn, does not affect ER binding. Consequently, neurofibromin depletion causes estradiol hypersensitivity and tamoxifen agonism, explaining the poor prognosis associated with neurofibromin loss in endocrine therapy-treated ER+ breast cancer. Neurofibromin-deficient ER+ breast cancer cells initially retain sensitivity to selective ER degraders (SERDs). However, Ras activation does play a role in acquired SERD resistance, which can be reversed upon MEK inhibitor addition, and SERD/MEK inhibitor combinations induce tumor regression. Thus, neurofibromin is a dual repressor for both Ras and ER signaling, and co-targeting may treat neurofibromin-deficient ER+ breast tumors.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Receptor alfa de Estrogênio/genética , Neurofibromina 1/genética , Motivos de Aminoácidos , Animais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proteínas Correpressoras , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Células MCF-7 , Camundongos Nus , Camundongos SCID , Mutação , Neurofibromina 1/química , Neurofibromina 1/metabolismo , Transdução de Sinais , Tamoxifeno/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas ras/metabolismo
18.
Cell Death Differ ; 27(4): 1415-1430, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31582804

RESUMO

Upregulation of Nell-1 has been associated with craniosynostosis (CS) in humans, and validated in a mouse transgenic Nell-1 overexpression model. Global Nell-1 inactivation in mice by N-ethyl-N-nitrosourea (ENU) mutagenesis results in neonatal lethality with skeletal abnormalities including cleidocranial dysplasia (CCD)-like calvarial bone defects. This study further defines the role of Nell-1 in craniofacial skeletogenesis by investigating specific inactivation of Nell-1 in Wnt1 expressing cell lineages due to the importance of cranial neural crest cells (CNCCs) in craniofacial tissue development. Nell-1flox/flox; Wnt1-Cre (Nell-1Wnt1 KO) mice were generated for comprehensive analysis, while the relevant reporter mice were created for CNCC lineage tracing. Nell-1Wnt1 KO mice were born alive, but revealed significant frontonasal and mandibular bone defects with complete penetrance. Immunostaining demonstrated that the affected craniofacial bones exhibited decreased osteogenic and Wnt/ß-catenin markers (Osteocalcin and active-ß-catenin). Nell-1-deficient CNCCs demonstrated a significant reduction in cell proliferation and osteogenic differentiation. Active-ß-catenin levels were significantly low in Nell-1-deficient CNCCs, but were rescued along with osteogenic capacity to a level close to that of wild-type (WT) cells via exogenous Nell-1 protein. Surprisingly, 5.4% of young adult Nell-1Wnt1 KO mice developed hydrocephalus with premature ossification of the intrasphenoidal synchondrosis and widened frontal, sagittal, and coronal sutures. Furthermore, the epithelial cells of the choroid plexus and ependymal cells exhibited degenerative changes with misplaced expression of their respective markers, transthyretin and vimentin, as well as dysregulated Pit-2 expression in hydrocephalic Nell-1Wnt1 KO mice. Nell-1Wnt1 KO embryos at E9.5, 14.5, 17.5, and newborn mice did not exhibit hydrocephalic phenotypes grossly and/or histologically. Collectively, Nell-1 is a pivotal modulator of CNCCs that is essential for normal development and growth of the cranial vault and base, and mandibles partially via activating the Wnt/ß-catenin pathway. Nell-1 may also be critically involved in regulating cerebrospinal fluid homeostasis and in the pathogenesis of postnatal hydrocephalus.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Linhagem da Célula , Anormalidades Craniofaciais/patologia , Hidrocefalia/patologia , Osteocondrodisplasias/patologia , Proteína Wnt1/metabolismo , Animais , Animais Recém-Nascidos , Diferenciação Celular , Anormalidades Craniofaciais/complicações , Regulação para Baixo , Feminino , Hidrocefalia/complicações , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Crista Neural/patologia , Osteocondrodisplasias/complicações , Osteogênese , Penetrância , Via de Sinalização Wnt
19.
NAR Genom Bioinform ; 2(3): lqaa069, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33575618

RESUMO

Circos plots are widely used to display multi-dimensional next-generation genomic data, but existing implementations of Circos are not interactive with limited support of data types. Here, we developed next-generation Circos (NG-Circos), a flexible JavaScript-based circular genome visualization tool for designing highly interactive Circos plots using 21 functional modules with various data types. To our knowledge, NG-Circos is the most powerful software to construct interactive Circos plots. By supporting diverse data types in a dynamic browser interface, NG-Circos will accelerate the next-generation data visualization and interpretation, thus promoting the reproducible research in biomedical sciences and beyond. NG-Circos is available at https://wlcb.oit.uci.edu/NG-Circos and https://github.com/YaCui/NG-Circos.

20.
Sheng Li Xue Bao ; 71(5): 799-805, 2019 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-31646334

RESUMO

Nephronectin (NPNT) is a novel extracellular matrix protein and a new ligand of integrin α8ß1. Recent studies showed that NPNT is highly expressed in kidney, lung, thyroid, etc, and it may play an important role in many pathological conditions. NPNT is involved in the process of kidney development and acute kidney injury, regulates proliferation and differentiation of osteoblast, and induces the vasculogenesis in vitro. NPNT may play a key role in pathological osteoporosis and therefore be a new therapeutic target of bone diseases. NPNT gene variants are not only associated with lung function, but also potentially implicated in chronic airway diseases development. Moreover, NPNT is also an important factor that mediates pathology of cardiac, epidermis, breast, liver and teeth diseases. In this paper, we reviewed some research progresses on the structure, distribution, physiological and pathophysiological functions of NPNT.


Assuntos
Proteínas da Matriz Extracelular/fisiologia , Rim/fisiologia , Osteoblastos/citologia , Diferenciação Celular , Proliferação de Células , Humanos , Osteoporose
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