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Tm3+/Ho3+ doping tellurite glasses (TeO2-ZnO-La2O3) were prepared by applying melt-quenching technique, and the â¼2.0â µm band luminescence characteristics were examined. A broadband and relatively flat luminescence at 1600 to 2200â nm was observed in the tellurite glass co-doped by 1.0â mol% Tm2O3 and 0.085â mol% Ho2O3 under the excitation of 808â nm laser diode (LD), which is the result of spectral overlapping of 1.83â µm band of Tm3+ ions and 2.0â µm band of Ho3+ ions. Further, about 103% enhancement was acquired after the introduction of 0.1â mol% CeO2 and 7.5â mol% WO3 at the same time, which is primarily caused by the cross-relaxation between Tm3+ and Ce3+ ions together with the enhanced energy transfer from the Tm3+:3F4 level to Ho3+:5I7 level due to the increase in phonon energy. Spectral characteristics associated with the radiative transition of Ho3+ and Tm3+ ions on the basis of Judd-Ofelt theory, and the fluorescence decay behaviors after the addition of Ce3+ ions and WO3 component were analyzed to understand the broadband and luminescence enhancement. The findings in this work indicate that tellurite glass with optimal Tm3+-Ho3+-Ce3+ tri-doping combination and appropriate amount of WO3 is a prospective candidate for broadband optoelectronic devices operated in the infrared bands.
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BACKGROUND: Papillary carcinoma is an uncommon type of breast cancer. Additionally, patients with huge breast papillary carcinoma are extremely rare in clinical practice. To improve therapeutic effect on such patients, it is urgent to explore biologically and clinically relevant models of the disease to discover effective drugs. METHODS: We collected surgical tumor specimens from a 63-year-old Chinese woman who has been diagnosed breast papillary carcinoma. The tumor was more than 15 cm in diameter, and applied to establish patient-derived papillary carcinoma organoids that could continuously propagate for more than 6 months. RESULTS: The papillary carcinoma organoids matched the histological characteristics of orginal tumor by H&E staining identification, and maintained the expression of the breast cancer biomarkers by IHC, including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER2) and antigen Ki-67 (Ki67). In addition, we performed a 3-D drug screening to examine the effects of endocrine drugs (Fulvestrant, Tamoxifen) and targeted therapy drugs (Palbociclib, Everolimus, BKM120) on breast papillary carcinoma in the mimic in vivo environment. The drug sensitivities of our breast papillary carcinoma organoids were investigated as follows, Fulvestrant (IC50 0.275 µmol), Palbociclib (IC50 2.21 µmol), BKM120 (IC50 3.81 µmol), Everolimus (IC50 4.45 µmol), Tamoxifen (IC50 19.13 µmol). CONCLUSIONS: These results showed that an effective organoid platform for 3-D in vitro culture of breast cancer organoids from patients with breast papillary carcinoma could be used to identify possible treatments, and might be commonly applied to explore clinicopathological characteristics of breast papillary carcinoma.
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BACKGROUND: Mammary Paget's disease (MPD) is an uncommon cutaneous intraepithelial malignancy with ulceration of the nipple or areola. Its pathogenesis and genomic mutation remain largely unknown and no cell lines are established from primary tumors. METHODS: We collected surgical tumor specimens from a 65-year-old Chinese woman diagnosed with MPD and established patient-derived breast cancer (BC) organoids from MPD using organoid culture technology. RESULTS: We successfully propagated BC organoids from a patient with MPD for more than 6 months. The organoids were cultured for long-term expansion without any change in spherical organoid morphology. Besides, the spherical organoid morphology did not change when they underwent cryopreservation after resuscitation. The H&E staining and immunohistochemistry analyses showed the similar morphological and histological features of the organoids compared with their paired original BC tissues. The organoids retained positive expression of breast cancer biomarkers: estrogen receptor, progesterone receptor, antigen Ki-67 and negative expression of human epidermal growth factor receptor 2. We also showed that MPD organoids recapitulated the unique genomic landscape including copy number alterations, mutational load, mutational signatures and cancer gene mutations by whole genome sequencing. In situ senescence-associated acid beta galactosidase assay confirmed senescence phenomenon existed in the process of organoids culture and there was no significant difference in the proportion of senescent organoids after organoid passage and resuscitation. CONCLUSIONS: Our results suggested that an effective platform for ex vivo BC organoids from MPD patients could be used to explore clinicopathological and genomic characteristics of these patients.
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In this work, the network structure of Er3+ doped tellurite glass was modified by incorporating MoO3/WO3 oxides and the effect of the structural modification on the near-infrared luminescence properties of Er3+ was investigated. The examination of fluorescence spectrum reveals that partial substituting TeO2 with MoO3/WO3 in the composition significantly enhances both the emission intensity and the FWHM (full width at half maximum) of the 1.53 µm band, and the improved local environment around Er3+ ions and phonon energy of glass host are considered to be responsible for these results. The XRD pattern, Raman spectrum and Judd-Ofelt intensity parameter disclosed the changes in network structure and phonon energy, the DSC curve showed an improvement in thermal stability, and fluorescence decay curve displayed the increase of Er3+ lifetime at the 4I13/2 level, all of these indicated the positive effect of MoO3/WO3 addition on the near-infrared luminescence properties of Er3+.
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The most severe form of epilepsy, status epilepticus (SE), causes brain damage and results in the development of recurring seizures. Currently, the management of SE remains a clinical challenge because patients do not respond adequately to conventional treatments. Evidence suggests that neural cell death worsens the occurrence and progression of SE. The main forms of cell death are apoptosis, necroptosis, pyroptosis, and ferroptosis. Herein, these mechanisms of neuronal death in relation to SE and the alleviation of SE by potential modulators that target neuronal death have been reviewed. An understanding of these pathways and their possible roles in SE may assist in the development of SE therapies and in the discovery of new agents.
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Ferroptose , Estado Epiléptico , Morte Celular , Humanos , Necroptose , Convulsões , Estado Epiléptico/tratamento farmacológicoRESUMO
Transient receptor potential melastatin (TRPM) channels are members of the transient receptor potential (TRP) channels, a family of evolutionarily conserved integral membrane proteins. TRPM channels are nonselective cation channels, mediating the influx of various ions including Ca2+, Na+ and Zn2+. The function of TRPM channels is vital for cell proliferation, cell development and cell death. Cell death is a key procedure during embryonic development, organism homeostasis, aging and disease. The category of cell death modalities, beyond the traditionally defined concepts of necrosis, autophagy, and apoptosis, were extended with the discovery of pyroptosis, necroptosis and ferroptosis. As upstream signaling regulators of cell death, TRPM channels have been involved inrelevant pathologies. In this review, we introduced several cell death modalities, then summarized the contribution of TRPM channels (especially TRPM2 and TRPM7) to different cell death modalities and discussed the underlying regulatory mechanisms. Our work highlighted the possibility of TRPM channels as potential therapeutic targets in cell death-related diseases.
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Morte Celular/fisiologia , Regulação da Expressão Gênica/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Canais de Cátion TRPM/metabolismo , Humanos , Filogenia , Proteínas Serina-Treonina Quinases/genética , Canais de Cátion TRPM/genéticaRESUMO
Malignant pleural effusion (MPE) presents a severe medical condition in patients with advanced breast cancer (BC). We applied organoid culture technology to culture preoperative puncture specimen and corresponding surgical specimen-derived tumor cells from early BC patients and pleural effusion-derived tumor cells from advanced BC patients with MPE to study whether in vitro models could predict therapies of clinical patients. We successfully expanded pleural effusion-derived tumor organoids from 1 advanced triple-negative breast cancer (TNBC) patient with MPE which had been continuously propagated for more than 3 months. The organoids matched the histological characteristics of primary BC and metastatic supraclavicular lymph nodes by H&E staining and retained negative expression of TNBC biomarkers: estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and positive expression of antigen Ki-67. Multiple mutations were detected from this advanced TNBC patient with MPE by high-throughput sequencing of metastatic supraclavicular lymph node and the plasma sample. We performed the 3D drug screening tests combined with the clinical medication situation of this patient. The pleural effusion-derived tumor organoids were sensitive to capecitabine (IC50 1.580 µmol) and everolimus (IC50 4.008 µmol) single-agent treatments. The sensitivity to capecitabine was consistent with the clinical treatment response of this patient for capecitabine and with the sequencing results that reported MTHFR gene polymorphism mutation and TYMS -6bp/-6bp polymorphism mutation indicating effectiveness to fluorouracil. Our results suggested that an effective platform for ex vivo pleural effusion-derived tumor organoids from advanced TNBC patients with MPE could be used to identify treatment options and explore the clinicopathological characteristics of these patients.
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Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Organoides/patologia , Derrame Pleural Maligno/citologia , Medicina de Precisão/métodos , Adulto , Neoplasias da Mama/patologia , Feminino , Humanos , Linfonodos/patologia , Organoides/efeitos dos fármacos , Derrame Pleural Maligno/patologia , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapiaRESUMO
OBJECTIVES: Inhibition of calcium-/calmodulin- (CaM-) dependent kinase II (CaMKII) is correlated with epilepsy. However, the specific mechanism that underlies learning and memory impairment and neuronal death by CaMKII inhibition remains unclear. MATERIALS AND METHODS: In this study, KN93, a CaMKII inhibitor, was used to investigate the role of CaMKII during epileptogenesis. We first identified differentially expressed genes (DEGs) in primary cultured hippocampal neurons with or without KN93 treatment using RNA-sequencing. Then, the impairment of learning and memory by KN93-induced CaMKII inhibition was assessed using the Morris water maze test. In addition, Western blotting, immunohistochemistry, and TUNEL staining were performed to determine neuronal death, apoptosis, and the relative signaling pathway. RESULTS: KN93-induced CaMKII inhibition decreased cAMP response element-binding (CREB) protein activity and impaired learning and memory in Wistar and tremor (TRM) rats, an animal model of genetic epilepsy. CaMKII inhibition also induced neuronal death and reactive astrocyte activation in both the Wistar and TRM hippocampi, deregulating mitogen-activated protein kinases. Meanwhile, neuronal death and neuron apoptosis were observed in PC12 and primary cultured hippocampal neurons after exposure to KN93, which was reversed by SP600125, an inhibitor of c-Jun N-terminal kinase (JNK). CONCLUSIONS: CaMKII inhibition caused learning and memory impairment and apoptosis, which might be related to dysregulated JNK signaling.
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Apoptose/fisiologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Aprendizagem/fisiologia , Transtornos da Memória/fisiopatologia , Animais , Feminino , Humanos , Masculino , Ratos , Ratos Endogâmicos WKY , Transdução de SinaisRESUMO
Drug development is hampered by poor target selection. Phenotypic screens using neurons differentiated from patient stem cells offer the possibility to validate known and discover novel disease targets in an unbiased fashion. To identify targets for managing hyperexcitability, a pathological feature of amyotrophic lateral sclerosis (ALS), we design a multi-step screening funnel using patient-derived motor neurons. High-content live cell imaging is used to evaluate neuronal excitability, and from a screen against a chemogenomic library of 2,899 target-annotated compounds, 67 reduce the hyperexcitability of ALS motor neurons carrying the SOD1(A4V) mutation, without cytotoxicity. Bioinformatic deconvolution identifies 13 targets that modulate motor neuron excitability, including two known ALS excitability modulators, AMPA receptors and Kv7.2/3 ion channels, constituting target validation. We also identify D2 dopamine receptors as modulators of ALS motor neuron excitability. This screen demonstrates the power of human disease cell-based phenotypic screens for identifying clinically relevant targets for neurological disorders.
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Esclerose Lateral Amiotrófica/genética , Diferenciação Celular , Humanos , FenótipoRESUMO
The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed protein that contains both an ion channel and an active kinase. TRPM7 has involved in a variety of cellular functions and critically participates in various diseases mainly including cancer and neurodegenerative disorders. However, the theme trends and knowledge structures for TRPM7 have not yet been studied bibliometrically. The main purposes of this research are to compare the scientific production in the research field of TRPM7 among countries and to evaluate the publication trend between 2004 and 2019. All publications were extracted from the Web of Science Core Collection (WoSCC) database from 2004 to 2019. Microsoft Excel 2018, Prism 6, and CiteSpace V were applied to analyze the scientific research outputs including journals, countries, territories, institutions, authors, and research hotspots. In this report, a total of 860 publications related to TRPM7 were analyzed. Biophysical Journal ranked top for publishing 31 papers. The United States of America had the largest number of publications (320) with a high citation frequency (11,298) and H-index (58). Chubanov V (38 publications) and Gudermann T (38 citations), who from Ludwig Maximilian University of Munich, were the most productive authors and had the greatest co-citation counts. Our study also combined the bibliometric study with a systematic review on TRPM7, highlighting the four research frontiers of TRPM7. This is the first study that demonstrated the trends and future development in TRPM7 publications, providing a clear and intuitive profile for the contributions in this field.
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Bibliometria , Canais de Cátion TRPM/metabolismo , Animais , Humanos , Canais de Cátion TRPM/química , Canais de Cátion TRPM/genética , Canais de Cátion TRPM/fisiologiaRESUMO
Although sodium channels have been a hot multidisciplinary focus for decades and most of nerve system drugs worked on alerting sodium channel function, the trends and future directions of sodium channel studies have not been comprehensive analyzed bibliometrically. Herein, we collected the scientific publications of sodium channels research and constructed a model to evaluate the current trend systematically. Publications were selected from the Web of Science Core Collection (WoSCC) database from 2013 to 2017. Microsoft Excel 2016, Prism 6, and CiteSpace V software were used to analyze publication outputs, journal sources, countries, territories, institutions, authors, and research areas. A total of 4,275 publications on sodium channel research were identified. PLoS ONE ranked top for publishing 170 papers. The United States of America had the largest number of publications (1,595), citation frequency (19,490), and H-index (53). S. G. Waxman (62 publications) and W. A. Catterall (585 citations) were the most productive authors and had the greatest co-citation counts. This is the first report that shows the trends and future development in sodium channel publications, and our study provides a clear profile for the contribution to this field by countries, authors, keywords, and institutions.
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Bibliometria , Pesquisa/estatística & dados numéricos , Canais de Sódio/metabolismo , Bases de Dados de Proteínas , Humanos , EditoraçãoRESUMO
Epileptic seizures are the main clinical manifestation of low-grade astrocytoma. Voltage-gated sodium channels (VGSCs) play a crucial role in epilepsy. Until now, the role of VGSCs and the relationships between calmodulin (CaM)/CaM-dependent protein kinase II (CaMKII) and VGSCs in low-grade astrocytoma have not been demonstrated. In our study, the protein expression of NaV1.3, NaV1.6 and CaM was significantly increased in the tumor compared to control tissue, while the level of p-CaMKII/CaMKII was significantly decreased in the tumor group as determined by Western Blotting and immunohistochemistry. Furthermore, double-labeling immunofluorescence results showed that NaV1.3/NaV1.6 and CaM co-localization was significantly increased in the tumor group compared to control tissue. This study represents the first evidence of the abnormal changes in VGSCs subtypes and CaM/CaMKII pathway in human brain low-grade astrocytoma, providing new potential targets for molecular therapies of this disease.