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1.
Stem Cells ; 42(6): 526-539, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38563224

RESUMO

To resist lineage-dependent therapies such as androgen receptor inhibition, prostate luminal epithelial adenocarcinoma cells often adopt a stem-like state resulting in lineage plasticity and phenotypic heterogeneity. Castrate-resistant prostate adenocarcinoma can transition to neuroendocrine (NE) and occasionally to amphicrine, co-expressed luminal and NE, phenotypes. We developed castrate-resistant prostate cancer (CRPC) patient-derived organoid models that preserve heterogeneity of the originating tumor, including an amphicrine model displaying a range of luminal and NE phenotypes. To gain biological insight and to identify potential treatment targets within heterogeneous tumor cell populations, we assessed the lineage hierarchy and molecular characteristics of various CRPC tumor subpopulations. Transcriptionally similar stem/progenitor (St/Pr) cells were identified for all lineage populations. Lineage tracing in amphicrine CRPC showed that heterogeneity originated from distinct subclones of infrequent St/Pr cells that produced mainly quiescent differentiated amphicrine progeny. By contrast, adenocarcinoma CRPC progeny originated from St/Pr cells and self-renewing differentiated luminal cells. Neuroendocrine prostate cancer (NEPC) was composed almost exclusively of self-renewing St/Pr cells. Amphicrine subpopulations were enriched for secretory luminal, mesenchymal, and enzalutamide treatment persistent signatures that characterize clinical progression. Finally, the amphicrine St/Pr subpopulation was specifically depleted with an AURKA inhibitor, which blocked tumor growth. These data illuminate distinct stem cell (SC) characteristics for subtype-specific CRPC in addition to demonstrating a context for targeting differentiation-competent prostate SCs.


Assuntos
Linhagem da Célula , Células-Tronco Neoplásicas , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/genética , Linhagem da Célula/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Animais , Diferenciação Celular , Feniltioidantoína/farmacologia , Feniltioidantoína/análogos & derivados , Camundongos , Benzamidas , Nitrilas
2.
Prostate ; 84(11): 1033-1046, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38708958

RESUMO

BACKGROUND: Preclinical models recapitulating the metastatic phenotypes are essential for developing the next-generation therapies for metastatic prostate cancer (mPC). We aimed to establish a cohort of clinically relevant mPC models, particularly androgen receptor positive (AR+) bone metastasis models, from LuCaP patient-derived xenografts (PDX) that reflect the heterogeneity and complexity of mPC. METHODS: PDX tumors were dissociated into single cells, modified to express luciferase, and were inoculated into NSG mice via intracardiac injection. The progression of metastases was monitored by bioluminescent imaging. Histological phenotypes of metastases were characterized by immunohistochemistry and immunofluorescence staining. Castration responses were further investigated in two AR-positive models. RESULTS: Our PDX-derived metastasis (PDM) model collection comprises three AR+ adenocarcinomas (ARPC) and one AR- neuroendocrine carcinoma (NEPC). All ARPC models developed bone metastases with either an osteoblastic, osteolytic, or mixed phenotype, while the NEPC model mainly developed brain metastasis. Different mechanisms of castration resistance were observed in two AR+ PDM models with distinct genotypes, such as combined loss of TP53 and RB1 in one model and expression of AR splice variant 7 (AR-V7) expression in another model. Intriguingly, the castration-resistant tumors displayed inter- and intra-tumor as well as organ-specific heterogeneity in lineage specification. CONCLUSION: Genetically diverse PDM models provide a clinically relevant system for biomarker identification and personalized medicine in metastatic castration-resistant prostate cancer.


Assuntos
Neoplasias Ósseas , Modelos Animais de Doenças , Neoplasias da Próstata , Receptores Androgênicos , Masculino , Neoplasias Ósseas/secundário , Neoplasias Ósseas/metabolismo , Animais , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Humanos , Camundongos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/genética , Adenocarcinoma/patologia , Adenocarcinoma/secundário , Adenocarcinoma/metabolismo , Adenocarcinoma/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/genética , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/genética
3.
BMC Nephrol ; 24(1): 202, 2023 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-37407942

RESUMO

BACKGROUND: Minimal change disease (MCD), a pathological type of nephrotic syndrome (NS), can occur in patients with tumors. We report two adult cases of MCD associated with papillary thyroid carcinoma (PTC), known to be extremely rare in adults. CASE PRESENTATION: A 35-year-old female patient was simultaneously diagnosed with MCD and PTC. The MCD was effectively treated with thyroidectomy and prednisone.In addition, a 50-year-old male patient, who had been diagnosed with PTC three years prior, had MCD confirmed by renal biopsy. The patient achieved complete remission following treatment with tacrolimus and rituximab. CONCLUSIONS: The present case report describes and discusses the diagnostic and treatment processes employed in these two patients. Clinicians need to be aware of the renal effects of treating patients with solid tumors.


Assuntos
Nefrose Lipoide , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nefrose Lipoide/complicações , Nefrose Lipoide/diagnóstico , Nefrose Lipoide/terapia , Prednisona/uso terapêutico , Câncer Papilífero da Tireoide/complicações , Neoplasias da Glândula Tireoide/complicações , Tireoidectomia , Síndrome Nefrótica
4.
Langmuir ; 37(3): 1267-1278, 2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33439659

RESUMO

Photocatalysts play an increasingly important role in environmental remediation polluted by industrial wastewater. However, the preparation of adsorbents and catalysts with high activity by simple and easy methods is still a great challenge. Here, sandwich-like composite catalyst Cu2O/TiO2/Ti3C2 was prepared by an easily available solvent reduction measure for the highly efficient catalytic nitro compounds. In particular, sandwich-like composite catalyst Cu2O/TiO2/Ti3C2 exhibits excellent catalysis for 2-nitroaniline (2-NA) and 4-nitrophenol (4-NP), and its pseudo-first-order reaction rate constants (k) are 0.163 and 0.114 min-1, respectively. Interestingly, even after eight consecutive cycles of catalytic experiments, the conversion rates of catalytic 2-NA and 4-NP are still greater than 95 and 92%, respectively, demonstrating that the obtained catalyst has excellent catalytic capability and a high reutilization rate. The excellent catalytic performances of Cu2O/TiO2/Ti3C2 can be attributed to the fact that Ti3C2 provides a greater reaction site for the formation of Cu2O and reduces the aggregation during the formation of Cu2O by in situ synthesis. Therefore, ternary composite catalyst Cu2O/TiO2/Ti3C2 prepared by solvent reduction not only supplies a technical method for the catalytic reaction of MXene-based material but also lays the foundation for the development of new photocatalysts.

5.
Langmuir ; 36(47): 14342-14351, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33205652

RESUMO

Constructing the nanostructure of transition metal oxides for high energy density lithium-ion batteries has been widely studied recently. Prompted by the idea that the transition metal can serve as a catalyzer influence on the reversibility of solid-electrolyte interphase films, Co/MnO@C composite nanofibers were designed by electrospinning and chemical vapor deposition methods. The Co/MnO@C electrode showed superior electrochemical performance with a large capacity increase for the first 400 cycles and a high rate performance of 1345 mA h g-1 at 1000 mA g-1. There was no obvious decay of capacity over the whole 1000 cycles, demonstrating the excellent cycling stability of the samples. The new design and synthesis of the anodic materials may offer a prototype for high-performance and strong-stability batteries.

6.
Nanotechnology ; 31(20): 205604, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31995537

RESUMO

The construction of low-cost, high-performance electrocatalysts instead of platinum catalysts is critical to solving the energy crisis. Here, using simple electrospinning and hydrothermal methods, new MoS2 nanosheets on SrTiO3 nanofibers (NFs) and 2D SrTiO3@MoS2 heterostructure NFs are synthesized. In addition, SrTiO3@MoS2 heterostructure NFs are compared with bare SrTiO3 NFs and MoS2 nanosheets. Importantly, the prepared SrTiO3@MoS2 heterostructure shows better hydrogen-evolution reaction performance than other MoS2-based electrocatalysts with an overpotential of 165 mV at 10 mA cm-2, a Tafel slope of 81.41 mV dec-1, and long-term electrochemical durability of 3000 cycles. Therefore, the present work strongly demonstrates the positive synergy between SrTiO3 NFs and layered MoS2, and also provides a strategy for preparing low-cost and high-activity water-decomposition electrocatalysts.

7.
J Cell Physiol ; 234(10): 18053-18064, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30843215

RESUMO

The matrix remodeling associated 7 (MXRA7) gene had been ill-studied and its biology remained to be discovered. Inspired by our previous findings and public datasets concerning MXRA7, we hypothesized that the MXRA7 gene might be involved in bone marrow mesenchymal stem cells (BMSCs) functions related to bone formation, which was checked by utilizing in vivo or in vitro methodologies. Micro-computed tomography of MXRA7-deficient mice demonstrated retarded osteogenesis, which was reflected by shorter femurs, lower bone mass in both trabecular and cortical bones compared with wild-type (WT) mice. Histology confirmed the osteopenia-like feature including thinner growth plates in MXRA7-deficient femurs. Immunofluorescence revealed less osteoblasts in MXRA7-deficient femurs. Polymerase chain reaction or western blot analysis showed that when WT BMSCs were induced to differentiate toward osteoblasts or adipocytes in culture, MXRA7 messenger RNA or protein levels were significantly increased alongside osteoblasts induction, but decreased upon adipocytes induction. Cultured MXRA7-deficient BMSCs showed decreased osteogenesis upon osteogenic differentiation induction as reflected by decreased calcium deposition or lower expression of genes responsible for osteogenesis. When recombinant MXRA7 proteins were supplemented in a culture of MXRA7-deficient BMSCs, osteogenesis or gene expression was fully restored. Upon osteoblast induction, the level of active ß-catenin or phospho-extracellular signal-regulated kinase in MXRA7-deficient BMSCs was decreased compared with that in WT BMSCs, and these impairments could be rescued by recombinant MXRA7 proteins. In adipogenesis induction settings, the potency of MXRA7-deficient BMSCs to differentiate into adipocytes was increased over the WT ones. In conclusion, this study demonstrated that MXRA7 influences bone formation via regulating the balance between osteogenesis and adipogenesis in BMSCs.


Assuntos
Doenças Ósseas Metabólicas/metabolismo , Diferenciação Celular , Fêmur/metabolismo , Proteínas de Membrana/metabolismo , Células-Tronco Mesenquimais/metabolismo , Osteoblastos/metabolismo , Osteogênese , Adipócitos/metabolismo , Adipócitos/patologia , Adipogenia , Animais , Doenças Ósseas Metabólicas/genética , Doenças Ósseas Metabólicas/patologia , Células Cultivadas , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fêmur/patologia , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Células-Tronco Mesenquimais/patologia , Camundongos Knockout , Osteoblastos/patologia , Fenótipo , Transdução de Sinais , beta Catenina/metabolismo
8.
Am J Pathol ; 188(4): 929-936, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29571325

RESUMO

The Fuhrman and World Health Organization/International Society of Urological Pathology (WHO/ISUP) grading systems are widely used to predict survival for patients with conventional renal cell carcinoma. To determine the validity of nuclear grading systems (both the Fuhrman and the WHO/ISUP) and the individual components of the Fuhrman grading system in predicting the prognosis of Xp11.2 translocation renal cell carcinoma (Xp11.2 tRCC), we identified and followed up 47 patients with Xp11.2 tRCC in our center from January 2007 to June 2017. The Fuhrman and WHO/ISUP grading was reassigned by two pathologists. Nuclear size and shape were determined for each case based on the greatest degree of nuclear pleomorphism using image analysis software. Univariate and multivariate analyses were performed to evaluate the capacity of the grading systems and nuclear parameters to predict overall survival and progression-free survival. On univariate Cox regression analysis, the parameters of nuclear size were associated significantly with overall survival and progression-free survival, whereas the grading systems and the parameters of nuclear shape failed to reach a significant correlation. On multivariate analysis, however, none of the parameters was associated independently with survival. Our findings indicate that neither the Fuhrman nor the WHO/ISUP grading system is applicable to Xp11.2 tRCC. The assessment of nuclear size instead may be novel outcome predictors for patients with Xp11.2 tRCC.


Assuntos
Carcinoma de Células Renais/genética , Cromossomos Humanos X/genética , Internacionalidade , Patologia , Sociedades Médicas , Translocação Genética , Urologia , Organização Mundial da Saúde , Adolescente , Adulto , Idoso , Carcinoma de Células Renais/patologia , Criança , Pré-Escolar , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Modelos de Riscos Proporcionais , Análise de Regressão , Adulto Jovem
9.
Nanotechnology ; 31(8): 085603, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31675731

RESUMO

The catalytic reduction of nitro compounds is currently a hot research area, how to efficiently and stably degrade such toxic and harmful substances has become the research goal of many researchers. In this work, an Artemia cyst shell (ACS)-TiO2-MoS2 ternary porous structure was proposed and prepared as a catalyst for the reduction of 2-nitroaniline (2-NA) and 4-nitrophenol (4-NP). The ACS has a large number of porous structures, exhibits a good binding ability with TiO2 and MoS2, and provides a large number of active sites for the catalytic reduction process. The obtained composite material has a good reduction effect on 4-NP and 2-NA, with a good stability and recyclability, which is obviously higher than the reduction effect of ACS-TiO2 and MoS2 under the same conditions. This work provides ideas for the design of porous catalytic materials.

10.
Guang Pu Xue Yu Guang Pu Fen Xi ; 35(8): 2231-5, 2015 Aug.
Artigo em Zh | MEDLINE | ID: mdl-26672300

RESUMO

Three-port tunable optical filter is a key device in the all-optic intelligent switching network and dense wavelength division multiplexing system. The characteristics of the reflecting spectrum, especially the reflectivity and the isolation degree are very important to the three-port filter. Angle-tuned thin film filter is widely used as a three-port tunable filter for its high rectangular degree and good temperature stability. The characteristics of the reflecting spectrum are greatly influenced not only by the incident angle, but also by the wedge angle parameter of the non-paralleled wedge thin film filter. In the present paper, the influences of the wedge angle parameter to the reflectivity and the half bandwidth are analyzed, and the reflecting spectrum characterstics are simulationed in different wedge angle parameter and polarity. The wedge angle-tuned thin film filter with 0.8° wedge angle parameter is fabricated. The experimental results show that keeping the wedge angle the same orientation to the incident angle will worsen the reflectivity and the rectangular degree of the reflecting spectrum. However, keeping the wedge angle orientation reverse to the incident angle will enhance the reflectivity and decrease the bandwidth, which will give higher reflectivity and isolation degree to the three-port filter than that of high parallel degree angle-tuned thin film filter.

11.
Guang Pu Xue Yu Guang Pu Fen Xi ; 33(8): 2290-3, 2013 Aug.
Artigo em Zh | MEDLINE | ID: mdl-24159896

RESUMO

Angle-tuned thin film filter is widely used in the DWDM system for its broad tunable wavelength range and high rectangular degree. The transmissivity and the half bandwidth is greatly influenced not only by the incident angle, but also by the wedge angle of the non-paralleled thin film filter. In the present paper, the influences of the wedge angle on the transmissivity and the half bandwidth were detailedly analyzed. The proper wedge angle and the orientation can greatly improve the characteristics of the transmittance spectrum. The angle-tuned thin film filter with 0.8 degrees wedge angle was also fabricated. The experimental results show that keeping the wedge angle with the same orientation to the incident angle will worsen the transmissivity and the rectangular degree of the transmittance spectrum. However, keeping the wedge angle orientation reverse to the incident angle will greatly enhance the transmissivity and the rectangular degree of the filter and its tunable wavelength range will broaden by 10 nm.

12.
Zhong Yao Cai ; 36(6): 953-8, 2013 Jun.
Artigo em Zh | MEDLINE | ID: mdl-24380284

RESUMO

OBJECTIVE: To investigate the effect of Chinese herbal medicine with Supplement Qi and Activating Blood Circulation (huangqi and danshen) on urinary protein, kidney function and tubular reabsorption of diabetic nephropathy rats. METHODS: SD rats were randomly divided into a nondiabetic control group (normal group) and three groups in which diabetes were induced by a single intraperitoneal injection of freshly prepared streptozotocin( STZ,55 mg/kg body weight). Then the diabetes rats were randomly assigned to three groups: diabetic model group, Supplement Qi and Activating Blood Circulation traditional Chinese medicine group (huangqi and danshen group) and Gliquidone group (as a reference hypoglycemic drug). Each group was treated with corresponding drugs for 6 weeks. At the end of the study, the rats from each group were injected with FITC-labeled BSA through tail vein. The 24 h urinary protein excretion were measured and blood was collected for measuring plasma glucose levels, serum creatinine (Cr), blood urea nitrogen (BUN), triglyceride (TG) and total cholesterol (T-CHO). Renal tissue was used to measure the level of LPO,SOD,GSH-Px and AGEs and Paraffin-embedded sections were stained with HE, PAS and immunohistochemistry. RESULTS: The plasma glucose, the 24 h urinary protein excretion, the levels of serum Cr, BUN, TG and T-CHO in STZ-induced diabetic rats were higher than those of nondiabetic rats. Diabetic rats showed significantly increase in LPO and AGEs (P < 0.01) and decrease in antioxidant enzyme activity (both GSH-Px and SOD) (P < 0.05) as compared with non-diabetic control rats. Treatment with the Supplement Qi and Activating Blood Circulation traditional Chinese medicine for 6 weeks in diabetic rats significantly reduced the 24 h urinary protein excretion compared with model control (P < 0.01), and markedly decreased the levels of serum Cr,BUN,TG and T-CHO as compared with those of diabetic rat (P < 0.05). The levels of LPO and AGEs were decreased and the activity of GSH-Px was increased by Supplement Qi and Activating Blood Circulation treatment. The kidney proximal tubule lesions were improved and the reabsorption of FITC-BSA in tubular was increased in diabetic rats treated by huangqi and danshen, and the expression of megalin in proximal tubular was enhanced as compared with diabetic rats. CONCLUSION: Diabetic nephropathy rats treated with traditional Chinese medicine therapeutic principles "Supplement Qi and Activating Blood Circulation" can reduce the 24 h urinary protein excretion and improve the function of tubular reabsorption. These protect effects may be in correlation with enhancement the renal tissue activity of antioxidant and up-regulation the expression of megalin in renal tubular epithelial cells in diabetic rats.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Túbulos Renais/efeitos dos fármacos , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Absorção/efeitos dos fármacos , Animais , Astragalus propinquus/química , Biomarcadores/sangue , Biomarcadores/urina , Glicemia/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/administração & dosagem , Testes de Função Renal , Túbulos Renais/metabolismo , Túbulos Renais/fisiopatologia , Masculino , Fitoterapia/métodos , Ratos , Ratos Sprague-Dawley , Salvia miltiorrhiza/química , Estreptozocina
13.
J Clin Invest ; 133(22)2023 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-37725435

RESUMO

Antibody-drug conjugates (ADCs) are a promising targeted cancer therapy; however, patient selection based solely on target antigen expression without consideration for cytotoxic payload vulnerabilities has plateaued clinical benefits. Biomarkers to capture patients who might benefit from specific ADCs have not been systematically determined for any cancer. We present a comprehensive therapeutic and biomarker analysis of a B7H3-ADC with pyrrolobenzodiazepine(PBD) payload in 26 treatment-resistant, metastatic prostate cancer (mPC) models. B7H3 is a tumor-specific surface protein widely expressed in mPC, and PBD is a DNA cross-linking agent. B7H3 expression was necessary but not sufficient for B7H3-PBD-ADC responsiveness. RB1 deficiency and/or replication stress, characteristics of poor prognosis, and conferred sensitivity were associated with complete tumor regression in both neuroendocrine (NEPC) and androgen receptor positive (ARPC) prostate cancer models, even with low B7H3 levels. Non-ARPC models, which are currently lacking efficacious treatment, demonstrated the highest replication stress and were most sensitive to treatment. In RB1 WT ARPC tumors, SLFN11 expression or select DNA repair mutations in SLFN11 nonexpressors governed response. Importantly, WT TP53 predicted nonresponsiveness (7 of 8 models). Overall, biomarker-focused selection of models led to high efficacy of in vivo treatment. These data enable a paradigm shift to biomarker-driven trial designs for maximizing clinical benefit of ADC therapies.


Assuntos
Antineoplásicos , Imunoconjugados , Neoplasias da Próstata , Masculino , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Antineoplásicos/uso terapêutico , Proteínas Nucleares
14.
Neural Netw ; 149: 84-94, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35217397

RESUMO

Single image super-resolution is an ill-posed problem, whose purpose is to acquire a high-resolution image from its degraded observation. Existing deep learning-based methods are compromised on their performance and speed due to the heavy design (i.e., huge model size) of networks. In this paper, we propose a novel high-performance cross-domain heterogeneous residual network for super-resolved image reconstruction. Our network models heterogeneous residuals between different feature layers by hierarchical residual learning. In outer residual learning, dual-domain enhancement modules extract the frequency-domain information to reinforce the space-domain features of network mapping. In middle residual learning, wide-activated residual-in-residual dense blocks are constructed by concatenating the outputs from previous blocks as the inputs into all subsequent blocks for better parameter efficacy. In inner residual learning, wide-activated residual attention blocks are introduced to capture direction- and location-aware feature maps. The proposed method was evaluated on four benchmark datasets, indicating that it can construct the high-quality super-resolved images and achieve the state-of-the-art performance. Code and pre-trained models are available at https://github.com/zhangyongqin/HRN.


Assuntos
Processamento de Imagem Assistida por Computador , Redes Neurais de Computação , Processamento de Imagem Assistida por Computador/métodos
15.
Cancer Gene Ther ; 29(10): 1463-1476, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35393570

RESUMO

ERG translocations are commonly involved in the initiation of prostate neoplasia, yet previous experimental approaches have not addressed mechanisms of oncogenic inception. Here, in a genetically engineered mouse model, combining TMPRSS2-driven ERG with KrasG12D led to invasive prostate adenocarcinomas, while ERG or KrasG12D alone were non-oncogenic. In primary prostate luminal epithelial cells, following inducible oncogenic Kras expression or Pten depletion, TMPRSS2-ERG suppressed oncogene-induced senescence, independent of TP53 induction and RB1 inhibition. Oncogenic KRAS and TMPRSS2-ERG synergized to promote tumorigenesis and metastasis of primary luminal cells. The presence of TMPRSS2-ERG compared to a wild-type background was associated with a stemness phenotype and with relatively increased RAS-induced differential gene expression for MYC and mTOR-regulated pathways, including protein translation and lipogenesis. In addition, mTOR inhibitors abrogated ERG-dependent senescence resistance. These studies reveal a previously unappreciated function whereby ERG expression primes preneoplastic cells for the accumulation of additional gene mutations by suppression of oncogene-induced senescence.


Assuntos
Neoplasias da Próstata , Proteínas Proto-Oncogênicas p21(ras) , Animais , Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Proteínas de Fusão Oncogênica/genética , Oncogenes , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Regulador Transcricional ERG/genética , Regulador Transcricional ERG/metabolismo
16.
Int J Biol Macromol ; 220: 90-96, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-35970366

RESUMO

Ionically-conductive hydrogels are attracting increasing interest as skin-like sensors, however, the fabrication of ion-conductive hydrogels with excellent mechanical properties, high conductivity, self-adhesion and anti-freezing ability for high-performance sensors remains a challenge. Herein, a highly ion-conductive hydrogel is prepared by introducing LiCl into polyacrylamide/hydroxypropyl methyl cellulose (PAM/HPMC) composite hydrogel. The introduction of LiCl simultaneously endows the PAM/HPMC/LiCl hydrogel with outstanding stretchability (1453 %), high tensile strength (135 kPa), skin-like elasticity (9.18 kPa), high conductivity (7.85 S/m), good adhesiveness and wide operating temperature range. Impressively, this ion-conductive hydrogel can be utilized in skin-like sensor, which achieves high strain sensitivity (GF = 11.19) with wide sensing ranges (up to 600 %), and excellent endurance over 250 consecutive stretching. As a result, the wearable sensor assembled from the hydrogels can be used to detect complex human activities with high stability even at -40 °C. This work promotes the development of ion-conductive hydrogels with broad operating temperature in advanced sensory platform.


Assuntos
Hidrogéis , Metilcelulose , Condutividade Elétrica , Humanos , Derivados da Hipromelose , Íons , Pele
17.
Int J Pharm ; 627: 122211, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36167187

RESUMO

A new kind of negatively charged polymer-shielded supramolecular nano-micelles with dual-responsive property was designed for tumor treatment, which was prepared on the basis of adamantane terminated linear PAsp(DIP) and disulfide-ß-cyclodextrin-terminated PAsp(EDA). The supramolecular nano-micelles comprised a 2,3-dimethylmaleic anhydride (DA) protective layer to stabilize the micelles, a pH-responsive core to package hydrophobic model drugs, and a disulfide-crosslinked interlayer to shackle the core against drug leakage under normal physiological conditions. After arriving at the tumor tissue via EPR, the targeting function could be turned on by dislodging DA groups on the surface of micelles, which allowed the drug-loaded nano-micelles to be easily phagocytized by the tumor cells, and then release the drug inside the cells induced by the increased glutathione level and acidic pH. The results indicated that the charge-conversional dual-responsive supramolecular nano-micelles showed excellent antitumor activity.


Assuntos
Adamantano , Antineoplásicos , beta-Ciclodextrinas , Antineoplásicos/química , beta-Ciclodextrinas/química , Dissulfetos , Doxorrubicina/química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Glutationa , Concentração de Íons de Hidrogênio , Micelas , Polímeros/química
18.
Int J Biol Macromol ; 220: 1177-1187, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36030977

RESUMO

In this work, a positively charged chitosan-grafted-polyarginine (CS-N-PArg) as the macro-molecular NO donor, and a negatively charged acetalated starch (AcSt-O-PAsp) as a glucose donor, have been synthesized. To achieve the multi-enzymatic cascade system for local generation of self-supply glucose to increase the H2O2 concentration for the subsequent oxidization of L-Arg into NO, the designed positively charged CS-N-PArg, negatively charged AcSt-O-PAsp, glucoamylase (GA) and glucose oxidase (GOx) are absorbed and assembled in the pore of the gelatin sponge via electrostatic interaction to establish a smart antibacterial dressings (CS/St + GOx/GA). Once stimulated by Escherichia coli (E. coli)-infected wounds (a slightly acidic environment), the cascade reaction system can sequentially induce to generate glucose, H2O2 and NO, which exhibits a meaningful alternative idea for a high-performance antibacterial therapy.


Assuntos
Quitosana , Infecção dos Ferimentos , Humanos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bandagens , Escherichia coli , Gelatina , Glucana 1,4-alfa-Glucosidase , Glucose , Glucose Oxidase , Peróxido de Hidrogênio , Amido , Cicatrização
19.
J Neural Transm (Vienna) ; 118(8): 1155-64, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21331461

RESUMO

Although abnormal aggregation of α-synuclein (α-syn) is involved in several neurodegenerative diseases, its biological functions remain poorly understood, which limits our understanding of its pathogenic mechanisms. α-Syn exhibits MAP-like activity and promotes the assembly of microtubules. Since microtubules play a pivotal role in proliferative cell division, it is possible that α-syn affects cell proliferation by facilitating microtubule assembly. The role of α-syn in promoting cell proliferation was reported previously in PC12 dopaminergic cells overexpressing α-syn. Here, we extended this study aiming at finding the association between the cell proliferation effect of α-syn and its microtubule assembly activity, and identifying the potential active domain for the effect of α-syn on cell proliferation. By exploiting the property that the 11-mer repeats of synuclein molecules are able to mediate a rapid intracellular translocation of these proteins across the plasma membrane without being degraded by the cellular proteolytic system, we added recombinant full-length α-syn (wild type and A53T and A30P mutants) and ß-syn to the culture medium of MES23.5 dopaminergic cells, and observed their intracellular translocation, subcellular distribution and effects on cell proliferation. We found that all the synuclein molecules could enter the cells where they were localized in both the cytoplasm and nucleus. However, only the wild-type α-syn, which had been shown to have microtubule assembly activity, was able to promote proliferation of the MES23.5 cells. The A53T and A30P mutant α-syn as well as ß-syn, which had been proved not to possess microtubule assembly activity, did not exhibit any effect on cell proliferation. Since the α-syn activity in microtubule assembly was shown to be related to its specific functional domain, we then generated different functional fragments (N-terminal aa1-65, NAC aa61-95 and C-terminal aa96-140) and tested their activities in cell proliferation. We showed that all the α-syn fragments could enter the cells, but with different subcellular localizations. The N-terminal and NAC fragments were localized in the cytoplasm and the C-terminal fragment mainly in the nucleus. In accordance with the activity for the C-terminal part of α-syn in microtubule assembly, only the NAC and C-terminal fragments exhibited the activity in cell proliferation. The N-terminal fragment without microtubule assembly activity did not promote cell proliferation. The above results suggest that the α-syn function in promoting cell proliferation is associated with its microtubule assembly activity with the functional domain localized in its C-terminal part.


Assuntos
Proliferação de Células , Neurônios Dopaminérgicos/fisiologia , alfa-Sinucleína/química , alfa-Sinucleína/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Microtúbulos/química , Microtúbulos/fisiologia , Estrutura Terciária de Proteína/fisiologia
20.
ACS Omega ; 6(7): 4958-4967, 2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33644603

RESUMO

Cellulose nanocrystals (CNCs) not only have environmental protection characteristics of being lightweight, degradable, green, and renewable but also have some nanocharacteristics of high strength, large specific surface area, and obvious small size effect, so they are often used as a reinforcing agent in various polymers. However, the hydrogen bonding between CNC molecules is relatively strong, and they can easily aggregate and get entangled with each other. In this work, several large-porosity composite nanofiber films, KH550-CNC/waterborne polyurethane (WPU)/poly(vinyl alcohol) (PVAL) with KH550-modified CNCs, are prepared using poly(vinyl alcohol) (PVAL) solution and electrospinning technology. A variety of characterization methods are used to discuss and analyze the nanofiber materials, and the effects of the added amount of CNCs modified with KH550, spinning voltage, curing distance, and advancing speed on the morphology and performance of composite fibers are discussed separately. The results show that when the content of KH550-CNC is 1%, the composite fiber film obtained has the most regular morphology and the best spinnability, which is convenient for the specific application of fiber materials in a later period. In addition, the porosity of the obtained composite fiber film is 62.61%. Therefore, this work provides a theoretical basis and research strategy for the preparation of higher-porosity composite films as well as the development of new textile materials.

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