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AMG232 effectively inhibits cancers with wild-type p53 (also known as TP53) by reactivating p53, but whether it inhibits glioma angiogenesis remains unclear. This study confirms that AMG232 inhibits the proliferation of glioma endothelial cells (GECs) in a dose-dependent manner and inhibits the angiogenesis of GECs. p53 and RNA-binding motif protein 4 (RBM4) were expressed at low levels in GECs, while MDM2 and vascular endothelial growth factor receptor 2 (VEGFR2, also known as KDR) were highly expressed. In vitro and in vivo experiments confirmed that AMG232 upregulated p53 and RBM4, and downregulated MDM2 and VEGFR2 by blocking the MDM2-p53 interaction. Both p53 silencing and RBM4 silencing significantly upregulated the expression of VEGFR2, promoted the proliferation, migration and tube formation of GECs, and reversed the effects of AMG232 on downregulating VEGFR2 and inhibiting the angiogenesis of GECs. AMG232 increased RBM4 expression by upregulating p53, and p53 bound to RBM4 and promoted its transcription. RBM4 bound to and shortened the half-life of VEGFR2, promoting its degradation. Finally, AMG232 produced a significant decrease in new vessels and hemoglobin content in vivo. This study proves that AMG232 inhibits glioma angiogenesis by blocking the MDM2-p53 interaction, in which the p53-RBM4-VEGFR2 pathway plays an important role.
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Células Endoteliais , Glioma , Humanos , Movimento Celular , Proliferação de Células/fisiologia , Células Endoteliais/metabolismo , Glioma/tratamento farmacológico , Glioma/genética , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer with high aggressive phenotype and poor prognosis. Accumulating evidence suggests that circRNAs have been identified as pivotal mediators in cancers. However, the role of circRNAs in ccRCC progression remains elusive. METHODS: The differentially expressed circRNAs in 4 paired human ccRCC and adjacent noncancerous tissues ccRCC were screened using circRNA microarrays and the candidate target was selected based on circRNA expression level using weighted gene correlation network analysis (WGCNA) and the gene expression omnibus (GEO) database. CircPDHK1 expression in ccRCC and adjacent noncancerous tissues (n = 148) were evaluated along with clinically relevant information. RT-qPCR, RNase R digestion, and actinomycin D (ActD) stability test were conducted to identify the characteristics of circPDHK1. The subcellular distribution of circPDHK1 was analyzed by subcellular fractionation assay and fluorescence in situ hybridization (FISH). Immunoprecipitation-mass spectrometry (IP-MS) and immunofluorescence (IF) were employed to evaluate the protein-coding ability of circPDHK1. ccRCC cells were transfected with siRNAs, plasmids or lentivirus approach, and cell proliferation, migration and invasion, as well as tumorigenesis and metastasis in nude mice were assessed to clarify the functional roles of circPDHK1 and its encoded peptide PDHK1-241aa. RNA-sequencing, western blot analysis, immunoprecipitation (IP) and chromatin immunoprecipitation (ChIP) assays were further employed to identify the underlying mechanisms regulated by PDHK1-241aa. RESULTS: CircPDHK1 was upregulated in ccRCC tissues and closely related to WHO/ISUP stage, T stage, distant metastasis, VHL mutation and Ki-67 levels. CircPDHK1 had a functional internal ribosome entry site (IRES) and encoded a novel peptide PDHK1-241aa. Functionally, we confirmed that PDHK1-241aa and not the circPDHK1 promoted the proliferation, migration and invasion of ccRCC. Mechanistically, circPDHK1 was activated by HIF-2A at the transcriptional level. PDHK1-241aa was upregulated and interacted with PPP1CA, causing the relocation of PPP1CA to the nucleus. This thereby inhibited AKT dephosphorylation and activated the AKT-mTOR signaling pathway. CONCLUSIONS: Our data indicated that circPDHK1-encoded PDHK1-241aa promotes ccRCC progression by interacting with PPP1CA to inhibit AKT dephosphorylation. This study provides novel insights into the multiplicity of circRNAs and highlights the potential use of circPDHK1 or PDHK1-241aa as a therapeutic target for ccRCC.
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Carcinoma de Células Renais , Neoplasias Renais , Animais , Camundongos , Humanos , Carcinoma de Células Renais/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Circular/genética , Camundongos Nus , Hibridização in Situ Fluorescente , Linhagem Celular Tumoral , Transdução de Sinais/genética , Neoplasias Renais/genética , Serina-Treonina Quinases TOR/metabolismo , Proliferação de Células/genética , Peptídeos/genética , Regulação Neoplásica da Expressão Gênica , Proteína Fosfatase 1/genética , Proteína Fosfatase 1/metabolismoRESUMO
BACKGROUND: Gastric cancer (GC) ranks fifth in global cancer incidence and third in mortality rate among all cancer types. Circular RNAs (circRNAs) have been extensively demonstrated to regulate multiple malignant biological behaviors in GC. Emerging evidence suggests that several circRNAs derived from FNDC3B play pivotal roles in cancer. However, the role of circFNDC3B in GC remains elusive. METHODS: We initially screened circFNDC3B with translation potential via bioinformatics algorithm prediction. Subsequently, Sanger sequencing, qRT-PCR, RNase R, RNA-FISH and nuclear-cytoplasmic fractionation assays were explored to assess the identification and localization of circ0003692, a circRNA derived from FNDC3B. qRT-PCR and ISH were performed to quantify expression of circ0003692 in human GC tissues and adjacent normal tissues. The protein-encoding ability of circ0003692 was investigated through dual-luciferase reporter assay and LC/MS. The biological behavior of circ0003692 in GC was confirmed via in vivo and in vitro experiments. Additionally, Co-IP and rescue experiments were performed to elucidate the interaction between the encoded protein and c-Myc. RESULTS: We found that circ0003692 was significantly downregulated in GC tissues. Circ0003692 had the potential to encode a novel protein FNDC3B-267aa, which was downregulated in GC cells. We verified that FNDC3B-267aa, rather than circ0003692, inhibited GC migration in vitro and in vivo. Mechanistically, FNDC3B-267aa directly interacted with c-Myc and promoted proteasomal degradation of c-Myc, resulting in the downregulation of c-Myc-Snail/Slug axis. CONCLUSIONS: Our study revealed that the novel protein FNDC3B-267aa encoded by circ0003692 suppressed GC metastasis through binding to c-Myc and enhancing proteasome-mediated degradation of c-Myc. The study offers the potential applications of circ0003692 or FNDC3B-267aa as therapeutic targets for GC.
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Fibronectinas , Metástase Neoplásica , Complexo de Endopeptidases do Proteassoma , Proteínas Proto-Oncogênicas c-myc , RNA Circular , Neoplasias Gástricas , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Humanos , RNA Circular/genética , RNA Circular/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Linhagem Celular Tumoral , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Animais , Fibronectinas/metabolismo , Regulação Neoplásica da Expressão Gênica , Masculino , Proteólise , Camundongos Nus , Sequência de Bases , Movimento Celular/genética , Feminino , CamundongosRESUMO
Acute kidney injury (AKI) is a worldwide public health problem characterized by the massive loss of tubular cells. However, the precise mechanism for initiating tubular cell death has not been fully elucidated. Here, we reported that phosphoglycerate mutase 5 (PGAM5) was upregulated in renal tubular epithelial cells during ischaemia/reperfusion or cisplatin-induced AKI in mice. PGAM5 knockout significantly alleviated the activation of the mitochondria-dependent apoptosis pathway and tubular apoptosis. Apoptosis inhibitors alleviated the activation of the mitochondria-dependent apoptosis pathway. Mechanistically, as a protein phosphatase, PGAM5 could dephosphorylate Bax and facilitate Bax translocation to the mitochondrial membrane. The translocation of Bax to mitochondria increased membrane permeability, decreased mitochondrial membrane potential and facilitated the release of mitochondrial cytochrome c (Cyt c) into the cytoplasm. Knockdown of Bax attenuated PGAM5 overexpression-induced Cyt c release and tubular cell apoptosis. Our results demonstrated that the increase in PGAM5-mediated Bax dephosphorylation and mitochondrial translocation was implicated in the development of AKI by initiating mitochondrial Cyt c release and activating the mitochondria-dependent apoptosis pathway. Targeting this axis might be beneficial for alleviating AKI.
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Injúria Renal Aguda , Citocromos c , Camundongos , Animais , Citocromos c/metabolismo , Fosfoglicerato Mutase/metabolismo , Proteína X Associada a bcl-2/metabolismo , Apoptose/fisiologia , Mitocôndrias/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Proteínas de Transporte/metabolismo , Fosfoproteínas Fosfatases/metabolismoRESUMO
The pyroptosis of renal tubular epithelial cells leads to tubular loss and inflammation and then promotes renal fibrosis. The transcription factor Krüppel-like factor 4 (KLF4) can bidirectionally regulate the transcription of target genes. Our previous study revealed that sustained elevation of KLF4 is responsible for the transition of acute kidney injury (AKI) into chronic kidney disease (CKD) and renal fibrosis. In this study, we explored the upstream mechanisms of renal tubular epithelial cell pyroptosis from the perspective of posttranslational regulation and focused on the transcription factor KLF4. Mice were subjected to unilateral ureteral obstruction (UUO) surgery and euthanized on D7 or D14 for renal tissue harvesting. We showed that the pyroptosis of renal tubular epithelial cells mediated by both the Caspase-1/GSDMD and Caspase-3/GSDME pathways was time-dependently increased in UUO mouse kidneys. Furthermore, we found that the expression of the transcription factor KLF4 was also upregulated in a time-dependent manner in UUO mouse kidneys. Tubular epithelial cell-specific Klf4 knockout alleviated UUO-induced pyroptosis and renal fibrosis. In Ang II-treated mouse renal proximal tubular epithelial cells (MTECs), we demonstrated that KLF4 bound to the promoter regions of Caspase-3 and Caspase-1 and directly increased their transcription. In addition, we found that ubiquitin-specific protease 11 (USP11) was increased in UUO mouse kidneys. USP11 deubiquitinated KLF4. Knockout of Usp11 or pretreatment with the USP11 inhibitor mitoxantrone (3 mg/kg, i.p., twice a week for two weeks before UUO surgery) significantly alleviated the increases in KLF4 expression, pyroptosis and renal fibrosis. These results demonstrated that the increased expression of USP11 in renal tubular cells prevents the ubiquitin degradation of KLF4 and that elevated KLF4 promotes inflammation and renal fibrosis by initiating tubular cell pyroptosis.
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BACKGROUND: Gastric cancer (GC) is a prevalent malignant tumor, and the RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1) has been identified as a crucial factor in various tumor types. Moreover, abnormal autophagy levels have been shown to significantly impact tumorigenesis and progression. Despite this, the precise regulatory mechanism of PTBP1 in autophagy regulation in GC remains poorly understood. METHODS: To assess the expression of PTBP1 in GC, we employed a comprehensive approach utilizing western blot, real-time quantitative polymerase chain reaction (RT-qPCR), and bioinformatics analysis. To further identify the downstream target genes that bind to PTBP1 in GC cells, we utilized RNA immunoprecipitation coupled with sequencing (si-PTBP1 RNA-seq). To evaluate the impact of PTBP1 on gastric carcinogenesis, we conducted CCK-8 assays, colony formation assays, and GC xenograft mouse model assays. Additionally, we utilized a transmission electron microscope, immunofluorescence, flow cytometry, western blot, RT-qPCR, and GC xenograft mouse model experiments to elucidate the specific mechanism underlying PTBP1's regulation of autophagy in GC. RESULTS: Our findings indicated that PTBP1 was significantly overexpressed in GC tissues compared with adjacent normal tissues. Silencing PTBP1 resulted in abnormal accumulation of autophagosomes, thereby inhibiting GC cell viability both in vitro and in vivo. Mechanistically, interference with PTBP1 promoted the stability of thioredoxin-interacting protein (TXNIP) mRNA, leading to increased TXNIP-mediated oxidative stress. Consequently, this impaired lysosomal function, ultimately resulting in blockage of autophagic flux. Furthermore, our results suggested that interference with PTBP1 enhanced the antitumor effects of chloroquine, both in vitro and in vivo. CONCLUSION: PTBP1 knockdown impairs GC progression by directly binding to TXNIP mRNA and promoting its expression. Based on these results, PTBP1 emerges as a promising therapeutic target for GC.
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Autofagia , Proteínas de Transporte , Ribonucleoproteínas Nucleares Heterogêneas , Estresse Oxidativo , Proteína de Ligação a Regiões Ricas em Polipirimidinas , Neoplasias Gástricas , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Autofagia/genética , Humanos , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/genética , Animais , Proteínas de Transporte/metabolismo , Proteínas de Transporte/genética , Estresse Oxidativo/genética , Linhagem Celular Tumoral , Camundongos , Progressão da Doença , Camundongos Nus , Regulação Neoplásica da Expressão Gênica , Proliferação de Células/genética , Técnicas de Silenciamento de Genes , Camundongos Endogâmicos BALB C , MasculinoRESUMO
BACKGROUND: Distal radius fractures (DRFs) have become a public health problem for all countries, bringing a heavier economic burden of disease globally, with China's disease economic burden being even more acute due to the trend of an aging population. This study aimed to explore the influencing factors of hospitalization cost of patients with DRFs in traditional Chinese medicine (TCMa) hospitals to provide a scientific basis for controlling hospitalization cost. METHODS: With 1306 cases of DRFs patients hospitalized in 15 public TCMa hospitals in two cities of Gansu Province in China from January 2017 to 2022 as the study object, the influencing factors of hospitalization cost were studied in depth gradually through univariate analysis, multiple linear regression, and path model. RESULTS: Hospitalization cost of patients with DRFs is mainly affected by the length of stay, surgery and operation, hospital levels, payment methods of medical insurance, use of TCMa preparations, complications and comorbidities, and clinical pathways. The length of stay is the most critical factor influencing the hospitalization cost, and the longer the length of stay, the higher the hospitalization cost. CONCLUSIONS: TCMa hospitals should actively take advantage of TCMb diagnostic modalities and therapeutic methods to ensure the efficacy of treatment and effectively reduce the length of stay at the same time, to lower hospitalization cost. It is also necessary to further deepen the reform of the medical insurance payment methods and strengthen the construction of the hierarchical diagnosis and treatment system, to make the patients receive reasonable reimbursement for medical expenses, thus effectively alleviating the economic burden of the disease in the patients with DRFs.
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Custos Hospitalares , Hospitalização , Tempo de Internação , Medicina Tradicional Chinesa , Fraturas do Punho , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , China , Custos Hospitalares/estatística & dados numéricos , Hospitalização/economia , Hospitais Públicos/economia , Tempo de Internação/economia , Medicina Tradicional Chinesa/economia , Fraturas do Punho/economia , Fraturas do Punho/terapiaRESUMO
BACKGROUND: Benign prostate hyperplasia (BPH) and prostate cancer (CaP) are among the most frequently occurring prostatic diseases. When CaP progressed to castration-resistant CaP (CRPC), the prognosis is poor. Although CaP/CRPC and BPH frequently coexist in prostate, the inter-relational mechanism between them is largely unknown. METHODS: Single-cell RNA sequencing, bulk-RNA sequencing, and microarray data of BPH, CaP in the Gene Expression Omnibus database were obtained and comprehensively analyzed. Weighted Gene Co-Expression Network Analysis (WGCNA) and lasso regression analysis were performed to explore the potential biomarkers. RESULTS: With WGCNA, five modules in BPH, two in CaP, and three in CRPC were identified as significant modules. Pathway enrichment analysis found that the epigenetics and chromosomal-related signaling were dominantly clustered in the CaP group but not in BPH and CRPC. Lasso regression analysis was used to analyze further the mutual genes between the BPH module and the CRPC module. As a result, DDA1, ERG28, OGFOD1, and OXA1L were significantly correlated with the transcriptomic features in both BPH and CRPC. More importantly, the role of the four gene signatures was validated in two independent anti-PD-1 immunotherapy cohort. CONCLUSION: This study revealed the shared gene signatures and immune microenvironment between BPH and CRPC. The identified hub genes, including DDA1, ERG28, OGFOD1, and OXA1L, might be potential therapeutic targets for facilitating immunotherapy in prostate cancer.
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Hiperplasia Prostática , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Hiperplasia Prostática/genética , Hiperplasia Prostática/metabolismo , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Próstata/metabolismo , Hiperplasia , Transdução de Sinais , Microambiente Tumoral/genética , Proteínas de Transporte/metabolismo , Proteínas de Transporte/uso terapêutico , Proteínas Nucleares/metabolismo , Proteínas Nucleares/uso terapêuticoRESUMO
Transforming growth factor-ß1 (TGF-ß1) is regarded as a key factor in promoting renal fibrosis during chronic kidney disease (CKD). Signaling transduction of TGF-ß1 starts with binding to TGF-ß type II receptor (Tgfbr2), a constitutively activated kinase that phosphorylates TGF-ß type I receptor (Tgfbr1), and then activates downstream Smad2/3 or noncanonical pathways. Previous studies show that cellular senescence is associated with the progression of CKD, and accelerated tubular cell senescence is implicated in promoting renal fibrosis. In the present study we investigated the renal parenchymal cell senescence in fibrosis from the sight of posttranslational regulation and focused on Tgfbr2, the important gatekeeper for TGF-ß1 downstream signaling. In mice with unilateral ureteral obstruction (UUO) and folic acid (FA)-induced fibrotic kidneys, we found that Tgfbr2 was markedly elevated without obvious change in its mRNA levels. As an important member of deubiquitinating enzymes, ubiquitin-specific protease 11 (Usp11) was also significantly increased in fibrotic kidneys, and co-distributed with Tgfbr2 in tubular epithelial cells. Pretreatment with Usp11 inhibitor mitoxantrone (MTX, 30 mg · kg-1 · d-1, i.p.) twice a week, for 2 weeks significantly attenuated the elevation of Tgfbr2, activation in downstream senescence-related signaling pathway, as well as renal senescence and fibrosis. In cultured mouse tubular epithelial cells (MTECs), treatment with angiotensin II (Ang-II, 10-7, 10-6 M) dose-dependently elevated both Tgfbr2 and Usp11 levels. Inhibition or knockdown on Usp11 attenuated Ang-II-induced elevation in Tgfbr2 level, and attenuated the activation of downstream senescent-related signaling pathway and as well as cell senescence. We conducted Co-IP experiments, which revealed that Usp11 was able to interact with Tgfbr2, and inhibition of Usp11 increased the ubiquitination of Tgfbr2. Taken together, these results demonstrate that the elevation of Usp11 under pathological condition is implicated in promoting renal fibrosis. Usp11 promotes the development of renal fibrosis by deubiquitinating Tgfbr2, reducing Tgfbr2 ubiquitination degradation, and then facilitating the activation of downstream senescent signaling pathway.
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Senescência Celular , Enzimas Desubiquitinantes , Insuficiência Renal Crônica , Animais , Camundongos , Senescência Celular/fisiologia , Enzimas Desubiquitinantes/metabolismo , Células Epiteliais/metabolismo , Fibrose/metabolismo , Rim/patologia , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Insuficiência Renal Crônica/patologia , Fator de Crescimento Transformador beta1/metabolismo , Ubiquitina/metabolismo , Obstrução Ureteral/complicaçõesRESUMO
We report a case of primary seminal vesicle spindle cell sarcoma of a 57-year-old man who underwent multiple surgical treatment. The first diagnosis of a local hospital was a right seminal vesicle cyst, so only laparoscopic decompression was performed. Postoperatively, the patient gradually developed lower abdominal discomfort, frequent and urgent urination, dysuria and constipation. Digital rectal examination palpated a heterogeneous mass. Magnetic resonance imaging showed a multilocular cystic mass of about 4.5 cm in diameter in the right seminal vesicle, which was diagnosed as a recurrent cyst. The patient underwent a second operation in our hospital, but the tumour could not be completely removed because of severe peripheral adhesions. The postoperative pathological diagnosis was seminal vesicle cystadenoma with spindle cell sarcoma. One month later, a computed tomography scan performed at another hospital showed that the mass had invaded the bladder and sigmoid colon. The pathological diagnosis of re-examination was spindle cell liposarcoma. After neoadjuvant chemotherapy, extended resection of the tumour was performed, and adjuvant chemotherapy was continued after surgery. The total duration of follow-up was 19 months and 3 months after the third surgery. The patient survived with no recurrence or metastasis.
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Cistadenoma , Neoplasias dos Genitais Masculinos , Sarcoma , Cistadenoma/cirurgia , Neoplasias dos Genitais Masculinos/diagnóstico por imagem , Neoplasias dos Genitais Masculinos/cirurgia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Sarcoma/diagnóstico por imagem , Sarcoma/cirurgia , Glândulas Seminais/diagnóstico por imagem , Glândulas Seminais/patologia , Glândulas Seminais/cirurgiaRESUMO
Renal angiomyolipoma (AML) is a benign tumor. However, rare cases of renal AML demonstrate aggressive behaviors such as tumor thrombus extension into the inferior vena cava (IVC). We successfully treated a case of epithelioid AML in the right kidney involving the IVC. We also reviewed and analyzed 45 case reports of the common type of AML. Radiologists and clinicians should know that epithelioid AML can be an aggressive tumor.
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Angiomiolipoma/patologia , Neoplasias Renais/patologia , Células Neoplásicas Circulantes , Veia Cava Inferior , Adulto , Humanos , Masculino , Invasividade NeoplásicaRESUMO
OBJECTIVE: To retrospectively evaluate the safety and efficacy of flexible ureteroscopy (FURS) in combination with holmium laser lithotripsy for the treatment of bilateral upper urinary calculi. MATERIALS AND METHODS: The stone-free status was defined as the absence of any stones or asymptomatic status, or the presence of clinically insignificant residual fragments <4 mm, and was assessed by plain kidney, ureter, and bladder X-ray. The operative time, stone-free rates (SFRs), serum creatinine (SCr), and complications were recorded. RESULTS: During the operation, there was no bleeding, ureteral perforation, avulsion, and rupture. Postoperative hematuria was observed in 2 patients. SCr increased significantly on the first day after the procedure compared with the preoperative SCr, but after 4 weeks, the renal function significantly improved (p < 0.05). The SFR was 71.6% (63/88) on the first day after the first surgical procedure; it then increased to 86.4% (76/88) in the fourth week, and rose to 97.4% (76/78) after the second operation. CONCLUSION: The results demonstrated that FURS in combination with holmium laser lithotripsy represented a favorable less-invasive alternative with high SFR and acceptable complication rates in the treatment of bilateral upper urinary tract calculi.
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Lasers de Estado Sólido , Litotripsia a Laser , Ureteroscópios , Cálculos Urinários/terapia , Adulto , Feminino , Hematúria/sangue , Hemorragia , Humanos , Litotripsia , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Segurança do Paciente , Estudos Retrospectivos , Resultado do Tratamento , Ureteroscopia , Raios XRESUMO
OBJECTIVE: Matrix metalloproteinase-9 (MMP-9) plays an important role in the remodeling of the extracellular matrix in atherosclerosis plaques. Autophagy protects macrophages against the processes of vascular disease. Our research explores how autophagy plays roles in macrophages to secret MMP-9. METHODS AND RESULTS: In response to increased doses of oxLDL or CQ we monitored the autophagic flux. Our results revealed that oxLDL was dynamically associated with autophagy and 100 µg/ml oxLDL blocked autophagic flux in THP-1 cells. Moreover p62/SQSTM1 knocking down and CQ respectively inhibited and increased MMP-9 transcriptional expression. These effects were mediated by inhibition of NF-κB. CONCLUSION: Abundant oxLDL blocked autophagic flux resulting in the aggregation of p62/SQSTM1. Then p62/SQSTM1 was involved in gene expression of MMP-9 via NF-κB-dependent signaling, and thus featuring novel plaque vulnerability properties of the atherosclerotic plaque. Understanding the mechanism that selectively modulates p62/SQSTM1 will provide a novel strategy for anti-atherogenesis.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Aterosclerose/metabolismo , Lipoproteínas LDL/administração & dosagem , Macrófagos/metabolismo , Macrófagos/patologia , Metaloproteinase 9 da Matriz/metabolismo , Aterosclerose/patologia , Autofagia/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Macrófagos/efeitos dos fármacos , Proteína Sequestossoma-1RESUMO
We demonstrated experimentally that graphene-Cu-graphene heterogeneous films reveal strongly enhanced thermal conductivity as compared to the reference Cu and annealed Cu films. Chemical vapor deposition of a single atomic plane of graphene on both sides of 9 µm thick Cu films increases their thermal conductivity by up to 24% near room temperature. Interestingly, the observed improvement of thermal properties of graphene-Cu-graphene heterofilms results primarily from the changes in Cu morphology during graphene deposition rather than from graphene's action as an additional heat conducting channel. Enhancement of thermal properties of graphene-capped Cu films is important for thermal management of advanced electronic chips and proposed applications of graphene in the hybrid graphene-Cu interconnect hierarchies.
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Tissue inhibitor of metalloproteinase-3 (TIMP-3) is one of a family of proteins inhibiting matrix metalloproteinases, which has also been identified as a mediator for checking inflammation. Meanwhile, it is well known that inflammation causes the activation of the immune response. However, it is not clear whether TIMP-3 plays a role in the immune system. In the present study, we demonstrated a novel function of TIMP-3 in Th1/Th2 polarization through its influence on the antigen-presenting cells. First, TIMP-3 was found strikingly up-regulated by IL-4 during the differentiation of human dendritic cells via the p38MAPK pathway. Second, the expression of costimulatory molecule-CD86 was repressed by TIMP-3. Besides, the induction of IL-12 in matured dendritic cells was significantly inhibited in a PI3K-dependent manner. Furthermore, dendritic cells matured in the presence of TIMP-3 could stimulate allogeneic naive T helper (Th) cells to display a prominent Th2 polarization. Importantly, in an autoimmune disorder-primary immune thrombocytopenia, TIMP-3 showed a statistically positive correlation with IL-4 and platelet count, but a negative correlation with IFN-γ in patient blood samples. Collectively, these in vitro and in vivo data clearly suggested a novel role of TIMP-3 in Th1/Th2 balance in humans.
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Polaridade Celular/genética , Células Dendríticas/fisiologia , Células Th1/fisiologia , Células Th2/fisiologia , Inibidor Tecidual de Metaloproteinase-3/fisiologia , Adolescente , Adulto , Estudos de Casos e Controles , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Polaridade Celular/efeitos dos fármacos , Polaridade Celular/imunologia , Células Cultivadas , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Monócitos/fisiologia , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/genética , Púrpura Trombocitopênica Idiopática/imunologia , Púrpura Trombocitopênica Idiopática/metabolismo , RNA Interferente Pequeno/farmacologia , Células Th1/citologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/citologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Inibidor Tecidual de Metaloproteinase-3/antagonistas & inibidores , Inibidor Tecidual de Metaloproteinase-3/genética , Inibidor Tecidual de Metaloproteinase-3/metabolismo , Adulto JovemRESUMO
Multicolor lasing and dynamic color-tuning in a wide spectrum range are challenging to realize but critically important in many areas of technology and daily life, such as general lighting, display, multicolor detection, and multiband communication. By exploring nanoscale growth and manipulation, we have demonstrated the first active dynamical color control of multicolor lasing, continuously tunable between red and green colors separated by 107 nm in wavelength. This is achieved in a purposely engineered single CdSSe alloy nanowire with composition varied along the wire axis. By looping the wide-gap end of the alloy nanowire through nanoscale manipulation, two largely independent (only weakly coupled) laser cavities are formed respectively for the green and red color modes. Our approach simultaneously overcomes the two fundamental challenges for multicolor lasing in material growth and cavity design. Such multicolor lasing and continuous color tuning in a wide spectral range represents a new paradigm shift and would eventually enable color-by-design and white-color lasers for lighting, illumination, and many other applications.
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Cor , Lasers , Nanofios/química , Ligas/química , Desenho de Equipamento , LuzRESUMO
Knowledge distillation is an effective approach for training robust multi-modal machine learning models when synchronous multimodal data are unavailable. However, traditional knowledge distillation techniques have limitations in comprehensively transferring knowledge across modalities and models. This paper proposes a multiscale knowledge distillation framework to address these limitations. Specifically, we introduce a multiscale semantic graph mapping (SGM) loss function to enable more comprehensive knowledge transfer between teacher and student networks at multiple feature scales. We also design a fusion and tuning (FT) module to fully utilize correlations within and between different data types of the same modality when training teacher networks. Furthermore, we adopt transformer-based backbones to improve feature learning compared to traditional convolutional neural networks. We apply the proposed techniques to multimodal human activity recognition and compared with the baseline method, it improved by 2.31% and 0.29% on the MMAct and UTD-MHAD datasets. Ablation studies validate the necessity of each component.
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Atividades Humanas , Aprendizado de Máquina , Redes Neurais de Computação , Humanos , Algoritmos , AtençãoRESUMO
BACKGROUND: Although a survival benefit was observed in patients with metastatic renal cell carcinoma (mRCC) who underwent cytoreductive nephrectomy (CN), there is a lack of effective tools for predicting which individuals are likely to benefit from surgical intervention. Herein, we developed a predictive model using data from the Surveillance, Epidemiology, and End Results (SEER) database. MATERIALS AND METHODS: Patients diagnosed with mRCC were screened from the SEER database (2010-2020), supplemented by patients from East Asia. Patients were categorized into surgical and non-surgical groups, with propensity score matching conducted to balance baseline characteristics. Logistic regression analysis was performed to identify independent factors associated with benefits and a nomogram was constructed based on these factors. RESULTS: This study included 11,044 cases from the SEER database and 50 cases from an external validation cohort. CN was identified as an independent protective factor for OS. A nomogram was established, and it performed well in the training and validation sets. The calibration curves and DCA confirmed that the nomogram model could precisely predict the probability of surgical benefit. We used the nomogram to classify surgical patients into benefit and non-benefit groups. Then, we found that OS was significantly higher in the benefit group than in the non-benefit group. The external validation cohort observed the same result (P=0.035). CONCLUSION: While CN offers potential benefits for patients with mRCC, its applicability varies across the patient population. Our study constructed a nomogram that quantitatively assesses the likelihood of surgical benefit in mRCC patients, facilitating more tailored therapeutic decision-making.
Assuntos
Carcinoma de Células Renais , Procedimentos Cirúrgicos de Citorredução , Neoplasias Renais , Nefrectomia , Nomogramas , Programa de SEER , Humanos , Carcinoma de Células Renais/cirurgia , Carcinoma de Células Renais/patologia , Nefrectomia/métodos , Masculino , Feminino , Neoplasias Renais/cirurgia , Neoplasias Renais/patologia , Pessoa de Meia-Idade , Idoso , Seleção de Pacientes , Pontuação de Propensão , PrognósticoRESUMO
The permeability of the blood-brain barrier (BBB) is increased in Alzheimer's disease (AD). This plays a key role in the instigation and maintenance of chronic inflammation during AD. Experiments using AD models showed that the increased permeability of the BBB was mainly caused by the decreased expression of tight junction-related proteins occludin and claudin-5. In this study, we found that ZNF787 and HDAC1 were upregulated in ß-amyloid (Aß)1-42-incubated endothelial cells, resulting in increased BBB permeability. Conversely, the silencing of ZNF787 and HDAC1 by RNAi led to reduced BBB permeability. The silencing of ZNF787 and HDAC1 enhanced the expression of occludin and claudin-5. Mechanistically, ZNF787 binds to promoter regions for occludin and claudin-5 and functions as a transcriptional regulator. Furthermore, we demonstrate that ZNF787 interacts with HDAC1, and this resulted in the downregulation of the expression of genes encoding tight junction-related proteins to increase in BBB permeability. Taken together, our study identifies critical roles for the interaction between ZNF787 and HDAC1 in regulating BBB permeability and the pathogenesis of AD.
Assuntos
Doença de Alzheimer , Barreira Hematoencefálica , Histona Desacetilase 1 , Humanos , Doença de Alzheimer/genética , Claudina-5/genética , Células Endoteliais , Histona Desacetilase 1/genética , Ocludina/genética , PermeabilidadeRESUMO
OBJECTIVES: To explore the features, treatment, and outcomes of primary urothelial carcinoma of the prostate (PUCP) in a multicenter study. METHODS: The clinical and imaging features, pathological findings, treatment, and outcomes of patients diagnosed with PUCP from January 2011 to April 2022 at three institutions were collected and analyzed. The Kaplan-Meier method and log-rank test were used to assess survival rates of the overall group and survival differences between groups according to TNM stage. RESULTS: The study cohort comprised 18 patients with PUCP of mean age 72.4±7.8 years. Dysuria and urinary frequency were the most common symptoms (77.8 %). Sixteen (88.9 %) patients had normal serum total PSA concentrations. Most patients showed abnormalities on urinalysis. MRI was the most accurate diagnostic imaging method (88.9 %). As to immunohistochemistry findings, GATA-3 (81.8 %) and P63 (84.6 %) were positive in most examined patients; however, no lesions were positive for PSA. Three (17.6 %) patients with T1N0M0 and T2N0M0 tumors underwent radical cystectomy. Eleven (64.7 %) patients which almost all had T4 tumors received systematic therapy, most of them receiving chemotherapy with gemcitabine and cisplatin, and radiotherapy. The median overall survival was 42 months, and the median progression-free survival 25 months, the latter being significantly longer in patients with T1-2 than in those with T3-4 disease (p=0.035). CONCLUSION: PUCP, a rare but highly aggressive type of prostate cancer, should be considered in men with abnormalities on MRI and normal serum PSA concentrations. Positive GATA-3, P63, and negative PSA are typical immunohistochemistry features. Radical cystectomy and systematic therapies can be effective.