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OBJECTIVE: To evaluate the efficiency of the four domestic language models, ERNIE Bot, ChatGLM2, Spark Desk and Qwen-14B-Chat, all with a massive user base and significant social attention, in response to consultations about PCa-related perioperative nursing and health education. METHODS: We designed a questionnaire that includes 15 questions commonly concerned by patients undergoing radical prostatectomy and 2 common nursing cases, and inputted the questions into each of the four language models for simulation consultation. Three nursing experts assessed the model responses based on a pre-designed Likert 5-point scale in terms of accuracy, comprehensiveness, understandability, humanistic care, and case analysis. We evaluated and compared the performance of the four models using visualization tools and statistical analyses. RESULTS: All the models generated high-quality texts with no misleading information and exhibited satisfactory performance. Qwen-14B-Chat scored the highest in all aspects and showed relatively stable outputs in multiple tests compared with ChatGLM2. Spark Desk performed well in terms of understandability but lacked comprehensiveness and humanistic care. Both Qwen-14B-Chat and ChatGLM2 demonstrated excellent performance in case analysis. The overall performance of ERNIE Bot was slightly inferior. All things considered, Qwen-14B-Chat was superior to the other three models in consultations about PCa-related perioperative nursing and health education. CONCLUSION: In PCa-related perioperative nursing, large language models represented by Qwen-14B-Chat are expected to become powerful auxiliary tools to provide patients with more medical expertise and information support, so as to improve the patient compliance and the quality of clinical treatment and nursing.
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Enfermería Perioperatoria , Humanos , Encuestas y Cuestionarios , Masculino , China , Educación en Salud/métodos , Lenguaje , Prostatectomía/métodosRESUMEN
Integrating genomics and histology for cancer prognosis demonstrates promise. Here, we develop a multi-classifier system integrating a lncRNA-based classifier, a deep learning whole-slide-image-based classifier, and a clinicopathological classifier to accurately predict post-surgery localized (stage I-III) papillary renal cell carcinoma (pRCC) recurrence. The multi-classifier system demonstrates significantly higher predictive accuracy for recurrence-free survival (RFS) compared to the three single classifiers alone in the training set and in both validation sets (C-index 0.831-0.858 vs. 0.642-0.777, p < 0.05). The RFS in our multi-classifier-defined high-risk stage I/II and grade 1/2 groups is significantly worse than in the low-risk stage III and grade 3/4 groups (p < 0.05). Our multi-classifier system is a practical and reliable predictor for recurrence of localized pRCC after surgery that can be used with the current staging system to more accurately predict disease course and inform strategies for individualized adjuvant therapy.
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Carcinoma de Células Renales , Neoplasias Renales , Recurrencia Local de Neoplasia , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/cirugía , Masculino , Femenino , Recurrencia Local de Neoplasia/genética , Persona de Mediana Edad , Anciano , Pronóstico , Genómica/métodos , Adulto , Estadificación de Neoplasias , Aprendizaje Profundo , Supervivencia sin EnfermedadRESUMEN
BACKGROUND: Accumulating evidence indicates the crucial role of microglia-mediated inflammation and the NLR family pyrin domain containing 3 (NLRP3) inflammasome-mediated pyroptosis in the pathogenesis of Parkinson's disease (PD). Baohuoside I, a natural flavonoid extracted from Herba Epimedii, has been shown to possess anti-inflammatory effects, but its potential neuroprotective effects and mechanism against PD have not been documented. STUDY DESIGN AND METHODS: The anti-inflammatory effects of Baohuoside I were evaluated by LPS-induced BV2 cells or primary microglia isolated from wide type or G protein-coupled estrogen receptor (GPER) gene knockout mice. The underlying mechanism related to GPER-mediated NLRP3 inflammasome inhibition was further explored using LPS-induced GPER+/+ or GPER-/- mouse models of PD. The neuroprotective effects of Baohuoside I were detected through western blot analysis, real-time PCR, molecular docking, mouse behavioral tests, immunofluorescence, and immunohistochemistry. RESULTS: Baohuoside I significantly alleviated LPS-induced neuroinflammation by inhibiting the activation of NF-κB signal and the increase of pyroptosis levels as evidenced by the downregulated expression of pyroptosis-related proteins (NLRP3, ASC, pro-Caspase-1, IL-1ß) in microglia cells. Intragastric administration of Baohuoside I protected against LPS-induced motor dysfunction and loss of dopaminergic neurons, reduced pro-inflammatory cytokines expressions, and inhibited microglial (Iba-1) and astrocyte (GFAP) activation in the nigrostriatal pathway in LPS-induced mouse model of PD. Pretreatment with GPER antagonist G15 in microglia cells or GPER gene deletion in mice significantly blocked the inhibitory effects of Baohuoside I on LPS-induced neuroinflammation and activation of the NLRP3/ASC/Caspase-1 pathway. Molecular docking further indicated that Baohuoside I might bind to GPER directly with a binding energy of -10.4 kcal/mol. CONCLUSION: Baohuoside I provides neuroprotective effects against PD by inhibiting the activation of the NF-κB signal and NLRP3/ASC/Caspase-1 pathway. The molecular target for its anti-inflammatory effects is proved to be GPER in the PD mouse model. Baohuoside I may be a valuable anti-neuroinflammatory agent and a drug with well-defined target for the treatment of PD.
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Fármacos Neuroprotectores , Enfermedad de Parkinson , Ratones , Animales , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , FN-kappa B/metabolismo , Enfermedades Neuroinflamatorias , Fármacos Neuroprotectores/farmacología , Lipopolisacáridos/farmacología , Simulación del Acoplamiento Molecular , Flavonoides/farmacología , Receptores Acoplados a Proteínas G/metabolismo , Caspasas/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/metabolismo , Microglía , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Improved markers for predicting recurrence are needed to stratify patients with localised (stage I-III) renal cell carcinoma after surgery for selection of adjuvant therapy. We developed a novel assay integrating three modalities-clinical, genomic, and histopathological-to improve the predictive accuracy for localised renal cell carcinoma recurrence. METHODS: In this retrospective analysis and validation study, we developed a histopathological whole-slide image (WSI)-based score using deep learning allied to digital scanning of conventional haematoxylin and eosin-stained tumour tissue sections, to predict tumour recurrence in a development dataset of 651 patients with distinctly good or poor disease outcome. The six single nucleotide polymorphism-based score, which was detected in paraffin-embedded tumour tissue samples, and the Leibovich score, which was established using clinicopathological risk factors, were combined with the WSI-based score to construct a multimodal recurrence score in the training dataset of 1125 patients. The multimodal recurrence score was validated in 1625 patients from the independent validation dataset and 418 patients from The Cancer Genome Atlas set. The primary outcome measured was the recurrence-free interval (RFI). FINDINGS: The multimodal recurrence score had significantly higher predictive accuracy than the three single-modal scores and clinicopathological risk factors, and it precisely predicted the RFI of patients in the training and two validation datasets (areas under the curve at 5 years: 0·825-0·876 vs 0·608-0·793; p<0·05). The RFI of patients with low stage or grade is usually better than that of patients with high stage or grade; however, the RFI in the multimodal recurrence score-defined high-risk stage I and II group was shorter than in the low-risk stage III group (hazard ratio [HR] 4·57, 95% CI 2·49-8·40; p<0·0001), and the RFI of the high-risk grade 1 and 2 group was shorter than in the low-risk grade 3 and 4 group (HR 4·58, 3·19-6·59; p<0·0001). INTERPRETATION: Our multimodal recurrence score is a practical and reliable predictor that can add value to the current staging system for predicting localised renal cell carcinoma recurrence after surgery, and this combined approach more precisely informs treatment decisions about adjuvant therapy. FUNDING: National Natural Science Foundation of China, and National Key Research and Development Program of China.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Pronóstico , Estudios Retrospectivos , Biomarcadores de Tumor , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Neoplasias Renales/diagnóstico , Neoplasias Renales/genética , Neoplasias Renales/patologíaRESUMEN
Benign prostatic hyperplasia (BPH) commonly occurs in middle-aged and elderly men, affecting their physical health while also triggering varying degrees of stigma. This leads to reduced treatment compliance and a lower quality of life for patients. This article elaborates on the conceptual development of stigma, the current state of stigma in BPH patients, sources and impacts of stigma, tools for investigating stigma, and intervention measures. The aim is to enhance medical professionals' understanding of stigma and provide a basis for effective nursing interventions.
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Investigación en Enfermería , Hiperplasia Prostática , Anciano , Masculino , Persona de Mediana Edad , Humanos , Calidad de Vida , Cooperación del PacienteRESUMEN
Mitochondrial dysfunction and oxidative stress play important roles in the neuropathogenesis of Parkinson's disease (PD). Epimedin B, the second highest active ingredient in the flavonoids of Herba Epimedii, has been proven effective in treating osteoporosis and oxaliplatin-induced peripheral neuropathy. The present study aims to investigate the neuroprotective effects of Epimedin B in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP)-induced mouse model of PD, and the involvement of G protein-coupled estrogen receptor (GPER)-mediated anti-apoptosis as well as anti-endoplasmic reticulum stress. Molecular docking revealed that Epimedin B could directly bind to GPER at the same site as GPER agonist G1 and the binding energy was - 7.3 kcal/mol. Epimedin B treatment ameliorated MPTP-induced motor dysfunction and alleviated the decreased contents of DA with its metabolites in the striatum and the loss of tyrosine hydroxylase-immunoreactive (TH-IR) neurons in the substantial nigra pars compacta (SNpc). Epimedin B treatment markedly prevented MPTP-induced changes in apoptosis-related protein Bcl-2 and Bax as well as endoplasmic reticulum stress-related protein glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP). Pharmacological blockade with GPER antagonist G15 could antagonize these neuroprotective effects of Epimedin B on the nigrostriatal system. Moreover, the anti-apoptosis and anti-endoplasmic reticulum stress effects of Epimedin B against MPTP toxicity were significantly reduced in GPER knockout (GPER-/-) mice. The present study provides the first evidence that Epimedin B can protect against MPTP-induced PD mice model. GPER may be a potential target for the neuroprotective effect of Epimedin B against PD.
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Fármacos Neuroprotectores , Enfermedad de Parkinson , Ratones , Animales , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Simulación del Acoplamiento Molecular , Flavonoides/farmacología , Flavonoides/uso terapéutico , Modelos Animales de Enfermedad , Estrógenos , Receptores Acoplados a Proteínas GRESUMEN
Neuroinflammation plays an important role in the pathogenesis of Parkinson's disease (PD). Genistein is an estrogen-like phytoestrogen that can exert biological effects via the crosstalk of estrogen receptor and insulin-like growth factor 1 receptor (IGF-1R). The present study aimed to evaluate the involvement of G protein-coupled estrogen receptor (GPER) and IGF-1R in the anti-inflammatory effects of genistein against lipopolysaccharide (LPS)-induced nigrostriatal injury in ovariectomized rats. Our results showed that genistein treatment could ameliorate the apomorphine-induced rotational behavior in LPS-induced inflammatory PD rat model. Genistein attenuated LPS-induced decrease of the contents of dopamine (DA) and its metabolites in striatum as well as the loss of tyrosine hydroxylase-immunoreactive (TH-IR) neurons in the substantia nigra (SN) of the lesioned side, which could be blocked by GPER antagonist G15 or IGF-1R antagonist JB1. Meanwhile, G15 or JB1 could attenuate the anti-inflammatory effects of genistein in LPS-induced microglial activation and production of tumor necrosis factor-α (TNF-α), interleukin 1ß (IL-1ß), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, genistein could inhibit the LPS-induced phosphorylation of p38, JNK, ERK and IκB in the lesioned side of SN and these effects could also be blocked by G15 or JB1. Taken together, our data provide the first evidence that genistein can inhibit the increase of microglia and protect dopaminergic neurons at least in part via GPER and IGF-1R signaling pathways in ovariectomized PD rat model.
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Genisteína/farmacología , Lipopolisacáridos/metabolismo , Microglía/efectos de los fármacos , Receptor IGF Tipo 1/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Sustancia Negra/efectos de los fármacos , Animales , Antiinflamatorios/farmacología , Neuronas Dopaminérgicas/metabolismo , Femenino , Sistema de Señalización de MAP Quinasas , FN-kappa B/metabolismo , Enfermedad de Parkinson/metabolismo , Ratas , Ratas Wistar , Transducción de SeñalRESUMEN
Icariin and icaritin, the major active components of Epimedii Genus, are considered as promising drugs with anti-inflammatory, anti-aging and neuroprotective effects. Our previous studies have demonstrated that icariin and icaritin can protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity on dopaminergic neurons via insulin-like growth factor-1 receptor (IGF-1 receptor) signaling. In the present study, we aimed to evaluate the role of IGF-1 receptor signaling in mediating the anti-inflammatory effects of icariin and icaritin against lipopolysaccharide (LPS)-induced neuroinflammation as well as their biological regulation effects in midbrain primary astrocytes. Our results showed that both icariin and icaritin significantly inhibited LPS-induced mRNA expressions of tumor necrosis factor (TNF-α) and interleukin-1ß (IL-1ß). Pre-treatment with IGF-1 receptor antagonist JB-1 could significantly block the anti-inflammatory effects of icariin and icaritin on LPS-induced up-regulations of TNF-α, IL-1ß, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Under basal conditions of astrocytes, icariin and icaritin treatment alone increased the phosphorylation of ERK1/2 and AKT, which could be blocked by JB-1. Moreover, the mRNA expressions of glutamate transptor-1 (GLT-1) and glutamate-aspartate transporter (GLAST) could be up-regulated by icariin and icaritin in a time-dependent manner via IGF-1 receptor. Taken together, our results suggest for the first time that both icariin and icaritin exert regulatory effects in astrocytes under basal conditions and after an inflammatory challenge via IGF-1 receptor signaling pathway.
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Astrocitos/patología , Flavonoides/farmacología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Receptor IGF Tipo 1/metabolismo , Animales , Astrocitos/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Flavonoides/aislamiento & purificación , Flavonoides/uso terapéutico , Humanos , Lipopolisacáridos/inmunología , Mesencéfalo/citología , Mesencéfalo/efectos de los fármacos , Mesencéfalo/patología , Ratones , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/patología , Cultivo Primario de Células , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunologíaRESUMEN
Insulin-like growth factor-1 (IGF-1) is a potent neuroprotective polypeptide that exerts neuroprotective effects via the IGF-1 receptor (IGF-1R). Our previous study reported that G protein-coupled estrogen receptor (GPER) was involved in the anti-apoptotic effect of IGF-1. The present study was designed to investigate the anti-inflammatory effect of IGF-1 in association with astrocyte activation and the molecular details of the interaction between IGF-1R and GPER. We showed that IGF-1 could improve 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor deficits and attenuate the upregulation of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) both in vivo and in vitro. The IGF-1R antagonist JB-1 and the GPER antagonist G15 could antagonize the anti-inflammatory effect of IGF-1. Silencing GPER abrogated the inhibitory effect of IGF-1 on 1-methyl-4-phenylpyridinium (MPP+)-induced upregulation of COX-2 and iNOS in primary astrocytes. Moreover, the MPP + -induced inflammatory response was related to the activation of mitogen-activated protein kinases (MAPKs) and NF-κB signaling pathways. The inhibitory effects of IGF-1 on the phosphorylation of p38, JNK and IκB could be blocked by JB-1. G15 antagonized the inhibitory effects of IGF-1 on p-JNK and p-IκB, but not p-p38. Furthermore, IGF-1 treatment alone increased the expression of GPER, which was blocked by JB-1, the phosphatidylinositol 3-kinase (PI3-K) antagonist LY294002 and the MEK antagonist PD98059 in primary astrocytes. Overall, we show for the first time that GPER may contribute to the anti-inflammatory effect of IGF-1 against MPTP/MPP + -induced astrocyte activation. IGF-1 could regulate the expression of GPER via the IGF-1R/PI3-K/MAPK signaling pathway in primary astrocytes.
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1-Metil-4-fenilpiridinio/toxicidad , Antiinflamatorios/farmacología , Astrocitos/metabolismo , Factor I del Crecimiento Similar a la Insulina/farmacología , Receptor IGF Tipo 1/metabolismo , Receptores de Estrógenos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Astrocitos/efectos de los fármacos , Conducta Animal , Benzodioxoles/farmacología , Células Cultivadas , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Quinolinas/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Sustancia Negra/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Background: The extent and depth of BK polyomavirus (BKPyV) infection in renal allograft correlate with prognosis. This study was designed to evaluate the value of urinary sediment double-immunostaining for predicting BKPyV infection in proximal tubular epithelium. Materials and methods: A total of 76 urine sediment cell blocks, as well as the corresponding transplanted kidney tissues with BK polyomavirus associated-nephropathy (BKPyVAN), were evaluated by automatic double-immunostaining with anti-58-kDa Golgi protein (58K, a proximal renal tubular marker) + anti-SV40-T and anti-homogentisate 1, 2-dioxygenase (HGD, a renal tubular marker) + anti-SV40-T. Results: Immunohistochemical staining demonstrated that 58K was expressed in proximal tubular epithelium but not in distal tubular epithelium or transitional epithelium. Of the 76 patients, 28 (36.8%) had urinary 58K(+)/SV40-T(+) cells and HGD(+)/SV40-T(+) cells, 41 (53.9%) had only HGD(+)/SV40-T(+) cells, one (1.3%) had only 58K(+)/SV40-T(+) cells, and six (7.9%) had only 58K(-)/HGD(-)/SV40-T(+) cells. The presence of urinary 58K(+)/SV40-T(+) cells was correlated with BKPyV infection in proximal tubular epithelium (P < 0.001, r = 0.806). The mean extent of SV40-T staining was significantly more extensive in patients with urinary 58K(+)/SV40-T(+) cells than those without urinary 58K(+)/SV40-T(+) cells (21.4 vs. 12.0%, P < 0.001). The positive predictive value, negative predictive value, sensitivity, and specificity of urinary 58K(+)/SV40-T(+) cells for predicting BKPyV infection in proximal tubular epithelium were 89.7% (95% CI: 71.5-97.3%), 91.5% (95% CI: 78.7-97.2%), 86.7% (95% CI: 68.4-95.6%), and 93.5% (95% CI: 81.1-98.3%), respectively. Conclusion: Urinary sediment double-immunostaining with anti-58K and anti-SV40-T is valuable for predicting the extent and depth of BKPyV infection in renal allograft.
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Aloinjertos/inmunología , Virus BK/fisiología , Rechazo de Injerto/inmunología , Trasplante de Riñón , Túbulos Renales Proximales/patología , Infecciones por Polyomavirus/inmunología , Urotelio/patología , Adulto , Aloinjertos/virología , Estudios Transversales , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Receptores de Trasplantes , Orina/citologíaRESUMEN
BACKGROUND: This study aimed to investigate the pathological characteristics of BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) with glomerular involvement in kidney transplant recipients. METHODS: Forty-four patients with glomerular BKPyV infection were retrospectively included for analysis. Immunohistochemical (IHC) staining was performed on paraffin sections using monoclonal mouse anti-SV40 large T antigen antibody. RESULTS: In BKPyV-infected glomeruli, the glomerular parietal epithelial cells (GPECs) were swollen, hyperchromatic, and enlarged, with an increased nuclear to cytoplasm (N/C) ratio and smudgy basophilic intra-nuclear viral inclusions. IHC staining revealed the distribution of BKPyV involvement in GPECs, podocytes, and shedding cells within Bowman's space. Notably, BKPyV affected GPEC proliferation and caused crescent formation (7 biopsies, 15.9%). Three biopsies exhibited fibrous crescents and the absence of viral inclusions. The other 4 biopsies exhibited cellular and fibro-cellular crescents, with viral cytopathic changes and positive IHC staining in the proliferative GPECs. Electron microscopy showed viral particles in both GPECs and podocytes. BKPyV-infected GPECs were degenerative, with mitochondrial swelling, endoplasmic reticulum expansion, and multi-layered membranous structure formation. Twelve (27.3%) patients received repeat biopsies within 1.6 to 39.5 months (median: 13.5 months), but none revealed persistent glomerular BKPyV infection. CONCLUSIONS: Distinct glomerular changes in BKPyVAN biopsies should raise the possibility of glomerular involvement.
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Background: Studies have shown that plasma donor-derived cell-free DNA (dd-cfDNA) can predict renal allograft antibody-mediated rejection. This study was performed to evaluate the value of urine dd-cfDNA concentration and dd-cfDNA fraction (%) for discriminating BK polyomavirus-associated nephropathy (BKPyVAN) in kidney transplant recipients with urinary BK polyomavirus (BKPyV) infection. Methods: In this retrospective single-center observational study, we enrolled kidney transplant recipients who were diagnosed with urine BKPyV infection between August 2018 and May 2019 at the First Affiliated Hospital of Sun Yat-sen University. Urine dd-cfDNA was measured by using a novel target region capture sequencing methodology. The pathological diagnosis of BKPyVAN was confirmed by anti-SV40-T immunohistochemical staining and classified using the American Society for Transplantation schema. Receiver operating characteristic curve analysis was used to investigate the relations of urine dd-cfDNA and dd-cfDNA% to intrarenal allograft BKPyV infection states. Results: In total, 93 patients were enrolled, including 40 cases of proven BKPyVAN, seven cases of probable BKPyVAN, 23 cases of possible BKPyVAN, and 23 cases of resolving BKPyVAN. Urine dd-cfDNA level in proven BKPyVAN (22.09 ± 21.27 ng/ml) was comparable to that in probable BKPyVAN (15.64 ± 6.73 ng/ml, P = 0.434) but was significantly higher than that in possible BKPyVAN (5.60 ± 3.53 ng/ml) and resolving BKPyVAN (5.30 ± 3.34 ng/ml) (both Ps < 0.05). Urine dd-cfDNA% of proven BKPyVAN (0.71 ± 0.21) was lower than that of probable BKPyVAN (0.91 ± 0.04, P < 0.001), but was significantly higher than that of possible BKPyVAN (0.56 ± 0.30) and resolving BKPyVAN (0.46 ± 0.28) (both Ps < 0.05). For distinguishing biopsy-proven BKPyVAN from biopsy-excluded BKPyVAN, the discrimination capacity of urine dd-cfDNA (AUC: 0.842, 95% CI: 0.735, 0.918) was superior to that of plasma BKPyV DNA load (AUC: 0.660, 95% CI: 0.537, 0.769) with 0.181 (95% CI: 0.043, 0.319) difference between areas under ROC curves (P = 0.010). Conclusion: The elevated urine dd-cfDNA level may help discriminate BKPyVAN in kidney transplant recipients with BKPyV viruria.
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Virus BK/genética , Ácidos Nucleicos Libres de Células/orina , ADN Viral/orina , Enfermedades Renales/diagnóstico , Trasplante de Riñón/efectos adversos , Infecciones por Polyomavirus/diagnóstico , Infecciones Tumorales por Virus/diagnóstico , Infecciones Urinarias/diagnóstico , Adulto , Diagnóstico Diferencial , Femenino , Humanos , Enfermedades Renales/orina , Enfermedades Renales/virología , Masculino , Persona de Mediana Edad , Infecciones por Polyomavirus/orina , Infecciones por Polyomavirus/virología , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Resultado del Tratamiento , Infecciones Tumorales por Virus/orina , Infecciones Tumorales por Virus/virología , Urinálisis , Infecciones Urinarias/orina , Infecciones Urinarias/virología , Carga ViralRESUMEN
Autophagy dysfunctions are involved in the pathogenesis of Parkinson's disease (PD). In the present study, we aimed to evaluate the involvement of G protein-coupled estrogen receptor (GPER) in the inhibitory effect of insulin-like growth factor-1 (IGF-1) against excessive autophagy in PD animal and cellular models. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment significantly induced mouse movement disorder and decreased the protein level of tyrosine hydroxylase (TH) in the substantia nigra (SN) and dopamine (DA) content in striatum. Along with the dopamine neuron injury, we observed significant upregulations of microtubule-associated light chain-3 II (LC3-II) and α-synuclein as well as a downregulation of P62 in MPTP-treated mice. These changes could be restored by IGF-1 pretreatment. Cotreatment with IGF-1R antagonist JB-1 or GPER antagonist G15 could block the neuroprotective effects of IGF-1. 1-Methy-4-phenylpyridinium (MPP+) treatment could also excessively activate autophagy along with the reduction of cell viability in SH-SY5Y cells. IGF-1 could inhibit the neurotoxicity through promoting the phosphorylation of Akt and mammalian target of rapamycin (mTOR), which could also be antagonized by JB-1 or G15. These data suggest that IGF-1 inhibits MPTP/MPP+-induced autophagy on dopaminergic neurons through the IGF-1R/PI3K-Akt-mTOR pathway and GPER.
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Autofagia/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/farmacología , Intoxicación por MPTP/prevención & control , Receptores de Estrógenos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Humanos , Intoxicación por MPTP/psicología , Masculino , Ratones , Ratones Endogámicos C57BL , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Proteína Oncogénica v-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Equilibrio Postural/efectos de los fármacos , Receptor IGF Tipo 1 , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
BACKGROUND: The positive predictive value (PPV) of urinary decoy cells for diagnosing BK polyomavirus associated-nephropathy (BKPyVAN) is low. This study was designed to increase the PPV of urinary decoy cells for diagnosing BKPyVAN in kidney transplant recipients. METHODS: A total of 105 urine sediment samples from 105 patients with positive BK viruria and decoy cells were evaluated by automatic double-immunostaining with anti-HGD (a renal tubular marker) antibody + anti-SV40-T antibody or anti-S100P (an urothelial marker) antibody + anti-SV40-T antibody. RESULTS: Of the 105 patients, 76 (72.4%) had both HGD(+)/SV40-T(+) cells and S100P(+)/SV40-T(+) cells (group A), 24 (22.9%) had only S100P(+)/SV40-T(+) cells (group B), and 5 (4.6%) had only S100P(-)/HGD(-)/SV40-T(+) cells (group C). Seventy patients in group A (92.1%), 3 patients in group B (12.5%), and no patients in group C were diagnosed with BKPyVAN. The area under the ROC curve of predicting BKPyVAN by decoy cells was 0.531 (0.431-0.630), with an optimal cut-off value of 29 (per 10 high power field), a sensitivity of 45.8% (95% CI: 34.0-58.0%), and a specificity of 68.8% (95% CI: 50.0-83.9%). Besides, the area under the ROC curve of predicting BKPyVAN by plasma BKPyV load was 0.735 (95% CI: 0.632-0.822), with an optimal cut-off value of 1,000 copies/mL, a sensitivity of 61.1% (95% CI: 48.9-72.4%) and a specificity of 84.2% (95% CI: 60.4-96.6%). In contrast, the PPV, negative predictive value, sensitivity, and specificity of HGD(+)/SV40-T(+) cells for diagnosing BKPyVAN were 92.1% [95% confidence interval (CI): 83.0-96.7%], 89.7% (95% CI: 71.5-97.3%), 95.9% (95% CI: 87.7-98.9%), and 81.3% (95% CI: 63.0-92.1%) respectively. CONCLUSIONS: Double-immunostaining with anti-HGD or anti-S100P and anti-SV40-T antibodies helps to identify the origin of decoy cells and diagnose BKPyVAN.
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BACKGROUND: BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) is an important cause of dysfunction and failure of renal transplants. This study aimed to assess the diagnostic performance of morning urine specific gravity (MUSG) in diagnosing BKPyVAN in kidney transplant recipients. METHODS: A total of 87 patients, including 27 with BKPyVAN, 22 with isolated BKPyV viruria, 18 with T cell-mediated rejection (TCMR), and 20 with stable graft function, were enrolled in the First Affiliated Hospital of Sun Yat-Sen University from March 2015 to February 2017. MUSG at biopsy and during a follow-up period of 24 months after biopsy was collected and analyzed. Receiver operating characteristic (ROC) curve analysis was used to determine the ability of MUSG to discriminate BKPyVAN. RESULTS: At biopsy, the MUSG of BKPyVAN group (1.008â±â0.003) was significantly lower than that of isolated BK viruria group (1.013â±â0.004, Pâ<â0.001), TCMR group (1.011â±â0.003, Pâ=â0.027), and control group (1.014â±â0.006, Pâ<â0.001). There was no significant difference in MUSG among the isolated BK viruria group, TCMR group, and control group (Pâ=â0.253). In BKPyVAN group, the timing and trend of MUSG elevate were consistent with the timing and trend of the decline of viral load in urine and plasma, reaching a statistical difference at 3 months after treatment (1.012â±â0.003, Pâ<â0.001) compared with values at diagnosis. ROC analysis indicated that the optimal cut-off value of MUSG for diagnosis of BKPyVAN was 1.009, with an area under the ROC curve (AUC) of 0.803 (95% confidence interval [CI]: 0.721-0.937). For differentiating BKPyVAN and TCMR, the optimal MUSG cut-off value was 1.010, with an AUC of 0.811 (95% CI: 0.687-0.934). CONCLUSION: Combined detection of MUSG and BKPyV viruria is valuable for predicting BKPyVAN and distinguishing BKPyVAN from TCMR in renal transplant recipients.
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Virus BK/patogenicidad , Trasplante de Riñón/efectos adversos , Infecciones por Polyomavirus/orina , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Gravedad Específica , Receptores de TrasplantesRESUMEN
Neuroinflammation plays a pivotal role in the pathogenesis of Parkinson's disease. Ginsenoside Rg1, the most active ingredient of ginseng, has been reported to exert neuroprotective effects via estrogen and glucocorticoid receptors. The present study evaluated the involvement of the G protein-coupled estrogen receptor (GPER) in the anti-inflammatory effects of ginsenoside Rg1 against lipopolysaccharide (LPS)-induced microglia activation in the BV2 microglial cell line and ventral mesencephalic primary microglial culture. The pharmacological blockade and lentivirus-mediated small interfering RNA (siRNA) knockdown of GPER were used to study the underlying mechanism. Rg1 attenuated LPS-induced upregulation of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) mRNA and protein levels. The GPER antagonist G15 blocked the inhibitory effects of Rg1 and the GPER-specific agonist G1 on LPS-induced microglia activation. Rg1 mimicked the effects of G1 by inhibiting the LPS-induced activation of nuclear transcription factor-kappa B (NF-κB) and mitogen activated protein kinase signaling pathways, which was also blocked by G15. Moreover, lentivirus-mediated siRNA knockdown of GPER inhibited the anti-inflammatory effects of Rg1. Taken together, our results indicate that GPER is involved in the anti-inflammatory effects of Rg1 against LPS-induced microglia activation. These findings provide a new biological target of Rg1 for the treatment of neuroinflammatory disorders.
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Insulin-like growth factor-1 (IGF-1), an endogenous peptide, exerts important role in brain development, neurogenesis and neuroprotection. There are accumulating evidence for the interaction of IGF-1 and 17ß-estradiol systems. IGF-1/IGF-1 receptor (IGF-1R) signaling has been reported to regulate G-protein estrogen receptor (GPER) expression in cancer cells. Whether GPER is involved in the neuroprotective effect of IGF-1 against MPTP/MPP+-induced dopaminergic neuronal injury remains unclear. We showed that IGF-1 could improve MPTP-induced motor deficits and ameliorate the decreased contents of DA and its metabolites in striatum as well as the loss of TH-IR neurons in the substantia nigra (SN). IGF-1 pretreatment also reversed the changes of Bcl-2 and Bax protein expressions in SN in MPTP mice. These effects were abolished by IGF-1 receptor (IGF-1R) antagonist JB-1 or GPER antagonist G15 except the inhibitory effect of G15 on Bax protein expression. Moreover, IGF-1 pretreatment enhanced cell survival against MPP+-induced neurotoxicity in SH-SY5Y cells. IGF-1 exerted anti-apoptotic effects by restoring MPP+-induced changes of Bcl-2 and Bax protein expressions as well as mitochondria membrane potential. Co-treatment with JB-1 or G15 could block these effects. Furthermore, IGF-1 regulated the protein expression of GPER through activation of phosphatidylinositol 3-kinase (PI3-K) and mitogen-activated protein kinase (MAPK) signaling pathways. Overall, we show for the first time that GPER may contribute to the neuroprotective effects of IGF-1 against MPTP/MPP+-induced dopaminergic neuronal injury.
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1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , Neuronas Dopaminérgicas/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/farmacología , Neuroblastoma/prevención & control , Enfermedad de Parkinson/prevención & control , Receptores de Estrógenos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Neuroblastoma/etiología , Neuroblastoma/metabolismo , Neuroblastoma/patología , Fármacos Neuroprotectores/farmacología , Neurotoxinas/efectos adversos , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Receptores de Estrógenos/genética , Receptores Acoplados a Proteínas G/genética , Transducción de Señal/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
BACKGROUND: Identification of high-risk localised renal cell carcinoma is key for the selection of patients for adjuvant treatment who are at truly higher risk of reccurrence. We developed a classifier based on single-nucleotide polymorphisms (SNPs) to improve the predictive accuracy for renal cell carcinoma recurrence and investigated whether intratumour heterogeneity affected the precision of the classifier. METHODS: In this retrospective analysis and multicentre validation study, we used paraffin-embedded specimens from the training set of 227 patients from Sun Yat-sen University (Guangzhou, Guangdong, China) with localised clear cell renal cell carcinoma to examine 44 potential recurrence-associated SNPs, which were identified by exploratory bioinformatics analyses of a genome-wide association study from The Cancer Genome Atlas (TCGA) Kidney Renal Clear Cell Carcinoma (KIRC) dataset (n=114, 906â600 SNPs). We developed a six-SNP-based classifier by use of LASSO Cox regression, based on the association between SNP status and patients' recurrence-free survival. Intratumour heterogeneity was investigated from two other regions within the same tumours in the training set. The six-SNP-based classifier was validated in the internal testing set (n=226), the independent validation set (Chinese multicentre study; 428 patients treated between Jan 1, 2004 and Dec 31, 2012, at three hospitals in China), and TCGA set (441 retrospectively identified patients who underwent resection between 1998 and 2010 for localised clear cell renal cell carcinoma in the USA). The main outcome was recurrence-free survival; the secondary outcome was overall survival. FINDINGS: Although intratumour heterogeneity was found in 48 (23%) of 206 cases in the internal testing set with complete SNP information, the predictive accuracy of the six-SNP-based classifier was similar in the three different regions of the training set (areas under the curve [AUC] at 5 years: 0·749 [95% CI 0·660-0·826] in region 1, 0·734 [0·651-0·814] in region 2, and 0·736 [0·649-0·824] in region 3). The six-SNP-based classifier precisely predicted recurrence-free survival of patients in three validation sets (hazard ratio [HR] 5·32 [95% CI 2·81-10·07] in the internal testing set, 5·39 [3·38-8·59] in the independent validation set, and 4·62 [2·48-8·61] in the TCGA set; all p<0·0001), independently of patient age or sex and tumour stage, grade, or necrosis. The classifier and the clinicopathological risk factors (tumour stage, grade, and necrosis) were combined to construct a nomogram, which had a predictive accuracy significantly higher than that of each variable alone (AUC at 5 years 0·811 [95% CI 0·756-0·861]). INTERPRETATION: Our six-SNP-based classifier could be a practical and reliable predictor that can complement the existing staging system for prediction of localised renal cell carcinoma recurrence after surgery, which might enable physicians to make more informed treatment decisions about adjuvant therapy. Intratumour heterogeneity does not seem to hamper the accuracy of the six-SNP-based classifier as a reliable predictor of recurrence. The classifier has the potential to guide treatment decisions for patients at differing risks of recurrence. FUNDING: National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Provincial Science and Technology Foundation of China, and Guangzhou Science and Technology Foundation of China.
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Carcinoma de Células Renales/genética , Neoplasias Renales/genética , Recurrencia Local de Neoplasia/genética , Polimorfismo de Nucleótido Simple/genética , Área Bajo la Curva , Biomarcadores de Tumor/genética , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/cirugía , Femenino , Genoma Humano/genética , Estudio de Asociación del Genoma Completo , Humanos , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Neoplasias Renales/cirugía , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Nomogramas , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: BK virus-associated nephropathy (BKVN) is an important cause of chronic allograft dysfunction. The objective of our study was to evaluate the prognosis of BKVN. METHODS: We retrospectively reviewed the data of 133 renal transplant recipients with BKVN treated at the First Affiliated Hospital of Sun Yat-Sen University between July 2007 and July 2017. BK viral loads, graft function, and pathologic indexes were compared between initial diagnosis and last follow-up. RESULTS: After a mean follow-up period of 14.4 (range, 0.3-109.6) months after diagnosis of BKVN, BK viruria, and BK viremia become negative in 19.5% and 90.2% of patients, respectively. The mean estimated glomerular filtration rate (eGFR) at last follow-up was lower than at diagnosis of BKVN (18.3â±â9.2 vs. 32.8â±â20.6âmL·min·1.73âm, tâ=â7.426, Pâ<â0.001). Eight (6.0%) patients developed acute rejection after reducing immunosuppression. At last follow-up, the eGFR was significantly lower in patients with subsequent rejection than those without (21.6â±â9.8 vs. 33.5â±â20.9âmL·min·1.73âm, tâ=â3.034, Pâ=â0.011). In 65 repeat biopsies, SV40-T antigen staining remained positive in 40 patients and became negative in the other 20 patients. The eGFR (42.6â±â14.3 vs. 26.5â±â12.3âmL·min·1.73âm), urine viral loads (median, 1.3â×â10vs. 1.4â×â10âcopies/mL), and plasma viral load (median, 0 vs. 0âcopies/mL) were all significantly lower in patients with negative SV40-T antigen staining than those with persistent BK involvement (all, Pâ<â0.05). Five (3.8%) recipients lost their graft at diagnosis of BKVN, and 13 (9.8%) lost their graft during the follow-up period. The 1-, 3-, and 5-year graft survival rates after diagnosis of BKVN were 99.2%, 90.7%, and 85.7%, respectively. Higher pathologic stage correlated with lower allograft survival rate (χâ=â6.341, Pâ=â0.042). CONCLUSION: Secondary rejection and persistent histologic infection in BKVN lead to poor prognosis.
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Virus BK , Supervivencia de Injerto , Enfermedades Renales/complicaciones , Trasplante de Riñón/efectos adversos , Infecciones por Polyomavirus/complicaciones , Adolescente , Adulto , Anciano , Niño , Femenino , Tasa de Filtración Glomerular , Rechazo de Injerto , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Carga Viral , Viremia/complicaciones , Adulto JovenRESUMEN
BACKGROUND: The purpose of this study was to investigate the effect of BK polyomavirus (BKPyV infection of glomerular parietal epithelial cells (GPECs) on graft outcome in kidney transplant recipients with BKPyV-associated nephropathy (BKPyVAN). METHODS: A total of 152 kidney transplant recipients with BKPyVAN were divided into 31 with (GPEC-positive group) and 121 without (GPEC-negative group) BKPyV-infected GPECs. Clinicopathological characteristics and allograft survival were compared between the groups. RESULTS: The GPEC-positive group had more patients with advanced-stage BKPyVAN than the GPEC-negative group (P < .001). At the last follow-up, the GPEC-positive group had a significantly higher serum creatinine level than the GPEC-negative group. The graft loss rate in the GPEC-positive group was higher than that in the GPEC-negative group (32.3% vs 12.4%; P = .008). Kaplan-Meier analysis showed that the graft survival rate in the GPEC-positive group was lower than that in the GPEC-negative group (log-rank test, P = .004). Multivariate Cox regression analysis demonstrated that BKPyV infection of GPECs was an independent risk factor for graft survival (hazard ratio, 3.54; 95% confidence interval, 1.43-8.76; P = .006). CONCLUSIONS: GPEC infection in patients with BKPyVAN indicates more-severe pathological damage and a rapid decline in renal function. BKPyV infection of GPECs is an independent risk factor for allograft loss.