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Electrochemical impedance spectroscopy (EIS), characterized by its non-destructive and in-situ nature, plays a crucial role in comprehending the thermodynamic and kinetic processes occurring with Li-ion batteries. However, there is a lack of consistent and coherent physical interpretations for the EIS of porous electrodes. Therefore, it is imperative to conduct thorough investigations into the underlying physical mechanisms of EIS. Herein, by employing reference electrode in batteries, we revisit the associated physical interpretation of EIS at different frequency. Combining different battery configurations, temperature-dependent experiments, and elaborated distribution of relaxation time analysis, we find that the ion transport in porous electrode channels and pseudo-capacitance behavior dominate the high-frequency and mid-frequency impedance arcs, respectively. This work offers a perspective for the physical interpretation of EIS and also sheds light on the understanding of EIS characteristics in other advanced energy storage systems.
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Glucose dysregulation is strongly correlated with cancer development, and cancer is prevalent in patients with Type 2 diabetes (T2D). We aimed to elucidate the mechanism underlying autophagy in response to glucose dysregulation in human bladder cancer (BC). 220 BC patients were included in this retrospective study. The expression of YAP1, TAZ and AMPK, EMT-associated markers, and autophagy marker proteins was analysed by immunohistochemistry, western blotting, and quantitative real-time PCR (qPCR). Further, T24 and UMUC-3 BC cells were cultured in media with different glucose concentrations, and the expression of YAP1, TAZ, AMPK and EMT-associated markers, and autophagy marker proteins was analysed by western blotting and qPCR. Autophagy was observed by immunofluorescence and electron microscopy. BC cell viability was tested using MTT assays. A xenograft nude mouse model of diabetes was used to evaluate tumour growth, metastasis and survival. A poorer pathologic grade and tumour-node-metastasis stage were observed in patients with BC with comorbid T2D than in others with BC. YAP1 and TAZ were upregulated in BC samples from patients with T2D. Mechanistically, high glucose (HG) promoted BC progression both in vitro and in vivo and inhibited autophagy. Specifically, various autophagy marker proteins and AMPK were negatively regulated under HG conditions and correlated with YAP1 and TAZ expression. These results demonstrate that HG inhibits autophagy and promotes cancer development in BC. YAP1/TAZ/AMPK signalling plays a crucial role in regulating glucose dysregulation during autophagy. Targeting these effectors exhibits therapeutic significance and can serve as prognostic markers in BC patients with T2D.
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Diabetes Mellitus Tipo 2 , Neoplasias da Bexiga Urinária , Animais , Camundongos , Humanos , Proteínas Quinases Ativadas por AMP , Estudos Retrospectivos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Neoplasias da Bexiga Urinária/patologia , Carcinogênese/patologia , Transformação Celular Neoplásica , Autofagia/genética , Linhagem Celular TumoralRESUMO
It is known that ribonucleotide reductase M2 (RRM2) could be induced by hepatitis B virus (HBV) via DNA damage response. However, whether RRM2 is a potential biomarker for diagnosing and monitoring liver fibrosis in chronic hepatitis B (CHB) patients is still unclear. In this study, CHB patients from GSE84044 (a transcriptome data from GEO data set) were downloaded and RRM2 was selected as a hub gene. Interestingly, a positive correlation was found between serum RRM2 and liver fibrosis stage. The similar results were found in CHB patients with normal alanine aminotransferase (ALT). Notably, RRM2 could effectively differentiate preliminary fibrosis from advanced fibrosis in CHB patients with/without normal ALT. In addition, RRM2 had a better performance in diagnosing liver fibrosis than two commonly used noninvasive methods (aspartate aminotransferase-to-platelet ratio index and fibrosis index based on the four factors), two classic fibrotic biomarkers (hyaluronic acid and type IV collagen) as well as Mac-2 binding protein glycosylation isomer, a known serum fibrosis marker. Moreover, CHB patients with high RRM2, who were associated with advanced fibrosis, had higher expressions of immune checkpoints. Overall, serum RRM2 may be a promising biomarker for diagnosing and monitoring liver fibrosis in CHB patients.
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Hepatite B Crônica , Humanos , Hepatite B Crônica/complicações , Hepatite B Crônica/diagnóstico , Curva ROC , Cirrose Hepática , Fígado/patologia , Vírus da Hepatite B , Fibrose , Biomarcadores , Alanina TransaminaseRESUMO
Diffusion magnetic resonance imaging has been demonstrated to be a simple, noninvasive and accurate method for the detection of renal microstructure and microcirculation, which are closely linked to renal function. Moreover, serum endothelin-1 (ET-1) was also reported as a good indicator of early renal injury. The aim of this study was to evaluate the feasibility and capability of diffusion MRI and ET-1 to detect acute kidney injury by an operation simulating high-pressure renal pelvic perfusion, which is commonly used during ureteroscopic lithotripsy. Histological findings were used as a reference. Fourteen New Zealand rabbits in an experimental group and 14 in a control group were used in this study. Diffusion tensor imaging and intravoxel incoherent motion diffusion-weighted imaging were acquired by a 3.0 T MRI scanner. Significant corticomedullary differences were found in the values of the apparent diffusion coefficient (ADC), pure tissue diffusion, volume fraction of pseudo-diffusion (fp) and fractional anisotropy (FA) (P < 0.05 for all) in both preoperation and postoperation experimental groups. Compared with the control group, the values of cortical fpmean , medullary ADCmean and FAmean decreased significantly (P < 0.05) after the operation in the experimental group. Also, the change rate of medullary ADCmean in the experimental group was more pronounced than that in the control group (P = 0.018). No significant change was found in serum ET-1 concentration after surgery in either the experimental (P = 0.80) or control (P = 0.17) groups. In the experimental group, histological changes were observed in the medulla, while no visible change was found in the cortex. This study demonstrated the feasibility of diffusion MRI to detect the changes of renal microstructure and microcirculation in acute kidney injury, with the potential to evaluate renal function. Moreover, the sensitivity of diffusion MRI to acute kidney injury appears to be superior to that of serum ET-1.
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Imagem de Difusão por Ressonância Magnética , Rim/diagnóstico por imagem , Doença Aguda , Animais , Anisotropia , Rim/patologia , Perfusão , CoelhosRESUMO
The error in estimating the separation of a pair of incoherent sources from radiation emitted by them and subsequently captured by an imager is fundamentally bounded below by the inverse of the corresponding quantum Fisher information (QFI) matrix. We calculate the QFI for estimating the full three-dimensional pair separation vector, extending previous work on pair separation in one and two dimensions. We also show that the pair-separation QFI is, in fact, identical to source localization QFI, which underscores the fundamental importance of photon-state localization in determining the ultimate estimation-theoretic bound for both problems. We also propose general coherent-projection bases that can attain the QFI in two special cases. We present simulations of an approximate experimental realization of such quantum limited pair superresolution using the Zernike basis, confirming the achievability of the QFI bounds.
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Tumor blood vessels support tumor growth and progression. Centrosomes are microtubule organization centers in cells, and often up to 30% of tumor endothelial cells (ECs) acquire excess (>2) centrosomes. Although excess centrosomes can lead to aneuploidy and chromosome instability in tumor cells, how untransformed ECs respond to excess centrosomes is poorly understood. We found that the frequency of primary human ECs with excess centrosomes was quickly reduced in a p53-dependent manner. Excess centrosomes in ECs were associated with p53 phosphorylation at Ser33, increased p21 levels, and decreased cell proliferation and expression of senescence markers, but independent of DNA damage and apoptosis. Aspects of the senescence-associated phenotype were also observed in mouse ECs that were isolated from tumors with excess centrosomes. Primary ECs with excess centrosomes in vascular sprouts also had elevated Ser33 p53 phosphorylation and expressed senescence markers. Our work demonstrates that nontransformed ECs respond differently to excess centrosomes than do most tumor cells-they undergo senescence in vascular sprouts and vessels, which suggests that pathologic outcomes of centrosome overduplication depend on the transformation status of cells.-Yu, Z., Ruter, D. L., Kushner, E. J., Bautch, V. L. Excess centrosomes induce p53-dependent senescence without DNA damage in endothelial cells.
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Centrossomo/metabolismo , Dano ao DNA/fisiologia , Células Endoteliais/metabolismo , Neoplasias/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Técnicas de Cultura de Células , Proliferação de Células/genética , Proliferação de Células/fisiologia , Humanos , Proteína Supressora de Tumor p53/genéticaRESUMO
OBJECTIVE: Wound healing is accompanied by neoangiogenesis, and new vessels are thought to originate primarily from the microcirculation; however, how these vessels form and resolve during wound healing is poorly understood. Here, we investigated properties of the smallest capillaries during wound healing to determine their spatial organization and the kinetics of formation and resolution. APPROACH AND RESULTS: We used intravital imaging and high-resolution microscopy to identify a new type of vessel in wounds, called tortuous microvessels. Longitudinal studies showed that tortuous microvessels increased in frequency after injury, normalized as the wound healed, and were closely associated with the wound site. Tortuous microvessels had aberrant cell shapes, increased permeability, and distinct interactions with circulating microspheres, suggesting altered flow dynamics. Moreover, tortuous microvessels disproportionately contributed to wound angiogenesis by sprouting exuberantly and significantly more frequently than nearby normal capillaries. CONCLUSIONS: A new type of transient wound vessel, tortuous microvessels, sprout dynamically and disproportionately contribute to wound-healing neoangiogenesis, likely as a result of altered properties downstream of flow disturbances. These new findings suggest entry points for therapeutic intervention.
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Capilares/fisiologia , Neovascularização Fisiológica , Cicatrização/fisiologia , Animais , Células Endoteliais/fisiologiaRESUMO
BACKGROUND: Glycaemic control is one of the most effective strategies for the treatment of diabetes-related erectile dysfunction (DMED). Compared to conventional anti-diabetic drugs and insulin, islet transplantation is more effective in the treatment of diabetic complications. The aim of this study was to investigate the efficacy of islet transplantation for reversing advanced-stage DMED in rats and to observe its influence on corpus cavernosum fibrosis. METHODS: Wistar rats were intraperitoneally injected with streptozotocin to establish a diabetes model. After 12 weeks, the rats were divided into 4 groups: diabetic, insulin, islet transplantation, and normal control. Following supplementation, the changes in blood glucose and weight were determined sequentially. Penile erectile function was evaluated by apomorphine experiments in the fourth week, and the penile corpus cavernosum was also collected for assessment by Masson staining, immunohistochemistry and Western blot to observe the spongy tissue and the related cellular changes at the molecular level. RESULTS: Islet transplantation significantly ameliorated penile erectile function in advanced-stage diabetic rats. The ratio of corpus cavernosum smooth muscle cells to fibroblasts and the expression level of α-SMA in the islet transplantation group were significantly higher than those in the diabetic and insulin groups. In addition, the expression levels of TGF-ß1, p-Samd2, and connective tissue growth factor (CTGF) in the islet transplantation and insulin groups were much lower than those in the diabetic group, while those in the islet transplantation group were significantly lower than those in the insulin group. CONCLUSIONS: Our findings strongly suggest that islet transplantation can promote the regeneration of smooth muscle cells and ameliorate corpus cavernosum fibrosis to restore its normal structure in advanced-stage diabetic rats. The possible mechanism of ameliorating corpus cavernosum fibrosis by islet transplantation may be associated with improvement of the hyperglycaemic status in diabetic rats, thereby inhibiting the TGF-ß1/Samd2/CTGF pathway.
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Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/terapia , Transplante das Ilhotas Pancreáticas , Doenças do Pênis/terapia , Pênis/patologia , Animais , Complicações do Diabetes/terapia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/complicações , Disfunção Erétil/etiologia , Disfunção Erétil/terapia , Fibrose/etiologia , Fibrose/terapia , Masculino , Doenças do Pênis/etiologia , Ratos , Ratos Wistar , EstreptozocinaRESUMO
Rotating point spread function (PSF) microscopy via spiral phase engineering can localize point sources over large focal depths in a snapshot mode. The present work gives an approximate vector-field analysis of an improved rotating PSF design that encodes both the 3D location and polarization state of a monochromatic point dipole emitter for high-numerical-aperture microscopy. By examining the angle of rotation and the spatial form of the PSF, one can jointly localize point sources and determine the polarization state of light emitted by them over a 3D field in a single snapshot. Results of numerical simulations of noisy data frames under Poisson shot noise conditions and the errors in the recovery of 3D location and dipole orientation for a single point source are discussed.
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OBJECTIVE: To investigate the polymorphism in the promoter region of PCA3 gene and its relationship with risk of prostate cancer (PCa). METHODS: The promoter region of PCA3 gene of the DNA of peripheral blood mononuclear cells was detected by sequence analysis in the 186 PCa and 141 BPH patients and 135 healthy control individuals. If the samples were detected with polymorphism of insection/deletion, clone sequence analysis was used with pBS-T carrier to verify it. RESULTS: There were 5 polymorphisms. TAAA repeat times: 4, 5, 6, 7, 8, and 8 genotypes (TAAA 4/5, TAAA 4/6, TAAA 5/5, TAAA 5/6, TAAA 5/7, TAAA 5/8, TAAA 6/6, and TAAA 6/7) were detected in the promoter region of PCA3 gene. The eight genotypes were divided into three groups: ≤10TAAA, 11TAAA, ≥12TAAA. Unconditional logistic regression analysis models were used to analyze the relationship between different genotypes and cancer risks adjusted by sex and age. The type 11TAAA and ≥12TAAA was associated with higher relative risk for prostate cancer than the group ≤10TAAA [OR=1.74, 95% CI=1.06-2.87 (for type 11TAAA); OR=5.63, 95% CI=1.85-17.19 (for type ≥12TAAA)]. In the 186 PCa patients, there was 62.4% allele of PCA3 gene with AG/CA mutation found in the promoter 18-19 bp region of PCA3 gene and it had a close relation with the development of prostate cancer. CONCLUSIONS: Short tandem repeats are found in the promoter region of the PCA3 gene in PCa patients, and the increase of TAAA repeat sequences highly enhance the relative risk of prostate cancer development. The occurrence of such STR might be related to the mutations in their upstream loci.
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Antígenos de Neoplasias/genética , Genes Neoplásicos/fisiologia , Neoplasias da Próstata/genética , Antígenos de Neoplasias/metabolismo , Sequência de Bases , Genótipo , Humanos , Leucócitos Mononucleares , Masculino , Repetições de Microssatélites , Mutação , Polimorfismo Genético , Regiões Promotoras Genéticas , Neoplasias da Próstata/epidemiologia , RiscoRESUMO
INTRODUCTION: Long noncoding RNA prostate cancer gene antigen 3 (PCA3) is one of the most prostate cancer-specific genes at present. Consequently, the prostate-specific expression and the sharp up-regulation of PCA3 RNA in prostate cancer suggest a unique transcriptional regulation, which possibly can be attributed to promoter polymorphism. In this study, we investigated a short tandem repeat (STR) polymorphism of TAAA in the promoter region of PCA3 gene found in our previous study in prostate cancer (PCa) patients and benign prostatic hypertrophy (BPH) patients, aiming to evaluate the association between the STR and increased risk for PCa. MATERIAL AND METHODS: 120 PCa cases and 120 benign prostatic hypertrophy (BPH) cases were identified among participants. The region encompassing the TAAA repeat was amplified with a specific primer set we designed and screened by PCR-based cloning and sequencing in paired peripheral blood leukocytes and prostate tissues. Genotype-specific risks were estimated as odds ratios (ORs) associated with 95% confidence intervals (CIs) and adjusted for age by means of unconditional logistic regression. RESULTS: 5 PCA3 TAAA STR polymorphisms and 8 genotypes were found in both peripheral blood leukocytes and prostate tissues, the carriers with more TAAA repeats were associated with increased risk for PCa than individuals having less TAAA repeats. Interestingly, 18 (15.0%) of 120 PCa patients had more (TAAA)n repeats in prostate tissues than that in peripheral blood leukocytes, and 3 (2.5%) of 120 had less (TAAA)n repeats in prostate tissues. CONCLUSIONS: The results of this study suggest that short tandem repeat polymorphism of TAAA in the promoter region of PCA3 gene is a risk-increasing factor for prostate cancer in the Chinese population. In addition to the hereditary factor, the insertion mutation of (TAAA)n in a local tissue maybe another mechanism of the onset of PCa.
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Antígenos de Neoplasias/genética , Povo Asiático/genética , Predisposição Genética para Doença/genética , Regiões Promotoras Genéticas/genética , Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Genótipo , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Razão de Chances , Hiperplasia Prostática/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Leukemoid reaction is defined as reactive leukocytosis exceeding 40 × 109/l, with a significant increase in early neutrophil precursors, and can be a paraneoplastic manifestation of various malignant tumors. Leukemoid reaction is a sign for poor prognosis in solid tumors so is sarcomatoid renal cell carcinoma (SRCC) when compared to more differentiated histologies. Here, we are reporting two cases of leukemoid reaction after radical nephrectomy, both of which were diagnosed as SRCC pathologically. The operations were successful: no complications were observed and the patients were discharged in good condition. However, a few weeks later, the white blood cell (WBC) count gradually increased. Even though routine management was done immediately, the count was still elevating. A diagnosis of a leukemoid reaction was established and both of them died shortly thereafter. Due to the poor prognosis of most patients with malignant leukemoid reaction, leukemoid reaction may be a predictor of prognosis in patients with SRCC, but more data are needed.
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Carcinoma de Células Renais/complicações , Reação Leucemoide/diagnóstico , Reação Leucemoide/etiologia , Nefrectomia/efeitos adversos , Adulto , Carcinoma de Células Renais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
A genetic linkage map of sunflower was constructed by combined applying the SSR and AFLP markers using 187 F5:6 individuals of recombinant inbred lines (RILs) which derived from the cross between Helianthus annuus K55 and Helianthus annuus K58 through single-seed descent (SSD). Using 78 pairs of SSR primers and 48 pairs of AFLP primer, 341 and 1119 bands were amplified, respectively. Among these 1460 bands, 557 bands (39.52%) were polymorphic, including 184 bands by SSR markers and 393 bands by AFLP markers. In the group of these polymorphic bands, 84 bands from SSR markers and 108 bands from AFLP markers showed the genetic distortion (P = 0.05). A total of 192 segregation distortion markers were obtained in this study. By using the JoinMap 4.0 software to do the linkage analysis, a genetic linkage map was established with length of 2759.4 cM, consisted of 17 linkage groups, and comprised of 495 polymorphic molecular markers including 170 segregation distortion markers. The mean marker interval distance is 5.57 cM between markers. In addition, the number of markers in the linkage groups varied from 5 to 72, and the length of linkage groups were from 68.88 cM to 250.17 cM. The genetic map developed in the present study could be used for QTL mapping and gene cloning of sunflower important genes.
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Mapeamento Cromossômico/métodos , DNA Recombinante/genética , Helianthus/genética , Endogamia , Ligação Genética , Variação GenéticaRESUMO
The advancement of highly effective heterojunction photocatalysts with improved charge separation and transfer has become a crucial scientific perspective for utilizing solar energy. In this study, we developed the S-scheme heterostructure by depositing N-doped CeO2-δ (NC) nanoparticles onto two-dimensional ZnIn2S4 (ZIS) nanosheets via hydrolysis strategy for significantly enhanced photocatalytic hydrogen evolution reaction. The optimal H2 generation rate of â¼ 798 µmol g-1 h-1 was achieved for NC-3@ZIS under solar light irradiation, which is about 18 and 2 times higher than those of pristine CeO2 (â¼44 µmol g-1 h-1) and ZIS (â¼358 µmol g-1 h-1), respectively. The photogenerated electrons from NC interact with the photogenerated holes of ZIS driven by an internal electric field, confirmed by In-situ KPFM, DFT calculation, and XPS results. According to EPR and photoelectrochemical measurements, NC-3@ZIS composite shows dramatically high separation efficiency of photogenerated charge carriers. This study provides a new approach for developing non-noble metal S-scheme heterojunctions with enhanced photocatalytic hydrogen evolution.
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BACKGROUND: Rising prostate-specific antigen (PSA) levels following radical prostatectomy are indicative of a poor prognosis, which may associate with periprostatic adipose tissue (PPAT). Accordingly, we aimed to construct a dynamic online nomogram to predict tumor short-term prognosis based on 18F-PSMA-1007 PET/CT of PPAT. METHODS: Data from 268 prostate cancer (PCa) patients who underwent 18F-PSMA-1007 PET/CT before prostatectomy were analyzed retrospectively for model construction and validation (training cohort: n = 156; internal validation cohort: n = 65; external validation cohort: n = 47). Radiomics features (RFs) from PET and CT were extracted. Then, the Rad-score was constructed using logistic regression analysis based on the 25 optimal RFs selected through maximal relevance and minimal redundancy, as well as the least absolute shrinkage and selection operator. A nomogram was constructed to predict short-term prognosis which determined by persistent PSA. RESULTS: The Rad-score consisting of 25 RFs showed good discrimination for classifying persistent PSA in all cohorts (all P < 0.05). Based on the logistic analysis, the radiomics-clinical combined model, which contained the optimal RFs and the predictive clinical variables, demonstrated optimal performance at an AUC of 0.85 (95% CI: 0.78-0.91), 0.77 (95% CI: 0.62-0.91) and 0.84 (95% CI: 0.70-0.93) in the training, internal validation and external validation cohorts. In all cohorts, the calibration curve was well-calibrated. Analysis of decision curves revealed greater clinical utility for the radiomics-clinical combined nomogram. CONCLUSION: The radiomics-clinical combined nomogram serves as a novel tool for preoperative individualized prediction of short-term prognosis among PCa patients.
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Several mechanisms underlying nephrolithiasis, one of the most common urological diseases, involve calcium oxalate formation, including oxidative stress, inflammatory reactions, fibrosis, pyroptosis, and apoptosis. Although lycopene has strong antioxidant activity, its protective effects against CaOx-induced injury have not yet been reported. This study aimed to systematically investigate the protective effects of lycopene and explore its mechanisms and molecular targets. Crystal deposition, renal function, oxidative stress, inflammatory response, fibrosis, pyroptosis, and apoptosis were assessed to evaluate the renoprotective effects of lycopene against crystal formation in a CaOx rat model and oxalate-stimulated NRK-52E and HK-2 cells. Lycopene markedly ameliorated crystal deposition, restored renal function, and suppressed kidney injury by reducing oxidative stress, apoptosis, inflammation, fibrosis, and pyroptosis in the rats. In cell models, lycopene pretreatment reversed reactive oxygen species increase, apoptotic damage, intracellular lactate dehydrogenase release, cytotoxicity, pyroptosis, and extracellular matrix deposition. Network pharmacology and proteomic analyses were performed to identify lycopene target proteins under CaOx-exposed conditions, and the results showed that Trappc4 might be a pivotal target gene for lycopene, as identified by cellular thermal shift assay and surface plasmon resonance analyses. Based on molecular docking, molecular dynamics simulations, alanine scanning mutagenesis, and saturation mutagenesis, we observed that lycopene directly interacts with Trappc4 via hydrophobic bonds, which may be attributed to the PHE4 and PHE142 residues, preventing ERK1/2 or elevating AMPK signaling pathway phosphorylation events. In conclusion, lycopene might ameliorate oxalate-induced renal tubular epithelial cell injury via the Trappc4/ERK1/2/AMPK pathway, indicating its potential for the treatment of nephrolithiasis.
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Apoptose , Fibrose , Licopeno , Nefrolitíase , Estresse Oxidativo , Piroptose , Ratos Sprague-Dawley , Solanum lycopersicum , Licopeno/farmacologia , Nefrolitíase/metabolismo , Nefrolitíase/tratamento farmacológico , Animais , Estresse Oxidativo/efeitos dos fármacos , Ratos , Piroptose/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Masculino , Solanum lycopersicum/química , Humanos , Oxalato de Cálcio/metabolismo , Oxalato de Cálcio/química , Linhagem Celular , Rim/efeitos dos fármacos , Rim/metabolismo , Inflamação/metabolismo , Substâncias Protetoras/farmacologiaRESUMO
It has been reported that metabolic disorders participate in the formation and progression of clear cell renal cell carcinoma (ccRCC). However, the predictive value of metabolism-related genes (MRGs) in clinical outcome of ccRCC is still largely unknown. Herein, a novel metabolism-related signature was generated to assess the effect of MRGs on the prognosis of ccRCC patients. Important module MRGs were selected by differentially expressed analysis and WGCNA. Subsequently, the hub MRGs were screened via univariate cox regression as well as LASSO regression. A new metabolism-related signature of 6 hub MRGs (PAFAH2, ACADSB, ACADM, HADH, PYCR1 and ITPKA) was constructed, with a good prognostic prediction ability in the TCGA cohort. The prediction accuracy of this signature was further confirmed in both GSE22541 and FAHWMU cohort. Interestingly, this MRG risk signature was highly correlated with tumor mutation burden and immune infiltration in ccRCC. Notably, lower PAFAH2, a member of 6 MRGs, was found in ccRCC. Knockdown of PAFAH2 contributed to renal cancer cell proliferation and migration. Collectively, a 6-MRG prognostic risk signature is generated to estimate the prognostic status of ccRCC patients, providing a novel insight in the prognosis prediction and treatment of ccRCC.
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Carcinoma de Células Renais , Carcinoma , Neoplasias Renais , Humanos , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Proliferação de CélulasRESUMO
Introduction: Population-based estimates of the incidence and prognosis of bone metastases in prostate cancer (PC) are lacking. We aimed to characterize the incidence and risk of bone metastases and develop a simple tool for the prediction of bone metastases among patients with PC. Methods: Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. A total of 75698 patients with PC with confirmed presence or absence of bone metastases at diagnosis between 1975 and 2019 in the United States were used for analysis. Data were stratified by age, race, residence, median income, prostate-specific antigen (PSA) values, tumor size, distant metastatic history, and positive lymph node scores. Multivariable logistic and Cox regressions were performed to identify predictors of bone metastases and factors correlated with all-cause mortality. Classification tree analysis was performed to establish a model. Results: After patients with PC with missing data were excluded, 75698 cases remained. Among these, 3835 patients had bone metastases. Incidence proportions were highest in patients with a high prostate-specific antigen (PSA) value (odds ratio (OR), 2.49; 95% confidence interval (CI), 1.35-4.35; p < 0.002). Multivariable Cox regression and risk analyses indicated that high PSA values (hazards ratio (HR), 19.8; 95% CI, 18.5-21.2; p < 0.001) and high positive lymph node scores (vs. score 0; HR, 8.65; 95% CI, 7.89-9.49; p < 0.001) were significant risk factors for mortality. Meanwhile, in the predication tree analysis, PSA values and lymph node scores were the most significant determining factors in two models. Median survival among the patients with PC was 78 months, but only 31 months among those with bone metastases. Conclusion: Patients with PC with high PSA values or high positive lymph node scores were at a significantly higher risk of bone metastases. Our study may provide a simple and accurate tool to identify patients with PC at high risk of bone metastases based on population-based estimates.
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Neoplasias Ósseas , Neoplasias da Próstata , Humanos , Masculino , Neoplasias Ósseas/secundário , Linfonodos , Prognóstico , Modelos de Riscos Proporcionais , Antígeno Prostático Específico , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Estados Unidos/epidemiologiaRESUMO
Metastatic prostate cancer (mPC) has a poor prognosis, and new treatment strategies are currently being offered for patients in clinical practice, but mPC is still incurable. A considerable proportion of patients with mPC harbor homologous recombination repair (HRR) mutations, which may be more sensitive to poly (ADP-ribose) polymerase inhibitors (PARPis). We retrospectively included genomic and clinical data from 147 patients with mPC from a single clinical center, with a total of 102 circulating tumor DNA (ctDNA) samples and 60 tissue samples. The frequency of genomic mutations was analyzed and compared with that in Western cohorts. Cox analysis was used to assess progression-free survival (PFS) and prognostic factors related to prostate-specific antigen (PSA) after standard systemic therapy for mPC. The most frequently mutated gene in the HRR pathway was CDK12 (18.3%), followed by ATM (13.7%) and BRCA2 (13.0%). The remaining common ones were TP53 (31.3%), PTEN (12.2%), and PIK3CA (11.5%). The frequency of BRCA2 mutation was close to that of the SU2C-PCF cohort (13.3%), but the frequency of CDK12, ATM, and PIK3CA mutations was significantly higher than that in the SU2C-PCF cohort: 4.7%, 7.3%, and 5.3%, respectively. CDK12 mutation were less responsive to androgen receptor signaling inhibitors (ARSIs), docetaxel, and PARPi. BRCA2 mutation helps predict PARPi efficacy. Additionally, androgen receptor (AR)-amplified patients do not respond well to ARSIs, and PTEN mutation are associated with poorer docetaxel response. These findings support the genetic profiling of patients with mPC after diagnosis to guide treatment stratification to customize personalized treatment.
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BACKGROUND: Sustained liver fibrosis may lead to cirrhosis. Activated hepatic stellate cells (HSCs) are crucial for liver fibrosis development. Ferroptosis, a newly iron-dependent regulated cell death, has been demonstrated to be involved in HSC inactivation. PURPOSE: Ginsenoside Rh2 (GRh2), a natural bioactive product derived from ginseng, has been shown to promote HSC inactivation. However, the effect of GRh2 on HSC ferroptosis remains unclear. METHODS: We explored the effects of GRh2 on liver fibrosis in vivo and in vitro. RNA-sequence analysis was performed in HSCs after GRh2 treatment. The crosstalk between ferroptotic HSCs and macrophages was also explored. RESULTS: GRh2 alleviated liver fibrosis in vivo. In vitro, GRh2 reduced HSC proliferation and activation via ferroptosis, with increased intracellular iron, reactive oxygen species, malondialdehyde and glutathione depletion. The expression of SLC7A11, a negative regulator of ferroptosis, was obviously reduced by GRh2. Interestingly, interferon regulatory factor 1 (IRF1), a transcription factor, was predicted to bind the promoter region of SCL7A11. The interaction between IRF1 and SCL7A11 was further confirmed by the results of chromatin immunoprecipitation and luciferase reporter assays. Furthermore, loss of IRF1 led to an increase in SCL7A11, which contributed to the suppression of HSC ferroptosis and the enhancement of HSC activation in GRh2-treated HSCs. Further studies revealed that GRh2-induced HSC ferroptosis contributed to the inhibition of macrophage recruitment via regulation of inflammation-related genes. Moreover, GRh2 caused a reduction in liver inflammation in vivo. CONCLUSION: Collectively, GRh2 up-regulates IRF1 expression, resulting in the suppression of SLC7A11, which contributes to HSC ferroptosis and inactivation. GRh2 ameliorates liver fibrosis through enhancing HSC ferroptosis and inhibiting liver inflammation. GRh2 may be a promising drug for treating liver fibrosis.