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Renal fibrosis is a common pathological feature of chronic kidney diseases (CKD), poses a significant burden in the aging population, and is a major cause of end-stage renal disease (ESRD). In this study, we investigated the role of G protein-coupled receptor kinases (GRKs) 5 in the pathogenesis of renal fibrosis. GRK5 is a serine/threonine kinase that regulates G protein-coupled receptor (GPCR) signaling. GRK5 has been shown to play a role in various diseases including cardiac disorders and cancer. However, the role of GRK5 in renal fibrosis remains largely unknown. Our finding revealed that GRK5 was significantly overexpressed in renal fibrosis. Specifically, GRK5 was transferred into the nucleus via its nuclear localization sequence to regulate histone deacetylases (HDAC) 5 expression under renal fibrosis. GRK5 acted as an upstream regulator of HDAC5/Smad3 signaling pathway. HDAC5 regulated and prevented the transcriptional activity of myocyte enhancer factor 2A (MEF2A) to repress the transcription of Smad7 which leading to the activation of Smad3. These findings first revealed that GRK5 may be a potential therapeutic target for the treatment of renal fibrosis. Inhibition of GRK5 activity may be a promising strategy to attenuate the progression of renal fibrosis.
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Quinase 5 de Receptor Acoplado a Proteína G , Insuficiência Renal Crônica , Transdução de Sinais , Humanos , Fibrose , Quinase 5 de Receptor Acoplado a Proteína G/genética , Histona Desacetilases/genética , Receptores Acoplados a Proteínas GRESUMO
Small cell cervical carcinoma (SCCC) is the most common neuroendocrine tumor in the female genital tract, with an unfavorable prognosis and lacking an evidence-based therapeutic approach. Until now, the distinct subtypes and immune characteristics of SCCC combined with genome and transcriptome have not been described. We performed genomic (n = 18), HPV integration (n = 18), and transcriptomic sequencing (n = 19) of SCCC samples. We assessed differences in immune characteristics between SCCC and conventional cervical cancer, and other small cell neuroendocrine carcinomas, through bioinformatics analysis and immunohistochemical assays. We stratified SCCC patients through non-negative matrix factorization and described the characteristics of these distinct types. We further validated it using multiplex immunofluorescence (n = 77) and investigated its clinical prognostic effect. We confirmed a high frequency of PIK3CA and TP53 alterations and HPV18 integrations in SCCC. SCCC and other small cell carcinoma had similar expression signatures and immune cell infiltration patterns. Comparing patients with SCCC to those with conventional cervical cancer, the former presented immune excluded or 'desert' infiltration. The number of CD8+ cells in the invasion margin of SCCC patients predicted favorable clinical outcomes. We identified three transcriptome subtypes: an inflamed phenotype with high-level expression of genes related to the MHC-II complex (CD74) and IFN-α/ß (SCCC-I), and two neuroendocrine subtypes with high-level expression of ASCL1 or NEUROD1, respectively. Combined with multiple technologies, we found that the neuroendocrine groups had more TP53 mutations and SCCC-I had more PIK3CA mutations. Multiplex immunofluorescence validated these subtypes and SCCC-I was an independent prognostic factor of overall survival. These results provide insights into SCCC tumor heterogeneity and potential therapies. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Carcinoma Neuroendócrino , Microambiente Tumoral , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/imunologia , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/mortalidade , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/imunologia , Carcinoma de Células Pequenas/patologia , Pessoa de Meia-Idade , Biomarcadores Tumorais/genética , Adulto , Mutação , Transcriptoma , Classe I de Fosfatidilinositol 3-Quinases/genética , Prognóstico , Perfilação da Expressão Gênica/métodos , Idoso , MultiômicaRESUMO
Senescence, an intricate and inevitable biological process, characterized by the gradual loss of homeostasis and declining organ functions. The pathological features of cellular senescence, including cell cycle arrest, metabolic disruptions, and the emergence of senescence-associated secretory phenotypes (SASP), collectively contribute to the intricate and multifaceted nature of senescence. Beyond its classical interaction with p53, murine double minute gene 2 (MDM2), traditionally known as an E3 ubiquitin ligase involved in protein degradation, plays a pivotal role in cellular processes governing senescence. Histone deacetylase (HDAC), a class of histone deacetylases mainly expressed in the nucleus, has emerged as a critical contributor to renal tissues senescence. In this study we investigated the interplay between MDM2 and HDAC1 in renal senescence. We established a natural aging model in mice over a 2-year period that was verified by SA-ß-GAL staining and increased expression of senescence-associated markers such as p21, p16, and TNF-α in the kidneys. Furthermore, we showed that the expression of MDM2 was markedly increased, while HDAC1 expression underwent downregulation during renal senescence. This phenomenon was confirmed in H2O2-stimulated HK2 cells in vitro. Knockout of renal tubular MDM2 alleviated renal senescence in aged mice and in H2O2-stimulated HK2 cells. Moreover, we demonstrated that MDM2 promoted renal senescence by orchestrating the ubiquitination and subsequent degradation of HDAC1. These mechanisms synergistically accelerate the aging process in renal tissues, highlighting the intricate interplay between MDM2 and HDAC1, underpinning the age-related organ function decline.
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BACKGROUND: An immunosuppressive tumor microenvironment in ovarian cancer facilitates tumor progression and resistance to immunotherapy. The function of MYB Proto-Oncogene Like 2 (MYBL2) in the tumor microenvironment remains largely unexplored. METHODS: A syngeneic intraovarian mouse model, flow cytometry analysis, and immunohistochemistry were used to explore the biological function of MYBL2 in tumor progression and immune escape. Molecular and biochemical strategies-namely RNA-sequencing, western blotting, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay, multiplex immunofluorescence, chromatic immunoprecipitation assay (CHIP) and luciferase assay-were used to reveal the mechanisms of MYBL2 in the OVC microenvironment. RESULTS: We found tumor derived MYBL2 indicated poor prognosis and selectively correlated with tumor associated macrophages (TAMs) in ovarian cancer. Mechanically, C-C motif chemokine ligand 2 (CCL2) transcriptionally activated by MYBL2 induced TAMs recruitment and M2-like polarization in vitro. Using a syngeneic intraovarian mouse model, we identified MYBL2 promoted tumor malignancyand increased tumor-infiltrating immunosuppressive macrophages. Cyclin-dependent kinase 2 (CDK2) was a known upstream kinase to phosphorylate MYBL2 and promote its transcriptional function. The upstream inhibitor of CDK2, CVT-313, reprogrammed the tumor microenvironment and reduced anti-PD-1 resistance. CONCLUSIONS: The MYBL2/CCL2 axis contributing to TAMs recruitment and M2-like polarization is crucial to immune evasion and anti-PD-1 resistance in ovarian cancer, which is a potential target to enhance the efficacy of immunotherapy.
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BACKGROUND & AIMS: Antiviral therapy improves the clinical outcomes of patients with chronic hepatitis B (CHB), including those with cirrhosis. In the present study, we validated the Baveno VII definition of recompensation and explored the criteria for stable improvement of liver function tests in entecavir-treated patients with CHB-related decompensated cirrhosis. METHODS: In this multicentre prospective study, patients with decompensated (ascites) CHB-related cirrhosis were enrolled and treated with entecavir for 120 weeks. Patients were followed up for clinical events, viral and biochemical tests, and ultrasonography every 6 months. The recompensation rate per Baveno VII criteria was calculated. Multivariate regression models were used to identify the predictors of recompensation. Finally, the criteria for stable improvement of liver function tests were explored. RESULTS: Of the 320 recruited patients, 283 completed the 120-week study, with 261/283 (92.2%) achieving HBV DNA levels <20 IU/ml and 171/283 (60.4%) achieving resolution of ascites, encephalopathy, and absence of recurrent variceal bleeding for at least 12 months. We identified model for end-stage liver disease <10 and/or liver function tests within Child-Pugh Class A (albumin >35 g/L, international normalised ratio <1.50 and total bilirubin <34 µmol/L) as the criteria for stable improvement of liver function tests. Accordingly, 56.2% (159/283) of patients fulfilled the Baveno VII definition of recompensation with a stable improvement of liver function tests defined by the current study. CONCLUSIONS: Our study defined the criteria for a stable improvement of liver function tests required by the Baveno VII definition of recompensation in patients with CHB-related decompensated cirrhosis on antiviral therapy. The criteria derived from this multicentre prospective study warrant further validation in patients with cirrhosis of other aetiologies. LAY SUMMARY: Decompensation of cirrhosis marks the point at which the liver is no longer able to function normally (and symptoms become apparent). Recently the idea of recompensation was proposed for individuals who may experience an improvement in liver function if the underlying cause of their liver disease is addressed (e.g. antivirals for viral cirrhosis). Herein, we show that over 50% of patients with hepatitis B-related decompensated cirrhosis treated with antivirals could recompensate and we propose laboratory criteria which could be used to define recompensation.
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Doença Hepática Terminal , Varizes Esofágicas e Gástricas , Hepatite B , Humanos , Ascite , Estudos Prospectivos , Hemorragia Gastrointestinal , Índice de Gravidade de Doença , Antivirais/uso terapêutico , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Cirrose Hepática/tratamento farmacológicoRESUMO
BACKGROUND & AIMS: We aimed to assess the safety and immunogenicity of inactivated whole-virion severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with chronic liver diseases (CLD) in this study. METHODS: This was a prospective, multi-center, open-label study. Participants aged over 18 years with confirmed CLD and healthy volunteers were enrolled. All participants received 2 doses of inactivated whole-virion SARS-CoV-2 vaccines. Adverse reactions were recorded within 14 days after any dose of SARS-CoV-2 vaccine, laboratory testing results were collected after the second dose, and serum samples of enrolled subjects were collected and tested for SARS-CoV-2 neutralizing antibodies at least 14 days after the second dose. RESULTS: A total of 581 participants (437 patients with CLD and 144 healthy volunteers) were enrolled from 15 sites in China. Most adverse reactions were mild and transient, and injection site pain (n = 36; 8.2%) was the most frequently reported adverse event. Three participants had grade 3 aminopherase elevation (defined as alanine aminopherase >5 upper limits of normal) after the second dose of inactivated whole-virion SARS-CoV-2 vaccination, and only 1 of them was judged as severe adverse event potentially related to SARS-CoV-2 vaccination. The positive rates of SARS-CoV-2 neutralizing antibodies were 76.8% in the noncirrhotic CLD group, 78.9% in the compensated cirrhotic group, 76.7% in the decompensated cirrhotic group (P = .894 among CLD subgroups), and 90.3% in healthy controls (P = .008 vs CLD group). CONCLUSION: Inactivated whole-virion SARS-CoV-2 vaccines are safe in patients with CLD. Patients with CLD had lower immunologic response to SARS-CoV-2 vaccines than healthy population. The immunogenicity is similarly low in noncirrhotic CLD, compensated cirrhosis, and decompensated cirrhosis.
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Vacinas contra COVID-19 , COVID-19 , Imunogenicidade da Vacina , Hepatopatias , Adulto , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/imunologia , Método Duplo-Cego , Humanos , Cirrose Hepática/complicações , Hepatopatias/complicações , Estudos Prospectivos , SARS-CoV-2RESUMO
Data on safety and immunogenicity of coronavirus disease 2019 (COVID-19) vaccinations in hepatocellular carcinoma (HCC) patients are limited. In this multicenter prospective study, HCC patients received two doses of inactivated whole-virion COVID-19 vaccines. The safety and neutralizing antibody were monitored. Totally, 74 patients were enrolled from 10 centers in China, and 37 (50.0%), 25 (33.8%), and 12 (16.2%) received the CoronaVac, BBIBP-CorV, and WIBP-CorV, respectively. The vaccines were well tolerated, where pain at the injection site (6.8% [5/74]) and anorexia (2.7% [2/74]) were the most frequent local and systemic adverse events. The median level of neutralizing antibody was 13.5 (interquartile range [IQR]: 6.9-23.2) AU/ml at 45 (IQR: 19-72) days after the second dose of vaccinations, and 60.8% (45/74) of patients had positive neutralizing antibody. Additionally, lower γ-glutamyl transpeptidase level was related to positive neutralizing antibody (odds ratio = 1.022 [1.003-1.049], p = 0.049). In conclusion, this study found that inactivated COVID-19 vaccinations are safe and the immunogenicity is acceptable or hyporesponsive in patients with HCC. Given that the potential benefits may outweigh the risks and the continuing emergences of novel severe acute respiratory syndrome coronavirus 2 variants, we suggest HCC patients to be vaccinated against COVID-19. Future validation studies are warranted.
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Vacinas contra COVID-19 , COVID-19 , Carcinoma Hepatocelular , Neoplasias Hepáticas , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Humanos , Imunogenicidade da Vacina , Estudos Prospectivos , SARS-CoV-2 , Vacinação/efeitos adversosRESUMO
OBJECTIVE: To summarize the risk factors and emphasize the prognostic importance of the site of recurrent neuroendocrine cervical cancer (NECC). METHODS: We enrolled 88 patients who developed recurrence after radical surgery for pathological stage I-IVa primary NECC between January 2003 and 30 December 2020 and classified these cases into 7 groups based on the initial recurrence. The risk factors for post-recurrence survival (PRS) were analyzed by Kaplan-Meier and Cox regression methods. RESULTS: Among 88 NECC patients, nearly all patients (95.50%) experienced progression within 3 years. The time to progression was significantly longer in patients with lung recurrence than in patients without lung recurrence (p = 0.008). After the first recurrence, the median follow-up was 11.1 months (range 2.37-65.50 months), and the 5-year PRS was only 20.6%. The depth of invasion in the primary surgery, number of recurrent sites, abdominal organ recurrence were correlated with PRS by univariate analysis. Multivariate analyses revealed that the number of recurrent sites (p = 0.025) and abdominal organ recurrence (p = 0.031) were independent prognostic factors. Notably, the combination of immune checkpoint inhibitors and chemotherapy, with or without surgery, showed a 43.8% objective response rate in recurrent NECC. CONCLUSION: Patients with abdominal organ recurrence need more sophisticated therapy. The combination of immune therapy and chemotherapy might be an opportunity for recurrent NECC.
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Carcinoma Neuroendócrino , Neoplasias do Colo do Útero , Carcinoma Neuroendócrino/cirurgia , Feminino , Humanos , Histerectomia/métodos , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias do Colo do Útero/patologiaRESUMO
BACKGROUND & AIMS: Increased nut consumption has been associated with reduced inflammation, insulin resistance, and oxidative stress. Although these factors are closely involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), few studies have focused on the association between nut consumption and NAFLD in the general population. We aimed to investigate the association of nut consumption and NAFLD in an adult population. METHODS: A total of 23 915 participants from Tianjin Chronic Low-Grade Systemic Inflammation and Health (TCLSIH) Cohort Study were included in this study. Information on dietary intake was collected using a validated food frequency questionnaire. Abdominal ultrasonography was done to diagnose NAFLD. Multivariable logistic regression was used to assess the association of nut consumption with NAFLD. RESULTS: After adjusting for sociodemographic, medical, dietary, and lifestyle variables, the odds ratios (95% confidence interval) for NAFLD across categories of nut consumption were 1.00 (reference) for <1 time/week, 0.91 (0.82, 1.02) for 1 time/week, 0.88 (0.76, 1.02) for 2-3 times/week, and 0.80 (0.69, 0.92) for ≥4 times/week (P for trend < 0.01). These associations were attenuated but remained significant after further adjustment for blood lipids, glucose, and inflammation markers. CONCLUSIONS: Higher nut consumption was significantly associated with lower prevalence of NAFLD. Further prospective studies and randomized trials are required to ascertain the causal association between nut consumption and NAFLD.
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Dieta , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Nozes , Adulto , China/epidemiologia , Estudos Transversais , Ingestão de Energia , Feminino , Humanos , Estilo de Vida , Modelos Logísticos , Masculino , Razão de Chances , Estudos ProspectivosRESUMO
OBJECTIVES: The diagnostic value of axillary ultrasound (US) for level II and III axillary lymph node metastasis after axillary lymph node dissection for invasive breast cancer is currently not clear. The objectives of this study were to retrospectively analyze the diagnostic value of axillar US for level II and III axillary lymph node metastasis and compare it with palpation and to analyze the US features of level II and III axillary lymph nodes that are predictive of metastatic recurrence during follow-up. METHODS: Cases with level II or III axillary lymph nodes detected by US between January 2005 and December 2017 at a cancer center were divided into 2 groups according to a retrospective analysis of US findings: potential malignancy group and follow-up group. Biopsy was performed in all patients in the potential malignancy group. In the follow-up group, the patients were followed for at least 2 years, and biopsy was performed if suspicious US features were detected. RESULTS: The 401 enrolled cases were followed by axillary US and physical examination (PE) for comparison. Finally, 55 axillary metastases were pathologically confirmed (14%). The sensitivity, specificity, and area under the receiver operating characteristic curve for axillary US were 92.7%, 93.9%, and 0.933, respectively, and the corresponding values for PE were 49.1%, 91.3%, and 0.702 (P < .001). An increase in the major or minor axis diameter of the lymph nodes of greater than 2 mm, a Solbiati index value of less than 1.5, and the presence of new suspicious lesions in other regions were significant predictors of lymph node metastasis based on the US findings (P = .013, .006, .015, and .036). CONCLUSIONS: Axillary is helpful in the follow-up of level II and III axillary lymph nodes after axillary lymph node dissection for invasive breast cancer and can detect cancer recurrence earlier than PE.
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Neoplasias da Mama/patologia , Excisão de Linfonodo , Linfonodos/diagnóstico por imagem , Metástase Linfática/diagnóstico por imagem , Ultrassonografia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Axila , Feminino , Humanos , Linfonodos/cirurgia , Pessoa de Meia-Idade , Invasividade Neoplásica , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto JovemRESUMO
OBJECTIVE: To compare the efficacies ofentecavir and adefovir in patients with chronic hepatitis B (CHB) and cirrhosis when administered as monotherapies using a 240-week course. METHODS: Ninety patients diagnosed with CHB and cirrhosis (compensated or decompensated) were randomly divided into two treatment groups for administration of either entecavir (0.5 mg/day, oral; n =38) or adefovir (10 mg/day, oral; n =52) for 240 weeks. All participants underwent B-ultrasound and were tested for levels of HBV-DNA, alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen, creatinine, alpha-fetoprotein (AFP) and various serological markers of the hepatitis B virus at baseline and at treatment weeks 24, 48, 96, 144, 192, and 240. Instances of drug-related complications and adverse reactions were recorded. Patients who did not achieve complete virological response by treatment week 48 or who experienced virological breakthrough at any time during the study course were recorded and started on an appropriate combination therapy regimen. Statistical analyses were carried out using the t-test, chi-square test, and Cox regression modeling. RESULTS: The dropout rate in the entecavir group was 2.6% and in the adefovir group was 13.5%. At treatment week 240, significantly more patients in the entecavir group had undetectable serum HBV-DNA (91.9% vs. adefovir group: 57.8%; x2=10.362, P=0.001), a negative conversion rate of hepatitis B e antigen (HBeAg) (46.2% vs. adefovir group: 24%; x2=5.055, P=0.025), and rate of HBeAg seroconversion (23.1% vs. adefovir group: 8%, P=0.047).The entecavir group and the adefovir group showed no significant differences upon per-protocol analysis and intention-to-treat analysis, nor in the rates of hepatocellular carcinoma development (entecavir group: 8.1% vs. adefovir group: 6.7%; x2=0.000, P=1.000) or mortality (entecavir group: 8.1% vs. adefovir group: 4.4%; x2=0.051, P=0.821). The possibility of achieving undetectable serum HBV-DNA was 2.761 times higher in the entecavir group than in the adefovir group (95.0% CI: 1.630 to 4.679). The possibility of HBeAg seroconversion was 0.192 times higher for males than for females (95.0% CI: 0.046 to 0.806). CONCLUSION: Compared to adefovir, entecavir provides high efficiency and rapid viral suppression as a monotherapy for CHB patients when administered in a 240-week course.
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Hepatite B Crônica , Cirrose Hepática , Adenina/análogos & derivados , Idoso , Alanina Transaminase , Antivirais , Aspartato Aminotransferases , Biomarcadores , Carcinoma Hepatocelular , Feminino , Guanina/análogos & derivados , Antígenos E da Hepatite B , Humanos , Neoplasias Hepáticas , Masculino , Organofosfonatos , Fatores de Tempo , alfa-FetoproteínasRESUMO
BACKGROUND: Cytokines/chemokines play essential roles in the occurrence and progression of hepatitis B virus (HBV) infection. This study aimed to observe the expression patterns of 10 related cytokines/chemokines in the serum of healthy individuals, self-limited patients and HBV-infected patients at different stages of disease (chronic hepatitis B (CHB), liver cirrhosis (LC), hepatocellular dysplastic nodules (DNs) and hepatocellular carcinoma (HCC)) and to analyze the relationships of these cytokines/chemokines with disease progression. METHODS: The levels of six cytokines (FGF-2, IFN-α2, IL-4, IL-6, IL-10 and VEGF-A) and four chemokines (GRO-α, IL-8, IP-10 and MCP-1) were quantified using Luminex multiplex technology. RESULTS: There were no significant differences in the expression of the 10 cytokines/chemokines between healthy individuals and self-limited patients. The levels of IL-4, IL-6, and IL-8 increased significantly in the CHB and LC groups. IL-10 was highly expressed in the HCC group. The level of IP-10 was significantly greater in all liver disease groups (CHB, LC, DN and HCC) than in the HI and SL-HBV groups, while the level of GRO was significantly lower in all liver disease groups than in the HI and SL-HBV groups. The levels of the 10 cytokines/chemokines were not significantly different between the preoperative group and the two-day postoperative group. Significant increases in the levels of IL-4, VEGF-A and IL-8 and significant decreases in those of IL-10 and GRO-α were observed 3 months after surgery. Correlation analysis revealed that most of the cytokines/chemokines with significant correlation differences were positively correlated before and after HCC surgery. CONCLUSION: Our results highlight the fluctuating status of specific cytokines in HBV infection-related disease progression. It is speculated that these cytokines may be used as serum markers to monitor dynamic changes during the progression of HBV-related liver disease and to predict patient prognosis.
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Chronic kidney disease (CKD) is a serious health problem worldwide, which ultimately leads to end-stage renal disease (ESRD). Renal fibrosis is the common pathway and major pathological manifestation for various CKD proceeding to ESRD. However, the underlying mechanisms and effective therapies are still ambiguous. Early growth response 2 (EGR2) is reportedly involved in organ formation and cell differentiation. To determine the role of EGR2 in renal fibrosis, we respectively confirmed the increased expression of EGR2 in kidney specimens from both CKD patients and mice with location in proximal tubules. Genetic deletion of EGR2 attenuated obstructive nephropathy while EGR2 overexpression further promoted renal fibrosis in mice subjected to unilateral ureteral obstruction (UUO) due to extracellular matrix (ECM) deposition mediating by partial epithelial-mesenchymal transition (EMT) as well as imbalance between matrix metalloproteinases (MMPs) and tissue inhibitor of MMPs (TIMPs). We found that EGR2 played a critical role in Smad3 phosphorylation, and inhibition of EGR2 reduced partial EMT leading to blockade of ECM accumulation in cultured human kidney 2 cells (HK2) treated with transforming growth factor ß1 (TGF-ß1). In addition, the transcription co-stimulator signal transducer and activator of transcription 3 (STAT3) phosphorylation was confirmed to regulate the transcription level of EGR2 in TGF-ß1-induced HK2 cells. In conclusion, this study demonstrated that EGR2 played a pathogenic role in renal fibrosis by a p-STAT3-EGR2-p-Smad3 axis. Thus, targeting EGR2 could be a promising strategy for CKD treatment.
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Transição Epitelial-Mesenquimal , Fibrose , Proteína Smad3 , Animais , Humanos , Masculino , Camundongos , Linhagem Celular , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Rim/patologia , Rim/metabolismo , Camundongos Endogâmicos C57BL , Fosforilação , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/genética , Proteína Smad3/metabolismo , Proteína Smad3/genética , Obstrução Ureteral/patologia , Obstrução Ureteral/complicações , Obstrução Ureteral/metabolismoRESUMO
Platinum resistance represents a major barrier to the survival of patients with ovarian cancer (OC). Cdc2-like kinase 2 (CLK2) is a major protein kinase associated with oncogenic phenotype and development in some solid tumors. However, the exact role and underlying mechanism of CLK2 in the progression of OC is currently unknown. Using microarray gene expression profiling and immunostaining on OC tissues, we found that CLK2 was upregulated in OC tissues and was associated with a short platinum-free interval in patients. Functional assays showed that CLK2 protected OC cells from platinum-induced apoptosis and allowed tumor xenografts to be more resistant to platinum. Mechanistically, CLK2 phosphorylated breast cancer gene 1 (BRCA1) at serine 1423 (Ser1423) to enhance DNA damage repair, resulting in platinum resistance in OC cells. Meanwhile, in OC cells treated with platinum, p38 stabilized CLK2 protein through phosphorylating at threonine 343 of CLK2. Consequently, the combination of CLK2 and poly ADP-ribose polymerase inhibitors achieved synergistic lethal effect to overcome platinum resistance in patient-derived xenografts, especially those with wild-type BRCA1. These findings provide evidence for a potential strategy to overcome platinum resistance in OC patients by targeting CLK2.
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Background & Aims: Hepatic recompensation may be achieved in patients with decompensated cirrhosis due to chronic hepatitis B (CHB) upon effective suppression of viral replication by nucleos(t)ide analogues (NAs). However, the optimal timing and predictors of recompensation and the subsequent clinical course of patients with CHB with vs. without recompensation are not well-defined. Methods: This study was a retrospective extension of a multi-centre prospective cohort, focusing on patients with CHB and decompensated cirrhosis treated with entecavir. We followed patients beyond treatment week 120 until a second decompensation event or June 2023. We identified the optimal timing and predictors of recompensation by week 120, evaluated durability of recompensation in patients fulfilling recompensation criteria by week 120 and examined late recompensation in those who did not fulfil it by week 120. Results: At treatment week 24, serum albumin ≥34 g/L predicted recompensation by week 120. The Brec-PAS model offered good predictive ability for recompensation by week 120. Of the 283 patients who finished 120 weeks of therapy, 175 were followed beyond week 120 (median follow-up: 240 weeks). Among the 106 patients achieving recompensation by week 120, 92 (86.8%) maintained recompensation for another 120 (72-168) weeks. Among the 69 patients without recompensation by week 120, 40.6% attained late recompensation during the subsequent 120 (72-168) weeks. Additionally, hepatocellular carcinoma incidence was lower in the recompensated group (5.0% vs. 16.13%, p = 0.002). Conclusions: A serum albumin ≥34 g/L at treatment week 24 predicted recompensation by week 120. Recompensation achieved by week 120 of NA treatment is maintained in >80% of patients in the long term. Some patients may achieve recompensation only after >120 weeks of NA treatment. The incidence of hepatocellular carcinoma was reduced but not completely abolished after recompensation. Impact and implications: Our research provides a meaningful contribution to understanding the long-term prognosis of recompensation in patients with chronic hepatitis B and decompensated cirrhosis, as well as to evaluating the predictive value of serum albumin levels, offering a comprehensive view of clinical outcomes after recompensation. The significance of early biomarkers in guiding therapeutic decisions is highlighted, shedding light on the continued benefits and possible risks after recompensation. This enhances the capability for more precise prognostic evaluations and informed therapeutic strategies. For healthcare providers, these insights afford a detailed perspective on patient monitoring and intervention planning, underscoring the need for ongoing assessment past the initial recompensation phase.
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Ovarian cancer, a group of heterogeneous diseases, presents with extensive characteristics with the highest mortality among gynecological malignancies. Accurate and early diagnosis of ovarian cancer is of great significance. Here, we present OvcaFinder, an interpretable model constructed from ultrasound images-based deep learning (DL) predictions, Ovarian-Adnexal Reporting and Data System scores from radiologists, and routine clinical variables. OvcaFinder outperforms the clinical model and the DL model with area under the curves (AUCs) of 0.978, and 0.947 in the internal and external test datasets, respectively. OvcaFinder assistance led to improved AUCs of radiologists and inter-reader agreement. The average AUCs were improved from 0.927 to 0.977 and from 0.904 to 0.941, and the false positive rates were decreased by 13.4% and 8.3% in the internal and external test datasets, respectively. This highlights the potential of OvcaFinder to improve the diagnostic accuracy, and consistency of radiologists in identifying ovarian cancer.
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Neoplasias Ovarianas , Feminino , Humanos , Neoplasias Ovarianas/diagnóstico por imagem , Área Sob a Curva , Extremidades , Radiologistas , Estudos RetrospectivosRESUMO
BACKGROUND: Identifying breast cancer (BC) patients with germline breast cancer susceptibility gene (gBRCA) mutation is important. The current criteria for germline testing for BC remain controversial. This study aimed to develop a nomogram incorporating ultrasound radiomic features and clinicopathological factors to predict gBRCA mutations in patients with BC. MATERIALS AND METHODS: In this retrospective study, 497 women with BC who underwent gBRCA genetic testing from March 2013 to May 2022 were included, including 348 for training (84 with and 264 without a gBRCA mutation) and 149 for validation(36 patients with and 113 without a gBRCA mutation). Factors associated with gBRCA mutations were identified to establish a clinicopathological model. Radiomics features were extracted from the intratumoral and peritumoral regions (3 mm and 5 mm) of each image. The least absolute shrinkage and selection operator regression algorithm was used to select the features and logistic regression analysis was used to construct three imaging models. Finally, a nomogram that combined clinicopathological and radiomics features was developed. The models were evaluated based on the area under the receiver operating characteristic curve (AUC), calibration, and clinical usefulness. RESULTS: Age at diagnosis, family history of BC, personal history of other BRCA-related cancers, and human epidermal growth factor receptor 2 status were independent predictors of the clinicopathological model. The AUC of the imaging radiomics model combining intratumoral and peritumoral 3 mm areas in the validation set was 0.783 (95% confidence interval [CI]: 0.702-0.862), which showed the best performance among three imaging models. The nomogram yielded better performance than the clinicopathological model in validation sets (AUC: 0.824 [0.755-0.894] versus 0.659 [0.563-0.755], p = 0.007). CONCLUSION: The nomogram based on ultrasound images and clinicopathological factors performs well in predicting gBRCA mutations in BC patients and may help to improve clinical decisions about genetic testing.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/genética , Radiômica , Estudos Retrospectivos , Mutação , Células GerminativasRESUMO
Minimal hepatic encephalopathy (MHE) has a substantial impact on the clinical outcomes and quality of life (QOL) of patients with cirrhosis. However, timely diagnosis and intervention are challenging due to sophisticated diagnostic methods. In this study, 673 healthy controls and 905 patients with cirrhosis were screened, and 660 healthy controls and 757 patients with cirrhosis, divided into the test (292 patients) and validation (465 patients) cohort, were analyzed after screening. A diagnostic model of the Stroop test (Stroop-CN) was constructed by multivariate linear regression based on the results of healthy controls. The prevalence of MHE and the comparison results with psychometric hepatic encephalopathy score through the Stroop-CN model were stable in the test and validation cohorts. Moreover, the prevalence of MHE remained significantly higher in patients with worse disease conditions marked as high Child-Pugh grades and the Model for End-stage Liver Disease and Sodium (MELD-Na) scores in the test and validation cohort. The EuroQol 5-D questionnaire revealed that patients with MHE had a worse QOL than those without MHE both in the test and validation cohort. In conclusion, an easy and practical Stroop-CN model for MHE diagnosis based on the EncephalApp is established. It is found that a considerable number of Chinese patients with cirrhosis experience MHE, which significantly impacts their QOL.
RESUMO
OBJECTIVE: To investigate the clinical value of FibroScan transient elastography for assessing portal hypertension in liver cirrhosis patients by determining the relationship between the liver or spleen stiffness measurement with the imaging parameters of esophageal varices, portal vein width, spleen volume, and splenic vein width. METHODS: A total of 259 patients with liver cirrhosis underwent FibroScan measurement, ultrasound, computed tomography and routine blood analyses. One-hundred-and-one of those patients also underwent endoscopy to diagnose esophageal varices. Receiver operating characteristic (ROC) curves were generated and the areas under the curves (AUCs) were calculated to assess the accuracy of the FibroScan liver and spleen stiffness measurements to predict esophageal varices. Pearson's correlation analysis was used to assess the relationship between clinical features. RESULTS: The median liver and spleen stiffness of the cirrhotic patients were 24.27 kPa and 44.64 kPa, respectively. Liver and spleen stiffness increased in conjunction with increases in Child-Pugh score. Liver stiffness was positively correlated with spleen stiffness (P less than 0.05). Liver and spleen stiffness were positively correlated with esophageal varices, portal vein width, spleen thickness, spleen volume, and splenic vein width. The correlation of spleen stiffness was higher than that of liver stiffness. Spleen stiffness was also negatively correlated with white blood cell count and platelet count. Liver and spleen stiffness also increased in conjunction with increased severity of esophageal varices. The AUC of spleen stiffness was higher than that of liver stiffness for predicting esophageal varices (0.804 vs. 0.737). The optimal cut-off level of spleen stiffness was 44.5 kPa (sensitivity: 88%; specificity: 68%). The estimated prevalence of esophageal varices was 97.87% and the optimized cut-off level of liver stiffness was 18.0 kPa. CONCLUSION: FibroScan appears to be a clinically valuable non-invasive method to assess portal hypertension in cirrhotic patients. Both liver and spleen stiffness measurements correlated with portal hypertension but the spleen stiffness measurement may be of higher clinical value.
Assuntos
Técnicas de Imagem por Elasticidade/métodos , Hipertensão Portal/fisiopatologia , Cirrose Hepática/fisiopatologia , Adolescente , Adulto , Idoso , Varizes Esofágicas e Gástricas/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Baço/fisiopatologia , Adulto JovemRESUMO
BACKGROUND: Sepsis-associated AKI has been shown to be related to sepsis mortality. Macrophage activation and endothelial cell damage are involved in the progression of sepsis-associated AKI, but the specific mechanisms are still unclear. METHODS: In vitro experiments, exosomes extracted from lipopolysaccharide (LPS) -stimulated macrophages were co-incubated with rat glomerular endothelial cells (RGECs) and then detected the injury markers of RGECs. Acid sphingomyelinase (ASM) inhibitor amitriptyline were used to investigate the role of ASM. In vivo experiment, exosomes produced by LPS-stimulated macrophages were injected into mice through tail vein to further explore the role of macrophage-derived exosomes. Moreover, ASM knockout mice were used to verify the mechanism. RESULT: In vitro, the secretion of macrophage exosomes increased upon the stimulation with LPS. Notably, macrophage-derived exosomes can cause glomerular endothelial cell dysfunction. In vivo, macrophage infiltration and exosome secretion in glomeruli of the LPS-induced AKI group increased. The exosomes produced by LPS-stimulated macrophages were injected into mice, which also led to the injury of renal endothelial cells. In addition, in the LPS-induced AKI mouse model, compared with wild-type mice, the secretion of exosomes in glomeruli of ASM gene knockout mice and the injury of endothelial cells were reduced. CONCLUSION: Our study shows that ASM regulates the secretion of macrophage exosomes, leading to endothelial cell injury, which may be a therapeutic target in sepsis-associated AKI.