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BACKGROUND: Sporadic parathyroid adenoma (PA) is the most common cause of hyperparathyroidism, yet the mechanisms involved in its pathogenesis remain incompletely understood. METHODS: Surgically removed PA samples, along with normal parathyroid gland (PG) tissues that were incidentally dissected during total thyroidectomy, were analysed using single-cell RNA-sequencing with the 10× Genomics Chromium Droplet platform and Cell Ranger software. Gene set variation analysis was conducted to characterise hallmark pathway gene signatures, and single-cell regulatory network inference and clustering were utilised to analyse transcription factor regulons. Immunohistochemistry and immunofluorescence were performed to validate cellular components of PA tissues. siRNA knockdown and gene overexpression, alongside quantitative polymerase chain reaction, Western blotting and cell proliferation assays, were conducted for functional investigations. RESULTS: There was a pervasive increase in gene transcription in PA cells (PACs) compared with PG cells. This is associated with high expression of histone-lysine N-methyltransferase 2A (KMT2A). High KMT2A levels potentially contribute to promoting PAC proliferation through upregulation of the proto-oncogene CCND2, which is mediated by the transcription factors signal transducer and activator of transcription 3 (STAT3) and GATA binding protein 3 (GATA3). PA tissues are heavily infiltrated with myeloid cells, while fibroblasts, endothelial cells and macrophages in PA tissues are commonly enriched with proinflammatory gene signatures relative to their counterparts in PG tissues. CONCLUSIONS: We revealed the previously underappreciated involvement of the KMT2AâSTAT3/GATA3âCCND2 axis and chronic inflammation in the pathogenesis of PA. These findings underscore the therapeutic promise of KMT2A inhibition and anti-inflammatory strategies, highlighting the need for future investigations to translate these molecular insights into practical applications. HIGHLIGHTS: Single-cell RNA-sequencing reveals a transcriptome catalogue comparing sporadic parathyroid adenomas (PAs) with normal parathyroid glands. PA cells show a pervasive increase in gene expression linked to KMT2A upregulation. KMT2A-mediated STAT3 and GATA3 upregulation is key to promoting PA cell proliferation via cyclin D2. PAs exhibit a proinflammatory microenvironment, suggesting a potential role of chronic inflammation in PA pathogenesis.
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Adenoma , N-Metiltransferasa de Histona-Lisina , Inflamación , Neoplasias de las Paratiroides , Humanos , Neoplasias de las Paratiroides/genética , Neoplasias de las Paratiroides/metabolismo , Neoplasias de las Paratiroides/patología , Adenoma/genética , Adenoma/metabolismo , Adenoma/patología , Inflamación/genética , Inflamación/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Proto-Oncogenes Mas , Proliferación Celular/genéticaRESUMEN
INTRODUCTION: Accumulating evidence has disclosed that IgA nephropathy (IgAN) could present shortly after the second dose of COVID-19 mRNA vaccine. However, the undying mechanism remains unclear and we aimed to investigate the potential molecular mechanisms. METHODS: We downloaded gene expression datasets of COVID-19 mRNA vaccination (GSE201535) and IgAN (GSE104948). Weighted Gene Co-Expression Network Analysis (WGCNA) was performed to identify co-expression modules related to the second dose of COVID-19 mRNA vaccination and IgAN. Differentially expressed genes (DEGs) were screened, and a transcription factor (TF)-miRNA regulatory network and protein-drug interaction were constructed for the shared genes. RESULTS: WGCNA identified one module associated with the second dose of COVID-19 mRNA vaccine and four modules associated with IgAN. Gene ontology (GO) analyses revealed enrichment of cell cycle-related processes for the COVID-19 mRNA vaccine hub genes and immune effector processes for the IgAN hub genes. We identified 74 DEGs for the second dose of COVID-19 mRNA vaccine and 574 DEGs for IgAN. Intersection analysis with COVID-19 vaccine-related genes led to the identification of two shared genes, TOP2A and CEP55. The TF-miRNA network analysis showed that hsa-miR-144 and ATF1 might regulate the shared hub genes. CONCLUSIONS: This study provides insights into the common pathogenesis of COVID-19 mRNA vaccination and IgAN. The identified pivotal genes may offer new directions for further mechanistic studies of IgAN secondary to COVID-19 mRNA vaccination.
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Vacunas contra la COVID-19 , COVID-19 , Glomerulonefritis por IGA , Glomerulonefritis por IGA/genética , Humanos , Vacunas contra la COVID-19/efectos adversos , COVID-19/prevención & control , COVID-19/complicaciones , MicroARNs/genética , Redes Reguladoras de Genes , Vacunas de ARNm , SARS-CoV-2 , Vacunación/efectos adversosRESUMEN
Disulfidptosis, a novel form of regulated cell death, occurs due to the aberrant accumulation of intracellular cystine and other disulfides. Moreover, targeting disulfidptosis could identify promising approaches for cancer treatment. Long non-coding RNAs (lncRNAs) are known to be critically implicated in clear cell renal cell carcinoma (ccRCC) development. Currently, the involvement of disulfidptosis-related lncRNAs in ccRCC is yet to be elucidated. This study primarily dealt with identifying and validating a disulfidptosis-related lncRNAs-based signature for predicting the prognosis and immune landscape of individuals with ccRCC. Clinical and RNA sequencing data of ccRCC samples were accessed from The Cancer Genome Atlas (TCGA) database. Pearson correlation analysis was conducted for the identification of the disulfidptosis-related lncRNAs. Additionally, univariate Cox regression analysis, Least Absolute Shrinkage and Selection Operator Cox regression, and stepwise multivariate Cox analysis were executed to develop a novel risk prognostic model. The prognosis-predictive capacity of the model was then assessed using an integrated method. Variation in biological function was noted using GO, KEGG, and GSEA. Additionally, immune cell infiltration, the tumor mutational burden (TMB), and tumor immune dysfunction and exclusion (TIDE) scores were calculated to investigate differences in the immune landscape. Finally, the expression of hub disulfidptosis-related lncRNAs was validated using qPCR. We established a novel signature comprised of eight lncRNAs that were associated with disulfidptosis (SPINT1-AS1, AL121944.1, AC131009.3, AC104088.3, AL035071.1, LINC00886, AL035587.2, and AC007743.1). Kaplan-Meier and receiver operating characteristic curves demonstrated the acceptable predictive potency of the model. The nomogram and C-index confirmed the strong correlation between the risk signature and clinical decision-making. Furthermore, immune cell infiltration analysis and ssGSEA revealed significantly different immune statuses among risk groups. TMB analysis revealed the link between the high-risk group and high TMB. It is worth noting that the cumulative effect of the patients belonging to the high-risk group and having elevated TMB led to decreased patient survival times. The high-risk group depicted greater TIDE scores in contrast with the low-risk group, indicating greater potential for immune escape. Finally, qPCR validated the hub disulfidptosis-related lncRNAs in cell lines. The established novel signature holds potential regarding the prognosis prediction of individuals with ccRCC as well as predicting their responses to immunotherapy.
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Carcinoma de Células Renales , Carcinoma , Neoplasias Renales , ARN Largo no Codificante , Humanos , Carcinoma de Células Renales/genética , Pronóstico , ARN Largo no Codificante/genética , Neoplasias Renales/genéticaRESUMEN
BACKGROUND: Sepsis-associated acute kidney injury (S-AKI) is a critical illness and is often associated with high morbidity and mortality rates. The soluble urokinase-type plasminogen activator receptor (suPAR) is an important immune mediator and is involved in kidney injury. However, its diagnostic value in S-AKI patients remains unclear. Therefore, we assessed the early predictive value of suPAR for S-AKI patients. METHODS: We prospectively enrolled adult patients, immediately after fulfilling the sepsis-3 criteria. Plasma suPAR levels at 0-, 12-, 24-, and 48-h post-sepsis diagnosis were measured. S-AKI development was the primary outcome. S-AKI risk factors were analyzed using logistic regression, and the value of plasma suPAR for early S-AKI diagnosis was assessed using receiver operating characteristic (ROC) curves. RESULTS: Of 179 sepsis patients, 63 (35.2%) developed AKI during hospitalization. At 12-, 24-, and 48-h post-sepsis diagnosis, plasma suPAR levels were significantly higher in patients with S-AKI than in patients without S-AKI (p < 0.05). The plasma suPAR had the highest area under the ROC curve of 0.700 (95% confidence interval (CI), 0.621-0.779) at 24-h post-sepsis diagnosis, at which the best discrimination ability for S-AKI was achieved with suPAR of ≥6.31 ng/mL (sensitivity 61.9% and specificity 71.6%). Logistic regression analysis showed that suPAR at 24-h post-sepsis diagnosis remained an independent S-AKI risk factor after adjusting for mechanical ventilation, blood urea nitrogen, and pH. CONCLUSIONS: The findings suggest that plasma suPAR may be a potential biomarker for early S-AKI diagnosis.
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Lesión Renal Aguda , Sepsis , Adulto , Humanos , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Sepsis/complicaciones , Sepsis/diagnóstico , Biomarcadores , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/etiología , Enfermedad Crítica , Curva ROC , PronósticoRESUMEN
PURPOSE: To study the efficacy and safety of peritoneal dialysis (PD) catheter removal using the pull technique. METHODS: We conducted a retrospective analysis of 36 patients in whom the pull technique was used to remove a PD catheter. We evaluated the efficacy, safety, and health economic benefits of this technique by analyzing the pain score, duration of the procedure, complications during or after the procedure, and cost. RESULTS: The mean age (± standard deviation) of the 36 patients was 51 ± 14 years involving 27 males and 9 females with a mean body mass index was 23.4 ± 2.6. The mean duration of PD was 28 months (range 4-96 months). The site of the pull technique for peritoneal dialysis catheter removal was at the bedside or in the treatment room, with local anesthesia or no anesthesia. The mean duration of the procedure (from anesthesia to complete removal of the PD catheter) was 5-15 min. Only one patient experienced catheter rupture and no patients developed procedural or post-procedural bleeding or abdominal wall leakage. Infection did not occur at the inner or outer cuffs, tunnel, or outlet. Pain scores analyzed by a 10-point visual analogue scoring technique both immediately and 24 h after the procedure were 3.5 ± 1.7 and 1.2 ± 0.8, respectively. CONCLUSIONS: The pull technique is simple to perform, takes a short time, results in few complications and small wounds, causes only mild pain, enables fast recovery, and results in low medical costs.
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Catéteres de Permanencia , Diálisis Peritoneal , Masculino , Femenino , Humanos , Adulto , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Cateterismo/métodos , Diálisis Peritoneal/métodos , DolorRESUMEN
Blood-brain barrier (BBB) dysfunction plays a pivotal role in the pathology of chronic cerebral hypoperfusion (CCH)-related neurodegenerative diseases. Continuous endothelial cells (EC) that line the blood vessels of the brain are important components of the BBB to strictly control the flow of substances and maintain the homeostatic environment of the brain. However, the molecular mechanisms from the perspective of EC-induced BBB dysfunction after CCH are largely unknown. In this study, the BBB function was assessed using immunostaining and transmission electron microscopy. The EC dysfunction profile was screened by using EC enrichment followed by RNA sequencing. After identified the key EC dysfunction factor, C-kit, we used the C-kit inhibition drug (imatinib) and C-kit down-regulation method (AAV-BR1-C-kit shRNA) to verify the role of C-kit on BBB integrity and EC transcytosis after CCH. Furthermore, we also activated C-kit with stem cell factor (SCF) to observe the effects of C-kit on BBB following CCH. We explored that macromolecular proteins entered the brain mainly through EC transcytosis after CCH and caused neuronal loss. Additionally, we identified receptor tyrosine kinase C-kit as a key EC dysfunction molecule. Furthermore, the pharmacological inhibition of C-kit with imatinib counteracted BBB leakage by reducing caveolae-mediated transcytosis. Moreover, treatment with AAV-BR1-C-kit shRNA, which targets brain EC to inhibit C-kit expression, also ameliorated BBB leakage by reducing caveolae-mediated transcytosis. Furthermore, the SCF increased the permeability of the BBB by actively increasing caveolae-mediated transcytosis. This study provides evidence that C-kit is a key BBB permeability regulator through caveolae-mediated transcytosis in EC after CCH.
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Barrera Hematoencefálica , Isquemia Encefálica , Humanos , Barrera Hematoencefálica/metabolismo , Caveolas/metabolismo , Células Endoteliales , Mesilato de Imatinib/farmacología , Transcitosis , Isquemia Encefálica/metabolismo , ARN Interferente Pequeño/metabolismo , PermeabilidadRESUMEN
Since a 25% mortality rate occurred in critical Coronavirus disease 2019 (COVID-19) patients, investigating the potential drivers remains to be important. Here, the authors applied Weighted Gene Co-expression Network Analysis to identify the potential drivers in the blood samples of multiple COVID-19 expression profiles. The authors found that the darkslateblue module was significantly correlated with critical COVID-19, and Gene Ontology analysis indicated terms associated with the inflammation pathway and apoptotic process. The authors intersected differentially expressed genes, Maximal Clique Centrality calculated hub genes, and COVID-19 related genes in the Genecards dataset, and two genes, toll-like receptor 5 (TLR5) and acyl-CoA synthetase long chain family member 1 (ACSL1), were screened out. The Gene Set Enrichment Analysis further supports their core role in the inflammatory pathway. Furthermore, the cell-type identification by estimating relative subsets of RNA transcript demonstrated that TLR5 and ACSL1 were associated with neutrophil enrichment in critical COVID-19 patients. Collectively, the aurthors identified two hub genes that were strongly correlated with critical COVID-19. These may help clarify the pathogenesis and assist the immunotherapy development.
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COVID-19 , Receptor Toll-Like 5 , Humanos , Apoptosis , COVID-19/genética , Familia , Perfilación de la Expresión GénicaRESUMEN
INTRODUCTION: Hyperphosphatemia in chronic kidney disease (CKD) patients is positively associated with mortality. Ferric citrate is a potent phosphorus binder that lowers serum phosphorus level and improves iron metabolism. We compared its efficacy and safety with active drugs in Chinese CKD patients with hemodialysis. METHODS: Chinese patients undergoing hemodialysis were randomized into two treatment groups in a 1:1 ratio, receiving either ferric citrate or sevelamer carbonate, respectively, for 12 weeks. Serum phosphorus levels, calcium concentration, and iron metabolism parameters were evaluated every 2 weeks. Frequency and severity of adverse events were recorded. RESULTS: 217 (90.4%) patients completed the study with balanced demographic and baseline characteristics between two groups. Ferric citrate decreased the serum phosphorus level to 0.59 ± 0.54 mmol/L, comparable to 0.56 ± 0.62 mmol/L by sevelamer carbonate. There was no significant difference between two groups (p > 0.05) in the proportion of patients with serum phosphorus levels reaching the target range, the response rate to the study drug, and the changes of corrected serum calcium concentrations, and intact-PTH levels at the end of treatment. The change of iron metabolism indicators in the ferric citrate group was significantly higher than those in the sevelamer carbonate group. There are 47 (40.5%) patients in the ferric citrate group, and 26 (21.3%) patients in the sevelamer carbonate group experienced drug-related treatment emergent adverse events (TEAEs); most were mild and tolerable. Common drug-related TEAEs were gastrointestinal disorders, including diarrhea (12.9 vs. 2.5%), fecal discoloration (14.7 vs. 0%), and constipation (1.7 vs. 7.4%) in ferric citrate and sevelamer carbonate group. CONCLUSION: Ferric citrate capsules have good efficacy and safety in the control of hyperphosphatemia in adult patients with CKD undergoing hemodialysis. Efficacy is not inferior to sevelamer carbonate. The TEAEs were mostly mild and tolerated by the patients.
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Hiperfosfatemia , Insuficiencia Renal Crónica , Adulto , Humanos , Hiperfosfatemia/tratamiento farmacológico , Hiperfosfatemia/etiología , Sevelamer/efectos adversos , Calcio , Quelantes/efectos adversos , Diálisis Renal/efectos adversos , Compuestos Férricos/efectos adversos , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/tratamiento farmacológico , Fósforo , Hierro/uso terapéutico , ChinaRESUMEN
Background: Identification of risk factors that have causal effects on the occurrence of diabetic kidney disease (DKD), is of great significance in early screening and intervening for DKD, and in delaying the progression of DKD to end-stage renal disease. Cathepsin S (Cat-S), a novel non-invasive diagnostic marker, mediates vascular endothelial dysfunction. The diagnostic value of Cat-S for DKD has rarely been reported in clinical studies. Objective: To analyze whether Cat-S is a risk factor for DKD and evaluate the diagnostic value of serum Cat-S for DKD. Methods: Forty-three healthy subjects and 200 type 2 diabetes mellitus (T2DM) patients were enrolled. T2DM patients were divided into subgroups according to various criteria. Enzyme-linked immunosorbent assay was used to detect serum Cat-S levels among different subgroups. Spearman correlation analysis was used to analyze correlations between serum Cat-S and clinical indicators. Multivariate logistic regression analysis was performed to analyze risk factors for the occurrence of DKD and decreased renal function in T2DM patients. Results: Spearman analysis showed that serum Cat-S level was positively correlated with urine albumin creatinine ratio (r=0.76, P<0.05) and negatively correlated with estimated glomerular filtration rate (r=-0.54, P<0.01). Logistic regression analysis showed that increased serum Cat-S and cystatin C(CysC) were independent risk factors for DKD and decreased renal function in T2DM patients (P<0.05). The area under the receiver operating characteristic (ROC) curve was 0.900 of serum Cat-S for diagnosing DKD, and when the best cut-off value was 827.42 pg/mL the sensitivity and specificity were 71.6% and 98.8%, respectively. Thus, serum Cat-S was better than CysC for diagnosing DKD (for CysC, the area under the ROC curve was 0.791, and when the cut-off value was 1.16 mg/L the sensitivity and specificity of CysC were 47.4% and 98.8%, respectively). Conclusion: Increased serum Cat-S were associated with the progression of albuminuria and decreased renal function in T2DM patients. The diagnostic value of serum Cat-S was better than that of CysC for DKD. Monitoring of serum Cat-S levels could be helpful for early screening DKD and assessing the severity of DKD and could provide a new strategy for diagnosing DKD.
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Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Humanos , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/etiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Catepsinas , Factores de RiesgoRESUMEN
BACKGROUND: Porokeratosis is a rare chronic progressive hypokeratotic skin disease, possibly related to the mevalonate pathway. Variations in four enzymes, including phosphomevalonate kinase (PMVK) may alter this pathway, ultimately leading to porokeratosis. OBJECTIVES: The aim of the study was to identify the causative gene variant of porokeratosis in a Chinese family and investigate its population frequency and pathogenicity. METHOD: In this study, Sanger sequencing was used to identify the gene variant causative of porokeratosis; its population frequency was investigated by polymerase chain reaction-restriction fragment length polymorphism in 4 patients and three normal individuals as well as in 100 normal unrelated controls; finally, the pathogenicity of the mutation and the associated structural changes were predicted. RESULTS: We identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in the PMVK gene. This variant was found in all patients but not in the normal individuals in this family or in the 100 controls. In silico analysis indicated that the variant was pathogenic; p.Lys69Asn changed the length of the α-helix and the hydrogen bond pattern compared with the wild-type protein. CONCLUSIONS: The novel variant c.207G>T (p. Lys69Asn) in the PMVK gene was the causative variant in this porokeratosis family. This finding provides further evidence for the genetic basis of this disease.
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Poroqueratosis , Humanos , Poroqueratosis/genética , Mutación , Fosfotransferasas (Aceptor del Grupo Fosfato)/genética , Mutación Missense , LinajeRESUMEN
BACKGROUND: Although the executive pathways of senescence are known, the underlying control mechanisms are diverse and not fully understood, particularly how cancer cells avoid triggering senescence despite experiencing exacerbated stress conditions within the tumor microenvironment. METHODS: Mass spectrometry (MS)-based proteomic screening was used to identify differentially regulated genes in serum-starved hepatocellular carcinoma cells and RNAi employed to determine knockdown phenotypes of prioritized genes. Thereafter, gene function was investigated using cell proliferation assays (colony-formation, CCK-8, Edu incorporation and cell cycle) together with cellular senescence assays (SA-ß-gal, SAHF and SASP). Gene overexpression and knockdown techniques were applied to examine mRNA and protein regulation in combination with luciferase reporter and proteasome degradation assays, respectively. Flow cytometry was applied to detect changes in cellular reactive oxygen species (ROS) and in vivo gene function examined using a xenograft model. RESULTS: Among the genes induced by serum deprivation, NIPSNAP1 was selected for investigation. Subsequent experiments revealed that NIPSNAP1 promotes cancer cell proliferation and inhibits P27-dependent induction of senescence via dual mechanisms. Firstly, NIPSNAP1 maintains the levels of c-Myc by sequestering the E3 ubiquitin ligase FBXL14 to prevent the proteasome-mediated turnover of c-Myc. Intriguingly, NIPSNAP1 levels are restrained by transcriptional repression mediated by c-Myc-Miz1, with repression lifted in response to serum withdrawal, thus identifying feedback regulation between NIPSNAP1 and c-Myc. Secondly, NIPSNAP1 was shown to modulate ROS levels by promoting interactions between the deacetylase SIRT3 and superoxide dismutase 2 (SOD2). Consequent activation of SOD2 serves to maintain cellular ROS levels below the critical levels required to induce cell cycle arrest and senescence. Importantly, the actions of NIPSNAP1 in promoting cancer cell proliferation and preventing senescence were recapitulated in vivo using xenograft models. CONCLUSIONS: Together, these findings reveal NIPSNAP1 as an important mediator of c-Myc function and a negative regulator of cellular senescence. These findings also provide a theoretical basis for cancer therapy where targeting NIPSNAP1 invokes cellular senescence.
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Neoplasias , Complejo de la Endopetidasa Proteasomal , Humanos , Especies Reactivas de Oxígeno/metabolismo , Proteómica , Neoplasias/genética , Línea Celular , Senescencia Celular/genética , Microambiente Tumoral , Péptidos y Proteínas de Señalización IntercelularRESUMEN
OBJECTIVE: This study mainly observes changes in perioperative mineral bone metabolism-related indicators and inflammatory factors in patients with secondary hyperparathyroidism (SHPT), and analyzed the correlation between mineral bone metabolism-related indicators and inflammatory factors. METHODS: Clinical data were collected. The study detects mineral bone metabolism-related indicators and inflammatory factor of perioperative patients with SHPT before and 4 days after operation. The production of high-sensitivity c-reactive protein (hs-CRP) in human hepatocytes cells (LO2 cells) stimulated by different concentrations of parathyroid hormone-associated protein was detected by enzyme-linked immunosorbent assay, reverse-transcription polymerase chain reaction (RT-PCR), and western blot. RESULTS: The levels of mineral bone metabolism-related indicators and hs-CRP in SHPT group were significantly higher than those of control group. After operation, serum calcium, serum phosphorus, iPTH, FGF-23 decreased, and the level of osteoblast active biomarkers increased, while the level of osteoclast active biomarkers decreased. The levels of hs-CRP decreased significantly after operation. With the increase of PTHrP concentration, hs-CRP level in supernatant of LO2 cells decreased first and then increased. RT-PCR and western blot shows the same trend. CONCLUSION: Parathyroidectomy can significantly improve bone resorption and inflammation in SHPT patients. We speculate that there may be an optimal range of PTH concentrations to minimize inflammation in the body.
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Proteína C-Reactiva , Hiperparatiroidismo Secundario , Humanos , Hiperparatiroidismo Secundario/cirugía , Minerales , Biomarcadores , Periodo PerioperatorioRESUMEN
BACKGROUND: Transplant renal artery stenosis (TRAS) is a vascular complication after kidney transplantation associated with poor outcomes. This study aimed to analyze the efficacy and safety of low-dose aspirin for preventing TRAS. METHODS: After kidney transplantation, patients were enrolled from January 2018 to December 2020 in Henan Provincial People's Hospital. A total of 351 enrolled recipients were randomized to an aspirin group with low-dose intake of aspirin in addition to standard treatment ( n = 178), or a control group with only standard treatment ( n = 173). The patients was initially diagnosed as TRAS (id-TRAS) by Doppler ultrasound, and confirmed cases were diagnosed by DSA (c-TRAS). RESULTS: In the aspirin and control groups, 15.7% (28/178) and 22.0% (38/173) of the recipients developed id-TRAS, respectively, with no statistical difference. However, for c-TRAS, the difference of incidence and cumulative incidence was statistically significant. The incidence of c-TRAS was lower in the aspirin group compared with the control group (2.8% [5/178] vs. 11.6% [20/173], P = 0.001). Kaplan-Meier estimates and Cox regression model identified the cumulative incidence and hazard ratio (HR) of TRAS over time in two groups, showing that recipients treated with aspirin had a significantly lower risk of c-TRAS than those who were not treated (log-rank P â=â0.001, HRâ=â0.23, 95% confidence interval [CI]: 0.09-0.62). The levels of platelet aggregation rate ( P â<â0.001), cholesterol ( P â=â0.028), and low-density lipoprotein cholesterol ( P â=â0.003) in the aspirin group were decreased compared with the control group in the third-month post-transplantation. For the incidence of adverse events, there was no statistical difference. CONCLUSION: Clinical application of low-dose aspirin after renal transplant could prevent the development of TRAS with no significant increase in adverse effects. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04260828.
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Obstrucción de la Arteria Renal , Humanos , Estudios Prospectivos , Resultado del Tratamiento , Angiografía , AspirinaRESUMEN
Introduction: To retrospectively investigate the clinical characteristics and risk factors of cardiac surgery associated-acute kidney injury (CS-AKI) progressed to chronic kidney disease (CKD) in adults and to evaluate the performance of clinical risk factor model for predicting CS-AKI to CKD. Methods: In this retrospective, observational cohort study, we included patients who were hospitalized for CS-AKI without a prior CKD [estimated glomerular filtration rate (eGFR) < 60â ml · min-1·1.73â m-2] at Central China Fuwai Hospital from January 2018 to December 2020. Survived patients were followed up for 90 days, the endpoint was CS-AKI to CKD, and then divided them into two groups (with or without CS-AKI to CKD). The baseline data including demographics, comorbidities, renal function, and other laboratory parameters were compared between two groups. The logistic regression model was used to analyze the risk factors for CS-AKI to CKD. Finally, receiver operator characteristic (ROC) curve was drawn to evaluate the performance of the clinical risk factor model for predicting CS-AKI to CKD. Results: We included 564 patients with CS-AKI (414 males, 150 females; age: 57.55 ± 11.86 years); 108 (19.1%) patients progressed to new-onset CKD 90 days after CS-AKI. Patients with CS-AKI to CKD had a higher proportion of females, hypertension, diabetes, congestive heart failure, coronary heart disease, low baseline eGFR and hemoglobin level, higher serum creatinine level at discharge (P < 0.05) than those without CS-AKI to CKD. Multivariate logistic regression analysis revealed that female sex(OR = 3.478, 95% CI: 1.844-6.559, P = 0.000), hypertension (OR = 1.835, 95% CI: 1.046-3.220, P = 0.034), coronary heart disease (OR = 1.779, 95% CI: 1.015-3.118, P = 0.044), congestive heart failure (OR = 1.908, 95% CI: 1.124-3.239, P = 0.017), preoperative low baseline eGFR (OR = 0.956, 95% CI: 0.938-0.975, P = 0.000), and higher serum creatinine level at discharge (OR = 1.109, 95% CI: 1.014-1.024, P = 0.000) were independent risk factors for CS-AKI to CKD. The clinical risk prediction model including female sex, hypertension, coronary heart disease, congestive heart failure, preoperative low baseline eGFR, and higher serum creatinine level at discharge produced a moderate performance for predicting CS-AKI to CKD (area under ROC curve = 0.859, 95% CI: 0.823-0.896). Conclusion: Patients with CS-AKI are at high risk for new-onset CKD. Female sex, comorbidities, and eGFR can help identify patients with a high risk for CS-AKI to CKD.
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Unveiling the principles governing embryonic stem cell (ESC) differentiation into specific lineages is critical for understanding embryonic development and for stem cell applications in regenerative medicine. Here, we establish an intersection between LIF-Stat3 signaling that is essential for maintaining murine (m) ESCs pluripotency, and the glycolytic enzyme, the platelet isoform of phosphofructokinase (Pfkp). In the pluripotent state, Stat3 transcriptionally suppresses Pfkp in mESCs while manipulating the cells to lift this repression results in differentiation towards the ectodermal lineage. Pfkp exhibits substrate specificity changes to act as a protein kinase, catalyzing serine phosphorylation of the developmental regulator Lin41. Such phosphorylation stabilizes Lin41 by impeding its autoubiquitination and proteasomal degradation, permitting Lin41-mediated binding and destabilization of mRNAs encoding ectodermal specification markers to favor the expression of endodermal specification genes. This provides new insights into the wiring of pluripotency-differentiation circuitry where Pfkp plays a role in germ layer specification during mESC differentiation.
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Fosfofructoquinasas , Proteínas Quinasas , Embarazo , Femenino , Ratones , Animales , Proteínas Quinasas/metabolismo , Fosfofructoquinasas/metabolismo , Células Madre Embrionarias/metabolismo , Diferenciación Celular/genética , Transducción de Señal , Células Madre Embrionarias de Ratones/metabolismoRESUMEN
P53 inactivation occurs in about 50% of human cancers, where p53-driven p21 activity is devoid and p27 becomes essential for the establishment of the G1/S checkpoint upon DNA damage. Here, this work shows that the E2F1-responsive lncRNA LIMp27 selectively represses p27 expression and contributes to proliferation, tumorigenicity, and treatment resistance in p53-defective colon adenocarcinoma (COAD) cells. LIMp27 competes with p27 mRNA for binding to cytoplasmically localized hnRNA0, which otherwise stabilizes p27 mRNA leading to cell cycle arrest at the G0/G1 phase. In response to DNA damage, LIMp27 is upregulated in both wild-type and p53-mutant COAD cells, whereas cytoplasmic hnRNPA0 is only increased in p53-mutant COAD cells due to translocation from the nucleus. Moreover, high LIMp27 expression is associated with poor survival of p53-mutant but not wild-type p53 COAD patients. These results uncover an lncRNA mechanism that promotes p53-defective cancer pathogenesis and suggest that LIMp27 may constitute a target for the treatment of such cancers.
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Adenocarcinoma , Neoplasias del Colon , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , ARN Largo no Codificante , Humanos , Daño del ADN/genética , ARN Largo no Codificante/genética , ARN Mensajero/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismoRESUMEN
Objectives: There are significant differences in the composition of intestinal flora in renal transplant recipients before and after an operation, which has a great impact on the prognosis of renal transplantation. The purpose of this project is to study the effect of intestinal flora imbalance on renal transplantation. Methods: The animal model of renal transplantation was established after intestinal flora imbalance (mice pretreated with compound antibiotics), or the animal model of renal transplantation was established after being pretreated with single antibiotics. HE, PAS, and Masson staining was used to detecting the histopathological changes of transplanted renal. The expression of inflammatory factors and infiltration of inflammatory cells of renal tissue were respectively been detected by ELISA kit and flow cytometry. Results: Antibiotic pretreatment restored weight loss, and decreased serum creatinine level in mice after renal transplantation. The tissue staining, ELISA assay, and flow cytometry data showed that antibiotic pretreatment alleviated injury of the renal allograft, inhibited the inflammatory factors levels, and reduced inflammatory cell infiltration in mice after renal transplantation. Furthermore, single antibiotic, especially ampicillin pretreatment can also play the same role as compound antibiotics, such as restoring weight loss, decreasing serum creatinine level, alleviating renal allograft injury, inhibiting inflammatory factors levels, and reducing inflammatory cell infiltration in mice after renal transplantation. Conclusions: Antibiotic ampicillin may inhibit inflammatory cell infiltration after renal transplantation by regulating the proportion of intestinal flora in mice, to reduce renal injury and play a role in renal protection.
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Microbioma Gastrointestinal , Trasplante de Riñón , Ratones , Animales , Antibacterianos/farmacología , Creatinina , Ampicilina/farmacología , Tolerancia Inmunológica , Modelos Animales de Enfermedad , Pérdida de PesoRESUMEN
OBJECTIVE: To explore the characteristics of peripheral blood, high resolution computed tomography (HRCT) imaging and the radiomics signature (RadScore) in patients infected with delta variant virus under different coronavirus disease (COVID-19) vaccination status. METHODS: 123 patients with delta variant virus infection collected from November 1, 2021 to March 1, 2022 were analyzed retrospectively. According to COVID-19 vaccination Status, they were divided into three groups: Unvaccinated group, partially vaccinated group and full vaccination group. The peripheral blood, chest HRCT manifestations and RadScore of each group were analyzed and compared. RESULTS: The mean lymphocyte count 1.22 ± 0.49 × 10^9/L, CT score 7.29 ± 3.48, RadScore 0.75 ± 0.63 in the unvaccinated group; The mean lymphocyte count 1.55 ± 0.70 × 10^9/L, CT score 5.27 ± 2.72, RadScore 1.03 ± 0.46 in the partially vaccinated group; The mean lymphocyte count 1.87 ± 0.70 × 10^9/L, CT score 3.59 ± 3.14, RadScore 1.23 ± 0.29 in the fully vaccinated group. There were significant differences in lymphocyte count, CT score and RadScore among the three groups (all p < 0.05); Compared with the other two groups, the lung lesions in the unvaccinated group were more involved in multiple lobes, of which 26 cases involved the whole lung. CONCLUSIONS: Through the analysis of clinical features, pulmonary imaging features and radiomics, we confirmed the positive effect of COVID-19 vaccine on pulmonary inflammatory symptoms and lymphocyte count (immune system) during delta mutant infection.
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Vacunas contra la COVID-19 , COVID-19 , Humanos , COVID-19/prevención & control , Estudios Retrospectivos , SARS-CoV-2 , Tomografía Computarizada por Rayos X , VacunaciónRESUMEN
Cisplatin is widely used as a chemotherapeutic drug to treat various solid tumors. However, it often induces severe side effects, including nephrotoxicity, which limits its application in clinical settings. Furthermore, the underlying mechanisms of action are unclear. Here, we applied whole-transcriptome RNA sequencing to a cisplatin-induced acute kidney injury (CP-AKI) mouse model to evaluate competing endogenous RNA (ceRNA) networks. We found 4460 mRNAs, 1851 long non-coding RNAs, 101 circular RNAs, and 102 microRNAs significantly differentially expressed between CP-AKI and control mice. We performed gene set enrichment analysis to reveal the biological functions of the mRNAs and constructed non-coding RNA-associated ceRNA networks in CP-AKI mice. Two ceRNA regulatory pathways, Lhx1os-203/mmu-miR-21a-3p/Slc7a13 and circular RNA_3907/mmu-miR-185-3p/Ptprn, were validated using quantitative real-time PCR. The protein-protein interaction network indicated that Il6, Cxcl1, Cxcl2, and Plk1 serve as hub genes and are highly connected with the inflammatory response or DNA damage. Transcription factors, such as Stat3, Cebpb, and Foxm1, regulate gene expression levels in CP-AKI. Our study provides insight into non-coding RNA-associated ceRNA networks and mRNAs in CP-AKI and identifies potential treatment targets.