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Phosphorus (P) is an essential macronutrient for plant growth and development. Rapid alkalisation factors (RALFs) play crucial roles in plant responses to nutrient stress. However, the functions of Glycine max RALFs (GmRALFs) under low P (LP) stress remain elusive. In this study, we first identified 27 GmRALFs in soybean and then revealed that, under LP conditions, GmRALF10, GmRALF11, and GmRALF22 were induced in both roots and leaves, whereas GmRALF5, GmRALF6, and GmRALF25 were upregulated in leaves. Furthermore, GmRALF22 was found to be the target gene of the transcription factor GmPHR1, which binds to the P1BS cis-element in the promoter of GmRALF22 via electrophoretic mobility shift assay and dual-luciferase experiments. Colonisation with Bacillus subtilis which delivers GmRALF22, increases the expression of the high-affinity phosphate (Pi) transporter genes GmPT2, GmPT11, GmPT13, and GmPT14, thus increasing the total amount of dry matter and soluble Pi in soybeans. RNA sequencing revealed that GmRALF22 alleviates LP stress by regulating the expression of jasmonic acid- (JA-), salicylic acid- (SA-), and immune-related genes. Finally, we verified that GmRALF22 was dependent on FERONIA (FER) to promote Arabidopsis primary root growth under LP conditions. In summary, the GmPHR1-GmRALF22 module positively regulates soybean tolerance to LP.
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BACKGROUND: Despite its excellent screening effectiveness and sensitivity for breast cancer (BC), digital breast tomosynthesis (DBT) is controversial due to its high radiation exposure and long reading time. This study examines the diagnostic accuracy of DBT and digital mammography (DM) for BC screening and diagnosis in women with dense or non-dense breast tissue. MATERIAL AND METHODS: PRISMA-compliant searches were performed on Medline, Embase, PubMed, Web of Science, and the Cochrane databases for articles comparing DBT and DM for BC screening until March 2023. Meta-analysis was performed using RevMan sofware, and the Cochrane Risk of Bias Assessment Tool was employed to assess study quality. RESULTS: This meta-analysis included 11 trials with a total of 2,124,018 individuals. Screening with DBT resulted in a greater cancer detection rate, as demonstrated by a risk ratio (RR) of 1.27 (95% confidence interval (95% CI): 1.14-1.41). Digital breast tomosynthesis also had a reduced recall rate, with a RR of 0.88 (95% CI: 0.78-0.99), higher sensitivity and specificity values (pooled sensitivity of 0.91 (95% CI: 0.59-0.99)) and pooled specificity of 0.90 (95% CI: 0.42-1.0)) than DM (pooled sensitivity of 0.86 (95% CI: 0.52-1.0) and pooled specificity of 0.81 (95% CI: 0.12-1.0)). All acquired data exhibited reliability, lack of bias and statistical significance (p < 0.05). CONCLUSION: Digital breast tomosynthesis is a more effective screening and diagnostic assessment tool for women with dense or non-dense breasts than DM in terms of incremental cancer detection, sensitivity and recall rate.
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Polyploidization produces abundant phenotypic variation. Little is currently known about adventitious root (AR) development variation due to polyploidization. In this study, we analyzed the morphological, cytological, and physiological variations in AR development between tetraploid and diploid Populus plants during in vitro rooting culture. Compared to the diploids, the AR formation times and rooting rates of the tetraploids' stem explants had non-significant changes. However, the tetraploid ARs exhibited significantly slower elongation growth than the diploid ARs. Cytological observation showed that the tetraploid ARs were characterized by shorter root meristems and reduced meristem cell numbers, suggesting the reasons for the slow AR elongation. Analysis of hormones and related metabolites during AR development demonstrated that the total auxin, cytokinin, and jasmonic acid contents were significantly lower in the tetraploid ARs than in those of the diploids, and that the ratio of total auxins to total CKs at 0 h of AR development was also lower in the tetraploids than in the diploids, whereas the total salicylic acid content of the tetraploids was consistently higher than that of the diploids. qPCR analysis showed that the expression levels of several hormone signaling and cell division-related genes in the tetraploid ARs significantly differed from those in the diploids. In conclusion, the slow elongation of the tetraploid ARs may be caused by the endogenous hormone-mediated meristem shortening. Our findings enhance the understanding of polyploidization-induced variation in AR development of forest trees.
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Phytoalexin sakuranetin functions in resistance against rice blast. However, the mechanisms underlying the effects of sakuranetin remains elusive. Here, we report that rice lines expressing resistance (R) genes were found to contain high levels of sakuranetin, which correlates with attenuated endocytic trafficking of plasma membrane (PM) proteins. Exogenous and endogenous sakuranetin attenuates the endocytosis of various PM proteins and the fungal effector PWL2. Moreover, accumulation of the avirulence protein AvrCO39, resulting from uptake into rice cells by Magnaporthe oryzae, was reduced following treatment with sakuranetin. Pharmacological manipulation of clathrin-mediated endocytic (CME) suggests that this pathway is targeted by sakuranetin. Indeed, attenuation of CME by sakuranetin is sufficient to convey resistance against rice blast. Our data reveals a mechanism of rice against M. oryzae by increasing sakuranetin levels and repressing the CME of pathogen effectors, which is distinct from the action of many R genes that mainly function by modulating transcription.
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Ascomicetos , Resistencia a la Enfermedad , Endocitosis , Flavonoides , Oryza , Fitoalexinas , Enfermedades de las Plantas , Proteínas de Plantas , Oryza/microbiología , Oryza/metabolismo , Oryza/efectos de los fármacos , Oryza/genética , Enfermedades de las Plantas/microbiología , Endocitosis/efectos de los fármacos , Resistencia a la Enfermedad/genética , Resistencia a la Enfermedad/efectos de los fármacos , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Sesquiterpenos/farmacología , Sesquiterpenos/metabolismo , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Membrana Celular/metabolismo , Membrana Celular/efectos de los fármacos , Plantas Modificadas Genéticamente , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genéticaRESUMEN
The treatment of diabetic periodontitis poses a significant challenge due to the presence of local inflammation characterized by excessive glucose concentration, bacterial infection, and high oxidative stress. Herein, mesoporous silica nanoparticles (MSN) are embellished with gold nanoparticles (Au NPs) and loaded with manganese carbonyl to prepare a carbon monoxide (CO) enhanced multienzyme cooperative hybrid nanoplatform (MSN-Au@CO). The Glucose-like oxidase activity of Au NPs catalyzes the oxidation of glucose to hydrogen peroxide (H2O2) and gluconic acidï¼and then converts H2O2 to hydroxyl radicals (â¢OH) by peroxidase-like activity to destroy bacteria. Moreover, CO production in response to H2O2, together with Au NPs exhibited a synergistic anti-inflammatory effect in macrophages challenged by lipopolysaccharides. The underlying mechanism can be the induction of nuclear factor erythroid 2-related factor 2 to reduce reactive oxygen species, and inhibition of nuclear factor kappa-B signaling to diminish inflammatory response. Importantly, the antibacterial and anti-inflammation effects of MSN-Au@CO are validated in diabetic rats with ligature-induced periodontitis by showing decreased periodontal bone loss with good biocompatibility. To summarize, MSN-Au@CO is fabricate to utilize glucose-activated cascade reaction to eliminate bacteria, and synergize with gas therapy to regulate the immune microenvironment, offering a potential direction for the treatment of diabetic periodontitis.
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Monóxido de Carbono , Diabetes Mellitus Experimental , Oro , Nanopartículas del Metal , Periodontitis , Animales , Periodontitis/metabolismo , Periodontitis/tratamiento farmacológico , Oro/química , Ratas , Nanopartículas del Metal/química , Nanopartículas del Metal/uso terapéutico , Monóxido de Carbono/metabolismo , Monóxido de Carbono/farmacología , Modelos Animales de Enfermedad , Catálisis , Ratas Sprague-Dawley , MasculinoRESUMEN
The red panda (Ailurus fulgens) is a distinctive mammal known for its reliance on a diet primarily consisting of bamboo. The gut microbiota and overall health of animals are strongly influenced by diets and environments. Therefore, conducting research to explore the taxonomical and functional variances within the gut microbiota of red pandas exposed to various dietary and environmental conditions could shed light on the dynamic complexities of their microbial communities. In this study, normal fecal samples were obtained from red pandas residing in captive and semi-free environments under different dietary regimes and used for metabolomic, 16S rRNA, and metagenomic sequencing analysis, with the pandas classified into four distinct cohorts according to diet and environment. In addition, metagenomic sequencing was conducted on mucus fecal samples to elucidate potential etiological agents of disease. Results revealed an increased risk of gastrointestinal diseases in red pandas consuming bamboo shoots due to the heightened presence of pathogenic bacteria, although an increased presence of microbiota-derived tryptophan metabolites appeared to facilitate intestinal balance. The red pandas fed bamboo leaves also exhibited a decrease in gut microbial diversity, which may be attributed to the antibacterial flavonoids and lower protein levels in leaves. Notably, red pandas residing in semi-free environments demonstrated an enriched gut microbial diversity. Moreover, the occurrence of mucus secretion may be due to an increased presence of species associated with diarrhea and a reduced level of microbiota-derived tryptophan metabolites. In summary, our findings substantiate the influential role of diet and environment in modulating the gut microbiota of red pandas, offering potential implications for improved captive breeding practices.
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Ailuridae , Dieta , Heces , Microbioma Gastrointestinal , ARN Ribosómico 16S , Animales , Microbioma Gastrointestinal/fisiología , Dieta/veterinaria , Ailuridae/microbiología , Heces/microbiología , ARN Ribosómico 16S/genética , Bacterias/clasificación , Alimentación Animal/análisis , AmbienteRESUMEN
BACKGROUND: The incidence of inflammatory bowel disease (IBD) continues to increase annually, accounting for about 6.8 million cases in 2017 worldwide. However, there is currently no gold standard for the diagnosis of IBD. METHODS: A method for the detection of four microorganisms in feces by two-dimensional polymerase chain reaction (2D-PCR) has been developed. Plasmids were used to validate the sensitivity and specificity of the method. Clinical samples were tested using a 2D-PCR method. Optimal diagnostic thresholds for IBD were determined based on ROC results. RESULTS: Of the 112 samples, 78 were from IBD patients and 34 from patients with other gastrointestinal (GI) diseases. Thomasclavelia ramosum and univ907-1062 positivity are necessary, and two or more positives of the three bacteria (Thomasclavelia spiroforme, Thomasclavelia saccharogumia or Clostridium cluster XVIII) are the optimal diagnostic thresholds for IBD. The area under the curve was 0.826 with a 95% confidence interval of 0.735-0.981 and a p-value of 0.000, corresponding to a sensitivity of 0.769 and a specificity of 0.853. CONCLUSIONS: Based on the detection results of microorganisms, IBD and GI can be effectively distinguished. The detection of four microorganisms in feces can assist clinicians in the differential diagnosis of IBD. Our experiment aims to provide a better program for early clinical diagnosis and regular dynamic monitoring of IBD.
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Enfermedades Inflamatorias del Intestino , Humanos , Enfermedades Inflamatorias del Intestino/diagnóstico , Heces , Bacterias , Sensibilidad y Especificidad , Reacción en Cadena de la Polimerasa/métodosRESUMEN
OBJECTIVES: Enhance the androstadienedione (Androst-1,4-diene-3,17-dione, ADD) production of rough morphotype Mycolicibacterium neoaurum R by repeated-batch fermentation of immobilized cells. RESULTS: M. neoaurum R was a rough colony morphotype variant, obtained from the routine plating of smooth M. neoaurum strain CICC 21097. M. neoaurum R showed rougher cell surface and aggregated in broth. The ADD production of M. neoaurum R was notably lower than that of M. neoaurum CICC 21097 during the free cell fermentation, but the yield gap could be erased after proper cell immobilization. Subsequently, repeated-batch fermentation of immobilized M. neoaurum R was performed to shorten the production cycle and enhance the bio-production efficiency of ADD. Through the optimization of the immobilization carriers and the co-solvents for phytosterols, the ADD productivity of M. neoaurum R immobilized by semi-expanded perlite reached 0.075 g/L/h during the repeated-batch fermentation for 40 days. CONCLUSIONS: The ADD production of the rough-type M. neoaurum R was notably enhanced by the immobilization onto semi-expanded perlite. Moreover, the ADD batch yields of M. neoaurum R immobilized by semi-expanded perlite were maintained at high levels during the repeated-batch fermentation.
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Mycobacteriaceae , Fitosteroles , Dióxido de Silicio , Fitosteroles/metabolismo , Mycobacteriaceae/metabolismo , Óxido de Aluminio/metabolismoRESUMEN
BACKGROUND: Electrocardiographic markers, as surrogates for sympathetic excitotoxicity, are widely predictive of cardiovascular adverse events, but whether these markers can predict postsurgical sepsis (SS) is unclear. METHODS: We retrospectively analyzed patients who underwent abdominal surgery from March 2013 to May 2023. We collected basic data, comorbidities, blood samples, echocardiology, electrocardiogram, and surgical data, as well as short-term outcome. The primary endpoints were postsurgical SS, in which logistic regression analyses can identify independent risk factors. The optimal cut-off value predictive postsurgical SS both P wave and PR interval were calculated in the receiver operating characteristic curve (ROC). RESULTS: A total of 1988 subjects were analyzed, and the incidence of postsurgical SS was 3.8%. The mean age at enrollment was 68.6 ± 7.1 years, and 53.2% of the participants were men. In the ROC analysis, the areas under the curve (AUC) for P wave and PR interval predictive postsurgical SS were 0.615 (95%CI, 0.548-0.683; p = 0.001) and 0.618 (95%CI, 0.554-0.682; p = 0.001), respectively. The P wave and PR interval predicted postoperative sepsis with optimal discrimination of 103 and 157 ms, with a sensitivity of 0.744 and 0.419, and a specificity of 0.427 and 0.760. P-wave less than 103 ms or PR interval less than 157 ms associated with a 2.06 or 2.33 fold increase occurred risk postsurgical SS. CONCLUSIONS: Shorter P-wave and PR intervals were both independently associated with postsurgical SS. These preoperative electrophysiological markers could have potential useful for early recognition of postoperative SS.
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Sepsis , Masculino , Humanos , Anciano , Femenino , Pronóstico , Estudios Retrospectivos , Sepsis/diagnóstico , Sepsis/epidemiología , Electrocardiografía , Factores de Riesgo , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/etiología , Curva ROCRESUMEN
BACKGROUND: To investigate the effect of preoperative high-intensity strength training combined with balance training on the knee function of end-stage knee osteoarthritis (KOA) patients after total knee arthroplasty (TKA). METHODS: A prospective study was conducted on end-stage KOA patients awaiting TKA. The patients were divided into an experimental group and a control group according to whether they received a preoperative training intervention. The differences in knee flexor-extensor strength, knee range of motion (ROM), timed up and go (TUG) test result, stair ascend/descend test result, Knee Society score (KSS) and Berg balance scale (BBS) score were assessed in both groups at baseline (T1), before operation (T2), 3 months after operation (T3), and 1 year after operation (T4). RESULTS: After high-intensity strength training and balance training, the knee flexor-extensor strength, TUG test result, stair ascend/descend test result, and KSS were all significantly improved at T2 in the experimental group over the control group. At T3, the knee ROM, knee flexor-extensor strength, TUG test result, BBS score, and KSS clinical and functional scores were all significantly superior in the experimental group. The experimental group enjoyed a superiority in KSS clinical and functional scores until T4. Group × time and between-group interactions were found in all assessment indicators in both groups (p < 0.01). CONCLUSION: Preoperative high-intensity strength training combined with balance training can enhance the knee flexor-extensor strength and balance of patients with end-stage KOA in the short term and help improve early outcomes after KOA. Trial registration ChiCTR2000032857, 2020-05-13.
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Artroplastia de Reemplazo de Rodilla , Osteoartritis de la Rodilla , Entrenamiento de Fuerza , Humanos , Estudios Prospectivos , Articulación de la Rodilla/cirugía , Osteoartritis de la Rodilla/cirugíaRESUMEN
The host immune system affects the treatment response to immune checkpoint inhibitors and can be reflected by circulating immune cells. This study aimed to evaluate whether circulating T cell subtypes are correlated with clinical response and dermatological toxicities in patients with advanced gastric and esophageal cancer receiving PD-1 inhibitor-based combination therapy (n = 203). In the training cohort, Eastern Cooperative Oncology Group performance status (ECOG PS), PD-L1 expression, antibiotic use, and CD4+/CD8+ ratio were identified as independent prognostic factors in these patients, using a Cox regression model. A nomogram to predict the overall survival (OS) and survival probabilities was constructed using these factors. The nomogram showed good discrimination ability (C-index, 0.767) and was externally confirmed in the validation and test cohorts. Kaplan-Meier analysis showed that median OS in patients with a CD4+/CD8+ ratio ≥1.10 was 6.2 months, which was significantly shorter than that in patients with a CD4+/CD8+ ratio <1.10 (P < 0.001). Patients with a CD4+/CD8+ ratio <1.10 had a superior objective response (43.8% vs. 23.1%) and disease control (72.9% vs. 59.0%) rate, relative to those with ratio ≥ 1.10. In addition, PD-L1 expression, corticosteroid use, and CD4+/CD8+ ratio can independently predict dermatological toxicities. In conclusion, baseline CD4+/CD8+ ratio is a potential prognostic factor for patients with advanced gastric and esophageal cancer treated with PD-1 inhibitor-based combination therapy, and can independently predict dermatological toxicities. In addition, a nomogram incorporating CD4+/CD8+ ratio, ECOG PS, PD-L1 expression, and antibiotic use can predict OS with considerable accuracy.
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Neoplasias Esofágicas , Neoplasias Pulmonares , Neoplasias Gástricas , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Esofágicas/tratamiento farmacológico , Antígeno B7-H1 , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , PronósticoRESUMEN
Background/objective: We retrospectively analyzed the effective and safety of continuous low-dose cyclophosphamide combined with prednisone (CP) in relapsed and refractory multiple myeloma (RRMM) patients with severe complications. Methods: A total of 130 RRMM patients with severe complications were enrolled in this study, among which 41 patients were further given bortezomib, lenalidomide, thalidomide or ixazomib on the basis of CP regimen (CP+X group). The response to therapy, adverse events (AEs), overall survival (OS) and progression-free survival (PFS) were recorded. Results: Among the 130 patients, 128 patients received therapeutic response assessment, with a complete remission rate (CRR) and objective response rate (ORR) of 4.7% and 58.6%, respectively. The median OS and PFS time were (38.0 ± 3.6) and (22.9±5.2) months, respectively. The most common AEs were hyperglycemia (7.7%), pneumonia (6.2%) and Cushing's syndrome (5.4%). In addition, we found the pro-BNP/BNP level was obviously decreased while the LVEF (left ventricular ejection fraction) was increased in RRMM patients following CP treatment as compared with those before treatment. Furthermore, CP+X regimen further improved the CRR compared with that before receiving the CP+X regimen (24.4% vs. 2.4%, P=0.007). Also, both the OS and PFS rates were significantly elevated in patients received CP+X regimen following CP regimen as compared with the patients received CP regimen only. Conclusion: This study demonstrates the metronomic chemotherapy regimen of CP is effective to RRMM patients with severe complications.
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Objective: To assess the immunogenicity and safety of the enterovirus 71 vaccine (Vero cell) (EV71 vaccine) and trivalent split-virion influenza vaccine (IIV3). Methods: Healthy infants aged 6-7 months were recruited from Zhejiang Province, Henan Province, and Guizhou Province and randomly assigned to the simultaneous vaccination group, EV71 group, and IIV3 group at a ratio of 1:1:1. Then, 3 mL blood samples were collected before vaccination and 28 days after the second dose of vaccine. Cytopathic effect inhibition assay was used to detect EV71 neutralization antibody, and cytopathic effect inhibition assay was used to detect influenza virus antibody. Results: A total of 378 infants were enrolled and received the first dose of vaccine and were included in the safety analysis, and 350 infants were involved in the immunogenicity analysis. The adverse events rates were 31.75%, 28.57%, and 34.13% in the simultaneous vaccination group, EV71 group, and IIV3 group (p > 0.05), respectively. No vaccine-related serious adverse events were reported. After two doses of EV71 vaccine, the seroconversion rates of EV71 neutralizing antibody were 98.26% and 97.37% in the simultaneous vaccination group and the EV71 group, respectively. After two doses of IIV3, the simultaneous vaccination group and the IIV3 group, respectively, had seroconversion rates of 80.00% and 86.78% for H1N1 antibody, 99.13% and 98.35% for H3N2 antibody, and 76.52% and 80.99% for B antibody. There was no statistically significant difference in the seroconversion rates of influenza virus antibodies between groups (p > 0.05). Conclusions: The coadministration of EV71 vaccine and IIV3 has good safety and immunogenicity in infants aged 6-7 months.
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Salicylic acid (SA) plays important roles in different aspects of plant development, including root growth, where auxin is also a major player by means of its asymmetric distribution. However, the mechanism underlying the effect of SA on the development of rice roots remains poorly understood. Here, we show that SA inhibits rice root growth by interfering with auxin transport associated with the OsPIN3t- and clathrin-mediated gene regulatory network (GRN). SA inhibits root growth as well as Brefeldin A-sensitive trafficking through a non-canonical SA signaling mechanism. Transcriptome analysis of rice seedlings treated with SA revealed that the OsPIN3t auxin transporter is at the center of a GRN involving the coat protein clathrin. The root growth and endocytic trafficking in both the pin3t and clathrin heavy chain mutants were SA insensitivity. SA inhibitory effect on the endocytosis of OsPIN3t was dependent on clathrin; however, the root growth and endocytic trafficking mediated by tyrphostin A23 (TyrA23) were independent of the pin3t mutant under SA treatment. These data reveal that SA affects rice root growth through the convergence of transcriptional and non-SA signaling mechanisms involving OsPIN3t-mediated auxin transport and clathrin-mediated trafficking as key components.
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Proteínas de Arabidopsis , Arabidopsis , Oryza , Clatrina/metabolismo , Proteínas de Arabidopsis/metabolismo , Oryza/metabolismo , Arabidopsis/genética , Ácido Salicílico/metabolismo , Raíces de Plantas/metabolismo , Transporte de Proteínas , Ácidos Indolacéticos/metabolismoRESUMEN
Helicobacter pylori (Hp) is a primary risk factor for gastric cancer. The fat mass and obesity-associated (FTO) gene is associated with the development and progression of various cancer types such as glioma, leukemia, breast cancer and colorectal cancer. The aim of the present study was to investigate the effect of Hp infection on the expression of FTO and its roles in gastric cancer. It was found that the expression levels of both FTO mRNA and protein were significantly increased in Hp-infected human gastric mucosal epithelial cells and Mongolian gerbil gastric tissues. The expression of FTO in gastric cancer tissues was higher than that in para-cancer tissues. Data from The Cancer Genome Atlas demonstrated that FTO expression in gastric cancer tissues was significantly higher than that in normal tissues. Patient survival rate was significantly decreased in patients with high expression levels of FTO. It was also demonstrated that FTO expression was associated with several pathological parameters, such as tumor stage, metastasis stage and the American Joint Committee on Cancer stage. The FTO gene was positively correlated with 16,601 genes in gastric cancer and negatively correlated with 3,623 genes. Gene Ontology enrichment analysis demonstrated that FTO was significantly enriched in the regulation of gene expression and oxidative RNA demethylase activity, and it was associated with components such as the RNA N6-methyladenosine methyltransferase complex and nuclear speckle. In addition, knockdown of the FTO gene inhibited the migration and invasion of Hp-infected cells. In conclusion, the data suggests that Hp infection leads to upregulation of the FTO gene, which may be related to patient survival rate, tumor staging and other pathological parameters of patients with gastric cancer. It also suggests that FTO promotes proliferation and migration of gastric cancer cells, which may be involved in the pathogenesis of Hp-induced gastric cancer.
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OBJECTIVE: Gain or amplification 1q21 (1q21+) is one of the most common recurrent cytogenetic abnormalities in multiple myeloma (MM). Our aim was to explore the presentation and outcomes of patients with MM harboring 1q21 + . METHODS: We retrospectively analyzed the clinical features and survival outcomes in 474 consecutive patients with MM receiving immunomodulatory drugs or proteasome inhibitor-based regimens as first-line therapies. RESULTS: 1q21 + was detected in 249 (52.5%) patients. Patients with 1q21 + had a higher proportion of subtypes of IgA, IgD, and λ-light chain than non-1q21 + . 1q21 + was associated with more advanced ISS stage and was more frequently accompanied by del(13q), elevated lactate dehydrogenase and lower levels of hemoglobin and platelets. Patients with 1q21 + had shorter PFS (21 months vs. 31 months, P = 0.001) and OS (43 months vs. 72 months, P < 0.001) than those without 1q21 + . Multivariate Cox regression analysis confirmed that 1q21 + was an independent prognostic factor for both PFS (HR 1.277, P = 0.031) and OS (HR 1.547, P = 0.003). Patients with 1q21 + del(13q) double-abnormality had shorter PFS (P < 0.001) and OS (P = 0.001) than those with no FISH abnormalities, and they also had shorter PFS (P = 0.018) and OS (P = 0.026) than those with del(13q) single abnormality. No significant difference in PFS (P = 0.525) or OS (P = 0.245) was found between patients with 1q21 + del(13q) double-abnormality and 1q21 + del(13q) multiple-abnormality. CONCLUSIONS: Patients with 1q21 + were more likely to have coexisting negative clinical features and del(13q). 1q21 + was an independent prognostic factor associated with poor outcomes. Concurrence with such unfavorable features may account for poor outcomes given 1q21 + .
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Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Estudios Retrospectivos , Pronóstico , Inhibidores de Proteasoma , Aberraciones CromosómicasRESUMEN
Senescence of activated hepatic stellate cells (aHSCs) is a stable growth arrest that is implicated in liver fibrosis regression. Senescent cells often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). Induction of aHSCs senescence by inhibiting SASP may be a potential therapeutic model against hepatic fibrosis. To evaluate the role of atractylenolide III (ATR III) in the development of chemotherapeutic drug-induced SASPs in hepatic stellate cells. Etoposide-induced senescent HSC-LX2 model was established and treated with ATR III at different concentrations (20, 30 and 40 µM). We found that ATR III dose-dependently enhanced senescence in etoposide-induced LX2 cells. ATR III dose-dependently decreased the release and expression of SASP factors (interleukin [IL]-1α, IL-1ß, IL6 and IL-8) in senescent cells. ATR III regulated cyclic GMP-AMP synthase (cGAS)/nuclear factor κ (NF-κB) signalling to affect SASP expression in senescent cells. The addition of 2'3' cGAMP counteracted the effect of ATR III. The release of SASP factors in the conditioned medium from senescent cells could affect cell migration, proliferation and contraction through paracrine manner. Our results indicated ATR III could still enter senescence and prevent the production of SASP and its paracrine effects in senescent cells, an effect that may be related to the possible inhibition of cGAS/NF-κB signalling by ATR III. Our study proves that ATR III may be an effective potential drug against liver fibrosis by promoting aHSC senescence, which can provide a new choice for the future clinical treatment of liver fibrosis.
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Células Estrelladas Hepáticas , FN-kappa B , Humanos , Senescencia Celular , Etopósido/farmacología , Cirrosis Hepática , FN-kappa B/metabolismo , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Nucleotidiltransferasas/farmacología , SecretomaRESUMEN
BACKGROUND: Pseudohypoparathyroidism (PHP) is a series of diseases related to pathological changes and neurocognitive and endocrine abnormalities, mainly due to the GNAS mutation on chromosome 20q13.2, which weakens receptor-mediated hormone signal transduction. Considering its complex genetic and epigenetic characteristics, GNAS may produce complex clinical phenotypes in families or sporadic cases. This study presented a case of familial PHP caused by a deletion mutation in the 20q13.2 region. METHODS AND RESULTS: The proband and her second daughter had PHP, and the proband's mother had pseudo-PHP. Whole-genome sequencing revealed that the proband had an 849.81 kb deletion spanning GNAS near the maternal 20q13.2 chromosome. Multiplex ligation-dependent probe amplification methylation analysis indicated that the proband as well as her mother and second daughter had seemingly abnormal GNAS methylation. This is different from the phenotype (feeding difficulty, slow growth, and special facial features) of previously reported cases with the deletion of fragments near the 20q13.2 chromosome. CONCLUSIONS: This report demonstrated the variability of 20q13.2 deletion phenotypes and the clinical importance of using multiple molecular genetic detection methods.
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Subunidades alfa de la Proteína de Unión al GTP Gs , Seudohipoparatiroidismo , Femenino , Humanos , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Metilación de ADN , Cromograninas/genética , Seudohipoparatiroidismo/genética , Seudohipoparatiroidismo/diagnóstico , Eliminación de SecuenciaRESUMEN
The Second Revision of the International Staging System (R2-ISS) was recently introduced to improve risk stratification over that provided by the extensively applied standard revised International Staging System (R-ISS). In addition to the variables included in the R-ISS, the R2-ISS incorporates chromosome 1q gain/amplification and divides the patients into 4 groups with different survival outcomes, better stratifying patients within the R-ISS intermediate-risk. The new model was developed based on a great quantity of data from patients participating in uniform clinical trials and has not been validated in real-world clinical practice. Therefore, we retrospectively analyzed the prognostic value of the R2-ISS in 474 consecutive patients with multiple myeloma receiving immunomodulatory drugs or proteasome inhibitor-based regimens as their first-line treatment. According to the R2-ISS, 41 (8.6%), 76 (16%), 275 (58%), and 82 (17.3%) patients were identified as R2-ISS I, R2-ISS II, R2-ISS III, and R2-ISS IV, respectively. The median progression-free survival (PFS) was 48 (95% CI: 38-58), 35 (95% CI: 23-47), 24 (95% CI: 21-27), and 12 (95% CI: 7-17) months, and the estimated median overall survival (OS) was 110 (95% CI: 42-178), 88 (95% CI: 75-101), 50 (95% CI: 43-57), and 26 (95% CI: 19-33) months (p < 0.001) in the 4 groups, respectively. The R2-ISS could also classify groups with distinct survival among patients with renal impairment or classified as R-ISS II. Adjusted by age, sex, treatment approaches and transplantation status, the R2-ISS was an independent prognostic factor associated with OS with a hazard ratio of 7.055 (95% CI: 3.626-13.726) (p < 0.001) for R2-ISS IV versus R2-ISS I and 2.707 (95% CI: 1.436-5.103) (p = 0.002) for R2-ISS III versus R2-ISS I. In conclusion, our results suggest that the R2-ISS is a simple and robust risk stratification tool for patients with multiple myeloma treated with novel drugs and could be used in everyday clinical practice.
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Mieloma Múltiple , Humanos , Mieloma Múltiple/patología , Inhibidores de Proteasoma/uso terapéutico , Agentes Inmunomoduladores , Estadificación de Neoplasias , Estudios Retrospectivos , PronósticoRESUMEN
OBJECTIVES: Recently, the Mayo Clinic introduced a new staging system (the Mayo Additive Staging System [MASS]) for patients with newly diagnosed multiple myeloma (NDMM) based on the number of high-risk (HR) abnormalities, including HR IgH translocations, 1q gain/amplification, chromosome 17 abnormalities, International Staging System (ISS)-III, and elevated lactate dehydrogenase. Patients with 0, 1, or ≥2 HR abnormalities were defined as stage I, II, or III, respectively. We aimed to validate the real-world prognostic value of the MASS. METHODS: We retrospectively analyzed the cytogenetic and laboratory results of 544 patients with NDMM at a single center. RESULTS: Ninety (16.5%) patients had no HR factors (MASS I), 193 (35.5%) had 1 HR factor (MASS II), and 261 (48%) had ≥2 HR factors (MASS III). The median progression-free survival (PFS) and overall survival (OS) times were 48, 28, and 20 months and 137, 73, and 39 months in the three groups, respectively (p < .001). In the subgroup analysis, patients had different OS outcomes based on the MASS when grouped by age, renal function, or therapeutic regimens. The MASS identified patients with the worst outcomes among those rated revised ISS II. CONCLUSION: The MASS system is a reliable risk stratification tool for patients with NDMM in real-world clinical practice.