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The Crumbs homolog 1 (CRB1) gene is associated with retinal degeneration, most commonly Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). Here, we demonstrate that murine retinas bearing the Rd8 mutation of Crb1 are characterized by the presence of intralesional bacteria. While normal CRB1 expression was enriched in the apical junctional complexes of retinal pigment epithelium and colonic enterocytes, Crb1 mutations dampened its expression at both sites. Consequent impairment of the outer blood retinal barrier and colonic intestinal epithelial barrier in Rd8 mice led to the translocation of intestinal bacteria from the lower gastrointestinal (GI) tract to the retina, resulting in secondary retinal degeneration. Either the depletion of bacteria systemically or the reintroduction of normal Crb1 expression colonically rescued Rd8-mutation-associated retinal degeneration without reversing the retinal barrier breach. Our data elucidate the pathogenesis of Crb1-mutation-associated retinal degenerations and suggest that antimicrobial agents have the potential to treat this devastating blinding disease.
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Proteínas del Tejido Nervioso , Degeneración Retiniana , Animales , Ratones , Traslocación Bacteriana , Proteínas del Ojo/genética , Amaurosis Congénita de Leber/genética , Mutación , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Retina/metabolismo , Degeneración Retiniana/genética , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/metabolismo , Retinitis Pigmentosa/patologíaRESUMEN
A dysfunctional immune response in coronavirus disease 2019 (COVID-19) patients is a recurrent theme impacting symptoms and mortality, yet a detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 196 COVID-19 patients and controls and created a comprehensive immune landscape with 1.46 million cells. The large dataset enabled us to identify that different peripheral immune subtype changes are associated with distinct clinical features, including age, sex, severity, and disease stages of COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was found in diverse epithelial and immune cell types, accompanied by dramatic transcriptomic changes within virus-positive cells. Systemic upregulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis of and developing effective therapeutic strategies for COVID-19.
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COVID-19/inmunología , Megacariocitos/inmunología , Monocitos/inmunología , ARN Viral , SARS-CoV-2/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , China , Estudios de Cohortes , Citocinas/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/sangre , ARN Viral/aislamiento & purificación , Análisis de la Célula Individual , Transcriptoma/inmunología , Adulto JovenRESUMEN
BACKGROUND: This study aimed to investigate the combined pathological risk factors (PRFs) to stratify low-risk (pT1-3N1) stage III colon cancer (CC), providing a basis for individualized treatment in the future. PATIENTS AND METHODS: PRFs for low-risk stage III CC were identified using COX model. Low-risk stage III CC was risk-grouped combining with PRFs, and survival analysis were performed using Kaplan-Meier. The Surveillance, Epidemiology, and End Results (SEER) databases was used for external validation. RESULTS: Nine hundred sixty-two stage III CC patients were included with 634 (65.9%) as low risk and 328 (34.1%) as high risk. Poor differentiation (OS: P = 0.048; DFS: P = 0.011), perineural invasion (OS: P = 0.003; DFS: P < 0.001) and tumor deposits (OS: P = 0.012; DFS: P = 0.003) were identified as PRFs. The prognosis of low-risk CC combined with 2 PRFs (OS: HR = 3.871, 95%CI, 2.004-7.479, P < 0.001; DFS: HR = 3.479, 95%CI, 2.158-5.610, P < 0.001) or 3 PRFs (OS: HR = 5.915, 95%CI, 1.953-17.420, P = 0.002; DFS: HR = 5.915, 95%CI, 2.623-13.335, P < 0.001) was similar to that of high-risk CC (OS: HR = 3.927, 95%CI, 2.317-6.656, P < 0.001; DFS: HR = 4.132, 95%CI, 2.858-5.974, P < 0.001). In the SEER database, 18,547 CC patients were enrolled with 10,023 (54.0%) as low risk and 8524 (46.0%) as high risk. Low-risk CC combined with 2 PRFs (OS: HR = 1.857, 95%CI, 1.613-2.139, P < 0.001) was similar to that of high-risk CC without PRFs (HR = 1.876, 95%CI, 1.731-2.033, P < 0.001). CONCLUSION: Combined PRFs improved the risk stratification of low-risk stage III CC, which could reduce the incidence of undertreatment and guide adjuvant chemotherapy.
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Neoplasias del Colon , Humanos , Estadificación de Neoplasias , Neoplasias del Colon/patología , Pronóstico , Factores de Riesgo , Quimioterapia Adyuvante , Medición de Riesgo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Alfosbuvir is a novel potent HCV NS5B polymerase inhibitor in development for the treatment of chronic HCV infection. Our previous studies indicated that alfosbuvir monotherapy was well-tolerated and druggable in healthy subjects and HCV-infected patients. Here, we evaluate the efficacy and safety of alfosbuvir in combination with daclatasvir in Chinese patients with HCV genotype 1, 2, 3 or 6. In this open-label study, patients with chronic HCV infection were randomly assigned with a 1:1:1 ratio to receive 12 weeks of daclatasvir 60 mg plus alfosbuvir at a dose of 400, 600 or 800 mg (Cohort A, B or C) daily. Randomization was stratified by HCV genotype and the presence or absence of cirrhosis at screening. The primary endpoint was a sustained virologic response 12 weeks after the end of treatment (SVR12). A total of 124 patients were enrolled in the study, all of whom were available for post-treatment week 12 assessments. SVR12 was achieved in 92.7% (38/41), 95.2% (40/42) and 100% (41/41) of patients in Cohort A, B and C respectively. The most common adverse events were hepatic steatosis, upper respiratory tract infection, hypercholesterolaemia, hypertriglyceridaemia, blood bilirubin increased, and total bile acids increased. There were no discontinuations due to adverse events, and no treatment-related serious adverse events were reported. Once-daily oral administration of alfosbuvir plus daclatasvir were highly effective and safe in Chinese patients infected with HCV genotype 1, 2, 3 or 6, suggesting this regimen could be a promising drug candidate for HCV treatment irrespective of genotype. (ClinicalTrials.gov number, NCT04070235).
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Hepacivirus , Hepatitis C Crónica , Antivirales/efectos adversos , Carbamatos , China , Quimioterapia Combinada , Genotipo , Hepacivirus/genética , Humanos , Imidazoles , Pirrolidinas , Ribavirina/uso terapéutico , Resultado del Tratamiento , Valina/análogos & derivadosRESUMEN
Although the influence of microplastics (MPs) in different soil environments has been investigated, their effects on the physiochemical properties and chemical speciation of heavy metals in yellow-brown soil remains unknown. This study aimed to determine the effects of various concentrations of linear low-density polyethylene (LLDPE), polyamide (PA), polyurethane (PU), polystyrene (PS), and low-density polyethylene (LDPE) MPs on the yellow-brown soil environment and chemical speciation of the heavy metals cadmium (Cd), copper (Cu), lead (Pb), and zinc (Zn). MPs influenced the physicochemical properties and chemical speciation of heavy metals in yellow-brown soil. The physicochemical properties of yellow-brown soil can be altered by changing the concentrations of LDPE MP. The relationship between changes in field capacity (FC) and LDPE concentrations was approximately linear. The physiochemical properties of yellow-brown soil containing added PA, PU, and LDPE MPs were substantially improved (control vs. MPs): FC, 39 % vs. 42.50 % for PU, cation exchange capacity (CEC) 45.77, 56.65, and 57.44 cmol.kg-1 for PA, PU, and LDPE respectively, and organic matter (OM) content, 40.16 vs. 51.68 g.kg-1 for PA. The LLDPE and PU MPs also simultaneously affected the chemical speciation of heavy metals in yellow-brown soil. The LLDPE MPs increased the acid-soluble (45.17-54.67 % (Cd-F1), 7.24-11.30 % (Cu-F1), 4.20-7.23 % (Pb-F1), 21.21-31.47 % (Zn-F1)) and reducible (24.02-29.41 % (Cd-F2), 25.69-34.95 % (Cu-F2), 74.29-81.07 % (Pb-F2), 28.77-34.19 % (Zn-F2)) fractions of heavy metals, which increased their bioavailability. However, PU MPs reduced the ecological risk of heavy metals in yellow-brown soil by increasing the content of the residual fraction (26.11-40.21 % (Cd-F4), 47.63-59.67 % (Cu-F4), 17.25-26.76 % (Pb-F4), 32.63-50.46 % (Zn-F4)). Changes in the properties of yellow-brown soil and the impact of MPs on heavy metals, might change the chemical speciation of heavy metals. The impact of MPs on heavy metals in yellow-brown soil requires further investigation.
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Metales Pesados , Contaminantes del Suelo , Cadmio , Plomo , Metales Pesados/análisis , Microplásticos , Plásticos , Polietileno , Suelo/química , Contaminantes del Suelo/análisis , ZincRESUMEN
MOTIVATION: Microbiome analyses of clinical samples with low microbial biomass are challenging because of the very small quantities of microbial DNA relative to the human host, ubiquitous contaminating DNA in sequencing experiments and the large and rapidly growing microbial reference databases. RESULTS: We present computational subtraction-based microbiome discovery (CSMD), a bioinformatics pipeline specifically developed to generate accurate species-level microbiome profiles for clinical samples with low microbial loads. CSMD applies strategies for the maximal elimination of host sequences with minimal loss of microbial signal and effectively detects microorganisms present in the sample with minimal false positives using a stepwise convergent solution. CSMD was benchmarked in a comparative evaluation with other classic tools on previously published well-characterized datasets. It showed higher sensitivity and specificity in host sequence removal and higher specificity in microbial identification, which led to more accurate abundance estimation. All these features are integrated into a free and easy-to-use tool. Additionally, CSMD applied to cell-free plasma DNA showed that microbial diversity within these samples is substantially broader than previously believed. AVAILABILITY AND IMPLEMENTATION: CSMD is freely available at https://github.com/liuyu8721/csmd. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Metagenoma , Microbiota , Biología Computacional , Humanos , Metagenómica , Programas InformáticosRESUMEN
BACKGROUND AND AIM: This single-arm, open-label, multicenter, phase 3 trial evaluated the efficacy and safety of seraprevir, an hepatitis C virus (HCV) nonstructural protein 3/4A (NS3/4A) inhibitor, combined with sofosbuvir for treating Chinese patients with chronic HCV infection without cirrhosis. METHODS: Treatment-naive or interferon-experienced adult patients without cirrhosis were treated with a universal, combinational regimen of seraprevir 100 mg, twice daily and sofosbuvir 400 mg, once daily, for 12 or 24 weeks. The primary efficacy endpoint was sustained virologic response at week 12 after treatment (SVR12). RESULTS: Overall, 205 patients with genotype 1 HCV infection without cirrhosis were enrolled from 23 sites, 202 of whom completed the full treatment and post-treatment course and 3 discontinued follow-up. In total, 27 patients (13.2%) were interferon experienced. SVR12 was achieved by 201 out of 205 (98.0% [95% CI, 95.1%, 99.5%]) patients, 100.0% of patients with genotype 1a, and 98.0% of genotype 1b. In the other exploratory study, SVR 12 was achieved by 100% patients with genotype 2 (n = 21), genotype 3 (n = 7), and genotype 6 (n = 8). The majority of adverse events were mild to moderate and transient and did not require a specific medical intervention. CONCLUSIONS: The all-oral, ribavirin-free regimen of seraprevir and sofosbuvir is an effective and well-tolerated treatment option for Chinese patients mono-infected with HCV, including those with a history of interferon treatment.
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Hepatitis C Crónica , Sofosbuvir , Proteínas no Estructurales Virales , Adulto , Antivirales/efectos adversos , China/epidemiología , Quimioterapia Combinada , Genotipo , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/genética , Humanos , Cirrosis Hepática/epidemiología , Sofosbuvir/efectos adversos , Resultado del Tratamiento , Proteínas no Estructurales Virales/efectos adversos , Proteínas no Estructurales Virales/antagonistas & inhibidoresRESUMEN
Despite decades of research, mechanisms controlling T cell activation remain only partially understood, which hampers T cell-based immune cancer therapies. Here, we performed a genome-wide CRISPR screen to search for genes that regulate T cell activation. Our screen confirmed many of the known regulators in proximal T cell receptor signaling and, importantly, also uncovered a previously uncharacterized regulator, FAM49B (family with sequence similarity 49 member B). FAM49B deficiency led to hyperactivation of Jurkat T cells following T cell receptor stimulation, as indicated by enhancement of CD69 induction, PAK phosphorylation, and actin assembly. FAM49B directly interacted with the active form of the small GTPase Rac, and genetic disruption of the FAM49B-Rac interaction compromised FAM49B function. Thus, FAM49B inhibits T cell activation by repressing Rac activity and modulating cytoskeleton reorganization.
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Activación de Linfocitos , Proteínas de Neoplasias/inmunología , Linfocitos T/inmunología , Actinas/genética , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/genética , Antígenos de Diferenciación de Linfocitos T/inmunología , Sistemas CRISPR-Cas , Citoesqueleto/genética , Citoesqueleto/inmunología , Estudio de Asociación del Genoma Completo , Humanos , Células Jurkat , Lectinas Tipo C/genética , Lectinas Tipo C/inmunología , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/inmunología , Linfocitos T/citologíaRESUMEN
BACKGROUND & AIM: An affordable, pangenotypic regimen remains as an unmet medical need for chronic hepatitis C patients in China. This single-arm, open-label, multicenter, phase 3 trial evaluated the efficacy and safety of coblopasvir, a pangenotypic non-structural protein 5A (NS5A) inhibitor, combined with sofosbuvir for treating Chinese patients with chronic hepatitis C virus (HCV) infection. METHODS: Treatment-naïve and interferon-experienced adult patients, including those with advanced fibrosis (F3) or compensated cirrhosis (F4), were treated with a universal, combinational regimen of coblopasvir 60 mg and sofosbuvir 400 mg, once daily, for 12 weeks. The primary efficacy endpoint was sustained virological response at post-treatment week 12 (SVR12). RESULTS: Overall, 371 patients (men, 51%; age, 47 ± 11 years; genotype 1a < 1%, 1b 48%, 2a 26%, 3a 6%, 3b 7% and 6 12%) were enrolled from 19 sites. Fifty-one patients (14%) had F3, 39 patients (11%) had F4 and 39 patients (11%) were interferon experienced. The overall SVR12 was 97% (95% CI, [94%, 98%]) for the full analysis set and was equal to or above 90% for all predefined subsets. Ten patients (3%) experienced virological relapse and two patients did not complete follow-up. No adverse events (AEs) occurred at a frequency ≥5%, and the most often reported AEs (≥1%) were neutropenia and fatigue. The majority of AEs were mild to moderate and transient without specific medical intervention. CONCLUSIONS: The universal, pangenotypic combo of coblopasvir plus sofosbuvir is an efficacious and safe treatment for Chinese patients monoinfected with HCV of genotype 1, 2, 3 and 6, including those with compensated cirrhosis. LAY SUMMARY: The regimen of coblopasvir and sofosbuvir is a safe and effective treatment for Chinese patients with genotype 1, 2, 3 and 6 HCV infection, including those with compensated cirrhosis. Therefore, this regimen would be a novel choice of treatment for this patient population.
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Hepatitis C Crónica , Sofosbuvir , Adulto , Antivirales/efectos adversos , China , Quimioterapia Combinada , Genotipo , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Sofosbuvir/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD) share a similar phenotype but are different in their clinical manifestations, responses to treatment and prognosis. Whether PCV is a subtype of AMD or a distinct entity from nAMD remains unknown. Therefore, we performed a whole-exome sequencing based association analysis to compare the genetic architecture of PCV and nAMD in Han Chinese. METHODS: Whole-exome sequencing analysis was performed on 21 nAMD cases, 20 PCV cases and 20 healthy controls. As a follow-up validation, 145 nAMD cases, 160 PCV cases and 193 controls were genotyped using the Sequenom MassARRAY platform (Sequenom, San Diego, CA, USA). RESULTS: A novel variant, c.6196A>G in the IGFN1 gene, was significantly associated with only PCV (combined p = 7.1 × 10-11 , odds ratio = 9.44), but not with nAMD (combined p = 0.683, odds ratio = 1.30). The minor allele G conferred an increased risk of PCV. CONCLUSIONS: The findings of the present study indicate that, although some of the susceptibility loci are shared between PCV and nAMD, a unique genetic signature may decide the pathogenesis of PCV.
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Proteínas Portadoras/genética , Neovascularización Coroidal/genética , Predisposición Genética a la Enfermedad , Degeneración Macular/genética , Proteínas Adaptadoras Transductoras de Señales , Anciano , Neovascularización Coroidal/patología , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Degeneración Macular/patología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Secuenciación del ExomaAsunto(s)
Conjuntivitis Alérgica , Microbiota , Conjuntiva , Conjuntivitis Alérgica/etiología , Disbiosis , HumanosRESUMEN
OBJECTIVE: To investigate the role of P53 and high mobility group protein 1 (HMGB1) protein expression in liver fibrosis stages in chronic hepatitis B patients.â© METHODS: According to the pathological grades, 103 patients were divided into 3 groups: no fibrosis group (n=18), low fibrosis group (n=49) or high fibrosis group (n=36). Serum HMGB1 levels were determined and receiver operating characteristic (ROC) curve was made based on the HMGB1 level and liver fibrosis score. Liver fibrosis model was developed by CCl4 in 60 male SD rats, which were sacrificed 6 or 12 weeks later. The degree of fibrosis was examined by Masson staining; HMGB1 and P53 protein expression were analyzed by Western blot; histone deacetylase (HDAC) activity, TNF-α, IL-1ß and IL-6 levels in serum were measured.â© RESULTS: The serum levels of HMGB1 level in low and high fibrosis groups were significantly higher than that in no fibrosis group (P<0.01, respectively). ROC curve showed that serum HMGB1 in the diagnosis of hepatic fibrosis with cut off at 74 pg/mL, specificity at 65% and sensitivity at 87%. Compared with the control group, HMGB1 expression in both low and high fibrosis group was decreased in nucleus but was increased in cytoplasm, accompanied by the elevated P53 expression, increased HDAC activity and inflammatory cytokine levels (all P<0.01, respectively).â© CONCLUSION: P53 and HMGB1 expression was significantly increased in chronic hepatitis B patients with liver fibrosis; serum HMGB1 level was positively correlated with the degree of liver cirrhosis and HMGB1 could be used as a sensitive and specific index for liver fibrosis prognosis.
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Proteína HMGB1/metabolismo , Hepatitis B Crónica/metabolismo , Cirrosis Hepática/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Hepatitis B Crónica/patología , Humanos , Interleucina-1beta/sangre , Interleucina-6/sangre , Cirrosis Hepática/patología , Masculino , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Introducing carbon quantum dots (CQDs) into photocatalysts is believed to boost the charge transfer rate and reduce charge complexation. Doping heteroatoms such as N, S, or P enable CQDs to have an uplifting electron transfer capability. However, the application of oxygen-doped CQDs to improve the performance of photocatalysts has rarely been reported. Herein, a type of carbon-oxygen quantum dots (COQDs) was in situ embedded into MIL-53(Fe) to aid peroxydisulfate (PDS)-activated degradation of oxytetracycline (OTC) under visible light irradiation. The successful embedding of COQDs was confirmed by XRD, FT-IR, XPS, SEM, and TEM techniques. Photoelectrochemical testing confirmed its better performance. The prepared COQDs1/MIL-53(Fe) showed 88.2% decomposition efficiency of OTC in 60 min, which was 1.45 times higher than that of pure MIL-53(Fe). In addition, the performance of the material was tested at different pH, OTC concentrations, catalyst dosing, and PDS dosing. It was also subjected to cyclic testing to check stability. Moreover, free radical trapping experiments and electron paramagnetic resonance were conducted to explore the possible OTC deterioration mechanism. Our work provides a new idea for the development of MOFs for water treatment and remediation.
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Carbono , Oxígeno , Oxitetraciclina , Puntos Cuánticos , Oxitetraciclina/química , Puntos Cuánticos/química , Carbono/química , Oxígeno/química , CatálisisRESUMEN
Microplastics (MPs) have attracted much attention in recent years, due to the difficulty of degradation and threats to ecological systems and humans. Based on the analysis of 1429 articles on MPs in soil, we found that we know little about the behavior and fate of manure-born MPs from the livestock and poultry production systems to agriculture soils. This review summarizes the analytical methods for sampling, separation, and identification and the occurrence of MPs in livestock and poultry manure, mainly based on 7 surveys related to manure-born MPs. Then, the sources, fate, and environmental risks of MPs in livestock and poultry manure are discussed. MPs, heavy metals, pathogens, antibiotic resistance genes, and persistent organic pollutants are common pollutants in livestock and poultry manure. Worse, manure-born MPs will become smaller, rougher, and more numerous and could easily form more toxic compound pollution after complicated processes of manure treatment, which seriously threatens agricultural soil safety. Finally, an outlook is offered for future research. We hope this article to attract attention to the risks of MPs in livestock and poultry manure and provide a reference for future research.
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Aves de Corral , Suelo , Humanos , Animales , Microplásticos , Plásticos , Ganado , Estiércol , AgriculturaRESUMEN
INTRODUCTION: The safety and effectiveness of prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) in pathological T3-4 locally advanced (pT3N + M0 and pT4NxM0) colon cancer (CC) patients with radical resection need further study. METHODS: Clinical and pathological information of pT3-4 locally advanced CC patients who received radical surgery in our hospital from January 2018 to December 2020 were analyzed. The prognosis of patients was estimated using Cox proportional hazards regression analysis and Kaplan-Meier method. RESULTS: Among 927 patients, 10.4% (96/927) received prophylactic HIPEC based on 5-FU, 4.6% (43/927) received prophylactic HIPEC based on lobaplatin, 85.0% (788/927) received conventional therapy. The incidence of metachronous peritoneal carcinomatosis (mPC) was 9.4%. Complications occurred in 32 patients (4.1%) in the conventional therapy group, 6 patients (6.3%) in the prophylactic HIPEC group based on 5-FU and 3 patients (7.0%) in the prophylactic HIPEC group based on lobaplatin within 30 days after surgery (5-FU vs. conventional therapy group, p = 0.464; Lobaplatin vs. conventional therapy group, p = 0.591). Multivariate Cox regression analysis revealed that prophylactic HIPEC based on either 5-FU or lobaplatin regimen could not effectively improve mPC-free survival (5-FU: p = 0.020, HR = 1.927, 95% CI, 1.111-3.343; Lobaplatin: p = 0.167, HR = 0.247, 95% CI, 0.034-1.796), overall survival (5-FU: p = 0.361, HR = 1.360, 95% CI, 0.703-2.634; Lobaplatin: p = 0.780, HR = 0.816, 95% CI, 0.195-3.416) and disease-free survival (5-FU: p = 0.525, HR = 1.149, 95% CI, 0.749-1.760; Lobaplatin: p = 0.117, HR = 0.488, 95% CI, 0.199-1.198). CONCLUSION: Early prophylactic HIPEC based on 5-FU or lobaplatin subsequent to radical resection for patients with pT3-4 locally advanced CC is safe, but not effective in reducing the risk for mPC.
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BACKGROUND & AIMS: As the most abundant memory T cells and major source of tumor necrosis factor α in the intestinal mucosa of Crohn's disease (CD) patients, CD4+ tissue-resident memory T (TRM) cells play a critical role in CD pathogenesis. We investigated the role of metabolic reprogramming in the regulation of proinflammatory and apoptosis-resistant phenotype for CD4+ TRM cells. METHODS: CD4+ TRM cells were collected from intestinal resection tissues from control and CD patients. Transcriptomic and metabolomic analysis were performed to identify metabolic characteristics of CD4+ TRM cells. Enzyme-linked immunosorbent assay and quantitative polymerase chain reaction experiments were used to assess cytokines level in CD4+ TRM cells; activation-induced cell apoptosis rate was evaluated by flow cytometry. Transwell assay and wound healing assay were performed to detect the effect of CD4+ TRM cells on the migration of normal intestinal epithelial cells. RESULTS: Transcriptomic data combined with unbiased metabolomic analysis revealed an increased fatty acid oxidation (FAO) phenotype existed in CD4+ TRM cells from CD patients. The lipidomic data and stable isotope tracer experiments demonstrated that CD4+ TRM cells up-regulated their lipid lipolysis and fatty acid uptake to fuel FAO in CD patients. Mechanistically, the activated nuclear factor kappa B signaling increased transcription of genes involved in lipid lipolysis, fatty acid uptake, and oxidation in CD4+ TRM cells from CD patients. Targeting FAO of CD4+ TRM cells reversed their apoptosis-resistant and proinflammatory phenotype in CD patients. CONCLUSIONS: CD4+ TRM cells process an accelerated FAO mediated by activated nuclear factor kappa B signaling in CD patients; targeting FAO could reverse their apoptosis-resistant and proinflammatory phenotype. These findings shed a new light on the pathogenic mechanism investigation and novel therapy development in CD patients.
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Apoptosis , Linfocitos T CD4-Positivos , Enfermedad de Crohn , Ácidos Grasos , Células T de Memoria , Oxidación-Reducción , Fenotipo , Humanos , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/patología , Enfermedad de Crohn/metabolismo , Ácidos Grasos/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Células T de Memoria/inmunología , Células T de Memoria/metabolismo , Adulto , Masculino , Femenino , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , FN-kappa B/metabolismo , Estudios de Casos y Controles , Memoria Inmunológica , Inflamación/patología , Inflamación/inmunología , Inflamación/metabolismo , Transducción de SeñalRESUMEN
The low oil recovery rate observed in current oil fields is largely attributed to the presence of remaining oil trapped in the pores of porous media during waterflooding. To improve the recovery rate, it is imperative to gain an understanding of the oil-water flow characteristics and displacement mechanisms during waterflooding, as well as to elucidate the underlying mobilization mechanisms of residual oil at the pore scale. In this paper, we explore these issues in depth by numerically investigating the influence of factors such as water injection velocities, oil-water viscosity ratios, and wettability conditions on pore-scale oil-water flow characteristics and oil recovery rate. To this end, we employ a direct numerical simulation (DNS) method in conjunction with the volume of fluid (VOF) method to study the microscopic displacement mechanisms of waterflooding in a reconstructed two-dimensional digital rock core based on micro-CT technology. In addition, the particle tracing method is adopted to identify the flow path and dominant areas during waterflooding in order to mobilize the residual oil within the pores. The findings indicate that the oil-water flow characteristics in porous media are determined by the interplay between capillary and viscous forces. Furthermore, the oil recovery rate is 10.6% and 24.7% lower under strong water-wet and oil-wet conditions than that (32.36%) under intermediate wettability conditions, and the final oil recovery rate is higher under water-wet conditions than under oil-wet conditions. The seepage path and the dominant areas are directly linked to the capillarity formed during waterflooding. The findings of this study are significant in terms of enhancing the recovery rate of residual oil and provide a novel perspective for understanding the waterflooding process.
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Wastewater treatment plants (WWTPs) are an important source of microplastics (MPs) entering the aquatic environment. As environmental awareness increases, WWTPs are gradually using constructed wetlands (CWs) in the depth treatment stage. There were few studies related to MPs removal efficiency of CWs, especially in multi-stage and multi-combinations CWs. Therefore, we studied MPs characteristics and removal in a typical CWs WWTP in Changsha, comparing the MPs removal efficiencies of different processes in a WWTP, focusing on the MPs abundance variation in different stages CWs. Result showed that the MPs removal efficiency of Phase â was 87.72% and that of Phase II was 80.65%. Approximate estimates showed that the daily discharge of MPs reached 7.20 * 108 items. The MPs removal efficiency of vertical flow CWs was 25.71%. The MPs removal efficiencies of secondary and tertiary horizontal subsurface flow CWs (HSSFCWs) were 32.00% and 21.43%. The MPs removal efficiencies of secondary and tertiary surface flow CWs were 23.53% and 12.50%. The MPs removal efficiencies of three bio-ponds were -23.08%, -12.90%, and -27.27%. Combined system of bio-pond + CWs reduced the MPs removal efficiency. The most dominant shape of MPs in wastewater was fibers. The most common MPs were polyethylene and polystyrene. The primary treatment in the Changsha WWTP had the highest MPs removal efficiency. Results of this investigation showed the multi-combination and multi-stage CWs WWTP can remove most of MPs in influent, which greatly reduced the amount of MPs discharged into the aquatic environment through WWTP and provided data for analyzing the distribution of MPs in the aquatic environment.
Asunto(s)
Contaminantes Químicos del Agua , Purificación del Agua , Microplásticos , Humedales , Plásticos , Eliminación de Residuos Líquidos/métodos , Contaminantes Químicos del Agua/análisis , Aguas Residuales/análisisRESUMEN
DNA doublestrand break repair is critically involved in oxaliplatin resistance in pancreatic ductal adenocarcinoma (PDAC). Hepatocyte nuclear factor 1 homeobox A (HNF1A) has received increased attention regarding its role in cancer progression. The present study explored the role of HNF1A in oxaliplatin resistance in PDAC. The results revealed that HNF1A expression was negatively associated with oxaliplatin chemoresistance in PDAC tissues and cell lines. HNF1A inhibition promoted the proliferation, colony formation and stemness of PDAC cells, and suppressed their apoptosis. Furthermore, HNF1A inhibition switched nonhomologous end joining to homologous recombination, thereby enhancing genomic stability and oxaliplatin resistance. Mechanistically, HNF1A transcriptionally activates p53binding protein 1 (53BP1) expression by directly interacting with the 53BP1 promoter region. Upregulation of HNF1A and 53BP1 induced significant inhibition of PDAC growth and oxaliplatin resistance in patientderived PDAC xenograft models and orthotopic models. In conclusion, the findings of the present study suggested that HNF1A/53BP1 may be a promising PDAC therapeutic target for overcoming oxaliplatin resistance.