RESUMO

Background: Metabolic dysfunction-associated fatty liver disease has been linked to negative outcomes in patients with end-stage liver disease following liver transplantation. However, the influence of immunosuppressive regimens on it has not been explored. Methods: A retrospective analysis was conducted using the preoperative and postoperative data from patients with end-stage liver disease. The study compared three different groups: tacrolimus-based group, sirolimus-based group, and combined tacrolimus- and sirolimus-based regimens. Binary logistic regression analysis was employed to identify risk factors for metabolic dysfunction-associated fatty liver disease. Results: A total of 171 patients participated in the study, consisting of 127 males and 44 females, with a mean age of 49.6 years. The prevalence of posttransplant metabolic dysfunction-associated fatty liver disease was 29.23%. Among the three groups, there were 111 liver transplant recipients in the tacrolimus-based group, 28 in the sirolimus-based group, and 32 in the combination group. A statistically significant difference was observed in the incidence of metabolic dysfunction-associated fatty liver disease (P < 0.05), whereas the other preoperative and postoperative parameters showed no significant differences. Multivariate analysis revealed that a low-calorie diet (95% confidence intervals: 0.15-0.90, P = 0.021) and a combination of tacrolimus- and sirolimus-based immunosuppressive regimen (95% confidence intervals: 1.01-2.77, P = 0.046) were associated with lower risk of posttransplant metabolic dysfunction-associated fatty liver disease. Conclusions: Our study indicates that implementing a low-calorie diet and utilizing a combination of tacrolimus- and sirolimus-based immunosuppressive regimen can effectively lower the risk of posttransplant metabolic dysfunction-associated fatty liver disease following liver transplantation.

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ETHNOPHARMACOLOGICAL RELEVANCE: Shuangdan Jiedu Decoction (SJD) is a formula composed of six Chinese herbs with heat-removing and detoxifying, antibacterial, and anti-inflammatory effects, which is clinically used in the therapy of various inflammatory diseases of the lungs including COVID-19, but the therapeutic material basis of its action as well as its molecular mechanism are still unclear. AIM OF THE STUDY: The study attempted to determine the therapeutic effect of SJD on LPS-induced acute lung injury (ALI), as well as to investigate its mechanism of action and assess its therapeutic potential for the cure of inflammation-related diseases in the clinical setting. MATERIALS AND METHODS: We established an ALI model by tracheal drip LPS, and after the administration of SJD, we collected the bronchoalveolar lavage fluid (BALF) and lung tissues of mice and examined the expression of inflammatory factors in them. In addition, we evaluated the effects of SJD on the cyclic guanosine monophosphate-adenosine monophosphate synthase -stimulator of interferon genes (cGAS-STING) and inflammasome by immunoblotting and real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: We demonstrated that SJD was effective in alleviating LPS-induced ALI by suppressing the levels of pro-inflammatory cytokines in the BALF, improving the level of lung histopathology and the number of neutrophils, as well as decreasing the inflammatory factor-associated gene expression. Importantly, we found that SJD could inhibit multiple stimulus-driven activation of cGAS-STING and inflammasome. Further studies showed that the Chinese herbal medicines in SJD had no influence on the cGAS-STING pathway and inflammasome alone at the formulated dose. By increasing the concentration of these herbs, we observed inhibitory effects on the cGAS-STING pathway and inflammasome, and the effect exerted was maximal when the six herbs were combined, indicating that the synergistic effects among these herbs plays a crucial role in the anti-inflammatory effects of SJD. CONCLUSIONS: Our research demonstrated that SJD has a favorable protective effect against ALI, and its mechanism of effect may be associated with the synergistic effect exerted between six Chinese medicines to inhibit the cGAS-STING and inflammasome abnormal activation. These results are favorable for the wide application of SJD in the clinic as well as for the development of drugs for ALI from herbal formulas.

Assuntos

Lesão Pulmonar Aguda , Medicamentos de Ervas Chinesas , Inflamassomos , Lipopolissacarídeos , Proteínas de Membrana , Nucleotidiltransferases , Transdução de Sinais , Animais , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lipopolissacarídeos/toxicidade , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Nucleotidiltransferases/metabolismo , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Camundongos , Masculino , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Modelos Animais de Doenças , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Líquido da Lavagem Broncoalveolar/citologia

RESUMO

Size-fractionated particulate matter (PM2.5 and PM>2.5) was collected at a traffic site in Kanazawa, Japan in a seasonal sampling work in 2020. Nine polycyclic aromatic hydrocarbons (4- to 6-ring PAHs) were determined in fine and coarse particles. The gas/particle partitioning coefficients (Kp) of the PAHs were calculated from the supercooled liquid vapour pressure and octanol-air partitioning coefficient based on the relationships obtained in previous traffic pollution-related studies. Gaseous PAHs were estimated by Kp and the concentrations of PM and particulate PAHs. The concentrations of total PAHs were 32.5, 320.1 and 5646.2 pg/m3 in the PM>2.5, PM2.5 and gas phases, respectively. Significant seasonal trends in PAHs were observed (particle phase: lowest in summer, gas phase: lowest in spring, particle and gas phase: lowest in spring). Compared to 2019, the total PAH concentrations (in particles) decreased in 2020, especially in spring and summer, which might be due to reduced traffic trips during the COVID-19 outbreak. The incremental lifetime cancer risk (ILCR) calculated from the toxic equivalent concentrations relative to benzo[a]pyrene (BaPeq) was lower than the acceptable limit issued by the US Environmental Protection Agency, indicating a low cancer risk in long-term exposure to current PAH levels. It is notable that gaseous PAHs considerably contributed to BaPeq and ILCR (over 50%), which highlighted the significance of gaseous PAH monitoring for public health protection. This low-cost estimation method for gaseous PAHs can be expected to reliably and conveniently obtain PAH concentrations as a surrogate for traditional sampling in the future work.

Assuntos

Poluentes Atmosféricos , Monitoramento Ambiental , Material Particulado , Hidrocarbonetos Policíclicos Aromáticos , Hidrocarbonetos Policíclicos Aromáticos/análise , Japão , Poluentes Atmosféricos/análise , Monitoramento Ambiental/métodos , Material Particulado/análise , Emissões de Veículos/análise , Estações do Ano

RESUMO

In this study, the effects of different salinity gradients and addition of compatible solutes on anaerobic treated effluent water qualities, sludge characteristics and microbial communities were investigated. The increase in salinity resulted in a decrease in particle size of the granular sludge, which was concentrated in the range of 0.5-1.0 mm. The content of EPS (extracellular polymeric substances) in the granular sludge gradually increased with increasing salinity and the addition of betaine (a typical compatible solute). Meanwhile, the microbial community structure was significantly affected by salinity, with high salinity reducing the diversity of bacteria. At higher salinity, Patescibacteria and Proteobacteria gradually became the dominant phylum, with relative abundance increasing to 13.53% and 12.16% at 20 g/L salinity. Desulfobacterota and its subordinate Desulfovibrio, which secrete EPS in large quantities, dominated significantly after betaine addition.Their relative abundance reached 13.65% and 7.86% at phylum level and genus level. The effect of these changes on the treated effluent was shown as the average chemical oxygen demand (COD) removal rate decreased from 82.10% to 79.71%, 78.01%, 68.51% and 64.55% when the salinity gradually increased from 2 g/L to 6, 10, 16 and 20 g/L. At the salinity of 20 g/L, average COD removal increased to 71.65% by the addition of 2 mmol/L betaine. The gradient elevated salinity and the exogenous addition of betaine played an important role in achieving stability of the anaerobic system in a highly saline environment, which provided a feasible strategy for anaerobic treatment of organic saline wastewater.

Assuntos

Betaína , Salinidade , Esgotos , Eliminação de Resíduos Líquidos , Águas Residuárias , Betaína/metabolismo , Esgotos/microbiologia , Eliminação de Resíduos Líquidos/métodos , Águas Residuárias/química , Anaerobiose , Microbiota/efeitos dos fármacos , Bactérias/metabolismo , Bactérias/efeitos dos fármacos

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease of unknown etiology. Despite the increasing global incidence and poor prognosis, the exact pathogenic mechanisms remain elusive. Currently, effective therapeutic targets and treatment methods for this disease are still lacking. This study tried to explore the pathogenic mechanisms of IPF. We found elevated expression of SULF1 in lung tissues of IPF patients compared to normal control lung tissues. SULF1 is an enzyme that modifies heparan sulfate chains of heparan sulfate proteoglycans, playing a critical role in biological regulation. However, the effect of SULF1 in pulmonary fibrosis remains incompletely understood. Our study aimed to investigate the impact and mechanisms of SULF1 in fibrosis. METHODS: We collected lung specimens from IPF patients for transcriptome sequencing. Validation of SULF1 expression in IPF patients was performed using Western blotting and RT-qPCR on lung tissues. ELISA experiments were employed to detect SULF1 concentrations in IPF patient plasma and TGF-ß1 levels in cell culture supernatants. We used lentiviral delivery of SULF1 shRNA to knock down SULF1 in HFL1 cells, evaluating its effects on fibroblast secretion, activation, proliferation, migration, and invasion capabilities. Furthermore, we employed Co-Immunoprecipitation (Co-IP) to investigate the regulatory mechanisms involved. RESULTS: Through bioinformatic analysis of IPF transcriptomic sequencing data (HTIPF) and datasets GSE24206, and GSE53845, we identified SULF1 may potentially play a crucial role in IPF. Subsequently, we verified that SULF1 was upregulated in IPF and predominantly increased in fibroblasts. Furthermore, SULF1 expression was induced in HFL1 cells following exposure to TGF-ß1. Knockdown of SULF1 suppressed fibroblast secretion, activation, proliferation, migration, and invasion under both TGF-ß1-driven and non-TGF-ß1-driven conditions. We found that SULF1 catalyzes the release of TGF-ß1 bound to TGFßRIII, thereby activating the TGF-ß1/SMAD pathway to promote fibrosis. Additionally, TGF-ß1 induces SULF1 expression through the TGF-ß1/SMAD pathway, suggesting a potential positive feedback loop between SULF1 and the TGF-ß1/SMAD pathway. CONCLUSIONS: Our findings reveal that SULF1 promotes fibrosis through the TGF-ß1/SMAD pathway in pulmonary fibrosis. Targeting SULF1 may offer a promising therapeutic strategy against IPF.

Assuntos

Fibrose Pulmonar Idiopática , Transdução de Sinais , Proteínas Smad , Sulfotransferases , Fator de Crescimento Transformador beta1 , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/genética , Fator de Crescimento Transformador beta1/metabolismo , Sulfotransferases/metabolismo , Sulfotransferases/genética , Proteínas Smad/metabolismo , Pulmão/patologia , Pulmão/metabolismo , Masculino , Proliferação de Células , Feminino , Movimento Celular , Fibroblastos/metabolismo , Fibroblastos/patologia , Pessoa de Meia-Idade , Linhagem Celular

RESUMO

Background: Acute Coronary Syndrome (ACS) continues to be a leading cause of death and illness worldwide. Differentiating stable from unstable coronary plaques is essential for enhancing patient outcomes. This research investigates the role of CD147 as a biomarker for plaque stability among coronary artery disease patients. Methods: The study began with high-throughput sequencing of blood samples from six patients, divided equally between those with Stable Angina (SA) and Unstable Angina (UA), followed by bioinformatics analysis. Expanding upon these findings, the study included 31 SA patients and 30 patients with ACS, using flow cytometry to examine CD147 expression on platelets and monocytes. Additionally, logistic regression was utilized to integrate traditional risk factors and evaluate the predictive value of CD147 expression for plaque stability. Results: Initial sequencing displayed a notable difference in CD147 expression between SA and UA groups, with a significant increase in UA patients. Further analysis confirmed that elevated platelet CD147 expression was strongly associated with unstable plaques (OR = 277.81, P < .001), after adjusting for conventional risk factors, whereas monocyte CD147 levels did not show a significant difference. Conclusion: Elevated CD147 expression on platelets is a crucial biomarker for identifying unstable coronary artery plaques, offering insights into patient risk stratification and the development of targeted treatment strategies. This underscores the pivotal role of molecular research in understanding and managing coronary artery disease, paving the way for improved clinical outcomes.

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Cottonseed meal and rapeseed meal exhibit a potential for fishmeal substitute in grass carp feed, while their excessive use contribute to growth decline and weakening immunity of aquatic animals. Clostridium butyricum metabolites (CBM) was recognized as a functional additive due to its antioxidant properties and maintenance of intestinal microbiota balance. CBM was added to a high of cottonseed and rapeseed meal diet to determine its effects on growth, immunity, and intestinal microbiota alterations of grass carp (Ctenopharyngodon idella) over 56 days. Eight hundred grass carp (mean weight, around 50 g) were randomized to five treatments and fed with the basic diet (CON), CBM0 diet (28% cottonseed and 27% rapeseed meal), and CBM diets (CBM0.5, CBM1, and CBM2, namely CBM0 diet supplemented with 500, 1000, and 2000 mg·kg-1 CBM). The results indicated that compared to CBM0, The ingestion of 1000 mg kg-1 CBM diet by grass carp significantly promoted growth as measured by intestinal lipase activity, villus height, and muscle thickness. Moreover, accompanied by a decrease in intestine MDA content, and enhance antioxidant capacity by activating Keap1/Nrf2 signaling pathway to increase enzyme activities (SOD, CAT and T-AOC) and corresponding gene expression (mnsod, cat, gsto and gpx1) in the intestine of grass crap fed CBM1 diet. The dietary CBM1 diet increased serum levels of C3 and IgM, increased ACP activity and expression of the corresponding anti-inflammatory factors (tgf-ß1 and il-15), and suppressed the expression of pro-inflammatory factors (tnf-α and il-12ß), resulting in enhanced immunity. The dietary CBM1 diet up-regulates gene expression of tight junction proteins (zo-1, occludin, occludin7a and occludin-c), coupled with the decreases in DAO and D-lactate contents, implying that the decreased mucosal permeability could be observed in the gut. The dietary CBM1 diet largely altered the intestinal microbial community, especially reducing the relative abundance of intestinal pathogenic bacteria (Streptococcus and Actinomyces). And it significantly increased the content of short-chain fatty acids (acetic acid, butyric acid, isobutyric acid, propionic acid and isovaleric acid). Taken above, dietary CBM supplementation improved growth in grass carp and attenuated the intestinal oxidative stress, inflammation and microflora dysbacteriosis caused by high proportions of cottonseed and rapeseed meal diets.

RESUMO

Thermokarst landslide (TL) activity in the Qinghai-Tibet Plateau (QTP) is intensifying due to climate warming-induced permafrost degradation. However, the mechanisms driving landslide formation and evolution remain poorly understood. This study investigates the spatial distribution, annual frequency, and monthly dynamics of TLs along the Qinghai-Tibet engineering corridor (QTEC), in conjunction with in-situ temperature and rainfall observations, to elucidate the interplay between warming, permafrost degradation, and landslide activity. Through the analysis of high-resolution satellite imagery and field surveys, we identified 1298 landslides along the QTEC between 2016 and 2022, with an additional 386 landslides recorded in a typical landslide-prone sub-area. In 2016, 621 new active-layer detachments (ALDs) were identified, 1.3 times the total historical record. This surge aligned with unprecedented mean annual and August temperatures. The ALDs emerged primarily between late August and early September, coinciding with maximum thaw depth. From 2016 to 2022, 97.8 % of these ALDs evolved into retrogressive thaw slumps (RTSs), identified as active landslides. Landslides typically occur in alpine meadows at moderate altitudes and on gentle northward slopes. The thick ice layer near the permafrost table serves as the material basis for ALD occurrence. Abnormally high temperature significantly increased the active layer thickness (ALT), resulting in melting of the ice layer and formation of a thawed interlayer, which was the direct causing factor for ALD. By altering the local material, micro-topography, and thermal conditions, ALD activity significantly increases RTS susceptibility. Understanding the mechanisms of ALD formation and evolution into RTS provides a theoretical foundation for infrastructure development and disaster mitigation in extreme environments.

RESUMO

The study is to evaluate the effects of collagen/hyaluronic acid coating with or without puerarin and exosomes (Exos) derived from adipose stem cells (ADSCs-Exos) on pre-osteoblast proliferation and differentiation on the surface of titanium materials. Titanium materials with different coatings were prepared by layer-by-layer technique, evaluating the surface characterization. Cell functions were assessed by cell biology experiments. Related genes and proteins were assessed by RT-qPCR and Western blot. Puerarin or ADSCs-Exos coating had better effects on promoting the adhesion, proliferation and differentiation of pre-osteoblasts, and the strongest effect was found after their co-coatings, manifesting as the up-regulations of alkaline phosphatase (ALP) activity, collagen type I alpha 1 (Col1a1), runt-related transcription factor 2 (Runx2), osterix and activating transcription factor-2 (ATF-2). Levels of phosphorylated-P38 (p-P38) and p-ATF-2 were up-regulated in pre-osteoblasts grown on puerarin and ADSCs-Exos-loaded titanium surfaces. Titanium surfaces loaded with puerarin and ADSCs-Exos promotes the proliferation and differentiation of pre-osteoblasts.

RESUMO

BACKGROUND: Patients with non-alcoholic fatty liver disease (NAFLD) often exhibit hepatic steatosis and dyslipidemia. Studies have shown that intestinal microorganisms are closely related to the occurrence of NAFLD and atherosclerosis. Our previous study has underscored the protective role of microRNA-30a-5p (miR-30a-5p) against atherosclerosis. METHODS AND RESULTS: In the present study, we aimed to elucidate the effect and underlying mechanism of the intestinal microorganisms of miR-30a-5p knockout (KO) mice on NAFLD. Our findings demonstrated that KO exacerbated high-fat diet (HFD)-induced hepatic steatosis and disrupted liver function, as evidenced by elevated levels of total cholesterol, low-density lipoprotein, alanine aminotransferase, aspartate transaminase, and total bile acids in serum. Fecal microbiota from HFD-fed KO mice induced hepatic steatosis, dyslipidemia, and higher levels of enzymes indicative of liver damage in wild-type mice. Remarkably, KO mice significantly intensified the above effects. 16s rDNA sequencing and metabolomics of the intestinal microbiota in the HFD-treated KO and WT mice showed that the loss of miR-30a-5p resulted in intestinal microbiota imbalance and was highly related to the arachidonic acid metabolic pathway. Targeted metabolomic in the liver tissues unveiled upregulation of COX-related (PGF2a, 8-iso-PGF2a and PGF2) and LOX-related (LTB4, LTD4, 12S-HETE and 15S-HETE) factors in HFD-treated KO mice. Immunohistochemistry and transcriptional analyses showed that miR-30a-5p affected arachidonic acid metabolism through the LOX/COX pathways. Besides, COX/LOX pathways and hepatic steatosis were reversed after reintroducing miR-30a-5p in HFD-treated KO mice. CONCLUSIONS: This study reveals the pivotal mechanism by which miR-30a-5p and intestinal microbes regulate hepatic steatosis and abnormal lipid metabolism, offering promising avenues for NAFLD and atherosclerosis therapeutics. HIGHLIGHTS: MiR-30a-5p deletion aggravated hepatic steatosis and lipid disorder induced by an HFD in mice. Gut microbiota participated in the regulation of hepatic steatosis in the context of miR-30a-5p. Gut microbiota metabolism-related arachidonic acid metabolic pathway contributed to miR-30a-5p-regulated hepatic steatosis and lipid disorder. Reintroducing miR-30a-5p reversed hepatic steatosis and arachidonic acid metabolism disorder caused by HFD and miR-30a-5p deletion.

Assuntos

Ácido Araquidônico , Dieta Hiperlipídica , Microbioma Gastrointestinal , Camundongos Knockout , MicroRNAs , Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ácido Araquidônico/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/microbiologia , Masculino , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL

RESUMO

Acute lung injury (ALI) is a lung disease characterized by an excessive inflammatory response and damage to lung epithelial cells. Atractylodin (ATL) has good anti-inflammatory activity and protects the integrity of the epithelial cell barrier. However, the efficacy of ATL in the treatment of ALI and its mechanism is unclear. We investigated the efficacy of ATL in treating ALI and explored its targets and mechanisms. The results showed that ATL significantly reduced the wet-dry ratio of lungs of rats with ALI, improved the pathological changes, and lowered the expression of the inflammatory factors. Combined metabolomic and transcriptomic analyses showed that ATL can reduce inflammation by inhibiting and activating the HIF-1 signaling pathway and modulating ASAH3L to improve galactose metabolism, thereby alleviating ALI. In conclusion, ATL may be a potential drug for the treatment of acute lung injury.

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This study aims to understand the repercussions of the COVID-19 pandemic on hospitalized patients with peripheral arterial disease (PAD) in China, who did not contract SARS-CoV-2. We conducted a multicenter cross-sectional analysis comparing the characteristics and outcomes of hospitalized PAD patients across two distinct periods: Pre-pandemic (P1, from January 2018 to December 2019) and during the pandemic (P2, from January 2020 to December 2021). During P1, 762 hospitalized patients were treated, with an average age of 72.3 years, while 478 patients were treated in P2, with an average age of 65.1 years. Notably, hospitalized patients admitted during the pandemic (P2) exhibited a significantly higher incidence of chronic limb-threatening ischemia (CLTI, 70% vs 54%), diabetic foot infection (47% vs 29%), and infra-popliteal lesions (28% vs 22%). Furthermore, these patients demonstrated a marked deterioration in their Rutherford category and an increased mean score in the Wound, Ischemia, and foot Infection classification system (WIfI). Treatment during the pandemic emerged as a predictor of reduced procedural success and increased major adverse limb events. Factors such as the presence of diabetic foot infection, renal impairment, and deteriorating WIfI scores were identified as independent risk indicators for major adverse limb events. Our results demonstrate that intensive care was provided to severe cases of PAD even during the challenging circumstances of the COVID-19 pandemic. Despite the unprecedented pressures on healthcare systems, patients with severe PAD, particularly those with CLTI, continued to receive necessary in-patient care. The findings underscore the importance of timely medical interventions and extended follow-up for patients exhibiting high-risk factors.

Assuntos

COVID-19 , Doença Arterial Periférica , Humanos , COVID-19/epidemiologia , COVID-19/complicações , Idoso , Doença Arterial Periférica/epidemiologia , Estudos Transversais , Feminino , Masculino , China/epidemiologia , Pessoa de Meia-Idade , SARS-CoV-2/isolamento & purificação , Pé Diabético/epidemiologia , Hospitalização , Pandemias , Fatores de Risco , Idoso de 80 Anos ou mais

RESUMO

Small-cell lung cancer (SCLC) transformation accounts for 3-14% of resistance in EGFR-TKI relapsed lung adenocarcinomas (LUADs), with unknown molecular mechanisms and optimal treatment strategies. We performed transcriptomic analyses (including bulk and spatial transcriptomics) and multiplex immunofluorescence on pre-treated samples from LUADs without transformation after EGFR-TKI treatment (LUAD-NT), primary SCLCs (SCLC-P) and LUADs with transformation after EGFR-TKI treatment (before transformation: LUAD-BT; after transformation: SCLC-AT). Our study found that LUAD-BT exhibited potential transcriptomic characteristics for transformation compared with LUAD-NT. We identified several pathways that shifted during transformation, and the transformation might be promoted by epigenetic alterations (such as HDAC10, HDAC1, DNMT3A) within the tumor cells instead of within the tumor microenvironment. For druggable pathways, transformed-SCLC were proved to be less dependent on EGF signaling but more relied on FGF signaling, while VEGF-VEGFR pathway remained active, indicating potential treatments after transformation. We also found transformed-SCLC showed an immuno-exhausted status which was associated with the duration of EGFR-TKI before transformation. Besides, SCLC-AT exhibited distinct molecular subtypes from SCLC-P. Moreover, we constructed an ideal 4-marker model based on transcriptomic and IHC data to predict SCLC transformation, which obtained a sensitivity of 100% and 87.5%, a specificity of 95.7% and 100% in the training and test cohorts, respectively. We provided insights into the molecular mechanisms of SCLC transformation and the differences between SCLC-AT and SCLC-P, which might shed light on prevention strategies and subsequent therapeutic strategies for SCLC transformation in the future.

Assuntos

Adenocarcinoma de Pulmão , Transformação Celular Neoplásica , Receptores ErbB , Neoplasias Pulmonares , Humanos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Transformação Celular Neoplásica/genética , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Mutação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Feminino , Masculino , Inibidores de Proteínas Quinases/farmacologia

RESUMO

BACKGROUND: Circulating cytokine levels not only correlate with the progression of liver disease but also serve as indicators for the infection status of the body. Growing evidence points to the connection between donor cytokines and graft function following transplantation. This study set out to explore the clinical significance of donor cytokines in predicting liver transplantation prognosis. METHODS: Data from 172 deceased donor liver transplantations conducted between 2017 and 2022, with available donor serum cytokine information, were collected. The subjects were randomly divided into estimation (n = 120) and validation (n = 52) groups to establish and validate the model. The newly developed SA10 score was compared against established models EAD, MEAF, L-GrAFT7, and L-GrAFT10. RESULTS: Donor IL-10, along with donor age and recipient AST peak value within the first 7 days post-operation, was identified as an independent factor associated with recipient survival and was incorporated into the SA10 score. SA10 exhibited robust predictive capability, particularly for 1-month survival (AUC = 0.90, 95% CI = 0.84-0.96), outperforming EAD (AUC = 0.75, 95% CI = 0.60-0.90, p = 0.04) and L-GrAFT7 (AUC = 0.65, 95% CI = 0.49-0.81, p < 0.01). Comparable performance was observed between SA10, MEAF, and L-GrAFT10. CONCLUSION: Donor IL-10 independently influences recipient survival, with the SA10 score demonstrating comparable and even superior predictive ability compared to existing models.

Assuntos

Transplante de Fígado , Doadores de Tecidos , Humanos , Transplante de Fígado/mortalidade , Transplante de Fígado/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Doadores de Tecidos/estatística & dados numéricos , Interleucina-10/sangue , Sobrevivência de Enxerto , Prognóstico , Citocinas/sangue , Transplantados/estatística & dados numéricos

RESUMO

Background: Earlier research has demonstrated a genetic basis for the susceptibility to ankylosing spondylitis (AS) and the severity of AS. By employing a genome-wide association study, recent work has established a correlation between the susceptibility to AS and the ANO6, HAPLN, and EDIL3 genes in a Western study population-though alternative studies have not corroborated these findings. This study aims to examine the effects of ANO6, HAPLN1, and EDIL3 polymorphisms on the susceptibility and severity of AS among the predominantly Chinese Han population. Methods: The study involved the collection of blood samples from 497 patients with AS and 498 nonrelated healthy individuals. All participants in the study were human leukocyte antigen (HLA) HLA-B27 positive and of Han Chinese descent. Illness severity was the criteria used for classifying patients with AS. Thirteen tagSNPs in ANO6, HAPLN1, and EDIL3 were chosen and then subjected to genetic typing. Analysis was conducted on the occurrence rates of various genotypes and alleles between the control group and patients with varying AS severity. Results: Following Bonferroni correction, it was found that the rs4768085 and rs17095830 single nucleotide polymorphism (SNPs) in ANO6 were related to the susceptibility to AS. Further, the rs6869296 SNP in HAPLN1 and the rs2301071 SNP between EDIL3 and HAPLN1 were also related to AS susceptibility. Regarding AS severity, the rs4768085, rs2897868, rs7965430, and rs11182965 SNPs in ANO6 were found to be associated. Conclusions: Among the Han population in China, the ANO6 and HAPLN1 genes are related to the susceptibility to AS; the ANO6 gene is also associated with the severity of AS.

RESUMO

BACKGROUND: To investigate the efficiency of a new method for the prevention of argentinian flag sign during the process of continuous, circular, and centered anterior capsulotomy (CCC) on the anterior capsule in cortically liquefied intumescent cataracts. This study was registered in an appropriate registry and the registration number of registration was xyy11[2022]-XJSFX-087; The date of of registration was 2022-04-29. METHODS: Preoperative examinations including slit-lamp examination, ocular A-scan ultrasonography, and Ultrasound Biomicroscopy (UBM) UBM were conducted on 61 patients with intumescent cataracts. Cases with cortically liquefied intumescent cataracts were selected and after staining with indocyanine green, the anterior chamber air bubble technique was used to compress the anterior capsule, and liquefied cortex was aspirated using a puncture needle. Corrected Distance Visual Acuity (CDVA) and intraocular pressure were recorded on postoperative days 1, 1 week, 1 month, and 6 months. Intraoperative and postoperative complications were documented and analyzed. RESULTS: Fifty eyes were identified as having cortically liquefied intumescent cataracts. No cases of the Argentinian flag sign occurred, and standard capsulorrhexis was achieved, facilitating smooth phacoemulsification. All patients achieved satisfactory outcomes at follow-ups of 1 day, 1 week, 1 month, and 6 months postoperatively. Mild corneal edema was observed in three cases on the first postoperative day, with no other complications noted. CONCLUSIONS: The anterior chamber air bubble technique combined with cortical fluid release technique can prevent the occurrence of the Argentinian flag sign in cortically liquefied intumescent cataracts, this method is simple, convenient and economic for the clinical promotion.

Assuntos

Câmara Anterior , Catarata , Facoemulsificação , Acuidade Visual , Humanos , Feminino , Masculino , Câmara Anterior/diagnóstico por imagem , Idoso , Pessoa de Meia-Idade , Acuidade Visual/fisiologia , Facoemulsificação/métodos , Microscopia Acústica , Ar , Capsulorrexe/métodos , Complicações Pós-Operatórias/prevenção & controle , Adulto , Idoso de 80 Anos ou mais , Cápsula do Cristalino/cirurgia , Cápsula do Cristalino/diagnóstico por imagem

RESUMO

Background: Nirmatrelvir-ritonavir (Paxlovid) has received emergency use authorization from the US Food and Drug Administration owing to its effectiveness and safety. However, data on the effectiveness and safety of Paxlovid use in COVID-19 patients with onset of more than 5 days are lacking. Methods: A real-world retrospective study was performed during the outbreak involving the SARS-CoV-2 BA.5.2 subvariant. Hospitalized COVID-19 patients (including mild, moderate, severe and critical cases) were divided into three groups: Paxlovid treatment within (Group A) or more than (Group B) 5 days of COVID-19 onset and no Paxlovid treatment during more than 5 days of COVID-19 onset with only basic symptomatic treatment (Group C). Endpoints were all-cause 28-day mortality, improvement in clinical classification, and a composite endpoint of disease progression, viral load and virus elimination time. Safety was assessed by comparing adverse events reported during treatment in each group. Results: During the period, 248 hospitalized COVID-19 patients, including 55 in Group A, 170 in Group B, and 23 in Group C, were enrolled. There were no significant differences in the clinical classification improvement rate [80.0% (16/20) vs. 81.3% (52/64), p = 1.000; 60.0% (21/35) vs. 55.7% (59/106), p = 0.653, respectively] or all-cause 28-day mortality [0% (0/20) vs. 1.6% (1/64), p = 1.000; 11.4% (4/35) vs. 6.6% (7/106), p = 0.576, respectively] between Groups A and B for nonsevere and severe cases. However, the clinical classification improvement rate in Group B was markedly higher than that in Group C [81.3% (52/64) vs. 50.0% (6/12), p = 0.049] among nonsevere cases. Cycle threshold values of the N and ORF genes in Group B were significantly increased after Paxlovid treatment [31.14 (IQR 26.81-33.93) vs. 38.14 (IQR 36.92-40.00), p < 0.001; 31.33 (IQR 26.00-33.47) vs. 38.62 (IQR 35.62-40.00), p < 0.001, respectively]. No significant differences in reported adverse events of neurological disease (p = 0.571), liver injury (p = 0.960) or kidney injury (p = 0.193) between Group A and Group B were found. Conclusion: Paxlovid treatment within 10 days of onset can shorten the disease course of COVID-19 by reducing the viral load. Paxlovid is effective and safe in treating COVID-19 with onset of more than five or even 10 days when patients have a high viral load.

RESUMO

OBJECTIVE: The purpose of this retrospective study was to establish a combined model based on ultrasound (US)-radiomics and clinical factors to predict preoperative lymph node metastasis (LNM) in cervical cancer (CC) patients non-invasively. METHODS: A total of 131 CC patients who had cervical lesions found by transvaginal sonography (TVS) from the First Affiliated Hospital of Anhui Medical University (Hefei, China) were retrospectively analyzed. The clinical independent predictors were selected using univariate and multivariate logistic regression analysis. US-radiomics features were extracted from US images; after selecting the most significant features by univariate analysis, Spearman's correlation analysis, and the least absolute shrinkage and selection operator (LASSO) algorithm; four machine-learning classification algorithms were used to build the US-radiomics model. Fivefold cross-validation was then used to test the performance of the model and compare the ability of the clinical, US-radiomics and combined models to predict LNM in CC patients. RESULTS: Red blood cell, platelet and squamous cell carcinoma-associated antigen were independent clinical predictors of LNM (+) in CC patients. eXtreme Gradient Boosting performed the best among the four machine-learning classification algorithms. Fivefold cross-validation confirmed that eXtreme Gradient Boosting indeed performs the best, with average area under the curve values in the training and validation sets of 0.897 and 0.898. In the three prediction models, both the US-radiomics model and the combined model showed good predictive efficacy, with average area under the curve values in the training and validation sets of 0.897, 0.898 and 0.912, 0.905, respectively. CONCLUSION: US-radiomics features combined with clinical factors can preoperatively predict LNM in CC patients non-invasively.

RESUMO

This study aims to investigate the effects of the Galectin-3 (Gal-3) inhibitor TD139 on inflammation and the extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK)/p38 pathway in gestational diabetes mellitus (GDM). Human placental tissues were treated with TD139 and TNF-α, assessing Gal-3, ERK/JNK/p38 activation, and inflammatory cytokines. GDM was induced in mice via subcutaneous injections of streptozotocin (STZ). After confirming GDM, mice were treated with 15 mg/kg TD139 on GD 10.5 12.5, 14.5, 16.5, and 18.5. Serum inflammatory cytokines were measured on GD 20.5, and post-delivery placental tissues were analyzed. Data were analyzed using one-way or two-way repeated measures ANOVA with post hoc tests. TD139 suppressed TNF-α-induced increases in Gal-3, IL-1ß, IL-6, MCP-1, and ERK/JNK/p38 activation in placental tissues. In STZ-induced GDM mice, TD139 reduced glucose levels, weight loss, and food and water intake. TD139 significantly lowered TNF-α, IL-1ß, IL-6, and MCP-1 in serum and placental tissues and inhibited the ERK/JNK/p38 pathway. TD139 improved pup numbers in GDM mice compared to untreated ones. TD139 reduces inflammation and inhibits the ERK/JNK/p38 pathway in TNF-α stimulated placental tissues and STZ-induced GDM mice, suggesting its therapeutic potential for managing GDM-related placental inflammation and improving pregnancy outcomes. The study used TNF-α to mimic GDM in placental tissues and an STZ-induced GDM mouse model, which may not fully represent human GDM complexity. Future research should explore alternative models, and broader signaling pathways, and thoroughly evaluate TD139's safety in pregnancy.