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BACKGROUND: Epithelial-mesenchymal transition (EMT) is central to HCC metastasis, in which RNA-binding proteins (RBPs) play a key role. METHODS: To explore the role of RBPs in metastasis of hepatocellular carcinoma (HCC), whole transcriptome sequencing was conducted to identify differential RBPs between HCC with metastasis and HCC without metastasis. The influence of RBPs on metastasis of HCC was verified by in vitro and in vivo experiments. The interaction of RBPs with non-coding RNAs was evaluated by RNA immunoprecipitation and pull-down assays. RNA sequencing, whole-genome sequencing, and alternative splicing analysis were further performed to clarify post-transcriptional regulation mechanisms. RESULTS: Whole transcriptome sequencing results showed that expression of thioredoxin (Trx) was significantly upregulated in HCC patients with metastasis. Trx was also found to be associated with poor prognosis in HCC patients. Overexpression of Trx could promote migration and invasion of HCC cells in vitro and increase the rate of lung metastasis of HCC cells in vivo. Moreover, binding assays showed that Trx could bind to LINC00152. As a result, LINC00152 was verified to determine the pro-metastasis function of Trx by knockdown assay. Furthermore, we revealed that Trx could regulate metastasis-associated alternative splicing program. Specifically, angiopoietin 1 (ANGPT1) was the splicing target; the splicing isoform switching of ANGPT1 could activate the PI3K-Akt pathway, upregulate EMT-associated proteins, and promote migration and invasion of HCC cells. CONCLUSIONS: We found that Trx could interact with LINC00152 and promote HCC metastasis via regulating alternative splicing, indicating that Trx may serve as a novel therapeutic target for HCC treatment.
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Regulating macrophage phenotypes to reconcile the conflict between bacterial suppression and tissue regeneration is ideal for treating infectious skin wounds. Here, an injectable immunoregulatory hydrogel (SrmE20) that sequentially drives macrophage phenotypic polarization (M0 to M1, then to M2) was constructed by integrating anti-inflammatory components and proinflammatory solvents. In vitro experiments demonstrated that the proinflammatory solvent ethanol stabilized the hydrogel structure, maintained the phenolic hydroxyl group activity, and achieved macrophages' proinflammatory transition (M0 to M1) to enhance antibacterial effects. With ethanol depletion, the hydrogel's cations and phenolic hydroxyl groups synergistically regulated macrophages' anti-inflammatory transition (M1 to M2) to initiate regeneration. In the anti-contraction full-thickness wound model with infection, this hydrogel effectively eliminated bacteria and even achieved anti-inflammatory M2 macrophage accumulation at three days post-surgery, accelerated angiogenesis and collagen deposition. By sequentially driving macrophage phenotypic polarization, this injectable immunoregulatory hydrogel will bring new guidance for the care and treatment of infected wounds.
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In situ mesenchymal stem cells (MSCs) regenerative therapy holds promising potential for treating osteoarthritis. However, MSCs engraftment and intra-articular inflammation limit the therapeutic efficacy of this approach. This study introduces porous microspheres (PMs) composed of aldehyde-modified poly(lactic-co-glycolic acid), that encapsulate platelet derived growth factor-AB and kartogenin. Metformin (Met) is also incorporated onto the microsphere through a Schiff base reaction to create PMs@Met. In vitro, in vivo and ex experiments revealed that PMs@Met can be injected into the joint cavity, effectively recruiting endogenous MSCs in situ. This approach creates a favorable environment for MSCs proliferation. It also controls the intra-articular inflammatory environment by modulating the polarization of synovial macrophages, ultimately promoting cartilage repair. In summary, our study presents an innovative tissue engineering strategy for the treatment of osteoarthritis-induced articular cartilage injuries. STATEMENT OF SIGNIFICANCE: Cell therapy using autologous mesenchymal stem cells (MSCs) has potential to slow the progression of osteoarthritis (OA). Nonetheless, there are some disadvantages to adopting in situ MSCs therapy, including difficulties with MSC engraftment into cartilage-deficient regions, the effect of intra-articular inflammation on MSC therapeutic efficacy, and attaining selective chondrogenic MSC differentiation. We created injectable PLGA microspheres (PMs) that were loaded with PDGF-AB and KGN. Metformin was bonded to the surface of microspheres using a Schiff base reaction. The microspheres can recruit intra-articular MSCs and encourage their development into chondrocytes. The microspheres actively modulate the inflammatory joint environment by altering synovial macrophage polarization, thereby supporting MSCs in effective cartilage treatment. To summarize, microspheres hold great potential in the treatment of OA.
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Cartilagem Articular , Macrófagos , Células-Tronco Mesenquimais , Microesferas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Regeneração , Animais , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , Porosidade , Regeneração/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Ácidos Ftálicos/farmacologia , Ácidos Ftálicos/química , Transplante de Células-Tronco Mesenquimais/métodos , Coelhos , Anilidas/farmacologia , Anilidas/química , Osteoartrite/terapia , Osteoartrite/patologia , MasculinoRESUMO
An effective treatment for the irregular partial-thickness cartilage defect in the early stages of osteoarthritis (OA) is lacking. Cartilage tissue engineering is effective for treating full-thickness cartilage defects with limited area. In this study, we designed an injectable multifunctional poly(lactic-co-glycolic acid) (PLGA) microsphere to repair partial-thickness cartilage defects. The microsphere was grafted with an E7 peptide after loading the microsphere with kartogenin (KGN) and modifying the outer layer through dopamine self-polymerization. The microsphere could adhere to the cartilage defect, recruit synovial mesenchymal stem cells (SMSCs) in situ, and stimulate their differentiation into chondrocytes after injection into the articular cavity. Through in vivo and in vitro experiments, we demonstrated the ability of multifunctional microspheres to adhere to cartilage matrix, recruit SMSCs, and promote their differentiation into cartilage. Following treatment, the cartilage surface of the model group with partial-thickness cartilage defect showed smooth recovery, and the glycosaminoglycan content remained normal; the untreated control group showed significant progression of OA. The microsphere, a framework for cartilage tissue engineering, promoted the expression of SMSCs involved in cartilage repair while adapting to cell migration and growth. Thus, for treating partial-thickness cartilage defects in OA, this innovative carrier system based on stem cell therapy can potentially improve therapeutic outcomes. STATEMENT OF SIGNIFICANCE: Mesenchymal stem cells (MSCs) therapy is effective in the repair of cartilage injury. However, because of the particularity of partial-thickness cartilage injury, it is difficult to recruit enough seed cells in situ, and there is a lack of suitable scaffolds for cell migration and growth. Here, we developed polydopamine surface-modified PLGA microspheres (PMS) containing KGN and E7 peptides. The adhesion ability of the microspheres is facilitated by the polydopamine layer wrapped in them; thus, the microspheres can adhere to the injured cartilage and recruit MSCs, thereby promoting their differentiation into chondrocytes and accomplishing cartilage repair. The multifunctional microspheres can be used as a safe and potential method to treat partial-thickness cartilage defects in OA.
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Anilidas , Células-Tronco Mesenquimais , Microesferas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Animais , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Coelhos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Diferenciação Celular/efeitos dos fármacos , Ácidos Ftálicos/química , Ácidos Ftálicos/farmacologia , Cartilagem Articular/patologia , Ácido Poliglicólico/química , Ácido Láctico/química , Injeções , Matriz Extracelular/metabolismo , Condrócitos/citologia , Condrócitos/metabolismo , Engenharia Tecidual/métodosRESUMO
Objective: To review the research progress of magnesium and magnesium alloy implants in the repair and reconstruction of sports injury. Methods: Relevant literature of magnesium and magnesium alloys for sports injury repair and reconstruction was extensively reviewed. The characteristics of magnesium and its alloys and their applications in the repair and reconstruction of sports injuries across various anatomical sites were thoroughly discussed and summarized. Results: Magnesium and magnesium alloys have advantages in mechanical properties, biosafety, and promoting tendon-bone interface healing. Many preclinical studies on magnesium and magnesium alloy implants for repairing and reconstructing sports injuries have yielded promising results. However, successful clinical translation still requires addressing issues related to mechanical strength and degradation behavior, where alloying and surface treatments offer feasible solutions. Conclusion: The clinical translation of magnesium and magnesium alloy implants for repairing and reconstructing sports injuries holds promise. Subsequent efforts should focus on optimizing the mechanical strength and degradation behavior of magnesium and magnesium alloy implants. Conducting larger-scale biocompatibility testing and developing novel magnesium-containing implants represent new directions for future research.
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Traumatismos em Atletas , Medicina Esportiva , Humanos , Magnésio , Ligas , Próteses e Implantes , Teste de Materiais , Implantes Absorvíveis , CorrosãoRESUMO
Glaucoma, a blind-leading disease largely since chronic pathological intraocular high pressure (ph-IOP). Hitherto, it is reckoned incurable for irreversible neural damage and challenges in managing IOP. Thus, it is significant to develop neuroprotective strategies. Ferroptosis, initially identified as an iron-dependent regulated death that triggers Fenton reactions and culminates in lipid peroxidation (LPO), has emerged as a focal point in multiple tumors and neurodegenerative diseases. Researches show that iron homeostasis play critical roles in the optic nerve (ON) and retinal ganglion cells (RGCs), suggesting targeted treatments could be effective. In glaucoma, apart from neural lesions, disrupted metal balance and increased oxidative stress in trabecular meshwork (TM) are observed. These disturbances lead to extracellular matrix excretion disorders, known as sclerotic mechanisms, resulting in refractory blockages. Importantly, oxidative stress, a significant downstream effect of ferroptosis, is also a key factor in cell senescence. It plays a crucial role in both the etiology and risk of glaucoma. Moreover, ferroptosis also induces non-infectious inflammation, which exacerbate glaucomatous injury. Therefore, the relevance of ferroptosis in glaucoma is extensive and multifaceted. In this review, the study delves into the current understanding of ferroptosis mechanisms in glaucoma, aiming to provide clues to inform clinical therapeutic practices.
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Ferroptose , Glaucoma , Estresse Oxidativo , Humanos , Ferroptose/efeitos dos fármacos , Ferroptose/fisiologia , Glaucoma/metabolismo , Glaucoma/tratamento farmacológico , Animais , Ferro/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Células Ganglionares da Retina/patologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/efeitos dos fármacosRESUMO
BACKGROUND: HBV infection is the leading risk factor for HCC. HBV infection has been confirmed to be associated with the exhaustion status of CD8+ T cells and immunotherapeutic efficacy in HCC. In this study, we aimed to investigate the prognostic value of the CD8+ T-cell exhaustion signature and immunotherapy response in patients with HBV-related HCC. METHODS: We identified different clusters of HBV-related HCC cells by single-cell RNA sequencing (scRNA-seq) and identified CD8+ T-cell exhaustion-related genes (TERGs) by pseudotime analysis. We conducted differential expression analysis and LASSO Cox regression to detect genes and construct a CD8+ T-cell exhaustion index (TEI). We next combined the TEI with other clinicopathological factors to design a prognostic nomogram for HCC patients. We also analysed the difference in the TEI between the non-responder and responder groups during anti-PD-L1 therapy. In addition, we investigated how HBV induces CD8+ T lymphocyte exhaustion through the inhibition of tyrosine metabolism in HCC using gene set enrichment analysis and RTâqPCR. RESULTS: A CD8+ T-cell exhaustion index (TEI) was established with 5 TERGs (EEF1E1, GAGE1, CHORDC1, IKBIP and MAGOH). An AFP level > 500 ng, vascular invasion, histologic grade (G3-G4), advanced TNM stage and poor five-year prognosis were related to a higher TEI score, while HBV infection was related to a lower TEI score. Among those receiving anti-PD-L1 therapy, responders had lower TEIs than non-responders did. The TEI also serves as an independent prognostic factor for HCC, and the nomogram incorporating the TEI, TNM stage, and vascular invasion exhibited excellent predictive value for the prognosis in HCC patients. RTâqPCR revealed that among the tyrosine metabolism-associated genes, TAT (tyrosine aminotransferase) and HGD (homogentisate 1,2 dioxygenase) were expressed at lower levels in HBV-HCC than in non-HBV HCC. CONCLUSION: Generally, we established a novel TEI model by comprehensively analysing the progression of CD8+ T-cell exhaustion, which shows promise for predicting the clinical prognosis and potential immunotherapeutic efficacy in HBV-related HCC patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Vírus da Hepatite B/genética , Linfócitos T CD8-Positivos , Exaustão das Células T , Neoplasias Hepáticas/genética , Prognóstico , Análise de Sequência de RNA , Tirosina , RNARESUMO
EpsteinâBarr virus (EBV) is a DNA virus that belongs to the human B lymphotropic herpesvirus family and is highly prevalent in the human population. Once infected, a host can experience latent infection because EBV evades the immune system, leading to hosts harboring the virus for their lifetime. EBV is associated with many diseases and causes significant challenges to human health. This review first offers a description of the natural history of EBV infection, clarifies the interaction between EBV and the immune system, and finally focuses on several major types of diseases caused by EBV infection.
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Infecções por Vírus Epstein-Barr , Humanos , Herpesvirus Humano 4/genéticaRESUMO
Hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC), one of the most prevalent malignant tumors worldwide that poses a significant threat to human health. The multifunctional regulator known as Hepatitis B virus X-protein (HBx) interacts with host factors, modulating gene transcription and signaling pathways and contributing to hepatocellular carcinogenesis. The p90 ribosomal S6 kinase 2 (RSK2) is a member of the 90 kDa ribosomal S6 kinase family involved in various intracellular processes and cancer pathogenesis. At present, the role and mechanism of RSK2 in the development of HBx-induced HCC are not yet clear. In this study, we found that HBx upregulates the expression of RSK2 in HBV-HCC tissues, HepG2, and SMMC-7721 cells. We further observed that reducing the expression of RSK2 inhibited HCC cell proliferation. In HCC cell lines with stable HBx expression, RSK2 knockdown impaired the ability of HBx to promote cell proliferation. The extracellularly regulated protein kinases (ERK) 1/2 signaling pathway, rather than the p38 signaling pathway, mediated HBx-induced upregulation of RSK2 expression. Additionally, RSK2 and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) were highly expressed and positively correlated in HBV-HCC tissues and associated with tumor size. This study showed that HBx upregulates the expression of RSK2 and CREB by activating the ERK1/2 signaling pathway, promoting the proliferation of HCC cells. Furthermore, we identified RSK2 and CREB as potential prognostic markers for HCC patients.
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Carcinoma Hepatocelular , Hepatite B , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Proteínas Quinases/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Células Hep G2 , Proteínas Virais Reguladoras e Acessórias/metabolismo , Hepatite B/complicações , Vírus da Hepatite B/fisiologia , Linhagem Celular TumoralRESUMO
OBJECTIVE: Circulating tumor cell (CTC) exerts diagnostic and prognostic value in colorectal cancer (CRC) patients. This study intended to further investigate the longitudinal change of CTC count, and its correlation with the prognosis of immune checkpoint inhibitor (ICI)-based treatments in unresectable, metastatic CRC patients. METHODS: Fifty-six unresectable, metastatic CRC patients receiving ICI-based treatments were enrolled. CTC count was assessed by the CellSearch system at baseline and month (M)2 in their peripheral blood samples. RESULTS: Forty-one (73.2%) and sixteen (28.5%) patients had CTC count ≥1 and ≥5 at baseline, respectively. Meanwhile, CTC count at M2 was decreased versus that at baseline (median (interquartile range): 1.0 (0.0-3.0) versus 3.0 (0.0-5.0)) (p < 0.001). Besides, increased CTC count at baseline (p = 0.009) and M2 (p = 0.006) associated with a reduced overall response rate. Baseline CTC count ≥5 related to worse progression-free survival (PFS) (p = 0.007), but baseline CTC count ≥1 did not; additionally, baseline CTC count ≥1 (p = 0.043) and ≥5 (p = 0.016) linked to shorter overall survival (OS). Furthermore, M2 CTC count ≥1 (p = 0.002) and ≥5 (p < 0.001) both correlated with poor PFS; meanwhile, M2 CTC count ≥1 (p = 0.006) and ≥5 (p < 0.001) also related to worse OS. After adjustment, only CTC count at M2 ≥ 5 independently associated with unsatisfactory PFS (hazard ratio (HR)=3.218, p = 0.011) and OS (HR = 3.229, p = 0.038). CONCLUSIONS: CTC count is decreased during ICI-based treatments, its reduction represents satisfactory treatment outcomes in unresectable, metastatic CRC patients. Notably, the CTC count at 5 as a cutting threshold after a two-month treatment has an impressive prognostic value.
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Neoplasias do Colo , Células Neoplásicas Circulantes , Humanos , Células Neoplásicas Circulantes/patologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Biomarcadores Tumorais , Resultado do Tratamento , PrognósticoRESUMO
Background and Aims: Chronic hepatitis B (CHB) can cause liver fibrosis and lead to cirrhosis and cancer. As the effectiveness of antiviral therapy to reverse liver fibrosis is limited, We aimed to evaluate the effect of An-Luo-Hua-Xian pill (ALHX) on fibrosis regression in CHB patients treated with entecavir (ETV). Methods: Treatment-naïve patients with CHB were randomly treated with ETV alone or combined with ALHX (ETV+ALHX) between October 1, 2013 and December 31, 2020. Demographic, laboratory, and liver histology data before and after 78 weeks of treatment were collected. The Ishak fibrosis score (F) was used and fibrosis regression required a decrease in F of ≥1 after treatment. Results: A total of 780 patients were enrolled, and 394 with a second liver biopsy after treatment were included in the per-protocol population, 132 in ETV group and 262 in ETV+ALHX group. After 78 weeks of treatment, the fibrosis regression rate in the ETV+ALHX group was significantly higher than that of the ETV group at baseline F≥3 patients: 124/211 (58.8%) vs. 45/98 (45.9%), p=0.035. The percentage of patients with a decreased liver stiffness measurement (LSM) was higher in the ETV+ALHX group: 156/211 (73.9%) vs. 62/98 (63.%), p=0.056. Logistic regression analysis showed that ETV combined with ALHX was associated with fibrosis regression [odds ratio (OR)=1.94, p=0.018], and a family history of hepatocellular carcinoma was on the contrary. (OR=0.41, p=0.031). Conclusions: ETV combined with ALHX increased liver fibrosis regression in CHB patients.
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BACKGROUND: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide, accounting for more than 700,000 deaths annually. Epithelial-mesenchymal transition (EMT) is posited to contribute to HCC progression. We, therefore, aimed to elucidate the relationship between EMT-related gene (ERG) expression and prognosis in patients with HCC. METHODS: Univariate and multivariate Cox regression analyses were performed to identify prognostic-related differentially expressed EMT-related genes (DE-ERGs). Time-dependent receiver operating characteristic and Kaplan-Meier curves were used to assess the prognostic performance of the EMT-related signature. pRRophetic R package was used to evaluate sorafenib sensitivity in the GSE14520 cohort. Gene expression in Huh7 and L02 cell lines was detected by real-time PCR and Western blotting. Differential expression of the three genes between HCC tissues and normal tissues was validated using immunohistochemical analyses. RESULTS: Of the 76 identified DE-ERGs, 29 were associated with overall survival. Three prognosis-related ERGs (GOLM1, SOX4, and CD14) were screened out by multivariate Cox regression. A gene signature was identified based on the three prognostic-related ERGs. HCC patients with a low-risk score had a better prognosis and were more sensitive to sorafenib compared to those with a high-risk score. Moreover, we further confirmed increased expression of GOLM1 and SOX4, and decreased expression of CD14, in liver cancer cell line and HCC tissue. CONCLUSIONS: The results of the present study demonstrate the utility of an ERG signature as a potential biomarker informing prognosis in patients with HCC, which may contribute to the implementation of personalized therapies.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Sorafenibe/farmacologia , Transição Epitelial-Mesenquimal/genética , Biomarcadores Tumorais/genética , Prognóstico , Medição de Risco/métodos , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/metabolismo , Proteínas de Membrana/genéticaRESUMO
Background: Hereditary spherocytosis (HS) is not a rare disease in the department of hematology; however, in the late stage of the disease, patients often have very severe cholestasis and are referred to the department of hepatology. Hepatologists may have trouble determining the source of cholestasis, causing treatment difficulties. Case Description: We report two 20-year-old patients complaining of "skin and eyes turned to yellow". Patient 1 had no previous hematologic disorders, and patient 2 had a history of anemia without treatment. Laboratory tests suggested anemia and elevated bilirubin in both patients. The direct bilirubin levels were more significantly elevated than the indirect bilirubin levels in both patients, and the patients both suffered from abdominal pain and pancreatitis. However, the degree of anemia could not fully explain the jaundice. Magnetic resonance imaging findings suggested the presence of hepatosplenomegaly and gallstones. Genetic testing identified new mutations in the relevant genes, ultimately confirming the diagnosis of HS. The liver biopsy results for both patients showed obvious intrahepatic cholestasis. Patient 1 underwent splenectomy at a bilirubin level of 125.4 µmol/L, and the bilirubin level returned to normal after surgery, with a good prognosis. However, Patient 2 suffered from pancreatitis during hospitalization and was unable to undergo splenectomy. Endoscopic retrograde cholangiopancreatography was implemented, but the bilirubin level continued to rise, and Patient 2 ultimately gave up treatment and passed away. Conclusions: For hepatologists, identifying the source of jaundice (hemolysis, hepatocyte destruction, or biliary obstruction) is important for treatment, supplemented by liver biopsy and genetic testing if necessary. In the 2 cases covered in this article, early-stage HS caused hemolytic jaundice with predominantly elevated indirect bilirubin, and as the disease progressed, patients developed severe cholestasis probably related to transient biliary obstruction caused by gallstones and hepatocellular injury due to abnormal bilirubin metabolism. In addition, in patients with HS combined by intrahepatic cholestasis, early consideration of splenectomy may delay disease progression and achieve a better prognosis. Of course, this conclusion needs to be confirmed by more clinical studies.
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The renal-clearable aspect of imaging agent with minimum toxicity issues and side effects is essential for clinical translation, yet clinical near-infrared-I/II (NIR-I/II) fluorophores with timely renal-clearance pathways are very limited. Herein, we rationally develop the cyanine-protein composite strategy through covalent bonding of ß-lactoglobulin (ß-LG) and chloride-cyanine dye to produce a brilliant and stable NIR-I/II fluorophore (e.g., ß-LG@IR-780). The ß-LG acts as a protecting shell with small molecular weight (18.4 kDa) and ultrasmall size (<5 nm), thus endowing the ß-LG@IR-780 with excellent biocompatibility and renal excretion. Our ß-LG@IR-780 probe enables noninvasive and precise NIR-II visualization of the physiological and pathological conditions of the vascular and lymphatic drainage system, facilitating intraoperative imaging-guided surgery and postoperative noninvasive monitoring. The minimum accumulation of our probes in the main organs improves the overall biosafety. This study provides a facile methodology for new-generation NIR-II fluorophores and largely improves the brightness and pharmacokinetics of small molecular dyes.
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Linfografia , Imagem Óptica , Angiografia , Cloretos , Corantes Fluorescentes/farmacocinética , Lactoglobulinas , Imagem Óptica/métodosRESUMO
Hepatitis B surface antigen (HBsAg) loss or seroconversion is an ideal treatment endpoint for patients with chronic hepatitis B but is rarely achievable in hepatitis B e-antigen (HBeAg)-positive patients using existing treatment strategies. In this study, the effect of pegylated interferon (peg-IFN) alfa-2b plus tenofovir disoproxil fumarate (TDF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and hepatitis B vaccine was evaluated. This randomized controlled trial was conducted at nine liver centers in Chinese university hospitals from May 2018 to July 2020. Patients (n = 303) enrolled were randomly administered peg-IFN-α-2b combined with TDF, GM-CSF, and hepatitis B vaccine (experimental group); peg-IFN-α-2b plus TDF (control group 2); or interferon-α-2b alone (control group 1). The primary efficacy endpoint was HBsAg seroconversion at 48 weeks and the secondary endpoint included safety. No differences in baseline HBsAg levels were observed among the groups. The primary endpoint was achieved in three (3.0%), one (1.03%), and one (1.19%) patient in the experimental group, control group 2, and control group 1, respectively. The incidence of HBsAg seroconversion at week 48 was not significantly different among the three groups (p = 0.629). However, the decrease in serum levels of HBsAg at week 48 was significantly higher in the experimental and control group 2 compared with that in control group 1 (p = 0.008 and 0.006, respectively). No significant difference between the experimental and control group 2 was observed (p = 0.619). Adverse events were not significantly different among the groups except for the lower incidence of neutropenia in the experimental group. Peg-IFN-α-2b combined with TDF, GM-CSF, and hepatitis B vaccine is not superior to peg-IFN-α-2b combined with TDF in HBeAg-positive naïve patients. Clinical Trials Registration: ChiCTR1800016173.
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Fator Estimulador de Colônias de Granulócitos e Macrófagos , Vacinas contra Hepatite B , Hepatite B Crônica , Tenofovir , Antivirais , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Antígenos de Superfície da Hepatite B , Vacinas contra Hepatite B/efeitos adversos , Antígenos E da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/prevenção & controle , Humanos , Interferon-alfa/efeitos adversos , Interferon-alfa/uso terapêutico , Polietilenoglicóis , Estudos Prospectivos , Proteínas Recombinantes/efeitos adversos , Tenofovir/efeitos adversos , Tenofovir/uso terapêutico , Resultado do TratamentoRESUMO
Near-infrared-II (NIR-II) dyes could be encapsulated by either exogenous or endogenous albumin to form stable complexes for deep tissue bioimaging. However, we still lack a complete understanding of the interaction mechanism of the dye@albumin complex. Studying this principle is essential to guide efficient dye synthesis and develop NIR-II probes with improved brightness, photostability, etc. Methods: Here, we screen and test the optical and chemical properties of dye@albumin fluorophores, and systematically investigate the binding sites and the relationship between dye structures and binding degree. Super-stable cyanine dye@albumin fluorophores are rationally obtained, and we also evaluate their pharmacokinetics and long-lasting NIR-II imaging abilities. Results: We identify several key parameters of cyanine dyes governing the supramolecular/covalent binding to albumin, including a six-membered ring with chlorine (Cl), the small size of side groups, and relatively high hydrophobicity. The tailored fluorophore (IR-780@albumin) exhibits much-improved photostability, serving as a long-lasting imaging probe for NIR-II bioimaging. Conclusion: Our study reveals that the chloride-containing cyanine dyes with the above-screened chemical structure (e.g. IR-780) could be lodged into albumin more efficiently, producing a much more stable fluorescent probe. Our finding partly solves the photobleaching issue of clinically-available cyanine dyes, enriching the probe library for NIR-II bioimaging and imaging-guided surgery.
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Corantes Fluorescentes , Imagem Óptica , Albuminas , Corantes Fluorescentes/química , Imagem Óptica/métodosRESUMO
Regulated necrosis is defined as cell death characterized by loss of the cell membrane integrity and release of the cytoplasmic content. It contributes to the development and progression of some diseases, including ischemic stroke injury, liver diseases, hypertension, and cancer. Various forms of regulated necrosis, particularly pyroptosis, necroptosis, and ferroptosis, have been implicated in the pathogenesis of corneal disease. Regulated necrosis of corneal cells enhances inflammatory reactions in the adjacent corneal tissues, leading to recurrence and aggravation of corneal disease. In this review, we summarize the molecular mechanisms of pyroptosis, necroptosis, and ferroptosis in corneal diseases and discuss the roles of regulated necrosis in inflammation regulation, tissue repair, and corneal disease outcomes.
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BACKGROUND: The incidence rate of breast cancer has exceeded that of lung cancer, and it has become the most malignant type of cancer in the world. BI-RADS 4 breast nodules have a wide range of malignant risks and are associated with challenging clinical decision-making. AIM: To explore the diagnostic value of artificial intelligence (AI) automatic detection systems for BI-RADS 4 breast nodules and to assess whether conventional ultrasound BI-RADS classification with AI automatic detection systems can reduce the probability of BI-RADS 4 biopsy. METHODS: A total of 107 BI-RADS breast nodules confirmed by pathology were selected between June 2019 and July 2020 at Hwa Mei Hospital, University of Chinese Academy of Sciences. These nodules were classified by ultrasound doctors and the AI-SONIC breast system. The diagnostic values of conventional ultrasound, the AI automatic detection system, conventional ultrasound combined with the AI automatic detection system and adjusted BI-RADS classification diagnosis were statistically analyzed. RESULTS: Among the 107 breast nodules, 61 were benign (57.01%), and 46 were malignant (42.99%). The pathology results were considered the gold standard; furthermore, the sensitivity, specificity, accuracy, Youden index, and positive and negative predictive values were 84.78%, 67.21%, 74.77%, 0.5199, 66.10% and 85.42% for conventional ultrasound BI-RADS classification diagnosis, 86.96%, 75.41%, 80.37%, 0.6237, 72.73%, and 88.46% for automatic AI detection, 80.43%, 90.16%, 85.98%, 0.7059, 86.05%, and 85.94% for conventional ultrasound BI-RADS classification with automatic AI detection and 93.48%, 67.21%, 78.50%, 0.6069, 68.25%, and 93.18% for adjusted BI-RADS classification, respectively. The biopsy rate, cancer detection rate and malignancy risk were 100%, 42.99% and 0% and 67.29%, 61.11%, and 1.87% before and after BI-RADS adjustment, respectively. CONCLUSION: Automatic AI detection has high accuracy in determining benign and malignant BI-RADS 4 breast nodules. Conventional ultrasound BI-RADS classification combined with AI automatic detection can reduce the biopsy rate of BI-RADS 4 breast nodules.
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Poor healing response after rotator cuff reconstruction is multifactorial, with the inflammatory microenvironment and deficiency of stem cell differentiation factors at the lesion site being most relevant. However, there is a lack of effective tissue engineering strategies that can simultaneously exert anti-inflammatory and pro-differentiation effects to promote rotator cuff healing. Methods: In this study, we synthesized and characterized a novel active drug delivery vector that successfully overcame the challenge of simultaneous high-efficiency loading and controlled release of Mg2+ and curcumin. The anti-inflammatory and pro-differentiation effects of the composite hydrogel were evaluated in vitro and in vivo. Moreover, healing of the rotator cuff tendon-to-bone interface was studied by histology, immunofluorescence, and biomechanical tests. Results: The composite hydrogel exhibited excellent biocompatibility and injectability, good adhesiveness, and rapid self-healing. The released curcumin showed obvious anti-inflammatory and antioxidation effects, which protected stem cells and tendon matrix. Furthermore, released Mg2+ promoted stem cell aggregation and chondrogenesis. Moreover, biomechanical tests and histological results of a rat rotator cuff tear model at 8 weeks after surgery indicated that the composite hydrogel significantly enhanced tendon-to-bone healing. Conclusions: The composite hydrogel mediated sustained in situ release of curcumin and Mg2+ to effectively promote rotator cuff tendon-to-bone healing via anti-inflammatory and pro-differentiation effects. Therefore, this composite hydrogel offers significant promise for rotator cuff repair.
Assuntos
Anti-Inflamatórios/farmacologia , Osso e Ossos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Curcumina/farmacologia , Preparações de Ação Retardada/farmacologia , Hidrogéis/farmacologia , Magnésio/farmacologia , Tendões/efeitos dos fármacos , Animais , Fenômenos Biomecânicos/efeitos dos fármacos , Condrogênese/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Manguito Rotador/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Cicatrização/efeitos dos fármacosRESUMO
BACKGROUND AND AIM: There is debate among the hepatology community regarding the simple non-invasive scoring systems and histological scores (even it was developed for histological classification) in predicting clinical outcomes in patients with non-alcoholic fatty liver disease (NAFLD). This study aimed to determine whether the presence of simple non-invasive scoring systems and histological scores could predict all-cause mortality, liver-related mortality, and liver disease decompensation (liver failure, cirrhosis, hepatocellular carcinoma, or decompensated liver disease). METHODS: The pooled hazard ratio of prognostic factors and incidence rate per 1000 person-years in patients with NAFLD was calculated and further adjusted by two different models of handling the duplicated data. RESULTS: A total of 19 longitudinal studies were included. Most simple non-invasive scoring systems (Fibrosis-4 Score, BARD, and aspartate aminotransferase-to-platelet ratio index ) and histological scores (NAFLD activity score, Brunt, and "steatosis, activity, and fibrosis" ) failed in predicting mortality, and only the NAFLD fibrosis score > 0.676 showed prognostic ability to all-cause mortality (four studies, 7564 patients, 118 352 person-years followed up, pooled hazard ratio 1.44, 95% confidence interval [CI] 1.05-1.96). The incidence rate per 1000 person-years of all-cause mortality, liver-related mortality, cardiovascular-related mortality, and liver disease decompensation resulted in a pooled incidence rate per 1000 person-years of 22.65 (14 studies, 95% CI 9.62-53.31), 3.19 (7 studies, 95% CI 1.14-8.93), 6.02 (6 studies, 95% CI 4.69-7.74), and 11.46 (4 studies, 95% CI 5.33-24.63), respectively. CONCLUSION: Non-alcoholic fatty liver disease fibrosis score showed promising prognostic value to all-cause mortality. Most present simple non-invasive scoring systems and histological scores failed to predict clinical outcomes.