RESUMO
Cardiac myxoma is a commonly encountered tumor within the heart that has the potential to be life-threatening. However, the cellular composition of this condition is still not well understood. To fill this gap, we analyzed 75,641 cells from cardiac myxoma tissues based on single-cell sequencing. We defined a population of myxoma cells, which exhibited a resemblance to fibroblasts, yet they were distinguished by an increased expression of phosphodiesterases and genes associated with cell proliferation, differentiation, and adhesion. The clinical relevance of the cell populations indicated a higher proportion of myxoma cells and M2-like macrophage infiltration, along with their enhanced spatial interaction, were found to significantly contribute to the occurrence of embolism. The immune cells surrounding the myxoma exhibit inhibitory characteristics, with impaired function of T cells characterized by the expression of GZMK and TOX, along with a substantial infiltration of tumor-promoting macrophages expressed growth factors such as PDGFC. Furthermore, in vitro co-culture experiments showed that macrophages promoted the growth of myxoma cells significantly. In summary, this study presents a comprehensive single-cell atlas of cardiac myxoma, highlighting the heterogeneity of myxoma cells and their collaborative impact on immune cells. These findings shed light on the complex pathobiology of cardiac myxoma and present potential targets for intervention.
Assuntos
Neoplasias Cardíacas , Mixoma , Microambiente Tumoral , Humanos , Mixoma/patologia , Mixoma/genética , Mixoma/imunologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Neoplasias Cardíacas/genética , Neoplasias Cardíacas/patologia , Neoplasias Cardíacas/imunologia , Macrófagos/imunologia , Macrófagos/patologia , Proliferação de Células/genética , Masculino , FemininoRESUMO
Background: The impact of transcatheter closure of coronary artery fistula (CAF) and residual shunt after occlusion on improving blood flow in the donor vessel remains uncertain. Objectives: To evaluate the functional impact on the donor vessel following CAFs closure using QFR (Quantitative Flow Ratio) analysis. Methods: A total of 46 patients with 48 CAFs who underwent transcatheter closure at Shanghai Chest Hospital and Shuguang Hospital between March 2015 and August 2023 were included in the review. The clinical, angiographic details, and QFR data were subjected to analysis. The size of the fistulae was defined according to the ratio between the diameters of the fistulae and the largest diameter of the coronary vessel not feeding the coronary fistula. Results: Among 48 CAFs, the average diameter of the fistulae ostium was 3.19 ± 1.04â mm, while the mean diameter of the donor vessel segment following fistulae was 3.45 ± 1.01â mm. The mean QFR value of the donor vessels with medium CAFs was found to be significantly lower than those with small CAFs (0.93 ± 0.10 vs. 0.98 ± 0.03; p < 0.05). Furthermore, the mean QFR value of donor vessels with medium CAFs was observed to be significantly improved after occlusion (0.99 ± 0.01 vs. 0.93 ± 0.10; p = 0.01). However, there was no statistical difference in the mean QFR value of donor vessels with small CAFs before and after occlusion (0.98 ± 0.03 vs. 0.98 ± 0.02; p > 0.05). Moreover, the changes in QFR were more pronounced in donor vessels with medium CAFs compared to those with small CAFs after occlusion (0.06 ± 0.10 vs. 0.005 ± 0.012; p = 0.01). There is no statistical difference in the mean QFR variation and QFR variation rate between donor vessels with CAFs that occurred residual shunt and those without residual shunt after occlusion (p > 0.05). Conclusions: The presence of medium CAFs has a significant impact on the blood flow of the donor vessel, as compared to small CAFs, and may benefit from occlusion. A small residual shunt has no significant impact on the effectiveness of CAFs occlusion in enhancing donor blood flow.
RESUMO
OBJECTIVE: We aimed to investigate the prevalence of vascular complications in acute pancreatitis (AP), to compare patient outcomes using various treatments, and to explore the related risk factors. METHODS: Consecutive AP patients admitted from January 2010 to July 2017 were retrospectively included. Demographics, vascular complications, laboratory indices, and imaging findings were collected. Univariate and multivariate analyses were used to explore potential risk factors of vascular complications. RESULTS: Of 3048 AP patients, 808 (26.5%) had vascular complications, including visceral vein thrombosis, sinistral portal hypertension, and arterial complications. And 38 (4.7%) patients received anticoagulant therapy and had a higher rate of recanalization (P < 0.001). Bleeding occurred in 95 (11.8%) patients, who received further treatment. Multivariate analysis identified male gender (odds ratio [OR] 1.650, 95% confidence interval [CI] 1.101-2.472), hyperlipidemia (OR 1.714, 95% CI 1.356-2.165), disease recurrence (OR 3.727, 95% CI 2.713-5.118), smoking (OR 1.519, 95% CI 1.011-2.283), hemoglobin level (OR 0.987, 95% CI 0.981-0.993), white blood cell (WBC) count (OR 1.094, 95% CI 1.068-1.122), non-vascular local complications (OR 3.018, 95% CI 1.992-4.573), computed tomography severity index (CTSI) (OR 1.425, 95% CI 1.273-1.596), and acute physiology and chronic health evaluation (APACHE) II score (OR 1.057, 95% CI 1.025-1.090) were related to vascular complications. CONCLUSIONS: Vascular complications in AP is prevalent and their treatment is challenging. Further investigations are warranted to determine the optimal treatment strategy. Independent risk factors included male gender, hyperlipidemia, disease recurrence, smoking, WBC count, non-vascular local complications, CTSI, and APACHE II score.
Assuntos
Pancreatite , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Fatores de Risco , Pancreatite/etiologia , Pancreatite/epidemiologia , Pancreatite/complicações , Estudos Retrospectivos , Adulto , Estudos de Casos e Controles , Prevalência , Resultado do Tratamento , Idoso , Doença Aguda , Anticoagulantes/uso terapêutico , Anticoagulantes/efeitos adversos , Doenças Vasculares/etiologia , Doenças Vasculares/epidemiologiaRESUMO
ABSTRACT: Notch signaling regulates cell-fate decisions in several developmental processes and cell functions. However, the role of Notch in hepatic thrombopoietin (TPO) production remains unclear. We noted thrombocytopenia in mice with hepatic Notch1 deficiency and so investigated TPO production and other features of platelets in these mice. We found that the liver ultrastructure and hepatocyte function were comparable between control and Notch1-deficient mice. However, the Notch1-deficient mice had significantly lower plasma TPO and hepatic TPO messenger RNA levels, concomitant with lower numbers of platelets and impaired megakaryocyte differentiation and maturation, which were rescued by addition of exogenous TPO. Additionally, JAK2/STAT3 phosphorylation was significantly inhibited in Notch1-deficient hepatocytes, consistent with the RNA-sequencing analysis. JAK2/STAT3 phosphorylation and TPO production was also impaired in cultured Notch1-deficient hepatocytes after treatment with desialylated platelets. Consistently, hepatocyte-specific Notch1 deletion inhibited JAK2/STAT3 phosphorylation and hepatic TPO production induced by administration of desialylated platelets in vivo. Interestingly, Notch1 deficiency downregulated the expression of HES5 but not HES1. Moreover, desialylated platelets promoted the binding of HES5 to JAK2/STAT3, leading to JAK2/STAT3 phosphorylation and pathway activation in hepatocytes. Hepatocyte Ashwell-Morell receptor (AMR), a heterodimer of asialoglycoprotein receptor 1 [ASGR1] and ASGR2, physically associates with Notch1, and inhibition of AMR impaired Notch1 signaling activation and hepatic TPO production. Furthermore, blockage of Delta-like 4 on desialylated platelets inhibited hepatocyte Notch1 activation and HES5 expression, JAK2/STAT3 phosphorylation, and subsequent TPO production. In conclusion, our study identifies a novel regulatory role of Notch1 in hepatic TPO production, indicating that it might be a target for modulating TPO level.
Assuntos
Hepatócitos , Janus Quinase 2 , Fígado , Receptor Notch1 , Trombopoetina , Animais , Receptor Notch1/metabolismo , Receptor Notch1/genética , Trombopoetina/metabolismo , Trombopoetina/genética , Camundongos , Fígado/metabolismo , Hepatócitos/metabolismo , Janus Quinase 2/metabolismo , Janus Quinase 2/genética , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Camundongos Knockout , Transdução de Sinais , Fosforilação , Plaquetas/metabolismo , Camundongos Endogâmicos C57BL , Trombocitopenia/metabolismo , Trombocitopenia/genética , Trombocitopenia/patologiaRESUMO
Liver kinase B1 (Lkb1), encoded by serine/threonine kinase (Stk11), is a serine/threonine kinase and tumor suppressor that is strongly implicated in Peutz-Jeghers syndrome (PJS). Numerous studies have shown that mesenchymal-specific Lkb1 is sufficient for the development of PJS-like polyps in mice. However, the cellular origin and components of these Lkb1-associated polyps and underlying mechanisms remain elusive. In this study, we generated tamoxifen-inducible Lkb1flox/flox;Myh11-Cre/ERT2 and Lkb1flox/flox;PDGFRα-Cre/ERT2 mice, performed single-cell RNA sequencing (scRNA-seq) and imaging-based lineage tracing, and aimed to investigate the cellular complexity of gastrointestinal polyps associated with PJS. We found that Lkb1flox/+;Myh11-Cre/ERT2 mice developed gastrointestinal polyps starting at 9 months after tamoxifen treatment. scRNA-seq revealed aberrant stem cell-like characteristics of epithelial cells from polyp tissues of Lkb1flox/+;Myh11-Cre/ERT2 mice. The Lkb1-associated polyps were further characterized by a branching smooth muscle core, abundant extracellular matrix deposition, and high immune cell infiltration. In addition, the Spp1-Cd44 or Spp1-Itga8/Itgb1 axes were identified as important interactions among epithelial, mesenchymal, and immune compartments in Lkb1-associated polyps. These characteristics of gastrointestinal polyps were also demonstrated in another mouse model, tamoxifen-inducible Lkb1flox/flox;PDGFRα-Cre/ERT2 mice, which developed obvious gastrointestinal polyps as early as 2-3 months after tamoxifen treatment. Our findings further confirm the critical role of mesenchymal Lkb1/Stk11 in gastrointestinal polyposis and provide novel insight into the cellular complexity of Lkb1-associated polyp biology. © 2024 The Pathological Society of Great Britain and Ireland.
Assuntos
Proteínas Quinases Ativadas por AMP , Síndrome de Peutz-Jeghers , Animais , Camundongos , Síndrome de Peutz-Jeghers/genética , Síndrome de Peutz-Jeghers/patologia , Proteínas Serina-Treonina Quinases/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Análise de Sequência de RNA , Serina , Tamoxifeno/farmacologiaRESUMO
Solid-state lithium batteries are promising next-generation energy storage systems for electric vehicles due to their high energy density and high safety and require achieving and maintaining intimate solid-solid interfaces for lithium-ion and electron transport. However, the solid-solid interfaces may evolve over cycling, disrupting the ion and electron diffusion pathways and leading to rapid performance degradation. The development of solid-state lithium batteries has been hindered by the lack of fundamental understanding of the interfacial microstructure change over cycling and its relation to electrochemical properties. Herein, we prepared a quasi-solid-state lithium battery, 30%LiFePO4-55%Li1.5Al0.5Ge1.5(PO4)3-15%C| Li1.5Al0.5Ge1.5(PO4)3|Li, by spark plasma sintering, and employed it as a model system to reveal the microstructure evolution at the solid-solid interfaces with electrochemical performance of the batteries. The electrochemical assessment showed that the quasi-solid-state lithium battery exhibited a discharge specific capacity of about 150 mAh g-1 in the first 80 cycles and then experienced severe capacity attenuation afterward, accompanied by a gradual internal resistance increase. Scanning electron microscopy observation showed that more cracks were formed inside the solid-state electrolyte and at the solid-solid interfaces as the battery cycled from 10 to 67 and 157 cycles. Detailed microstructure and phase analysis by high-resolution transmission electron microscopy and selected area electron diffraction discovered that the crack formation and performance decay were mainly caused by (1) the volume change of the LiFePO4 composite cathode during cycling, (2) the grain expansion of the Li1.5Al0.5Ge1.5(PO4)3 solid-state electrolyte at its interface with lithium anode, and (3) the formation of a solid electrolyte interphase layer, comprising Li2CO3, LiF, and LiTFSI, at the cathode-solid-state electrolyte interface. These microstructure changes built up over repeated battery cycling, ultimately causing the structure collapse and battery failure. The microstructure evolution information is expected to guide the design of better structures and interfaces for solid-state lithium batteries.
RESUMO
Pathological cardiac hypertrophy is the leading cause of heart failure and has an extremely complicated pathogenesis. TEA domain transcription factor 1 (TEAD1) is recognized as an important transcription factor that plays a key regulatory role in cardiovascular disease. This study aimed to explore the role of TEAD1 in cardiac hypertrophy and to clarify the regulatory role of small ubiquitin-like modifier (SUMO)-mediated modifications. First, the expression level of TEAD1 in patients with heart failure, mice, and cardiomyocytes is investigated. It is discovered that TEAD1 is modified by SUMO1 during cardiac hypertrophy and that the process of deSUMOylation is regulated by SUMO-specific protease 1 (SENP1). Lysine 173 is an essential site for TEAD1 SUMOylation, which affects the protein stability, nuclear localization, and DNA-binding ability of TEAD1 and enhances the interaction between TEAD1 and its transcriptional co-activator yes-associated protein 1 in the Hippo pathway. Finally, adeno-associated virus serotype 9 is used to construct TEAD1 wild-type and KR mutant mice and demonstrated that the deSUMOylation of TEAD1 markedly exacerbated cardiomyocyte enlargement in vitro and in a mouse model of cardiac hypertrophy. The results provide novel evidence that the SUMOylation of TEAD1 is a promising therapeutic strategy for hypertrophy-related heart failure.
Assuntos
Insuficiência Cardíaca , Sumoilação , Humanos , Camundongos , Animais , Cardiomegalia , Fatores de Transcrição/metabolismo , Insuficiência Cardíaca/metabolismo , Regulação da Expressão Gênica , Fatores de Transcrição de Domínio TEARESUMO
INTRODUCTION: The aim of this study was to explore the association between parental myopia and high myopia with children's refraction and ocular biometry in large-scale Chinese preschool children from the Beijing Hyperopia Reserve Study. SUBJECTS/METHODS: This cross-sectional kindergarten-based study enrolled children aged 3-6 years. Cycloplegic refraction, axial length (AL), and corneal radius (CR) were measured for all children. Parents were asked to complete a questionnaire about refractive status (no myopia, mild myopia <-3 D, moderate myopia ≥-3 D and ≤-6, and high myopia >-6 D). RESULTS: The study enrolled 2,053 children (1,069 boys and 984 girls), with a mean age of 4.26 ± 0.96 years and mean spherical equivalent refraction (SER) of 1.11 ± 0.97 diopter. Of the children, 90.7% had at least one myopic parent, and 511 children (24.9%) had at least one highly myopic parent. SER decreased significantly with increasing severity of parental myopia (p < 0.001). Preschool children's myopia was independently associated with parental myopia (OR, 10.4 and 11.5 for one and two highly myopic parent[s]). Age (OR = 1.1), gender (OR = 1.7; girls as references), near work time (OR = 1.2), and both maternal (OR, 1.4 and 2.0 for moderate and high myopia) and paternal myopia (OR, 1.6 and 1.9 for moderate and high myopia) were independent risk factors for lacking hyperopia reserve. CONCLUSION: Severe parental myopia was associated with a lower SER, longer AL, and higher AL/CR ratio in preschool children. Parental myopia and near work may predispose children to faster elimination of hyperopia reserves before exposure to higher educational stress.
Assuntos
Hiperopia , Miopia , Masculino , Feminino , Humanos , Pré-Escolar , Hiperopia/diagnóstico , Estudos Transversais , Miopia/diagnóstico , Refração Ocular , Pais , Córnea , BiometriaRESUMO
BACKGROUND: Transforming growth factor-ß1 (TGF-ß1) modulates multiple cellular functions during development and tissue homeostasis. A large amount of TGF-ß1 is stored in platelet α-granules and released upon platelet activation. Whether platelet-derived TGF-ß1 plays a role in venous thrombosis remains unclear. This study intends to assess the role of platelet-derived TGF-ß1 in the development of venous thrombosis in mice. MATERIAL AND METHODS: TGF-ß1flox/flox and platelet-specific TGF-ß1-/- mice were utilized to assess platelet function in vitro, arterial thrombosis induced by FeCl3, tail bleeding time, prothrombin time (PT), activated partial thromboplastin time (APTT), and deep vein thrombosis induced through ligation of the inferior vena cava (IVC). The IVC sample was collected to measure accumulation of neutrophils, monocytes, and the formation of neutrophil extracellular traps (NETs) by immunofluorescence staining. RESULTS: TGF-ß1 deficiency in platelets did not affect the number of circulating platelets, platelet aggregation, adenosine triphosphate release, and integrin αIIbß3 activation. Meanwhile, TGF-ß1 deficiency did not alter the arterial thrombus formation, hemostasis, and coagulation time (PT and APTT), but significantly impaired venous thrombus formation, inhibited the recruitment and accumulation of neutrophils and monocytes in thrombi, as well as reduced formation of NETs and platelet-neutrophil complex. In addition, adoptive transfer of TGF-ß1flox/flox platelets to TGF-ß1-/- mice rescued the impaired venous thrombus formation, recruitment of leukocytes and monocytes, as well as the NETs formation. CONCLUSION: In conclusion, platelet-derived TGF-ß1 positively modulates venous thrombus formation in mice, indicating that targeting TGF-ß1 might be a novel approach for treating venous thrombosis without increasing the risk of bleeding.
Assuntos
Plaquetas , Camundongos Knockout , Fator de Crescimento Transformador beta1 , Trombose Venosa , Animais , Trombose Venosa/sangue , Trombose Venosa/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Plaquetas/metabolismo , Camundongos , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Ativação Plaquetária , Coagulação Sanguínea , Agregação Plaquetária , Armadilhas Extracelulares/metabolismo , Masculino , Neutrófilos/metabolismo , Veia Cava Inferior/patologia , Veia Cava Inferior/metabolismo , HemostasiaRESUMO
Surgical residual tumor lesions (R1 resection of surgical procedures (e.g., liver cancer infiltrating the diaphragm, surgical residual breast cancer, postoperative residual ovarian cancer) or boundary residual after ablation) and lymph node metastasis that cannot be surgically resected (retroperitoneal lymph nodes) significantly affect postoperative survival of tumor patients. This clinical conundrum poses three challenges for local drug delivery systems: stable and continuous delivery, good biocompatibility, and the ability to package new targeted drugs that can synergize with other treatments. Here, a drug-laden hydrogel generated from pure DNA strands and highly programmable in adjusting its mesh size is reported. Meanwhile, the DNA hydrogel can assist the microcrystallization of novel radiosensitizing drugs, ataxia telangiectasia and rad3-related protein (ATR) inhibitor (Elimusertib), further facilitating its long-term release. When applied to the tumor site, the hydrogel system demonstrates significant antitumor activity, minimized systemic toxicity, and has a modulatory effect on the tumor-immune cell interface. This drug-loaded DNA-hydrogel platform represents a novel modality for adjuvant therapy in patients with surgical residual tumor lesions and lymph node metastasis.
RESUMO
OBJECTIVES: To analyze the hemostatic effect of different application methods and time of tranexamic acid (TXA) on primary unilateral total hip arthroplasty. METHODS: A total of 126 patients with primary unilateral total hip replacement admitted between January 2019 and January 2021 were recruited. The patients were divided into three groups (42 people in each group) by random number table method. In group I, 2.0 g TXA was perfused locally into the hip joint cavity through the drainage tube for 2 h. Group II was perfused locally with the same method for 4 h. Group III was given TXA 15 mg/kg intravenously 5-10 min before surgical incision. The hemoglobin concentration, red blood cell (RBC) count, international normalized ratio (INR), activated partial thromboplastin time (APTT), fibrinogen (FIB), D-Dimer (D-D), intraoperative blood loss, postoperative blood loss, implicit blood loss, total blood loss, postoperative blood transfusion and complications were compared. RESULTS: The postoperative drainage volume of group I (195.07 ± 34.65) mL and group II (199.62 ± 38.07) mL was significantly lower than that of group III (213.12 ± 25.05) mL (P = 0.037). There was no significant difference in postoperative drainage between group I and group II (P > 0.05). There was no significant difference in intraoperative blood loss, hidden blood loss and total blood loss between the three groups (P > 0.05). There was no difference in the incidence of deep vein thrombosis among the three groups (P > 0.05). CONCLUSIONS: TXA is a safe and effective way of hemostasis in total hip arthroplasty. Local intraarticular application of TXA can reduce the postoperative drainage, but the difference is not clinically significant, probably due to the number of samples. There is no difference in the postoperative drainage after local application of 2 or 4 h, and there is no difference in the overall hemostasis effect between intravenous or local application of TXA.
RESUMO
B cells can promote liver fibrosis, but the mechanism of B cell infiltration and therapy against culprit B cells are lacking. We postulated that the disruption of cholangiocyte-B-cell crosstalk could attenuate liver fibrosis by blocking the CXCL12-CXCR4 axis via a cyclooxygenase-2-independent effect of celecoxib. In wild-type mice subjected to thioacetamide, celecoxib ameliorated lymphocytic infiltration and liver fibrosis. By single-cell RNA sequencing and flow cytometry, CXCR4 was established as a marker for profibrotic and liver-homing phenotype of B cells. Celecoxib reduced liver-homing B cells without suppressing CXCR4. Cholangiocytes expressed CXCL12, attracting B cells to fibrotic areas in human and mouse. The proliferation and CXCL12 expression of cholangiocytes were suppressed by celecoxib. In CXCL12-deficient mice, liver fibrosis was also attenuated with less B-cell infiltration. In the intrahepatic biliary epithelial cell line HIBEpiC, bulk RNA sequencing indicated that both celecoxib and 2,5-dimethyl-celecoxib (an analog of celecoxib that does not show a COX-2-dependent effect) regulated the TGF-ß signaling pathway and cell cycle. Moreover, celecoxib and 2,5-dimethyl-celecoxib decreased the proliferation, and expression of collagen I and CXCL12 in HIBEpiC cells stimulated by TGF-ß or EGF. Taken together, liver fibrosis can be ameliorated by disrupting cholangiocyte-B cell crosstalk by blocking the CXCL12-CXCR4 axis with a COX-2-independent effect of celecoxib.
Assuntos
Cirrose Hepática , Transdução de Sinais , Camundongos , Animais , Humanos , Celecoxib/farmacologia , Celecoxib/uso terapêutico , Celecoxib/metabolismo , Ciclo-Oxigenase 2 , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Quimiocina CXCL12/farmacologia , Células Epiteliais/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Receptores CXCR4/genética , Proliferação de CélulasRESUMO
Background: Allergen immunotherapy is the only etiological treatment for allergic rhinitis. Objective: To analyze the efficacy, safety, and mechanism of subcutaneous immunotherapy (SCIT). Methods: The efficacy, safety, and serum immunological changes of 3 modes of subcutaneous immunotherapy were compared. Peripheral blood mononuclear cells (PBMC) transcriptome changes were obtained on the Illumina sequencing platforms. We confirmed differentially expressed genes (DEGs) by quantitative real-time polymerase chain reaction (PCR). The DEGs were analyzed by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) networks. The correlation between the common DEGs and clinical indicators was analyzed by Origin 2022. Results: The 3 SCITs were all effective after 1 year. The Combined Symptom and Medication Score (CSMS) and Visual Analog Score (VAS) in rush immunotherapy (RIT) are lowest after 24 and 48 weeks of treatment among the 3 groups. After treatment, the levels of sIgE, sIgE/tIgE, Th2 cytokines, Th17 cytokines, and percentage of peripheral eosinophils (EOS%) decreased significantly (Pï¼0.05), while the levels of Th1 type cytokines did not change significantly. Transcriptome analysis identified 24, 24, and 91 DEGs at W3 and 42, 52, 175 DEGs at W7 in conventional immunotherapy (CIT), cluster immunotherapy (CLIT), and RIT groups, respectively. The pathways and functions involved in SCIT include secretion of Th1/2 cytokines, immune cell differentiation. Unlike CIT and CLIT, DEGs are also involved in T cell tolerance induction, T cell anergy, and lymphocyte anergy in RIT. CXCR1, CXCR2, and IER3 had a specific effect on reflecting the improvement of symptoms in allergic rhinitis patients with SCIT. Conclusion: The clinical efficacy of RIT appeared earlier than CIT and CLIT. Clinicians can use the highly conserved gene expression profile to evaluate responses to immunotherapy.
RESUMO
Human MutT Homolog 1 (MTH1) is a nucleotide pool sanitization enzyme that hydrolyzes oxidized nucleotides to prevent their mis-incorporation into DNA under oxidative stress. Expression and functional roles of MTH1 in platelets are not known. Here, we show MTH1 expression in platelets and its deficiency impairs hemostasis and arterial/venous thrombosis in vivo. MTH1 deficiency reduced platelet aggregation, phosphatidylserine exposure and calcium mobilization induced by thrombin but not by collagen-related peptide (CRP) along with decreased mitochondrial ATP production. Thrombin but not CRP induced Ca2+-dependent mitochondria reactive oxygen species generation. Mechanistically, MTH1 deficiency caused mitochondrial DNA oxidative damage and reduced the expression of cytochrome c oxidase 1. Furthermore, MTH1 exerts a similar role in human platelet function. Our study suggests that MTH1 exerts a protective function against oxidative stress in platelets and indicates that MTH1 could be a potential therapeutic target for the prevention of thrombotic diseases.
Assuntos
Plaquetas , Trombose , Humanos , Plaquetas/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Trombina/farmacologia , Trombina/metabolismo , Estresse Oxidativo , Hemostasia , Nucleotídeos/metabolismo , Mitocôndrias/metabolismo , Trombose/genética , Trombose/prevenção & controle , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismoRESUMO
A solitary large ulcerated mass is the common morphological feature of diffuse large B-cell lymphoma (DLBCL) in the large intestine under endoscopy. Here we report a 54-year-old man with DLBCL presenting with multiple polypoid lesions in the large intestine, which is an uncommon morphological form of DLBCL.
RESUMO
BACKGROUND: Hepatocyte-cholangiocyte transdifferentiation (HCT) is a potential origin of proliferating cholangiocytes in liver regeneration after chronic injury. This study aimed to determine HCT after chronic liver injury, verify the impacts of HCT on liver repair, and avoid harmful regeneration by understanding the mechanism. METHODS: A thioacetamide (TAA)-induced liver injury model was established in wild-type (WT-TAA group) and COX-2 panknockout (KO-TAA group) mice. HCT was identified by costaining of hepatocyte and cholangiocyte markers in vivo and in isolated mouse hepatocytes in vitro. The biliary tract was injected with ink and visualized by whole liver optical clearing. Serum and liver bile acid (BA) concentrations were measured. Either a COX-2 selective inhibitor or a ß-catenin pathway inhibitor was administered in vitro. RESULTS: Intrahepatic ductular reaction was associated with COX-2 upregulation in chronic liver injury. Immunofluorescence and RNA sequencing indicated that atypical cholangiocytes were characterized by an intermediate genetic phenotype between hepatocytes and cholangiocytes and might be derived from hepatocytes. The structure of the biliary system was impaired, and BA metabolism was dysregulated by HCT, which was mediated by the TGF-ß/ß-catenin signaling pathway. Genetic deletion or pharmaceutical inhibition of COX-2 significantly reduced HCT in vivo. The COX-2 selective inhibitor etoricoxib suppressed HCT through the TGF-ß-TGFBR1-ß-catenin pathway in vitro. CONCLUSIONS: Atypical cholangiocytes can be derived from HCT, which forms a secondary strike by maldevelopment of the bile drainage system and BA homeostasis disequilibrium during chronic liver injury. Inhibition of COX-2 could ameliorate HCT through the COX-2-TGF-ß-TGFBR1-ß-catenin pathway and improve liver function.
RESUMO
OBJECTIVE: This study (NCT05588531) aimed to evaluate the safety and pharmacokinetics of cefepime-avibactam (YK-1169) in healthy Chinese subjects and explore the optimal regimen for treating carbapenem-resistant Klebsiella pneumoniae (CRKP) based on the pharmacokinetic/pharmacodynamic evaluation. METHODS: YK-1169 single-ascending doses (0.5, 1.25, 2.5 or 3.75 g, 2-h infusion) and multiple doses (2.5 or 3.75 g every 8 h [q8h], 2-h infusion) given for 7 days were evaluated in pharmacokinetic studies. Subjects were randomized to receive cefepime (2 g), avibactam (0.5 g) or YK-1169 (2.5 g) to assess drug-drug interactions. The minimum inhibitory concentrations (MICs) of YK-1169 were determined by the broth microdilution method. Monte Carlo simulation was used to evaluate 10 different dose regimens. RESULTS: Cefepime and avibactam both showed a linear pharmacokinetic profile. No accumulation was found after multiple doses. The cefepime Cmax,ss and AUC0-∞,ss were 9.20 and 16.0 µg/mL, 407.2 and 659.45 µg·h/mL in the 2.5 and 3.75 g multiple-dose groups, respectively. The avibactam Cmax,ss and AUC0-∞,ss were 0.545 and 0.837 µg/mL, 53.31 and 79.55 µg·h/mL in the 2.5 and 3.75 g multiple-dose groups, respectively. Cefepime and avibactam did not affect each other's pharmacokinetics. No serious adverse events occurred. All regimens achieved 90% probability of target attainment (PTA) goals when the MIC was ≤8 mg/L. The regimens of 2.5 (q8h, 2-h infusion), 3.75 (q8h, 2-, 3- and 4-h infusions) and 7.5 g (24-h continuous infusion) reached a 90% cumulative fraction of response. CONCLUSION: YK-1169 had good antibacterial activity against CRKP and could be an option for CRKP infections. The regimen of 2.5 g q8h intravenously guttae (ivgtt) 2 h should be considered in future clinical trials.
Assuntos
Antibacterianos , Humanos , Cefepima/efeitos adversos , Método de Monte Carlo , Voluntários Saudáveis , Antibacterianos/efeitos adversos , Testes de Sensibilidade MicrobianaRESUMO
BACKGROUND AND AIMS: Sodium-hydrogen exchanger 8 (NHE8) is expressed in array of tissues and has pleiotropic functions beyond simply exchanging sodium and hydrogen across cell membrane. This study investigates the expression pattern of liver NHE8 and its roles in carbon tetrachloride (CCl4)-induced liver injury. METHODS: NHE8 expression pattern was investigated in mouse livers of different ages and in HepG2 cells. CCl4 was given to mice to determine NHE8 expression in CCl4-induced liver injury. Tumor necrosis factor (TNF)-α and interleukin (IL)-1ß were used to treat HepG2 cells to evaluate their effect on NHE8 expression. The CCl4-induced acute and chronic liver injuries were also used in NHE8KO mice to determine the role of NHE8 deficiency in liver injury. RESULTS: NHE8 was mainly detected in the peripheral area of hepatocytes in mouse liver and in HepG2 cells. The liver NHE8 expression was 47% of NHE1, and liver NHE8 expression was the lowest at suckling age and reached plateau at 4 weeks of age. Similar to dextran sulfate sodium colitis reduced intestinal NHE8, CCl4-induced acute liver injury also inhibited NHE8 expression. The absence of NHE8 in the liver displayed abnormal hepatocyte morphology and has elevated expression of IL-1ß and Lgr5. However, unlike NHE8 deficiency enhanced dextran sulfate sodium-induced colon tissue damage, the absence of NHE8 in the liver did not exacerbate CCl4-induced liver injury. Although both TNF-α and IL-1ß were elevated in CCl4-induced liver injury, they could not inhibit NHE8 expression in hepatocytes, which is in contrast with TNF-α-mediated NHE8 inhibition in the intestine. CONCLUSION: Liver NHE8 has unique roles that are different from the intestine.