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BACKGROUND: Myelin sheath is a crucial accessory to the functional nerve-fiber unit, its disruption or loss can lead to axonal degeneration and subsequent neurodegenerative diseases (NDs). Notwithstanding of substantial progress in possible molecular mechanisms underlying myelination, there is no therapeutics that prevent demyelination in NDs. Therefore, it is crucial to seek for potential intervention targets. Here, we focused on the transcriptional factor, signal transducer and activator of transcription 1 (Stat1), to explore its effects on myelination and its potential as a drug target. METHODS: By analyzing the transcriptome data obtained from Schwann cells (SCs) at different stages of myelination, it was found that Stat1 might be involved in myelination. To test this, we used the following experiments: (1) In vivo, the effect of Stat1 on remyelination was observed in an in vivo myelination mode with Stat1 knockdown in sciatic nerves or specific knockdown in SCs. (2) In vitro, the RNA interference combined with cell proliferation assay, scratch assay, SC aggregate sphere migration assay, and a SC differentiation model, were used to assess the effects of Stat1 on SC proliferation, migration and differentiation. Chromatin immunoprecipitation sequencing (ChIP-Seq), RNA-Seq, ChIP-qPCR and luciferase activity reporter assay were performed to investigate the possible mechanisms of Stat1 regulating myelination. RESULTS: Stat1 is important for myelination. Stat1 knockdown in nerve or in SCs reduces the axonal remyelination in the injured sciatic nerve of rats. Deletion of Stat1 in SCs blocks SC differentiation thereby inhibiting the myelination program. Stat1 interacts with the promoter of Rab11-family interacting protein 1 (Rab11fip1) to initiate SC differentiation. CONCLUSION: Our findings demonstrate that Stat1 regulates SC differentiation to control myelinogenic programs and repair, uncover a novel function of Stat1, providing a candidate molecule for clinical intervention in demyelinating diseases.
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Bainha de Mielina , Fator de Transcrição STAT1 , Células de Schwann , Animais , Ratos , Axônios , Diferenciação Celular , Regeneração Nervosa , Células de Schwann/metabolismo , Nervo Isquiático , Fator de Transcrição STAT1/metabolismoRESUMO
Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by hyperinflammation and organ failure, with a high mortality rate. Current first-line treatments for adult patients have limited efficacy and significant toxicity. The novel selective histone deacetylase inhibitor (HDACi), chidamide, has shown promise in preclinical studies for the potential treatment of HLH. Methods: An open-label, single-center study was conducted to evaluate the efficacy and safety of chidamide in combination with etoposide and glucocorticoids for the treatment of HLH in adult patients. Seventeen patients who fulfilled at least five of the eight HLH-2004 criteria were enrolled and treated with the combination therapy. The primary outcome was overall response rate (ORR), and secondary outcomes included survival, safety and tolerability, and changes in laboratory indicators. Results: A total of 17 HLH patients who met the inclusion criteria were enrolled in this study, with a male to female ratio of 1.8:1. The age range at enrollment was 31 to 71 years old, with a median age of 52 years old. The ORR was 76.5% (13/17 patients), with a complete response (CR) rate of 17.6% (3/17 patients) and a partial response (PR) rate of 58.8% (10/17 patients). The median overall survival (OS) was not achieved, with OS at 6 months and 12 months being 81% and 65%, respectively. The median progression free survival (PFS) was not achieved, with PFS at 6 months and 12 months being 68% and 55%, respectively. Hematologic toxicities is the most common. Safety profile was favorable, with very few cases of grade 3/4 toxicities observed. The results showed that the levels of sCD25, platelets, aspartate aminotransferase, lactate dehydrogenase, and albumin in these patients were significantly improved 3 weeks after treatment. Conclusion: The addition of chidamide to etoposide and glucocorticoids may be a promising new treatment option for patients with HLH, with a high ORR, manageable safety profile, and significant improvement in laboratory indicators. Further research is needed to confirm these findings and determine the optimal dosing and duration of therapy.
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Aminopiridinas , Benzamidas , Etoposídeo , Glucocorticoides , Linfo-Histiocitose Hemofagocítica , Humanos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Masculino , Feminino , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/mortalidade , Adulto , Pessoa de Meia-Idade , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Benzamidas/uso terapêutico , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Glucocorticoides/efeitos adversos , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Aminopiridinas/uso terapêutico , Resultado do Tratamento , Idoso , Quimioterapia Combinada , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Histona Desacetilases/efeitos adversos , Inibidores de Histona Desacetilases/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: Although Klotho-related research has seen a significant upsurge, the field lacks comprehensive analytical representation and in-depth exploration of pertinent areas such as prevailing research trends and key focus areas. METHOD: This review presents a bibliometric analysis of literature data gathered from the Web of Science Core Collection databases from January 1, 2000, to April 30, 2023. Parameters such as co-authorship, co-citation, co-occurrence, and the emergence of publications, countries, categories, references, and keywords were scrutinized predominantly using Citespace software. RESULTS: Our investigation amassed a total of 3548 papers, with the United States leading in the quantity of publications (1175, accounting for 33.12%), followed by China (867, representing 24.44%), and Japan (439, accounting for 12.37%). While the United States is preeminent in the overall volume of publications, Scotland holds prominence in terms of centrality. Out of a total of 96 subject categories, urology and nephrology (573), and endocrinology and metabolism (542) were the two leading domains of Klotho-related publications. The 2011 paper titled "FGF23 induces left ventricular hypertrophy" by Faul C et al. holds the distinction of being the most frequently cited. The keywords "fibroblast growth factor 23," "phosphate homeostasis," and "functional variants" demonstrated the highest intensity, underscoring the potential of these research areas. CONCLUSION: As the volume of literature grows, the role of Klotho in disease management and its applicability as a marker in disease progression warrant vigilant tracking and study.
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Bibliometria , Gerenciamento Clínico , Humanos , China , Bases de Dados Factuais , Hipertrofia Ventricular EsquerdaRESUMO
Background And Objectives: Chronic active Epstein-Barr virus disease (CAEBV) is a proliferative disease of EBV+ T or natural killer (NK) cells with an unclear pathogenesis. This study aimed to examine the frequency and exhaustion levels of lymphocyte subsets in patients with CAEBV to further investigate the pathogenesis. Methods: Using flow cytometry, we detected the frequency, expression levels of programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1), and EBV infection status of peripheral T subsets and NK cells in patients with CAEBV and healthy individuals. Results: 24 patients and 15 healthy individuals were enrolled in this study. Patients showed notably higher expression levels of PD-1 and PD-L1 in peripheral T subsets and NK cells compared to healthy individuals (P < 0.05). EBV+ lymphocytes exhibited significantly higher PD-L1 expression levels than EBV- lymphocytes. Additionally, the frequency of effector memory T (Tem) cells was significantly increased in patients, and the PD-L1 expression level was positively correlated with the EBV load. Besides, helper T cell 2 (Th2) immune bias, also favoring EBV amplification, was found in patients, including increased Th2 cell frequency, enhanced response capacity, and elevated serum levels of associated cytokines. The distribution and PD-1 expression levels of peripheral T subsets returned to normal in patients who responded to PD-1 blockade therapy. Conclusions: The up-regulation of the PD-1/PD-L1 pathway of peripheral T and NK cells and Th2 immune predominance jointly promoted EBV replication and the development of CAEBV. PD-1 blockade therapy reduced the PD-1 expression level of lymphocytes and helped normalize the distribution of the T subsets.
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Germline HAVCR2 mutation has been reported to be associated with subcutaneous panniculitis-like T-cell lymphoma (SPTCL) leading to Hemophagocytic lymphohistiocytosis (HLH). Several studies have indicated that HAVCR2 mutation can cause HLH even in the absence of lymphoma, though the exact mechanism remains unclear. In this article, we reported five cases of HAVCR2 mutation-associated HLH. Our analysis revealed an elevated level of IL-1RA in the serum of these patients. Furthermore, we investigated the potential mechanisms underlying HLH associated with HAVCR2 mutation based on changes in cytokine levels. Our findings suggest that HAVCR2 mutation may represent a distinct genetic defect underlying HLH, differing from traditional primary HLH.
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Linfo-Histiocitose Hemofagocítica , Linfoma de Células T , Paniculite , Humanos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/complicações , Paniculite/patologia , Linfoma de Células T/patologia , Mutação , Mutação em Linhagem Germinativa , Receptor Celular 2 do Vírus da Hepatite A/genéticaRESUMO
The band level landscape in quantum dots is of great significance toward achieving stable and efficient electroluminescent devices. A series of quantum dots with specific emission and band structure of the intermediate layer is designed, including rich CdS (R-CdS), thick ZnSe (T-ZnSe), thin ZnSe (t-ZnSe) and ZnCdS (R-ZnCdS) intermediate alloy shell layers. These quantum dots in QLEDs show superior performance, including maximum current efficiency, external quantum efficiencies and a T50 lifetime (at 1000 cd/m2) of 47.2 cd/A, 11.2% and 504 h for R-CdS; 61.6 cd/A, 14.7% and 612 h for t-ZnSe; 70.5 cd/A, 16.8% and 924 h for T-ZnSe; and 82.0 cd/A, 19.6% and 1104 h for R-ZnCdS. Among them, the quantum dots with the ZnCdS interlayer exhibit deep electron confinement and shallow hole confinement capabilities, which facilitate the efficient injection and radiative recombination of carriers into the emitting layer. Furthermore, the optimal devices show a superior T50 lifetime of more than 1000 h. The proposed novel methodology of quantum dot band engineering is expected to start a new way for further enhancing QLED exploration.
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We reported a case of a 19-year-old male patient with central nervous system symptoms as the main clinical manifestations, and multiple intracranial and abdominal occupying lesions visualized by imaging examinations, who was initially misdiagnosed as NK/T-cell lymphoma but poorly responsive to the treatment. Finally, he was diagnosed as familial hemophagocytic lymphohistiocytosis type-2 by genome sequencing, perforin test and pedigree study. The patient survived well after allogeneic hematopoietic stem cell transplantation. Central nervous system symptoms could be the main clinical manifestations in patients with primary hemophagocytic lymphohistiocytosis , whose early-stage manifestations of blood system were usually atypical, easily leading to misdiagnosis. In clinical practice, primary hemophagocytic lymphohistiocytosis should be considered in patients with central nervous system symptoms and unknown causes. The combination of rapid immunological function test and genome sequencing contributes to the diagnosis of primary hemophagocytic lymphohistiocytosis.
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Background: Axonal myelination is critical for the functioning of vertebrate nervous system. Myelin sheath malformation or degeneration can cause a variety of neurological diseases. Our previous study identified multiple potential myelination-related transcriptional factors (TFs), including expressed sequence tag (ETS) variant transcription factor 1 (Etv1)/Er81, via gene microarray analysis of Schwann cells (SCs) at various myelination stages. Etv1 is known to be involved in the regulation of neuronal specialization, muscle spindle differentiation, and sensorimotor connectivity. However, to our knowledge, to date, there are no relevant studies that Etv1 regulates SC myelination. Methods: To investigate the roles of Etv1 in SC re-myelination, an in vivo mouse myelination model was used, in which the sciatic nerve is crushed. Etv1 in nerves was knocked down via in situ injection of cholesterol-modified Etv1-small interfering (si)RNA. The expression of myelin-associated glycoprotein (MAG) was evaluated by Western blotting (WB) and immunohistochemistry (IHC). Myelination was assessed by transmission electron microscopy (TEM). The effects of Etv1 on SC proliferation, migration, and differentiation were assessed in vitro using the EdU cell proliferation kit, a culture-insert scratch assay, a SC aggregate sphere migration assay on the axons of dorsal root ganglions (DRGs), and a SC differentiation model. Chromatin immunoprecipitation (ChIP) united with quantitative real-time PCR (qPCR), known as ChIP-qPCR, and luciferase activity reporter assays were performed to explore the possible mechanisms by which Etv1 controls SC differentiation and myelination. Results: The results demonstrated that Etv1 promoted myelination by facilitating SC proliferation, migration, and differentiation. Etv1 expression in SCs was upregulated during re-myelination, and knocking down Etv1 expression dramatically abrogated SC re-myelination in the crushed sciatic nerves. Moreover, silencing of Etv1 by siRNA in SCs in vitro inhibited its migration, proliferation, and differentiation. The results of ChIP-qPCR and luciferase reporter assay showed that Etv1 may regulate SC differentiation and myelination by binding to the promoters of myelination-related genes, such as MAG and Runx2, to initiate their transcription. Conclusions: Taken together, these findings demonstrated a previously unknown role of Etv1 in SC differentiation and myelination, providing a candidate molecular target for clinical interventions in demyelinating diseases.
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Background: Acellular tissue has been transplanted into the injury site as an external microenvironment to intervene with imbalance microenvironment that occurs after spinal cord injury (SCI) and stimulating axonal regeneration, although the mechanism is unclear. Given decellularization is the key means to obtain acellular tissues, we speculated changes in the internal components of tissue caused by decellularization may be the key reason why acellular tissues affect remodeling of the microenvironment. Methods: Complete spinal cord crush in a mouse model was established, and the dynamic of extracellular matrix (ECM) expression and distribution during SCI was studied with immunohistochemistry (IHC). Normal spinal cord (NSC) and 14-day injury spinal cord (ISC) were obtained to prepare the decellularized NSC (DNSC) and decellularized ISC (DISC) through a well-designed decellularization method, and the decellularization effects were evaluated by residual DNA content determination, hematoxylin and eosin staining (H&E), and IHC. Rat dorsal root ganglia (DRG) were co-cultured with NSC, ISC, DNSC, and DISC to evaluate their effect on neurite outgrowth. Furthermore, the mechanisms by which decellularized tissue promotes axonal growth were explored with proteomics analysis of the protein components and function of 14-day ISC and DISC. Results: We found the expression of the four main ECM components (collagen type I and IV, fibronectin, and laminin) gradually increased with the progression of SCI compared to NSC, peaking at 14 days of injury then slightly decreasing at 21 days, and the distribution of the four ECM proteins in the ISC also changed dynamically. H&E staining, residual DNA content determination, and IHC showed decellularization removed cellular components and preserved an intact ECM. The results of co-cultured DRG with NSCs, ISCs, DNSCs, and DISCs showed DNSCs and DISCs had a stronger ability in supporting neurite outgrowth than NSC and ISC. We found through proteomics that decellularization could remove proteins associated with inflammatory responses, scarring, and other pathological factors, while completely retaining the ECM proteins. Conclusions: Taken together, our findings demonstrate decellularization can optimize the imbalanced microenvironment after SCI by removing components that inhibit spinal cord regeneration, providing a theoretical basis for clinical application of acellular tissue transplantation to repair SCI.
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Enhancing remyelination after injury is of utmost importance for optimizing the recovery of nerve function. While the formation of myelin by Schwann cells (SCs) is critical for the function of the peripheral nervous system, the temporal dynamics and regulatory mechanisms that control the progress of the SC lineage through myelination require further elucidation. Here, using in vitro co-culture models, gene expression profiling of laser capture-microdissected SCs at various stages of myelination, and multilevel bioinformatic analysis, we demonstrated that SCs exhibit three distinct transcriptional characteristics during myelination: the immature, promyelinating, and myelinating states. We showed that suppressor interacting 3a (Sin3A) and 16 other transcription factors and chromatin regulators play important roles in the progress of myelination. Sin3A knockdown in the sciatic nerve or specifically in SCs reduced or delayed the myelination of regenerating axons in a rat crushed sciatic nerve model, while overexpression of Sin3A greatly promoted the remyelination of axons. Further, in vitro experiments revealed that Sin3A silencing inhibited SC migration and differentiation at the promyelination stage and promoted SC proliferation at the immature stage. In addition, SC differentiation and maturation may be regulated by the Sin3A/histone deacetylase2 (HDAC2) complex functionally cooperating with Sox10, as demonstrated by rescue assays. Together, these results complement the recent genome and proteome analyses of SCs during peripheral nerve myelin formation. The results also reveal a key role of Sin3A-dependent chromatin organization in promoting myelinogenic programs and SC differentiation to control peripheral myelination and repair. These findings may inform new treatments for enhancing remyelination and nerve regeneration.
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Cromatina , Células de Schwann , Animais , Axônios , Cromatina/metabolismo , Perfilação da Expressão Gênica , Bainha de Mielina/metabolismo , Regeneração Nervosa/fisiologia , Ratos , Células de Schwann/metabolismo , Nervo Isquiático/lesõesRESUMO
A favorable microenvironment plays an important role in nerve regeneration. Extracellular matrix (ECM) derived from cultured cells or natural tissues can facilitate nerve regeneration in the presence of various microenvironmental cues, including biochemical, spatial, and biomechanical factors. This study, through proteomics and three-dimensional image analysis, determines that the components and spatial organization of the ECM secreted by bone marrow mesenchymal cells (BMSCs) are more similar to acellular nerves than those of the ECMs derived from Schwann cells (SCs), skin-derived precursor Schwann cells (SKP-SCs), or fibroblasts (FBs). ECM-modified nerve grafts (ECM-NGs) are engineered by co-cultivating BMSCs, SCs, FBs, SKP-SCs with well-designed nerve grafts used to bridge nerve defects. BMSC-ECM-NGs exhibit the most promising nerve repair properties based on the histology, neurophysiology, and behavioral analyses. The regeneration microenvironment formed by the ECM-NGs is also characterized by proteomics, and the advantages of BMSC-ECM-NGs are evidenced by the enhanced expression of factors related to neural regeneration and reduced immune response. Together, these findings indicate that BMSC-derived ECMs create a more superior microenvironment for nerve regeneration than that by the other ECMs and may, therefore, represent a potential alternative for the clinical repair of peripheral nerve defects.
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Regeneração Nervosa , Células de Schwann , Células da Medula Óssea , Matriz Extracelular/metabolismo , Regeneração Nervosa/fisiologia , Nervos Periféricos , Células de Schwann/transplante , Nervo IsquiáticoRESUMO
Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia. Although the clear mechanisms of DM and insulin resistance are still to be cleared, it has been well documented that reactive oxygen species (ROS) play a pivotal role in DM and multiple types of insulin resistance. For the past few years, natural substances have been shown to have the potential to treatment DM. Attention has been especially focused on plants rich in triterpenoids, which generally show antioxidant and antiglycation effect. In our previous studies, it was shown that oleanolic acid (OA), a natural triterpenoid and an aglycone of many saponins, is a potent antioxidant acting as not only a free radical-scavenger through direct chemical reactions but also as a biological molecule, which may enhance the antioxidant defenses. The present study aimed to investigate the potential antidiabetic effect of OA. Oleanolic acid showed a significant blood glucose-lowering and weight-losing effect in diabetic animals induced by streptozotocin (STZ). In the insulin resistant model, it was also shown that OA may promote insulin signal transduction and inhibit oxidative stress-induced hepatic insulin resistance and gluconeogenesis, in which process the phosphorylation of ERK and the protective effect on mitochondrial function may be involved. These findings may significantly better the understanding of the pharmacological actions of OA and advance therapeutic approaches to DM.
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Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Ácido Oleanólico/farmacologia , Animais , Antioxidantes/farmacologia , Glicemia/efeitos dos fármacos , Linhagem Celular , Hepatócitos/efeitos dos fármacos , Humanos , Insulina/metabolismo , Resistência à Insulina , Masculino , Potencial da Membrana Mitocondrial , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Aortic dissection (AD) and aortic aneurysm (AA) are critical illnesses with an unclear pathogenetic mechanism that seriously threaten human life. Aortic medial degeneration (AMD) is the main pathological feature of AD and AA. Diseases of iron metabolism can cause a variety of physiological dysfunctions. In this study, we aimed to clarify the state of iron metabolism in patients with AD and AA, and to explore the effect of iron metabolism on AMD. METHODS: A total of 200 patients with AD or AA, and 60 patients with hypertension were included in the study. Blood samples were drawn immediately when patients were admitted to the hospital. Aortic specimens from patients with Stanford type A AD were obtained at the time of surgery. The status of iron metabolism in the circulation and the aortic wall was analyzed. In addition, apolipoprotein E knockout mice were fed chow with a different iron content, and angiotensin II (Ang II) was used to induce AMD. Furthermore, transferrin receptor 1 knockout (TFR1-/-) mice were used to study the effects of iron deficiency (ID) on aortic development, to observe the effects of different iron metabolism status on the formation of AMD in mice, and to explore the cytoskeleton of vascular smooth muscle cells (VSMCs) under different iron metabolism. RESULTS: Patients with AMD were iron deficient. ID is associated with the development of AMD in hypertensive patients. Iron-deficient feeding combined with Ang II pumping promoted the formation of AMD and significantly shortened the survival time of mice. ID significantly impaired the cytoskeleton of VSMCs. CONCLUSIONS: Our results highlighted that ID was associated with the formation of AMD in patients with hypertension. In this study, we identified a novel mechanism behind VSMCs dysfunction that was induced by ID, thereby suggesting iron homeostasis as a future precaution in patients with hypertension based on its important role in the maintenance of VSMC function.
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Anemia Ferropriva/complicações , Anemia Ferropriva/metabolismo , Aneurisma Aórtico/metabolismo , Dissecção Aórtica/metabolismo , Músculo Liso Vascular/metabolismo , Dissecção Aórtica/complicações , Animais , Aorta/metabolismo , Aneurisma Aórtico/complicações , Modelos Animais de Doenças , Feminino , Humanos , Ferro/metabolismo , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-IdadeRESUMO
Extranodal natural killer/T-cell lymphoma, nasal type (ENKL) is a rare peripheral T-cell lymphoma that predominantly occurs in Asian and South American populations. The treatment of ENKL has been a challenge for a long time. This study was conducted to compare the clinical efficacy and safety of cisplatin, dexamethasone, gemcitabine, and pegaspargase (DDGP) and methotrexate, dexamethasone, ifosfamide, L-asparaginase, and etoposide (SMILE) regimens for relapsed/refractory ENKL and explore the prognostic factors. From October 2014 to July 2019, 54 patients with relapsed/refractory ENKL who received DDGP or SMILE chemotherapy were retrospectively assessed in this study. Thirty-one patients received DDGP chemotherapy and 23 patients received SMILE chemotherapy. A higher complete response rate was observed in patients treated with DDGP regimen (61.3% vs. 30.4%, P = 0.025). The DDGP group (95% confidence interval (CI) of 5-year progression-free survival (PFS): 24.6-66.2%; 95% CI of 5-year overall survival (OS): 8.5-91.7%) was also significantly associated with longer 5-year PFS and 5-year OS (P = 0.008 for 5-year PFS, P = 0.023 for 5-year OS). More serious leucopenia (P = 0.021), neutropenia (P = 0.041), and allergy (P = 0.040) were observed in the SMILE group. Post-treatment Epstein-Barr virus (EBV)-DNA status (P = 0.001 for PFS, P = 0.018 for OS) was identified as a significant prognostic factor for PFS and OS in multivariate analysis. The present research suggested that compared with SMILE chemotherapy, DDGP chemotherapy can significantly improve the response and survival of relapsed/refractory ENKL with better tolerance. Post-treatment EBV-DNA status was identified as a significant prognostic factor for PFS and OS in relapsed/refractory ENKL.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , DNA Viral/isolamento & purificação , Resistencia a Medicamentos Antineoplásicos , Infecções por Vírus Epstein-Barr/mortalidade , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Seguimentos , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Humanos , Linfoma Extranodal de Células T-NK/mortalidade , Linfoma Extranodal de Células T-NK/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/virologia , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
OBJECTIVE: The prognosis for patients with relapsed or refractory diffuse large B-cell lymphoma (R/R-DLBCL) after second-line treatment failure is extremely poor. This study prospectively observed the efficacy and safety of decitabine with a modified cisplatin, cytarabine, and dexamethasone (DHAP) regimen in R/R-DLBCL patients who failed second-line treatment. METHODS: Twenty-one R/R-DLBCL patients were enrolled and treated with decitabine and a modified DHAP regimen. The primary endpoints were overall response rate (ORR) and safety. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: ORR reached 50% (complete response rate, 35%), five patients (25%) had stable disease (SD) with disease control rate (DCR) of 75%. Subgroup analysis revealed patients over fifty years old had a higher complete response rate compared to younger patients (P = 0.005), and relapsed patients had a better complete response rate than refractory patients (P = 0.031). Median PFS was 7 months (95% confidence interval, 5.1-8.9 months). Median OS was not achieved. One-year OS was 59.0% (95% CI, 35.5%-82.5%), and two-year OS was 51.6% (95% confidence interval, 26.9%-76.3%). The main adverse events (AEs) were grade 3/4 hematologic toxicities such as neutropenia (90%), anemia (50%), and thrombocytopenia (70%). Other main non-hematologic AEs were grade 1/2 nausea/vomiting (40%) and infection (50%). No renal toxicity or treatment-related death occurred. CONCLUSION: Decitabine with a modified DHAP regimen can improve the treatment response and prognosis of R/R-DLBCL patients with good tolerance to AEs, suggesting this regimen has potential as a possible new treatment option for R/R-DLBCL patients after second-line treatment failure. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT03579082.
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The pathogenesis of abdominal aortic aneurysm remains unclear. The aim of the present study was to establish whether isoleucyl-tRNA synthetase (Iars) regulates the differentiation and apoptosis of vascular smooth muscle cells (VSMCs) during the development of abdominal aortic aneurysm (AAA). In addition, the contribution of various signaling pathways towards this process was ascertained. The study demonstrated that the expression of Iars, p-p38, osteopontin (OPN) and Bcl-2-associated X protein (Bax) clearly increased, while levels of p-PI3K and smooth muscle 22 alpha (SM22α) decreased significantly in AAA tissues. Inhibition of Iars significantly reduced the incidence of angiotensin II (AngII)-induced AAA in mice, coincident with decreased activity of the p38 MAPK pathway and increased PI3K pathway activity. AngII-induced phenotypic switching and apoptosis of VSMCs decreased following the inhibition of Iars in vitro. Upregulation of the IARS gene induced phenotypic switching and apoptosis in VSMCs in addition to increased p38 MAPK pathway activation and reduced PI3K pathway activation. Following pretreatment with an activator of the PI3K pathway, expression of Iars and the phenotypic markers of VSMCs were not affected, while apoptosis of VSMCs decreased. Similarly, inhibition of the p38 MAPK pathway in VSMCs did not affect the expression of Iars or the degree of cell apoptosis, but reduced phenotypic switching was observed. Conclusively, upregulation of Iars regulates the phenotypic switching and apoptosis of VSMCs. Targeting Iars may be a promising strategy to prevent abdominal aortic aneurysm.
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Aneurisma da Aorta Abdominal/patologia , Apoptose , Regulação da Expressão Gênica , Isoleucina-tRNA Ligase/metabolismo , Músculo Liso Vascular/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Aneurisma da Aorta Abdominal/metabolismo , Proliferação de Células , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Transdução de SinaisRESUMO
Background: Microarray analysis of clinical aortic samples suggested a potential role for stromal interaction molecule 1 (STIM1) in the modulation of aortic medial degeneration (AMD), despite the uncertainty about STIM1 in normal aortic smooth muscle cells (ASMCs). Here, we aimed to explore changes in STIM1 expression in AMD, and the possible mechanisms. Methods: An AMD model was established using auto-delivery of angiotensin II (Ang II) into ApoE-/- mice. We assessed the effects of SKF96365, a STIM1 inhibitor, in AMD model and in vitro cultured ASMCs. Elastic van Gieson (EVG) staining was used to visualize elastic fiber injury. Mitochondria changes were viewed by TEM. Cytoplasmic calcium was quantified by measuring fluo-4 staining in a flow cytometer. Mechanical stretching device was used to mimic stretching that ASMCs experience in vivo Cell apoptosis was determined by using Annexin V/propidium iodide (PI) staining. The expression of STIM1, contractile related proteins (α-smooth muscle actin (α-SMA), myosin light chain (MLC)), endoplasmic reticulum (ER) stress-related proteins (CHOP, activating transcription factor 6 (ATF-6)) and smad2/3 were assessed by Western blotting, immunohistochemistry (IHC), and immunofluorescence (IF). Results: SKF96365 exacerbated aortic injury in the AMD model. SKF96365 reduced cytoplasmic calcium concentration in ASMCs, caused mitochondrial swelling, and elevated the expression of ATF-6 and CHOP. SKF96365 decreased the expression of MLC and α-SMA in ASMCs, causing them to be vulnerable to mechanical stretch. SKF96365 suppressed smad2/3 activation after treatment with transforming growth factor (TGF) ß1 (TGFß1). Conclusions: STIM1 is indispensable in ASMCs. Interfering with STIM1 exaggerated the AMD process by modulating the expression of contractile proteins, inducing ER stress in ASMCs.
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Aorta/metabolismo , Cálcio/metabolismo , Regulação da Expressão Gênica , Miócitos de Músculo Liso/metabolismo , Molécula 1 de Interação Estromal/genética , Actinas/genética , Actinas/metabolismo , Fator 6 Ativador da Transcrição/genética , Fator 6 Ativador da Transcrição/metabolismo , Angiotensina II/administração & dosagem , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Apoptose/efeitos dos fármacos , Tecido Elástico/efeitos dos fármacos , Tecido Elástico/metabolismo , Tecido Elástico/patologia , Humanos , Imidazóis/farmacologia , Transporte de Íons/efeitos dos fármacos , Mecanotransdução Celular , Camundongos , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Cadeias Leves de Miosina/genética , Cadeias Leves de Miosina/metabolismo , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Molécula 1 de Interação Estromal/antagonistas & inibidores , Molécula 1 de Interação Estromal/metabolismo , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Ribosome biogenesis is a crucial biological process related to cell proliferation, redox balance, and muscle contractility. Aortic smooth muscle cells (ASMCs) show inhibition of proliferation and apoptosis, along with high levels of oxidative stress in aortic dissection (AD). Theoretically, ribosome biogenesis should be enhanced in the ASMCs at its proliferative state but suppressed during apoptosis and oxidative stress. However, the exact status and role of ribosome biogenesis in AD are unknown. We therefore analyzed the expression levels of BOP1, a component of the PeBoW complex which is crucial to ribosome biogenesis, in AD patients and a murine AD model and its influence on the ASMCs. BOP1 was downregulated in the aortic tissues of AD patients compared to healthy donors. In addition, overexpression of BOP1 in human aortic smooth muscle cells (HASMCs) inhibited apoptosis and accumulation of p53 under hypoxic conditions, while knockdown of BOP1 decreased the protein synthesis rate and motility of HASMCs. The RNA polymerase I inhibitor cx-5461 induced apoptosis, ROS production, and proliferative inhibition in the HASMCs, which was partly attenuated by p53 knockout. Furthermore, cx-5461 aggravated the severity of AD in vivo, but a p53-/- background extended the life-span and lowered AD incidence in the mice. Taken together, decreased ribosome biogenesis in ASMCs resulting in p53-dependent proliferative inhibition, oxidative stress, and apoptosis is one of the underlying mechanisms of AD.
Assuntos
Aorta/metabolismo , Dissecção Aórtica/metabolismo , Apoptose , Miócitos de Músculo Liso/metabolismo , Estresse Oxidativo , Ribossomos/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Túnica Média/metabolismo , Adulto , Dissecção Aórtica/patologia , Aorta/patologia , Benzotiazóis/farmacologia , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miócitos de Músculo Liso/patologia , Naftiridinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Túnica Média/patologiaRESUMO
BACKGROUND: Doxorubicin (DOX) is an anticancer drug that has been widely used in the clinic. However, recently its application has been limited due to the cardiotoxic effects it has caused. Severe cardiotoxicity of DOX causes cardiac hypertrophy that may lead to heart failure. It has previously been demonstrated that CACNA1H is re-expressed in hypertrophic cardiomyocytes. In this study, we aimed to investigate the role of CACNA1H in DOX-induced acute cardiotoxicity, and to investigate its possible underlying mechanisms of action involved. METHODS: Firstly, DOX-induced cardiac injury and changes in the expression of CACNA1H were evaluated. We explored the role of endoplasmic reticulum (ER) stress and apoptosis in mice that underwent DOX-induced cardiac injury. Next, to explore the role of CACNA1H in this process, we evaluated the changes in DOX-induced cardiac injury and ER stress after treatment with the CACNA1H specific inhibitor ABT-639. Next, we used ER stress inhibitor UR906 to verify the role of ER stress in DOX induced cardiotoxicity in H9C2 cells. RESULTS: DOX-treatment caused acute heart injury, leading to a decrease in cardiac function in mice, an increase in apoptosis of cardiac myocytes, and a significant increase in the expression level of CACNA1H in heart tissue. Next, mice were treated with CACNA1H inhibitor ABT-639 and we demonstrated that it partly protects myocardial function and reduces myocardial cell apoptosis. In addition, our data indicated that CACNA1H may play a role in alleviating DOX-induced cardiotoxicity by reducing the severity of ER stress because the use of ABT-639 significantly changed ER stress-related proteins, including p-PERK, PERK, CHOP, GRP78, ATF6, and ATF4. Furthermore, we found that the use of ER stress inhibitor UR906 in H9C2 cells significantly alleviated the increased expression of ER stress related proteins and apoptosis related proteins caused by DOX, and meanwhile reduced the degree of intracellular oxidative stress and intracellular calcium ion concentration. CONCLUSION: CACNA1H inhibitors significantly alleviated DOX-induced cardiotoxicity and apoptosis induced by ER stress.
Assuntos
Canais de Cálcio Tipo T/metabolismo , Cardiotoxicidade/tratamento farmacológico , Doxorrubicina/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Cardiotoxicidade/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Chaperona BiP do Retículo Endoplasmático , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologiaRESUMO
BACKGROUND: Constipation is a common complication after stroke that can severely influence a patient's quality of life and rehabilitation. Treatments for constipation after stroke vary. Acupuncture may improve spontaneous bowel movements, quality of life, and clinical symptoms. The study seeks to assess the preliminary effects of acupuncture on constipation after an ischemic stroke. METHODS/DESIGN: This is a prospective randomized controlled pilot trial design in which 120 eligible patients will be randomly allocated to one of three groups. The acupuncture group (n = 40) will receive acupuncture and routine care, the medication group (n = 40) will receive mosapride citrate and routine care, and the control group (n = 40) will receive only routine care for ischemic stroke. Patients will be recruited 2 weeks to 6 months after stroke onset and will receive the intervention continuously over 4 weeks, with a follow-up period of 4 additional weeks. Adverse events will be recorded to assess the safety and tolerability of acupuncture for constipation after an ischemic stroke. The primary outcome will be the change in the weekly mean number of complete spontaneous bowel movements. Secondary outcomes will include any change in the weekly mean number of spontaneous bowel movements, mean stool consistency scores, mean straining scores during defecation, and frequency of laxative use. All outcome measures will be assessed at inception, after the intervention (4 weeks), and at the follow-up (8 weeks). DISCUSSION: This study will provide evidence of the preliminary effects and inform future sample size calculations for studies of acupuncture for constipation following an ischemic stroke. These findings will inform subsequent large-scale randomized controlled trials. TRIAL REGISTRATION: ISRCTN, 22214747 . Registered on 17 August 2015.