RESUMO
Indolent lymphoma, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma (FL), can undergo histological transformation into an aggressive subtype, typically diffuse large B-cell lymphoma (DLBCL). The prognosis of transformed lymphoma is poor. In this study, we reported the efficacy and toxicity of a combination of venetoclax, dose-adjusted rituximab or obinutuzumab, etoposide, prednisone, vincristine, doxorubicin, and cyclophosphamide (VR-DA-EPOCH or VG-DA-EPOCH) in 11 patients with biopsy-proven histology transformation into DLBCL, including 8 patients with RT and 3 with transformed FL (tFL). The study was conducted between October 2019 and March 2023 at our single center. The median age of participants at enrolment was 53 years. Six patients (85.7%, 6/7) achieved complete remission (CR) at the end of treatment. The best overall response rate (ORR) and CR rate were both 72.7%, respectively. Two patients received autologous hemopoietic stem cell transplant (ASCT) while two patients received ASCT concurrently with CAR-T therapy for consolidation. With a median follow-up of 13.5 (range, 2.4-29.8) months after enrollment, the median event-free survival, progression-free survival, and overall survival were 9.4, 11.5, and 17.5 months, respectively. Hematologic toxicities of grade ≥3 consisted of neutropenia (90.9%, 10/11), thrombocytopenia (63.6%, 7/11), and febrile neutropenia (54.5%, 6/11). In conclusion, VR-DA-EPOCH or VG-DA-EPOCH was a promising strategy to achieve an early remission, bridging to cellular therapy within this population.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Sulfonamidas , Realidade Virtual , Humanos , Pessoa de Meia-Idade , Prednisona , Vincristina , Etoposídeo , Anticorpos Monoclonais Murinos , Ciclofosfamida , Rituximab , Linfoma não Hodgkin/tratamento farmacológico , Doxorrubicina , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Complement component C3, mainly synthesized by hepatocytes, acts as the convergence point of three different pathways in activating the complement cascade. Besides its well-established roles in the extracellular milieu, C3 performs various intracellular functions such as immunomodulation and pathogen recognition. Although C3 is present at extremely high concentrations in hepatocytes, little is known about its intrahepatic function. In this study, we found that C3 knockout (C3-/- ) mice displayed accelerated hepatic triglyceride (TG) accumulation compared with C57BL/6J wild type mice. Mechanistically, C3 deficiency impaired lipophagy in hepatocytes, owing to the disrupted interaction between C3 and autophagy-related 16 like 1, which is essential for autolysosome assembly. Furthermore, lipophagy deficiency affected the function of the endoplasmic reticulum in C3-/- mice, subsequently affecting the expression of protein disulfide isomerase and activity of microsomal TG transfer protein, and ultimately impairing the production of hepatic very-low-density lipoproteins (VLDLs). Rapamycin and thapsigargin treatment accelerated VLDL secretion and alleviated hepatic lipid accumulation in C3-/- mice. Our study demonstrates that C3 promotes lipophagy to facilitate VLDL secretion in hepatocytes, thus playing an essential role in balancing TG levels in the liver.
Assuntos
Proteínas Relacionadas à Autofagia/metabolismo , Autofagia , Complemento C3/fisiologia , Lipoproteínas VLDL/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Sirolimo/farmacologia , Animais , Proteínas Relacionadas à Autofagia/genética , Imunossupressores/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologiaRESUMO
AIMS: His-Purkinje system pacing has been demonstrated as a synchronized ventricular pacing strategy via pacing His-Purkinje system directly, which can decrease the incidence of adverse cardiac structure alteration compared with right ventricular pacing (RVP). The purpose of this meta-analysis was to compare the effects of His-Purkinje system pacing and RVP in patients with bradycardia and cardiac conduction dysfunction. METHODS: PubMed, Embase, Cochrane Library, and Web of Science were systematically searched from the establishment of databases up to 15 December 2019. Studies on long-term clinical outcomes of His-Purkinje system pacing and RVP were included. Chronic paced QRS duration, chronic pacing threshold, left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), all-cause mortality, and heart failure hospitalization were collected for meta-analysis. RESULTS: A total of 13 studies comprising 2348 patients were included in this meta-analysis. Compared with RVP group, patients receiving His-Purkinje system pacing showed improvement of LVEF (mean difference [MD], 5.65; 95% confidence interval [CI], 4.38-6.92), shorter chronic paced QRS duration (MD, - 39.29; 95% CI, - 41.90 to - 36.68), higher pacing threshold (MD, 0.8; 95% CI, 0.71-0.89) and lower risk of heart failure hospitalization (odds ratio [OR], 0.65; 95% CI, 0.44-0.96) during the follow-up. However, no statistical difference existed in LVEDV, LVESV and all-cause mortality between the two groups. CONCLUSION: Our meta-analysis suggests that His-bundle pacing is more suitable for the treatment of patients with bradycardia and cardiac conduction dysfunction.
Assuntos
Bradicardia/terapia , Fascículo Atrioventricular/fisiopatologia , Doença do Sistema de Condução Cardíaco/terapia , Estimulação Cardíaca Artificial , Frequência Cardíaca , Ramos Subendocárdicos/fisiopatologia , Potenciais de Ação , Idoso , Bradicardia/diagnóstico , Bradicardia/mortalidade , Bradicardia/fisiopatologia , Doença do Sistema de Condução Cardíaco/diagnóstico , Doença do Sistema de Condução Cardíaco/mortalidade , Doença do Sistema de Condução Cardíaco/fisiopatologia , Estimulação Cardíaca Artificial/efeitos adversos , Estimulação Cardíaca Artificial/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Fatores de Tempo , Função Ventricular Esquerda , Função Ventricular DireitaRESUMO
Immunotherapy has emerged as one of the most promising therapeutic strategies in cancer. The clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (CRISPR-Cas9) system, as an RNA-guided genome editing technology, is triggering a revolutionary change in cancer immunotherapy. With its versatility and ease of use, CRISPR-Cas9 can be implemented to fuel the production of therapeutic immune cells, such as construction of chimeric antigen receptor T (CAR-T) cells and programmed cell death protein 1 knockout. Therefore, CRISPR-Cas9 technology holds great promise in cancer immunotherapy. In this review, we will introduce the origin, development and mechanism of CRISPR-Cas9. Also, we will focus on its various applications in cancer immunotherapy, especially CAR-T cell-based immunotherapy, and discuss the potential challenges it faces.
Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Neoplasias/genética , Neoplasias/imunologia , Biomarcadores Tumorais , Terapia Genética , Humanos , Imunoterapia , Neoplasias/terapiaRESUMO
BACKGROUND: The role of interleukin family in colon cancer remained controversial. The purpose of this study was to investigate the association between interleukin family and colon cancer progression through bioinformatics methods and to validate such association in clinical patients. METHODS: A total of 15 differentially expressed interleukins between the colon cancer tissue and normal colon tissue were evaluated from the Cancer Genome Atlas (TCGA) database with R software and only interleukin-7 (IL-7) was significantly associated with survival. The signaling pathway associated with IL-7 was then investigated using gene enrichment analysis. In addition, subsets of TNM were analyzed in detail and univariate and multivariate COX regression analysis were conducted. Finally, we performed western blotting, immunohistochemistry, cell proliferation and cell apoptosis analysis to examine the expression of IL-7 in patients with intestinal cancer. RESULTS: The study demonstrated that IL-7 could inhibit the progression of colon cancer. In addition, IL-7 was found to be associated with overall survival (OS) and pathological stage. Further analysis of IL-7 expression with clinical data indicated that IL-7 was a key factor in inhibiting colon cancer progression. CONCLUSION: IL-7 was a key factor in inhibiting the progression of colon cancer and was closely related to overall survival.
Assuntos
Adenocarcinoma/metabolismo , Neoplasias do Colo/metabolismo , Interleucina-7/metabolismo , Idoso , Apoptose , Western Blotting , Proliferação de Células , Biologia Computacional , Progressão da Doença , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Masculino , Estadiamento de Neoplasias , Transdução de SinaisRESUMO
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world with great heterogeneity. Pyroptosis has recently been recognized as an inflammatory form of programmed cell death (PCD) and shares a close relationship with apoptosis. Although the role of apoptosis in CLL was comprehensively studied and successfully applied in clinical treatment, the relationship between pyroptosis genes and CLL remained largely unknown. In this study, eight differentially expressed pyroptosis-related genes (PRGs) were identified between CLL and normal B cells. In order to screen out the prognostic value of differentially expressed PRGs, univariate and multivariate Cox regression analyses were conducted and a risk model with three PRG signatures (GSDME, NLRP3, and PLCG1) was constructed. All CLL samples were stratified into high- and low-risk subgroups according to risk scores. The risk model showed high efficacy in predicting both overall survival (OS) and time to first treatment (TTFT). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) showed the dysregulation of immune and inflammatory response in the high-risk group. Single-sample GSEA (ssGSEA) of immune cell infiltration and the activity of immune-related pathways also displayed decreased antitumor immunity in the high-risk group. In conclusion, PRGs are of prognostic value in CLL and may play important roles in tumor immunity, and the underlying relationship between PRGs and CLL needs to be explored further.
Assuntos
Leucemia Linfocítica Crônica de Células B , Ontologia Genética , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Prognóstico , Piroptose/genética , Microambiente Tumoral/genéticaRESUMO
Rationale: Invariant natural killer T (iNKT) cells and Kupffer cells represent major hepatic populations of innate immune cells. However, their roles in steatohepatitis remain poorly understood. To elucidate their functions in steatohepatitis development, real-time, in vivo analysis is necessary to understand the pathophysiological events in the dynamic interactions between them during diet-induced steatohepatitis. Methods: We used a steatohepatitis animal model induced by a methionine-choline-deficient (MCD) diet. Multi-photon confocal live imaging and conventional experimental techniques were employed to investigate the hepatic pathological microenvironment of iNKT and Kupffer cells, interactions between them, and the biological effects of these interactions in steatohepatitis. Results: We found that iNKT cells were recruited and aggregated into small clusters and interacted dynamically with Kupffer cells in the early stage of steatohepatitis. Most significantly, the iNKT cells in the cluster cleared free lipids released by necrotic hepatocytes and presented a non-classical activation state with high IFN-γ expression. Furthermore, the Kupffer cells in the cell cluster were polarized to type M1. The transcriptome sequencing of iNKT cells showed upregulation of genes related to phagocytosis and lipid processing. Adoptive transfer of iNKT cells to Jα18-/- mice showed that iNKT and Kupffer cell clusters were essential for balancing the liver and peripheral lipid levels and inhibiting liver fibrosis development. Conclusions: Our study identified an essential role for dynamic interactions between iNKT cells and Kupffer cells in promoting lipid phagocytosis and clearance by iNKT cells during early liver steatohepatitis. Therefore, modulating iNKT cells is a potential therapeutic strategy for early steatohepatitis.
Assuntos
Modelos Animais de Doenças , Microscopia Intravital/métodos , Células de Kupffer/patologia , Lipídeos/química , Células T Matadoras Naturais/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Animais , Células de Kupffer/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismoRESUMO
Iron is one of the most important trace elements in the body, and its homeostasis is essential to the normal function of the immune system. Complement component C3, which is the converging of three main pathways of complement system activation, plays a key role in the innate immunity. However, the relationship between iron homeostasis and complement C3 remains unknown. The aim of our study was to analyze the relationship between serum iron and ferritin level and complement C3 and C4. A total of 590 healthy individuals were recruited in our study. Higher serum complement C3 level (p < 0.001) was found in individuals with higher serum ferritin level (> 104.0 µg/L). Moreover, serum iron level and serum ferritin level were positively correlated with complement C3 (r = 0.133, p = 0.001; r = 0.221, p < 0.001) and complement C4 (r = 0.117, p = 0.004; r = 0.123, p = 0.003). The linear regression analysis displayed that both serum iron level and serum ferritin level were linearly correlated with serum complement C3 level (adjusted beta: 2.382, 95% CI: 0.841-3.923; adjusted beta: 42.911, 95% CI: 29.070-56.751). To explore the relationship between iron homeostasis and complement C3 further, the serum samples from C3-/- mice and the wild-type (WT) control mice were obtained. Significantly lower serum iron level and higher ferritin level were found in C3-/- mice than those in WT mice (p < 0.001; p < 0.001), indicating that complement C3 might influence iron distribution and utilization. Overall, these data suggested that serum iron and ferritin levels were correlated with complement C3. The deficiency of complement C3 may disrupt the regular iron metabolism in the body.
Assuntos
Complemento C3 , Complemento C4 , Animais , Complemento C3/metabolismo , Complemento C4/metabolismo , Ferritinas , Ferro , CamundongosRESUMO
BACKGROUND: To establish and validate nomograms for predicting the overall survival (OS) and cancer-specific survival (CSS) in patients with papillary renal cell carcinoma (pRCC). METHODS: Patients diagnosed with pRCC between 2010 and 2014 in the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively included in this study and divided into training and validation groups randomly. Uni- and multivariate Cox regression analyses were used to identify significant variables related to OS and CSS in the training group. Based on results of multivariate Cox regression analysis, nomograms for 3- and 5-year CSS and OS were established, respectively. Additionally, Kaplan-Meier (KM) survival curves were produced to learn the actual effects of different variables. Finally, the nomograms were evaluated both in the training group and the validation group using the area under the receiver operating characteristic (ROC) curve, the concordance index (C-index) and calibration curves. RESULTS: A total of 4,859 eligible patients were enrolled, with 3,403 categorized into the training group and 1,456 into the validation group. Seven factors [age, T stage, N stage, M stage, use of surgery/lymph node removal (LNR) and insurance status] were significantly related to OS and seven factors (age, T stage, N stage, M stage and use of surgery/chemotherapy/LNR) were significantly associated with CSS. These factors were eventually included in the predictive nomograms. The C-indexes for OS in the training and validation groups were 0.764 and 0.723 respectively, and 0.859 and 0.824 for CSS. The 3- and 5-year AUCs for OS were 0.779 and 0.752 in the training cohort, and 0.749 and 0.722 in the validation cohort. Similarly, 3- and 5-year AUCs for OS were 0.871 and 0.844 in the training cohort, and 0.853 and 0.822 in the validation group. Finally, the calibration curves suggested that the predictive nomograms had a good consistency between the observed and the predicted survival. CONCLUSIONS: It was the first time to develop nomograms to predict the survival outcomes of pRCC patients. The prognostic nomograms were reliable with high accuracy, which might have guiding significance for clinical practice.
RESUMO
BACKGROUND: To develop and validate survival nomograms for predicting the overall survival (OS) and cancer-specific survival (CSS) in upper tract urothelial carcinoma (UTUC) patients. METHOD: Patients diagnosed with UTUC from 2010 to 2015 in the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively enrolled. Clinical characteristics and survival outcomes were respectively collected from the included patients. Then, eligible patients were divided into the training cohort and the validation cohort. Additionally, survival nomograms were developed based on the results of multivariate Cox analysis in the training cohort. Furthermore, Kaplan-Meier (KM) survival curves were generated to assess the actual effect of each variable. Lastly, the nomograms were validated using the concordance index (C-index), the area under the receiver operating characteristic (ROC) curve and calibration curves. RESULTS: Totally, 3,556 patients were included, with 2,492 in the training cohort and 1,064 in the validation cohort. No significant differences were detected in comparisons in clinical characteristics between two cohorts. Based on the results of uni- and multivariate Cox regression analysis, seven factors (age, TNM stage, use of surgery/radiation and marital status) for OS and six factors (age, TNM stage and use of surgery/radiation) for CSS were selected to develop the survival nomograms. The C-index for OS and CSS was 0.763 and 0.793 in the training cohort, and 0.759 and 0.784 in the validation cohort. Additionally, the 3- and 5-year AUCs for OS were 0.808 and 0.780 in the training cohort, and 0.785 and 0.778 in the validation group. As for CSS, it was 0.833 and 0.803 in the training cohort, and 0.815 and 0.810 in the validation cohort. Lastly, the calibration curves indicated a good consistency between the actual survival and the predictive survival. CONCLUSIONS: It was the first time to conduct survival models for UTUC patients with predictive performance. It might be valuable of clinical application and further exploration with more studies in the future.
RESUMO
Dexmedetomidine (DEX) was widely used in clinical work. However, the effectiveness of DEX on postoperative cognitive dysfunction (POCD) was still need to be confirmed. The aim of this meta-analysis was to explore whether DEX can reduce the incidence of POCD on the first day and seventh postoperative day. The results showed that lower incidence of POCD associated with DEX treatment on the first (odds ratio [OR]: 0.41; 95% confidence interval [CI]: 0.31-0.54) or seventh postoperative day (OR: 0.53; 95% CI: 0.36-0.77). Mini-Mental State Examination scores on the first (mean difference [MD]: 4.67; 95% CI: 1.72-7.63) and seventh postoperative days (MD: 3.71; 95% CI: 2.51-4.90) were higher in DEX use group than that in physiological saline group. Meanwhile, neuron-specific enolase (NSE; MD: -3.99; 95% CI: -6.20 to -1.78) and interleukin 6 (IL-6) levels (MD: -17.53; 95% CI: -21.51 to -13.54) on the first postoperative day in DEX group were lower than that in the physiological saline group. This meta-analysis suggested that DEX use could reduce the risk of POCD and the reduction in levels of NSE and IL-6 can improve long-term cognitive dysfunction and anti-inflammation.
RESUMO
CONTEXT: Increasing evidence has indicated an association between immune cell infiltration in lung adenocarcinoma (LUAD) and clinical outcomes. AIMS: This study aimed to investigate the effect of 22 tumor-infiltrating immune cells (TIICs) on the prognosis of patients with LUAD. SETTINGS AND DESIGN: This was a case-control study. MATERIALS AND METHODS: The CIBERSORT algorithm calculated the proportion of cases from the Cancer Genome Atlas (TCGA) cohort. Cox regression analysis evaluated the effect of TIICs on the prognosis of LUAD. The immune risk score model was constructed based on a statistical correlation. Multivariate cox regression analysis investigated independent factors. P < 0.05 was considered to be statistically significant. RESULTS: Certain immune cells had differential infiltration between normal tissues and LUAD. Univariate Cox regression analysis revealed that four immune cell types were statistically correlated with LUAD-related survival risk, and an immune risk scoring model was constructed. The results indicated that patients in the high-risk group were associated with poor outcomes. In addition, the multivariate cox analysis revealed that the immune risk scoring model was an independent factor for LUAD prognosis prediction. Ultimately, a nomogram was established to comprehensively predict the survival of LUAD patients. CONCLUSIONS: TIICs played an essential role in the prognosis of LUAD. Furthermore, the immune risk score was a poor predictive factor of LUAD, and the established model was reliable in predicting the prognosis of LUAD.
Assuntos
Adenocarcinoma de Pulmão/imunologia , Biomarcadores Tumorais/genética , Biologia Computacional/métodos , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Evasão Tumoral/imunologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Idoso , Algoritmos , Biomarcadores Tumorais/imunologia , Estudos de Casos e Controles , Estudos de Coortes , Bases de Dados Genéticas , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Evasão Tumoral/genéticaRESUMO
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease and hypocomplementemia signifies disease activity. Several studies have shown that calcium may help maintain optimum function of immune system and metabolism in SLE. The aim of our study was to analyze the relationship between total serum calcium level and SLE activity. A total of 66 patients with SLE and 214 healthy controls were included in this study. Our results showed lower serum levels of calcium (P < .001), complement C3 (P < .001), complement C4 (P < .001), and albumin (P < .001) in patients with SLE. A negative correlation was found between serum calcium level and systemic lupus erythematosus disease activity index (SLEDAI) rating (r = -0.394, P = .001). Additionally, serum level of calcium was positively correlated with serum complement C3 level (r = 0.366, P = .003) in patients with SLE, while no such correlation was found between serum calcium level and complement C4 (r = -0.190, P = .126). Likewise, patients with SLE with normal serum calcium level showed higher complement C3 level (P < .01) than that of patients with low serum calcium level. Overall, the results displayed that patients with SLE have lower serum calcium level compared to healthy controls, and the serum calcium level is positively correlated with SLEDAI rating and serum complement C3 level in patients with SLE. In conclusion, the total serum calcium level is negatively correlated with SLE disease activity.
RESUMO
Acetaminophen (APAP) is the leading cause of drug-induced acute liver failure. Sphingosine-1-phosphate (S1P), whose formation is catalyzed by sphingosine kinase (SPHK)-1 or -2, is a bioactive lipid implicated in human health and disease. Here, we show that APAP-treated sphK1-deficient (sphK1-/-) mice exhibited markedly less liver damage and reduced inflammation compared with the wild-type mice. SPHK1 deficiency alleviated APAP-induced endoplasmic reticulum (ER) stress by affecting the phosphorylation of inositol-requiring enzyme 1α (IRE1α) and protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)-eukaryotic translation initiation factor 2α (eIF2α), levels of activating transcription factor 4 (ATF4), and activation of activating transcription factor 6 (ATF6). SPHK1 deficiency also inhibited mitochondrial permeability transition (MPT), as evidenced by the impaired phosphorylation of JNK, apoptosis signal-regulated kinase 1 (ASK1), and glycogen synthase kinase 3ß (GSK3ß). In addition, SPHK1 deficiency reduced the levels of histone deacetylase and promoted the acetylation of p65 and STAT1, thereby impairing the transcription of inflammatory genes. Supplementation with exogenous S1P significantly reversed the activation of the PERK-eIF2α-ATF4 pathway and ATF6 during ER stress as well as the activation of GSK3ß, ASK1, and JNK during MPT. Both FTY720, a functional S1P receptor antagonist, and PF543, an SPHK1 inhibitor, significantly ameliorated APAP-induced liver injury and improved animal survival. Our study reveals a critical role for SPHK1 in mediating APAP-induced hepatotoxicity by promoting ER stress and MPT.
Assuntos
Acetaminofen/toxicidade , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Cloridrato de Fingolimode/farmacologia , Necrose Dirigida por Permeabilidade Transmembrânica da Mitocôndria/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Pirrolidinas/farmacologia , Sulfonas/farmacologia , Animais , Inibidores Enzimáticos , Metanol/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidoresRESUMO
BACKGROUND: The cardiotoxicity of isoniazid on zebrafish embryos and its underlying mechanism is unclear. METHODS: Here, we exposed zebrafish embryos at 4 h post-fertilization to different levels of isoniazid and recorded the morphology and number of malformed and dead embryos under the microscope. RESULTS: The high concentration of isoniazid group showed more malformed and dead embryos than the low concentration of isoniazid group and control group. The morphology of the heart and its alteration were visualized using transgenic zebrafish (cmlc2: GFP) and confirmed by in situ hybridization. The negative effects of isoniazid on the developing heart were characterized by lower heart rate and more heart looping disorders. Mechanistically, PCR showed decreased expression of heart-specific transcription factors when exposed to isoniazid. Oxidative stress was induced by isoniazid in cardiomyocytes, mediated by decreased activities of catalase and superoxide dismutase, which were rescued by scavengers of reactive oxygen species. CONCLUSION: In conclusion, this study demonstrated that isoniazid led to heart looping disturbance by the downregulation of cardiac-specific transcription factors and induction of cardiomyocyte apoptosis.
Assuntos
Antituberculosos/efeitos adversos , Desenvolvimento Embrionário/efeitos dos fármacos , Cardiopatias Congênitas/induzido quimicamente , Isoniazida/efeitos adversos , Animais , Animais Geneticamente Modificados , Apoptose/efeitos dos fármacos , Regulação para Baixo , Embrião não Mamífero/anormalidades , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/fisiopatologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/genética , Peixe-ZebraAssuntos
Leucemia Linfocítica Crônica de Células B , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Rituximab/uso terapêutico , População do Leste Asiático , Estudos Prospectivos , Ciclofosfamida/uso terapêutico , Vidarabina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína Supressora de Tumor p53/genéticaAssuntos
Transição Epitelial-Mesenquimal/genética , Glioblastoma/patologia , MicroRNAs , Células-Tronco Neoplásicas/patologia , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Genes Neoplásicos , Glioblastoma/genética , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismoAssuntos
Anestesia por Condução/métodos , Raquianestesia/métodos , Músculos Intercostais/diagnóstico por imagem , Bloqueio Nervoso/métodos , Cirurgia Torácica Vídeoassistida/métodos , Vértebras Torácicas/diagnóstico por imagem , Ultrassonografia de Intervenção/métodos , Humanos , Nervos Intercostais , Dor Pós-OperatóriaRESUMO
BACKGROUND: The role of interleukin family in colon cancer remained controversial. The purpose of this study was to investigate the association between interleukin family and colon cancer progression through bioinformatics methods and to validate such association in clinical patients. METHODS: A total of 15 differentially expressed interleukins between the colon cancer tissue and normal colon tissue were evaluated from the Cancer Genome Atlas (TCGA) database with R software and only interleukin-7 (IL-7) was significantly associated with survival. The signaling pathway associated with IL-7 was then investigated using gene enrichment analysis. In addition, subsets of TNM were analyzed in detail and univariate and multivariate COX regression analysis were conducted. Finally, we performed western blotting, immunohistochemistry, cell proliferation and cell apoptosis analysis to examine the expression of IL-7 in patients with intestinal cancer. RESULTS: The study demonstrated that IL-7 could inhibit the progression of colon cancer. In addition, IL-7 was found to be associated with overall survival (OS) and pathological stage. Further analysis of IL-7 expression with clinical data indicated that IL-7 was a key factor in inhibiting colon cancer progression. CONCLUSION: IL-7 was a key factor in inhibiting the progression of colon cancer and was closely related to overall survival.