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INTRODUCTION: Steroid-refractory cGVHD (SR-cGVHD) presents new great challenges for treatment. We have reported imatinib monotherapy was effective to SR-cGVHD, but the CR rate was not satisfactory and the benefit was not showed specific to some target organs, previously. Imatinib and statin drugs have been recognized to regulate T-cell function, statins also have been demonstrated endothelia protection, but whether this combination therapy was able to improve the efficacy remains unknown. Therefore, we designed this prospective, single-arm, open-label trial to investigate the efficacy of imatinib-based combination therapy in the treatment of SR-cGVHD for the first time. METHODS: 60 SR-cGVHD patients were entered into this trial to investigated the combination of imatinib mesylate and atorvastatin calcium for the treatment of SR-cGVHD. The primary endpoint included the overall response rate (ORR) after 6 months of combined treatment. The secondary endpoints included an evaluation of survival, changes in T-cell subsets and adverse events. RESULTS: At baseline, 45% (27/60) of patients had moderate cGVHD, and 55.0% (33/60) of patients had severe cGVHD. At the 6-month follow-up, a clinical response was achieved in 70.0% of patients, and a complete response (CR) was achieved in 26.7%. A total of 11.7% (7/60) of patients stopped immunosuppressive therapy at this point. After 6 months of treatment, the ORR rates of the liver, skin, eyes and oral cavity were 80.6%, 78.1%, 61.5%, and 60.9%, respectively, with the liver also having the highest CR of 58.1%. The patients with moderate cGVHD had a better CR rate than those with severe cGVHD (55.6% vs. 3.0%, P<0.0001). The overall survival in patients who with ORR was improved (P = 0.0106). Lung involvement is an independent risk factor to affected ORR achievement (P = 0.021, HR = 0.335, 95%CI 0.133-0.847), and the dosage of steroids was reduced in ORR patients. In clinical response patients, the ratio of CD8+ T cells (P = 0.0117) and Th17 cells (P = 0.0171) decreased, while the number of Treg cells (P = 0.0147) increased after 3 months. The most common adverse events were edema, nausea, and neutropenia which were 13.3%, 11.7%, and 11.7%, respectively. CONCLUSION: Combination treatment with imatinib mesylate and atorvastatin calcium was effective in treating SR-cGVHD and significantly decreased target organ injury, especially liver damage, indicating that T-cell regulatory function may play an important role in this process.
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To compare the outcomes of patients with hematological malignancies who received ATG-Fresenius (ATG-F) 20 mg/kg versus those who received ATG-Genzyme (ATG-G) 10 mg/kg in an unrelated donor hematopoietic stem cell transplantation (HSCT) procedure, a total of 186 patients who underwent their first allogeneic HSCT with an unrelated donor were retrospectively analyzed. One hundred and seven patients received ATG-F, and seventy-nine patients received ATG-G. Multivariate analysis showed that the type of ATG preparation had no effect on neutrophil engraftment (P = 0.61), cumulative incidence of relapse (P = 0.092), nonrelapse mortality (P = 0.44), grade II-IV acute graft-versus-host disease (GVHD) (P = 0.47), chronic GVHD (P = 0.29), overall survival (P = 0.795), recurrence-free survival (P = 0.945) or GVHD-free relapse-free survival (P = 0.082). ATG-G was associated with a lower risk of extensive chronic GVHD and a higher risk of cytomegaloviremia (P = 0.01 and HR = 0.41, P < 0.001 and HR = 4.244, respectively). The results of this study suggest that the preparation of rabbit ATG used for unrelated HSCT should be selected based on the incidence of extensive chronic GVHD of each center, and the posttransplant management strategy should be adjusted according to the ATG preparation.
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Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Animais , Coelhos , Humanos , Estudos Retrospectivos , Doadores não Relacionados , Transplante Homólogo/efeitos adversos , Recidiva Local de Neoplasia/complicações , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Soro Antilinfocitário/efeitos adversos , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/complicações , Condicionamento Pré-Transplante/métodosRESUMO
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell malignancy, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curable treatment. The outcomes after transplant are influenced by both disease characteristics and patient comorbidities. To develop a novel prognostic model to predict the post-transplant survival of CMML patients, we identified risk factors by applying univariable and multivariable Cox proportional hazards regression to a derivation cohort. In multivariable analysis, advanced age (hazard ratio [HR] 3.583), leukocyte count (HR 3.499), anemia (HR 3.439), bone marrow blast cell count (HR 2.095), and no chronic graft versus host disease (cGVHD; HR 4.799) were independently associated with worse survival. A novel prognostic model termed ABLAG (Age, Blast, Leukocyte, Anemia, cGVHD) was developed and the points were assigned according to the regression equation. The patients were categorized into low risk (0-1), intermediate risk (2, 3), and high risk (4-6) three groups and the 3-year overall survival (OS) were 93.3% (95%CI, 61%-99%), 78.9% (95%CI, 60%-90%), and 51.6% (95%CI, 32%-68%; p < .001), respectively. In internal and external validation cohort, the area under the receiver operating characteristic (ROC) curves of the ABLAG model were 0.829 (95% CI, 0.776-0.902) and 0.749 (95% CI, 0.684-0.854). Compared with existing models designed for the nontransplant setting, calibration plots, and decision curve analysis showed that the ABLAG model revealed a high consistency between predicted and observed outcomes and patients could benefit from this model. In conclusion, combining disease and patient characteristic, the ABLAG model provides better survival stratification for CMML patients receiving allo-HSCT.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mielomonocítica Crônica , Humanos , Prognóstico , Transplante Homólogo/efeitos adversos , Estudos Retrospectivos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/etiologiaRESUMO
Previous studies have demonstrated that sirolimus (SRL) is an effective agent for the treatment of refractory/relapsed (R/R) ITP. However, the therapeutic window of sirolimus in the treatment of ITP has not been established. As the toxicity of sirolimus increases with higher blood concentrations, it is crucial to determine the optimal therapeutic concentration of SRL for the treatment of ITP. Thus, in this study, we used a retrospective cohort of ITP patients treated with sirolimus to propose the therapeutic dosage window for sirolimus. A total of 275 laboratory results of SRL blood concentration from 63 ITP patients treated with SRL were analyzed retrospectively. The ITP patients were divided into five groups based on their SRL blood concentration: 0-4 ng/ml, 4-8 ng/ml, 8-12 ng/ml, 12-16 ng/ml and ≥16 ng/ml. In addition to the SRL blood concentration, platelet counts and adverse events that occurred during the first 6 weeks of SRL treatment were analyzed. These findings were then used to establish the decision matrix tables and ROC curves, which helped identify the therapeutic window of SRL. Based on the values and trends of true-positive rate (TPR) and false-positive rate (FPR) in the ROC curve, patients who achieved a SRL blood concentration of 4-12 ng/ml displayed a higher response rate compared to those with a SRL concentration of 0-4 ng/ml or ≥16ng/ml. Additionally, the response rate was better for patients with a SRL concentration of 8-12 ng/ml compared to 4-8 ng/ml. Adverse events were related to the concentration of SRL; however, there was no significant difference in the incidence of adverse events between the concentrations of 4-8 ng/ml and 8-12 ng/ml (P > .05). Regression analysis suggested that the concentration of SRL correlated with the patient's age, PLT count at the start of SRL administration, and the dose of SRL. It is suggested that the optimal blood concentration of SRL monotherapy for managing ITP is 8-12 ng/ml. This range may achieve a favorable balance between clinical efficacy and the severity of adverse events.
Although sirolimus (SRL) has been proven to be an effective alternative agent for refractory/relapsed immune thrombocytopenia (R/R ITP), there is currently no recommended optimal blood concentration during its administration. We collected data on SRL drug concentration, platelet response, and drug side effects in ITP patients, constructed ROC curves to evaluate the relationship between the SRL concentration and both efficacy and side effects, and finally suggested a most appropriate SRL blood concentration (812ng/ml). This concentration window ensured optimal efficacy of SRL in the treatment of ITP while maintaining tolerable side effects. Additionally, we conducted a multivariate analysis to explore factors that may influence SRL blood concentration. The present study made an important contribution to the precision therapy of ITP with sirolimus by clarifying the optimal blood concentration range.
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Transplante de Rim , Púrpura Trombocitopênica Idiopática , Trombocitopenia , Humanos , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Imunossupressores/uso terapêutico , Estudos Retrospectivos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Trombocitopenia/tratamento farmacológicoRESUMO
BACKGROUND: Coronavirus disease 2019 (COVID-19) has spread around the world. This retrospective study aims to analyze the clinical features of COVID-19 patients with cancer and identify death outcome related risk factors. METHODS: From February 10th to April 15th, 2020, 103 COVID-19 patients with cancer were enrolled. Difference analyses were performed between severe and non-severe patients. A propensity score matching (PSM) analysis was performed, including 103 COVID-19 patients with cancer and 206 matched non-cancer COVID-19 patients. Next, we identified death related risk factors and developed a nomogram for predicting the probability. RESULTS: In 103 COVID-19 patients with cancer, the main cancer categories were breast cancer, lung cancer and bladder cancer. Compared to non-severe patients, severe patients had a higher median age, and a higher proportion of smokers, diabetes, heart disease and dyspnea. In addition, most of the laboratory results between two groups were significantly different. PSM analysis found that the proportion of dyspnea was much higher in COVID-19 patients with cancer. The severity incidence in two groups were similar, while a much higher mortality was found in COVID-19 patients with cancer compared to that in COVID-19 patients without cancer (11.7% vs. 4.4%, P = 0.028). Furthermore, we found that neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) were related to death outcome. And a nomogram based on the factors was developed. CONCLUSION: In COVID-19 patients with cancer, the clinical features and laboratory results between severe group and non-severe group were significantly different. NLR and CRP were the risk factors that could predict death outcome.
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COVID-19 , Neoplasias , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/análise , COVID-19/complicações , COVID-19/mortalidade , Feminino , Humanos , Linfócitos/citologia , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Neoplasias/mortalidade , Neutrófilos/citologia , Nomogramas , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: The novel coronavirus disease 2019 (COVID-19) spreads rapidly among people and causes a pandemic. It is of great clinical significance to identify COVID-19 patients with high risk of death. METHODS: A total of 2169 adult COVID-19 patients were enrolled from Wuhan, China, from February 10th to April 15th, 2020. Difference analyses of medical records were performed between severe and non-severe groups, as well as between survivors and non-survivors. In addition, we developed a decision tree model to predict death outcome in severe patients. RESULTS: Of the 2169 COVID-19 patients, the median age was 61 years and male patients accounted for 48%. A total of 646 patients were diagnosed as severe illness, and 75 patients died. An older median age and a higher proportion of male patients were found in severe group or non-survivors compared to their counterparts. Significant differences in clinical characteristics and laboratory examinations were found between severe and non-severe groups, as well as between survivors and non-survivors. A decision tree, including three biomarkers, neutrophil-to-lymphocyte ratio, C-reactive protein and lactic dehydrogenase, was developed to predict death outcome in severe patients. This model performed well both in training and test datasets. The accuracy of this model were 0.98 in both datasets. CONCLUSION: We performed a comprehensive analysis of COVID-19 patients from the outbreak in Wuhan, China, and proposed a simple and clinically operable decision tree to help clinicians rapidly identify COVID-19 patients at high risk of death, to whom priority treatment and intensive care should be given.
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COVID-19 , Adulto , China/epidemiologia , Árvores de Decisões , Humanos , Recém-Nascido , Masculino , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2RESUMO
The COVID-19 pandemic has lasted over 1 year and will not disappear in a short time. There is no specific remedy against the virus as yet. Vaccination is thus far one of the most important strategies for preventing COVID-19. Cancer patients with COVID-19 have a higher mortality because of immunosuppression. Immune checkpoint inhibitors (ICIs) are a novel anticancer strategy for blocking inhibitory pathways, which are related to the immune response. There is a question regarding whether COVID-19 vaccination and ICI treatment impact each other in cancer patients. This review explores both sides of the relationship between ICI treatment and COVID-19 vaccination and suggests good efficacy and safety of ICI treatment after COVID-19 vaccination as well as little impact on the virus protection and toxicity associated with COVID-19 vaccination during ICI treatment.
Lay abstract The COVID-19 pandemic has lasted over 1 year. Vaccination is a promising strategy for preventing COVID-19. Cancer patients are prone to infection with COVID-19, and these patients have high mortality. Immune checkpoint inhibitors (ICIs) are a novel anticancer strategy. Whether COVID-19 vaccination and ICI treatment impact each other in cancer patients remains unknown. This review explores both sides of the relationship between ICI treatment and COVID-19 vaccination and suggests good efficacy and safety of ICI treatment after COVID-19 vaccination as well as little impact on the virus protection and toxicity associated with COVID-19 vaccination during ICI treatment.
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Vacinas contra COVID-19/efeitos adversos , COVID-19/prevenção & controle , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias/tratamento farmacológico , SARS-CoV-2/patogenicidade , COVID-19/epidemiologia , COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , Tomada de Decisão Clínica , Contraindicações de Medicamentos , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Imunogenicidade da Vacina , Neoplasias/imunologia , Pandemias/prevenção & controle , Seleção de Pacientes , SARS-CoV-2/imunologia , Resultado do TratamentoRESUMO
Protein-specific glycoform analysis is essential for the thorough understanding of cellular chemistry and signaling but presents a significant assay challenge for small-sized, free-floating exosomes, ubiquitous regulators of cellular physiological functions and mediators of intercellular communication. We report herein a quantitative localized analysis (QLA) method for the first-time achievement of a protein-specific glycosignature assay on these important extracellular vesicles. The integration of localized chemical remodeling and quantitative electrochemistry allows the proof-of-concept QLA examination of exosomal mucin 1 (MUC1)-specific terminal galactose/N-acetylgalactosamine (Gal/GalNAc). In combination with sialic acid (Sia) cleavage manipulation for the exposure of originally capped Gal/GalNAc, QLA has revealed distinct MUC1-specific sialylation capping ratios for MCF-7 and MDA-MB-231 exosomes, as well as when compared to parent cells. These findings suggest a useful noninvasive indicator for subtyping cancer cells and exosome secretion as a likely venue for the preservation of cellular compositional and functional integrity. The QLA method also permits dynamic monitoring of changes in the exosomal MUC1-specific sialylation capping ratio, enabling the distinction of biogenesis pathways of exosomes.
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Exossomos/química , Vesículas Extracelulares/metabolismo , Neoplasias/genética , Humanos , Transdução de SinaisRESUMO
Chronic graft-versus-host disease (cGVHD) is a major complication affecting the long-term survival of patients after allogeneic haematopoietic stem cell transplantation. The mechanism of cGVHD is unclear, and while previous studies have primarily focused on T cells, the role of B cells in the pathogenesis of cGVHD has been less reported. However, current studies on cGVHD are increasingly focused on the important role of B cells. In this review, we will introduce the newest studies and examine the role of B cells in cGVHD in detail with respect to the following aspects: altered B cell subpopulations, aberrant B cell signalling pathways, autoantibodies and T-B cell interactions. Treatment strategies for the targeting of B cells during cGVHD will also be discussed.
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Linfócitos B/imunologia , Comunicação Celular/imunologia , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Aloenxertos , Animais , Autoanticorpos/imunologia , Doença Crônica , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Humanos , Linfócitos T/patologiaRESUMO
As an investigative tool, live-cell imaging requires superior probe design to guarantee imaging quality and data validity. The ability to simultaneously address the robustness, sensitivity, and consistency issues in a single-assay system is highly desired, but it remains a largely unsolved challenge. We describe herein a probe-design strategy called a nanoamplicon comparator (NAC) and demonstrate its proof-of-concept utility in intracellular microRNA (miRNA) imaging. This novel designer architecture builds upon spherical nucleic acids (SNAs) for robustness, catalytic hairpin assembly (CHA) for sensitivity, and upconversion nanoparticles (UNPs) for consistency. A catalytic circuit comprising a UNP-hairpin-DNA (UNP-HDNA) conjugate and a hairpin-DNA-organic-fluorophore (HDNA-F) conjugate as probe responds to target miRNA and generates the UNP-HDNA-HDNA-F complex as an NAC for quantitative UNP-to-organic-fluorophore-luminescence-resonance-energy-transfer (LRET) imaging against a native UNP-emission reference channel. An imaging application with miR21 shows the ability to monitor miRNA-expression levels across different cell lines and under an external stimulus.
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Transferência Ressonante de Energia de Fluorescência/métodos , Nanopartículas Metálicas/química , MicroRNAs/metabolismo , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/metabolismo , Linhagem Celular , DNA/química , Corantes Fluorescentes/química , Humanos , Sequências Repetidas Invertidas , Limite de Detecção , MicroRNAs/química , Microscopia ConfocalRESUMO
Live cell imaging of protein-specific glycoforms holds great promise for revolutionizing the study of glycochemistry. The imaging protocols developed thus far build upon the paired interplay of probe units, thus limiting the number of monosaccharide identification channels. A hierarchical coding (HieCo) imaging strategy, with DNA coding and decoding of protein and monosaccharides executed in fidelity to the hierarchical order of target glycoprotein, is reported herein and features expandable monosaccharide identification channels. A proof-of-concept protocol has been developed for MUC1-specific imaging of terminal sialic acid (Sia) and fucose (Fuc) on MCF-7, T47D, MDA-MB-231, and PANC-1 cells, revealing distinct monosaccharide patterns for four types of cells. The protocol also permits dynamic monitoring of changes in MUC1-specific monosaccharide patterns associated with both the alteration of cellular physiological states and the occurrence of a biologically important process.
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Mucina-1/metabolismo , Linhagem Celular Tumoral , Fucose/química , Fucose/metabolismo , Glicosilação , Humanos , Microscopia de Fluorescência , Ácido N-Acetilneuramínico/química , Ácido N-Acetilneuramínico/metabolismoRESUMO
Live cell imaging of protein-specific glycoforms is important for the elucidation of glycosylation mechanisms and identification of disease states. The currently used metabolic oligosaccharide engineering (MOE) technology permits routinely global chemical remodeling (GCM) for carbohydrate site of interest, but can exert unnecessary whole-cell scale perturbation and generate unpredictable metabolic efficiency issue. A localized chemical remodeling (LCM) strategy for efficient and reliable access to protein-specific glycoform information is reported. The proof-of-concept protocol developed for MUC1-specific terminal galactose/N-acetylgalactosamine (Gal/GalNAc) combines affinity binding, off-on switchable catalytic activity, and proximity catalysis to create a reactive handle for bioorthogonal labeling and imaging. Noteworthy assay features associated with LCM as compared with MOE include minimum target cell perturbation, short reaction timeframe, effectiveness as a molecular ruler, and quantitative analysis capability.
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Rastreamento de Células , Oligossacarídeos/química , Proteínas/química , Acetilgalactosamina/química , Catálise , Eletroforese em Gel de Poliacrilamida , Galactose/química , Galactose Oxidase/química , Glicosilação , Humanos , Células MCF-7 , Mucina-1/química , Estudo de Prova de ConceitoRESUMO
Graft-versus-host disease (GVHD) reduces the clinical effect and life quality of patients after allogeneic hematopoietic stem cell transplantation (HSCT). Especially for steroid-resistant GVHD, it becomes essential to explore new prevention and treatment strategies. Rapamycin has shown certain clinical advantages in the prevention and treatment of acute and chronic GVHD by inhibiting the mTOR signal pathway. Furthermore, rapamycin exhibits the ability to regulate cell subsets, including T cells, B cell, dendritic cells and myeloidîderived suppressor cells, which elucidates the mechanism on effective preventing and treating GVHD. This article reviewed the roles of mTOR inhibitor-rapamycin on GVHD, and discussed how to optimize the usage of rapamycin.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/terapia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR , Transplante HomólogoRESUMO
With the clarification of the important roles of microRNAs (miRNAs) in diverse physiologic and pathologic processes, the effects of miRNAs in wound healing have attracted more attention recently. However, the global pattern of miRNA expression in wound tissue is still unknown. In the present study, we depicted the miRNA profile and identified at least 54 miRNAs, including miR-21, changed for more than twofold at the stage of granulation formation during wound healing. These miRNAs were closely related to the major events of wound healing, including cell migration and proliferation, angiogenesis, and matrix remolding. Furthermore, we found that miR-21 was up-regulated after skin injury, mainly in activated and migrating epithelial cells of epidermis and mesenchymal cells of dermis. Locally antagonizing miR-21 by directly injecting antagomir to wound edge caused significant delay of wound closure with impaired collagen deposition. Unexpectedly, we found wounds treated with miR-21 antagomir had an obvious defect in wound contraction at an early stage of wound healing. The significant role of miR-21 in wound contraction was further confirmed by in vivo gain-of-function and in vitro loss-of-function experiments. In conclusion, the present study has for the first time depicted miRNA profiling of wound healing and demonstrated the involvement of miR-21 in regulating the wound contraction and collagen deposition. These results suggest that miR-21 may be a new medical target in skin wound manipulation.
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MicroRNAs/metabolismo , Pele/metabolismo , Pele/patologia , Cicatrização/genética , Animais , Colágeno/metabolismo , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Regulação para Cima/genéticaRESUMO
BACKGROUND: Alginate oligosaccharide (AOS) holds great potential as a novel feed supplement in farm animals. However, the effects of AOS on chicken health and the underlying mechanisms are not fully understood. This study aimed to optimize the enzymatic preparation of AOS by using bacterial alginate lyases expressed in yeast, investigate the effects of the prepared AOS on the growth performance and gut health of broiler chickens, and reveal the underlying mechanisms. RESULTS: Five alginate lyases from bacteria were cloned into Pichia pastoris GS115 and the alginate lyase PDE9 was expressed at relatively high yield, activity and stability in P. pastoris. Animal trials were carried out using 320 1-day-old male Arbor Acres broilers (four groups; 8 replicates/group × 10 chicks/replicate) receiving either a basal diet or the same diet supplemented with 100, 200 and 400 mg/kg PDE9-prepared AOS for 42 d. The results showed that dietary supplementation of 200 mg/kg AOS displayed the highest activity in promoting the birds' ADG and ADFI (P < 0.05). AOS ameliorated the intestinal morphology, absorption function and barrier function, as indicated by the enhanced (P < 0.05) intestinal villus height, maltase activity, and the expression of PEPT, SGLT1, ZNT1, and occludin. AOS also increased serum insulin-like growth factor-1, ghrelin (P < 0.05), and growth hormone (P < 0.1). Moreover, the concentrations of acetate, isobutyrate, isovalerate, valerate, and total SCFAs in cecum of birds fed AOS were significantly higher than the control birds (P < 0.05). Metagenomic analysis indicated that AOS modulated the chicken gut microbiota structure, function, and microbial interactions and promoted the growth of SCFAs-producing bacteria, for example, Dorea sp. 002160985; SCFAs, especially acetate, were found positively correlated with the chicken growth performance and growth-related hormone signals (P < 0.05). We further verified that AOS can be utilized by Dorea sp. to grow and to produce acetate in vitro. CONCLUSIONS: We demonstrated that the enzymatically produced AOS effectively promoted broiler chicken growth performance by modulating the chicken gut microbiota structure and function. For the first time, we established the connections among AOS, chicken gut microbiota/SCFAs, growth hormone signals and chicken growth performance.
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The ß-cyclocitric acid (ß-CCA) is a bioactive apocarotenoid previously shown to improve drought tolerance in annual plants. However, the underlying molecular mechanism of this process remains largely elusive. Moreover, the question about the activity of ß-CCA in perennial fruit crops is still open. Here, we found that treatment of ß-CCA enhances drought tolerance in peach seedlings. The application of ß-CCA significantly increased the relative water content and root activity and reduced the electrolyte leakage of peach seedlings under drought stress. Moreover, treatment with ß-CCA under drought stress increased chlorophyll fluorescence, indicating a positive effect on photosynthesis, while also enhancing superoxide dismutase and peroxidase activity and reducing reactive oxygen species (ROS) levels. Consistent with these alterations, transcriptome analysis revealed an up-regulation of photosynthesis and antioxidant-related genes upon the application of ß-CCA under drought stress. We also detected an induction in genes related to detoxification, environmental adaptation, primary metabolism, phytohormone, phenylpropanoid and the biosynthesis of cutin, suberine and wax, which might contribute to the induction of drought resistance. Altogether, our study reveals that ß-CCA positively modulates peach drought tolerance, which is mainly mediated by enhancing photosynthesis and reducing ROS, indicating the potential of utilizing ß-CCA for drought control in peach and perhaps other fruit crops.
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Prunus persica , Prunus persica/metabolismo , Resistência à Seca , Plântula/genética , Plântula/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fotossíntese/fisiologia , Antioxidantes/metabolismo , Secas , Estresse Fisiológico/genéticaRESUMO
The ETV6::PDGFRB fusion gene is commonly reported in chronic myelomonocytic leukemia with eosinophilia, yet patients with ETV6::PDGFRB presenting myeloid and lymphoid neoplasms successively have not been reported. Here, we report the first case of a 35-year-old man with myeloid and lymphoid neoplasms harboring an ETV6::PDGFRB fusion gene who demonstrated poor response to imatinib. The patient was diagnosed with an ETV6::PDGFRB fusion gene myeloid neoplasm on initial diagnosis at our hospital. After 5 months of treatment with imatinib, he was diagnosed with T-cell lymphoblastic lymphoma. ETV6::PDGFRB turned negative after increasing the dose of imatinib, but enlarged superficial lymph nodes reappeared the following year. Notably, the patient exhibited a worse response to imatinib treatment. This study describes this rare case and speculates on a possible mechanism.
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OBJECTIVE: Autologous hematopoietic stem cell (ASC) transplantation (ASCT) is an effective treatment method for patients with hematological disorders and malignant diseases. The patient's ASCs are harvested prior to radiotherapy/chemotherapy, cryopreserved and then transfused back after the high-dose radiotherapy/chemotherapy conditioning treatment. Since some patients develop thrombocytopenia after receiving ASCT, it is difficult for them to bear simultaneously the management of their original disease and thrombocytopenia. The present study aimed to evaluate the efficacy and safety of thrombocytopenia therapy with thrombopoietin receptor agonists (TPORAs) after ASCT. METHODS: We retrospectively analyzed the clinical safety and efficacy of TPORA treatment for the enrolled 20 patients who developed thrombocytopenia after ASCT. The measured parameters were prolonged isolated thrombocytopenia (PIT), secondary failure of platelet recovery (SFPR) and other calculated response index. Patients with platelet count (PC) ≤ 50×109/L were treated with TPORA, namely with either eltrombopag (Elt), hetrombopag (Het), or avatrobopag (Ava). RESULTS: The group of 20 patients, who received TPORA administration for their thrombocytopenia after ASCT, had a median age of 50 years (ranging between 17 and 60 years). The median administration time of TPORA application was 48 days (ranging from 7 to 451 days); an overall response rate (ORR) was 85% with no response in 15% of patients, while with complete response (CR) in 70% of patients and partial response (PR) in 15% of patients. The median platelet count was 19 × 109/L before TPORA treatment and increased to 87×109)/L after the treatment. The TPORA treatment was safe as only 4 patients (20%) displayed a mild transaminase elevation. No other reported side effects occurred, such as thrombosis, joint pain, diarrhea, and myelofibrosis. It was demonstrated that the short response time to TPORA treatment correlated to the fast platelet recovery, when the number of megakaryocytes in the bone marrow smear exceeded 35/4.5 cm2 under a low magnification of 100 times (p = 0.015). CONCLUSION: TPORA therapy for thrombocytopenia occurring after the radiotherapy/ chemotherapy-conditioned ASCT was well tolerated and effective for platelets recovery.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Trombocitopenia , Humanos , Pessoa de Meia-Idade , Receptores de Trombopoetina/uso terapêutico , Estudos Retrospectivos , Trombocitopenia/tratamento farmacológico , Contagem de PlaquetasRESUMO
Introduction: While allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be a curative regimen for acute myeloid leukemia (AML), relapse of AML remains a serious risk post-transplantation. Once relapsed, salvage options are limited and management of AML is difficult. Here we designed a prospective study to examine the efficacy and tolerability of maintenance therapy with azacytidine (AZA) plus low-dose lenalidomide (LEN) to prevent relapse after allo-HSCT for AML patients (ChiCTR2200061803). Methods: AML patients post-allo-HSCT were treated with AZA (75 mg/m2 for 7 days), followed by LEN (5 mg/m2, day 10-28), and a 4-week resting interval, which was defined as one treatment cycle. A total of 8 cycles was recommended. Results: 37 patients were enrolled, 25 patients received at least 5 cycles, and 16 patients finished all 8 cycles. With a median follow-up time of 608 (43-1440) days, the estimated 1-year disease free survival (DFS) was 82%, cumulative incidence of relapse (CIR) was 18%, and overall survival (OS) was 100%. Three patients (8%) had grade 1-2 neutropenia without fever; one patient developed grade 3-4 thrombocytopenia and minor subdural hematoma; 4/37 patients (11%) developed chronic GVHD with a score of 1-2, without requiring systemic treatment; No patient developed acute GVHD. After AZA/LEN prophylaxis, increasing numbers of CD56+NK and CD8+ T, and decreasing of CD19+ B cells were observed. Discussion: Azacitidine combined with low-dose lenalidomide was observed to be an effective relapse prophylaxis option after allo-HSCT in AML patients, and can be administered safely without significantly increasing the risk of GVHD, infection and other AEs. Clinical Trial Registration: www.chictr.org, identifier ChiCTR2200061803.