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The Qingfei Paidu decoction (QFPDD) is a widely acclaimed therapeutic formula employed nationwide for the clinical management of coronavirus disease 2019 (COVID-19). QFPDD exerts a synergistic therapeutic effect, characterized by its multi-component, multi-target, and multi-pathway action. However, the intricate interactions among the ingredients and targets within QFPDD and their systematic effects in multiple tissues remain undetermined. To address this, we qualitatively characterized the chemical components of QFPDD. We integrated multi-tissue transcriptomic analysis with GraphDTA, a deep learning model, to screen for potential compound-target interactions of QFPDD in multiple tissues. We predicted 13 key active compounds, 127 potential targets and 27 pathways associated with QFPDD across six different tissues. Notably, oleanolic acid-AXL exhibited leading affinity in the heart, blood, and liver. Molecular docking and molecular dynamics simulation confirmed their strong binding affinity. The robust interaction between oleanolic acid and the AXL receptor suggests that AXL is a promising target for developing clinical intervention strategies. Through the construction of a multi-tissue compound-target interaction network, our study further elucidated the mechanisms through which QFPDD effectively combats COVID-19 in multiple tissues. Our work also establishes a framework for future investigations into the systemic effects of other Traditional Chinese Medicine (TCM) formulas in disease treatment.
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Chimeric antigen receptor (CAR) T cells show suboptimal efficacy in acute myeloid leukemia (AML). We find that CAR T cells exposed to myeloid leukemia show impaired activation and cytolytic function, accompanied by impaired antigen receptor downstream calcium, ZAP70, ERK, and C-JUN signaling, compared to those exposed to B-cell leukemia. These defects are caused in part by the high expression of CD155 by AML. Overexpressing C-JUN, but not other antigen receptor downstream components, maximally restores anti-tumor function. C-JUN overexpression increases costimulatory molecules and cytokines through reinvigoration of ERK or transcriptional activation, independent of anti-exhaustion. We conduct an open-label, non-randomized, single-arm, phase I trial of C-JUN-overexpressing CAR-T in AML (NCT04835519) with safety and efficacy as primary and secondary endpoints, respectively. Of the four patients treated, one has grade 4 (dose-limiting toxicity) and three have grade 1-2 cytokine release syndrome. Two patients have no detectable bone marrow blasts and one patient has blast reduction after treatment. Thus, overexpressing C-JUN endows CAR-T efficacy in AML.
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Imunoterapia Adotiva , Leucemia Mieloide Aguda , Proteínas Proto-Oncogênicas c-jun , Receptores de Antígenos Quiméricos , Humanos , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , Imunoterapia Adotiva/métodos , Pessoa de Meia-Idade , Masculino , Feminino , Proteínas Proto-Oncogênicas c-jun/metabolismo , Animais , Linfócitos T/imunologia , Linfócitos T/metabolismo , Idoso , Adulto , Linhagem Celular Tumoral , CamundongosRESUMO
BACKGROUND: The absence of clinically-validated biomarkers or objective protocols hinders effective major depressive disorder (MDD) diagnosis. Compared to healthy control (HC), MDD exhibits anomalies in plasma protein levels and neuroimaging presentations. Despite extensive machine learning studies in psychiatric diagnosis, a reliable tool integrating multi-modality data is still lacking. METHODS: In this study, blood samples from 100 MDD and 100 HC were analyzed, along with MRI images from 46 MDD and 49 HC. Here, we devised a novel algorithm, integrating graph neural networks and attention modules, for MDD diagnosis based on inflammatory cytokines, neurotrophic factors, and Orexin A levels in the blood samples. Model performance was assessed via accuracy and F1 value in 3-fold cross-validation, comparing with 9 traditional algorithms. We then applied our algorithm to a dataset containing both the aforementioned protein quantifications and neuroimages, evaluating if integrating neuroimages into the model improves performance. RESULTS: Compared to HC, MDD showed significant alterations in plasma protein levels and gray matter volume revealed by MRI. Our new algorithm exhibited superior performance, achieving an F1 value and accuracy of 0.9436 and 94.08 %, respectively. Integration of neuroimaging data enhanced our novel algorithm's performance, resulting in an improved F1 value and accuracy, reaching 0.9543 and 95.06 %. LIMITATIONS: This single-center study with a small sample size requires future evaluations on a larger test set for improved reliability. CONCLUSIONS: In comparison to traditional machine learning models, our newly developed MDD diagnostic model exhibited superior performance and showed promising potential for inclusion in routine clinical diagnosis for MDD.
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Biomarcadores , Transtorno Depressivo Maior , Imageamento por Ressonância Magnética , Redes Neurais de Computação , Neuroimagem , Humanos , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/diagnóstico por imagem , Biomarcadores/sangue , Imageamento por Ressonância Magnética/métodos , Adulto , Feminino , Masculino , Neuroimagem/métodos , Pessoa de Meia-Idade , Algoritmos , Orexinas/sangue , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Citocinas/sangue , Aprendizado de Máquina , Atenção , Estudos de Casos e ControlesRESUMO
BACKGROUND & AIMS: Patients with metastatic, treatment-refractory, and relapsed hepatoblastoma (HB) have survival rates of less than 50% due to limited treatment options. To develop new therapeutic strategies for these patients, our laboratory has developed a preclinical testing pipeline. Given that histone deacetylase (HDAC) inhibition has been proposed for HB, we hypothesized that we could find an effective combination treatment strategy utilizing HDAC inhibition. METHODS: RNA sequencing, microarray, NanoString, and immunohistochemistry data of patient HB samples were analyzed for HDAC class expression. Patient-derived spheroids (PDSp) were used to screen combination chemotherapy with an HDAC inhibitor, panobinostat. Patient-derived xenograft (PDX) mouse models were developed and treated with the combination therapy that showed the highest efficacy in the PDSp drug screen. RESULTS: HDAC RNA and protein expression were elevated in HB tumors compared to normal livers. Panobinostat (IC50 of 0.013-0.059 µM) showed strong in vitro effects and was associated with lower cell viability than other HDAC inhibitors. PDSp demonstrated the highest level of cell death with combination treatment of vincristine/irinotecan/panobinostat (VIP). All four models responded to VIP therapy with a decrease in tumor size compared to placebo. After 6 weeks of treatment, two models demonstrated necrotic cell death, with lower Ki67 expression, decreased serum alpha fetoprotein and reduced tumor burden compared to paired VI- and placebo-treated groups. CONCLUSIONS: Utilizing a preclinical HB pipeline, we demonstrate that panobinostat in combination with VI chemotherapy can induce an effective tumor response in models developed from patients with high-risk, relapsed, and treatment-refractory HB. IMPACT AND IMPLICATIONS: Patients with treatment-refractory hepatoblastoma have limited treatment options with survival rates of less than 50%. Our manuscript demonstrates that combination therapy with vincristine, irinotecan, and panobinostat reduces the size of high-risk, relapsed, and treatment-refractory tumors. With this work we provide preclinical evidence to support utilizing this combination therapy as an arm in future clinical trials.
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Hepatoblastoma , Neoplasias Hepáticas , Humanos , Camundongos , Animais , Panobinostat/farmacologia , Panobinostat/uso terapêutico , Hepatoblastoma/tratamento farmacológico , Irinotecano/uso terapêutico , Vincristina/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/induzido quimicamente , Inibidores de Histona Desacetilases/uso terapêutico , Neoplasias Hepáticas/patologia , Ácidos Hidroxâmicos/farmacologiaRESUMO
With the gradual improvement of individuals' living standards, there has been a concurrent escalation in the consumption of fats and sugars in the daily dietary habits. Consequently, an increasing number of individuals are afflicted by hyperlipidemia, a condition that, could elevate blood viscosity, thereby engendering serious complications in a long run. Traditional lipid-lowering medications, such as statins, manifest substantial side effects, thereby imposing a significant metabolic burden on the liver and kidneys. Conversely, antisense oligonucleotides (ASOs) exhibit attributes such as rapid absorption, prolonged efficacy, and minimal side effects. In light of these considerations, a novel ASO was meticulously designed, sebsequently, its efficacy and toxicity assessments were conducted both in vitro and in vivo. The results unequivocally demonstrate the effectiveness and safety of this ASO.
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Hiperlipidemias , Pró-Proteína Convertase 9 , Humanos , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , Fígado/metabolismoRESUMO
OBJECTIVE: Hepatoblastoma (HB) is the most common primary hepatic malignancy in childhood. Relapse occurs in more than 50% of high-risk patients with a high mortality due to ineffective salvage therapies. The purpose of this study is to identify risk factors for relapsed HB and predictors of survival in a single tertiary referral center. METHODS: A retrospective chart review showed 129 surgically treated HB patients from October 2004 to July 2020. Of the cohort, 22 patients presented with relapsed HB. Relapse was defined as re-appearance of malignancy after 4 weeks of normalized AFP and disappearance of all tumors on imaging. RESULTS: Patients with relapsed HB had a 5-year overall survival (OS) of 45.4% compared to 93.1% in those without relapse (p = 0.001). When comparing PRETEXT IV, microvascular invasion, metastatic disease, and age on multivariate logistic regression, only PRETEXT IV was an independent risk factor for relapsed HB with an OR of 2.39 (95% CI: 1.16-4.96; p = 0.019). Mixed epithelial and mesenchymal HB (12/19, 63.2%) was the most common histology of primary tumors while pure epithelial HB (13/15, 86.6%) was the most common relapsed histology. Combination of surgical and medical therapy for relapsed disease was predictive of survival with an HR of 16.3 (95% CI: 1.783-149.091; p = 0.013) compared to only chemotherapy. CONCLUSIONS: This study demonstrates that PRETEXT IV staging is an independent predictor of relapsed disease. The most common relapsed histology was epithelial, suggesting a potential selection or resistance of this component. Surgical resection is a critical component of multimodal therapy for relapsed HB.
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Hepatoblastoma , Neoplasias Hepáticas , Humanos , Lactente , Hepatoblastoma/cirurgia , Hepatoblastoma/patologia , Estudos Retrospectivos , Prognóstico , Neoplasias Hepáticas/patologia , Recidiva , Resultado do TratamentoRESUMO
BACKGROUND: Relapses frequently occur following CD19-directed chimeric antigen receptor (CAR) T-cell treatment for relapsed or refractory B-cell acute lymphocytic leukaemia in children. We aimed to assess the activity and safety of sequential CD19-directed and CD22-directed CAR T-cell treatments. METHODS: This single-centre, single-arm, phase 2 trial, done at Beijing GoBroad Boren Hospital, Beijing, China, included patients aged 1-18 years who had relapsed or refractory B-cell acute lymphocytic leukaemia with CD19 and CD22 positivity greater than 95% and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were initially infused with CD19-directed CAR T cells intravenously, followed by CD22-directed CAR T-cell infusion after minimal residual disease-negative complete remission (or complete remission with incomplete haematological recovery) was reached and all adverse events (except haematological adverse events) were grade 2 or better. The target dose for each infusion was 0·5 × 106 to 5·0 × 106 cells per kg. The primary endpoint was objective response rate at 3 months after the first infusion. Secondary endpoints were duration of remission, event-free survival, disease-free survival, overall survival, safety, pharmacokinetics, and B-cell quantification. The prespecified activity analysis included patients who received the target dose and the safety analysis included all treated patients. This study is registered with ClinicalTrials.gov, NCT04340154, and enrolment has ended. FINDINGS: Between May 28, 2020, and Aug 16, 2022, 81 participants were enrolled, of whom 31 (38%) were female and 50 (62%) were male. Median age was 8 years (IQR 6-10), all patients were Asian. All 81 patients received the first infusion and 79 (98%) patients received sequential infusions, CD19-directed CAR T cells at a median dose of 2·7 × 106 per kg (IQR 1·1 × 106 to 3·7 × 106) and CD22-directed CAR T cells at a median dose of 2·2 × 106 per kg (1·1 × 106 to 3·7 × 106), with a median interval of 39 days (37-41) between the two infusions. 62 (77%) patients received the target dose, including two patients who did not receive CD22 CAR T cells. At 3 months, 60 (97%, 95% CI 89-100) of the 62 patients who received the target dose had an objective response. Median follow-up was 17·7 months (IQR 11·4-20·9). 18-month event-free survival for patients who received the target dose was 79% (95% CI 66-91), duration of remission was 80% (68-92), and disease-free survival was 80% (68-92) with transplantation censoring; overall survival was 96% (91-100). Common adverse events of grade 3 or 4 between CD19-directed CAR T-cell infusion and 30 days after CD22-directed CAR T-cell infusion included cytopenias (64 [79%] of 81 patients), cytokine release syndrome (15 [19%]), neurotoxicity (four [5%]), and infections (five [6%]). Non-haematological adverse events of grade 3 or worse more than 30 days after CD22-directed CAR T-cell infusion occurred in six (8%) of 79 patients. No treatment-related deaths occurred. CAR T-cell expansion was observed in all patients, with a median peak at 9 days (IQR 7-14) after CD19-directed and 12 days (10-15) after CD22-directed CAR T-cell infusion. At data cutoff, 35 (45%) of 77 evaluable patients had CAR transgenes and 59 (77%) had B-cell aplasia. INTERPRETATION: This sequential strategy induced deep and sustained responses with an acceptable toxicity profile, and thus potentially provides long-term benefits for children with this condition. FUNDING: The National Key Research & Development Program of China, the CAMS Innovation Fund for Medical Sciences (CIFMS), and the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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Leucemia Linfocítica Crônica de Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Humanos , Masculino , Criança , Feminino , Receptores de Antígenos Quiméricos/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Imunoterapia Adotiva/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Terapia Baseada em Transplante de Células e Tecidos , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/uso terapêuticoRESUMO
BACKGROUND: Donor-derived CD7-directed chimeric antigen receptor (CAR) T cells showed feasibility and early efficacy in patients with refractory or relapsed T-cell acute lymphoblastic leukemia (r/r T-ALL), in a previous phase I trial report, at a median follow-up of 6.3 months. Here we report long-term safety and activity of the therapy after a 2-year follow-up. METHODS: Participants received CD7-directed CAR T cells derived from prior stem cell transplantation (SCT) donors or from HLA-matched new donors after lymphodepletion. The target dose was 1 × 106 (± 30%) CAR T cells per kg of patient weight. The primary endpoint was safety with efficacy secondary. This report focuses on the long-term follow-up and discusses them in the context of previously reported early outcomes. RESULTS: Twenty participants were enrolled and received infusion with CD7 CAR T cells. After a median follow-up time of 27.0 (range, 24.0-29.3) months, the overall response rate and complete response rate were 95% (19/20 patients) and 85% (17/20 patients), respectively, and 35% (7/20) of patients proceeded to SCT. Six patients experienced disease relapse with a median time-to-relapse of 6 (range, 4.0-10.9) months, and 4 of these 6 patients were found to have lost CD7 expression on tumor cells. Progression-free survival (PFS) and overall survival (OS) rates 24 months after treatment were respectively 36.8% (95% CI, 13.8-59.8%) and 42.3% (95% CI, 18.8-65.8%), with median PFS and OS of respectively 11.0 (95% CI, 6.7-12.5) months and 18.3 (95% CI, 12.5-20.8) months. Previously reported short-term adverse events (< 30 days after treatment) included grade 3-4 cytokine release syndrome (CRS; 10%) and grade 1-2 graft-versus-host disease (GVHD; 60%). Serious adverse events reported > 30 days after treatment included five infections and one grade 4 intestinal GVHD. Despite good CD7 CAR T-cell persistence, non-CAR T and natural killer cells were predominantly CD7-negative and eventually returned to normal levels in about half of the participants. CONCLUSIONS: In this 2-year follow-up analysis, donor-derived CD7 CAR T-cell treatment demonstrated durable efficacy in a subset of patients with r/r T-ALL. Disease relapse was the main cause of treatment failure, and severe infection was a noteworthy late-onset adverse event. TRIAL REGISTRATION: ChiCTR2000034762.
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Doença Enxerto-Hospedeiro , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Antígenos CD19 , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Imunoterapia Adotiva/efeitos adversos , Recidiva , Linfócitos T , Antígenos CD7/imunologiaRESUMO
Triple-negative breast cancer (TNBC) is a heterogeneous disease with diverse, often poor prognoses and treatment responses. In order to identify targetable biomarkers and guide personalized care, scientists have developed multiple molecular classification systems for TNBC based on transcriptomic profiling. However, there is no consensus on the molecular subtypes of TNBC, likely due to discrepancies in technical and computational methods used by different research groups. Here, we reassessed the major steps for TNBC subtyping, validated the reproducibility of established TNBC subtypes, and identified two more subtypes with a larger sample size. By comparing results from different workflows, we demonstrated the limitations of formalin-fixed, paraffin-embedded samples, as well as batch effect removal across microarray platforms. We also refined the usage of computational tools for TNBC subtyping. Furthermore, we integrated high-quality multi-institutional TNBC datasets (discovery set: n = 457; validation set: n = 165). Performing unsupervised clustering on the discovery and validation sets independently, we validated four previously discovered subtypes: luminal androgen receptor, mesenchymal, immunomodulatory, and basal-like immunosuppressed. Additionally, we identified two potential intermediate states of TNBC tumors based on their resemblance with more than one well-characterized subtype. In summary, we addressed the issues and limitations of previous TNBC subtyping through comprehensive analyses. Our results promote the rational design of future subtyping studies and provide new insights into TNBC patient stratification.
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With the dramatic increase in anthropogenic threats to the Pearl River Estuary (PRE), the population size of the Indo-Pacific humpback dolphins (Sousa chinensis) has significantly decreased over the past decade. To understand the impact and potential risks of intense human activities on these dolphins, factors related to the mortality of humpback dolphins in the PRE were investigated by a detailed examination of 343 dolphin specimens stranded during 2003-2017. There was a significant (p < 0.01) increasing trend for humpback dolphin stranding, reflecting the accelerating rate of the population decline. A large proportion of strandings (35.88%) were neonates. A low recruitment rate implies slow population growth, and hence, limited capacity to resist anthropogenic stress. The most commonly diagnosed causes of death were vessel collision and net entanglement. The concentrations of trace metals, polychlorinated biphenyl (PCB) congeners, dichlorodiphenyltrichloroethane, polycyclic aromatic hydrocarbons, and most of per- and polyfluoroalkyl substances (PFASs) in the dolphin samples were greater than those previously reported in cetaceans globally. Furthermore, Cu, PCB77, PCB169, PCB81, PCB37, and PFASs (excluding PFBA, PFPeA, PFHxA, PFHxDA, and PFODA) were the major pollutants accumulated in neonates. 67% of PCB, 78% of Cu, and 100% of perfluorooctane sulfonate concentrations in the neonates exceeded the threshold for toxicological effects in marine mammals, suggesting that these compounds could be important factors contributing to the low survival rate of calves in this area. This study revealed that vessel transportation, fishing activities, and pollutant bioaccumulation are the three major causes of humpback dolphin mortality in the PRE. These results highlight the need for more efforts to restrict anthropogenic activities, especially vessel traffic, the catching of these marine animals and fishing, and pollutant discharge, in order to prevent vulnerable species from continuous population decline and further extinction.
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Golfinhos , Poluentes Ambientais , Fluorocarbonos , Animais , China , Estuários , RiosRESUMO
Background: Rose acne is a chronic inflammatory skin disease that can cause paroxysmal flushing, persistent erythema, papules or papules on the face, and pustules, and it has a greater impact on the life of patients, so it is important to treat it. Objective: To investigate the effect of Danzhi Xiaoyao Powder combined with photodynamic therapy (PDT) on the curative effect evaluation and prognosis of patients with rose acne. Patients and Methods. The clinical data of 110 rose acne patients who were treated in our hospital from January 2019 to January 2021 were selected as the subject of this retrospective study. They were divided into a control group and a treatment group according to the random residue grouping method. The new crown epidemic, loss to follow-up, etc. fell out of 5 cases in each group, and finally, 50 cases in each group were left. Among them, the control group was treated with PDT, and the treatment group was combined with Danzhi Xiaoyao Powder on the basis of the control group. Then we observe and compare the effects of skin lesion scores and clinical symptom scores and differences in clinical efficacy between the two groups. Results: The comparison of the clinical symptom scores of the two groups of patients before treatment was not statistically significant (P > 0.05), while the burning score, tingling score, dryness score, and pruritus score of the treatment group after treatment were significantly different. The internal comparison after treatment was lower than before treatment, and the comparison between the treatment groups was significantly higher than the control group, which was statistically significant (P < 0.05). There was no statistically significant difference in the skin lesion scores of the two groups before treatment (P > 0.05), while the papules score, pustule score, erythema score, and telangiectasia score of the treatment group after treatment were significantly different and compared within the group. After treatment, the treatment group was significantly higher than the control group, and the comparison was statistically significant (P < 0.05). The effective rate of 98.00% in the treatment group was significantly higher than the 76.00% in the control group, and the difference was statistically significant (P < 0.05). The clinical efficacy of the two groups of patients showed that the rash, chest tightness, nausea, and diarrhea of the treatment group were significantly lower than those of the control group, and the difference was statistically significant (P < 0.05). Conclusion: Danzhi Xiaoyao Powder combined with PDT to treat rose acne is effective, can quickly control inflammatory papules and inflammatory erythema, effectively improve the clinical symptoms of patients, and reduce adverse reactions.
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Medicamentos de Ervas Chinesas/uso terapêutico , Fotoquimioterapia , Fitoterapia , Rosácea/tratamento farmacológico , Adolescente , Adulto , Terapia Combinada , Biologia Computacional , Medicamentos de Ervas Chinesas/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pós , Prognóstico , Estudos Retrospectivos , Rosácea/diagnóstico por imagem , Resultado do Tratamento , Adulto JovemRESUMO
The detrimental effects of contaminant exposure and changes in the availability of food resources are still of concern for Indo-Pacific humpback dolphins (Sousa chinensis) of the Pearl River Estuary (PRE). Here, we validated and applied a blubber cortisol biomarker approach to assess the physiological responses of PRE dolphins to various pollutants and diet changes during 2008-2018 (n = 70). For calves, generalized additive models (GAMs) revealed that cortisol levels varied significantly by month and were positively correlated with the body length, owing to significant maternal transfer of hormones. The significantly positive correlation between length-adjusted cortisol levels in calf and the annual calf mortality ratios suggested that during years of high calf mortality, these animals were highly stressed before they die. For noncalves, blubber cortisol levels in diseased animals were significantly higher than those in "healthy" ones. Chromium (Cr) and dichlorodiphenyltrichloroethanes displayed a significant and positive relationship with blubber cortisol levels, suggesting that contaminant-mediated endocrine disruption effects may have occurred in noncalves. The GAMs indicated a decreasing trend of noncalf's blubber cortisol levels over an 11-year span, which can be explained by their declining contaminant accumulation levels due to a significant dietary shift from eating highly contaminated fishes to less polluted ones.
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Golfinhos , Poluentes Químicos da Água , Animais , China , Dieta , Estuários , Hidrocortisona , Poluentes Químicos da Água/análiseRESUMO
Single antigen-targeted chimeric antigen receptor (CAR) T-cell therapy may be insufficient to induce a durable response in pediatric aggressive B-cell lymphomas. This clinical trial examined the feasibility of sequential different B-cell antigen-targeted CAR T-cell therapy for pediatric relapsed/refractory (R/R) Burkitt lymphoma. Twenty-three patients received the first CD19 CAR T-cell infusion. The patients who did not achieve an ongoing complete response (CR) underwent 1 or more sequential infusions of CAR T-cell therapy that targeted CD22 followed by CD20 according to their disease status and CAR T-cell persistence after each infusion. The median time from the last infusion to the cutoff date was 17 months (range, 15-23 months). The estimated 18-month CR rate was 78% (95% confidence interval [CI], 54%-91%). The estimated 18-month progression-free survival rate was 78% (95% CI, 55%-90%), with 78% (95% CI, 37%-94%) in patients with bulky disease and 60% (95% CI, 25%-83%) in patients with central nervous system (CNS) involvement. During the first CD19 CAR T-cell infusion, grade ≥3 cytokine release syndrome (CRS) occurred in 34.8% and neurotoxicity occurred in 21.7% of all patients. During subsequent infusions, there were only a few incidences of grade >2 CRS and neurotoxicity. All adverse events were reversible. The severity of neurotoxicity was not significantly different between patients with CNS involvement and those who did not have CNS involvement. Sequential CAR T-cell therapy may result in a durable response and is safe in pediatric R/R Burkitt lymphoma. Patients with CNS involvement may benefit from sequential CAR T-cell therapy. This trial was registered at www.chictr.org.cn/index.aspx as #ChiCTR1800014457.
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Linfoma de Burkitt , Receptores de Antígenos Quiméricos , Antígenos CD19 , Linfoma de Burkitt/terapia , Criança , Síndrome da Liberação de Citocina , Humanos , Imunoterapia Adotiva/efeitos adversos , Linfócitos TRESUMO
Our previous clinical study achieved complete remission (CR) rates of >90% following chimeric antigen receptor T cells targeting CD19 (CART19) treatment of refractory/relapsed B cell acute lymphoblastic leukemia (r/r B-ALL); however, the influence of the leukemia burden in peripheral blood (PB) blasts remains unclear. Here, we retrospectively analyzed 143 patients treated with CART19 (including 36 patients with PB blasts) to evaluate the effect of peripheral leukemia burden at the time of apheresis. One hundred seventeen patients with high disease burdens achieved 91.5% CR or incomplete count recovery CR and 86.3% minimal residual disease-negative CR, and 26 patients with low disease burdens obtained 96.2% MRD- CR. Collectively, 9 of 36 (25%) patients with PB blasts and 2 of 107 (1.87%) patients without PB blasts did not respond to CART19 therapy. The leukemia burden in PB negatively influenced ex vivo cell characteristics, including the transduction efficiency of CD3+ T cells and their fold expansion, and in vivo cell dynamics, including peak CART19 proportion and absolute count, fold expansion, and persistence duration. Further studies showed that these patients had higher programmed death-1 expression in CART19 products. Our data imply that PB blasts negatively affected CART19 production and the clinical efficacy of CART19 therapy in patients with r/r B-ALL.
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PURPOSE: Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (r/r T-ALL) have few options and poor prognosis. The aim was to assess donor-derived anti-CD7 chimeric antigen receptor (CAR) T-cell safety and efficacy in patients with r/r T-ALL. METHODS: In this single-center, phase I trial, we administered anti-CD7 CAR T cells, manufactured from either previous stem-cell transplantation donors or new donors, to patients with r/r T-ALL, in single infusions at doses of 5 × 105 or 1 × 106 (±30%) cells per kilogram of body weight. The primary end point was safety with efficacy secondary. RESULTS: Twenty participants received infusions. Adverse events including cytokine release syndrome grade 1-2 occurred in 90% (n = 18) and grade 3-4 in 10% (n = 2), cytopenia grade 3-4 in 100% (n = 20), neurotoxicity grade 1-2 in 15% (n = 3), graft-versus-host disease grade 1-2 in 60% (n = 12), and viral activation grade 1-2 in 20% (n = 4). All adverse events were reversible, except in one patient who died through pulmonary hemorrhage related to fungal pneumonia, which occurred at 5.5 months, postinfusion. Ninety percent (n = 18) achieved complete remission with seven patients proceeding to stem-cell transplantation. At a median follow-up of 6.3 months (range, 4.0-9.2), 15 remained in remission. CAR T cells were still detectable in five of five patients assessed in month 6, postinfusion. Although patients' CD7-positive normal T cells were depleted, CD7-negative T cells expanded and likely alleviated treatment-related T-cell immunodeficiency. CONCLUSION: Among 20 patients with r/r T-ALL enrolled in this trial, donor-derived CD7 CAR T cells exhibited efficient expansion and achieved a high complete remission rate with manageable safety profile. A multicenter, phase II trial of donor-derived CD7 CAR T cells is in progress (NCT04689659).
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Antígenos CD7/imunologia , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/transplante , Adolescente , Adulto , Terapia Baseada em Transplante de Células e Tecidos , Criança , Pré-Escolar , Síndrome da Liberação de Citocina/etiologia , Infecções por Citomegalovirus/etiologia , Infecções por Vírus Epstein-Barr/etiologia , Feminino , Doença Enxerto-Hospedeiro/etiologia , Humanos , Imunoterapia Adotiva/efeitos adversos , Contagem de Linfócitos , Linfopenia/etiologia , Masculino , Neutropenia/etiologia , Indução de Remissão , Trombocitopenia/etiologia , Doadores de Tecidos , Transplante Homólogo/efeitos adversos , Ativação Viral , Adulto JovemAssuntos
Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Adolescente , Animais , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Criança , Pré-Escolar , Humanos , Imunoterapia Adotiva/efeitos adversos , Células Jurkat , Células K562 , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/antagonistas & inibidores , Resultado do TratamentoRESUMO
The prognosis of relapsed acute lymphoblastic leukemia (ALL) after allogeneic transplantation is dismal when treated with conventional approaches. While single-target CD19 or CD22 chimeric antigen receptor (CAR) T-cell therapy has achieved high complete remission (CR) rates in refractory/relapsed B-ALL, it could not maintain a durable remission in most patients. To prolong relapse-free survival, we sequentially combined CD19 and CD22 CAR-T cells to treat post-transplant relapsed B-ALL patients with both CD19/CD22 antigen expression on lymphoblasts. Patient-derived donor cells were collected to produce CAR-T cells that were transfected by lentiviral vectors encoding second generation CARs composed of CD3ζ and 4-1BB. The second T-cell infusion was scheduled at least 1 month, and usually within 6 months after the first CAR-T treatment. Twenty-seven adult and pediatric patients, including 11 (41%) with extramedullary diseases (EMD), received the first CD19 CAR-T and 23 (85%) achieved CR. Subsequently, 21 out of 27 patients received the second CD22 CAR-T and were followed-up for a median of 19.7 (range, 5.6-27.3) months; 14 cases remained in CR, seven relapsed and two of them died from disease progression; Kaplan-Meier survival analysis showed overall survival and event-free survival rates of 88.5% and 67.5%, respectively, at both 12 months and 18 months. CAR-T associated graft-versus-host disease (GVHD) occurred in 23% of patients, with 8% new-onset acute GVHD and 15% persistent or worsened pre-existing cGVHD before CAR-T. This combination strategy of sequential CD19 and CD22 CAR-T therapy significantly improved the long-term survival in B-ALL patients who relapsed after transplantation.
Assuntos
Antígenos CD19/imunologia , Antígenos de Neoplasias/imunologia , Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Terapia de Salvação , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Ligante 4-1BB/genética , Adolescente , Adulto , Aloenxertos , Complexo CD3/genética , Criança , Pré-Escolar , Terapia Combinada , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Intervalo Livre de Progressão , Recidiva , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Although recent clinical trials have demonstrated the efficacy of CD19-directed chimeric antigen receptor (CAR) T-cell therapy for refractory or relapsed B acute lymphoblastic leukemia (r/r B-ALL), most trials exclude patients with high-burden CNS leukemia (CNSL) to avoid the risk of severe neurotoxicity. There were only sparse cases describing the effect of CAR T cells on low-burden CNSL, and the safety and effectiveness of CAR T cells in high-burden CNSL remains unknown. METHODS: Here, we retrospectively analyzed the results of CD19 CAR T-cell therapy in 12 pediatric patients that had low (Blasts < 20/µL in CSF) or high-burdens (Blasts or intracranial solid mass) of CNS B-ALL, that are enrolled in three clinical trials and one pilot study at Beijing Boren Hospital RESULTS: Eleven patients (91.7%) achieved complete remission (CR) on day 30, and one patient got CR on day 90 after infusion. Most patient experienced mild cytokine-release syndrome. However, of the five patients who retained > 5/µL blasts in CSF or a solid mass before CAR T-cell expansion, four developed severe (grade 3-4) neurotoxicity featured by persistent cerebral edema and seizure, and they fully recovered after intensive managements. Sustained remission was achieved in 9 of the 12 patients, resulted in a 6-month leukemia-free survival rate of 81.8% (95% CI 59.0-100). Only one patient has CNS relapse again. CONCLUSION: Our study demonstrates that CAR T cells are effective in clearing both low- and high-burden CNSL, but a high CNSL burden before CAR T-cell expansion may cause severe neurotoxicity requiring intense intervention.