RESUMEN
The advent of drones has revolutionized various aspects of our lives, and in the realm of biological systems, molecular drones hold immense promise as "magic bullets" for major diseases. Herein, we introduce a unique class of fluorinated macromolecular amphiphiles, designed in the shape of jellyfish, serving as exemplary molecular drones for fluorine-19 MRI (19F MRI) and fluorescence imaging (FLI)-guided drug delivery, status reporting, and targeted cancer therapy. Functioning akin to their mechanical counterparts, these biocompatible molecular drones autonomously assemble with hydrophobic drugs to form uniform nanoparticles, facilitating efficient drug delivery into cells. The status of drug delivery can be tracked through aggregation-induced emission (AIE) of FLI and 19F MRI. Furthermore, when loaded with a heptamethine cyanine fluorescent dye IR-780, these molecular drones enable near-infrared (NIR) FL detection of tumors and precise delivery of the photosensitizer. Similarly, when loaded with doxorubicin (DOX), they enable targeted chemotherapy with fluorescence resonance energy transfer (FRET) FL for real-time status updates, resulting in enhanced therapeutic efficacy. Compared to conventional drug delivery systems, molecular drones stand out for their simplicity, precise structure, versatility, and ability to provide instantaneous status updates. This study presents prototype molecular drones capable of executing fundamental drone functions, laying the groundwork for the development of more sophisticated molecular machines with significant biomedical implications.
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Doxorrubicina , Sistemas de Liberación de Medicamentos , Humanos , Animales , Sistemas de Liberación de Medicamentos/métodos , Doxorrubicina/química , Doxorrubicina/farmacología , Halogenación , Ratones , Nanopartículas/química , Colorantes Fluorescentes/química , Sustancias Macromoleculares/química , Imagen Óptica/métodos , Imagen por Resonancia Magnética con Fluor-19/métodos , Neoplasias/tratamiento farmacológico , Línea Celular TumoralRESUMEN
The small, heavily glycosylated protein CD24 is primarily expressed by many immune cells and is highly expressed mostly in cancer cells. As one of the most crucial biomarkers of cancers, CD24 is frequently highly expressed in solid tumors, while tumor-associated macrophages express Siglec-10 at high levels, Siglec-10 and CD24 can interact on innate immune cells to lessen inflammatory responses to a variety of disorders. Inhibiting inflammation brought on by SHP-1 and/or SHP-2 phosphatases as well as cell phagocytosis by macrophages, the binding of CD24 to Siglec-10 can prevent toll-like receptor-mediated inflammation. Targeted immunotherapy with immune checkpoint inhibitors (ICI) has lately gained popularity as one of the best ways to treat different tumors. CD24 is a prominent innate immune checkpoint that may be a useful target for cancer immunotherapy. In recent years, numerous CD24/Siglec-10-related research studies have made tremendous progress. This study discusses the characteristics and workings of CD24/Siglec-10-targeted immunotherapy and offers a summary of current advances in CD24/Siglec-10-related immunotherapy research for cancer. We then suggested potential directions for CD24-targeted immunotherapy, basing our speculation mostly on the results of recent preclinical and clinical trials.
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Macrófagos , Neoplasias , Humanos , Transducción de Señal , Inflamación , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico , Inmunoterapia/métodos , Antígeno CD24/metabolismoRESUMEN
BACKGROUND: Although chimeric antigen receptor T (CAR-T) cells have been proven to be an effective way of treating B cell malignancies, a lot of patients could not benefit from it because of failure in CAR-T cell manufacturing, disease progression, and unaffordable price. The study aimed to explore universal CAR-T cell products to extend the clinical accessibility. METHODS: The antitumor activity of CRISPR/Cas9-edited allogeneic anti-CD19 CAR-T (CAR-T19) cells was assessed in vitro, in animal models, and in patients with relapsed/refractory (R/R) acute B cell lymphoblastic leukemia (B-ALL) or diffuse large B cell lymphoma. RESULTS: B2M-/TRAC- universal CAR-T19 (U-CAR-T19) cells exhibited powerful anti-leukemia abilities both in vitro and in animal models, as did primary CD19+ leukemia cells from leukemia patients. However, expansion, antitumor efficacy, or graft-versus-host-disease (GvHD) was not observed in six patients with R/R B cell malignancies after U-CAR-T19 cell infusion. Accordingly, significant activation of natural killer (NK) cells by U-CAR-T19 cells was proven both clinically and in vitro. HLA-A-/B-/TRAC- novel CAR-T19 (nU-CAR-T19) cells were constructed with similar tumoricidal capacity but resistance to NK cells in vitro. Surprisingly, robust expansion of nU-CAR-T19 cells, along with rapid eradication of CD19+ abnormal B cells, was observed in the peripheral blood and bone marrow of another three patients with R/R B-ALL. The patients achieved complete remission with no detectable minimal residual disease 14 days after the infusion of nU-CAR-T19 cells. Two of the three patients had grade 2 cytokine release syndrome, which were managed using an IL-6 receptor blocker. Most importantly, GvHD was not observed in any patient, suggesting the safety of TRAC-disrupted CAR-T cells generated using the CRISPR/Cas9 method for clinical application. CONCLUSIONS: The nU-CAR-T19 cells showed a strong response in R/R B-ALL. nU-CAR-T19 cells have the potential to be a promising new approach for treating R/R B cell malignancies.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Linfocítica Crónica de Células B , Leucemia , Receptores Quiméricos de Antígenos , Animales , Humanos , Receptores Quiméricos de Antígenos/genética , Anticuerpos , Antígenos CD19 , Linfocitos T , Antígenos HLA-ARESUMEN
While studies have explored the feasibility of switching between various thrombopoietin receptor agonists in treating immune thrombocytopenia (ITP), data on the switching from eltrombopag to hetrombopag remains scarce. This post-hoc analysis of a phase III hetrombopag trial aimed to assess the outcomes of ITP patients who switched from eltrombopag to hetrombopag. In the original phase III trial, patients initially randomized to the placebo group were switched to eltrombopag. Those who completed this 14-week eltrombopag were eligible to switch to a 24-week hetrombopag. Treatment response, defined as a platelet count of ≥ 50 × 109/L, and safety were evaluated before and after the switch. Sixty-three patients who completed the 14-week eltrombopag and switched to hetrombopag were included in this post-hoc analysis. Response rates before and after the switch were 66.7% and 88.9%, respectively. Among those with pre-switching platelet counts below 30 × 109/L, eight out of 12 patients (66.7%) responded, while eight out of nine patients (88.9%) with pre-switching platelet counts between 30 × 109/L and 50 × 109/L responded post-switching. Treatment-related adverse events were observed in 50.8% of patients during eltrombopag treatment and 38.1% during hetrombopag treatment. No severe adverse events were noted during hetrombopag treatment. Switching from eltrombopag to hetrombopag in ITP management appears to be effective and well-tolerated. Notably, hetrombopag yielded high response rates, even among patients who had previously shown limited response to eltrombopag. However, these observations need to be confirmed in future trials.
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Benzoatos , Hidrazinas , Púrpura Trombocitopénica Idiopática , Pirazoles , Pirazolonas , Receptores de Trombopoyetina , Humanos , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Pirazoles/administración & dosificación , Masculino , Femenino , Benzoatos/uso terapéutico , Benzoatos/efectos adversos , Benzoatos/administración & dosificación , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/sangre , Persona de Mediana Edad , Adulto , Anciano , Hidrazinas/uso terapéutico , Hidrazinas/efectos adversos , Hidrazinas/administración & dosificación , Receptores de Trombopoyetina/agonistas , Pirazolonas/uso terapéutico , Sustitución de Medicamentos , Recuento de Plaquetas , Resultado del Tratamiento , HidrazonasRESUMEN
Jaktinib, a novel JAK and ACVR1 inhibitor, has exhibited promising results in treating patients with myelofibrosis (MF). ZGJAK002 is a Phase 2 trial aimed to assess the efficacy and safety of jaktinib 100 mg BID (N = 66) and 200 mg QD (N = 52) in JAK inhibitor-naive patients with intermediate- or high-risk MF. We herein present the long-term data with a median follow-up of 30.7 months. At data cutoff, 30.3% of patients in 100 mg BID and 28.8% in 200 mg QD were still continuing their treatment. The 100 mg BID group displayed a numerically higher best spleen response compared with the 200 mg QD group (69.7% vs. 46.2%), with 50.4% from the BID and 51.2% from the QD group maintaining spleen responses over 120 weeks. The 36-month survival rates were 78.2% in BID and 73.6% in QD group. The tolerability of jaktinib remained well, and common grade ≥3 adverse drug reactions included anemia (15.2% vs. 21.2%), thrombocytopenia (15.2% vs. 11.5%), and infectious pneumonia (10.6% vs. 1.9%) in BID and QD groups, respectively. By comparing the two groups, the incidence of adverse events (AEs) were similar, except for drug-related serious AEs (24.2% vs. 9.6%) and AEs leading to treatment discontinuation (15.2% vs. 7.7%), which were higher in BID group. The percentages of AEs resulting in death were comparable, with 6.1% in BID and 5.8% in QD group. These analyses further support the long-term durable efficacy and acceptable safety of jaktinib at 100 mg BID and 200 mg QD doses for treating MF.
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Mielofibrosis Primaria , Humanos , Estudios de Seguimiento , Mielofibrosis Primaria/tratamiento farmacológico , Resultado del TratamientoRESUMEN
The immune checkpoint blockade strategy has improved the survival rate of late-stage lung cancer patients. However, the low immune response rate limits the immunotherapy efficiency. Here, we report a ROS-responsive Fe3O4-based nanoparticle that undergoes charge reversal and disassembly in the tumor microenvironment, enhancing the uptake of Fe3O4 by tumor cells and triggering a more severe ferroptosis. In the tumor microenvironment, the nanoparticle rapidly disassembles and releases the loaded GOx and the immune-activating peptide Tuftsin under overexpressed H2O2. GOx can consume the glucose of tumor cells and generate more H2O2, promoting the disassembly of the nanoparticle and drug release, thereby enhancing the therapeutic effect of ferroptosis. Combined with Tuftsin, it can more effectively reverse the immune-suppressive microenvironment and promote the recruitment of effector T cells in tumor tissues. Ultimately, in combination with α-PD-L1, there is significant inhibition of the growth of lung metastases. Additionally, the hyperpolarized 129Xe method has been used to evaluate the Fe3O4 nanoparticle-mediated immunotherapy, where the ventilation defects in lung metastases have been significantly improved with complete lung structure and function recovered. The ferroptosis-enhanced immunotherapy combined with non-radiation evaluation methodology paves a new way for designing novel theranostic agents for cancer therapy.
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Ferroptosis , Inmunoterapia , Imagen por Resonancia Magnética , Especies Reactivas de Oxígeno , Ferroptosis/efectos de los fármacos , Humanos , Especies Reactivas de Oxígeno/metabolismo , Microambiente Tumoral/efectos de los fármacos , Ratones , Animales , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patología , Isótopos de Xenón/química , Nanopartículas de Magnetita/química , Línea Celular TumoralRESUMEN
The drug-to-antibody ratio (DAR) value and dual-drug combination greatly influence the therapeutic index of antibody-drug conjugates (ADCs). The reported approaches usually require multifunctional branched linkers, a combination of complicated technologies, or protein-protein ligation, which may incorporate multihydrophobic fragments or result in low coupling efficiency. Herein, we developed a facile and efficient one-pot method to assemble dual-site-specific ADCs with defined DARs at both the N-glycosylation site and K248 site, either with the same payloads or with two types of payloads. The constructed dual-site ADCs showed acceptable homogeneity, excellent buffer stability, and enhanced in vitro and in vivo efficiency.
RESUMEN
The classic BCR-ABL1-negative myeloproliferative neoplasm (MPN) is a highly heterogeneous hematologic tumor that includes three subtypes, namely polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). Despite having the same JAK2V617F mutation, the clinical manifestations of these three subtypes of MPN differ significantly, which suggests that the bone marrow (BM) immune microenvironment may also play an important role. In recent years, several studies have shown that peripheral blood monocytes play an important role in promoting MPN. However, to date, the role of BM monocytes/macrophages in MPN and their transcriptomic alterations remain incompletely understood. The purpose of this study was to clarify the role of BM monocytes/macrophages in MPN patients with the JAK2V617F mutation. MPN patients with the JAK2V617F mutation were enrolled in this study. We investigated the roles of monocytes/macrophages in the BM of MPN patients, using flow cytometry, monocyte/macrophage enrichment sorting, cytospins and Giemsa-Wright staining, and RNA-seq. Pearson correlation coefficient analysis was also used to detect the correlation between BM monocytes/macrophages and the MPN phenotype. In the present study, the proportion of CD163+ monocytes/macrophages increased significantly in all three subtypes of MPN. Interestingly, the percentages of CD163+ monocytes/macrophages are positively correlated with HGB in PV patients and PLT in ET patients. In contrast, the percentages of CD163+ monocytes/macrophages are negatively correlated with HGB and PLT in PMF patients. It was also found that CD14+CD16+ monocytes/macrophages increased and correlated with MPN clinical phenotypes. RNA-seq analyses demonstrated that the transcriptional expressions of monocytes/macrophages in MPN patients are relatively distinct. Gene expression profiles of BM monocytes/macrophages suggest a specialized function in support of megakaryopoiesis in ET patients. In contrast, BM monocytes/macrophages yielded a heterogeneous status in the support or inhibition of erythropoiesis. Significantly, BM monocytes/macrophages shaped an inflammatory microenvironment, which, in turn, promotes myelofibrosis. Thus, we characterized the roles of increased monocytes/macrophages in the occurrence and progression of MPNs. Our findings of the comprehensive transcriptomic characterization of BM monocytes/macrophages provide important resources to serve as a basis for future studies and future targets for the treatment of MPN patients.
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Neoplasias de la Médula Ósea , Trastornos Mieloproliferativos , Policitemia Vera , Trombocitemia Esencial , Humanos , Médula Ósea/patología , Monocitos/patología , Trastornos Mieloproliferativos/genética , Policitemia Vera/genética , Mutación , Neoplasias de la Médula Ósea/patología , Trombocitemia Esencial/genética , Janus Quinasa 2/genética , Microambiente TumoralRESUMEN
Hematologic malignancies are the most common hematopoietic diseases and a major public health concern. However, the mechanisms underlying myeloid tumors remain unknown owing to the intricate interplay between mutations and diverse clonal evolution patterns, as evidenced by the analysis of bulk cell-derived omics data. Several single-cell omics techniques have been used to characterize the hierarchies and altered immune microenvironments of hematologic malignancies. The comprehensive single-cell atlas of hematologic malignancies provides novel opportunities for personalized combinatorial targeted treatments, avoiding unwanted chemo-toxicity. In the present study, we performed transcriptome sequencing by combining single-cell RNA sequencing (scRNA-seq) with a targeted oncogenic gene panel for acute myeloid leukemia, overcoming the limitations of scRNA-seq in detecting oncogenic mutations. The distribution of oncogenic IDH1, IDH2, and KRAS mutations in each cell type was identified in the bone marrow (BM) samples of each patient. Our findings suggest that ferroptosis and metabolic reprogramming are involved in the tumorigenesis and chemotherapy resistance of oncogenic mutation-carrying cells. Biological progression via IDH1, IDH2, and KRAS mutations arrests hematopoietic maturation. Our study findings provide a rationale for using primary BM cells for personalized treatment in clinical settings.
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Ferroptosis , Neoplasias Hematológicas , Humanos , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/genética , Mutación , Análisis de Secuencia de ARN , Microambiente TumoralRESUMEN
To explore the characteristics of hemogram in patients with aplastic anemia (AA), especially mean corpuscular volume (MCV) and red cell distribution width (RDW). We examined the blood routine of 180 new-onset AA patients and used 166 patients with myelodysplastic syndrome (MDS) as controls. Among the 180 AA patients, 105 (58.3%) were diagnosed with severe AA (SAA), while 75 (41.7%) were diagnosed with non-severe AA (NSAA). Compared to MDS, patients with SAA generally had unfavorable hemogram, including significantly lower white blood cell (WBC), absolute neutrophil count (ANC), hemoglobin (Hb), platelet (PLT) and reticulocyte counts (RET). However, WBC, ANC and lymphocyte counts were higher in the NSAA group than in the MDS group; Hb and Ret were comparable between the two groups. 8.5% of SAA patients and 58.1% of NSAA patients presented with macrocytic anemia, whereas 25.7% of SAA and 64.0% of NSAA had a high RDW. In the MDS group, 54.7% of patients presented with macrocytic anemia, and 84.7% had increased RDW. WBC, ANC, PLT, and Ret in a high-RDW group (25.7% of SAA) were significantly higher than in a normal-RDW group (74.3% of SAA). Overall, most SAA patients exhibited normocytic-normochromic anemia, and their hemograms decreased more significantly; more than half of NSAA patients showed macrocytic-heterogeneous anemia, and their hemograms were similar to those of MDS. Patients with elevated RDW may have better residual bone marrow hematopoietic function than those with normal RDW but with more severe anemia.
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Anemia Aplásica , Anemia Macrocítica , Humanos , Anemia Aplásica/diagnóstico , Índices de Eritrocitos , Médula Ósea , HemoglobinasRESUMEN
Anemia is a significant complication of chronic inflammation and may be related to dysregulated activities among erythroblastic island (EBI) macrophages. GM-CSF was reported to be upregulated and attracted as a therapeutic target in many inflammatory diseases. Among EBIs, we found that the GM-CSF receptor is preferentially and highly expressed among EBI macrophages but not among erythroblasts. GM-CSF treatment significantly decreases human EBI formation in vitro by decreasing the adhesion molecule expression of CD163. RNA-sequence analysis suggests that GM-CSF treatment impairs the supporting function of human EBI macrophages during erythropoiesis. GM-CSF treatment also polarizes human EBI macrophages from M2-like type to M1-like type. In addition, GM-CSF decreases mouse bone marrow (BM) erythroblasts as well as EBI macrophages, leading to a reduction in EBI numbers. In defining the molecular mechanism at work, we found that GM-CSF treatment significantly decreases the adhesion molecule expression of CD163 and Vcam1 in vivo. Importantly, GM-CSF treatment also decreases the phagocytosis rate of EBI macrophages in mouse BM as well as decreases the expression of the engulfment-related molecules Mertk, Axl, and Timd4. In addition, GM-CSF treatment polarizes mouse BM EBI macrophages from M2-like type to M1-like type. Thus, we document that GM-CSF impairs EBI formation in mice and humans. Our findings support that targeting GM-CSF or reprogramming EBI macrophages might be a novel strategy to treat anemia resulting from inflammatory diseases.
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Eritropoyesis , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Animales , Eritroblastos/metabolismo , Eritropoyesis/fisiología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Macrófagos/metabolismo , Ratones , FagocitosisRESUMEN
BACKGROUND: Acute myeloid leukemia (AML) patients with normal karyotype (NK-AML) have significant variabilities in outcomes. The European Leukemia Net stratification system and some prognostic models have been used to evaluate risk stratification. However, these common standards still have some limitations. The biological functions and mechanisms of Small Integral Membrane Protein 3 (SMIM3) have seldomly been investigated. To this date, the prognostic value of SMIM3 in AML has not been reported. This study aimed to explore the clinical significance, biological effects and molecular mechanisms of SMIM3 in AML. METHODS: RT-qPCR was applied to detect the expression level of SMIM3 in bone marrow specimens from 236 newly diagnosed adult AML patients and 23 healthy volunteers. AML cell lines, Kasumi-1 and THP-1, were used for lentiviral transfection. CCK8 and colony formation assays were used to detect cell proliferation. Cell cycle and apoptosis were analyzed by flow cytometry. Western blot was performed to explore relevant signaling pathways. The biological functions of SMIM3 in vivo were validated by xenograft tumor mouse model. Survival rate was evaluated by Log-Rank test and Kaplan-Meier. Cox regression model was used to analyze multivariate analysis. The correlations between SMIM3 and drug resistance were also explored. RESULTS: Through multiple datasets and our clinical group, SMIM3 was shown to be significantly upregulated in adult AML compared to healthy subjects. SMIM3 overexpression conferred a worse prognosis and was identified as an independent prognostic factor in 95 adult NK-AML patients. Knockdown of SMIM3 inhibited cell proliferation and cell cycle progression, and induced cell apoptosis in AML cells. The reduced SMIM3 expression significantly suppressed tumor growth in the xenograft mouse model. Western blot analysis showed downregulation of p-PI3K and p-AKT in SMIM3-knockdown AML cell lines. SMIM3 may also be associated with some PI3K-AKT and first-line targeted drugs. CONCLUSIONS: SMIM3 was highly expressed in adult AML, and such high-level expression of SMIM3 was associated with a poor prognosis in adult AML. Knockdown of SMIM3 inhibited the proliferation of AML through regulation of the PI3K-AKT signaling pathway. SMIM3 may serve as a potential prognostic marker and a therapeutic target for AML in the future.
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Leucemia Mieloide Aguda , Proteínas Proto-Oncogénicas c-akt , Humanos , Animales , Ratones , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Regulación hacia Abajo/genética , Leucemia Mieloide Aguda/metabolismo , Transducción de Señal , Pronóstico , Proliferación Celular/genética , Apoptosis/genética , Cariotipo , Línea Celular TumoralRESUMEN
BACKGROUND: Approximately 8-9% of the world's population is affected by autoimmune diseases, and yet the mechanism of autoimmunity trigger is largely understudied. Two unique cell death modalities, ferroptosis and pyroptosis, provide a new perspective on the mechanisms leading to autoimmune diseases, and development of new treatment strategies. METHODS: Using scRNA-seq datasets, the aberrant trend of ferroptosis and pyroptosis-related genes were analyzed in several representative autoimmune diseases (psoriasis, atopic dermatitis, vitiligo, multiple sclerosis, systemic sclerosis-associated interstitial lung disease, Crohn's disease, and experimental autoimmune orchitis). Cell line models were also assessed using bulk RNA-seq and qPCR. RESULTS: A substantial difference was observed between normal and autoimmune disease samples involving ferroptosis and pyroptosis. In the present study, ferroptosis and pyroptosis showed an imbalance in different keratinocyte lineages of psoriatic skinin addition to a unique pyroptosis-sensitive keratinocyte subset in atopic dermatitis (AD) skin. The results also revealed that pyroptosis and ferroptosis are involved in epidermal melanocyte destruction in vitiligo. Aberrant ferroptosis has been detected in multiple sclerosis, systemic sclerosis-associated interstitial lung disease, Crohn's disease, and autoimmune orchitis. Cell line models adopted in the study also identified pro-inflammatory factors that can drive changes in ferroptosis and pyroptosis. CONCLUSION: These results provide a unique perspective on the involvement of ferroptosis and pyroptosis in the pathological process of autoimmune diseases at the scRNA-seq level. IFN-γ is a critical inducer of pyroptosis sensitivity, and has been identified in two cell line models.
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Enfermedades Autoinmunes , Enfermedad de Crohn , Dermatitis Atópica , Ferroptosis , Enfermedades Pulmonares Intersticiales , Esclerosis Múltiple , Orquitis , Esclerodermia Sistémica , Vitíligo , Enfermedades Autoinmunes/genética , Enfermedad de Crohn/genética , Humanos , Masculino , Piroptosis/genética , Esclerosis , Transcriptoma/genética , Vitíligo/genéticaRESUMEN
Myeloid-derived suppressor cells (MDSC) are a group of heterogeneous immature myeloid cells and display immunosuppressive function. In this study, MDSC populations were evaluated in acquired aplastic anemia (AA) (n=65) in which aberrant immune mechanisms contributed to bone marrow destruction. Our data demonstrate that both the proportion and immunosuppressive function of MDSC are impaired in AA patients. Decreased percentage of MDSC, especially monocytic MDSC, in the blood of AA patients (n=15) is positively correlated with the frequency of T-regulatory cells, bone marrow level of WT1 and decreased plasma level of arginase-1. RNA sequencing analyses reveal that multiple pathways including DNA damage, interleukin 4, apoptosis, and Jak kinase singnal transducer and activator of transcription are upregulated, whereas transcription, IL-6, IL-18, glycolysis, transforming growth factor and reactive oxygen species are downregulated in MDSC of AA (n=4), compared with that of healthy donors (n=3). These data suggest that AA MDSC are defective. Administration of rapamycin significantly increases the absolute number of MDSC and levels of intracellular enzymes, including arginase-1 and inducible nitric-oxide synthase. Moreover, rapamycin inhibits MDSC from differentiating into mature myeloid cells. These findings reveal that impaired MDSC are involved in the immunopathogenesis of AA. Pharmacologically targeting of MDSC by rapamycin might provide a promising therapeutic strategy for AA.
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Anemia Aplásica , Células Supresoras de Origen Mieloide , Humanos , Células Supresoras de Origen Mieloide/metabolismo , Arginasa/genética , Anemia Aplásica/metabolismo , Diferenciación Celular , Inmunosupresores , Sirolimus/farmacologíaRESUMEN
Intestinal microbiota is an important prognostic factor for allogeneic hematopoietic stem cell transplantation (allo-HSCT), but its role in predicting survival has not been determined. Here, stool samples at day 15 ± 1 posttransplant were obtained from 209 patients at two centers. Microbiota was examined using 16S rRNA sequencing. The microbiota diversity and abundance of specific bacteria (including Lachnospiraceae, Ruminococcaceae, Erysipelotrichaceae, and Enterobacteriaceae) were assigned a value of 0 or 1 depending on whether they were positive or negative associated with survival, respectively. An accumulated intestinal microbiota (AIM) score was generated, and patients were divided into low- and high-score groups. A low score was associated with a better 3-year cumulative overall survival (OS) as well as lower mortality than a high score (88.5 vs. 43.9% and 7.1 vs. 35.8%, respectively; both P < 0.001). In multivariate analysis, a high score was found to be an independent risk factor for OS and transplant-related mortality (hazard ratio = 5.68 and 3.92, respectively; P < 0.001 and 0.003, respectively). Furthermore, the AIM score could serve as a predictor for survival (area under receiver operating characteristic curve = 0.836, P < 0.001). Therefore, the intestinal microbiota score at neutrophil recovery could predict survival following allo-HSCT.
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Microbioma Gastrointestinal , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Microbiota , Firmicutes/genética , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/microbiología , Humanos , ARN Ribosómico 16S/genéticaRESUMEN
Myelofibrosis (MF) is associated with several constitutional symptoms. Currently, there are few therapeutic options for MF. Jaktinib, a novel, small-molecule inhibitor of JAK, is currently being studied for its potential to treat MF. This phase 2 trial investigated efficacy and safety of jaktinib in the treatment of MF patients. The primary end point was the proportion of patients with ≥35% reduction in spleen volume (SVR35, proportion of patients with ≥35% reduction in spleen volume) at week 24. The secondary end points included improvement of anemia, rates of symptom response, and safety profile. Between January 8, 2019 and August 29, 2020, 118 patients were recruited and treated with either jaktinib 100 mg BID or 200 mg QD. At week 24, 54.8% (34/62) of patients in the 100 mg BID group and 31.3% (15/48) in the 200 mg QD group achieved SVR35 (p = .0199). Jaktinib treatment increased hemoglobin level to ≥20 g/L in 35.6% (21/59) of patients with hemoglobin ≤100 g/L at baseline. The proportion of patients who achieved a ≥50% improvement in total symptom score at week 24 was 69.6% (39/56) in the BID group and 57.5% (23/40) in the QD group. The most common ≥ grade 3 hematological treatment-emergent adverse events (TEAEs; ≥ 10%) were anemia (100 mg BID: 24.2%, 200 mg QD: 28.8%), thrombocytopenia (16.7%, 11.5%), and neutropenia (3.0%, 11.5%). All non-hematological TEAEs were mild. These results indicate that jaktinib can shrink the spleen, improve anemia, and other clinical symptoms with good tolerability.
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Anemia , Inhibidores de las Cinasas Janus , Mielofibrosis Primaria , Humanos , Mielofibrosis Primaria/diagnóstico , Inhibidores de las Cinasas Janus/efectos adversos , Pirimidinas/efectos adversos , Pirazoles/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Nitrilos/uso terapéutico , Anemia/inducido químicamente , Anemia/tratamiento farmacológico , Resultado del Tratamiento , Janus Quinasa 2RESUMEN
The synergistic chemotherapy and photodynamic therapy (PDT) may significantly improve the cancer therapeutic efficacy, in which fluorinated nanoemulsions are highly advantageous for their ability to deliver oxygen to hypoxic tumors and provide fluorine-19 magnetic resonance imaging (19F MRI). The low solubility of chemotherapy drugs and photosensitizers in current perfluorocarbon (PFC)-based 19F MRI agents usually leads to complicated formulations or chemical modifications and low nanoemulsion stability and performance. Herein, we employ readily available partially fluorinated ethyl 2-(3,5-bis(trifluoromethyl)phenyl)acetate as the 19F MRI agent and the solvent to dissolve the cancer stem cell inhibitor salinomycin and the photosensitizer ICG for the convenient preparation of 19F MRI-fluorescence dual imaging and synergistic chemotherapy, photothermal and photodynamic therapy nanoemulsions. The chemotherapy drug salinomycin has a high solubility in the partially fluorinated reagent, facilitating its high loading and efficient delivery. Paramagnetic iron(III) (Fe3+) is incorporated into the nanoemulsion through the dissolved chelator to significantly improve the 19F MRI sensitivity. Furthermore, the dissolved fluorinated 2-pyridone enables the efficient capture and sustained release of singlet oxygen in the dark for high PDT efficacy. The multifunctional nanoemulsions show sensitive 19F MRI and fluorescence dual imaging capability and high synergistic chemotherapy, photothermal and photodynamic therapy efficacy in cancer cells, which may be valuable oxygen delivery, sustained ROS generating and release, dual imaging and multimodal therapy agents for hypoxic tumors. This study provided a convenient co-solubilization strategy for the rapid construction of multifunctional theranostics for hypoxic tumors.
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FotoquimioterapiaRESUMEN
Dual-imaging agents with highly sensitive fluorescence (FL) imaging and highly selective fluorine-19 magnetic resonance imaging (19F MRI) are valuable for biomedical research. At the same time, photosensitizers with a high reactive oxygen species (ROS) generating capability are crucial for photodynamic therapy (PDT) of cancer. Herein, a series of tetra-trifluoromethylated aza-boron dipyrromethenes (aza-BODIPYs) were conveniently synthesized from readily available building blocks and their physicochemical properties, including ultraviolet-visible (UV-Vis) absorption, FL emission, photothermal efficacy, ROS generating efficacy, and 19F MRI sensitivity, were systematically investigated. An aza-BODIPY with 12 symmetrical fluorines was identified as a potent FL-19F MRI dual-imaging traceable photodynamic agent. It was found that the selective introduction of trifluoromethyl (CF3) groups into aza-BODIPYs may considerably improve their UV absorption, FL emission, photothermal efficacy, and ROS generating properties, which lays the foundation for the rational design of trifluoromethylated aza-BODIPYs in biomedical applications.
Asunto(s)
Compuestos de Boro , Fotoquimioterapia , Compuestos de Boro/química , Imagen por Resonancia Magnética , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Especies Reactivas de OxígenoRESUMEN
Monodisperse oligoethylene glycols (M-OEGs)-containing symmetrical secondary amines are highly valuable synthetic intermediates in drug development and materials sciences. Scalable three-step synthesis of M-OEGs secondary amines with flexible M-OEGs and/or alkyl chains is described herein. Through reduction amination of diethanolamine, Williamson ether synthesis, and subsequent deprotection, a series of M-OEGs secondary amines with diverse and fine-tunable chemical structures were conveniently prepared. The presented strategy is attractive with readily available starting materials, simple catalytic systems, scalable synthesis, and avoids the use of explosive sodium azide.
Asunto(s)
Aminas , Etanolaminas , Aminación , Aminas/química , CatálisisRESUMEN
Background: Targeting the CD47/SIRPα signaling pathway represents a novel approach to enhance anti-tumor immunity. However, the crystal structure of the CD47/SIRPα has not been fully studied. This study aims to analyze the structure interface of the complex of CD47 and IMM01, a novel recombinant SIRPα-Fc fusion protein. Methods: IMM01-Fab/CD47 complex was crystalized, and diffraction images were collected. The complex structure was determined by molecular replacement using the program PHASER with the CD47-SIRPαv2 structure (PDB code 2JJT) as a search model. The model was manually built using the COOT program and refined using TLS parameters in REFMAC from the CCP4 program suite. Results: Crystallization and structure determination analysis of the interface of IMM01/CD47 structure demonstrated CD47 surface buried by IMM01. Comparison with the literature structure (PDB ID 2JJT) showed that the interactions of IMM01/CD47 structure are the same. All the hydrogen bonds that appear in the literature structure are also present in the IMM01/CD47 structure. These common hydrogen bonds are stable under different crystal packing styles, suggesting that these hydrogen bonds are important for protein binding. In the structure of human CD47 in complex with human SIRPα, except SER66, the amino acids that form hydrogen bonds are all conserved. Furthermore, comparing with the structure of PDB ID 2JJT, the salt bridge interaction from IMM01/CD47 structure are very similar, except the salt bridge bond between LYS53 in IMM01 and GLU106 in CD47, which only occurs between the B and D chains. However, as the side chain conformation of LYS53 in chain A is slightly different, the salt bridge bond is absent between the A and C chains. At this site between chain A and chain C, there are a salt bridge bond between LYS53 (A) and GLU104 (C) and a salt bridge bond between HIS56 (A) and GLU106 (C) instead. According to the sequence alignment results of SIRPα, SIRPß and SIRPγ in the literature of PDB ID 2JJT, except ASP100, the amino acids that form common salt bridge bonds are all conserved. Conclusion: Our data demonstrated crystal structure of the IMM01/CD47 complex and provides a structural basis for the structural binding interface and future clinical applications.