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Introduction: Immunotherapies targeting T cells in solid cancers are revolutionizing clinical treatment. Novel immunotherapies have had extremely limited benefit for acute myeloid leukemia (AML). Here, we characterized the immune microenvironment of t(8;21) AML patients to determine how immune cell infiltration status influenced prognosis. Methods: Through multi-omics studies of primary and longitudinal t(8;21) AML samples, we characterized the heterogeneous immune cell infiltration in the tumor microenvironment and their immune checkpoint gene expression. Further external cohorts were also included in this research. Results: CD8+ T cells were enriched and HAVCR2 and TIGIT were upregulated in the CD34+CD117dim%-High group; these features are known to be associated with immune exhaustion. Data integration analysis of single-cell dynamics revealed that a subset of T cells (cluster_2) (highly expressing GZMB, NKG7, PRF1 and GNLY) evolved and expanded markedly in the drug-resistant stage after relapse. External cohort analysis confirmed that the cluster_2 T-cell signature could be utilized to stratify patients by overall survival outcome. Discussion: In conclusion, we discovered a distinct T-cell signature by scRNA-seq that was correlated with disease progression and drug resistance. Our research provides a novel system for classifying patients based on their immune microenvironment.
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Cromosomas Humanos Par 8 , Leucemia Mieloide Aguda , Análisis de la Célula Individual , Microambiente Tumoral , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Análisis de la Célula Individual/métodos , Pronóstico , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Cromosomas Humanos Par 8/genética , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Femenino , Translocación Genética , Cromosomas Humanos Par 21/genética , Linfocitos T CD8-positivos/inmunología , Adulto , Persona de Mediana Edad , Biomarcadores de Tumor/genéticaRESUMEN
Neurons, exhibiting unique polarized structures, rely primarily on the mitochondrial production of ATP to maintain their hypermetabolic energy requirements. To maintain a normal energy supply, mitochondria are transported to the distal end of the axon. When mitochondria within the axon are critically damaged beyond their compensatory capacity, they are cleared via autophagosomal phagocytosis, and the degradation products are recycled to replenish energy. When the mitochondria are dysfunctional or their transport processes are blocked, axons become susceptible to degeneration triggered by energy depletion, resulting in neurodegenerative diseases. As the final checkpoint for mitochondrial quality control, axonal mitophagy is vital for neuronal growth, development, injury, and regeneration. Furthermore, abnormal axonal mitophagy is crucial in the pathogenesis of optic nerve-related diseases such as glaucoma. We review recent studies on axonal mitophagy and summarize the progress of research on axonal mitophagy in optic nerve-related diseases to provide insights into diseases associated with axonal damage in optic ganglion cells.
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Axones , Mitofagia , Células Ganglionares de la Retina , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Humanos , Axones/metabolismo , Axones/patología , Animales , Mitocondrias/metabolismo , Mitocondrias/patologíaRESUMEN
Upregulation of metabolism-related gene cytidine triphosphate synthase 1 (CTPS1) is associated with poor prognosis in multiple myeloma (MM). However, its role in MM remains unclear. In this study, bioinformatics analysis revealed significant differences in CTPS1 expression levels among various plasma cell malignancies. The patients with high CTPS1 expression had poor overall survival, progression-free survival, and event-free survival. CTPS1 was significantly correlated with sex, albumin, ß2 microglobulin, lactate dehydrogenase, and advanced disease. In vitro experiments demonstrated that CTPS1-overexpressing (CTPS1-OE) cells proliferated faster than CTPS1-short hairpin RNA (CTPS1-sh) cells. NRG-SGM3 mice showed significantly accelerated tumor growth in the CTPS1-OE group. CTPS1-OE decreased sensitivity to bortezomib, whereas CTPS1-sh increased sensitivity to bortezomib in MM cell lines. Mechanistically, CTPS1 was primarily involved in metabolism processes. Additionally, CTPS1 was closely related to several co-expressed genes such as MYC and the bone marrow immune microenvironment. In conclusion, CTPS1 is a significant prognostic biomarker for patients with MM, suggesting a potential therapeutic target.
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Ivosidenib, an isocitrate dehydrogenase 1 (IDH1) inhibitor, has demonstrated clinical benefits in a pivotal study (AG120-C-001) in patients with IDH1-mutated (mIDH1) acute myeloid leukemia (AML). A registry study (CS3010-101: NCT04176393) was conducted to assess the pharmacokinetic (PK) characteristics, safety, and efficacy of ivosidenib in Chinese patients with relapsed or refractory (R/R) mIDH1 AML. Patients received ivosidenib 500 mg once daily for 28-day cycles until disease progression. Ten subjects underwent intensive PK/progressive disease (PD) assessments. All subjects had the clinical response assessed at screening, every 28 days through month 12, and then every 56 days. Between November 12, 2019, and April 2, 2021, 30 patients were enrolled; 26 (86.7%) had de novo AML and 18 (60.0%) were transfusion-dependent at baseline. Following single and repeated doses of ivosidenib, median time to maximum plasma concentration (T max) was 4.0 and 2.0 hours, respectively. The inter-individual variability of pharmacokinetic exposure was moderate to high (coefficient of variation [CV], 25%-53%). No obvious accumulation was observed after repeated doses at cycle 2 day 1. Regarding the clinical response, the CR + CRh rate was 36.7% (95% confidence interval [CI]: 19.9%-56.1%), the median duration of CR + CRh was 19.7 months (95% CI: 2.9 months-not reached [NR]), and median duration of response (DoR) was 14.3 months (95% CI: 6.4 months-NR). Consistent clinical benefits and safety of ivosidenib were consistently observed at the final data cutoff with median follow-up time 26.0 months, as compared with primary data cutoff, and the data from Chinese R/R mIDH1 AML patients were also consistent with results from pivotal study.
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Aflatoxin B1 (AFB1), the most toxic and harmful mycotoxin, has a high likelihood of occurring in animal feed and human food, which seriously affects agriculture and food safety and endangers animal and human health. Recently, natural plant products have attracted widespread attention due to their low toxicity, high biocompatibility, and simple composition, indicating significant potential for resisting AFB1. The mechanisms by which these phytochemicals resist toxins mainly involve antioxidative, anti-inflammatory, and antiapoptotic pathways. Moreover, these substances also inhibit the genotoxicity of AFB1 by directly influencing its metabolism in vivo, which contributes to its elimination. Here, we review various phytochemicals that resist AFB1 and their anti-AFB1 mechanisms in different animals, as well as the common characteristics of phytochemicals with anti-AFB1 function. Additionally, the shortcomings of current research and future research directions will be discussed. Overall, this comprehensive summary contributes to the better application of phytochemicals in agriculture and food safety.
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Aflatoxina B1 , Agricultura , Contaminación de Alimentos , Fitoquímicos , Aflatoxina B1/metabolismo , Aflatoxina B1/química , Fitoquímicos/química , Fitoquímicos/metabolismo , Fitoquímicos/farmacología , Animales , Humanos , Contaminación de Alimentos/análisis , Contaminación de Alimentos/prevención & control , Inactivación Metabólica , Inocuidad de los Alimentos , Tecnología de AlimentosAsunto(s)
Agammaglobulinemia Tirosina Quinasa , Ensayos Clínicos como Asunto , Leucemia Linfocítica Crónica de Células B , Inhibidores de Proteínas Quinasas , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Humanos , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Eucommia ulmoides is a traditional Chinese herbal medicine, with pharmacological effects such as lowering blood pressure and enhancing immune function. The effects of dietary Eucommia ulmoides polysaccharide (EUP) on immune function and meat quality were studied in Songliao Black Pigs. Blood lymphocyte counts and percentage, concentrations of serum total protein and of albumin increased, whereas those of urea nitrogen and triglyceride decreased. White blood cell and lymphocyte counts, and serum IgA, IgE, IgG2 a and IFN-γ increased. Average daily weight gain, slaughter weight, lean meat rate and cooked meat rate increased, whereas pH24, feed-weight ratio, fat rate, yellowness (b#) and centrifugal dehydration rate decreased. Transcriptome sequencing of longissimus dorsi muscle detected 32 differentially expressed genes (DEGs), of which 26 were up-regulated and 6 down-regulated. A total of 19 genes were differentially expressed in the four groups, 18 of which were up-regulated. The DEGs included ADAMTS4, PER1, STAC, SERPINE1, FASN, THRSP, SP7 and KRT80 and the protein interaction network showed 20 up-regulated nodes, three down-regulated nodes and 14 DEGs. GO functional annotation and enrichment analysis showed that 34 items were significantly enriched, including transferase activity, actin binding, acetyl coenzyme A, acyl coenzyme A metabolism, adipose tissue development and acyl glycerol homeostasis. KEGG pathway analysis showed that the AMPK and PPAR signaling pathways were enriched. Dietary Eucommia polysaccharide enhanced immune function in Songliao Black Pigs, improved growth and carcass performance, increased the expression of genes related to meat quality traits and improved meat quality.
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Eucommiaceae , Polisacáridos , Animales , Polisacáridos/farmacología , Eucommiaceae/química , Porcinos , Alimentación Animal/análisis , Carne/análisis , Transcriptoma , Suplementos Dietéticos , Carne de Cerdo/análisis , Perfilación de la Expresión Génica , Dieta/veterinariaRESUMEN
Serum B-cell maturation antigen (sBCMA) levels can serve as a sensitive biomarker in multiple myeloma (MM). In the research setting, sBCMA levels can be accurately detected by enzyme-linked immunosorbent assay (ELISA), but the approach has not been approved for clinical use. Here, we used a novel chemiluminescence method to assess sBCMA levels in 759 serum samples from 17 healthy donors and 443 patients with plasma cell (PC) diseases including AL amyloidosis, POEMS syndrome, and MM. Serum BCMA levels were elevated 16.1-fold in patients with newly diagnosed MM compared to healthy donors and rare PC diseases patients. Specifically, the sBCMA levels in patients with progressive disease were 64.6-fold higher than those who showed partial response or above to treatment. The sBCMA level also correlated negatively with the response depth of MM patients. In newly diagnosed and relapsed MM patients, survival was significantly longer among those subjects whose sBCMA levels are below the median levels compared with those above the median value. We optimized the accuracy of the survival prediction further by integrating sBCMA level into the Second Revised International Staging System (R2-ISS). Our findings provide evidence that the novel chemiluminescence method is sensitive and practical for measuring sBCMA levels in clinical samples and confirm that sBCMA might serve as an independent prognostic biomarker for MM.
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Antígeno de Maduración de Linfocitos B , Biomarcadores de Tumor , Mieloma Múltiple , Humanos , Mieloma Múltiple/sangre , Mieloma Múltiple/inmunología , Mieloma Múltiple/diagnóstico , Antígeno de Maduración de Linfocitos B/sangre , Antígeno de Maduración de Linfocitos B/inmunología , Masculino , Femenino , Biomarcadores de Tumor/sangre , Pronóstico , Persona de Mediana Edad , Anciano , Adulto , Anciano de 80 o más Años , Mediciones Luminiscentes/métodosAsunto(s)
Leucemia Linfocítica Crónica de Células B , Neoplasia Residual , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Neoplasia Residual/sangre , Neoplasia Residual/diagnóstico , Neoplasia Residual/tratamiento farmacológico , Médula Ósea/patología , Análisis de Supervivencia , Ensayos Clínicos Controlados Aleatorios como Asunto , Rituximab/administración & dosificación , Ciclofosfamida/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores/análisis , Biomarcadores/sangreRESUMEN
Chronic myeloid leukaemia (CML) is caused by BCR::ABL1. Tyrosine kinase-inhibitors (TKIs) are the initial therapy. Several organizations have reported milestones to evaluate response to initial TKI-therapy and suggest when a change of TKI should be considered. Achieving treatment-free remission (TFR) is increasingly recognized as the optimal therapy goal. Which TKI is the best initial therapy for which persons and what depth and duration of molecular remission is needed to achieve TFR are controversial. In this review we discuss these issues and suggest future research directions.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Humanos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/etiología , Inducción de Remisión , BiologíaRESUMEN
BACKGROUND: The preservation of retinal ganglion cells (RGCs) and the facilitation of axon regeneration are crucial considerations in the management of various vision-threatening disorders. Therefore, we investigate the efficacy of interleukin-4 (IL-4), a potential therapeutic agent, in promoting neuroprotection and axon regeneration of retinal ganglion cells (RGCs) as identified through whole transcriptome sequencing in an in vitro axon growth model. METHODS: A low concentration of staurosporine (STS) was employed to induce in vitro axon growth. Whole transcriptome sequencing was utilized to identify key target factors involved in the molecular mechanism underlying axon growth. The efficacy of recombinant IL-4 protein on promoting RGC axon growth was validated through in vitro experiments. The protective effect of recombinant IL-4 protein on somas of RGCs was assessed using RBPMS-specific immunofluorescent staining in mouse models with optic nerve crush (ONC) and N-methyl-D-aspartic acid (NMDA) injury. The protective effect on RGC axons was evaluated by anterograde labeling of cholera toxin subunit B (CTB), while the promotion of RGC axon regeneration was assessed through both anterograde labeling of CTB and immunofluorescent staining for growth associated protein-43 (GAP43). RESULTS: Whole-transcriptome sequencing of staurosporine-treated 661 W cells revealed a significant upregulation in intracellular IL-4 transcription levels during the process of axon regeneration. In vitro experiments demonstrated that recombinant IL-4 protein effectively stimulated axon outgrowth. Subsequent immunostaining with RBPMS revealed a significantly higher survival rate of RGCs in the rIL-4 group compared to the vehicle group in both NMDA and ONC injury models. Axonal tracing with CTB confirmed that recombinant IL-4 protein preserved long-distance projection of RGC axons, and there was a notably higher number of surviving axons in the rIL-4 group compared to the vehicle group following NMDA-induced injury. Moreover, intravitreal delivery of recombinant IL-4 protein substantially facilitated RGC axon regeneration after ONC injury. CONCLUSION: The recombinant IL-4 protein exhibits the potential to enhance the survival rate of RGCs, protect RGC axons against NMDA-induced injury, and facilitate axon regeneration following ONC. This study provides an experimental foundation for further investigation and development of therapeutic agents aimed at protecting the optic nerve and promoting axon regeneration.
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Axones , Interleucina-4 , Regeneración Nerviosa , Células Ganglionares de la Retina , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/metabolismo , Animales , Interleucina-4/farmacología , Axones/efectos de los fármacos , Axones/metabolismo , Regeneración Nerviosa/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Traumatismos del Nervio Óptico/patología , Traumatismos del Nervio Óptico/tratamiento farmacológico , N-Metilaspartato/farmacología , Estaurosporina/farmacología , Fármacos Neuroprotectores/farmacología , Proteínas Recombinantes/farmacologíaRESUMEN
This cross-sectional study uses data from the Youth Risk Behavior surveys to assess the association of state-level recreational marijuana laws and youth marijuana use.
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Uso de la Marihuana , Humanos , Adolescente , Uso de la Marihuana/legislación & jurisprudencia , Uso de la Marihuana/epidemiología , Estados Unidos/epidemiología , Femenino , Masculino , Legislación de Medicamentos , Conducta del Adolescente , Cannabis/efectos adversosRESUMEN
This case-control study uses state-by-year workplace injury data to assess recreational marijuana legalization adoption and workplace injuries among younger workers aged 20 to 34 years.
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Cannabis , Fumar Marihuana , Marihuana Medicinal , Humanos , Cannabis/efectos adversos , Fumar Marihuana/efectos adversos , Fumar Marihuana/epidemiología , Lugar de Trabajo , Condiciones de TrabajoRESUMEN
Natural killer/T-cell lymphoma (NKTCL) is a highly heterogeneous disease with a poor prognosis. However, the genomic characteristics and proper treatment strategies for non-upper aerodigestive tract NKTCL (NUAT-NKTCL), a rare subtype of NKTCL, remain largely unexplored. In this study, 1589 patients newly diagnosed with NKTCL at 14 hospitals were assessed, 196 (12.3%) of whom had NUAT-NKTCL with adverse clinical characteristics and an inferior prognosis. By using whole-genome sequencing (WGS) and whole-exome sequencing (WES) data, we found strikingly different mutation profiles between upper aerodigestive tract (UAT)- and NUAT-NKTCL patients, with the latter group exhibiting significantly higher genomic instability. In the NUAT-NKTCL cohort, 128 patients received frontline P-GEMOX chemotherapy, 37 of whom also received anti-PD-1 immunotherapy. The application of anti-PD-1 significantly improved progression-free survival (3-year PFS rate 53.9% versus 17.0%, P = 0.009) and overall survival (3-year OS rate 63.7% versus 29.2%, P = 0.01) in the matched NUAT-NKTCL cohort. WES revealed frequent mutations involving immune regulation and genomic instability in immunochemotherapy responders. Our study showed distinct clinical characteristics and mutational profiles in NUAT-NKTCL compared with UAT patients and suggested adding anti-PD-1 immunotherapy in front-line treatment of NUAT-NKTCL. Further studies are needed to validate the efficacy and related biomarkers for immunochemotherapy proposed in this study.
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Linfoma Extranodal de Células NK-T , Humanos , Linfoma Extranodal de Células NK-T/genética , Linfoma Extranodal de Células NK-T/terapia , Linfoma Extranodal de Células NK-T/diagnóstico , Genómica , Inmunoterapia , Inestabilidad Genómica , Células Asesinas Naturales/patologíaRESUMEN
Background: Inflammatory responses influence the outcome of immunotherapy and tumorigenesis by modulating host immunity. However, systematic inflammatory response assessment models for predicting cancer immunotherapy (CIT) responses and survival across human cancers remain unexplored. Here, we investigated an inflammatory response score model to predict CIT responses and patient survival in a pan-cancer analysis. Methods: We retrieved 12 CIT response gene expression datasets from the Gene Expression Omnibus database (GSE78220, GSE19423, GSE100797, GSE126044, GSE35640, GSE67501, GSE115821 and GSE168204), Tumor Immune Dysfunction and Exclusion database (PRJEB23709, PRJEB25780 and phs000452.v2.p1), European Genome-phenome Archive database (EGAD00001005738), and IMvigor210 cohort. The tumor samples from six cancers types: metastatic urothelial cancer, metastatic melanoma, gastric cancer, primary bladder cancer, renal cell carcinoma, and non-small cell lung cancer.We further established a binary classification model to predict CIT responses using the least absolute shrinkage and selection operator (LASSO) computational algorithm. Findings: The model had high predictive accuracy in both the training and validation cohorts. During sub-group analysis, area under the curve (AUC) values of 0.82, 0.80, 0.71, 0.7, 0.67, and 0.64 were obtained for the non-small cell lung cancer, gastric cancer, metastatic urothelial cancer, primary bladder cancer, metastatic melanoma, and renal cell carcinoma cohorts, respectively. CIT response rates were higher in the high-scoring training cohort subjects (51%) than the low-scoring subjects (27%). The five-year survival rates in the high- and low score groups of the training cohorts were 62% and 21%, respectively, while those of the validation cohorts were 54% and 22%, respectively (P < 0·001 in all cases). Inflammatory response signature score derived from on-treatment tumor specimens are highly predictive of response to CIT in patients with metastatic melanoma. A significant correlation was observed between the inflammatory response scores and tumor purity. Regardless of the tumor purity, patients in the low score group had a significantly poorer prognosis than those in the high score group. Immune cell infiltration analysis indicated that in the high score cohort, tumor-infiltrating lymphocytes were significantly enriched, particularly effector and natural killer cells. Inflammatory response scores were positively correlated with immune checkpoint genes, suggesting that immune checkpoint inhibitors may have benefited patients with high scores. Analysis of signature scores across different cancer types from The Cancer Genome Atlas revealed that the prognostic performance of inflammatory response scores for survival in patients who have not undergone immunotherapy can be affected by tumor purity. Interleukin 21 (IL21) had the highest weight in the inflammatory response model, suggesting its vital role in the prediction mode. Since the number of metastatic melanoma patients (n = 429) was relatively large among CIT cohorts, we further performed a co-culture experiment using a melanoma cell line and CD8 + T cell populations generated from peripheral blood monocytes. The results showed that IL21 therapy combined with anti-PD1 (programmed cell death 1) antibodies (trepril monoclonal antibodies) significantly enhanced the cytotoxic activity of CD8 + T cells against the melanoma cell line. Conclusion: In this study, we developed an inflammatory response gene signature model that predicts patient survival and immunotherapy response in multiple malignancies. We further found that the predictive performance in the non-small cell lung cancer and gastric cancer group had the highest value among the six different malignancy subgroups. When compared with existing signatures, the inflammatory response gene signature scores for on-treatment samples were more robust predictors of the response to CIT in metastatic melanoma.
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The role of Epstein-Barr virus (EBV) in lymphoma cells of nodular sclerosis classic Hodgkin lymphoma (NScHL) is controversial. Our aim was to explore this and establish a clinically feasible model for risk stratification. We interrogated data from 542 consecutive subjects with NScHL receiving ABVD therapy and demonstrated EBV-infection in their lymphoma cells with EBV-encoded small RNAs (EBERs) in situ hybridization. Subjects were divided into training and validation datasets. As data from the training dataset suggested EBERs-positivity was the only independent prognostic factor for both progression-free survival (PFS) and overall survival (OS), we developed corresponding prognostic models based on it. Our models showed excellent performance in both training and validation cohort. These data indicate the close association of EBV infection and the outcomes of persons with NScHL receiving ABVD. Additionally, our newly developed models should help physicians estimate prognosis and select individualized therapy.
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Over the past three decades, considerable efforts have been expended on understanding the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in leukemia, following the identification of the JAK2V617F mutation in myeloproliferative neoplasms (MPNs). The aim of this review is to summarize the latest progress in our understanding of the involvement of the JAK/STAT signaling pathway in the development of leukemia. We also attempt to provide insights into the current use of JAK/STAT inhibitors in leukemia therapy and explore pertinent clinical trials in this field.
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Leucemia , Trastornos Mieloproliferativos , Humanos , Quinasas Janus/genética , Quinasas Janus/metabolismo , Factores de Transcripción STAT/genética , Factores de Transcripción STAT/metabolismo , Trastornos Mieloproliferativos/tratamiento farmacológico , Trastornos Mieloproliferativos/genética , Transducción de SeñalRESUMEN
Objective To investigate the safety and efficacy of Embosphere microsphere in the treatment of massive hemoptysis during bronchial arterial embolization(BAE).To analyze the factors influencing the recurrence by Cox regression model.Methods Ninety patients with massive hemoptysis who underwent BAE using Embosphere microsphere were included.The immediate hemo-stasis rate within 24 hours,clinical success rate and prognostic factors were statistically analyzed.Results The immediate hemosta-sis rate within 24 hours was 94.4%(85/90).The clinical success rate was 56.7%(51/90).Cumulative hemoptysis-free recurrence con-trol rates at 6 months,1 year and 2 years postoperative were 81%,78%and 57%,respectively.Cox regression model analysis showed that the variables associated with recurrence were long-term hemoptysis,lung cancer,tuberculosis and lung destruction.Conclusion Embosphere microsphere are safe and effective embolic particles in the treatment of massive hemoptysis during BAE.Risk factors for hemoptysis recurrence include long-term hemoptysis,lung cancer,tuberculosis and lung destruction.