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Acute myeloid leukemia (AML) is an aging-related and heterogeneous hematopoietic malignancy. In this study, a total of 1,474 newly diagnosed AML patients with RNA sequencing data were enrolled, and targeted or whole exome sequencing data were obtained in 94% cases. The correlation of aging-related factors including age and clonal hematopoiesis (CH), gender, and genomic/transcriptomic profiles (gene fusions, genetic mutations, and gene expression networks or pathways) was systematically analyzed. Overall, AML patients aged 60 y and older showed an apparently dismal prognosis. Alongside age, the frequency of gene fusions defined in the World Health Organization classification decreased, while the positive rate of gene mutations, especially CH-related ones, increased. Additionally, the number of genetic mutations was higher in gene fusion-negative (GF-) patients than those with GF. Based on the status of CH- and myelodysplastic syndromes (MDS)-related mutations, three mutant subgroups were identified among the GF- AML cohort, namely, CH-AML, CH-MDS-AML, and other GF- AML. Notably, CH-MDS-AML demonstrated a predominance of elderly and male cases, cytopenia, and significantly adverse clinical outcomes. Besides, gene expression networks including HOXA/B, platelet factors, and inflammatory responses were most striking features associated with aging and poor prognosis in AML. Our work has thus unraveled the intricate regulatory circuitry of interactions among different age, gender, and molecular groups of AML.
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Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Anciano , Humanos , Masculino , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Envejecimiento/genética , Mutación , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , PronósticoRESUMEN
Objective: The aim of this study was to identify genetic biomarkers and cellular communications associated with severe asthma in microarray data sets and single cell data sets. The potential gene expression levels were verified in a mouse model of asthma.Methods: We identified differentially expressed genes from the microarray datasets (GSE130499 and GSE63142) of severe asthma, and then constructed models to screen the most relevant biomarkers to severe asthma by machine learning algorithms (LASSO and SVM-RFE), with further validation of the results by GSE43696. Single-cell datasets (GSE193816 and GSE227744) were identified for potential biomarker-specific expression and intercellular communication. Finally, The expression levels of potential biomarkers were verified with a mouse model of asthma.Results: The 73 genes were differentially expressed between severe asthma and normal control. LASSO and SVM-RFE recognized three genes BCL3, DDIT4 and S100A14 as biomarkers of severe asthma and had good diagnostic effect. Among them, BCL3 transcript level was down-regulated in severe asthma, while S100A14 and DDIT4 transcript levels were up-regulated. The transcript levels of the three genes were confirmed in the mouse model. Infiltration of neutrophils and mast cells were found to be increased in severe asthma and may be associated with bronchial epithelial cells through BMP and NRG signalingConclusions: We identified three differentially expressed genes (BCL3, DDIT4 and S100A14) of diagnostic significance that may be involved in the development of severe asthma and these gene expressions could be serviced as biomarker of severe asthma and investigating the function roles could bring new insights into the underlying mechanisms.
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Scorpions, a group of oldest animals with wide distribution in the world, have a long history of medicinal use. Scorpio, the dried body of Buthus martensii, is a rare animal medicine mainly used for the treatment of liver diseases, spasm, and convulsions in children in China. The venom has been considered as the active substance of scorpions. However, little is known about the small molecules in the venom of scorpions. According to the articles published in recent years, scorpions contain amino acids, fatty acids, steroids, and alkaloids, which endow scorpions with antimicrobial, anticoagulant, metabolism-regulating, and antitumor activities. This paper summarizes the small molecule chemical components and pharmacological activities of scorpions, with a view to providing valuable information for the discovery of new active molecules and the clinical use of scorpions.
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Animales Ponzoñosos , Antiinfecciosos , Venenos de Escorpión , Animales , Niño , Humanos , Péptidos/química , Escorpiones/química , Escorpiones/metabolismo , ADN Complementario , Venenos de Escorpión/farmacologíaRESUMEN
t(8;21)(q22;q22) acute myelogenous leukemia (AML) is morphologically characterized by a continuum of heterogeneous leukemia cells from myeloblasts to differentiated myeloid elements. Thus, t(8;21) AML is an excellent model for studying heterogeneous cell populations and cellular evolution during disease progression. Using integrative analyses of immunophenotype, RNA-sequencing (RNA-seq), and single-cell RNA-sequencing (scRNA-seq), we identified three distinct intrapatient leukemic cell populations that were arrested at different stages of myeloid differentiation: CD34+CD117dim blasts, CD34+CD117bri blasts, and abnormal myeloid cells with partial maturation (AM). CD117 is also known as c-KIT protein. CD34+CD117dim cells were blocked in the G0/G1 phase at disease onset, presenting with the regular morphology of myeloblasts showing features of granulocyte-monocyte progenitors (GMP), and were drug-resistant to chemotherapy. Genes associated with cell migration and adhesion (LGALS1, EMP3, and ANXA2) were highly expressed in the CD34+CD117dim population. CD34+CD117bri blasts were blocked a bit later than the CD34+CD117dim population in the hematopoietic differentiation stage and displayed high proliferation ability. AM cells, which bear abnormal myelocyte morphology, especially overexpressed granule genes AZU1, ELANE, and PRTN3 and were sensitive to chemotherapy. scRNA-seq at different time points identified CD34+CD117dim blasts as an important leukemic cluster that expanded at postrelapse refractory stage after several cycles of chemotherapy. Patients with t(8;21) AML with a higher proportion of CD34+CD117dim cells had significantly worse clinical outcomes than those with a lower CD34+CD117dim proportion. Univariate and multivariate analyses identified CD34+CD117dim proportion as an independent factor for poor disease outcome. Our study provides evidence for the multidimensional heterogeneity of t(8;21)AML and may offer new tools for future disease stratification.
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Leucemia Mieloide Aguda/clasificación , Leucemia Mieloide Aguda/patología , Subgrupos de Linfocitos T/clasificación , Subgrupos de Linfocitos T/metabolismo , Adulto , Regulación Neoplásica de la Expresión Génica , Humanos , Leucemia Mieloide Aguda/metabolismo , TranscriptomaRESUMEN
Retinoic acid-inducible gene I (RIG-I) is up-regulated during granulocytic differentiation of acute promyelocytic leukemia (APL) cells induced by all-trans retinoic acid (ATRA). It has been reported that RIG-I recognizes virus-specific 5'-ppp-double-stranded RNA (dsRNA) and activates the type I interferons signaling pathways in innate immunity. However, the functions of RIG-I in hematopoiesis remain unclear, especially regarding its possible interaction with endogenous RNAs and the associated pathways that could contribute to the cellular differentiation and maturation. Herein, we identified a number of RIG-I-binding endogenous RNAs in APL cells following ATRA treatment, including the tripartite motif-containing protein 25 (TRIM25) messenger RNA (mRNA). TRIM25 encodes the protein known as an E3 ligase for ubiquitin/interferon (IFN)-induced 15-kDa protein (ISG15) that is involved in RIG-I-mediated antiviral signaling. We show that RIG-I could bind TRIM25 mRNA via its helicase domain and C-terminal regulatory domain, enhancing the stability of TRIM25 transcripts. RIG-I could increase the transcriptional expression of TRIM25 by caspase recruitment domain (CARD) domain through an IFN-stimulated response element. In addition, RIG-I activated other key genes in the ISGylation pathway by activating signal transducer and activator of transcription 1 (STAT1), including the modifier ISG15 and several enzymes responsible for the conjugation of ISG15 to protein substrates. RIG-I cooperated with STAT1/2 and interferon regulatory factor 1 (IRF1) to promote the activation of the ISGylation pathway. The integrity of ISGylation in ATRA or RIG-I-induced cell differentiation was essential given that knockdown of TRIM25 or ISG15 resulted in significant inhibition of this process. Our results provide insight into the role of the RIG-I-TRIM25-ISGylation axis in myeloid differentiation.
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Diferenciación Celular , Citocinas/metabolismo , Proteína 58 DEAD Box/metabolismo , Granulocitos/fisiología , Factores de Transcripción/metabolismo , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinas/metabolismo , Línea Celular Tumoral , Citocinas/genética , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Estabilidad del ARN , ARN Mensajero/metabolismo , Receptores Inmunológicos , Factores de Transcripción/genética , Proteínas de Motivos Tripartitos/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitinas/genética , Regulación hacia ArribaRESUMEN
BACKGROUND: Midostaurin combined with chemotherapy is currently used to treat newly diagnosed acute myeloid leukemia (AML) patients with FMS-like tyrosine kinase 3 (FLT3)-mutations. However, midostaurin acts as an antagonist to some chemotherapeutic agents in leukemia cell lines without FLT3 mutations. All-trans retinoic acid (ATRA) induces apoptosis when used in combination with midostaurin in FLT3-mutated AML cells. This combination has been shown to be safe in AML patients. However, the effect of this combination has not been investigated in AML without FLT3 mutations. METHODS: Cell proliferation was assessed by a cell counting assay. Cell death was evaluated by cell viability and Annexin-V assays. Cell differentiation was assessed by CD11b expression profiling and morphological analysis. To explore the underlying mechanisms, we studied the role of caspase3/7, Lyn, Fgr, Hck, RAF, MEK, ERK, AKT, PU.1, CCAAT/enhancer binding protein ß (C/EBPß) and C/EBPε by Western blot analysis and immunoprecipitation assays. Antitumor activity was also confirmed in mouse xenograft models established with AML cells. RESULTS: In this study, 0.1 - 0.25 µM midostaurin (mido(L)) combined with ATRA induced differentiation while 0.25 - 0.5 µM midostaurin (mido(H)) combined with ATRA triggered apoptosis in some AML cell lines without FLT3-mutations. Midostaurin combined with ATRA (mido-ATRA) also exhibited antitumor activity in mouse xenograft models established with AML cells. Mechanistically, mido(H)-ATRA-induced apoptosis was dependent on caspase-3/7. Mido(L)-ATRA inhibited Akt activation which was associated with decreased activity of Lyn/Fgr/Hck, resulted in dephosphorylation of RAF S259, activated RAF/MEK/ERK, along with upregulating the protein levels of C/EBPß, C/EBPε and PU.1. A MEK specific inhibitor was observed to suppress mido(L)-ATRA-induced increases in the protein levels of C/EBPs and PU.1 and mido(L)-ATRA-induced differentiation. Furthermore, inhibition of Akt activity promoted mido(L)-ATRA-induced downregulation of RAF S259 phosphorylation and mido(L)-ATRA-induced differentiation. Therefore, Lyn/Fgr/Hck-associated Akt inhibition activated RAF/MEK/ERK and controlled mido(L)-ATRA-induced differentiation by upregulation of C/EBPs and PU.1. Mido(L)-ATRA also promoted assembly of the signalosome, which may facilitate RAF activation. CONCLUSIONS: Midostaurin combined with ATRA exerts antitumor activity against AML with wild-type FLT3 mutations in vitro and in vivo. These findings may provide novel therapeutic strategies for some AML patients without FLT3 mutations and imply a new target of midostaurin.
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Leucemia Mieloide Aguda , Tirosina Quinasa 3 Similar a fms , Animales , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Ratones , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/genética , Estaurosporina/análogos & derivados , Tretinoina/farmacología , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
Relapsed and refractory (R/R) multiple myeloma (MM) patients have very poor prognosis. Chimeric antigen receptor modified T (CAR T) cells is an emerging approach in treating hematopoietic malignancies. Here we conducted the clinical trial of a biepitope-targeting CAR T against B cell maturation antigen (BCMA) (LCAR-B38M) in 17 R/R MM cases. CAR T cells were i.v. infused after lymphodepleting chemotherapy. Two delivery methods, three infusions versus one infusion of the total CAR T dose, were tested in, respectively, 8 and 9 cases. No response differences were noted among the two delivery subgroups. Together, after CAR T cell infusion, 10 cases experienced a mild cytokine release syndrome (CRS), 6 had severe but manageable CRS, and 1 died of a very severe toxic reaction. The abundance of BCMA and cytogenetic marker del(17p) and the elevation of IL-6 were the key indicators for severe CRS. Among 17 cases, the overall response rate was 88.2%, with 13 achieving stringent complete response (sCR) and 2 reaching very good partial response (VGPR), while 1 was a nonresponder. With a median follow-up of 417 days, 8 patients remained in sCR or VGPR, whereas 6 relapsed after sCR and 1 had progressive disease (PD) after VGPR. CAR T cells were high in most cases with stable response but low in 6 out of 7 relapse/PD cases. Notably, positive anti-CAR antibody constituted a high-risk factor for relapse/PD, and patients who received prior autologous hematopoietic stem cell transplantation had more durable response. Thus, biepitopic CAR T against BCMA represents a promising therapy for R/R MM, while most adverse effects are clinically manageable.
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Antígeno de Maduración de Linfocitos B , Trasplante de Células Madre Hematopoyéticas , Inmunoterapia Adoptiva , Mieloma Múltiple , Proteínas de Neoplasias , Receptores Quiméricos de Antígenos , Adolescente , Adulto , Anciano , Autoinjertos , Antígeno de Maduración de Linfocitos B/análisis , Antígeno de Maduración de Linfocitos B/genética , Antígeno de Maduración de Linfocitos B/inmunología , Deleción Cromosómica , Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 17/inmunología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/genética , Mieloma Múltiple/inmunología , Mieloma Múltiple/patología , Mieloma Múltiple/terapia , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/inmunologíaRESUMEN
T-cell acute lymphoblastic leukemia (T-ALL) is a clonal malignancy of immature T cells. Recently, the next-generation sequencing approach has allowed systematic identification of molecular features in pediatric T-ALL. Here, by performing RNA-sequencing and other genomewide analysis, we investigated the genomic landscape in 61 adult and 69 pediatric T-ALL cases. Thirty-six distinct gene fusion transcripts were identified, with SET-NUP214 being highly related to adult cases. Among 18 previously unknown fusions, ZBTB16-ABL1, TRA-SALL2, and involvement of NKX2-1 were recurrent events. ZBTB16-ABL1 functioned as a leukemogenic driver and responded to the effect of tyrosine kinase inhibitors. Among 48 genes with mutation rates >3%, 6 were newly found in T-ALL. An aberrantly overexpressed short mRNA transcript of the SLC17A9 gene was revealed in most cases with overexpressed TAL1, which predicted a poor prognosis in the adult group. Up-regulation of HOXA, MEF2C, and LYL1 was often present in adult cases, while TAL1 overexpression was detected mainly in the pediatric group. Although most gene fusions were mutually exclusive, they coexisted with gene mutations. These genetic abnormalities were correlated with deregulated gene expression markers in three subgroups. This study may further enrich the current knowledge of T-ALL molecular pathogenesis.
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Regulación Leucémica de la Expresión Génica , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Transcriptoma , Adulto , Niño , Estudios de Cohortes , Perfilación de la Expresión Génica/métodos , Ontología de Genes , Células HEK293 , Humanos , Células Jurkat , Estimación de Kaplan-Meier , MutaciónRESUMEN
Lung cancer is the leading cause of cancer death worldwide. PARP inhibitors have become a new line of cancer therapy and a successful demonstration of the synthetic lethality concept. The mechanism and efficacy of PARP inhibitors have been well studied in some cancers, especially homologous recombination (HR)-deficient ovarian cancer and breast cancer, yet such studies are still relatively fewer in lung cancer. Here we found that HR genes are frequently mutated in lung cancer patients, exposing a window for targeted therapies by PARP inhibitors. We depleted BRCA1 and BRCA2 in non-small cell lung cancer (NSCLC) cancer cells and found these cells are hypersensitive to the PARP inhibitor olaparib in cell viability and clonogenic survival assays. Olaparib specifically induces apoptosis in A549â¯cells with BRCA1 or BRCA2 depletion, as determined by positive Annexin-V staining. In addition, we show that A549â¯cells with ATM shRNA knockdown are also hypersensitive to Olaparib. In summary, our data support the potential use of PARP inhibitors in NSCLC with HR deficiency.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Células A549 , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Supervivencia Celular , Recombinación Homóloga/efectos de los fármacos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Proteína Homóloga de MRE11/genética , Mutación , Ftalazinas/farmacología , Piperazinas/farmacología , Recombinasa Rad51/genética , Proteína Recombinante y Reparadora de ADN Rad52/genéticaRESUMEN
BACKGROUND: MicroRNAs (miRs) are involved in lymphoma progression by regulating tumor cell interaction with microenvironment. MiR155 is overexpressed in diffuse large B-cell lymphoma (DLBCL) and its biological effect on tumor microenvironment needs to be futher investigated. METHODS: MiR155 was detected by quantitative real-time PCR in patients with newly diagnosed DLBCL. The mechanism of action of miR155 on lymphoma progression and tumor microenvironment was examined in vitro in B-lymphoma cell lines and in vivo in a murine xenograft model. RESULTS: Serum miR155 was significantly elevated, correlated with tumor miR155 expression, and indicated poor disease outcome in DLBCL. MiR155 overexpression was associated with decreased peripheral blood CD8+T cells and inhibition of T-cell receptor signaling. Of note, EBV-positive patients showed higher serum miR155 than EBV-negative patients. In co-culture systems of B-lymphoma cells with immune cells, miR155 induced Fas-mediated apoptosis of CD8+T cells, which could be targeted by anti-PD-1 and anti-PD-L1 antibodies. Moreover, miR155 enhanced lymphoma cell PD-L1 expression, recruited CD8+T cells by PD-1/PD-L1 interaction and inhibited CD8+T cell function via dephosphorylating AKT and ERK. MiR155-induced AKT/ERK inactivation was more obvious in CD8+T cells co-cultured with EBV-infected B-lymphoma cells. In vivo in a murine xenograft model established with subcutaneous injection of A20 cells, PD-L1 blockade particularly retarded miR155-overexpressing tumor growth, consistent with maintenance of CD8+T cells and their function. CONCLUSIONS: As a oncogenic biomarker of B-cell lymphoma, serum miR155 was related to lymphoma progression through modulating PD-1/PD-L1-mediated interaction with CD8+T cells of tumor microenvironment, indicating the sensitivity of B-cell lymphoma to PD-L1 blockade. Also CD8+T cells could be a therapeutic mediator of immune checkpoint inhibitors in treating EBV-associated lymphoid malignancies.
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Antineoplásicos Inmunológicos/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Linfocitos T CD8-positivos/inmunología , Comunicación Celular , Resistencia a Antineoplásicos/genética , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , MicroARNs/genética , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Animales , Apoptosis , Antígeno B7-H1/inmunología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Estudios de Casos y Controles , Proliferación Celular , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Linfocitos/metabolismo , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Pronóstico , Receptor de Muerte Celular Programada 1/inmunología , Transducción de Señal , Tasa de Supervivencia , Células Tumorales Cultivadas , Microambiente Tumoral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Based on the leukemia-associated immunophenotypes (LAIPs), minimal residual disease (MRD) related to the outcome can be detected by multiparameter flow cytometry in acute myeloid leukemia (AML) patients. Although 0.1% was commonly used as a cutoff value, measurable MRD or MRD level below 0.1% has also been associated with prognostic significance and more sensitive thresholds (<0.1%) are required for improving AML prognosis prediction. In this study, 292 adult patients diagnosed with AML (non-M3) were enrolled, 36 kinds of LAIPs were identified, and the baseline expression levels in normal or regenerating bone marrows of each kind of LAIP were established, which ranged from <2.00 × 10-5 to 5.71 × 10-4 . The baseline level of each LAIP was considered as the individual threshold for MRD assessment. MRD statuses stratified by 0.1% and individual threshold were termed as 0.1%-MRD and individual-MRD, respectively. The patients of individual-MRDneg showed significantly better survival compared with those of 0.1%-MRDneg /individual-MRDpos or 0.1%-MRDpos . Multivariate analysis showed that when time points of complete remission, post the first and second consolidation courses, were considered, only individual-MRD post second consolidation presented independent prognostic value. Notably, in patients of cytogenetic/molecular low-risk (LR) or intermediate-risk (IR), the individual-MRD status could identify the patients with significantly different outcomes, while 0.1%-MRD status could not. Furthermore, among the patients of the LR or IR group which received chemotherapy only, those with individual-MRDneg status presented favorable survival, which was comparable with that of the patients accepted allogeneic hematopoietic stem cell transplantation (ASCT). This approach is useful in the selection of an ASCT strategy for clinical practice.
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Médula Ósea , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Adolescente , Adulto , Anciano , Aloinjertos , Médula Ósea/metabolismo , Médula Ósea/patología , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Inmunofenotipificación , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Neoplasia Residual , Tasa de SupervivenciaRESUMEN
BACKGROUND This study aimed to investigate the diagnostic values of serum levels of Hcy and UA for predicting vascular mild cognitive impairment (VMCI) in patients with cerebral small vessel disease (SVD). MATERIAL AND METHODS We selected 172 cerebral SVD patients and divided them into a VMCI group and a non-VMCI group. Eighty-six healthy individuals without nervous system diseases were selected as the control group. Enzymatic cycling method was performed to detect serum Hcy and UA levels. Serum levels of folic acid (FOA) and vitamin B12 (VitB12) were detected by chemiluminescence immunoassay. Montreal cognitive assessment (MoCA) was applied to evaluate the cognitive function. The ROC curve was used to evaluate the diagnostic values of serum Hcy and UA levels for predicting VMCI. Logistic regression analysis was used to determine the possible risk factors. RESULTS Compared with the non-VMCI and control groups, serum FOA and VitB12 levels were lower and serum Hcy and UA levels were higher in the VMCI group. AUC values of serum Hcy and UA levels were 0.703 and 0.829, respectively. Serum Hcy and UA levels were negatively correlated with serum FOA and VitB12 levels, total MoCA score, and subscores on visuospatial ability and executive function, on language ability and on delayed recall, and they were positively correlated with serum cholesterol (CH) level. Serum Hcy and UA levels were indicated as risk factors for VMCI in cerebral SVD patients. CONCLUSIONS These results suggest that serum Hcy and UA levels may serve as predictive factors for VMCI in cerebral SVD patients.
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Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Disfunción Cognitiva/sangre , Disfunción Cognitiva/diagnóstico , Homocisteína/sangre , Ácido Úrico/sangre , Anciano , Estudios de Casos y Controles , Colesterol/sangre , Disfunción Cognitiva/complicaciones , Femenino , Ácido Fólico/sangre , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Curva ROC , Vitamina B 12/sangreRESUMEN
OBJECTIVE: To explore the clinical diagnosis and treatment of seminal vesicle cyst (SVC) associated with ipsilateral renal agenesis (Zinner syndrome) in order to promote the understanding of the disease. METHODS: We retrospectively analyzed the clinical data about 1 case ofZinner syndrome diagnosed and treated in our hospital and reviewed the literature related to this disease in domestic and foreign authoritative databases. RESULTS: The patient was a 23-year-old male, diagnosed with Zinner syndrome, treated bytransrectal aspiration of SVC, and discharged from hospital 3 days postoperatively. Follow-upat 6 months after discharge found that the patient no longer felt perineal discomfort in the endstage of urination, but transrectal ultrasonography of the prostate revealedthe samevolume of fluid in the left seminal vesicles as before,which indicated recurrence. CONCLUSIONS: SVC associated with ipsilateral renal agenesis can be considered asZinner syndrome. Transrectal aspiration of SVCcan relieve the local symptoms of the patient but relapse may easilyoccur. Therefore it is not recommended as the first-choice treatment of the disease.
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Quistes/diagnóstico por imagen , Enfermedades de los Genitales Masculinos/diagnóstico por imagen , Vesículas Seminales/diagnóstico por imagen , Riñón Único/complicaciones , Quistes/terapia , Enfermedades de los Genitales Masculinos/terapia , Humanos , Masculino , Perineo , Recurrencia , Estudios Retrospectivos , Síndrome , Ultrasonografía , Adulto JovenRESUMEN
The BCR-ABL fusion protein generated by t(9;22)(q34;q11) in chronic myeloid leukemia (CML) plays an essential role in the pathogenesis of the myeloproliferative disorder status at the chronic phase of the disease, but progression from the chronic phase to blast crisis (BC) is believed to require additional mutations. To explore the underlying mechanisms for BC, which is characterized by a blockage of blood cell differentiation, we screened several genes crucial to hematopoiesis and identified 10 types of mutations in RUNX1 among 11 of 85 (12.9%) patients with acute transformation of CML. Most of the mutations occurred in the runt homology domain, including H78Q, W79C, R139G, D171G, R174Q, L71fs-ter94, and V91fs-ter94. Further studies indicated that RUNX1 mutants not only exhibited decreased transactivation activity but also had an inhibitory effect on the WT RUNX1. To investigate the leukemogenic effect of mutated RUNX1, H78Q and V91fs-ter94 were transduced into 32D cells or BCR-ABL-harboring murine cells, respectively. Consistent with the myeloblastic features of advanced CML patients with RUNX1 mutations, H78Q and V91fs-ter94 disturbed myeloid differentiation and induced a BC or accelerated phase-like phenotype in mice. These results suggest that RUNX1 abnormalities may promote acute myeloid leukemic transformation in a subset of CML patients.
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Crisis Blástica/genética , Transformación Celular Neoplásica/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Mutación , Adolescente , Adulto , Animales , Diferenciación Celular/genética , Femenino , Humanos , Inmunoprecipitación , Masculino , Ratones , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transfección , Adulto JovenRESUMEN
Soil is the basis of agricultural production and accessing accurate information on soil nutrients is essential. Traditional methods of soil composition detection, which are based on chemical analysis, are characterized by being costly and polluting. Spectroscopic analysis has proven to be a rapid, non-destructive and effective technique for predicting soil properties in general and potassium, phosphorus and organic matter in particular. However, previous research on soils has rarely combined optimization algorithms with machine learning techniques, which has led to suboptimal model accuracy and convergence speed. In this study, a total of 184 soil samples were collected from three cities of Linhai, Yueqing and Longyou County, Zhejiang Province, China. After measuring pH values, alkali-hydrolyzable nitrogen (SAN), available phosphorus (SAP), available potassium (SAK) and soil organic matter (SOM) contents, along with their corresponding spectroscopic measurements, nine pretreatment methods and their combinations are adopted. A novel assessment model, integrating support vector machine and dung beetle optimization algorithm (DBO-SVR), is proposed to predict pH values and SAN, SAP, SAK, SOM content. Meanwhile, the DBO algorithm is compared with three mainstream optimization algorithms (particle swarm optimization (PSO), whale optimization algorithm (WOA) and grey wolf optimizer (GWO)). Results showed that the DBO-SVR model was shown best performance with Rp, RMSEP and RPD of 0.9842, 0.1306, 5.6485 respectively for prediction of pH value, with Rp, RMSEP and RPD of 0.8802, 15.0574 mg/kg and 2.0508, respectively for assessment of SAN content, with Rp, RMSEP and RPD of 0.9790, 12.8298 mg/kg, and 4.5132, respectively for assessment of SAP content, with Rp, RMSEP and RPD of 0.8677, 22.5107 mg/kg, and 1.9546, respectively for assessment of SAK content, and with Rp, RMSEP and RPD of 0.9273, 2.6427g/kg , and 2.1821, respectively for assessment of SOM content. This study demonstrates that the combination of near-infrared (NIR) spectroscopy and the DBO-SVR algorithm is capable of predicting soil nutrient composition with greater accuracy and efficiency.
RESUMEN
In the study, the adjuvant features of the immunoregulatory polysaccharide component CARP2 isolated from cultivated Artemisia rupestris L. for influenza virus vaccine (IVV) and the mechanism responsible for its action in DCs were further explored. CARP2 showed a typical absorbance peak of polysaccharides in spectral analysis. At two doses of CARP2-adjuvanted IVV, IgG, hemagglutination inhibition (HI) titers, and effector/memory T cells were generated and lasted for 275 days without adverse events. CARP2 primed rapid HI and IgG, IgG2a/IgG1 ratio, splenocyte proliferation, and cytotoxic T lymphocyte (CTL), and facilitated the generation of INF-γ and IL-4 by activating DCs and regulatory T cells (Tregs). Additionally, CARP2 achieved the ten-fold dose-sparing effect. In vitro, CARP2 stimulated DCs to prime the production of Th1/Th2 cytokines and CCR7 and activated MyD88-dependent pathway by upregulating the expressions of TLR4, MyD88, TRAF-6, and p65. In contrast, MyD88, TRAF-6, and NF-κB inhibitors partially blocked the effect through reducing related cytokines and proteins. Overall, CARP2 promoted IVV efficacy, which was involved in the modulation of Th1/Th2 responses and shifted toward Th1-polarizing response via TLR4/MyD88/TRAF/NF-κB activation in DCs.
Asunto(s)
Artemisia , Vacunas contra la Influenza , Animales , Ratones , Artemisia/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Receptor Toll-Like 4/metabolismo , FN-kappa B/metabolismo , Adyuvantes Inmunológicos/farmacología , Citocinas/metabolismo , Inmunoglobulina G , Polisacáridos , Inmunidad , Anticuerpos Antivirales , Ratones Endogámicos BALB CRESUMEN
BACKGROUND AND OBJECTIVE: All-trans retinoic acid (ATRA) is only effective in acute promyelocytic leukemia (APL), but not in other subtype of acute myeloid leukemia (AML). Salinomycin targets tumor cells rather than non-tumorigenic cells, and WNT/ß-catenin pathway inhibition is one of the mechanisms of its anti-tumor activity. There is a crosstalk between RA and WNT/ß-catenin pathway. Here, we investigate the effect of the combination of salinomycin and ATRA (S+RA) in non-APL AML cells. METHODS: Apoptosis was evaluated by cell viability and Annexin-V assay. Cell differentiation was analyzed by CD11c expression and morphology. To explore the underlying mechanisms, Western blot analysis and mitochondrial transmembrane potentials (ΔΨm) were used. RESULTS & DISCUSSION: S+RA induced differentiation and apoptosis in AML cell lines and AML primary cells. S+RA inhibited the ß-catenin signal pathway as determined by the decreased protein levels of ß-catenin, the low-density lipoprotein receptor-related proteins 6 (LRP6), and its downstream proteins such as survivin, c-Myc, caspase-3/7, cdc25A and cyclinD1 and reduced phosphorylation level of GSK3ß S9. S+RA also increased the protein levels of CCAAT/enhancer-binding proteins (C/EBPs) and PU.1 and collapsed Δψm. The above molecular and cellular changes induced by S+RA were inhibited by ß-catenin specific activator and promoted by ß-catenin specific inhibitor. CONCLUSION: S+RA induced differentiation by ß-catenin-inhibition-mediated up-regulation of C/EBPs and PU.1 and suppression of c-Myc. S+RA triggered apoptosis through ß-catenin-inhibition-regulated ΔΨm collapse and caspase-3/7 activation. Taken together, our findings may provide novel therapeutic strategies for AML patients by targeting the WNT/ß-catenin pathway.
Asunto(s)
Leucemia Mieloide Aguda , Leucemia Promielocítica Aguda , Humanos , beta Catenina/metabolismo , Caspasa 3/metabolismo , Leucemia Mieloide Aguda/patología , Tretinoina/farmacología , Tretinoina/uso terapéutico , Apoptosis , Leucemia Promielocítica Aguda/tratamiento farmacológico , Diferenciación Celular , Vía de Señalización Wnt , Línea Celular TumoralRESUMEN
BACKGROUND: Aggressive variant prostate cancer (AVPC) is a rare disease that progresses rapidly. The first-line treatment for AVPC is currently unknown. We examined a rare case of AVPC with rare brain and bladder metastases. A summary review of the mechanism of development, clinicopathological manifestations, associated treatments and prognosis of this disease is presented. CASE SUMMARY: The patient was diagnosed with prostate cancer (PCA), and was actively treated with endocrine therapy, radiotherapy, chemotherapy, and traditional Chinese medicine. Unfortunately, he was insensitive to treatment, and the disease progressed rapidly. He died five years after being diagnosed with PCA. CONCLUSION: We should reach consensus definitions of the AVPC and other androgen receptor-independent subtypes of PCA and develop new biomarkers to identify groups of high-risk variants. It is crucial to complete a puncture biopsy of the tumor or metastatic lesion as soon as possible in patients with advanced PCA who exhibit clinical features such as low Prostate-specific antigen levels, high carcinoembryonic antigen levels, and insensitivity to hormones to determine the pathological histological type and to create a more aggressive monitoring and treatment regimens.
RESUMEN
Mast cell leukemia is a rare and aggressive disease, predominantly with KIT D816V mutation. With poor response to conventional poly-chemotherapy, mast cell leukemia responded to the midostaurin treatment with a 50% overall response rate (ORR), but complete remission rate is approximately 0%. Therefore, the potential mechanisms of midostaurin resistance and the exact impacts of midostaurin on both gene expression profile and mast cell leukemia microenvironment in vivo are essential for design tailored combination therapy targeting both the tumor cells and the tumor microenvironment. Here we report a 59-year-old male mast cell leukemia patient with KIT F522C mutation treated with midostaurin. Single-cell sequencing of peripheral blood and whole exome sequencing (WES) of bone marrow were performed before and 10 months after midostaurin treatment. In accordance with the clinical response, compared to the pretreatment aberration, the decline of mast cells and increase of T-, NK, B-cells in peripheral blood, and the decrease of the KIT F522C mutation burden in bone marrow were observed. Meanwhile, the emergence of RUNX1 mutation, upregulations of genes expression (RPS27A, RPS6, UBA52, RACK1) on tumor cells, and increased frequencies of T and NK cells with TIGIT, CTLA4, and LAG3 expression were observed after midostaurin treatment, predicting the disease progression of this patient. As far as we know, this is the first case reporting the clinical, immunological, and molecular changes in mast cell leukemia patients before and after midostaurin treatment, illustrating the in vivo mechanisms of midostaurin resistance in mast cell leukemia, providing important clues to develop a sequential option to circumvent tumor progression after targeting oncogene addiction and prolong patients' survival.
Asunto(s)
Leucemia de Mastocitos , Masculino , Humanos , Persona de Mediana Edad , Leucemia de Mastocitos/tratamiento farmacológico , Leucemia de Mastocitos/genética , Estaurosporina/uso terapéutico , Terapia Combinada , Mastocitos , Microambiente TumoralRESUMEN
The study aims to investigate the constituents, adjuvant effects, and underlying mechanisms of purified polysaccharides from cultivated Cistanche deserticola (C. deserticola). Two macromolecules designated as CCDP-1 (26.5 kDa) and CCDP-2 (32.3 kDa) from C. deserticola were respectively identified as carbohydrate-lignin complexes with 44.1 % and 43.8 % lignin. CCDP-1 and CCDP-2 were composed of glucose, rhamnose, galactose, arabinose, and mannose respectively in the molar ratios of 7.22: 5.98:2.51:1.81:1.00 and 6.57:8.48:4.20:2.72:1.00. An in vitro experiment revealed that endotoxin-free CCDP-1 and CCDP-2 promoted splenocyte proliferation without cytotoxicity, but CCDP-2 induced dendritic cell (DC) maturation more efficiently than CCDP-1. An in vivo experiment suggested that CCDP-2 enhanced OVA-specific antibody production, antigen-specific T-cell activation, IFN-γ production, IL-4 production, and DC activation. Notably, CCDP-2 elicited a Th1-biased response. Mechanically, CCDP-2 upregulated CD40, CD80, CD86, and MHC II, facilitated allogeneic T-cell proliferation and Th1/Th2 cytokines, improved IFN-γ, IL-12, IL-6, and TNF-α production, and decreased endocytosis from DCs in vitro. Blocking assays indicated that TLR2 and TLR4 were the membrane receptor candidates of DCs. Western blot implied that CCDP-2 with the immune-enhancing activities were involved in the activation of MAPKs and NF-κB pathways in a dose-/time-related manner and could be employed as a more balanced Th1/Th2 adjuvant for vaccine exploitation.