Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 19 de 19
Filtrar
1.
Acta Pharmacol Sin ; 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39284878

RESUMO

Chronic itch is a maladaptive and debilitating symptom in patients with allergic contact dermatitis (ACD), adversely affecting their quality of life. There is a lack of effective treatments for ACD-associated uncontrollable itch. In this study, we explored the antipruritic effects of baicalein (BE), a bioactive flavonoid extracted from the root of Scutellaria baicalensis Georgi, and the underlying mechanisms in alleviating chronic itch triggered by diphenylcyclopropenone (DCP) in a mouse model of ACD. The ACD mice were intraperitoneally injected with BE (5, 30, and 60 mg·kg-1·d-1) for 7 days during the DCP challenge phase. The results showed that DCP-treated mice exhibited severe spontaneous scratching behaviors that was reduced after BE injections in a dose-dependent manner accompanied by inhibition of spinal astrocyte activation. We observed that the spinal astrocytic STAT3-LCN2 cascade plays a crucial role in controlling the activation of astrocytes in chronic itch. Intrathecal injection of the STAT3 inhibitor AG490 or Lcn2 siRNA significantly reduced scratching behavior and astrocyte activation in ACD mice. Moreover, BE markedly attenuated the increased phosphorylation of STAT3 (p-STAT3) and LCN2 expression in the spinal cords of ACD mice and in lipopolysaccharide-stimulated primary spinal astrocytes. Altogether, BE relieved chronic itch by suppressing the spinal astrocytic STAT3-LCN2 cascade. These findings provide a potential avenue for the management of chronic itch. Schematic summary of the main findings illustrating that BE alleviates chronic itch through suppressing the spinal astrocytic STAT3-LCN2 cascade. Specifically, BE suppresses the expression of p-STAT3 to inhibit the reactive state of astrocytes in spinal dorsal horn, and then decreases the expression of astrocytic LCN2 to alleviate chronic itch in ACD mice.

2.
J Transl Med ; 22(1): 613, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38956649

RESUMO

BACKGROUND: CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy stands out as a revolutionary intervention, exhibiting remarkable remission rates in patients with refractory/relapsed (R/R) B-cell malignancies. However, the potential side effects of therapy, particularly cytokine release syndrome (CRS) and infections, pose significant challenges due to their overlapping clinical features. Promptly distinguishing between CRS and infection post CD19 target CAR-T cell infusion (CTI) remains a clinical dilemma. Our study aimed to analyze the incidence of infections and identify key indicators for early infection detection in febrile patients within 30 days post-CTI for B-cell malignancies. METHODS: In this retrospective cohort study, a cohort of 104 consecutive patients with R/R B-cell malignancies who underwent CAR-T therapy was reviewed. Clinical data including age, gender, CRS, ICANS, treatment history, infection incidence, and treatment responses were collected. Serum biomarkers procalcitonin (PCT), interleukin-6 (IL-6), and C-reactive protein (CRP) levels were analyzed using chemiluminescent assays. Statistical analyses employed Pearson's Chi-square test, t-test, Mann-Whitney U-test, Kaplan-Meier survival analysis, Cox proportional hazards regression model, Spearman rank correlation, and receiver operating characteristic (ROC) curve analysis to evaluate diagnostic accuracy and develop predictive models through multivariate logistic regression. RESULTS: In this study, 38 patients (36.5%) experienced infections (30 bacterial, 5 fungal, and 3 viral) within the first 30 days of CAR T-cell infusion. In general, bacterial, fungal, and viral infections were detected at a median of 7, 8, and 9 days, respectively, after CAR T-cell infusion. Prior allogeneic hematopoietic cell transplantation (HCT) was an independent risk factor for infection (Hazard Ratio [HR]: 4.432 [1.262-15.565], P = 0.020). Furthermore, CRS was an independent risk factor for both infection ((HR: 2.903 [1.577-5.345], P < 0.001) and severe infection (9.040 [2.256-36.232], P < 0.001). Serum PCT, IL-6, and CRP were valuable in early infection prediction post-CAR-T therapy, particularly PCT with the highest area under the ROC curve (AUC) of 0.897. A diagnostic model incorporating PCT and CRP demonstrated an AUC of 0.903 with sensitivity and specificity above 83%. For severe infections, a model including CRS severity and PCT showed an exceptional AUC of 0.991 with perfect sensitivity and high specificity. Based on the aforementioned analysis, we proposed a workflow for the rapid identification of early infection during CAR-T cell therapy. CONCLUSIONS: CRS and prior allogeneic HCT are independent infection risk factors post-CTI in febrile B-cell malignancy patients. Our identification of novel models using PCT and CRP for predicting infection, and PCT and CRS for predicting severe infection, offers potential to guide therapeutic decisions and enhance the efficacy of CAR-T cell therapy in the future.


Assuntos
Antígenos CD19 , Febre , Imunoterapia Adotiva , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Imunoterapia Adotiva/métodos , Adulto , Antígenos CD19/metabolismo , Infecções/sangue , Idoso , Curva ROC , Adulto Jovem , Estudos Retrospectivos
3.
Biochem Biophys Res Commun ; 725: 150272, 2024 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-38901224

RESUMO

Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, induces deficits in cognition and information processing following chronic abuse. Adolescent ketamine misuse represents a significant global public health issue; however, the neurodevelopmental mechanisms underlying this phenomenon remain largely elusive. This study investigated the long-term effects of sub-chronic ketamine (Ket) administration on the medial prefrontal cortex (mPFC) and associated behaviors. In this study, Ket administration during early adolescence displayed a reduced density of excitatory synapses on parvalbumin (PV) neurons persisting into adulthood. However, the synaptic development of excitatory pyramidal neurons was not affected by ketamine administration. Furthermore, the adult Ket group exhibited hyperexcitability and impaired socialization and working memory compared to the saline (Sal) administration group. These results strongly suggest that sub-chronic ketamine administration during adolescence results in functional deficits that persist into adulthood. Bioinformatic analysis indicated that the gene co-expression module1 (M1) decreased expression after ketamine exposure, which is crucial for synapse development in inhibitory neurons during adolescence. Collectively, these findings demonstrate that sub-chronic ketamine administration irreversibly impairs synaptic development, offering insights into potential new therapeutic strategies.


Assuntos
Neurônios GABAérgicos , Interneurônios , Ketamina , Parvalbuminas , Córtex Pré-Frontal , Sinapses , Animais , Ketamina/farmacologia , Ketamina/administração & dosagem , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Parvalbuminas/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Masculino , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Camundongos , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Camundongos Endogâmicos C57BL , Antagonistas de Aminoácidos Excitatórios/farmacologia
4.
J Leukoc Biol ; 115(6): 1094-1107, 2024 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-38369808

RESUMO

Myeloid-derived suppressor cells (MDSCs) are implicated in the regulation of immune responses closely associated with poor clinical outcomes in cancer. However, the MDSC subtypes in non-Hodgkin's lymphoma (NHL) have not been systematically investigated. So, we investigated the percentage of MDSC subsets in 78 newly diagnosed NHL patients by flow cytometry. The results showed that all MDSC subsets increased in NHL patients compared with healthy donors. Notably, MDSCs, monocytic MDSCs, and CD14 + CD66b + MDSCs significantly increased in NHL patients compared with those with lymphadenitis donors. polymorphonuclear MDSCs (PMN-MDSCs), early-stage MDSCs (e-MDSCs), and the International Prognostic Index were independent risk factors for poor clinical efficacy and were involved in constructing the nomogram for predicting clinical efficacy. Progression-free survival (PFS) was significantly shorter in patients with high level of MDSC subsets, and PMN-MDSCs emerged as an independent prognostic factor for PFS. PMN-MDSCs, e-MDSCs, and the International Prognostic Index were involved in constructing the nomogram for predicting PFS. Patients with a higher percentage of MDSCs, PMN-MDSCs, e-MDSCs, and CD14 + CD66b + MDSCs experienced a shorter overall survival compared with those with lower percentages. In addition, research on mechanisms found that T cell function was suppressed and mediated by the expansion of MDSCs via involving arginase-1 and interleukin-10 in vitro and in vivo. In conclusion, our study demonstrates that the increased circulating MDSC subsets predict poor clinical efficacy and prognosis in NHL, potentially involving T cell suppression through MDSC subset expansion. These findings indicate the potential of MDSC subsets as comprehensive diagnostic, prognostic biomarkers, and therapeutic targets for NHL.


Assuntos
Linfoma não Hodgkin , Células Supressoras Mieloides , Humanos , Células Supressoras Mieloides/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/patologia , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/diagnóstico , Prognóstico , Adulto , Linfócitos T/imunologia , Idoso , Animais , Camundongos , Arginase/metabolismo
5.
Res Sq ; 2023 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-37961674

RESUMO

Refractoriness to initial chemotherapy and relapse after remission are the main obstacles to cure in T-cell Acute Lymphoblastic Leukemia (T-ALL). Biomarker guided risk stratification and targeted therapy have the potential to improve outcomes in high-risk T-ALL; however, cellular and genetic factors contributing to treatment resistance remain unknown. Previous bulk genomic studies in T-ALL have implicated tumor heterogeneity as an unexplored mechanism for treatment failure. To link tumor subpopulations with clinical outcome, we created an atlas of healthy pediatric hematopoiesis and applied single-cell multiomic (CITE-seq/snATAC-seq) analysis to a cohort of 40 cases of T-ALL treated on the Children's Oncology Group AALL0434 clinical trial. The cohort was carefully selected to capture the immunophenotypic diversity of T-ALL, with early T-cell precursor (ETP) and Near/Non-ETP subtypes represented, as well as enriched with both relapsed and treatment refractory cases. Integrated analyses of T-ALL blasts and normal T-cell precursors identified a bone-marrow progenitor-like (BMP-like) leukemia sub-population associated with treatment failure and poor overall survival. The single-cell-derived molecular signature of BMP-like blasts predicted poor outcome across multiple subtypes of T-ALL within two independent patient cohorts using bulk RNA-sequencing data from over 1300 patients. We defined the mutational landscape of BMP-like T-ALL, finding that NOTCH1 mutations additively drive T-ALL blasts away from the BMP-like state. We transcriptionally matched BMP-like blasts to early thymic seeding progenitors that have low NR3C1 expression and high stem cell gene expression, corresponding to a corticosteroid and conventional cytotoxic resistant phenotype we observed in ex vivo drug screening. To identify novel targets for BMP-like blasts, we performed in silico and in vitro drug screening against the BMP-like signature and prioritized BMP-like overexpressed cell-surface (CD44, ITGA4, LGALS1) and intracellular proteins (BCL-2, MCL-1, BTK, NF-κB) as candidates for precision targeted therapy. We established patient derived xenograft models of BMP-high and BMP-low leukemias, which revealed vulnerability of BMP-like blasts to apoptosis-inducing agents, TEC-kinase inhibitors, and proteasome inhibitors. Our study establishes the first multi-omic signatures for rapid risk-stratification and targeted treatment of high-risk T-ALL.

6.
Blood ; 139(14): 2198-2211, 2022 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-34864916

RESUMO

KMT2A-rearranged (KMT2A-r) infant acute lymphoblastic leukemia (ALL) is a devastating malignancy with a dismal outcome, and younger age at diagnosis is associated with increased risk of relapse. To discover age-specific differences and critical drivers that mediate poor outcome in KMT2A-r ALL, we subjected KMT2A-r leukemias and normal hematopoietic cells from patients of different ages to single-cell multiomics analyses. We uncovered the following critical new insights: leukemia cells from patients <6 months have significantly increased lineage plasticity. Steroid response pathways are downregulated in the most immature blasts from younger patients. We identify a hematopoietic stem and progenitor-like (HSPC-like) population in the blood of younger patients that contains leukemic blasts and form an immunosuppressive signaling circuit with cytotoxic lymphocytes. These observations offer a compelling explanation for the ability of leukemias in young patients to evade chemotherapy and immune-mediated control. Our analysis also revealed preexisting lymphomyeloid primed progenitors and myeloid blasts at initial diagnosis of B-ALL. Tracking of leukemic clones in 2 patients whose leukemia underwent a lineage switch documented the evolution of such clones into frank acute myeloid leukemia (AML). These findings provide critical insights into KMT2A-r ALL and have clinical implications for molecularly targeted and immunotherapy approaches. Beyond infant ALL, our study demonstrates the power of single-cell multiomics to detect tumor intrinsic and extrinsic factors affecting rare but critical subpopulations within a malignant population that ultimately determines patient outcome.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Antineoplásicos/uso terapêutico , Rearranjo Gênico , Humanos , Imunoterapia , Lactente , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
7.
Clin Cancer Res ; 27(18): 5109-5122, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34210682

RESUMO

PURPOSE: Systems biology approaches can identify critical targets in complex cancer signaling networks to inform new therapy combinations that may overcome conventional treatment resistance. EXPERIMENTAL DESIGN: We performed integrated analysis of 1,046 childhood B-ALL cases and developed a data-driven network controllability-based approach to identify synergistic key regulator targets in Philadelphia chromosome-like B-acute lymphoblastic leukemia (Ph-like B-ALL), a common high-risk leukemia subtype associated with hyperactive signal transduction and chemoresistance. RESULTS: We identified 14 dysregulated network nodes in Ph-like ALL involved in aberrant JAK/STAT, Ras/MAPK, and apoptosis pathways and other critical processes. Genetic cotargeting of the synergistic key regulator pair STAT5B and BCL2-associated athanogene 1 (BAG1) significantly reduced leukemia cell viability in vitro. Pharmacologic inhibition with dual small molecule inhibitor therapy targeting this pair of key nodes further demonstrated enhanced antileukemia efficacy of combining the BCL-2 inhibitor venetoclax with the tyrosine kinase inhibitors ruxolitinib or dasatinib in vitro in human Ph-like ALL cell lines and in vivo in multiple childhood Ph-like ALL patient-derived xenograft models. Consistent with network controllability theory, co-inhibitor treatment also shifted the transcriptomic state of Ph-like ALL cells to become less like kinase-activated BCR-ABL1-rearranged (Ph+) B-ALL and more similar to prognostically favorable childhood B-ALL subtypes. CONCLUSIONS: Our study represents a powerful conceptual framework for combinatorial drug discovery based on systematic interrogation of synergistic vulnerability pathways with pharmacologic inhibitor validation in preclinical human leukemia models.


Assuntos
Antineoplásicos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Antineoplásicos/uso terapêutico , Criança , Dasatinibe/farmacologia , Dasatinibe/uso terapêutico , Humanos , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
8.
Cancer Discov ; 11(9): 2186-2199, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33820778

RESUMO

The adoptive transfer of chimeric antigen receptor (CAR) T cells represents a breakthrough in clinical oncology, yet both between- and within-patient differences in autologously derived T cells are a major contributor to therapy failure. To interrogate the molecular determinants of clinical CAR T-cell persistence, we extensively characterized the premanufacture T cells of 71 patients with B-cell malignancies on trial to receive anti-CD19 CAR T-cell therapy. We performed RNA-sequencing analysis on sorted T-cell subsets from all 71 patients, followed by paired Cellular Indexing of Transcriptomes and Epitopes (CITE) sequencing and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) on T cells from six of these patients. We found that chronic IFN signaling regulated by IRF7 was associated with poor CAR T-cell persistence across T-cell subsets, and that the TCF7 regulon not only associates with the favorable naïve T-cell state, but is maintained in effector T cells among patients with long-term CAR T-cell persistence. These findings provide key insights into the underlying molecular determinants of clinical CAR T-cell function. SIGNIFICANCE: To improve clinical outcomes for CAR T-cell therapy, there is a need to understand the molecular determinants of CAR T-cell persistence. These data represent the largest clinically annotated molecular atlas in CAR T-cell therapy to date, and significantly advance our understanding of the mechanisms underlying therapeutic efficacy.This article is highlighted in the In This Issue feature, p. 2113.


Assuntos
Imunoterapia Adotiva , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/transplante , Adolescente , Criança , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Philadelphia , Linfócitos T/imunologia
9.
Sci Adv ; 6(30): eaba3064, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32832663

RESUMO

Interpreting the function of noncoding mutations in cancer genomes remains a major challenge. Here, we developed a computational framework to identify putative causal noncoding mutations of all classes by joint analysis of mutation and gene expression data. We identified thousands of SNVs/small indels and structural variants as putative causal mutations in five major pediatric cancers. We experimentally validated the oncogenic role of CHD4 overexpression via enhancer hijacking in B-ALL. We observed a general exclusivity of coding and noncoding mutations affecting the same genes and pathways. We showed that integrated mutation profiles can help define novel patient subtypes with different clinical outcomes. Our study introduces a general strategy to systematically identify and characterize the full spectrum of noncoding mutations in cancers.


Assuntos
Linfoma de Células B , Neoplasias , Criança , Genoma , Humanos , Mutação , Neoplasias/genética , Sequências Reguladoras de Ácido Nucleico/genética
11.
Clin Cancer Res ; 26(14): 3505-3513, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32127393

RESUMO

The adoptive transfer of genetically engineered chimeric antigen receptor (CAR) T cells has opened a new frontier in cancer therapy. Unlike the paradigm of targeted therapies, the efficacy of CAR T-cell therapy depends not only on the choice of target but also on a complex interplay of tumor, immune, and stromal cell communication. This presents both challenges and opportunities from a discovery standpoint. Whereas cancer consortia have traditionally focused on the genomic, transcriptomic, epigenomic, and proteomic landscape of cancer cells, there is an increasing need to expand studies to analyze the interactions between tumor, immune, and stromal cell populations in their relevant anatomical and functional compartments. Here, we focus on the promising application of systems biology to address key challenges in CAR T-cell therapy, from understanding the mechanisms of therapeutic resistance in hematologic and solid tumors to addressing important clinical challenges in biomarker discovery and therapeutic toxicity. We propose a systems biology view of key clinical objectives in CAR T-cell therapy and suggest a path forward for a biomedical discovery process that leverages modern technological approaches in systems biology.


Assuntos
Pesquisa Biomédica/métodos , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Receptores de Antígenos Quiméricos/imunologia , Biologia de Sistemas , Animais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/imunologia , Modelos Animais de Doenças , Humanos , Imunoterapia Adotiva/efeitos adversos , Modelos Imunológicos , Neoplasias/diagnóstico , Neoplasias/imunologia , Receptores de Antígenos Quiméricos/genética , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
12.
Med Sci Monit ; 26: e919150, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32052794

RESUMO

BACKGROUND Myasthenia gravis (MG) is a progressive autoimmune disorder caused by the production of antibodies directed against acetylcholine receptors (AChRs), resulting in muscle weakness and fatigue. This study aimed to explore the effect and mechanism of grilled nux vomica (GNV) in experimental autoimmune myasthenia gravis (EAMG) rats. MATERIAL AND METHODS Rat 97-116 peptides were used to mediate disease in the EAMG model in SPF female Lewis rats. The treatment groups received grilled nux vomica (75 mg/kg, 150 mg/kg, and 225 mg/kg). The autoantibody and inflammatory cytokines levels were measured by enzyme-linked immunosorbent assay (ELISA). RNA profiling was performed on high-dose and model group rats. Profiling results and TLR-4/NF-kappaB signaling were validated by q-PCR and Western blot analysis. RESULTS The results showed that GNV could attenuate the symptoms of EAMG rats. There was a decreased level of AChR-ab, IFN-γ, TNF-alpha, IL-2, IL-4, and IL-17 levels, and an increased level of TGF-ß1. In total, 235 differentially expressed genes (DEGs), consisting of 175 upregulated DEGs and 60 downregulated DEGs, were identified. Functional annotation demonstrated that DEGs were largely associated with leukocyte cell-cell adhesion, NF-kappa B signaling pathway, muscle contraction, and cardiac muscle contraction pathway. Rac2, Itgb2, Lcp2, Myl3, and Tnni1 were considered as hub genes with a higher degree value in the protein-protein interaction (PPI) network. The q-PCR and Western blot results of hub genes were consistent with RNA profiles. GNV treatment also significantly reduced the TLR-4 and NF-kappaB p65 protein expression in EAMG rats. CONCLUSIONS These results indicate that grilled nux vomica ameliorates EAMG by depressing the TLR-4/NF-kappaB signaling pathway, and hub genes may serve as potential targets for MG treatment.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Miastenia Gravis Autoimune Experimental/tratamento farmacológico , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Strychnos nux-vomica/química , Animais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Músculo Esquelético/imunologia , Músculo Esquelético/patologia , Miastenia Gravis Autoimune Experimental/imunologia , Miastenia Gravis Autoimune Experimental/patologia , NF-kappa B/metabolismo , RNA-Seq , Ratos , Ratos Endogâmicos Lew , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Organismos Livres de Patógenos Específicos , Receptor 4 Toll-Like/metabolismo
13.
Nat Commun ; 10(1): 2180, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31097707

RESUMO

Most combination therapies are developed based on targets of existing drugs, which only represent a small portion of the human proteome. We introduce a network controllability-based method, OptiCon, for de novo identification of synergistic regulators as candidates for combination therapy. These regulators jointly exert maximal control over deregulated genes but minimal control over unperturbed genes in a disease. Using data from three cancer types, we show that 68% of predicted regulators are either known drug targets or have a critical role in cancer development. Predicted regulators are depleted for known proteins associated with side effects. Predicted synergy is supported by disease-specific and clinically relevant synthetic lethal interactions and experimental validation. A significant portion of genes regulated by synergistic regulators participate in dense interactions between co-regulated subnetworks and contribute to therapy resistance. OptiCon represents a general framework for systemic and de novo identification of synergistic regulators underlying a cellular state transition.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biologia Computacional/métodos , Redes Reguladoras de Genes/efeitos dos fármacos , Neoplasias/genética , Mapas de Interação de Proteínas/efeitos dos fármacos , Células A549 , Algoritmos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Conjuntos de Dados como Assunto , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/genética , Células HEK293 , Humanos , Células MCF-7 , Modelos Genéticos , Terapia de Alvo Molecular/métodos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Mapas de Interação de Proteínas/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
14.
Int J Biol Macromol ; 121: 930-935, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30342137

RESUMO

GP11 had been reported to have effectively anti-tumor activity by improving the immune function in our previous study. To avoid drawbacks of the 5-Fu, GP11 in combination with 5-Fu was investigated in this study. The results demonstrated that such synergism displayed enhance the anti-tumor activity of 5-Fu. Additionally, a strength effect was also observed in regulating immune function of GP11 and 5-Fu simultaneous administration, such as enhancing serum interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-α) secretion, and increasing immune organs weights. Moreover, GP11 could improve the haematological and biochemical parameters deterioration, superoxide dismutase (SOD) activities reduction and malondialdehyde (MDA) levels enhancement in non-immune organs induced by 5-Fu. All these results illustrated that GP11 exhibited attenuated and synergized effect on 5-Fu by improving the immune function. It could be developed as an auxiliary preparation for chemotherapeutic drugs.


Assuntos
Antineoplásicos/farmacologia , Fluoruracila/farmacologia , Polissacarídeos Fúngicos/farmacologia , Grifola/química , Neoplasias/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Interações Medicamentosas , Feminino , Interleucina-2/sangue , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Neoplasias/sangue , Neoplasias/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Superóxidos/metabolismo , Fator de Necrose Tumoral alfa/sangue
15.
Pediatr Blood Cancer ; 65(1)2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28748630

RESUMO

Immunotherapy with the anti-GD2 monoclonal antibody ch14.18, or dinutuximab, represents an important therapeutic advance in the treatment of pediatric high-risk neuroblastoma and is now considered part of standard of care in this patient population. To date, transverse myelitis as a result of dinutuximab therapy has not been reported in clinical trials or in the published literature. We describe three patients with clinical symptoms of transverse myelitis, confirmed via magnetic resonance imaging, shortly following initiation of dinutuximab. All patients were discontinued from dinutuximab treatment and received urgent treatment, with rapid improvement in symptoms and resultant functional recovery.


Assuntos
Anticorpos Monoclonais , Imageamento por Ressonância Magnética , Mielite Transversa , Neuroblastoma , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Mielite Transversa/induzido quimicamente , Mielite Transversa/diagnóstico por imagem , Neuroblastoma/diagnóstico por imagem , Neuroblastoma/tratamento farmacológico
16.
Oncol Lett ; 14(5): 5619-5623, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29113191

RESUMO

The Philadelphia (Ph; BCR-ABL) chromosome originates from a translocation event between chromosomes 9 and 22, and results in the BCR-ABL fusion gene. In chronic myelogenous leukemia (CML), the BCR-ABL gene is mainly coded for by a major breakpoint cluster region (M-bcr, e13a2 and e14a2). However, in some patients, BCR-ABL genes are encoded by a minor (m)-bcr, e1a2, and a micro (µ)-bcr region, e19a2. These transcripts revealed a different clinical course. The present study described a CML patient whose cytogenetics and FISH analyses of bone marrow revealed a karyotype of 46, XY t(9,22) (q34;q11), while the commercial kits of quantitative PCR (qPCR) failed to detect the BCR-ABL fusion gene. Further multiplex Reverse transcription-PCR (RT-PCR) and sequencing analyses identified a rare e14a3 (b3a3) fusion transcript.

17.
Clin Chem Lab Med ; 55(1): 82-90, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27337741

RESUMO

BACKGROUND: In the hematology department, the availability of biomarkers for early detection of infection is difficult to obtain. The present study aimed to compare the diagnostic values of neutrophil CD64 Index, procalcitonin (PCT), interleukin-6 (IL-6) and C-reactive protein (CRP) and to determine whether the combined analysis of these biomarkers offer stronger predictive power in the diagnosis for the infection of febrile patients. METHODS: Neutrophil CD64 Index, PCT, IL-6 and CRP levels were determined in 356 febrile patients in the hematology ward from May 2013 to May 2015. Sensitivity, specificity, positive and negative likelihood ratios, positive and negative predictive values, receiver operating characteristic (ROC) areas under the curve (AUC), and logistic regression analysis were determined to evaluate the diagnostic values of these biomarkers. RESULTS: The levels of the four biomarkers were higher in the infection patients (p<0.001), and the PCT and IL-6 were higher in the patients with positive microbial blood culture (p<0.01). The neutrophil CD64 Index, PCT, IL-6, CRP had AUCs of 0.95, 0.83, 0.75 and 0.73, respectively. The best cut-off value of the neutrophil CD64 Index to detect infections was 5.06, with high specificity (87.5%) and sensitivity (88.4%). Furthermore, neutrophil CD64 Index, PCT and IL-6 offered the best combination of diagnosis with sensitivity of 93.9% and an AUC of 0.95. In addition, the neutrophil CD64 Index may have a special value to assist the physician to diagnose infection in the neutropenic patients with fever. CONCLUSIONS: The neutrophil CD64 Index is useful for early identification of infections in febrile patients in the hematology department. The combined analysis of the CD64 Index, PCT and IL-6 could further improve its sensitivity.


Assuntos
Febre/complicações , Infecções/sangue , Infecções/diagnóstico , Neutrófilos/metabolismo , Receptores de IgG/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Febre/sangue , Humanos , Infecções/complicações , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
J Biol Chem ; 283(23): 15701-8, 2008 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-18390547

RESUMO

The BLAP75 protein combines with the BLM helicase and topoisomerase (Topo) IIIalpha to form an evolutionarily conserved complex, termed the BTB complex, that functions to regulate homologous recombination. BLAP75 binds DNA, associates with both BLM and Topo IIIalpha, and enhances the ability of the BLM-Topo IIIalpha pair to branch migrate the Holliday junction (HJ) or dissolve the double Holliday junction (dHJ) structure to yield non-crossover recombinants. Here we seek to understand the relevance of the biochemical attributes of BLAP75 in HJ processing. With the use of a series of BLAP75 protein fragments, we show that the evolutionarily conserved N-terminal third of BLAP75 mediates complex formation with BLM and Topo IIIalpha and that the DNA binding activity resides in the C-terminal third of this novel protein. Interestingly, the N-terminal third of BLAP75 is just as adept as the full-length protein in the promotion of dHJ dissolution and HJ unwinding by BLM-Topo IIIalpha. Thus, the BLAP75 DNA binding activity is dispensable for the ability of the BTB complex to process the HJ in vitro. Lastly, we show that a BLAP75 point mutant (K166A), defective in Topo IIIalpha interaction, is unable to promote dHJ dissolution and HJ unwinding by BLM-Topo IIIalpha. This result provides proof that the functional integrity of the BTB complex is contingent upon the interaction of BLAP75 with Topo IIIalpha.


Assuntos
Adenosina Trifosfatases/metabolismo , Proteínas de Transporte/metabolismo , DNA Helicases/metabolismo , DNA Topoisomerases Tipo I/metabolismo , DNA Cruciforme/metabolismo , Complexos Multienzimáticos/metabolismo , Proteínas Nucleares/metabolismo , Adenosina Trifosfatases/química , Adenosina Trifosfatases/genética , Substituição de Aminoácidos , Proteínas de Transporte/química , Proteínas de Transporte/genética , DNA Helicases/química , DNA Helicases/genética , DNA Topoisomerases Tipo I/química , DNA Topoisomerases Tipo I/genética , DNA Cruciforme/química , DNA Cruciforme/genética , Proteínas de Ligação a DNA , Humanos , Complexos Multienzimáticos/química , Complexos Multienzimáticos/genética , Proteínas Nucleares/química , Proteínas Nucleares/genética , Mutação Puntual , RecQ Helicases
19.
Endocrinology ; 145(1): 367-83, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14576179

RESUMO

Adiponectin is a plasma protein expressed exclusively in adipose tissue. Adiponectin levels are linked to insulin sensitivity, but a direct effect of chronically elevated adiponectin on improved insulin sensitivity has not yet been demonstrated. We identified a dominant mutation in the collagenous domain of adiponectin that elevated circulating adiponectin values in mice by 3-fold. Adiponectinemia raised lipid clearance and lipoprotein lipase activity, and suppressed insulin-mediated endogenous glucose production. The induction of adiponectin during puberty and the sexual dimorphism in adult adiponectin values were preserved in these transgenic animals. As a result of elevated adiponectin, serum PRL values and brown adipose mass both increased. The effects on carbohydrate and lipid metabolism were associated with elevated phosphorylation of 5'-AMP-activated protein kinase in liver and elevated expression of peroxisomal proliferator-activated receptor gamma2, caveolin-1, and mitochondrial markers in white adipose tissue. These studies strongly suggest that increasing endogenous adiponectin levels has direct effects on insulin sensitivity and may induce similar physiological responses as prolonged treatment with peroxisomal proliferator-activated receptor gamma agonists.


Assuntos
Resistência à Insulina , Peptídeos e Proteínas de Sinalização Intercelular , Proteínas/genética , Proteínas/metabolismo , Células 3T3-L1 , Adipócitos/citologia , Adiponectina , Tecido Adiposo/anatomia & histologia , Tecido Adiposo/metabolismo , Animais , Composição Corporal , Calorimetria Indireta , Colágeno/genética , Ingestão de Alimentos , Feminino , Deleção de Genes , Regulação da Expressão Gênica no Desenvolvimento , Técnica Clamp de Glucose , Intolerância à Glucose/metabolismo , Camundongos , Camundongos Transgênicos , Prolactina/sangue , Estrutura Terciária de Proteína , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Transcrição Gênica
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA