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2.
Front Immunol ; 15: 1363454, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38487536

RESUMEN

Pediatric hepatoblastoma (HB) is the most common primary liver malignancy in infants and children. With great diversity and plasticity, tumor-infiltrating neutrophils were one of the most determining factors for poor prognosis in many malignant tumors. In this study, through bulk RNA sequencing for sorted blood and tumor-infiltrated neutrophils and comparison of neutrophils in tumor and para-tumor tissue by single-cell sequencing, we found that intratumoral neutrophils were composed of heterogenous functional populations at different development stages. Our study showed that terminally differentiated neutrophils with active ferroptosis prevailed in tumor tissue, whereas, in para-tumor, pre-fate naïve neutrophils were dominant and ferroptotic neutrophils dispersed in a broad spectrum of cell maturation. Gene profiling and in vitro T-cell coculture experiment confirmed that one of main functional intratumoral neutrophils was mainly immunosuppressive, which relied on the activation of ferroptosis. Combining the bulk RNA-seq, scRNA-seq data, and immunochemistry staining of tumor samples, CXCL12/CXCR4 chemotaxis pathway was suggested to mediate the migration of neutrophils in tumors as CXCR4 highly expressed by intratumoral neutrophils and its ligand CXCL12 expressed much higher level in tumor than that in para-tumor. Moreover, our study pinpointed that infiltrated CXCR4hi neutrophils, regardless of their differential distribution of cell maturation status in HB tumor and para-tumor regions, were the genuine perpetrators for immune suppression. Our data characterized the ferroptosis-dependent immunosuppression energized by intratumoral CXCR4 expression neutrophils and suggest a potential cell target for cancer immunotherapies.


Asunto(s)
Hepatoblastoma , Neoplasias Hepáticas , Lactante , Niño , Humanos , Neutrófilos , Hepatoblastoma/genética , Hepatoblastoma/metabolismo , Hepatoblastoma/patología , Transducción de Señal , Quimiotaxis , Neoplasias Hepáticas/patología , Receptores CXCR4/metabolismo
3.
J Clin Immunol ; 43(8): 2165-2180, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37831401

RESUMEN

While most missense mutations of the IKBKG gene typically result in Ectodermal Dysplasia with Immunodeficiency, there have been rare reported instances of missense mutations of the IKBKG gene causing both Incontinentia Pigmenti (IP) and immunodeficiency in female patients. In this study, we described an atypical IP case in a 19-year-old girl, characterized by hyperpigmented and verrucous skin areas over the entire body. Remarkably, she experienced recurrent red papules whenever she had a feverish upper respiratory tract infection. Immunohistochemical staining unveiled a substantial accumulation of CD68+ macrophages alongside the TNF-α positive cells in the dermis tissue of new pustules, with increased apoptotic basal keratinocytes in the epidermis tissue of these lesions. Starting from the age of 8 years old, the patient suffered from severe and sustained chronic respiratory mucous membrane scar hyperplasia and occluded subglottic lumen. In addition to elevated erythrocyte sedimentation rate values, inflammatory cells were observed in the pathologic lesions of endobronchial biopsies and Bronchoalveolar Lavage Fluid (BALF) smear. Further histological analysis revealed a destructive bronchus epithelium integrity with extensive necrosis. Simultaneously, the patient experienced recurrent incomplete intestinal obstructions and lips contracture. The patient's BALF sample displayed an augmented profile of proinflammatory cytokines and chemokines, suggesting a potential link to systemic hyperinflammation, possibly underlying the pathogenic injuries affecting the subglottic, respiratory, and digestive systems. Furthermore, the patient presented with recurrent pneumonias and multiple warts accompanied by a T+BlowNKlow immunophenotype. Next generation sequencing showed that the patient carried a novel de novo germline heterozygous missense mutation in the IKBKG gene (c. 821T>C, p. L274P), located in the highly conserved CC2 domain. TA-cloning sequencing of patient's cDNA yielded 30 mutant transcripts out of 44 clones. In silico analysis indicated that the hydrogen bond present between Ala270 and Leu274 in the wild-type NEMO was disrupted by the Leu274Pro mutation. However, this mutation did not affect NEMO expression in peripheral blood mononuclear cells (PBMCs). Moreover, patient PBMCs exhibited significantly impaired TNF-α production following Lipopolysaccharide (LPS) stimulation. X-chromosome inactivation in T cells and neutrophils were not severely skewed. Reduced levels of IκBα phosphorylation and degradation in patient's PBMCs were observed. The NF-κB luciferase reporter assay conducted using IKBKG-deficient HEK293T cells revealed a significant reduction in NF-kB activity upon LPS stimulation. These findings adds to the ever-growing knowledge on female IP that might contribute to the better understanding of this challenging disorder.


Asunto(s)
Síndromes de Inmunodeficiencia , Incontinencia Pigmentaria , Niño , Femenino , Humanos , Adulto Joven , Células HEK293 , Quinasa I-kappa B/genética , Incontinencia Pigmentaria/diagnóstico , Incontinencia Pigmentaria/genética , Leucocitos Mononucleares , Lipopolisacáridos , Mutación Missense , Factor de Necrosis Tumoral alfa
4.
J Transl Med ; 21(1): 500, 2023 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-37491263

RESUMEN

BACKGROUND: Oncolytic virotherapy (OVT) is a promising anti-tumor modality that utilizes oncolytic viruses (OVs) to preferentially attack cancers rather than normal tissues. With the understanding particularly in the characteristics of viruses and tumor cells, numerous innovative OVs have been engineered to conquer cancers, such as Talimogene Laherparepvec (T-VEC) and tasadenoturev (DNX-2401). However, the therapeutic safety and efficacy must be further optimized and balanced to ensure the superior safe and efficient OVT in clinics, and reasonable combination therapy strategies are also important challenges worthy to be explored. MAIN BODY: Here we provided a critical review of the development history and status of OVT, emphasizing the mechanisms of enhancing both safety and efficacy. We propose that oncolytic virotherapy has evolved into the fourth generation as tumor immunotherapy. Particularly, to arouse T cells by designing OVs expressing bi-specific T cell activator (BiTA) is a promising strategy of killing two birds with one stone. Amazing combination of therapeutic strategies of OVs and immune cells confers immense potential for managing cancers. Moreover, the attractive preclinical OVT addressed recently, and the OVT in clinical trials were systematically reviewed. CONCLUSION: OVs, which are advancing into clinical trials, are being envisioned as the frontier clinical anti-tumor agents coming soon.


Asunto(s)
Melanoma , Neoplasias , Viroterapia Oncolítica , Virus Oncolíticos , Humanos , Melanoma/terapia , Neoplasias/terapia , Inmunoterapia , Terapia Combinada
5.
Scand J Immunol ; 97(4): e13256, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37401643

RESUMEN

B cell expansion with NF-κB and T cell anergy (BENTA) is a disease genetically linked with heterozygous gain-of-function (GOF) mutations in the CARD11 gene with an autosomal dominant expression. Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous group of disorders characterized by systemic inflammation and hypercytokinaemia. Some BENTA patients share similar clinical manifestations as HLH in various aspects, including fever and splenomegaly. In this study, we reported a 15-month-old boy diagnosed as BENTA meeting with diagnostic criteria of HLH. The complications were resolved by antibiotics for controlling severe infection, together with the reduced format of dexamethasone and etoposide for subsiding HLH activities. While the patient was not subjected to disease recurrence and maintained free of infection, a persistent lymphocytosis derived mainly from the expansion of polyclonal B cells was ascertained. Flow cytometry analysis indicated that the subdued degranulation of NK cells prior to treatment had been restored as the HLH-related complications waned. With largely reduced number and ratios in CD4 and CD8 T cells, their proliferation and Vß diversity remained in normal ranges. In vitro stimulation experiment revealed a functional abbreviation of T cells as the percentage of IFNγ-releasing CD3+CD4+ T cells augmented while the percentage reduced in CD3+CD4- T cells. Whole exome sequencing revealed a de novo G123D missense mutation in the CARD11 gene. This new case of BENTA showcased a scenario of predominant HLH activities accompanied by a severe infection normally associated with BENTA. In addition, a brief treatment quenching HLH complication in cooperation with antibiotics for infection control was not able to solve the underlined T cell abnormality as well as B cell expansion caused by CARD11 mutation. A haematopoietic stem cell transplantation or gene therapy is still a pursuit to remedy this inborn error of immunity.


Asunto(s)
Linfohistiocitosis Hemofagocítica , FN-kappa B , Humanos , Lactante , Masculino , Linfocitos T CD8-positivos/metabolismo , Proliferación Celular , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/genética , Mutación , FN-kappa B/metabolismo
6.
Clin Immunol ; 250: 109322, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37024023

RESUMEN

NK cells are one of key immune components in neuroblastoma (NB) surveillance and eradication. Glucose metabolism as a major source of fuel for NK activation is exquisitely regulated. Our data revealed a diminished NK activation and a disproportionally augmented CD56bright subset in NB. Further study showed that NK cells in NB presented with an arrested glycolysis accompanied by an elevated expression of the long noncoding RNA (lncRNA) EPB41L4A-AS1, a known crucial participant in glycolysis regulation, in the CD56bright NK subset. The inhibitory function of lncRNA EPB41L4A-AS1 was recapitulated. Interestingly, our study demonstrated that exosomal lncRNA EPB41L4A-AS1 was transferrable from CD56bright NK to CD56dim NK and was able to quench the glycolysis of target NK. Our data demonstrated that an arrested glycolysis in patient NK cells was associated with an elevated lncRNA in CD56bright NK subset and a cross-talk between heterogeneous NK subsets was achieved by transferring metabolic inhibitory lncRNA through exosomes.


Asunto(s)
Exosomas , Neuroblastoma , ARN Largo no Codificante , Humanos , Antígeno CD56 , Exosomas/metabolismo , Glucólisis , Células Asesinas Naturales , Neuroblastoma/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo
7.
Acta Biochim Biophys Sin (Shanghai) ; 55(3): 356-366, 2023 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-36916296

RESUMEN

Neuroblastoma (NB) is a pediatric cancer of the peripheral sympathetic nervous system and represents the most frequent solid malignancy in infants. Nectin2 belongs to the immunoglobulin superfamily and has been shown to play a role in tumorigenesis. In the current study, we demonstrate that serum Nectin2 level is increased in NB patients compared with that in healthy controls and Nectin2 level is correlated with neuroblastoma international neuroblastoma staging system (INSS) classification. There is a positive correlation between Nectin2 level and shorter overall survival in NB patients. Knockdown of Nectin2 reduces the migration of SH-SY5Y and SK-N-BE2 cells and induces their apoptosis and cell cycle arrest. RNA-seq analysis demonstrates that Nectin2 knockdown affects the expressions of 258 genes, including 240 that are upregulated and 18 that are downregulated compared with negative controls. qRT-PCR and western blot analysis confirm that ANXA2 expression is decreased in Nectin2-knockdown SH-SY5Y cells, consistent with the RNA-seq results. ANXA2 overexpression rescues the percentage of apoptotic NB cells induced by Nectin2 knockdown and compensates for the impact of Nectin2 knockdown on cleaved caspase3 and bax expressions. In addition, western blot analysis results show that ANXA2 overexpression rescues the effect of Nectin2 knockdown on MMP2 and MMP9 expressions. The current data highlight the importance of Nectin2 in NB progression and the potential of Nectin2 as a novel candidate target for gene therapy.


Asunto(s)
Anexina A2 , Neuroblastoma , Niño , Humanos , Lactante , Anexina A2/genética , Anexina A2/metabolismo , Anexina A2/farmacología , Apoptosis/genética , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patología
8.
J Virol ; 96(19): e0094622, 2022 10 12.
Artículo en Inglés | MEDLINE | ID: mdl-36154611

RESUMEN

Laryngopharynx epithelium neoplasia induced by HPV6/11 infection in juvenile-onset recurrent respiratory papillomatosis (JO-RRP) causes a great health issue characteristic of frequent relapse and aggressive disease progression. Local cell-mediated immunity shaped by the recruitment and activation of cytotoxic effector cells is critical for viral clearance. In this study, we found that NK cells in the papillomas of aggressive JO-RRP patients, in contrast to massive infiltrated T cells, were scarce in number and impaired in activation and cytotoxicity as they were in peripheral blood. Data from cell infiltration analysis indicated that the migration of NK cell to papilloma was restricted in aggressive JO-RRP patients. Further study showed that the skewed chemokine expression in the papillomas and elevated ICAM-1 expression in hyperplastic epithelia cells favored the T cell but not NK cell recruitment in aggressive JO-RRP patients. In parallel to the increased CD3+ T cells, we observed a dramatical increase in Tregs and Treg-promoting cytokines such as IL-4, IL-10 and TGFß in papillomas of aggressive JO-RRP patients. Our study suggested that likely initialized by the intrinsic change in neoplastic epithelial cells with persistent HPV infection, the aggressive papillomas built an entry barrier for NK cell infiltration and formed an immunosuppressive clump to fend off the immune attack from intra-papillomas NK cells. IMPORTANCE Frequent relapse and aggressive disease progression of juvenile-onset recurrent respiratory papillomatosis (JO-RRP) pose a great challenge to the complete remission of HPV 6/11 related laryngeal neoplasia. Local immune responses in papillomas are more relevant to the disease control considering the locale infected restriction of HPV virus in epitheliums. In our study, the restricted NK cell number and reduced expression of activating NKp30 receptor suggested one possible mechanism underlying impaired NK cell defense ability in aggressive JO-RRP papillomas. Meanwhile, the negative impact of HPV persistent infection on NK cell number and function represented yet another example of a chronic pathogen subverting NK cell behavior, affirming a potentially important role for NK cells in viral containment. Further, the skewed chemokine/cytokine expression in the papillomas and the elevated adhesion molecules expression in hyperplastic epithelia cells provided important clues for understanding blocked infiltration and antiviral dysfunction of NK cells in papilloma.


Asunto(s)
Células Asesinas Naturales , Papiloma , Infecciones por Papillomavirus , Infecciones del Sistema Respiratorio , Progresión de la Enfermedad , Papillomavirus Humano 11 , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , Interleucina-10/inmunología , Interleucina-4/inmunología , Células Asesinas Naturales/inmunología , Receptor 3 Gatillante de la Citotoxidad Natural/metabolismo , Recurrencia Local de Neoplasia , Papiloma/inmunología , Papiloma/virología , Infecciones por Papillomavirus/inmunología , Infecciones del Sistema Respiratorio/inmunología , Infecciones del Sistema Respiratorio/virología , Factor de Crecimiento Transformador beta/inmunología
9.
Cancers (Basel) ; 14(14)2022 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-35884407

RESUMEN

Neuroblastoma is the most common extracranial solid tumor in children. Tumor metastasis in high-risk NB patients is an essential problem that impairs the survival of patients. In this study, we aimed to use a comprehensive bioinformatics analysis to identify differentially expressed genes between NB and control cells, and to explore novel prognostic markers or treatment targets in tumors. In this way, FN1, PIK3R5, LPAR6 and LPAR1 were screened out via KEGG, GO and PPI network analysis, and we verified the expression and function of LPAR1 experimentally. Our research verified the decreased expression of LPAR1 in NB cells, and the tumor migration inhibitory effects of LPA on NB cells via LPAR1. Moreover, knockdown of LPAR1 promoted NB cell migration and abolished the migration-inhibitory effects mediated by LPA-LPAR1. The tumor-suppressing effects of the LPA-LPAR1 axis suggest that LPAR1 might be a potential target for future treatment of NB.

10.
Clin Immunol ; 241: 109046, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35644521

RESUMEN

Immunologic dysfunction is one of the most important mechanisms underlying the initiation and development of JORRP. The study aimed to explore whether HPV-specific T-cell response was impaired in JORRP patients. We found JORRP patients had a Th2-biased cytokine profile correlated with disease severity in peripheral system. JORRP patients had an increased memory T cells and a reduced naive T cells in circulation. Upon HPV6/11 antigens stimulation, T cells from JORRP patients exhibited a greater activation profile. Of note, JORRP patients presented with a greater number of IL-10- and IL-4-secreting HPV6/11 antigen responding cells than that of IFN-γ and TNF-α secreting responders. Furthermore, in response to HPV6/11 antigen stimulation, JORRP patients showed a reduced level of cell proliferation, an increased level of apoptosis and higher percentage of the differentiated T cells expressing the replicative senescent cell marker CD57. Impaired HPV-specific T-cell responses could be partly responsible for JORRP development.


Asunto(s)
Infecciones por Papillomavirus , Infecciones del Sistema Respiratorio , Humanos , Infecciones por Papillomavirus/complicaciones , Linfocitos T
11.
Front Immunol ; 13: 843247, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35693824

RESUMEN

Background: Tic disorder is a neurodevelopmental disorder characterized by motor and phonic tic symptoms. Tourette syndrome (TS) is a subtype of tic disorder that shows more persistent tic symptoms. The etiological mechanism of TS concerning immune dysfunction remains unclear due to limited evidence, especially for pediatric TS patients. Method: In the present study, a meta-analysis was performed to confirm the identified changes in proinflammatory cytokines and T cells of pediatric TS patients. A total of five databases, including PubMed, Web of Science, PsycINFO, Google Scholar and the China National Knowledge Infrastructure (CNKI), were used for the literature search. The standardized mean difference (SMD) and mean difference (MD) with a 95% confidence interval (CI) were used to present the effect size of each type of proinflammatory cytokine and T cell. Sensitivity analysis, subgroup analysis and meta-regression analysis were used to explore the heterogeneity of the meta-analysis. This meta-analysis was registered in the International Platform of Registered Systematic Review and Meta-analysis Protocols (number: INPLASY2021110079). Results: In the 25 studies included in this meta-analysis, thirteen studies focused on the levels of T cells, and twelve studies focused on the levels of proinflammatory cytokines. Based on the random-effects model, the pooled MDs are -1.45 (95% CI: -3.44, 0.54) for CD3 cells, -4.44 (95% CI: -6.80, -2.08) for CD4 cells, and 1.94 (95% CI: -0.08, 3.97) for CD8 cells. The pooled SMDs are1.36 for IL-6 (95% CI: 0.00, 2.72) and 2.39 for tumor necrosis factor alpha (TNF-α) (95% CI: 0.93, 3.84). Conclusion: We provided evidence of immune dysfunction in pediatric TS patients, with elevated levels of particular proinflammatory cytokines and disproportionate changes in T-cell subpopulations. Small to large effect sizes were identified for increased IL-6 levels as well as a reduced number of T helper cells, while a large effect size was identified for increased TNF-α levels. These results indicate a close association between peripheral immune activation and TS. However, the most direct and meaningful interaction between peripheral immune status and microglial activation in the central nervous system in TS patients requires further exploration.


Asunto(s)
Citocinas , Linfocitos T , Síndrome de Tourette , Niño , Citocinas/inmunología , Humanos , Interleucina-6 , Linfocitos T/inmunología , Síndrome de Tourette/inmunología , Factor de Necrosis Tumoral alfa
12.
Immunol Lett ; 248: 16-25, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35691410

RESUMEN

T-cell exhaustion is one of the key reasons for attenuated T-cell cytotoxicity against tumours. At both the expression and epigenetic levels, a number of genes, including the transcription factor TOX, are believed to be implicated in regulating T-cell exhaustion. In the present study, we found that in NB patients, the ratio of exhausted T cells, featuring upregulated PD-1 and Tim-3, was increased. Meanwhile, the expression of inhibitory surface receptors, including Lag-3, CD160, VISTA and KLRG1, was also increased, but this was accompanied by a reduced ability to release the effector molecules IL-2, IFN-γ, TNF-α and Granzyme B in CD3+ T cells from NB patients. It is noteworthy that NB-derived memory T cells (Tm) showed more obvious exhausted characteristics than other T cells. Moreover, the T cells from NB patients possessed a higher potential for exhaustion conversion upon in vitro TCR stimulation in our time-course culture experiment. In NB patients, T-cell exhaustion was demonstrated to correlate with the elevated expression of TOX in freshly sorted CD3+ T cells as well as in anti-CD3 stimulated PBMCs. Most importantly, our data supported the idea that the hypomethylation of the TOX promoter may be one of the initiators that regulates TOX expression and enables TOX to play a crucial role in T-cell exhaustion reprogramming in NB patients.


Asunto(s)
Proteínas del Grupo de Alta Movilidad/metabolismo , Neuroblastoma , Factores de Transcripción , Linfocitos T CD8-positivos/patología , Regulación de la Expresión Génica , Humanos , Neuroblastoma/genética , Neuroblastoma/patología , Factores de Transcripción/genética
13.
Cell Death Discov ; 8(1): 139, 2022 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-35351861

RESUMEN

Neuroblastoma (NB) is the most common extracranial solid tumor and the treatment efficacy of high-risk NB is unsatisfactory. γδT-cell-based adoptive cell transfer is a promising approach for high-risk NB treatment. Our previous study has revealed that γδT cells in NB patients exhibit a poor proliferation activity and a decreased anti-tumor capacity in vitro. In the present study, we found that IL-15 could effectively enhance the proliferation of NB γδT cells, to a level that remains lower than healthy controls though. In addition, IL-15-fostered NB γδT cells robustly boosted cell survival against apoptosis induced by cytokines depletion. Our data revealed that Mcl-1 was a key anti-apoptotic protein in IL-15-fostered γδT cells during cytokine withdrawal and its expression was regulated via the activation of STAT5 and ERK. In addition, IL-2 and IL-15-fostered γδT cells harbored higher levels of tumoricidal capacity which is also beneficial for γδ T-cell based immune therapy in NB. Understanding the survival control of γδT cells in a sub-optimal cytokine supportive microenvironment will expedite the clinical application of γδT cells for immunotherapy.

14.
Front Pediatr ; 10: 1014249, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36741091

RESUMEN

Background: DiGeorge Syndrome (DGS) is a rare disease associated with 22q11.2 chromosomal microdeletion, also known as a velocardiofacial syndrome, based on the frequent involvements of the palate, facial, and heart problems. Hematologic autoimmunity is rare in DGS but presents with a refractory course and poor prognosis. Herein, we report a case of partial DGS in a patient with refractory immune cytopenia and autoimmune lymphoproliferative syndrome (ALPS)-like manifestations. Case description: A 10-year-old boy with growth retardation presented initially with a ventricular septal defect at 7 months old, which had been repaired soon after. The patient suffered from thrombocytopenia and progressed into chronic refractory immune thrombocytopenia (ITP) at 30 months old. One year later, the patient developed multilineage cytopenias including thrombocytopenia, neutropenia, and anemia. First-line treatment of ITP, like high-dose dexamethasone and intravenous immunoglobulin, had little or short-term effect on controlling symptoms. Whole-exome sequencing revealed the presence of a de novo heterozygous 2.520 Mb deletion on chromosome 22q11.21. Moreover, decreased proportion of naive T cells and elevated double-negative T cells were found. The patient was given sirolimus therapy (1.5 mg/m2, actual blood concentration range: 4.0-5.2 ng/ml) without adding other immunosuppressive agents. The whole blood cell count was gradually restored after a month, and the disease severity was soothed with less frequency of infections and bleeding events. Decreased spleen size and restrained lymph node expansion were achieved after 3-month sirolimus monotherapy. Conclusions: This case is the first description on the efficacy of sirolimus monotherapy to treat refractory multilineage cytopenias of DGS presented with ALPS-like features.

15.
Pediatr Investig ; 5(2): 106-111, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34179706

RESUMEN

IMPORTANCE: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. More than 90% of cases are classified as embryonic RMS (ERMS) or alveolar RMS (ARMS). ERMS has a worse prognosis than ARMS. Early differential diagnosis is of paramount importance for optimization of treatment. OBJECTIVE: To identify genes that are differentially expressed between ARMS and ERMS, which can be used for accurate rhabdomyosarcoma classification. METHODS: Three Gene Expression Omnibus datasets composed of ARMS and ERMS samples were screened and 35 differentially expressed genes (DEGs) were identified. Receiver operating characteristic curve analysis and area under the curve analysis was performed for these 35 DEGs and seven candidate genes with the best differential expression scores between ARMS and ERMS were determined. The expression of these seven candidate genes was validated by immunohistochemical analysis of pre-chemotherapy ARMS and ERMS specimens. RESULTS: The levels of DCX and CRABP2 were confirmed to be remarkably different between paraffin-embedded ARMS and ERMS tissues, while EGFR abundance was only marginally different between these two RMS subtypes. INTERPRETATION: DCX and CRABP2 are potential biomarkers for distinguishing ARMS from ERMS in pre-chemotherapy pediatric patients.

16.
Clin Immunol ; 222: 108641, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33271370

RESUMEN

The mechanism of the characteristic intermittent hypoxia (IH) of obstructive sleep apnea syndrome (OSAS) on monocyte remain unclear. Our study found that OSAS children had a significantly upregulated expression in circulating proinflammatory cytokines IL-6 and IL-12, and endothelial injury markers VEGF and ICAM1. Association analysis revealed that the plasma TNFα, IL-1ß, IL-6, IL-10 and IL-12 concentration were negatively associated with the minimal SpO2, a negative index for disease severity. OSAS monocytes presented an inflammatory phenotype with higher mRNA levels of inflammatory cytokines. Importantly, we noted a significant decrease in T-cell immunoglobulin and mucin domain (Tim)-3 expression in OSAS monocytes with the increase of the plasma proinflammatory cytokines. In vitro assay demonstrated that IH induced THP-1 cell overactivation via NF-κB dependent pathway was inhibited by the Tim-3 signal. Our results indicated that activation of monocyte inflammatory responses is closely related to OSAS-induced IH, and negatively mediated by a Tim-3 signaling pathway.


Asunto(s)
Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Hipoxia/patología , Monocitos/metabolismo , Apnea Obstructiva del Sueño/patología , Receptor 2 Celular del Virus de la Hepatitis A/genética , Humanos , Inflamación/inmunología , Molécula 1 de Adhesión Intercelular/sangre , Subunidad p35 de la Interleucina-12/sangre , Interleucina-6/sangre , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/sangre
17.
BMC Immunol ; 21(1): 53, 2020 10 09.
Artículo en Inglés | MEDLINE | ID: mdl-33036556

RESUMEN

BACKGROUND: Henoch-Schonlein purpura (HSP) is the most common systemic vasculitis of the childhood. However, its mechanisms and pathogenesis still need more exploration. Natural killer (NK) cells are innate lymphocytes, and there is a growing appreciation that cellular metabolism is important in determining the immune responsiveness of lymphocytes. Thus, we aimed to analyze the NK cells phenotype and explore the association between glucose metabolism and NK cells function in HSP patients. RESULTS: A total number of 64 HSP patients and 34 healthy children were included. The HSP patients were divided into two groups according to whether accompanied with nephritis or not. NK cells in HSP patients without nephritis showed a reduced frequency in peripheral blood, a down-regulated expression of activating receptors both NKp30 and NKp46, and an attenuated cytotoxic function against tumor cells. In addition, the function impairment of NK cells was shown to exacerbate in HSPN. Our data further revealed an aberrant metabolic reprogramming of NK cells in HSP patients. Upon stimulation with cytokines (IL-15, IL-12 and IL-2), NK cells from healthy controls switched to an elevated glycolysis rate to support their effector function. By contrast, the glycolysis rate of activated NK cells in HSP group was not significantly up-regulated from the resting level possibly owing to the inhibition of mTORC1. CONCLUSIONS: Our study found that HSP patients were accompanied with dysfunction of NK cells. We concluded that the dysfunction of NK cells in HSP patients was induced with a decreased glycolysis rate and suggested that metabolic reprogramming of NK cells might be a player in the pathogenesis of HSP.


Asunto(s)
Glucólisis/fisiología , Vasculitis por IgA/inmunología , Células Asesinas Naturales/inmunología , Células Cultivadas , Reprogramación Celular , Niño , Citocinas/metabolismo , Citotoxicidad Inmunológica , Femenino , Humanos , Vasculitis por IgA/metabolismo , Activación de Linfocitos , Masculino , Receptor 1 Gatillante de la Citotoxidad Natural/metabolismo , Receptor 3 Gatillante de la Citotoxidad Natural/metabolismo , Nefritis
18.
Acta Otolaryngol ; 140(9): 779-784, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32491958

RESUMEN

Background: Aggressive juvenile-onset recurrent respiratory papillomatosis (JORRP) threatens patient lives if not receives immediate surgical intervene. Even with surgical intervene, complete remission of this disease is not approachable. Therefore, understanding the factors relevant to disease severity and prognosis will do help to the treatment strategy and health management of this disease.Objective: This study aimed to explore the clinic, laboratory and socioeconomic characteristics of patients and evaluate the risk factors for aggressive JORRP.Methods: The information of clinical and socioeconomic status of the patients was reviewed and its association with disease severity was analyzed. Papilloma from JORRP patients undergone surgeries was used to determine HPV subtypes by real-time PCR. The profiles of mRNA expression in the papilloma were assessed using microarray.Results: Age at diagnosis and socioeconomic status were shown to associate with the severity of JORRP. There was no differential severity considering different HPV subtype. The mRNA expression of nucleotide binding oligomerization domain receptor protein 3 (NLRP3) and Gasdermin B (GSDMB) was reduced in papillomas.Conclusions: A younger age at diagnosis and low socioeconomic status were associated with the severity of JORRP. mRNA expression of NLRP3 and GSDMB in the papillomas of JORRP patients was significantly reduced.Abbreviation: JORRP: Juvenile-onset recurrent respiratory papillomatosis; RRP: Recurrent respiratory papillomatosis; OSAS: Obstructive sleep apnea syndrome; NLRP3: Nucleotide binding oligomerization domain receptor protein 3; GSDMB: Gasdermin B.


Asunto(s)
Edad de Inicio , Expresión Génica , Infecciones por Papillomavirus , ARN Neoplásico/metabolismo , Infecciones del Sistema Respiratorio , Clase Social , Pueblo Asiatico , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Modelos Logísticos , Masculino , Infecciones por Papillomavirus/genética , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Recurrencia , Infecciones del Sistema Respiratorio/genética , Factores de Riesgo
19.
Thorax ; 75(7): 600-605, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32303624

RESUMEN

Eosinophils are key effector cells in allergic diseases. Here we investigated Mcl-1 (an anti-apoptotic protein) in experimental allergic airway inflammation using transgenic overexpressing human Mcl-1 mice (hMcl-1) and reducing Mcl-1 by a cyclin-dependent kinase inhibitor. Overexpression of Mcl-1 exacerbated allergic airway inflammation, with increased bronchoalveolar lavage fluid cellularity, eosinophil numbers and total protein, and an increase in airway mucus production. Eosinophil apoptosis was suppressed by Mcl-1 overexpression, with this resistance to apoptosis attenuated by cyclin-dependent kinase inhibition which also rescued Mcl-1-exacerbated allergic airway inflammation. We propose that targeting Mcl-1 may be beneficial in treatment of allergic airway disease.


Asunto(s)
Asma/genética , Eosinófilos/patología , Regulación de la Expresión Génica , Hipersensibilidad/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , ARN/genética , Animales , Apoptosis , Asma/metabolismo , Asma/patología , Líquido del Lavado Bronquioalveolar , Modelos Animales de Enfermedad , Eosinófilos/metabolismo , Femenino , Hipersensibilidad/metabolismo , Hipersensibilidad/patología , Recuento de Leucocitos , Ratones , Ratones Transgénicos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/biosíntesis
20.
Clin Immunol ; 211: 108343, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31931123

RESUMEN

Neuroblastoma (NB) is the most common solid extracranial malignancy in children with a considerable chance of metastatic progression. Prevalent evidence supports the anti-tumor role of γδT cells and these cells have been testing in clinical trials for constraining tumor growth. A small subpopulation of γδT cells releasing IL-17, however, were demonstrated to exert tumor-promoting effects in many aspects. In this study, we found an augment of IL-17+ γδT cells both in in vitro PAM-stimulated γδT-cell expanding culture and circulating γδT cells in NB patients. These patient-origin cells expanded in vitro by PAM in the presence of IL-17 polarizing condition were shown to promote the proliferation and migration of NB cells. Furthermore, an intrinsic preference for IL-17 polarization in NB γδT cells was revealed by mRNA microarray and Western Blot, which pointed to an up-regulated expression of multiple Th17-development related genes in addition to an increased phosphorylation level of STAT3.


Asunto(s)
Interleucina-17/inmunología , Linfocitos Intraepiteliales/inmunología , Neuroblastoma/inmunología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Preescolar , Femenino , Humanos , Masculino , Neuroblastoma/patología
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