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1.
BMC Immunol ; 22(1): 19, 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33731004

RESUMO

BACKGROUND: We aimed to report the clinical characteristics, immunological features, and treatment of one patient with a de novo STAT3 gain-of-function mutation identified by next generation sequencing. We investigated the efficacy of tocilizumab therapy in immune dysregulation diseases caused by STAT3 mutation. RESULTS: The patient was a 16-year-old girl. She presented with recurrent respiratory infections and chronic diarrhea after birth. She had life-threatening autoimmune pancytopenia at 14 years old. After receiving glucocorticoid therapy, she developed diabetes. However, her pancytopenia relapsed when the glucocorticoid was tapered. Next-generation sequencing showed a de novo heterozygous mutation in the STAT3 gene, c.1261G > A (p. G421R), which was previously described as a gain-of-function mutation. After tocilizumab therapy, her pancytopenia fully resolved, and insulin and glucocorticoid therapies were gradually discontinued within 12 months. She had lymphopenia and an inverted CD4/CD8 ratio before therapy. Lymphocyte subpopulation analysis indicated an expansion of effector memory CD4+, effector memory CD8+ and central memory CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased. None of the abnormal lymphocytic changes improved significantly. STAT3 GOF mutations were identified by next gene sequencing in those with early-onset multi-organ autoimmunity. Including our patient, 13 patients with STAT3 GOF mutations received targeted treatment. Twelve of them were treated with tocilizumab alone or combination tocilizumab with JAK inhibitor, and ten patients improved. CONCLUSIONS: Gene sequencing should be performed for patients with early-onset refractory or multiorgan immune dysregulation diseases. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.

2.
Sci Total Environ ; 773: 145604, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33592467

RESUMO

This study will help to clarify the relationship between organophosphate pesticides (OPs) and attention deficit/hyperactivity disorder (ADHD) related to oxidative stress and paraoxonases (PON) polymorphisms to further characterize the gene-environment interaction. This case-control study enrolled 85 children with ADHD and 96 control subjects. Urinary OP levels were analyzed by using gas chromatography-mass spectrometry (GC-MS). Oxidative stress biomarkers, such as 8-hydroxy-2-deoxyguanosine (8-OHdG), 8-nitroguanine (8-NO2-Gua), 8-iso-prostaglandin F2α (8-iso-PGF2α), and 4-hydroxy-2-nonenoic acid-mercapturic acid (HNE-MA), were analyzed by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (S) were calculated to evaluate the additive interactions between OP exposure and PON genetic polymorphism on ADHD. A causal mediation analysis was conducted to clarify the mediation effects of oxidative stress due to OP exposure on ADHD. Children with ADHD had significantly higher DMP (238.95 nmol/g cre. vs. 164.83 nmol/g cre., p value = 0.01) and HNE-MA (30.75 µg/g cre. vs. 18.41 µg/g cre., p value<0.01) concentrations than control children. Children who carried the PON1 GG genotype (rs705379) had low urinary DMP levels, and the level increased with increasing numbers of allele variants. The risk for developing ADHD reached 2.06-fold (OR = 2.06, 95% CI:1.23-3.44) and 1.43-fold (OR = 1.45, 95% CI:1.04-2.03) when the DMP and HNE-MA levels increased by 1 natural log of the concentration, respectively. The estimated AP value was 0.66 (95% CI: 0.17-1.15), indicating that 66% of ADHD cases in DMP-exposed children with the PON1 CT/TT (rs705381) genotype were due to gene-environment interactions. No significant mediation of HNE-MA was observed between DMP exposure and the risk of ADHD. The estimated proportion mediated was only 7.0% (95% CI: -0.08-0.46). This research suggests the role of OP exposure in the occurrence of ADHD after adjusting for covariates.


Assuntos
Arildialquilfosfatase , Transtorno do Deficit de Atenção com Hiperatividade , Arildialquilfosfatase/genética , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Estudos de Casos e Controles , Criança , Cromatografia Líquida , Humanos , Organofosfatos/efeitos adversos , Estresse Oxidativo , Polimorfismo Genético , Espectrometria de Massas em Tandem
3.
Neuroimage ; 230: 117791, 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33545348

RESUMO

Mounting evidence shows that brain functions and cognitive states are dynamically changing even in the resting state rather than remaining at a single constant state. Due to the relatively small changes in BOLD (blood-oxygen-level-dependent) signals across tasks, it is difficult to detect the change of cognitive status without requiring prior knowledge of the experimental design. To address this challenge, we present a dynamic graph learning approach to generate an ensemble of subject-specific dynamic graph embeddings, which allows us to use brain networks to disentangle cognitive events more accurately than using raw BOLD signals. The backbone of our method is essentially a representation learning process for projecting BOLD signals into a latent vertex-temporal domain with the greater biological underpinning of brain activities. Specifically, the learned representation domain is jointly formed by (1) a set of harmonic waves that govern the topology of whole-brain functional connectivities and (2) a set of Fourier bases that characterize the temporal dynamics of functional changes. In this regard, our dynamic graph embeddings provide a new methodology to investigate how these self-organized functional fluctuation patterns oscillate along with the evolving cognitive status. We have evaluated our proposed method on both simulated data and working memory task-based fMRI datasets, where our dynamic graph embeddings achieve higher accuracy in detecting multiple cognitive states than other state-of-the-art methods.

4.
Med Phys ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33300143

RESUMO

PURPOSE: Retinal vein occlusion (RVO) is the second most common cause of vision loss after diabetic retinopathy due to retinal vascular disease. Retinal nonperfusion (RNP) identified on fluorescein angiograms (FA) and appearing as hypofluorescence regions, is one of the most significant characteristics of RVO. Quantification of RNP is crucial for assessing the severity and progression of RVO. However, in current clinical practice, it is mostly conducted manually, which is time-consuming, subjective and error-prone. The purpose of this study is to develop fully automated methods for segmentation of RNP using convolutional neural networks (CNNs). METHODS: FA images from 161 patients were analyzed, and RNP areas were annotated by three independent physicians. The optimal method to use multi-physicians' labeled data to train the CNNs was evaluated. An adaptive histogram based data augmentation method was utilized to boost the CNN performance. CNN methods based on context encoder module were developed for automated segmentation of RNP and compared with existing state-of-the-art methods. RESULTS: The proposed methods achieved excellent agreements with physicians for segmentation of RNP in FA images. The CNN performance can be improved significantly by the proposed adaptive histogram based data augmentation method. Using the averaged labels from physicians to train the CNNs achieved the best consensus with all physicians, with a mean accuracy of 0.883±0.166 with 5-fold cross validation. CONCLUSIONS: We reported CNN methods to segment RNP in RVO in FA images. Our work can help improve clinical workflow, and can be useful for further investigating the association between RNP and retinal disease progression, as well as for evaluating the optimal treatments for the management of RVO.

5.
Diagnostics (Basel) ; 10(11)2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33142777

RESUMO

Sarcopenia is common in patients undergoing chronic hemodialysis, which leads to poor outcomes. SARC-F (sluggishness, assistance in walking, rising from a chair, climb stairs, falls), a self-report questionnaire, is recommended as an easily applied tool for screening sarcopenia in older people. However, there are limited data regarding its use in patients undergoing chronic hemodialysis. Therefore, we aimed to evaluate the association between SARC-F and mortality in these patients. SARC-F questionnaire was applied in 271 hemodialysis patients (mean age 64.4 ± 14.3 years) at baseline. The association between SARC-F and mortality during a 24-month follow-up was analyzed. During this follow-up period, 40 patients (14.8%) died. The discriminative power of SARC-F score for predicting mortality was 0.716 (95% confidence interval (CI) = 0.659-0.769; p < 0.001). The best cut-off was a score ≥ 1, which provided 85.0% sensitivity, 47.2% specificity, 21.8% positive predictive value, and 94.8% negative predictive value. Kaplan-Meier curves showed that patients with SARC-F ≥ 1 exhibited a higher risk of mortality than those with SARC-F < 1 (p < 0.001). Moreover, a stepwise decline in survival with higher SARC-F scores was also observed. After full adjustments, SARC-F ≥ 1 was independently associated with increased mortality (hazard ratio = 2.87, 95% CI = 1.11-7.38; p = 0.029). In conclusion, SARC-F applied for sarcopenia screening predicted mortality in patients undergoing chronic hemodialysis.

6.
Fungal Biol ; 124(12): 1052-1057, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33213785

RESUMO

Autophagy is a conserved intracellular recycling mechanism, in which autophagy-related genes 12 and 16 (ATG12 and ATG16) function in a complex controlling the ubiquitin-like conjugation system. In the insect-pathogenic fungus Beauveria bassiana, ATG12 and ATG16 were functionally characterized. Disruption of BbATG12 or BbATG16 resulted in the absence of autophagic bodies under starvation stress. ΔBbATG12 and ΔBbATG16 mutant strains displayed similar defects in asexual development (conidiation and blastospore formation) and tolerance to oxidative stress. ΔBbATG16 strain exhibited the impaired growth on the media with gelatin or chitin as a single nitrogen source, and ΔBbATG12 displayed decreased growth on the media with sucrose, fructose or maltose as a single carbon source. Both BbATG12 and BbATG16 were required for fungal virulence. BbATG16 mutation had more effects on fungal virulence than BbATG12 in topical infection assay, although both genes had similar contributions to fungal virulence in intrahemocoel injection assay. This study indicates that BbATG12 and BbATG16 mediate diverse biological functions in addition to their convergent roles in autophagy.

7.
Virulence ; 11(1): 1352-1365, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33017218

RESUMO

Entomopathogenic fungi naturally infect insect hosts in environment. Fungal invasion and host immune defense are still in the progress of co-evolution. In this study, entomopathogenic fungus Beauveria bassiana and lepidopteran insect Galleria mellonella were used to investigate host cellular immunity and fungal strategy to evade host defense. First of all, genome-wide expression revealed the transcriptomic responses of hemocytes to insect mycopathogen, which dynamically varied during infection process. Enrichment analysis indicated that differentially expressed genes were primarily involved in metabolism, cellular process and immune system. Notably, cellular response involved a series of hydrolytic enzyme and antimicrobial peptide genes which were sorted together in clustering analysis. In B. bassiana, a cell-wall protein gene (BbCwp) contributes to fungal development in host hemocoel and virulence. RT-qPCR analyses indicated that infection by ΔBbCwp mutant strain caused the up-regulated expression of a series of immunity-related genes, including ß-1, 3-glucan recognition protein, hydrolytic enzyme and antimicrobial peptide genes. Disruption of BbCwp resulted in a significant change in conidial lectin-binding feature and the enhanced encapsulation by the host hemocytes. After being treated with hydrolytic enzymes, ΔBbCwp mutant displayed a significantly enhanced sensitivity to osmotic and oxidative stresses. In conclusion, fungal invasion initiates comprehensive physiological responses in the host hemocytes. For mycopathogen, cell-wall protein plays an important role in fungal evasion of immunity defense and colonization in host. Our studies provide an initial framework for exploring more mechanistic details about the fungus-host interaction.

8.
Zootaxa ; 4845(4): zootaxa.4845.4.9, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-33056760

RESUMO

A new species of the genus Misolampidius Solsky, 1875, Misolampidius qiaoweipengi sp. nov. from Henan, China, is described. In addition, supplementary descriptions for Misolampidius tentyrioides Solsky, 1876, M. qianshanensis Li, 1992 and M. satoi Masumoto, Akita Utsunomiya, 2003 are provided.


Assuntos
Besouros , Distribuição Animal , Animais
9.
Ci Ji Yi Xue Za Zhi ; 32(3): 272-277, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32955506

RESUMO

Objective: Adiponectin has antidiabetic, anti-atherosclerotic, and anti-inflammatory functions and protects against vascular damage. Carotid-femoral pulse wave velocity (cfPWV) is a noninvasive method for measuring central artery stiffness, which is known to be associated with cardiovascular disease in peritoneal dialysis (PD) patients. This study was conducted to evaluate the relationship between central arterial stiffness and serum adiponectin levels in PD patients. Materials and Methods: Fasting blood samples were obtained from 60 PD patients, and the cfPWV value was measured using a validated tonometry system. In this study, cfPWV values of >10 m/s were used to define the high arterial stiffness group according to the European Society of Hypertension and the European Society of Cardiology guidelines. Results: Among 60 patients with PD, 19 patients (31.7%) were included in the high arterial stiffness group. When compared to those in the control group, the high arterial stiffness group patients were older (P = 0.029), had longer PD vintage (P = 0.001), higher diastolic blood pressures (P = 0.030), higher fasting glucose (P = 0.014), and lower serum adiponectin levels (P = 0.001). After multivariable logistic regression analysis, serum adiponectin (odds ratio, 0.612; 95% confidence interval: 0.426-0.879; P = 0.008) was identified as an independent predictor of arterial stiffness. The multivariable regression analysis also showed that the adiponectin level (ß = -0.408; adjusted R 2 change = 0.183; P < 0.001) was negatively associated with cfPWV values in patients undergoing PD. Conclusion: Low serum adiponectin level is an independent marker of arterial stiffness in patients undergoing PD.

10.
Artigo em Inglês | MEDLINE | ID: mdl-32944025

RESUMO

Background: Loss-of-function (LOF) mutations in signal transducer and activator of transcription 3 (STAT3) is one of the causes of STAT3 hyperimmunoglobulin E (IgE) syndrome (STAT3-HIES), while gain-of-function (GOF) mutations in STAT3 lead to immune dysregulation diseases. We retrospectively analyzed the age, common clinical symptoms, immunologic and molecular manifestations in 11 patients with LOF STAT3 mutations and 1 patient with a GOF STAT3 mutation. Methods: Twelve patients were enrolled in our study. Serum immunoglobulin measurements, lymphocyte subset detection and whole-exome sequencing were performed. Results: The median age at diagnosis of STAT3-HIES patients was 4.74 years. Eczema, recurrent respiratory infections, fevers, abscesses and Staphylococcus aureus infections were the classic manifestations. Elevated serum IgE levels are not always observed in conjunction with high eosinophil counts. A moderate viral DNA load was also measured in peripheral blood mononuclear cells. We noticed that c. 1144C>T was the most common mutation site, followed by c.1311C>A. Additionally, c.1311C>A and c. 1826G>C are two novel mutations. Eight patients achieved notable improvement after receiving intravenous immunoglobulin. Conclusion: We updated the current knowledge of this topic. We found an earlier median age at diagnosis, a higher survival rate, and a general lack of nonimmunological abnormalities; we also described the treatment details and novel mutations involve in STAT3-HIES and compared STAT3 LOF and GOF mutations.

11.
Biomed Res Int ; 2020: 1840415, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32934956

RESUMO

Cutaneous melanoma (CM) is known as an aggressive malignant cancer; some of which are directly derived from melanocytic nevi, which have been attracting growing attention from the last decades. This study focused on comprehensive identification, validation, and functional annotations of prognostic differentially expressed genes (DEGs) between melanocytic nevus and malignant melanoma in genome-wide profiles. DEGs were obtained using three chip datasets from GEO database to identify after standardization annotation. A total of 73 DEGs were identified as possible candidate prognostic biomarkers between melanocytic nevus and malignant melanoma. In addition, survival curves indicated that six hub genes, including FABP5, IVL, KRT6A, KRT15, KRT16, and TIMP2, were significant prognostic signatures for CM and of significant value to predict transformation from nevi to melanoma. Furthermore, immunohistochemistry staining was performed to validate differential expression levels and prognostic implications of six hub genes between CM tissue and nevus tissues from the First Affiliated Hospital of Soochow University cohort. It suggested that significantly elevated FABP5, IVL, KRT6A, KRT15, KRT16, and TIMP2 proteins expressed in the CM than in the nevus tissues. Functional enrichment and significant pathways of the six significant hub genes indicated that the mostly involved hallmarks include the P53 pathway, K-ras signaling, estrogen response late, and estrogen response early. In summary, this study identified significant DEGs participating in the process of malignant transformation from nevus to melanoma tissues based on comprehensive genomic profiles. Transcription profiles of FABP5, IVL, KRT6A, KRT15, KRT16, and TIMP2 provided clues of prognostic implications, which might help us evaluate malignant potential of nevus and underlying carcinogenesis progress from melanocytic nevus to melanoma.

12.
Front Pediatr ; 8: 402, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32793529

RESUMO

Dermatological disorders are the most common extrapulmonary complications of Mycoplasma pneumoniae, of which Mycoplasma-induced rash and mucositis (MIRM) has recently been proposed to be a separate diagnostic entity. MIRM could easily be misdiagnosed as atypical Stevens-Johnson syndrome by clinicians due to the unawareness of this rare disease. We retrospectively reviewed the inpatient database from Jan. 2016 to Dec. 2019 of the Children's Hospital of Fudan University. In total, five patients (mean age 5.5 years, three male) matched the diagnostic criteria of MIRM. All patients had scattered lesions and more than two sites of mucosal involvement. The serum IgA level of three patients was higher than normal. Two patients had a significant decrease in peripheral blood CD3+ T and CD4+ T cells that improved with recovery. The percentage of TCRαß+ CD4-CD8-T cells of Patient five was higher than normal. All patients received treatments with antibiotics and corticosteroids, 3 patients received intravenous immunoglobulin. Among five patients, three patients complained of dyspigmentation, and two patients had an uneventful recovery. MIRM is a separate entity with predominant mucosal involvement and excellent prognosis that more often affects younger patients. Excessive inflammatory reactions may lead to immune disorders, including lymphopenia and a redistribution of CD4+ T cells. We recommend that pneumonia accompanied by mucocutaneous eruptions, especially in young patients, should raise clinical suspicion of MIRM.

13.
Pathol Res Pract ; 216(9): 153103, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32825967

RESUMO

BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) accounts for about 85%-90% of all cases of laryngeal cancer. So far, the role and molecular mechanism of circular RNA 0,000,218 (circ_0000218)/microRNA (miR)-139-3p in laryngeal cancer are not clear. The present study aimed to investigate the role and regulatory mechanism of circ_0000218/miR-139-3p in laryngeal cancerin vitro and in vivo. METHODS: quantitative real time polymerase chain reaction (qRT-PCR) was used to detect the expression of circ_0000218/miR-139-3p in LSCC cells. Dual luciferase reporter assay and RNA immunoprecipitation (RIP) assay were used to confirm binding sites between miR-139-3p and smad family member 3 (Smad3), and circ_0000218 and miR-139-3p. Cell Counting Kit-8 (CCK-8) and cell apoptosis analysis were used to detect cell viability and apoptosis. Xenograft experiment was performed to show in vivo effect of circ_0000218/miR-139-3p on the growth of LSCC. RESULTS: Circ_0000218 was highly expressed in LSCC cells. miR-139-3p, lower expressed in LSCC cells, was negatively regulated by circ_0000218 in LSCC cells. Besides, the findings suggested that circ_0000218 silencing inhibited the LSCC cell viability and promoted apoptosis by negatively regulating miR-139-3p expression. Furthermore, the data indicated that miR-139-3p inhibited the viability of LSCC cells and promoted apoptosis, and these effects were reversed by Smad3 over-expression. In addition, the in vivo effects of circ_0000218/miR-139-3p on LSCC were consistent with the in vitro study. CONCLUSIONS: circ_0000218 inhibition inhibited the growth of LSCC by targeting miR-139-3p/Smad3 axis. Our present study provided a new target for laryngeal cancer treatment.

14.
Front Genet ; 11: 899, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849853

RESUMO

Malignant pleural mesothelioma (MPM), predominantly caused by asbestos exposure, is a highly aggressive cancer with poor prognosis. The staging systems currently used in clinics is inadequate in evaluating the prognosis of MPM. In this study, a five-gene signature was developed and enrolled into a prognostic risk score model by LASSO Cox regression analysis based on two expression profiling datasets (GSE2549 and GSE51024) from Gene Expression Omnibus (GEO). The five-gene signature was further validated using the Cancer Genome Atlas (TCGA) MPM dataset. Univariate and multivariate Cox analyses proved that the five-gene signature was an independent prognostic factor for MPM. The signature remained statistically significant upon stratification by Brigham stage, AJCC stage, gender, tumor size, and lymph node status. Time-dependent receiver operating characteristic (ROC) curve indicated good performance of our model in predicting 1- and 2-years overall survival in MPM patients. The C-index was 0.784 for GSE2549 and 0.753 for the TCGA dataset showing moderate predictive accuracy of our model. Furthermore, Gene Set Enrichment Analysis suggested that the five-gene signature was related to pathways resulting in MPM tumor progression. Together, we have established a five-gene signature significantly associated with prognosis in MPM patients. Hence, the five-genes signature may serve as a potentially useful prognostic tool for MPM patients.

15.
Nutrients ; 12(7)2020 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-32708072

RESUMO

Circulating malondialdehyde-modified low-density lipoprotein (MDA-LDL) acts as a marker of oxidative stress and is associated with atherosclerotic cardiovascular disease. The relationship between serum MDA-LDL levels and aortic stiffness (AS) in patients with hemodialysis (HD) was evaluated. There were 155 HD patients enrolled in this study. Carotid-femoral pulse wave velocity (cfPWV) was measured by a validated tonometry system. Patients with cfPWV >10 m/s were used to define the AS group, while those with values of ≤10 m/s were regarded as the control group. Serum MDA-LDL levels were measured using a commercial enzyme-linked immunosorbent assay. Sixty-eight patients (43.9%) who were defined as AS sufferers, and were older, had a higher percentage of diabetes and hypertension and higher systolic blood pressure and serum MDA-LDL level compared to subjects in the control group. After adjusting for factors significantly associated with AS by multivariable logistic regression analysis, it was revealed that serum MDA-LDL levels, diabetes, and hypertension were independent predictors of AS in HD patients. Multivariable forward stepwise linear regression analysis also showed that a logarithmically transformed MDA-LDL level was significantly correlated with cfPWV values in HD patients. In HD patients, a high serum MDA-LDL level was positively associated with cfPWV values and was a significant predictor of the development of high AS.

16.
Front Immunol ; 11: 723, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32411140

RESUMO

Chronic obstructive pulmonary disease (COPD) is a complex chronic disease in which T cell-mediated pulmonary inflammation has been shown to play a key role. Accumulating evidence shows that COPD has many of the characteristics of an autoimmune response. An adaptive immune response directed against lung self-antigens, which are released during the initial innate inflammatory response and are triggered by constant exposure to cigarette smoke and epithelial injury, drives the persistent inflammatory response found in smokers. The development and severity of adaptive inflammation depend on the level of tolerance to self-antigens. For these reasons, the effect of regulatory T (Treg) cells on adaptive immunity in COPD patients is of particular interest and could be targeted therapeutically. The disturbance in immune homeostasis caused by changes in the number or function of Treg cells, which is related to cigarette smoke exposure, may be of importance in understanding the development and progression of COPD.

17.
Orphanet J Rare Dis ; 15(1): 131, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32471509

RESUMO

BACKGROUND: DNA Ligase IV (LIG4) syndrome is a rare disease with few reports to date. Patients suffer from a broad spectrum of clinical features, including microcephaly, growth retardation, developmental delay, dysmorphic facial features, combined immunodeficiency, and malignancy predisposition. There may be a potential association between genotypes and phenotypes. We investigated the characteristics of LIG4 syndrome in a Chinese cohort. RESULTS: All seven patients had growth restriction. Most patients (6/7) had significant microcephaly (< - 3 SD). Recurrent bacterial infections of the lungs and intestines were the most common symptoms. One patient had myelodysplastic syndromes. One patient presented with an inflammatory bowel disease (IBD)-like phenotype. Patients presented with combined immunodeficiency. The proportions of naïve CD4+ and naïve CD8+ T cells decreased notably in five patients. All patients harbored compound heterozygous mutations in the LIG4 gene, which consisted of a missense mutation (c.833G > T, p.R278L) and a deletion shift mutation, primarily c.1271_1275delAAAGA (p.K424Rfs*20). Two other deletion mutations, c.1144_1145delCT and c.1277_1278delAA, were novel. Patients with p.K424Rfs*20/p.R278 may have milder dysmorphism but more significant IgA/IgM deficiency compared to the frequently reported genotype p.R814X/p.K424Rfs*20. One patient underwent umbilical cord blood stem cell transplantation (UCBSCT) but died. CONCLUSIONS: The present study reported the clinical and molecular characteristics of a Chinese cohort with LIG4 syndrome, and the results further expand the phenotypic and genotypic spectrum and our understanding of genotype-to-phenotype correlations in LIG4 syndrome.

18.
Cell Death Dis ; 11(4): 288, 2020 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-32341347

RESUMO

Parkinson's disease (PD) is a progressively debilitating neurodegenerative condition that leads to motor and cognitive dysfunction. At present, clinical treatment can only improve symptoms, but cannot effectively protect dopaminergic neurons. Several reports have demonstrated that human umbilical cord mesenchymal stem cells (hucMSCs) afford neuroprotection, while their application is limited because of their uncontrollable differentiation and other reasons. Stem cells communicate with cells through secreted exosomes (Exos), the present study aimed to explore whether Exos secreted by hucMSCs could function instead of hucMSCs. hucMSCs were successfully isolated and characterized, and shown to contribute to 6-hydroxydopamine (6-OHDA)-stimulated SH-SY5Y cell proliferation; hucMSC-derived Exos were also involved in this process. The Exos were purified and identified, and then labeled with PKH 26, it was found that the Exos could be efficiently taken up by SH-SY5Y cells after 12 h of incubation. Pretreatment with Exos promoted 6-OHDA-stimulated SH-SY5Y cells to proliferate and inhibited apoptosis by inducing autophagy. Furthermore, Exos reached the substantia nigra through the blood-brain barrier (BBB) in vivo, relieved apomorphine-induced asymmetric rotation, reduced substantia nigra dopaminergic neuron loss and apoptosis, and upregulated the level of dopamine in the striatum. These results demonstrate that hucMSCs-Exos have a treatment capability for PD and can traverse the BBB, indicating their potential for the effective treatment of PD.

19.
Oxid Med Cell Longev ; 2020: 6954764, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32256957

RESUMO

Aims: Ischemic postconditioning (IPO) has a strong protective effect against intestinal ischemia-reperfusion (IIR) injury that is partly related to autophagy. However, the precise mechanisms involved are unknown. Methods: C57BL/6J mice were subjected to unilateral IIR with or without IPO. After 45 min ischemia and 120 min reperfusion, intestinal tissues and blood were collected for examination. HE staining and Chiu's score were used to evaluate pathologic injury. We test markers of intestinal barrier function and oxidative stress. Finally, we used WB to detect the expression of key proteins of autophagy and the Akt/GSK-3ß/Nrf2 pathway. Results: IPO significantly attenuated IIR injury. Expression levels of LC3 II/I, Beclin-1, and p62 were altered during IIR, indicating that IPO enhanced autophagy. IPO also activated Akt, inhibited GSK-3ß/Nrf2 pathway. Conclusion: Our study indicates that IPO can ameliorate IIR injury by evoking autophagy, activating Akt, inactivating GSK-3ß, and activating Nrf2. These findings may provide novel insights for the alleviation of IIR injury.ß/Nrf2 pathway.

20.
PLoS One ; 15(4): e0231003, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32240238

RESUMO

Systematic interrogation of tumor-infiltrating immune cells (TIICs) is key to the prediction of clinical outcome and development of immunotherapies. However, little is known about the TIICs of hepatocellular carcinoma (HCC) and its impact on the prognosis of patients and potential for immunotherapy. We applied CIBERSORT of 1090 tumors to infer the infiltration of 22 subsets of TIICs using gene expression data. Unsupervised clustering analysis by 22 TIICs revealed 4 clusters of tumors, mainly defined by macrophages and T cells, with distinct prognosis and associations with immune checkpoint molecules, including PD-1, CD274, CTLA-4, LAG-3 and IFNG. We found tumors with decreased number of M1 macrophages or increased regulatory T cells were associated with poor prognosis. Based on the multivariate Cox analysis, a nomogram was also established for clinical application. In conclusion, composition of the TIICs in HCC was quite different, which is an important determinant of prognosis with great potential to identify candidates for immunotherapy.


Assuntos
Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T Reguladores/imunologia , Antígeno B7-H1/imunologia , Antígeno CTLA-4/imunologia , Feminino , Expressão Gênica/imunologia , Humanos , Imunoterapia/métodos , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptor de Morte Celular Programada 1/imunologia
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