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1.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34074038

RESUMO

Glioblastoma multiforme (GBM) has remained one of the most lethal and challenging cancers to treat. Previous studies have shown encouraging results when irinotecan was used in combination with temozolomide (TMZ) for treating GBM. However, irinotecan has a narrow therapeutic index: a slight dose increase in irinotecan can induce toxicities that outweigh its therapeutic benefits. SN-38 is the active metabolite of irinotecan that accounts for both its anti-tumor efficacy and toxicity. In our previous paper, we showed that SN-38 embedded into 50:50 biodegradable poly[(d,l)-lactide-co-glycolide] (PLGA) microparticles (SMPs) provides an efficient delivery and sustained release of SN-38 from SMPs in the brain tissues of rats. These properties of SMPs give them potential for therapeutic application due to their high efficacy and low toxicity. In this study, we tested the anti-tumor activity of SMP-based interstitial chemotherapy combined with TMZ using TMZ-resistant human glioblastoma cell line-derived xenograft models. Our data suggest that treatment in which SMPs are combined with TMZ reduces tumor growth and extends survival in mice bearing xenograft tumors derived from both TMZ-resistant and TMZ-sensitive human glioblastoma cell lines. Our findings demonstrate that combining SMPs with TMZ may have potential as a promising strategy for the treatment of GBM.

2.
Theranostics ; 11(14): 7018-7028, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093868

RESUMO

Rationale: Hepatectomy and adjuvant chemotherapy after resection of colorectal liver metastases (CRLM) may improve survival, however, patients which may benefit cannot currently be identified. Postoperative circulating tumor DNA (ctDNA) analysis can detect minimal residual disease (MRD) and predict the prognosis and efficacy of adjuvant chemotherapy. Our study aims to determine the impact of serial ctDNA analysis to predict the outcome among patients undergoing resection of CRLM. Methods: Between May 2018 and October 2019, 91 CRLM patients were prospectively enrolled. Whole exome sequencing was performed in 50 primary and 48 metastatic liver tissues. Targeted sequencing of 451 cancer relevant genes was performed in 50 baseline plasma to determine plasma-tissue concordance. We prospectively investigated changes in the amount and constitution of ctDNA in 271 serial plasma samples taken at different time points (baseline, pre-operation, post-operation, post-operative adjuvant chemotherapy (post-ACT) and recurrence) during the treatment of CRLM. Results: Detected molecular alterations were highly consistent among baseline ctDNA, primary and liver metastases tissue. Patients with a higher variant allele frequency (VAF) level at baseline ctDNA represent a higher tumor burden, and decreased ctDNA during pre-operative chemotherapy predicted better tumor response. Patients with detectable post-operative and post-ACT ctDNA were associated with significantly shorter recurrence-free survival (RFS). ROC analysis showed that post-ACT ctDNA status was superior to post-operative ctDNA status in predicting RFS with an AUROC of 0.79. A significant difference in overall recurrence rate was observed in patients with detectable vs undetectable levels of ctDNA after resection of CRLM (79.4% vs 41.7%) and after completion of adjuvant chemotherapy (77.3% vs 40.7%). During adjuvant chemotherapy, patients with decreased ctDNA VAF after adjuvant chemotherapy had a recurrence rate of 63.6%, compared to 92.3% in patients with increased ctDNA VAF. Conclusions: We envision that dynamic ctDNA analysis, especially in a post-ACT setting, might be used to not only reflect MRD but also to determine rational personalized adjuvant therapy after the resection of CRLM.

3.
Ann Clin Transl Neurol ; 8(6): 1330-1342, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33943039

RESUMO

BACKGROUND: The expansion of GGC repeat in the 5' untranslated region of the NOTCH2NLC has been associated with various neurogenerative disorders of the central nervous system and, more recently, oculopharyngodistal myopathy. This study aimed to report patients with distal weakness with both neuropathic and myopathic features on electrophysiology and pathology who present GGC repeat expansions in the NOTCH2NLC. METHODS: Whole-exome sequencing (WES) and long-read sequencing were implemented to identify the candidate genes. In addition, the available clinical data and the pathological changes associated with peripheral nerve and muscle biopsies were reviewed and studied. RESULTS: We identified and validated GGC repeat expansions of NOTCH2NLC in three unrelated patients who presented with progressive weakness predominantly affecting distal lower limb muscles, following negative results in an initial WES. We found intranuclear inclusions with multiple proteins deposits in the nuclei of both myofibers and Schwann cells. The clinical features of these patients are compatible with the diagnosis of distal motor neuropathy and rimmed vacuolar myopathy. INTERPRETATION: These phenotypes enrich the class of features associated with NOTCH2NLC-related repeat expansion disorders (NRED), and provide further evidence that the neurological symptoms of NRED include not only brain, spinal cord, and peripheral nerves damage, but also myopathy, and that overlapping symptoms might exist.

4.
Adv Sci (Weinh) ; 8(7): 2003094, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33854885

RESUMO

Many long noncoding RNAs (lncRNAs) have been annotated, but their functions remain unknown. The authors found a novel lnc-APUE (lncRNA accelerating proliferation by upregulating E2F1) that is upregulated in different cancer types, including hepatocellular carcinoma (HCC), and high lnc-APUE level is associated with short recurrence-free survival (RFS) of HCC patients. Gain- and loss-of-function analyses showed that lnc-APUE accelerated G1/S transition and tumor cell growth in vitro and allows hepatoma xenografts to grow faster in vivo. Mechanistically, lnc-APUE binds to miR-20b and relieves its repression on E2F1 expression, resulting in increased E2F1 level and accelerated G1/S phase transition and cell proliferation. Consistently, lnc-APUE level is positively associated with the expression of E2F1 and its downstream target genes in HCC tissues. Further investigations disclose that hepatocyte nuclear factor 4 alpha (HNF4α) binds to the lnc-APUE promoter, represses lnc-APUE transcription, then diminishes E2F1 expression and cell proliferation. HNF4α expression is reduced in HCC tissues and low HNF4α level is correlated with high lnc-APUE expression. Collectively, a HNF4α/lnc-APUE/miR-20b/E2F1 axis in which HNF4α represses lnc-APUE expression and keeps E2F1 at a low level is identified. In tumor cells, HNF4α downregulation leads to lnc-APUE upregulation, which prevents the inhibition of miR-20b on E2F1 expression and thereby promotes cell cycle progression and tumor growth.

5.
Braz. j. otorhinolaryngol. (Impr.) ; 87(2): 152-156, mar.-abr. 2021. tab, graf
Artigo em Português | LILACS-Express | LILACS | ID: biblio-1249361

RESUMO

Resumo Introdução: A apneia obstrutiva do sono é o tipo mais comum de apneia do sono, causada por obstrução completa ou parcial da via aérea superior. A obstrução nasal também é considerada como um dos fatores de risco independentes da apneia obstrutiva do sono. Objetivo: Avaliar pacientes com apneia obstrutiva do sono. Método: Pacientes com apneia obstrutiva do sono foram incluídos no estudo de junho a dezembro de 2015, tratados com spray de corticosteroide intranasal por quatro semanas. Vários parâmetros foram obtidos antes e após o tratamento, inclusive os escores da escala Nasal Obstruction Symptom Evaluation, do Pittsburgh Sleep Quality Index e do questionário Escala de Sonolência de Epworth. Resultados: Cinquenta pacientes completaram os questionários antes e após o tratamento intranasal com fluticasona. A média de idade era de 39,7 ± 15,6 anos, com uma proporção de homens para mulheres de 3:2. Os escores pós-tratamento da Escala de Sonolência de Epworth, do Pittsburgh Sleep Quality Index e do Nasal Obstruction Symptom Evaluation indicaram uma diminuição em comparação aos escores pré-tratamento, de 10,4 para 8,74, 7,86 para 6,66 e 9,08 para 6,48, respectivamente. Uma diminuição significativa foi observada no grupo Nasal Obstruction Symptom Evaluation ≥ 10 em todas as três categorias, mas não no grupo Nasal Obstruction Symptom Evaluation <10. Conclusões: Os autores concluíram que o tratamento com fluticasona intranasal pode ser útil em pacientes com apneia obstrutiva do sono relacionada a obstrução nasal para melhorar a qualidade do sono e limitar a disfunção diurna.

6.
Brain ; 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33693509

RESUMO

Oculopharyngodistal myopathy (OPDM) is an adult-onset neuromuscular disease characterized by progressive ocular, facial, pharyngeal and distal limb muscle involvement. Trinucleotide repeat expansions in LRP12 or GIPC1 were recently reported to be associated with OPDM. However, a significant portion of OPDM patients have unknown genetic causes. In this study long-read whole-genome sequencing and repeat-primed polymerase chain reaction were performed and we identified GGC repeat expansions in the NOTCH2NLC gene in 16.7% (4/24) of a cohort of Chinese OPDM patients, designated as OPDM type 3 (OPDM3). Methylation analysis indicated that methylation levels of the NOTCH2NLC gene were unaltered in OPDM3 patients, but increased significantly in asymptomatic carriers. Quantitative real-time PCR analysis indicated that NOTCH2NLC mRNA levels were increased in muscle but not in blood of OPDM3 patients. Immunofluorescence on OPDM muscle samples and expressing mutant NOTCH2NLC with (GGC)69 repeat expansions in HEK293 cells indicated that mutant NOTCH2NLC-polyGlycine protein might be a major component of intranuclear inclusions, and contribute to toxicity in cultured cells. In addition, two RNA-binding proteins, hnRNP A/B and MBNL1, were both co-localized with p62 in intranuclear inclusions in OPDM muscle samples. These results indicated that a toxic protein gain-of-function mechanism and RNA gain-of-function mechanism may both play a vital role in the pathogenic processes of OPDM3. This study extended the spectrum of NOTCH2NLC repeat expansion related diseases to a predominant myopathy phenotype presenting as OPDM, and provided evidence for possible pathogenesis of these diseases.

7.
J Med Genet ; 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33766934

RESUMO

BACKGROUND: GGC repeat expansion in NOTCH2NLC has been recently linked to neuronal intranuclear inclusion disease (NIID) via unknown disease mechanisms. Herein, we explore the genetic origin of the sporadic cases and toxic RNA gain-of-function mechanism in NIID. METHODS: Multiple genetic screenings were performed on NIID individuals and their available family members. Methylation status of blood DNA, NOTCH2NLC mRNA level from muscle biopsies and RNA foci from skin biopsies of NIID individuals or asymptomatic carriers were evaluated and compared. RESULTS: In two sporadic NIID families, we identified two clinically and pathologically asymptomatic fathers carrying large GGC repeat expansion, above 300 repeats, with offspring repeat numbers of 172 and 148, respectively. Further evaluation revealed that the GGC repeat numbers in the sperm from two asymptomatic fathers were only 63 and 98, respectively. The CpG island in NOTCH2NLC of the asymptomatic carriers was hypermethylated, and accordingly, the NOTCH2NLC mRNA levels were decreased in the asymptomatic fathers. GGC repeat expansion RNA formed RNA foci and sequestered RNA binding proteins into p62 positive intranuclear inclusions in NIID individuals but not in the control or asymptomatic carrier. CONCLUSION: Our study suggested the GGC repeat expansion in NOTCH2NLC might have a disease-causing number ranging from ~41 to ~300 repeats. The contraction of GGC repeat expansion in sperm could be a possible mechanism for the paternal-biased origin in some sporadic or recessive inherited NIID individuals. The toxic RNA gain-of-function mechanism was identified to be involved in the pathogenicity of this disease.

8.
Nat Commun ; 12(1): 1518, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33750796

RESUMO

Growing evidences suggest that cancer stem cells exhibit many molecular characteristics and phenotypes similar to their ancestral progenitor cells. In the present study, human embryonic stem cells are induced to differentiate into hepatocytes along hepatic lineages to mimic liver development in vitro. A liver progenitor specific gene, RALY RNA binding protein like (RALYL), is identified. RALYL expression is associated with poor prognosis, poor differentiation, and metastasis in clinical HCC patients. Functional studies reveal that RALYL could promote HCC tumorigenicity, self-renewal, chemoresistance, and metastasis. Moreover, molecular mechanism studies show that RALYL could upregulate TGF-ß2 mRNA stability by decreasing N6-methyladenosine (m6A) modification. TGF-ß signaling and the subsequent PI3K/AKT and STAT3 pathways, upregulated by RALYL, contribute to the enhancement of HCC stemness. Collectively, RALYL is a liver progenitor specific gene and regulates HCC stemness by sustaining TGF-ß2 mRNA stability. These findings may inspire precise therapeutic strategies for HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/metabolismo , Neoplasias Hepáticas/metabolismo , Estabilidade de RNA/fisiologia , Fator de Crescimento Transformador beta2/metabolismo , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Movimento Celular , Células-Tronco Embrionárias , Feminino , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/genética , Humanos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/genética , Regulação para Cima
9.
Ann Clin Transl Neurol ; 8(4): 831-841, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33739616

RESUMO

OBJECTIVE: This study aims to report the genotypes and phenotypes of hereditary transthyretin amyloidosis (ATTR) in a large Chinese cohort, yet the clinical and genetic profiles of ATTR remain elusive in mainland China. METHODS: Fifty-four patients with molecularly confirmed ATTR from 39 unrelated families were identified by sequencing the TTR gene. Sural nerve biopsies were performed in 40 of these cases. The clinical and electrophysiological data were retrospectively collected and analyzed. RESULTS: The male/female ratio was 42:12. The average age of patients at the onset of the disease was 47.8 ± 13.0 years. The late-onset type occurred in 29 cases (53.7%). Twenty-two probands (56.4%) had a family history with ATTR. The initial symptoms were limb paresthesia in 33 cases (61.1%), autonomic dysfunction in 15 cases (27.8%), and blurred vision in 6 cases (11.1%). A total of 22 different TTR mutations were identified, including Val30Met (25.6%) in 10 families in North China and Ala97Ser in 4 families (10.3%) in South China. Electrophysiological studies revealed general sensorimotor axonal polyneuropathy in 33/44 cases (75.0%), mixed neuropathy with axonal and demyelinating impairment features in 9/44 cases (20.5%) and isolated carpal tunnel syndrome in two cases. Sural nerve biopsies revealed positive Congo red staining in 16/40 cases (40.0%). CONCLUSION: Chinese patients with ATTR exhibited heterogeneous TTR genotypes and clinical phenotypes. Val30Met remains the most common mutation type in mainland China.

10.
Ann Clin Transl Neurol ; 8(4): 898-907, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33756069

RESUMO

OBJECTIVE: We aimed to summarize the clinical, genetic, and myopathological features of a cohort of Chinese patients with congenital myasthenic syndrome, and follow up on therapeutic outcomes. METHODS: The clinical spectrum, mutational frequency of genes, and pathological diagnostic clues of various subtypes of patients with congenital myasthenic syndrome were summarized. Therapeutic effects were followed up. RESULTS: Thirty-five patients from 29 families were recruited. Ten genes were identified: GFPT1 (27.6%), AGRN (17.2%), CHRNE (17.2%), COLQ (13.8%), GMPPB (6.9%), CHAT, CHRNA1, DOK7, COG7, and SLC25A1 (3.4% each, respectively). Sole limb-girdle weakness was found in patients with AGRN (1/8) and GFPT1 (7/8) mutations, whereas distal weakness was all observed in patients with AGRN (6/8) mutations. Tubular aggregates were only found in patients with GFPT1 mutations (5/6). The patients with GMPPB mutations (2/2) had decreased alpha-dystroglycan. Acetylcholinesterase inhibitor therapy resulted in no response or worsened symptoms in patients with COLQ mutations, a diverse response in patients with AGRN mutations, and a good response in patients with other subtypes. Albuterol therapy was effective or harmless in most subtypes. Therapy effects became attenuated with long-term use in patients with COLQ or AGRN mutations. INTERPRETATION: The genetic distribution of congenital myasthenic syndrome in China is distinct from that of other ethnic origins. The appearance of distal weakness, selective limb-girdle myasthenic syndrome, tubular aggregates, and decreased alpha-dystroglycan were indicative of the specific subtypes. Based on the follow-up findings, we suggest cautious evaluation of the long-term efficacy of therapeutic agents in congenital myasthenic syndrome.

11.
Anal Chim Acta ; 1156: 338359, 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33781459

RESUMO

Ligand fishing for screening of enzyme inhibitors from complex chemical systems using baits prepared by cell surface display of the enzyme is herein demonstrated for the first time. Tyrosine phosphatase 1B (PTP1B), used as a model enzyme in this work, is displayed on the surface of E. coli cells by using ice nucleation protein (INP) as the anchoring motif. Infusion of PTP1B is characterized by western blot, immunofluorescence, proteinase K accessibility, and enzyme activity assays. Surface displayed PTP1B exhibits a maximum of 5.62 ± 0.251 U/OD600 enzymatic activity and a better stability compared with free enzyme. PTP1B displayed cells are used as solid-phase extraction adsorbent in combination with HPLC-MS to screen the inhibitors from the extracts of Rhodiola rosea, a traditional Chinese medicinal plant. Among many well-known active ingredients only arbutin is fished out with an IC50 value of 20.5 ± 0.873 µM, showing the inhibitor screening is highly selective. Furthermore, the equilibrium dissociation constant (KD) of the complex of arbutin and PTP1B was determined to be 79.6 µM by localized surface plasma resonance (LSPR) assay. The proposed ligand fishing technique using recombinant cells as baits opens a new avenue for screening of active compounds from natural products with accuracy and specificity.


Assuntos
Escherichia coli , Plantas Medicinais , Inibidores Enzimáticos/farmacologia , Ligantes , Proteína Tirosina Fosfatase não Receptora Tipo 1
12.
Ann Clin Transl Neurol ; 8(3): 677-686, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33576578

RESUMO

OBJECTIVE: This study aimed to investigate mitochondrial changes and the mitochondrial antiviral-signaling protein (MAVS)-type I interferon (IFN1) signaling pathway in the muscles of anti-melanoma differentiation gene 5(MDA5) dermatomyositis (DM) patients. METHODS: Eleven anti-MDA5 DM and ten antibody-negative DM patients were included. Muscle biopsies were performed in all patients. Muscle pathology and mitochondrial morphology in particular were compared between two groups. The expression of MDA5, MAVS, interferon (IFN) regulatory factor 7, and IFN-stimulated gene 15, which are components of the MAVS-IFN1 signaling pathway, was measured in muscle specimen. The correlation between MAVS expression in muscles and disease phenotypes and muscle pathology were analyzed. RESULTS: Anti-MDA5 DM showed a significantly lower incidence of the characteristic DM pathology (P < 0.05) than antibody-negative DM, including perifascicular fiber atrophy, inflammation, and vasculopathy. Mitochondrial abnormalities in anti-MDA5 patients revealed a high incidence of (8/11,72.7%) and different pattern from that in antibody-negative DM. MDA5, MAVS, IFN regulatory factor 7, and IFN stimulated gene 15 expression levels in the muscles of anti-MDA5 DM patients were higher than those of the controls (P < 0.05) but lower than those of antibody-negative DM patients (P < 0.05). The MAVS levels negatively correlated with manual muscle test 8 scores (r = 0.701, P = 0.016). CONCLUSIONS: Compared to antibody-negative DM, we presented a different distribution of the mitochondrial pathology and less severe morphology in anti-MDA5 DM. We also revealed the enhanced but less intensive MAVS-IFN1 signaling pathway activity in muscles of anti-MDA5 DM. Such disparity suggested the potentially different mechanism of muscle injury in two DM groups.

13.
Cancer Med ; 10(5): 1535-1544, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33539664

RESUMO

PURPOSE: We aimed to construct a nomogram to predict personalized post-recurrence survival (PRS) among colorectal cancer liver metastasis (CRLM) patients with post-hepatectomy recurrence. METHODS: Colorectal cancer liver metastasis patients who received initial hepatectomy and had subsequent recurrence between 2001 and 2019 in Sun Yat-sen University Cancer Center from China were included in the study. Patients were randomly assigned to a training cohort and a validation cohort on a ratio of 2:1. Univariable analysis was first employed to select potential predictive factors for PRS. Then, the multivariable Cox regression model was applied to recognize independent prognostic factors. According to the model, a nomogram to predict PRS was established. The nomogram's predictive capacity was further assessed utilizing concordance index (C-index) values, calibration plots, and Kaplan-Meier curves. RESULTS: About 376 patients were finally enrolled, with a 3-year PRS rate of 37.3% and a 5-year PRS rate of 24.6%. The following five independent predictors for PRS were determined to construct the nomogram: the largest size of liver metastases at initial hepatectomy, relapse-free survival, CEA level at recurrence, recurrent sites, and treatment for recurrence. The nomogram displayed fairly good discrimination and calibration. The C-index value was 0.742 for the training cohort and 0.773 for the validation cohort. Patients were grouped into three risk groups very well by the nomogram, with 5-year PRS rates of 45.2%, 23.3%, and 9.0%, respectively (p < 0.001) in the training cohort and 36.0%, 9.2%, and 4.6%, respectively (p < 0.001) in the validation cohort. CONCLUSION: A novel nomogram was built and validated to enable the prediction of personal PRS in CRLM patients with post-hepatectomy recurrence. The nomogram may help physicians in decision making.

14.
Mol Cancer ; 20(1): 20, 2021 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-33485358

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common human malignancies worldwide with very poor prognosis. Resistance to targeted therapeutic drugs such as sorafenib remains one of the major challenges in clinical treatment. In the present study, PARP1 was found to be highly expressed in human embryonic stem cells, but progressively decreased upon specified hepatic differentiation. Reactivation of PARP1 expression was also detected in HCC residual tumors after sorafenib treatment in xenograft mouse model, indicating the potential important roles of PARP1 in stem cell pluripotency and HCC sorafenib treatment resistance. Overexpression of PARP1 was frequently observed in HCC patients, and closely associated with poor clinical outcome. Treatment of Sorafenib induced activation of DNA damage repair signaling, which is highly active and essential for maintenance of stem cell pluripotency in HCC residual tumors. PARP inhibitor Olaparib extensively suppressed the DNA damage repair signaling, and significantly inhibited the global pluripotent transcriptional network. The repression of key pluripotent transcriptional factors and DNA damage repair signaling by Olaparib was mainly through CHD1L-mediated condensation of the chromatin structure at their promotor regions. The global reshaping of the pluripotent transcriptome by Olaparib might reinforce Sorafenib in eliminating HCC residual tumors and enhance therapeutic efficiency.

15.
Anal Chem ; 93(5): 3010-3017, 2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33499597

RESUMO

Lateral flow assay (LFA) has played pivotal roles in many emergency public safety incidents, such as coronavirus disease diagnostics; however, the present double-line (test and control line) design strategy for LFA strips greatly restricts their applications in high-throughput quantitative analysis because the limited sample diffusion distance on the strips constrains the number of test/control lines. Herein, a novel single-line-based LFA (sLFA) strip, which combines test and control line, is developed by exploiting an orthogonal emissive upconversion nanoparticle (UCNP) as a signal reporter on the test line, where one emission can be used as a reporting signal and the other as a calibrating signal. This UCNP-based test line with an interior reference also can play a validating role as a control line, and hence capturing antibodies are not needed for control lines, greatly saving fabrication costs. As a proof-of-concept, this novel sLFA strip is successfully explored to accurately and rapidly detect aflatoxin B1. Moreover, due to the removal of control lines, such a novel strategy greatly reduces the strip size, facilitating the design of a testing array for multiple detections of different samples. The test line herein is designed in a ring shape, and several test rings are assembled to be a chip for the testing of multiple samples. To our knowledge, this is the first demonstration of single-line-based LFA strips, which will significantly improve the detection capacities and accuracies and reduce the testing costs of LFA strips in real sample applications ranging from food analysis to in vitro diagnostics.


Assuntos
Aflatoxina B1/análise , Técnicas Biossensoriais/métodos , Nanopartículas Metálicas/química , Aflatoxina B1/imunologia , Anticorpos Imobilizados/química , Anticorpos Imobilizados/imunologia , Técnicas Biossensoriais/instrumentação , COVID-19/diagnóstico , COVID-19/virologia , Análise de Alimentos/métodos , Ouro/química , Humanos , Medições Luminescentes , SARS-CoV-2/isolamento & purificação
16.
BMC Neurol ; 21(1): 13, 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33430797

RESUMO

BACKGROUND: Dystrophinopathies are the most common type of inherited muscular diseases. Muscle biopsy and genetic tests are effective to diagnose the disease but cost much more than primary hospitals can reach. The more available muscle MRI is promising but its diagnostic results highly depends on doctors' experiences. This study intends to explore a way of deploying a deep learning model for muscle MRI images to diagnose dystrophinopathies. METHODS: This study collected 2536 T1WI images from 432 cases who had been diagnosed by genetic analysis and/or muscle biopsy, including 148 cases with dystrophinopathies and 284 cases with other diseases. The data was randomly divided into three sets: the data from 233 cases were used to train the CNN model, the data from 97 cases for the validation experiments, and the data from 102 cases for the test experiments. We also validated our models expertise at diagnosing by comparing the model's results on the 102 cases with those of three skilled radiologists. RESULTS: The proposed model achieved 91% (95% CI: 0.88, 0.93) accuracy on the test set, higher than the best accuracy of 84% in radiologists. It also performed better than the skilled radiologists in sensitivity : sensitivities of the models and the doctors were 0.89 (95% CI: 0.85 0.93) versus 0.79 (95% CI:0.73, 0.84; p = 0.190). CONCLUSIONS: The deep model achieved excellent accuracy and sensitivity in identifying cases with dystrophinopathies. The comparable performance of the model and skilled radiologists demonstrates the potential application of the model in diagnosing dystrophinopathies through MRI images.


Assuntos
Aprendizado Profundo , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Músculo Esquelético/diagnóstico por imagem , Distrofias Musculares/diagnóstico por imagem , Adolescente , Adulto , Criança , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Coxa da Perna , Adulto Jovem
17.
Cell Death Differ ; 28(6): 1955-1970, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33500560

RESUMO

Poorly differentiated tumors usually exhibit phenotypes similar to that of their developmental precursor cells. Tumor cells that acquire the lineage progenitor cells feature usually exploit developmental signaling to potentiate cancer progression. However, the underlying molecular events remain elusive. In this study, based on analysis of an in vitro hepatocyte differentiation model, the maternal factor PGC7 (also known as DPPA3, STELLA) was found closely associated with liver development and tumor differentiation in hepatocellular carcinoma (HCC). Expression of PGC7 decreased during hepatocyte maturation and increased progressively from well-differentiated HCCs to poorly differentiated HCCs. Whole-genome methylation sequencing found that PGC7 could induce promoter demethylation of genes related to development. Pathway-based network analysis indicated that downstream targets of PGC7 might form networks associated with developmental transcription factor activation. Overexpression of PGC7 conferred progenitor-like features of HCC cells both in vitro and in vivo. Mechanism studies revealed that PGC7 could impede nuclear translocation of UHRF1, and thus facilitate promoter demethylation of GLI1 and MYCN, both of which are important regulators of HCC self-renewal and differentiation. Depletion or inhibition of GLI1 effectively downregulated MYCN, abolished the effect of PGC7, and sensitized HCC cells to sorafenib treatment. In addition, we found a significant correlation of PGC7 with GLI1/MYCN and lineage differentiation markers in clinical HCC patients. PGC7 expression might drive HCC toward a "dedifferentiated" progenitor lineage through facilitating promoter demethylation of key developmental transcription factors; further inhibition of PGC7/GLI1/MYCN might reverse poorly differentiated HCCs and provide novel therapeutic strategies.

18.
J Periodontal Res ; 2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33296525

RESUMO

Inflammatory alveolar bone defects are caused by periodontal pathogens, are one of the most common oral diseases in the clinic, and are characterized by periodontal support tissue damage. MicroRNAs (miRNAs) can participate in a variety of inflammatory lesions and modulate bone metabolism through the posttranscriptional regulation of target genes. In recent years, studies have confirmed that some miRNAs play significant roles in the development of inflammatory alveolar bone defects. Therefore, we reviewed the correlation between miRNAs and inflammatory alveolar bone defects and elucidated the underlying mechanisms to provide new ideas for the prevention and treatment of inflammatory alveolar bone defects.

19.
Orphanet J Rare Dis ; 15(1): 344, 2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33298082

RESUMO

BACKGROUND: Laing distal myopathy is a rare autosomal dominant inherited distal myopathy caused by mutations of the MYH7 gene affecting mainly the rod region. We described the clinical features, muscle MRI and pathological changes as well as genetic mutations in a group of Chinese patients with Laing distal myopathy. RESULTS: Six patients with the confirmed diagnoses of Laing distal myopathy were recruited. Ankle dorsiflexion and finger extension weakness, as well as neck flexion weakness were common in our patients. Myopathic as well as neurogenic lesions were suggested by electromyography in different patients. Respiratory abnormality of sleep apnea was detected in two of our patients stressing the necessity of close respiratory monitoring in this disease. Muscle MRIs showed similar features of concentric fatty infiltration of anterior thigh muscles together with early involvement of tibialis anterior and extensor hallucis longus. However, muscle pathological presentations were varied depending on the biopsied muscles and the severity of the disease. In-frame deletions of the MYH7 gene made up 3/4 of mutations in our patients, suggesting that these are common mutations of Laing distal myopathy. CONCLUSIONS: Our study further expanded the phenotypes and genotypes of Laing distal myopathy. In-frame deletions of the MYH7 gene are common causes of Laing distal myopathy.

20.
Clin Neuropathol ; 2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33261722

RESUMO

AIMS: A subset of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is characterized by the presence of anti-neurofascin 155 (anti-NF155) autoantibodies. In this paper, we investigated an anti-NF155 CIDP patient via clinical, electrophysiological, and neuropathological tests. MATERIALS AND METHODS: The patient was a 15-year-old Chinese boy affected by distal limb weakness and tremor for a 6-month period. The patient was positive for serum anti-NF155 antibodies, high cerebrospinal fluid protein levels and symmetric hypertrophy of lumbosacral roots in MRI. Elongation of distal and F-wave latencies and decrease of compound muscle action potentials in motor nerves were recorded. Sensory nerve action potentials were absent. He accepted sural nerve biopsy. RESULTS: Sural nerve biopsy demonstrated the typical pathological change of loss of transverse bands with mild detachment of terminal myelin loop from axon at the paranode. Some thin myelinated fibers and axonal degeneration were recorded. Besides, we found some myelin balloon formations with compressed axons. CONCLUSION: We suggest that antibodies against F155 might be responsible for axo-glial junction disruptions leading to the dissociation of myelin and axon. Both conduction block and axonal impairment contributed to the neuropathy in anti-NF155 CIDP.

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