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1.
Front Immunol ; 13: 946825, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35911688

RESUMO

Background: Guillain-Barré syndrome (GBS) is the most common severe acute paralytic neuropathy, with a mortality rate of 5% and permanent sequelae rate of 10%. Currently, the cause of GBS remains unclear. Therefore, we sought to determine potential predictors for GBS and its severity. Methods: A case-control study was performed at Tiantan Hospital in Beijing from January 2017 to December 2021. Laboratory and clinical characteristics were assessed in recruited GBS patients and healthy control individuals (matched by sex and age). The potential risk factors for GBS and severe GBS were assessed using a logistic regression analysis. The mRNA levels of toll-like receptor 4 (TLR4), toll-like receptor 2 (TLR2) and nuclear factor κB (NF-κB) in GBS patients and control PBMCs were detected by fluorescence quantitative PCR. THP-1 cells were costimulated with LPS and free cholesterol to demonstrate the effect of free cholesterol on monocyte activation. Results: A total of 147 GBS patients and 153 healthy individuals were included in the study. Logistic regression analyses showed that preceding infection, alcohol consumption, remnant cholesterol, homocysteine and the dyslipidemia index were correlated with a higher risk of GBS. In contrast, increased HDL cholesterol was correlated with a lower risk of GBS. Moreover, remnant cholesterol and the dyslipidemia index were significantly correlated with severe GBS. The mRNA levels of TLR4, TLR2 and NF-κB in the PBMCs of GBS patients were significantly higher than those of healthy individuals. LPS activated THP-1 cells, and free cholesterol treatment increased the expression of TLR4, TLR2, NF-κB and IL-1ß mRNA in LPS-activated THP-1 cells. Conclusion: Dyslipidemia was correlated with the risk of GBS and severe GBS. Remnant cholesterol may promote the activation of monocytes in GBS patients. It may be valuable to control lipid levels in the prevention of GBS and severe GBS.


Assuntos
Colesterol , Dislipidemias , Síndrome de Guillain-Barré , Monócitos , Estudos de Casos e Controles , Dislipidemias/complicações , Síndrome de Guillain-Barré/etiologia , Síndrome de Guillain-Barré/metabolismo , Humanos , Lipopolissacarídeos , Monócitos/metabolismo , NF-kappa B , RNA Mensageiro , Fatores de Risco , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética
2.
Biomed Microdevices ; 24(3): 27, 2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-35953589

RESUMO

To acquire high-quality electrocardiogram (ECG) signals, traditional Ag/AgCl wet electrodes used together with conductive gel can effectively reduce electrode-skin interface impedance (EII) in a short term. However, their weaknesses of poor flexibility and instability can no longer meet the long-term monitoring requirements of intelligent wearable devices. Owing to the flexible dry electrode without conductive gel, it is a good choice to solve the critical problem on drying-out of conductive gel. Therefore, we develop a flexible microneedle array electrode (FMAE) based on polydimethylsiloxane (PDMS) substrate, which obtains reliable bioelectrical signals by way of penetrating into the stratum corneum (SC) of the skin. The fabrication process, including silicon mold, twice PDMS shape-transferring and encapsulation, has advantages of low cost, repeatable production and good biocompatibility. Afterwards, by comparing the performance with different electrodes, impedance test results indicate that the impedance of FMAE are smaller and more stable, and ECG tests in long term and at resting/jogging states also verify that FMAE can obtain durable, stable and reliable signals. In conclusion, FMAE is promising in long-term ECG monitoring.


Assuntos
Eletrocardiografia , Dispositivos Eletrônicos Vestíveis , Dimetilpolisiloxanos , Impedância Elétrica , Eletrodos
3.
Research (Wash D C) ; 2022: 9873831, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35935138

RESUMO

The SARS-CoV-2 variants have been emerging and have made great challenges to current vaccine and pandemic control strategies. It is urgent to understand the current immune status of various Chinese populations given that the preexisting immunity has been established by national vaccination or exposure to past variants. Using sera from 85 individuals (including 21 convalescents of natural infection, 15 cases which suffered a breakthrough infection after being fully vaccinated, and 49 healthy vaccinees), we showed significantly enhanced neutralizing activities against SRAS-CoV-2 variants in convalescent sera, especially those who had been fully vaccinated. The neutralizing antibodies against Omicron were detectable in 75% of convalescents and 44.9% of healthy vaccinees (p = 0.006), with a GMT of 289.5, 180.9-463.3, and 42.6, 31.3-59, respectively. However, the neutralizing activities were weaker in young convalescents (aged < 18 y), with a detectable rate of 50% and a GMT of 46.4 against Omicron. We also examined and found no pan-sarbecovirus neutralizing activities in vaccinated SARS-CoV-1 survivors. A booster dose could further increase the breadth and magnitude of neutralization against WT and variants of concern (VOCs) to different degrees. In addition, we showed that COVID-19-inactivated vaccines can elicit Omicron-specific T-cell responses. The positive rates of ELISpot reactions were 26.7% (4/15) and 43.8% (7/16) in the full vaccination group and the booster vaccination group, respectively, although without statistically significant difference. The neutralizing antibody titers declined while T-cell responses remain consistent over 6 months. These findings will inform the optimization of public health vaccination and intervention strategies to protect diverse populations against SARS-CoV-2 variants. Advances. Breakthrough infection significantly boosted neutralizing activities against SARS-CoV-2 variants as compared to booster immunization with inactivated vaccine. Vaccine-induced virus-specific T-cell immunity, on the other hand, may compensate for the shortfall. Furthermore, the public health system should target the most vulnerable group due to a poorer protective serological response in both infected and vaccinated adolescents.

4.
Orphanet J Rare Dis ; 17(1): 283, 2022 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-35854386

RESUMO

BACKGROUND: Primary ciliary dyskinesia (PCD) represents a highly heterogenous disorder with extensive clinical and genetic patterns among populations of different geographic location and ethnic origin. However, data about Chinese patients are limited. We aimed to summarize the clinical and genetic spectrum of Chinese PCD patients based on all available literatures. METHODS: We searched Embase, Pubmed, Web of Science and Chinese databases including CNKI, SinoMed and Wanfang from 1981 to 2021, to identify articles reporting patients with PCD in China, which had included information about transmission electron microscopy and/or genetic testing. RESULTS: A total of 244 Chinese PCD patients in 52 articles were included. Of these patients, the mean age was 13.1 years, and 55 patients (22.5%) were diagnosed with PCD after 18 years old. Compared with patients diagnosed with PCD in childhood or infancy, patients diagnosed with PCD in adulthood had a higher prevalence of chronic wet cough, sinusitis, Pseudomonas aeruginosa (PA) isolation and radiological bronchiectasis as well as worse lung function. 25 PCD-related genes were identified in 142 patients, and DNAH5, DNAH11, CCDC39 and CCDC40 were the most frequently detected mutations. More than half of genetic variants were loss-of-function mutations, and the majority of these variants were seen only once. Correlations between PCD phenotype, genotype and ciliary ultrastructure were also evidenced. CONCLUSIONS: Diagnostic delay and under-recognition of PCD remain a big issue in China, which contributes to progressive lung disease and PA infection indicating worse outcome. Specialist equipment and expertise are urgently required to facilitate the early diagnosis and treatment of PCD. TRIAL REGISTRY: PROSPERO; No.: CRD42021257804; URL: www.crd.york.ac.uk/prospero/.


Assuntos
Transtornos da Motilidade Ciliar , Síndrome de Kartagener , Cílios/genética , Cílios/ultraestrutura , Transtornos da Motilidade Ciliar/genética , Diagnóstico Tardio , Genótipo , Humanos , Síndrome de Kartagener/diagnóstico , Síndrome de Kartagener/genética , Mutação/genética , Fenótipo
5.
Chin Med J (Engl) ; 135(9): 1087-1095, 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35773966

RESUMO

BACKGROUND: The combination of high-frequency oscillations (HFOs) with single-mode imaging methods has been proved useful in identifying epileptogenic zones, whereas few studies have examined HFOs combined with multimodal imaging methods. The aim of this study was to evaluate the prognostic value of ripples, an HFO subtype with a frequency of 80 to 200 Hz is combined with multimodal imaging methods in predicting epilepsy surgery outcome. METHODS: HFOs were analyzed in 21 consecutive medically refractory epilepsy patients who underwent epilepsy surgery. All patients underwent positron emission tomography (PET) and deep electrode implantation for stereo-electroencephalography (SEEG); 11 patients underwent magnetoencephalography (MEG). Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy in predicting surgical outcome were calculated for ripples combined with PET, MEG, both PET and MEG, and PET combined with MEG. Kaplan-Meier survival analyses were conducted in each group to estimate prognostic value. RESULTS: The study included 13 men and 8 women. Accuracy for ripples, PET, and MEG alone in predicting surgical outcome was 42.9%, 42.9%, and 81.8%, respectively. Accuracy for ripples combined with PET and MEG was the highest. Resection of regions identified by ripples, MEG dipoles, and combined PET findings was significantly associated with better surgical outcome (P  < 0.05). CONCLUSIONS: Intracranial electrodes are essential to detect regions which generate ripples and to remove these areas which indicate good surgical outcome for medically intractable epilepsy. With the assistance of presurgical noninvasive imaging examinations, PET and MEG, for example, the SEEG electrodes would identify epileptogenic regions more effectively.


Assuntos
Epilepsia Resistente a Medicamentos , Epilepsia , Epilepsia Resistente a Medicamentos/cirurgia , Eletroencefalografia/métodos , Epilepsia/diagnóstico por imagem , Epilepsia/cirurgia , Feminino , Humanos , Magnetoencefalografia/métodos , Masculino , Imagem Multimodal , Prognóstico , Resultado do Tratamento
6.
Biochem Biophys Res Commun ; 619: 159-165, 2022 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-35780518

RESUMO

Although computer-aided diagnosis (CAD) have shown excellent performance in Breast cancer (BC) histopathological image, it commonly requires a high-level network, and the recognition efficiency is frequently unsatisfied due to the complex structure of histopathological image. In this study, a ten-layers convolutional neural network (CNN) model called "ColorDeep" is used to extract color features corresponding to the different tissue parts in cell, pure color image slices obtained by a three-channel separation and reconstruction method are used as model input. Two models are tested on the BreaKHis dataset show that images under four magnifications achieved the recognition accuracy of 96.89%-99.67% at the image level, which is better than many state-of-the-art methods. The characteristics contained by the B channel have the largest effect on BC recognition, and compared to other research results, the proposed model improves the recognition speed on a single image by about 0.1s. More importantly, instead of using large histopathological images to input into the model for BC diagnosis, and instead of segmenting the nuclei, only the reconstructed B-channel features containing the nuclei region in the stained BC image need to be input into the model to enable accurate diagnosis of BC.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Redes Neurais de Computação
7.
Cell Mol Life Sci ; 79(8): 398, 2022 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-35790583

RESUMO

Glioblastoma (GBM), a highly malignant and lethal brain tumor, is characterized by diffuse invasion into the brain and chemo-radiotherapy resistance resulting in poor prognosis. In this study, we examined the involvement of the cell adhesion molecule CD146/MCAM in regulating GBM aggressiveness. Analyses of GBM transcript expression databases revealed correlations of elevated CD146 levels with higher glioma grades, IDH-wildtype and unmethylated MGMT phenotypes, poor response to chemo-radiotherapy and worse overall survival. In a panel of GBM stem cells (GSCs) variable expression levels of CD146 were detected, which strongly increased upon adherent growth. CD146 was linked with mesenchymal transition since expression increased in TGF-ß-treated U-87MG cells. Ectopic overexpression of CD146/GFP in GG16 cells enhanced the mesenchymal phenotype and resulted in increased cell invasion. Conversely, GSC23-CD146 knockouts had decreased mesenchymal marker expression and reduced cell invasion in transwell and GBM-cortical assembloid assays. Moreover, using GSC23 xenografted zebrafish, we found that CD146 depletion resulted in more compact delineated tumor formation and reduced tumor cell dissemination. Stem cell marker expression and neurosphere formation assays showed that CD146 increased the stem cell potential of GSCs. Furthermore, CD146 mediated radioresistance by stimulating cell survival signaling through suppression of p53 expression and activation of NF-κB. Interestingly, CD146 was also identified as an inducer of the oncogenic Yes-associated protein (YAP). In conclusion, CD146 carries out various pro-tumorigenic roles in GBM involving its cell surface receptor function, which include the stimulation of mesenchymal and invasive properties, stemness, and radiotherapy resistance, thus providing an interesting target for therapy.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Animais , Neoplasias Encefálicas/patologia , Antígeno CD146/genética , Antígeno CD146/metabolismo , Glioblastoma/patologia , Glioma/patologia , Peixe-Zebra/metabolismo
8.
Transl Neurosci ; 13(1): 125-133, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-35795196

RESUMO

Background: The first Chinese family with paroxysmal non-kinesigenic dystonia (PNKD) was confirmed to harbour a PNKD mutation. However, the pathogenic mechanism of the PNKD-causing gene mutation was unclear. Methods: Wild-type and mutant PNKD-L plasmids were prepared and transfected into the C6 cell line to study the distribution and stability of PNKD protein in C6 cells and its effect on the glutathione content. The blood and cerebrospinal fluid (CSF) of 3 PNKD patients and 3 healthy controls were collected. The differentially expressed proteins were identified using isobaric tags for relative and absolute quantitation. Furthermore, Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analyses were performed, and the protein-protein interaction network was constructed. Results: Wild-type PNKD protein was mainly distributed in the membranes, whereas mutant PNKD protein was distributed throughout the C6 cells. After transfection with mutant PNKD-L plasmid, the glutathione content decreased significantly in C6 cells; the stability of the mutant PNKD protein was significantly low. There were 172 and 163 differentially expressed proteins in CSF and plasma, respectively, of PNKD patients and healthy controls. For these proteins, blood microparticle and complex activation (classical pathway) were the common GO enrichment term, and complex and coordination cascade pathway were the common KEGG enrichment pathway. Recombinant mothers against decapentaplegic homolog 4 (SMAD4) was one of the differentially expressed proteins; it exhibited a relationship with the aforementioned enrichment GO terms and KEGG pathway. Conclusion: PNKD protein was mainly distributed in cell membranes. PNKD-L mutation affected subcellular localisation, PNKD protein stability, and glutathione content. SMAD4 was found to be a potential biomarker for PNKD diagnosis.

9.
Chest ; 2022 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-35863486

RESUMO

BACKGROUND: Few large-scale studies demonstrated the efficacy of tobramycin nebulization in bronchiectasis. We evaluated the efficacy and safety of nebulized tobramycin inhalation solution (TIS) in adults with bronchiectasis with Pseudomonas aeruginosa infection. RESEARCH QUESTION: Can TIS effectively reduce sputum Pseudomonas aeruginosa density and improve the bronchiectasis-specific quality-of-life in bronchiectasis patients with Pseudomonas aeruginosa infection? STUDY DESIGN: S AND METHODS: This was a phase III, 16-week, multi-center, randomized, double-blind, placebo-controlled trial. Eligible adults with bronchiectasis were recruited from October 2018 to July 2021. Based on usual care, patients nebulized TIS (300 mg/5 ml twice daily) or normal saline (5 ml twice daily) via vibrating-mesh nebulizer. Treatment consisted of two cycles of 28 days on- and off-treatment alternating periods. The co-primary endpoints were changes from baseline in P. aeruginosa density and Quality-of-life-Bronchiectasis Respiratory Symptom Score at day 29. RESULTS: The modified intention-to-treat population consisted of 167 patients in tobramycin group and 172 patients in placebo group. Compared with placebo, TIS resulted in a significantly greater reduction in P. aeruginosa density (adjusted mean difference: 1.74 Log10 colony forming units/g, 95% confidence interval: 1.12 to 2.35, P<0.001) and greater improvement in Quality-of-life-Bronchiectasis Respiratory Symptom Score (adjusted mean difference: 7.91, 95% confidence interval: 5.72 to 10.11, P<0.001) at day 29. Similar findings were observed at day 85. TIS resulted in a significant reduction in 24-hour sputum volume and sputum purulence score at days 29, 57 and 85. More patients became culture negative for P. aeruginosa in tobramycin group than in placebo group at day 29 (29.3% vs. 10.6%). The incidence of adverse events and serious adverse events were comparable between the two groups. INTERPRETATION: TIS is an effective treatment option and has an acceptable safety profile in bronchiectasis patients with P. aeruginosa infection.

10.
Front Oncol ; 12: 791332, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35903698

RESUMO

N6-methyladenosine (m6A) is the most abundant internal modification on eukaryotic mRNAs. There is increasing evidence that m6A plays a key role in tumor progression, so it is important to analyze m6A modifications within the transcriptome-wide in lung adenocarcinoma (LUAD). Three pairs of LUAD samples and tumor-adjacent normal tissues were obtained from the South University of Science and Technology Hospital. And then methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were used to identify differential m6A modifications between tumor and tumor-adjacent normal tissues. We identified 4041 aberrant m6A peaks, of which 1192 m6A peaks were upregulated and 2849 m6A peaks downregulated. It was found that genes with the dysregulated m6A peaks were enriched in the pathways in cancer, Rap1 signaling pathway, and insulin resistance. Additionally, 612 genes with abnormal regulation of m6A peaks and RNA expression were identified by combining MeRIP-seq and RNA-seq data. Through KEGG analysis, the 612 genes were enriched in cancer-related signaling pathways, such as the cGMP-PKG signaling pathway, and the Rap1 signaling pathway. What's more, GSEA enrichment analysis showed these genes were enriched in cell cycle phase transition, cell division, cellular response to DNA damage stimulus, and chromosome organization. To further explore the relationship between differential m6A modified genes and clinical parameters of LUAD patients, we searched The Cancer Genome Atlas (TCGA) and identified 2 genes (FCRL5 and GPRIN1) that were associated with the prognosis and diagnosis of LUAD patients. Furthermore, we found a positive correlation between GPRIN1 and m6A reader YTHDF1 in the GEPIA2 database. It was verified that YTHDF1 binds to GPRIN1 mRNA and regulates its expression. Our study results suggest that m6A modification plays important role in the progression and prognosis of LUAD and maybe a potential new therapeutic target for LUAD patients in the future.

11.
Biosensors (Basel) ; 12(7)2022 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-35884337

RESUMO

The biomedical acoustic signal plays an important role in clinical non-invasive diagnosis. In view of the deficiencies in early diagnosis of cardiovascular diseases, acoustic properties of S1 and S2 heart sounds are utilized. In this paper, we propose an integrated concave cilium MEMS heart sound sensor. The concave structure enlarges the area for receiving sound waves to improve the low-frequency sensitivity, and realizes the low-frequency and high-sensitivity characteristics of an MEMS heart sound sensor by adopting a reasonable acoustic package design, reducing the loss of heart sound distortion and faint heart murmurs, and improving the auscultation effect. Finally, experimental results show that the integrated concave ciliated MEMS heart sound sensor's sensitivity reaches -180.6 dB@500 Hz, as compared with the traditional bionic ciliated MEMS heart sound sensor; the sensitivity is 8.9 dB higher. The sensor has a signal-to-noise ratio of 27.05 dB, and has good heart sound detection ability, improving the accuracy of clinical detection methods.


Assuntos
Ruídos Cardíacos , Sistemas Microeletromecânicos , Cílios , Coração , Razão Sinal-Ruído
12.
Front Endocrinol (Lausanne) ; 13: 894754, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35898471

RESUMO

Purpose: The immunotherapy of lung adenocarcinoma (LUAD) has received much attention in recent years and metabolic reprogramming is linked to immune infiltration in the tumor microenvironment. Therefore, it is indispensable to dissect the role of immune-related metabolic genes in lung adenocarcinoma. Methods: In this study, we screened immune-related genes by Pearson correlation. The function of these genes was explored by gene ontology (GO) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis. The differently expressed immune-related genes were analyzed by Limma. Furthermore, the LUAD patients were clustered based on immune-related genes through consensus clustering. The Unicox was used to identify survival-immune-related metabolic genes. The Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis was used to optimize the gene sets. A prediction model was constructed and tested. The potential therapeutic target was selected based on two criteria, these immune-related metabolic genes that were highly expressed in tumor tissues and negatively correlated with the survival of patients in LUAD. Quantitative real-time PCR (qRT-PCR) was used for in vitro experimental validations. Results: We identified 346 immune-related genes, mainly involved in arachidonic acid metabolism and peroxisome proliferator-activated receptor (PPAR) signaling. Moreover, a total of 141 immune-related genes were dysregulated between tumor and normal tissues. We clustered three subtypes of LUAD based on immune-related metabolic genes and these subtypes exhibited different survival and immune status. We found Ribonucleotide Reductase Regulatory Subunit M2 (RRM2) as a potential therapeutic target, which is positively correlated with the cyclin-dependent kinase family of genes. Conclusion: We comprehensively analyzed the immune-related metabolic genes in LUAD. RRM2 was determined as a promising metabolic checkpoint for lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Microambiente Tumoral
13.
J Thorac Oncol ; 2022 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-35659581

RESUMO

INTRODUCTION: Limertinib (ASK120067) is a newly developed third-generation EGFR tyrosine kinase inhibitor targeting both sensitizing EGFR and EGFR Thr790Met (T790M) mutations. This study aimed to evaluate the efficacy and safety of limertinib in patients with locally advanced or metastatic EGFR T790M-mutated NSCLC. METHODS: This is a single-arm, open-label, phase 2b study conducted at 62 hospitals across the People's Republic of China. Patients with locally advanced or metastatic NSCLC with centrally confirmed EGFR T790M mutations in tumor tissue or blood plasma who progressed after first- or second-generation EGFR tyrosine kinase inhibitors or with primary EGFR T790M mutations were enrolled. Patients received limertinib 160 mg orally twice daily until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR) assessed by independent review committee per the Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included disease control rate, progression-free survival (PFS), duration of response (DoR), overall survival, and safety. Safety was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. RESULTS: From July 16, 2019, to March 10, 2021, a total of 301 patients were enrolled and started the treatment of limertinib. All patients entered the full analysis set and safety set. By the data cutoff date on September 9, 2021, 76 (25.2%) remained on treatment. The median follow-up time was 10.4 months (range: 0.3-26.3). On the basis of full analysis set, the independent review committee-assessed ORR was 68.8% (95% confidence interval [CI]: 63.2%-74.0%) and disease control rate was 92.4% (95% CI: 88.8%-95.1%). The median PFS was 11.0 months (95% CI: 9.7-12.4), median DoR was 11.1 months (95% CI: 9.6-13.8), and median OS was not reached (95% CI 19.7 months-not evaluable). Objective responses were achieved across all prespecified subgroups. For 99 patients (32.9%) with central nervous system (CNS) metastases, the ORR was 64.6% (95% CI: 54.4%-74.0%), median PFS was 9.7 months (95% CI: 5.9-11.6), and median DoR was 9.6 months (95% CI: 8.1-15.2). For 41 patients who had assessable CNS lesion, the confirmed CNS-ORR was 56.1% (95% CI: 39.7%-71.5%) and median CNS-PFS was 10.6 months (95% CI: 5.6-not evaluable). In safety set, 289 patients (96.0%) experienced at least one treatment-related adverse event (TRAE), with the most common being diarrhea (81.7%), anemia (32.6%), rash (29.9%), and anorexia (28.2%). Grade ≥3 TRAEs occurred in 104 patients (34.6%), with the most common including diarrhea (13.0%), hypokalemia (4.3%), anemia (4.0%), and rash (3.3%). TRAEs leading to dose interruption and dose discontinuation occurred in 24.6% and 2% of patients, respectively. No TRAE leading to death occurred. CONCLUSIONS: Limertinib (ASK120067) was found to have promising efficacy and an acceptable safety profile for the treatment of patients with locally advanced or metastatic EGFR T790M-mutated NSCLC. CLINICAL TRIAL INFORMATION: NCT03502850.

14.
iScience ; 25(7): 104522, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35754714

RESUMO

Compared with the conventional DNA probe immobilization on the planar surface, nanoparticles-based DNA probes enable more RNA molecules to be anchored to the sensor surface, thereby improving the detection sensitivity. In this work, we report phosphorodiamidate morpholino oligomers (PMO)-graphene quantum dots (GQDs)-functionalized reduced graphene oxide (RGO) field effect transistor (FET) biosensors for ultrasensitive detection of exosomal microRNAs. After the RGO FET sensor was fabricated, polylysine (PLL) film was deposited onto the RGO surface. GQDs-PMO hybrid was prepared and covalently bound to PLL surface, enabling detection of exosomal microRNAs (miRNAs). The method achieved a detection limit as low as 85 aM and high specificity. Furthermore, the FET sensor was able to detect exosomal miRNAs in plasma samples and distinguish breast cancer samples from healthy samples. Compared with other methods, we use GQDs to further improve the sensitivity of FET, making it a potential tool for early diagnosis of breast cancer.

15.
Front Neurol ; 13: 868633, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35711264

RESUMO

Objective: To analyze the interictal discharge (IID) patterns on pre-operative scalp electroencephalogram (EEG) and compare the changes in IID patterns after removal of epileptogenic tubers in preschool children with tuberous sclerosis complex (TSC)-related epilepsy. Methods: Thirty-five preschool children who underwent resective surgery for TSC-related epilepsy were enrolled retrospectively, and their EEG data collected before surgery to 3 years after surgery were analyzed. Results: Twenty-three (65.7%) patients were seizure-free post-operatively at 1-year follow-up, and 37-40% of post-operative patients rendered non-IID on scalp EEGs, and patients with focal IIDs or generalized IID patterns on pre-operative EEG presented a high percentage of normal post-operative scalp EEGs. IID patterns on pre-operative scalp EEGs did not influence the outcomes of post-operative seizure controls, while patients with non-IID and focal IID on post-operative EEGs were likely to achieve post-operative seizure freedom. Patients with new focal IIDs presented a significantly lower percentage of seizure freedom than those without new focal IIDs on post-operative EEGs at 3-year follow-up. Conclusion: Over 1/3 children with TSC presented normal scalp EEGs after resective epileptsy surgery. Patients with post-operative seizure freedom were more likely to have non-IIDs on post-operative EEGs. New focal IIDs were negative factors for seizure freedom at the 3-year follow-up.

16.
MedComm (2020) ; 3(3): e136, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35711853

RESUMO

The CDK4/6-Rb axis is a crucial target of cancer therapy and several selective inhibitors of it have been approved for clinical application. However, current therapeutic efficacy evaluation mostly relies on anatomical imaging, which cannot directly reflect changes in drug targets, leading to a delay in the selection of optimal treatment. In this study, we constructed a novel fluorescent probe, CPP30-Lipo/CDKACT4, for real-time monitoring of CDK4 activity and the therapeutic efficacy of its inhibitor in HR+/HER2- breast cancer. CPP30-Lipo/CDKACT4 exhibited good optical stability and targetability. The signal of the probe in living cells decreased after CDK4 knockdown or palbociclib treatment. Moreover, the fluorescence intensity of the tumors after 7 days of palbociclib treatment was significantly lower than that before treatment, while no significant change in tumor diameter was observed under magnetic resonance imaging. Overall, we developed an innovative fluorescent probe that can monitor CDK4 activity and the early therapeutic response to CDK4 inhibitors in living cells and in vivo. It may provide a new strategy for evaluating antitumor therapeutic efficacy in a clinical context and for drug development.

17.
Materials (Basel) ; 15(12)2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35744157

RESUMO

In wire electrical discharge machining, due to the random distribution of the insulating SiC particles, frequent wire rupture, low machining efficiency and surface quality when the common brass wire electrode (BWE) is used to process high-volume content SiCp/Al composite often appears. To address this issue, this paper proposes a new preparation method of zinc coating and surface microstructure on wire electrodes (ZCSMWE). The preparation process of ZCSMWE includes casting, coating, annealing and plastic processing. The experimental results show that, compared with BWE, ZCSMWE can increase material removal rate (MRR) by 16.67%, reduce surface roughness (Ra) by 21.18% and reduce wire rupture under the same discharge parameters. The analysis of workpiece surface topography shows that ZCSMWE can significantly decrease the recast layer and microcrack on the machined surface. The improvement mechanism of ZCSMWE main includes: The low work function zinc can promote the forming of the discharge channel. The vaporization of low boiling temperature zinc can reduce the temperature of the discharge gap and promote the ejecting of workpiece material. In addition, the surface microstructure on ZCSMWE can make the discharge spark more uniformly distributed and increase the proportion of the effective discharge, which contributes to making the discharge crater on the workpiece and wire electrode shallower and more uniform. The surface microstructure on ZCSMWE can also effectively improve the dielectric circulation, which can promote discharge debris to be expelled out and reduce the temperature in the discharge gap. Then, the wire rupture and microcracks on the workpiece surface can be reduced.

18.
Micromachines (Basel) ; 13(6)2022 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-35744458

RESUMO

This paper proposed a hybrid intelligent process model, based on a hybrid model combining the two-temperature model (TTM) and molecular dynamics simulation (MDS) (TTM-MDS). Combined atomistic-continuum modeling of short-pulse laser melting and disintegration of metal films [Physical Review B, 68, (064114):1-22.], and Gaussian process regression (GPR), for micro-electrical discharge machining (micro-EDM) were also used. A model of single-spark micro-EDM process has been constructed based on TTM-MDS model to predict the removed depth (RD) and material removal rate (MRR). Then, a GPR model was proposed to establish the relationship between input process parameters (energy area density and pulse-on duration) and the process responses (RD and MRR) for micro-EDM machining. The GPR model was trained, tested, and tuned using the data generated from the numerical simulations. Through the GPR model, it was found that micro-EDM process responses can be accurately predicted for the chosen process conditions. Therefore, the hybrid intelligent model proposed in this paper can be used for a micro-EDM process to predict the performance.

19.
Crit Rev Oncol Hematol ; 176: 103746, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35752425

RESUMO

Recently, immune checkpoint therapy (ICT) represented by programmed cell death1 (PD-1) and its major ligands, programmed death ligand 1 (PD-L1), has achieved significant success. Detection of PD-L1 by immunohistochemistry (IHC) is a classic method to guide the treatment of ICT patients. However, PD-L1 expression in the tumor microenvironment is highly complex. Thus, PD-L1 IHC is inadequate to fully understand the relevance of PD-L1 levels in the whole body and their dynamics to improve therapeutic outcomes. Intriguingly, numerous studies have revealed that molecular imaging technologies could potentially meet this need. Therefore, the purpose of this narrative review is to summarize the preclinical and clinical application of ICT guided by molecular imaging technology, and to explore the future opportunities and practical difficulties of these innovations.


Assuntos
Antígeno B7-H1 , Microambiente Tumoral , Humanos , Imuno-Histoquímica , Imagem Molecular , Prognóstico
20.
J Thorac Oncol ; 2022 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-35724798

RESUMO

INTRODUCTION: Befotertinib (D-0316) is a novel, third-generation EGFR tyrosine kinase inhibitor (TKI). This study evaluated befotertinib in patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy. METHODS: This was a single-arm, open-label, phase 2 study at 49 hospitals across mainland China. Patients with locally advanced or metastatic NSCLC harboring EGFR T790M mutations with disease progression after prior first- or second-generation EGFR TKI therapy received oral befotertinib of 50 mg (cohort A) or 75 to 100 mg (cohort B) once daily. The primary end point was objective response rate (ORR) assessed by an independent review committee in intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT03861156. RESULTS: A total of 176 patients and 290 patients were included in cohorts A (50 mg) and B (75-100 mg), respectively. At data cutoff (August 15, 2021), independent review committee-assessed ORR was 67.6% (95% confidence interval [CI]: 61.9%-72.9%) in cohort B. The investigator-assessed ORR was 54.0% (95% CI: 46.3%-61.5%) in cohort A and 65.9% (95% CI: 60.1%-71.3%) in cohort B. The median investigator-assessed progression-free survival was 11.0 (95% CI: 9.6-12.5) months in cohort A and 12.5 (95% CI: 11.1-13.8) months in cohort B. The median independent review committee-assessed progression-free survival in cohort B was 16.6 (95% CI: 15.0-not evaluable [NE]) months. The intracranial ORR was 26.7% (95% CI: 7.8%-55.1%) in cohort A by investigator assessment, while 57.1% (95% CI: 34.0%-78.2%) and 55.9% (95% CI: 37.9%-72.8%) in cohort B by investigator and independent review committee assessment, respectively. The median investigator-assessed intracranial progression-free survival was 16.5 (95% CI: 8.6-NE) months in cohort A, while the median intracranial progression-free survival was not evaluable in cohort B due to immature data regardless of investigator or independent review committee assessment. and NE (95% CI: 13.8-NE) in cohort B. The overall survival was immature. Grade 3 or higher treatment-related adverse events and treatment-related serious adverse events occurred in 20.5% and 11.4% of patients in cohort A and in 29.3% and 10.0% of patients in cohort B, respectively. CONCLUSIONS: Befotertinib of 75 to 100 mg has satisfying efficacy and manageable toxicity in patients with locally advanced or metastatic NSCLC harboring T790M mutation with resistance to first- or second-generation EGFR TKIs. A phase 3 randomized trial is underway (NCT04206072).

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