Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.318
Filtrar
1.
Front Pediatr ; 9: 682738, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34604132

RESUMO

Background: Histiocytic necrotizing lymphadenitis, also known as Kikuchi-Fujimoto disease (KFD), is a self-limiting inflammatory disease with low incidence and high misdiagnosis rate in children. Furthermore, cases where the clinical presentation resembles acute appendicitis are very rare. Case Presentation: A 14-year-old boy was misdiagnosed as acute appendicitis and received operative treatment at his early visit. He suffered from abdominal pain, vomiting, diarrhea, fever, and lymphadenitis at the ileocecal junction, which were found by B-ultrasonography examination and surgery. Lymphadenectomy, as well as appendectomy, was performed, and KFD was identified by pathological examination. The patient was transferred to our hospital for further therapy because of recurrent fever and abdominal pain after the appendectomy. His temperature became normal after methylprednisolone was administered, and no recurrence was observed till now during follow-up. Conclusions: Necrotizing lymphadenitis involving mesenteric lymph nodes may cause acute-appendicitis-like symptom; KFD should be a diagnostic consideration for mesenteric lymphadenitis.

2.
J Mech Behav Biomed Mater ; 124: 104851, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34600430

RESUMO

The current study reports the use of small amplitude oscillatory rheometry to investigate the dynamics of blood clot formation upon heparin neutralization under three different oscillatory frequencies, two of which were mimicking physiological heart rates. We utilized two different heparin antidotes, namely protamine and newly developed universal heparin reversal agent (UHRA-7), at different concentrations to determine the quality of blood clot formed upon heparin neutralization by analyzing several key rheological parameters. Scanning electron microscopy (SEM) was used to determine the morphology and microstructure of the blood clot after heparin neutralization to support the rheological observations. The current study revealed that the structure of blood clots formed had significant differences when an oscillatory frequency that mimicked the physiological heart rate was used in comparison to a lower frequency commonly used in current clinical measurements. The limited working dose range for protamine and its intrinsic anticoagulation behaviour was observed. The neutralization profile of UHRA-7 showed a large window of activity. The global assessment of rheological parameters and microstructure of the clot together revealed additional details describing anticoagulant reversal and blood coagulation dynamics by relating the blood clot's fiber thickness and the oscillatory measurements, including storage modulus and blood clot's contractile force. Additionally, a mechanical characterization was conducted to provide a further assessment of blood coagulation using the rheological data.

3.
Nat Neurosci ; 2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663958

RESUMO

The basolateral amygdala (BLA) plays essential roles in behaviors motivated by stimuli with either positive or negative valence, but how it processes motivationally opposing information and participates in establishing valence-specific behaviors remains unclear. Here, by targeting Fezf2-expressing neurons in the BLA, we identify and characterize two functionally distinct classes in behaving mice, the negative-valence neurons and positive-valence neurons, which innately represent aversive and rewarding stimuli, respectively, and through learning acquire predictive responses that are essential for punishment avoidance or reward seeking. Notably, these two classes of neurons receive inputs from separate sets of sensory and limbic areas, and convey punishment and reward information through projections to the nucleus accumbens and olfactory tubercle, respectively, to drive negative and positive reinforcement. Thus, valence-specific BLA neurons are wired with distinctive input-output structures, forming a circuit framework that supports the roles of the BLA in encoding, learning and executing valence-specific motivated behaviors.

4.
Exp Biol Med (Maywood) ; : 15353702211053580, 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34674573

RESUMO

Cervical cancer mortality is the second highest in gynecological cancers. This study developed a new model based on copy number variation data and mRNA data for overall survival prediction of cervical cancer. Differentially expressed genes from The Cancer Genome Atlas dataset detected by univariate Cox regression analysis were further simplified to six by least absolute shrinkage and selection operator (Lasso) and stepwise Akaike information criterion (stepAIC). The study developed a six-gene signature, which was further verified in independent dataset. Association between immune infiltration and risk score was investigated by immune score. The relation between the signature and functional pathways was examined by gene set enrichment analysis. Ninety-nine differentially expressed genes were detected, and C11orf80, FOXP3, GSN, HCCS, PGAM5, and RIBC2 were identified as key genes to construct a six-gene signature. The prognostic signature showed a significant correlation with overall survival (hazard ratio, HR = 3.45, 95% confidence interval (CI) = 2.08-5.72, p < 0.00001). Immune score showed a negative correlation with the risk score calculated by the signature (p < 0.05). Four immune-related pathways were closely associated with risk score (p < 0.0001). The six-gene prognostic signature was an effective tool to predict overall survival of cervical cancer. In conclusion, the newly identified six genes may be considered as new drug targets for cervical cancer treatment.

5.
Front Neurol ; 12: 738329, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630307

RESUMO

Objective: Coronavirus disease (COVID-19) vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but fatal complication observed within 2 weeks of adenovirus-vectored vaccination. Case Report: A 52-year-old male patient, with a family history of autoimmune diseases, presented with a new onset of worsening headache with nausea and vomiting post-vaccination. The patient was diagnosed with VITT based on laboratory findings demonstrating thrombocytopenia, elevated D-dimer, and dural sinus thrombosis identified on neuroimaging. The patient was successfully treated with high-dose immunoglobulin, steroids, and non-heparin anticoagulants, without any neurologic sequelae. Finally, a confirmatory test with anti-platelet factor 4 antibody was strongly positive. Conclusion: Physicians should be vigilant when treating patients presenting with new-onset thunderclap headache, progressive worsening headache, and awakening headache accompanied by nausea or vomiting after vaccination, even if no definite clinical neurological deficits are identified. Emergency laboratory test results for demonstrating elevated D-dimer levels, decreased platelet count, and neuroimaging correlation are integral for diagnosis and must be the standard protocol. Treatment with non-heparin anticoagulants, high-dose intravenous immunoglobulin, and steroids that halt or slow the immune-mediated prothrombotic process should be initiated immediately. Considering the high mortality rate of VITT, treatment should be initiated prior to confirmatory test results.

6.
Int J Biol Sci ; 17(14): 3898-3910, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34671207

RESUMO

Hypoxia and angiogenesis play key roles in the pathogenesis of esophageal squamous cell carcinoma (ESCC), but regulators linking these two pathways to drive tumor progression remain elusive. Here we provide evidence of ADAM9's novel function in ESCC progression. Increasing expression of ADAM9 was correlated with poor clinical outcomes in ESCC patients. Suppression of ADAM9 function diminished ESCC cell migration and in vivo metastasis in ESCC xenograft mouse models. Using cellular fractionation and imaging, we found a fraction of ADAM9 was present in the nucleus and was uniquely associated with gene loci known to be linked to the angiogenesis pathway demonstrated by genome-wide ChIP-seq. Mechanistically, nuclear ADAM9, triggered by hypoxia-induced translocation, functions as a transcriptional repressor by binding to promoters of genes involved in the negative regulation of angiogenesis, and thereby promotes tumor angiogenesis in plasminogen/plasmin pathway. Moreover, ADAM9 suppresses plasminogen activator inhibitor-1 gene transcription by interacting with its transcription factors at the promoter. Our findings uncover a novel regulatory mechanism of ADAM9 as a transcriptional regulator in angiogenesis and highlight ADAM9 as a promising therapeutic target for ESCC treatment.

7.
Inorg Chem ; 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34669382

RESUMO

Organic rigid ligand-modified polyoxometalate-based materials possess complex and diverse structures, promising electrochemical energy storage properties and outstanding photocatalytic capabilities. Hence, two new [BW12O40]5-(abbreviated as {BW12O40})-based inorganic-organic hybrids [{Cu(en)2(H2O)}][{Cu(pdc)(en)}{Cu(en)2}(BW12O40)]·2H2O (1) and [{CuI5(pz)6(H2O)4}(BW12O40)] (2) (pdc = 2-picolinate, en = ethylenediamine, pz = pyrazine) were successfully synthesized through a hydrothermal method. Among them, pdc and pz were obtained by in situ transformation from 2,6-pyridinedicarboxylic acid (H2 pydc) and 2,3-pyrazinedicarboxylic acid (H2pzdc), respectively. In compound 1, the {BW12O40} clusters as an intermediate junction connect with {Cu(pdc)(en)}{Cu(en)2} and {Cu(en)2(H2O)} to form monomers, which in turn form supramolecular chains, sheets, and space network via hydrogen bonding. The {BW12O40} clusters are packed into copper-pyrazine frameworks in compound 2, and a unique polyoxometalate-based metal organic frameworks (POMOFs) structure with a new topology of {12}2{6.123.142}2{62.12.142.18}{62.123.16}{6}6 is formed via covalent bonds. When used as electrode materials for supercapacitors, the values of specific capacitance are 651.56 F g-1 for 1-GCE and 584.43 F g-1 for 2-GCE at a current density of 2.16 A g-1 and good cycling stability (90.94%, 94.81% of the initial capacity after 5000 cycles at 15.12 A g-1, respectively). The kinetic analysis reveals that surface capacitance plays a major role. Furthermore, both compounds can effectively degrade Rhodamine B (RhB) and Methylene blue (MB), showing the outstanding photocatalytic performance.

8.
Ann Palliat Med ; 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34670383

RESUMO

BACKGROUND: Acute kidney injury (AKI) is a common and multifactorial complication after liver transplantation (LT). Myoglobin (Mb) which can be served as O2 storage and delivery depot is present in muscles and cardiac myocytes. Previous studies had shown the close relationship between Mb and AKI. But there is a lack of clinical studies for Mb with the risk of AKI due to LT. This study was performed to determine the association between the serum level of Mb and incidence of AKI in patients underwent LT. METHODS: The clinical data of 140 consecutive adult patients who underwent LT at our center from June 2018 to August 2020 were analyzed in this study. One hundred and fifteen patients met the inclusion criteria. The performances of postoperative laboratory variables (including serum Mb) were evaluated. The outcomes after LT, including the duration of intensive care unit (ICU) stay, hospital stay and 28-day mortality, were also measured. RESULTS: We divided 115 patients into AKI group (n=44) and non-AKI group (n=71). Serum Mb on postoperative day 0 (POD0) was significantly higher in AKI group than those in non-AKI group (P<0.001). According to univariate and multivariable logistic regression analysis, the levels of serum albumin (P=0.024), alanine transaminase (P=0.007) and Mb (P=0.006) on POD0 were independently associated with development of new AKI. The area under curve (AUC) of serum Mb after LT immediately had the best value for predicting AKI [AUC: 0.755, sensitivity: 63.6%, specificity: 77.3%, 95% confidence interval (CI): 0.661-0.849], its cut-off value was 957 ng/mL. CONCLUSIONS: Postoperative serum Mb was an independent risk factor for new AKI and could increase the accuracy of predicting the occurrence of post-LT AKI. TRIAL REGISTRATION: The study was registered in Chinese Clinical Trial Registry (registration number: ChiCTR2100044257).

10.
J Hazard Mater ; 423(Pt A): 126921, 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34523506

RESUMO

Colourants, micropollutants and heavy metals are regarded as the most notorious hazardous contaminants found in rivers, oceans and sewage treatment plants, with detrimental impacts on human health and environment. In recent development, algal biomass showed great potential for the synthesis of engineered algal adsorbents suitable for the adsorptive management of various pollutants. This review presents comprehensive investigations on the engineered synthesis routes focusing mainly on mechanical, thermochemical and activation processes to produce algal adsorbents. The adsorptive performances of engineered algal adsorbents are assessed in accordance with different categories of hazardous pollutants as well as in terms of their experimental and modelled adsorption capacities. Due to the unique physicochemical properties of macroalgae and microalgae in their adsorbent forms, the adsorption of hazardous pollutants was found to be highly effective, which involved different mechanisms such as physisorption, chemisorption, ion-exchange, complexation and others depending on the types of pollutants. Overall, both macroalgae and microalgae not only can be tailored into different forms of adsorbents based on the applications, their adsorption capacities are also far more superior compared to the conventional adsorbents.

11.
J Colloid Interface Sci ; 607(Pt 1): 1-15, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34500412

RESUMO

The intracellular O2-supply not only can relieve tumor hypoxia but also enhance the effects of photodynamic therapy (PDT). In this work, metallic Mo2C@N-carbon@PEG nanoparticles were constructed to reveal the near infrared (NIR)-photocatalytic O2 generation and promote photodynamic therapy (PDT). Here, (NH4)6Mo7O24·4H2O nanorods and urea were adopted as resources that were calcined to obtain Mo2C@N-carbon nanoparticles (20 nm). All samples displayed high NIR absorption as well as photothermal conversion efficiency of up to 52.7 % (Mo2C@N-Carbon-3@PEG). The density functional theory calculations demonstrated the metallic characteristic of Mo2C and that the consecutive interband/intraband charge-transition was responsible for the high NIR harvest and redox ability of electron-hole pairs, making the NIR-photocatalytic O2 and reactive oxygen species (ROS) generation. In comparison with the pure Mo2C, the heterostructure displayed twice the performance due to the enhanced charge-segregation between Mo2C and N-carbon. Given the high X-ray absorption coefficient and photothermal ability, the nanocomposite could be used in novel computer tomography and photothermal imaging contrast. Furthermore, the novel biodegradation and metabolism behaviors of nanocomposites were investigated, which were reflected as elimination from the body (mouse) via feces and urine within 14 days. The as-synthesized Mo2C@N-Carbon@PEG nanocomposites integrated the dual-model imaging, intracellular O2-supply, and phototherapy into one nanoplatform, revealing its potential for anti-cancer therapy.

12.
J Colloid Interface Sci ; 607(Pt 2): 1446-1456, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34583047

RESUMO

Solar-driven interface water evaporation is a promising strategy for desalination and wastewater treatment. However, it remains a huge challenge to simultaneously achieve a high light-to-heat conversion efficiency (η) and multi-media evaporation applications. In this study, a highly efficient Janus hydrogel photothermal film was developed using yolk-like non-stoichiometric nickel sulfide (NiS2-x) microspheres and agar hydrogel. The NiS2-x immobilized in the agar hydrogel has full-spectrum absorption characteristics at 200-2500 nm, which can perform efficient light-to-heat conversion and regulate water transport channels. Additionally, the pure agar in the bottom can transport water effectively and avoid heat loss. By the pouring method, the Janus hydrogel film can be easily prepared into various shapes; hence, it can be adjusted depending on the environment in which it is used. The optimized Janus hydrogel film (Janus hydrogel-1) possessed good hydrophilicity and showed an excellent solar evaporation rate of 1.45 kg m-2h-1, and a high η of 97% under one-sun irradiation. Theoretical simulation results showed that the outstanding water evaporation performance of Janus hydrogel-1 was mainly due to its relatively free water transport channels. Janus hydrogel-1 can be used for water evaporation applications in various media, including seawater, heavy metal ion/organic wastewater, and domestic sewage. Our work highlights the great potential of Janus hydrogel-1 for realizing a highly effective solar energy-driven interface water evaporation and multi-media purification.

13.
ACS Sens ; 6(10): 3744-3752, 2021 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-34553592

RESUMO

We present BioChemPen, a portable wireless biosensor device for rapid analysis of substances adsorbed on solid surfaces. The device takes advantage of (bio)luminescent reactions taking place in a hydrogel matrix. In a typical embodiment, the active element of this device is a hydrogel disk (chemotransducer) containing enzyme(s), electrolyte solution, and all of the necessary substrates. When the hydrogel is exposed to a solid sample surface containing the target analyte, light is produced. A photoresistor (phototransducer), placed in close proximity to the hydrogel disk, detects the light. The operation of the BioChemPen is enabled by a MicroPython PyBoard microcontroller board and other low-cost electronic modules. The obtained results are immediately uploaded to the Internet cloud. In one application, we demonstrate an analysis of hypochlorite-containing cleaning agents present on the surfaces of daily use objects by an assay based on hydrogel embedded with luminol and hydrogen peroxide. In another application, we use hydrogel embedded with luciferin, luciferase, and pyruvate kinase to detect adenosine triphosphate (ATP), and adenosine diphosphate (ADP), and link the ATP content with meat freshness. Lastly, we demonstrate the detection of organophosphate pesticides present on vegetables with the hydrogel containing acetylcholinesterase, choline oxidase, and horseradish peroxidase. The limits of detection for sodium hypochlorite, ATP, ADP, and chlorpyrifos-methyl (a pesticide) were 7.95 × 10-11, 2.73 × 10-13, 2.35 × 10-12, and 2.59 × 10-10 mol mm-2, respectively.

14.
Pharmaceuticals (Basel) ; 14(9)2021 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-34577576

RESUMO

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with a median duration of survival of approximately 14 months after diagnosis. High resistance to chemotherapy remains a major problem. Previously, BTK has been shown to be involved in the intracellular signal transduction including Akt/mTOR signaling and be critical for tumorigenesis. Thus, we aim to evaluate the effect of BTK and mTOR inhibition in GBM. We evaluated the viability of GBM cell lines after treatment with acalabrutinib and/or rapamycin through a SRB staining assay. We then evaluated the effect of both drugs on GBM stem cell-like phenotypes through various in vitro assay. Furthermore, we incubated HUVEC cells with tumorsphere conditioned media and observed their angiogenesis potential, with or without treatment. Finally, we conducted an in vivo study to confirm our in vitro findings and analyzed the effect of this combination on xenograft mice models. Drug combination assay demonstrated a synergistic relationship between acalabrutinib and rapamycin. CSCs phenotypes, including tumorsphere and colony formation with the associated expression of markers of pluripotency are inhibited by either acalabrutinib or rapamycin singly and these effects are enhanced upon combining acalabrutinib and rapamycin. We showed that the angiogenesis capabilities of HUVEC cells are significantly reduced after treatment with acalabrutinib and/or rapamycin. Xenograft tumors treated with both drugs showed significant volume reduction with minimal toxicity. Samples taken from the combined treatment group demonstrated an increased Desmin/CD31 and col IV/vessel ratio, suggesting an increased rate of vascular normalization. Our results demonstrate that BTK-mTOR inhibition disrupts the population of GBM-CSCs and contributes to normalizing GBM vascularization and thus, may serve as a basis for developing therapeutic strategies for chemoresistant/radioresistant GBM.

15.
IEEE Trans Med Imaging ; PP2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34520349

RESUMO

Drusen is considered as the landmark for diagnosis of AMD and important risk factor for the development of AMD. Therefore, accurate segmentation of drusen in retinal OCT images is crucial for early diagnosis of AMD. However, drusen segmentation in retinal OCT images is still very challenging due to the large variations in size and shape of drusen, blurred boundaries, and speckle noise interference. Moreover, the lack of OCT dataset with pixel-level annotation is also a vital factor hindering the improvement of drusen segmentation accuracy. To solve these problems, a novel multi-scale transformer global attention network (MsTGANet) is proposed for drusen segmentation in retinal OCT images. In MsTGANet, which is based on U-Shape architecture, a novel multi-scale transformer non-local (MsTNL) module is designed and inserted into the top of encoder path, aiming at capturing multi-scale non-local features with long-range dependencies from different layers of encoder. Meanwhile, a novel multi-semantic global channel and spatial joint attention module (MsGCS) between encoder and decoder is proposed to guide the model to fuse different semantic features, thereby improving the model's ability to learn multi-semantic global contextual information. Furthermore, to alleviate the shortage of labeled data, we propose a novel semi-supervised version of MsTGANet (Semi-MsTGANet) based on pseudo-labeled data augmentation strategy, which can leverage a large amount of unlabeled data to further improve the segmentation performance. Finally, comprehensive experiments are conducted to evaluate the performance of the proposed MsTGANet and Semi-MsTGANet. The experimental results show that our proposed methods achieve better segmentation accuracy than other state-of-the-art CNN-based methods.

16.
Exp Ther Med ; 22(5): 1204, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34584549

RESUMO

The present study investigated the role of tubulin polymerization promoting protein (TPPP) in the regulation of bladder cancer (BC) cell proliferation and migration, in addition to the association between TPPP gene copy number amplification and clinicopathological characteristics of BC. TPPP gene amplification was measured in human BC epithelial cells and samples obtained from 52 patients with BC via fluorescence in situ hybridization. TPPP gain was defined as mean TPPP copy number >2.2 per nucleus (cutoff). The neutrophil-to-lymphocyte ratio (NLR) was also obtained from the preoperative data of the patients. For in vitro assays, BC cell lines were transfected with either TPPP small interfering RNAs or scrambled control, following which cell proliferation and migration were determined using Cell Counting Kit-8 and Transwell migration assays, respectively. The percentage of cells with TPPP copy number amplification in the four BC epithelial cell lines (MGH-U1, -U1R, -U3, -U4) examined (86.0-100.0%) was found to be higher compared with that in the normal human uroepithelial cell lines (3.0 and 9.0%). Patients were divided into one- (1.9%), two- (55.8%), three- (7.7%), four- (26.9%) and five-copy (7.7%) types. Results calculated using Fisher's exact test indicated that the gain of TPPP in patients with BC associated significantly with age (P<0.05), advanced histological grade (P<0.001), tumor stage (P<0.05), histological type (P<0.001) and NLR (P<0.05). In MGH-U1R and MGH-U4 cells, cell proliferation and migration were revealed to be significantly lower following TPPP knockdown compared with those in cells transfected with the scrambled control. In conclusion, findings from the present study suggest that TPPP is important for cell proliferation, cell migration and BC progression, such that TPPP copy number assessment would be advised for preoperative urine cytology for urothelial neoplasia diagnosis.

17.
Blood Adv ; 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34492681

RESUMO

RUNX1 is essential for the generation of hematopoietic stem cells (HSCs). Runx1 null mouse embryos lack definitive hematopoiesis and die in mid-gestation. However, even though zebrafish embryos with a runx1 W84X mutation have defects in early definitive hematopoiesis, some runx1W84X/W84X embryos can develop to fertile adults with blood cells of multi-lineages, raising the possibility that HSCs can emerge without RUNX1. Here, using three new zebrafish runx1-/- lines we uncovered the compensatory mechanism for runx1-independent hematopoiesis. We show that, in the absence of a functional runx1, a cd41-GFP+ population of hematopoietic precursors still emerge from the hemogenic endothelium and can colonize the hematopoietic tissues of the mutant embryos. Single-cell RNA sequencing of the cd41-GFP+ cells identified a set of runx1-/--specific signature genes during hematopoiesis. Significantly, gata2b, which normally acts upstream of runx1 for the generation of HSCs, was increased in the cd41-GFP+ cells in runx1- /- embryos. Interestingly, genetic inactivation of both gata2b and its paralog, gata2a, did not affect hematopoiesis. However, knocking out runx1 and any three of the four alleles of gata2a and gata2b abolished definitive hematopoiesis. Gata2 expression was also upregulated in hematopoietic cells in Runx1-/- mice, suggesting the compensatory mechanism is conserved. Our findings indicate that RUNX1 and GATA2 serve redundant roles for HSC production, acting as each other's safeguard.

18.
J Immunother Cancer ; 9(9)2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34518289

RESUMO

BACKGROUND: Neoantigens derived from somatic mutations correlate with therapeutic responses mediated by treatment with immune checkpoint inhibitors. Neoantigens are therefore highly attractive targets for the development of therapeutic approaches in personalized medicine, although many aspects of their quality and associated immune responses are not yet well understood. In a case study of metastatic malignant melanoma, we aimed to perform an in-depth characterization of neoantigens and respective T-cell responses in the context of immune checkpoint modulation. METHODS: Three neoantigens, which we identified either by immunopeptidomics or in silico prediction, were investigated using binding affinity analyses and structural simulations. We isolated seven T-cell receptors (TCRs) from the patient's immune repertoire recognizing these antigens. TCRs were compared in vitro by multiparametric analyses including functional avidity, multicytokine secretion, and cross-reactivity screenings. A xenograft mouse model served to study in vivo functionality of selected TCRs. We investigated the patient's TCR repertoire in blood and different tumor-related tissues over 3 years using TCR beta deep sequencing. RESULTS: Selected mutated peptide ligands with proven immunogenicity showed similar binding affinities to the human leukocyte antigen complex and comparable disparity to their wild-type counterparts in molecular dynamic simulations. Nevertheless, isolated TCRs recognizing these antigens demonstrated distinct patterns in functionality and frequency. TCRs with lower functional avidity showed at least equal antitumor immune responses in vivo. Moreover, they occurred at high frequencies and particularly demonstrated long-term persistence within tumor tissues, lymph nodes and various blood samples associated with a reduced activation pattern on primary in vitro stimulation. CONCLUSIONS: We performed a so far unique fine characterization of neoantigen-specific T-cell responses revealing defined reactivity patterns of neoantigen-specific TCRs. Our data highlight qualitative differences of these TCRs associated with function and longevity of respective T cells. Such features need to be considered for further optimization of neoantigen targeting including adoptive T-cell therapies using TCR-transgenic T cells.

19.
Chem Sci ; 12(33): 11236, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34522321

RESUMO

[This corrects the article DOI: 10.1039/D1SC01385H.].

20.
Am J Cancer Res ; 11(8): 3794-3812, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34522450

RESUMO

Hepatocellular carcinoma (HCC) is the sixth most deadly malignant cancer in the world and has the third highest mortality rate among cancer-related deaths worldwide. Its poor prognosis can be attributed to late diagnosis, high risk of recurrence and drug resistance. Therefore, finding a new biomarker to help us in the early diagnosis, and exploring the molecular mechanisms involved in recurrence and drug resistance is a reasonable research direction for clinical treatment of HCC. At present, the exosomes related to HCC have been confirmed to carry ncRNAs, transfer them to target cells, and bind corresponding target molecules. Furthermore, they affect the proliferation and metastasis of hepatocellular carcinoma by promoting angiogenesis, epithelial-mesenchymal transition (EMT), and inhibiting the function of the body's immune system. They play an important role in the recurrence and resistance of HCC. Besides, exosomes are stably expressed in body fluids such as sera, are easy to collect and cause little harm to the human body. They are the best candidates for liquid biopsy. Therefore, exosomal ncRNAs have application prospects as biomarkers and targeted molecules for therapy. This article summarizes the current research involving ncRNAs in HCC-related exosomes.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...