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1.
J Nanobiotechnology ; 20(1): 23, 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-34991618

RESUMO

Regulation of stimulator of interferon genes (STING) pathway using agonists can boost antitumor immunity for cancer treatment, while the rapid plasma clearance, limited membrane permeability, and inefficient cytosolic transport of STING agonists greatly compromise their therapeutic efficacy. In this study, we describe an extracellular matrix (ECM)-degrading nanoagonist (dNAc) with second near-infrared (NIR-II) light controlled activation of intracellular STING pathway for mild photothermal-augmented chemodynamic-immunotherapy of breast cancer. The dNAc consists of a thermal-responsive liposome inside loading with ferrous sulfide (FeS2) nanoparticles as both NIR-II photothermal converters and Fenton catalysts, 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) as the STING agonist, and an ECM-degrading enzyme (bromelain) on the liposome surface. Mild heat generated by dNAc upon NIR-II photoirradiation improves Fenton reaction efficacy to kill tumor cells and cause immunogenic cell death (ICD). Meanwhile, the generated heat triggers a controlled release of cGAMP from thermal-responsive liposomes to active STING pathway. The mild photothermal activation of STING pathway combined with ICD promotes anti-tumor immune responses, which leads to improved infiltration of effector T cells into tumor tissues after bromelain-mediated ECM degradation. As a result, after treatment with dNAc upon NIR-II photoactivation, both primary and distant tumors in a murine mouse model are inhibited and the liver and lung metastasis are effectively suppressed. This work presents a photoactivatable system for STING pathway and combinational immunotherapy with improved therapeutic outcome.

2.
J Transl Med ; 20(1): 18, 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-34991628

RESUMO

BACKGROUND: Cervical cancer is the most fatal gynecological carcinoma in the world. It is urgent to explore novel prognostic biomarkers and intervention targets for cervical cancer. METHODS: Through integrated quantitative proteomic strategy, we investigated the protein expression profiles of cervical cancer; 28 fresh frozen tissue samples (11 adenocarcinoma (AC), 12 squamous cell carcinoma (SCC) and 5 normal cervixes (HC)) were included in discover cohort; 45 fresh frozen tissue samples (19 AC, 18 SCC and 8 HC) were included in verification cohort; 140 paraffin-embedded tissues samples of cervical cancer (85 AC and 55 SCC) were used for immunohistochemical evaluation (IHC) of coatomer protein subunit alpha (COPA) as a prognostic biomarker for cervical cancer; how deficiency of COPA affects cell viability and tumorigenic ability of cervical cancer cells (SiHa cells and HeLa cells) were evaluated by cell counting kit-8 and clone formation in vitro. RESULTS: We identified COPA is a potential prognostic biomarker for cervical cancer in quantitative proteomics analysis. By retrospective IHC analysis, we additionally verified the proteomics results and demonstrated moderate or strong IHC staining for COPA is an unfavourable independent prognostic factor for cervical cancer. We also identified COPA is a potential pharmacological intervention target of cervical cancer by a series of in vitro experiments. CONCLUSION: This study is the first to demonstrate that COPA may contribute to progression of cervical cancer. It can serve as a potential prognostic biomarker and promising intervention target for cervical cancer.

3.
Eur Radiol ; 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-34988656

RESUMO

BACKGROUND: Main challenges for COVID-19 include the lack of a rapid diagnostic test, a suitable tool to monitor and predict a patient's clinical course and an efficient way for data sharing among multicenters. We thus developed a novel artificial intelligence system based on deep learning (DL) and federated learning (FL) for the diagnosis, monitoring, and prediction of a patient's clinical course. METHODS: CT imaging derived from 6 different multicenter cohorts were used for stepwise diagnostic algorithm to diagnose COVID-19, with or without clinical data. Patients with more than 3 consecutive CT images were trained for the monitoring algorithm. FL has been applied for decentralized refinement of independently built DL models. RESULTS: A total of 1,552,988 CT slices from 4804 patients were used. The model can diagnose COVID-19 based on CT alone with the AUC being 0.98 (95% CI 0.97-0.99), and outperforms the radiologist's assessment. We have also successfully tested the incorporation of the DL diagnostic model with the FL framework. Its auto-segmentation analyses co-related well with those by radiologists and achieved a high Dice's coefficient of 0.77. It can produce a predictive curve of a patient's clinical course if serial CT assessments are available. INTERPRETATION: The system has high consistency in diagnosing COVID-19 based on CT, with or without clinical data. Alternatively, it can be implemented on a FL platform, which would potentially encourage the data sharing in the future. It also can produce an objective predictive curve of a patient's clinical course for visualization. KEY POINTS: • CoviDet could diagnose COVID-19 based on chest CT with high consistency; this outperformed the radiologist's assessment. Its auto-segmentation analyses co-related well with those by radiologists and could potentially monitor and predict a patient's clinical course if serial CT assessments are available. It can be integrated into the federated learning framework. • CoviDet can be used as an adjunct to aid clinicians with the CT diagnosis of COVID-19 and can potentially be used for disease monitoring; federated learning can potentially open opportunities for global collaboration.

4.
Front Microbiol ; 12: 729952, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34867846

RESUMO

New Delhi metallo-ß-lactamases (NDMs), including at least 28 variants, are a rapidly emerging family of ß-lactamases worldwide, with a variety of infections caused by NDM-positive strains usually associated with very poor prognosis and high mortality. NDMs are the most prevalent carbapenemases in Escherichia coli (E. coli) worldwide, especially in China. The vast majority of bla NDM cases occur on plasmids, which play a vital role in the dissemination of bla NDM. To systematically explore the relationships between plasmids and bla NDM genes in E. coli and obtain an overall picture of the conjugative and mobilizable bla NDM-positive plasmids, we analyzed the variants of bla NDM, replicon types, phylogenetic patterns, conjugative transfer modules, host STs, and geographical distributions of 114 bla NDM-positive plasmids, which were selected from 3786 plasmids from 1346 complete whole genomes of E. coli from the GenBank database. We also established links among the characteristics of bla NDM-positive plasmids in E. coli. Eight variants of bla NDM were found among the 114 bla NDM-positive plasmids, with bla NDM - 5 (74 bla NDM - 5 genes in 73 plasmids), and bla NDM - 1 (31 bla NDM - 1 genes in 28 plasmids) being the most dominant. The variant bla NDM - 5 was mainly carried by the IncX3 plasmids and IncF plasmids in E. coli, the former were mainly geographically distributed in East Asia (especially in China) and the United States, and the latter were widely distributed worldwide. IncC plasmids were observed to be the predominant carriers of bla NDM - 1 genes in E. coli, which were mainly geographically distributed in the United States and China. Other bla NDM - 1-carrying plasmids also included IncM2, IncN2, and IncHI1. Moreover, the overall picture of the conjugative and mobilizable bla NDM-positive plasmids in E. coli was described in our study. Our findings enhance our understanding of the genetic diversity and characteristics of bla NDM-positive plasmids in in E. coli.

5.
J Hepatocell Carcinoma ; 8: 1445-1458, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34858889

RESUMO

Purpose: To evaluate the safety and efficacy of drug-eluting bead transarterial chemoembolization (DEB-TACE) combined with oxaliplatin plus fluorouracil and leucovorin (FOLFOX)-based hepatic arterial infusion chemotherapy (D-TACE-HAIC) for unresectable large (5.1-10 cm) or huge (>10 cm) hepatocellular carcinoma (HCC). Methods: This retrospective study evaluated consecutive patients with unresectable large or huge HCC who underwent D-TACE-HAIC (D-TACE-HAIC group) or DEB-TACE (DEB-TACE group) from January 2017 to December 2020. At imaging, tumor infiltrating appearance was classified into smooth tumor margin, non-smooth tumor margin, and macrovascular invasion. Adverse events, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared between the two groups. Results: A total of 133 patients (mean age, 53 years ± 12; 117 men) were included: 69 underwent D-TACE-HAIC and 64 underwent DEB-TACE. The patients who underwent D-TACE-HAIC had higher ORR (71.0% vs 53.1%; P = 0.033), longer PFS (median, 9.3 vs 6.3 months; P = 0.005), and better OS (median, 19.0 vs 14.0 months; P = 0.008) than those who underwent DEB-TACE. In subgroup analysis, patients with non-smooth tumor margin (median, 20.8 vs 13.0 months; P = 0.031) or macrovascular invasion (median, 15.0 vs 11.0 months; P = 0.015) had significantly longer OS in D-TACE-HAIC group than in DEB-TACE group; but in patients with smooth tumor margin, OS between the two groups was similar (median, 37.0 vs 35.0 months; P = 0.458). DEB-TACE, non-smooth tumor margin, and macrovascular invasion were independent prognostic factors for poor OS in uni- and multivariable analyses. The incidence of grade 3/4 adverse events was not statistically different between the two groups (37.7% vs 28.1%; P = 0.242). Conclusion: D-TACE-HAIC was tolerable and led to better OS than DEB-TACE in patients with large or huge HCC, especially in those with non-smooth tumor margin or macrovascular invasion.

6.
Cell Death Dis ; 12(12): 1126, 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34862372

RESUMO

Metastasis is an important cause of death from malignant tumors. It is of great significance to explore the molecular mechanism of metastasis for the development of anti-cancer drugs. Here, we find that the Hippo pathway hampers tumor cell metastasis in vivo. Silence of hpo or its downstream wts promotes tumor cell migration in a Yki-dependent manner. Furthermore, we identify that inhibition of the Hippo pathway promotes tumor cell migration through transcriptional activating src42A, a Drosophila homolog of the SRC oncogene. Yki activates src42A transcription through direct binding its intron region. Intriguingly, Src42A further increases Yki transcriptional activity to form a positive feedback loop. Finally, we show that SRC is also a target of YAP and important for YAP to promote the migration of human hepatocellular carcinoma cells. Together, our findings uncover a conserved Yki/YAP-Src42A/SRC positive feedback loop promoting tumor cell migration and provide SRC as a potential therapeutic target for YAP-driven metastatic tumors.

7.
J Nanobiotechnology ; 19(1): 443, 2021 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-34949202

RESUMO

Gas therapy (GT) has attracted increasing attention in recent years as a new cancer treatment method with favorable therapeutic efficacy and reduced side effects. Several gas molecules, such as nitric oxide (NO), carbon monoxide (CO), hydrogen (H2), hydrogen sulfide (H2S) and sulfur dioxide (SO2), have been employed to treat cancers by directly killing tumor cells, enhancing drug accumulation in tumors or sensitizing tumor cells to chemotherapy, photodynamic therapy or radiotherapy. Despite the great progress of gas therapy, most gas molecules are prone to nonspecific distribution when administered systemically, resulting in strong toxicity to normal tissues. Therefore, how to deliver and release gas molecules to targeted tissues on demand is the main issue to be considered before clinical applications of gas therapy. As a specific and noninvasive stimulus with deep penetration, near-infrared (NIR) light has been widely used to trigger the cleavage and release of gas from nano-prodrugs via photothermal or photodynamic effects, achieving the on-demand release of gas molecules with high controllability. In this review, we will summarize the recent progress in cancer gas therapy triggered by NIR light. Furthermore, the prospects and challenges in this field are presented, with the hope for ongoing development.

8.
Front Chem ; 9: 755419, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34796162

RESUMO

Pathogenic microorganisms pose great challenges to public health, which is constantly urgent to develop extra strategies for the fast staining and efficient treatments. In addition, once bacteria form stubborn biofilm, extracellular polymeric substance (EPS) within biofilm can act as protective barriers to prevent external damage and inward diffusion of traditional antibiotics, which makes it frequently develop drug-resistant ones and even hard to treat. Therefore, it is imperative to develop more efficient methods for the imaging/detection and efficient inhibition of pathogenic microorganisms. Here, a water-soluble aggregation-induced emission (AIE)-active photosensitizer TPA-PyOH was employed for fast imaging and photodynamic treatment of several typical pathogens, such as S. aureus, methicillin-resistant Staphylococcus aureus, L. monocytogenes, C. albicans, and E. coli. TPA-PyOH was non-fluorescent in water, upon incubation with pathogen, positively charged TPA-PyOH rapidly adhered to pathogenic membrane, thus the molecular motion of TPA-PyOH was restricted to exhibit AIE-active fluorescence for turn-on imaging with minimal background. Upon further white light irradiation, efficient reactive oxygen species (ROS) was in-situ generated to damage the membrane and inhibit the pathogen eventually. Furthermore, S. aureus biofilm could be suppressed in vitro. Thus, water-soluble TPA-PyOH was a potent AIE-active photosensitizer for fast fluorescent imaging with minimal background and photodynamic inhibition of pathogenic microorganisms.

9.
Cell Death Dis ; 12(12): 1119, 2021 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-34845199

RESUMO

Nicotinamide, the amide form of Vitamin B3, is a common nutrient supplement that plays important role in human fetal development. Nicotinamide has been widely used in clinical treatments, including the treatment of diseases during pregnancy. However, its impacts during embryogenesis have not been fully understood. In this study, we show that nicotinamide plays multiplex roles in mesoderm differentiation of human embryonic stem cells (hESCs). Nicotinamide promotes cardiomyocyte fate from mesoderm progenitor cells, and suppresses the emergence of other cell types. Independent of its functions in PARP and Sirtuin pathways, nicotinamide modulates differentiation through kinase inhibition. A KINOMEscan assay identifies 14 novel nicotinamide targets among 468 kinase candidates. We demonstrate that nicotinamide promotes cardiomyocyte differentiation through p38 MAP kinase inhibition. Furthermore, we show that nicotinamide enhances cardiomyocyte survival as a Rho-associated protein kinase (ROCK) inhibitor. This study reveals nicotinamide as a pleiotropic molecule that promotes the derivation and survival of cardiomyocytes, and it could become a useful tool for cardiomyocyte production for regenerative medicine. It also provides a theoretical foundation for physicians when nicotinamide is considered for treatments for pregnant women.

10.
BMC Genomics ; 22(1): 835, 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34794394

RESUMO

BACKGROUND: A large number of variants have been employed in various medical applications, such as providing medication instructions, disease susceptibility testing, paternity testing, and tumour diagnosis. A high multiplicity PCR will outperform other technologies because of its lower cost, reaction time and sample consumption. To conduct a multiplex PCR with higher than 100 plex multiplicity, primers need to be carefully designed to avoid the formation of secondary structures and nonspecific amplification between primers, templates and products. Thus, a user-friendly, highly automated and highly user-defined web-based multiplex PCR primer design software is needed to minimize the work of primer design and experimental verification. RESULTS: Ultiplex was developed as a free online multiplex primer design tool with a user-friendly web-based interface ( http://ultiplex.igenebook.cn ). To evaluate the performance of Ultiplex, 294 out of 295 (99.7%) target primers were successfully designed. A total of 275 targets produced qualified primers after primer filtration, and 271 of those targets were successfully clustered into one compatible PCR group and could be covered by 108 primers. The designed primer group stably detected the rs28934573(C > T) mutation at lower than a 0.25% mutation rate in a series of samples with different ratios of HCT-15 and HaCaT cell line DNA. CONCLUSION: Ultiplex is a web-based multiplex PCR primer tool that has several functions, including batch design and compatibility checking for the exclusion of mutual secondary structures and mutual false alignments across the whole genome. It offers flexible arguments for users to define their own references, primer Tm values, product lengths, plex numbers and tag oligos. With its user-friendly reports and web-based interface, Ultiplex will provide assistance for biological applications and research involving genomic variants.


Assuntos
Reação em Cadeia da Polimerase Multiplex , Software , Primers do DNA/genética , Internet , Fluxo de Trabalho
11.
Chemosphere ; : 132563, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34653480

RESUMO

Bisphenols (BPs), benzophenone-type UV filters (BP-type UV filters), triclosan (TCS), and triclocarban (TCC) are endocrine-disrupting chemicals (EDCs) and commonly used in consumer and personal care products. In the present study, seven BPs, eight BP-type UV filters, TCS, and TCC were quantified in 196 paired urine and blood samples collected from young adults in South China. Benzophenone-7 and benzophenone-9 were not detected in all samples, while other target compounds were widely detected in 39%-96% of the urine and 14%-96% of the blood samples, and the median concentrations ranged from <0.02 (specific gravity adjusted: < 0.02) to 2.33 (2.05) ng/mL and <0.01-2.66 ng/mL in the urine and blood samples, respectively. Females had higher levels of most target analytes, and gender-related differences (p < 0.05) were found in the blood levels of benzophenone-2 (females vs. males: 0.84 vs. <0.01 ng/mL), ΣBP (sum of BP-type UV filters; 1.61 vs. 0.98 ng/mL), TCS (3.89 vs. 1.69 ng/mL), and ΣTC (sum of TCS and TCC; 5.77 vs. 3.02 ng/mL). We calculated the portioning of the target compounds between blood and urine (B/U ratios). The B/U ratios of bisphenol F, benzophenone-2, benzophenone-6, 4-hydroxy benzophenone, TCS, and TCC were higher than 1, showing that these analytes have higher enrichment capacities in human blood. To the best of our knowledge, this is the first study to simultaneously analyze the concentrations of BPs, BP-type UV filters, TCS, and TCC in the paired urine and blood samples of young adults in South China.

12.
Cell Death Discov ; 7(1): 263, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34561426

RESUMO

Apoptosis is a strictly coordinated process to eliminate superfluous or damaged cells, and its deregulation leads to birth defects and various human diseases. The regulatory mechanism underlying apoptosis still remains incompletely understood. To identify novel components in apoptosis, we carry out a modifier screen and find that the Hh pathway aggravates Hid-induced apoptosis. In addition, we reveal that the Hh pathway triggers apoptosis through its transcriptional target gene rdx, which encodes an E3 ubiquitin ligase. Rdx physically binds Diap1 to promote its K63-linked polyubiquitination, culminating in attenuating Diap1-Dronc interaction without affecting Diap1 stability. Taken together, our findings unexpectedly uncover the oncogenic Hh pathway is able to promote apoptosis through Ci-Rdx-Diap1 module, raising a concern to choose Hh pathway inhibitors as anti-tumor drugs.

13.
Acta Pharm Sin B ; 11(6): 1526-1540, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34221866

RESUMO

Acute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults, with increasing incidence with age and a generally poor prognosis. Almost 20% of AML patients express mutant isocitrate dehydrogenase 2 (mIDH2), which leads to the accumulation of the carcinogenic metabolite 2-hydroxyglutarate (2-HG), resulting in poor prognosis. Thus, global institutions have been working to develop mIDH2 inhibitors. SH1573 is a novel mIDH2 inhibitor that we independently designed and synthesised. We have conducted a comprehensive study on its pharmacodynamics, pharmacokinetics and safety. First, SH1573 exhibited a strong selective inhibition of mIDH2 R140Q protein, which could effectively reduce the production of 2-HG in cell lines, serum and tumors of an animal model. It could also promote the differentiation of mutant AML cell lines and granulocytes in PDX models. Then, it was confirmed that SH1573 possessed characteristics of high bioavailability, good metabolic stability and wide tissue distribution. Finally, toxicological data showed that SH1573 had no effects on the respiratory system, cardiovascular system and nervous system, and was genetically safe. This research successfully promoted the approval of SH1573 for clinical trials (CTR20200247). All experiments demonstrated that, as a potential drug against mIDH2 R140Q acute myeloid leukaemia, SH1573 was effective and safe.

14.
Biochem Pharmacol ; 190: 114641, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34077738

RESUMO

Hepatocellular carcinoma (HCC), a hypervascular solid tumor, is the most leading cause of cancer mortality worldwide. Microtubule binding agents targeting tumor vasculature have been investigated and employed clinically. C118P is a newly synthesized analog of CA4 with improved water solubility and extended half-life. The current studies investigated the pharmacological effects of C118P and its active metabolite C118. Here, we first confirmed by in vitro assays that C118 exerts microtubule depolymerization activity and by molecular docking revealed that it fits to the colchicine binding site of tubulin. In addition, we found that C118P and C118 altered microtubule dynamics and cytoskeleton in human umbilical vein endothelial cells. Accordingly, we observed that C118P and C118 inhibited angiogenesis and disrupted established vascular networks using tube formation assays and chick chorioallantoic membrane angiogenesis assays. In addition, our data showed that C118P and C118 exhibited board anti-proliferative effect on various cancer cells, including HCC cell lines, in MTT assays or Sulforhodamine B assays. Moreover, we found that C118P induced G2/M phase cell cycle arrest and apoptosis in HCC cell lines BEL7402 and SMMC7721 using flow cytometry analysis and immunoblotting assays. Finally, we confirmed that C118P suppressed HCC growth via targeting tumor vasculature and inducing apoptosis in the SMMC7721 xenograft mouse model. In conclusion, our studies revealed that C118P, as a potent microtubule destabilizing agent, exerts its multiple pharmacological effects against HCC by inducing cell cycle arrest and apoptosis, as well as targeting tumor vasculature. Thus, C118P might be a promising drug candidate for liver cancer treatment.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Microtúbulos/efeitos dos fármacos , Neovascularização Patológica/prevenção & controle , Moduladores de Tubulina/farmacologia , Animais , Antineoplásicos , Apoptose , Vasos Sanguíneos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Conformação Proteica , Tubulina (Proteína)/química , Moduladores de Tubulina/química
15.
Hum Vaccin Immunother ; 17(10): 3478-3480, 2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34114926

RESUMO

Vaccines are urgently needed to control the COVID-19 pandemic. To gradually increase the vaccination rate among residents, temporary vaccination clinic for COVID-19 plays an important role. It should be located in an area with convenient transportation and concentrated population. Functional zones including waiting and inquiry, registration and notification, injection, observation and emergency room should be established. All vaccine recipients' information should be uploaded to the national immunization information system. Medical staff at the temporary vaccination clinic should be professionally trained. A cautious disinfection and wiping are essential for the temporary vaccination clinic.


Assuntos
COVID-19 , China/epidemiologia , Humanos , Pandemias , SARS-CoV-2 , Vacinação
16.
Comput Methods Programs Biomed ; 208: 106206, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34146772

RESUMO

BACKGROUND AND OBJECTIVES: Automatic retinal vessel segmentation (RVS) in fundus images is expected to be a vital step in the early image diagnosis of ophthalmologic diseases. However, it is a challenging task to detect the retinal vessel accurately mainly due to the vascular intricacies, lesion areas and optic disc edges in retinal fundus images. METHODS: In this paper, we propose a high resolution representation network with multi-path scale (MPS-Net) for RVS aiming to improve the performance of extracting the retinal blood vessels. In the MPS-Net, there exist one high resolution main road and two lower resolution branch roads where the proposed multi-path scale modules are embedded to enhance the representation ability of network. Besides, in order to guide the network focus on learning the features of hard examples in retinal images, we design a hard-focused cross-entropy loss function. RESULTS: We evaluate our network structure on DRIVE, STARE, CHASE and synthetic images and the quantitative comparisons with respect to the existing methods are presented. The experimental results show that our approach is superior to most methods in terms of F1-score, sensitivity, G-mean and Matthews correlation coefficient. CONCLUSIONS: The promising segmentation performances reveal that our method has potential in real-world applications and can be exploited for other medical images with further analysis.


Assuntos
Redes Neurais de Computação , Disco Óptico , Fundo de Olho , Humanos , Processamento de Imagem Assistida por Computador , Vasos Retinianos/diagnóstico por imagem
17.
J Hepatocell Carcinoma ; 8: 529-543, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34136421

RESUMO

Background: The response rate of immunotherapy via immune checkpoint blockade in hepatocellular carcinoma (HCC) is limited due to multiple immune evasion mechanisms. OX40 is a T cell co-stimulating molecule which suppresses the cancer immune evasion by activating effector T cells (Teffs) and counteracting regulatory T cells (Tregs). TLR9 belongs to the toll-like receptor superfamily which promotes tumour antigen presentation by stimulating the maturation of dendritic cells. Though the combination immunotherapy of TLR9 agonist (CpG) and OX40 agonist (anti-OX40 antibody) has shown encouraging efficacy in various tumours, its effect on HCC remains unknown. Materials and Methods: Orthotopic and ectopic HCC models were constructed by implanting Hepa1-6 cells at different body sites of the mice. Immune agents were administrated via three ways, including intratumoural injection into one site of the tumour, intraperitoneal injection, and subcutaneous injection. The anti-tumour immune response was evaluated by the regression of both the local treated tumour and distant untreated tumour. The ratio and function of CD4+ T cells, CD8+ T cells, Tregs and myeloid-derived suppressor cells (MDSCs) were analyzed by flow cytometry. Results: CpG via intratumoural injection remarkably upregulated the weakly expressed OX40 of intratumoural T cells. The combination immunotherapy of CpG and anti-OX40 antibody via intratumoural injection significantly inhibited the growth of local and distant tumours, and also effectively prevented their recurrence. Excitingly, drug administration via intratumoural injection, rather than via intraperitoneal or subcutaneous injections, induced potent anti-tumour immune response. Furthermore, we demonstrated that the combination immunotherapy promoted CD8+ and CD4+ T cells, and inhibited Tregs and myeloid-derived suppressor cells, contributing to the effective inhibition on HCC. Noteworthily, the combination immunotherapy also induced an immune memory response. Conclusion: The intratumoural administration of combined CpG and anti-OX40 antibody serves as a promising immunotherapy against HCC.

18.
Biomater Sci ; 9(9): 3401-3409, 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33949448

RESUMO

The combination of chemotherapy and radiotherapy (chemoradiotherapy) is a promising strategy, extensively studied and applied clinically. Meanwhile, radiosensitizers play an important role in improving clinical radiotherapy therapeutic efficacy. There are still some disadvantages in practical applications, because radiosensitizers and drugs are difficult to deliver spatio-temporally to tumor sites and work simultaneously with low efficiency for DNA damage and repair inhibition, leading to an inferior synergistic effect. Herein, a suitable radiosensitizer of nano-enabled coordination platform (NP@PVP) with bismuth nitrate and cisplatin prodrug is developed by a simple synthetic route to improve the effectiveness of chemo-radiation synergistic therapy. When NP@PVP is internalized by a tumor cell, the bismuth in NP@PVP can sensitize radiation therapy (RT) by increasing the amount of reactive oxygen species generation to enhance DNA damage after X-ray radiation; meanwhile, the cisplatin in NP@PVP can inhibit DNA damage repair with spatio-temporal synchronization. NP@PVP is demonstrated to exhibit higher sensitization enhancement ratio (SER) of 2.29 and excellent tumor ablation capability upon irradiation in vivo in comparison with cisplatin (SER of 1.78). Our strategy demonstrates that the RT sensitization effect of bismuth and cisplatin based NP@PVP has great anticancer potential in chemo-radiation synergistic therapy, which is promising for clinical application.


Assuntos
Neoplasias , Pró-Fármacos , Bismuto/farmacologia , Linhagem Celular Tumoral , Quimiorradioterapia , Cisplatino/farmacologia , Dano ao DNA , Humanos , Neoplasias/tratamento farmacológico , Nitratos , Pró-Fármacos/farmacologia
19.
Environ Res ; 199: 111175, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33964309

RESUMO

Neonicotinoid insecticides (NEOs) are widely used for pest control worldwide. The profile of NEOs in paired urine and indoor dust has not yet been reported in China. In this study, 40 paired samples (i.e., 160 urine and 40 indoor dust) were collected from university students and dormitories from Guangzhou City of China to measure the concentrations of six NEOs and their three metabolites. Target analytes were frequently detected in paired urine (81%-98%) and indoor dust (75%-95%) samples, with median concentrations ranging from 0.02 [specific gravity (SG) adjusted: 0.02] to 2.08 (SG-adjusted: 2.38) ng/mL in urine and from 0.05 to 2.74 ng/g in indoor dust. 5-Hydroxy-imidacloprid was predominant in urine, while N-desmethyl acetamiprid was predominant in indoor dust samples, accounting for 56% and 37%, respectively. 1-Methyl-3-(tetrahydro-3-furylmethyl) urea, a dinotefuran degradate, was measured for the first time in indoor dust, with the median level of 1.02 ng/g. Significant gender-related differences (p < 0.05) in the urinary concentrations of most NEOs were found. We calculated the estimated daily intake (EDI) of target compounds from urine and indoor measurements. The EDIs of target analytes varied among all urine and indoor dust samples, with median values ranging from 0.51 (SG-adjusted: 0.56) to 51.6 (SG-adjusted: 52.8) ng/kg bw/day and from 0.04 to 2.10 pg/kg bw/day, respectively. Moreover, the median EDIsurine of most target analytes in females were significantly higher than (p < 0.05) those in males. The median EDIsdust of target compounds in dust from female dormitories were slightly higher than that in dust from male dormitories. These findings indicated that females were more exposed to NEO than males. Thus, the potential health risks of exposure to NEOs and their metabolites in female adults should be addressed in future studies. To our knowledge, this study is the first to report the profiles of NEOs and their metabolites in paired urine and indoor dust samples from young adults in China.


Assuntos
Poluição do Ar em Ambientes Fechados , Inseticidas , China , Poeira/análise , Feminino , Habitação , Humanos , Inseticidas/análise , Masculino , Neonicotinoides/análise , Adulto Jovem
20.
Aging (Albany NY) ; 13(8): 11257-11280, 2021 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-33820866

RESUMO

In order to explore the prognosis of tumor mutation burden (TMB) and the relationship with tumor infiltrating immune cells in hepatocellular carcinoma (HCC), we downloaded somatic mutation data and transcriptome profiles of 376 HCC patients from The Cancer Genome Atlas (TCGA) cohort. We divided the samples into high-TMB and low-TMB groups. A higher TMB level indicated improved overall survival (OS) and was associated with early pathological stages. One hundred and nine differentially expressed genes (DEGs) were identified in HCC. Moreover, based on four hub TMB-related signatures, we constructed a TMB Prognostic model (TMBPM) that possessed good predictive value with area under curve (AUC) of 0.701. HCC patients with higher TMBPM scores showed worse OS outcomes (p < 0.0001). Moreover, DCs subsets not only revealed higher infiltrating abundance in the high-TMB group, but also correlated with worse OS and hazard risk for high-TMB patients in HCC. Meanwhile, CD8+ T cells and B cells were associated with improved survival outcomes. In sum, high TMB indicates good prognosis for HCC and promotes HCC immune infiltration. Hence, DCs and the four hub TMB-related signatures can be used for predicting the prognosis in HCC as supplements to TMB.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/mortalidade , Recidiva Local de Neoplasia/epidemiologia , Microambiente Tumoral/imunologia , Idoso , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Estudos de Coortes , Análise Mutacional de DNA , Bases de Dados Genéticas , Conjuntos de Dados como Assunto , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Estimativa de Kaplan-Meier , Fígado/imunologia , Fígado/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Mutação , Recidiva Local de Neoplasia/genética , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Medição de Risco/métodos , Microambiente Tumoral/genética
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