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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.
EClinicalMedicine ; 42: 101201, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34917908

RESUMO

Background: Models predicting future macrovascular invasion in hepatocellular carcinoma are constructed to assist timely interventions. Methods: A total of 366 HCC cases were retrospectively collected from five Chinese hospitals between April 2007 and November 2016: the training dataset comprised 281 patients from four hospitals; the external validation dataset comprised 85 patients from another hospital. Multi-task deep learning network-based models were constructed to predict future macrovascular invasion. The discrimination, calibration, and decision curves were compared to identify the best model. We compared the time to macrovascular invasion and overall survival using the best model and related image heterogeneity scores (H-score). Then, we determined the need for a segmentation subnet or the replacement deep learning algorithm by logistic regression in screening clinical/radiological factors. Finally, an applet was constructed for future application. Findings: The best model combined clinical/radiological factors and radiomic features. It achieved best discrimination (areas under the curve: 0·877 in the training dataset and 0·836 in the validation dataset), calibration, and decision curve. Its performance was not affected by the treatments and disease stages. The subgroups had statistical significance for time to macrovascular invasion (training: hazard ratio [HR] = 0·073, 95% confidence interval [CI]: 0·032-0·167, p < 0·001 and validation: HR = 0·090, 95%CI: 0·022-0·366, p < 0·001) and overall survival (training: HR = 0·344, 95%CI: 0·246-0·547, p < 0·001 and validation: HR = 0·489, 95%CI: 0·279 - 0·859, p = 0·003). Similar results were achieved when the patients were subdivided by the H-score. The subnet for segmentation and end-to-end deep learning algorithms improved the performance of the model. Interpretation: Our multi-task deep learning network-based model successfully predicted future macrovascular invasion. In high-risk populations, besides the current first-line treatments, more therapies may be explored for macrovascular invasion.

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.
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.

9.
Nature ; 600(7888): 314-318, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34819664

RESUMO

Thermogenesis in brown and beige adipose tissue has important roles in maintaining body temperature and countering the development of metabolic disorders such as obesity and type 2 diabetes1,2. Although much is known about commitment and activation of brown and beige adipose tissue, its multiple and abundant immunological factors have not been well characterized3-6. Here we define a critical role of IL-27-IL-27Rα signalling in improving thermogenesis, protecting against diet-induced obesity and ameliorating insulin resistance. Mechanistic studies demonstrate that IL-27 directly targets adipocytes, activating p38 MAPK-PGC-1α signalling and stimulating the production of UCP1. Notably, therapeutic administration of IL-27 ameliorated metabolic morbidities in well-established mouse models of obesity. Consistently, individuals with obesity show significantly decreased levels of serum IL-27, which can be restored after bariatric surgery. Collectively, these findings show that IL-27 has an important role in orchestrating metabolic programs, and is a highly promising target for anti-obesity immunotherapy.

10.
Int J Biol Sci ; 17(15): 4176-4191, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34803491

RESUMO

Cholangiocarcinoma (CC), the most lethal type of liver cancer, remains very difficult to treat due to an incomplete understanding of the cancer initiation and progression mechanisms and no effective therapeutic drugs. Thus, identification of genomic drivers and delineation of the underlying mechanisms are urgently needed. Here, we conducted a genome-wide CRISPR-Cas9 screening in liver-specific Smad4/Pten knockout mice (Smad4co/co;Ptenco/co;Alb-Cre, abbreviated as SPC), and identified 15 putative tumor suppressor genes, including Cullin3 (Cul3), whose deficiency increases protein levels of Nrf2 and Cyclin D1 that accelerate cholangiocytes expansion leading to the initiation of CC. Meanwhile, Cul3 deficiency also increases the secretion of Cxcl9 in stromal cells to attract T cells infiltration, and increases the production of Amphiregulin (Areg) mediated by Nrf2, which paracrinely induces inflammation in the liver, and promotes accumulation of exhausted PD1high CD8 T cells at the expenses of their cytotoxic activity, allowing CC progression. We demonstrate that the anti-PD1/PD-L1 blockade inhibits CC growth, and the effect is enhanced by combining with sorafenib selected from organoid mediated drug sensitive test. This model makes it possible to further identify more liver cancer suppressors, study molecular mechanisms, and develop effective therapeutic strategies.

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.
Artigo em Inglês | MEDLINE | ID: mdl-34674948

RESUMO

BACKGROUND: Macrovascular invasion (MaVI) occurs in nearly half of hepatocellular carcinoma (HCC) patients at diagnosis or during follow-up, which causes severe disease deterioration, and limits the possibility of surgical approaches. This study aimed to investigate whether computed tomography (CT)-based radiomics analysis could help predict development of MaVI in HCC. METHODS: A cohort of 226 patients diagnosed with HCC was enrolled from 5 hospitals with complete MaVI and prognosis follow-ups. CT-based radiomics signature was built via multi-strategy machine learning methods. Afterwards, MaVI-related clinical factors and radiomics signature were integrated to construct the final prediction model (CRIM, clinical-radiomics integrated model) via random forest modeling. Cox-regression analysis was used to select independent risk factors to predict the time of MaVI development. Kaplan-Meier analysis was conducted to stratify patients according to the time of MaVI development, progression-free survival (PFS), and overall survival (OS) based on the selected risk factors. RESULTS: The radiomics signature showed significant improvement for MaVI prediction compared with conventional clinical/radiological predictors (P < 0.001). CRIM could predict MaVI with satisfactory areas under the curve (AUC) of 0.986 and 0.979 in the training (n = 154) and external validation (n = 72) datasets, respectively. CRIM presented with excellent generalization with AUC of 0.956, 1.000, and 1.000 in each external cohort that accepted disparate CT scanning protocol/manufactory. Peel9_fos_InterquartileRange [hazard ratio (HR) = 1.98; P < 0.001] was selected as the independent risk factor. The cox-regression model successfully stratified patients into the high-risk and low-risk groups regarding the time of MaVI development (P < 0.001), PFS (P < 0.001) and OS (P = 0.002). CONCLUSIONS: The CT-based quantitative radiomics analysis could enable high accuracy prediction of subsequent MaVI development in HCC with prognostic implications.

13.
J Hepatocell Carcinoma ; 8: 1065-1076, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34513748

RESUMO

Purpose: For timely treatment of extrahepatic metastasis and macrovascular invasion (aggressive progressive disease [PD]) in hepatocellular carcinoma, models aimed at stratifying the risks of subsequent aggressive PD should be constructed. Patients and Methods: After dividing 332 patients from five hospitals into training (n = 236) and validation (n = 96) datasets, non-invasive models, including clinical/semantic factors (ModelCS), deep learning radiomics (ModelD), and both (ModelCSD), were constructed to stratify patients according to the risk of aggressive PD. We examined the discrimination and calibration; similarly, we plotted a decision curve and devised a nomogram. Furthermore, we performed analyses of subgroups who received different treatments or those in different disease stages and compared time to aggressive PD and overall survival in the high- and low-risk subgroups. Results: Among the constructed models, ModelCSD, combining clinical/semantic factors and deep learning radiomics, outperformed ModelCS and ModelD (areas under the curve [AUCs] for the training dataset: 0.741, 0.815, and 0.856; validation dataset: 0.780, 0.836, and 0.862), with statistical difference per the net reclassification improvement, the integrated discrimination improvement, and/or the DeLong test in both datasets. Besides, ModelCSD had the best calibration and decision curves. The performance of ModelCSD was not affected by treatment types (AUC: resection = 0.839; transarterial chemoembolization = 0.895; p = 0.183) or disease stages (AUC: BCLC [Barcelona Clinic Liver Cancer] stage 0 and A = 0.827; BCLC stage AB &B = 0.861; p = 0.537). Moreover, the high-risk group had a significantly shorter median time to aggressive PD than the low-risk group (training dataset hazard ratio [HR] = 0.108, p < 0.001; validation dataset HR = 0.058, p < 0.001) and poorer overall survival (training dataset HR = 0.357, p < 0.001; validation dataset HR = 0.204, p < 0.001). Conclusion: Our deep learning-based model successfully stratified the risks of aggressive PD. In the high-risk population, current guideline indicates that first-line treatments are insufficient to prevent extrahepatic metastasis and macrovascular invasion and ensure survival benefits, so more therapies may be explored for these patients.

14.
Lasers Med Sci ; 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34398384

RESUMO

The injury of common bile duct (CBD) is one of the most common complications during laparoscopic cholecystectomy. Consequences of CBD injury are grave since CBD is the only pathway of bile from biliary tracts to duodenum. When CBD injury occurs, extra surgical procedures repairing CBD or reconstructing biliary tracts have to be performed on patients, which increase expenses of patients and physical trauma. A total of 238 patients undergoing laparoscopic cholecystectomy (LC) in Zhuhai People's Hospital from July 2020 to April 2021 were enrolled in this observational study, including 126 patients undergoing conventional LC and 112 patients undergoing ICG angiography-guided LC. Method of propensity score matching was used to balance the preoperative data of patients in the two groups. For both groups, the "Critical View of Safety" (CVS) was introduced. For the ICG group, the CBD, cystic duct (CD), and gallbladder were identified using near-infrared (NIR) ray. Intraoperative blood loss, operation time, postoperative hospitalization time, and the incidence rate of intraoperative complications were compared between the two groups. ICG angiography in LC shows safe and effective outcomes. The intraoperative blood loss, operation duration, postoperative hospitalization time, and complication incidence rate of the ICG group are significantly lower than those of the conventional group. ICG angiography in LC was a useful and effective method to identify the CBD and prevent intraoperative complications. Registration at Chinese Clinical Trial Registry, No: ChiCTR1900024594. Registration time: 18/07/2019.

15.
World J Clin Cases ; 9(22): 6457-6463, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34435012

RESUMO

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is a type of spindle cell sarcoma originating from the peripheral nerve, which usually results in the corresponding nerve sign on magnetic resonance imaging (MRI). Patients with MPNST may also have neurofibromatosis type 1. CASE SUMMARY: A 78-year-old male was admitted to the hospital due to a tumor in his left knee. He had a previous history of superficial spreading melanoma on the left thigh. Color Doppler ultrasonography showed a hypoechoic mass in the subcutaneous soft tissues of the medial left knee with an abundant rich blood flow. Computed tomography scanning did not show obvious signs of bone destruction, but the skin adjacent to the tumor was slightly thickened. MRI examination revealed that the hypervascular lesion was well-circumscribed, lobulated, invaded the surrounding soft tissues and demonstrated heterogeneous enhancement but lacked an entering and exiting nerve sign. The MRI result indicated the invasiveness of the tumor. The patient underwent a left knee joint mass expanded resection and the first histopathological examination showed a MPNST with positive surgical margins. Therefore, the second extended resection was performed, and the patient had a good outcome in the short term. CONCLUSION: MRI is a useful technique for revealing the biological characteristics of MPNST and provides clinical support for evaluation of the surgical area before operation.

16.
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.

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.
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
19.
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
20.
Stem Cell Res Ther ; 12(1): 362, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172095

RESUMO

BACKGROUND: Vitamin B3 (nicotinamide) plays important roles in metabolism as well as in SIRT and PARP pathways. It is also recently reported as a novel kinase inhibitor with multiple targets. Nicotinamide promotes pancreatic cell differentiation from human embryonic stem cells (hESCs). However, its molecular mechanism is still unclear. In order to understand the molecular mechanism involved in pancreatic cell fate determination, we analyzed the downstream pathways of nicotinamide in the derivation of NKX6.1+ pancreatic progenitors from hESCs. METHODS: We applied downstream modulators of nicotinamide during the induction from posterior foregut to pancreatic progenitors, including niacin, PARP inhibitor, SIRT inhibitor, CK1 inhibitor and ROCK inhibitor. The impact of those treatments was evaluated by quantitative real-time PCR, flow cytometry and immunostaining of pancreatic markers. Furthermore, CK1 isoforms were knocked down to validate CK1 function in the induction of pancreatic progenitors. Finally, RNA-seq was used to demonstrate pancreatic induction on the transcriptomic level. RESULTS: First, we demonstrated that nicotinamide promoted pancreatic progenitor differentiation in chemically defined conditions, but it did not act through either niacin-associated metabolism or the inhibition of PARP and SIRT pathways. In contrast, nicotinamide modulated differentiation through CK1 and ROCK inhibition. We demonstrated that CK1 inhibitors promoted the generation of PDX1/NKX6.1 double-positive pancreatic progenitor cells. shRNA knockdown revealed that the inhibition of CK1α and CK1ε promoted pancreatic progenitor differentiation. We then showed that nicotinamide also improved pancreatic progenitor differentiation through ROCK inhibition. Finally, RNA-seq data showed that CK1 and ROCK inhibition led to pancreatic gene expression, similar to nicotinamide treatment. CONCLUSIONS: In this report, we revealed that nicotinamide promotes generation of pancreatic progenitors from hESCs through CK1 and ROCK inhibition. Furthermore, we discovered the novel role of CK1 in pancreatic cell fate determination.


Assuntos
Células-Tronco Embrionárias Humanas , Diferenciação Celular , Endoderma , Humanos , Niacinamida/farmacologia , Pâncreas
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