Bone marrow mesenchymal stem cells inhibit ferroptosis via regulating the Nrf2-keap1/p53 pathway to ameliorate chronic kidney disease injury in the rats.

PURPOSE: Although bone marrow mesenchymal stem cells (BMMSCs) have been reported to exhibit a protective effect on animal models of chronic kidney disease (CKD), the exact mechanisms involved require further investigation. This study aims to investigate the underlying molecular mechanisms of BMMSCs in inhibiting ferroptosis and preventing an Adriamycin (ADR)-induced CKD injury. METHODS: A rat model of long-term CKD induced through the injection of ADR administered twice weekly via the tail vein was used in this study. After BMMSCs were systemically administered through the renal artery, pathological staining, western blotting, ELISA, and transmission electron microscopy were used to analyze ferroptosis. RESULTS: Analyses of renal function and histopathological findings indicated that ADR-mediated renal dysfunction improved in response to the BMMSC treatment, which was also sufficient to mediate the partial reversal of renal injury and mitochondrial pathological changes. BMMSCs decreased the ferrous iron (Fe2+) and reactive oxygen species and elevated glutathione (GSH) and GSH peroxidase 4. Moreover, the BMMSC treatment activated the expression of ferroptosis-related regulator NF-E2-related factor 2 (Nrf2) and inhibited Keap1 and p53 in CKD rat kidney tissues. CONCLUSIONS: BMMSCs alleviate CKD, possibly resulting from the inhibition of kidney ferroptosis by regulating the Nrf2-Keap1/p53 pathway.

KHGCN: Knowledge-Enhanced Recommendation with Hierarchical Graph Capsule Network.

Knowledge graphs as external information has become one of the mainstream directions of current recommendation systems. Various knowledge-graph-representation methods have been proposed to promote the development of knowledge graphs in related fields. Knowledge-graph-embedding methods can learn entity information and complex relationships between the entities in knowledge graphs. Furthermore, recently proposed graph neural networks can learn higher-order representations of entities and relationships in knowledge graphs. Therefore, the complete presentation in the knowledge graph enriches the item information and alleviates the cold start of the recommendation process and too-sparse data. However, the knowledge graph's entire entity and relation representation in personalized recommendation tasks will introduce unnecessary noise information for different users. To learn the entity-relationship presentation in the knowledge graph while effectively removing noise information, we innovatively propose a model named knowledge-enhanced hierarchical graph capsule network (KHGCN), which can extract node embeddings in graphs while learning the hierarchical structure of graphs. Our model eliminates noisy entities and relationship representations in the knowledge graph by the entity disentangling for the recommendation and introduces the attentive mechanism to strengthen the knowledge-graph aggregation. Our model learns the presentation of entity relationships by an original graph capsule network. The capsule neural networks represent the structured information between the entities more completely. We validate the proposed model on real-world datasets, and the validation results demonstrate the model's effectiveness.

Evaluation of drug efficacy based on the spatial position comparison of drug-target interaction centers.

The spatial position and interaction of drugs and their targets is the most important characteristics for understanding a drug's pharmacological effect, and it could help both in finding new and more precise treatment targets for diseases and in exploring the targeting effects of the new drugs. In this work, we develop a computational pipeline to confirm the spatial interaction relationship of the drugs and their targets and compare the drugs' efficacies based on the interaction centers. First, we produce a 100-sample set to reconstruct a stable docking model of the confirmed drug-target pairs. Second, we set 5.5 Å as the maximum distance threshold for the drug-amino acid residue atom interaction and construct 3-dimensional interaction surface models. Third, by calculating the spatial position of the 3-dimensional interaction surface center, we develop a comparison strategy for estimating the efficacy of different drug-target pairs. For the 1199 drug-target interactions of the 649 drugs and 355 targets, the drugs that have similar interaction center positions tend to have similar efficacies in disease treatment, especially in the analysis of the 37 targeted relationships between the 15 known anti-cancer drugs and 10 target molecules. Furthermore, the analysis of the unpaired anti-cancer drug and target molecules suggests that there is a potential application for discovering new drug actions using the sampling molecular docking and analyzing method. The comparison of the drug-target interaction center spatial position method better reflect the drug-target interaction situations and could support the discovery of new efficacies among the known anti-cancer drugs.

Landscape of SNPs-mediated lncRNA structural variations and their implication in human complex diseases.

An increasing number of functional studies shows that long noncoding RNAs (lncRNAs) are involved in many aspects of cellular physiology and fulfills a wide variety of regulatory roles at almost every stage of gene expression. A major feature of lncRNAs is the highly folded modular domains in transcripts. With improved modeling and definition, it is now feasible to explore and gain novel insights into the structural-functional relationship of lncRNAs and their association with complex human diseases. In this study, we utilized an automatic computational pipeline to scan lncRNA architecture at the genome-wide scale and to obtain a landscape of functional domains. An accurate alignment algorithm was performed to identify 40 triple pairs between single-nucleotide polymorphisms (SNPs), lncRNAs and diseases. In order to detect the potential contribution of a lncRNA's modular character, we estimated and evaluated structural rearrangements, which were derived from disease-associated SNPs. In addition, we focused on annotating and comparing the global and local heterogeneity of the wild-type and mutant lncRNAs. Assessing lncRNA architecture has yielded how variations in structured regions impact the molecular mechanisms of lncRNAs and how SNPs disturb binding and recruiting ability. These observations are the first glimpse of the 'lncRNA structurome' and make it possible to robustly explore and assemble intricate space conformation and their stress variation. This result also successfully demonstrates that lncRNA transcripts contain a complex structural landscape and highlights the proposed contribution of lncRNA structure in controlling RNA functions and disease mechanisms.

circ-PSD3 promoted proliferation and invasion of papillary thyroid cancer cells via regulating the miR-7-5p/METTL7B axis.

Papillary thyroid cancer (PTC) is a common tumor malignancy of the endocrine system worldwide. Recently, circular RNAs (circRNAs) have been reported to participate in diverse pathological processes, especially in tumorigenesis. However, the functional role and mechanism of circRNA pleckstrin and Sec7 domain containing 3 (circ-PSD3) in PTC are still unclear. In this study, qRT-PCR results showed that circ-PSD3 was significantly upregulated in PTC tissues and cell lines. Meanwhile, circ-PSD3 overexpression was positively associated with larger tumor size, TNM stage, and lymph node metastasis. Knockdown of circ-PSD3 suppressed the proliferation and invasion of PTC cells. Besides, circ-PSD3 interacted with miR-7-5p to reduce its expression, and methyltransferase like 7B (METTL7B) was verified as a target gene of miR-7-5p. Functionally, inhibition of circ-PSD3 impeded PTC cell proliferation and invasion via targeting miR-7-5p to downregulate METTL7B expression. Taken together, silencing of circ-PSD3 hampered the proliferation and invasion of PTC cells via upregulating the inhibitory effect of miR-7-5p on METTL7B expression. Therefore, circ-PSD3 could be a potential diagnostic biomarker or molecular treatment target for PTC.

M2-like tumor-associated macrophages-secreted Wnt1 and Wnt3a promotes dedifferentiation and metastasis via activating ß-catenin pathway in thyroid cancer.

BACKGROUND: Thyroid carcinoma (TC) has been a global issue for its rapid increasing incidence worldwide. Although most TC was not so aggressive with a good prognosis, treatment against anaplastic TC was relatively limited and the mechanisms are not well elucidated yet. METHODS: TC cell lines (IHH4 and TPC-1) were used. Flow cytometry was used to identify the surface marker of M2-like tumor-associated macrophages (TAMs) from cell culture. Quantitative real-time polymerase chain reaction, western blot analysis, immunostaining, and immunohistochemistry were used to detect the expression of Wnt1, Wnt3a, components of Wnt/ß-catenin pathway, and proliferation/epithelial-mesenchymal transition (EMT)-related proteins. Alkaline phosphatase activity assay, colony formation assay, and transwell assay were used to examine the roles of Wnt1, Wnt3a, and ß-catenin pathway in cell dedifferentiation, proliferation, migration, and invasion of TC cells, respectively. Subcutaneous tumor growth was monitored in nude mice. RESULTS: Coculture with M2-like TAMs facilitated dedifferentiation, proliferation, migration, and invasion in TC cells. EMT and proliferation-related proteins were also promoted in cocultured TC cells. The level of Wnt1 and Wnt3a was increased in the coculture system. Block of Wnt1 or Wnt3a suppressed malignant behaviors in cocultured tumor cells. Furthermore, Wnt1 or Wnt3a knockdown inhibited Wnt/ß-catenin signaling pathway, and suppressed EMT and proliferation-related signals in cocultured tumor cells. Knockdown of Wnt1 or Wnt3a inhibited tumor growth in xenograft model. CONCLUSION: M2-like TAMs promoted dedifferentiation, proliferation, and metastasis of TC by Wnt1 and Wnt3a secretion and ensuing ß-catenin activation.

The preablation monocyte/ high density lipoprotein ratio predicts the late recurrence of paroxysmal atrial fibrillation after radiofrequency ablation.

BACKGROUND: The monocyte/high-density lipoprotein ratio (MHR) has emerged as a promising alternative biomarker in the fields of cardiovascular disease and atrial fibrillation (AF). This retrospective study was aimed to explore the predictive value of the MHR for the late recurrence of AF after radiofrequency ablation. METHODS: From April 2015 to October 2018, patients with paroxysmal AF who had undergone radiofrequency catheter ablation at Subei People's Hospital of Jiangsu Province were enrolled in our study. All the participants were observed until November 2019 after the procedure. During the postoperative follow up, the patients were categorized into the recurrence group and maintenance of sinus rhythm group based on who had experienced AF recurrence. RESULTS: One hundred twenty-five patients were diagnosed with paroxysmal AF, with an average age of 61.2 ± 9.3 years. Forty-seven patients had developed late recurrence during a mean follow up of 25.1 ± 12.0 months. The AF recurrence event rates were significantly increased in the highest MHR tertile compared with those in the lowest MHR tertile (22.0% vs. 57.1%; P < 0.05). On multivariate logistic regression analysis, the preablation MHR (OR = 1.34; 95% CI = 1.12 ~ 1.60; P = 0.001) and left atrial diameter (LAD) (OR = 1.21, 95% CI = 1.08 ~ 1.35; P = 0.001) were independent risk factors predicting the recurrence of AF after radiofrequency ablation. Furthermore, receiver operating characteristic (ROC) curve analysis revealed that the area under the curve (AUC) of the MHR was 0.712 (95% CI = 0.618 ~ 0.806; P = 0.000) and that of LAD was 0.739 (95% CI = 0.653 ~ 0.814; P = 0.000). Z-test found no significant difference between the MHR and LAD regarding the AUC (Z = 0.451; P = 0.652). CONCLUSION: An elevated preablation MHR was associated with an increased risk of the postoperative recurrence of AF. Additionally, the MHR independently predicted the late recurrence of paroxysmal AF after radiofrequency ablation, with the same predictive value as LAD.

Diagnostic and grading accuracy of 18F-FDOPA PET and PET/CT in patients with gliomas: a systematic review and meta-analysis.

BACKGROUND: Positron emission tomography (PET) and PET/computed tomography (PET/CT) imaging with 3,4-dihydroxy-6-[18F] fluoro-L-phenylalanine (18F-FDOPA) has been used in the evaluation of gliomas. We performed a meta-analysis to obtain the diagnostic and grading accuracy of 18F-FDOPA PET and PET/CT in patients with gliomas. METHODS: PubMed, Embase, Cochrane Library and Web of Science were searched through 13 May 2019. We included studies reporting the diagnostic performance of 18F-FDOPA PET or PET/CT in glioma patients. Pooled sensitivity, specificity, and area under the summary receiver operating characteristic (SROC) curve were calculated from eligible studies on a per-lesion basis. RESULTS: Eventually, 19 studies were included. Across 13 studies (370 patients) for glioma diagnosis, the pooled sensitivity and specificity of 18F-FDOPA PET and PET/CT were 0.90 (95%CI: 0.86-0.93) and 0.75 (95%CI: 0.65-0.83). Across 7 studies (219 patients) for glioma grading, 18F-FDOPA PET and PET/CT showed a pooled sensitivity of 0.88 (95%CI: 0.81-0.93) and a pooled specificity of 0.73 (95%CI: 0.64-0.81). CONCLUSIONS: 18F-FDOPA PET and PET/CT demonstrated good performance for diagnosing gliomas and differentiating high-grade gliomas (HGGs) from low-grade gliomas (LGGs). Further studies implementing standardized PET protocols and investigating the grading parameters are needed.

Can men with atrial fibrillation really rest easy with a CHA2DS2-VASc score of 0?

BACKGROUND: Atrial fibrillation (AF) significantly increases the risk of ischemic stroke depending on various risk factors. The CHA2DS2-VASc score is used widely to improve stratification of AF-related stroke to identify for whom anticoagulation could be safely withheld. As upstream therapy, the management of lifestyle for AF and related stroke prevention has been ongoing for past decades. CASE PRESENTATION: A 56-year-old male was taken to our hospital because of acute ischemic stroke. Without intracranial vascular malformation and angiostenosis, two small emboli were successfully taken out from the left middle cerebral artery by mechanical thrombectomy. During the hospitalisation, no apparent abnormalities were found in various laboratory tests, echocardiogram or the coronary computed tomography angiography. However, asymptomatic paroxysmal AF was first diagnosed and was presumed to be responsible for his stroke. Noticeable, he was always in good fitness benefiting from the formed good habits of no smoking and drinking. With a CHA2DS2-VASc score of 0, he had no history of any known diseases or risk factors associated with AF and related stroke. Instead of lacking exercise, he persisted in playing table tennis faithfully 3-4 times a week and 2-3 h each time over the past 30 years, and, in fact, has won several amateur table tennis championships. CONCLUSION: In view of the possible pathophysiological mechanisms resulting from the long-term vigorous endurance exercise, it may be a potential risk factor for developing AF and even for subsequent stroke. Not merely should strengthen the screening for AF in specific individuals as sports enthusiasts, but the necessity of oral anticoagulant for those with a CHA2DS2-VASc score of 0 might deserve the further investigation.

Mesenchymal stem cells and ferroptosis: Clinical opportunities and challenges.

Objective: This review discusses recent experimental and clinical findings related to ferroptosis, with a focus on the role of MSCs. Therapeutic efficacy and current applications of MSC-based ferroptosis therapies are also discussed. Background: Ferroptosis is a type of programmed cell death that differs from apoptosis, necrosis, and autophagy; it involves iron metabolism and is related to the pathogenesis of many diseases, such as Parkinson's disease, cancers, and liver diseases. In recent years, the use of mesenchymal stem cells (MSCs) and MSC-derived exosomes has become a trend in cell-free therapies. MSCs are a heterogeneous cell population isolated from a diverse range of human tissues that exhibit immunomodulatory functions, regulate cell growth, and repair damaged tissues. In addition, accumulating evidence indicates that MSC-derived exosomes play an important role, mainly by carrying a variety of bioactive substances that affect recipient cells. The potential mechanism by which MSC-derived exosomes mediate the effects of MSCs on ferroptosis has been previously demonstrated. This review provides the first overview of the current knowledge on ferroptosis, MSCs, and MSC-derived exosomes and highlights the potential application of MSCs exosomes in the treatment of ferroptotic conditions. It summarizes their mechanisms of action and techniques for enhancing MSC functionality. Results obtained from a large number of experimental studies revealed that both local and systemic administration of MSCs effectively suppressed ferroptosis in injured hepatocytes, neurons, cardiomyocytes, and nucleus pulposus cells and promoted the survival and regeneration of injured organs. Methods: We reviewed the role of ferroptosis in related tissues and organs, focusing on its characteristics in different diseases. Additionally, the effects of MSCs and MSC-derived exosomes on ferroptosis-related pathways in various organs were reviewed, and the mechanism of action was elucidated. MSCs were shown to improve the disease course by regulating ferroptosis.

Role of sodium/iodide symporter overexpression in inhibiting thyroid cancer cell invasion and stem cell maintenance by inhibiting the ß-catenin/LEF-1 pathway.

Background: In thyroid cancers, a reduction in the expression of the sodium/iodide symporter (NIS) is observed concomitant with a diminution in cancer cell differentiation. The ß-catenin/LEF-1 pathway emerges as a crucial regulatory pathway influencing the functional expression of NIS in human thyroid cancer cells. Further research is required to comprehensively elucidate the role of NIS overexpression in impeding the progression of thyroid cancer cells. Methods: Human papillary thyroid carcinoma (PTC) cell lines, specifically PTC-1 and KTC-1, were subjected to Scratch and Transwell assays, colony formation, and tumor sphere formation tests to investigate invasion and migration, focusing on the impact of NIS overexpression. The assessment involved the use of western blot to analyze the expression levels of ß-catenin, NIS, CD133, SRY-related HMG box2 (Sox2), lymphoid enhancer-binding factor 1 (LEF-1), NANOG, octamer-binding transcription factor 4 (Oct4), aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), and epithelial cellular adhesion molecule (EpCAM). Statistical analysis was conducted using SPSS version 20.0, and the graphs were developed using GraphPad Prism 7 (GraphPad Software, Inc.). Results: Our observations revealed that Nthy-ori-3-1 cell lines exhibited notably higher average expression levels of NIS, yet significantly lower levels of LEF-1 and ß-catenin compared to PTC-1 and KTC-1 cell lines. Furthermore, the overexpression of ß-catenin resulted in reduced binding of LEF-1 to NIF promotion but concurrently increased the expression of NIS. The downregulation of NIS markedly enhanced the expression of ALDH1A1, CD133, OCT4, Nanog, SOX2, and EpCam-all of which are targets within the Wnt/ß-catenin signaling pathway. Conversely, the upregulation of NIS suppressed the expression of these proteins. Moreover, cells treated with ß-catenin activators demonstrated an increased capability to form more spheroids and displayed heightened aggressiveness. Conversely, the NIS overexpression (OE) group exhibited suppressed abilities in invasion and colony formation. Conclusion: Thyroid cancer cells exhibit diminished expression of NIS, and the invasion and maintenance of stem cells in thyroid cancer cells were hindered by NIS OE through the inhibition of the ß-catenin/LEF-1 pathway. Further research is warranted to comprehensively assess this outcome, which holds promise as a potential targeted treatment for thyroid cancer.

Biomarker identification and risk prediction model development for differentiated thyroid carcinoma lung metastasis based on primary lesion proteomics.

PURPOSE: The rising global high incidence of differentiated thyroid carcinoma (DTC) has led to a significant increase in patients presenting with lung metastasis of DTC (LMDTC). This population poses a significant challenge in clinical practice, necessitating the urgent development of effective risk stratification methods and predictive tools for lung metastasis. EXPERIMENTAL DESIGN: Through proteomic analysis of large samples of primary lesion and dual validation employing parallel reaction monitoring and immunohistochemistry, we identified eight hub proteins as potential biomarkers. By expanding the sample size and conducting statistical analysis on clinical features and hub protein expression, we constructed three risk prediction models. RESULTS: This study identified eight hub proteins-SUCLG1/2, DLAT, IDH3B, ACSF2, ACO2, CYCS and VDAC2- as potential biomarkers for predicting DTC lung metastasis risk. We developed and internally validated three risk prediction models incorporating both clinical characteristics and hub protein expression. Our findings demonstrated that the combined prediction model exhibited optimal predictive performance, with the highest discrimination (AUC: 0.986) and calibration (Brier score: 0.043). Application of the combined prediction model within a specific risk threshold (0-0.97) yielded maximal clinical benefit. Finally, we constructed a nomogram based on the combined prediction model. CONCLUSIONS: As a large sample size study in lung metastatic DTC research, the identification of biomarkers through primary lesion proteomics and the development of risk prediction models integrating clinical features and hub protein biomarkers offer valuable insights for predicting DTC lung metastasis and establishing personalised treatment strategies.

Mesenchymal Stem Cell Therapy in Kidney Diseases: Potential and Challenges.

Kidney disease (KD) is a life-threatening disease characterized by high morbidity and mortality in clinical settings, which can be caused by many reasons, and the incidence increases with age. However, supportive therapy and kidney transplantation still have limitations in alleviating KD progression. Recently, mesenchymal stem cells (MSCs) have shown great potential in repairing injury through their multidirectional differentiation and self-renewal ability. Of note, MSCs serve as a safe and effective therapeutic strategy for treating KD in preclinical and clinical trials. Functionally, MSCs ameliorate KD progression by regulating the immune response, renal tubular cell apoptosis, tubular epithelial-mesenchymal transition, oxidative stress, angiogenesis, and so on. In addition, MSCs exhibit remarkable efficacy in both acute kidney injury (AKI) and chronic kidney disease (CKD) through paracrine mechanisms. In this review, we outline the biological characteristics of MSCs, discuss the efficacy and mechanisms of MSCs-based therapy for KD, summarize the completed and ongoing clinical trials, as well as analyze limitations and new strategies, aiming to provide new ideas and approaches for the preclinical experiments and clinical trials of MSCs transplantation for KD.

Disulfidptosis-associated LncRNAs index predicts prognosis and chemotherapy drugs sensitivity in cervical cancer.

Disulfidptosis is a newly discovered form of cell death. Not yet clearly classified as programmed cell death or accidental cell death. This study aimed to create a novel disulfidptosis-related lncRNA index (DLI) that can be used to predict survival and chemotherapy drugs sensitivity in patients with cervical cancer. First of all, we found lncRNAs associated with disulfidptosis between cervical cancer tissues and normal tissues. By LASSO-Cox analysis, overlapping lncRNAs were then used to construct lncRNA index associated with disulfidptosis, which can be served to predict the prognosis of patients with CC, especially the chemotherapy drugs sensitivity. ROC curves and PCA based on DLI and clinical signatures were developed and demonstrated to have good predictive potential. In addition, differences in immune cell subset infiltration and differences in immune checkpoint expression between high-DLI and low-DLI groups were analyzed, and we investigated the relationship between the DLI and tumor mutation burden (TMB). In summary, we constructed a lncRNA prediction index associated with disulfidptosis. This has important clinical implications, including improving the predictive value of cervical cancer patients and providing a biomarker for cervical cancer guiding individualized treatment.

Sequencing of 19,219 exomes identifies a low-frequency variant in FKBP5 promoter predisposing to high myopia in a Han Chinese population.

High myopia (HM) is one of the leading causes of visual impairment and blindness worldwide. Here, we report a whole-exome sequencing (WES) study in 9,613 HM cases and 9,606 controls of Han Chinese ancestry to pinpoint HM-associated risk variants. Single-variant association analysis identified three newly identified -genetic loci associated with HM, including an East Asian ancestry-specific low-frequency variant (rs533280354) in FKBP5. Multi-ancestry meta-analysis with WES data of 2,696 HM cases and 7,186 controls of European ancestry from the UK Biobank discerned a newly identified European ancestry-specific rare variant in FOLH1. Functional experiments revealed a mechanism whereby a single G-to-A transition at rs533280354 disrupted the binding of transcription activator KLF15 to the promoter of FKBP5, resulting in decreased transcription of FKBP5. Furthermore, burden tests showed a significant excess of rare protein-truncating variants among HM cases involved in retinal blood vessel morphogenesis and neurotransmitter transport.

CAR-T cell therapy for lung cancer: Potential and perspective.

Lung cancer is the highest incidence and mortality of all cancers around the world. In the present immunotherapy era, an increasing number of immunotherapeutic agents including monoclonal antibody-targeted drugs have been used in the clinical treatment of malignancy, but it still has many limitations. Chimeric antigen receptor-modified T (CAR-T) cells, a novel adoptive immunotherapy strategy, have not only been used successfully against hematological tumors, but have also opened up new avenues for immunotherapy of solid tumors, including lung cancer. However, targeting lung cancer-specific antigens using engineered CAR-T cells is complicated by the lack of proper tumor-specific antigens, an immunosuppressive tumor microenvironment, a low level of CAR-T cell infiltration into tumor tissues, along with off-target effect, etc. Simultaneously, the clinical application of CAR-T cells remains limited because of many challenges such as tumor lysis syndrome, neurotoxicity syndrome, and cytokine release syndrome. In this review, we outline the basic structure and generation characteristic of CAR-T cells and summarize the common tumor-associated antigens in clinical trials of CAR-T cell therapy for lung cancer, and point out the current challenges and new strategies, aiming to provide new ideas and approaches for the pre-clinical experiments and clinical trials of CAR-T cell therapy in lung cancer.

Small activating RNA-activated NIS gene promotes 131I uptake and inhibits thyroid cancer via AMPK/mTOR pathway.

BACKGROUND: Sodium/iodide symporter (NIS) acts as a vital role in regulation of iodide uptake in thyroid cancer. However, the efficient approach to increase NIS expression and the mechanism of NIS-mediated iodide uptake in thyroid cancer remain unclear. METHODS: Small activating RNA (saRNA) was used to promote NIS expression. And the cell viability, apoptosis, and autophagy were detected using Cell count-kit 8 (CCK-8), Annexin V-FITC/PI double staining, and GFP-LC3 immunofluorescence assays, respectively. The protein levels of caspase 3, Bax, Bcl-2, ATG5, ATG12, LC3B Ⅱ to LC3B Ⅰ, Beclin 1, P62, AMPK, mTOR, P70S6K, actin, and phosphorylation of AMPK, mTOR, P70S6K were determined by western blotting. Moreover, a nude murine node with transplanted NC-dsRNA or NIS-482-transfected SW579 cells was used to examine the effect of NIS-mediated autophagy in vivo. And the levels of caspase 3 and ki67 were examined by immunohistochemical staining assay. RESULTS: saRNA mediated NIS mRNA and protein upregulated in SW579 cells. saRNA-mediated NIS expression inhibited cell proliferation, induced apoptosis and autophagy, and promoted iodide uptake in SW579 cells. Moreover, the effects of NIS on cells were enhanced by autophagy activator Rapamycin whereas reversed by autophagy inhibitor 3-Methyladenine (3-MA). For mechanism analysis, we found that NIS upregulation exerted the effects on cell proliferation, apoptosis, autophagy, and iodide uptake via regulating AMPK/mTOR pathway. We also demonstrated that saRNA-mediated NIS expression promoted iodide uptake in vivo. CONCLUSION: saRNA-mediated NIS expression acted as a critical role in increasing iodide uptake via AMPK/mTOR pathway in thyroid cancer.

Analysis of factors influencing the distribution of 131-I in combined treatment of Licartin with transcatheter arterial chemoembolization in primary hepatic carcinoma.

Objective: To analyze the factors influencing the distribution of 131-I in the liver of patients with advanced hepatic carcinoma treated with the combination of Licartin (131I Metuximab) and transcatheter arterial chemoembolization (TACE). This study provides a reference and basis for the clinic on how to choose the best time for the treatment of Licartin and how to reduce other possible factors affecting the role of Licartin. Methods: Data from 41 patients with advanced hepatic carcinoma treated with the combination of Licartin and TACE in the Interventional Department of our hospital from March 2014 to December 2020 were collected. This included general characteristics, history of open and interventional surgery, interval between the last interventional surgery and the Licartin treatment, selected arteries in the Licartin perfusion, and 131-I distribution in the liver. Regression analysis was conducted to investigate the factors affecting the distribution of 131I in the liver. Results: In 14 cases (34.1%), 131-I was evenly distributed in the liver, and there was no correlation between the cause of even distribution with age(OR=0.961, P = 0.939), previous open surgery history(OR=3.547,P= 0.128), previous history of interventional therapy(OR=0.140,P = 0.072), the interval between the last interventional surgery and the Licartin treatment(OR=0.858,P = 0.883), or the choice of the perfusion artery in the Licartin treatment (OR=1.489,P = 0.419). In 14 cases (34.1%), there was higher aggregation in the tumor than in the normal liver, which was related to previous interventional surgery (OR=7.443,P = 0.043). In 13 cases (31.7%), there was lower aggregation in the tumor than in the normal liver, which was related to the selected vessels in the Licartin perfusion (OR=0.23,P = 0.013). Conclusion: The effective aggregation of 131-I in the liver, even in tumors, the previous history of TACE, and the choice of vessels in the Licartin infusion might be the factors influencing the distribution of 131-I in the liver during hepatic artery infusion of Licartin in combination with TACE therapy.

Chimeric Antigen Receptor (CAR)-T Cell Immunotherapy Against Thoracic Malignancies: Challenges and Opportunities.

Different from surgery, chemical therapy, radio-therapy and target therapy, Chimeric antigen receptor-modified T (CAR-T) cells, a novel adoptive immunotherapy strategy, have been used successfully against both hematological tumors and solid tumors. Although several problems have reduced engineered CAR-T cell therapeutic outcomes in clinical trials for the treatment of thoracic malignancies, including the lack of specific antigens, an immunosuppressive tumor microenvironment, a low level of CAR-T cell infiltration into tumor tissues, off-target toxicity, and other safety issues, CAR-T cell treatment is still full of bright future. In this review, we outline the basic structure and characteristics of CAR-T cells among different period, summarize the common tumor-associated antigens in clinical trials of CAR-T cell therapy for thoracic malignancies, and point out the current challenges and new strategies, aiming to provide new ideas and approaches for preclinical experiments and clinical trials of CAR-T cell therapy for thoracic malignancies.