Recognition and cleavage mechanism of intron-containing pre-tRNA by human TSEN endonuclease complex.

Removal of introns from transfer RNA precursors (pre-tRNAs) occurs in all living organisms. This is a vital phase in the maturation and functionality of tRNA. Here we present a 3.2 Å-resolution cryo-EM structure of an active human tRNA splicing endonuclease complex bound to an intron-containing pre-tRNA. TSEN54, along with the unique regions of TSEN34 and TSEN2, cooperatively recognizes the mature body of pre-tRNA and guides the anticodon-intron stem to the correct position for splicing. We capture the moment when the endonucleases are poised for cleavage, illuminating the molecular mechanism for both 3' and 5' cleavage reactions. Two insertion loops from TSEN54 and TSEN2 cover the 3' and 5' splice sites, respectively, trapping the scissile phosphate in the center of the catalytic triad of residues. Our findings reveal the molecular mechanism for eukaryotic pre-tRNA recognition and cleavage, as well as the evolutionary relationship between archaeal and eukaryotic TSENs.

The dual role of ferroptosis in anthracycline-based chemotherapy includes reducing resistance and increasing toxicity.

In conjunction with previous studies, we have noted that ferroptosis, as an emerging mode of regulated cell death (RCD), is intimately related to anthracycline pharmacotherapy. Not only does ferroptosis significantly modulate tumour resistance and drug toxicity, which are core links of the relevant chemotherapeutic process, but it also appears to play a conflicting role that has yet to be appreciated. By targeting the dual role of ferroptosis in anthracycline-based chemotherapy, this review aims to focus on the latest findings at this stage, identify the potential associations and provide novel perspectives for subsequent research directions and therapeutic strategies.

Percutaneous pedicle screw fixation combined with percutaneous vertebroplasty for the treatment of thoracic and lumbar metastatic tumors.

Background and Aim: With the greatly prolonged survival of cancer patients, more and more patients develop bone metastasis, especially spinal metastasis. Therefore, it is very important to choose the best surgical plan for patients with spinal metastasis in different conditions. This paper aims to evaluate the clinical efficacy of percutaneous pedicle screw fixation (PPSF) combined with percutaneous vertebroplasty (PVP) for the treatment of thoracic and lumbar metastatic tumors. Methods: Forty patients with thoracic and lumbar metastatic tumors were treated with PPSF combined with PVP and followed up for 6-33 months. The visual analog scale (VAS) and the Barthel Index of activities of daily living (BIADL) were used to evaluate the pain intensity and quality of life before surgery and at 7 days, 3 months, and 6 months after the treatment. Results: In this study, a total of 40 patients were followed up for 6-33 months (the mean time was 14.87 months). The VAS scores of all patients were significantly decreased, while the BIADL scores were significantly increased. No patients suffered from complications such as infection, pedicle screw loosening, or polymethylmethacrylate leakage. Spine stability was observed in all surviving patients during the follow-up. Conclusions: PPSF combined with PVP is a new and viable treatment for thoracolumbar metastases in patients with a poor systemic condition, patients who refuse to undergo a conventional open procedure such as en bloc corpectomy, and in patients with vertebral instability or pathological fracture without significant spinal compression. Relevance for Patients: Patients with spinal metastases have a great risk of spinal instability and even spinal cord compression while enduring pain. Therefore, timely and appropriate surgical treatment is an effective means to stabilize the spine and avoid spinal cord compression. PPSF combined with PVP is an effective new surgical method for the treatment of multilevel spinal metastases.

Innovation in proximal femoral replacement for oncology patients-A novel eggshell procedure.

Purpose: Proximal femoral replacement (PFR) for oncology patients is gaining interest as a limb salvage operation due to its obvious advantages. However, almost all hip replacement surgeries including PFR, are faced with the challenge of how to reconstruct the functional musculature in an optimal way. To address the challenge, we have developed an innovative eggshell procedure and through this study we aim to investigate the specific efficacy of the procedure. Methods: A total of 44 tumor patients with PFR surgery were incorporated into the study, including 12 who underwent the eggshell procedure and 32 who did not. General characteristics, short-term indicators, long-term indicators and complication outcomes were compared successively between the two groups of patients. Results: No significant differences were identified in general characteristics between the two groups. Overall, in terms of both short-term and long-term indicators, the patients with eggshell procedure performed significantly superior to the patients without it. Moreover, the eggshell procedure significantly reduced the incidence of associated complications, including prosthesis dislocation and hip pain. Conclusions: Our eggshell procedure is convenient and accessible. On the one hand, it can reduce surgical side injuries without adding additional complications, and on the other it allows to improve joint mobility and life quality while diminishing the incidence of prosthesis dislocation and hip pain. Despite it may still remain limitations, we have reasons to believe that this procedure can be further promoted and applied.

Targeting iron metabolism in osteosarcoma.

Osteosarcoma (OS) is the most common primary solid malignant tumour of bone, with rapid progression and a very poor prognosis. Iron is an essential nutrient that makes it an important player in cellular activities due to its inherent ability to exchange electrons, and its metabolic abnormalities are associated with a variety of diseases. The body tightly regulates iron content at the systemic and cellular levels through various mechanisms to prevent iron deficiency and overload from damaging the body. OS cells regulate various mechanisms to increase the intracellular iron concentration to accelerate proliferation, and some studies have revealed the hidden link between iron metabolism and the occurrence and development of OS. This article briefly describes the process of normal iron metabolism, and focuses on the research progress of abnormal iron metabolism in OS from the systemic and cellular levels.

Remarkable immune and clinical value of novel ferroptosis-related genes in glioma.

Ferroptosis is a neoteric model of regulated cell death that shows great potential for the understanding of tumor immunology and as a target for therapy. The present study aimed to identify ferroptosis-related differentially expressed genes (DEGs) in glioma and to explore their value through systematic analysis. Ferroptosis-related DEGs were identified through the Gene Expression Omnibus database in combination with the FerrDb database and analyzed in the Genotype-Tissue Expression database and The Cancer Genome Atlas database. Possible signaling pathways involved were explored by construction of enrichment analysis and protein-protein interaction of these DEGs. Potential regulation of the immune microenvironment, immune checkpoint and chemokine was postulated by immune analysis. A prognosis model for glioma was developed using survival analysis, exhibited by the nomogram and evaluated by the calibration curve. The prognostic value of the model was validated by using an independent cohort. A total of 15 ferroptosis-related DEGs were identified, including 7 down-regulated and 8 up-regulated, with ATP6V1G2, GABARAPL1 and GOT1 as hub genes. The expression of all 3 hub genes was positively correlated with T follicular helper cells and natural killer CD56bright cells. These hub genes were negatively correlated with the macrophage cell type as well as B7H3, PDCD1, LAG3 and CXCL16, CXCR4, CCR5. Low expression of all 3 hub genes was associated with poor prognosis in glioma cases. ATP6V1G2 might be an independent prognostic factor and, as such, a high-precision prognostic model of glioma was constructed. We identified novel ferroptosis-related genes with clinical value in glioma and revealed their possible tumor immune relevance. Furthermore, in glioma, we pinpointed underlying critical elements of the chemokine, immune microenvironment and immune checkpoint, and were able to develop a predictive model of prognosis.

Multimodal Sonographic Appearance and Survival Outcomes of 69 Cases of Primary Thyroid Lymphoma Over 10 Years.

OBJECTIVES: To investigate ultrasound appearance and the survival outcomes for patients with primary thyroid lymphoma (PTL). METHODS: Ultrasonic images and clinical characteristics from pathologically confirmed 69 PTL patients (2008-2019) were retrospectively analyzed. The clinical characteristics, ultrasonic characters, and prognostic factors were analyzed. Survival curves were plotted using the Kaplan-Meier method. Univariate and multivariate analyses were performed. RESULTS: Of the 69 study patients, 23 were indolent PTL and 46 were aggressive PTL. Age (>70 years old) and elevated lactate dehydrogenase levels were statistically different clinical features between aggressive and indolent PTL. From ultrasonic images, 34 cases were nodular, 11 diffuse, and 24 mixed pattern. Mixed types displayed high invasiveness (45.7%) while diffuse types displayed higher inertness (39.1%), with statistically significant differences (P = .000). Invaded thyroid capsule and increased chaotic vascularity also showed significant differences between aggressive and indolent PTL. We also observed statistical difference in overall survival rates between aggressive and indolent PTL (P = .032). Single factor K-M analyses showed that age >70 years, aggressive pathology, and Ki67 >30% were positively correlated with the risk of poor PTL survival (P < .05). CONCLUSIONS: Multimodal ultrasound provides accurate ultrasonographic information and facilitates PTL invasiveness diagnostics for improved clinical treatment. In addition, PTL patients aged >70 years, with aggressive pathology, and Ki67 >30% were more likely to have a poor survival outcome.

Hsa_circ_0058129 regulates papillary thyroid cancer development via miR-873-5p/follistatin-like 1 axis.

BACKGROUND: Papillary thyroid cancer (PTC) is an endocrine malignancy with a high incidence. Circular RNAs (circRNAs) participate in regulating PTC. Here, we analyzed the role of hsa_circ_0058129 (circ_0058129) in PTC. METHODS: The expression of circ_0058129, fibronectin 1 (FN1) mRNA, microRNA-873-5p (miR-873-5p), and follistatin-like 1 (FSTL1) was detected by qRT-PCR and western blot. Cell proliferation was analyzed by CCK-8, EdU, and flow cytometry analysis assays. Cell migration and invasion were evaluated by Transwell assay. The targeting relationship of miR-873-5p and circ_0058129 or FSTL1 was identified through dual-luciferase reporter assay, RIP assay, and RNA pull-down assay. Xenograft mouse model assay was implemented to determine the effect of circ_0058129 on tumor formation in vivo. RESULTS: The circ_0058129 and FSTL1 abundances were increased, while the miR-873-5p content was decreased in PTC tissues and cells compared with control groups. Circ_0058129 shortage inhibited PTC cell proliferation, migration, and invasion. Moreover, miR-873-5p repressed PTC cell malignancy by binding to FSTL1. Circ_0058129 targeted miR-873-5p to regulate FSTL1. CONCLUSION: Circ_0058129 expedited PTC progression through the miR-873-5p/FSTL1 pathway.

Comprehensive imaging and pathology of solitary patellar metastasis from breast cancer with literature review on its diagnosis and prognosis.

BACKGROUND: Breast cancer is the most frequent non-skin cancer in women and bone is its most common site of metastasis. The patella, as the largest sesamoid bone in the human body, is a rare site for cancer metastasis to occur. We reported the comprehensive auxiliary examination data and complete process of diagnosis, management and follow-up for a case of solitary patellar metastasis from breast cancer. CASE PRESENTATION: A 47-year-old woman presented with patellar pain 6 years after breast cancer surgery. Thorough imaging and pathology examinations were carried out leading to a diagnosis of breast-derived patellar metastasis. Subsequent treatment and follow-up were performed. The patient recovered function slightly at 3 months postoperatively, but tibia and femur metastases developed at 6 months postoperatively and the patient started radiotherapy. DISCUSSION: Cases of patellar metastases from malignant tumors are extremely rare but do exist. Due to the insidious onset and non-specific symptoms, it is worthwhile to alert clinicians. The diagnostic value of positron emission tomography/computed tomography for patellar metastases is significant and still provides certain advantages compared to pathologic examination, so it can be given priority. Prompt postoperative radiotherapy is necessary, while imaging should be actively performed with a short review interval.

Outstanding prognostic value of novel ferroptosis-related genes in chemoresistance osteosarcoma patients.

Osteosarcoma (OS) is the most common bone-derived tumor, and chemoresistance is a pivotal factor in the poor prognosis of patients with OS. Ferroptosis, as an emerging modality of regulated cell death, has demonstrated potential value in tumor chemoresistance studies. Through the gene expression omnibus database in conjunction with the FerrDb database, we identified novel ferroptosis-related differentially expressed genes (DEGs) involving chemoresistance in OS patients. Subsequently, enrichment analysis, protein-protein interaction network analysis and survival analysis were performed sequentially to recognize the hub genes and ultimately to construct a predictive model. The model constructed from the TARGET database was exhibited in a nomogram and assessed by calibration curves. The prognostic value of the model and hub genes was validated separately by an independent cohort. Twenty-two ferroptosis-related DEGs were identified, including 16 up-regulated and 6 down-regulated. Among them, expressions of CBS, COCS1, EGFR, as hub genes, were significantly associated with the prognosis of OS patients and were evidenced as independent prognostic factors. An efficient prognostic model covering hub gene expressions and clinical variables was developed and validated. Combining the results of hub genes in differential analysis, the actions of hub genes in ferroptosis, and the prognostic relevance of hub genes in patients, we revealed that CBS, SOCS1 and EGFR might play essential roles in OS and its chemoresistance with potential research and clinical value.

Mechanisms and Molecular Targets of BuShenHuoXue Formula for Osteoarthritis.

The aim was to identify latent mechanism of BuShenHuoXue (BSHX) formula for the management of osteoarthritis (OA) through the network pharmacology approach and experimental validation. We obtained OA-related targets through the Gene Expression Omnibus database and bioactive ingredients with corresponding targets in the formula via the Traditional Chinese Medicine Systems Pharmacology database. Subsequently, networks of the protein-protein interaction and compound-disease target were created and enrichment analysis was implemented. Furthermore, in vitro, IL-1ß was applied to rat chondrocytes to mediate apoptosis through inflammation and the Alcian blue and type II collagen staining was used to observe cell morphology. The TUNEL and DAPI staining was performed to observe chondrocyte apoptosis, and the apoptosis rates were gauged via flow cytometry. In addition, we utilized Western blot and PCR to detect the protein and mRNA expression, respectively. A total of 104 potential chemicals and 42 intersecting targets were screened out. Quercetin and luteolin from BSHX formula were principal ingredients. The experiment validated quercetin might suppress chondrocyte apoptosis mediated by IL-1ß and reduce SELE, MMP2, and COL1 expression. Via the AGE-RAGE signaling pathway in diabetic complications, quercetin could aim at SELE, MMP2, and COL1 and exert antagonistic effects against OA.

Immunological and prognostic significance of novel ferroptosis-related genes in soft tissue sarcoma.

BACKGROUND: Ferroptosis has exhibited great potential in the treatment of cancer and has gained widespread attention in soft tissue sarcoma (STS). The aim was to explore the immunological and prognostic significance of novel ferroptosis-related genes in STS. METHODS: We identified ferroptosis-related differentially expressed genes (DEGs) in STS to construct the networks of enrichment analysis and protein-protein interaction. Subsequently, hub genes with prognostic significance were localized and a series of prognostic and immune analyses were performed. RESULTS: 40 ferroptosis-related DEGs were identified, of which HELLS, STMN1 EPAS1, CXCL2, NQO1, and IL6 were classified as hub genes and were associated with the prognosis in STS patients. In the results of the immune analysis, PDCD1, CTLA4, TIGIT, IDO1 and CD27 exhibited consistent intense correlations as immune checkpoint genes, as well as macrophage, neutrophil, cytotoxic cell, dendritic cell, interdigitating dendritic cell and plasmacytoid dendritic cell as immune cells. EPAS1 and HELLS might be independent prognostic factors for STS patients, and separate prognostic models were constructed by using them. CONCLUSIONS: We recognized novel ferroptosis-related genes with prognostic value in STS. Furthermore, we searched out potential immune checkpoints and critical immune cells.

Weighted Gene Co-expression Network Analysis Identifies Five Hub Genes Associated with Metastasis in Synovial Sarcoma.

BACKGROUND: Synovial Sarcoma (SS) refers to a malignant Soft Tissue Sarcoma (STS) which often comes about to children and adults and has a poor prognosis in elderly patients. Patients with local lesions can be treated with extensive surgical resection combined with adjuvant or radiotherapy, whereas about half of the cases have recurrent diseases and metastatic lesions, and five-year survival ratio is assessed within the range of 27% - 55% only. METHODS: We downloaded a set of expression profile data (GSE40021) related to SS metastasis based on the Gene Expression Omnibus (GEO) database, and selected distinctly represented genes (DEGs) related to tumor metastasis. WGCNA was used to emphasize the DEGs related to tumor metastasis, and obtain co-expression modules. Then, the module most related to SS metastasis was screened out. The genes of enriched in this module were analyzed by Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway improvement analysis. Cytoscape software was used for constructing protein-protein interaction (PPI) networks, and screening hub genes were made in virtue of Oncomine analysis. RESULT: We selected 514 DEGs, consisting of 210 up-regulated genes and 304 down-regulated genes. Through WGCAN, we got seven co-expression modules and the module most related to SS metastasis was turquoise module, which contained 66 genes. Finally, we screened out five hub genes (HJURP, NCAPG, TPX2, CENPA, NDC80) through CytoHubba and Oncomine analysis. CONCLUSION: In this study, we screened out five hub genes to help clinical diagnosis and serve as the latent purpose of SS treatment.

Prognosis and role of clinical and imaging features in patients with malignant pericardial effusion: a single-center study in China.

BACKGROUND: The diagnosis of malignant pericardial effusion (MPE) is often associated with a poor prognosis, but due to the complexity and unspecific nature of MPE patients' clinical manifestations, imaging often performs an essential role in diagnosis and prognosis. METHODS: Patients diagnosed with MPE between 2013 and 2018 at one tumor hospital were included and followed up. The data covered the basic clinical features, imaging findings, treatments and prognosis of patients with MPE, and the factors that may have affected the prognosis were explored. RESULTS: A total of 216 patients with MPE were included with the median age of 60 years. The most common primary cancer type was lung cancer (73.6%), the most common symptom was dyspnea (62.9%) and the most common abnormal electrocardiogram finding was sinus tachycardia (42.1%). The median survival time of the 216 patients with MPE was 13.7 months. The factors affecting prognosis were echocardiographic fluid signs (HR = 2.37, P = 0.010), electrocardiographic evidence of sinus tachycardia (HR = 1.76, P = 0.006) and echocardiographic evidence of cardiac tamponade (HR = 3.33, P < 0.001). CONCLUSIONS: MPE has complex clinical manifestations and an unsatisfactory prognosis. Echocardiographic fluid signs, electrocardiographic evidence of sinus tachycardia, and echocardiographic evidence of cardiac tamponade are independent risk factors affecting prognosis.

Targeting ferroptosis in osteosarcoma.

Osteosarcoma (OS) is the most common primary bone tumour in children and adolescents, with high degree of malignancy and an extremely poor prognosis. Ferroptosis, a non-traditional mode of regulated cell death (RCD) characterised by iron-dependent accumulation of lipid reactive oxygen species (ROS), is closely associated with a variety of cancers. It has been demonstrated that ferroptosis can regulate OS progression and exert an essential role in the treatment of OS, which is potentially of great value. By targeting ferroptosis in OS, the present review article summarises the relevant mechanisms and therapeutic applications along with discussing current limitations and future directions, which may provide a new strategy for the treatment of OS.

Durvalumab monotherapy as a third-line treatment for extensive-stage small-cell lung cancer: a case report.

The global incidence and mortality rates of lung cancer are the highest of any cancer. Smallcell lung cancer (SCLC) is an undifferentiated carcinoma which accounts for 15-20% of all lung cancers. Compared with the other major lung cancer type, non-small cell lung cancer, SCLC exhibits worse biological behavior, has a higher degree of malignancy, and develops more rapidly. The majority of SCLC present with extensive-stage disease, and the prognosis for these patients remains poor. Recently, immunotherapy has been demonstrated clinical activity in extensive-stage SCLC (ES-SCLC); however, the efficacy and safety of immunotherapy in ES-SCLC needs further confirmation. Durvalumab, a selective, high-affinity human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80, showed durable clinical activity and a manageable safety profile in patients with pretreated ES-SCLC as a first-line treatment. Here, we report the case of an ES-SCLC patient who achieved complete remission (CR) of local lesions after receiving durvalumab monotherapy as a third-line treatment, experiencing no obvious immune-related side effects, such as rash, diarrhea, fatigue, myelosuppression, or thyroid dysfunction. No immune-related pulmonary or hepatorenal toxicities occurred. The case suggests that immunotherapy can be selected for third-line or multi-line treatment of ES-SCLC, and anti-PD-L1 antibody may be the better choice for patients who have poor performance status (PS) scores.

Knockdown of lncRNA NEAT1 suppresses hypoxia-induced migration, invasion and glycolysis in anaplastic thyroid carcinoma cells through regulation of miR-206 and miR-599.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive and lethal malignancies. Long non-coding RNAs (lncRNAs) are being found to play crucial roles in ATC progression. Herein, we focused on the role of nuclear paraspeckle assembly transcript 1 (NEAT1) on ATC progression under hypoxia and underlying mechanisms governing it. METHODS: The expression levels of NEAT1, miR-206 and miR-599 were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). Cell migration and invasion abilities were detected using transwell assays. Glucose consumption and lactate production were determined using a corresponding commercial assay kit. Western blot was performed to evaluate the level of hexokinase 2 (HK2). The targeted interplays between NEAT1 and miR-206 or miR-599 were confirmed by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Xenograft model was established to observe the effect of NEAT1 on tumor growth in vivo. RESULTS: Our data indicated that NEAT1 was highly expressed in ATC tissues and cells, and hypoxia induced NEAT1 expression in ATC cells. NEAT1 depletion repressed ATC cell migration, invasion and glycolysis under hypoxia. Mechanistically, NEAT1 acted as a molecular sponge of miR-206 and miR-599. Moreover, the repressive effects of NEAT1 knockdown on ATC cell migration, invasion and glycolysis under hypoxia were mediated by miR-206 or miR-599. Additionally, NEAT1 knockdown weakened tumor growth in vivo. CONCLUSION: In conclusion, our study suggested that a low NEAT1 expression suppressed the migration, invasion, and glycolysis in ATC cells under hypoxia at least partially through modulating miR-206 and miR-599, providing new therapeutic strategies for ATC treatment.

[Sequence analysis of 16S rDNA and genes of soluble methane monooxygenase from Methylomonas sp. GYJ3].

Soluble methane monooxygenase (MMO) from methanotrophs is a member of binuclear iron-containing multicomponent oxygenases, which can catalyze bioconversion of methane to methanol at ambient temperature and regulate methane recycle in nature. The research focused mainly on the sequence analysis of 16S rDNA and sMMO genes from Methylomonas sp. GYJ3. With the aid of the information from GenBank, the PCR primers and the sequence primers were designed, obtained a 5690bp of sMMO fragment and a 1280bp of 16S rDNA. Sequence comparison for MMOX with counterpart of other five strains showed that from 78% to 99% identity in protein level and from 71 % to 97% identity in gene level, in the separate comparison of six components, only orfY component had a lower identical. The multiple alignment of MMOX amino acid sequence with other four strains showed that there is a high conservation, especially in two Fe binding regions. 16S rDNA phylogenetic analysis demonstrated that Methylomonas sp. GYJ3 is relative with gamma proteobacteria. Phylogenetic analysis of MMOX amino acid sequence showed that Methylomonas sp. GYJ3 is closer to Methylomonas sp. KSW III of type I methanotrophs. It was concluded that Methylomonas sp. GYJ3 is belong to the genus of type I methanotroph Methylomonas, and the result was a direct evidence for the sMMO can be expressed in type I methanotrophs. The theoretical pI of hydroxylase was 6.28 and the theoretical MW of hydroxylase was 248874.41Da.