Background: Nonalcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC) is becoming a major health-related problem. The exploration of NASH-related prognostic biomarkers and therapeutic targets is necessary. Methods: Data were downloaded from the GEO database. The "glmnet" package was used to identify differentially expressed genes (DEGs). The prognostic model was constructed by the univariate Cox and LASSO regression analyses. Validation of the expression and prognosis by immunohistochemistry (IHC) in vitro. Drug sensitivity and immune cell infiltration were analyzed by CTR-DB and ImmuCellAI. Results: We constructed a prognostic model that identified the NASH-related gene set (DLAT, IDH3B, and MAP3K4), which was validated in a real-world cohort. Next, seven prognostic transcription factors (TFs) were identified. The prognostic ceRNA network included three mRNAs, four miRNAs, and seven lncRNAs. Finally, we found that the gene set was associated with drug response which was validated in six clinical trial cohorts. Moreover, the expression level of the gene set was inversely correlated with CD8 T cell infiltration in HCC. Conclusions: We established a NASH-related prognostic model. Upstream transcriptome analysis and the ceRNA network provided clues for mechanism exploration. The mutant profile, drug sensitivity, and immune infiltration analysis further guided precise diagnosis and treatment strategies.
The embryonic stem cell test (EST), an alternative model to animal studies, is a reliable and scientifically validated in vitro system for testing embryotoxicity. In contrast to most in vivo animal tests, two permanent cell lines, murine fibroblasts (BALB/c‑3T3 cells) and murine embryonic stem cells (mES‑D3 cells), are used in EST instead of animals in standard tests of toxicity. The embryotoxic potential of compounds (non, weak or strong embryotoxicity) may be obtained with a biostatistics‑based prediction model and calculated from three different experimental endpoint values: The potency to inhibit growth of i) BALB/c‑3T3 cells and ii) mES‑D3 cells (IC503T3 and IC50ES) as presented using a cell cytotoxicity assay, and iii) the potency to inhibit differentiation of mES‑D3 cells into contracting cardiomyocytes (ID50 D3) as demonstrated in a mES‑D3 cell differentiation assay. In the present study, a model of EST with mES‑D3 cells and BALB/c‑3T3 cells was established, according to the standard EST system of the EU Center for the Validation of Alternative Methods, and verified it with 5‑fluorouracil (strong embryotoxicity) as a positive control and penicillin G (non‑embryotoxic) as a negative control. In addition, the authors further assessed the embryotoxicity of four compounds (eugenol, carnosic acid, procyanidin and dioctyl phthalate) with this model. The embryotoxic potentials of the four compounds were successfully classified by the EST system. Eugenol exhibited strong embryotoxicity, carnosic acid and dioctyl phthalate exhibited weak embryotoxicity, while procyanidin exhibited non‑embryotoxicity.
Objective: Medial elbow incision is obligatory for cubital tunnel syndrome surgical treatment. However, the terminal branches of both the medial antebrachial cutaneous nerve (MACN) and the medial brachial cutaneous nerve (MBCN) are likely to be harmed using the current incision technique. The aim of this study was to seek a new incision to avoid damaging the branches of MACN and MBCN during the operation for cubital tunnel syndrome. Methods: Ten fresh frozen cadaver upper extremities and 20 clinical cases (elbows) were analyzed. A conventional incision and a new incision were used in the cadaveric specimens and the clinical cases, respectively. The medial epicondyle was set as the reference landmark to quantify the location of the terminal branches, with the elbow at full extension. The numbers of the terminal branches and their locations were noted for MACN and MBCN, and the locations of the posterior branch of the MACN were recorded in the elbow medial incision. Results: The average numbers of MACN’s posterior terminal branches were 2.6 ± 1.6 and 4.4 ± 2.4 in the cadaveric specimens and clinical cases, respectively. The average number of MBCN’s terminal branches was 2 ± 0.87 in the cadaveric specimens. The MACN’s posterior terminal branches were located at 19 and 45 mm, respectively, measuring from the medial epicondyle. And the posterior branch of MACN was always located in between the medial epicondyle and the basilic vein, and the average distance was 10 ± 6 mm to the medial epicondyle. We could preserve all the MBCN’s terminal branches in the new incision. The MACN’s posterior terminal branches could be perfectly exposed by the use of the antegrade dissection technique, finding the MACN’s posterior branch in advance. Conclusions: The new elbow medial incision technique could reduce the risk of injuring the terminal branches from the MBCN. The medial epicondyle and the basilic vein are reliable anatomical landmarks to identify the posterior branch of the MACN. An antegrade method of dissection can effectively identify and avoid the injury to the terminal branches of the MACN in the elbow medial incision.
Paclitaxel (PTX) is a first-line drug for ovarian cancer (OC) treatment. However, the regulatory mechanism of STUB1 on ferroptosis and PTX resistance in OC remains unclear. Genes and proteins levels were evaluated by RT-qPCR, western blot and IHC. Cell viability and proliferation were measured by CCK-8 and clone formation. The changes of mitochondrial morphology were observed under a transmission electron microscope (TEM). Reactive oxygen species (ROS), iron, malondialdehyde (MDA) and glutathione (GSH) were measured using suitable kits. The interactions among STUB1, HOXB3 and PARK7 were validated using Co-IP, and dual luciferase reporter assay. Our study found that STUB1 was decreased and PARK7 was increased in tumor tissue, especially from chemotherapy resistant ovarian cancer tissue and resistant OC cells. STUB1 overexpression or PARK7 silencing suppressed cell growth and promoted ferroptosis in PTX-resistant OC cells, which was reversed by HOXB3 overexpression. Mechanistically, STUB1 mediated ubiquitination of HOXB3 to inhibit HOXB3 expression, and HOXB3 promoted the transcription of PARK7 by binding to the promoter region of PARK7. Furthermore, STUB1 overexpression or PARK7 silencing suppressed tumor formation in nude mice. In short, STUB1 promoted ferroptosis through regulating HOXB3/PARK7 axis, thereby suppressing chemotherapy resistance in OC. STUB1 mediates the degradation of HOXB3 through ubiquitin, and the decrease of HOXB3 inhibits the level of PARK7, thereby promoting ferroptosis in drug-resistant ovarian cancer cells.
Objective To probe the clinical curative effect of nail-baculum internal fixation system to heal the several S-T segement S-T francture of thoracic waist centra with spinal cord injury.Methods Retrospective analysis the 18 cases in the department of orthopacdics in our department which used nail-baculum internal fixation system to heal several S-T segement S-T francture of thoracic waist centra from June,2003 to May,2007.According to ASIA class and score spinal cord function contrast preoperative with after operation,18 cases are all used nail-baculum internal fixation system to do internal fixation and vertebral cunal decompression.Later we measure the elevation of centra after operation to see how it recrperate and Cobb Angel's alleosis by X aetinogram.And we analysis bone healing by CT.Results There are 18 cases following to visit between 44 weeks to 286 weeks.(Average:100 weeks)A11 the elevition of centra recuperate to be normal or almost normal and bone healing.According to ASIA class and score spinal cord function improve at the average of 2.6 grade after operation.Conclusion Nail-baculum internal fixation system in clinical treating several ST segement S-T francture of thoracic waist centra have its distinct adventage.It is not only convenient of handling operation,but also safety fixation.It can recuperate effectually the elevation of wound centra.
Length change in the distal oblique band during forearm rotation was measured using four-dimensional CT in seven volunteers. There was no significant change in length, which provides more theoretical support for distal oblique band reinforcement for treatment of instability of the distal radioulnar joint.
Glioma is the common histological subtype of malignancy in the central nervous system, with high morbidity and mortality. Glioma cancer stem cells (CSCs) play essential roles in tumor recurrence and treatment resistance. Thus, exploring the stem cell-related genes and subtypes in glioma is important. In this study, we collected the RNA-sequencing (RNA-seq) data and clinical information of glioma patients from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. With the differentially expressed genes (DEGs) and weighted gene correlation network analysis (WGCNA), we identified 86 mRNA expression-based stemness index (mRNAsi)-related genes in 583 samples from TCGA RNA-seq dataset. Furthermore, these samples from TCGA database could be divided into two significantly different subtypes with different prognoses based on the mRNAsi corresponding gene, which could also be validated in the CGGA database. The clinical characteristics and immune cell infiltrate distribution of the two stemness subtypes are different. Then, functional enrichment analyses were performed to identify the different gene ontology (GO) terms and pathways in the two different subtypes. Moreover, we constructed a stemness subtype-related risk score model and nomogram to predict the prognosis of glioma patients. Finally, we selected one gene (ETV2) from the risk score model for experimental validation. The results showed that ETV2 can contribute to the invasion, migration, and epithelial-mesenchymal transition (EMT) process of glioma. In conclusion, we identified two distinct molecular subtypes and potential therapeutic targets of glioma, which could provide new insights for the development of precision diagnosis and prognostic prediction for glioma patients.
Abstract Background Cancer cells frequently evolve necroptotic resistance to overcome various survival stress during tumorigenesis. However, we have previously showed that necroptosis is widespread in head and neck squamous cell carcinoma (HNSCC) and contributes to tumor progression and poor survival via DAMPs-induced migration and invasiveness in peri-necroptotic tumor cells. This implicated an alternative strategy that cancers cope with necroptotic stress by reprogramming a pro-invasive necroptotic microenvironment (NME). Here, we aim to decipher how necroptotic cells shape the NME and affect HNSCC progression. Methods Both our pre-established cellular necroptotic model and newly established Dox-induce intratumoral necroptosis model were used to investigate how necroptosis affect HNSCC progression. Transcriptomic alterations in peri-necroptotic tumor cells were analyzed by RNA-seq and validated in the NME in mice and patients’ samples. The differential DAMPs compositon among apopotosis. Necrosis, and necroptosis were analyzed by label-free proteomic technique, and the necroptosis-specific DAMPs were then identified and validated. The potential receptor for ISG15 were simulated using molecular docking and further validated by in vitro assays. Then the ISG15-RAGE axis was blocked by either knockdown of necroptotic-ISG15 release and RAGE inhibitor FPS-ZM1, and the impact on tumor progression were tested. Last, we further tested our findings in a HNSCC-patients cohort. Results Necroptosis played a crucial role in driving tumor-cell invasiveness and lymphatic metastasis via tumor-type dependent DAMPs-releasing. Mechanistically, necroptotic DAMPs induced peri-necroptotic EMT via NF-κB and STAT3 signaling. Furthermore, intrinsic orchestration between necroptotic and cGAS-STING signaling resulted in producing a group of interferon stimulated genes (ISGs) as HNSCC-dependent necroptotic DAMPs. Among them, ISG15 played an essential role in reprogramming the NME. We then identified RAGE as a novel receptor for extracellular ISG15. Either blockage of ISG15 release or ISG15-RAGE interaction dramatically impeded necroptosis-driven EMT and lymphatic metastasis in HNSCC. Lastly, clinicopathological analysis showed high ISG15 expression in NME. Extensive necroptosis and high tumor-cell RAGE expression correlated with tumor progression and poor survival of HNSCC patients. Conclusions Our data revealed a previously unknown cGAS-ISG15-RAGE dependent reprogramming of the necroptotic microenvironment which converts the necroptotic stress into invasive force to foster HNSCC-cell dissemination. By demonstrating the programmatic production of ISG15 via necroptosis-cGAS orchestration and its downstream signaling through RAGE, we shed light on the unique role of ISG15 in HNSCC progression. Targeting such machineries may hold therapeutic potential for restoring intratumoral survival stress and preventing lymphatic metastasis in HNSCC. Graphical Abstract
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)