Prognostic significance of systemic immune inflammatory index in NSCLC: a meta-analysis.

Aim: The aim of this meta-analysis was to investigate the relationship between the baseline systemic immune inflammatory index (SII) and prognosis in patients with NSCLC. Materials & methods: The relation between pretreatment SII and overall survival, disease-free survival, cancer-specific survival, progression-free survival and recurrence-free survival in NSCLC patients was analyzed combined with hazard ratio and 95% CI. Results: The results showed that high SII was significantly correlated with overall survival and progression-free survival of NSCLC patients, but not with disease-free survival, cancer-specific survival and recurrence-free survival. Conclusion: The study suggests that a higher SII has association with worse prognosis in NSCLC patients. PROSPERO registration number: CRD42022336270.

Cigarette smoking inhibits myoblast regeneration by promoting proteasomal degradation of NPAT protein and hindering cell cycle progression.

Cigarette smoking (CS) causes skeletal muscle dysfunction, leading to sarcopenia and worse prognosis of patients with diverse systemic diseases. Here, we found that CS exposure prevented C2C12 myoblasts proliferation in a dose-dependent manner. Immunoblotting assays verified that CS exposure promoted the expression of cell cycle suppressor protein p21. Furthermore, CS exposure significantly inhibited replication-dependent (RD) histone transcription and caused S phase arrest in the cell cycle during C2C12 proliferation. Mechanistically, CS deregulated the expression levels of Nuclear Protein Ataxia-Telangiectasia Locus (NPAT/p220). Notably, the proteasome inhibitor MG132 was able to reverse the expression of NPAT in myoblasts, implying that the degradation of CS-mediated NPAT is proteasome-dependent. Overexpression of NPAT also rescued the defective proliferation phenotype induced by CS in C2C12 myoblasts. Taken together, we suggest that CS exposure induces NPAT degradation in C2C12 myoblasts and impairs myogenic proliferation through NPAT associated proteasomal-dependent mechanisms. As an application of the proteasome inhibitor MG132 or overexpression of NPAT could reverse the impaired proliferation of myoblasts induced by CS, the recovery of myoblast proliferation may be potential strategies to treat CS-related skeletal muscle dysfunction.

Deep learning for differentiation of osteolytic osteosarcoma and giant cell tumor around the knee joint on radiographs: a multicenter study.

OBJECTIVES: To develop a deep learning (DL) model for differentiating between osteolytic osteosarcoma (OS) and giant cell tumor (GCT) on radiographs. METHODS: Patients with osteolytic OS and GCT proven by postoperative pathology were retrospectively recruited from four centers (center A, training and internal testing; centers B, C, and D, external testing). Sixteen radiologists with different experiences in musculoskeletal imaging diagnosis were divided into three groups and participated with or without the DL model's assistance. DL model was generated using EfficientNet-B6 architecture, and the clinical model was trained using clinical variables. The performance of various models was compared using McNemar's test. RESULTS: Three hundred thirty-three patients were included (mean age, 27 years ± 12 [SD]; 186 men). Compared to the clinical model, the DL model achieved a higher area under the curve (AUC) in both the internal (0.97 vs. 0.77, p = 0.008) and external test set (0.97 vs. 0.64, p < 0.001). In the total test set (including the internal and external test sets), the DL model achieved higher accuracy than the junior expert committee (93.1% vs. 72.4%; p < 0.001) and was comparable to the intermediate and senior expert committee (93.1% vs. 88.8%, p = 0.25; 87.1%, p = 0.35). With DL model assistance, the accuracy of the junior expert committee was improved from 72.4% to 91.4% (p = 0.051). CONCLUSION: The DL model accurately distinguished osteolytic OS and GCT with better performance than the junior radiologists, whose own diagnostic performances were significantly improved with the aid of the model, indicating the potential for the differential diagnosis of the two bone tumors on radiographs. CRITICAL RELEVANCE STATEMENT: The deep learning model can accurately distinguish osteolytic osteosarcoma and giant cell tumor on radiographs, which may help radiologists improve the diagnostic accuracy of two types of tumors. KEY POINTS: • The DL model shows robust performance in distinguishing osteolytic osteosarcoma and giant cell tumor. • The diagnosis performance of the DL model is better than junior radiologists'. • The DL model shows potential for differentiating osteolytic osteosarcoma and giant cell tumor.

Synthesis of Tough and Fluorescent Self-Healing Elastomers by Scandium-Catalyzed Terpolymerization of Pyrenylethenylstyrene, Ethylene, and Anisylpropylene.

The synthesis of fluorescent self-healing polymers by the incorporation of a fluorophore-containing olefin into a polyolefin backbone through catalyst-controlled multicomponent copolymerization is of fundamental interest and practical importance, but such an approach has remained unexplored to date. Herein, we report for the first time the synthesis of tough and fluorescent self-healing polymers by sequence-controlled terpolymerization of 4-[2-(1-pyrenyl)ethenyl]styrene (Pyr), ethylene (E), and anisylpropylene (AP) using a sterically demanding half-sandwich scandium catalyst. The resulting terpolymers consisted of relatively long alternating E-alt-AP sequences, isolated Pyr units, and short E-E blocks, which exhibited excellent tensile strength, remarkable self-healability, and high fluorescence quantum yield. The excellent mechanical and self-healing properties could be attributed to the nanophase separation of the crystalline E-E segments and the hard Pyr aggregates from a flexible E-alt-AP segment matrix, in which the Pyr units not only served as an efficient fluorophore but also played an important role in forming nanodomains and enhancing the polymer mobility. Furthermore, the styrenyl C═C bond of the Pyr unit in the terpolymers could undergo [2 + 2] cycloaddition under photoirradiation, which thus enabled the fabrication of a self-healable fluorescent two-dimensional image on a terpolymer film through photolithography. This work offers an unprecedented efficient protocol for the synthesis of a brand-new family of fluorescent self-healing materials, showcasing the high potential of catalyst-controlled sequence-regular copolymerization of different olefins for the creation of novel functional polymers.

Britannin as a novel NLRP3 inhibitor, suppresses inflammasome activation in macrophages and alleviates NLRP3-related diseases in mice.

Overactivation of the NLRP3 inflammasomes induces production of pro-inflammatory cytokines and drives pathological processes. Pharmacological inhibition of NLRP3 is an explicit strategy for the treatment of inflammatory diseases. Thus far no drug specifically targeting NLRP3 has been approved by the FDA for clinical use. This study was aimed to discover novel NLRP3 inhibitors that could suppress NLRP3-mediated pyroptosis. We screened 95 natural products from our in-house library for their inhibitory activity on IL-1ß secretion in LPS + ATP-challenged BMDMs, found that Britannin exerted the most potent inhibitory effect with an IC50 value of 3.630 µM. We showed that Britannin (1, 5, 10 µM) dose-dependently inhibited secretion of the cleaved Caspase-1 (p20) and the mature IL-1ß, and suppressed NLRP3-mediated pyroptosis in both murine and human macrophages. We demonstrated that Britannin specifically inhibited the activation step of NLRP3 inflammasome in BMDMs via interrupting the assembly step, especially the interaction between NLRP3 and NEK7. We revealed that Britannin directly bound to NLRP3 NACHT domain at Arg335 and Gly271. Moreover, Britannin suppressed NLRP3 activation in an ATPase-independent way, suggesting it as a lead compound for design and development of novel NLRP3 inhibitors. In mouse models of MSU-induced gouty arthritis and LPS-induced acute lung injury (ALI), administration of Britannin (20 mg/kg, i.p.) significantly alleviated NLRP3-mediated inflammation; the therapeutic effects of Britannin were dismissed by NLRP3 knockout. In conclusion, Britannin is an effective natural NLRP3 inhibitor and a potential lead compound for the development of drugs targeting NLRP3.

Protective Effect of Ginsenoside CK against Autoimmune Hepatitis Induced by Concanavalin A.

Ginsenoside CK, a kind of rare ginsenoside transformed from protopanaxadiol saponins extracted from the genus Panax, has been proven to possess favorable bioactivities such as anti-inflammatory, anti-cancer, anti-diabetes, and hepatoprotective effects. The current study is targeted to determine the effect of ginsenoside CK on hepatitis induced by concanavalin A (Con A). Mice were treated with different dosages of ginsenoside CK for 7 days, and Con A (15 mg/kg) was intravenously injected to induce autoimmune hepatitis (AIH) after the last administration. The results demonstrated that pretreatment with ginsenoside CK (40 mg/kg) could obviously ameliorate the increase in serum indicators related to liver function such as AST, ALT, and ALP, and hepatic lesions induced by Con A. Meanwhile, ginsenoside CK suppressed hepatocyte apoptosis, which was observed in pathological data, and immunoblotting results showed that the expression of Bax, Bcl-2, and other proteins was regulated by CK. Furthermore, the release of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and IL-6 in mice with AIH were lowered by the administration of 40 mg/kg of ginsenoside CK. Furthermore, ginsenoside CK elevated the gene expression of Nrf2 and Sirt1 and augmented downstream target genes such as HO-1. In addition, a significant inhibition effect of the TLR4/NF-κB signal was observed in 40 mg/kg CK-pretreated mice compared with the model group. To sum up, the results indicated that ginsenoside CK has a notable hepatoprotective effect against AIH by activating Sirt1/Nrf2 and suppressing the TLR4/NF-κB signaling pathway.

Transcriptomic characterization of interactions between sodium selenite and coenzyme Q10 on preventing cadmium-induced testicular defects.

The effect of heavy metal cadmium (Cd) on testicular function is recognized. However, the mechanism involved is not well-established. In the present study, we analyzed the testicular transcriptomic changes induced by acute Cd exposure of adult rats with and without supplementation of antioxidants selenium (Se) and/or coenzyme Q10 (CoQ). Cd significantly decreased serum testosterone and two steroidogenic proteins SCARB1 and STAR. RNA-Seq analyses of testicular RNAs revealed specific activation of oxidative stress-, inflammation-, MAPK- and NF-κB-related signaling molecules. In addition, Cd treatment down-regulated gene for I, III and IV complexes of mitochondrial electron transport chain and up-regulated genes for NADPH-oxidase, major cascade in ROS production. The decrease in steroidogenesis and increase in inflammation may result from oxidative stress since supplementation of Se and CoQ, but not with either alone, almost completely prevented these changes, including overall alterations in transcriptome. Cd exposure induced total of 1192 differentially expressed genes (DEGs), which was reduced to 29 without considering confounding factors associated with Se/CoQ, a 97.6% protection rate. In conclusion, Cd exposure inhibited Leydig cell steroidogenesis by down-regulating SCARB1 and STAR through increasing oxidative stress and inflammation, but Se plus CoQ synergistically prevented all the changes induced by the Cd exposure.

Effects of aging and macrophages on mice stem Leydig cell proliferation and differentiation in vitro.

Background: Testosterone plays a critical role in maintaining reproductive functions and well-beings of the males. Adult testicular Leydig cells (LCs) produce testosterone and are generated from stem Leydig cells (SLCs) during puberty through adulthood. In addition, macrophages are critical in the SLC regulatory niche for normal testicular function. Age-related reduction in serum testosterone contributes to a number of metabolic and quality-of-life changes in males, as well as age-related changes in immunological functions. How aging and testicular macrophages may affect SLC function is still unclear. Methods: SLCs and macrophages were purified from adult and aged mice via FACS using CD51 as a marker protein. The sorted cells were first characterized and then co-cultured in vitro to examine how aging and macrophages may affect SLC proliferation and differentiation. To elucidate specific aging effects on both cell types, co-culture of sorted SLCs and macrophages were also carried out across two ages. Results: CD51+ (weakly positive) and CD51++ (strongly positive) cells expressed typical SLC and macrophage markers, respectively. However, with aging, both cell types increased expression of multiple cytokine genes, such as IL-1b, IL-6 and IL-8. Moreover, old CD51+ SLCs reduced their proliferation and differentiation, with a more significant reduction in differentiation (2X) than proliferation (30%). Age matched CD51++ macrophages inhibited CD51+ SLC development, with a more significant reduction in old cells (60%) than young (40%). Crossed-age co-culture experiments indicated that the age of CD51+ SLCs plays a more significant role in determining age-related inhibitory effects. In LC lineage formation, CD51+ SLC had both reduced LC lineage markers and increased myoid cell lineage markers, suggesting an age-related lineage shift for SLCs. Conclusion: The results suggest that aging affected both SLC function and their regulatory niche cell, macrophages.

Tanshinone IIA analogue 15a inhibits NLRP3-mediated inflammation by activating mitophagy in macrophages to alleviate acute tubular necrosis.

BACKGROUND: Acute tubular necrosis (ATN) is a common type of acute renal failure. Recent studies have shown that NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-mediated pyroptosis in macrophages plays a crucial role in the progression of ATN. Previously, we synthesized an anti-inflammatory compound 15a based on Tanshinone IIA (Tan IIA). In the present study, we found that compound 15a exhibited a greater inhibitory effect on NLRP3-mediated pyroptosis than Tan IIA in vitro. METHODS: C57BL/6 and NLRP3-knockout (NLRP3-KO) mice were intraperitoneally injected with LPS or folic acid (FA) to develop ATN. In vitro, bone marrow-derived macrophages (BMDMs) were treated with LPS for 3 h and then treated with ATP for 0.5 h. RESULTS: We explored the mechanism by which compound 15a inhibited NLRP3 inflammasome in BMDMs as well as its renal protective effect against ATN in mice. We found that compound 15a exhibited a protective effect on mitochondria and reduced the production of mitochondrial reactive oxygen species (mtROS). Moreover, we revealed that compound 15a remarkably reduced the production of mtROS by promoting mitophagy, which resulted in the inhibition of NLRP3 inflammasome to alleviates ATN in mice. CONCLUSION: In summary, compound 15a inhibited NLRP3-mediated inflammation by activating mitophagy in macrophages to alleviate ATN. Our results identified compound 15a as a promising candidate for the treatment of NLRP3-driven ATN.

Glycolytic Genes Predict Immune Status and Prognosis Non-Small-Cell Lung Cancer Patients with Radiotherapy and Chemotherapy.

Background: Non-small-cell lung cancer (NSCLC) is a major health problem that endangers human health. The prognosis of radiotherapy or chemotherapy is still unsatisfactory. This study is aimed at investigating the predictive value of glycolysis-related genes (GRGs) on the prognosis of NSCLC patients with radiotherapy or chemotherapy. Methods: Download the clinical information and RNA data of NSCLC patients receiving radiotherapy or chemotherapy from TCGA and geo databases and obtain GRGs from MsigDB. The two clusters were identified by consistent cluster analysis, the potential mechanism was explored by KEGG and GO enrichment analyses, and the immune status was evaluated by estimate, TIMER, and quanTIseq algorithms. Lasso algorithm is used to build the corresponding prognostic risk model. Results: Two clusters with different GRG expression were identified. The high-expression subgroup had poor overall survival. The results of KEGG and GO enrichment analyses suggest that the differential genes of the two clusters are mainly reflected in metabolic and immune-related pathways. The risk model constructed with GRGs can effectively predict the prognosis. The nomogram combined with the model and clinical characteristics has good clinical application potential. Conclusion: In this study, we found that GRGs are associated with tumor immune status and can assess the prognosis of NSCLC patients receiving radiotherapy or chemotherapy.

Discovery of a potent and selective allosteric inhibitor targeting the SHP2 tunnel site for RTK-driven cancer treatment.

Src homology 2 domain-containing phosphatase 2 (SHP2) is a cytoplasmic protein tyrosine phosphatase (PTP) that regulates signal transduction of receptor tyrosine kinases (RTKs). Abnormal SHP2 activity is associated with tumorigenesis and metastasis. Because SHP2 contains multiple allosteric sites, identifying inhibitors at specific allosteric binding sites remains challenging. Here, we used structure-based virtual screening to directly search for the SHP2 "tunnel site" allosteric inhibitor. A novel hit (70) was identified as the SHP2 allosteric inhibitor with an IC50 of 10.2 µM against full-length SHP2. Derivatization of hit compound 70 using molecular modeling-guided structure-based modification allowed the discovery of an effective and selective SHP2 inhibitor, compound 129, with 122-fold improved potency compared to the hit. Further studies revealed that 129 effectively inhibited signaling in multiple RTK-driven cancers and RTK inhibitor-resistant cancer cells. Remarkably, 129 was orally bioavailable (F = 55%) and significantly inhibited tumor growth in haematological malignancy. Taken together, compound 129 developed in this study may serve as a promising lead or candidate for cancers bearing RTK oncogenic drivers and SHP2-related diseases.

Costunolide covalently targets NACHT domain of NLRP3 to inhibit inflammasome activation and alleviate NLRP3-driven inflammatory diseases.

The NLRP3 inflammasome's core and most specific protein, NLRP3, has a variety of functions in inflammation-driven diseases. Costunolide (COS) is the major active ingredient of the traditional Chinese medicinal herb Saussurea lappa and has anti-inflammatory activity, but the principal mechanism and molecular target of COS remain unclear. Here, we show that COS covalently binds to cysteine 598 in NACHT domain of NLRP3, altering the ATPase activity and assembly of NLRP3 inflammasome. We declare COS's great anti-inflammasome efficacy in macrophages and disease models of gouty arthritis and ulcerative colitis via inhibiting NLRP3 inflammasome activation. We also reveal that the α-methylene-γ-butyrolactone motif in sesquiterpene lactone is the certain active group in inhibiting NLRP3 activation. Taken together, NLRP3 is identified as a direct target of COS for its anti-inflammasome activity. COS, especially the α-methylene-γ-butyrolactone motif in COS structure, might be used to design and produce novel NLRP3 inhibitors as a lead compound.

An Integrated Plasma-Photocatalytic System for Upcycling of Polyolefin Plastics.

Nondegradable polyolefin plastics, which account for >60 % of total plastic waste, trigger severe global concerns and thus demand effective management technologies. However, owing to the chemical inertness of non-polar C-C backbones in the polyolefin structure, efficient upcycling of polyolefin plastics under ambient conditions remains a great challenge. This study introduces an integrated plasma-photocatalytic technology, coupling plasma treatment with solar-driven reforming under mild conditions, for the efficient upcycling of polyolefin plastics into value-added hydrogen and gaseous fuels. The first plasma step grafts oxygenated groups, such as -OH, O-C=O, and C=O, onto the polyolefin chains, which leads to the formation of a polar and hydrophilic polymer that facilitates the subsequent reforming in the photocatalytic step. Therefore, high hydrogen production activity with a benchmark efficiency of >100 µmol g-1 h-1 was achieved. Moreover, the integrated process also demonstrates high versatility in upcycling different polyolefin plastics including polyethylene, polypropylene and polyvinyl chloride. The findings provide a new avenue for plastic upcycling in an efficient and sustainable way.

Abdominal surgery plus sevoflurane exposure induces abnormal emotional changes and cognitive dysfunction in aged rats.

BACKGROUND: Cognitive impairment, which includes perioperative psychological distress and cognitive dysfunction, can be determined by preoperative and post-operative neuropsychological tests. Several mechanisms have been proposed regarding the two-way communication between the immune system and the brain after surgery. We aimed to understand the mechanisms underlying perioperative neurocognitive disorders (PND) in elderly rats using an experimental abdominal surgery model. METHODS: 24-month-old SD rats were exposed to the abdominal surgery model (AEL) under 3% anesthesia. On day 15 and day 30 post-surgery, fractional anisotropy (FA) using diffusion kurtosis imaging (DKI) was measured. From day 25 to day 30 post-surgery, behavioral tests, including open field test (OFT), Morris water maze (MWM), novel object recognition (NOR), force swimming test (FST), and elevated plus maze (EPM), were performed. Then, the rats were euthanized to perform pathological analysis and western blot measurement. RESULTS: The rats exposed to AEL surgical treatment demonstrated significantly decreased time crossing the platform in the MWM, decreased recognition index in the NOR, reduced time in the open arm in the EPM, increased immobility time in the FST, and increased number of crossings in the OFT. Aged rats, after AEL exposure, further demonstrated decreased FA in the mPFC, nucleus accumbens (NAc), and hippocampus, together with reduced MAP2 intensity, attenuation of GAD65, VGlut2, CHAT, and phosphorylated P38MAPK expression, and increased reactive astrocytes and microglia. CONCLUSIONS: In this study, the aged rats exposed to abdominal surgery demonstrated both emotional changes and cognitive dysfunction, which may be associated with neuronal degeneration and reduced phosphorylated P38MAPK.

Spautin-1 administration mitigates mild TBI-induced cognitive and memory dysfunction in mice via activation of caspase-3.

BACKGROUND: Cognitive and memory dysfunction, a common sequela of traumatic brain injury (TBI), places a heavy social and economic burden on individuals, families, communities, and countries. Although the potent anti-tumor effects of spautin-1, a novel autophagy inhibitor, have been documented in malignant melanoma, little is known regarding its efficacy on alleviation of cognitive and memory dysfunction. Here, we describe the effect of spautin-1 administration on cognitive and memory impairment post-TBI, and reveal its underlying mechanism of action. METHODS: We first induced mild TBI in mice through Feeney's weight-drop model, then immediately administered spautin-1 (10 mmol/µl, 2 µl) into the left lateral ventricle. Behavioral and pathological changes were assessed at 24 h, 7 and 30 days after TBI by analyzing neurological severity scores (NSS), novel objective recognition (NOR), Morris water maze (MWM) test, recording of local field potential (LFP), as well as western blot, and immunofluorescence assays. RESULTS: Mild TBI not only reduced recognition index and times crossing platform, but also aggravated neuronal injury, including reduced MAP2, GAD2, VGlut2, and CHAT intensity. It also elevated activated microglia and CD86-occupied areas in TMEM119-positive cells, but suppressed θ, ß, and γ oscillation power in the hippocampal CA1. However, spautin-1 administration significantly reversed these changes, whereas AC-DEVD-CHO an inhibitor of caspase-3 partially blocked the neuroprotective effects of spautin-1. CONCLUSION: Spautin-1 administration mitigates mild TBI-induced cognitive and memory dysfunction in mice, potentially through activation of caspase-3.

Tabersonine, a natural NLRP3 inhibitor, suppresses inflammasome activation in macrophages and attenuate NLRP3-driven diseases in mice.

Aberrant activation of NLRP3 inflammasome causes the progression of various inflammation-related diseases, but the small-molecule inhibitors of NLRP3 are not currently available for clinical use. Tabersonine (Tab) is a natural product derived from a traditional Chinese herb Catharanthus roseus that is usually used as an anti-tumor agent. In this study we investigated the anti-inflammatory effects and molecular targets of Tab. We first screened 151 in-house natural compounds for their inhibitory activity against IL-1ß production in BMDMs. We found that Tab potently inhibited NLRP3-mediated IL-1ß production with an IC50 value of 0.71 µM. Furthermore, we demonstrated that Tab suppressed the assembly of NLRP3 inflammasome, especially the interaction between NLRP3 and ASC. Interestingly, we found that Tab directly bound to NLRP3 NACHT domain, thereby reducing the self-oligomerization of NLRP3. In addition, we showed that administration of Tab significantly ameliorated NLRP3-driven diseases, such as peritonitis, acute lung injury, and sepsis in mouse models. The preventive effects of Tab were not observed in the models of NLRP3 knockout mouse. In conclusion, we have identified Tab as a natural NLRP3 inhibitor and a lead compound for the design and discovery of novel NLRP3 inhibitors.

Intratumoral and peritumoral radiomics nomograms for the preoperative prediction of lymphovascular invasion and overall survival in non-small cell lung cancer.

OBJECTIVES: To evaluate the predictive value of intratumoral and peritumoral radiomics and radiomics nomogram for preoperative lymphovascular invasion (LVI) status and overall survival (OS) in patients with non-small cell lung cancer (NSCLC). METHODS: In total, 240 NSCLC patients from our institution were randomly divided into the training cohort (n = 145) and internal validation cohort (n = 95) with a ratio of 6:4, and 65 patients from the Cancer Imaging Archive were enrolled as the external validation cohort. We extracted 1217 CT-based radiomics features from the gross tumor volume (GTV) and gross tumor volume incorporating peritumoral 3, 6, and 9 mm regions (GPTV3, GPTV6, GPTV9). A radiomics nomogram based on clinical independent predictors and radiomics score (Radscore) of the best radiomics model was constructed. The correlation between factors and OS was evaluated with the Kaplan-Meier survival analysis and Cox proportional hazards regression analysis. RESULTS: Compared with GTV, GPTV3, and GPTV6 radiomics models, GPTV9 radiomics model exhibited better prediction performance with the AUCs of 0.82, 0.75, and 0.67 in the training, internal validation, and external validation cohorts, respectively. In the clinical model, smoking and clinical stage were independent predictors. The nomogram incorporating independent predictors and GPTV9-Radscore was clinically useful, with the AUCs of 0.89, 0.83, and 0.66 in three cohorts. Pathological LVI, GPTV9-Radscore-predicted, and Nomoscore-predicted LVI were associated with poor OS (p < 0.05). CONCLUSIONS: CT-based radiomics nomogram can predict LVI and OS in patients with NSCLC and may help in making personalized treatment strategies before surgery. KEY POINTS: • Compared with GTV, GPTV3, and GPTV6 radiomics models, GPTV9 radiomics model showed better prediction performance for LVI status in NSCLC. • The radiomics nomogram based on GPTV9 radiomics features and clinical independent predictors could effectively predict LVI status and OS in NSCLC and outperformed the clinical model. • The radiomics nomogram had a wider scope of clinical application.

Significance of Spliceosome-Related Genes in the Prediction of Prognosis and Treatment Strategies for Lung Adenocarcinoma.

Background: The leading cause of cancer-related fatalities globally is lung cancer; lung adenocarcinoma (LUAD) is the most common histological type in it. The spliceosome plays an important role in a majority of malignancies. However, it is yet unclear how spliceosome-related genes affect patients with LUAD in terms of treatment course and prognosis. Methods: Spliceosome-related genes were assessed from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database to obtain clinical information and gene expression in patients with LUAD. A spliceosome-related gene signature and prognostic model were constructed by using the least absolute shrinkage and selection operator (LASSO), time-dependent receiver operating characteristic (ROC), and nomogram. Immune infiltrate levels, mutation analysis, and pathway enrichment were predicted potential mechanisms of the signature by using single-sample gene set enrichment analysis (ssGSEA), Gene Set Cancer Analysis (GSCA) database, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO) database. Then, a protein-protein interaction (PPI) network and transcription factor- (TF-) hub gene and drug mining network were also established by Cytoscape software. Results: Firstly, we constructed a prognostic model for 11 spliceosome signature genes. Based on the prognostic risk score, we stratified patients with LUAD into high- and low-risk groups. The high- and low-risk groups were closely related to the OS, tumor immune infiltration level, immune checkpoint molecules, and tumor mutation burden (TMB) of LUAD patients. Based on PPI networks, we also predict relevant TF genes that may regulate signature prognostic genes. Finally, drugs including oxaliplatin, arsenic trioxide, cisplatin, and sunitinib were excavated for the treatment of the 11 spliceosome signature genes in LUAD patients. Conclusion: In conclusion, this study is the first to explore the importance of spliceosome-related genes in the prognosis and treatment of LUAD. Through our study, we have innovatively provided potential prognosis genes and new therapeutic drug targets for the treatment of LUAD patients.

EHD2 inhibits the invasive ability of lung adenocarcinoma and improves the prognosis of patients.

Background: EH domain contains protein 2 (EHD2) may be involved in tumorigenesis and development. However, the role of EHD2 in lung adenocarcinoma (LUAD) is unknown. Methods: The link between EHD2 and LUAD and the associated underlying mechanism was determined using bioinformatics analysis. Then, immunohistochemistry (IHC) was employed to detect EHD2 expression level in LUAD patients. The stable transfection cell line was used to establish with lentivirus vector, and then the transfection efficiency was detected by western blot. Phagokinetic motility assays, transwell assays, and western blotting were also employed to investigate EHD2 impacts on cell viability. Results: The results indicated that EHD2 protein expression in human LUAD samples was significantly lower than that in the adjacent normal tissues. Low EHD2 expression was significantly linked to lymph node metastasis as well as advanced tumor-node-metastasis (TNM) staging (P<0.05). The Kaplan-Meier survival curve showed that low EHD2 expression was significantly associated with low survival (P=0.01). The multivariate Cox regression analysis confirmed that EHD2 expression and TNM stage were independent prognostic factors for LUAD patients (all P<0.05). The in vitro experiments demonstrated that EHD2 knockdown markedly contributed to an increase in migration and invasion in A549 cells. Overexpression of EHD2 substantially suppressed H1299 cell migration and invasion. Furthermore, decreased E-cadherin expression was observed in A549 cells with EHD2 knockdown, as well as increased N-cadherin and vimentin expressions. By contrast, E-cadherin expression was increased in H1299 cells, whereas N-cadherin and vimentin expressions were decreased as a result of EHD2 overexpression. Conclusions: Our study demonstrated that EHD2 reduces LUAD migration and invasion by preventing the epithelial-mesenchymal transition (EMT) process. Furthermore, the results suggest that EHD2 may be a novel biomarker for prognosis prediction.

Low expression of PRDM5 predicts poor prognosis of esophageal squamous cell carcinoma.

BACKGROUND: The role of the PRDM5 in esophageal squamous cell carcinoma (ESCC) has not been revealed. This study investigated the relationship between PRDM5 expression and survival outcome in esophageal squamous cell carcinoma and explored the mechanism in tumor development. METHODS: In present study, expression of PRDM5 mRNA in esophageal squamous cell carcinoma patients was conducted using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. The expression of PRDM5 was assessed by immunohistochemical staining. Kaplan-Meier curve and Cox regression analysis was performed to analyze the survival outcome and independent predictive factors. qRT-PCR and Methylation-specific PCR were performed to identify the mRNA level of PRDM5 and Methylation rate. Cibersort algorithm to analyze the relationship between PRDM5 expression and immune cell invasion. Western-blot was performed to confirm the expression of esophageal tumor tissues and adjacent tissues. RESULTS: The TCGA database and GEO database show that PRDM5 mRNA level in esophageal squamous cell carcinoma adjacent tissues was higher than that of cancer tissues, and ESCC patients with high expression of PRDM5 mRNA had better overall survival. Tissue microarray showed that the protein level of PRDM5 in the adjacent tissues of patients with ESCC was higher than that in cancer tissues, and the expression level of PRDM5 was significantly correlated with the grade of clinicopathological characteristics (P < 0.001). Patients with high expression of PRDM5 displayed a better OS and DFS. Cox regression analysis showed that PRDM5 was an independent risk factor and prognostic factor for ESCC patients (HR: 2.626, 95%CI: 1.824-3.781; P < 0.001). The protein level of PRDM5 matched with the transcriptional level, whereas the DNA methylation affected the transcriptional level. Cibersort showed that T cells CD4 memory resting, mast cells resting, eosinophils, M2 macrophages and mast cells activated were significantly positively correlated with PRDM5 expression (P < 0.05), while regulatory T cells, monocytes and dendritic cells negatively correlated with PRDM5 expression (P < 0.05). CONCLUSION: PRDM5 can be used as a biomarker to predict the survival of ESCC patients. Furthermore, PRDM5 expression in ESCC cells may affect WNT/ß-catenin signaling pathways, thus further affect the ESCC cell proliferation, migration, and invasion capacity.