Revealing prognostic insights of programmed cell death (PCD)-associated genes in advanced non-small cell lung cancer.

The management of patients with advanced non-small cell lung cancer (NSCLC) presents significant challenges due to cancer cells' intricate and heterogeneous nature. Programmed cell death (PCD) pathways are crucial in diverse biological processes. Nevertheless, the prognostic significance of cell death in NSCLC remains incompletely understood. Our study aims to investigate the prognostic importance of PCD genes and their ability to precisely stratify and evaluate the survival outcomes of patients with advanced NSCLC. We employed Weighted Gene Co-expression Network Analysis (WGCNA), Least Absolute Shrinkage and Selection Operator (LASSO), univariate and multivariate Cox regression analyses for prognostic gene screening. Ultimately, we identified seven PCD-related genes to establish the PCD-related risk score for the advanced NSCLC model (PRAN), effectively stratifying overall survival (OS) in patients with advanced NSCLC. Multivariate Cox regression analysis revealed that the PRAN was the independent prognostic factor than clinical baseline factors. It was positively related to specific metabolic pathways, including hexosamine biosynthesis pathways, which play crucial roles in reprogramming cancer cell metabolism. Furthermore, drug prediction for different PRAN risk groups identified several sensitive drugs explicitly targeting the cell death pathway. Molecular docking analysis suggested the potential therapeutic efficacy of navitoclax in NSCLC, as it demonstrated strong binding with the amino acid residues of C-C motif chemokine ligand 14 (CCL14), carboxypeptidase A3 (CPA3), and C-X3-C motif chemokine receptor 1 (CX3CR1) proteins. The PRAN provides a robust personalized treatment and survival assessment tool in advanced NSCLC patients. Furthermore, identifying sensitive drugs for distinct PRAN risk groups holds promise for advancing targeted therapies in NSCLC.

Strong Swelling and Symmetrization in Siliceous Zeolites due to Hydrogen Insertion at High Pressure.

Hydrogen and helium saturate the 1D pore systems of the high-silica (Si/Al>30) zeolites Theta-One (TON), and Mobile-Twelve (MTW) at high pressure based on x-ray diffraction, Raman spectroscopy and Monte Carlo simulations. In TON, a strong 22% volume increase occurs above 5 GPa with a transition from the collapsed P21 to a symmetrical, swelled Cmc21 form linked to an increase in H2 content from 12 H2/unit cell in the pores to 35 H2/unit cell in the pores and in the framework of the material. No transition and continuous collapse of TON is observed in helium indicating that the mechanism of H2 insertion is distinct from other fluids. The insertion of hydrogen in the larger pores of MTW results in a strong 11% volume increase at 4.3 GPa with partial symmetrization followed by a second volume increase of 4.5% at 7.5 GPa, corresponding to increases in hydrogen content from 43 to 67 and then to 93 H2/unit cell. Flexible 1D siliceous zeolites have a very high H2 capacity (1.5 and 1.7 H2/SiO2 unit for TON and MTW, respectively) due to H2 insertion in the pores and the framework, in contrast to other atoms and molecules, thereby providing a mechanism for strong swelling.

Unveiling the microbiota of sauce-flavor Daqu and its relationships with flavors and color during maturation.

This study investigated the microbial community in three-color sauce-flavor Daqu (black, yellow, and white) throughout their maturation processes, together with their physicochemical factors, culturable microbes, flavor components, and fermenting vitalities. Results from high-throughput sequencing revealed distinct microbial diversity, with more pronounced variations in bacterial community than in fungal community. Firmicutes and Ascomycota emerged as the most dominant bacterial and fungal phyla, respectively, during maturation. Genus-level analysis identified Kroppenstedia, Virgibacillus, and Bacillus as dominant bacteria in black Daqu, yellow Daqu, and white Daqu, severally, while Thermoascus was shared as the core dominant fungi for these Daqu. Physicochemical factors, particularly acidity, were found to exert a significant impact on microbial community. Kroppenstedtia was the key bacteria influencing the color formation of these Daqu. Furthermore, correlations between dominant microbes and flavor compounds highlighted their role in Daqu quality. Molds (Aspergillus, Rhizomucor, and Rhizopus), excepting Bacillus, played a crucial role in the formation of pyrazine compounds. Consequently, this study offers innovative insights into the microbial perspectives on color and pyrazine formation, establishing a groundwork for future mechanized Daqu production and quality control of sauce-flavor baijiu.

Metagenome-assembled genome reveals species and functional composition of Jianghan chicken gut microbiota and isolation of Pediococcus acidilactic with probiotic properties.

BACKGROUND: Chickens are one of the most widely farmed animals worldwide and play a crucial role in meat and egg production. Gut microbiota is essential for chickens' health, disease, growth, and egg production. However, native chickens such as Jianghan chickens have better meat and egg production quality than centralized chickens, their intestinal microbial diversity is richer, and the potential gut microbial resources may bring health benefits to the host. RESULTS: The bacterial species composition in the gut microbiota of Jianghan chickens is similar to that of other chicken breeds, with Phocaeicola and Bacteroides being the most abundant bacterial genera. The LEfSe analysis revealed significant differences in species composition and functional profiles between samples from Jingzhou and the other three groups. Functional annotation indicated that the gut microbiota of Jianghan chickens were dominated by metabolic genes, with the highest number of genes related to carbohydrate metabolism. Several antibiotic resistance genes (ARGs) were found, and the composition of ARGs was similar to that of factory-farmed chickens, suggesting that antibiotics were widely present in the gut microbiota of Jianghan chickens. The resistance genes of Jianghan chickens are mainly carried by microorganisms of the Bacteroidota and Bacillota phylum. In addition, more than 829 isolates were selected from the microbiota of Jianghan chickens. Following three rounds of acid and bile tolerance experiments performed on all the isolated strains, it was determined that six strains of Pediococcus acidilactici exhibited consistent tolerance. Further experiments confirmed that three of these strains (A4, B9, and C2) held substantial probiotic potential, with P. acidilactici B9 displaying the highest probiotic potential. CONCLUSIONS: This study elucidates the composition of the intestinal microbiota and functional gene repertoire in Jianghan chickens. Despite the absence of antibiotic supplementation, the intestinal microbial community of Jianghan chickens still demonstrates a profile of antibiotic resistance genes similar to that of intensively reared chickens, suggesting resistance genes are prevalent in free-ranging poultry. Moreover, Jianghan and intensively reared chickens host major resistance genes differently, an aspect seldom explored between free-range and pastured chickens. Furthermore, among the 829 isolates, three strains of P. acidilatici exhibited strong probiotic potential. These findings provide insights into the unique gut microbiota of Jianghan chickens and highlight potential probiotic strains offering benefits to the host. Video Abstract.

Lower Gluteal Liposuction Combined With Upper Gluteal and Infragluteal Region Fat Grafting: A Novel Concept to Improve Gluteal Ptosis.

BACKGROUND: Gluteal ptosis results in a severe disturbance of gluteal aesthetics. Currently, satisfactory procedures for improving gluteal ptosis are lacking. OBJECTIVES: To improve gluteal ptosis, the authors propose a novel concept of combined liposuction of the lower gluteal region and fat grafting to the upper gluteal and infragluteal regions, and verify its efficacy and safety. METHODS: Patients who underwent liposuction of the lower gluteal region combined with fat grafting to the upper gluteal and infragluteal regions between January 2020 and July 2023 were retrospectively reviewed. Postoperative changes in the gluteal ptosis grade, complications, and patient satisfaction were evaluated. RESULTS: A total of 28 patients were enrolled in this study; 21 (75.0%) patients had gluteal ptosis grade 4 and 7 (25.0%) patients had gluteal ptosis grade 5. The median fat removal volume was 210 mL, and the median fat graft injected volume was 355 mL in the gluteal region and 180 mL in the infragluteal region. All patients showed improvement in gluteal ptosis; 16 (57.1%) patients improved by 1 grade and 12 (42.9%) patients showed a 2-grade improvement. All patients were satisfied with their posttreatment outcomes. Only 1 patient showed lateral translocation of the fat graft. No other complications were observed. CONCLUSIONS: Liposuction of the lower gluteal region combined with fat grafting to the upper gluteal and infragluteal regions is effective in improving gluteal ptosis, with a low risk of complications and high patient satisfaction.

Association of the blood levels of specific volatile organic compounds with nonfatal cardio-cerebrovascular events in US adults.

BACKGROUND: Cardio-cerebrovascular diseases constitute a major global public health burden. Volatile organic compounds (VOCs) exposure has become progressively severe, endangering human health and becoming one of the main concerns in environmental pollution. The associations of VOCs exposure with nonfatal cardio-cerebrovascular events have not been identified in observational study with a large sample size, so we aim to examine the association in US adult population. METHODS: Adults aged > 18 years with complete data regarding selected blood levels of VOCs (including benzene, ethylbenzene, o-xylene, and m-/p-xylene) and nonfatal cardio-cerebrovascular events were included in the analysis (n = 3,968, National Health and Nutrition Examination Survey, NHANES, 2013-2018 survey cycle). Participants were classified into low- and high-exposure based on whether above selected VOCs low limit detect concentration or median value. Weighted multivariate logistic analyses and subgroup analyses were used to detect the association between selected VOCs exposure and nonfatal cardio-cerebrovascular events in US adults. RESULTS: Weighted multivariate logistic analyses showed that the high-VOCs exposure group had an increased risk of nonfatal cardio-cerebrovascular events compared with the low-VOCs exposure group; the adjusted odds ratios (OR) and 95% confidence intervals (CI) of nonfatal cardio-cerebrovascular events for the high-VOCs exposure group were 1.41 (0.91, 2.19), 1.37 (0.96, 1.95), 1.32 (0.96, 1.82), and 1.17 (0.82, 1.67) for benzene, ethylbenzene, o-xylene, and m-/p-xylene, respectively, which was not significant assuming statistical significance at a 0.05 significance level (95% CI) for a two-tailed test. Lastly, we found high-VOCs exposure was associated with increased incidence of nonfatal cardio-cerebrovascular events in both daily smokers an non-daily smokers (p-interaction > 0.01), but the association was not statistically significant in non-daily smokers. CONCLUSIONS: This study found that VOCs (benzene, ethylbenzene, o-xylene, and m-/p-xylene) exposure was associated with increased incidence of nonfatal cardio-cerebrovascular events in US adults, and the results need to be confirmed by larger cohort studies.

A multicenter, real-world study on effectiveness and safety of first-line modified PD-1 inhibitors with chemotherapy in advanced non-small cell lung cancer (aNSCLC) with drive gene-negative.

OBJECTIVES: The use of immune checkpoint inhibitors, particularly PD-1 inhibitors, has revolutionized the treatment of advanced tumors and shown significant improvements in patient survival rates. However, which PD-1 inhibitor is more effective and safer for a specific indication remains unclear. To address this problem, our study aimed to evaluate the effectiveness and safety of different PD-1 inhibitors in combination with chemotherapy as first-line therapy for individuals with advanced non-small-cell lung cancer (NSCLC) without driver genes in the real world. MATERIALS AND METHODS: We conducted a retrospective study of individuals diagnosed with aNSCLC who received immune checkpoint inhibitors (ICIs) with modified PD-1 inhibitors, including Sintilimab, Toripalimab, Tislelizumab, Camrelizumab, or Pembrolizumab as first-line treatment between March 5th, 2016 and October 20th, 2022. We assessed demographic and clinical information and analyzed clinical response, survival outcomes, and safety profiles. The primary endpoint was overall survival (OS), and the secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. RESULTS: As of the date cut-off on October 20th, 2022, the median follow-up time was 20.62 months. A total of 204 patients were enrolled in the study, including 56 (27.5%) patients receiving modified PD-1 inhibitors (Sintilimab, Toripalimab, Tislelizumab, or Camrelizumab) in combination with chemotherapy and 148 (72.5%) patients receiving Pembrolizumab in combination with chemotherapy. In the overall cohort, the median overall survival (OS) was 26.9 months (95%CI, 22.3-31.6), the median progression-free survival (PFS) was 8.4 months (95%CI, 6.9-9.8), and the objective response rate (ORR) and disease control rate (DCR) were 47.6% (95%CI, 29.9-43.6) and 84.3% (95%CI, 78.4-88.9). The mOS of modified PD-1 inhibitors group and Pembrolizumab group were 30.7 (95%CI, 17.3-44.4) months and 26.8 (95%CI, 22.2-31.4) months. The mPFS of two groups were 8.3(95%CI, 6.9-9.6) months and 8.8 (95%CI, 6.9-10.7) months, respectively. There was no statistical difference between the two groups in terms of OS or PFS. The ORR for the two groups was 48.2% (95%CI, 34.8-61.8) and 47.3% (95%CI, 39.1-5.6), respectively. However, due to the limited sample size, the difference was not statistically significant. On the other hand, the DCR tended to be higher in the Pembrolizumab group (86.5%; 95%CI, 79.7-91.4) compared to the modified PD-1 inhibitors group (78.6%; 95%CI, 65.2-87.9), and this difference was statistically significant (p = 0.006). In terms of safety, both groups exhibited favorable clinical safety profiles. The only two types of potentially immune-related adverse events reported were pneumonitis and reactive cutaneous capillary endothelial proliferation (RCCEP). CONCLUSIONS: The modified PD-1 inhibitors showed comparable survival outcomes and manageable safety profiles in NSCLC compared to Pembrolizumab. Moreover, these inhibitors exhibited improved accessibility and economic outcomes compared to Pembrolizumab. While there were similarities in drug-related and immunotherapy-related adverse reactions between the modified PD-1 inhibitors and Pembrolizumab, there were some slight differences. Further prospective and retrospective studies would be necessary to validate these findings beyond the scope of the CTONG1901 study.

Correction of Lying Ear and Aesthetic Modification of Helix and Ear Lobule with Hyaluronic Acid Filler Injection: Experience in Chinese Patients.

BACKGROUND: Large and long ears are regarded as symbols of wealth and health in eastern Asian culture, patients with lying ears wish their ears to be more exposed and prominent. Surgeries correcting lying ears have been documented. OBJECTIVES: We report correction of lying ears and aesthetic modification of helix and ear lobule with HA injections. METHODS: We performed HA injections at auriculocephalic sulcus (AS) to increase cranioauricular angle (CA) and correct lying ears. The injections at helix and lobule were case-specific. The CA was measured and photographs were taken at baseline and 1-, 3-, 6-, and 10-month follow-ups. Efficacy was assessed using a 5-point global aesthetic improvement scale (GAIS). Adverse events (AEs) were recorded. RESULTS: Forty-six patients (92 ears) received HA injections and completed follow-ups. Instant correction outcomes were observed. Sixteen (34.8%) patients received one touch-up injection, whose clinical efficacy persisted for 1 to 1.5 years. The GAIS for over 90% of cases with touch-up treatment was "very much improved" or "much improved" at all follow-ups. The GAIS for over 70% of cases without touch-up treatment was "very much improved" or "much improved" at 1, 3, and 6-month follow-ups. CA increased significantly compared with the baseline. Patients also reported "more V-shaped face shape" and "lifted jawline" effects. No serious AEs occurred. CONCLUSIONS: As an alternative technique to surgeries, HA filler injections at AS effectively corrected lying ears. This technique produced immediate, long-lasting, and aesthetically pleasing results. The side effects and downtime were minimal.

Association between dietary selenium intake and severe abdominal aortic calcification in the United States: a cross-sectional study.

Abdominal aortic calcification (AAC) is an important predictor of cardiovascular disease. The purpose of the current study was to detect the association between dietary selenium intake and severe AAC. We included 2651 participants from the National Health and Nutrition Examination Survey (NHANES, 2013-2014). Dietary selenium intake was measured using the 24-hour recall method. AAC was quantified using the Kauppila score system based on dual-energy X-ray absorptiometry, with a score of >6 indicating severe AAC. The association between dietary selenium intake and severe AAC was analyzed by using a weighted multivariate logistic regression model, smooth curve fitting, and stratified subgroup analysis. After adjusting for multiple covariates, we found that higher dietary selenium intake was negatively associated with severe AAC incidence. When selenium intake was converted into tertiles, the highest tertile of dietary selenium intake was significantly associated with the incidence of severe AAC (odds ratio = 0.66). Smooth curve fitting revealed that this relationship was nonlinear. Subgroup analysis revealed that this negative association was present in participants with chronic kidney disease, but was absent when participants had hypertension or diabetes mellitus. Higher dietary selenium intake was negatively associated with severe AAC incidence in a nonlinear pattern, except in participants with diabetes mellitus or hypertension. However, further cohort studies are required to validate these findings.

Effect of simplified inoculum agent on performance and microbiome during cow manure-composting at industrial-scale.

A simplified inoculum agent, only comprising Bacillus subtilis and Aspergillus niger, was utilized for industrial-scale cow-manure composting to investigate its impact on composting performance and microbiome. Inoculants elevated the average and peak temperatures by up to 7 and 10 °C, respectively, during the thermophilic stage, reduced organic matter content, and raised germination index. Inoculation also extended the period of composting above 50 °C from 12 to 26 days. Sequencing unveiled significant shifts in microbial diversity, composition, and function. Aspergillus thrived during the mesophilic phase, potentially initiating composting, whereas Bacillus, Lysinibacillus, and Clostridium were enriched during the thermophilic stage. Metagenomic sequencing revealed an increased abundance of carbohydrate-active enzymes and glycometabolism-related genes responsible for lignocellulose degradation and heat generation after inoculation. These enriched microbes and functional genes contributed to organic matter degradation and temperature maintenance during thermophilic stage, expediting composting. This suggests the effectiveness of this simplified inoculum in industrial-level cow-manure composting.

m5C modification of LINC00324 promotes angiogenesis in glioma through CBX3/VEGFR2 pathway.

Angiogenesis plays a major role in tumor initiation, progression, and metastasis. This is why finding antiangiogenic targets is essential in the treatment of gliomas. In this study, NSUN2 and LINC00324 were significantly upregulated in conditionally cultured glioblastoma endothelial cells (GECs). Knockdown of NSUN2 or LINC00324 inhibits GECs angiogenesis. NSUN2 increased the stability of LINC00324 by m5C modification and upregulated LINC00324 expression. LINC00324 competes with the 3'UTR of CBX3 mRNA to bind to AUH protein, reducing the degradation of CBX3 mRNA. In addition, CBX3 directly binds to the promoter region of VEGFR2, enhances VEGFR2 transcription, and promotes GECs angiogenesis. These findings demonstrated NSUN2/LINC00324/CBX3 axis plays a crucial role in regulating glioma angiogenesis, which provides new strategies for glioma therapy.

Preparation of MIL-88(Fe)@Fe2O3@FeSiCr double core-shell-structural composites and their wave-absorbing properties.

To tackle the aggravating electromagnetic wave (EMW) pollution issues, high-efficiency EMW absorption materials are being urgently explored. The FeSiCr soft magnetic alloy is one of the more widely used and well-received iron-based soft magnetic alloy materials with high permeability; however, the development of high-performance FeSiCr alloy wave-absorbing materials is still a major challenge. In this study, double core-shell-structured composites of MIL-88(Fe)@Fe2O3@FeSiCr were successfully prepared by the oxidative heat treatment of the flaky FeSiCr obtained after ball milling and then in situ composited with MIL-88(Fe). The heterogeneous interfacial composition and microstructure were regulated to balance the microwave-loss capability and impedance matching of the material, and an enhancement of the composite absorbing performance was achieved. The composite material had a reflection-loss minimization (RLmin) of -72.65 dB, corresponding to a frequency of 6.61 GHz, with an absorbing coating thickness of 2.97 mm and an effective absorbing bandwidth (RL ≤ -10 dB) of 2.38 GHz (5.42-7.80 GHz). The results of this study provide useful ideas for wave-absorbing materials by applying high permeability soft magnetic alloy micropowders.

Proteomic and metabolomic analysis of ageing beef exudate to determine that iron metabolism enhances muscle protein and lipid oxidation.

The study aimed to assess differences in proteomic and metabolite profiles in ageing (1, 2, 4, and 6 days at 4 °C) beef exudates and determine their relationship with beef muscle iron metabolism and oxidation. Proteomic and metabolomic analyses identified 877 metabolites and 1957 proteins. The joint analysis identified 24 differential metabolites (DMs) and 56 differentially expressed proteins (DEPs) involved in 15 shared pathways. Ferroptosis was identified as the only iron metabolic pathway, and 4 DMs (l-glutamic acid, arachidonic acid, glutathione and gamma-glutamylcysteine) and 5 DEPs (ferritin, phospholipid hydroperoxide glutathione peroxidase, heme oxygenase 1, major prion protein, and acyl-CoA synthetase long chain family member 4) were involved in iron metabolism by regulating heme and ferritin degradation, Fe2+ and Fe3+ conversion, arachidonic acid oxidation and inactivation of glutathione peroxidase (GPX) 4, leading to increased levels of free iron, ROS, protein and lipid oxidation (P < 0.05). Overall, abnormal iron metabolism during ageing induced oxidative stress in muscle tissue.

Single-cell RNA-seq analyses inform necroptosis-associated myeloid lineages influence the immune landscape of pancreas cancer.

Introduction: Tumor-infiltrating myeloid cells (TIMs) are key regulators in tumor progression, but the similarity and distinction of their fundamental properties in pancreatic ductal adenocarcinoma (PDAC) remain elusive. Method: In this study, we conducted scRNA-seq data analysis of cells from 12 primary tumor (PT) tissues, 4 metastatic (Met) tumor tissues, 3 adjacent normal pancreas tissues (Para), and PBMC samples across 16 PDAC patients, and revealed a heterogeneous TIMs environment in PDAC. Result: Systematic comparisons between tumor and non-tumor samples of myeloid lineages identified 10 necroptosis-associated genes upregulated in PDAC tumors compared to 5 upregulated in paratumor or healthy peripheral blood. A novel RTM (resident tissue macrophages), GLUL-SQSTM1- RTM, was found to act as a positive regulator of immunity. Additionally, HSP90AA1+HSP90AB1+ mast cells exhibited pro-immune characteristics, and JAK3+TLR4+ CD16 monocytes were found to be anti-immune. The findings were validated through clinical outcomes and cytokines analyses. Lastly, intercellular network reconstruction supported the associations between the identified novel clusters, cancer cells, and immune cell populations. Conclusion: Our analysis comprehensively characterized major myeloid cell lineages and identified three subsets of myeloid-derived cells associated with necroptosis. These findings not only provide a valuable resource for understanding the multi-dimensional characterization of the tumor microenvironment in PDAC but also offer valuable mechanistic insights that can guide the design of effective immuno-oncology treatment strategies.

Synthesis of 3- and 5-ß-anhydroicaritine norcantharidin conjugates.

Using molecular hybridisation to develop conjugates of natural antitumor drugs is one of the research hotspots in recent drug development. In this study, ß-anhydroicaritine with anticancer activity was conjugated to norcantharidine selectively to develop new antitumor lead candidates. In the condition of EDCI/DMAP/DCM, the C-3 and C-5 hydroxyl groups of ß-anhydroicaritine was coupled with norcantharidin monoacid ester respectively, and the inhibitory activity of the synthesised conjugates against HepG2, MCF-7 and L-02 cells were tested by CCK-8 method. Most of these conjugates showed a better activity against HepG2 and MCF-7 cell lines compared to parent compound icaritin, but weaker than another parent compound norcantharidin.

RBMS3-induced circHECTD1 encoded a novel protein to suppress the vasculogenic mimicry formation in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is a highly vascularized malignant cancer of the central nervous system, and the presence of vasculogenic mimicry (VM) severely limits the effectiveness of anti-vascular therapy. In this study, we identified downregulated circHECTD1, which acted as a key VM-suppressed factor in GBM. circHECTD1 elevation significantly inhibited cell proliferation, migration, invasion and tube-like structure formation in GBM. RIP assay was used to demonstrate that the flanking intron sequence of circHECTD1 can be specifically bound by RBMS3, thereby inducing circHECTD1 formation to regulate VM formation in GBM. circHECTD1 was confirmed to possess a strong protein-encoding capacity and the encoded functional peptide 463aa was identified by LC-MS/MS. Both circHECTD1 and 463aa significantly inhibited GBM VM formation in vivo and in vitro. Analysis of the 463aa protein sequence revealed that it contained a ubiquitination-related domain and promoted NR2F1 degradation by regulating the ubiquitination of the NR2F1 at K396. ChIP assay verified that NR2F1 could directly bind to the promoter region of MMP2, MMP9 and VE-cadherin, transcriptionally promoting the expression of VM-related proteins, which in turn enhanced VM formation in GBM. In summary, we clarified a novel pathway for RBMS3-induced circHECTD1 encoding functional peptide 463aa to mediate the ubiquitination of NR2F1, which inhibited VM formation in GBM. This study aimed to reveal new mechanisms of GBM progression in order to provide novel approaches and strategies for the anti-vascular therapy of GBM. The schematic illustration showed the inhibitory effect of circHECTD1-463aa in the VM formation in GBM.

SUMOylation of RALY promotes vasculogenic mimicry in glioma cells via the FOXD1/DKK1 pathway.

Human malignant gliomas are the most common and aggressive primary malignant tumors of the human central nervous system. Vasculogenic mimicry (VM), which refers to the formation of a tumor blood supply system independently of endothelial cells, contributes to the malignant progression of glioma. Therefore, VM is considered a potential target for glioma therapy. Accumulated evidence indicates that alterations in SUMOylation, a reversible post-translational modification, are involved in tumorigenesis and progression. In the present study, we found that UBA2 and RALY were upregulated in glioma tissues and cell lines. Downregulation of UBA2 and RALY inhibited the migration, invasion, and VM of glioma cells. RALY can be SUMOylated by conjugation with SUMO1, which is facilitated by the overexpression of UBA2. The SUMOylation of RALY increases its stability, which in turn increases its expression as well as its promoting effect on FOXD1 mRNA. The overexpression of FOXD1 promotes DKK1 transcription by activating its promoter, thereby promoting glioma cell migration, invasion, and VM. Remarkably, the combined knockdown of UBA2, RALY, and FOXD1 resulted in the smallest tumor volumes and the longest survivals of nude mice in vivo. UBA2/RALY/FOXD1/DKK1 axis may play crucial roles in regulating VM in glioma, which may contribute to the development of potential strategies for the treatment of gliomas.

Pseudogene MAPK6P4-encoded functional peptide promotes glioblastoma vasculogenic mimicry development.

Glioma is the most common primary malignancy of the central nervous system. Glioblastoma (GBM) has the highest degree of malignancy among the gliomas and the strongest resistance to chemotherapy and radiotherapy. Vasculogenic mimicry (VM) provides tumor cells with a blood supply independent of endothelial cells and greatly restricts the therapeutic effect of anti-angiogenic tumor therapy for glioma patients. Vascular endothelial growth factor receptor 2 (VEGFR2) and vascular endothelial cadherin (VE-cadherin) are currently recognized molecular markers of VM in tumors. In the present study, we show that pseudogene MAPK6P4 deficiency represses VEGFR2 and VE-cadherin protein expression levels, as well as inhibits the proliferation, migration, invasion, and VM development of GBM cells. The MAPK6P4-encoded functional peptide P4-135aa phosphorylates KLF15 at the S238 site, promoting KLF15 protein stability and nuclear entry to promote GBM VM formation. KLF15 was further confirmed as a transcriptional activator of LDHA, where LDHA binds and promotes VEGFR2 and VE-cadherin lactylation, thereby increasing their protein expression. Finally, we used orthotopic and subcutaneous xenografted nude mouse models of GBM to verify the inhibitory effect of the above factors on GBM VM development. In summary, this study may represent new targets for the comprehensive treatment of glioma.

A novel peptide P1-121aa encoded by STK24P1 regulates vasculogenic mimicry via ELF2 phosphorylation in glioblastoma.

Glioblastoma (GBM) is the most common malignant tumor of the central nervous system. Vasculogenic mimicry (VM) is a hematological system composed of tumor cells that exert blood perfusion without relying on vascular endothelial cells. The current poor results of anti-vascular therapy for clinical GBM are associated with the presence of VM; therefore, it is important to investigate VM formation in GBM. Our results demonstrate that STK24P1 encodes P1-121aa with a kinase structural domain, and in vitro kinase assays demonstrated that P1-121aa mediates modification of ELF2 phosphorylation. ChIP and dual luciferase reporter gene assays demonstrated that the transcription factor ELF2 binds to VE-cadherin and the VEGFR2 promoter region, thereby promoting VM formation in glioma cells. P1-121aa, encoded by the pseudogene STK24P1, phosphorylates ELF2 at S107, increasing the stability of the ELF2 protein. ELF2 promotes VEGFR2 and VE-cadherin expression at the transcriptional level, which in turn promotes VM in GBM. This study demonstrates the important roles of STK24P1, P1-121aa, and ELF2 in regulating VM in GBM, which could provide potential targets for GBM treatment.

Association of nickel exposure with body mass index, waist circumference and incidence of obesity in US adults.

This study aimed to detect the relationship between nickel exposure and body mass index (BMI), waist circumference and incidence of obesity in the general population of the United States. The National Health and Nutrition Examination Survey (NHANES) 2017-2018 database was utilized, and the sample comprised 1702 participants aged 18 years and above with complete urinary nickel, body mass index, and waist circumference data. Obesity was determined using BMI and waist circumference data. The multivariate linear regression and logistic regression models were utilized to detect the association between urinary nickel concentration and BMI, waist circumference, and incidence of obesity. After multivariable adjustment, the log-transformed urinary nickel concentration was inversely associated with BMI [ß = -0.87; 95% confidence interval (CI): (-1.36, -0.38)] and waist circumference [ß = -1.51; 95% CI: (-2.93, -0.08)]. Compared with the lowest tertile of urinary nickel, the ß value and 95% CI of BMI and waist circumference for the highest tertile were ß = -1.65.95% CI: (-2.85, -0.45) and ß = -2.78, 95% CI: (-6.17, 0.62), respectively. The log-transformed urinary nickel concentration was also negatively associated with obesity status [adjusted odds ratio (OR) = 0.81, 95% CI: (0.64, 1.01)]. Compared with the lowest tertile of urinary nickel, the adjusted OR and 95% CI of obesity status for the highest tertile were OR = 0.64 and 95% CI: (0.37, 1.12). Smooth curve fitting and the generalized additive model indicated that elevated urinary nickel concentration was associated with decreased BMI, waist circumference, and incidence of obesity. The negative association was consistent and robust in different subgroups, according to stratified analysis. This study found that nickel exposure may be negatively associated with BMI, waist circumference and incidence of obesity in US Adults.