High albumen height by expression of GALNT9 and thin eggshell by decreased Ca2+ transportation caused high hatchability in Huainan partridge chicken.

Hatchability could be quite different among individuals of indigenous chicken breed which might be affected by the egg quality. In this study, hatchability was individually recorded among 800 forty-wk-old Huainan partridge chickens. The chickens were then divided into high and low hatchability groups (HH and LH group) with 50 birds in each group. Egg quality was further determined in the 2 groups. Eight birds from each group were selected for slaughtering and tissue, responsible for egg formation, collection for structure observation by staining and candidate gene expression by transcriptome analysis. The hatchability in HH was 100% and 61.18% in LH. The eggshell thickness and shell strength were significantly lower, while the albumen height and Haugh unit were significantly higher in HH group than those in LH group (P < 0.05). The magnum weight and index, and the expression of polypeptide N-acetylgalactosaminyltransferase 9 (GALNT9), which responsible for thick albumen synthesis, in HH group were also significantly higher than that of LH group (P < 0.05). Compared with the LH group, there were 702 differentially expressed genes (DEGs) in HH group, of which 402 were up-regulated and 300 were down-regulated. Candidate genes of calbindin 1 (CALB1) and solute carrier family 26 member 9 (SLC26A9), which regulate calcium signaling pathway so as to affect Ca2+ transportation, exhibited significant high and low expression, respectively, in HH group compared to those in LH group (P < 0.05). Therefore, indigenous chicken with high expression of GALNT9 in magnum to form thick albumen to provide more protein for embryo, while high CALB1 and low expression of SLC26A9 to decrease Ca2+ transportation so as to form a thinner eggshell and provide better gas exchange during embryo development.

Differentiation of testicular seminomas from nonseminomas based on multiphase CT radiomics combined with machine learning: A multicenter study.

BACKGROUND: Differentiating seminomas from nonseminomas is crucial for formulating optimal treatment strategies for testicular germ cell tumors (TGCTs). Therefore, our study aimed to develop and validate a clinical-radiomics model for this purpose. METHODS: In this study, 221 patients with TGCTs confirmed by pathology from four hospitals were enrolled and classified into training (n = 126), internal validation (n = 55) and external test (n = 40) cohorts. Radiomics features were extracted from the CT images. After feature selection, we constructed a clinical model, radiomics models and clinical-radiomics model with different machine learning algorithms. The top-performing model was chosen utilizing receiver operating characteristic (ROC) curve analysis. Decision curve analysis (DCA) was also conducted to assess its practical utility. RESULTS: Compared with those of the clinical and radiomics models, the clinical-radiomics model demonstrated the highest discriminatory ability, with AUCs of 0.918 (95 % CI: 0.870 - 0.966), 0.909 (95 % CI: 0.829 - 0.988) and 0.839 (95 % CI: 0.709 - 0.968) in the training, validation and test cohorts, respectively. Moreover, DCA confirmed that the combined model had a greater net benefit in predicting seminomas and nonseminomas. CONCLUSION: The clinical-radiomics model serves as a potential tool for noninvasive differentiation between testicular seminomas and nonseminomas, offering valuable guidance for clinical treatment.

Maintaining moderate versus lower PEEP after cardiac surgery: a propensity-scored matched analysis.

BACKGROUND: Setting positive end-expiratory pressure (PEEP) at around 5 cm H2O in the early postoperative period seems a common practice for most patients. It remains unclear if the routine application of higher levels of PEEP confers any meaningful clinical benefit for cardiac surgical patients. The aim of this study was to compare moderate versus conventional lower PEEP on patient-centered outcomes in the intensive care unit (ICU). METHODS: This is a single-center retrospective study involving patients receiving cardiac surgery from June 2022 to May 2023. Propensity-score matching (PSM) was used to balance the baseline differences. Primary outcomes were the duration of mechanical ventilation and ICU length of stay. Secondary outcomes included PaO2/FiO2 ratio at 24 h and the need for prone positioning during ICU stay. RESULTS: A total of 334 patients were included in the study, 102 (31%) of them received moderate PEEP (≥ 7 cm H2O) for the major time in the early postoperative period (12 h). After PSM, 79 pairs of patients were matched with balanced baseline data. The results showed that there was marginal difference in the distribution of mechanical ventilation duration (p = 0.05) and the Moderate PEEP group had a higher extubation rate at the day of T-piece trial (65 [82.3%] vs 52 [65.8%], p = 0.029). Applying moderate PEEP was also associated with better oxygenation. No differences were found regarding ICU length of stay and patients requiring prone positioning between groups. CONCLUSION: In selective cardiac surgical patients, using moderate PEEP compared with conventional lower PEEP in the early postoperative period correlated to better oxygenation, which may have potential for earlier liberation of mechanical ventilation.

The deubiquitinase USP40 preserves endothelial integrity by targeting the heat shock protein HSP90ß.

Endothelial cell (EC) barrier disruption and inflammation are the pathological hallmarks of vascular disorders and acute infectious diseases and related conditions, including the coronavirus disease 2019 (COVID-19) and sepsis. Ubiquitination plays a critical role in regulating the stability, intracellular trafficking, and enzymatic activity of proteins and is reversed by deubiquitinating enzymes (DUBs). The role of DUBs in endothelial biology is largely unknown. In this study, we report that USP40, a poorly characterized DUB, prevents EC barrier disruption through reductions in the activation of RhoA and phosphorylation of myosin light chain (MLC) and cofilin. Furthermore, USP40 reduces EC inflammation through the attenuation of NF-ĸB activation, ICAM1 expression, and leukocyte-EC adhesion. We further show that USP40 activity and expression are reduced in response to endotoxin challenge. Global depletion of USP40 and EC-targeted USP40 depletion in mice exacerbated experimental lung injury, whereas lentiviral gene transfer of USP40 protected against endotoxin-induced lung injury. Using an unbiased approach, we discovered that the protective effect of USP40 occurs through the targeting of heat shock protein 90ß (HSP90ß) for its deubiquitination and inactivation. Together, these data reveal a critical protective role of USP40 in vascular injury, identifying a unique mechanistic pathway that profoundly impacts endothelial function via DUBs.

Towards optimal heterogeneous prostate radiotherapy dose prescriptions based on patient-specific or population-based biological features.

BACKGROUND: Escalation of prescribed dose in prostate cancer (PCa) radiotherapy enables improvement in tumor control at the expense of increased toxicity. Opportunities for reduction of treatment toxicity may emerge if more efficient dose escalation can be achieved by redistributing the prescribed dose distribution according to the known heterogeneous, spatially-varying characteristics of the disease. PURPOSE: To examine the potential benefits, limitations and characteristics of heterogeneous boost dose redistribution in PCa radiotherapy based on patient-specific and population-based spatial maps of tumor biological features. METHOD: High-resolution prostate histology images, from a cohort of 63 patients, annotated with tumor location and grade, provided patient-specific "maps" and a population-based "atlas" of cell density and tumor probability. Dose prescriptions were derived for each patient based on a heterogeneous redistribution of the boost dose to the intraprostatic lesions, with the prescription maximizing patient tumor control probability (TCP). The impact on TCP was assessed under scenarios where the distribution of population-based biological data was ignored, partially included, or fully included in prescription generation. Heterogeneous dose prescriptions were generated for three combinations of maps and atlas, and for conventional fractionation (CF), extreme hypo-fractionation (EH), moderate hypo-fractionation (MH), and whole Pelvic RT + SBRT Boost (WPRT + SBRT). The predicted efficacy of the heterogeneous prescriptions was compared with equivalent homogeneous dose prescriptions. RESULTS: TCPs for heterogeneous dose prescriptions were generally higher than those for homogeneous dose prescriptions. TCP escalation by heterogeneous dose prescription was the largest for CF. When only using population-based atlas data, the generated heterogeneous dose prescriptions of 55 to 58 patients (out of 63) had a higher TCP than for the corresponding homogeneous dose prescriptions. The TCPs of the heterogeneous dose prescriptions generated with the population-based atlas and tumor probability maps did not differ significantly from those using patient-specific biological information. The generated heterogeneous dose prescriptions achieved significantly higher TCP than homogeneous dose prescriptions in the posterior section of the prostate. CONCLUSION: Heterogeneous dose prescriptions generated via biologically-optimized dose redistribution can produce higher TCP than the homogeneous dose prescriptions for the majority of the patients in the studied cohort. For scenarios where patient-specific biological information was unavailable or partially available, the generated heterogeneous dose prescriptions can still achieve TCP improvement relative to homogeneous dose prescriptions.

Integrative Multianalytical Model Based on Novel Plasma Protein Biomarkers for Distinguishing Lung Adenocarcinoma and Benign Pulmonary Nodules.

Given the pressing clinical problem of making a decision in diagnosis for subjects with pulmonary nodules, we aimed to discover novel plasma protein biomarkers for lung adenocarcinoma (LUAD) and benign pulmonary nodules (BPNs) and then develop an integrative multianalytical model to guide the clinical management of LUAD and BPN patients. Through label-free quantitative plasma proteomic analysis (data are available via ProteomeXchange with identifier PXD046731), 12 differentially expressed proteins (DEPs) in LUAD and BPN were screened. The diagnostic abilities of DEPs were validated in two independent validation cohorts. The results showed that the levels of three candidate proteins (PRDX2, PON1, and APOC3) were lower in the plasma of LUAD than in BPN. The three candidate proteins were combined with three promising computed tomography indicators (spiculation, vascular notch sign, and lobulation) and three traditional markers (CEA, CA125, and CYFRA21-1) to construct an integrative multianalytical model, which was effective in distinguishing LUAD from BPN, with an AUC of 0.904, a sensitivity of 81.44%, and a specificity of 90.14%. Moreover, the model possessed impressive diagnostic performance between early LUADs and BPNs, with the AUC, sensitivity, specificity, and accuracy of 0.868, 65.63%, 90.14%, and 82.52%, respectively. This model may be a useful auxiliary diagnostic tool for LUAD and BPN by achieving a better balance of sensitivity and specificity.

Focal Boost in Prostate Cancer Radiotherapy: A Review of Planning Studies and Clinical Trials.

BACKGROUND: Focal boost radiotherapy was developed to deliver elevated doses to functional sub-volumes within a target. Such a technique was hypothesized to improve treatment outcomes without increasing toxicity in prostate cancer treatment. PURPOSE: To summarize and evaluate the efficacy and variability of focal boost radiotherapy by reviewing focal boost planning studies and clinical trials that have been published in the last ten years. METHODS: Published reports of focal boost radiotherapy, that specifically incorporate dose escalation to intra-prostatic lesions (IPLs), were reviewed and summarized. Correlations between acute/late ≥G2 genitourinary (GU) or gastrointestinal (GI) toxicity and clinical factors were determined by a meta-analysis. RESULTS: By reviewing and summarizing 34 planning studies and 35 trials, a significant dose escalation to the GTV and thus higher tumor control of focal boost radiotherapy were reported consistently by all reviewed studies. Reviewed trials reported a not significant difference in toxicity between focal boost and conventional radiotherapy. Acute ≥G2 GU and late ≥G2 GI toxicities were reported the most and least prevalent, respectively, and a negative correlation was found between the rate of toxicity and proportion of low-risk or intermediate-risk patients in the cohort. CONCLUSION: Focal boost prostate cancer radiotherapy has the potential to be a new standard of care.

The Comprehensive Analysis of m6A-Associated Anoikis Genes in Low-Grade Gliomas.

The relationship between N6-methyladenosine (m6A) regulators and anoikis and their effects on low-grade glioma (LGG) is not clear yet. The TCGA-LGG cohort, mRNAseq 325 dataset, and GSE16011 validation set were separately obtained via the Cancer Genome Atlas (TCGA), Chinese Glioma Genome Altas (CGGA), and Gene Expression Omnibus (GEO) databases. In total, 27 m6A-related genes (m6A-RGs) and 508 anoikis-related genes (ANRGs) were extracted from published articles individually. First, differentially expressed genes (DEGs) between LGG and normal samples were sifted out by differential expression analysis. DEGs were respectively intersected with m6A-RGs and ANRGs to acquire differentially expressed m6A-RGs (DE-m6A-RGs) and differentially expressed ANRGs (DE-ANRGs). A correlation analysis of DE-m6A-RGs and DE-ANRGs was performed to obtain DE-m6A-ANRGs. Next, univariate Cox and least absolute shrinkage and selection operator (LASSO) were performed on DE-m6A-ANRGs to sift out risk model genes, and a risk score was gained according to them. Then, gene set enrichment analysis (GSEA) was implemented based on risk model genes. After that, we constructed an independent prognostic model and performed immune infiltration analysis and drug sensitivity analysis. Finally, an mRNA-miRNA-lncRNA regulatory network was constructed. There were 6901 DEGs between LGG and normal samples. Six DE-m6A-RGs and 214 DE-ANRGs were gained through intersecting DEGs with m6A-RGs and ANRGs, respectively. A total of 149 DE-m6A-ANRGs were derived after correlation analysis. Four genes, namely ANXA5, KIF18A, BRCA1, and HOXA10, composed the risk model, and they were involved in apoptosis, fatty acid metabolism, and glycolysis. The age and risk scores were finally sifted out to construct an independent prognostic model. Activated CD4 T cells, gamma delta T cells, and natural killer T cells had the largest positive correlations with risk model genes, while activated B cells were significantly negatively correlated with KIF18A and BRCA1. AT.9283, EXEL.2280, Gilteritinib, and Pracinostat had the largest correlation (absolute value) with a risk score. Four risk model genes (mRNAs), 12 miRNAs, and 21 lncRNAs formed an mRNA-miRNA-lncRNA network, containing HOXA10-hsa-miR-129-5p-LINC00689 and KIF18A-hsa-miR-221-3p-DANCR. Through bioinformatics, we constructed a prognostic model of m6A-associated anoikis genes in LGG, providing new ideas for research related to the prognosis and treatment of LGG.

E2F1 Mediates SOX17 Deficiency-Induced Pulmonary Hypertension.

BACKGROUND: Rare genetic variants and genetic variation at loci in an enhancer in SOX17 (SRY-box transcription factor 17) are identified in patients with idiopathic pulmonary arterial hypertension (PAH) and PAH with congenital heart disease. However, the exact role of genetic variants or mutations in SOX17 in PAH pathogenesis has not been reported. METHODS: SOX17 expression was evaluated in the lungs and pulmonary endothelial cells (ECs) of patients with idiopathic PAH. Mice with Tie2Cre-mediated Sox17 knockdown and EC-specific Sox17 deletion were generated to determine the role of SOX17 deficiency in the pathogenesis of PAH. Human pulmonary ECs were cultured to understand the role of SOX17 deficiency. Single-cell RNA sequencing, RNA-sequencing analysis, and luciferase assay were performed to understand the underlying molecular mechanisms of SOX17 deficiency-induced PAH. E2F1 (E2F transcription factor 1) inhibitor HLM006474 was used in EC-specific Sox17 mice. RESULTS: SOX17 expression was downregulated in the lung and pulmonary ECs from patients with idiopathic PAH. Mice with Tie2Cre-mediated Sox17 knockdown and EC-specific Sox17 deletion induced spontaneously mild pulmonary hypertension. Loss of endothelial Sox17 in EC exacerbated hypoxia-induced pulmonary hypertension in mice. Loss of SOX17 in lung ECs induced endothelial dysfunctions including upregulation of cell cycle programming, proliferative and antiapoptotic phenotypes, augmentation of paracrine effect on pulmonary arterial smooth muscle cells, impaired cellular junction, and BMP (bone morphogenetic protein) signaling. E2F1 signaling was shown to mediate the SOX17 deficiency-induced EC dysfunction. Pharmacological inhibition of E2F1 in Sox17 EC-deficient mice attenuated pulmonary hypertension development. CONCLUSIONS: Our study demonstrated that endothelial SOX17 deficiency induces pulmonary hypertension through E2F1. Thus, targeting E2F1 signaling represents a promising approach in patients with PAH.

USP13 regulates cell senescence through mediating MDM2 stability.

AIMS: Lung aging results in altered lung function, reduced lung remodeling and regenerative capacity, and increased susceptibility to acute and chronic lung diseases. The molecular and physiological underlying mechanisms of lung aging remain unclear. Mounting evidence suggests that deubiquitinating enzymes (DUBs) play a critical role in tissue aging and diseases through regulation of cellular signaling pathways. Here we investigate the role of Ubiquitin-Specific Protease 13 (USP13) in cell senescence and lung aging and its underlying mechanisms. MAIN METHODS: Protein levels of USP13 and MDM2 in lung tissues from aged and young mice were compared. Gene silencing and overexpression of USP13 in human cell lines were performed. MDM2 levels were examined by Quantitative Real-Time PCR and Western blotting analysis. The cell senescence levels of human cells were checked by the ß-galactosidase staining. KEY FINDINGS: Lung tissues from aged mice showed higher levels of USP13 compared to younger mice. We found a negative correlation between USP13 and MDM2 expression in lung tissues of aged mice. The increased protein levels of MDM2 were detected in lung tissues of USP13 deficient mice. Furthermore, overexpression of USP13 promoted cell senescence. Knockdown of USP13 increased MDM2 levels in lung cells, while overexpression of USP13 reduced it. The degradation of MDM2 caused by USP13 was prevented by the proteasome inhibitor MG132. Furthermore, we showed that USP13 targeted and reduced K63-linked polyubiquitination of MDM2. These results demonstrate that USP13 is involved in the aging signaling pathway in lungs through regulation of MDM2.

DHX38 restricts chemoresistance by regulating the alternative pre-mRNA splicing of RELL2 in pancreatic ductal adenocarcinoma.

Intron retention plays an important role in cancer progression and chemotherapy resistance and seems to be essential for the maintenance of genome stability in cancer. Here, our goal was to analyze the role of receptor expressed in lymphoid tissue (Relt)-like 2 (RELL2) intron 4 retention in promoting pancreatic ductal adenocarcinoma (PDAC) progression. Our results showed that intron retention (IR) occurs at the fourth intron of RELL2 transcript in gemcitabine resistant PDAC cells, however, the regulatory mechanism and the clinical implications of IR of RELL2 are unclear. Firstly, we found that RELL2 plays an anti-oncogenic role in PDAC by performing in vitro functional assays including cell proliferation, GEM cytotoxicity assay and apoptosis. Subsequently, we identified the upstream gene of RELL2, DEAH-Box Helicase 38 (DHX38), and demonstrated the direct interaction between DHX38 and RELL2 by RIP-qPCR. We also found that altered expression of DHX38 resulted in corresponding changes in intron 4 retention of RELL2. Importantly, we unveiled that overexpression of DHX38 on the basis of knocking down of the fourth intron of RELL2 resulted in an impaired intron 4 intention. Overall, our study identified a new IR site in PDAC, which could be a possible target for PDAC therapy.

Mechanical confinement promotes heat resistance of hepatocellular carcinoma via SP1/IL4I1/AHR axis.

Mechanical stress can modulate the fate of cells in both physiological and extreme conditions. Recurrence of tumors after thermal ablation, a radical therapy for many cancers, indicates that some tumor cells can endure temperatures far beyond physiological ones. This unusual heat resistance with unknown mechanisms remains a key obstacle to fully realizing the clinical potential of thermal ablation. By developing a 3D bioprinting-based thermal ablation system, we demonstrate that hepatocellular carcinoma (HCC) cells in this 3D model exhibit enhanced heat resistance as compared with cells on plates. Mechanistically, the activation of transcription factor SP1 under mechanical confinement enhances the transcription of Interleukin-4-Induced-1, which catalyzes tryptophan metabolites to activate the aryl hydrocarbon receptor (AHR), leading to heat resistance. Encouragingly, the AHR inhibitor prevents HCC recurrence after thermal ablation. These findings reveal a previously unknown role of mechanical confinement in heat resistance and provide a rationale for AHR inhibitors as neoadjuvant therapy.

The Osaka prognostic score and Naples prognostic score: novel biomarkers for predicting short-term outcomes after spontaneous intracerebral hemorrhage.

OBJECTIVES: Poor immune-nutritional status has been associated with an unfavorable outcome in critical illness. The Osaka prognostic score (OPS) and the Naples prognostic score (NPS), based on inflammatory and nutritional status, has been shown to predict prognosis following cancer and other diseases. The aim of this study was to investigate the relationship between the OPS and NPS and the short-term outcomes of patients with intracerebral hemorrhage (ICH). METHODS: We retrospectively analyzed the clinical data of patients hospitalized with spontaneous ICH (n = 340) at The Second Affiliated Hospital of Chongqing Medical University between August 2016 and August 2021. Inclusion criteria included patients aged between 18 and 70, and if a blood sample was taken for laboratory testing within 24 h of admission (serum C-reactive protein, albumin, total cholesterol, and counts for neutrophils, lymphocytes, and monocytes were collected on admission). Exclusion criteria included a non-spontaneous cause of ICH and patient death during hospitalization. Patients were divided into four groups based on OPS or five groups according to NPS. Outcomes were evaluated by the modified Rankin Scale (mRS) at six months post-ICH hospitalization. An unfavorable outcome was defined as a mRS score ≥ 3. RESULTS: A total of 289 patients met our inclusion criteria. The unfavorable outcome group had older age, a lower Glasgow Coma Scale score, a higher rate of complications and cerebral herniation, a longer hospital stay, and higher OPS and NPS when compared with the favorable outcome group. Univariate analysis showed that both OPS and NPS were strongly correlated with mRS (r = 0.196,P < 0.001; r = 0.244, P = 0.001, respectively). Multivariate analysis further showed that OPS and NPS were both independent predictors of unfavorable outcomes for patients with ICH with adjusted odds ratios of 1.802 (95% confidence interval [CI]:1.140-2.847, P = 0.012) and 1.702 (95% CI: 1.225-2.635, P = 0.02), respectively. The area under the curve (AUC) of NPS for predicting a poor outcome was 0.732 (95% CI: 0.665-0.799), which was similar to the AUC of OPS 0.724 (95% CI: 0.657-0.792). CONCLUSIONS: In this cohort, a higher OPS and NPS on admission was associated with poor outcome at six months following ICH, supporting their potential role as markers for predicting the outcome of patients with ICH.

The association between CTSZ methylation in peripheral blood and breast cancer in Chinese women.

Purpose: Previous studies have shown that DNA methylation in peripheral blood may be associated with breast cancer (BC). To explore the association between the methylation level of the Cathepsin Z (CTSZ) gene in peripheral blood and BC, we conducted a case-control study in the Chinese population. Methods: Peripheral blood samples were collected from 567 BC cases, 635 healthy controls, and 303 benign breast disease (BBD) cases. DNA extraction and bisulfite-specific PCR amplification were performed for all samples. The methylation levels of seven sites of the CTSZ gene were quantitatively determined by Mass spectrometry. The odds ratios (ORs) of CpG sites were evaluated for BC risk using per 10% reduction and quartiles analyses by logistic regression. Results: Our analysis showed that five out of the seven CpG sites exhibited significant associations with hypomethylation of CTSZ and BC, compared to healthy controls. The highest OR was for Q2 of CTSZ_CpG_1 (OR: 1.62, P=0.006), particularly for early-stage breast cancer in the case of per 10% reduction of CTSZ_CpG_1 (OR: 1.20, P=0.003). We also found that per 10% reduction of CTSZ_CpG_5 (OR: 1.39, P=0.004) and CTSZ_CpG_7,8 (OR: 1.35, P=0.005) were associated with increased BC risk. Our study also revealed that four out of seven CpG sites were linked to increased BC risk in women under 50 years of age, compared to healthy controls. The highest OR was for per 10% reduction of CTSZ_CpG_1 (OR: 1.47, P<0.001). Additionally, we found that BC exhibited lower methylation levels than BBD at CTSZ_CpG_4 (OR for Q1: 2.18, P<0.001) and CTSZ_CpG_7,8 (OR for Q1: 2.01, P=0.001). Furthermore, we observed a correlation between methylation levels and tumor stage, ER, and HER2 status in BC patients. Conclusion: Overall, our findings suggest that altered CTSZ methylation levels in peripheral blood may be associated with breast cancer, particularly in young women, and may serve as a potential biomarker for early-stage BC.

Pancreatic cancer stemness: dynamic status in malignant progression.

Pancreatic cancer (PC) is one of the most aggressive malignancies worldwide. Increasing evidence suggests that the capacity for self-renewal, proliferation, and differentiation of pancreatic cancer stem cells (PCSCs) contribute to major challenges with current PC therapies, causing metastasis and therapeutic resistance, leading to recurrence and death in patients. The concept that PCSCs are characterized by their high plasticity and self-renewal capacities is central to this review. We focused specifically on the regulation of PCSCs, such as stemness-related signaling pathways, stimuli in tumor cells and the tumor microenvironment (TME), as well as the development of innovative stemness-targeted therapies. Understanding the biological behavior of PCSCs with plasticity and the molecular mechanisms regulating PC stemness will help to identify new treatment strategies to treat this horrible disease.

Ferroptosis in calcium oxalate kidney stone formation and the possible regulatory mechanism of ANKRD1.

The objective of this study was to explore the role of ferroptosis in the formation of calcium oxalate (CaOx) kidney stones and the regulatory mechanism of the ankyrin repeat domain 1 (ANKRD1) gene. The study found that the Nrf2/HO-1 and p53/SLC7A11 signaling pathways were activated in the kidney stone model group, and the expression of the ferroptosis marker proteins SLC7A11 and GPX4 was significantly reduced, while the expression of ACSL4 was significantly increased. The expression of the iron transport-related proteins CP and TF increased significantly, and Fe2+ accumulated in the cell. The expression of HMGB1 increased significantly. In addition, the level of intracellular oxidative stress was increased. The gene with the most significant difference caused by CaOx crystals in HK-2 cells was ANKRD1. Silencing or overexpression of ANKRD1 by lentiviral infection technology regulated the expression of the p53/SLC7A11 signaling pathway, which regulated the ferroptosis induced by CaOx crystals. In conclusion, CaOx crystals can mediate ferroptosis through the Nrf2/HO-1 and p53/SLC7A11 pathways, thereby weakening the resistance of HK-2 cells to oxidative stress and other unfavorable factors, enhancing cell damage, and increasing crystal adhesion and CaOx crystal deposition in the kidney. ANKRD1 participates in the formation and development of CaOx kidney stones by activating ferroptosis mediated by the p53/SLC7A11 pathway.

ISGylation of NF-κBp65 by SCFFBXL19 E3 Ligase Diminishes Endothelial Inflammation.

BACKGROUND: NF-κB (nuclear factor kappa B) plays a pivotal role in endothelial cell (EC) inflammation. Protein ISGylation is regulated by E3 ISG15 (interferon-stimulated gene 15) ligases; however, ISGylation of NF-κBp65 and its role in EC functions have not been investigated. Here, we investigate whether p65 is ISGylated and the role of its ISGylation in endothelial functions. METHODS: In vitro ISGylation assay and EC inflammation were performed. EC-specific transgenic mice were utilized in a murine model of acute lung injury. RESULTS: We find that NF-κBp65 is ISGylated in resting ECs and that the posttranslational modification is reversible. TNFα (tumor necrosis factor alpha) and endotoxin stimulation of EC reduce p65 ISGylation, promoting its serine phosphorylation through reducing its association with a phosphatase WIP1 (wild-type p53-induced phosphatase 1). Mechanistically, an SCF (Skp1-Cul1-F-box) protein E3 ligase SCFFBXL19 is identified as a new ISG15 E3 ligase that targets and catalyzes ISGylation of p65. Depletion of FBXL19 (F-box and leucine-rich repeat protein 19) increases p65 phosphorylation and EC inflammation, suggesting a negative correlation between p65 ISGylation and phosphorylation. Moreover, EC-specific FBXL19 overexpressing humanized transgenic mice exhibit reduced lung inflammation and severity of experimental acute lung injury. CONCLUSIONS: Together, our data reveal a new posttranslational modification of p65 catalyzed by a previously unrecognized role of SCFFBXL19 as an ISG15 E3 ligase that modulates EC inflammation.

High-value utilisation of PGM-containing residual oil: Recovery of inorganic acids, potassium, and PGMs using a zero-waste approach.

Residual oil containing platinum group metals (PGMs), which is under-researched, can easily pose resource waste and environmental risks. PGMs feature as scarce strategic metals, and inorganic acids and potassium salts are also considered valuable. An integrated process for the harmless treatment and recovery of useful resources from residual oil is proposed herein. This work developed a zero-waste process based on the study of the main components and characteristics of the PGM-containing residual oil. The process consists of three modules: pre-treatment for phase separation, liquid-phase resource utilisation, and solid-phase resource utilisation. Separating the residual oil into liquid and solid phases allows for the maximum recovery of valuable components. However, concerns about the accurate determination of valued components emerged. Findings revealed that Fe and Ni are highly susceptible to spectral interference in the PGMs test when using the inductively coupled plasma method. After studying 26 PGM emission lines, Ir 212.681 nm, Pd 342.124 nm, Pt 299.797 nm, and Rh 343.489 nm were reliably identified. Finally, formic acid (81.5 g/t), acetic acid (117.2 kg/t), propionic acid (291.9 kg/t), butyric acid (3.6 kg/t), potassium salt (553.3 kg/t), Ir (27.8 g/t), Pd (10960.0 g/t), Pt (193.1 g/t), and Rh (109.8 g/t) were successfully obtained from the PGM-containing residual oil. This study provides a helpful reference for the determination of PGM concentrations and high-value utilisation of PGM-containing residual oil.

EGR1 induces EMT in pancreatic cancer via a P300/SNAI2 pathway.

BACKGROUND: The prognosis of pancreatic cancer patients remains relatively poor. Although some patients would receive surgical resection, distant metastasis frequently occurs within one year. Epithelial-mesenchymal transition (EMT), as a pathological mechanism in cancer progression, contributed to the local and distant metastasis of pancreatic cancer. METHODS: Tissue microarray analysis and immunohistochemistry assays were used to compare the expression of EGR1 in pancreatic cancer and normal pancreatic tissues. Transwell chambers were used to evaluated the migration and invasion ability of cancer cells. Immunofluorescence was utilized to assess the expression of E-cadherin. ChIP-qPCR assay was applied to verify the combination of EGR1 and SNAI2 promoter sequences. Dual-luciferase reporter assay was used to detect the gene promoter activation. Co-IP assay was conducted to verify the interaction of EGR1 and p300/CBP. RESULTS: EGR1 was highly expressed in pancreatic cancer rather than normal pancreatic tissues and correlated with poor prognosis and cancer metastasis. EGR1 was proved to enhance the migration and invasion ability of pancreatic cells. Besides, EGR1 was positively correlated with EMT process in pancreatic cancer, via a SNAI2-dependent pathway. P300/CBP was found to play an auxiliary role in the transcriptional activation of the SNAI2 gene by EGR1. Finally, in vivo experiments also proved that EGR1 promoted liver metastasis of pancreatic cancer. CONCLUSION: Our findings implied the EMT-promoting effect of EGR1 in pancreatic cancer and revealed the intrinsic mechanism. Blocking the expression of EGR1 may be a new anticancer strategy for pancreatic cancer.

STOML2 restricts mitophagy and increases chemosensitivity in pancreatic cancer through stabilizing PARL-induced PINK1 degradation.

Pancreatic cancer remains one of the most lethal diseases with a relatively low 5-year survival rate, and gemcitabine-based chemoresistance occurs constantly. Mitochondria, as the power factory in cancer cells, are involved in the process of chemoresistance. The dynamic balance of mitochondria is under the control of mitophagy. Stomatin-like protein 2 (STOML2) is located in the mitochondrial inner membrane and is highly expressed in cancer cells. In this study, using a tissue microarray (TMA), we found that high STOML2 expression was correlated with higher survival of patients with pancreatic cancer. Meanwhile, the proliferation and chemoresistance of pancreatic cancer cells could be retarded by STOML2. In addition, we found that STOML2 was positively related to mitochondrial mass and negatively related to mitophagy in pancreatic cancer cells. STOML2 stabilized PARL and further prevented gemcitabine-induced PINK1-dependent mitophagy. We also generated subcutaneous xenografts to verify the enhancement of gemcitabine therapy induced by STOML2. These findings suggested that STOML2 regulated the mitophagy process through the PARL/PINK1 pathway, thereby reducing the chemoresistance of pancreatic cancer. STOML2-overexpression targeted therapy might be helpful for gemcitabine sensitization in the future.