Identification and validation of a novel robust glioblastoma prognosis model based on bioinformatics.

Background: Glioblastoma (GBM) is a very common primary malignant tumor of the central nervous system (CNS). Aging, macrophage, autophagy, and methylation related genes are hypothesized to be crucial to its pathogenesis. In this study, we aimed to explore the role of these genes in the prognosis of GBM. Methods: The RNA sequence (RNA-seq) and clinical information were downloaded from The Cancer Genome Atlas database (TCGA) and the Chinese Glioma Genome Atlas database (CGGA). We performed univariate and least absolute shrinkage and selection operator (LASSO) multivariate Cox regression analysis to identify risk signatures related to overall survival (OS). We further developed a nomogram to predict individual outcomes. In addition, the immune microenvironment was analyzed by CIBERSORT. Results: 256 differentially expressed genes (DEGs) were obtained based on aging, macrophage, autophagy, and methylation related genes between GBM samples and normal tissues in TCGA-GBM cohort. We identified five optimal risk signatures with prognostic values in TCGA-GBM cohort and established a prognostic risk score model. The validity of the model was verified in the CGGA cohort and Huanhu cohort. Finally, we constructed a nomogram for clinical application by combining age, O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, and risk score. Activated NK cells and resting mast cells were highly expressed and memory B cells, plasma cells, resting NK cells, M1 macrophages, and neutrophils exhibited low expression in the high-risk score group. GBM patients with a low-risk score had a higher Tumor Immune Dysfunction and Exclusion (TIDE) score. The risk score of hot tumors was higher than that of the cold tumors. Additionally, 29 genes involved in glucose and lipid metabolism were highly expressed with a high-risk score. 31 metabolism-related pathways were significantly different between high-risk and low-risk groups. Conclusions: We constructed and validated a novel prognostic model for GBM. Aging, macrophage, autophagy, and methylation related genes may serve as prognostic and therapeutic biomarkers. The model developed may assist in guiding treatment for GBM patients. Our research had great significance in accurately predicting the prognosis of GBM and may offer reference for immunotherapy decision for GBM patients.

Imaging findings of Budd-Chiari syndrome caused by intravenous leiomyomatosis: a case report.

Intravenous leiomyomatosis (IVL) is a rare gynecological-related tumor. It can invade and extend in the blood vessel and eventually involve the cardiac cavity or even the pulmonary artery. IVL generally does not adhere to the vein wall and infrequently leads to the manifestation of Budd-Chiari syndrome (BCS). In this case report, the presence of a sizable tumor obstructed the second hepatic portal, impeding the return flow of the hepatic veins, thereby precipitating the development of BCS. The presence of collateral veins and dilation of the accessory hepatic vein were identified through computed tomography venography and ultrasonography, thus supporting the diagnosis of BCS. The patient underwent a comprehensive surgical resection and was found to have a favorable prognosis.

Role of 8-hydroxyguanine DNA glycosidase 1 deficiency in exacerbating diabetic cardiomyopathy through the regulation of insulin resistance.

Diabetic cardiomyopathy (DCM) is a heart failure syndrome, and is one of the major causes of morbidity and mortality in diabetes. DCM is mainly characterized by ventricular dilation, myocardial hypertrophy, myocardial fibrosis and cardiac dysfunction. Clinical studies have found that insulin resistance is an independent risk factor for DCM. However, its specific mechanism of DCM remains unclear. 8-hydroxyguanine DNA glycosylase 1(OGG1)is involved in DNA base repair and the regulation of inflammatory genes. In this study, we show that OGG1 was associated with the occurrence of DCM. for the first time. The expression of OGG1 was increased in the heart tissue of DCM mice, and OGG1 deficiency aggravated the cardiac dysfunction of DCM mice. Metabolomics show that OGG1 deficiency resulted in obstruction of glycolytic pathway. At the molecular level, OGG1 regulated glucose uptake and insulin resistance by interacting with PPAR-γ in vitro. In order to explore the protective effect of exogenous OGG1 on DCM, OGG1 adeno-associated virus was injected into DCM mice through tail vein in the middle stage of the disease. We found that the overexpression of OGG1 could improve cardiac dysfunction of DCM mice, indicating that OGG1 had a certain therapeutic effect on DCM. These results demonstrate that OGG1 is a new molecular target for the treatment of DCM and has certain clinical significance.

Pitfalls of ultrasound for deep vein thrombosis of the lower extremities.

Venous ultrasound is the primary, widely accepted diagnostic tool to assess deep vein thrombosis (DVT) in the lower extremities. However, other focal lesions in the lower extremities can be identified on ultrasound. The sonographic appearance of these abnormalities may overlap the thrombosis, which included vascular tumors, Baker's cyst, hematoma, cancer thrombosis, and peripheral nerve tumors. This essay derives from cases diagnosed in our centers and published literature, with images available for illustrations, which may help to improve the clinical management of these findings.

Nanoparticle-Based Immunotherapy for Reversing T-Cell Exhaustion.

T-cell exhaustion refers to a state of T-cell dysfunction commonly observed in chronic infections and cancer. Immune checkpoint molecules blockading using PD-1 and TIM-3 antibodies have shown promising results in reversing exhaustion, but this approach has several limitations. The treatment of T-cell exhaustion is still facing great challenges, making it imperative to explore new therapeutic strategies. With the development of nanotechnology, nanoparticles have successfully been applied as drug carriers and delivery systems in the treatment of cancer and infectious diseases. Furthermore, nanoparticle-based immunotherapy has emerged as a crucial approach to reverse exhaustion. Here, we have compiled the latest advances in T-cell exhaustion, with a particular focus on the characteristics of exhaustion that can be targeted. Additionally, the emerging nanoparticle-based delivery systems were also reviewed. Moreover, we have discussed, in detail, nanoparticle-based immunotherapies that aim to reverse exhaustion, including targeting immune checkpoint blockades, remodeling the tumor microenvironment, and targeting the metabolism of exhausted T cells, etc. These data could aid in comprehending the immunopathogenesis of exhaustion and accomplishing the objective of preventing and treating chronic diseases or cancer.

8-Oxoguanine DNA glycosylase protects cells from senescence via the p53-p21 pathway.

Cellular senescence is an important factor leading to pulmonary fibrosis. Deficiency of 8-oxoguanine DNA glycosylase (OGG1) in mice leads to alleviation of bleomycin (BLM)-induced mouse pulmonary fibrosis, and inhibition of the OGG1 enzyme reduces the epithelial mesenchymal transition (EMT) in lung cells. In the present study, we find decreased expression of OGG1 in aged mice and BLM-induced cell senescence. In addition, a decrease in OGG1 expression results in cell senescence, such as increases in the percentage of SA-ß-gal-positive cells, and in the p21 and p-H2AX protein levels in response to BLM in lung cells. Furthermore, OGG1 promotes cell transformation in A549 cells in the presence of BLM. We also find that OGG1 siRNA impedes cell cycle progression and inhibits the levels of telomerase reverse transcriptase (TERT) and LaminB1 in BLM-treated lung cells. The increase in OGG1 expression results in the opposite phenomenon. The mRNA levels of senescence-associated secretory phenotype (SASP) components, including IL-1α, IL-1ß, IL-6, IL-8, CXCL1/CXCL2, and MMP-3, in the absence of OGG1 are obviously increased in A549 cells treated with BLM. Interestingly, we demonstrate that OGG1 binds to p53 to inhibit the activation of p53 and that silencing of p53 reverses the inhibition of OGG1 on senescence in lung cells. Additionally, the augmented cell senescence is shown in vivo in OGG1-deficient mice. Overall, we provide direct evidence in vivo and in vitro that OGG1 plays an important role in protecting tissue cells against aging associated with the p53 pathway.

Diagnostic experience of intravenous leiomyomatosis with emphasis on conventional ultrasonography imaging: a single-center study.

Objective: Intravenous leiomyomatosis (IVL) is a rare and aggressive tumor type that has the potential to extend into the inferior vena cava (IVC) and is susceptible to be misdiagnosed and neglected. Despite its clinical significance, there is a paucity of research that has focused on the specific manifestations of IVL on ultrasonography. Therefore, this study aims to systematically analyze the specific ultrasound features of IVL and augment its diagnostic accuracy. Materials and method: Prospective inclusion was granted to patients admitted to our hospital between December 2016 and March 2021 for an IVC-occupying lesion. Multi-modal ultrasonography, encompassing gray-scale and color Doppler, was conducted. Lesions were categorized as IVL or non-IVL based on pathological or follow-up data. Two ultrasound sonographers with over 5 years of experience read and recorded ultrasound data for all lesions, which were subsequently comparatively analyzed to identify specific signs of IVL. Results: A total of 284 patients diagnosed with IVC-occupying lesions were included in the study. The lesion types comprised of IVL (n=67, 23.6%), IVC thrombus (n=135, 47.5%), tumor thrombus of renal carcinoma involving the IVC (n=35, 12.4%), tumor thrombus of liver carcinoma involving the IVC (n=24, 8.5%), leiomyosarcoma of the IVC (n=14, 4.9%), and tumor thrombus of adrenocortical adenocarcinoma (n=9, 4.1%). The presence of "sieve hole" and "multi-track" signs was observed in 20 IVL lesions under the grey-scale modality, while both signs were absent in the non-IVL group (P<0.01). The study found no statistically significant differences in the presentation of "sieve hole" and "multi-track" signs under the grey-scale and color Doppler modalities in cases of intravascular lithotripsy (IVL) (P>0.05). Using these two signs as diagnostic criteria for IVL, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), miss rate, misdiagnosis rate, and accuracy were determined to be 29.9%, 100%, 100%, 82.2%, 70.1%, 0, and 83.5%, respectively (AUC ROC=0.649; 95%CI: 0.537-0.761). Conclusion: IVL exhibits distinct ultrasound presentations, including "sieve hole" and "multi-track" signs, which demonstrate high specificity and accuracy as diagnostic indicators. Furthermore, these signs are corroborated by pathological evidence and effectively distinguish IVL from other lesions occupying the IVC.

Rationality of FIGO 2018 IIIC restaging of cervical cancer according to local tumor size: A cohort study.

INTRODUCTION: FIGO 2018 IIIC remains controversial for the heterogeneity of its prognoses. To ensure a better management of cervical cancer patients in Stage IIIC, a revision of the FIGO IIIC version classification is required according to local tumor size. MATERIAL AND METHODS: We retrospectively enrolled cervical cancer patients of FIGO 2018 Stages I-IIIC who had undergone radical surgery or chemoradiotherapy. Based on the tumor factors from the Tumor Node Metastasis staging system, IIIC cases were divided into IIIC-T1, IIIC-T2a, IIIC-T2b, and IIIC-(T3a+T3b). Oncologcial outcomes of all stages were compared. RESULTS: A total of 63 926 cervical cancer cases were identified, among which 9452 fulfilled the inclusion criteria and were included in this study. Kaplan-Meier pairwise analysis showed that: the oncology outcomes of I and IIA were significantly better than of IIB, IIIA+IIIB, and IIIC; the oncology outcome of IIIC-(T1-T2b) was significantly better than of IIIA+IIIB and IIIC-(T3a+T3b); no significant difference was noted between IIB and IIIC-(T1-T2b), or IIIC-(T3a+T3b) and IIIA+IIIB. Multivariate analysis indicated that, compared with IIIC-T1, Stages T2a, T2b, IIIA+IIIB and IIIC-(T3a+T3b) were associated with a higher risk of death and recurrence/death. There was no significant difference in the risk of death or recurrence/death between patients with IIIC-(T1-T2b) and IIB. Also, compared with IIB, IIIC-(T3a+T3b) was associated with a higher risk of death and recurrence/death. No significant differences in the risk of death and recurrence/death were noted between IIIC-(T3a+T3b) and IIIA+IIIB. CONCLUSIONS: In terms of oncology outcomes of the study, FIGO 2018 Stage IIIC of cervical cancer is unreasonable. Stages IIIC-T1, T2a, and T2b may be integrated as IIC, and it might be unnecessary for T3a/T3b cases to be subdivided by lymph node status.

Basic characterization, antioxidant and immunomodulatory activities of polysaccharides from sea buckthorn leaves.

The polysaccharides from Sea buckthorn leaves (SBLPs) were extracted by hot water and purified by DEAE cellulose, then separated into six polysaccharides (SBLP-S) by DEAE-52 column. Six separated polysaccharides were characterized by Ultraviolet Spectroscopy, Infrared Spectrum, High Performance Liquid Chromatographic and Congo red analysis. The antioxidant activity and immunological activity were investigated in vitro. The results revealed that the monosaccharide composition of SBLP-S-1, SBLP-S-2, SBLP-S-3, SBLP-S-5 and SBLP-S-6 contained Man, GlcN, Rib, Rha, GluA, GalA, Glu, Gal, Xyl, Ara and Fuc, among them, rare glucosamine was found. And SBLP-S-4 contained all above components except GlcN and GluA. FT-IR showed that SBLP-S were sulfated polysaccharide containing uronic acid. Molecular weights of SBLP-S were 338.659, 401.305, 599.849, 393.904, 626.895 and 176.862 kDa. The Congo-red test indicated that SBLP-S-2, SBLP-S-4, SBLP-S-5, and SBLP-S-6 had triple helix conformation. Crude polysaccharides had the strong scavenging activities on DPPH radicals, ABTS radicals and hydroxyl radicals. The six polysaccharides had the activity of immune stimulation on RAW264.7 cell. SBLP-S-2 promoted the phagocytosis best and SBLP-S-6 promoted the NO production best. The results suggested that SBLPs could be used as potential antioxidants and immunomodulatory agents in pharmaceutical and functional food fields.

Comparative Efficacy of Secukinumab Versus Tumor Necrosis Factor Inhibitors for the Treatment of Takayasu Arteritis.

OBJECTIVE: Tumor necrosis factor (TNF) alpha and interleukin-17 (IL-17) are thought to be involved in the pathogenesis of Takayasu arteritis (TAK), and TNF inhibitors (TNFi) are recommended for the treatment of TAK. The present study was undertaken to investigate the efficacy of secukinumab, an IL-17A monoclonal antibody, compared to treatment with TNFi. METHODS: This was a prospective, single-center, open-label cohort study. Patients with active TAK who did not respond to treatment with glucocorticoids combined with 2 immunosuppressive agents were treated with either secukinumab or TNFi as an add-on therapy without an increased dosage of glucocorticoids. A complete response was defined as complete resolution of signs and symptoms of active disease, normal values of inflammatory markers, no progression on imaging of involved arteries, and dose of glucocorticoid <15 mg/day. A partial response was similarly defined as a complete response except with an erythrocyte sedimentation rate <40 mm/hour and C-reactive protein level of <20 mg/liter. RESULTS: Nineteen patients in the secukinumab group and 34 patients in the TNFi group were enrolled. The demographic data and inflammatory markers of the 2 groups were comparable at baseline. Complete response and partial response for patients treated with secukinumab and TNFi were 31.6% and 58.8% (P = 0.057), respectively, at 3 months and 52.6% and 64.7%, respectively, at 6 months (P = 0.389). CONCLUSION: Our findings suggest that secukinumab and TNFi are effective for patients with TAK who do not respond to oral glucocorticoids and conventional immunosuppressive agents, with similar response rates at 3 and 6 months.

The correlation between the costs and clinical benefits of PD-1/PD-L1 inhibitors in malignant tumors: An evaluation based on ASCO and ESMO frameworks.

Background: Life expectancy for patients with malignant tumors has been significantly improved since the presence of the programmed cell death protein-1/programmed cell death protein ligand-1 (PD-1/PD-L1) inhibitors in 2014, but they impose heavy financial burdens for patients, the healthcare system and the nations. The objective of this study was to determine the survival benefits, toxicities, and monetary of programmed cell death protein-1/programmed cell death protein ligand-1 inhibitors and quantify their values. Methods: Randomized controlled trials (RCTs) of PD-1/PD-L1 inhibitors for malignant tumors were identified and clinical benefits were quantified by American Society of Clinical Oncology Value Framework (ASCO-VF) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). The drug price in Micromedex REDBOOK was used to estimate monthly incremental drug costs (IDCs) and the correlation between clinical benefits and incremental drug costs of experimental and control groups in each randomized controlled trial, and the agreement between two frameworks were calculated. Results: Up to December 2022, 52 randomized controlled trials were included in the quantitative synthesis. All the randomized controlled trials were evaluated by American society of clinical oncology value framework, and 26 (50%) met the American society of clinical oncology value framework "clinical meaningful value." 49 of 52 randomized controlled trials were graded by European society for medical oncology magnitude of clinical benefit scale, and 30 (61.2%) randomized controlled trials achieved European Society for Medical Oncology criteria of meaningful value. p-values of Spearman correlation analyses between monthly incremental drug costs and American society of clinical oncology value framework/European society for medical oncology magnitude of clinical benefit scale scores were 0.9695 and 0.3013, respectively. In addition, agreement between two framework thresholds was fair (κ = 0.417, p = 0.00354). Conclusion: This study suggests that there might be no correlation between the cost and clinical benefit of programmed cell death protein-1/programmed cell death protein ligand-1 inhibitors in malignancy, and the same results were observed in subgroups stratified by drug or indication. The results should be a wake-up call for oncologists, pharmaceutical enterprises and policymakers, and meanwhile advocate the refining of American Society of Clinical Oncology and European Society for Medical Oncology frameworks.

Effect of recruitment manoeuvres under lung ultrasound-guidance and positive end-expiratory pressure on postoperative atelectasis and hypoxemia in major open upper abdominal surgery: A randomized controlled trial.

Background: Postoperative pulmonary complications (PPCs) especially atelectasis and hypoxemia are common during abdominal surgery. Studies on the effect of either recruitment manoeuvres (RMs) or positive end-expiratory pressure (PEEP) on PPCs are controversial. The objective of this study is to evaluate the effect of perioperative lung ultrasound (LUS)-guided RMs combined with PEEP on the reduction of postoperative atelectasis and hypoxemia in major open upper abdominal surgery. Methods: In this randomized controlled trial, 122 adult patients undergoing major open upper abdominal surgery were allocated into three groups: control (C) group (n = 42); PEEP (P) group (n = 40); RMs combined with PEEP (RP) group (n = 40). All patients were scheduled for general anaesthesia using the lung-protective ventilation (LPV) strategy. The levels of PEEP in the three groups were 0 cmH2O, 5 cmH2O and 5 cmH2O. LUS examination was carried out at 3 predetermined time points in each group: 5 min after intubation (T1), at the end of surgery (T2) and 15 min after extubation (T3). Patients with atelectasis on the sonogram in the RP group received LUS-guided RMs at point T2. LUS scores were used to estimate the severity of aeration loss. The P/F ratio (PaO2/FiO2) at 15min after extubation was used to assess the incidence of postoperative hypoxemia. Primary outcomes were the incidences of postoperative atelectasis and hypoxemia (PaO2/FiO2 < 300 mmHg). The secondary outcome was the distribution of LUS scores in each lung area. Results: From July 2021 to December 2021, 122 consecutive patients were enrolled. No typical atelectasis was observed 5 min after intubation. The incidence of atelectasis was 52.4%, 50.0% and 42.5% in the C group, P group and RP group at the end of surgery, respectively. The rate of atelectasis in the C group, P group and RP group (after RMs) was 52.4%, 50.0% and 17.5%, respectively, 15 min after extubation (P < 0.01). The frequency of postoperative hypoxemia was 27.5%, 15.0% and 5.0% in the C group, P group and RP group, respectively (P < 0.017). The increased LUS scores mainly occurred in the superoposterior and inferoposterior quadrants at the end of surgery. Only in the RP group demonstrated a decreased LUS score in the posteriorquadrants after extubation. Conclusions: In patients undergoing major open upper abdominal surgery, an intraoperative mechanical ventilation strategy without PEEP or with PEEP alone did not reduce PPCs. However, PEEP of 5 cmH2O combined with LUS-guided RMs proved feasible and beneficial to decrease the occurrence of postoperative atelectasis and hypoxemia in major open upper abdominal surgeries.

Diagnostic value of contrast-enhanced ultrasound in intravenous leiomyomatosis: a single-center experiences.

Objective: Intravenous leiomyomatosis (IVL) is a rare disease, and few studies have focused on the diagnostic value of contrast-enhanced ultrasound (CEUS) in this condition. This study aimed to investigate the diagnostic value of CEUS in IVL and summarize the specific CEUS characteristics of IVL. Materials and Method: From December 2016 to March 2021, 93 patients admitted to our hospital with inferior vena cava (IVC) occupying lesions were prospectively enrolled and underwent detailed ultrasound multi-modality examinations, including conventional and contrast-enhanced ultrasound scans. The diagnostic value of CEUS and conventional ultrasound (CU) in IVL was compared, and the specific IVL signs were summarized. Results: Among the 93 patients with inferior vena cava mass, 67 were IVL while 26 were non-IVL. The inter-observer agreement of the two senior doctors was good, with Kappa coefficient = 0.71 (95% CI: 0.572-0.885). The area under the ROC curve of CU for IVL diagnosis was 0.652 (95% CI: 0.528-0.776), and its sensitivity, specificity, accuracy, positive predictive value, negative predictive value, missed diagnosis rate, and misdiagnosis rate were 61.1%, 69.2%, 63.4%, 83.7%, 40.9%, 38.8%, and 30.8%, respectively. The area under curve (AUC) for IVL diagnosis by CEUS was 0.807 (95% CI: 0.701-0.911), and the sensitivity, specificity, accuracy, positive predictive value, negative predictive value, missed diagnosis rate, and misdiagnosis rate were 82.0%, 84.6%, 82.8%, 93.2%, 64.7%, 15.4%, and 17.9%, respectively. In CEUS mode, "sieve hole sign" and "multi-track sign" were detected in 57 lesions, and the detected rate was higher than that of CU (https://loop.frontiersin.org/people/1014187 < 0.01). Conclusion: CEUS can better show the fine blood flow inside the IVL, which is important for IVL differential diagnosis. Moreover, CEUS can obtain more information about IVL diagnosis than CU, compensating for the shortcomings of CU in detecting more blood flow within the lesion. Thus, this technique has great significance for IVL diagnosis.

Therapeutic Effects of Modified Si-Miao-Yong-An Decoction in the Treatment of Rat Myocardial Ischemia/Reperfusion Injury.

Objective: Modified Si-Miao-Yong-An decoction (MSMYA) was empirically originated from Si-Miao-Yong-An Decoction, which has been utilized for centuries to treat vasculopathy as well as heart diseases through clearing heat and detoxifying. This study aimed at confirming MSMYA's therapeutic effects for treating myocardial ischemia/reperfusion (I/R) injury and its underlying mechanisms. Methods: Rats were intragastrically administered with MSMYA for 4 weeks after ischemia/reperfusion (I/R) operation. Superoxide dismutase (SOD) and malondialdehyde (MDA) concentration were determined by calorimetry. Coagulation function was determined using an automated coagulation analyzer. Levels of cysteinyl aspartate specific proteinase (caspase)-1, interleukin (IL)-1ß, interleukin (IL)-18, and lactate dehydrogenase (LDH) were measured by an enzyme-linked immunosorbent assay (ELISA). Infarct size was determined by triphenyltetrazolium chloride (TTC) staining. Myocardial histopathological and ultrastructure changes were examined by H&E staining and electron microscopy, respectively. Relative mRNA expression of NLRP3, an apoptosis-associated speck-like proteins containing the caspase activation and recruitment domain (ASC), caspase-1, IL-1ß, and IL-18 were analyzed using quantitative real-time polymerase chain reaction (PCR). Meanwhile, their relative protein expressions were measured using western blotting. Results: The results showed MSMYA can inhibit oxidative stress by increasing SOD and reducing MDA, suppress inflammatory reaction by decreasing NLRP3 inflammasome-related cytokines' level, improve coagulation function by increasing prothrombin time (PT) and activating partial thromboplastin time (APTT), and ameliorate myocardial histopathological and ultrastructural changes. In addition, MSMYA's cardioprotective effects probably related to suppressing NLRP3 inflammasome pathway activation by reducing NLRP3 inflammasome molecular mRNA and protein relative expression. Conclusion: The results indicated that MSMYA played an important role in protecting the myocardium from I/R injury. The likely mechanism is the inhibition of oxidative stress, improvement of cardiac injury, and the reduction of NLRP3-related inflammatory cytokines release. This provides a basis for further research on the mechanism and clinical application of MSMYA to improve myocardial I/R injury.

TH5487, a small molecule inhibitor of OGG1, attenuates pulmonary fibrosis by NEDD4L-mediated OGG1 degradation.

Pulmonary fibrosis is a highly aggressive and lethal disease that currently lacks effective targeting therapies. Herein, we established a mouse model of pulmonary fibrosis induced by intratracheal instillation of bleomycin (BLM) in wild-type (WT) and 8-oxoguanine DNA glycosylase-1 (OGG1) knockout (Ogg1-/-) mice. TH5487, a specific small-molecule inhibitor of OGG1, was found to ameliorate BLM-induced pulmonary fibrosis in WT mice. Concomitantly, TH5487 treatment markedly suppressed the BLM-mediated alveolar epithelial-mesenchymal transition (EMT) and increase in OGG1 protein level in the lungs of WT mice. However, administration of TH5487 did not further improve this fibrotic transformation in Ogg1-/- mice. More importantly, adeno-associated virus-mediated lung-specific OGG1 overexpression accelerated alveolar EMT and the resultant fibrosis progression antagonized by TH5487 in the fibrotic lungs of WT mice, suggesting that the down-regulation of OGG1 protein level could be essential for TH5487 to exert its anti-fibrogenic function. Mechanism study in alveolar epithelial cells demonstrated that TH5487 treatment canceled TGF-ß1-mediated suppression of NEDD4-like E3 ubiquitin ligase (NEDD4L), which ubiquitinated OGG1 and targeted it for proteasomal degradation. Furthermore, TH5487-mediated suppression of alveolar EMT and the fibrotic processes was counteracted by silencing NEDD4L in TGF-ß1-induced alveolar epithelial cells. Collectively, these data underline the potential of TH5487 as an effective anti-fibrotic agent for pulmonary fibrosis.

Propofol and Sevoflurane Alleviate Malignant Biological Behavior and Cisplatin Resistance of Xuanwei Lung Adenocarcinoma by Modulating the Wnt/ß-catenin Pathway and PI3K/AKT Pathway.

BACKGROUND: Recent studies have shown that propofol and sevoflurane, two common anesthetics, can prevent tumor development. The prevalence of lung adenocarcinoma in China is highest in Yunnan Xuanwei, and many patients with lung cancer in this area are often resistant to platinum-based treatments. OBJECTIVE: The objective of the study was to investigate the effects of propofol and sevoflurane on malignant biological behavior and cisplatin resistance of Xuanwei lung adenocarcinoma. METHODS: Herein, XWLC-05/R, a cisplatin-resistant cell line of XWLC-05 cells from Xuanwei lung adenocarcinoma, was constructed. The XWLC-05 cells and XWLC-05/R cells were treated with propofol and sevoflurane singly or as a combination and subjected to CCK-8 assay, clone formation tests, and flow cytometry analysis to assess the proliferation level of cells. The morphology and number of apoptotic bodies in XWLC-05 cells and XWLC-05/R were examined with a transmission electron microscope. The ANNEXIN V-FITC/PI and transwell assays were performed to evaluate apoptosis, invasion, and migration of the cells. Subsequently, we constructed a Xuanwei lung adenocarcinoma xenograft model to investigate the effects of propofol and sevoflurane on the tumorigenicity of XWLC-05 cells in vivo. RESULTS: Treatment with propofol and sevoflurane significantly inhibited proliferation, invasion, migration, and induced apoptosis of XWLC-05 and XWLC-05/R cells. These effects were more pronounced when propofol and sevoflurane were co-incubated with the cells. Moreover, both propofol and sevoflurane significantly inhibited Wnt/ß- catenin and PI3K/AKT pathways. Moreover, the two drugs effects suppressed the malignant biological behavior of XWLC-05 cells and XWLC-05/R cells, and this effect was counteracted by 740Y-P (PI3K/AKT pathway activator) and Wnt pathway activator 1 (Wnt/ß-catenin pathway activator). In vivo experiments confirmed that propofol and sevoflurane alleviated the tumorigenicity of XWLC-05 cells. CONCLUSIONS: In summary, this study shows, for the first time, that propofol and sevoflurane decrease the proliferation, invasion, migration and induce apoptosis of XWLC-05 cells and XWLC-05/R cells by impeding the Wnt/ß-catenin and PI3K/AKT signaling pathways, thereby alleviating the development of Xuanwei lung adenocarcinoma in vivo. Moreover, these effects are more pronounced when the two drugs are combined.

3.5-GHz radiofrequency electromagnetic radiation promotes the development of Drosophila melanogaster.

With the rapidly increasing popularity of 5G mobile technology, the effect of radiofrequency radiation on human health has caused public concern. This study explores the effects of a simulated 3.5 GHz radiofrequency electromagnetic radiation (RF-EMF) environment on the development and microbiome of flies under intensities of 0.1 W/m2, 1 W/m2 and 10 W/m2. We found that the pupation percentages in the first 3 days and eclosion rate in the first 2 days were increased under exposure to RF-EMF, and the mean development time was shortened. In a study on third-instar larvae, the expression levels of the heat shock protein genes hsp22, hsp26 and hsp70 and humoral immune system genes AttC, TotC and TotA were all significantly increased. In the oxidative stress system, DuoX gene expression was decreased, sod2 and cat gene expression levels were increased, and SOD and CAT enzyme activity also showed a significant increase. According to the 16S rDNA results, the diversity and species abundance of the microbial community decreased significantly, and according to the functional prediction analysis, the genera Acetobacter and Lactobacillus were significantly increased. In conclusion, 3.5 GHz RF-EMF may enhance thermal stress, oxidative stress and humoral immunity, cause changes in the microbial community, and regulate the insulin/TOR and ecdysteroid signalling pathways to promote fly development.

Clinical and ultrasound characteristics of virilizing ovarian tumors in pre- and postmenopausal patients: a single tertiary center experience.

BACKGROUND: A virilizing ovarian tumor (VOT) is a rare cause of hyperandrogenism in pre- and postmenopausal women. Although transvaginal ultrasound is considered as the first-line imaging method for ovarian tumors, it is examiner-dependent. We aimed to summarize the clinical and ultrasound manifestations of VOTs to help establish the diagnosis with emphasis on those causing diagnostic difficulty. METHOD: We retrospectively identified 31 patients with VOTs who underwent surgery at Peking Union Medical College Hospital. RESULTS: Patients with VOTs were predominantly premenopausal. All patients showed androgenic manifestations with serum testosterone levels elevated to varying degrees. The tumor size of VOTs was significantly correlated with age (P < 0.001). The VOTs in the postmenopausal group were significantly smaller than those in the premenopausal group (median 1.8 cm [range, 1.3-4.8 cm] vs 4.5 cm [range, 0.7-11.9 cm]; P = 0.018). Twenty-seven out of 31 VOTs were successfully identified by ultrasound. On ultrasound, VOTs are mostly solid and hypoechoic masses with enhanced vascularity. Four VOTs (0.7-1.5 cm) were radiologically negative, and they were the smallest among all patients. CONCLUSION: Patients with VOTs showed androgenic manifestations with varying degrees of hyperandrogenemia. Older patients tend to have smaller VOTs. Ultrasound is an effective method for the detection of VOTs. Some VOTs can be very small and difficult to visualize radiologically, especially in postmenopausal patients. Examiners must remain vigilant about very small VOTs on the basis of endocrine symptoms.

Identification of a small molecule SR9009 that activates NRF2 to counteract cellular senescence.

The senescence-associated secretory phenotype (SASP) is a striking characteristic of senescence. Accumulation of SASP factors causes a pro-inflammatory response linked to chronic disease. Suppressing senescence and SASP represents a strategy to prevent or control senescence-associated diseases. Here, we identified a small molecule SR9009 as a potent SASP suppressor in therapy-induced senescence (TIS) and oncogene-induced senescence (OIS). The mechanism studies revealed that SR9009 inhibits the SASP and full DNA damage response (DDR) activation through the activation of the NRF2 pathway, thereby decreasing the ROS level by regulating the expression of antioxidant enzymes. We further identified that SR9009 effectively prevents cellular senescence and suppresses the SASP in the livers of both radiation-induced and oncogene-induced senescence mouse models, leading to alleviation of immune cell infiltration. Taken together, our findings suggested that SR9009 prevents cellular senescence via the NRF2 pathway in vitro and in vivo, and activation of NRF2 may be a novel therapeutic strategy for preventing cellular senescence.

Discovery of LYC-55716: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor-γ (RORγ) Agonist for Use in Treating Cancer.

Retinoic acid receptor-related orphan receptor γ (RORc, RORγ, or NR1F3) is the nuclear receptor master transcription factor that drives the function and development of IL-17-producing T helper cells (Th17), cytotoxic T cells (Tc17), and subsets of innate lymphoid cells. Activation of RORγ+ T cells in the tumor microenvironment is hypothesized to render immune infiltrates more effective at countering tumor growth. To test this hypothesis, a family of benzoxazines was optimized to provide LYC-55716 (37c), a potent, selective, and orally bioavailable small-molecule RORγ agonist. LYC-55716 decreases tumor growth and enhances survival in preclinical tumor models and was nominated as a clinical development candidate for evaluation in patients with solid tumors.