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Cedirogant is an inverse agonist of retinoic acid-related orphan receptor gamma thymus (RORγt) developed for the treatment of moderate to severe chronic plaque psoriasis. Here, we report the results from two phase I studies in which the pharmacokinetics (PK), safety, and efficacy of cedirogant in healthy participants and patients with moderate to severe chronic plaque psoriasis were evaluated. The studies consisted of single (20-750 mg) and multiple (75-375 mg once-daily [q.d.]) ascending dose designs, with effect of food and itraconazole on cedirogant exposure also evaluated. Safety and PK were evaluated for both healthy participants and psoriasis patients, and efficacy was assessed in psoriasis patients. Following single and multiple doses, cedirogant mean terminal half-life ranged from 16 to 28 h and median time to reach maximum plasma concentration ranged from 2 to 5 h across both populations. Cedirogant plasma exposures were dose-proportional after single doses and less than dose-proportional from 75 to 375 mg q.d. doses. Steady-state concentrations were achieved within 12 days. Accumulation ratios ranged from approximately 1.2 to 1.8 across tested doses. Food had minimal effect and itraconazole had limited impact on cedirogant exposure. No discontinuations or serious adverse events due to cedirogant were recorded. Psoriasis Area and Severity Index (PASI) and Self-Assessment of Psoriasis Symptoms (SAPS) assessments demonstrated numerical improvement with treatment of cedirogant 375 mg q.d. compared with placebo. The PK, safety, and efficacy profiles of cedirogant supported advancing it to phase II clinical trial in psoriasis patients.

Electron spin resonance spectroscopy(ESR) was used to investigate the effects of hydrogen ion concentration and hydroxide concentration in perchloric acid system and sodium hydroxide system on the state and behavior of free radicals generated by hydrazine bond breaking catalyzed by catalysts. The difference of free radicals generated by Pt/SiO2 catalyzed hydrazine decomposition in acid-base system was determined. The results show that in the alkaline system, with the increase of hydroxide concentration, the N-H bond breaking rate increases significantly, and the hydrolysis reaction is the main decomposition reaction. In acidic systems, with the increase of hydrogen ion concentration in the pH range from 6.9 to 1.1, the N-N bond breaking rate increases rapidly and is much higher than the N-H bond breaking rate. In the range of pH

Hypothyroidism has been suggested to play a role in tumor progression. However, the causal association between hypothyroidism and lung cancer remains unknow. To elucidate the potential association between hypothyroidism and lung cancer risk, we employ a Mendelian randomization (MR) approach. MR was performed to analyze pooled data from the International Lung Cancer Consortium (11,348 cases and 15,861 controls; European ancestry) to determine the causal relationship between hypothyroidism and lung cancer. We used 36, 83, and 14 single nucleotide polymorphisms as instrumental variables for hypothyroidism/myxoedema, hypothyroidism, and exercise, respectively. We further investigated the mechanisms involved in transcriptome analysis using data from The Cancer Genome Atlas and Genotype-Tissue Expression database. We conducted an initial validation of intermediary factor using a two-step MR analysis. Genetically predicted hypothyroidism was significantly related to the risk of overall lung cancer, specifically the risk of lung squamous cell cancer (LSCC) but not with the risk of lung adenocarcinoma (LUAD) as assessed using the inverse-variance weighted (IVM) method. A similar causal association was found between hypothyroidism/myxoedema and the risk of lung cancer, LSCC, and LUAD. Transcriptome analysis showed that genes associated with hypothyroidism, lung cancer, and LSCC were enriched in the PI3K/Akt signaling pathway and oxidative stress response. However, genes related to hypothyroidism and LUAD did not exhibit enrichment in these pathways. Hypothyroidism was significantly associated with strenuous sports or other exercises. Moreover, genetically predicted exercise was significantly related to the risk of overall lung cancer, and LSCC, but not LUAD. We detected no horizontal pleiotropy using the MR-PRESSO and MR Egger regression intercept. Hypothyroidism was causally associated with a lower risk of lung cancer, and these effects might be mediated by the oxidative stress response and the PI3K/Akt signaling pathway. Therefore, our study suggests that the potential factors and viable etiologies of hypothyroidism that contributed to lung cancer risk deserve further investigation.

Abstract Background This study aimed to identify the key genes involved in the development of multiple primary lung cancers. Methods Differential expression analysis was performed, followed by comparing the infiltration levels of 22 immune cell types between multiple and single primary lung adenocarcinomas. Marker genes for epithelial cells with different proportions between the two types of lung adenocarcinomas were identified. The common genes between the marker genes and differentially expressed genes were identified. Finally, the effects of the key genes were tested on the in vitro proliferation, migration and morphology. Results: The infiltration levels of helper follicular T cells, resting NK cells, activated NK cells, M2 macrophages and resting mast cells were higher in the patients with multiple than in those with single primary lung adenocarcinomas. A total of 1553 differentially expressed genes and 4414 marker genes of epithelial cells were identified. Logistic regression analysis was performed on the 164 resulting genes. The macrophage migration inhibitory factor expression was positively associated with the occurrence of multiple primary lung adenocarcinomas. Moreover, its signalling pathway was the key pathway among the epithelial cells and multiple and single primary lung adenocarcinoma cells, and it was upregulated in lung adenocarcinoma cells. It also increased the expression of lung cancer markers, including NES and CA125, induced morphological changes in alveolar epithelial type II cells, and promoted their proliferation, migration and invasion. Conclusions Multiple and single primary lung adenocarcinomas have different tumour immune microenvironments, and migration inhibitory factor may be a key factor in the occurrence of multiple primary lung adenocarcinomas.

H2C2O4 is widely used in spent fuel reprocessing. For example, in order to recovery plutonium oxalate precipitated mother liquor before returning, it is necessary to reduce the H2C2O4 concentration from 0.1 mol/L to about 10-4 mol/L. Among the methods of H2C2O4 destroyed in waste liquid, the process of H2C2O4 oxidized in nitric acid solution with Mn2+ as a catalyst is the most mature and suitable for industrialization, and its research is very rich. Nitrite plays an important role in destroying oxalic process in the process of H2C2O4 destroyed with Mn2+ as a catalyst in nitric acid solution was mentioned in many past studies. However, the specific reaction chain is still ambiguous and controversial on nitrite oxidation of H2C2O4 with Mn2+ as a catalyst, and the catalytic reaction mechanism is not clear. To solve these issues in the area of post-processing, the optimization of the treatment of the mother liquor of plutonium oxalate precipitation in the Purex process and the acquisition of H2C2O4 deep destruction technology in spent fuel reprocessing are to be benefited. Firstly, sodium nitrite solutions were continuously added into reaction solutions, at the same time the concentration of H2C2O4 in solutions was determined. H2C2O4 is obviously oxidized in the presence of nitrite and Mn2+ in sulfuric acid solutions. Secondly, Mn(Ⅱ) complexed oxalate oxidized to Mn(Ⅲ) with nitrous acid as a oxidant was studied. The results demonstrate that the complexation of Mn2+ with H2C2O4 reduces the reaction activation energy of Mn(Ⅱ) oxidized to Mn(Ⅲ), and MnC2O4 can be oxidized to ［Mn(C2O4)3］3- by nitrous acid. Finally, free radicals and substates in reaction process were detected by EPR’s spin capture technique. H2C2O4 is oxidized to ·OOC—COOH with the Mn(Ⅲ) complexed with itself, and Mn(Ⅲ) is reduced to Mn(Ⅱ). The ·OOC—COOH radicals with poor stability rapidly decompose and release reducing substances in acidic solution, and decomposition of H2C2O4 is completed. With the increase of acidity of nitrous acid, the concentration of HNO3 molecule increases. Thus, the concentration of HNO3 molecule in the solution can no longer be neglected compared with the concentration of nitrous acid. Therefore, when the concentration of nitric acid is more than 6 mol/L, the decomposition rate of H2C2O4 in the nitric acid solution with Mn2+ as a catalyst may be controlled by various reactions, which needs to be further studied.

In order to overcome the problem of multiple solutions and uncertainties in the identification of collapsed columns with a single seismic attribute and the problem of identification accuracy shift caused by unbalanced sample data, a binary classification collapsed column based on K-means SMOTE and random forest was constructed. The model can identify collapse columns by joint analysis of multiple seismic attributes. Taking the southern mining area of the east wing of the first mining area of Shanxi Xinyuan Coal Company as the research area, 12 seismic attributes extracted by the front interpreters through 3D seismic exploration technology are used as sample features, and the actually revealed collapse column information is used as sample labels to build a seismic multi-attribute attribute dataset; seismic attribute selection is carried out through correlation analysis, cluster analysis evaluation and random forest importance analysis, and 6 relatively independent seismic attributes are finally selected as sample features; the K-means SMOTE algorithm is used to balance the data set, and 8 992 data are obtained, of which 6 294 data are selected as the training set and 2 698 data are used as the test set; the random forest binary classification model is built based on the python language platform, and the final accuracy of predicting the collapsed column can reach 87%. By comparing three common machine learning classification algorithms, the model identified collapsed columns with higher accuracy.

The improvement of treatment for patients with ‘driver‐gene‐negative’ lung adenocarcinoma (LUAD) remains a critical problem to be solved. We aimed to explore the role of methylation of N6 adenosine (m6A)‐related long noncoding RNA (lncRNA) in stratifying ‘driver‐gene‐negative’ LUAD risk. Patients negative for mutations in EGFR, KRAS, BRAF, HER2, MET, ALK, RET, and ROS1 were identified as ‘driver‐gene‐negative’ cases. RNA sequencing was performed in 46 paired tumors and adjacent normal tissues from patients with ‘driver‐gene‐negative’ LUAD. Twenty‐three m6A regulators and relevant lncRNAs were identified using Pearson's correlation analysis. K‐means cluster analysis was used to stratify patients, and a prognostic nomogram was developed. The CIBERSORT and pRRophetic algorithms were employed to quantify the immune microenvironment and chemosensitivity. We identified two clusters highly consistent with the prognosis based on their unique expression profiles for 46 m6AlncRNAs. A risk model constructed from nine m6A lncRNAs could stratify patients into high‐ and low‐risk groups with promising predictive power (C‐index = 0.824), and the risk score was an independent prognostic factor. The clusters and risk models were closely related to immune characteristics and chemosensitivity. Additional pan‐cancer analysis using the nine m6AlncRNAs showed that the expression of DIO3 opposite strand upstream RNA (DIO3OS) is closely related to the immune/stromal score and tumor stemness in a variety of cancers. Our results show that m6AlncRNAs are a reliable prognostic tool and can aid treatment decision‐making in ‘driver‐gene‐negative’ LUAD. DIO3OS is associated with the development of various cancers and has potential clinical applications.