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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

A kind of nitrile rubber (NBR) with high bound acrylonitrile content was prepared by low-temperature emulsion-polymerization and the sequence structure of the polymer was characterized by proton nuclear magnetic resonance spectroscopy, and the effects of different coagulants on the coagulation behavior and physico-mechanical properties of the polymer were studied. The results showed that the BAA sequence structure appeared in NBR with high bound acrylonitrile content, and the content of BAA, BAB, and ABA sequence structures increased gradually and that of BBB and BBA sequence structures decreased gradually with the increase in bound acrylonitrile content; the coagulation efficiency of CaCl2 and Al2(SO4)3 was much higher than those of NaCl and H2SO4, and the coagulation efficiency of the first two both reached about 98%; Al2(SO4)3 could improve the hardness, tensile strength, modulus, and elongation at break of NBR, and the elongation at break of NBR prepared from Al2(SO4)3 was 566%.

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.

Abstract Background General transcription factor IIi (GTF2I) mutations are very common in thymic epithelial tumors (TETs) and are related to a more favorable prognosis in TET patients. However, limited research has been conducted on the role of GTF2I in the tumor immune microenvironment (TIME). Further, long non-coding RNAs (lncRNAs) have been associated with the survival of patients with TETs. Therefore, this study aimed to explore the relationship between GTF2I mutations and TIME and build a new potential signature for predicting tumor recurrence in the TETs. Research data was downloaded from The Cancer Genome Atlas database and the CIBERSORT algorithm was used to evaluate TIME differences between GTF2I mutant and wild-type TETs. Relevant differentially expressed lncRNAs based on differentially expressed immune-related genes were identified to establish lncRNA pairs. We constructed a signature using univariate and multivariate Cox regression analyses. Results GTF2I is the most commonly mutated gene in TETs, and is associated with an increased number of early-stage pathological types, as well as no history of myasthenia gravis or radiotherapy treatment. In the GTF2I wild-type group, immune score and immune cell infiltrations with M2 macrophages, activated mast cells, neutrophils, plasma, T helper follicular cells, and activated memory CD4 T cells were higher than the GTF2I mutant group. A risk model was built using five lncRNA pairs, and the 1-, 3-, and 5-year area under the curves were 0.782, 0.873, and 0.895, respectively. A higher risk score was related to more advanced histologic type. Conclusion We can define the GTF2I mutant-type TET as an immune stable type and the GTF2I wild-type as an immune stressed type. A signature based on lncRNA pairs was also constructed to effectively predict tumor recurrence.

Abstract Background Oxidative stress plays an important role in the progression of various types of tumors. However, its role in esophageal squamous cell carcinoma (ESCC) has seldom been explored. This study aimed to discover prognostic markers associated with oxidative stress in ESCC to improve the prediction of prognosis and help in the selection of effective immunotherapy for patients. Results A consensus cluster was constructed using 14 prognostic differentially expressed oxidative stress-related genes (DEOSGs) that were remarkably related to the prognosis of patients with ESCC. The infiltration levels of neutrophils, plasma cells, and activated mast cells, along with immune score, stromal score, and estimated score, were higher in cluster 1 than in cluster 2. A prognostic signature based on 10 prognostic DEOSGs was devised that could evaluate the prognosis of patients with ESCC. Calculated risk score proved to be an independent clinical prognostic factor in the training, testing, and entire sets. P53 signaling pathway was highly enriched in the high-risk group. The calculated risk score was positively related to the infiltration levels of resting mast cells, memory B cells, and activated natural killer (NK) cells and negatively associated with the infiltration levels of M1 and M2 macrophages. The relationship between clinical characteristics and risk score has not been certified. The half-maximal inhibitory concentration (IC50) values for sorafenib and gefitinib were lower for patients in the low-risk group. Conclusion Our prognostic signature based on 10 prognostic DEOSGs could predict the disease outcomes of patients with ESCC and had strong clinical value. Our study improves the understanding of oxidative stress in tumor immune microenvironment (TIME) and provides insights for developing improved and efficient immunotherapy strategies.

Abstract Objective Examining the role of immune‐related genes (IRGs) in “driver gene negative” lung adenocarcinoma (LUAD) may provide new ideas for the treatment and study for this LUAD subgroup. We aimed to find the hub immune‐related gene pairs can stratify the risk of “driver‐gene‐negative” LUAD. Materials and Methods IRGs were identified according to ImmPort database based on RNA sequencing results of tumors and normal tissues from 46 patients with “driver gene negative” LUAD at The First Affiliated Hospital of Sun Yat‐sen University and cyclically singly paired as immune‐related gene pairs (IRGPs). Multivariate Cox analysis was used to construct an immune risk model and a prognostic nomogram combining was also been developed. Immune microenvironment landscape described by CIBERSORT and drug sensitivity calculated by pRRophetic algorithm were used to explore possible treatment improvements. Results A novel immune risk model with 5‐IRGPs (CD1A|CXCL135, CD1A|S100A7L2, IFNA7|CMTM2, IFNA7|CSF3, CAMP|TFR2) can accurately distinguish patients in the high‐ and low‐risk groups. Risk score act as an independent prognostic factor and is related to clinical stage. There are significant differences in tumor immune microenvironment and PD‐1/PD‐L1/CTLA‐4 expression between groups. The low‐risk patient may benefit more from the commonly used chemotherapy regimens such as gemcitabine and paclitaxel. Conclusion This study constructed 5‐IRGPs as a reliable prognostic tool and may represent genes pairs that are potential rationale for choice of treatment for “driver gene negative” LUAD.

Blast furnace slag and steelmaking slag, as the main accessory products of iron and steel smelting, are piled up in large quantities due to their huge output, high treatment difficulty and low comprehensive utilization rate, which has a serious impact on the land and environment. In order to improve the comprehensive utilization of steelmaking slag, low basicity blast furnace slag was added to the existing steel slag for quenching and tempering. The influence of basicity on the chemical composition and phase precipitation of mixed slag was analyzed. In the research process, the phase composition and morphology of blast furnace slag and steel slag of Baotou Steel were analyzed using FactSage7.1 thermodynamic calculation software, ZEISS high-resolution scanning electron microscope (SEM), modern fast high-resolution Bruker energy dispersive spectrometer and AMICS-Mining automatic mineral analysis software. The results show that the mineral phase composition of blast furnace slag is mainly calcium aluminum yellow feldspar and that of steelmaking slag is mainly dicalcium silicate(C2S), magnesium-iron phase solid solution, rose pyroxene and calcium iron aluminate. When the basicity of the mixed slag is 2.0, it can effectively inhibit the formation of non-cementitious mineral anorthite and promote the formation of better cementitious mineral C2S. At the same time, it is found that the melting temperature of mixed slag decreases with the increase in Al2O3 content.