Structural simulation and selective inhibitor discovery study for histone demethylases KDM4E/6B from a computational perspective.

The methylation and demethylation of lysine and arginine side chains are fundamental processes in gene regulation and disease development. Histone lysine methylation, controlled by histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs), plays a vital role in maintaining cellular homeostasis and has been implicated in diseases such as cancer and aging. This study focuses on two members of the lysine demethylase (KDM) family, KDM4E and KDM6B, which are significant in gene regulation and disease pathogenesis. KDM4E demonstrates selectivity for gene regulation, particularly concerning cancer, while KDM6B is implicated in inflammation and cancer. The study utilizes specific inhibitors, DA-24905 and GSK-J1, showcasing their exceptional selectivity for KDM4E and KDM6B, respectively. Employing an array of computational simulations, including sequence alignment, molecular docking, dynamics simulations, and free energy calculations, we conclude that although the binding cavities of KDM4E and KDM6B has high similarity, there are still some different crucial amino acid residues, indicating diverse binding forms between protein and ligands. Various interaction predominates when proteins are bound to different ligands, which also has significant effect on selective inhibition. These findings provide insights into potential therapeutic strategies for diseases by selectively targeting these KDM members.

Standardized uptake valuemax of the primary lesion combined with tumor markers for clinically predicting distant metastasis in de novo lung adenocarcinoma.

BACKGROUND: To examine standardized uptake valuemax of the primary lesion (pSUVmax) and tumor markers (TMs) for clinically predicting distant metastasis in novo lung adenocarcinoma. METHODS: The current retrospective observational study examined individuals diagnosed with de novo lung adenocarcinoma at Shanxi Cancer Hospital between February 2015 and December 2019. RESULTS: Totally, 532 de novo lung adenocarcinoma cases were included. They were aged 60.8 ± 9.7 years and comprised 224 women and 268 patients with distant metastasis. The areas under the curves (AUCs) of pSUVmax, lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), cytokeratin-19 fragment (CYFRA21-1), carbohydrate antigen 125 (CA125), and Grade of TMs for predicting distant metastasis were 0.742, 0.601, 0.671, 0.700, 0.736, and 0.745, respectively. The combination of pSUVmax, LDH, CEA, CYFRA21-1, CA125, and grade of TMs in predicting distant metastasis had an AUC value of 0.816 (95%CI: 0.781-0.851), with sensitivity of 89.2%, specificity of 58.7%, positive predictive value of 73.7%, and negative predictive value of 79.7%, respectively. CONCLUSIONS: pSUVmax combined with serum levels of LDH, CEA, CYFRA21-1, CA125, and the grade of TMs may have good performance in predicting distant metastasis of de novo lung adenocarcinoma.

Significance of thyroid transcription factor 1 and Napsin A for prompting the status of EGFR mutations in lung adenocarcinoma patients.

Background: To evaluate the prompting value of thyroid transcription factor 1 (TTF-1) and Napsin A for the status of epidermal growth factor receptor (EGFR) mutations in an independent cohort of lung adenocarcinomas (LUADs) when genetic testing is unavailable. Methods: In this study, 976 untreated primary LUADs were retrospectively reviewed. The clinical and pathological data, including age, gender, smoking history, predictive values of TTF-1 and Napsin A, EGFR status, and tumor-node-metastasis (TNM) stage were obtained through medical records available in Shanxi Province Cancer Hospital. All patients were divided into 2 groups, a mutant group (n=362) and wild-type group (n=614), according to their EGFR status. The clinical data and the expression of TTF-1 and Napsin A were compared between the 2 groups. TTF-1 and Napsin A are detected by fully automated IHC.PCR was carried out to detect the EGFR mutation. Univariate and multivariate logistic regression analyses were undertaken to distinguish independent factors of EGFR mutations. Results: A total of 362 cases (37.1%) of EGFR mutations were detected, which were more frequent in females, never smokers, lymphatic metastasis, distant metastasis, and the positive expression of TTF-1 and Napsin A. Multivariate analysis indicated that females [odds ratio (OR), 1.950; 95% confidence interval (CI): 1.2958 to 2.938; P=0.001], never smokers (OR, 2.040; 95% CI: 1.345 to 3.094; P=0.001), and the positive expression of TTF-1 (OR, 2.366; 95% CI: 1.440 to 3.887; P=0.001) and Napsin A (OR, 2.295; 95% CI: 1.448 to 3.638; P<0.001) were effective prompting for EGFR mutations. Conclusions: The positive expression of TTF-1 and Napsin A had the prompting value for EGFR mutations in patients with LUAD, and the indicators could be combined with other clinical characteristics to enhance the prediction of the EGFR status in LUAD.

The predictive value of 18F-FDG PET/CT in an EGFR-mutated lung adenocarcinoma population.

Background: A non-invasive, simple, and convenient method to evaluate the presence of epidermal growth factor receptor (EGFR) mutations is important for initial treatment decisions in lung adenocarcinoma. Methods: We retrospectively reviewed 297 untreated primary lung adenocarcinoma patients with exact EGFR status. Based on their EGFR status, the patients were divided into a mutant-type group (138 patients) and wild-type group (159 patients). General patient characteristics and possible factors reflecting the status of EGFR were also evaluated. Results: Of the 297 lung adenocarcinoma patients analyzed for EGFR status who underwent positron emission tomography (PET)/computed tomography (CT) between January 2013 and December 2017, mutations in the EGFR gene were detected in 138 patients (46.5%). EGFR mutations were more frequently associated with women, never smokers, and low 18F-fluoro-2-deoxy-glucose (18F-FDG) PET/CT maximal standard uptake value of the primary tumor (pSUVmax). Multivariate analysis indicated that women [odds ratio (OR) =2.853; 95% confidence interval (CI): 1.451-5.611; P=0.002], never smokers (OR =2.414; 95% CI: 1.217-4.789; P=0.012), tumor size <3.5 cm (OR, 2.170; 95% CI: 1.205-3.908; P=0.010), and pSUVmax <8.2 (OR =1.904; 95% CI: 1.098-3.302; P=0.022) were effective predictors of EGFR mutation. In addition, the area under the curve (AUC) of pSUVmax and tumor size was 0.623 and 0.600, respectively. Combined with clinical characteristics, including sex and smoking status, the AUC of the 4 predictors was 0.770. Conclusions: These indicators could be helpful for enhancing predictive accuracy of EGFR mutations in lung adenocarcinoma patients, especially in those for whom EGFR detection is unavailable.

Prognostic role of epidermal growth factor receptor mutation status in patients with de novo lung adenocarcinoma.

BACKGROUND: To explore the relationship between the status of epidermal growth factor receptor (EGFR) and overall survival (OS) in de novo lung adenocarcinoma. METHODS: We retrospectively analyzed 291 lung adenocarcinoma subjects with exact EGFR status. The cases were divided into a mutant-type group (124 patients) and wild-type group (167 patients) according to the status of EGFR. The general information, OS, and possible risk factors influencing the OS were also evaluated. RESULTS: The EGFR mutation rate was 42.6% (124/291 patients), and there were statistically significant differences in gender, smoking history, and OS (P<0.05), but no significant difference in diagnosed age, alcohol history, TNM stage, clinical stage, and immunohistochemistry between the two groups (P>0.05). The most common subtypes of EGFR mutations were exon 19 and exon 21. The median OS of the total population was 30.20 months [95% confidence interval (CI): 25.94-34.46 months] and the OS in the mutant-type group was better than in the wild-type group (P<0.001). Cox regression demonstrated that N stage, M stage, and EGFR status were the risk factors for OS in de novo lung adenocarcinoma patients (P<0.001), and the relative risk were 1.398 (95% CI: 1.214-1.609), 2.427 (95% CI: 1.780-3.310), and 2.030 (95% CI: 1.528-2.699), respectively. CONCLUSIONS: The OS of EGFR mutant individuals was better than that of wild-type patients in de novo lung adenocarcinoma patients. EGFR mutation may be a useful prognostic indicator in lung adenocarcinoma.

Prophylactic administration of mecapegfilgrastim after chemotherapy in patients with lymphoma.

BACKGROUND: Neutropenia is a common and serious complication encountered during chemotherapy treatment of cancer patients. The incidence of neutropenia increases the risk of infection and can influence the chemotherapy treatment in terms of drug dosage and treatment duration. Mecapegfilgrastim is a novel, long-acting pegylated recombinant human granulocyte-colony stimulating factor (PEG-rhG-CSF) designed to prevent the incidence of neutropenia. The study aims to observe the effectiveness and safety of mecapegfilgrastim as prophylaxis for chemotherapy-induced neutropenia in patients with lymphoma. METHODS: Ninety-one patients with lymphoma were enrolled and received mecapegfilgrastim as either primary or secondary prophylaxis. The incidence of grade III/IV neutropenia, the duration of grade III/IV neutropenia in the overall population, and the differences between the primary and secondary prophylaxis groups were investigated. Adverse events were also recorded. RESULTS: During the first chemotherapy cycle, the incidence of grade III and grade IV neutropenia was 5% and 7%, respectively. Of the 71 patients who received mecapegfilgrastim as primary prophylaxis, the incidence of grade III and grade IV neutropenia was 4% and 1%, respectively. Of the 20 patients who received mecapegfilgrastim as secondary prophylaxis, the incidence of grade III and grade IV neutropenia was 10% and 25%, respectively. The mean duration of grade III neutropenia was 0.85 days. The mean duration of grade III neutropenia in patients who received mecapegfilgrastim as primary prophylaxis was one day less than patients who received mecapegfilgrastim as secondary prophylaxis. Fever and bone/muscle pain were the most frequently observed adverse events. CONCLUSIONS: Mecapegfilgrastim is more effective in reducing the incidence of grade III/IV neutropenia and the mean duration of febrile neutropenia (FN) when used as primary prophylaxis rather than secondary prophylaxis in patients with lymphoma. The toxicity of mecapegfilgrastim was tolerable.