Trifluoromethyl quinoline derivative targets inhibiting HDAC1 for promoting the acetylation of histone in cervical cancer cells.

Cervical cancer is the leading cause of death among gynecological malignant tumors, especially due to the poor prognosis of patients with advanced tumors due to recurrence, metastasis, and chemotherapy resistance. Therefore, exploring new antineoplastic drugs with high efficacy and low toxicity may bring new expectations in patients with cervical cancer. Natural products and their derivatives exert an antitumor activity. Therefore, in this work, combined with network pharmacology analysis and experimental validation, we investigated the anti-cervical cancer activity and molecular mechanism of a new trifluoromethyl quinoline (FKL) derivative in vivo and in vitro. FKL117 inhibited the proliferation of cervical cancer cells in a dose and time-dependent manner, induced apoptosis in HeLa cells, arrested the cell cycle in the G2/M phase, and regulated the expression of the apoptotic and cell cycle-related proteins Bcl-2, Bax, cyclin B1, and CDC2. We used online databases to obtain HDAC1 as one of the possible targets of FKL117 and the target binding and binding affinity were modeled by molecular docking. The results showed that FKL117 formed a hydrogen bond with HDAC1 and had good binding ability. We found that FKL117 targeted to inhibit the expression and function of HDAC1 and increased the acetylation of histone H3 and H4, which was also confirmed in vivo. The migration of HMGB1 from the nucleus to the cytoplasm further verified the above results. In conclusion, our study suggested that FKL117 might be used as a novel candidate for targeting the inhibition of HDAC1 against cervical cancer.

Werner helicase mediates the senescence and cell cycle of leukemia cells by regulating DNA repair pathways.

Leukemia is a type of malignant hematological disease that is generally resistant to chemotherapy and has poor therapeutic outcomes. Werner (WRN) DNA helicase, an important member of the RecQ family of helicases, plays an important role in DNA repair and telomere stability maintenance. WRN gene dysfunction leads to premature aging and predisposes humans to various types of cancers. However, the biological function of WRN in cancer remains unknown. In this study, the expression of this RecQ family helicase was investigated in different types of leukemia cells, and the leukemia cell line K562 with high WRN expression was selected to construct a WRN knockdown cell line. The results showed that WRN knockdown inhibited leukemia occurrence and development by regulating the proliferation, cell cycle, differentiation, and aging of cells and other biological processes. The results of transcriptome sequencing revealed that WRN promoted the sensitivity of leukemia cells to the DNA damage inducer Etoposide by regulating cell cycle-related proteins, such as CDC2, cyclin B1, p16, and p21, as well as key proteins in DNA damage repair pathways, such as p53, RAD50, RAD51, and MER11. Our findings show that WRN helicase is a promising potential target for leukemia treatment, providing new ideas for the development of targeted drugs against leukemia.

Deciphering essential druggable genes reveals potential immune-inflammatory axis in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant tumor with a high mortality rate and poor prognosis in patients. Its pathogenesis is a complex process of multi-factors and multi-steps. However, the etiology and exact molecular mechanism are not completely clear. METHODS: Here, we constructed a specific-expressed network based on RNA sequencing data. Gene and miRNA expression profiles and clinical evidence were integrated to detect hepatocellular carcinoma survival modules. Finally, we attempted to identify potential key biomarkers and drug targets by integrating drug sensitivity analysis and immune infiltration analysis. RESULTS: A total of 42 prognostic modules for hepatocellular carcinoma were detected. The prognostic modules were significantly enriched with known cancer-related molecules and 12.93 % molecules of prognostic modules had been found were the targets of small molecule drug. In addition, we found that 38 of 42 (90.48 %) essential genes were associated with the proportions of at least one of the 7 immune cell types. CONCLUSION: We integrated clinical prognosis information, RNA sequencing data, and drug activity data to explore risk modules of hepatocellular carcinoma. Through drug sensitivity analysis and immune infiltration analysis, we assessed the value of hub genes in the modules as potential biomarkers and drug targets for hepatocellular carcinoma. The protocol provides new insight into parsing the molecular mechanism and theoretical basis of hepatocellular carcinoma.

Osteopontin regulates the growth and invasion of liver cancer cells via DTL.

Osteopontin (OPN), a secreted phosphoglycoprotein, has important roles in tumor growth, invasion and metastasis in numerous types of cancers. Denticleless E3 ubiquitin protein ligase homolog (DTL), one of the CUL4-DDB1-associated factors (DCAFs), has also been associated with the invasion and metastasis of cancer cells. In the present study, OPN was found to induce DTL expression in liver cancer cells, and the results obtained using luciferase activity assays demonstrated that OPN could transcriptionally activate DTL expression in liver cancer cells. Furthermore, the results of the present study demonstrated that OPN could increase the expression of DTL via PI3K/AKT signaling. In conclusion, the present study demonstrated that OPN, as an extracellular matrix protein, is able to promote the growth and invasion of liver cancer cells through stimulation of the expression of DTL via the PI3K/AKT signaling pathway.

A deep learning-based interpretable decision tool for predicting high risk of chemotherapy-induced nausea and vomiting in cancer patients prescribed highly emetogenic chemotherapy.

OBJECTIVE: This study aims to develop a risk prediction model for chemotherapy-induced nausea and vomiting (CINV) in cancer patients receiving highly emetogenic chemotherapy (HEC) and identify the variables that have the most significant impact on prediction. METHODS: Data from Tianjin Medical University General Hospital were collected and subjected to stepwise data preprocessing. Deep learning algorithms, including deep forest, and typical machine learning algorithms such as support vector machine (SVM), categorical boosting (CatBoost), random forest, decision tree, and neural network were used to develop the prediction model. After training the model and conducting hyperparameter optimization (HPO) through cross-validation in the training set, the performance was evaluated using the test set. Shapley additive explanations (SHAP), partial dependence plot (PDP), and Local Interpretable Model-Agnostic Explanations (LIME) techniques were employed to explain the optimal model. Model performance was assessed using AUC, F1 score, accuracy, specificity, sensitivity, and Brier score. RESULTS: The deep forest model exhibited good discrimination, outperforming typical machine learning models, with an AUC of 0.850 (95%CI, 0.780-0.919), an F1 score of 0.757, an accuracy of 0.852, a specificity of 0.863, a sensitivity of 0.784, and a Brier score of 0.082. The top five important features in the model were creatinine clearance (Ccr), age, gender, anticipatory nausea and vomiting, and antiemetic regimen. Among these, Ccr had the most significant predictive value. The risk of CINV decreased with increased Ccr and age, while it was higher in the presence of anticipatory nausea and vomiting, female gender, and non-standard antiemetic regimen. CONCLUSION: The deep forest model demonstrated good discrimination in predicting the risk of CINV in cancer patients prescribed HEC. Kidney function, as represented by Ccr, played a crucial role in the model's prediction. The clinical application of this predictive tool can help assess individual risks and improve patient care by proactively optimizing the use of antiemetics in cancer patients receiving HEC.

MedOptNet: Meta-Learning Framework for Few-shot Medical Image Classification.

In the medical research domain, limited data and high annotation costs have made efficient classification under few-shot conditions a popular research area. This paper proposes a meta-learning framework, termed MedOptNet, for few-shot medical image classification. The framework enables the use of various high-performance convex optimization models as classifiers, such as multi-class kernel support vector machines, ridge regression, and other models. End-to-end training is then implemented using dual problems and differentiation in the paper. Additionally, various regularization techniques are employed to enhance the model's generalization capabilities. Experiments on the BreakHis, ISIC2018, and Pap smear medical few-shot datasets demonstrate that the MedOptNet framework outperforms benchmark models. Moreover, the model training time is also compared to prove its effectiveness in the paper, and an ablation study is conducted to validate the effectiveness of each module.

Long Noncoding RNA TFAP2A-AS1 Suppressed Hepatitis B Virus Replication by Modulating miR-933/HDAC11.

Objective: Studies have shown that long noncoding RNAs (lncRNAs) play crucial roles in multiple tumor types and regulate various biological processes. The present study tried to study lncRNA TFAP2A-AS1 in HBV infection hepatocellular carcinoma. Methods: The level of TFAP2A-AS1 and miR-933 in HCC cell and samples were detected by qRT-PCR assay. Luciferase reporter gene assay was carried out to study the mechanism of TFAP2A-AS1 and miR-933. Cell proliferation was measured by CCK-8 assay. HBV DNA replication was detected by RT-qPCR. Results: We firstly demonstrated that TFAP2A-AS1 was downregulated in HCC cell lines and HBV-infected HCC samples compared with nontumor tissues. However, miR-933 was upregulated in HCC cell lines and HBV-infected HCC samples compared with nontumor tissues, and miR-933 was negatively associated with the expression of TFAP2A-AS1 in HBV-correlated HCC samples. TFAP2A-AS1 and HDAC11 expression was decreased and miR-933 was upregulated in the HBV-infected cell HepG2.2.15. TFAP2A-AS1 acted as a sponge for miR-933 and HDAC11 was one direct target gene for miR-933. Overexpression of TFAP2A-AS1 suppressed cell growth, HBV DNA replication, HbeAg, and HbsAg expression, while knockdown of TFAP2A-AS1 enhanced cell proliferation, HBV DNA replication, HbeAg, and HbsAg expression in HepG2.2.15 cell. In addition, ectopic expression of miR-933 promoted cell growth, HBV DNA replication, HbeAg, and HbsAg expression in HepG2.2.15 cell. TFAP2A-AS1 suppressed HBV replication and infection through regulating HDAC11. Conclusion: These data demonstrated that TFAP2A-AS1 acted crucial roles in the modulation of HbeAg and HbsAg expression and HBV replication and may be one potential target for HBV infection treatment.

Facile Preparation of Micrometer KClO4/Zr Energetic Composite Particles with Enhanced Light Radiation.

Developing energetic composite materials consisting of fuel and oxidizer is an effective strategy to enhance the energy release property. However, this strategy has rarely been applied in Potassium Perchlorate (KClO4)-containing energetic materials, even though KClO4 is a much stronger oxidizer than most previously reported metal-oxide oxidizer. One of the main obstacles is the lack of simple and in situ ways to introduce KClO4 into the composite. In present work, micrometer KClO4/Zirconium (KClO4/Zr) composite particles were successfully prepared using a facile chemical solution-deposition method. The structure and particle morphologies of as-obtained KClO4/Zr composite were characterized by X-ray diffraction (XRD) and scanning electronic microscope (SEM)-EDS (Energy Dispersive Spectrometer). The evolutionary combustion behavior was evaluated using flame-based light-radiation spectra and successive photography technique. Results showed that the morphology, light-radiation properties and flame-evolution characteristics of KClO4/Zr composite varied with the content of KClO4 and the particle size of Zr. Compared with the mechanical mixture of KClO4/Zr, the KClO4/Zr composite showed much higher light-radiation intensity and longer light-emission duration time after reasonably controlling the preparation parameters. Flame photographs revealed that the enhanced light radiation of KClO4/Zr composite should be ascribed to higher use efficiency of "oxygen" in the oxidizer, which promoted both the solid⁻solid and solid⁻gas reaction pathways between KClO4 and Zr.

Mid- to long-term results of total disc replacement for lumbar degenerative disc disease: a systematic review.

BACKGROUND: Lumbar total disc replacement (TDR) has shown satisfactory clinical outcomes with few complications and reoperations at short-term follow-up, but the mid- to long-term results are not clear. PURPOSE: The objective of this study was to evaluate the mid- to long-term clinical outcomes of artificial TDR for lumbar degenerative disc diseases. PATIENTS AND METHODS: A systematic search was conducted using the PubMed database to identify studies of TDR surgery that included at least 3 years of follow-up. The search keywords were as follows: lumbar, total disc replacement, and arthroplasty. The following data were extracted: patient demographics, visual analogue scale (VAS) and Oswestry disability index (ODI) scores, satisfactory rate, clinical success rate, complications, and reoperations. RESULTS: Thirteen studies, including eight prospective studies and five retrospective studies, met the criteria. A total of 946 patients were identified who reported at least 3 years of follow-up results. The artificial prostheses in these studies were ProDisc-L, Charité, AcroFlex, Maverick, and XL TDR. Patients with lumbar TDR demonstrated significant improvements in VAS scores of 51.1 to 70.5% and of - 15.6 to - 44.4 for Oswestry disability index (ODI) scores at the last follow-up. Patient satisfaction rates were reported in eight studies and ranged from 75.5 to 93.3%. Complication rates were reported in 11 studies, ranging from 0 to 34.4%. The overall reoperation rate was 12.1% (119/986), ranging from 0 to 39.3%, with eight of the 13 studies reporting a reoperation rate of less than 10%. CONCLUSIONS: This review shows that lumbar TDR effectively results in pain relief and an improvement in quality of life at mid- to long-term follow-up. Complication and reoperation rates were acceptable. However, this study did not provide sufficient evidence to show that lumbar TDR is superior to fusion surgery. To answer that question, a greater number of high-quality randomized controlled trials (RCTs) are needed.