Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators (e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result, the design of new epigenetic modulators (e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging (HyT) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review, we aim to provide an in-depth illustration of new degrading strategies (2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

Objective To investigate the relationship between the expression levels of thyroid transcription factor-1(TTF-1)and Galectin-3 in differentiated thyroid carcinoma(DTC)tissues and clinical manifestations and prognosis of patients.Methods A total of 76 DTC patients admitted to the hospital from January 1,2017 to May 30,2020 were selected as the study objects.Cancer tissue specimens obtained during surgery were in-cluded in the DTC group(n=76),and corresponding paracancer tissue specimens were included in the para-cancer group(n=76).The expressions of TTF-1 and Galectin-3 in DTC group and paracancer group were de-tected by immunohistochemistry,and the relationship between the expression levels of TTF-1 and Galectin-3 and the clinicopathological characteristics of DTC patients was analyzed.Multivariate Cox regression analysis was used to investigate the prognostic factors of DTC patients.Results The positive expression rates of TTF-1 and Galectin-3 in DTC group were higher than those in paracancer group,and the difference was statistically significant(P＜0.05).The TTF-1 positive expression rate and Galectin-3 positive expression rate in DTC pa-tients with TNM stage Ⅲ to Ⅳ,low differentiation,tissue type of papillary thyroid carcinoma and lymph node metastasis were higher than those in DTC patients with TNM stage Ⅰ to Ⅱ,medium/high differentiation,tis-sue type of thyroid follicular carcinoma and no lymph node metastasis.The difference was statistically signifi-cant(P＜0.05).The 3-year overall survival rate of TTF-1 negative and Galectin-3 negative DTC patients was higher than that of TTF-1 positive and Galectin-3 positive DTC patients,and the difference was statistically significant(P＜0.05).Multivariate Cox regression analysis showed that lymph node metastasis,positive TTF-1 and positive Galectin-3 were prognostic factors in DTC patients(P＜0.05).Conclusion TTF-1 and Galectin-3 are related to TNM stage,differentiation degree,tissue type,lymph node metastasis and 3-year sur-vival rate of DTC patients,and have important reference value for the diagnosis and prognosis evaluation of DTC patients.

Objective To compare the application effects of simple artery ligation and modified inflation-deflation method in determining the lung intersegment plane during thoracoscopic precision segmentectomy.Methods A total of 80 patients who underwent thoracoscopic precision segmentectomy in our hospital from August 2021 to February 2023 were prospectively included and divided into the observation group and the control group by random number table method,with 40 cases in each group.Patients in the observation group were determined the lung intersegment plane by simple artery ligation,while patients in the control group were determined the lung intersegment plane by modified inflation-deflation method.The perioperative related indexes,lung function indexes,postoperative complications and follow-up of patients between the two groups were compared.Results The operative time and blood loss of patients in the observation group were significantly shorter/lower than those in the control group(P<0.05).There was no significant difference in the time to reveal the interseg-mental planes, total drainage volume after operation, indwelling time of drainage tube, postoperative hospital stay or lung segmentectomy distribution of patients between the two groups (P>0. 05). The percentage of forced vital capacity to the predicted values (FVC％pred) and percentage of forced expiratory volume in 1 second to the predicted values (FEV1％pred) after operation of patients in the two groups were significantly decreased compared with those before operation (P<0. 05), and FVC％pred and FEV1％pred after operation of patients in the observation group were significantly higher than those in the control group (P<0. 05). There was no statistically significant difference in the occurrence of postoperative complications of patients between the two groups (P>0. 05). There was no death, local recurrence or distant metastasis occurred in all patients during follow-up. Conclusion Compared with the modified inflation-deflation method, the application of simple artery ligation to determine the intersegment plane during thoracoscopic precision segmentectomy has significant advantages such as simple operation, less injury, and less impact on the lung function of patients, which is a feasible and effective technique, with high safety.

【Objective】 To explore the effects of finasteride on the gene expression in patients with benign prostatic hyperplasia (BPH) through transcriptome analysis. 【Methods】 Postoperative prostate tissues from patients who underwent prostatectomy at Peking University Third Hospital during Oct.2020 and Oct.2021 were collected.The patients were divided into medication group and non-medication group based on whether they had taken finasteride for a long time before surgery, with 8 patients in either groups.Transcriptome sequencing analysis was performed and the results were validated with qPCR and immunohistochemistry analysis. 【Results】 Compared with the non-medication group, 857 up-regulated and 806 down-regulated genes were screened in the medication group.Pathway enrichment analysis showed that finasteride induced down-regulation of vascular endothelial growth factor D (VEGFD) expression in the focal adhesion pathway.Inter group network analysis suggested that the calcium signaling pathway was key in the entire process.GSEA enrichment analysis further revealed the up regulation of CD38 gene expression in the calcium signaling pathway.The qPCR and immunohistochemistry analysis supported the transcriptome results mentioned above, and found that androgen receptor (AR) expression was also increased. 【Conclusion】 Finasteride reduces prostate microvascular formation by downregulating the expression of VEGFD in the focal adhesion pathway, thereby reducing the risk of bleeding during prostate hyperplasia surgery. Long-term use of finasteride leads to the up regulation of CD38 expression in the calcium signaling pathway, which may lead to the development of finasteride resistance.

Acute liver injury (ALI) is one of the common severe diseases in clinic, which is characterized by redox imbalance and inflammatory storm. Untimely treatment can easily lead to liver failure and even death. Rosmarinic acid (RA) has been proved to have anti-inflammatory and antioxidant activity, but it is not clear how to protect ALI through antioxidation and inhibition of inflammation. Therefore, this study explored the therapeutic effect and molecular mechanism of RA on ALI through in vitro and in vivo experiments. In the mouse ALI model, the effects of RA on liver function and inflammatory indexes were studied, the pathological changes of liver were observed by HE, the effect of RA on reactive oxygen species in liver was detected by fluorescence method, and the level of F4/80 in liver tissue was detected by immunohistochemical method. The levels of thioredoxin interacting protein (TXNIP), NOD-like receptor protein 3 (NLRP3) and cysteinyl aspartate specific proteinase-1 (CASPASE-1) in liver tissue were measured by Western blot. All animal welfare and experimental procedures follow the rules of the Animal Ethics Committee of Southwest Minzu University. In vitro, human hepatoma cell line HepG2 was used to establish the model of oxidative damage induced by H₂O₂. The cell viability was detected by CCK-8 method. The level of interleukin-1β (IL-1β) in the supernatant was detected by enzyme linked immunosorbent assay (ELISA), the activity of lactatede hydrogenase (LDH) was detected by LDH kit, and the level of ROS was detected by fluorescence probe DCFH-DA labeling. The mRNA expression of Txnip, Nlrp3, Caspase 1, Il1β was detected by real-time fluorescence quantitative PCR (qPCR), and the protein levels of nuclear factor erythroid-2 related factor 2 (NRF2), TXNIP, NLRP3 and CASPASE-1 were measured by Western blot. The results showed that compared with the model group, the degree of liver swelling, tissue injury, liver function index in RA group were significantly lower than those in model group. And RA significantly attenuated the increases of ROS in liver tissue. The expression levels of TXNIP, NLRP3 and CASPASE-1 in liver tissue were significantly lower than those in model group. Additionally, RA inhibited the expressions of F4/80 and IL-1β. In vitro experiment, compared with model group, RA effectively inhibited the secretion of IL-1β and LDH. The level of ROS also decreased significantly. RA inhibited the mRNA expressions of Txnip, Caspase 1, Il1β. Furthermore, RA significantly increased the expression level of NRF2 protein in nucleus, and decreased the expression level of TXNIP and NLRP3 protein. Specifically, with the addition of ML385, the effect of RA on NRF2, TXNIP, NLRP3, CASPASE-1 protein expression was reversed. Collectively, these findings suggested that RA may inhibit the production of ROS by promoting NRF2 nuclear transfer, and then reduce the activation of NLRP3 inflammatory bodies by TXNIP, reduce cell death and inflammatory response to prevent the liver injury.

Objective:To analyze the predictive value of echocardiography combined with diaphragmatic ultrasound on the outcome of removing machine for patients who underwent cardiac valve replacement for mechanical ventilation.Methods:Retrospectively,a total of 57 patients who adopt mechanical ventilation after underwent cardiac valve replacement in the First People's Hospital of Yibin from January 2022 to March 2023 were selected as the study subjects.According to the results of removing machine,the patients were divided into failed group(11 cases)and successful group(46 cases).All patients underwent echocardiography combined with diaphragmatic ultrasound examination.The indicators of echocardiography,included left ventricular ejection fractions(LVEF),right ventricular fractional area change(RVFAC)and systolic myocardial velocity(Sa),between different groups were compared.The early diastolic mitral annular tissue velocity(e')was recorded to calculate the ratio of early diastolic transmitral flow velocity(E)to e'(E/e'),and the indicators of echocardiography and diaphragmatic ultrasound.Logistic regression analysis was performed to analyze the factors affecting the failure of removing machine.Receiver operating characteristic(ROC)curve was drawn to evaluate the predictive values of echocardiography and diaphragmatic ultrasound indicators for the failure of removing machine in mechanical ventilation.Results:The differences of the differences of LVEF,RVFAC and Sa between failed group and successful group were no significant(P>0.05).The E/e'value of the successful group was 10.06±1.30,which was significantly lower than 12.69±2.96 of the failed group,and the difference was statistically significant(t=2.084,P＜0.05).The diaphragm thickening fraction(DTF)and diaphragm excursion(DE)values of the successful group were respectively 41.34±10.74 and 13.04±1.18,which were significantly higher than 19.67±5.37 and 11.27±0.94 of the failed group,respectively,and the differences between the two groups were statistically significant(t=2.148,2.776,P＜0.05).The results of logistic regression analysis showed that low expression of DTF and DE,as well as high expression of E/e',were all influence factors for the failure of removing machine for patients adopted mechanical ventilation after underwent cardiac valve replacement.The ROC results showed that the best cut-off value of the prediction model was 0.0893,and the area under curve(AUC)values were 0.713(95%CI:0.646～0.758),0.710(95%CI:0.651～0.779),0.752(95%CI:0.657～0.805)and 0.886(95%CI:0.782～0.991).Conclusion:The combination of echocardiography and diaphragm ultrasound has better prediction for the outcome of removing machine,which high higher clinical application value.

This study was aimed at understanding the detection rate,drug resistance characteristics,virulence characteris-tics,multi-locus sequence typing,and other molecular epidemic and pathogenic characteristics of Campylobacter jejuni and Campylobacter coli in children in Guangdong Province from 2020 to 2022.Anal swabs or stool samples of suspected infection cases in children from 2020 to 2022 were collected from two hospitals in Guangzhou,Guangdong Province.Campylobacter was isolated and cultured through the filtration method,and identified with a microbial mass spectrometry system;antibiotic resist-ance was analyzed with the agar dilution method;bacterial genome nucleic acids were extracted,and whole-genome sequencing was conducted;and drug resistance genes,virulence genes,multi-locus sequence typing,and phylogenetic analysis based on whole-genome single nucleotide polymorphisms were analyzed from whole-genome sequencing results.First,53 strains of Campy-lobacter were detected through continuous routine monitoring in this study,with a positive detection rate of 2.94％.Among them,Campylobacter jejuni accounted for 81.13％(43/53)and Campylobacter coli accounted for 18.87％(10/53).In addition,16 strains of Campylobacter were screened through multi-pathogen surveillance,including 11 strains of Campylobacter jejuni and 5 strains of Campylobacter coli.Drug resistance ex-periments and whole genome sequencing were conducted on 46 Campylobacter isolates,including 33 isolates of Campylobacter jejuni and 13 isolates of Campylobacter coli.The resistance rate of Campylobacter to erythromycin,a widely used clinical treatment,was21.73％(10/46);that to tetracycline was 80.43％(37/46);those to the quinolone antibiotics nalidixic acid and ciprofloxacin were 76.08％(35/46)and 71.73％(33/46)respectively;and that to chloramphenicol was lowest,at 2.17％(1/46).The drug resistance rate was generally higher for Campylobacter coli than Campylobacter jejuni,and the differences in the indicators of erythromycin,gentamicin,streptomycin,telithromycin,and clindamycin were statistically significant.A total of 30 isolates of multidrug-resistant Campylobacter were detected,including nine multidrug-resistant phenotypes.Whole-ge-nome sequence analysis indicated that 46 Campylobacter isolates carried antibiotic resistance genes for antibiotics such as quino-lones,tetracyclines,β-lactams,and aminoglycosides,and carried 128 virulence factor genes in five categories.All 46 isolates of Campylobacter were identified as 35 ST type through MLST typing,and phylogenetic analysis indicated no obvious dominant ST type.Campylobacter coli had more SNPs than Campylobacter jejuni.In conclusion,the positive detection rate of Campy-lobacter in Guangzhou City,Guangdong Province stabilized from 2020 to 2022,and the detection rate of Campylobacter jejuni was higher than that of Campylobacter coli.Campylobacter isolates were resistant to tetracyclines and quinolone,and showed a wide spectrum of multi-drug resistance,which was relatively severe among Campylobacter coli.Resistance genes and drug-resistant phenotypes were correlated and had predictive significance.The virulence genes of Campylobacter jejuni were more a-bundant than those of Campylobacter coli,possibly because of the higher detection rate and pathogenicity of Campylobacter jejuni.The phylogenetic tree showed clear branches with high genetic diversity and no clearly dominant clonal group.

Liver size is regulated by circadian clock and exhibits a diurnal rhythm. Pregnane X receptor (PXR) and peroxisome proliferator-activated receptor α (PPARα), members of nuclear receptor superfamily, are important regulators of liver size. We previously demonstrated that mPXR agonist pregnenolone 16α-carbonitrile (PCN) and mPPARα agonist pirinixic acid (WY-14643) promoted liver enlargement and liver regeneration after partial hepatectomy. However, whether PXR or PPARα activation-induced liver enlargement exhibits diurnal rhythm with normal liver diurnal oscillations remains unclear. The aim of this study was to investigate the diurnal rhythm of PXR or PPARα activation-induced liver enlargement. Male C57BL/6 mice were intraperitoneally injected with corn oil, PCN or WY-14643 for three days, and liver samples were weighed and collected at various time points for analysis. The animal experiment protocol was reviewed and approved by Institutional Animal Care and Use Committee of Sun Yat-sen University (approval No. SYSU-IACUC-2023-001613, SYSU-IACUC-2023-001783). The results showed that PXR or PPARα activation at various time points significantly induced liver enlargement, and liver size maintained normal diurnal oscillations during PXR or PPARα activation-induced hepatomegaly, without significant effects on the expression of core clock genes. This study reveals PXR or PPARα activation-induced liver enlargement exhibits diurnal rhythm with normal liver diurnal oscillations, and provides novel data for nuclear receptor-induced liver enlargement and liver diurnal rhythm.

Purpose: The aim of this study was to assess the risk of postoperative deep vein thrombosis (DVT) in breast cancer patients with coronavirus disease 2019 (COVID-19) to determine the optimal timing for surgery in the era of “post COVID-19 pandemic.” Methods: This prospective study included breast cancer patients who contracted COVID-19 and underwent surgery from December 20th, 2022, to March 20th, 2023 (n = 577). A control group comprised patients who underwent surgery from May 1st, 2019, to October 1st, 2019 (n = 327) and had not contracted COVID-19 prior to surgery. Patients were categorized based on the timing of their surgery relative to their COVID-19 infection. Data were analyzed using logistic regression. Results: Patients with COVID-19 had a higher incidence of postoperative DVT compared to those without COVID-19 (3.64% vs. 1.21%). Multivariable logistic regression analysis indicated that the timing of surgery was significantly associated with the risk of DVT (odds ratio [OR], 2.795; 95% confidence interval [CI], 0.692–11.278; p = 0.024). Patients who underwent surgery within two weeks of COVID-19 infection experienced the highest DVT rates (OR, 10.556; 95% CI, 1.095–303.313; p = 0.003). However, the incidence decreased to 2.85% when surgery was delayed until two weeks or more after infection. The median followup period was 10 months, all patients with DVT after surgery were recovered without serious complications or death. There were no adverse effects on subsequent anti-tumor therapy. Conclusion Caution is advised when performing breast cancer surgery within two weeks after a COVID-19 infection. Although the risk of DVT remains somewhat elevated even after two weeks, surgery can be considered safe given the urgency of treatment, favorable complication outcomes, and lack of impact on subsequent adjuvant therapy.

This study aims to investigate the role of slient mating-type information regulation 2 homolog 1(SIRT1)/tuberous sclerosis complex 2(TSC2)/mammalian target of rapamycin(mTOR) signaling pathways in the Periplaneta americana extract CⅡ-3-induced senescence of human leukemia K562 cells. K562 cells were cultured in vitro and treated with 0(control), 5, 10, 20, 40, 80, and 160 μg·mL~(-1) of P. americana extract CⅡ-3. Cell counting kit-8(CCK-8) and flow cytometry were employed to examine the proliferation and cell cycle of the K562 cells. Senescence-associated β-galactosidase stain kit(SA-β-gal) was used to detect the positive rate of senescent cells. Mitochondrial membrane potential was detected by flow cytometry. The relative mRNA level of telomerase reverse transcriptase(TERT) was determined by fluorescence quantitative PCR. The mRNA and protein levels of SIRT1, TSC2, and mTOR were determined by fluorescence quantitative PCR and Western blot, respectively. The results showed that CⅡ-3 significantly inhibited the proliferation of K562 cells and the treatment with 80 μg·mL~(-1) CⅡ-3 for 72 h had the highest inhibition rate. Therefore, 80 μg·mL~(-1) CⅡ-3 treatment for 72 h was selected as the standard for subsequent experiments. Compared with the control group, CⅡ-3 increased the proportion of cells arrested in G_0/G_1 phase, decreased the proportion of cells in S phase, increased the positive rate of SA-β-Gal staining, elevated the mitochondrial membrane potential and down-regulated the mRNA expression of TERT. Furthermore, the mRNA expression of SIRT1 and TSC2 was down-regulated, while the mRNA expression of mTOR was up-regulated. The protein expression of SIRT1 and p-TSC2 was down-regulated, while the protein expression of p-mTOR was up-regulated. The results indicated that P. americana extract CⅡ-3 induced the senescence of K562 cells via the SIRT1/mTOR signaling pathway.
Humans ; Animals ; Periplaneta ; Sirtuin 1/genetics* ; K562 Cells ; Signal Transduction ; TOR Serine-Threonine Kinases/genetics* ; RNA, Messenger ; Mammals