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.

As an important biological resource of a country or region, human genetic resources (HGR) are increasingly attracting attention and concern from many countries internationally, and even have been elevated to the dimension of national sovereignty by many countries. As a large country with rich and diverse HGR, relevant regulatory work in China started relatively late compared to foreign countries, but has developed rapidly. However, looking around the world, there is still room for further improvement and development of domestic HGR regulation. By reviewing the regulatory legislation of HGR in some countries abroad, this paper sorted out their advanced experience and highlighted measures in detail, and summarized their deep-seated legislative guidance. A detailed analysis and evaluation were conducted from seven aspects:the advanced level of HGR legislation and the enhancement of legal effectiveness, the systematization and systematization of policies and regulations, the unification of platforms and relevant standards, the highlight of the concept of ethics and the rule of law, the strengthening of anti-discrimination protection, the special protection of major human genetic family resources and national special protection areas of HGR, and the establishment of principled consensus or agreement on HGR in international and local regions, to provide reference for the construction of regulatory policies and legal systems for HGR in China.

Objective:To investigate the effects of orlistat on the viability of human gall-bladder cancer (GBC) cells.Methods:The experimental study was conducted. The human GBC NOZ cells with high expression of FSAN was screened out through in vitro cultivating human GBC-SD, SGC-996 and NOZ cells. The cell proliferation assay, clone formation assay and protein detection experiment were used to analysis of the effects of orlistat on the viability of human GBC cells. Cell grouping: NOZ cells cultured with medium were set as the control group, cultured with medium + 10 μmol/L orlistat were set as the low-dose orlistat group, cultured with medium + 100 μmol/L orlistat were set as the high-dose orlistat group, respectively. Observation indicators: (1) expression of FASN protein in human GBC cells; (2) effects of orlistat on the proliferation of human GBC NOZ cells; (3) effects of orlistat on apoptosis of human GBC NOZ cells. Measurement data with normal distribution were represented as Mean± SD, the ANOVA test was used for comparison between groups and the least significant difference method was used for pairwise comparison. Results:(1) Expression of FASN protein in human GBC cells. Results of western blot showed that the relative expression of FASN protein in human GBC NOZ, GBC-SD and SGC-996 cells was 0.57±0.06, 0.12±0.04 and 0.10±0.02, respectively, showing a significant difference among them ( F=115.67, P<0.05). There were significant differences between the NOZ cells and the GBC-SD or the SGC-996 cells ( P<0.05), and there was no significant difference between the GBC-SD cells and the SGC-996 cells ( P>0.05). (2) Effects of orlistat on the proliferation of human GBC NOZ cells. ① Results of cell proliferation assay showed that the absorbance value of NOZ cells was 2.34±0.12, 1.57±0.08 and 1.07±0.13 in the control group, low-dose orlistat group and high-dose orlistat group, respectively, showing a significant difference among them ( F=205.88, P<0.05). ② Results of clone formation assay showed that the number of NOZ cells clones was 257±23, 153±11 and 83±11 in the control group, low-dose orlistat group and high-dose orlistat group, respectively, showing a significant difference among them ( F=92.64, P<0.05). ③Results of western blot showed that the relative expression of Cyclin-D1 protein of NOZ cells was 2.31±0.10, 1.52±0.05 and 1.23±0.11 in the control group, low-dose orlistat group and high-dose orlistat group, respectively, showing a significant difference among them ( F=120.73, P<0.05). The relative expression of CDK-4 protein of NOZ cells was 1.58±0.04, 1.21±0.02 and 1.19±0.04 in the control group, low-dose orlistat group and high-dose orlistat group, respectively, showing a signifi-cant difference among them ( F=110.45, P<0.05). (3) Effects of orlistat on apoptosis of human GBC NOZ cells. Results of western blot showed that the relative expression of Bcl-2 protein of NOZ cells was 1.07±0.03, 0.36±0.03 and 0.15±0.02 in the control group, low-dose orlistat group and high-dose orlistat group, respectively, showing a significant difference among them ( F=1 242.93, P<0.05). The relative expression of Bax protein of NOZ cells was 0.51±0.03, 0.38±0.05 and 1.38±0.04 in the control group, low-dose orlistat group and high-dose orlistat group, respectively, showing a signifi-cant difference among them ( F=583.51, P<0.05). Conclusion:Orlistat can inhibit the growth of human GBC NOZ cells and promote their apoptosis.

Objective:To explore the significance of triggering receptor expressed on myeloid cells-2 (TREM-2) prognostic evaluation so as to provide novel biological markers in clinical practice for patients with hepatitis B virus-related acute-on-chronic liver failure ( HBV-ACLF).Methods:The research subjects of this study were divided into an experimental group and a control group. Fifty HBV-ACLF cases admitted to the Department of Infectious Diseases of the First Affiliated Hospital of Nanchang University from January 1, 2019 to December 31, 2019 were selected as the experimental group. Patients were divided into survival and death groups according to the actual prognosis at discharge (self-discharge and dead patients were considered death groups, and all enrolled patients were hospitalized for more than 28 days). Twenty-five healthy subjects were chosen as the control group. Peripheral venous blood was collected from the experimental group and the control group. Plasma and peripheral blood mononuclear cells (PBMC) were isolated. The concentrations of TREM-2, interleukin (IL)-6, and IL-8 were detected in the plasma. TREM-2 mRNA expression was detected in PBMC. A single blood sample was collected from the control group, whereas five blood samples were dynamically collected from the experimental group on the day of admittance and at 7, 14, 21, and 28 days after treatment commenced. Simultaneously, upon admission, the relevant clinical indicators of HBV-ACLF patients were monitored, including the liver function test: alanine aminotransferase, aspartate aminotransferase, total bilirubin, albumin, coagulation function test: international normalized ratio, prothrombin time, and other indicators. Measurement data were expressed as mean±standard deviation (x±s). Count data were compared and analyzed using the χ 2 test. The intra-group factor mean was compared using a repeated measures ANOVA. The means were analyzed by t-tests between the two groups. Bivariate correlation analysis was used to analyze the correlation between the two variables. The value of TREM-2 as a diagnostic marker was analyzed using the receiver operating characteristic (ROC) curve. Results:The mRNA expression of TREM-2 in the PBMC of HBV-ACLF patients showed a gradually increasing trend at various time points and was significantly higher in the survival group than that of the control group at 28 days ( P < 0.01), while the death group showed a gradually weakening trend at various time points and was significantly lower than the control group at 28 days ( P < 0.01). (1) The levels of TREM-2 in the plasma of HBV-ACLF patients generally showed a gradually increasing trend at various time points in the survival group. The levels on the day of admission and 7, 14, 21, and 28 days after the initiation of treatment were (1.49±0.85), (1.62±0.58), (1.95±0.69), (2.33±0.71), and (2.00±0.67) ng/ml, respectively. The expression of TREM-2 in the death group showed a gradually weakening trend at various time points. The levels on the day of admission and 7, 14, 21, and 28 days after initiation of treatment were (1.40±0.73), (1.59±0.79), (1.56±0.80), (1.05±0.49), and (0.81±0.21) ng/ml, respectively. The survival group's various detection time points were higher than those of the death group, and the difference was statistically significant. The plasma level of TREM-2 in the healthy control group was (1.25±0.35) ng/ml. (2) The concentrations of IL-6 and IL-8 in the plasma of HBV-ACLF patients showed a gradually decreasing trend at various time points in the survival group. The levels on the day of admission and 7, 14, 21, and 28 days after initiation of treatment were (46.70±26.31), (33.98±20.28), (19.07±10.24), (14.76±7.84), (9.12±7.65) and (108.29±47.07), (93.85±26.53), (79.27±34.63), (56.72 ±18.30), (37.81±13.88) pg/ml, respectively. However, its concentration in the death group fluctuated within a relatively high range. The levels on the day of admission and 7, 14, 21, and 28 days after the initiation of treatment were (41.94±24.19), (36.99±19.78), (34.30±20.62), (34.14±14.52), (36.64±23.61) and (104.65±50.16), (112.98±45.03), (118.43±45.00), (111.67±40.44), (109.55±27.54) pg/ml, respectively. (3) Bivariate correlation analysis results indicated that the plasma TREM-2 content was negatively correlated with the plasma levels of pro-inflammatory cytokines IL-6 and IL-8 ( r = -0.224, P = 0.025; r = - 0.223, P = 0.026). ROC curve analysis showed that the mRNA levels of TREM-2 in PBMCs at various time points for prognostic evaluation of HBV-ACLF patients were 1d=0.667, 7d=0.757, 14d=0.979, 21d=0.986, and 28d= 0.993. The areas under the ROC curve of the TREM-2 content in the plasma at various time points were 1d=0.522, 7d=0.571, 14d=0.658, 21d=0.927, and 28d=0.994. Conclusion:TREM-2 mRNA expression in PBMC and TREM-2 content in plasma have a significant relationship to the prognosis of HBV-ACLF patients and may inhibit the liver inflammatory response by regulating the secretion of pro-inflammatory cytokines IL-6 and IL-8. Dynamic monitoring of TREM-2 expression in peripheral blood is favorable for evaluating the prognostic condition of HBV-ACLF patients.

Purpose: This study aimed to identify prognostic factors for patients with distant lymph node-involved gastric cancer (GC) using a machine learning algorithm, a method that offers considerable advantages and new prospects for high-dimensional biomedical data exploration. Materials and Methods: This study employed 79 features of clinical pathology, laboratory tests, and therapeutic details from 289 GC patients whose distant lymphadenopathy was presented as the first episode of recurrence or metastasis. Outcomes were measured as anycause death events and survival months after distant lymph node metastasis. A prediction model was built based on possible outcome predictors using a random survival forest algorithm and confirmed by 5×5 nested cross-validation. The effects of single variables were interpreted using partial dependence plots. A contour plot was used to visually represent survival prediction based on 2 predictive features. Results: The median survival time of patients with GC with distant nodal metastasis was 9.2 months. The optimal model incorporated the prealbumin level and the prothrombin time (PT), and yielded a prediction error of 0.353. The inclusion of other variables resulted in poorer model performance. Patients with higher serum prealbumin levels or shorter PTs had a significantly better prognosis. The predicted one-year survival rate was stratified and illustrated as a contour plot based on the combined effect the prealbumin level and the PT. Conclusions Machine learning is useful for identifying the important determinants of cancer survival using high-dimensional datasets. The prealbumin level and the PT on distant lymph node metastasis are the 2 most crucial factors in predicting the subsequent survival time of advanced GC.Trial Registration: ChiCTR Identifier: ChiCTR1800019978

Objective To investigate the difference in the prognosis of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) caused by hepatitis recurrence after withdrawal of nucleos(t)ide analogues (NUC) and possible causes in HBeAg-positive versus HBeAg-negative chronic hepatitis B (CHB) patients. Methods A total of 108 CHB patients with HBV-ACLF caused by withdrawal of NUC who were admitted to The First Affiliated Hospital of Nanchang University from January 2017 to December 2018 were enrolled, and according to HBeAg status, these patients were divided into HBeAg-positive group with 57 patients and HBeAg-negative group with 51 patients. The two groups were compared in terms of sex, age, clinical manifestation, signs, levels of total bilirubin, direct bilirubin, alanine aminotransferase, aspartate aminotransferase, prothrombin time, activated partial thromboplastin time, prothrombin time/international normalized ratio, and HBV DNA quantification on admission, complications (including hepatic encephalopathy, hepatorenal syndrome, and spontaneous bacterial peritonitis), and prognosis of HBV-ACLF. In addition, 48 CHB patients with continuous NUC antiviral therapy for > 2 years and HBV DNA < 20 IU/mL were enrolled, and the serum level of HBV pgRNA was measured to investigate the possible causes of the difference in the prognosis of HBV-ACLF between the patients with different HBeAg statuses. The two-independent-samples t test was used for comparison of normally distributed continuous data between two groups, and the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test was used for comparison of categorical data. Results For the 108 patients with HBV-ACLF caused by drug withdrawal and recurrence, the HBeAg-positive group had an improvement rate of 49.1% and the HBeAg-negative group had an improvement rate of 74.5%. The HBeAg-negative group had a significantly higher improvement rate than the HBeAg-positive group ( χ 2 =2.811, P =0.006). The HBeAg-positive group had a significantly higher level of HBV DNA than the HBeAg-negative group on admission ( t =-3.138, P =0.002). For the 48 CHB patients who achieved virologic response after long-term antiviral therapy, the HBeAg-positive group had a significantly higher HBV pgRNA load than the HBeAg-negative group ( H =2.814, P =0.049). Conclusion Compared with the HBeAg-positive CHB patients, HBeAg-negative CHB patients have a significantly better improvement rate of HBV-ACLF caused by hepatitis recurrence after withdrawal of NUC antiviral therapy. The difference in baseline HBV pgRNA level may be associated with the difference in the prognosis of HBV-ACLF in patients with different HBeAg statuses.

Background::The calcineurin inhibitor (CNI)-based immune maintenance regimen that is commonly used after renal transplantation has greatly improved early graft survival after transplantation; however, the long-term prognosis of grafts has not been significantly improved. The nephrotoxicity of CNI drugs is one of the main risk factors for the poor long-term prognosis of grafts. Sirolimus (SRL) has been employed as an immunosuppressant in clinical practice for over 20 years and has been found to have no nephrotoxic effects on grafts. Presently, the regimen and timing of SRL application after renal transplantation vary, and clinical data are scarce. Multicenter prospective randomized controlled studies are particularly rare. This study aims to investigate the effects of early conversion to a low-dose CNI combined with SRL on the long-term prognosis of renal transplantation.Methods::Patients who receive four weeks of a standard regimen with CNI + mycophenolic acid (MPA) + glucocorticoid after renal transplantation in multiple transplant centers across China will be included in this study. At week 5, after the operation, patients in the experimental group will receive an additional administration of SRL, a reduction in the CNI drug doses, withdrawal of MPA medication, and maintenance of glucocorticoids. In addition, patients in the control group will receive the maintained standard of care. The patients’ vital signs, routine blood tests, routine urine tests, blood biochemistry, serum creatinine, BK virus (BKV)/cytomegalovirus (CMV), and trough concentrations of CNI drugs and SRL at the baseline and weeks 12, 24, 36, 48, 72, and 104 after conversion will be recorded. Patient survival, graft survival, and estimated glomerular filtration rate will be calculated, and concomitant medications and adverse events will also be recorded.Conclusion::The study data will be utilized to evaluate the efficacy and safety of early conversion to low-dose CNIs combined with SRL in renal transplant patients.Trial registration::Chinese Clinical Trial Registry, ChiCTR1800017277.

Purpose: While several prognostic models for the stratification of death risk have been developed for patients with advanced gastric cancer receiving first-line chemotherapy, they have seldom been tested in the Chinese population. This study investigated the performance of these models and identified the optimal tools for Chinese patients. Materials and Methods: Patients diagnosed with metastatic or recurrent gastric adenocarcinoma who received first-line chemotherapy were eligible for inclusion in the validation cohort. Their clinical data and survival outcomes were retrieved and documented. Time-dependent receiver operating characteristic (ROC) and calibration curves were used to evaluate the predictive ability of the models. Kaplan-Meier curves were plotted for patients in different risk groups divided by 7 published stratification tools. Log-rank tests with pairwise comparisons were used to compare survival differences. Results: The analysis included a total of 346 patients with metastatic or recurrent disease.The median overall survival time was 11.9 months. The patients were different into different risk groups according to the prognostic stratification models, which showed variability in distinguishing mortality risk in these patients. The model proposed by Kim et al. showed relative higher predicting abilities compared to the other models, with the highest χ 2 (25.8) value in log-rank tests across subgroups, and areas under the curve values at 6, 12, and 24 months of 0.65 (95% confidence interval [CI]: 0.59–0.72), 0.60 (0.54–0.65), and 0.63 (0.56–0.69), respectively. Conclusions Among existing prognostic tools, the models constructed by Kim et al., which incorporated performance status score, neutrophil-to-lymphocyte ratio, alkaline phosphatase, albumin, and tumor differentiation, were more effective in stratifying Chinese patients with gastric cancer receiving first-line chemotherapy.

Objective:To investigate the changes of related indicators of right heart hypofunction in patients with primary myelofibrosis (PMF).Methods:The clinical data of 55 PMF patients in the Second People's Hospital of Lianyungang in Jiangsu Province and Jiangsu Province Hospital from January 2015 to August 2019 were retrospectively analyzed. The differences in right heart function-related echocardiographic indexes and biochemical indexes between pre-fibrosis/early stage fibrosis patients and obvious stage fibrosis patients were compared. Single factor linear regression method was used to analyze the correlations of pulmonary artery pressure with biochemical indexes.Results:The hemoglobin level [119 g/L (47-224 g/L) vs. 78 g/L (33-182 g/L)] and platelet count [233×10 12/L (5×10 12/L-984×10 12/L) vs. 117×10 12/L (7×10 12/L-731×10 12/L)] of patients in the pre-fibrosis/early stage fibrosis group were higher than those in the obvious stage fibrosis group, and the differences were statistically significant (both P<0.05). Among 22 patients with complete results of cardiac ultrasound, 90.9% (20/22) patients had increased pulmonary artery pressure, 72.7% (16/22) patients had increased left atrial diameter, and 90.9% (20/22) patients had increased right ventricular diastolic diameter. There were no patients with abnormal ejection fraction. The pulmonary artery pressure [48 mmHg (46-90 mmHg) vs. 33 mmHg (20-50 mmHg) (1 mmHg = 0.133 kPa)], left ventricular diastolic diameter [46 mm (36-50 mm) vs. 47 mm (43-53 mm)] and fractional shortening rate [38.1% (36.0%-38.9%) vs. 35.4% (32.7%-37.8%)] of patients in the pre-fibrosis/early stage fibrosis group were higher than those in the obvious stage fibrosis group, and the differences were statistically significant (all P < 0.05). The pulmonary artery pressure of patients had positive correlations with age ( r = 0.590), serum ferritin (SF) ( r = 0.608), lactate dehydrogenase (LDH) ( r = 0.711) and soluble growth-stimulating expression gene 2 (ST-2) ( r = 0.580)(all P<0.05), and had negative correlation with platelet count ( r = -0.596, P = 0.003). Conclusion:PMF patients are prone to right heart hypofunction, the pulmonary artery pressure is higher in older patients and patients with high SF, LDH and ST-2 levels and low platelet count.

Objective:To investigate the risk factors for tumor recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer, and application value of a nomogram prediction model.Methods:The retrospective case-control study was conducted. The clinicopathological data of 228 patients with stage Ⅱ-Ⅲ colon cancer who underwent radical resection in the First Affiliated Hospital of Xi′an Jiaotong University from January 2013 to June 2016 were collected. There were 118 males and 110 females, aged from 25 to 87 years, with a median age of 62 years. All patients underwent open or laparoscopic-assisted radical resection of colon cancer. Observation indicators: (1) postoperative tumor recurrence; (2) risk factors analysis for tumor recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer; (3) development and evaluation of a nomogram prediction model for tumor recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer. Follow-up using outpatient examination and telephone interview was performed to detect postoperative 3-year tumor recurrence up to June 2019. Measurement data with skewed distribution were represented as M (range). Count data were described as absolute numbers, and comparison between groups was analyzed using the Pearson chi-square test or Fisher exact probability. Multivariate analysis was performed using Logistic stepwise regression analysis. The independent risk factors were included into R 3.6.1 software to construct a nomogram prediction model. The receiver operating characteristic curve (ROC) was drawed, and the area under curve (AUC) was used to evaluate discrimination of the nomogram prediction model. The calibration chart with R software was used to evaluate consistency of the nomogram prediction model. Results:(1)Postoperative tumor recurrence: 53 of 228 patients had postoperative tumor recurrence including 19 cases with locoregional recurrence and 34 cases with distant metastasis. Of the 34 patients with distant metastasis, there were 14 cases with liver metastasis, 7 cases with lung metastasis, 4 cases with brain metastasis, and 9 cases with multiple metastasis or isolated metastasis in other sites. The time to recurrence was 12 months (range, 6-19 months). (2) Risk factors analysis for tumor recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer:results of univariate analysis showed that bowel obstruction, preoperative carcinoembryonic antigen (CEA) level, ascites, vascular invasion were related factors for tumor recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer ( χ2=4.463, 13.622, 10.914, 5.911, P<0.05). Pathological N stage was also a related factor for tumor recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer ( P<0.05). Results of multivariate analysis showed that preoperative CEA level >5 μg/L, ascites, vascular invasion and pathological N stage as stage N1 or N2 were independent risk factors for tumor recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer ( odds ratio=3.129, 3.071, 7.634, 3.439, 15.467, 95% confidence interval as 1.328-7.373, 1.047-9.007, 1.103-52.824, 1.422-8.319, 3.498-68.397, P<0.05). (3) Development and evaluation of a nomogram prediction model for tumor recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer: based on preoperative CEA level, ascites, vascular invasion and pathological N stage of multivariate analysis, a nomogram prediction model for tumor recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer was developed using R 3.6.1 software. The nomogram score was 41.7 for preoperative CEA level >5 μg/L, 41.0 for ascites, 74.2 for vascular invasion, 45.1 and 100.0 for pathological N stage as stage N1 and N2, respectively. The total of different scores for risk factors corresponded to the probability of postoperative recurrence. The ROC of nomogram for recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer was drawed,with the AUC of 0.805(95% confidence interval as 0.737-0.873, P<0.05). The calibration chart showed a good consistency between the probability of recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer predicted by nomogram and the actual probability of postoperative recurrence. Conclusions:Preoperative CEA level >5 μg/L, ascites, vascular invasion and pathological N stage as stage N1 or N2 are independent risk factors for tumor recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer. The nomogram prediction model contributes to prediction of the recurrent risks after radical resection of stage Ⅱ-Ⅲ colon cancer.