Expression and significance of cyclin dependent kinase inhibitor 3 in HPV16-positive cervical cancer / 重庆医学

Objective To investigate the expression and significance of cyclin dependent kinase inhibitor 3(CDKN3)in human papillomavirus type 16(HPV16)-positive cervical cancer.Methods CDKN3 expression in pan-cancer was retrieved and downloaded from the Gene Expression Profiling Interactive Analysis(GEPIA)platform,and the expression levels of CDKN3 between normal cervical tissues(13 samples)and cervical cancer tissues(306 samples)were compared.Subsequently,GSE39001 data of HPV16-positive cervical cancer was sourced and downloaded from the Gene Expression Omnibus(GEO)database,and the expression levels of CDKN3 mRNA in HPV16-positive cervical cancer tissues(43 samples)and normal cervical tissues(12 samples)were compared.Immunohistochemical method was used to detect the expression of CDKN3 in 12 ca-ses of HPV16-positive cervical cancer,12 cases of HPV16-positive cervical precancerous lesions,10 cases of HPV16-positive chronic cervicitis and 7 cases of HPV-negative normal cervical samples collected from the Af-filiated Hospital of Guizhou Medical University.SiHa(HPV16-positive),HeLa(HPV18-positive)and HCC94(HPV-negative)cervical cancer cell lines were selected,and their CDKN3 expression were detected by West-ern blot.Results The GEPIA platform analysis showed that CDKN3 was highly expressed in pan-cancer,and the expression level of CDKN3 in cervical cancer tissue was significantly higher than that in normal cervical tissue(P<0.05).The GEO dataset reflected a significantly increased CDKN3 mRNA expression level in HPV16-positive cervical cancer compared to normal cervical tissue(P<0.001).Immunohistochemical verifi-cation showed that the positive expression rates of CDKN3 in HPV16-positive cervical cancer,HPV16-positive cervical precancerous lesion,HPV16-positive chronic cervicitis and HPV-negative normal cervical tissues were 91.7%,58.3%,0 and 0,respectively.Western blot analysis of cervical cancer cells showed that the expression level of CDKN3 in SiHa(HPV16-positive)cells was significantly higher than that in HeLa(HPV18-positive)and HCC94(HPV-negative)cells(P<0.05).Conclusion CDKN3 is a new oncogene of HPV16-positive cer-vical cancer,which may be used as a marker of cervical precancerous lesions and cervical cancer screening,and may provide a theoretical basis for subsequent mechanism research and targeted therapy.

Study on the role of miR-567 in proliferation,migration and cell cycle of NSCLC through regulation of CDK8 and its clinical relevance / 国际检验医学杂志

Objective To investigate the role of microRNA(miR)-567 in the proliferation,migration and cell cycle of non-small cell lung cancer(NSCLC)through regulation of cyclin dependent kinase 8(CDK8)and its clinical relevance.Methods Tumor tissues and adjacent tissues of 40 NSCLC patients were collected,and the expressions of miR-567 and CDK8 were detected by real-time quantitative fluorescent PCR(qRT-PCR).miR-NC mimic,miR-567 mimic,oe-NC,and oe-CDK8 were transfected into A549 and H1975 cells.The ex-pressions of miR-567 and CDK8 were detected using qRT-PCR.Cell proliferation was detected by CCK-8 method,and cell migration was detected by Transwell assay.Cell cycle changes were detected by flow cytome-try.The targeting of miR-567 and CDK8 was detected by luciferase reporter gene assay.Results In the tumor tissues of NSCLC patients,the expression of miR-567 was decreased,while the expression of CDK8 was in-creased,and the two were negatively correlated(P＜0.05).In A549 and H1975 cells,miR-567 mimic group was compared with miR-NC mimic group,the expression of miR-567 was increased,the expression of CDK8 was decreased,the proliferation and migration levels of cells were decreased,the proportion of G1 phase was increased,and the proportion of S phase was decreased.The fluorescence intensity of miR-567 mimic group was lower than that of miR-NC mimic group in normal CDK8.miR-567 mimic+oe-CDK8 group was compared with miR-567 mimic+oe-NC group,the expression of CDK8 was increased,the proliferation and migration levels of cells were increased,the proportion of cells in G1 phase was decreased,and the proportion of cells in S phase was increased.Conclusion miR-567 can inhibit NSCLC proliferation and migration by targeting CDK8 expression and controlling tumor cell arrest in the S phase.

Effects of occupational radiation exposure on peripheral blood lymphocyte count and cell cycle in logging workers / 中国辐射卫生

Objective To investigate the effects of prolonged low-dose neutron-γ radiation on peripheral blood lymphocytes of logging workers. Methods The health information of workers in a logging company was collected by on-site blood sample collection and questionnaire survey. Individual doses of γ and neutron radiation were recorded using LiF elements and CR-39, respectively. Lymphocyte count in peripheral blood was measured by blood cytometer. Cell cycle and cyclins were detected by flow cytometry. Results The annual dose of some logging workers exceeded 5 mSv. Lymphocyte counts showed a difference of 15% between the group exposed to the lowest annual dose of 0–1 mSv (mean: 2.45 × 109/L) and the group exposed to the highest annual dose of 5–25 mSv (mean: 2.08 × 109/L). In comparison to pre-shift workers, logging workers exhibited a G1-phase arrest in the lymphocyte cycle, along with increased expression of cyclins p21 and CDK2. Conclusion Prolonged exposure to low-dose neutron-γ radiation leads to reduced lymphocyte counts as well as changes in lymphocyte cycle and cyclin expression.

Study on the expression, prognosis and mechanism of minichromosome maintenance protein 10 in hepatocellular carcinoma / 中华肝胆外科杂志

Objective:To investigate the expression, prognostic value and mechanism of MCM10 in hepatocellular carcinoma (LIHC).Methods:The transcriptome and clinical data of hepatocellular carcinoma were obtained from The Cancer Genome Atlas database, and the rank sum test was used to analyze the expression level of MCM10 in tumor tissues and adjacent tissues. Cox regression analysis was used to analyze the relationship between MCM10 expression level and the survival prognosis of patients with hepatocellular carcinoma. Gene set enrichment analysis (GSEA) was utilized for pathway enrichment analysis between MCM10 high and low group gene expression profiles. The effect of MCM10 knockdown on the proliferation of HepG2 cells was determined by cell counting kit-8 (CCK-8) cell viability assay. The effect of MCM10 knockdown on the expression of G1/S-specific cyclin D1 was detected by Western blot.Results:The expression value of MCM10 in hepatocellular carcinoma was 0.709±0.595, and that in adjacent tissues was 0.077±0.094 ( P<0.0 001). Cox regression analysis showed that high expression of MCM10 was a risk factor and prognostic predictor of overall survival ( HR=1.32, 95% CI: 1.19~1.48) and disease-specific survival ( HR=1.40, 95% CI: 1.22~1.61) in LIHC. GSEA analysis showed that the differentially expressed genes were mainly enriched in cell cycle, p53 signaling pathway and positive regulation of G1-S phase transition, et al. CCK-8 assay showed that MCM10 knockdown could inhibit the proliferation of HepG2 cells. Western blot analysis further confirmed that knockdown of MCM10 expression inhibited the expression of cyclin D1 in HepG2 cells. Conclusions:MCM10 is a risk factor for the prognosis of patients with hepatocellular carcinoma, which can promote the proliferation of hepatoma cells through cyclin D1.

CDK12/CDK13: New Hope for Targeted Therapy of Human Malignant Tumors / 肿瘤防治研究

Cell cycle turnover depends on cyclin-dependent kinase (CDKs). CDK is the protein kinase family that plays the key role in regulating cell cycle and gene transcription. CDK12 and CDK13 perform the essential work in DNA damage response, RNA splicing regulation, transcription, and cell cycle regulation. In recent years, CDK12 and CDK13 are expressed abnormally or mutated in a variety of cancers; thus, they are necessary in cancer development and have become popular topics of research. Based on literature from Google Scholar, PubMed, and WanFang database, aspects of CDK12 and CDK13 such as basic structure, biological function, correlation with malignant tumors, and research progress of targeted inhibitors are summarized to provide the direction for the subsequent research of the new targets and mechanisms for targeting therapy while offering a novel approach for the prevention, diagnosis, and treatment of malignant tumors in the future.

Expression and clinical significance of cell cycle protein-dependent kinase 1 and aurora kinase A in the serum of patients with hepatitis B virus-related hepatocellular carcinoma / 临床肝胆病杂志

ObjectiveTo investigate the value of serum cell cycle protein-dependent kinase 1 （CDK1） and aurora kinase A （AURKA） in the diagnosis of patients with hepatitis B virus-related hepatocellular carcinoma （HBV-HCC）. MethodsA total of 50 HBV-HCC patients， 50 patients with hepatitis B virus-related liver cirrhosis （HBV-LC）， and 50 chronic hepatitis B （CHB） patients who were hospitalized in Department of Gastroenterology， Gansu Provincial Hospital， from June 2022 to December 2023 were enrolled， and 50 healthy individuals， matched for age and sex， who received physical examination at Physical Examination Center during the same period of time were enrolled as control group. Related data were recorded for all patients， including age， sex， complications， and the results of routine blood test， liver function， and coagulation for the first time after admission. ELISA was used to measure the serum levels of CDK1 and AURKA. A one-way analysis of variance was used for comparison of normally distributed continuous data between multiple groups， and the least significant difference t-test was used for further comparison between two groups； the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups and the least significant difference Bonferroni test was used for further comparison between two groups； the chi-square test or the Fisher’s exact test was used for comparison of categorical data between groups. The Spearman correlation analysis was used to investigate the correlation between CDK1 and AURKA， and the receiver operating characteristic （ROC） curve and the area under the ROC curve （AUC） were used to investigate the value of CDK1 and AURKA in the diagnosis of HBV-HCC. ResultsThere were significant differences in liver function parameters between the HBV-HCC patients and the control group （all P<0.05）； there were significant differences between the CHB group and the HBV-HCC group in albumin， Glb， direct bilirubin， aspartate aminotransferase （AST）， gamma-glutamyl transpeptidase （GGT）， and alkaline phosphatase （all P<0.05）； there were significant differences between the HBV-LC group and the HBV-HCC group in Glb， AST， and GGT （all P<0.05）. The HBV-HCC group had significantly higher serum levels of CDK1 and AURKA than the HBV-LC group， the CHB group， and the control group （all P<0.05）. There was a significant positive correlation between CDK1 and AURKA in the overall study population and the HBV-HCC patients （r=0.526 6 and 0.815 2， P<0.001）. With the control group as reference， CDK1 had an AUC of 0.832 3 in the diagnosis of HBV-HCC， with a sensitivity of 92.86% and a specificity of 75%， and AURKA had an AUC of 0.886 6 in the diagnosis of HCC， with a sensitivity of 95.80% and a specificity of 74%. With the CHB group as reference， CDK1 had an AUC of 0.833 3 in the diagnosis of HBV-HCC， with a sensitivity of 93.75% and a specificity of 75%， and AURKA had an AUC of 0.972 7 in the diagnosis of HBV-HCC， with a sensitivity of 95.83% and a specificity of 91.67%. With the HBV-LC group as reference， CDK1 had an AUC of 0.608 5 in the diagnosis of HBV-HCC， with a sensitivity of 66.67% and a specificity of 54.17%， and AURKA had an AUC of 0.762 2 in the diagnosis of HBV-HCC， with a sensitivity of 95.83% and a specificity of 47.92%. ConclusionThe serum levels of CDK1 and AURKA increase with the progression of hepatitis B-associated chronic liver disease， and significant increases in serum CDK1 and AURKA have a certain value in the diagnosis of HBV-HCC.

Effect and mechanism of protein kinase N1 on the proliferation of mouse cardiomyocytes / 新乡医学院学报

Objective To explore the effect and mechanism of protein kinase N1(PKN1)on the proliferation of mouse cardiomyocytes.Methods Two 1-day-old mice were anesthetized with isoflurane,and their cardiomyocytes were isolated and divided into the control group and the interference group.The cardiomyocytes in the interference group were transfected with PKN1 fragments,while the cardiomyocytes in the control group were transfected with control fragments.According to the random number table method,10 mice were divided into the normal group and the observation group,with 5 mice in each group.The mice in the observation group were injected with PKN1 adenovirus in situ in the heart,while the mice in the normal group were injected with empty adenovirus in situ in the heart.The Ki-67 positive expression in myocardial cells and tissues of mice in the four groups was detected by immunofluorescence assay,indicating the proliferation ability of cardiomyocytes.The PKN1 mRNA expression in cardiomyocytes of mice in the control group and interference group was measured by real-time fluorescence quan-titative polymerase chain reaction.The expression of PKN1 and cyclin D1 proteins in cardiomyocytes of mice in the control group and interference group was determined by Western blot.Results The positive expression rates of Ki-67 in myocardial cells of mice in the interference group was significantly lower than that in the control group(t=11.201,P＜0.01);the positive expression rate of Ki-67 in myocardial tissue of mice in the observation group was significantly lower than that in the normal group(t=11.851,P＜0.01).The relative expression level of PKN1 mRNA in cardiomyocytes of mice in the interference group was significantly lower than that in the control group(t=7.022,P＜0.01).The relative expression levels of PKN1 and cyclin D1 proteins in cardiomyocytes of mice in the interference group were significantly lower than those in the control group(t=5.762,6.884;P＜0.01).Conclusion The decreased expression of PKN1 in mouse cardiomyocytes can inhibit the expression of cyclin D1 protein,thereby restraining cardiomyocyte proliferation.

Real-World Study on Hematological Toxicities of Cyclin-dependent Kinase 4/6 Inhibitors Based on FAERS Database / 医药导报

Objective To evaluate adverse events(AEs)of hematological toxicities in cyclin-dependent kinase 4/6(CDK4/6)inhibitors based on the FDA adverse event reporting system(FAERS)database,and to provide a reference for rational drug use in the clinic.Methods A total of 29 quarterly AEs were extracted from the FAERS database from January 2015 to March 2022.Reported odds ratio(ROR)and proportional reported ratio(PRR)were used for data mining of CDK4/6 inhibitor AEs.Results A total of 7 872 AEs related to CDK4/6 inhibitors were reported,and the proportion of hematological AEs of each inhibitor was palbociclib(80.31%),ribociclib(15.36%),and abemaciclib(4.33%).Neutropenia and anemia were common in hematological toxicities.Palbociclib(2 982/6 322,47.17%)and ribociclib(613/1 209,50.70%)caused more neutropenia than abemaciclib(117/341,34.31%).Hematological toxicities mainly occurred 60 days after drug initiation(1 630,61.86%).Palbociclib had the longest median onset time,and 32.9%of patients still had hematological toxicities after 90 days of treatment.The clinical features and intensity were different among CDK4/6 inhibitors.Conclusions Palbociclib,abemaciclib,and ribociclib all cause significant hematological toxicities,among which abemaciclib has fewest reports of hematological toxicities.Still,the risk of death after anemia caused by abemaciclib should be noted.Complete blood cell count should be closely monitored within the first two months after treatment to monitor the patient's neutrophils and hemoglobin.The occurrence of hematological AEs associated with CDK4/6 inhibitors should be noted in the clinic.

Prognostic value of MET, Cyclin D1, and MET gene copy number for non-small cell lung cancer / 中国基层医药

Objective:To analyze the prognostic value of MET, Cyclin D1, and MET gene copy number (GCN) for non-small cell lung cancer (NSCLC).Methods:This study included 61 patients with NSCLC who received treatment at the Enze Hospital, Taizhou Enze Medical Center (Group) between January 2018 and June 2019. The expression levels of MET and Cyclin D1 were determined using immunohistochemistry. MET GCN was evaluated using a quantitative polymerase chain reaction. Clinicopathological characteristics were compared among patients with different expression levels of these proteins. The Spearman correlation coefficient was used to assess the relationship between MET, Cyclin D1, and MET GCN. The Kaplan-Meier method was used to analyze survival rates. Univariate and multivariate Cox regression analyses were conducted to investigate the correlation between MET, Cyclin D1, and MET GCN and survival rates.Results:Thirty-six cases (59.02%) tested positive for MET, which was mainly expressed in the cytoplasm and membrane. Similarly, 36 cases (59.02%) were positive for Cyclin D1, which was mainly expressed in the cytoplasm. Patients with MET ( χ2 = 6.89, P = 0.009) and MET/Cyclin D1 ( χ2 = 4.05, P = 0.004) had a high proportion of poorly differentiated histology. Moreover, patients with MET GCN ≥ 3 had a relatively high proportion of lymph node metastasis ( χ2 = 8.11, P = 0.004) and TNM stages III-IV ( χ2 = 3.91, P = 0.048). Furthermore, patients with MET GCN ≥ 3/Cyclin D1 also had a high proportion of lymph node metastasis ( χ2 = 6.73, P = 0.009). MET was significantly associated with MET GCN ( r = 0.39, P = 0.002) and Cyclin D1 ( r = 0.39, P = 0.002), while MET GCN was significantly associated with Cyclin D1 ( r = 0.30, P = 0.017). The median survival time of patients with and without MET was 24.0 and 32.5 months, respectively, while the median survival time of patients with MET GCN ≥ 3 and < 3 was 11.0 and 30.5 months, respectively. Multivariate analysis showed that TNM stages III-IV, positive expression of MET, and MET GCN ≥ 3 were significantly associated with a high risk of death. Conclusion:The positive expression of MET and MET GCN ≥ 3 may be adverse prognostic factors in patients with NSCLC. The activation of the MET/Cyclin D1 signaling pathway could potentially contribute to the development and progression of NSCLC.

Cervical Intraepithelial Neoplasia grade 2 biopsy: Do p16INK4a and Ki-67 biomarkers contribute to the decision to treat? A cross-sectional study

ABSTRACT BACKGROUND: Managing cervical intraepithelial neoplasia grade 2 (CIN2) is challenging, considering the CIN2 regression rate, perinatal risks associated with excisional procedures, and insufficient well-established risk factors to predict progression. OBJECTIVES: To determine the ability of p16INK4a and Ki-67 staining in biopsies diagnosed with CIN2 to identify patients with higher-grade lesions (CIN3 or carcinoma). DESIGN AND SETTING: Cross-sectional study conducted at a referral center for treating uterine cervical lesions. METHODS: In 79 women, we analyzed the correlation of p16INK4a and Ki-67 expression in CIN2 biopsies with the presence of a higher-grade lesions, as determined via histopathology in surgical specimens from treated women or via two colposcopies and two cytological tests during follow-up for untreated women with at least a 6-month interval. The expression of these two biomarkers was verified by at least two independent pathologists and quantified using digital algorithms. RESULTS: Thirteen (16.8%) women with CIN2 biopsy exhibited higher-grade lesions on the surgical excision specimen or during follow-up. p16INK4a expression positively and negatively predicted the presence of higher-grade lesions in 17.19% and 86.67% patients, respectively. Ki-67 expression positively and negatively predicted the presence of higher-grade lesions in 40% and 88.24% patients, respectively. CONCLUSIONS: Negative p16INK4a and Ki67 immunohistochemical staining can assure absence of a higher-grade lesion in more than 85% of patients with CIN2 biopsies and can be used to prevent overtreatment of these patients. Positive IHC staining for p16INK4a and Ki-67 did not predict CIN3 in patients with CIN2 biopsies.

Role of cyclin D1 in glial tumors—A retrospective and observational study

Aim: High-grade glial tumors remain as one of the most lethal malignancies. Cyclin D1 is expressed in some human malignancies and is the potential target of intervention. The present study aims to determine the relationship of cyclin D1 expression with other clinicopathological parameters. Materials and Methods: A cross-sectional study was carried out in a tertiary care center. Biopsy proven 66 cases of glial tumor patients were included in the study. The patients with incomplete clinical details were excluded from the study. Immunohistochemistry using antibodies for IDH 1 and cyclin d1 was done in all the cases. Glial tumors were reclassified according to WHO 2016 classification. Data analysis was performed using SPSS 26.0 for the windows. Result: Among 66 patients, 49 (74.3%) were males and 17 (25.7%) were females. The age of the patients ranged from 20 years to 70 years. Overall, 6.02% were of grade I Glial tumors, 22.7% were of grade II Glial tumors, 19.6% patients were of grade III Glial tumors, and 51.6% patients were of grade IV Glial tumors. Of 66 samples tested cyclin D1 was positive in 25 (37.87%) as high expressers and 7 (10.60%) were low expressers. Our study showed a significant correlation between the expression of cyclin D1 with grade and IDH mutation status, No significant correlation of cyclin D1 was noted with age or sex of the patient. Conclusion: Cyclin D1 was associated with a higher grade of the glial tumor. It can be a potential marker both for prognosis and treatment of glial tumors.

Application value of thyroid fine needle aspiration fluid-based thin layer cytology combined with p21 and Cyclin D1 detection in the preoperative diagnosis of papillary thyroid carcinoma / 临床与实验病理学杂志

Purpose To explore the application value of ultrasound-guided thyroid fine needle aspiration liquid-based thin layer cytopathology combined with p21 and Cyclin D1 detection in preoperative diagnosis of papillary thyroid carcinoma.Meth-ods Immunocytochemical staining was used to detect the ex-pression differences of p21 and Cyclin D1 between benign and malignant thyroid nodules,and their correlations the clinicopath-ological features.The diagnostic efficacy of US-FNAB,p21,Cyclin D1 and the three combined detection in benign and malig-nant thyroid nodules was evaluated by constructing receiver oper-ating curve.Results The expression of p21 and Cyclin D1 was up-regulated in the papillary thyroid carcinoma group,86.36%(57/66)and 93.94%(62/66),and 1.96%(1/52)and 5.77%(3/52)in the benign nodule group,respectively;the difference between the two groups was significant(P<0.05).The positive rates of p21 and Cyclin D1 in BRAF V600E wild type PTC were 88.89%(8/9).The expression of p21 and Cyc-lin D1 was correlated with the tumor size of PTC(P<0.05),but not with gender,age,number of tumor foci,lymph node metastasis,and TNM stage(P>0.05).The sensitivity,speci-ficity,positive predictive value and negative predictive value of US-FNAB,p21 and Cyclin D1 combined detection were 95.45%,98.07%,98.43%and 94.44%,respectively,which were higher than those of US-FNAB independent detection,and the sensitivity and negative predictive value were higher than those of BRAF V600E.The area under ROC curve of US-FNAB,p21 and Cyclin D1 combined detection(AUC = 0.967 7)was larger than that of US-FNAB(AUC = 0.849 9)and the difference between the two was statistically significant(P<0.05).The area under ROC curve of the combined detection of the three was greater than that of independent detection of BRAF V600E(AUC =0.931 8),and the combined detection of US-FNAB with p21(AUC = 0.946 4)or Cyclin D1(AUC = 0.944 3).It was close to that of US-FNAB combined BRAF V600E detection(AUC = 0.971 2).Conclusion US-FNAB combined with p21 and Cyclin D1 immunohistochemical detec-tion can help improve the sensitivity of preoperative diagnosis of papillary thyroid carcinoma,and it has high diagnostic value for BRAF V600E wild-type papillary carcinoma.

Correlation analysis between serum FOXP1 and CDK2 levels and the occurrence of osteoporosis in perimenopausal women / 中华内分泌外科杂志

Objective:To investigate the correlation between serum forkhead box protein P1 (FOXP1) and cyclin-dependent kinase2 (CDK2) and bone mineral density in perimenopausal women with osteoporosis (OP) .Methods:A total of 80 perimenopausal women treated in our hospital from Feb. 2021 to Aug. 2022 were selected as study objects. Among them, 38 were in the OP group and 42 were in the control group. The expression levels of FOXP1 and CDK2 in serum were detected by ELISA. BMD expression levels of lumbar spine (L1-L4) and femoral neck were measured by DEXA BMD analyzer. The correlation between serum FOXP1 and CDK2 and bone mineral density in perimenopausal women with osteoporosis was analyzed by Pearson method.Results:Compared with the control group, the contents of FOXP1 and CDK2 in serum of the control group were (42.94±3.37) pg/ml and (102.46±12.247) pg/ml, respectively. Serum FOXP1 and CDK2 contents in OP group were (25.91±4.38) pg/ml and (60.59±10.777) pg/ml, respectively. Compared with the control group, serum FOXP1 and CDK2 expression levels and bone mineral density of lumbar spine (L1-L4) and femoral neck in OP group were significantly decreased. The BMD of lumbar spine (L1-L4) and femoral neck of women in the control group were 0.68±0.28 and 0.43±0.99, respectively. BMD of lumbar spine (L1-L4) and femoral neck of women in the OP group were 0.40±0.10 and 0.21±0.15, respectively. Bone mineral density decreased in the lumbar spine (L1-L4) and femoral neck in the OP group. The differences were statistically significant ( P<0.05). In addition, the correlation analysis results showed that the expression level of FOXP1 in serum was positively correlated with bone mineral density of lumbar spine (L1-L4) and femoral neck ( r=0.546, 0.245, P<0.05), and the expression level of CDK2 was positively correlated with bone mineral density of lumbar spine (L1-L4) ( r=0.600, P<0.05) . Conclusions:In perimenopausal women with osteoporosis, the expression of FOXP1 and CDK2 in serum was significantly decreased, and there was a correlation with bone mineral density. It is suggested that FOXP1 and CDK2 may be used as biological indicators and clinical predictors of osteoporosis in perimenopausal women.

Roscovitine rescuing neuronal loss and neuroinflammation in brain regions associated with Parkinson’s disease mice / 解剖学报

[Abstract] Objective To investigate the effect and possible mechanism of cell cycle-dependent kinase (Cdk)5 inhibitor Roscovitine on 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced pathological changes in brain regions associated with Parkinson’ s disease (PD) model mice. Methods The effect of Roscovitine on the relative expression levels of P25 and Cdk5 proteins was detected by Western blotting in MPP

Discovery of small molecule degraders for modulating cell cycle / 医学前沿

The cell cycle is a complex process that involves DNA replication, protein expression, and cell division. Dysregulation of the cell cycle is associated with various diseases. Cyclin-dependent kinases (CDKs) and their corresponding cyclins are major proteins that regulate the cell cycle. In contrast to inhibition, a new approach called proteolysis-targeting chimeras (PROTACs) and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins, achieving targeted degradation. The field of PROTACs and molecular glues has developed rapidly in recent years. In this article, we aim to summarize the latest developments of CDKs and cyclin protein degraders. The selectivity, application, validation and the current state of each CDK degrader will be overviewed. Additionally, possible methods are discussed for the development of degraders for CDK members that still lack them. Overall, this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders, which will be helpful for researchers working on this topic.

Study on the Biological Function of Abemecilib in Inhibiting the Proliferation, Invasion and Migration of Small Cell Lung Cancer with High c-Myc Expression / 中国肺癌杂志

BACKGROUND@#Small cell lung cancer (SCLC) with high c-Myc expression is prone to relapse and metastasis, leading to extremely low survival rate. Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor Abemaciclib plays a key role in the treatment of tumors, but the effects and mechanisms on SCLC remain unclear. This study was to analyze the effect and molecular mechanism of Abemaciclib in inhibiting proliferation, migration and invasion of SCLC with high c-Myc expression, with a view to expanding a new direction for reducing the recurrence and metastasis.@*METHODS@#Proteins interacting with CDK4/6 were predicted using the STRING database. The expressions of CDK4/6 and c-Myc in 31 cases of SCLC cancer tissues and paired adjacent normal tissues were analyzed by immunohistochemistry. The effects of Abemaciclib on the proliferation, invasion and migration of SCLC were detected by CCK-8, colony formation assay, Transwell and migration assay. Western blot was used to detect the expressions of CDK4/6 and related transcription factors. Flow cytometry was used to analyze the effects of Abemaciclib on the cell cycle and checkpoint of SCLC.@*RESULTS@#The expression of CDK4/6 was associated with c-Myc by STRING protein interaction network. c-Myc can directly modalize achaete-scute complex homolog 1 (ASCL1), neuronal differentiation 1 (NEUROD1) and Yes-associated protein 1 (YAP1). Moreover, CDK4 and c-Myc regulate the expression of programmed cell death ligand 1 (PD-L1). Immunohistochemistry showed that the expressions of CDK4/6 and c-Myc in cancer tissues were higher than those in adjacent tissues(P<0.0001). CCK-8, colony formation assay, Transwell and migration assay verified that Abemaciclib could effectively inhibit the proliferation, invasion and migration of SBC-2 and H446OE(P<0.0001). Western blot analysis further showed that Abemaciclib not only inhibited CDK4 (P<0.05) and CDK6 (P<0.05), but also affected c-Myc (P<0.05), ASCL1 (P<0.05), NEUROD1 (P<0.05) and YAP1 (P<0.05), which are related to SCLC invasion and metastasis. Flow cytometry showed that Abemaciclib not only inhibited the cell cycle progression of SCLC cells (P<0.0001), but also significantly increased PD-L1 expression on SBC-2 (P<0.01) and H446OE (P<0.001).@*CONCLUSIONS@#Abemaciclib significantly inhibits the proliferation, invasion, migration and cell cycle progression of SCLC by inhibiting the expressions of CDK4/6, c-Myc, ASCL1, YAP1 and NEUROD1. Abemaciclib can also increase the expression of PD-L1 in SCLC.

Advances of the regulatory mechanism of cyclin, cyclin- dependent kinases and related kinase inhibitors in cell cycle progression / 生物工程学报

Cell cycle plays a crucial role in cell development. Cell cycle progression is mainly regulated by cyclin dependent kinase (CDK), cyclin and endogenous CDK inhibitor (CKI). Among these, CDK is the main cell cycle regulator, binding to cyclin to form the cyclin-CDK complex, which phosphorylates hundreds of substrates and regulates interphase and mitotic progression. Abnormal activity of various cell cycle proteins can cause uncontrolled proliferation of cancer cells, which leads to cancer development. Therefore, understanding the changes in CDK activity, cyclin-CDK assembly and the role of CDK inhibitors will help to understand the underlying regulatory processes in cell cycle progression, as well as provide a basis for the treatment of cancer and disease and the development of CDK inhibitor-based therapeutic agents. This review focuses on the key events of CDK activation or inactivation, and summarizes the regulatory processes of cyclin-CDK at specific times and locations, as well as the progress of research on relevant CDK inhibitor therapeutics in cancer and disease. The review concludes with a brief description of the current challenges of the cell cycle process, with the aim to provide scientific references and new ideas for further research on cell cycle process.

Repurposed benzydamine targeting CDK2 suppresses the growth of esophageal squamous cell carcinoma / 医学前沿

Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of cancer death worldwide. It is urgent to develop new drugs to improve the prognosis of ESCC patients. Here, we found benzydamine, a locally acting non-steroidal anti-inflammatory drug, had potent cytotoxic effect on ESCC cells. Benzydamine could suppress ESCC proliferation in vivo and in vitro. In terms of mechanism, CDK2 was identified as a target of benzydamine by molecular docking, pull-down assay and in vitro kinase assay. Specifically, benzydamine inhibited the growth of ESCC cells by inhibiting CDK2 activity and affecting downstream phosphorylation of MCM2, c-Myc and Rb, resulting in cell cycle arrest. Our study illustrates that benzydamine inhibits the growth of ESCC cells by downregulating the CDK2 pathway.

YAP regulates the liver size during the fasting-refeeding transition in mice

Liver is the central hub regulating energy metabolism during feeding-fasting transition. Evidence suggests that fasting and refeeding induce dynamic changes in liver size, but the underlying mechanisms remain unclear. Yes-associated protein (YAP) is a key regulator of organ size. This study aims to explore the role of YAP in fasting- and refeeding-induced changes in liver size. Here, fasting significantly reduced liver size, which was recovered to the normal level after refeeding. Moreover, hepatocyte size was decreased and hepatocyte proliferation was inhibited after fasting. Conversely, refeeding promoted hepatocyte enlargement and proliferation compared to fasted state. Mechanistically, fasting or refeeding regulated the expression of YAP and its downstream targets, as well as the proliferation-related protein cyclin D1 (CCND1). Furthermore, fasting significantly reduced the liver size in AAV-control mice, which was mitigated in AAV Yap (5SA) mice. Yap overexpression also prevented the effect of fasting on hepatocyte size and proliferation. Besides, the recovery of liver size after refeeding was delayed in AAV Yap shRNA mice. Yap knockdown attenuated refeeding-induced hepatocyte enlargement and proliferation. In summary, this study demonstrated that YAP plays an important role in dynamic changes of liver size during fasting-refeeding transition, which provides new evidence for YAP in regulating liver size under energy stress.

Progress of CDK4/6 inhibitors in treatment of hormone receptor-positive and human epithelial growth factor receptor 2-negative breast cancer / 肿瘤研究与临床

Cyclin-dependent kinase (CDK)4/6 inhibitors combined with traditional endocrine therapy can significantly improve the progression-free survival and overall survival of hormone receptor-positive and human epithelial growth factor receptor 2-negative breast cancer patients. But different drugs, dosage and medication cycle will also bring different efficacy and safety incidents to patients. At the same time, confirming whether CDK4/6 inhibitors are equally applicable to Chinese breast cancer patients is not only an academic hotspot concerned by domestic clinicians, but also a practical need in actual diagnosis and treatment. This article reviews the classic clinical trials of drugs and the latest research progress.