Cancer is characterized by abnormal cell proliferation. Cyclins and cyclin-dependent kinases (CDKs) have been recognized as essential regulators of the intricate cell cycle, orchestrating DNA replication and transcription, RNA splicing, and protein synthesis. Dysregulation of the CDK pathway is prevalent in the development and progression of human cancers, rendering cyclins and CDKs attractive therapeutic targets. Several CDK4/6 inhibitors have demonstrated promising anti-cancer efficacy and have been successfully translated into clinical use, fueling the development of CDK-targeted therapies. With this enthusiasm for finding novel CDK-targeting anti-cancer agents, there have also been exciting advances in the field of targeted protein degradation through innovative strategies, such as using proteolysis-targeting chimera, heat shock protein 90 (HSP90)‍-mediated targeting chimera, hydrophobic tag-based protein degradation, and molecular glue. With a focus on the translational potential of cyclin- and CDK-targeting strategies in cancer, this review presents the fundamental roles of cyclins and CDKs in cancer. Furthermore, it summarizes current strategies for the proteasome-dependent targeted degradation of cyclins and CDKs, detailing the underlying mechanisms of action for each approach. A comprehensive overview of the structure and activity of existing CDK degraders is also provided. By examining the structure‍‒‍activity relationships, target profiles, and biological effects of reported cyclin/CDK degraders, this review provides a valuable reference for both CDK pathway-targeted biomedical research and cancer therapeutics.
Humans ; Neoplasms/metabolism* ; Cyclin-Dependent Kinases/antagonists & inhibitors* ; Cyclins/metabolism* ; Proteolysis ; Antineoplastic Agents/pharmacology* ; Molecular Targeted Therapy ; Proteasome Endopeptidase Complex/metabolism* ; Animals

OBJECTIVE: To identify the protective effect of empagliflozin on ischemic brain injury and neurological dysfunction in mice, and further explore its potential mechanism. METHODS: Acute cerebral ischemia model was induced by the permanent middle cerebral artery occlusion surgery in C57BL/6J mice. Empagliflozin(10 and 30 mg·kg−1) was administered to mice one hour after the onset of occlusion. Brain infarct volume and neurological defect score were assayed 24 h after surgery. Mice were subjected to photo-thrombosis and further administered with empagliflozin 3, 10, 30 mg·kg−1 intragastricly for either 7 or 14 consecutive days. The grid-walking task and the cylinder task were performed daily to determine the sensory-motor function of the mice. Alternatively, the mice were treated with 10 mg·kg−1 empagliflozin simultaneously with 10% glucose(i.p.) for 7 consecutive days after the photo-thrombosis model to evaluate their motor sensory function. Immunofluorescence staining was used to detect the activation of microglia within the infarct area 7 d after the photo-thrombosis. RESULTS: One hour after permanent middle cerebral artery occlusion surgery, gavage of empagliflozin significantly increased the brain infarct volume and neurological dysfunction. While in photo-thrombosis surgery, treatment of empagliflozin(10 mg·kg−1) for consecutive 7 or 14 days significantly decreased the rate of false foot in grid-walking task and the assymetric index in cylinder task. At the dose of 30 mg·kg−1, however, empagliflozin even aggravated photo-thrombosis-induced neurological dysfunction, while the dose of 3 mg·kg−1 showed no effect. Unexpectedly, the protective effect of empagliflozin(10 mg·kg−1) could not be reversed by glucose treatment. The results of immunofluorescence showed that empagliflozin(10 mg·kg−1) significantly alleviated the microglia activation in the ischemic area after the photo-thrombosis operation. CONCLUSION Empagliflozin cannot protect against acute ischemia-induced brain injury in mice. Empagliflozin alleviated ischemia-induced neurological dysfunction with consecutive administration in a dose-related manner. Empagliflozin-conferred neuroprotection may not be attributable to its effects on lowing blood glucose. Alternatively, empagliflozin may play a neuroprotective effect by inhibiting the excessive activation of microglia in ischemic brains.

Objective:To analyze the whole genome sequence and key site mutations of hepatitis B virus (HBV) in patients with different stages of disease progression, and to understand the relationship between HBV genetic characteristics and disease progression.Methods:Serum samples and basic information of hepatitis B patients with asymptomatic HBV carrier, chronic hepatitis B patients, cirrhosis patients and primary hepatocellular carcinoma patients were collected. Nested PCR was used to amplify the samples to obtain HBV whole gene sequences. Phylogenetic trees were constructed to determine the genotype of the samples, and gene mutations of the samples were analyzed combined with reference sequences of each type.Results:A total of 256 samples were successfully amplified, including 68 asymptomatic HBV carrier patients, 118 CHB patients, 15 LC patients and 55 HCC patients, and five genotypes (B, C, D, I and C/D) were detected. The result of comparative analysis showed that the mutation rate of 56 nucleotide sites was significantly different among the four groups ( P<0.05). In addition to the discovery of C105T, A1762T/G1764A and G1899A and other previously reported key site mutations, the mutation rates of T53A, C1485T and C1628T in newly diagnosed HCC group were significantly higher than those in other groups, and the mutation rates of T2150G and T2151C in asymptomatic HBV infection group were significantly higher than those in other groups. A total of 26 sequences were deleted, mainly distributed in the pre-C and pre-S regions. The deletion mutation rate in the HCC group was significantly higher than that in the other groups. Conclusions:The data of this study indicate that some nucleotide substitution mutations and deletion mutations may be closely related to the occurrence and development of HBV-related diseases, and HCC patients are more likely to have gene mutations than non-HCC patients. These result provide a reference for understanding the relationship between viral mutation and the progression of HBV infection-related diseases.

Objective:To compare the diagnostic values of C-TIRADS, ACR-TIRADS and EU-TIRADS.Methods:According to the classification methods of the 3 guidelines, the ultrasonographic features of 283 thyroid nodules from 266 patients in Sir Run Run Shaw Hospital from January 2019 to June 2020 were analyzed retrospectively. The pathological results were taken as the gold standard, the malignant percentage of different classification was calculated, the ROC curve was plotted, the area under the ROC curve (AUC) and the best diagnostic cut-off value were calculated, and the diagnostic values of the three guidelines were compared. According to the FNA recommendations of the guidelines, the recommended number of thyroid nodules and the detection rate of malignant nodules in different guidelines were analyzed.Results:The AUCs of C-TIRADS, ACR-TIRADS and EU-TIRADS were 0.80, 0.66, 0.61, respectively. The AUC of C-TIRADS was higher than those of ACR-TIRADS and EU-TIRADS ( P<0.001, P<0.001). The best diagnostic cutoff values of C-TIRADS, ACR-TIRADS and EU-TIRADS were 4C, 5 and 5, respectively. Under the critical points, the sensitivities of the 3 guidelines were 95.27%, 98.10%, 99.53%, the specificities were 54.17%, 33.33%, 20.83%, respectively. There was no significant difference in the number of FNA recommendations among the 3 guidelines(all P>0.05), their FNA recommendations were highly consistent (Kappa>0.9). Conclusions:The diagnostic value of C-TIRADS in the classification of benign and malignant thyroid nodules is higher than those of ACR-TIRADS and EU-TIRADS. The best critical value for diagnosis of thyroid nodules is C-TIRADS 4C. The three guidelines are similar in the number of FNA recommendations and the detection rate of malignancy.

Objective To investigate the clinical efficacy of transthoracic echocardiography (TTE) in catheter interventional treatment of congenital heart disease. Methods 57 patients with congenital heart disease were selected by preoperative TTE screening and then received Amplatzer occluder interventional treatment under X-ray monitoring. 23 of them were atrial septal defect (ASD), 29 were ventricular septal defect (VSD), 4 were patent ductus arteriosus (PDA), and one was VSD complicated with ASD. Results All the patients were treated successfully. The occlusion effect was observed by follow-up immediately after the procedure, and one week, one month, three months, six months, and one year after the procedure. The position of the occluder did not change, the surrounding of the occluder has no residual shunt. 3 cases of ASD and 2 of VSD were failed to plugged. Conclusions TTE has important clinical values in selection of the patients with indication , intraoperative detection of the release of Amplatzer, and postoperatve assessment of the efficacy.

Objective To invcstigate the effects of Maixiansan on insulin-like growth factor binding protein 7 (IGFBP7) and apoptosis in rats with ulcerative colitis related colorectal cancer.Methods The rat model of ulcerative colitis-related coloreetal cancer was induced by dextran sulfate sodium (DSS) and azoxymethane(AOM). 40 male SD rats [weight (160 ± 10) g] were randomly divided into 4 groups: model, Maixiansan and Meisalazine treatment as well as normal group peritoneally irjected with saline.The expression of IGFBP7 and apoptosis in coloreetal tissue were detected by real-time PCR and TUNEL after 16 weeks. Results The numbers of colorectal cancer in model group( 1.2 ± 0.4 ),in Maixiansan group ( 0.70 ± 0.15 ),in Meisalazine group ( 0.60 ± 0.16 )were higher than in normal control (P ＜ 0.05), but no differences were found among model,Maixiansan and Meisalazine groups(P＞0.05).The apoptosis in colonic mucosa for Meixiansan(8.70±3.47) group and Mesalazine group were enhanced as compared with that in model group( 1.20 ±0.26 vs.0.38±0.11,P＜0.05).The mRNA expression of IGFBP7 in colon for Meixiansan group were higher than those in model group,Meisalazine group,and normal control(50.5 ± 14.0 vs.18.0 ±3.9 and 39.3±11.4,46.4±6.0,P＜0.05). Conclusions Maixiansan may resist the occurrence and development of ulcerative colitis-related colorectal cancer through upregulating IGFBP7 expression of colorectal tissue and promoting apoptosis of tumor cell.