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

Prostate cancer is the most prevalent malignant tumor among men, ranking first in incidence and second in mortality globally. Novel hormone therapies (NHT) targeting the androgen receptor (AR) pathway have become the standard of care for metastatic prostate cancer. This review offers a comprehensive overview of NHT, including abiraterone, enzalutamide, apalutamide, darolutamide, and rezvilutamide, which have demonstrated efficacy in delaying disease progression and improving patient survival and quality of life. Nevertheless, resistance to NHT remains a critical challenge. The mechanisms underlying resistance are complex, involving AR gene amplification, mutations, splice variants, increased intratumoral androgens, and AR-independent pathways such as the glucocorticoid receptor, neuroendocrine differentiation, DNA repair defects, autophagy, immune evasion, and activation of alternative signaling pathways. This review discusses these resistance mechanisms and examines strategies to counteract them, including sequential treatment with novel AR-targeted drugs, chemotherapy, poly ADP-ribose polymerase inhibitors, radionuclide therapy, bipolar androgen therapy, and approaches targeting specific resistance pathways. Future research should prioritize elucidating the molecular basis of NHT resistance, optimizing existing therapeutic strategies, and developing more effective combination regimens. Additionally, advanced sequencing technologies and resistance research models should be leveraged to identify novel therapeutic targets and improve drug delivery efficiencies. These advancements hold the potential to overcome NHT resistance and significantly enhance the management and prognosis of patients with advanced prostate cancer.

Primary aldosteronism (PA) mainly includes aldosteronoma (APA) and idiopathic aldosteronism (IHA). APA often presents as unilateral adrenal nodules, but can also be accompanied by non-functional adrenal nodules, which leads to difficulty of the identification. In this paper, the clinical characteristics, diagnosis and treatment process of two cases of PA with non-functional adrenal nodules were analyzed and discussed to provide some references for the accurate diagnosis and treatment of PA.

Purpose To use CT-arterial phase images of pre-treatment ovarian cancer patients,combined with deep learning algorithms and machine learning to build a model to predict the efficacy of neoadjuvant chemotherapy in ovarian cancer.Materials and Methods A total of 302 consecutive patients who underwent surgery and were pathologically diagnosed with ovarian cancer from March 2013 to August 2019 in Tianjin Medical University were retrospectively collected.All patients were partitioned into training and test sets according to the ratio of 7∶3.In the python environment,VGG13 model was integrated via combining deep learning network and machine learning,and features were filtered via least absolute shrinkage and selection operator algorithm to build a prediction model for classification and prediction of CT images.The area under the curve(AUC),accuracy,sensitivity,specificity,and Fl-Score were calculated,respectively.Results The AUC,accuracy,sensitivity,specificity,and Fl-Score of the model in the training set were 0.87,0.81,0.80,0.82 and 0.79,and 0.90,0.84,0.93,0.77 and 0.83 in the test set,respectively.The AUC of five-fold cross-validation were 0.86,0.88,0.88,0.90 and 0.87,respectively.Conclusion Predictive model based on CT images combined with deep learning and machine learning methods can provide a new clinical perspective for developing chemotherapy regimens for ovarian cancer.

Objective To evaluate the efficacy of Jianpi Yang'er Ointment for children with anorexia of spleen deficiency type in Lingnan area;To analyze its effects on children's intestinal flora and functional information by means of metagenome sequencing.Methods Totolly 144 children with anorexia in Guangzhou Women and Children Medical Center of Guangzhou Medical University from August 2022 to January 2023 were orally treated with Jianpi Yang'er Ointment,one bag per time,twice a day,after meal,for 28 d.Visits were conducted at 0 and 28 days,respectively,to measure height and body mass,record symptoms and signs,observe adverse reactions,collect feces,and fill out the"Clinical Index Scoring Table for Children with Spleen Deficiency Type Anorexia in Lingnan Area".Clinically cured children were included in the anorexia group,with healthy children as a healthy control group(HC group),perform metagenomic analysis on feces of HC group and anorexia group 0 and 28 days of treatment.Results Compared with 0 d of treatment,there was no significant difference in the height of children(P>0.05),while there was a significant difference in body mass(P<0.05),the total syndrome score,main symptom score,and secondary symptom score decreased at 28 d of treatment(P<0.05).The efficacy index was 57.03%,and the total effective rate was 99.31%(143/144).All patients did not experience symptoms such as allergies,vomiting,or diarrhea.7 clinically cured children and 6 healthy children were included in metagenome analysis on feces.PCoA showed that the structure of intestinal flora in anorexia group with 28 d treatment(JP2 group)was more similar to that in HC group at the phylum and genus levels;at the phylum level,there was no significant difference in the distribution of intestinal flora between anorexia group with 0 d treatment(JP1)group and JP2 group and HC group.At the genus level,compared with JP1 group,the abundance of Bacteroides in JP2 group decreased,but the difference was not statistically significant(P>0.05);at the species level,both JP1 and JP2 groups were mainly composed of Phocaeicola plebeius et al.and Bifidobacterium pseudocatenatum et al.The biomarker with significant differences between the two groups was s_Phascolarctobacterium_faecium,while the HC group was mainly composed of Prevotella copri and Bifidobacterium pseudocatenatum.The functional annotation results indicated that a significant change in microbial functional genes related to carbohydrate metabolism occurred after the treatment with Jianpi Yang'er Ointment.Conclusion Jianpi Yang'er Ointment can effectively improve the clinical symptoms of children with spleen deficiency anorexia in Lingnan area,adjust the structure of intestinal flora,increase the content of key probiotics,and regulate the production of intestinal microbiota short-chain fatty acids.

Objective To investigate the involvement of phosphofurin acidic cluster sorting protein-2(PACS-2)in mitochondrial function and apoptosis in N2a/APP695swe cells and further explore the role and significance of PACS-2 in the development of Alzheimer's disease(AD).Methods The CCK8 method was used to analyze the cell survival rate of N2a/APP695swe cells treated with different concentrations of tetrahydroxy stilbene glycoside(TSG)for 48h and to select the appropriate concentration of TSG for subsequent experiments.N2a/WT cells and N2a/APP695swe cells were routinely cultured in vitro,and the experimental cells were divided into 3 groups:blank control group(WT group):N2a/WT cells;model group(APP group):N2a/APP695swe cells;treatment group(TSG group):N2a/APP695swe cells with appropriate concentrations of TSG intervention.TUNEL method to observe apoptosis by fluorescence microscopy;JC-1 method for flow detection of cellular mitochondrial membrane potential;WB to detect protein expression of PACS-2;RT-qPCR to detect PACS-2 mRNA expression.Results CCK8 method was used to analyze the cell survival rate of different concentrations of TSG acting on cells after 48h:the protective effect of 100 μmol/L TSG was the most significant and the difference was statistically significant(P<0.01).The TUNEL method of fluorescence microscopy observed the apoptosis:compared with the WT group,the apoptosis rate of APP group was increased,compared with the APP group,the apoptosis rate of TSG group was decreased,and the differences were statistically significant(P<0.05).The JC-1 method was used to detect the mitochondrial membrane potential of cells:compared with the WT group,the membrane potential of APP group was decreased,compared with the APP group,the membrane potential of TSG group was increased,and the differences were statistically significant(P<0.05);Western blot(WB)detection of PACS-2 protein expression:compared with the WT group,PACS-2 expression was significantly higher in the APP group,and compared with the APP group,PACS-2 expression was significantly lower in the TSG group,with statistically significant differences(P<0.05);The RT-qPCR detected the mRNA expression of PACS-2:the expression of PACS-2 was elevated in the APP group compared with the WT group and decreased in the TSG group compared with the APP group,with statistically significant differences(P<0.05).Conclusion PACS-2 has an important role in the development of AD,and its upregulation may promote the development of AD.The cerebroprotective drug TSG may exert cytoprotective effects by downregulating PACS-2 to inhibit apoptosis and improve mitochondrial function in AD model cells.

In order to realize the diagnosis of slit lamp in cross-regional patients and improve the real-time and convenience of diagnosis,a remote slit lamp diagnosis platform based on Internet of Things(IoT)technology is designed.Firstly,the feasibility of remote slit lamp is analyzed.Secondly,the IoT platform architecture of doctor/server/facility(D/S/F)is proposed and a remote slit lamp is designed.Finally,the performance of the remote slit lamp diagnostic platform is tested.The platform solves the communication problem of distributed slit lamps and realizes respectively numerical control of multi-area slit lamp by multi-eye experts.The test results show that the remote control delay of the platform is less than 20 ms,which supports multiple experts to diagnose multiple patients separately.

Mesenchymal stem cell (MSC)-based therapy has emerged as a promising treatment for spinal cord injury (SCI), but improving the neurogenic potential of MSCs remains a challenge. Mixed lineage leukemia 1 (MLL1), an H3K4me3 methyltransferases, plays a critical role in regulating lineage-specific gene expression and influences neurogenesis. In this study, we investigated the role and mechanism of MLL1 in the neurogenesis of stem cells from apical papilla (SCAPs). We examined the expression of neural markers, and the nerve repair and regeneration ability of SCAPs using dynamic changes in neuron-like cells, immunofluorescence staining, and a SCI model. We employed a coimmunoprecipitation (Co-IP) assay, real-time RT-PCR, microarray analysis, and chromatin immunoprecipitation (ChIP) assay to investigate the molecular mechanism. The results showed that MLL1 knock-down increased the expression of neural markers, including neurogenic differentiation factor (NeuroD), neural cell adhesion molecule (NCAM), tyrosine hydroxylase (TH), βIII-tubulin and Nestin, and promoted neuron-like cell formation in SCAPs. In vivo, a transplantation experiment showed that depletion of MLL 1 in SCAPs can restore motor function in a rat SCI model. MLL1 can combine with WD repeat domain 5 (WDR5) and WDR5 inhibit the expression of neural markers in SCAPs. MLL1 regulates Hairy and enhancer of split 1 (HES1) expression by directly binds to HES1 promoters via regulating H3K4me3 methylation by interacting with WDR5. Additionally, HES1 enhances the expression of neural markers in SCAPs. Our findings demonstrate that MLL1 inhibits the neurogenic potential of SCAPs by interacting with WDR5 and repressing HES1. These results provide a potential therapeutic target for promoting the recovery of motor function in SCI patients.
Animals ; Humans ; Rats ; Cell Differentiation ; Intracellular Signaling Peptides and Proteins/therapeutic use* ; Leukemia/metabolism* ; Mesenchymal Stem Cells ; Neurogenesis ; Stem Cells ; Transcription Factor HES-1/metabolism*

Objective:To explore the application value of 3D-slicer software in measuring renal volume parameters of renal transplant donors in evaluating renal function.Methods:The data of 31 renal donors admitted to Beijing Friendship Hospital, Capital Medical University from October 2019 to September 2022 were retrospectively analyzed. Glomerular filtration rate (GFR) were measured by SPECT radioactive dynamic imaging, and renal cortex volume (RCV), renal parenchymal volume (RPV) were measured after 3D reconstruction of urinary enhanced CT based on 3D slicer software. The estimated GFR(eGFR) predicted by creatinine-based GFR estimation equations (C-G equation, modified and simplified MDRD equation) and volume-based GFR estimation equations (Herts equation, Choi equation). Different eGFR were calculated, and the correlation between kidney volume parameters, eGFR equations and measured GFR was analyzed. The deviation, accuracy and consistency between different equations eGFR and measured GFR were analyzed and compared. The measurement data of normal distribution were expressed as mean±standard deviation ( ± s), and t-test was used for inter-group comparison. Measurement data with non-normal distribution were represented by M( Q1, Q3), and non-parametric test was used for comparison between groups. Results:The correlation between different eGFR and measured GFR is poor, and the deviation is small, and with good accuracy and consistency. Except for the weak correlation between the Choi equation eGFR and measured GFR ( r=0.382, P=0.034), there was no significant correlation between eGFR by other equations and measured GFR ( P>0.05). Among them, the deviation between the Herts equation-eGFR and measured GFR was the smallest (0.30 mL·min -1·1.73 m -2), with a 10% coincidence rate (61.29%) and a 30% coincidence rate (96.77%), and the best consistency with measured GFR, with a consistency limit of -28.75 to 29.34 mL·min -1·1.73 m -2. Conclusion:Compared with the laboratory index formula method, the Herts equation has better prediction efficiency in estimating GFR, The measurement of renal volume parameters by 3D slicer software has a certain clinical value in evaluating the renal function of renal donors, which is worthy of further application.

Objective To explore the clinical efficacy of Delta endoscopic lumbar decompression fusion for the treatment of giant lumbar disc herniation(GILDH).Method A retrospective analysis was performed on 36 cases of GILDH from April 2020 to May 2022,including 18 cases in the Delta group and 18 cases in the open group.There was no statistically significant difference in gender,age,and responsible section between the two groups of patients.Compare the surgical time,perioperative indicators,and clinical efficacy between the two groups.Results The intraoperative bleeding and drainage volume in the Delta group were lower than those in the open group,the incision length and hospital stay were shorter than those in the open group,the degree of paraspinal muscle injury was lighter than that in the open group,and the surgical time was longer than that in the open group,with statistical significance(P＜0.05);The lumbago visual analogue scale(VAS)of the two groups of patients at each postoperative period was significantly reduced compared to preoperative,and the lumbar spine function score of the Japanese Orthopaedic Association(JOA)was significantly increased compared to preoperative,with statistical significance(P＜0.05);The lumbago VAS of the Delta group was significantly lower than that of the open group at all postoperative stages,and the lumbar spine function JOA score was significantly higher than that of the open group,with statistical significance(P＜0.05);There was no statistically significant difference in the modified MacNab score between the two groups of patients at the last follow-up after surgery(P＞0.05).Conclusion Delta endoscopic lumbar decompression fusion for GILDH has significant therapeutic effects,with advantages such as less bleeding,small surgical incision,and fast postoperative recovery;After crossing the Delta endoscopic learning curve and optimizing the surgical process,this technology can become an alternative to conventional open surgery.