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

Bone repair remains an important target in tissue engineering, making the development of bioactive scaffolds for effective bone defect repair a critical objective. In this study, β-tricalcium phosphate (β-TCP) scaffolds incorporated with processed pyritum decoction (PPD) were fabricated using three-dimensional (3D) printing-assisted freeze-casting. The produced composite scaffolds were evaluated for their mechanical strength, physicochemical properties, biocompatibility, in vitro pro-angiogenic activity, and in vivo efficacy in repairing rabbit femoral defects. They not only demonstrated excellent physicochemical properties, enhanced mechanical strength, and good biosafety but also significantly promoted the proliferation, migration, and aggregation of pro-angiogenic human umbilical vein endothelial cells (HUVECs). In vivo studies revealed that all scaffold groups facilitated osteogenesis at the bone defect site, with the β-TCP scaffolds loaded with PPD markedly enhancing the expression of neurogenic locus Notch homolog protein 1 (Notch1), vascular endothelial growth factor (VEGF), bone morphogenetic protein-2 (BMP-2), and osteopontin (OPN). Overall, the scaffolds developed in this study exhibited strong angiogenic and osteogenic capabilities both in vitro and in vivo. The incorporation of PPD notably promoted the angiogenic-osteogenic coupling, thereby accelerating bone repair, which suggests that PPD is a promising material for bone repair and that the PPD/β-TCP scaffolds hold great potential as a bone graft alternative.
Calcium Phosphates/chemistry* ; Animals ; Bone Regeneration ; Rabbits ; Tissue Scaffolds ; Printing, Three-Dimensional ; Humans ; Human Umbilical Vein Endothelial Cells ; Neovascularization, Physiologic ; Osteogenesis ; Tissue Engineering/methods* ; Biomimetic Materials ; Cell Proliferation ; Angiogenesis

Objective:To investigate the rate-limiting steps of hand-assisted laparoscopic donor nephrectomy, analyze the relevant factors affecting surgical difficulty, and subsequently construct a mathematical model to predict the difficulty of the procedure preoperatively.Methods:A retrospective study was conducted on 100 kidney donors who underwent hand-assisted laparoscopic donor nephrectomy performed by the same surgeon at Beijing Friendship Hospital, Capital Medical University from January 2021 to January 2024. Preoperative demographic data, imaging findings, general condition, donor kidney size, and postoperative complications were collected and analyzed. The surgeon′s subjective rating (1-3 points) was used as a quantitative measure of surgical difficulty. ANOVA and Chi-square tests were employed to explore the differences in postoperative complications, recovery, operative time, and intraoperative blood loss among groups with varying levels of difficulty. The main procedure was divided into four steps (excluding abdominal closure): Trocar placement, renal hilar dissection, perinephric dissection, and kidney retrieval. The time for each step and the total operative time were recorded. Pearson correlation test was used to analyze the relationship between each step and the total operative time, and ANOVA test was used to assess the time differences between steps and to determine if the time for the same step varied across different difficulty subgroups, thereby identifying the rate-limiting step of hand-assisted laparoscopic donor nephrectomy. In terms of the risk factors influencing the difficulty of surgery, Pearson and Spearman correlation tests were used to investigate the relationship between preoperative donor data and surgical difficulty scores, and a predictive model was constructed using multiple linear regression. Finally, the model was internally and externally validated to confirm its accuracy and effectiveness.Results:As the surgical difficulty increased (groups 1, 2, and 3), the postoperative drainage tube duration was correspondingly prolonged [(5.92±1.48) d, (8.00±1.75) d, and (11.88±4.45) d, respectively, P<0.05], and the severity of postoperative complications also significantly increased (the incidence of Clavien-Dindo grade ≥2 was 5.66%, 31.82% and 64.00%, respectively, P<0.01). In the analysis of rate-limiting steps, the time taken for all steps, except for Trocar placement, showed significant differences among the difficulty subgroups ( P<0.001). However, the average time for renal hilar dissection was (19.82±5.65) min, which was significantly longer than the other steps ( P<0.001). Therefore, renal hilar dissection was identified as the rate-limiting step of hand-assisted laparoscopic donor nephrectomy. In terms of the influencing factors of surgical difficulty, donor obesity, kidney width, abdominal anteroposterior sagittal diameter, number of renal arteries, distance from renal artery bifurcation to the abdominal aorta, degree of renal artery calcification, and mayo adhesive probability (MAP) score were all correlated with the surgical difficulty score ( P<0.05). However, multiple linear regression analysis revealed that only the number of renal arteries and the MAP score were the independent risk factors for higher surgical difficulty of hand-assisted laparoscopic donor nephrectomy. The predictive equation was: surgical difficulty=0.649×number of renal arteries+ 0.770×MAP score. Both internal and external validation confirmed the model's good accuracy. Conclusions:This study established a reliable and objective predictive model for the difficulty of hand-assisted laparoscopic donor nephrectomy based on the number of renal arteries and the MAP score. Renal hilar dissection was identified as the rate-limiting step of the procedure. This provides a reference for selecting an appropriate surgeon based on the predicted surgical difficulty.

ObjectiveTo observe the efficacy of Huoxue Jiedu Formulas （活血解毒方药， HJF） as an adjunctive treatement for patients with binding of stasis and toxin syndrome during the vulnerable period after acute myocardial infarction （AMI） percutaneous coronary intervention （PCI） surgery， and to explore its potential mechanism from the perspective of serum neutrophil extracellular traps （NETs）. MethodsA total of 129 patients with binding of stasis and toxin syndrome within 6 months after PCI for AMI were enrolled and divided into a treatment group （65 cases） and a control group （64 cases） based on patients' willingness to take Chinese herbal medicine. The control group received standard western medical therapy alone， while the treatment group additionally received HJF， one dose daily. Both groups were treated for four weeks. Before and after treatment， TCM syndrome scores were assessed. Seattle angina questionnaire （SAQ） was used to record angina stability and frequency scores， while the short form-36 health survey （SF-36） was employed to assess quality of life across eight dimensions， including physical functioning， role-physical， bodily pain， general health， vitality， social functioning， role-emotional， and mental health. The Pittsburgh sleep quality index （PSQI） was used to evaluate sleep quality， and the patient health questionnaire-15 （PHQ-15） was used to assess psychosomatic symptoms； Duke activity status index （DASI） was used to measure daily physical activity. Serum levels of neutrophil extracellular traps （NET） markers including myeloperoxidase-DNA （MPO-DNA）， neutrophil elastase-DNA （NE-DNA）， and citrullinated histone H3 （CitH3） were measured in 20 patients from the treatment group. ResultsAfter treatment， TCM syndrome score， PSQI score and PHQ-15 score in both groups significantly decreased， while DASI score， angina stability and frequency scores， and all eight dimensions of the SF-36 scale significantly increased （P＜0.05）. Compared to the control group， the treatment group had significantly lower TCM syndrome scores and significantly higher DASI， angina stability and frequency scores （P＜0.05）， as well as higher scores in the SF-36 dimensions of physical functioning， role-physical， social functioning， bodily pain， and vitality （P＜0.05）. After treatment， serum levels of MPO-DNA， CitH3， and NE-DNA in the treatment group were significantly reduced （P＜0.05）. ConclusionHJF combined with conventional therapy can significantly improve angina symptoms， TCM syndrome scores， and psychosomatic conditions in patients with binding of stasis and toxin syndrome during the vulnerable period after AMI. It also enhances quality of life， sleep quality， and daily physical activity. The underlying mechanism may be associated with the inhibition of serum NETs level.

Objective:To compare four postmastectomy radiotherapy plans with different arc angles for left-sided breast cancer prepared using deep inspiration breath hold (DIBH) technique, in order to explore the feasibility of selecting optimal arc angles based on the parameters of patients′ anatomical structures.Methods:A total of 51 patients who underwent postmastectomy radiotherapy for left-sided breast cancer using DIBH at the Second Affiliated Hospital of Guangxi Medical University and the First Affiliated Hospital of Guangzhou Medical University were selected. Among these, 40 patients selected using simple random sampling were treated with four radiotherapy plans with different arc angles, labeled as SV120, SV100, SV80, and SV60, while the remaining 11 patients were treated with only the SV60 plans. The dose parameters of the target volumes (TVs) and organs at risk (the heart, lungs, and contralateral breast), as well as the beam-on times of individual arcs, in these plans were compared. The parameters of the anatomical structures (i.e., the heart, lung, and breast) of the 51 patients, including PHeart, PLungl, and PBreast, were extracted. Taking these parameters as independent variables and the quality of the SV60 plans as the dependent variable, fitting was conducted using P(SV60)—a multivariate logistic regression model—based on a training set (45 patients) and a testing set (six patients). The classification threshold of the plans was set at 0.5. Results:As the arc angle increased, the plans exhibited improved modulation capabilities for TVs and the left lung. However, the V5 of the right lung and the average beam-on time of a single arc also increased. The SV120 plans demonstrated significantly better V107% of planning target volume (PTV; 6.84%), homogeneity index (HI; 0.13), conformity index (CI; 0.81), and mean dose to the left lung (1 330.97 cGy) compared to the other three types of plans, with statistically significant differences ( W = 0-99, P < 0.001). The SV60 plans displayed lower mean doses to the contralateral breast (198.97 cGy) and the heart (440.35 cGy) and lower V5 of the right lung (0.27%) than the other three types of plans, with significant differences in V5 of the right lung and the mean dose to the contralateral breast ( W = 0-157, P < 0.001). In contrast, no significant difference was observed in these parameters (except for V5 of the right lung) among the other three types of plans. The four types of plans exhibited average beam-on times of individual arcs of 22.0, 19.1, 16.1, and 14.4 s, respectively, with statistically significant differences ( χ2= 93.0, P < 0.001). A multivariate logistic regression model revealed that PLungl, PHeart, and PBreast were negatively correlated with the quality of the SV60 plans ( t = -64.84, -28.20, -24.45, P<0.001). This model yielded an accuracy of 93.33% and a precision of 92.86% in the training set, while its accuracy and precision reached 100% in the testing set. Conclusions:For patients treated with postmastectomy radiotherapy for left-sided breast cancer using DIBH, it is feasible to select appropriate arc angles based on patients’ anatomical structures.

ObjectiveTo analyze the distribution characteristics of traditional Chinese medicine （TCM） syndrome elements in different risk populations of heart failure complicated with type 2 diabetes. MethodsClinical data of 675 type 2 diabetes patients were retrospectively collected. Lasso-multivariate Logistic regression was used to construct a clinical prediction nomogram model. Based on this， 441 non-heart failure patients were divided into a low-risk group （325 cases） and a high-risk group （116 cases） according to the median risk score of heart failure complicated with type 2 diabetes. TCM diagnostic information （four diagnostic methods） was collected for both groups， and factor analysis was applied to summarize the distribution of TCM syndrome elements in different risk populations. ResultsLasso-multivariate Logistic regression analysis identified age， disease duration， coronary heart disease， old myocardial infarction， arrhythmia， absolute neutrophil count， activated partial thromboplastin time， and α-hydroxybutyrate dehydrogenase as independent risk factors for heart failure complicated with type 2 diabetes. These were used as final predictive factors to construct the nomogram model. Model validation results showed that the area under the curve （AUC） of the receiver operating characteristic （ROC） curve for the modeling group and validation group were 0.934 and 0.935， respectively. The Hosmer-Lemeshow test （modeling group P = 0.996， validation group P = 0.121） indicated good model discrimination. Decision curve analysis showed that the curves for All and None crossed in the upper right corner， indicating high clinical utility. The low-risk and high-risk groups each obtained 14 common factors. Preliminary analysis revealed that the main disease elements in the low-risk group were qi deficiency （175 cases， 53.85%）， dampness （118 cases， 36.31%）， and heat （118 cases， 36.31%）， with the primary locations in the spleen （125 cases， 38.46%） and lungs （99 cases， 30.46%）. In the high-risk group， the main disease elements were yang deficiency （73 cases， 62.93%）， blood stasis （68 cases， 58.62%）， and heat （49 cases， 42.24%）， with the primary locations in the kidney （84 cases， 72.41%） and heart （70 cases， 60.34%）. ConclusionThe overall disease characteristics in different risk populations of type 2 diabetes patients with heart failure are a combination of deficiency and excess， with deficiency being predominant. Deficiency and heat are present throughout. The low-risk population mainly shows qi deficiency with dampness and heat， related to the spleen and lungs. The high-risk population shows yang deficiency with blood stasis and heat， related to the kidneys and heart.

Objective:To explore the impacts of Yiqi Wenfei Tongqiao Formula on inflammatory response and T helper cell(Th)1/Th2 immune balance in rats with lung Qi deficiency cold type allergic rhinitis.Methods:Sixty SD rats were randomly divided into model group,low dose Yiqi Wenfei Tongqiao Formula group,medium dose Yiqi Wenfei Tongqiao Formula group,high dose Yiqi Wenfei Tongqiao Formula group,and desloratadine group,with 12 rats in each group,using a combination of smoking,cold stimula-tion combined with ovalbumin(OVA)sensitization and stimulation construct lung Qi deficiency cold type allergic rhinitis model.An-other 12 normal SD rats were selected as control group.Each group of rats was treated with corresponding drugs once a day for 14 days.Model group and control group rats were given physiological saline.Scoring method was used to analyze the behavioral score and lung index of rats with allergic rhinitis.HE staining was applied to detect pathological changes in rat nasal mucosa tissue.ELISA was ap-plied to detect levels of IFN-γ,IL-4 and TNF-α in rats serum;flow cytometry was applied to detect Th1/Th2.Western blot was applied to detect expressions of T-bet and GATA-3 protein in nasal mucosa tissues of rats in each group.Results:Compared with control group,pathological damage to nasal mucosa tissue of model group rats was severe,allergic rhinitis behavior score(days 41,48,56),lung index,levels of IL-4 and TNF-α,Th2 and protein expression of GATA-3 were increased,while levels of IFN-γ,Th1,Th1/Th2,and protein expression of T-bet were decreased(P<0.05);compared with model group,pathological damage to nasal mucosa tissue of rats in low,medium,high doses Yiqi Wenfei Tongqiao Formula groups and desloratadine group were alleviated,the allergic rhinitis behavior score(days 48,56),lung index,levels of IL-4 and TNF-α,Th2 and protein expression of GATA-3 were decreased,while levels of IFN-γ,Th1,Th1/Th2,and protein expression of T-bet were increased(P<0.05).Conclusion:Yiqi Wenfei Tongqiao Formula can inhibit inflammatory response of lung Qi deficiency cold type allergic rhinitis rats By regulating Th1/Th2 immune balance.

Objective To investigate the effect of Yiqi Wenfei Tongqiao decoction on the inflammatory response in rats with allergic rhi-nitis(AR)of lung qi deficiency and cold type based on the Janus kinase 1(JAK1)/signal transducer and activator of transcription 3(STAT3)signaling pathway.Methods A AR model of lung qi deficiency and cold type was established in rats using ovalbumin(OVA)combined with smoking and cold stimulation.After modeling,the rats were randomly divided into model,loratadine,low-dose Chinese medicine,high-dose Chinese medicine,and high-dose Chinese medicine+RO8191(JAK1/STAT3 signaling pathway activator)groups,with 12 rats per group.Twelve healthy rats were used as controls.After 14 days of drug intervention,the changes in the symptoms of lung qi deficiency and cold syndrome and AR were observed in the rats.Enzyme-linked immunosorbent assay was used to detect the serum levels of tumor necrosis factor α(TNF-α),interleukin(IL)-4,interferon-γ(IFN--γ),and ovalbumin-specific immunoglobulin E(OVA-sIgE).The number of inflammatory cells in the nasal lavage fluid was determined and the eosinophil(EOS)percentage was calculated.Pathological changes in the nasal mucosal tissue were observed after hematoxylin and eosin(HE)staining.Western blotting was used to detect the expression of JAK1/STAT3 signaling pathway-related proteins in nasal mucosal tissue.Results Compared with those in the model group,the AR symptom score,serum IL-4,TNF-α,and OVA-sIgE levels,EOS percentage in nasal lavage fluid,and levels of p-JAK1/JAK1 and p-STAT3/STAT3 in the nasal mucosal tissue of rats in the loratadine,low-dose Chinese medicine,and high-dose Chinese medicine groups were lower,whereas the serum IFN-γ level was higher(P＜0.05).RO8191 weakened the inhibitory effect of Yiqi Wenfei Tongqiao decoction on the inflammatory response in rats with AR of lung qi deficiency and cold type.Conclusion Overall,Yiqi Wenfei Tongqiao decoction can alleviate the inflammatory response in rats with AR of lung qi deficiency and cold type by inhibiting JAK1/STAT3 signaling pathway acti-vation and regulating the balance of Th1/Th2 cytokines.

Objective To explore the effect of home-based pharmaceutical care for patients with stable chronic obstruc-tive pulmonary diseases(COPD)based on a digital remote management applet.Methods A total of 237 patients with stable COPD from a hospital pharmaceutical outpatient service from March 2022 to March 2023 were divided into a control group,a home visit group,and a remote management group according to the random number table method.Patients in the home visit and re-mote management groups received home-based pharmaceutical interventions such as health science popularization,medication con-sultation,medication guidance,effect evaluation of pharmacotherapy,prescription simplification,and reorganization.Such interven-tions were not provided in the control group.Regular follow-up was performed for 12 months.Results After a pharmaceutical intervention,the operating scores of the inhalation device and medication compliance scores of the home visit and remote manage-ment groups were significantly better than the control group(P＜0.05).The improvement in medication compliance was greater in the remote management group than in the home visit group(54.3％ vs.44.6％).In the three groups between enrollment and 12 months follow-up,CAT scores decreased by 0.78,6.16,and 7.30 points in the control group,home visit group,and remote manage-ment group,respectively.The mean scores of SGRQ symptom decreased by 1.19,4.24,and 6.10 points,the mean activity scores decreased by 1.65,3.56,4.80 points,the impact mean score decreased by 1.08,4.19,5.16 points,and the mean score of the total score decreased by 1.29,4.00,4.80 points in the control group,home visit group,and remote management group,respectively.The remote management group showed dia better decline in CAT score and SGRQ score than the home visit group,and there were sig-nificant differences between the two groups compared with the control group after intervention(P＜0.05).Conclusions Digital remote management of home-based pharmaceutical care mode can effectively improve medication compliance,operation accuracy of inhalation devices,clinical symptoms,and the patient quality of life.This is an effective and efficient pharmaceutical care mode for the long-term home medication management of stable COPD patients.

Objective To explore the effect of home-based pharmaceutical care for patients with stable chronic obstruc-tive pulmonary diseases(COPD)based on a digital remote management applet.Methods A total of 237 patients with stable COPD from a hospital pharmaceutical outpatient service from March 2022 to March 2023 were divided into a control group,a home visit group,and a remote management group according to the random number table method.Patients in the home visit and re-mote management groups received home-based pharmaceutical interventions such as health science popularization,medication con-sultation,medication guidance,effect evaluation of pharmacotherapy,prescription simplification,and reorganization.Such interven-tions were not provided in the control group.Regular follow-up was performed for 12 months.Results After a pharmaceutical intervention,the operating scores of the inhalation device and medication compliance scores of the home visit and remote manage-ment groups were significantly better than the control group(P＜0.05).The improvement in medication compliance was greater in the remote management group than in the home visit group(54.3％ vs.44.6％).In the three groups between enrollment and 12 months follow-up,CAT scores decreased by 0.78,6.16,and 7.30 points in the control group,home visit group,and remote manage-ment group,respectively.The mean scores of SGRQ symptom decreased by 1.19,4.24,and 6.10 points,the mean activity scores decreased by 1.65,3.56,4.80 points,the impact mean score decreased by 1.08,4.19,5.16 points,and the mean score of the total score decreased by 1.29,4.00,4.80 points in the control group,home visit group,and remote management group,respectively.The remote management group showed dia better decline in CAT score and SGRQ score than the home visit group,and there were sig-nificant differences between the two groups compared with the control group after intervention(P＜0.05).Conclusions Digital remote management of home-based pharmaceutical care mode can effectively improve medication compliance,operation accuracy of inhalation devices,clinical symptoms,and the patient quality of life.This is an effective and efficient pharmaceutical care mode for the long-term home medication management of stable COPD patients.