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

In recent years, a variety of innovative fast algorithm techniques have emerged in the field of transcranial magnetic stimulation (TMS) electric field solving, which show great potential to meet the requirements of real-time clinical applications. In this review, the crucial processes of TMS electric field modeling were summarized, focusing on two prominent fast algorithm techniques, namely the basis function method and the deep neural network (DNN)-based method. The advantages and limitations of these two techniques were analyzed in detail. Commonly used software tools for electric field modeling were discussed, and a prospective discussion of future developments was offered, aiming to provide a reference for the further development of TMS electric field modeling technology.

Objective To assess the medical cost consciousness status among catheterization lab nurses in grade-Ⅲ general hospitals where the diagnosis-related group(DRG)payment method has been implemented,and to explore its influencing factors.Methods By using the general data questionnaire form,the medical cost consciousness scale of medical staff and the Chinese version of the safety attitude scale,a total of 251 nurses working in the interventional catheterization room from 39 grade-Ⅲ general hospitals(being member unit of China Cardiovascular Health Alliance and being distributed in 13 provinces and cities)were surveyed.Results The total score of medical cost consciousness in nurses working in interventional catheterization room was(49.11±6.80)points.A positive correlation existed between the medical cost consciousness of nurses working in interventional catheterization room and the patient safety attitudes(P＜0.01).Multivariate linear regression analysis showed that team collaboration,job satisfaction,stress perception,management mode of medical consumables,and cost-effectiveness training were the main factors influencing cost awareness.Conclusion The interventional catheterization room nurses have a good consciousness of medical costs,but their actual participation degree is insufficient.Under the regulation of DRG payment method the hospital administration and nursing care managers should take targeted measures to enhance the efficiency of catheter room cost management.

ObjectiveTo analyze the spectrum distribution characteristics of high-intensity productive noise in key industries in Guangdong Province. Methods A total of 2 806 enterprises in 21 prefecture-level cities in Guangdong Province were selected as the study subjects using the stratified sampling method. On-site investigations were conducted in workplaces. Noise in workplaces and work-sites, and the noise spectrum of the workplaces with sound pressure level ≥85.0 dB(A) were detected. Results The noise of a total of 23 076 workplaces and 20 969 work sites from 30 key industries were monitored. The median (M) and 25th and 75th percentiles (P₂₅, P₇₅) of workplace sound pressure level were 82.3 (78.6, 86.5) dB(A). The rate of the noise exceeded national standard was 30.4%. The sound pressure level M (P₂₅, P₇₅) of work-site was 78.6 (70.0, 83.5) dB(A). The rate of the noise exceeded national standard was 18.0%. Workplace noise and work site noise were positively correlated (Spearman correlation coefficient=0.86, P<0.01). The rate of the noise exceeded national standard was 46.5% in key work sites where the rate of noise exceeded the national standard was ≥25.0%, and corresponding rate of the workplace noise exceeded national standard was 58.1%. The noise spectrum result of 5 636 workplaces sound pressure level>85.0 dB(A) showed that most of the noise source was from grinding machines (441 cases), and the highest average sound pressure level of noise source was from screening machines [93.0 dB(A)]. Cluster analysis results showed that the main noise sources could be divided into three categories, including wideband noise with levels >80.0 dB in all frequency bands except 8 000.0 Hz, medium-high-frequency noise with the highest sound pressure level at 1 000.0, 2 000.0, and 4 000.0 Hz and low frequencies <75.0 dB, and medium-low-frequency noise below 500.0 Hz with sound pressure level >85.0 dB. Conclusion The rate of the noise exceeded national standard in workplace of key industries in Guangdong Province is high, involving a wide range of industries, with high sound pressure levels and obvious spectrum characteristics of corresponding noise sources. Corresponding noise control strategies can be formulated based on different spectrum characteristics and magnitudes.

Objective:To evaluate the effectiveness of low-dose of prophylactic indomethacin in reducing the incidence of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in elderly patients.Methods:From July 2021 to October 2022, patients undergoing ERCP in Zhongshan Hospital, Fudan University and Shanghai Xuhui District Central Hospital were enrolled prospectively and assigned to either the low-dose (50 mg) indomethacin group or the conventional-dose (100 mg) group using the DAS electronic central randomization system. Data from elderly patients aged≥60 were collected and compared for the incidence of PEP and other adverse reactions.Results:A total of 418 elderly patients (Zhongshan Hospital, Fudan University, n=122; Shanghai Xuhui Distric Central Hospital, n=296) were ultimately included in the study, with 201 in the low-dose group and 217 in the conventional-dose group. There was no significant difference in the incidence of PEP between the low-dose group and the conventional-dose group [5.97% (12/201) VS 7.37% (16/217), χ2=0.33, P=0.566]. There was also no significant difference in drug-related adverse events between the two groups [4.98% (10/201) VS 4.15% (9/217), χ2=0.16, P=0.685]. Further subgroup analysis revealed that among elderly patients aged 60-<70, there were 13 patients diagnosed as having PEP. The incidence of PEP between the low-dose group and the conventional-dose group was not statistically significant [6.19% (6/97) VS 6.60% (7/106), χ2=0.01, P=0.903], and the occurrence of drug-related adverse events between the two groups was not statistically significant [6.19% (6/97) VS 2.83% (3/106), P=0.315]. Among elderly patients aged≥70, there were 15 patients diagnosed as having PEP. The incidence of PEP between the low-dose group and the conventional-dose group was not statistically significant [5.77% (6/104) VS 8.11% (9/111), χ2=0.45, P=0.501], and the occurrence of drug-related adverse events between the two groups was not statistically significant [3.85% (4/104) VS 5.41% (6/111), P=0.749]. Conclusion:The prophylactic use of 50 mg indomethacin showed similar efficacy in reducing the incidence of PEP in elderly patients compared with 100 mg indomethacin. Therefore, elderly patients can use 50 mg indomethacin prophylactically to reduce the incidence of PEP.

Objective:To investigate the changing trends in cardiac function following xenogeneic heterotopic heart transplantation of multi-gene edited pig hearts and assess the impact of recipient immune responses on donor heart, laying experimental groundwork for the clinical application of gene editing technology.Methods:On December 16, 2023, xenogeneic heterotopic heart transplantation was performed between pigs and rhesus monkeys. Functional status of the graft under post-transplantation load conditions and recipient immune indicators were observed.Results:The recipient monkeys survived for 40 days with satisfactory functionality of both donor and recipient hearts, and no hyperacute or acute immune rejection reactions were observed.Conclusion:Multi-gene editing technology provides potential for xenotransplantation, yet further exploration is needed for its clinical application.

Objective To explore the mechanism of Yangxue Qingnao Granules(Siwu Decoction modified)in the treatment of hypertension based on network pharmacology and molecular docking.Methods The chemical composition analysis results of Yangxue Qingnao Granules in the early stage of the research group were used as the basis for the screening of active compounds.The oral bioavailability≥30%and drug-likeness≥0.18 were used as the screening conditions,and the blood components were supplemented in combination with the literature.TCMSP,chemical professional database and SWISS database were used to predict the targets of potential active compounds of Yangxue Qingnao Granules.Hypertension-related targets were obtained through GeneCards and DiGSeE databases.The intersection of the targets related to hypertension disease and the targets of the potential active compounds of Yangxue Qingnao Granules(common targets)is the potential target of Yangxue Qingnao Granules for the treatment of hypertension.The potential targets were matched with the potential active compounds of Yangxue Qingnao Granules to obtain the antihypertensive active compounds of Yangxue Qingnao Granules.PPI analysis was performed on the potential targets of serum brain granules in the treatment of hypertension through the STRING database,and the core targets were screened according to the degree value.The David database was used to analyze the GO function and KEGG pathway enrichment of the core targets.The core targets with the top six degrees were selected as the docking target proteins,and molecular docking verification was performed with the antihypertensive active compounds.Results A total of 32 potential active compounds,161 active compound targets and 1 539 hypertension-related targets were obtained.After intersection,88 potential targets(common targets)of Yangxue Qingnao Granules in the treatment of hypertension were obtained,involving 29 antihypertensive active compounds.PPI analysis screened 14 core targets:PPARG,ACHE,IL4,CCL2,JUN,NOS3,APP,IL1B,CAT,PTGS2,CASP3,TP53,TNF,IL6,involving 158 GO entries and 13 signaling pathways.Five key active ingredients,chlorogenic acid,rosmarinic acid,paeoniflorin catechinic acid and aloe emodin,were obtained by molecular docking,which were combined with PTGS2,CASP3,TNF,CAT,TP53 and IL6,respectively.Conclusion Yangxue Qingnao Granules may act on core targets such as PTGS2 and CASP3 through key active components such as chlorogenic acid and rosmarinic acid,regulate key pathways such as TNF signaling pathway,MAPK signaling pathway and Toll-like receptor signaling pathway,and play a role in the treatment of hypertension through anti-inflammatory effects.

Objective:To establish the ultra high performance liquid chromatography (UPLC) fingerprints of Mume flos at different flowering stages; To provide reference for the quality research of Mume flos.Methods:The fingerprints of Mume flos were established by UPLC method, and the common peaks were identified by high performance liquid chromatography high resolution mass spectrometry (LC-MS). Chemometrics analysis was carried out with the fingerprints' common peak area of plum blossom at different flowering stages as a variable. Semiquantitative analysis of changes in flavonoids and phenolic acids in Mume flos at different flowering stages was conduct using peak area calculation method.Results:Totally 31 common peaks were identified in the fingerprints of plum blossom medicinal materials at different flowering stages and 9 components were identified. Clustering analysis (HCA) and principal component analysis (PCA) both classified plum blossom medicinal herbs at different flowering stages into three categories. Among them, there were significant differences between the groups at the bud stage, blooming period, and final flowering period, while the differences between the groups at blooming period and final flowering period were relatively small. The orthogonal partial least squares discriminant analysis (OPLS-DA) screened 16 different components with VIP>1.0. The contents of phenolic acids in different flowering stages were as follows: bud stage>blooming period>final flowering period, while the contents of flavonoids were as follows: blooming period>final flowering period>bud stage.Conclusions:This method is simple and reliable, and can provide reference for the quality evaluation of plum blossom medicinal materials at different flowering stages.

Methods: This retrospective study analyzed patients who underwent chest CT and DXA at our hospital between August 2021 and August 2022. Thoracic thoracolumbar segment HU values, lumbar T-scores, and hip T-scores were computed for comparison, and thoracic thoracolumbar segment HU thresholds suggestive of potential bone density abnormalities were established using receiver operating characteristic curves. Results: In total, 470 patients (72.4% women; mean age, 65.5±12.3 years) were included in this study. DXA revealed that of the 470 patients, 90 (19%) had osteoporosis, 180 (38%) had reduced osteopenia, and 200 (43%) had normal bone mineral density (BMD). To differentiate osteoporosis from osteopenia, the HU threshold was established as 105.1 (sensitivity, 54.4%; specificity, 72.2%) for T11 and 85.7 (sensitivity, 69.4%; specificity, 61.1%) for T12. To differentiate between osteopenia and normal BMD, the HU threshold was 146.7 for T11 (sensitivity, 57.5%; specificity, 84.4%) and 135.7 for T12 (sensitivity, 59.5%; specificity, 80%). Conclusions This study supports the significance of HU values from chest CT for BMD assessment. Chest CT provides a new method for clinical opportunistic screening of osteoporosis. When the T11 HU is >146.7 or the T12 HU is >135.7, additional osteoporosis testing is not needed unless a vertebral fracture is detected. If the T11 HU is <105.1 or the T12 HU is <85.7, further DXA testing is strongly advised. In addition, vertebral HU values that fall faster than those of the T11 and L1 vertebrae may explain the high incidence of T12 vertebral fractures.

Blood glucose fluctuation leads to poor bone defect repair in patients with type 2 diabetes (T2DM). Strategies to safely and efficiently improve the bone regeneration disorder caused by blood glucose fluctuation are still a challenge. Neutral sphingophospholipase 2 (Smpd3) is downregulated in jawbone-derived bone marrow mesenchymal stem cells (BMSCs) from T2DM patients. Here, we investigated the effect of Smpd3 on the osteogenic differentiation of BMSCs and utilized exosomes from stem cells overexpressing Smpd3 as the main treatment based on the glucose responsiveness of phenylboronic acid-based polyvinyl alcohol crosslinkers and the protease degradability of gelatin nanoparticles. The combined loading of Smpd3-overexpressing stem cell-derived exosomes (Exos-Smpd3) and nanosilver ions (Ns) to construct a hydrogel delivery system (Exos-Smpd3@Ns) promoted osteogenesis and differentiation of BMSCs in a glucose-fluctuating environment, ectopic osteogenesis of BMSCs in a glucose-fluctuating environment and jawbone regeneration of diabetic dogs in vitro. Mechanistically, Smpd3 promoted the osteogenesis and differentiation of jawbone-derived BMSCs by activating autophagy in the jawbone and inhibiting macrophage polarization and oxidative stress caused by blood glucose fluctuations. These results reveal the role and mechanism of Smpd3 and the Smpd3 overexpression exosome delivery system in promoting BMSC function and bone regeneration under blood glucose fluctuations, providing a theoretical basis and candidate methods for the treatment of bone defects in T2DM patients.
Exosomes ; Animals ; Bone Regeneration/drug effects* ; Dogs ; Mesenchymal Stem Cells ; Humans ; Blood Glucose ; Cell Differentiation ; Osteogenesis/drug effects* ; Diabetes Mellitus, Type 2/therapy* ; Diabetes Mellitus, Experimental ; Cells, Cultured ; Hydrogels ; Male