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 assess the application value of one-hour post-load glucose (1hPG) for detecting prediabetes among individuals with high risk of type 2 diabetes mellitus (T2DM).Methods:The study was conducted between August 2023 and January 2024, and individuals with a high risk of T2DM were invited to receive an oral glucose tolerance test (OGTT), structural questionnaires, physical measurements, and other biochemical examinations. The fasting, one-, and two-hour glucose and insulin were tested. According to the 1hPG cut point on hyperglycemia suggested by International Diabetes Federation (IDF), normal glucose tolerance (NGT) and prediabetes were further divided into two subgroups, respectively, i.e., NGT with 1hPG<8.6 mmol/L (NGT-1hPG-normal), NGT with 1hPG≥8.6 mmol/L (NGT-1hPG-high), prediabetes with 1hPG<8.6 mmol/L (PDM-1hPG-normal), and prediabetes with 1hPG≥8.6 mmol/L (PDM-1hPG-high). The insulin release curve was drawn by the groups as above. Insulin resistance was evaluated by homeostasis model assessment for insulin resistance (HOMA-IR), and β-cell secretory function was evaluated by homeostasis model assessment for β cell function (HOMA-β)/HOMA-IR. Spearman rank correlation analysis was used to calculate the correlation coefficients among 1hPG, 2hPG and HOMA indices, and Steiger′s Z test was used to compare the difference between two correlation coefficients. Receiver operating characteristics (ROC) curves and area under the curve (AUC) were used to assess the accuracy of 1hPG for detecting prediabetes. Results:A total of 2 469 subjects consisting of 1 485 men (60.1%) and 984 (39.9%) women, with a mean age of (45.76±6.20) years, of which 1 844 (74.7%) had 1hPG≥8.6 mmol/L. The prevalence of 1hPG≥8.6 mmol/L was 46.8%, 93.0% and 99.8% in individuals with NGT, prediabetes and newly diagnosed T2DM, respectively ( χ 2=763.78, P<0.001). The insulin release curve showed that insulin secretion increased rapidly in subjects with NGT-1hPG-high, and peaked at one hour, then decreased rapidly, with a significantly higher level of one- and two-hour insulin than those with NGT-1hPG-normal ( P<0.001). Compared to individuals with NGT-1hPG-normal, the counterparts with NGT-1hPG-high exhibited higher HOMA-IR and lower adjusted HOMA-β ( P<0.001). Spearman rank correlation analysis showed that the correlation coefficient of 1hPG with HOMA-IR was similar to the correlation coefficient of 2hPG with HOMA-IR (0.493 vs. 0.480, P=0.550), while the correlation of 1hPG with adjusted HOMA-β was significantly stronger than that of 2hPG (-0.692 vs. -0.587, P<0.001). Excluding patients with T2DM, according to the cut point recommended by IDF, the AUC of 1hPG≥8.6 mmol/L for detecting prediabetes was 0.731 (95% CI: 0.714-0.748), and the sensitivity and specificity were 0.930 and 0.532, respectively, with the kappa value of 0.45. Conclusion:1hPG is closely related to insulin resistance and islet function, and there′s substantial value for individuals with a high risk of T2DM to detect prediabetes by using the 1hPG cut points recommended by IDF.

Objective:To investigate the distribution of CGG repeat numbers in the FMR1 gene among reproductive-age women in China, providing data reference for carrier screening and genetic counseling of Fragile X syndrome. Methods:This cross-sectional study recruited 16 610 reproductive-age women from 12 medical institutions between July 2022 and October 2023. Peripheral venous blood samples (3 mL) were collected, and genomic DNA was extracted. The number of CGG repeats in the FMR1 gene was determined using the triplet-primed polymerase chain reaction (TP-PCR) combined with capillary electrophoresis technology. Statistical analyses were performed to assess the prevalence and distribution of CGG repeat expansions. Results:Among 16 610 women of childbearing age, 5 684 (34.220%) women had the same number of CGG repeats in the two alleles of FMR1 gene, and 10 926 (65.780%) women had different numbers of repeats in the two alleles. Among the 33 220 FMR1 alleles in 16 610 women of reproductive age, the most common CGG repeat numbers were 29 [48.645% (16 160/33 220)] and 30 [26.276% (8 729/33 220)], while the most frequent CGG genotype was CGG 29/29 [24.726% (4 107/16 610)]. The CGG repeat numbers of FMR1 gene were normal in 16 498 women (99.326%). Among the 112 women (0.674%) with CGG repeat abnormities, 96 (0.578%) women were classified as intermediate carriers, 15 (0.090%) as premutation carriers, and 1 (0.006%) as a full mutation carrier, whose CGG genotype was (36, >200). Conclusion:In the general reproductive-age female population in China, the normal CGG repeat numbers of the FMR1 gene account for 99.326%, while the intermediate carrier rate is 0.578%, and the combined carrier rate of the premutation and full mutation types is 0.096%.

Objective:To assess the application value of one-hour post-load glucose (1hPG) for detecting prediabetes among individuals with high risk of type 2 diabetes mellitus (T2DM).Methods:The study was conducted between August 2023 and January 2024, and individuals with a high risk of T2DM were invited to receive an oral glucose tolerance test (OGTT), structural questionnaires, physical measurements, and other biochemical examinations. The fasting, one-, and two-hour glucose and insulin were tested. According to the 1hPG cut point on hyperglycemia suggested by International Diabetes Federation (IDF), normal glucose tolerance (NGT) and prediabetes were further divided into two subgroups, respectively, i.e., NGT with 1hPG<8.6 mmol/L (NGT-1hPG-normal), NGT with 1hPG≥8.6 mmol/L (NGT-1hPG-high), prediabetes with 1hPG<8.6 mmol/L (PDM-1hPG-normal), and prediabetes with 1hPG≥8.6 mmol/L (PDM-1hPG-high). The insulin release curve was drawn by the groups as above. Insulin resistance was evaluated by homeostasis model assessment for insulin resistance (HOMA-IR), and β-cell secretory function was evaluated by homeostasis model assessment for β cell function (HOMA-β)/HOMA-IR. Spearman rank correlation analysis was used to calculate the correlation coefficients among 1hPG, 2hPG and HOMA indices, and Steiger′s Z test was used to compare the difference between two correlation coefficients. Receiver operating characteristics (ROC) curves and area under the curve (AUC) were used to assess the accuracy of 1hPG for detecting prediabetes. Results:A total of 2 469 subjects consisting of 1 485 men (60.1%) and 984 (39.9%) women, with a mean age of (45.76±6.20) years, of which 1 844 (74.7%) had 1hPG≥8.6 mmol/L. The prevalence of 1hPG≥8.6 mmol/L was 46.8%, 93.0% and 99.8% in individuals with NGT, prediabetes and newly diagnosed T2DM, respectively ( χ 2=763.78, P<0.001). The insulin release curve showed that insulin secretion increased rapidly in subjects with NGT-1hPG-high, and peaked at one hour, then decreased rapidly, with a significantly higher level of one- and two-hour insulin than those with NGT-1hPG-normal ( P<0.001). Compared to individuals with NGT-1hPG-normal, the counterparts with NGT-1hPG-high exhibited higher HOMA-IR and lower adjusted HOMA-β ( P<0.001). Spearman rank correlation analysis showed that the correlation coefficient of 1hPG with HOMA-IR was similar to the correlation coefficient of 2hPG with HOMA-IR (0.493 vs. 0.480, P=0.550), while the correlation of 1hPG with adjusted HOMA-β was significantly stronger than that of 2hPG (-0.692 vs. -0.587, P<0.001). Excluding patients with T2DM, according to the cut point recommended by IDF, the AUC of 1hPG≥8.6 mmol/L for detecting prediabetes was 0.731 (95% CI: 0.714-0.748), and the sensitivity and specificity were 0.930 and 0.532, respectively, with the kappa value of 0.45. Conclusion:1hPG is closely related to insulin resistance and islet function, and there′s substantial value for individuals with a high risk of T2DM to detect prediabetes by using the 1hPG cut points recommended by IDF.

Objective:To investigate the distribution of CGG repeat numbers in the FMR1 gene among reproductive-age women in China, providing data reference for carrier screening and genetic counseling of Fragile X syndrome. Methods:This cross-sectional study recruited 16 610 reproductive-age women from 12 medical institutions between July 2022 and October 2023. Peripheral venous blood samples (3 mL) were collected, and genomic DNA was extracted. The number of CGG repeats in the FMR1 gene was determined using the triplet-primed polymerase chain reaction (TP-PCR) combined with capillary electrophoresis technology. Statistical analyses were performed to assess the prevalence and distribution of CGG repeat expansions. Results:Among 16 610 women of childbearing age, 5 684 (34.220%) women had the same number of CGG repeats in the two alleles of FMR1 gene, and 10 926 (65.780%) women had different numbers of repeats in the two alleles. Among the 33 220 FMR1 alleles in 16 610 women of reproductive age, the most common CGG repeat numbers were 29 [48.645% (16 160/33 220)] and 30 [26.276% (8 729/33 220)], while the most frequent CGG genotype was CGG 29/29 [24.726% (4 107/16 610)]. The CGG repeat numbers of FMR1 gene were normal in 16 498 women (99.326%). Among the 112 women (0.674%) with CGG repeat abnormities, 96 (0.578%) women were classified as intermediate carriers, 15 (0.090%) as premutation carriers, and 1 (0.006%) as a full mutation carrier, whose CGG genotype was (36, >200). Conclusion:In the general reproductive-age female population in China, the normal CGG repeat numbers of the FMR1 gene account for 99.326%, while the intermediate carrier rate is 0.578%, and the combined carrier rate of the premutation and full mutation types is 0.096%.

Abstract Alzheimer′s disease(AD) is a common neurodegenerative disease. It has been found that AD is related to various pathogenic factors such as genetics, cardiovascular and cerebrovascular disease, and excessive phosphorylation of tau protein. However, no definitive conclusions on its pathogenesis have been reached. In this paper, the research progress on the pathogenesis of AD inC.elegansmodel and the therapeutic effects of traditional Chinese medicine extracts on AD are reviewed, providing a basis for further research on the alleviating effects of Chinese medicine extracts on AD.

Objective:To construct a curriculum system for malignant fungating wounds based on Kolb experience learning theory.Methods:The first draft of a curriculum system for malignant fungating wounds was constructed based on literature search and group discussion using Kolb experience learning theory as a guide. Between February and May 2024, purposive sampling was used to select 16 experts for two rounds of expert consultation based on the Delphi method to form the final draft of the curriculum system for malignant fungating wounds.Results:A total of 16 questionnaires were distributed in both rounds of expert consultation and 16 questionnaires were effectively recovered with an effective recovery rate of 100.00%. The expert authority coefficients in two rounds of consultation were all 0.916, and Kendall's W values ranged from 0.089 to 0.192 (all P<0.05). The final curriculum system for malignant fungating wounds included four primary indicators, 10 secondary indicators, and 32 tertiary indicators. Conclusions:The curriculum system for malignant fungating wounds constructed under the guidance of Kolb experience learning theory is scientific and practical, and can provide a basis for conducting malignant fungating wound training.

Objective:To construct a curriculum system for malignant fungating wounds based on Kolb experience learning theory.Methods:The first draft of a curriculum system for malignant fungating wounds was constructed based on literature search and group discussion using Kolb experience learning theory as a guide. Between February and May 2024, purposive sampling was used to select 16 experts for two rounds of expert consultation based on the Delphi method to form the final draft of the curriculum system for malignant fungating wounds.Results:A total of 16 questionnaires were distributed in both rounds of expert consultation and 16 questionnaires were effectively recovered with an effective recovery rate of 100.00%. The expert authority coefficients in two rounds of consultation were all 0.916, and Kendall's W values ranged from 0.089 to 0.192 (all P<0.05). The final curriculum system for malignant fungating wounds included four primary indicators, 10 secondary indicators, and 32 tertiary indicators. Conclusions:The curriculum system for malignant fungating wounds constructed under the guidance of Kolb experience learning theory is scientific and practical, and can provide a basis for conducting malignant fungating wound training.

Objective:To explore the efficacy and safety of Neuroform Atlas stent-assisted coil embolization in ruptured anterior communicating wide-necked aneurysms.Methods:Thirty-two patients with ruptured anterior communicating wide-necked aneurysms accepted Neuroform Atlas stent assisted coil embolization in Department of Neurosurgery, People's Hospital Affiliated to Shandong First Medical University from January 2022 to June 2023 were chosen. DSA was performed immediately after surgery, and aneurysm embolization was assessed using Raymond grading. Prognoses were assessed by modified Rankin Scale (mRS, mRS scores≤2 as good prognosis and mRS scores>2 as poor prognosis) at last follow-up. DSA was performed again 6 months after surgery to assess the aneurysm healingResults:Neuroform Atlas stents were successfully implanted in all 32 patients; Postoperative DSA showed that aneurysm embolization reached Raymond grading I in all 32 patients(100%). No such complications as in-stent thrombosis, cerebral vasospasm, or poor opening of the stent were noted excepted for one with intraoperative aneurysm rupture hemorrhage. At the last follow-up, 31 patients had good prognosis and 1 had poor prognosis; in 22 patients underwent DSA re-examination, Raymond grading I was noted in 20 patients (90.91%) and grading II in 2 (9.09%).Conclusion:Neuroform Atlas stent-assisted coil embolization for ruptured anterior communicating wide-necked aneurysms seems safe and effective.

Objective:To investigate the feasibility and safety of a treatment system for stentless discharge after flexible ureteroscopic lithotripsy assisted by flexible negative pressure sheath.Methods:The clinical data of 72 patients with upper urinary calculi admitted to the Second Hospital of Tianjin Medical University from November 2022 to February 2023 were retrospectively analyzed. All patients achieved stentless discharge after flexible ureteroscopic lithotripsy assisted by flexible negative pressure sheath. There were 50 males and 22 females. The average age was (54.7±12.1) years. Preoperative urine culture was positive in 14 cases, negative in 3 cases (4.2%)with nitrite positive, and 11 cases were negative for urine culture and nitrites but positive of white blood cells (+ + + ). There were 29 cases of renal calculi, 33 cases of upper ureteral calculi, and 10 cases of upper ureteral calculi combined with renal calculi.The mean stone diameter was 17.0(14.0, 24.0)mm. CT value was (1 049.3±258.6)HU. Twenty-four patients carried ureteral stents before operation. A total of 42 cases used ureteral sheaths with diameters of F11/13, and 30 cases used sheaths with diameters of F12/14.During the operation, an infusion pump was used to provide sufficient irrigation pressure. The negative pressure suction was attached to the distal end of the sheath. The flexible head of the sheath was guided to the target renal calyx, to completely aspirate stone fragments. Stone baskets was used in 11 cases during the procedure. The level of ureteral injury was assessed according to the Traxer grading system at the end of the operation. A ureteral stent with extraction string was retained.On the first day postoperatively, CT scanning was performed to evaluate the residual stone fragments. Patients were discharged on postoperative day 2-3 after the removal of the ureteral stent and catheter. Follow-up was conducted for 30 days postoperatively, during which the Ureteral Stent Symptom Questionnaire (USSQ) was used to assess voiding symptoms and pain. Painkiller usage and emergency revisit situations were recorded. CT scans were performed to evaluate the stone-free rate on postoperative day 30.Results:The average operation time was 30.0 (20.0, 44.5) minutes. A total of 70 cases had no ureteral injuries, and 2 cases had Grade 1 ureteral injuries (minor mucosal damage). Three cases developed fever within 72 hours postoperatively, with no cases of septic shock or fever after stent removal. Eight patients reported waist and abdominal discomfort after discharge and took oral pain medication. Among them, one patient returned to the emergency department for pain treatment. Five patients reported moderate or severe genitourinary symptoms (including voiding frequency, nocturia, urgency/incontinence, dysuria, hematuria, and incomplete emptying) based on subjective evaluation. All patients could work and recovered a normal daily life after discharge and there was no readmission or additional surgical procedures. There were 61 patients achieved immediate stone-free status on the first day after surgery, and 66 patients achieved stone-free status during follow-up at 30 days postoperatively.Conclusions:Stentless discharge after flexible ureteroscopic lithotripsy assisted by flexible negative pressure sheath is safe and feasible.