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The cell cycle is a complex process that involves DNA replication, protein expression, and cell division. Dysregulation of the cell cycle is associated with various diseases. Cyclin-dependent kinases (CDKs) and their corresponding cyclins are major proteins that regulate the cell cycle. In contrast to inhibition, a new approach called proteolysis-targeting chimeras (PROTACs) and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins, achieving targeted degradation. The field of PROTACs and molecular glues has developed rapidly in recent years. In this article, we aim to summarize the latest developments of CDKs and cyclin protein degraders. The selectivity, application, validation and the current state of each CDK degrader will be overviewed. Additionally, possible methods are discussed for the development of degraders for CDK members that still lack them. Overall, this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders, which will be helpful for researchers working on this topic.
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Humanos , Ciclo Celular/fisiología , División Celular , Quinasas Ciclina-Dependientes/metabolismo , Ciclinas/metabolismoRESUMEN
Objective:To evaluate the optimized effect of infiltration between the popliteal artery and the capsule of the knee (IPACK)-adductor canal block (ACB) combined with general anesthesia when used for the total knee arthroplasty.Methods:Sixty patients of both sexes, aged 18-64 yr, with body mass index of 18-24 kg/m 2, of American Society of Anesthesiologists physical status Ⅰ or Ⅱ, scheduled for elective unilateral total knee arthroplasty, were divided into 2 groups ( n=30 each) using a random number table method: IPACK-ACB combined with general anesthesia group (group IA) and conventional anesthesia femoral nerve block-popliteal superior sciatic nerve block combined with general anesthesia group (group C). Before induction of general anaesthesia, 0.375% ropivacaine 15 ml was injected for IPACK and 0.375% ropivacaine 25 ml for ACB under the ultrasound guidance in group IA, femoral nerve block and popliteal superior sciatic nerve block was performed under the guidance of ultrasound combined with a nerve stimulator and 0.375% ropivacaine 20 ml was injected in group C. After confirming the efficacy of nerve block, total intravenous anesthesia was carried out to maintain bispectral index values at 40-60.Patient-controlled intravenous analgesia was performed with sufentanil after operation, and the visual analog scale score was maintained ≤ 3.The quadriceps muscle strength score was recorded when discharge from postanesthesia care unit and at 24, 48 and 72 h after surgery.The first postoperative off-bed time and development of foot drop in awake patients after surgery, requirement for rescue analgesia and adverse reactions were recorded.The postoperative length of hospital stay and score for patients′ satisfaction with postoperative recovery were also recorded. Results:Compared with group C, the postoperative quadriceps muscle strength scores and score for patients′ satisfaction with postoperative recovery were significantly increased, the incidence of postoperative foot drop was decreased, and the length of hospital stay and first postoperative off-bed time were shortened in group IA ( P<0.05). Conclusion:IPACK-ACB combined with general anesthesia may be an optimized strategy which is helpful for outcomes after total knee arthroplasty.
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Objective To investigate the effect of dexmedetomidine on median effective target effect-site concentration ( EC50) of sufentanil inhibiting body movement evoked by skin incision in patients undergoing bilateral subtotal thyroidectomy. Methods Thirty-nine ASA I or II patients of both sexes aged 20-64 yr with a body mass index of 20-25 kg/m2 undergoing bilateral subtotal thyroidectomy were randomly divided into 2 groups: control group (group C) and dexmedetomidine group (group D). The patients were premedicated with intramuscular phenobarbital 0.1 g and scopolamine 0.3 mg. In group D dexmedetomidine 0.6 μg/kg was injected iv over 10 min at S min before induction of anesthesia. Anesthesia was induced with target-controlled infusion (TCI) of propofol and sufentanil. The target plasma concentration of propofol was set at 3.0 μg/ml which was maintained until the end of operation. TCI of sufentanil was started at 10 min after initiation of propofol TCI. The initial target effect-site concentration was set at 0.20 ng/ml and decreased/increased by 20% in the next patient according to whether the patient's body moved or not within 1 min after skin incision. Laryngeal mask airway was inserted at 3 min after initiation of sufentanil TCI. Spontaneous breathing was maintained. Skin incision was made at 10 min after initiation of sufentanil TCI. The EC50 and 95% confidence interval (CI) of sufentanil inhibiting skin incision-evoked body movement were calculated with sequential method. Results EC50, of sufentanil was 0.1148 ng/ml (95% CI 0.1055-0.1249 ng/ml) in group D and 0.1454 ng/ml (95% CI 0.1339-0.1580 ng/ml) in group C, and was significantly lower in group D than in group C. Conclusion Dexmedetomidine 0.6 μg/kg infused iv before operation can reduce the EC50 of sufentanil inhibiting body movement evoked by skin incision in patients undergoing bilateral subtotal thyroidectomy.
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Objective To determine the half-effective target effect-site concentration (Ce) (EC50) of sufentanil required to inhibit the body movement during insertion of ureteroscopes when combined with propofol in patients undergoing transureteroscopic holmium laser lithotripsy. Methods Fifty ASA Ⅰ or Ⅱ patients of both sexes, aged 20-60 yr, BMI ＜ 30 kg/m2 , undergoing transureteroscopic holmium laser lithotripsy were randomly divided into 5 groups according to the different C es of sufentanil ( n = 10 each): group S1 (Ce 0.21 ng/ml), group S2(Ce 0.14 ng/ml), group S3(Ce 0.09 ng/ml), group S4(Ce 0.06 ng/ml), group S5(Ce 0.04 ng/ml). TCI of propofol with target plasma concentration set at 2.5-3.0 μg/ml was given. Sufentanil with the corresponding Ce was infused in each group. The ureteroscopes were inserted as soon as the patients lost consciousness and the effect-site concentration of sunfentanil was achieved. The response was defined as positive when body movement occurred within 1 min after insertion of ureteroscopes. The EC50 of sufentanil required to inhibit the body movement during insertion of ureteroscopes when combined with propofol and 95% confidence interval (CI) were calculated. Results The EC50 of sufentanil required to inhibit the body movement during insertion of ureteroscopes when combined with propofol was 0.084 ng/ml and 95% CI was 0.066-0.107 ng/ml. Conclusion The EC50 of sufentanil required to inhibit the body movement during insertion of ureteroscopes was 0.084 ng/ml when combined with propofol.
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Objective To study the convenient, safe and effective surgical intervention methods for correcting prominent wide lower face. Methods According to the wideness of mandibular angles, single or combined surgical treatments were performed by an intraoral approach under nerve block and local infiltration anesthesia, such as grinding mandibular angles, curved osteotomy of the angles and osteotomy of ascending ramus outer layer, partial masseter muscle resection, partial buccal fat pad removal and liposuction of cheek to reconstruct the whole lower face contour. Resnlts In the 71 cases followed up for 4 to 24 months, 60 cases were excellent, 9 were acceptable and 2 were unsatisfactory. The total satisfactory rate was 97 %. Conclusion According to the characteristics of prominent wide lower face, single or combined surgical treatments are performed to reconstruct the bone and soft tissue of lower face. This operative method is simple, safe and consistent with cosmetic surgery principle with little complications.
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Objective To report the experience of surgical treatment of 4 patients with complete transposition of great areteries (TGA). Methods 4 cases received arterial switch operation and senning operation from November 2004 to January 2008, including 1 case of TGA without VSD(TGA - IVS), 3 TGA with VSD (TGA -VSD), 2 TGA with Mild pulmonary valve stenosis. Results There no death during the operation or postoperation. Patients were followed up from 5 months to 3years. All the patients got better ,grew faster and cyanosis relieved apparently. 2 patients had mild to moderate mitral regurgitation preoperatively. I patient had mild mitral regurgitation post-operatively and 1 patient had no mitral regurgitation. There was no aortic stenosis or pulmonary valve stenosis after operation. I patient assis-ted respiration for 62 days after operation because of old age. All the patients recovered smoothly after operation. Conclusion Using arte-rial switch operation and senning operation to correct complete transposition of great artery could get satisfying operative results, and the ar-terial switch operation will also get good effect in older children with better left ventricular development.
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@#Objective To build a method of mandible 3D model to measure and analysis, then to finish the operation simulation, providing anatomic data to avoiding the complicafious of mandible osteotomy. Methods Using CT data to reconstruct 3D model of mandible with blood vessel and bone, then using Simpleware to measure and analysis, and using Freeform system and an incision method of Boolean to simulation mandible osteotomy safely. Re, tits It was possible to use CT data to rebuild 3D model for 3D measure and analysis for operation simulation. The inferior alveolar artery and never were the main tiasues which went through the madibhilar. The length of mandibular foramen to anterior minus was (19.13±0.66) ram,and the ones to posterior ramus was (18.96± 0.64)mm. The angle of the mandible was (109.70±4.67)°. The rages of the remus for safe operation was (12.62±0.28)mm, and the safe rages about angle of the body and bottom of the mandible was (22.30±4.67)°. There were obvious differences from children to the aged in the mandible physiological and anatomic study. We can use Freeform system to simulate the operation on 3D model. Conclusion It is a new method to build 3D model and use Freefonn system to simulate operation and a new path to communion with patients for a good operation.
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BACKGROUND:Keloid is the outcome of wound-healing process,and the result of massive accumulation of life-prolonged fibroblasts with gene mutation as well as the excessive synthesis of collagenous fibers.OBJECTIVE:To probe the relationship between the fibroblasts and the mutations of the exon-8 of Fas gene in keloid.DESIGN:An open study with gene sequence as the subjects of observation.SETTING :The Department of Plastic Surgery of Southern Hospital of the First Military Medical University.PARTICIPANTS:This experiment was carried out at the Tropical Disease Research Institute of the First Military Medical University of Chinese PLA in 2001. All keloid and hypertrophic scar tissues were obtained from the patients who received orthopedic surgical operations at the Southern Hospital, including 15 patients with keloid whose pathological areas were located respectively at the earlobe and the prothorax and 12patients with hypertrophic scars whose pathological areas being located at the instep and the elbow. At the same time, normal skin and the peripheral blood samples from the patients themselves with keloid were taken as the self-control and the skin and the peripheral blood samples from the normal people and the patients with hypertrophic scars were taken as the normal control.METHODS: PCR-SCCM technique and gene sequence analysis were used to detect the gene structure of exon-8 in the Fas gene from 15 patients.MAIN OUTCOME MEASURES:The gene structure of exon-8 in the Fas gene derived from the tissues and the peripheral blood samples of all the groups.RESULTS: ① Heterozygous loss was observed in the exon-8 of the Fas gene in all 15 keloid patients; ② Gene sequence was found to be abnormal in 11 cases out of 15 keloid patients, presenting gene mutation in 4 loci.CONCLUSION: Heterozygous loss and gene mutation was detected in the exon 8 of Fas gene of keloid, suggesting that Fas protein in keloid has functional defect that is closely associated with gene mutation.
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BACKGROUND:Keloid is the outcome of wound-healing process,and the result of massive accumulation of life-prolonged fibroblasts with gene mutation as well as the excessive synthesis of collagenous fibers.OBJECTIVE:To probe into the structural relations of exons 7-9 of fibroblastic Fas gene in keloid tissues.DESIGN:A self-controlled experimental study with cicatricial tissues as the subjects.SETTING:Department of Plastic Surgery of Southern Hospital of the First Military Medical University of Chinese PLA.PARTICIPANTS:This experiment was carried out at the Tropical Disease Research Institute of the First Military Medical University of Chinese PLA in 2001. All keloid and hypertrophic scar tissues were obtained from the patients who received orthopedic surgical operations at the Southern Hospital, including 15 patients with keloid and 12 patients with hypertrophic Scars. Normal skin and peripheral blood were obtained from the keloid patients as self-control. Meanwhile pathological tissues and normal skin and peripheral blood were obtained from patients with hypertrophic scars as normal control.INTERVENTION:PCR-single strand conformation polymorphism was used to find the structure of the exons 7-9 in Fas gene in15 patients with keloid.MAIN OUTCOME MEASURES:The structure of the exons 7-9 in Fas gene.RESULTS:Heterozygous loss of Fas gene exon-8 was observed in all the 15 keloid patients, and 20% of them displayed an increase in exon-9 allele band.CONCLUSION: The genetic structure of Fas gene showed no mutation in hypertrophic scars, normal skin and the peripheral blood,but mutations were detected in exons-8 ,and -9 of Fas gene in keloid. This was closely related with the disfunction of its encoded proteins.
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<p><b>OBJECTIVE</b>To investigate whether there are abnormal fibroblasts derived from the surrounding skin of keloids so that a more accurate therapy for keloids could be obtained.</p><p><b>METHODS</b>Samples were taken for cell culture. When primary cells fully covered the culture bottle, the shape and distributing characteristics of fibroblasts were observed under the light microscope. 6-8 passage fibroblasts were selected for comparing the proliferating activity by MTT contrasting color method.</p><p><b>RESULTS</b>The fibroblasts have the same shape in all groups. But the fibroblasts derived from the surrounding skin grow crossly and overlapped just as the fibroblasts from keloids. The proliferating activity of the fibroblasts from surrounding skin is not as high as that from the border of keloids, but is higher than the normal skin fibroblasts derived either from a normal person or a patient with keloid.</p><p><b>CONCLUSION</b>It is likely that there are abnormal fibroblasts in the surrounding skin of keloids.</p>