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BACKGROUND:For dislocation of acromioclavicular joint induced by coracoclavicular ligament fracture,single EndoButton Plate reconstruction and double EndoButton Plates reconstruction are common repair methods.Further study on the stress distribution and fracture risk of the two repair methods is of great significance. OBJECTIVE:To study the biomechanical properties of the coracoclavicular ligament,and compare the fixation effect,stress distribution and failure mode of single and double EndoButton Plates reconstruction. METHODS:(1)Finite element simulation analysis:Mimics,Wrap and SolidWorks were used to establish normal coracoclavicular ligament,single EndoButton Plate reconstruction and double EndoButton Plates reconstruction.Ansys software was used to analyze the stress and deformation of the scapula and clavicle of each model under vertical load.(2)Sample experiment:Fifteen intact scapular-clavicle specimens were randomly grouped into five groups,with three specimens in each group.In group A,the acromioclavicular ligament was severed and the coracoclavicular ligament remained intact.In group B,acromioclavicular ligaments and trapeoid ligaments were severed,leaving intact conical ligaments.In group C,acromioclavicular ligaments and conical ligaments were cut off,and the intact traprex ligaments were retained.In group D,acromioclavicular and coracoclavicular ligaments were severed,and coracoclavicular ligaments were repaired by single EndoButton Plate reconstruction.In group E,acromioclavicular and coracoclavicular ligaments were severed,and the coracoclavicular ligaments were repaired by double EndoButton Plates reconstruction.The mechanical experiment was carried out by a mechanical testing machine to analyze the biomechanical status,stress distribution and failure patterns of the scapular-clavicle and clavicle. RESULTS AND CONCLUSION:(1)Finite element simulation analysis:The average stress of coracoclavicular ligament attached specimens was the lowest,and the risk of coracoclavicular fracture was less than that of single and double EndoButton Plates reconstruction.The mean stress of the coracoid process was similar in single and double EndoButton Plates reconstruction,and the fracture risk was similar.(2)Sample experiment:In groups A,B,C,D and E,the stiffness of specimens was(26.4±3.5),(19.8±2.8),(21.3±3.2),(57.7±4.1),and(46.2±2.8)N/mm,respectively;the ultimate loads were(545.5±53.7),(360.1±42.1),(250.9±44.4),(643.5±39.1),and(511.9±31.7)N,respectively;global stiffness in groups D and E was higher than that in group A(P=0.000 06,0.000 3);ultimate load in group D was higher than that in group A(P<0.05);the ultimate load was not significantly different between the group E and group A(P>0.05).Ligament fracture was observed in groups A,B and C and coracoid process fracture was found in groups D and E.(3)These results suggest that from the biomechanical analysis,Single EndoButton Plate reconstruction and double EndoButton Plates reconstruction are effective treatment techniques for coracoclavicular ligament fracture in acromioclavicular joint dislocation,but increase the risk of fracture.The double EndoButton Plates reconstruction dispersed the stress of the steel plate and reduced the contact force between the steel plate and bone,but slightly reduced the ultimate bearing capacity.Single and double EndoButton Plates reconstruction should be selected according to the actual clinical situation.
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BACKGROUND:The stability of the pelvis is mainly determined by the posterior pelvic ring and the sacroiliac joint.The posterior pelvic ring injury and the dislocation of the sacroiliac joint caused by high energy impacts such as car accidents increase year by year.Surgical treatment is the best method,and there are many kinds of endophytorepair methods in clinical practice,but which treatment method has the best biomechanical properties is still controversial. OBJECTIVE:To compare the biomechanical properties of three kinds of internal implants:anterior double plates,posterior bridging plate and tension nail in the repair of unilateral unstable pelvic posterior ring injury,to provide a reference for the clinical treatment and development of a new pelvic tension screw. METHODS:(1)Finite element simulation:Mimics,Wrap and SolidWorks were used to establish normal pelvic model,unilateral injured pelvis model,and three kinds of internal implant repaired models(anterior double plates,posterior bridging plate and tension nail).Ansys was used to analyze the stress and deformation of the models.(2)Biomechanical test:A total of 15 intact pelvic specimens were randomly grouped into five groups,normal pelvic model,unilateral injured pelvis model,anterior double plates,posterior bridging plate and tension nail groups.The mechanical test was performed using an Instron E10000 testing machine. RESULTS AND CONCLUSION:(1)Simulation:In the normal pelvic model,the average displacement of the sacrum was 0.174 mm,and the maximum stress of the sacral iliac bone was 10.51 MPa,and the stress distribution was uniform.The mean sacral displacement of the unilateral injured pelvis model was 0.267 mm,and the stress concentration of the model was obvious.The mean displacement of the sacrum in the three repaired models was close to that in the normal pelvic model,and the stress distribution of the sacral iliac bone in the tension nail repaired model was uniform.(2)Mechanical test:The stiffness of the normal pelvic model was(226.38±4.18)N/mm,and that of the unilateral unstable pelvic model was the smallest(130.02±2.19)N/mm.The deviation of the normal pelvic model stiffness and the three repaired models'stiffness were all within(±10%),and the repair effect was obvious.(3)The simulation results were in agreement with the experimental results.(4)The biomechanics of the tension nail repaired model was the most similar to that of the normal pelvis,and this method was the best.The repairing stiffness of the anterior double plate was too large,and the stress shielding effect was more significant.The posterior bridging plate repair could not solve the compensatory effect of the normal side soft tissue and had defects.This study provides an optimal basis for clinical surgery.(5)The new type of pelvic tension nail should be improved from the point of view of the tension nail to retain the good biomechanical properties of the tension nail,while adding other advantages,such as being used for the osteoporotic pelvis.
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Objective:To investigate the effects of different tube voltages combined with artificial intelligence reconstruction algorithm(CI)on the computed tomography(CT)imaging quality and radiation dose of chest phantom on the basis of the CT scan for an adult male simulated chest phantom(PH-N1).Methods:A 512-slice CT scanner of ultrahigh-end was adopted to conduct scan,and the images were divided into 70 kV group,80 kV group,100 kV group and 120 kV group according to different tube voltage.For 4 groups of CT scan images with different tube voltages,the 10%,30%,50%,70%and 90%CI were adopted to reconstruct 1mm thin layer image.The CT volume dose index(CTDIvol)and the dose-length product(DLP)of the scans of 4 groups were compared.The CT values and standard deviation(SD)values of the aorta,abdominal wall fat and erector spine muscle were measured.Two senior diagnostic physicians with more than 5 years of work experience independently and double-blindly evaluated the image quality by using 5-point scale.A Kappa consistency test was conducted.One-way analysis of variance was adopted to compare the differences of CT values and SD values of the tissues of image targets.The Friedman rank-sum test was adopted to compare the differences of subjective image qualities among different groups.Results:The differences of CTDIvol and DLP among 4 groups with different tube voltages were significant(F=1855.617,3996.118,P<0.05),respectively.Under 70 kV tube voltage,there were no significant differences in CT values of the aorta,abdominal wall fat and erector spine muscle,which were reconstructed by using 10%,30%,50%,70%and 90%CI(P>0.05),while the differences of SD values among them were statistically significant(F=32.267,53.327,14.873,P<0.05),respectively.Under the different tube voltages of 4 groups,which were reconstructed by 90%CI,the CT values of aorta,abdominal wall fat and erector spine muscle gradually decreased with decreasing of tube voltage,the differences were significant(F=139.899,2563.93,219.231,P<0.05),respectively.The consistency of subjective scores between two diagnostic physicians was better for each group of images(Kappa=0.712～0.869).Conclusion:Compared with 80 kV,90 kV and 120 kV images,the reconstructed images with 90%CI algorithm under 70 kV tube voltage can significantly reduce the radiation dose,and the images have a favorable signal-to-noise ratio at the same time.
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Objective:To explore the application value of compute tomography(CT)scan with 16cm wide body detector in chest examination of patients who could not cooperate with breath-holding.Methods:A total of 100 patients who could not cooperate with breath-holding during chest examination in the second affiliated hospital of Shenyang Medical College from May to August in 2022 were selected,and they were randomly divided into observation group and control group,with 50 patients in each group.The collimation width of CT scan with 16cm wide body detector was 256 mm×0.625 mm in the observation group,and that with 8 cm wide body detector was 128 mm×0.625 mm in the control group,and other parameters of two groups were same.A series of indicators included age,height,weight and body mass index(BMI)of patients were recorded,and the CT dose index(CTDIvol),dose length product(DLP),effective dose(ED)were measured and calculated.And then,the Contrast to Noise ratio(CNR),signal to noise(SNR)and Standard Deviation(SD)between two groups were compared,and the image quality was evaluated objectively and subjectively.Results:The average age and the average weight of the patients in the observation group were respectively(78.81±6.84)years old and(64.46±9.86)kg,and the mean values of BMI,CTDIvol,DLP,ED and exposure time were respectively(22.89±3.09)kg/m2,(4.61±1.00)mGy,(1 471.02±345.25)mGy·cm,(20.59±4.83)mSv,(1.01±0.61)s.The average age and the average weight of the patients in the control group were respectively(77.70±6.76)years old and(62.84±4.75)kg.The mean values of BMI,CTDIvol,DLP,Ed and exposure time were respectively(22.89±2.29)kg/m2,(14.5±0.00)mGy,(4 561.70±346.32)mGy·cm,(63.86±4.85)mSv and(4.07±0.12)s.The differences of subjective evaluations of main pulmonary artery,right inferior pulmonary vein trunk and aortic arch between the observation group and the control group were not significant(P>0.05).The subjective scores of image qualities both two groups were larger than 4,and the image qualities of two groups could meet the diagnostic requirements.The CTDIvol,DLP,ED and exposure time of observation group were significantly lower than those in control group(t=-69.42,-44.231,-44.234,-107.10,P<0.05),respectively.Conclusion:Compared with the CT scan with conventional 8 cm detector,the CT scan with 16 cm wide body detector can greatly shorten the scanning time and reduce the radiation dose in the chest CT scan of patients with free breathing,and the image quality of that can meet the requirement of clinical diagnosis,which has very high application value in the fast diagnosis of clinical emergency.
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OBJECTIVE To explore the predictive factors of cefoperazone/sulbactam-induced thrombocytopenia in adult inpatients， and to establish and validate the nomogram prediction model. METHODS Data of adult inpatients treated with cefoperazone/sulbactam in Xi’an Central Hospital from Jun. 30th， 2021 to Jun. 30th， 2023 were retrospectively collected. The training set and internal validation set were randomly constructed in a 7∶3 ratio. Singler factor and multifactor Logistic regression analysis were used to screen the independent predictors of cefoperazone/sulbactam-induced thrombocytopenia. The nomogram was drawn by using “RMS” of R 4.0.3 software， and the predictive performance of the model was evaluated by the receiver operating characteristic curve and C-index curve. Hosmer-Lemeshow goodness-of-fit test was used to evaluate the calibration degree of the model. Using the same standard， the clinical data of hospitalized patients receiving cefoperazone/sulbactam in Xi’an First Hospital in the same period were collected for external validation of the nomogram prediction model. RESULTS A total of 1 045 patients in Xi’an Central Hospital were included in this study， among which 67 patients suffered from cefoperazone/sulbactam-induced thrombocytopenia， with an incidence of 6.41%. After the false positive patients were excluded， 473 patients were included finally， including 331 in the training set and 142 in theinternal validation set. Multifactor Logistic regression analysis showed that age [OR＝1.043， 95%CI （1.017， 1.070）]， estimated glomerular filtration rate （eGFR） [OR＝0.988，95%CI（0.977， 0.998）]， baseline platelet （PLT） [OR＝0.989， 95%CI（0.982， 0.996）]， nutritional risk [OR＝3.863， 95%CI（1.884， 7.921）] and cumulative defined daily doses （DDDs） [OR＝1.082， 95%CI（1.020， 1.147）] were independent predictors for cefoperazone/sulbactam-induced thrombocytopenia （P＜0.05）. The C-index values of the training set and the internal validation set were 0.824 [95%CI （0.759， 0.890）] and 0.828 [95%CI （0.749， 0.933）]， respectively. The results of the Hosmer-Lemeshow test showed that χ 2 values were 0.441 （P＝0.802） and 1.804 （P＝0.406）. In the external validation set， the C-index value was 0.808 [95%CI （0.672， 0.945）]， the χ 2 value of the Hosmer-Lemeshow test was 0.899 （P＝0.638）. CONCLUSIONS The independent predictors of cefoperazone/sulbactam-induced thrombocytopenia include age， baseline PLT， eGFR， nutritional risk and cumulative DDDs. The model has good predictive efficacy and extrapolation ability， which can help clinic identify the potential risk of cefoperazone/sulbactam-induced thrombocytopenia quickly and accurately.
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Protein-protein interactions (PPIs) are fundamental to many biological processes that play an important role in the occurrence and development of a variety of diseases. Targeting the interaction between tumour-related proteins with emerging small molecule drugs has become an attractive approach for treatment of human diseases, especially tumours. Encouragingly, selective PPI-based therapeutic agents have been rapidly advancing over the past decade, providing promising perspectives for novel therapies for patients with cancer. In this review we comprehensively clarify the discovery and development of small molecule modulators of PPIs from multiple aspects, focusing on PPIs in disease, drug design and discovery strategies, structure-activity relationships, inherent dilemmas, and future directions.
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Alkaloids are a class of naturally occurring bioactive compounds that are widely distributed in various food sources and Traditional Chinese Medicine. This study aimed to investigate the therapeutic effects and underlying mechanisms of alkaloid extract from Codonopsis Radix (ACR) in ameliorating hepatic lipid accumulation in a mouse model of non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet (HFD). The results revealed that ACR treatment effectively mitigated the abnormal weight gain and hepatic injury associated with HFD. Furthermore, ACR ameliorated the dysregulated lipid metabolism in NAFLD mice, as evidenced by reductions in serum triglyceride, total cholesterol, and low-density lipoprotein levels, accompanied by a concomitant increase in the high-density lipoprotein level. ACR treatment also demonstrated a profound anti-oxidative effect, effectively alleviating HFD-induced oxidative stress and promoting ATP production. These effects were achieved through the up-regulation of the activities of mitochondrial electron transfer chain complexes I, II, IV, and V, in addition to the activation of the AMPK/PGC-1α pathway, suggesting that ACR exhibits therapeutic potential in alleviating the HFD-induced dysregulation of mitochondrial energy metabolism. Moreover, ACR administration mitigated HFD-induced endoplasmic reticulum (ER) stress and suppressed the overexpression of ubiquitin-specific protease 14 (USP14) in NAFLD mice. In summary, the present study provides compelling evidence supporting the hepatoprotective role of ACR in alleviating lipid deposition in NAFLD by improving energy metabolism and reducing oxidative stress and ER stress. These findings warrant further investigation and merit the development of ACR as a potential therapeutic agent for NAFLD.
الموضوعات
Mice , Animals , Non-alcoholic Fatty Liver Disease/metabolism , Codonopsis , Liver , Lipid Metabolism , Antineoplastic Agents/pharmacology , Alkaloids/pharmacology , Endoplasmic Reticulum Stress , Energy Metabolism , Lipids , Diet, High-Fat/adverse effects , Mice, Inbred C57BLالملخص
Objective:To explore alterations of myocardial mechanics in mice models of physiological aging.Methods:Mice aged from 3 weeks to 24 months were chosen(n=50). Conventional echocardiography and layer speckle tracking echocardiography(LS-STE)were applied to evaluate alterations of myocardial mechanics in different ages(each for 10 mise). Pathological myocardial alterations in the aging process were detected using HE and Masson's trichrome staining.Results:Clear age-dependent changes in mice of different ages were observed when assessed using parameters of conventional echocardiography( P<0.05 for all). Values from parameters of LS-STE also showed that longitudinal, circumferential and radial strain in both the endocardium and the epicardium gradually decreased during physiological aging( P<0.05 for all). Compared with the 3-weeks old group, longitudinal strain in the endocardium was significantly reduced in the 14-months old group[(-23.49±2.32) vs.(-17.19±2.28), P<0.05]; Compared with the 3-weeks old group, radial strain, longitudinal strain in the endocardium, longitudinal strain in the epicardium, circumferential strain in the endocardium and circumferential strain in the epicardium were significantly reduced in the 24-months old group[(32.90±5.01) vs.(21.80±5.54), (-23.49±2.32) vs.(-15.44±2.27), (-13.23±3.19) vs.(-7.59±2.21), (-25.93±4.09) vs.(-20.31±4.08), (-9.30±1.92) vs.(-6.01±1.04), P<0.05)]; HE and Masson's trichrome staining of the myocardium indicated increases in the cross-sectional area of cardiomyocytes and fibrosis during the aging process. Conclusions:LS-STE can accurately detect early cardiac dysfunction and pathological myocardial alterations associated with aging in mice and may serve as an effective tool in evaluating anti-myocardial aging.
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[This corrects the article DOI: 10.1016/j.apsb.2020.05.004.].
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Objective:To establish a set of scientific and reasonable indicator system of common prosperity in the field of health, so as to promote the construction and evaluation of the demonstration area of common prosperity with high quality of health.Methods:According to the requirements of promoting common prosperity demonstration area with high quality of health in Zhejiang province, the initial indicator pool was established through literature research and theoretical analysis in July 2021, and experts were convened to carry out expert brainstorming to determine indicator system in the form of meetings. Delphi method was used to conduct two rounds of expert consultation on the indicator system.Finally, the analytic hierarchy process and percentage weight method were used to calculate the indicator weight value.Results:The final indicator system included 4 first-level indicators and 30 second-level indicators. Among the first-level indicators, the weight values of the development, equilibrium, inclusiveness, and sustainability were 0.326 4, 0.242 8, 0.245 8, and 0.185 0. There were 8 second-level indicators in developmental indicator dimension, of which the indicator with the highest weight was the per capita health expectancy. The balance indicator dimension included 6 second-level indicators, of which the indicator with the highest weight was the per capita financing difference of basic medical insurance between the urban workers with the urban-rural residents. The inclusive indicator dimension included 6 second-level indicators, and the proportion of personal health expenditure to total health expenditure had the highest weight. The sustainability indicator dimension included 10 second-level indicators, and the proportion of government health expenditure in fiscal expenditure had the highest weight.Conclusions:The indicator system constructed in this research could provide certain guidance and reference for promoting the construction of common prosperity in health, and provide some reference for follow-up research in this field.
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Objective:To investigate the clinical efficacy of pancreaticoduodenectomy with TRIANGLE operation in the treatment of pancreatic head cancer.Methods:The retrospective cohort study was conducted. The clinicopathological data of 51 patients with pancreatic head cancer who were admitted to the Sichuan Provincial People′s Hospital, Affiliated Hospital of School of Medicine of University of Electronic Science and Technology of China from January 2017 to July 2018 were collected. There were 33 males and 18 females, aged from 42 to 74 years, with a median age of 56 years. Of the 51 patients, 24 cases undergoing standard pancreaticoduodenectomy, in which No.12, 13 and 17 lymph nodes were dissected, combined with transcatheter arterial infusion chemo-therapy (TAI) were allocated into the standard group, and 27 cases undergoing pancreaticoduo-denectomy with TRIANGLE operation, in which No.7, 8, 9, 12, 13, 16, 17 lymph nodes were dissected, combined with TAI were allocated into the TRIANGLE group, respectively. Observation indicators: (1) intraoperative conditions of the two groups; (2) postoperative conditions of the two groups; (3) follow-up and survival. Follow-up was conducted using outpatient examination and telephone interview once three months to detect tumor recurrence and metastasis and survival of patients up to July 2021 or the death of patient. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was analyzed using the t test. Measurement data with skewed distribution were represented as M(range), and comparison between groups was analyzed using the chi-square test or the Fisher exact probability. Comparison of ordinal data was analyzed using the rank sum test. Kaplan‐Meier method was used to calculate the survival rate and median survival time and draw survival curve. Log‐Rank test was used for survival analysis. Results:(1) Comparison of intraoperative conditions between the two groups. The operation time, volume of intraoperative blood loss, cases with intraoperative blood transfusion were (501±61)minutes, (563±278)mL, 4 in the standard group, versus (556±46)minutes, (489±234)mL, 6 in the TRIANGLE group, respectively. There was a significant difference in the operation time between the two groups ( t=3.62, P<0.05) but there was no significant difference in the volume of intraoperative blood loss or cases with intraoperative blood transfusion between the two groups ( t=1.03, χ2=0.25, P>0.05). (2) Comparison of postoperative conditions between the two groups. Of the 51 patients, 30 had 50 times of postoperative complications, including 18 times of grade Ⅰ complications of Clavien-Dindo classification, 29 times of grade Ⅱ complications of Clavien-Dindo classification, 2 times of grade Ⅲa complications of Clavien-Dindo classification, 1 time of grade Ⅲb complications of Clavien-Dindo classification, respectively. Cases with postoperative complications, cases with delayed gastric emptying, cases without or with pancreatic fistula as class A or class B, cases with biliary fistula, cases with bleeding, cases with diarrhea were 15, 4, 13, 7, 4, 4, 2, 2 in the standard group, versus 15, 6, 14, 10, 3, 4, 1, 3 in the TRIANGLE group, respectively. There was no significant difference in cases with postoperative complications, cases with delayed gastric emptying, cases with pancreatic fistula between the two groups ( χ2=0.16, 0.02, Z=-0.04, P>0.05) and there was no significant difference in cases with biliary fistula, cases with bleeding, cases with diarrhea between the two groups ( P>0.05). Cases with complications as Clavien-Dindo grade Ⅰ, grade Ⅱ, grade Ⅲ were 10, 11, 2 in the standard group, versus 8, 18, 1 in the TRIANGLE group, showing no significant difference between the two groups ( Z=-0.67, P>0.05). The duration of postoperative hospital stay was (23±8)days in both of the standard group and the TRIANGLE group, showing no significant difference between the two groups ( t=0.31, P>0.05). (3) Follow-up and survival. All the 51 patients were followed-up for 6 to 54 months, with a median follow-up time of 17 months. The postoperative 1-year overall survival rate was 75.0% and 81.5% in the standard group and the TRIANGLE group, respectively. The postoperative 3-year overall survival rate was 12.5% and 22.2% in the standard group and the TRIANGLE group, respectively. The median postoperative survival time was 15.00 months (95% confidence interval as 12.63 to 17.37 months) and 21.00 months (95% confidence interval as 15.91 to 19.62 months) in the standard group and the TRIANGLE group, respectively. There was a significant difference in survival of patients between the two groups ( χ2=4.30, P<0.05). Cases with tumor recurrence during post-operative 1 year and 3 year were 9 and 20 in the standard group, versus 6 and 15 in the TRIANGLE group, respectively. There was no significant difference in cases with tumor recurrence during postoperative 1 year between the two groups ( P>0.05) and there was a significant difference in cases with tumor recurrence during postoperative 3 year between the two groups ( P<0.05). Conclusion:Compared with standard pancreaticoduodenectomy, pancreaticoduodenectomy with TRIANGLE operation can prolong the median survival time of patients with pancreatic head cancer without increasing surgical related complications.
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Objective:To determine the mechanical properties of our self-designed novel cross-locking intramedullary nails and the impact of number of conical locking nails on the fixation through a finite element analysis and specimen experiments.Methods:Mimics 19.0 and SolidWorks 2014 were used to create transverse fracture models of the olecranon which were subjected to fixation with respectively K-wire tension band (KTB) and our self-designed novel cross-locking intramedullary nails (NIN). The strengths of KTB and NIN fixation were analyzed by Ansys. Fifteen human ulna specimens were used to construct a transverse fracture model of the olecranon; an Instron E10000 mechanical testing machine was used to determine mechanical properties in fixation respectively with KTB, one NIN (NIN-1) and 3 NINs (NIN-3).Results:In the finite element analysis, in simulation of the forearm flexed at 45° under a 100 N load, the deformation of the fracture surface of the olecranon in fixation with KTB, NIN-1 and NIN-3 was respectively 0.131 mm, 0.123 mm and 0.121 mm. In the specimen experiments, in simulation of the forearm flexed at 45°, the maximum failure loads for fixation with KTB, NIN-1 and NIN-3 were (313.38±27.68) N, (528.56±53.58) N and (871.04±94.95) N, respectively, showing significant differences among the 3 groups ( P<0.05). The maximum failure load for NIN-3 fixation was significantly greater than that for KTB or NIN-1 fixation, and the maximum failure load for NIN-1 fixation was significantly greater than that for KTB fixation ( P<0.05). Conclusions:Compared with KTB fixation, NIN fixation is more convenient in operation and has better mechanical properties. NIN-3 fixation has the best mechanical properties.
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The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway is widely activated by a variety of extracellular stimuli, and its dysregulation is associated with the proliferation, invasion, and migration of cancer cells. ERK1/2 is located at the distal end of this pathway and rarely undergoes mutations, making it an attractive target for anticancer drug development. Currently, an increasing number of ERK1/2 inhibitors have been designed and synthesized for antitumor therapy, among which representative compounds have entered clinical trials. When ERK1/2 signal transduction is eliminated, ERK5 may provide a bypass route to rescue proliferation, and weaken the potency of ERK1/2 inhibitors. Therefore, drug research targeting ERK5 or based on the compensatory mechanism of ERK5 for ERK1/2 opens up a new way for oncotherapy. This review provides an overview of the physiological and biological functions of ERKs, focuses on the structure-activity relationships of small molecule inhibitors targeting ERKs, with a view to providing guidance for future drug design and optimization, and discusses the potential therapeutic strategies to overcome drug resistance.
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Objective To study mechanical properties of the novel micro-movement elastic implant of distal tibiofibular syndesmosis in dorsiflexion position.Methods A combination of simulation and experiment was used. The normal ankle dorsiflexion model, the bone nail repaired model and the micro-movement elastic implant repaired model were established by using Mimics and CT data. Besides, ANSYS Workbench was used for finite element analysis. Mechanical experiments on lower limb specimens were conducted on Instron E10000 mechanical test instrument, and five sets of experimental data were measured and analyzed.Results Mechanical properties of the micro-movement elastic implant repaired model were closer to those of the normal ankle dorsiflexion model, but stress of the micro-movement elastic implant repaired mode was greater than that of the bone nail repaired model. The results of two-sample heteroscedasticity t test indicated that there was no significant difference in resistance torque between the micro-movement elastic implant repaired model and the normal ankle dorsiflexion model.Conclusions For dorsiflexion position, repairing mechanical properties of the novel micro-movement elastic implant are much better than those of the bone nail, and there is still room for optimizing the micro-movement elastic implant.
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Objective To study the effect of interlocking intramedullary nail on fixing transverse olecranon fracture. Methods Nine pairs of fresh ulna specimens were collected and the transverse fracture model of olecranon was established. Kirschner wire tension band and interlocking intramedullary nail were used to repair the fracture. Cyclic dynamic tension loads with amplitude of 25 N, mean value of 45 N and frequency of 05 Hz were applied to the triceps tendon under simulated elbow flexion conditions of 30°, 45° and 60°, respectively. The fracture displacements of specimens within 300 cycles were recorded in three groups. ResultsAt 30° flexion angle, the fracture displacement of interlocking intramedullary nail group and Kirschner wire tension band group was (1.831±0.333) mm and (3.723±2.390) mm, respectively. At 45° flexion angle, the fracture displacement of interlocking intramedullary nail group and Kirschner wire tension band group was (1.167±0.374) mm and (2.455±0.609) mm, respectively. At 60° flexion angle, the fracture displacement of interlocking intramedullary nail group and Kirschner wire tension band group was (1.407±0.342) mm and (3.112±1.025) mm, respectively. The fracture displacement of interlocking intramedullary nail was smaller. Conclusions The mechanical properties of interlocking intramedullary nail are better than those of Kirschner wire tension band, and the interlocking intramedullary nail is more stable and firmer for fixing transverse olecranon fracture. Moreover, the interlocking intramedullary nail is installed with the operating tool, thus the operation is more accurate and faster, and the operation efficiency is greatly improved.
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Objective To analyze factors that affect axial mechanical performance of the posterior pedicle fixation system. Methods The mechanical model for axial mechanical properties of the posterior pedicle fixation system was established to perform mechanical analysis. By referring to the Standard YY/T 0961-2014, tests on axial ejection force and axial clamping torque of JHL-I multi-axis components, JHL-I single-axis components, JHL-V multi-axis components and JHL-V single-axis components were performed by using Instron E3000 and Instron E10000 mechanical testing machines. Results The ejection rigidity of the single-axis component of vertebral nail system was significantly higher than that of the multi-axis component of vertebral nail system; the torsion rigidity of JHL-V was higher than that of JHL-I. The type and size of the locking bolt as well as its locking torque were the main factors affecting axial ejection force of the posterior spinal pedicle fixation system; the size of the locking bolt and the diameter of the connection rod were the main factors affecting axial clamping torque of the system; axial mechanical properties of the system could be improved by increasing the diameter of the connecting rod, the coefficient of friction between each connecting element, and the pitch diameter of the locking bolt. Conclusions The research findings provide references for optimizing and improving axial mechanical properties of the posterior pedicle fixation system.
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Objective:To analyze clinicopathological characteristics of trauma-related melanoma and their relationship with the prognosis of patients.Methods:Clinical data were collected from 87 cases of trauma-related melanomas in Department of Dermatology, Xijing Hospital, the Fourth Military Medical University from 2009 to 2020, and their clinicopathological characteristics were retrospectively analyzed. Mann-Whitney test was used to analyze the difference in Breslow thickness of tumors between patients of different ages or genders; Spearman rank correlation analysis was used to analyze the correlation between the time from trauma to the notice of melanoma and Breslow thickness, Kaplan-Meier survival analysis and Log-Rank test were employed to analyze the relationship between clinicopathological characteristics of melanoma and the prognosis of patients; Cox regression model was used to analyze risk factors for survival duration of patients with trauma-related melanoma.Results:Among the 87 patients with trauma-related melanoma, 47 (54.02%) were males and 40 (45.98%) were females. Among them, melanoma occurred in 50 (57.47%) cases after sharp injuries, and in 37 (42.53%) after blunt injuries. In addition, 31 (35.63%) cases presented with primary lesions on the hands, and 48 (55.17%) on the feet. The Breslow thickness of the primary tumors was significantly higher in the group aged > 55 years than in the group aged ≤ 55 years ( U= 623.500, P= 0.010) , but there was no significant difference between patients of different genders ( P= 0.138) . The time from trauma to the notice of melanoma was negatively correlated with the Breslow thickness of tumors ( r=-0.203, P= 0.037) . The age of patients, Breslow thickness of tumors, Ki67 proliferation index and genetic background of tumor significantly affect the survival duration of patients with trauma-related melanoma ( P= 0.011, 0.031, 0.002 and 0.031, respectively) ; the gender, type of trauma and ulceration of tumor mass did not significantly affect the survival duration of patients ( P= 0.618, 0.114 and 0.379, respectively) . Cox regression model analysis showed that the Ki67 proliferation index and Breslow thickness were independent risk factors affecting the prognosis of trauma-related melanoma (risk ratio [ RR] and 95% confidence interval [ CI] were 1.946 (1.234, 4.217) and 1.839 (1.014, 3.332) , P= 0.039 and 0.045, respectively) . Conclusion:The Breslow thickness of trauma-related melanoma is related to the age of patients and time from trauma to the notice of melanoma; the age, Breslow thickness of tumors, Ki67 proliferation index and genetic background of tumor all affect the survival duration of patients with melanoma, and Ki67 proliferation index and Breslow thickness are independent risk factors affecting prognosis.
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@#This study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly (ADP-ribose) polymerase-1 (PARP1) and bromodomain containing protein 4 (BRD4), which had important cross relation in the global network of breast cancer, reflecting the synthetic lethal effect. A series of new BRD4 and PARP1 dual-target inhibitors were discovered and synthesized by fragment-based combinatorial screening and activity assays that together led to the chemical optimization. Among these compounds, 19d was selected and exhibited micromole enzymatic potencies against BRD4 and PARP1, respectively. Compound 19d was further shown to efficiently modulate the expression of BRD4 and PARP1. Subsequently, compound 19d was found to induce breast cancer cell apoptosis and stimulate cell cycle arrest at G1 phase. Following pharmacokinetic studies, compound 19d showed its antitumor activity in breast cancer susceptibility gene 1/2 (BRCA1/2) wild-type MDA-MB-468 and MCF-7 xenograft models without apparent toxicity and loss of body weight. These results together demonstrated that a highly potent dual-targeted inhibitor was successfully synthesized and indicated that co-targeting of BRD4 and PARP1 based on the concept of synthetic lethality would be a promising therapeutic strategy for breast cancer.
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Parkinson's disease (PD), known as one of the most universal neurodegenerative diseases, is a serious threat to the health of the elderly. The current treatment has been demonstrated to relieve symptoms, and the discovery of new small-molecule compounds has been regarded as a promising strategy. Of note, the homeostasis of the autolysosome pathway (ALP) is closely associated with PD, and impaired autophagy may cause the death of neurons and thereby accelerating the progress of PD. Thus, pharmacological targeting autophagy with small-molecule compounds has been drawn a rising attention so far. In this review, we focus on summarizing several autophagy-associated targets, such as AMPK, mTORC1, ULK1, IMPase, LRRK2, beclin-1, TFEB, GCase, ERR
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Mitotic catastrophe (MC) is a form of programmed cell death induced by mitotic process disorders, which is very important in tumor prevention, development, and drug resistance. Because rapidly increased data for MC is vigorously promoting the tumor-related biomedical and clinical study, it is urgent for us to develop a professional and comprehensive database to curate MC-related data. Mitotic Catastrophe Database (MCDB) consists of 1214 genes/proteins and 5014 compounds collected and organized from more than 8000 research articles. Also, MCDB defines the confidence level, classification criteria, and uniform naming rules for MC-related data, which greatly improves data reliability and retrieval convenience. Moreover, MCDB develops protein sequence alignment and target prediction functions. The former can be used to predict new potential MC-related genes and proteins, and the latter can facilitate the identification of potential target proteins of unknown MC-related compounds. In short, MCDB is such a proprietary, standard, and comprehensive database for MC-relate data that will facilitate the exploration of MC from chemists to biologists in the fields of medicinal chemistry, molecular biology, bioinformatics, oncology and so on. The MCDB is distributed on http://www.combio-lezhang.online/MCDB/index_html/.