The p21-activated kinase 4 (PAK4), a key regulator of malignancy, is negatively correlated with immune infiltration and has become an emergent drug target of cancer therapy. Given the lack of high efficacy PAK4 inhibitors, we herein reported the identification of a novel inhibitor 13 bearing a tetrahydrobenzofuro[2,3-c]pyridine tricyclic core and possessing high potency against MIA PaCa-2 and Pan02 cell lines with IC₅₀ values of 0.38 and 0.50 μmol/L, respectively. This compound directly binds to PAK4 in a non-ATP competitive manner. In the mouse Pan02 model, compound 13 exhibited significant tumor growth inhibition at a dose of 100 mg/kg, accompanied by reduced levels of PAK4 and its phosphorylation together with immune infiltration in mice tumor tissue. Overall, compound 13 is a novel allosteric PAK4 inhibitor with a unique tricyclic structural feature and high potency both in vitro and in vivo, thus making it worthy of further exploration.

Investigating the correlation between micronucleus formation and male infertility has the potential to improve clinical diagnosis and deepen our understanding of pathological progression. Our study enrolled 2252 male patients whose semen was analyzed from March 2023 to July 2023. Their clinical data, including semen parameters and age, were also collected. Genetic analysis was used to determine whether the sex chromosome involved in male infertility was abnormal (including the increase, deletion, and translocation of the X and Y chromosomes), and subsequent semen analysis was conducted for clinical grouping purposes. The participants were categorized into five groups: normozoospermia, asthenozoospermia, oligozoospermia, oligoasthenozoospermia, and azoospermia. Patients were randomly selected for further study; 41 patients with normozoospermia were included in the control group and 117 patients with non-normozoospermia were included in the study group according to the proportions of all enrolled patients. Cytokinesis-block micronucleus (CBMN) screening was conducted through peripheral blood. Statistical analysis was used to determine the differences in micronuclei (MNi) among the groups and the relationships between MNi and clinical data. There was a significant increase in MNi in infertile men, including those with azoospermia, compared with normozoospermic patients, but there was no significant difference between the genetic and nongenetic groups in azoospermic men. The presence of MNi was associated with sperm concentration, progressive sperm motility, immotile spermatozoa, malformed spermatozoa, total sperm count, and total sperm motility. This study underscores the potential utility of MNi as a diagnostic tool and highlights the need for further research to elucidate the underlying mechanisms of male infertility.
Humans ; Male ; Infertility, Male/genetics* ; Adult ; Micronucleus Tests ; Semen Analysis ; Oligospermia/genetics* ; Azoospermia/genetics* ; Chromosome Aberrations ; Sperm Count ; Micronuclei, Chromosome-Defective ; Middle Aged

ObjectiveThe proteome of biological evidence contains rich genetic information, namely single amino acid polymorphisms (SAPs) in protein sequences. However, due to the lack of efficient and convenient analysis tools, the application of SAP in public security still faces many challenges. This paper aims to meet the application requirements of SAP analysis for forensic biological evidence’s proteome data. MethodsThe software is divided into three modules. First, based on a built-in database of common non-synonymous single nucleotide polymorphisms (nsSNPs) and SAPs in East Asian populations, the software integrates and annotates newly identified exonic nsSNPs as SAPs, thereby constructing a customized SAP protein sequence database. It then utilizes a pre-installed search engine—either pFind or MaxQuant—to perform analysis and output SAP typing results, identifying both reference and variant types, along with their corresponding imputed nsSNPs. Finally, SAPTyper compares the proteome-based typing results with the individual’s exome-derived nsSNP profile and outputs the comparison report. ResultsSAPTyper accepts proteomic DDA mass spectrometry raw data (DDA acquisition mode) and exome sequencing results of nsSNPs as input and outputs the report of SAPs result. The pFind and Maxquant search engines were used to test the proteome data of 2 hair shafts of2 individuals, and both obtained SAP results. It was found that the results of the Maxquant search engine were slightly less than those of pFind. This result shows that SAPTyper can achieve SAP fingding function. Moreover, the pFind search engine was used to test the proteome data of 3 hair shafts from 1 European person and 1 African person in the literature. Among the sites fully matched by the literature method, sites detected by SAPTyper are also included; for semi-matching sites, that is, nsSNPs are heterozygous, both literature method and SAPTyper method had the risk of missing detection for one type of the allele. Comparing the analysis results of SAPTyper with the SAP test results reported in the literature, it was found that some imputed nsSNP sites identified by the literature method but not detected by SAPTyper had a MAF of less than 0.1% in East Asian populations, and therefore they were not included in the common nsSNP database of East Asian populations constructed by this software. Since the database construction of this software is based on the genetic variation information of East Asian populations, it is currently unable to effectively identify representative unique common variation sites in European or African populations, but it can still identify SAP sites shared by these populations and East Asian populations. ConclusionAn automated SAP analysis algorithm was developed for East Asian populations, and the software named SAPTyper was developed. This software provides a convenient and efficient analysis tool for the research and application of forensic proteomic SAP and has important application prospects in individual identification and phenotypic inference based on SAP.

Objective:To explore gait symmetry of unilateral functional ankle instability(FAI).Method:Fifteen male subjects with right functional ankle instability were recruited,Qualisys was used to col-lect and intercept gait cycle data on both sides.Coupling angle and standard deviation of the coupling angle were calculated using Matlab and the effect size was evaluated using Cohen's d.Result:①The coupling angles of the healthy side and the affected side were different in the sagittal plane.The average coupling angles of the hip-knee joint and the hip-ankle joint were higher on the healthy side than on the affected side in the pre-swing period(P<0.05,d=1.02;d=1.11);The average coupling angle of the knee to ankle was higher in 50%of the healthy side than the affected side after the end of support(P<0.05,d=1.21),higher in the pre-swing stage than in the affected side(P<0.05,d=1.07),and lower in 25%—50%of the healthy side during the swing stage than in the affected side(P<0.01,d=1.51).②The coupling angle between the healthy side and the affected side was different in the coronal plane only between the hip and an-kle joint,that is,the healthy side was higher than the affected side in the pre-swing stage(P<0.05,d=1.07)and the healthy side was higher than the affected side in the last part of the gait swing stage(P<0.05,d=1.06).③The standard deviation of coupling angle of sagittal plane of healthy side was lower than that of af-fected side(P<0.01),and the standard deviation of coupling angle of coronal plane of healthy side was high-er than that of affected side(P<0.01).Conclusion:①In patients with functional ankle instability,the coordination pattern of the affected side was mainly in the same pattern of proximal sagittal domination and the reverse pattern of distal coronal domina-tion,that is,the dominance of the ankle joint increased,while the dominance of the hip and knee joint de-creased.②The lower or higher variability of knee-ankle joint in sagittal plane or hip-ankle joint in coronal plane respectively than that of healthy side suggest that ankle joint on the affected side has lower gait adapt-ability,resulting in gait asymmetry and increasing the risk of ankle joint injury.③Based on the above re-sults,it is suggested that future rehabilitation therapy should focus on strengthening the strength of the knee extensor and abductor muscles of the affected hip,improving the symmetry of the left and right gait of unilat-eral FAI,and reducing the risk of recurrent injury in patients with ankle instability.

Objective:To compare the efficacy of body posture combined with pharmacotherapy and pharmacotherapy alone in the treatment of chronic subdural hematoma(CSDH).Methods:Firstly, retrospective case series study was conducted. Thirty cases of CSDH that had received body posture combined with pharmacotherapy at Department of Neurosurgery, Huashan Hospital Affiliated to Fudan University from December 2016 to October 2020 were studied retrospectively. Twenty-seven patients were male, and 3 patients were female. The age of patients ( M(IQR)) was 66(16) years (range:28 to 84). Nineteen patients had unilateral hematoma, and 11 patients had bilateral hematoma. All patients received pharmacotherapy and body posture therapy that was to raise their lower limbs 20 to 30 cm with leg lift pad and get abdominal compressed with customized abdominal belt in supine position. Patients were required to maintain the body posture as much as possible, with the maximum to 16 to 18 hours per day. Patients with unilateral hematoma should tilt the head to the affected side and avoid tilting it to the opposite side. For patients with bilateral hematoma, there was no need for head lateralization. Patient were treated with oral dexamethasone and atorvastatin simultaneously. The preliminary efficacy of body posture combined with pharmacotherapy was determined by hematoma improvement rate which was analyzed by Clopper-Pearson method. Then, the multi-center, prospective, randomized controlled trial had carried out in 9 medical centers from August 2020 to November 2021. The stratified block randomization method was adopted. Patients were randomized in a ratio of 1∶1 to either receive pharmacotherapy alone(the control group) or body posture combined with pharmacotherapy(the experiment group) for 3 months and followed up for 6 months. Effective treatment was defined as complete absorption of hematoma, or the hematoma volume decreased by more than 10 ml and Markwalder grading scale score had improved by more than 1 point compared to the baseline. The efficacy rate and surgery conversion rate at 3 months and recurrence at 6 months were observed. Comparison between groups was performed with paired sample t test, Mann-Whitney U test, χ2 test, corrected χ2 test, or Fisher exact probability method. Logistic regression was used to compare the effective rate and operation rate between the two groups. Results:In the respective study, 30 patients completed follow-up 13 to 353 days after treatment. At the last follow-up, the incidence of almost complete absorption or significantly absorption of hematoma (hematoma volume was significantly reduced accompanied by symptom improvement) was 93.3%. The 95% CI for the incidence that analyzed by the Clopper-Pearson method was 77.9% to 99.2%. One hundred and six patients were enrolled in the multicenter study. Fifty-five patients underwent body posture combined with pharmacotherapy. The age was 74(17) years (range:26 to 92). Thirty-nine patients were males and 16 were females. Fifty-one patients underwent pharmacotherapy alone. The age was 69(12) years (range:48 to 84). Thirty-seven patients were males and 14 were females. The length of body posture recorded in diary card was (15.7±2.3) hours(range:7.6 to 19.3 hours). The efficacy rate in the body posture combined with pharmacotherapy group and pharmacotherapy alone group were 83.6% (46/55) and 56.9% (29/51), respectively at 3 months. The result of the logistic regression analysis showed that the efficacy of body posture combined with pharmacotherapy group was better than that of pharmacotherapy alone group ( OR=3.88,95% CI:1.57 to 9.58, P=0.003). Surgery rate in the body posture combined with pharmacotherapy group and pharmacotherapy alone group were 5.5% (3/55) and 21.6% (11/51) respectively. The result of Logistic regression showed that the pharmacotherapy alone group was more likely to be converted to surgery ( OR=0.21,95% CI:0.05 to 0.80, P=0.023). At the 6 months, no recurrence of cases was found in the body posture combined with pharmacotherapy group. However, the recurrence rate of pharmacotherapy alone group was 6.3% (3/48), there was no significant difference between the two groups ( P>0.05). Conclusion:The effect of body posture combined with pharmacotherapy for chronic subdural hematoma is better than that of pharmacotherapy alone.

Objective:To explore gait symmetry of unilateral functional ankle instability(FAI).Method:Fifteen male subjects with right functional ankle instability were recruited,Qualisys was used to col-lect and intercept gait cycle data on both sides.Coupling angle and standard deviation of the coupling angle were calculated using Matlab and the effect size was evaluated using Cohen's d.Result:①The coupling angles of the healthy side and the affected side were different in the sagittal plane.The average coupling angles of the hip-knee joint and the hip-ankle joint were higher on the healthy side than on the affected side in the pre-swing period(P<0.05,d=1.02;d=1.11);The average coupling angle of the knee to ankle was higher in 50%of the healthy side than the affected side after the end of support(P<0.05,d=1.21),higher in the pre-swing stage than in the affected side(P<0.05,d=1.07),and lower in 25%—50%of the healthy side during the swing stage than in the affected side(P<0.01,d=1.51).②The coupling angle between the healthy side and the affected side was different in the coronal plane only between the hip and an-kle joint,that is,the healthy side was higher than the affected side in the pre-swing stage(P<0.05,d=1.07)and the healthy side was higher than the affected side in the last part of the gait swing stage(P<0.05,d=1.06).③The standard deviation of coupling angle of sagittal plane of healthy side was lower than that of af-fected side(P<0.01),and the standard deviation of coupling angle of coronal plane of healthy side was high-er than that of affected side(P<0.01).Conclusion:①In patients with functional ankle instability,the coordination pattern of the affected side was mainly in the same pattern of proximal sagittal domination and the reverse pattern of distal coronal domina-tion,that is,the dominance of the ankle joint increased,while the dominance of the hip and knee joint de-creased.②The lower or higher variability of knee-ankle joint in sagittal plane or hip-ankle joint in coronal plane respectively than that of healthy side suggest that ankle joint on the affected side has lower gait adapt-ability,resulting in gait asymmetry and increasing the risk of ankle joint injury.③Based on the above re-sults,it is suggested that future rehabilitation therapy should focus on strengthening the strength of the knee extensor and abductor muscles of the affected hip,improving the symmetry of the left and right gait of unilat-eral FAI,and reducing the risk of recurrent injury in patients with ankle instability.

Objective:To investigate the influencing factors of pathological positive surgical margins(PSM)after radical resec-tion of prostate cancer.Methods:The clinical data of 407 patients who underwent radical resection of prostate cancer in our hospital from 2011 to 2020 were retrospectively analyzed.And the patients were divided into two groups according to postoperative pathological results.Single factor analysis was used to evaluate the differences in postoperative Gleason score,preoperative total prostate-specific antigen(tPSA),preoperative serum free prostate-specific antigen to preoperative tPSA ratio(fPSA/tPSA),clinical stage,postopera-tive pathological stage,operation method,age,body mass index(BMI),diameter and volume of prostate tumor.Multivariate logistic regression was used to determine the independent risk factor of PSM.Results:Among 407 patients with prostate cancer,179 cases(43.98％)were positive.Univariate analysis showed that there were significant differences in postoperative Gleason score,preopera-tive tPSA,clinical stage and postoperative pathological stage between the two groups(P＜0.05).And Gleason score,preoperative tPSA and pathologic stage were independent risk factors for PSM.Conclusion:There are relationships between PSM and post opera-tive Gleason score,tPSA,clinical T stage,postoperative pathologic pT stage.Among them,postoperative Gleason score(Gleason=7 points,Gleason≥8 points),preoperative total prostate-specific antigen(tPSA＞20 μg/L),and postoperative pathologic pT stage(pT3a,pT3b)were independent risk factors for positive pathological margins of prostate cancer.

Objective:To compare the efficacy of body posture combined with pharmacotherapy and pharmacotherapy alone in the treatment of chronic subdural hematoma(CSDH).Methods:Firstly, retrospective case series study was conducted. Thirty cases of CSDH that had received body posture combined with pharmacotherapy at Department of Neurosurgery, Huashan Hospital Affiliated to Fudan University from December 2016 to October 2020 were studied retrospectively. Twenty-seven patients were male, and 3 patients were female. The age of patients ( M(IQR)) was 66(16) years (range:28 to 84). Nineteen patients had unilateral hematoma, and 11 patients had bilateral hematoma. All patients received pharmacotherapy and body posture therapy that was to raise their lower limbs 20 to 30 cm with leg lift pad and get abdominal compressed with customized abdominal belt in supine position. Patients were required to maintain the body posture as much as possible, with the maximum to 16 to 18 hours per day. Patients with unilateral hematoma should tilt the head to the affected side and avoid tilting it to the opposite side. For patients with bilateral hematoma, there was no need for head lateralization. Patient were treated with oral dexamethasone and atorvastatin simultaneously. The preliminary efficacy of body posture combined with pharmacotherapy was determined by hematoma improvement rate which was analyzed by Clopper-Pearson method. Then, the multi-center, prospective, randomized controlled trial had carried out in 9 medical centers from August 2020 to November 2021. The stratified block randomization method was adopted. Patients were randomized in a ratio of 1∶1 to either receive pharmacotherapy alone(the control group) or body posture combined with pharmacotherapy(the experiment group) for 3 months and followed up for 6 months. Effective treatment was defined as complete absorption of hematoma, or the hematoma volume decreased by more than 10 ml and Markwalder grading scale score had improved by more than 1 point compared to the baseline. The efficacy rate and surgery conversion rate at 3 months and recurrence at 6 months were observed. Comparison between groups was performed with paired sample t test, Mann-Whitney U test, χ2 test, corrected χ2 test, or Fisher exact probability method. Logistic regression was used to compare the effective rate and operation rate between the two groups. Results:In the respective study, 30 patients completed follow-up 13 to 353 days after treatment. At the last follow-up, the incidence of almost complete absorption or significantly absorption of hematoma (hematoma volume was significantly reduced accompanied by symptom improvement) was 93.3%. The 95% CI for the incidence that analyzed by the Clopper-Pearson method was 77.9% to 99.2%. One hundred and six patients were enrolled in the multicenter study. Fifty-five patients underwent body posture combined with pharmacotherapy. The age was 74(17) years (range:26 to 92). Thirty-nine patients were males and 16 were females. Fifty-one patients underwent pharmacotherapy alone. The age was 69(12) years (range:48 to 84). Thirty-seven patients were males and 14 were females. The length of body posture recorded in diary card was (15.7±2.3) hours(range:7.6 to 19.3 hours). The efficacy rate in the body posture combined with pharmacotherapy group and pharmacotherapy alone group were 83.6% (46/55) and 56.9% (29/51), respectively at 3 months. The result of the logistic regression analysis showed that the efficacy of body posture combined with pharmacotherapy group was better than that of pharmacotherapy alone group ( OR=3.88,95% CI:1.57 to 9.58, P=0.003). Surgery rate in the body posture combined with pharmacotherapy group and pharmacotherapy alone group were 5.5% (3/55) and 21.6% (11/51) respectively. The result of Logistic regression showed that the pharmacotherapy alone group was more likely to be converted to surgery ( OR=0.21,95% CI:0.05 to 0.80, P=0.023). At the 6 months, no recurrence of cases was found in the body posture combined with pharmacotherapy group. However, the recurrence rate of pharmacotherapy alone group was 6.3% (3/48), there was no significant difference between the two groups ( P>0.05). Conclusion:The effect of body posture combined with pharmacotherapy for chronic subdural hematoma is better than that of pharmacotherapy alone.

The different fate of liposomes among species has been discovered and mentioned in many studies, but the underlying mechanisms have not been explored. In the present work, we concentrated on the in vivo fate of PEGylated liposomes (sLip) in three commonly used species (mice, rats, and dogs). It was exhibited that the accelerated blood clearance (ABC) phenomenon and hypersensitivity in large animals (beagle dogs) were much more significant than that in rodents. We demonstrated that anti-PEG IgM (partially) and complement (mostly) determined the elimination of sLip and linked the distinct interspecies performances with the diverse complement capacity among species. Based on the data from animals and clinical patients, it was revealed that the fate of sLip in large animals was closer to that in humans, for the sufficient complement capacity could expose the potential adverse reactions caused by anti-PEG antibodies. Our results suggested that the distinctive interspecies performances of sLip were highly related to the physiological variabilities among species, which should not be overlooked in the innovation and translation of nanomedicines.

OBJECTIVE: To investigate the efficacy of posterior three-columns osteotomy in the treatment of severe tuberculous angular kyphosis. METHODS: Total of 33 patients with severe tuberculous angular kyphosis were treated with posterior three-columns osteotomy from January 2006 to January 2019 including 24 males and 9 females with an average age of (40.6±23.3) years old ranging from 15 to 62 years old and an average disease duration of (23.5±15.5) years ranging from 4 to 40 years. The Cobb's angle of kyphosis was (118.65±28.82)°. Interradicular bone-disc-bone osteotomy(BDBO), posterior-only vertebral column resection (PVCR) and posterior multilevel vertebral osteotomy (PMVO) were performed to correct spinal deformity individually. The visual analogue scale (VAS), Oswestry disability index (ODI), sagittal vertical axis (SVA), ASIA spinal cord functional classification and motor function score, and deformity correction rate were measured and statistically analyzed before, after and at the final follow-up. RESULTS: Total of 33 patients were followed up from 15 to 96 months with an average of (38.00±6.38) months. The last follow-up of kyphosis Cobb angle (23.88±5.45)° showed no significant loss from postoperative 12 months (20.40±9.13)°, P>0.05. The SVA, VAS, ODI and ASIA spinal cord functional classification and motor function score were significantly improved at 1 year and last follow-up after operation(P<0.01). The fusion time of the osteotomy site was (18.50±5.16) months. The ASIA classification of 15 patients with spinal cord injury were improved by at least 2 grades after operation, and their daily life and work ability were various levels of restored. Postoperative complications of spinal cord injury occurred in 3 cases. CONCLUSION Posterior three-columns osteotomy is the most effective method for the treatment of angular kyphosis of spinal tuberculosis.Careful preoperative design and individualized osteotomy can not only correct the deformity, but also a successful decompression to the spinal cord and promote the recovery of spinal cord function.
Humans ; Male ; Female ; Osteotomy/methods* ; Kyphosis/surgery* ; Adult ; Adolescent ; Middle Aged ; Young Adult ; Tuberculosis, Spinal/complications* ; Treatment Outcome