Free energy perturbation (FEP)-guided scaffold hopping

Scaffold hopping refers to computer-aided screening for active compounds with different structures against the same receptor to enrich privileged scaffolds, which is a topic of high interest in organic and medicinal chemistry. However, most approaches cannot efficiently predict the potency level of candidates after scaffold hopping. Herein, we identified potent PDE5 inhibitors with a novel scaffold via a free energy perturbation (FEP)-guided scaffold-hopping strategy, and FEP shows great advantages to precisely predict the theoretical binding potencies ΔG FEP between ligands and their target, which were more consistent with the experimental binding potencies ΔG EXP (the mean absolute deviations | Δ G FEP - Δ G EXP |  < 2 kcal/mol) than those ΔG MM-PBSA or ΔG MM-GBSA predicted by the MM-PBSA or MM-GBSA method. Lead L12 had an IC50 of 8.7 nmol/L and exhibited a different binding pattern in its crystal structure with PDE5 from the famous starting drug tadalafil. Our work provides the first report via the FEP-guided scaffold hopping strategy for potent inhibitor discovery with a novel scaffold, implying that it will have a variety of future applications in rational molecular design and drug discovery.

A novel inhibitor of N 6-methyladenosine demethylase FTO induces mRNA methylation and shows anti-cancer activities

N 6-methyladenosine (m6A) modification is critical for mRNA splicing, nuclear export, stability and translation. Fat mass and obesity-associated protein (FTO), the first identified m6A demethylase, is critical for cancer progression. Herein, we developed small-molecule inhibitors of FTO by virtual screening, structural optimization, and bioassay. As a result, two FTO inhibitors namely 18077 and 18097 were identified, which can selectively inhibit demethylase activity of FTO. Specifically, 18097 bound to the active site of FTO and then inhibited cell cycle process and migration of cancer cells. In addition, 18097 reprogrammed the epi-transcriptome of breast cancer cells, particularly for genes related to P53 pathway. 18097 increased the abundance of m6A modification of suppressor of cytokine signaling 1 (SOCS1) mRNA, which recruited IGF2BP1 to increase mRNA stability of SOCS1 and subsequently activated the P53 signaling pathway. Further, 18097 suppressed cellular lipogenesis via downregulation of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), and C/EBPβ. Animal studies confirmed that 18097 can significantly suppress in vivo growth and lung colonization of breast cancer cells. Collectively, we identified that FTO can work as a potential drug target and the small-molecule inhibitor 18097 can serve as a potential agent against breast cancer.

Medial parapatellar soft tissue overlapping suture in total knee arthroplasty for severe osteoarthritis with permanent patellar dislocation: early and mid-term results / 南方医科大学学报

OBJECTIVE@#To evaluate the early and mid-term clinical results of medial parapatellar soft tissue overlapping suture in total knee arthroplasty for treatment of severe osteoarthritis combined with permanent patellar dislocation.@*METHODS@#We retrospectively analyzed the data of 12 patients (12 knees) diagnosed with severe knee osteoarthritis combined with permanent patellar dislocation undergoing total knee arthroplasty with medial parapatellar soft tissue overlapping suture. Knee Society Score (KSS), University of California Los Angeles (UCLA) activity-level rating, Visual Analog Scale (VAS) pain score, and knee range of motion of the patients were assessed before and 2 years after the surgery. Anteroposterior and lateral radiographs of the knee joint, full-length standing radiographs of the lower limbs and patellar axial radiographs were evaluated.@*RESULTS@#The mean Knee Society Score of the patients increased from 34.2±11.1 before surgery to 73.5±6.3 at two years after the surgery (P < 0.001). The UCLA activity-level rating increased from an average of 3.8 ± 0.8 before surgery to 5.8 ± 0.6 at two years postoperatively (P=0.003). The mean VAS pain score decreased from 42.8±6.0 before surgery to 20.1±3.7 (P < 0.001) and the range of motion of the knee joint increased from 74.6±8.9 degrees to 97.5±4.5 degrees at two years (P < 0.001). The radiographs showed no signs of subluxation or dislocation of the patella in all the patients.@*CONCLUSIONS@#Medial parapatellar soft tissue overlapping suture in total knee arthroplasty can achieve good early and mid-term clinical results for treatment of severe osteoarthritis combined with permanent patellar dislocation.

Near infrared spectroscopy assessed oxygenated hemoglobin with sleep quality among college students / 中国学校卫生

Objective@#Functional near infrared spectroscopy (fNIRS) was used to assess brain oxygenated hemoglobin (Oxy Hb) activation in college students with different sleep quality under the verbal fluency task (VFT), so as to better provide a theoretical basis for the neural mechanism for sleep quality improvement of college students.@*Methods@#A simple random sampling method was used to investigate 96 college students from one university during 2020 and 2021. According to the results of the Pittsburgh Sleep Quality Index(PSQI), participants were divided into 3 groups: good sleep quality group( n =45), moderate group( n =33), and poor group( n =18). The 53 channel near infrared spectroscopy to collect cerebral blood oxygen signals under the VFT task. Association between oxygenated hemoglobin with sleep quality was analyzed.@*Results@#About 18.75% of college students reported sleep quality problems, including long sleep latency (0.97±0.97) and poor subjective sleep quality (0.96±0.72). There was a significant negative correlation between PSQI score and average oxygenated hemoglobin (Avg HbO) index of dorsolateral prefrontal lobe ( r =-0.23, P =0.03). The Avg HbO index differed significantly between good and poor sleep quality groups on dorsolateral prefrontal lobe( P =0.05).@*Conclusion@#This study verified that there is a positive correlation between sleep quality and cognitive ability among college students. The fNIRS technique could accurately collect blood oxygen signals from dorsolateral prefrontal lobe during cognitive tasks, which proves to be an effective tool for identifying sleep quality of college students.

Structure-based discovery of orally efficient inhibitors via unique interactions with H-pocket of PDE8 for the treatment of vascular dementia

Our previous study demonstrated that phosphodiesterase 8 (PDE8) could work as a potential target for vascular dementia (VaD) using a chemical probe 3a. However, compound 3a is a chiral compound which was obtained by chiral resolution on HPLC, restricting its usage in clinic. Herein, a series of non-chiral 9-benzyl-2-chloro-adenine derivatives were discovered as novel PDE8 inhibitors. Lead 15 exhibited potent inhibitory activity against PDE8A (IC50 = 11 nmol/L), high selectivity over other PDEs, and remarkable drug-like properties (worthy to mention is that its bioavailability was up to 100%). Oral administration of 15 significantly improved the cAMP level of the right brain and exhibited dose-dependent effects on cognitive improvement in a VaD mouse model. Notably, the X-ray crystal structure of the PDE8A-15 complex showed that the potent affinity and high selectivity of 15 might come from the distinctive interactions with H-pocket including T-shaped π-π interactions with Phe785 as well as a unique H-bond network, which have never been observed in other PDE-inhibitor complex before, providing new strategies for the further rational design of novel selective inhibitors against PDE8.

20% ethanol assists the excision of primary pterygium / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To introduce a technique to improve the excision of primary pterygium and evaluate the surgical outcomes.<p>METHODS: Recorded of consecutive cases were reviewed of pterygium patients treated with pterygium removal between March 2015 and February 2016 in People's Hospital of Guangxi Zhuang Autonomous Region, China. Primary nasal pterygium patients with at least 3mo follow-up periods were included. Finally, 85 patients(85 eyes)were investigated, 44 eyes were operated with 20% ethanol(the study group)and 41 eyes were operated without 20% ethanol(the control group).<p>RESULTS: All of the 85 patients enrolled had no intraoperative and postoperative complications. The mean healing time of the corneal epithelium for the study group was statistically significant different of 2.84±0.43d compared with the control group of 3.12±0.64d(<i>P</i><0.05). Overall, postoperative symptoms(pain, irritation, foreign body sensation and epiphora)were significantly different in postoperative 3d between the two groups(<i>P</i><0.05). No statistically significant differences in corneal endothelium morphologies were found in two groups between preoperative and 2wk, 1 and 3mo postoperative, or between the two groups at any corresponding time point(all <i>P</i>>0.05). Between the two groups, there were no statistically significant differences in best-corrected visual acuity(BCVA)at preoperative, postoperative 2wk and 1mo(all <i>P</i>>0.05), but statistically significant difference was found in BCVA at the 3mo after surgery(<i>P</i><0.05).<p>CONCLUSION: The removal of primary pterygium with 20% ethanol is a simple and safe technique that helps to establish a clear separation plane between the pterygium and the underlying cornea.

Establishment and application of chemical fingerprint and pattern recognition for Panacis Japonici Rhizoma / 中草药

Objective To establish and identify HPLC fingerprints of Panacis Japonici Rhizoma from different regions, and provide a scientific method for quality its control and standardization. Methods The fingerprints of Panacis Japonici Rhizoma were established based on HPLC method. The similarity evaluation, cluster analysis (CA), and principal component analysis (PCA) were applied for the experimental data, in order to find out the similarities and differences among the 10 batches of Panacis Japonici Rhizoma from different regions. Meanwhile, the qualitatively and quantitatively analyze were adopted in the common peaks of Panacis Japonici Rhizoma by total statistical moment method. Results The HPLC fingerprint with 16 common peaks was established, for the common chemical components, six were identified as ginsenoside Rg1, ginsenoside Re, ginsenoside Rb1, chikusetsusaponin V, chikusetsusaponin IV, and chikusetsusaponin IVa, respectively. Among them, the contents of chikusetsusaponin V and IV in different batches of Panacis JaponiciRhizoma samples showed little differences. The similarities of samples from various regions except S7 were over 0.90. The samples were classified into three categories by CA and PCA methods. The parameters of total statistical moment for five species of Panax genus showed significantly differences. Conclusion The developed HPLC fingerprint of Panacis Japonici Rhizoma combined with chemical pattern recognition can provide a scientific instruction for the quality control of Panacis Japonici Rhizoma and the differentiation of five herb medicines from Panax genus.

Structure-based design, synthesis, and biological evaluation of novel pyrimidinone derivatives as PDE9 inhibitors

The pathological processes of Alzheimer's disease and type 2 diabetes mellitus have been demonstrated to be linked together. Both PDE9 inhibitors and PPAR agonists such as rosiglitazone exhibited remarkable preclinical and clinical treatment effects for these two diseases. In this study, a series of PDE9 inhibitors combining the pharmacophore of rosiglitazone were discovered. All the compounds possessed remarkable affinities towards PDE9 and four of them have the IC values <5 nmol/L. In addition, these four compounds showed low cell toxicity in human SH-SY5Y neuroblastoma cells. Compound , the most effective one, gave the IC of 1.1 nmol/L towards PDE9, which is significantly better than the reference compounds PF-04447943 and BAY 73-6691. The analysis of putative binding patterns and binding free energy of the designed compounds with PDE9 may explain the structure-activity relationships and provide evidence for further structural modifications.

A preliminary study of a deep learning-assisted diagnostic system with an artificial intelligence for detection of diabetic retinopathy / 国际眼科杂志(Guoji Yanke Zazhi)

·AIM: To evaluate a deep learning - assisted diagnostic system with an artificial intelligence for the detection of diabetic retinopathy (DR). ·METHODS:A total of 186 patients (372 eyes) with diabetes were recruited from January to July 2017. Discrepancies between manual grades and artificial intelligence results were sent to a reading center for arbitration. The sensitivity and specificity in the detection of DR were determined by comparison with artificial intelligence diagnostic system and experts human grading. ·RESULTS:Based on manual grades, the results as follows:non DR (NDR) in 42 eyes (11.3%), 330 eyes (88.7%) in different stages of DR. Among 330 DR eyes, there were mild non proliferative DR (NPDR) in 62 eyes (16.7%), moderate NPDR in 55 eyes (14.8%), severe NPDR in 155 eyes (41.7%), and proliferative DR (PDR) in 58 eyes (15. 6%). Based on artificial intelligence diagnostic system, the results were as follows: NDR in 38 eyes (10.2%),PDR in 44 eyes (11.8%), others were NPDR. The sensitivity and specificity of artificial intelligence diagnostic system, compared with human expert grading, for the detection of any DR were 0.82 and 0.91, and the kappa value was 0.77 (x2=20.39, P<0.05). ·CONCLUSION:This study shows that a deep learning-assisted diagnostic system with an artificial intelligence for grading diabetic retinopathy is a reliable alternative to diabetic retinopathy assessment, thus the use of this system may be a valuable tool in evaluating the DR.

Total knee arthroplasty with 3D printing technique versus conventional surgery: comparison of the outcomes / 南方医科大学学报

<p><b>OBJECTIVE</b>To compare the clinical outcomes of patients receiving total knee arthroplasty (TKA) using 3D printing technique and conventional surgical methods.</p><p><b>METHODS</b>From October, 2015 to February, 2017, 17 patients (20 knees) underwent TKA with the assistance of individualized navigation template and 16 concurrent patients (18 knees) matched for age, gender and knee society score received conventional TKA. The operation time, blood loss, and osteotomy data of the femoral condyle and tibia plateau were recorded. The mean femorotibial angle (MFTA) and sagittal tibial component angle (STCA) after the operation and the KSS at the last follow-up were compared between the two groups.</p><p><b>RESULTS</b>All the patients were followed up for 7-23 months, during which no infection or prosthesis loosening or motion was found. In patients receiving surgery with 3D printing technique, the osteotomy data of the femoral condyle and tibia plateau in the actual surgeries were consistent with those in surgical plans (P>0.05). The patients in the 3D group had a significantly shorter operation time and a higher KSS score than those in the conventional group (P<0.05). Significant differences were found between the two groups in postoperative MFTA and STCA (P<0.05).</p><p><b>CONCLUSION</b>The application of 3D printing technique can simplify the surgical procedure and improve the surgical precision and efficacy of TKA.</p>

Expression of EphB4 in hepatocellular carcinoma tissues and its clinical significance / 重庆医学

Objective To study the expression of Ephrin‐B4 receptor (EphB4) in hepatocellular carcinoma (HCC) and its clinical significance ,and to analyze the effect of EphB4 on the proliferation of HCC cells .Methods The expression level of EphB4 in HCC tissues and matched paracancerous liver tissues of 60 cases of HCC patients was assessed by reverse transcriptase‐polymer‐ase chain reaction (RT‐PCR) and immunohistochemistry .The correlation between the expression of EphB4 in HCC tissues and clin‐ical pathologic parameters was analyzed by chi‐square test .Univariate survival analysis was carried out by Kaplan‐Meier Log‐rank test .The effect of EphB4 on the viability of HCC cells was furtherly analyzed by MTS .Results The results of RT‐PCR showed that the mRNA level of EphB4 in HCC tissues (1 .39 ± 0 .80) was significantly higher than in matched paracancerous liver tissues (0 .56 ± 0 .33) ,the difference was statistically significant (P< 0 .01) .Data from immunohistochemistry showed that the positive rates of EphB4 protein in HCC tissues and matched paracancerous liver tissues were 81 .7% and 23 .3% ,respectively .Moreover ,the expression of EphB4 in HCC tissues was relevant to AFP level ,tumor size and TNM stage(P<0 .05) .The three‐year survival rate of HCC patients with positive expression of EphB4 protein was 22 .5% ,and that of HCC patients with negative expression of EphB4 protein was 54 .5% ,the difference was statistically significant (P<0 .05) .Overexpression of EphB4 significantly enhanced the ability of hepatocellular carcinoma cell proliferation (P<0 .05) .Conclusion EphB4 expression was significantly up‐regulated in HCC ,which was associated with HCC progression and prognosis ,and EphB4 could promote the proliferation of HCC cells ,which could be used as a marker of HCC progression .

Nerve growth factor potentiates bone morphogenetic protein-9-induced osteogenic differentiation in mouse embryonic fibroblasts / 中华创伤杂志

Objective To investigate the effect of nerve growth factor (NGF) on osteogenesis induced by bone morphogenetic protein-9 (BMP-9) in mouse embryonic fibroblasts (MEFs).Methods MEFs were respectively transfected with adenovirus-mediated NGF (NGF group), BMP-9 (BMP-9 group) and NGF + BMP-9 (combined group) and green fluorescence protein (GFP) (control group).Cytochemical staining was used to test the activity of alkaline phosphatase (ALP) 3 d and 5 d after treatment.Level of osteopontin (OPN) mRNA was detected by RT-PCR 9 d after treatment.Level of OPN protein was assayed by Western blot and immunocytochemistry 9 d after treatment.Mineralization was detected by Alizarin red staining 14 d after treatment.Results ALP activity in MEFs was elevated in BMP-9 group rather than in NGF group, but a significant increase in ALP activity was noted in combined group.In control group, BMP-9 group, NGF group and combined group, level of OPN mRNA was 0.92 ± 0.03, 1.28 ± 0.04, 0.94 ± 0.03 and 1.62 ± 0.04 respectively (F =214.60, P ＜ 0.01);level of OPN protein was 0.60 ± 0.05, 0.84 ± 0.03, 0.53 ± 0.05 and 1.27 ± 0.05 respectively (F =162.5, P ＜ 0.01).In comparison, OPN mRNA and protein were significantly up-regulated in combined group than in BMP-9 group (t =10.569 and 11.778,P ＜ 0.05).In control group, BMP-9 group, NGF group and combined group, relative density of OPN protein was 3.63 ±0.17, 6.27 ±0.30, 3.86 ±0.18 and 10.16 ±0.18respectively (F =602.6, P ＜ 0.01), with a significant higher level in combined group than in BMP-9 group (t =22.280, P ＜ 0.05).Level of mineralization was significantly higher in combined group than in BMP-9 or NGF group.Conclusion NGF can potentiate the osteogenesis induced by BMP-9 in MEFs.

Correlation of Skp2 overexpression to prognosis of patients with nasopharyngeal carcinoma from South China / 癌症

S-phase kinase-associated protein 2 (Skp2), which plays a role in cell cycle regulation, is commonly overexpressed in a variety of human cancers and associated with poor prognosis. However, its role in nasopharyngeal carcinoma (NPC) is not well understood. In this study, we examined the clinical significance of Skp2, with a particular emphasis on overall survival (OS) and disease-free survival (DFS), in NPC cases in South China, where NPC is an epidemic. Additionally, we explored the function of Skp2 in maintaining a cancer stem cell-like phenotype in NPC cell lines. Skp2 expression was assessed for 127 NPC patients using tissue microarrays and immunohistochemistry and analyzed together with clinicopathologic features, OS, and DFS. Skp2 expression was detectable, or positive, in 75.6% of patients. Although there was no correlation between Skp2 and any clinicopathologic factor, Skp2 expression significantly portended inferior OS (P = 0.013) and DFS (P = 0.012). In the multivariate model, Skp2 expression remained significantly predictive of poor OS [P = 0.009, risk ratio (RR) = 4.06] and DFS (P = 0.008, RR = 3.56), and this was also true for clinical stage (P = 0.012 and RR=3.201 for OS; P = 0.002 and RR=1.94 for DFS) and sex (P = 0.016 and RR=0.31 for OS; P = 0.006 and RR = 0.27 for DFS). After Skp2 knockdown, a colony formation assay was used to evaluate the self-renewal property of stem-like cells in the NPC cell lines CNE-1 and CNE-2. The colony formation efficiency in CNE-1 and CNE-2 cells was decreased. In Skp2-transfected CNE-1 and CNE-2 cells, side population (SP) proportion was increased as detected by flow cytometry. Skp2 is an independent prognostic marker for OS and DFS in NPC. Skp2 may play a role in maintaining the cancer stem cell-like phenotype of NPC cell lines.

Cephalometry of Li people through 3-dimensional CT / 中华整形外科杂志

<p><b>OBJECTIVE</b>To investigate the skull characteristics of the Li people in Hainan through 3-D CT.</p><p><b>METHODS</b>CT scan and 3-D reconstruction are very helpful for the cephalometry including the distance and angle measurement. The image can also be enlarged to make the measurement more precisely. 80 Li volunteers underwent the cephalometry through 3-D CT. The data were analyzed and compared with those an people.</p><p><b>RESULTS</b>The results showed difference between the genders of Li people. Compared with Han people, Li people has their own facial characteristics, such as wider face and wider orbital distance.</p><p><b>CONCLUSIONS</b>Cephalometry through 3-D CT can show the skull characteristics precisely. The data in this study has great significance in craniomaxillofacial surgery and ethnology.</p>

Repairing large alar defects by using a retro-grade auricular flap / 中华整形外科杂志

<p><b>OBJECTIVE</b>To evaluate a retro-grade auricular flap for repairing large alar defects.</p><p><b>METHODS</b>Twenty-nine adult cadavers were anatomically used for vascular investigation of the frontal, nasal and temporal regions by injecting a dye into the main vessels. Based on the anatomical study in these regions, a retro-grade auricular flap was designed for repairing alar defects in 16 patients.</p><p><b>RESULTS</b>The blood supply of the auricle could be nourished by the inner carotid artery system from the supratrachlear artery and supraorbital artery through the frontal arterial anastomotical network into the frontal branch of the superficial temporal artery. It is then passing the main trunk of the superficial temporal artery into the ear area through the auricular branches of the superficial temporal artery. The retro-grade auricular island flap could be formed by basing the supratrachlear artery and the supraorbital artery through the vascular network between the superficial temporal artery and the supratrachlear artery or the supraorbital artery. Sixteen patients with large alar defects and half-sized nasal defects were successfully repaired by this technique.</p><p><b>CONCLUSIONS</b>The retro-grade auricular island flap, based on the inner carotid artery system, could be a good and safe flap for repairing a large alar defect or half-sized nasal reconstruction.</p>

APPLICATION OF THE REVERSED ISLAND FLAP BASED ON SURAL NEUROVASCUALR PEDICLE / 中国医师进修杂志

Objective To report the method for repair of the heel and ankle.Method On the basis of applied anatomy,the reversed island flap based on sural neurovascular pedicle has been designed for repair of heel and ankle defects.Results The flaps have been used in 14 cases,the maximum size 9 cm×15 cm,and all flaps were survival compeletely except partial necrosis in one flap.Conclusion The blood supply of the flap is good.The length of pedicle can reach 12 cm.It is an effective method for repair of heel and ankle defects.