Long-term outcome and prognostic factors of syringo-subarachnoid shunt for syringomyelia.

BACKGROUND: Syringo-subarachnoid shunt (SSS) is often considered a rescue procedure or a second-line treatment option for syringomyelia. However, the clinical efficacy of SSS in treating this condition remains controversial. OBJECTIVE: To evaluate the long-term outcome of the SSS and its relationship with the syrinx area, as well as to investigate the factors that influence the prognosis. METHODS: This retrospective study included twenty-seven consecutive patients who underwent SSS between 2014 and 2020. The study evaluated several independent variables such as age, sex, duration of progressive symptoms, morphological characteristics of the syrinx, changes in the syrinx area, and Chiari malformation. The long-term follow-up (>2 years) Japanese Orthopaedic Association (JOA) score was used to assess neurological function and outcome. Statistical analysis was performed using a stepwise logistic regression test. RESULTS: All patients were followed up for an average of 48.6 ± 14.8(26.8 to 78.0) months. Follow-up magnetic resonance imaging showed syrinx collapse to different degrees occurred in 96.3% (26 of 27) patients. The JOA score was improvedinonly6patients (22.2%), remained stable in 5 patients (18.5%),and deteriorated in 16 patients(59.3%).A logistic regression test showed that the tension syrinx (odds ratio 0.111) and early shunting intervention (odds ratio 0.138) were favorable independent prognostic factors. CONCLUSIONS: It is important to note that the shrinkage of the syrinx does not necessarily translate to an improvement in clinical outcomes. Therefore, the decision to perform SSS should be made with caution and considered as a last resort.

Clinical management and prognosis of spinal myxopapillary ependymoma: a single-institution cohort of 72 patients.

PURPOSE: Myxopapillary ependymoma (MPE) was classified as grade 2 tumor in the 2021 World Health Organization central nervous system classification because of its high recurrence probability. This study aimed to investigate predictive factors and management of tumor recurrence. METHODS: Seventy-two patients with spinal MPE underwent initial surgical treatment at our hospital between 2011 and 2021. Kaplan-Meier curves and Cox regression were used to analyze the correlation between clinical variables and progression-free survival (PFS). RESULTS: The median age at diagnosis was 33.5 years (range 8-60 years). Twenty-one patients (29.2%) had preoperative spinal drop metastases. Gross total resection (GTR) was performed in 37 patients (51.4%). The median follow-up was 7.2 years, and the follow-up rate was 88.9% (64 of 72 cases). Twelve of the 64 patients (18.9%) relapsed, and preoperative drop metastasis occurred in 7 patients (58.3%). The estimated 5-year and 10-year PFS rates were 82% and 77%, respectively. Univariate analysis showed that GTR was associated with improved PFS (hazard ratio [HR] 0.149, p = 0.014), while preoperative drop metastasis (HR 3.648, p = 0.027) and tumor involvement sacrococcygeal region (HR 7.563, p = 0.003) were associated with tumor recurrence. Adjuvant radiotherapy (RT) was significantly associated with improved PFS in patients with preoperative drop metastasis (p = 0.039). CONCLUSION: Complete surgical resection under the premise of protecting neurological function is an important factor in reducing spinal MPE recurrence. Adjuvant RT is recommended when the tumor invades the capsule with preoperative drop metastasis or adhesion to the nerve and cannot reach GTR.

Long-term outcomes of foramen magnum decompression with duraplasty for Chiari malformation type I in adults: a series of 297 patients.

OBJECTIVE: Foramen magnum decompression with duraplasty (FMDD) is one of the most frequently utilized surgical treatments for Chiari malformation type I (CMI) in adults. However, its long-term outcomes remain controversial. The object of this study was to evaluate the long-term outcomes of FMDD in adults with CMI. METHODS: In total, 297 adults with CMI who had undergone FMDD at the authors' institution between 2011 and 2020 were included in this retrospective study. Long-term (> 1 year) outcomes were evaluated using the Chicago Chiari Outcome Scale (CCOS), visual analog scale (VAS), and Japanese Orthopaedic Association (JOA) scale. RESULTS: The median patient age was 44 years (range 18-65 years). The mean clinical follow-up period was 67 months (range 14-123 months). Compared with preoperative conditions, the postoperative syringomyelia regression rate was 91.3% (242/265), and the cerebellar tonsil ascended in 18.2% of patients (54/297), was stable in 64.3% (191/297), and continuously descended in 17.5% (52/297). Long-term clinical follow-up data were acquired from 267 patients. According to the CCOS score, the patient's condition improved in 62.5% of cases (167/267), was stable in 31.8% (85/267), and worsened in 5.6% (15/267). According to the VAS score, the patient's condition improved in 59.5% of cases (110/185), remained unchanged in 27.6% (51/185), and worsened in 13.0% (24/185) among the follow-up patients with relevant data. According to the JOA score, the patient's condition improved in 40.1% of cases (107/267), remained unchanged in 50.2% (134/267), and worsened in 9.7% (26/267). Notably, there was no association between clinical outcomes and syringomyelia regression (p = 0.227) or changes in the cerebellar tonsillar position (p = 0.323). CONCLUSIONS: FMDD is a simple, safe, and effective surgical procedure for adult CMI that yields significant and sustained improvement in clinical and radiological outcomes. However, clinical improvement does not always correlate with syringomyelia regression and cerebellar tonsillar shift.

Genomic profiling and prognostic factors of H3 K27M-mutant spinal cord diffuse glioma.

H3 K27-altered diffuse midline glioma is a highly lethal pediatric-type tumor without efficacious treatments. Recent findings have highlighted the heterogeneity among diffuse midline gliomas with different locations and ages. Compared to tumors located in the brain stem and thalamus, the molecular and clinicopathological features of H3 K27-altered spinal cord glioma are still largely elusive, thus hindering the accurate management of patients. Here we aimed to characterize the clinicopathological and molecular features of H3 K27M-mutant spinal cord glioma in 77 consecutive cases. We found that the H3 K27M-mutant spinal cord glioma, with a median age of 35 years old, had a significantly better prognosis than H3 K27M-mutant brain tumors. We noticed a molecular heterogeneity of H3 K27M-mutant spinal cord astrocytoma via targeted sequencing with 34 cases. TP53 mutation which occurred in 58.8% of cases is mutually exclusive with PPM1D (26%) and NF1 (44%) mutations. The TP53-mutant cases had a significantly higher number of copy number variants (CNV) and a marginally higher proportion of pediatric patients (age at diagnosis <18 years old, p = 0.056). Cox regression and Kaplan-Meier curve analysis showed that the higher number of CNV events (≥3), chromosome (Chr) 9p deletion, Chr 10p deletion, ATRX mutation, CDK6 amplification, and retinoblastoma protein (RB) pathway alteration are associated with worse survival. Cox regression analysis with clinicopathological features showed that glioblastoma histological type and a high Ki-67 index (>10%) are associated with a worse prognosis. Interestingly, the histological type, an independent prognostic factor in multivariate Cox regression, can also stratify molecular features of H3 K27M-mutant spinal cord glioma, including the RB pathway, KRAS/PI3K pathway, and chromosome arms CNV. In conclusion, although all H3 K27M-mutant spinal cord diffuse glioma were diagnosed as WHO Grade 4, the histological type, molecular features representing chromatin instability, and molecular alterations associated with accelerated cell proliferative activity should not be ignored in clinical management.

Spinal Cord Diffuse Midline Gliomas With H3 K27m-Mutant: Clinicopathological Features and Prognosis.

BACKGROUND: "Diffuse midline glioma, H3 K27M-mutant" (DMG) mainly arises within the pontine, thalamic, and spinal cord regions. Because of the rarity of spinal cord gliomas, the general knowledge surrounding DMGs is mainly based on pontine and thalamic gliomas, whereas tumor location tends to influence the clinicopathological features and prognosis. OBJECTIVE: To determine the clinicopathological characteristics and molecular profiles of DMGs located in the spinal cord. METHODS: The clinical and molecular pathologic features and prognosis were comprehensively analyzed in a series of 44 patients with spinal cord DMGs. RESULTS: The median age was 36 yr, and 88.7% of patients (39/44) were adults (≥18 yr). Histopathologically, malignant grades included grade II (16 cases), grade III (20 cases), and grade IV (8 cases). Compared with patients with histological grade IV, patients with lower histological grade (grade II/III) were older (37 vs 24 yr, P = .020) and were associated with longer overall survival (24.1 vs 8.6 mo, P = .007). All 30 tested tumors were isocitrate dehydrogenase (IDH) wild type, and 96% of cases (22/23) presented with unmethylated O6-methylguanine-DNA methyltransferase. Univariate and multivariate analyses showed that histological grade and presurgery McCormick Scale scores were independent prognostic factors for overall survival, whereas extensive surgical resection and chemoradiotherapy were not significantly associated with improved survival. The most frequent anatomic locations were the cervical enlargement (C4-T1, n = 16) and conus medullaris (T12-L1, n = 13), which exhibited distinctive clinical characteristics and molecular features. CONCLUSION: The findings provide guidelines for the evidence-based practice of the specialized management of spinal cord DMGs.

A comprehensive model including preoperative peripheral blood inflammatory markers for prediction of the prognosis of diffuse spinal cord astrocytoma following surgery.

PURPOSE: Due to the rarity of diffuse spinal cord astrocytoma, an effective model is still lacking to stratify their prognosis. Here, we aimed to establish a prognostic model through comprehensively evaluating clinicopathological features and preoperative peripheral blood inflammatory markers in 89 cases. METHODS: We performed univariate and multivariate Cox regression to identify prognosis factors. The Kaplan-Meier curves and ROC curves were employed to compare the prognostic value of selected factors. RESULTS: In addition to clinicopathological factors, we revealed the preoperative peripheral blood leukocyte count, neutrophils-to-lymphocytes ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were also significantly correlated with overall survival of spinal cord astrocytoma in univariate Cox regression, and NLR was still significant in multivariate Cox analysis. Further, we demonstrated that NLR ≤ 3.65 and preoperative McCormick score (MMS) ≤ 3 were independently correlated with better survival of WHO grade IV tumors. Meanwhile, Ki-67 < 10% and resection extent ≥ 90% were independent prognostic factors in WHO grade II/III tumors. Finally, we developed a prognostic model that had better predictive efficiencies than WHO grade and histological grade for 1-year (AUC = 76.6), 2- year (AUC = 80.9), and 3-year (AUC = 80.3) survival. This model could classify tumors into 4 classifications with increasingly poor prognosis: 1, WHO grade II/III, with Ki-67 < 10% and resection extent ≥ 90%; 2, WHO grade II/III, Ki-67 ≥ 10% or resection < 90%; 3, WHO grade IV, NLR ≤ 3.65 and MMS ≤ 3; 4, WHO grade IV, with NRL > 3.65 or MMS = 4. CONCLUSION: We successfully constructed a comprehensive prognostic model including preoperative peripheral blood inflammatory markers, which can stratify diffuse spinal cord astrocytoma into 4 subgroups.

Clinicopathological characteristics and survival of spinal cord astrocytomas.

BACKGROUND: Due to their rarity, the clinicopathological characteristics and prognostic factors of spinal cord gliomas are still unclear. Here, we aimed to clarify these issues in a cohort of 108 spinal cord astrocytomas. METHODS: We characterized the clinicopathological characteristics, including 2016 World Health Organization (WHO) grade, age, sex, location, segment length, resection, pre- and postsurgery, Modified McCormick Scale (MMS), radio- and chemotherapy, and Ki-67 and H3 K27M mutations, in 108 spinal cord astrocytomas through heatmaps. The Cox regression analysis and Kaplan-Meier curves were used to study the prognostic value of these clinicopathological features. RESULTS: There are a total 38 H3 K27M-mutant tumors, including 31 cases with histological grade II/III tumors. The age of low-grade astrocytoma patients (WHO grade I/II, n = 54) was significantly younger (27.0 vs 35.5 years, P = .001) than those with high-grade tumors (WHO grade III/IV, n = 54). All patients underwent surgical resection with neurophysiological monitoring, and the surgery did not result in significant changes in MMS. The presurgery MMS was associated with overall survival in the high-grade subgroup (P = .008) but not in the low-grade subgroup (P = .312). While, the high content of resection improved the survival of only patients with low-grade astrocytomas (P = .016) but not those with high-grade astrocytomas (P = .475). Both the low-grade and high-grade astrocytomas had no obvious benefit from neither adjuvant chemotherapy nor radiotherapy (all P > .05). CONCLUSIONS: We characterized the clinicopathological characteristics and their prognostic values in 108 spinal cord astrocytomas, which could help with evidence-based management of spinal cord astrocytomas.

The molecular characteristics of spinal cord gliomas with or without H3 K27M mutation.

Due to the rare incidence of spinal cord astrocytomas, their molecular features remain unclear. Here, we characterized the landscapes of mutations in H3 K27M, isocitrate dehydrogenase 1 (IDH1) R132H, BRAF V600E, and the TERT promoter in 83 diffuse spinal cord astrocytic tumors. Among these samples, thirty-five patients had the H3 K27M mutation; this mutant could be observed in histological grade II (40%), III (40%), and IV (20%) astrocytomas. IDH1 mutations were absent in 58 of 58 cases tested. The BRAF V600E mutation (7/57) was only observed in H3-wildtype astrocytomas, and was associated with a better prognosis in all histological grade II/III astrocytomas. TERT promoter mutations were observed in both H3 K27M-mutant (4/25) and -wildtype (9/33) astrocytomas, and were associated with a poor prognosis in H3-wildtype histological grade II/III astrocytomas. In the 2016 WHO classification of CNS tumors, H3 K27M-mutant diffuse midline gliomas, including spinal cord astrocytomas, are categorized as WHO grade IV. Here, we noticed that the median overall survival of histological grade II/III H3 K27M-mutant cases (n = 28) was significantly longer than that of either the total histological grade IV cases (n = 12) or the H3 K27M-mutant histological grade IV cases (n = 7). We also directly compared H3 K27M-mutant astrocytomas to H3-wildtype astrocytomas of the same histological grade. In histological grade II astrocytomas, compared to H3-wildtype cases (n = 37), H3 K27M-mutant patients (n = 14) had showed a significantly higher Ki-67-positive rate and poorer survival rate. However, no significant differences in these parameters were observed in histological grade III and IV astrocytoma patients. In conclusion, these findings indicate that spinal cord astrocytomas are considerably different from hemispheric and brainstem astrocytomas in terms of their molecular profiles, and that the histological grade cannot be ignored when assessing the prognosis of H3 K27M-mutant spinal cord astrocytomas.

Therapeutic Strategies and Prognostic Factors Based on 121 Spinal Neurenteric Cysts.

BACKGROUND: Limited data existed to guide the management of intraspinal neurenteric cysts (ISNECs). OBJECTIVE: To evaluate the risk factors for progression-free survival (PFS), elucidate the radiological features of ISNECs, and propose a treatment protocol. METHODS: From 2003 to 2015, 121 patients with pathologically confirmed ISNECs treated at our institute were included in this study. Pertinent risk factors were evaluated. RESULTS: Gross total resection (GTR) was achieved in 55 (44.6%) patients; 106 (87.6%), 12 (9.9%), and 3 (2.5%) ISNECs were classified as Wilkins A, B, and C, respectively. After a median follow-up duration of 64.2 mo, recurrence occurred in 25 (22.7%) patients, with a median PFS time of 43.1 mo. The actuarial PFS rates at 5 and 10 yr were 73.2% and 66.2%, respectively. The actuarial overall survival rates at 5 and 10 yr were 100% and 97.6%, respectively. Non-GTR (hazard ratio [HR], 5.836; 95% confidence interval [CI], 1.698-20.058; P = .005), Wilkins B/C (HR, 3.129; 95% CI, 1.009-9.702; P = .048), and a history of surgical resection (HR, 3.690; 95% CI, 1.536-8.864; P = .004) were adverse factors. CONCLUSION: GTR and Wilkins A were favorable factors for PFS. If tolerable, GTR alone was advocated as an optimal treatment. Because of the benign nature and favorable prognosis, non-GTR was an alternative if GTR failed. Close follow-up was needed because of the recurrent tendency of ISNEC. Future study with a large cohort is necessary to verify our findings.

Discovery of novel and highly selective PI3Kδ inhibitors based on the p110δ crystal structure.

Communicated by Ramaswamy H. Sarma.

Virtual identification of novel PPARα/γ dual agonists by 3D-QSAR, molecule docking and molecular dynamics studies.

Peroxisome proliferator-activated receptors (PPARs) are considered important targets for the treatment of Type 2 diabetes (T2DM). To accelerate the discovery of PPAR α/γ dual agonists, the comparative molecular field analysis (CoMFA) were performed for PPARα and PPARγ, respectively. Based on the molecular alignment, highly predictive CoMFA model for PPARα was obtained with a cross-validated q2 value of 0.741 and a conventional r2 of 0.975 in the non-cross-validated partial least-squares (PLS) analysis, while the CoMFA model for PPARγ with a better predictive ability was shown with q2 and r2 values of 0.557 and 0.996, respectively. Contour maps derived from the 3D-QSAR models provided information on main factors towards the activity. Then, we carried out structural optimization and designed several new compounds to improve the predicted biological activity. To investigate the binding modes of the predicted compounds in the active site of PPARα/γ, a molecular docking simulation was carried out. Molecular dynamic (MD) simulations indicated that the predicted ligands were stable in the active site of PPARα/γ. Therefore, combination of the CoMFA and structure-based drug design results could be used for further structural alteration and synthesis and development of novel and potent dual agonists. AbbreviationsDMdiabetes mellitusT2DMtype 2 diabetesPPARsperoxisome proliferator-activated receptorsLBDDligand based drug design3D-QSARthree-dimensional quantitative structure activity relationshipCoMFAcomparative molecular field analysisPLSpartial least squareLOOleave-one-outq2cross-validated correlation coefficientONCoptimal number of principal componentsr2non-cross-validated correlation coefficientSEEstandard error of estimateFthe Fischer ratior2predpredictive correlation coefficientDBDDNA binding domainMDmolecular dynamicsRMSDroot-mean-square deviationRMSFroot mean square fluctuationsCommunicated by Ramaswamy H. Sarma.

Identification of novel PPARα/γ dual agonists by pharmacophore screening, docking analysis, ADMET prediction and molecular dynamics simulations.

PPARα and PPARγ play an important role in regulating glucose and lipid metabolism. The single and selective PPARα or PPARγ agonists have caused several side effects such as edema, weight gain and cardiac failure. In the recent years, the dual PPARs agonist development has become a hot topic in the antidiabetic medicinal chemistry field. In this paper, the compound CHEMBL230490 were gained from CHEMBL database, by means of complex-based pharmacophore (CBP) virtual screening, molecular docking, ADMET prediction and molecular dynamics (MD) simulations. The compound CHEMBL230490 not only displayed higher binding scores and better binding modes with the active site of PPARα a/γ, but also had more favorable the pharmacokinetic properties and toxicity evaluated by ADMET prediction. The representative compound CHEMBL230490 was performed to MDs for studying a stable binding conformation. The results indicated that the CHEMBL230490 might be a potential antidiabetic lead compound. The research provided a valuable approach in developing novel PPARα/γ dual agonists for the treatment of type 2 diabetes mellitus (T2DM).

Identification of novel PI3Kδ inhibitors by docking, ADMET prediction and molecular dynamics simulations.

BACKGROUND: Phosphoinositide-3-kinase Delta (PI3Kδ) plays a key role in B-cell signal transduction and inhibition of PI3Kδ is confirmed to have clinical benefit in certain types of activation of B-cell malignancies. Virtual screening techniques have been used to discover new molecules for developing novel PI3Kδ inhibitors with little side effects. METHOD: Computer aided drug design method were used to rapidly screen optimal PI3Kδ inhibitors from the Asinex database. Virtual screening based molecular docking was performed to find novel and potential lead compound targeting PI3Kδ, at first. Subsequently, drug likeness studies were carried out on the retrieved hits to evaluate and analyze their drug like properties such as absorption, distribution, metabolism, excretion, and toxicity (ADMET) for toxicity prediction. Three least toxic compounds were selected for the molecular dynamics (MD) simulations for 30 ns in order to validate its stability inside the active site of PI3Kδ receptor. RESULTS: Based on the present in silico analysis, two molecules have been identified which occupied the same binding pocket confirming the selection of active site. ASN 16296138 (Glide score: -12.175 kcal/mol, cdocker binding energy: -42.975 kcal/mol and ΔGbind value: -90.457 kcal/mol) and BAS 00227397 (Glide score: -10.988 kcal/mol, cdocker binding energy: -39.3376 kcal/mol and ΔGbind value: -81.953 kcal/mol) showed docking affinities comparatively much stronger than those of already reported known inhibitors against PI3Kδ. These two ligand's behaviors also showed consistency during the simulation of protein-ligand complexes for 30000 ps respectively, which is indicative of its stability in the receptor pocket. CONCLUSION: Compound ASN 16296138 and BAS 00227397 are potential candidates for experimental validation of biological activity against PI3Kδ in future drug discovery studies. This study smoothes the path for the development of novel leads with improved binding properties, high drug likeness, and low toxicity to humans for the treatment of cancer.

Identification of novel PPARα/γ dual agonists by virtual screening, ADMET prediction and molecular dynamics simulations.

PPARα and PPARγ have been the most widely studied Peroxisome proliferator-activated receptor (PPAR) subtypes due to their important roles in regulating glucose, lipids, and cholesterol metabolism. By combining the lowering serum triglyceride levels benefit of PPARα agonists (such as fibrates) with the glycemic advantages of the PPARγ agonists (such as TZD), the dual PPAR agonists approach can both improve the metabolic effects and minimize the side effects caused by either agent alone, and hence, has become a promising strategy for designing effective drugs against type-2 diabetes. In this study, by means of virtual screening, ADMET prediction and molecular dynamics (MD) simulations techniques, one compound-ASN15761007 with high binding score, low toxicity were gained. It was observed by MD simulations that ASN15761007 not only possessed the same function as AZ242 did in activating PPARα and BRL did in activating PPARγ, but also had more favorable conformation for binding to the two receptors. Our results provided an approach to rapidly produce novel PPARα/γ dual agonists which might be a potential lead compound to develop against insulin resistance and hyperlipidemia.

Intradural Extramedullary Bronchogenic Cyst: Clinical and Radiologic Characteristics, Surgical Outcomes, and Literature Review.

OBJECTIVE: An intradural extramedullary bronchogenic cyst (IEBC) is a congenital malformation and an extremely rare type of endodermal cyst. This study aims to report the clinical and radiologic characteristics and surgical outcomes of IEBCs and to review the available literature. METHODS: The medical records of 6 patients (3 female) with pathologically confirmed bronchogenic cysts involving the spinal cord between 2009 and 2016 were retrospectively reviewed, and follow-up evaluations were performed. RESULTS: Of the 6 symptomatic lesions, 4 were located in the cervical vertebra, 1 at the lumbar vertebra, and the remaining 1 at the craniocervical junction. Radiographs showed signals similar to cerebral spinal fluid on all magnetic resonance imaging sequences without contrast enhancement. Total resection was achieved in 3 patients. Histopathology revealed simple and pseudostratified respiratory epithelium with benign subepithelial mucous glands and fat components neighboring the cyst. After a mean follow-up duration of 49.2 months, 2 asymptomatic residual lesions regrew after nontotal resection. In previous literature including 19 cases, most IEBCs (84.2%) tended to be homogeneous and well demarcated on radiologic images, and 85.7% were not contrast enhancing. Cervical or upper thoracic segments were predilection sites with intradural extramedullary localization. The majority of IEBCs had similar benign histological features. The recurrence rate was 15.4% after nontotal resection but nil after total resection. CONCLUSIONS: IEBCs displayed an indolent course, and the most effective management with positive outcomes was total resection. Nontotal resection, cystic fenestration, and biopsy, which were associated with recurrence, should be avoided.

Virtual identification of novel PPARα/γ dual agonists by scaffold hopping of saroglitazar.

The thiazolidinedione class PPARγ agonists as antidiabetic agents are restricted in clinical use because of the side effects such as edema, weight gain, and heart failure. The single and selective agonism of PPARγ is the main cause of side effects. The multi-target cooperative PPARα/γ dual agonist development is a hot topic in the antidiabetic medicinal chemistry field. Saroglitazar is the first approved PPARα/γ dual agonist, available in India for the treatment of diabetic dyslipidemia. It got rid of these side effects. With the aim of finding more protent PPARα/γ dual agonists, the scaffold hopping was used to replace α-o phenylpropionic acid skeleton of saroglitazar with L-tyrosine skeleton. Then, the structural modification was carried out designing 72 compounds. Considering the importance of chirality, opposite configuration of 72 compounds was also studied. 12 compounds with better -cdocker energy were screened by molecular docking. Subsequently, the pharmacokinetic properties and toxicity evaluated by ADMET prediction, 11 of them showed better properties. Comp#L-17-1 and comp#L-3-1 were regarded as representatives to study the binding stability by molecular dynamics (MD) simulations. The MD simulation results of comp#L-17-1-PPARs (α, γ) and comp#L-3-1-PPARs (α, γ) provided structure reference for the research and development of novel PPARα/γ dual agonists.

Molecular docking, 3D-QSAR and structural optimization on imidazo-pyridine derivatives dually targeting AT1 and PPARg.

Telmisartan, a bifunctional agent of blood pressure lowering and glycemia reduction, was previously reported to antagonize angiotensin II type 1 (AT1) receptor and partially activate peroxisome proliferator-activated receptor γ (PPARγ) simultaneously. Through the modification to telmisartan, researchers designed and obtained imidazo-\pyridine derivatives with the IC50s of 0.49~94.1 nM against AT1 and EC50s of 20~3640 nM towards PPARγ partial activation. For minutely inquiring the interaction modes with the relevant receptor and analyzing the structure-activity relationships, molecular docking and 3D-QSAR (Quantitative structure-activity relationships) analysis of these imidazo-\pyridines on dual targets were conducted in this work. Docking approaches of these derivatives with both receptors provided explicit interaction behaviors and excellent matching degree with the binding pockets. The best CoMFA (Comparative Molecular Field Analysis) models exhibited predictive results of q2=0.553, r2=0.954, SEE=0.127, r2pred=0.779 for AT1 and q2=0.503, r2=1.00, SEE=0.019, r2pred=0.604 for PPARγ, respectively. The contour maps from the optimal model showed detailed information of structural features (steric and electrostatic fields) towards the biological activity. Combining the bioisosterism with the valuable information from above studies, we designed six molecules with better predicted activities towards AT1 and PPARγ partial activation. Overall, these results could be useful for designing potential dual AT1 antagonists and partial PPARγ agonists.

Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists.

Peroxisome proliferators-activated receptors (PPARα, γ and δ) are potentially effective targets for Type 2 diabetes mellitus therapy. The severe effects of known glitazones and the successfully approved agents (saroglitazar and lobeglitazone) motivated us to study novelly potent PPARs drugs with improved safety profile. In this work, we received 15 carboxylic acids based on the combination principle to integrate the polar head of bezafibrate with the hydrophobic tail of pioglitazone. Another 12 tetrazoles based on the bioisosterism principle were obtained accordingly. Furthermore, in vitro PPARs transactivation assays on these 3- or 4-alkoxy substituted phenoxy derivatives afforded six compounds. Interactions and binding stability from the docking analysis and 20 ns molecular dynamic simulations confirmed the representative compounds to be suitable and plausible for PPARs pockets. The above-mentioned results demonstrated that the compounds may be used as reference for further optimization for enhanced PPARs activities and wide safety range.

IL-4R suppresses airway inflammation in bronchial asthma by inhibiting the IL-4/STAT6 pathway.

OBJECTIVE: This study aims to explore the mechanisms of how IL-4R suppresses airway inflammation in bronchial asthma by inhibiting the IL-4/STAT6 pathway. METHODS: A total of 27 BALB/c male mice were selected and divided into control, asthma and IL-4R groups. Ovalbumin-induced mouse asthma model was established. Maximal pulmonary resistance was recorded. Hematoxylin and eosin (HE) and periodic acid Schiff (PAS) staining were conducted to observe the pathological changes in lung tissue. Optical microscope was used to detect numbers of total cells, mastocytes, eosinophils (EOS), neutrophils, and lymphocytes. Enzyme-linked immunosorbent assay (ELISA) was adopted for the levels of immunoglobulin (IgE), IL-4, IL-5, IL-13 and interferon (IFN)-γ, flow cytometry for the percentages of IL-4+ CD4+, IFN-γ+ CD4+ and IFN-γ+/IL-4+ in total thymus-derived (T) cells, qRT-PCR for the mRNA expressions of IL-4, IL-5, IL-13, STAT6, pSTAT6, suppressor of cytokine signaling (SOCS), inducible nitric oxide synthase (iNOS) and vascular cell adhesion molecule (VCAM)-1, and Western blotting for the protein expressions of STAT6 and pSTAT6. RESULTS: Compared with the control group, the asthma group had irregular tissue structure and severe inflammation, increases in maximal pulmonary resistance, numbers of total cells, EOS, neutrophils, and lymphocytes, levels of IgE, IL-4, IL-5 and IL-13, percentages of IFN-γ+ CD4+ and IFN-γ+/IL-4+ in total T cells, mRNA expressions of IL-4, IL-5, IL-13, STAT6, pSTAT6, SOCS, iNOS and VCAM-1, and protein expressions of STAT6 and pSTAT6, but decreases in IFN-γ level and percentage of IL-4+ CD4+ in total T cells. Compared with the asthma group, the IL-4R group had relatively regular tissue structure and light inflammation, declined maximal RL, numbers of total cells, EOS, neutrophils, and lymphocytes, contents of IgE, IL-4, IL-5 and IL-13, percentages of IFN-γ+ CD4+ and IFN-γ+/IL-4+ in total T cells, mRNA expressions of IL-4, IL-5, IL-13, STAT6, pSTAT6, SOCS, iNOS and VCAM-1, and protein expressions of STAT6 and pSTAT6, but elevated IFN-γ content and percentage of IL-4+ CD4+ in total T cells. CONCLUSION: Our results demonstrate that IL-4R can suppress airway inflammation in bronchial asthma by inhibited the IL-4/STAT6 pathway, which may provide a new therapeutic approach for the treatment of bronchial asthma.

[To explore treatment of neurogenic tumors of the peripheral nerve].

OBJECTIVE: To discuss the clinical features and surgical tactics of neurogenic tumors external spinal canal. METHODS: The investigators retrospectively analyzed the clinical data of 56 cases with neurogenic tumors external spinal canal as confirmed by pathology at our department from January 2000 to June 2010. And the follow-up results were tracked. Among the patients, 51 cases underwent microsurgery and 5 cases routine retro-peritoneal operation. RESULTS: Fifty cases received total resection and 5 cases subtotal resection. Partial tumor removal was performed in 1 case with multiple Schwannoma only because nerve roots were densely distributed around the tumor. Postoperative complications included declining myodynamia (n = 3), extremity pain (n = 2), topical sensory disturbance (n = 7), hoarseness (n = 5), ipsilateral facioplegia & hypophysis (n = 1) and Horner's syndrome (n = 2). Thirty-six cases had a follow-up period of 0.5 year to 10 years. No in situ recurrence was found in 34 cases. Two cases with in situ recurrence were re-operated. There was no operative death. CONCLUSION: The surgery of neurogenic tumors external spinal canal can improve the symptoms and quality of life for the patients. A better outcome is based on anatomic familiarity and skilled micromanipulation. The key aspects of tumor resection are a maximal protection of proximal important vessels and nerves and thorough tumor dissection.