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Background Hard tissues, especially teeth and bones, are highly mineralized and the large-scale defect or total loss of them is irreversible. Scaffolds fabricated with polyether ether ketone (PEEK) and hydroxyapatite (HA) were considered as substitute materials with osteogenic properties but poor mechanical properties. There is a lack of a construction strategy of HA/PEEK scaffolds that can balance mechanical and biological properties and the in vitro and in vivo evaluation of them. Methods Based on fused deposition melting (FDM), we regulated the crystallinity and mixing ratio of HA of HA/PEEK scaffolds, and explored the material characterization including crystallinity, element content and mechanical properties and biological properties including cell proliferation, migration, osteogenic differentiation of different scaffolds. And we further mimicked the clinical application on the Beagles by implanting the scaffolds to reconstruct the defect of teeth, mandibles and ribs. Results We found that the 3D-20%HA/PEEK scaffolds with low crystallinity achieved the required strength and elasticity, and exhibited the characteristics of promoting the proliferation, migration and osteogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs). The results of the implantation of Beagles’ teeth, mandible and rib showed that the 3D-20%HA/PEEK scaffold with low crystallinity could well withstand the local complex force in the defect area and combine well with natural bone tissue. Conclusion The HA/PEEK scaffolds constructed with this strategy had appropriate mechanical properties to withstand complex forces, and good bone regeneration effect, which made them practical and versatile on hard tissue engineering.

Microtubule-targeting agents (MTAs) are the most commonly used anti-cancer drugs. At least fourteen microtubule inhibitors and ten antibody drug conjugates (ADCs) linking MTAs are approved by FDA for clinical use in cancer therapy. In current research, we determined the crystal structure of tubulysin analogue TGL in complex with tubulin at a high resolution (2.65 A). In addition, we summarized all of the previously published high-resolution crystal structures of ligands in the vinca site to provide structural insights for the rational design of the new vinca-site ligands. Moreover, based on the aligned results of the vinca site ligands, we provided three possible routes for designing new tubulysin analogues, namely macrocyclization between the N-14 side chain and the N-9 side chain, the hybird of tubulysin M and phomopsin A, and growing new aryl group at C-21. These designed structures will inspire the development of new MTAs or payloads in cancer therapy.

Previous studies have investigated the association between rs2304016 and rs17183814 polymorphisms in sodium voltage-gated channel alpha subunit 2 (SCN2A) and epilepsy risk and responsiveness to antiepileptic drugs (AEDs) but with conflicting results. Our aim was to reevaluate the relationship by performing a systematic review and meta-analysis. By searching PubMed, Medline, and CNKI, 14 studies were selected. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were computed to measure the association between rs17183814 and rs2304016 polymorphisms and the risk of epilepsy and AEDs response using the fixed-effects model or the random-effects model. No significant association between the rs17183814 in SCN2A and the risk of epilepsy was observed (heterozygous comparison: OR = 0.78, 95% CI: 0.61–1.00; homozygous comparison: OR = 1.34, 95% CI: 0.63–2.86; dominant model: OR = 0.82, 95% CI: 0.64–1.04; recessive model: OR = 1.44, 95% CI: 0.68–3.05; allele comparison: OR = 0.88, 95%CI: 0.71–1.10). Moreover, neither the rs17183814 nor the rs2304016 was associated with AEDs response. This meta-analysis suggests that the rs17183814 and rs2304016 polymorphisms in SCN2A are not associated with the risk of epilepsy and response to AEDs.

Purpose Accumulating evidence indicates that genetic polymorphisms in ATP-binding cassette superfamily members, such asABCC2 and ABCG2, alter responses to antiepileptic drugs (AEDs); however, this evidence is controversial and inconclusive. To provide strong evidence of the association between common polymorphisms in ABCC2 and ABCG2 and AED responses in patients with epilepsy, we performed a systematic review and meta-analysis. Methods A literature search of electronic databases (PubMed, EBSCO, Ovid and the China National Knowledge Infrastructure) was performed. To evaluate the association of genetic polymorphisms inABCC2 and ABCG2 and risk of AED treatment, we calculated pooled odds ratios (ORs) and 95 % confidence intervals (CIs) using a fixed- or random-effect model. Results A significant association of theABCC2 rs717620 polymorphism with resistance to AEDs was found in the overall pooled populations (homozygous comparison: OR = 1.77, 95 % CI, 1.27–2.48; dominant model: OR = 1.23, 95 % CI, 1.06–1.43; recessive model: OR = 1.75, 95 % CI, 1.28–2.40) and Asians (dominant model: OR = 1.21, 95 % CI, 1.03–1.42; recessive model: OR = 1.80, 95 % CI, 1.30–2.50). Using a recessive model, a similarly significant association of ABCC2 rs3740066 with AED resistance was observed in the overall pooled populations (OR = 2.29, 95 % CI, 1.44–3.64) and Asians (OR = 2.53, 95 % CI, 1.56–4.08). However, ABCC2 rs2273697, ABCG2 rs2231137 and rs2231142 were not found to be associated with AED responsiveness. Conclusion This meta-analysis suggests thatABCC2 rs717620 and rs3740066 are risk factors that predict responses to AEDs in epileptic patients.

Background and Objective Recurrence is a major problem in craniopharyngioma (CP) management. Recent study shows that high FABP5/CRABPII may be related to tumor growth and that all- trans retinoic acid (ATRA) may suppress primary CP growth. We studied the expression profile of FABP5 and CRABPII in recurrent CP tissue and the effect of ATRA on recurrent CP cells. Methods Fifty cases of patients with CP were enrolled in the retrospective study. Among them, 15 were recurrent. Fresh specimens were collected for immunohistochemistry, reverse transcription polymerase chain reaction, and western blotting analysis of FABP5 and CRABPII. Fresh specimens from 6 primary and recurrent CPs were collected and subjected to cell culture using an explants method. ATRA at various concentrations was applied to recurrent CP cell culture, and cell growth was recorded and analyzed. Results Immunohistochemistry, reverse transcription polymerase chain reaction, and western blot study showed that FABP5 was expressed significantly higher in recurrent tumors, whereas CRABPII was expressed significantly higher in primary tumors. The FABP5/CRABPII ratio was significantly higher in recurrent rather than primary tumors. Recurrent CP cells grew faster than primary cells, and ATRA induced cellular apoptosis and inhibited CP cell growth in a dose-dependent manner. Conclusions A high expression ratio between FABP5 and CRABPII may be related to CP tumor recurrence and ATRA could be a potential therapeutic agent for CP chemotherapy.

A genome-wide association study (GWAS) identified that BET1L rs2280543 at chromosome 11p15.5 was a susceptibility loci of intracranial aneurysm (IA). Long noncoding RNA H19, located in this region, was reported to play a crucial role in the formation of IA. In this study, we aimed to examine whether BET1L rs2280543 and potentially functional polymorphisms in H19 influence the risk of IA. A hospital-based case-control study was performed involving 542 IA patients and 588 age- and gender-matched controls. The BET1L rs2280543 and H19 polymorphisms were genotyped using the TaqMan assay. The BET1L rs2280543 CT, CT/TT genotypes, and T allele were associated with an increased risk of IA (CT vs. CC, adjusted OR = 1.43, 95% CI: 1.08-1.90, P = 0.01; CT/TT vs. CC, adjusted OR = 1.48, 95% CI: 1.12-1.94, P = 0.005; and T vs. C, adjusted OR = 1.44, 95% CI: 1.13-1.83, P = 0.003). Similarly, the H19 rs217727 TT genotype and T allele were associated with an increased risk of IA (TT vs. CC, adjusted OR = 1.90, 95% CI: 1.35-2.67, P < 0.001; T vs. C, adjusted OR = 1.38, 95% CI: 1.16-1.64, P < 0.001). Combined analyses revealed that the rs2280543 CC-rs217727 CT/TT, rs2280543 CT/TT-rs2735971 GG, and rs217727 CT/TT-rs2735971 GG genotypes were related to the risk of IA. Interaction analysis showed that the 3-loci model of rs2280543-rs217727-rs2839698 contributed to an increased risk of IA. These findings suggest that the GWAS-discovered risk loci BET1L rs2280543 may increase IA susceptibility by interacting with lncRNA H19.

MicroRNAs (miRs)-143/145 are involved in various biological processes related to aneurysm formation and are downregulated in patients with intracranial aneurysm (IA). We aimed to determine whether two functional polymorphisms (i.e. rs4705342 and rs4705343) in the promoter of miR-143/145 are related to IA risk. A case-control study was undertaken to examine the association of rs4705342 and rs4705343 with IA risk, including 565 patients with IA and 622 age- and gender-matched controls. rs4705342 was analysed by TaqMan Assay, and rs4705343 was genotyped using polymerase chain reaction-restriction fragment length polymorphism. miR-143/145 expression was quantified using RT-PCR. rs4705342 was associated with a significantly lower risk of IA, with adjusted ORs of 0.74 (95% CI: 0.58–0.95) for TC genotype carriers and 0.74 (95% CI: 0.59–0.94) for TC/CC genotypes carriers. Individuals carrying the rs4705342 C allele had a reduced risk of IA (adjusted OR = 0.82; 95% CI: 0.68–0.98). Haplotype of the two loci of rs4705342 and rs4705343 showed that the CT haplotype carried a lower IA risk and higher miR-143 level. Moreover, the rs4705342 CC/CT genotypes were associated with higher miR-143 levels. Thus, the rs4705342C-rs4705343T haplotype in the promoter of miR-143/145 cluster may be related to IA development.

Let-7 family plays a key role in the progression of atherosclerosis and intracranial aneurysm (IA). We hypothesized that rs10877887 and rs13293512 polymorphisms in the promoters of let-7 family may be associated with the susceptibility of IA. We genotyped the 2 single nucleotide polymorphisms (SNPs) in 305 patients with IA and 401 healthy controls. The rs10877887 was analyzed using a polymerase chain reaction-restriction fragment length polymorphism assay, and the rs13293512 was analyzed using a TaqMan SNP genotyping method. The relative expression of let-7 family was measured in plasma of cases and controls using real-time PCR. We found that the rs13293512CT genotype was associated with a significantly increased risk of developing IA in a heterozygote comparison (adjusted OR = 1.43, 95% CI, 1.00–2.05, P = 0.048) and dominant comparison (adjusted OR = 1.44, 95% CI, 1.02–2.03, P = 0.04). Combined analysis showed that the rs10877887TT and rs13293512CC/CT genotypes had a significantly increased risk of IA (OR = 1.67, 95% CI, 1.04–2.68, P = 0.03). Moreover, the levels of let-7a, let-7d, and let-7f were downregulated in IA patients, and patients with the rs13293512CC/CT genotypes had a lower level of let-7a than those with rs13293512TT genotype (P = 0.03). These findings indicate that the rs13293512CC/CT is a risk factor for the development of IA, possibly because of the genotypes resulting in a lower level of let-7a.

Vascular inflammation has been shown to be involved in the pathogenesis of intracranial aneurysms (IA). MiRNAs are key molecules that participate in the regulation of many important biological processes including inflammation. Studies on the hsa-miR-146a rs2910164 polymorphism and its association with different inflammatory related diseases have engendered inconsistent results, and until now, there have been no reports on the association between this polymorphism and the susceptibility to IA. In this study, we aimed to investigate whether the rs2910164 polymorphism is involved in the process of IA. We genotyped 164 patients with IA and 478 healthy controls using a polymerase chain reaction-restriction fragment length polymorphism assay. All subjects were Chinese. The distributions of rs2910164 genotypes and alleles between patients with IA and healthy controls were similar [CG vs CC: odds ratio (OR) = 0.701, 95% confidence interval (CI) = 0.456-1.080; GG vs CC: OR = 0.920, 95%CI = 0.524-1.617; G vs C: OR = 0.939, 95%CI = 0.731-1.208, respectively]. No association was found between the hsa-miR-146a rs2910164 polymorphism and the risk of IA in the analyzed population.