A xenogeneic extracellular matrix-based 3D printing scaffold modified by ceria nanoparticles for craniomaxillofacial hard tissue regeneration via osteo-immunomodulation.

Hard tissue engineering scaffolds especially 3D printed scaffolds were considered an excellent strategy for craniomaxillofacial hard tissue regeneration, involving crania and facial bones and teeth. Porcine treated dentin matrix (pTDM) as xenogeneic extracellular matrix has the potential to promote the stem cell differentiation and mineralization as it contains plenty of bioactive factors similar with human-derived dentin tissue. However, its application might be impeded by the foreign body response induced by the damage-associated molecular patterns of pTDM, which would cause strong inflammation and hinder the regeneration. Ceria nanoparticles (CNPs) show a great promise at protecting tissue from oxidative stress and influence the macrophages polarization. Using 3D-bioprinting technology, we fabricated a xenogeneic hard tissue scaffold based on pTDM xenogeneic TDM-polycaprolactone (xTDM/PCL) and we modified the scaffolds by CNPs (xTDM/PCL/CNPs). Through series ofin vitroverification, we found xTDM/PCL/CNPs scaffolds held promise at up-regulating the expression of osteogenesis and odontogenesis related genes including collagen type 1, Runt-related transcription factor 2 (RUNX2), bone morphogenetic protein-2, osteoprotegerin, alkaline phosphatase (ALP) and DMP1 and inducing macrophages to polarize to M2 phenotype. Regeneration of bone tissues was further evaluated in rats by conducting the models of mandibular and skull bone defects. Thein vivoevaluation showed that xTDM/PCL/CNPs scaffolds could promote the bone tissue regeneration by up-regulating the expression of osteogenic genes involving ALP, RUNX2 and bone sialoprotein 2 and macrophage polarization into M2. Regeneration of teeth evaluated on beagles demonstrated that xTDM/PCL/CNPs scaffolds expedited the calcification inside the scaffolds and helped form periodontal ligament-like tissues surrounding the scaffolds.

Febuxostat attenuates secondary brain injury caused by cerebral hemorrhage through inhibiting inflammatory pathways.

Objectives: Neuroinflammation is considered an important step in the progression of secondary brain injury (SBI) induced by cerebral hemorrhage (ICH). The nucleotide-binding and oligomerization structural domain-like receptor family of pyridine structural domain-containing 3 (NLRP3) inflammasomes play an important role in the immune pathophysiology of SBI. Febuxostat (Feb) is a xanthine oxidase inhibitor that is approved for the treatment of gout and has been found to have potent anti-inflammatory effects. However, it has been less studied after ICH and we aimed to explore its protective role in ICH. Materials and Methods: We established an autologous blood-brain hemorrhage model in C57BL/6 mice. Functions of co-expressed genes were analyzed by trend analysis and bioinformatics analysis. Enzyme-linked immunosorbent assay were used to assess the inflammatory factor levels. Fluoro-Jade B histochemistry and TUNEL staining were used to detect neuronal apoptosis. Immunofluorescence staining and western blotting were used to detect the expression of NLRP3 inflammasomes. Results: Pretreatment with Feb reduced neuronal cell death and degeneration and alleviated neurobehavioral disorders in vivo. Feb was found to modulate inflammation-related pathways by trend analysis and bioinformatics analysis. In addition, Feb inhibited microglia activation and elevated cytokine levels after ICH. Furthermore, double immunofluorescence staining showed that co-localization of NLRP3 with Iba1 positive cells was reduced after treatment with Feb. Finally, we found that Feb inhibited the activation of the NLRP3/ASC/caspase-1 pathway after ICH. Conclusion: By inhibiting the NLRP3 inflammasome, preconditioning Feb attenuates inflammatory injury after ICH. Our findings may provide new insights into the role of Feb in neuroprotection.

Identification of four biotypes in temporal lobe epilepsy via machine learning on brain images.

Artificial intelligence provides an opportunity to try to redefine disease subtypes based on similar pathobiology. Using a machine-learning algorithm (Subtype and Stage Inference) with cross-sectional MRI from 296 individuals with focal epilepsy originating from the temporal lobe (TLE) and 91 healthy controls, we show phenotypic heterogeneity in the pathophysiological progression of TLE. This study was registered in the Chinese Clinical Trials Registry (number: ChiCTR2200062562). We identify two hippocampus-predominant phenotypes, characterized by atrophy beginning in the left or right hippocampus; a third cortex-predominant phenotype, characterized by hippocampus atrophy after the neocortex; and a fourth phenotype without atrophy but amygdala enlargement. These four subtypes are replicated in the independent validation cohort (109 individuals). These subtypes show differences in neuroanatomical signature, disease progression and epilepsy characteristics. Five-year follow-up observations of these individuals reveal differential seizure outcomes among subtypes, indicating that specific subtypes may benefit from temporal surgery or pharmacological treatment. These findings suggest a diverse pathobiological basis underlying focal epilepsy that potentially yields to stratification and prognostication - a necessary step for precise medicine.

Comparison of the quality of Nurse-Led palliative care with standard medical care during six months in 405 patients with Parkinson's disease and burdens of their Caregivers: A retrospective study at a single center in China.

BACKGROUND: Palliative care is mainly used to improve the quality of life of patients with chronic diseases by addressing their medical conditions and psychological problems. End-stage Parkinson's disease (PD) is also a progressive disease like cancer and could be managed by palliative care. This study was conducted at a single center in China and aimed to compare the quality of nurse-led palliative care with standard medical care during six months in 405 patients with Parkinson's disease (PPD) and their caregivers using the Chinese version of the 39-item Parkinson's Disease Questionnaire (PDQ-39) and the Chinese Zarit Burden Interview (ZBI) scale. METHODS: PPD (stage 2-5) received nurse-led palliative care (NP cohort, 103 patients; 103 caregivers) or neurologist-led standard care (NS cohort, 134 patients; 134 caregivers), or primary care practitioner-led usual care (PS cohort, 168 patients; 168 caregivers) for six months. RESULTS: Before the health professional-led care (BN), the PDQ-39 score of PPD was 68 (71-64) and their caregivers had 54.86 ± 7.64 a ZBI scale. After 6-months of the health professional-led care (AN), the PDQ-39 score of PPD and a ZBI scale of their caregivers decreased for the NP cohort as compared to those of BN condition and those of patients in the NS and PS cohorts at AN condition (p < 0.001 for all). CONCLUSIONS: The quality of life of PPD must be improved and the burden on their caregivers must be relieved. Nurse-led palliative care successfully improved the quality of life of PPD and reduced their caregiver burden.

Neurological autoantibody prevalence in chronic epilepsy: Clinical and neuropathologic findings.

BACKGROUND: We aimed to explore the prevalence of autoimmune antibodies (Abs) in a large consecutive series with "chronic" epilepsy and without symptoms of autoimmune encephalitis; and to compare the immunopathology of brain tissue from drug-resistant epilepsy (DRE) with and without Abs positivity. METHODS: Neuronal and glial antibodies were detected in the serum of patients who were admitted to the wards of West China Hospital from October 2016 to September 2019 and had epilepsy by cell-based assays and tissue-based assays. RESULTS: Twenty-one (6.8 %) of 328 patients had positive Ab findings for the following: dipeptidyl-peptidase-like protein-6 (n = 7), contactin-associated protein-like 2 (n = 5), glutamic acid decarboxylase 65 (n = 4), gamma aminobutyric acid beta receptor (n = 2), N-methyl-d-aspartate receptor (n = 2), and dopamine D2 receptor (n = 1). Antibodies were detected in 6.9 % (13/187) of epilepsy people with unknown etiology and 5.6 % (8/141) of patients with known etiology, respectively. Among 190 patients with DRE, 14 (7.3 %) patients were Abs-positive. There was no significant difference between individuals with seropositive and seronegative results in clinical manifestations, except that the history of febrile seizure was significantly more frequent in the seropositive group. Moreover, brain samples from 3 patients with Abs-positive DRE (with DPPX in 2 patients, and CASPR2 in 1 patient) and 18 patients with Abs-negative DRE were analyzed for immunopathology. We found higher expression of CD8-positive T-cells in the hippocampus of Abs-positive DRE group. CONCLUSIONS: Neuronal antibodies are potentially involved in the process of "chronic" epilepsy, and CD8-positive T-cells may play an important role in this process.

An HA/PEEK scaffold with modified crystallinity via 3D-bioprinting for multiple applications in hard tissue engineering.

Hard tissues, especially teeth and bones, are highly mineralized and the large-scale defect or total loss of them is irreversible. There is still no ideal strategy for the reconstruction of various hard tissue defects that can achieve the balance between biological and mechanical properties. Polyether ether ketone (PEEK) has the potential to substitute for natural hard tissue in defect areas but is limited by its biological inertness. The addition of hydroxyapatite (HA) can significantly improve the osteogenic properties and osteointegration of PEEK materials. But the mechanical properties of HA/PEEK scaffolds are far from satisfaction making scaffolds easy to fracture. We put forward a strategy to balance the mechanical and biological properties of HA/PEEK scaffolds via the regulation of the inner crystallinity and HA mixing ratio and we systematically evaluated the modified HA/PEEK scaffolds through material characterization,in vitroandin vivoexperiments. And we found that the 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. The results of the implantation of beagles' teeth, mandible and rib showed that the 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, which made it a candidate for a practical versatile hard tissue engineering scaffold.

Personalized 3D-Printed Scaffolds with Multiple Bioactivities for Bioroot Regeneration.

Recent advances in 3D printing offer a prospective avenue for producing transplantable human tissues with complex geometries; however, the appropriate 3D-printed scaffolds possessing the biological compatibility for tooth regeneration remain unidentified. This study proposes a personalized scaffold of multiple bioactivities, including induction of stem cell proliferation and differentiation, biomimetic mineralization, and angiogenesis. A brand-new bioink system comprising a biocompatible and biodegradable polymer is developed and reinforced with extracellular matrix generated from dentin tissue (treated dentin matrix, TDM). Adding TDM optimizes physical properties including microstructure, hydrophilicity, and mechanical strength of the scaffolds. Proteomics analysis reveals that the released proteins of the 3D-printed TDM scaffolds relate to multiple biological processes and interact closely with each other. Additionally, 3D-printed TDM scaffolds establish a favorable microenvironment for cell attachment, proliferation, and differentiation in vitro. The 3D-printed TDM scaffolds are proangiogenic and facilitate whole-thickness vascularization of the graft in a subcutaneous model. Notably, the personalized TDM scaffold combined with dental follicle cells mimics the anatomy and physiology of the native tooth root three months after in situ transplantation in beagles. The remarkable in vitro and in vivo outcomes suggest that the 3D-printed TDM scaffolds have multiple bioactivities and immense clinical potential for tooth-loss therapy.

Automated detection of hippocampal sclerosis using real-world clinical MRI images.

Background: Hippocampal sclerosis (HS) is the most common pathological type of temporal lobe epilepsy (TLE) and one of the important surgical markers. Currently, HS is mainly diagnosed manually by radiologists based on visual inspection of MRI, which greatly relies on MRI quality and physician experience. In clinical practice, non-thin MRI scans are often used due to the time and efficiency needed for the acquisition. However, these scans can be difficult for junior physicians to interpret accurately. Thus, the rapid and accurate diagnosis of HS using real-world MRI images in clinical settings is a challenging task. Objective: Our aim was to explore the feasibility of using computer vision methods to diagnose HS on real-world clinical MRI images and to provide a reference for future clinical applications of artificial intelligence methods to aid in detecting HS. Methods: We proposed a deep learning algorithm called "HS-Net" to discriminate HS using real-world clinical MRI images. First, we delineated and segmented a region of interest (ROI) around the hippocampus. Then, we utilized the fractional differential (FD) method to enhance the textures of the ROIs. Finally, we used a small-sample image classification method based on transfer learning to fine-tune the feature extraction part of a pretrained model and added two fully connected layers and an output layer. In the study, 96 TLE patients with HS confirmed by postoperative pathology and 89 healthy controls were retrospectively enrolled. All subjects were cross-validated, and models were evaluated for performance, robustness, and clinical utility. Results: The HS-Net model achieved an area under the curve (AUC) of 0.894, an accuracy of 82.88%, an F1-score of 84.08% in the test cohort based on real, routine, clinical T2-weighted fluid attenuated inversion recovery (FLAIR) sequence MRI images. Additionally, the AUC, accuracy and F1 scores of our model all increased by around 3 percentage points when the inputs were augmented with the ROIs of the textures enhanced using the FD method. Conclusions: Our computational model has the potential to be used for the diagnosis of HS in real clinical MRI images, which could assist physicians, particularly junior physicians, in improving the accuracy of discrimination.

An in vivo evaluation of clear aligners for optimal orthodontic force and movement to determine high-efficacy and periodontal-friendly aligner staging.

Objectives: To investigate the effect of aligner displacement on tooth movement and periodontal health to improve the efficiency of aligner treatment and explore the mechanism in vivo. Methods: A two-tooth site was established by a finite element (FE) model to virtually evaluate aligner staging. A randomized controlled experiment was conducted when the tooth sites in beagles were treated with fixed or aligner appliances with different movement and force, and tooth movement and internal structure were recorded during the alignment. After sacrificing five dogs, bone-periodontal ligament (PDL)-tooth specimens were removed and processed to conduct uniaxial compression and tensile tests as well as micro-CT imaging and histological analysis. Results: Three displacements of 0.25, 0.35 and 0.45 mm were obtained from FE analysis and applied in beagles. In general, aligners had poorer performance on movement compared to fixed systems in vivo, but the aligner with a staging of 0.35 mm had the highest accuracy (67.46%) (P < 0.01). Loaded with severe force, fixed sites exhibited tissue damage due to excess force and rapid movement, while aligners showed better safety. The PDL under a 0.35-mm aligner treatment had the highest elastic modulus in the biomechanical test (551.4275 and 1298.305 kPa) (P < 0.05). Conclusions: Compared to fixed appliances, aligners achieve slightly slower movement but better periodontal condition. Aligners with an interval of 0.35 mm have the highest accuracy and best PDL biomechanical and biological capacities, achieving the most effective and safest movement. Even with complexity of oral cavity and lack of evaluation of other factors, these results provide insight into faster displacement as a method to improve the efficacy of aligners.

No association of GABRA1 rs2279020 and GABRA6 rs3219151 polymorphisms with risk of epilepsy and antiepileptic drug responsiveness in Asian and Arabic populations: Evidence from a meta-analysis with trial sequential analysis.

The γ-aminobutyric acid type A receptors (GABAAR) have been reported to contribute to the pathogenesis of epilepsy and the recurrence of chronic seizures. Genetic polymorphisms in GABRA1 and GABRA6 may confer a high risk of epilepsy and multiple drug resistance, but with conflicting results. We aimed to assess the association of GABRA1 rs2279020 and GABRA6 rs3219151 with epilepsy risk using a meta-analysis. The databases of Pubmed, Ovid, Web of Science, and China National Knowledge Infrastructure were searched. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were computed to evaluate the association between the polymorphisms and epilepsy risk using a fixed- or random-effect model. Trial sequential analysis (TSA) was performed to assess the results of the meta-analysis. No significant association between the GABRA1 rs2279020 and GABRA6 rs3219151 and the risk of epilepsy was found in the Asian and Arabic populations. The negative results were also observed when comparing the GABRA1 rs2279020 and GABRA6 rs3219151 polymorphism to antiepileptic drug responsiveness. The trial sequential analysis confirmed the results of the meta-analysis. This meta-analysis suggests that GABRA1 rs2279020 and GABRA6 rs3219151 are not risk factors for the etiology of epilepsy and antiepileptic drug responsiveness in the Asian and Arabic populations.

A systematic review and meta-analysis of the association of ABCC2/ABCG2 polymorphisms with antiepileptic drug responses in epileptic patients.

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.

The X-ray structure of tubulysin analogue TGL in complex with tubulin and three possible routes for the development of next-generation tubulysin analogues.

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 Å). 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.

Genetic polymorphisms in SCN2A are not associated with epilepsy risk and AEDs response: evidence from a meta-analysis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: This meta-analysis suggests that the rs17183814 and rs2304016 polymorphisms in SCN2A are not associated with the risk of epilepsy and response to AEDs.

Replication of GWAS Loci Revealed an Increased Risk of BET1L and H19 Polymorphisms with Intracranial Aneurysm.

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.

Association between functional polymorphisms in the promoter of the miR-143/145 cluster and risk of intracranial aneurysm.

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.

High FABP5 Versus CRABPII Expression Ratio in Recurrent Craniopharyngiomas: Implications for Future Treatment.

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 Potential Polymorphism in the Promoter of Let-7 is Associated With an Increased Risk of Intracranial Aneurysm: A Case-Control Study.

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.

Expression of ß-amyloid precursor protein in refractory epilepsy.

ß-amyloid precursor protein (ß-APP), also known as Aß peptide, has a key role in the pathogenesis of Alzheimer's disease, and is also likely to be involved in the development of refractory epilepsy. The mechanism behind the association between ß-APP and refractory epilepsy remains to be elucidated. The aim of the present study was to examine the levels of APP mRNA and ß-APP protein in patients with refractory epilepsy. Tissue samples were obtained from patients with chronic pharmacoresistant epilepsy who underwent surgery. Levels of APP mRNA and ß-APP protein in epileptic temporal lobe and hippocampal tissue were assessed using quantitative polymerase chain reaction, immunohistochemistry and immunofluorescence. The expression levels of protein significantly increased in the temporal cortex and the hippocampus of the patients with epilepsy. ß-APP may thus contribute to the pathogenesis of refractory epilepsy.

Association between NFKB1 -94 insertion/deletion ATTG polymorphism and risk of intracranial aneurysm.

OBJECTIVE: Growing evidence indicates that vascular inflammation is a common phenomenon in the pathogenesis of intracranial aneurysms (IAs). Nuclear factor kappa B is a key molecule that is involved in the vascular inflammation of IA. We hypothesized that an insertion/deletion (ins/del) ATTG polymorphism located between two putative key promoter regulatory elements in the NFKB1 gene may be related to the risk of IA. METHODS: We performed a case-control study, including 164 patients with IA and 525 healthy controls in a Chinese population using a polymerase chain reaction-polyacrylamide gel electrophoresis assay. RESULTS: A significantly decreased risk of IA was observed in the ATTG1/ATTG2 and ATTG2/ATTG2 genotypes compared with the ATTG1/ATTG1 genotype (ATTG1/ATTG2 vs. ATTG1/ATTG1: odds ratio [OR]=0.58, 95% confidence interval [95% CI]=0.39-0.87, p=0.007; ATTG2/ATTG2 vs. ATTG1/ATTG1: OR=0.12, 95% CI=0.06-0.23, p<0.001), and also the ATTG2 allele (ATTG2 vs. ATTG1: OR=0.41, 95% CI=0.32-0.54, p<0.001). CONCLUSION: These findings suggest that the NFKB1 -94ins/del ATTG polymorphism may contribute to the risk of IA.

Interactions of miR-34b/c and TP-53 polymorphisms on the risk of nasopharyngeal carcinoma.

Growing evidence indicates that tumor suppressor gene TP-53 and non-coding RNA miR-34b/c independently and/or jointly play crucial roles in carcinogenesis. We hypothesized that the polymorphisms of rs4938723 in the promoter region of pri-miR-34b/c and TP-53 Arg72-Pro may be related to the risk of nasopharyngeal carcinoma (NPC). We performed a case-control study between 217 patients with NPC and 360 healthy controls in a Chinese population using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. A significantly increased risk of NPC was observed in the miR-34b/c rs4938723 CT/CC genotypes compared with the TT genotype (adjusted OR=1.44, 95 % CI 1.02-2.03, p=0.04), and also the C allele (adjusted OR=1.33, 95 % CI 1.04-1.70, p=0.03). The gene-gene interaction of miR-34b/c rs4938723 and TP-53 Arg72-Pro showed that the combined genotypes of rs4938723CT/CC and TP-53CG/CC increased the risk of NPC (rs4938723CT/CC + TP-53CG/CC vs. rs4938723 TT+TP-53 CG/CC: OR=1.58, 95 % CI 1.04-2.42, p=0.03). These findings suggest that miR-34b/c rs4938723 and TP-53 Arg72Pro polymorphisms may singly or collaboratively contribute to the risk of NPC.