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.

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.

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.

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.

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.

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.

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.

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.

All-trans retinoic acid inhibits craniopharyngioma cell growth: study on an explant cell model.

The ratio between FABP5 and CRABPII determines cellular response to physiological level of retinoic acid; tumor cells undergo proliferation with high level of FABP5 and apoptosis with high level of CRABPII. We intended to study FABP5 and CRABPII expression in craniopharyngiomas, to establish craniopharyngioma cell model using explants method, and to study the effect of pharmacological dose of retinoic acid on craniopharyngioma cells. Expression of FABP5 and CRABPII in craniopharyngioma tissue from 20 patients was studied using immunohistochemistry. Primary craniopharyngioma cell cultures were established using tissue explants method. Craniopharyngioma cells were treated using various concentrations of all-trans retinoic acid, and cell growth curve, apoptosis, expression of FABP5, CRABPII and NF-κB were assayed in different groups. FABP5/CRABPII ratio was significantly higher in adamatinomatous group than that in papillary group. Cell cultures were established in 19 cases (95 %). Pharmacological level retinoic acid inhibited cell growth and induced cellular apoptosis in dose dependent manner, and apoptosis rate cells treated with 30 µM retinoic acid for 24 h was 43 %. Also, retinoic acid increased CRABPII, and decreased FABP5 and NF-κB expression in craniopharyngioma cells. High FABP5/CRABPII ratio is observed in adamatinomatous craniopharyngioma. Retinoic acid at pharmacological level induced craniopharyngioma cell apoptosis via increasing FABP5/CRABPII ratio and inhibiting NF-κB signaling pathway. Our study demonstrated that all-trans retinoic acid might be a candidate for craniopharyngioma adjuvant chemotherapy in future.

Craniopharyngioma cell growth is promoted by growth hormone (GH) and is inhibited by tamoxifen: involvement of growth hormone receptor (GHR) and IGF-1 receptor (IGF-1R).

Hormone receptors are related to the biological behavior and recurrence of craniopharyngioma (CP). The effect of therapeutic growth hormone (GH) replacement on CP growth remains largely unclear. We intended to study expression patterns of GH-related receptors in CP, and to study the effect of GH and its mediator, insulin-like growth factor-1 (IGF-1), as well as tamoxifen, on primary CP cell cultures. Primary cell cultures were established from fresh tumor specimens. The expression of GH receptor (GHR) and IGF-1 receptor (IGF-1R) in tumor specimens was studied using immunohistochemistry. Cell cultures were treated with various concentrations of recombinant GH, IGF-1 and tamoxifen. Cell growth promotion or inhibition was assayed using the Trypan blue dye exclusion test of cell viability. Expression of GHR, IGF-1R, phosphorylated-Akt and Akt after treatment was studied using Western blot assay. Twenty-nine primary cultures from 36 patients were established. GHR and IGF-1R were expressed in tumor tissue. The promotion of cell growth by GH compared to control was most prominent at 100 ng/mL, while inhibition by tamoxifen was concentration dependent. IGF-1 was more effective in promoting growth in CP cell cultures with high IGF-1R expression, and it increased phosphorylation of Akt protein. Primary cell cultures can be established in more than 80% of fresh CP specimens. GH and its endogenous mediator, IGF-1, promotes CP cell growth in vitro, while tamoxifen inhibits growth.

Interactions of miR-34b/c and TP53 polymorphisms on the risk of intracranial aneurysm.

Several lines of evidence indicate that inflammatory processes play a key role in the happening and development of intracranial aneurysm (IA). Recently, polymorphisms in the TP53 gene were shown to be associated with inflammation and inflammatory disease. The aim of this study was to investigate the interactions of miR-34b/c and TP53 Arg72-Pro polymorphisms on the risk of IA in a Chinese population. A total of 590 individuals (including 164 patients with IA and 426 controls) were involved in this study. The polymorphisms (i.e., miR-34b/c rs4938723 and TP53 Arg72-Pro) were genotyped by polymerase chain reaction-restriction fragment length polymorphism assay and DNA sequencing. We found that the CC genotype of miR-34b/c rs4938723 was significantly associated with a decreased risk of IA compared with the TT genotype. Moreover, a significant gene interaction of the carriers with the combined genotypes of miR-34b/c rs4938723CC and TP53 Arg72Pro CG/CC/GG had a decreased risk of IA, compared with those carrying miR-34b/c rs4938723CT/TT+TP53 Arg72Pro GG/CG/CC combined genotypes. These findings suggest that the miR-34b/c rs4938723CC and TP53 Arg72-Pro polymorphisms may be involved in the susceptibility to IA.

Lack of association between GSTM1 and GSTT1 polymorphisms and brain tumour risk.

OBJECTIVE: Glutathione S-transferases (GSTs) are important enzymes that are involved in detoxification of environmental carcinogens. Molecular epidemiological studies have been conducted to investigate the association between GSTM1 and GSTT1 homozygous deletion polymorphisms and brain tumours but results have been conflicting. The aim of this study was to clarify this problem using a meta-analysis. METHODS: A total of 9 records were identified by searching the PubMed and Embase databases. Fixed- and random-effects models were performed to estimate the pooled odds ratios. RESULTS: No significant association was found between the GSTM1 and GSTT1 homozygous deletion polymorphisms and risk of brain tumours, including glioma and meningioma. Similar negative results were also observed in both population-based and hospital-based studies. CONCLUSION: These findings indicate that the GSTM1 and GSTT1 polymorphisms may not be related to the development of brain tumours.

A spinal epidural dumbbell cellular schwannoma in an infant.

Intraspinal schwannoma is a rare neoplasm in pediatric patients; cellular schwannoma is an unusual histological subtype of schwannoma. A six-month-old infant with an epidural dumbbell cellular schwannoma presented with progressive weakness of his arms and legs. A spinal MRI revealed an epidural mass from C5 to T4, and a complete surgical resection was achieved after laminotomy and facetectomy. The patient experienced a gradual neurological improvement and was still healthy without recurrence at the latest follow-up. The diagnosis of cellular schwannoma was confirmed on immunohistological examination.

Gene-gene interactions between interleukin-12A and interleukin-12B with the risk of brain tumor.

Emerging evidence from preclinical and clinical studies has shown that interleukin-12 (IL-12) has some effectiveness against endogenously arising brain tumor. The aim of this study was to investigate interactions of IL-12A and IL-12B polymorphisms on the risk of brain tumor. We analyzed IL-12A rs2243115 and IL-12B rs3212227 polymorphisms in 170 patients with brain tumor and 222 healthy controls in a Chinese population using a polymerase chain reaction-restriction fragment length polymorphism assay and DNA sequencing method. Individuals carrying a G allele of IL-12A rs2243115 had a significantly higher risk of developing brain tumor compared with those carrying a T allele (odds ratio [OR]=2.01, 95% confidence interval [CI], 1.17-3.45). After stratification analysis according to tumor types, a similarly higher risk was detected in patients with glioma (OR=2.56, 95% CI, 1.25-5.21). When gene-gene interactions were examined, carriers at both loci rs2243115 TG/GG and rs3212227 AC/CC had a 2.62-fold increased risk of glioma compared with those with rs2243115 TT and rs3212227 AC/CC genotypes (OR=2.62, 95% CI, 1.05-6.50). This study provides evidence that IL-12A rs2243115 may be associated with the risk of brain tumor. Additionally, gene-gene interactions of IL-12A rs2243115 and IL-12B rs3212227 may contribute to brain tumor susceptibility.

[The establishment of craniopharyngioma cell line].

OBJECTIVE: To establish the craniopharyngioma cell line with primary culture which might provide experiment background and evidence for future eternal tumor cell line establishment. METHODS: Thirty six surgical specimens were collected from patients with craniopharyngiomas definited by iconography and pathology examinations in West China Hospital, Sichuan University, including twenty one adamantine epitheliomas and fifteen squamous papillary tumors. The tumor cell was treated through primary cukture, purification, passage, freezing, resuscitation, and identified by keratin 7 staining through SP method. The growth curve and double time were detected through trypan blue dye cell count and MTT assay. The growth of the tumor cells treated with growth hormone (GH) and Tamoxifen was also observed. RESULTS: Thirty six primary cultures were done, 29 of which were successful and subculture was achieved in 80.6% of all primary cultures. These cell lines were from squamous epithelium by keratin 7 antibody identification, with three days of double time. Proloferative effect of GH was most prevalent at 100 ng/mL, while tamoxifen suppressed cell growth. CONCLUSION: The finite craniopharyngioma cell lines were obtained through primary culture.

The association between ACE polymorphism and risk of colorectal cancer in a Chinese population.

OBJECTIVES: Angiotensin I-converting enzyme (ACE) plays crucial roles not only in the regulation of circulatory homeostasis but also in the pathology of carcinomas. An insertion-deletion (I/D) polymorphism in intron 16 of ACE gene was identified to be functional. We aimed to investigate the association between ACE I/D polymorphism and risk of colorectal cancer (CRC). DESIGN AND METHODS: Using genomic DNA from 241 CRC patients and 299 control subjects, we genotyped the ACE I/D polymorphism using a polymerase chain reaction analysis. RESULTS: We found that patients carrying the D allele were associated with an increased risk of developing poorly differentiated cancer and metastasis compared with those carrying the I allele (OR=1.54, 95%CI, 1.04-2.28; OR=1.56, 95%CI, 1.08-2.26, respectively), although no significant association was observed between cases and controls in overall analysis. CONCLUSIONS: These findings indicate that the ACE I/D polymorphism is likely to play a role in CRC progression.

Interleukin-6 -174G/C polymorphism and the risk of Alzheimer's disease in Caucasians: a meta-analysis.

Interleukin-6 (IL-6), identified as a pleiotropic inflammatory cytokine, plays important roles in the acute inflammatory response and in the modulation of the neuroimmune response. To date, large amounts of epidemiological studies have been performed to investigate the association between the IL-6 -174G/C polymorphism and Alzheimer's disease (AD) risk. Inconclusive results, however, have been reported. We aimed to assess the effect of the IL-6 -174G/C polymorphism on AD susceptibility with the use of a meta-analysis. 14 studies involving 3769 cases of AD and 9431 control subjects were identified by a search of Pubmed, Embase and ISI Web of Science databases. Crude odds ratios (ORs) with 95% confidence intervals (CIs) for the IL-6 -174G/C polymorphism and AD risk were computed using fixed- or random-effects model when appropriate. Obvious heterogeneity among studies was detected, and a borderline statistically significant association was observed between the IL-6 -174G/C polymorphism and AD risk in Caucasians (GG vs. CC: OR=1.35, 95%CI, 1.06-1.72; GG/GC vs. CC: OR=1.27, 95%CI, 1.05-1.53, respectively). After exclusion of one study, the heterogeneity disappeared and no significant association was observed between the polymorphism and AD risk. These findings indicate that the IL-6 -174G/C polymorphism may not be an independent risk factor for the development of AD.