Identification of novel susceptibility loci for non-syndromic cleft lip with or without cleft palate.

Although several genome-wide association studies (GWAS) of non-syndromic cleft lip with or without cleft palate (NSCL/P) have been reported, more novel association signals are remained to be exploited. Here, we performed an in-depth analysis of our previously published Chinese GWAS cohort study with replication in an extra dbGaP case-parent trios and another in-house Nanjing cohort, and finally identified five novel significant association signals (rs11119445: 3' of SERTAD4, P = 6.44 × 10-14 ; rs227227 and rs12561877: intron of SYT14, P = 5.02 × 10-13 and 2.80 × 10-11 , respectively; rs643118: intron of TRAF3IP3, P = 4.45 × 10-6 ; rs2095293: intron of NR6A1, P = 2.98 × 10-5 ). The mean (standard deviation) of the weighted genetic risk score (wGRS) from these SNPs was 1.83 (0.65) for NSCL/P cases and 1.58 (0.68) for controls, respectively (P = 2.67 × 10-16 ). Rs643118 was identified as a shared susceptible factor of NSCL/P among Asians and Europeans, while rs227227 may contribute to the risk of NSCL/P as well as NSCPO. In addition, sertad4 knockdown zebrafish models resulted in down-regulation of sox2 and caused oedema around the heart and mandibular deficiency, compared with control embryos. Taken together, this study has improved our understanding of the genetic susceptibility to NSCL/P and provided further clues to its aetiology in the Chinese population.

GSH/pH Dual Activatable Cross-linked and Fluorinated PEI for Cancer Gene Therapy Through Endogenous Iron De-Hijacking and in Situ ROS Amplification.

Ferroptosis-related cancer therapy is limited by insufficient Fe2+ /Fe3+ redox pair and hydrogen peroxide (H2 O2 ) for producing lethal hydroxyl radicals (·OH). Although exogenous iron or ROS-producing drugs can enhance ferroptosis, exploiting endogenous iron (labile iron pool, LIP) stored in ferritin and promoting ROS generation may be safer. Herein, a metal/drug-free nanomedicine is developed for responsive LIP release and H2 O2 generation on the mitochondria membranes, amplifying hydroxyl radical production to enhance ferroptosis-mediated antitumor effects. A glutathione(GSH)/pH dual activatable fluorinated and cross-linked polyethyleneimine (PEI) with dialdehyde polyethylene glycol layer nanocomplex loaded with MTS-KR-SOD (Mitochondria-targeting-sequence-KillerRed-Superoxide Dismutase) and CRISPR/Cas9-CA IX (Carbonic anhydrase IX (CA IX)) plasmids (FP@MC) are developed for enhanced ferroptosis through endogenous iron de-hijacking and in situ ROS amplification. Two plasmids are constructed to knockdown CA IX and translate KillerRed-SOD recombinant protein specifically on mitochondria membranes, respectively. The CA IX knockdown acidifies the intracellular environment, leading the release of LIP from ferritin as a "flare" to initiate endogenous chemodynamic therapy. Meanwhile, MTS-KR-SOD generates H2 O2 when irradiated by a 590 nm laser to assist chemodynamic therapy, leading to ROS amplification for mitochondria damage and lipid peroxide accumulation. The combined therapeutic effects aggravate cancer ferroptosis and suppress tumor growth, providing a new paradigm for amplifying ROS and iron ions to promote ferroptosis-related cancer therapy.

MMP-9 -1562C>T contributes to periodontitis susceptibility.

AIM: The study was conducted to explore the potential association of Matrix metalloproteinases (MMP)-9 -1562C>T with susceptibility to periodontitis. MATERIALS AND METHODS: Electronic literature searches of PubMed, EMBASE and EBSCO databases were performed. Fixed-effects or random-effects models were used to calculate the pooled odds ratios (ORs) for four genetic comparisons. RESULTS: Seven eligible studies with a total of 628 cases and 689 controls were recruited in the pooled analysis. We found MMP-9 -1562C>T contributed to decreased risk of chronic periodontitis. Furthermore, the polymorphism was associated with modified risk of periodontitis among Caucasian populations. CONCLUSIONS: This study indicated that MP-9 -1562C>T might be involved in the development of periodontitis. A replication of our results in independent large analysis populations is necessary to give evidence to our observation.

Interleukin-10 gene polymorphisms and chronic/aggressive periodontitis susceptibility: a meta-analysis based on 14 case-control studies.

Interleukin-10 (IL-10) has been described as an anti-inflammatory cytokine and IL-10 gene polymorphisms was associated with altered interleukin-10 levels, therefore, we aimed to conduct a meta-analysis assessing the association of IL-10 genetic polymorphisms with the risk of both chronic periodontitis (CP) and aggressive periodontitis (AgP). Electronic databases were acquired from PubMed, Embase, the Sinomed and WANFANG. Fourteen studies with 1438 patients and 1303 control subjects investigated the association of the three single-nucleotide polymorphisms (SNPs) of IL-10 (-1082A>G, -819C>T, -592C>A) and chronic/aggressive periodontitis risk were brought into this study. We found that there was no association between IL-10 -1082 gene polymorphism and periodontitis risk (either CP or AgP), even when we separately investigated sub-group analysis among Caucasians. The -819 polymorphism seemed to be a genetic risk factor to CP among Caucasians (T allele vs. C allele: OR=1.55, 95%CI=1.07-2.24; CT vs. CC: OR=1.64, 95%CI=1.00-2.67). When excluding one study deviated from HWE, the results showed that the T allele carriers had a significantly risk of CP in overall population (T allele vs. C allele: OR=1.23, 95%CI=1.03-1.48). Furthermore, the results of this meta-analysis showed that -592 polymorphism was associated with a significantly increased risk of CP (A allele vs. C allele: OR=1.38, 95%CI=1.04-1.85; AA vs. CA+CC: OR=1.39, 95%CI=1.05-1.85 for overall analysis; A allele vs. C allele: OR=1.97, 95%CI=1.36-3.86; AA vs. CC: OR=3.70, 95%CI=1.32-10.39; CA vs. CC: OR=2.22, 95%CI=1.36-3.64, AA+CA vs. CC: OR=2.35, 95%CI=1.46-3.79 for Caucasian descent analysis). This meta-analysis suggested that IL-10 -819 and -592 gene polymorphisms were associated with CP, especially among Caucasians. Further research is needed to assess possible gene-gene or gene-environment-lifestyle interactions on periodontal disease..

Case report: A Chinese boy with facial dysmorphism, immunodeficiency, livedo, and short stature syndrome.

Facial dysmorphism, immunodeficiency, livedo, and short stature (FILS) syndrome is a rare autosomal recessive disease. In this study we reported the first Chinese patient with FILS syndrome. The patient had short stature and suffered from recurrent respiratory infections up to the age of 4 years. Other symptoms of the disease included livedo on the inner side of upper limbs and thigh skin, prominent forehead, low anterior and posterior hairline, short and down-slanting palpebral fissure, low-set ears, long nasal tip and columella, and a small mouth with irregular teeth. A whole exome sequencing (WES) was performed and revealed two variants within the polymerase ε (POLE) gene. One of the variants was a splicing variant (c.5811 + 2T > C) derived from the mother, while the other was a nonsense variant (c.2006G > A) derived from the father. These two variants were not reported in previous FILS syndrome cases. Therefore this case provides further insight into the POLE gene variant spectrum that enriches the clinical phenotype.

A Protein-Like Nanogel for Spinning Hierarchically Structured Artificial Spider Silk.

Spider dragline silk is draw-spun from soluble, ß-sheet-crosslinked spidroin in aqueous solution. This spider silk has an excellent combination of strength and toughness, which originates from the hierarchical structure containing ß-sheet crosslinking points, spiral nanoassemblies, a rigid sheath, and a soft core. Inspired by the spidroin structure and spider spinning process, a soluble and crosslinked nanogel is prepared and crosslinked fibers are drew spun with spider-silk-like hierarchical structures containing cross-links, aligned nanoassemblies, and sheath-core structures. Introducing nucleation seeds in the nanogel solution, and applying prestretch and a spiral architecture in the nanogel fiber, further tunes the alignment and assembly of the polymer chains, and enhances the breaking strength (1.27 GPa) and toughness (383 MJ m-3 ) to approach those of the best dragline silk. Theoretical modeling provides understanding for the dependence of the fiber's spinning capacity on the nanogel size. This work provides a new strategy for the direct spinning of tough fiber materials.

Virus-esque nucleus-targeting nanoparticles deliver trojan plasmid for release of anti-tumor shuttle protein.

Gene therapy has gathered vast interest and been proved promising and prospective. While gene therapy evolves fast, demands of high transfecting efficiency and less toxic gene vectors are not sufficiently fulfilled. The progression of materials is doing the favor from which therapeutic application benefited is helping reshape treatments of cancer. In this work, we synthesized fluorinated branched polyethylenimine (PF33) and RGD-R8-PEG-HA (RRPH). When mixed with plasmids, the PF33 could form a compact nanoparticle PFC (Fluorinated PEI/plasmid Complex) and showed high transfection efficiency (>70% in A549 cells). Peptide modification and PEGylation on HA constituted the RRPH, and coating on the PFC would enable the ultimate nanoparticle RRPHC (RRPH coating PFC Complex) achieve long-term circulation and tumor tissue-penetration while maintaining the high transfection efficiency of PFC. Observations about the behavior in cellular organisms of RRPHC revealed its nucleus-targeting tendency. The in vivo distribution images revealed the RRPHC nanoparticles, compared to HAC (HA coated PFC, used as control) could achieve extended accumulation specifically on tumor regions rather than stay in other organs. While loaded with plasmids encoding our rationally designed trojan Apoptin (pSTA), RRPHC could establish compounds for the massive production of membrane-penetrating protein. Hence these cancer-killing proteins would charge at nucleus once phosphorylated and finish the task of destruction. Both in vitro and in vivo treatment using RRPHC/pSTA nanoparticles resulted in remarkable tumor suppression and the cytotoxicity tests demonstrated its low toxicity. In summary, pSTA encapsulating RRPHC nanoparticles may have potential applications in cancer gene therapy.

PAX9 polymorphisms and susceptibility to sporadic tooth agenesis: a case-control study in southeast China.

Tooth agenesis is one of the most common developmental disorders in humans. The PAX9 gene, which plays an important role in odontogenesis, is associated with familial and sporadic tooth agenesis. A case-control study was performed in 102 subjects with tooth agenesis (cases) and 116 healthy controls. We genotyped four PAX9 gene polymorphisms using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The allele and genotype frequencies of the four polymorphisms were not significantly different between the controls and the subjects with tooth agenesis. Similar results were observed in a subgroup analysis of test subjects only with mandibular incisor agenesis. Further analysis showed no significant difference in the haplotype distribution between the controls and the subjects with tooth agenesis or mandibular incisor agenesis. However, we found that the AGGC haplotype was associated with a decreased risk of tooth agenesis, compared with the most common haplotype, AGCC (odds ratio, 0.14; 95% confidence interval: 0.00-0.95). These results suggest that the four PAX9 polymorphisms alone have a non-significant main effect on the risk of tooth agenesis but that the AGGC haplotype may have a protective effect associated with a decreased risk of tooth agenesis.

Gene therapy for human glioblastoma using neurotropic JC virus-like particles as a gene delivery vector.

Glioblastoma multiforme (GBM), the most common malignant brain tumor, has a short period of survival even with recent multimodality treatment. The neurotropic JC polyomavirus (JCPyV) infects glial cells and oligodendrocytes and causes fatal progressive multifocal leukoencephalopathy in patients with AIDS. In this study, a possible gene therapy strategy for GBM using JCPyV virus-like particles (VLPs) as a gene delivery vector was investigated. We found that JCPyV VLPs were able to deliver the GFP reporter gene into tumor cells (U87-MG) for expression. In an orthotopic xenograft model, nude mice implanted with U87 cells expressing the near-infrared fluorescent protein and then treated by intratumoral injection of JCPyV VLPs carrying the thymidine kinase suicide gene, combined with ganciclovir administration, exhibited significantly prolonged survival and less tumor fluorescence during the experiment compared with controls. Furthermore, JCPyV VLPs were able to protect and deliver a suicide gene to distal subcutaneously implanted U87 cells in nude mice via blood circulation and inhibit tumor growth. These findings show that metastatic brain tumors can be targeted by JCPyV VLPs carrying a therapeutic gene, thus demonstrating the potential of JCPyV VLPs to serve as a gene therapy vector for the far highly treatment-refractory GBM.

Association between MMP-1 g.-1607dupG polymorphism and periodontitis susceptibility: a meta-analysis.

BACKGROUND: Matrix metalloproteinase-1 (MMP-1) plays an important role during the destruction of periodontal tissue. Although multiple studies had focused on the association between MMP-1 g.-1607dupG and periodontitis susceptibility, the results remained inconclusive. The purpose of this meta-analysis was to explore its role in the development of periodontitis. METHODS: Retrieved studies from Pubmed, Web of Science, Medline and Google Scholar Search regarding MMP-1 g.-1607dupG and periodontitis susceptibility were included into the final analysis with definite selection and exclusion criteria. Overall and stratified analyses based on disease type, severity, ethnicity and smoking status were performed. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the association between MMP-1 g.-1607dupG and periodontitis susceptibility, while Q test and Egger's test were adopted respectively to assess heterogeneity among studies and publication bias. RESULTS: A total of 1580 periodontitis cases and 1386 controls in 11 case-control studies were included in the meta-analysis. The pooled results showed significant association between periodontitis susceptibility and MMP-1 g.-1607dupG polymorphism in homozygote (2G/2G versus 1G/1G, OR = 1.50, 95% CI = 1.02-2.20) and dominant model analysis (2G/2G+2G/1G versus 1G/1G, OR = 1.28, 95% CI = 1.04-1.57). For subgroups by type of periodontitis, increased risk of chronic periodontitis was observed on heterozygote (2G/1G versus 1G/1G, OR = 2.01, 95% CI = 1.58-2.56) and dominant model (OR = 1.27, 95% CI = 1.03-1.57). Furthermore, similar association was also detected in severe chronic periodontitis (2G/2G versus 1G/1G, OR = 2.15, 95% CI = 1.35-3.43; 2G/2G+2G/1G versus 1G/1G, OR = 1.64, 95% CI = 1.12-2.39; 2G/2G versus 2G/1G+1G/1G, OR = 1.86, 95% CI = 1.31-2.64). CONCLUSIONS: Our meta-analysis demonstrated that MMP-1 g.-1607dupG polymorphism was associated with chronic periodontitis, especially the severity of the disease condition.

Flock workers' exposures and respiratory symptoms in five plants.

BACKGROUND: Sentinel cases of lymphocytic bronchiolitis in flock production and coating operations triggered a five-plant study of airborne respirable dust and fiber exposures and health symptoms. METHODS: Job histories from 219 current workers were linked to a job-exposure matrix derived from personal exposure measurements of respirable dust and fibers. Univariate group comparisons and multivariate modeling tested for relations between indices of cumulative and current exposure, and respiratory and systemic symptom outcomes. RESULTS: Respiratory symptoms and repeated flu-like illnesses were associated with use of compressed air to clear equipment (blow-downs) and with respirable dust exposure (current and cumulative) after controlling for smoking. Blow-downs had an equal or greater effect than smoking status on most symptoms. CONCLUSIONS: Eliminating compressed air cleaning, engineering control of dust exposure, and respirators are needed to limit exposures to particulates. Longitudinal follow up may provide guidance for a dust or fiber level without adverse respiratory health effects.