Endodontic microsurgery and prosthodontic treatment of a permanent anterior concrescence: A case report.

Concrescence is a rare dental anomaly in which two adjacent teeth are united only by their cementum. Concrescence most frequently occurs in molars, especially a third mandibular molar and a supernumerary tooth. It is rarely seen in the maxillary anterior teeth. This case report is the first in the literature which details the successful treatment of a concrescence between the maxillary central incisor and a supernumerary tooth through multidisciplinary therapy. The treatment plan included root canal treatment, endodontic microsurgery, and prosthodontic treatment.

A Collaborative Assembly Strategy for Tumor-Targeted siRNA Delivery.

A novel "collaborative assembly" approach was reported for the synthesis of an siRNA delivery system via a combination of an electrostatically driven physical assembly and a facile click reaction-mediated chemical assembly, which showed various advantages of more safety, efficiency, and flexibility over the conventional approach that is only based on the physical assembly. This strategy remained a high cationic property of lipid-based complex for high siRNA loading capacity. The direct chemical modification of a model polyanion, hyaluronic acid (HA) on the cationic complex via click chemistry shielded the positive charge of complex without affecting the siRNA binding, which reduced the toxicity and enhanced the blood stability of the complex. In addition, the incorporated polyanion might be prefunctionalized, which endued the carrier with better biological characteristics such as long circulating or tumor targeting. We demonstrated that the obtained lipid-polymer hybrid nanoparticle (RSC-HA) using collaborative assembly presented greater in vivo stability in the blood for efficient tumor targeting than the physically assembled RSC/HA in which HA was physically adsorbed on the complex. After endocytosis into the cells, the protection of RSC-HA on siRNA turned off, while the release of siRNA induced by the intracellular signals for enhanced gene-silencing capacity. This combination of physical and chemical assemblies provides an efficient strategy for the exploitation of safe, stable, and functionalized siRNA delivery systems.

Association between type 1 diabetes mellitus and ankylosing spondylitis: a two-sample Mendelian randomization study.

Objective: The development of ankylosing spondylitis (AS) is closely related to autoimmune system dysfunction. Type 1 diabetes mellitus (T1DM) is an autoimmune disease that is a risk factor for many diseases. This study aimed to investigate the causal relationship between T1DM mellitus and AS genetically. Methods: A genome-wide association study (GWAS) of causal relationships between exposure (T1DM) and outcome (AS) was performed using summary data from the GWAS database. We conducted a two-sample Mendelian randomization (MR) study of these two diseases. Inverse variance weighting (IVW) was used as the primary analysis method, with MR Egger, weighted median, and weighted mode used as supplementary methods. Sensitivity analyses were performed using Cochran's Q test, MR-Egger intercept, MR-Pleiotropy RESidual Sum and outlier methods, leave-one-out analysis, and funnel plots. Results: A total of 11 single nucleotide polymorphisms (SNPs)were identified for instrumental variables(IVs) for MR analysis.IVW found that T1DM was causally associated with AS ((IVW: OR = 1.0006 (95% CI 1.0001, 1.0011), p = 0.0057; MR-Egger: OR = 1.0003 (95% CI 0.9995, 1.0012), p = 0.4147; weighted median: OR = 1.0006 (95% CI 1.0003, 1.0008), p = 0.0001; weighted mode: OR = 1.0007 (95% CI 1.0005, 1.0009), p = 0.0001). No horizontal pleiotropy was found for the MR-Egger intercept, and leave -one-out analysis found that the results remained stable after the removal of individual SNPs. Conclusion: The results of the two-sample MR analysis supported a causal relationship between T1DM and AS risk.

Biomimetic Macroporous PCL Scaffolds for Ex Vivo Expansion of Cord Blood-Derived CD34+ Cells with Feeder Cells Support.

Ex vivo expansion of hematopoietic stem cells (HSCs) with most current methods can hardly satisfy clinical application requirement. While in vivo, HSCs efficiently self-renew in niche where they interact with 3D extracellular matrix and stromal cells. Therefore, co-cultures of CD34+ cells and mesenchyme stem cells derived from human amniotic membrane (hAMSCs) on the basis of biomimetic macroporous three-dimensional (3D) poly(ε-caprolactone) (PCL) scaffolds are developed, where scaffolds and hAMSCs are applied to mimic structural and cellular microenvironment of HSCs. The influence of scaffolds, feeder cells, and contact manners on expansion and stemness maintenance of CD34+ cells is investigated in this protocol. Biomimetic scaffolds-dependent co-cultures of CD34+ cells and hAMSCs can effectively promote the expansion of CD34+ cells; meanwhile, indirect contact is superior to direct contact. The combination of biomimetic scaffolds and hAMSCs represents a new strategy for achieving clinical-scale ex vivo expansion of CD34+ cells.

Co-delivery of paclitaxel and anti-survivin siRNA via redox-sensitive oligopeptide liposomes for the synergistic treatment of breast cancer and metastasis.

The overexpression of survivin in breast cancer cells is an important factor of paclitaxel (PTX) resistance in breast cancer. To overcome PTX resistance and improve the antitumor effect of PTX, we developed a novel liposome-based nanosystem (PTX/siRNA/SS-L), composed of a redox-sensitive cationic oligopeptide lipid (LHSSG2C14) with a proton sponge effect, natural soybean phosphatidylcholine (SPC), and cholesterol for co-delivery of PTX and anti-survivin siRNA, which could specifically downregulate survivin overexpression. PTX/siRNA/SS-L exhibited high encapsulation efficiency and rapid redox-responsive release of both PTX and siRNA. Moreover, in vitro studies on the 4T1 breast cancer cells revealed that PTX/siRNA/SS-L offered significant advantages over other experimental groups, such as higher cellular uptake, successful endolysosomal escape, reduced survivin expression, the lowest cell viability and wound healing rate, as well as the highest apoptosis rate. In particular, in vivo evaluation of 4T1 tumor-bearing mice showed that PTX/siRNA/SS-L had lower toxicity and induced a synergistic inhibitory effect on tumor growth and pulmonary metastasis. Collectively, the collaboration of anti-survivin siRNA and PTX via redox-sensitive oligopeptide liposomes provides a promising strategy for the treatment of breast cancer and metastasis.

Intracellular delivery and antitumor effects of pH-sensitive liposomes based on zwitterionic oligopeptide lipids.

pH-sensitive liposomes (HHG2C(18)-L and PEGHG2C(18)-L) based on zwitterionic oligopeptide lipids as anticancer drug carriers were developed and evaluated for effective intracellular delivery and enhanced antitumor activity. The amino acid-based lipids, 1,5-dioctadecyl-l-glutamyl 2-histidyl-hexahydrobenzoic acid (HHG2C(18)) and 1,5-distearyl N-(N-α-(4-mPEG2000) butanedione)-histidyl-l-glutamate (PEGHG2C(18)), were synthesized, which have the multistage pH-response to tumor microenvironmental pH (pH(e), pH 6.0-7.0) and endosomal/lysosomal pH (pH(i), pH 4.0-6.0) successively. HHG2C(18)-L contains HHG2C(18), while PEGHG2C(18)-L includes HHG2C(18) and PEGHG2C(18). Both of them displayed the capability of charge conversion to the surrounding pH. The zeta potentials of HHG2C(18)-L and PEGHG2C(18)-L were negative at pH 7.4, whereas positive at pH 6.5 and more positive at lower pH. Coumarin 6-loaded HHG2C(18)-L (C6/HHG2C(18)-L) and PEGHG2C(18)-L (C6/PEGHG2C(18)-L) showed higher tumor cellular uptake due to electrostatic absorptive endocytosis at pH(e) (pH 6.5), produced proton sponge effect for endo-lysosomal escape, and accumulated to the mitochondria based on stronger positive charge by the hydrolysis of a pH-sensitive linker at pH(i) (pH 5.5 and pH 4.5). Furthermore, temsirolimus (CCI-779)-loaded HHG2C(18)-L (CCI-779/HHG2C(18)-L) and PEGHG2C(18)-L (CCI-779/PEGHG2C(18)-L) had significantly higher antiproliferative and apoptosis inducing effects toward the human renal carcinoma (A498) cells at pH 6.5 relative to that at pH 7.4. The half maximal inhibitory concentration (IC50) of CCI-779/HHG2C(18)-L and CCI-779/PEGHG2C(18)-L were about 3 µg/mL and 5 µg/mL at pH 6.5, 1.67-fold and 1.60-fold improved relative to that at pH 7.4, respectively. The total apoptotic ratio of CCI-779/HHG2C(18)-L and CCI-779/PEGHG2C(18)-L increased from 9.90% and 7.78% at pH 7.4 to 19.53% and 12.10% at pH 6.5, respectively. In vivo, CCI-779/PEGHG2C(18)-L after intravenous administration presented remarkably higher bioavailability and blood persistence compared with unPEGylated CCI-779/HHG2C(18)-L, and had the strongest antitumor efficacy against xenograft renal cancer (Renca) tumor models. Accordingly, the results provide the feasibility of using pH-sensitive zwitterionic oligopeptide lipids to extend the applications of liposomes to efficient anticancer drug delivery in cancer therapy.

Multistage pH-responsive liposomes for mitochondrial-targeted anticancer drug delivery.

Zwitterionic oligopeptide liposomes (HHG2C(18)-L) containing a smart lipid (1,5-dioctadecyl-L-glutamyl 2-histidyl-hexahydrobenzoic acid, HHG2C(18)) are developed to overcome the barriers faced by anticancer drugs on the route from the site of injection into the body to the final antitumor target within transport steps with multiple physiological and biological barriers. HHG2C(18)-L show the multistage pH-responsive to the tumor cell (the mitochondria in this case). Their multistage pH response leads to more effective entry of the tumor cell, improved escape from the endolysosomes, and accumulation at the mitochondria (see picture).