B7-H3×4-1BB bispecific antibody augments antitumor immunity by enhancing terminally differentiated CD8+ tumor-infiltrating lymphocytes.

Cancer immunotherapy with 4-1BB agonists has limited further clinical development because of dose-limiting toxicity. Here, we developed a bispecific antibody (bsAb; B7-H3×4-1BB), targeting human B7-H3 (hB7-H3) and mouse or human 4-1BB, to restrict the 4-1BB stimulation in tumors. B7-H3×m4-1BB elicited a 4-1BB-dependent antitumor response in hB7-H3-overexpressing tumor models without systemic toxicity. BsAb primarily targets CD8 T cells in the tumor and increases their proliferation and cytokine production. Among the CD8 T cell population in the tumor, 4-1BB is solely expressed on PD-1+Tim-3+ "terminally differentiated" subset, and bsAb potentiates these cells for eliminating the tumor. Furthermore, the combination of bsAb and PD-1 blockade synergistically inhibits tumor growth accompanied by further increasing terminally differentiated CD8 T cells. B7-H3×h4-1BB also shows antitumor activity in h4-1BB-expressing mice. Our data suggest that B7-H3×4-1BB is an effective and safe therapeutic agent against B7-H3-positive cancers as monotherapy and combination therapy with PD-1 blockade.

EGGTART: A tool to visualize the dynamics of biophysical transport under the inhomogeneous l-TASEP.

The totally asymmetric simple exclusion process (TASEP), which describes the stochastic dynamics of interacting particles on a lattice, has been actively studied over the past several decades and applied to model important biological transport processes. Here, we present a software package, called EGGTART (Extensive GUI gives TASEP-realization in Real Time), which quantifies and visualizes the dynamics associated with a generalized version of the TASEP with an extended particle size and heterogeneous jump rates. This computational tool is based on analytic formulas obtained from deriving and solving the hydrodynamic limit of the process. It allows an immediate quantification of the particle density, flux, and phase diagram, as a function of a few key parameters associated with the system, which would be difficult to achieve via conventional stochastic simulations. Our software should therefore be of interest to biophysicists studying general transport processes and can in particular be used in the context of gene expression to model and quantify mRNA translation of different coding sequences.

Combined effects of simvastatin and enamel matrix derivative on odontoblastic differentiation of human dental pulp cells.

INTRODUCTION: We previously reported that simvastatin and enamel matrix derivative (EMD) have a dentinogenic effect. However, there is little information about the combined effects of these 2 agents on odontoblastic differentiation. The aim of this study was to investigate the effects of combined treatment with simvastatin and EMD on odontoblastic differentiation of human dental pulp cells (hDPCs). This study further explored the role of extracellular signal-regulated kinase (ERK) as a target and mediator of the differentiation induced by simvastatin in hDPCs. METHODS: The odontoblastic differentiation was analyzed by alkaline phosphatase activity, real-time polymerase chain reaction (PCR) for odontoblastic/osteoblastic markers (ie, dentin sialophosphoprotein, dentin matrix protein 1, and osteonectin), and alizarin red S staining. We also explored the role of ERK signaling as a mediator of simvastatin by Western blotting and real-time PCR. The expression of osteoblast-specific transcription factors was detected by reverse-transcription PCR. RESULTS: The alkaline phosphatase activity and the expression of odontoblastic markers (ie, dentin sialophosphoprotein and dentin matrix protein 1) increased in simvastatin/EMD-treated cells. Mineralized nodule formation increased in EMD- and simvastatin/EMD-treated cells. Notably, the combined use of both simvastatin and EMD resulted in more potent differentiation than that observed after a single therapy. Simvastatin activated ERK phosphorylation and treatment with ERK inhibitor blocked the messenger RNA expression of odontoblastic markers. However, in simvastatin/EMD-treated cells, the expression of these genes did not decrease significantly. Compared with other groups, the EMD- and simvastatin/EMD-treated group showed a greater expression of osterix. CONCLUSIONS: Simvastatin promotes odontoblastic differentiation of hDPCs via the ERK signaling pathway. In addition, simvastatin-induced differentiation is facilitated by co-treatment with EMD. Collectively, these results suggest a new strategy to induce odontoblastic differentiation of hDPCs.

Chemical interaction of alexidine and sodium hypochlorite.

INTRODUCTION: Recent studies have reported the color change and formation of precipitates containing para-chloroaniline (PCA) after a reaction of sodium hypochlorite (NaOCl) and chlorhexidine (CHX). Alexidine (ALX), a biguanide disinfectant similar to CHX, has greater affinity for bacterial virulence factors than CHX. This study determined by electrospray ionization mass spectrometry (ESI-MS) and scanning electron microscopy (SEM) whether the chemical interaction between ALX and NaOCl results in PCA or precipitates. METHODS: ESI-MS was performed on 4 different concentrations of ALX (1%, 0.5%, 0.25%, and 0.125%) with 4% NaOCl to detect the presence of PCA. As control groups, 1% ALX, 0.5% PCA, and a mixture of 2% CHX and 4% NaOCl were analyzed. The formation of precipitates on the dentinal surfaces of premolar root canals treated with the solutions of ALX and NaOCl (AN) or CHX and NaOCl (CN) was observed by SEM and the color change in the reaction solutions was also analyzed. RESULTS: ESI-MS showed that the peak (mass/charge ratio = 128.026) in the PCA spectrum was not detected in any of the 4 AN solutions, whereas the peak was found in the CN solution. SEM revealed precipitates covering dentinal surfaces in the CN solution. The AN solutions produced no precipitate. The AN solutions changed in color from light yellow to transparent with decreasing ALX concentration, whereas peach-brown discoloration was observed in the CN solution. CONCLUSIONS: The interaction of ALX and NaOCl did not produce PCA or precipitates, and the color of the reacted solution changed transparent with decreasing ALX concentration.

Mesiobuccal root canal anatomy of Korean maxillary first and second molars by cone-beam computed tomography.

OBJECTIVE: The aim of this study was to investigate the types of canal configurations and the incidence of a second mesiobuccal (MB2) canal in Korean maxillary molar mesiobuccal (MB) roots by analyzing cone-beam computed tomographic (CBCT) images. STUDY DESIGN: Three-dimensional CBCT images of 458 maxillary first molars and 467 second molars from 276 Korean patients were analyzed to determine the incidence of an MB2 canal, the types of canal configurations, and the correlations between the incidence of an MB2 canal and age, gender, and tooth position. RESULTS: The incidence of 2-canaled MB roots was 71.8% in first molars and 42.2% in second molars, with the most common configurations being Weine types III and II. The frequency of an MB2 canal decreased with age in both molars (P < .05). CONCLUSIONS: Types III and II canal configurations were the most prevalent in the 2-canaled MB roots of Korean maxillary molars.

A comparison of nickel-titanium rotary instruments manufactured using different methods and cross-sectional areas: ability to resist cyclic fatigue.

OBJECTIVE: This study examined the effect of the manufacturing methods (ground, electropolished, and twisted) and the cross-sectional area (CSA) of nickel-titanium (NiTi) rotary instruments on their cyclic fatigue resistance. STUDY DESIGN: A total of 80 NiTi rotary instruments (ISO 25/.06 taper) from 4 brands (K3, ProFile, RaCe, and TF) were rotated in a simulated root canal with pecking motion until fracture. The number of cycles to failure (NCF) was calculated. The CSA at 3 mm from the tip of new instruments of each brand was calculated. The correlation between the CSA and NCF was evaluated. All fractured surfaces were analyzed using a scanning electron microscope to determine the fracture mode. RESULTS: The TF instruments were the most resistant to fatigue failure. The resistance to cyclic failure increased with decreasing CSA. All fractured surfaces showed the coexistence of ductile and brittle properties. CONCLUSION: The CSA had a significant effect on the fatigue resistance of NiTi rotary instruments.

Chlorhexidine gluconate attenuates the ability of lipoteichoic acid from Enterococcus faecalis to stimulate toll-like receptor 2.

Chlorhexidine gluconate (CHX) has been widely used as a canal irrigant or an intracanal medicament on account of its antibacterial substantivity. This in vitro study aimed to determine if CHX attenuates the inflammatory activity of Enterococcus faecalis and its major virulence factor, lipoteichoic acid (LTA). An enzyme-linked immunosorbent assay showed that CHX-killed E. faecalis was less potent than heat-killed E. faecalis in the production of tumor necrosis factor alpha (TNF-alpha) by a murine macrophage cell line, RAW 264.7 (p < 0.05). Interestingly, pretreatment of LTA with 2% CHX for 6 hours or with 0.2% CHX for 24 hours almost eliminated the TNF-alpha inducibility (p < 0.05). Furthermore, CHX abrogated the ability of LTA to stimulate Toll-like receptor 2, resulting in the attenuated induction of TNF-alpha expression. Collectively, our results suggest that CHX can inactivate LTA of E. faecalis leading to the alleviation of inflammatory responses induced by E. faecalis and its LTA.