Research Spotlight

Park, Y.J., Derderian, C. and Oppedisano, M. (2021). “Interdisciplinary Approach for the Treatment of Complex Bilateral Cleft Lip and Palate With Missing Premaxilla.” Cleft Palate Craniofac J Jun 23;10556656211023241. [Epub ahead of print]. 10556656211023241.

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Complex craniofacial deformities such as complete bilateral cleft lip and palate require interdisciplinary approach for proper diagnosis and treatment. A severe skeletal discrepancy caused by bilateral cleft lip and palate and missing premaxilla was successfully managed with orthodontic preparation and distraction osteogenesis. Conventional prosthodontic treatment combined with orthodontic preparation was proven to be a viable option to manage multiple missing teeth in cleft lip and palate.

Liang, Y., Hu, Z., Li, Q. and Liu, X. (2021). “Pyrophosphate inhibits periodontal ligament stem cell differentiation and mineralization through MAPK signaling pathways.” J Periodontal Res Jun 17. [Epub ahead of print].

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BACKGROUND AND OBJECTIVE: Periodontal ligament stem cells (PDLSCs) are the primary cell source for the regeneration and remodeling of periodontal ligament (PDL). It is crucial to prevent PDLSCs from mineralization when using the PDLSCs for PDL regeneration. At present, little is known about how to inhibit PDLSC mineralization. This study investigates the effects of pyrophosphate (PPi) on inhibiting PDLSC osteogenic differentiation and mineralization as well as the underlying mechanism. MATERIALS AND METHODS: Human PDLSCs were cultured in an osteogenic differentiation medium with different PPi concentrations (0, 10, or 100 μM). The effects of PPi on osteogenic differentiation were assessed by ALP activity and the expressions of osteogenic related proteins (OPN, RUNX2, OSX, and DMP1). The mineralization formation was detected by alizarin red staining. The activation of MAPK signaling pathways (ERK1/2, JNK, and p38) was determined by western blotting and pathway blockade assays. The gene expressions of PPi’s regulators (Ank, Enpp1, and Alpl) were assessed by real-time PCR. RESULTS: Both low and high concentrations (10 μM and 100 μM) of PPi inhibited the mineralization of PDLSCs. The addition of PPi (10 μM or 100 μM) decreased the ALP activity of the PDLSCs to approximately two-thirds of the control group on day 3. PPi reduced the expressions of RUNX2, OSX, and DMP1 on days 7, 14, and 21, while it increased the expression of OPN at the three time points. PPi enhanced the phosphorylation of MAPK pathways, and the application of corresponding MAPK pathway inhibitors reversed the osteogenic inhibition effects of PPi. CONCLUSION: PPi inhibits the osteogenic differentiation and mineralization of PDLSCs in vitro through activating ERK1/2, JNK, and p38 signaling pathways.

Warner, B.E., Yee, M.B., Zhang, M., Hornung, R.S., Kaufer, B.B., Visalli, R.J., Kramer, P.R., Goins, W.F. and Kinchington, P.R. (2021). “Varicella-zoster virus early infection but not complete replication is required for the induction of chronic hypersensitivity in rat models of postherpetic neuralgia.” PLoS Pathog 17(7): e1009689.

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Herpes zoster, the result of varicella-zoster virus (VZV) reactivation, is frequently complicated by difficult-to-treat chronic pain states termed postherpetic neuralgia (PHN). While there are no animal models of VZV-induced pain following viral reactivation, subcutaneous VZV inoculation of the rat causes long-term nocifensive behaviors indicative of mechanical and thermal hypersensitivity. Previous studies using UV-inactivated VZV in the rat model suggest viral gene expression is required for the development of pain behaviors. However, it remains unclear if complete infection processes are needed for VZV to induce hypersensitivity in this host. To further assess how gene expression and replication contribute, we developed and characterized three replication-conditional VZV using a protein degron system to achieve drug-dependent stability of essential viral proteins. Each virus was then assessed for induction of hypersensitivity in rats under replication permissive and nonpermissive conditions. VZV with a degron fused to ORF9p, a late structural protein that is required for virion assembly, induced nocifensive behaviors under both replication permissive and nonpermissive conditions, indicating that complete VZV replication is dispensable for the induction of hypersensitivity. This conclusion was confirmed by showing that a genetic deletion recombinant VZV lacking DNA packaging protein ORF54p still induced prolonged hypersensitivities in the rat. In contrast, VZV with a degron fused to the essential IE4 or IE63 proteins, which are involved in early gene regulation of expression, induced nocifensive behaviors only under replication permissive conditions, indicating importance of early gene expression events for induction of hypersensitivity. These data establish that while early viral gene expression is required for the development of nocifensive behaviors in the rat, complete replication is dispensable. We postulate this model reflects events leading to clinical PHN, in which a population of ganglionic neurons become abortively infected with VZV during reactivation and survive, but host signaling becomes altered in order to transmit ongoing pain.

Panetta, J.C., Liu, Y., Bottiglieri, T., Arning, E., Cheng, C., Karol, S.E., Yang, J.J., Zhou, Y., Inaba, H., Pui, C.H., Jeha, S. and Relling, M.V. (2021). “Pharmacodynamics of cerebrospinal fluid asparagine after asparaginase.” Cancer Chemother Pharmacol Jun 25. [Epub ahead of print].

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PURPOSE: We evaluated effects of asparaginase dosage, schedule, and formulation on CSF asparagine in children with acute lymphoblastic leukemia (ALL). METHODS: We evaluated CSF asparagine (2114 samples) and serum asparaginase (5007 samples) in 482 children with ALL treated on the Total XVI study (NCT00549848). Patients received one or two 3000 IU/m(2) IV pegaspargase doses during induction and were then randomized in continuation to receive 2500 IU/m(2) or 3500 IU/m(2) IV intermittently (four doses) on the low-risk (LR) or continuously (15 doses) on the standard/high risk (SHR) arms. A pharmacokinetic-pharmacodynamic model was used to estimate the duration of CSF asparagine depletion below 1 uM. RESULTS: During induction, CSF asparagine depletion after two doses of pegaspargase was twice as long as one dose (median 30.7 vs 15.3 days, p < 0.001). During continuation, the higher dose increased the CSF asparagine depletion duration by only 9% on the LR and 1% in the SHR arm, consistent with the nonlinear pharmacokinetics of serum asparaginase. Pegaspargase caused a longer CSF asparagine depletion duration (1.3-5.3-fold) compared to those who were switched to erwinase (p < 0.001). The median (quartile range) serum asparaginase activity needed to maintain CSF asparagine below 1 µM was 0.44 (0.20, 0.99) IU/mL. Although rare, CNS relapse was higher with decreased CSF asparagine depletion (p = 0.0486); there was no association with relapse at any site (p = 0.3). CONCLUSIONS: The number of pegaspargase doses has a stronger influence on CSF asparagine depletion than did dosage, pegaspargase depleted CSF asparagine longer than erwinase, and CSF asparagine depletion may prevent CNS relapses.

Aminoshariae, A., Azarpazhooh, A., Diogenes, A.R., Fouad, A.F., Glickman, G.N., Kishen, A., Letra, A.M., Levin, L., Roda, R.S., Setzer, F.C., Tay, F.R. and Hargreaves, K.M. (2021). “Insights into the July 2021 Issue of the Journal of Endodontics.” J Endod 47(7): 1043-1045.

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Welcome to the July 2021 issue of the Journal of Endodontics (JOE). Here we share some of our favorite articles that are published in this issue of the journal. We hope you look forward to reading these and other articles in JOE.