Research Spotlight

Zhao, Q., Zhang, L., Hai, B., Wang, J., Baetge, C.L., Deveau, M.A., Kapler, G.M., Feng, J.Q. and Liu, F. (2020). “Transient Activation of the Hedgehog-Gli Pathway Rescues Radiotherapy-Induced Dry Mouth via Recovering Salivary Gland Resident Macrophages.” Cancer Res 80(24): 5531-5542.

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Irreversible hypofunction of salivary glands is a common side effect of radiotherapy for head and neck cancer and is difficult to remedy. Recent studies indicate that transient activation of Hedgehog signaling rescues irradiation-impaired salivary function in animal models, but the underlying mechanisms are largely unclear. Here, we show in mice that activation of canonical Gli-dependent Hedgehog signaling by Gli1 gene transfer is sufficient to recover salivary function impaired by irradiation. Salivary gland cells responsive to Hedgehog/Gli signaling comprised small subsets of macrophages, epithelial cells, and endothelial cells, and their progeny remained relatively rare long after irradiation and transient Hedgehog activation. Quantities and activities of salivary gland resident macrophages were substantially and rapidly impaired by irradiation and restored by Hedgehog activation. Conversely, depletion of salivary gland macrophages by clodronate liposomes compromised the restoration of irradiation-impaired salivary function by transient Hedgehog activation. Single-cell RNA sequencing and qRT-PCR of sorted cells indicated that Hedgehog activation greatly enhances paracrine interactions between salivary gland resident macrophages, epithelial progenitors, and endothelial cells through Csf1, Hgf, and C1q signaling pathways. Consistently, expression of these paracrine factors and their receptors in salivary glands decreased following irradiation but were restored by transient Hedgehog activation. These findings reveal that resident macrophages and their prorepair paracrine factors are essential for the rescue of irradiation-impaired salivary function by transient Hedgehog activation and are promising therapeutic targets of radiotherapy-induced irreversible dry mouth. SIGNIFICANCE: These findings illuminate a novel direction for developing effective treatment of irreversible dry mouth, which is common after radiotherapy for head and neck cancer and for which no effective treatments are available.

Eaton, B.C., Vesselinov, R., Ahmeti, M., Stansbury, J.J., Regner, J., Sadler, C., Nevarez, S., Lissauer, M., Stout, L., Harmon, L., Glassett, B., Hampton, D.A., Castro, H.J., Cunningham, K., Mulkey, S., O’Meara, L., Dia, J.J. and Bruns, B.R. (2020). “Surgical Faculty Perception of Service-Based Advanced Practice Provider Impact: A Southwestern Surgical Congress Multicenter Survey.” Am Surg Dec 9;3134820956929. [Epub ahead of print].

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BACKGROUND: A previous single-center survey of trauma and general surgery faculty demonstrated perceived positive impact of trauma and surgical subspecialty service-based advanced practice providers (SB APPs). The aim of this multicenter survey was to further validate these findings. METHODS: Faculty surgeons on teams that employ SB APPs at 8 academic centers completed an electronic survey querying perception about advanced practice provider (APP) competency and impact. RESULTS: Respondents agreed that SB APPs decrease workload (88%), length of stay (72%), contribute to continuity (92%), facilitate care coordination (87%), enhance patient satisfaction (88%), and contribute to best practice/safe patient care (83%). Fewer agreed that APPs contribute to resident education (50%) and quality improvement (QI)/research (36%). Although 93% acknowledged variability in the APP level of function, 91% reported trusting their clinical judgment. CONCLUSION: This study supports the perception that SB APPs have a positive impact on patient care and quality indicators. Areas for potential improvement include APP contribution to resident education and research/QI initiatives.

Azarpazhooh, A., Diogenes, A.R., Fouad, A.F., Glickman, G.N., Kishen, A., Levin, L., Roda, R.S., Sedgley, C.M., Tay, F.R. and Hargreaves, K.M. (2020). “Insights into the December 2020 Issue of the JOE.” J Endod 46(12): 1809-1810.

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Welcome to the December 2020 issue of the 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 the JOE. [No abstract; excerpt from Editorial.].

Godot, V., Tcherakian, C., Gil, L., Cervera-Marzal, I., Li, G., Cheng, L., Ortonne, N., Lelièvre, J.D., Pantaleo, G., Fenwick, C., Centlivre, M., Mouquet, H., Cardinaud, S., Zurawski, S.M., Zurawski, G., Milpied, P., Su, L. and Lévy, Y. (2020). “TLR-9 agonist and CD40-targeting vaccination induces HIV-1 envelope-specific B cells with a diversified immunoglobulin repertoire in humanized mice.” PLoS Pathog 16(11): e1009025.

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The development of HIV-1 vaccines is challenged by the lack of relevant models to accurately induce human B- and T-cell responses in lymphoid organs. In humanized mice reconstituted with human hematopoietic stem cells (hu-mice), human B cell-development and function are impaired and cells fail to efficiently transition from IgM B cells to IgG B cells. Here, we found that CD40-targeted vaccination combined with CpG-B adjuvant overcomes the usual defect of human B-cell switch and maturation in hu-mice. We further dissected hu-B cell responses directed against the HIV-1 Env protein elicited by targeting Env gp140 clade C to the CD40 receptor of antigen-presenting cells. The anti-CD40.Env gp140 vaccine was injected with CpG-B in a homologous prime/boost regimen or as a boost of a NYVAC-KC pox vector encoding Env gp140 clade C. Both regimens elicited Env-specific IgG-switched memory hu-B cells at a greater magnitude in hu-mice primed with NYVAC-KC. Single-cell RNA-seq analysis showed gp140-specific hu-B cells to express polyclonal IgG1 and IgG3 isotypes and a broad Ig VH/VL repertoire, with predominant VH3 family gene usage. These cells exhibited a higher rate of somatic hypermutation than the non-specific IgG+ hu-B-cell counterpart. Both vaccine regimens induced splenic GC-like structures containing hu-B and hu-Tfh-like cells expressing PD-1 and BCL-6. We confirmed in this model that circulating ICOS+ memory hu-Tfh cells correlated with the magnitude of gp140-specific B-cell responses. Finally, the NYVAC-KC heterologous prime led to a more diverse clonal expansion of specific hu-B cells. Thus, this study shows that CD40-targeted vaccination induces human IgG production in hu-mice and provides insights for the development of a CD40-targeting vaccine to prevent HIV-1 infection in humans.

Harris, M.C., Hedrick, B.N., Zide, J.R., Thomas, D.M., Shivers, C., Seibert, M., Pierce, W.A., Kanaan, Y. and Riccio, A.I. (2020). “Effect of Lateral Column Lengthening on Subtalar Motion in a Cadaveric Model[Formula: see text].” Foot Ankle Int Nov 17;1071100720970189. [Epub ahead of print.]. 1071100720970189.

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BACKGROUND: Although lengthening of the lateral column through a calcaneal neck osteotomy is an integral component of flatfoot reconstruction in younger patients with flexible planovalgus deformities, concern exists as to the effect of this intra-articular osteotomy on subtalar motion. The purpose of this study was to quantify the alterations in subtalar motion following lateral column lengthening (LCL). METHODS: The subtalar motion of 14 fresh-frozen cadaveric feet was assessed using a 3-dimensional motion capture system and materials testing system (MTS). Following potting of the tibia and calcaneus, optic markers were placed into the tibia, calcaneus, and talus. The MTS was used to apply a rotational force across the subtalar joint to a torque of 5 Nm. Abduction/adduction, supination/pronation, and plantarflexion/dorsiflexion about the talus were recorded. Specimens then underwent LCL via a calcaneal neck osteotomy, which was maintained with a 12-mm porous titanium wedge. Repeat subtalar motion analysis was performed and compared to pre-LCL motion using a paired t test. RESULTS: No statistically significant differences in subtalar abduction/adduction (10.9 vs 11.8 degrees, P = .48), supination/pronation (3.5 vs 2.7 degrees, P = .31), or plantarflexion/dorsiflexion (1.6 vs 1.0 degrees, P = .10) were identified following LCL. CONCLUSION: No significant changes in subtalar motion were observed following lateral column lengthening in this biomechanical cadaveric study. CLINICAL RELEVANCE: Although these findings do not obviate concerns of clinical subtalar stiffness following lateral column lengthening for planovalgus deformity correction, they suggest that diminished postoperative subtalar motion, when it occurs, may be due to soft tissue scarring rather than alterations of joint anatomy.