Promoting Polarization and Differentiation of Primary Human Salivary Gland Stem/Progenitor Cells in Protease-Degradable Hydrogels via ROCK Inhibition.

Towards the goal of engineering of functional salivary gland tissues, we cultured primary human salivary stem/progenitor cells (hS/PCs) in hyaluronic acid-based matrices with varying percentages of proteolytically degradable crosslinks in the presence of Rho kinase (ROCK) inhibitor. Single cells encapsulated in the hydrogel grew into organized multicellular structures by day 15, and over 60% of the structures developed in the non-degradable and 50% degradable hydrogels contained a central lumen. Importantly, ROCK inhibition led to the establishment of multicellular structures that were correctly polarized, as evidenced by apical localization of a Golgi marker GM130, apical/lateral localization of tight junction protein zonula occludens-1 (ZO-1), and basal localization of integrin β1 and basement membrane proteins laminin α1 and collagen IV.

Basement Membrane Mimetic Hydrogel Cooperates with Rho-Associated Protein Kinase Inhibitor to Promote the Development of Acini-Like Salivary Gland Spheroids.

Successful engineering of functional salivary glands necessitates the creation of cell-instructive environments for expansion and lineage specification of primary human salivary gland stem cells (hS/PCs). Herein, basement membrane mimetic hydrogels were prepared using hyaluronic acid, cell adhesive peptides, and hyperbranched polyglycerol (HPG), with or without sulfate groups, to produce "hyperGel+" or "hyperGel", respectively. Differential scanning fluorescence experiments confirmed the ability of the sulphated HPG precursor to stabilize fibroblast growth factor 10.

Proposal for standardized ultrasound analysis of the salivary glands: Part 1 submandibular gland.

Objectives: The Salivary Gland Committee of the American Academy of Otolaryngology-Head and Neck Surgery seeks to standardize terminology and technique for ultrasonograpy used in the evaluation and treatment of salivary gland disorders.

Methods: Development of expert opinion obtained through interaction with international practitioners representing multiple specialties. This committee work includes a comprehensive literature review with presentation of case examples to propose a standardized protocol for the language used in ultrasound salivary gland assessment.

Matrix Degradability Contributes to the Development of Salivary Gland Progenitor Cells with Secretory Functions.

Synthetic matrices that are cytocompatible, cell adhesive, and cell responsive are needed for the engineering of implantable, secretory salivary gland constructs to treat radiation induced xerostomia or dry mouth. Here, taking advantage of the bioorthogonality of the Michael-type addition reaction, hydrogels with comparable stiffness but varying degrees of degradability (100% degradable, 100DEG; 50% degradable, 50DEG; and nondegradable, 0DEG) by cell-secreted matrix metalloproteases (MMPs) were synthesized using thiolated HA (HA-SH), maleimide (MI)-conjugated integrin-binding peptide (RGD-MI), and MI-functionalized peptide cross-linkers that are protease degradable (GIW-bisMI) or nondegradable (GIQ-bisMI). Organized multicellular structures developed readily in all hydrogels from dispersed primary human salivary gland stem cells (hS/PCs).

A TGFβR inhibitor represses keratin-7 expression in 3D cultures of human salivary gland progenitor cells.

Salivary gland tissue engineering offers an attractive alternative for the treatment of radiation-induced xerostomia. Key to the success of this approach is the maintenance and expansion of secretory acinar cells in vitro. However, recent studies revealed that in vitro culture of primary salivary gland epithelial cells led to undesirable upregulation of the expression of keratin-7 (K7), a marker of ductal phenotype and frequently associated with cellular stress.

RGDSP-Decorated Hyaluronate Hydrogels Facilitate Rapid 3D Expansion of Amylase-Expressing Salivary Gland Progenitor Cells.

engineering of salivary glands relies on the availability of synthetic matrices presenting essential cell-instructive signals to guide tissue growth. Here, we describe a biomimetic, hyaluronic acid (HA)-based hydrogel platform containing covalently immobilized bioactive peptides derived from perlecan domain IV (TWSKV), laminin-111 (YIGSR, IKVAV), and fibronectin (RGDSP). The HA network was established by the thiol/acrylate reaction, and bioactive peptides were conjugated to the network with high efficiency without significantly altering the mechanical property of the matrix.

Immunosuppressed Miniswine as a Model for Testing Cell Therapy Success: Experience With Implants of Human Salivary Stem/Progenitor Cell Constructs.

An urgent need exists to develop large animal models for preclinical testing of new cell therapies designed to replace lost or damaged tissues. Patients receiving irradiation for treatment of head and neck cancers frequently develop xerostomia/dry mouth, a condition that could one day be treated by cell therapy to repopulate functional saliva-producing cells. Using immunosuppression protocols developed for patients receiving whole face transplants, we successfully used immunosuppressed miniswine as a suitable host animal to evaluate the long-term stability, biocompatibility, and fate of matrix-modified hyaluronate (HA) hydrogel/bioscaffold materials containing encapsulated salivary human stem/progenitor cells (hS/PCs).

Novel Multidisciplinary Salivary Gland Society (MSGS) Questionnaire: An International Consensus.

Objectives: First, establishment and validation of a novel questionnaire documenting the burden of xerostomia and sialadenitis symptoms, including quality of life. Second, to compare two versions regarding the answering scale (proposed developed answers Q3 vs. 0-10 visual analogue scale Q10) of our newly developed questionnaire, in order to evaluate their comprehension by patients and their reproducibility in time.

Sialendoscopy and Sjogren's Disease: A Systematic Review.

Objectives/hypothesis: This study is a systematic review of the literature which seeks to estimate the expected treatment outcomes of a patient with Sjogren's syndrome (SS) undergoing therapeutic sialendoscopy.

Study Design: Systematic Review.

Methods: PubMed, Scopus, and Cochrane library databases were used to search for studies published as of August 2020 regarding the treatment outcomes of SS with sialendoscopy.

Salivary gland disease in the era of COVID-19 pandemic.

Coronavirus disease 2019 (COVID-19) pandemic forced significant changes in current approach to outpatient evaluation of common otolaryngology complaints as hospitals around the world are trying to limit the spread of the virus and to preserve health care resources. These changes raise a lot of questions regarding patient triage and treatment decisions in clinical situations when it is unclear if the workup and management can be postponed. In this communication, we present our approach to evaluation and triage of new patients with complaints concerning for salivary gland disease.

Dynamic Assembly of Human Salivary Stem/Progenitor Microstructures Requires Coordinated αβ Integrin-Mediated Motility.

A tissue engineering approach can provide replacement salivary gland structures to patients with hyposalivation disorders and xerostomia. Salivary human stem/progenitor cells (hS/PCs) were isolated from healthy regions of parotid glands of head and neck surgery patients, expanded, then encapsulated in biocompatible hyaluronate (HA)-based hydrogels. These bioactive hydrogels provide a surrogate territorial matrix suitable for the dynamic assembly, growth and reorganization of salivary gland components.

Serial patient-derived orthotopic xenografting of adenoid cystic carcinomas recapitulates stable expression of phenotypic alterations and innervation.

Background: Patient-derived xenograft (PDX) models have significantly enhanced cancer research, and often serve as a robust model. However, enhanced growth rate and altered pathological phenotype with serial passages have repeatedly been shown in adenoid cystic carcinoma (ACC) PDX tumors, which is a major concern.

Methods: We evaluated the fidelity of ACCs in their natural habitat by performing ACC orthotopic xenotransplantation (PDOX) in salivary glands.

Combination of post-operative radiotherapy and cetuximab for high-risk cutaneous squamous cell cancer of the head and neck: A propensity score analysis.

Objectives: The objective of this study was to investigate the safety, tolerability and preliminary efficacy of radiotherapy plus cetuximab in high risk CSCC patients.

Materials And Methods: Patients with high-risk CSCC diagnosed between 2006 and 2013 were analyzed. Patients were divided into two groups: radiotherapy alone versus radiotherapy plus cetuximab.

Bottom-up assembly of salivary gland microtissues for assessing myoepithelial cell function.

Myoepithelial cells are flat, stellate cells present in exocrine tissues including the salivary glands. While myoepithelial cells have been studied extensively in mammary and lacrimal gland tissues, less is known of the function of myoepithelial cells derived from human salivary glands. Several groups have isolated tumorigenic myoepithelial cells from cancer specimens, however, only one report has demonstrated isolation of normal human salivary myoepithelial cells needed for use in salivary gland tissue engineering applications.

Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients.

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) are important regulators of immune responses in cancer and have been directly implicated in promotion of tumor progression. However, the heterogeneity of these cells and lack of distinct markers hampers the progress in understanding of the biology and clinical importance of these cells. Using partial enrichment of PMN-MDSC with gradient centrifugation we determined that low density PMN-MDSC and high density neutrophils from the same cancer patients had a distinct gene profile.

Primary Salivary Human Stem/Progenitor Cells Undergo Microenvironment-Driven Acinar-Like Differentiation in Hyaluronate Hydrogel Culture.

Radiotherapy for head and neck cancer often has undesirable effects on salivary glands that lead to xerostomia or severe dry mouth, which can increase oral infections. Our goal is to engineer functional, three-dimensional (3D) salivary gland neotissue for autologous implantation to provide permanent relief. An immediate need exists to obtain autologous adult progenitor cells as the use of embryonic and induced pluripotent stem cells potentially pose serious risks such as teratogenicity and immunogenic rejection.

Warthin tumor within the superficial lobe of the parotid gland: a suggested criterion for diagnosis.

The location of Warthin tumor (WT) in the parotid gland impacts the surgical approach and may be indicative of the elusive origin of this intriguing entity. Location in the deep versus superficial lobe of the gland is not directly addressed when defining WT characteristics. Our observation, of rare occurrence of deep lobe WT, if at all, led to the current investigation.

Tuning Hydrogel Properties to Promote the Assembly of Salivary Gland Spheroids in 3D.

Current treatments for chronic xerostomia, or "dry mouth", do not offer long-term therapeutic benefits for head and neck cancer survivors previously treated with curative radiation. Towards the goal of creating tissue-engineered constructs for the restoration of salivary gland functions, we developed new hyaluronic acid (HA)-based hydrogels using thiolated HA (HA-SH) and acrylated HA (HA-AES) with a significant molecular weight mismatch. Four hydrogel formulations with varying HA concentration, (1-2.

Selective Targeting of Myeloid-Derived Suppressor Cells in Cancer Patients Using DS-8273a, an Agonistic TRAIL-R2 Antibody.

Myeloid-derived suppressor cells (MDSC) are one of the major contributors to immune suppression in cancer. We recently have demonstrated in preclinical study that MDSCs are sensitive to TRAIL receptor 2 (TRAIL-R2) agonist. The goal of this study was to clinically test the hypothesis that targeting TRAIL-R2 can selectively eliminate MDSCs.

Targeted Next Generation Sequencing with ThyroSeq v2.1 for Indeterminate Thyroid Nodules in Clinical Practice.

Objective: To determine if patients elect molecular testing over diagnostic surgery or repeat fine needle aspiration for indeterminate thyroid nodules. Can ThyroSeq v2.1 molecular testing reduce diagnostic thyroid surgery and rule out cancer?

Study Design: Retrospective review Setting: Single institution, single-practice surgeon.

Recurrent Benign Salivary Gland Neoplasms.

The most important causes of recurrence of benign pleomorphic adenoma are enucleation with intraoperative spillage and incomplete tumor excision in association with characteristic histologic findings for the lesion (incomplete pseudocapsule and the presence of pseudopodia). Most recurrent pleomorphic adenomas (RPAs) are multinodular. MRI is the imaging method of choice for their assessment.