Adenoid cystic carcinoma (ACC) is a rare malignant tumor derived mainly from the salivary glands, representing approximately 1% of all head and neck carcinomas and 10% of all salivary gland neoplasms. ACC displays a paradoxical behavioral combination of an indolent growth pattern but an aggressive progression, with local recurrence and distant metastasis. The propensity of ACC of the head and neck (ACCHN) for perineural invasion and its anatomical location, especially if it extends to the nasal cavity and paranasal sinuses, facilitates tumor involvement in the surrounding structures, such as the orbit, pterygopalatine fossa, Meckel's cave, and cavernous sinus, which can lead to skull base involvement and intracranial extension. Despite advances in molecular mechanisms and diagnostic imaging, ACC treatment remains challenging due to the lack of consensus on treatment patterns. In this review, we aimed to provide an updated insight into the understanding of ACCHN by focusing on clinical behavior, imaging diagnosis, pathological features, and therapeutic strategies. We reviewed the molecular mechanisms, especially in ACCHN with perineural invasion, and elaborated on treatment options, including chemotherapy, targeted therapies, and immunotherapy, to establish a comprehensive understanding of ACC to arrive at a policy for proper diagnosis, preoperative evaluation, and therapeutic strategies. 

Current opinions on diagnosis and treatment of adenoid cystic carcinoma.

Cancer of the salivary glands is one of the five major types of head and neck cancer. Due to radioresistance and a strong propensity for metastasis, the survival rate for nonresectable malignant tumors is dismal. Hence, more research is needed on salivary cancer's pathophysiology, particularly at the molecular level. The microRNAs (miRNAs) are a type of noncoding RNA that controls as many as 30% of all genes that code for proteins at the posttranscriptional level. Signature miRNA expression profiles have been established in several cancer types, suggesting a role for miRNAs in the incidence and progression of human malignancies. Salivary cancer tissues were shown to have significantly aberrant levels of miRNAs compared to normal salivary gland tissues, supporting the hypothesis that miRNAs play a crucial role in the carcinogenesis of salivary gland cancer (SGC). Besides, several SGC research articles reported potential biomarkers and therapeutic targets for the miRNA-based treatment of this malignancy. In this review, we will explore the regulatory impact of miRNAs on the processes underlying the molecular pathology of SGC and provide an up-to-date summary of the literature on miRNAs that impacted this malignancy. We will eventually share information about their possible use as diagnostic, prognostic, and therapeutic biomarkers in SGC. 

miRNAs orchestration of salivary gland cancer- Particular emphasis on diagnosis, progression, and drug resistance.

Diabetes mellitus is a common disease affecting more than 537 million adults worldwide. The microvascular complications that occur during the course of the disease are widespread and affect a variety of organ systems in the body. Diabetic retinopathy is one of the most common long-term complications, which include, amongst others, endothelial dysfunction, and thus, alterations in the blood-retinal barrier (BRB). This particularly restrictive physiological barrier is important for maintaining the neuroretina as a privileged site in the body by controlling the inflow and outflow of fluid, nutrients, metabolic end products, ions, and proteins. In addition, people with diabetic retinopathy (DR) have been shown to be at increased risk for systemic vascular complications, including subclinical and clinical stroke, coronary heart disease, heart failure, and nephropathy. DR is, therefore, considered an independent predictor of heart failure. In the present review, the effects of diabetes on the retina, heart, and kidneys are described. In addition, a putative common microRNA signature in diabetic retinopathy, nephropathy, and heart failure is discussed, which may be used in the future as a biomarker to better monitor disease progression. Finally, the use of miRNA, targeted neurotrophin delivery, and nanoparticles as novel therapeutic strategies is highlighted.

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The Protective Effects of Neurotrophins and MicroRNA in Diabetic Retinopathy, Nephropathy and Heart Failure via Regulating Endothelial Function

Salivary gland tumors (SGTs) include a large group of rare neoplasms in the head and neck region, and the heterogeneous and overlapping features among the subtypes frequently make diagnostic difficulties. There is an urgent need to understand the cellular mechanisms underlying the heterogeneity and overlap among the subtypes, and explore the subtype-specific diagnostic biomarkers.The tumor tissue and the adjacent normal tissue from the 6 most common types of SGTs were processed for organoid culture which only maintained tumor epithelial cells. Organoids were histologically evaluated based on phenotype markers, followed by transcriptional profiling using RNA-sequencing. The transcriptomic similarities and differences among the subtypes were analyzed by subtype consensus clustering and hierarchical clustering. Furthermore, by comparative transcriptional analysis for these 6 types of SGTs and the matched organoids, the potential diagnostic biomarkers from tumor epithelium were identified, in which two selected biomarkers were evaluated by qPCR and confirmed by immunohistochemistry staining using a tissue microarray.We generated a biobank of patient-derived organoids (PDOs) with 6 subtypes of SGTs, including 21 benign and 24 malignant SGTs. The PDOs recapitulated the morphological and transcriptional characteristics of the parental tumors. The overlap in the cell types and the heterogenous growth patterns were observed in the different subtypes of organoids. Comparing the bulk tissues, the cluster analysis of the PDOs remarkably revealed the epithelial characteristics, and visualized the intrinsic relationship among these subtypes. Finally, the exclusive biomarkers for the 6 most common types of SGTs were uncovered by comparative analysis, and PTP4A1 was demonstrated as a useful diagnostic biomarker for mucoepidermoid carcinoma.We established the first organoid biobank with multiple subtypes of SGTs. PDOs of SGTs recapitulate the morphological and transcriptional characteristics of the original tumors, which uncovers subtype-specific biomarkers and reveals the molecular distance among the subtype of SGTs. 

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An organoid library of salivary gland tumors reveals subtype-specific characteristics and biomarkers

Simple Summary Salivary glands carcinoma are prevalent in head and neck surgical oncology practice. The treatment is challenging due to late diagnosis and high recurrence risk. The epigenetic event is one of the most important etiologies known for this cancer. At present, numerous pathways and epigenetic alteration has been identified. This epigenetic event may serve as a novel avenue for the development of effective diagnostic and therapeutic agents at near future. This will enhance the management of this type of cancer. In this review, we discuss the main epigenetic events in salivary gland carcinogenesis and highlight their roles in the prognostication and refined management of this cancer. Abstract Salivary gland carcinomas (SGCs) are a diverse collection of malignant tumors with marked differences in biological activity, clinical presentation and microscopic appearance. Although the etiology is varied, secondary radiation, oncogenic viruses as well as chromosomal rearrangements have all been linked to the formation of SGCs. Epigenetic modifications may also contribute to the genesis and progression of SGCs. Epigenetic modifications are any heritable changes in gene expression that are not caused by changes in DNA sequence. It is now widely accepted that epigenetics plays an important role in SGCs development. A basic epigenetic process that has been linked to a variety of pathological as well as physiological conditions including cancer formation, is DNA methylation. Transcriptional repression is caused by CpG islands hypermethylation at gene promoters, whereas hypomethylation causes overexpression of a gene. Epigenetic changes in SGCs have been identified, and they have been linked to the genesis, progression as well as prognosis of these neoplasms. Thus, we conduct a thorough evaluation of the currently known evidence on the involvement of epigenetic processes in SGCs.

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The Epigenesis of Salivary Glands Carcinoma: From Field Cancerization to Carcinogenesis

Salivary gland neoplasms (SGN) remain a diagnostic dilemma due to their heterogenic complex behavior. Their diverse histomorphological appearance is attributed to the underlying cellular mechanisms and differentiation into various histopathological subtypes with overlapping fea-tures. Diagnostic tools such as fine needle aspiration biopsy, computerized tomography, magnetic resonance imaging, and positron emission tomography help evaluate the structure and assess the staging of SGN. Advances in molecular pathology have uncovered genetic patterns and oncogenes by immunohistochemistry, fluorescent in situ hybridization, and next-generation sequencing, that may potentially contribute to innovating diagnostic approaches in identifying various SGN. Surgical resection is the principal treatment for most SGN. Other modalities such as radiotherapy, chemotherapy, targeted therapy (agents like tyrosine kinase inhibitors, monoclonal antibodies, and proteasome inhibitors), and potential hormone therapy may be applied, depending on the clinical behaviors, histopathologic grading, tumor stage and location, and the extent of tissue invasion. This review delves into the molecular pathways of salivary gland tumorigenesis, highlighting recent diagnostic protocols that may facilitate the identification and management of SGN.

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An Overview on the Histogenesis and Morphogenesis of Salivary Gland Neoplasms and Evolving Diagnostic Approaches.

With the prevalence of eye diseases, such as cataracts, retinal degenerative diseases, and glaucoma, different treatments including lens replacement, vitrectomy, and stem cell transplantation have been developed; however, they are not without their respective shortcomings. For example, current methods to seal corneal incisions induced by cataract surgery, such as suturing and stromal hydration, are less than ideal due to the potential for surgically induced astigmatism or wound leakage. Vitrectomy performed on patients with diabetic retinopathy requires an artificial vitreous substitute, with current offerings having many shortcomings such as retinal toxicity. The use of stem cells has also been investigated in retinal degenerative diseases; however, an optimal delivery system is required for successful transplantation. The incorporation of hydrogels into ocular therapy has been a critical focus in overcoming the limitations of current treatments. Previous reviews have extensively documented the use of hydrogels in drug delivery; thus, the goal of this review is to discuss recent advances in hydrogel technology in surgical applications, including dendrimer and gelatin-based hydrogels for ocular adhesives and a variety of different polymers for vitreous substitutes, as well as recent advances in hydrogel-based retinal pigment epithelium (RPE) and retinal progenitor cell (RPC) delivery to the retina.

Recent Advances in Hydrogels: Ophthalmic Applications in Cell Delivery, Vitreous Substitutes, and Ocular Adhesives

The craniofacial region hosts a variety of stem cells, all isolated from different sources of bone and cartilage. However, despite scientific advancements, their role in tissue development and regeneration is not entirely understood. The goal of this review is to discuss recent advances in stem cell tracking methods and how these can be advantageously used to understand oro-facial tissue development and regeneration. Stem cell tracking methods have gained importance in recent times, mainly with the introduction of several molecular imaging techniques, like optical imaging, computed tomography, magnetic resonance imaging, and ultrasound. Labelling of stem cells, assisted by these imaging techniques, has proven to be useful in establishing stem cell lineage for regenerative therapy of the oro-facial tissue complex. Novel labelling methods complementing imaging techniques have been pivotal in understanding craniofacial tissue development and regeneration. These stem cell tracking methods have the potential to facilitate the development of innovative cell-based therapies.

Athena Wang

Papers

An Overview on the Histogenesis and Morphogenesis of Salivary Gland Neoplasms and Evolving Diagnostic Approaches.

Recent Advances in Hydrogels: Ophthalmic Applications in Cell Delivery, Vitreous Substitutes, and Ocular Adhesives

Tracking of Oral and Craniofacial Stem Cells in Tissue Development, Regeneration, and Diseases