Radiographic and diagnostic approaches for mandibular asymmetries in orthodontic practice: a narrative review.

Mandibular asymmetry refers to dimensional differences between the left and right sides of the mandible in terms of size, form and volume. This condition may result in problems with functionality as well as appearance. Early intervention is often deemed optimal for addressing mandibular asymmetry; however, there is a lack of consensus regarding the diagnostic approach and strategy for identifying asymmetries in developing individuals. The purpose of this narrative review (NR) is to provide a clinician-focused update on the radiographic techniques for identifying mandibular asymmetries in orthodontic patients. Selective database searches were conducted until November 2023 to assess the available literature on mandibular asymmetry diagnosis. A health-sciences librarian developed a search strategy utilizing appropriate terms associated with mandibular asymmetry diagnosis. The databases used were Web of Science, Embase, Scopus, Liliacs and PubMed. Fifty-two studies were included in this review and data regarding the evaluation of mandibular asymmetries were presented with a narrative approach delineating clinical indications based on retrieved findings. There is no unanimous consensus on the method for diagnosing mandibular asymmetries. Cone beam computed tomography emerges as the preferred examination method for diagnosing mandibular asymmetry, thanks to the assessment of a 3D structure with a 3D image. However, the use of only orthopantomography could be advisable as a first-line diagnostic tool in children due to less radiation exposure.

The Implications of Artificial Intelligence in Pedodontics: A Scoping Review of Evidence-Based Literature.

BACKGROUND: Artificial intelligence (AI) has emerged as a revolutionary technology with several applications across different dental fields, including pedodontics. This systematic review has the objective to catalog and explore the various uses of artificial intelligence in pediatric dentistry. METHODS: A thorough exploration of scientific databases was carried out to identify studies addressing the usage of AI in pediatric dentistry until December 2023 in the Embase, Scopus, PubMed, and Web of Science databases by two researchers, S.L.R. and A.L.G. RESULTS: From a pool of 1301 articles, only 64 met the predefined criteria and were considered for inclusion in this review. From the data retrieved, it was possible to provide a narrative discussion of the potential implications of AI in the specialized area of pediatric dentistry. The use of AI algorithms and machine learning techniques has shown promising results in several applications of daily dental pediatric practice, including the following: (1) assisting the diagnostic and recognizing processes of early signs of dental pathologies, (2) enhancing orthodontic diagnosis by automating cephalometric tracing and estimating growth and development, (3) assisting and educating children to develop appropriate behavior for dental hygiene. CONCLUSION: AI holds significant potential in transforming clinical practice, improving patient outcomes, and elevating the standards of care in pediatric patients. Future directions may involve developing cloud-based platforms for data integration and sharing, leveraging large datasets for improved predictive results, and expanding AI applications for the pediatric population.

Off-the-Shelf Cord-Blood Mesenchymal Stromal Cells: Production, Quality Control, and Clinical Use.

Background Recently, mesenchymal stromal cells (MSCs) have gained recognition for their clinical utility in transplantation to induce tolerance and to improve/replace pharmacological immunosuppression. Cord blood (CB)-derived MSCs are particularly attractive for their immunological naivety and peculiar anti-inflammatory and anti-apoptotic properties. OBJECTIVES: The objective of this study was to obtain an inventory of CB MSCs able to support large-scale advanced therapy medicinal product (ATMP)-based clinical trials. STUDY DESIGN: We isolated MSCs by plastic adherence in a GMP-compliant culture system. We established a well-characterized master cell bank and expanded a working cell bank to generate batches of finished MSC(CB) products certified for clinical use. The MSC(CB) produced by our facility was used in approved clinical trials or for therapeutic use, following single-patient authorization as an immune-suppressant agent. RESULTS: We show the feasibility of a well-defined MSC manufacturing process and describe the main indications for which the MSCs were employed. We delve into a regulatory framework governing advanced therapy medicinal products (ATMPs), emphasizing the need of stringent quality control and safety assessments. From March 2012 to June 2023, 263 of our Good Manufacturing Practice (GMP)-certified MSC(CB) preparations were administered as ATMPs in 40 subjects affected by Graft-vs.-Host Disease, nephrotic syndrome, or bronco-pulmonary dysplasia of the newborn. There was no infusion-related adverse event. No patient experienced any grade toxicity. Encouraging preliminary outcome results were reported. Clinical response was registered in the majority of patients treated under therapeutic use authorization. CONCLUSIONS: Our 10 years of experience with MSC(CB) described here provides valuable insights into the use of this innovative cell product in immune-mediated diseases.

Indications for Dental Specialists for Treating Obstructive Sleep Apnea with Mandibular Advancement Devices: A Narrative Review.

Obstructive sleep apnea (OSA) syndrome is characterized by repeated airway collapse during sleep. It determines cardiovascular, pulmonary, and neurocognitive consequences and is associated with several daytime and nighttime symptoms that influence the patient's quality of life. The contribution of the dental specialist in the clinical management of OSA patients entails participating in the screening process as diagnostic sentinels and providing adequate treatment using mandibular advancement devices (MADs). Since the treatment of OSA requires a multidisciplinary approach, including different medical specialists, dentists should have a comprehensive understanding of medical and dental factors that influence the strategy and effectiveness of OSA treatment with MAD. Such expertise is crucial in determining the appropriate treatment indications and helps clinicians establish a consolidated position within the multidisciplinary OSA team. In this regard, this review summarizes the evidence of the clinical indications for MAD treatment and provides the dental specialist with helpful information about medical, functional, and other relevant factors that should be considered during diagnosis, treatment plan, and follow-up stages. Information retrieved was organized and discussed, generating specific domains/queries oriented to the clinical management of OSA patients from the clinical perspective of dental specialists.

Elastodontic Appliances for the Interception of Malocclusion in Children: A Systematic Narrative Hybrid Review.

BACKGROUND: Interceptive orthodontic treatment aims to eliminate factors that prevent the harmonious development of the maxillary and mandibular arches during childhood, and elastodontic appliances (EAs) represent a group of devices with an increasingly important role. This systematic narrative hybrid review (HR) aims to provide an overview of the clinical indications for the use of EAs according to the available evidence and to identify potential research areas for unexplored applications. MATERIALS AND METHODS: To assess the available literature on the subject, selective database searches were performed between July 2023 and September 2023. With the assistance of a health sciences librarian, a search strategy that utilized terms related to elastodontic therapy was developed. Embase, Scopus, PubMed, and Web of Science were the databases used. RESULTS: The current literature addressing the usability of EAs is scarce and mostly limited to case reports and case series. After 2168 citations were found through the searches, 13 studies were ultimately included. In this regard, information about the clinical use and effectiveness of EAs are reported in a narrative form, defining specific domains of the application that are clinically oriented, including sagittal and transversal discrepancies, atypical swallowing, teeth malposition, two-phase orthodontics and a lack of teeth retention. CONCLUSIONS: Within the intrinsic quality limitation of the available literature, it seems that EAs may represent a promising treatment alternative for managing mild-to-moderate malocclusion in children as an adjuvant therapy to the interruption of spoiled habits.

Comparative Analysis of Skeletal Changes, Occlusal Changes, and Palatal Morphology in Children with Mild Class III Malocclusion Treated with Elastodontic Appliances and Bimaxillary Plates.

BACKGROUND: The aim of the present study was to compare the changes observed in children after the early treatment of mild class III malocclusion using bimaxillary removable plates supported by class III elastics and elastodontic devices. METHODS: Twenty children (mean age 7.6 ± 1.1 years) with signs of class III malocclusion were treated using by-maxillary plates (PG group) with class III elastics (10 subjects = mean age 7.9 ± 1.3 years) or using class III elastodontic devices (EG group) (10 subjects = mean age 7.4 ± 0.8 years). Digital models and lateral cephalograms were obtained before treatment (T0) and at the end of treatment (T1). The digital models were analyzed to assess occlusal changes and maxillary morphology using the surface-to-surface matching technique. Changes in cephalometric parameters were also analyzed. The data outcomes were statistically analyzed using the paired Student's t test for inter-timing assessments and the independent Student's t test for inter-group assessments. RESULTS: Both groups showed correction of class III malocclusions, with a significant increase in the ANB angle and the overjet (p < 0.05). Subjects in the PG group exhibited a greater reduction in the inter-incisal angle compared to the EG group (p < 0.05). The children in the EG group had a significantly lower percentage of palatal morphology matching between T0 and T1 compared to the PG group (p < 0.05), suggesting greater morphological changes in the palate. CONCLUSIONS: Elastodontic appliances (EAs) and bi-maxillary plates successfully correct class III malocclusions in children. However, elastodontic devices significantly improved the morphology of the palate, both in the transverse and anteroposterior directions.

Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK.

Neurofibromatosis Type 2 (NF2) is an autosomal dominant genetic syndrome caused by mutations in the NF2 tumor suppressor gene resulting in multiple schwannomas and meningiomas. There are no FDA approved therapies for these tumors and their relentless progression results in high rates of morbidity and mortality. Through a combination of high throughput screens, preclinical in vivo modeling, and evaluation of the kinome en masse, we identified actionable drug targets and efficacious experimental therapeutics for the treatment of NF2 related schwannomas and meningiomas. These efforts identified brigatinib (ALUNBRIG®), an FDA-approved inhibitor of multiple tyrosine kinases including ALK, to be a potent inhibitor of tumor growth in established NF2 deficient xenograft meningiomas and a genetically engineered murine model of spontaneous NF2 schwannomas. Surprisingly, neither meningioma nor schwannoma cells express ALK. Instead, we demonstrate that brigatinib inhibited multiple tyrosine kinases, including EphA2, Fer and focal adhesion kinase 1 (FAK1). These data demonstrate the power of the de novo unbiased approach for drug discovery and represents a major step forward in the advancement of therapeutics for the treatment of NF2 related malignancies.

Funding community collaboration to develop effective therapies for neurofibromatosis type 1 tumors.

The time from identifying a drug target to a new drug approval is often measured in decades and can take even longer for therapies to treat rare diseases. In fact, 95% of rare diseases do not have a specific therapy approved at all. Coordinated efforts to augment the drug development pipeline along with long-term and comprehensive support that enable scientific breakthroughs for rare diseases are possible, but it requires integration across multiple stakeholders. This article analyzes the coordinated funding efforts of four federal and philanthropic organizations to advance drug development for neurofibromatosis type 1-associated tumors and discusses how these organizations have been collaborating and evolved practices to optimize funding and research support.

Probing the chemical-biological relationship space with the Drug Target Explorer.

Modern phenotypic high-throughput screens (HTS) present several challenges including identifying the target(s) that mediate the effect seen in the screen, characterizing 'hits' with a polypharmacologic target profile, and contextualizing screen data within the large space of drugs and screening models. To address these challenges, we developed the Drug-Target Explorer. This tool allows users to query molecules within a database of experimentally-derived and curated compound-target interactions to identify structurally similar molecules and their targets. It enables network-based visualizations of the compound-target interaction space, and incorporates comparisons to publicly-available in vitro HTS datasets. Furthermore, users can identify molecules using a query target or set of targets. The Drug Target Explorer is a multifunctional platform for exploring chemical space as it relates to biological targets, and may be useful at several steps along the drug development pipeline including target discovery, structure-activity relationship, and lead compound identification studies.

Traditional and systems biology based drug discovery for the rare tumor syndrome neurofibromatosis type 2.

Neurofibromatosis 2 (NF2) is a rare tumor suppressor syndrome that manifests with multiple schwannomas and meningiomas. There are no effective drug therapies for these benign tumors and conventional therapies have limited efficacy. Various model systems have been created and several drug targets have been implicated in NF2-driven tumorigenesis based on known effects of the absence of merlin, the product of the NF2 gene. We tested priority compounds based on known biology with traditional dose-concentration studies in meningioma and schwann cell systems. Concurrently, we studied functional kinome and gene expression in these cells pre- and post-treatment to determine merlin deficient molecular phenotypes. Cell viability results showed that three agents (GSK2126458, Panobinostat, CUDC-907) had the greatest activity across schwannoma and meningioma cell systems, but merlin status did not significantly influence response. In vivo, drug effect was tumor specific with meningioma, but not schwannoma, showing response to GSK2126458 and Panobinostat. In culture, changes in both the transcriptome and kinome in response to treatment clustered predominantly based on tumor type. However, there were differences in both gene expression and functional kinome at baseline between meningioma and schwannoma cell systems that may form the basis for future selective therapies. This work has created an openly accessible resource (www.synapse.org/SynodosNF2) of fully characterized isogenic schwannoma and meningioma cell systems as well as a rich data source of kinome and transcriptome data from these assay systems before and after treatment that enables single and combination drug discovery based on molecular phenotype.

Cutaneous neurofibromas in the genomics era: current understanding and open questions.

Cutaneous neurofibromas (cNF) are a nearly ubiquitous symptom of neurofibromatosis type 1 (NF1), a disorder with a broad phenotypic spectrum caused by germline mutation of the neurofibromatosis type 1 tumour suppressor gene (NF1). Symptoms of NF1 can include learning disabilities, bone abnormalities and predisposition to tumours such as cNFs, plexiform neurofibromas, malignant peripheral nerve sheath tumours and optic nerve tumours. There are no therapies currently approved for cNFs aside from elective surgery, and the molecular aetiology of cNF remains relatively uncharacterised. Furthermore, whereas the biallelic inactivation of NF1 in neoplastic Schwann cells is critical for cNF formation, it is still unclear which additional genetic, transcriptional, epigenetic, microenvironmental or endocrine changes are important. Significant inroads have been made into cNF understanding, including NF1 genotype-phenotype correlations in NF1 microdeletion patients, the identification of recurring somatic mutations, studies of cNF-invading mast cells and macrophages, and clinical trials of putative therapeutic targets such as mTOR, MEK and c-KIT. Despite these advances, several gaps remain in our knowledge of the associated pathogenesis, which is further hampered by a lack of translationally relevant animal models. Some of these questions may be addressed in part by the adoption of genomic analysis techniques. Understanding the aetiology of cNF at the genomic level may assist in the development of new therapies for cNF, and may also contribute to a greater understanding of NF1/RAS signalling in cancers beyond those associated with NF1. Here, we summarise the present understanding of cNF biology, including the pathogenesis, mutational landscape, contribution of the tumour microenvironment and endocrine signalling, and the historical and current state of clinical trials for cNF. We also highlight open access data resources and potential avenues for future research that leverage recently developed genomics-based methods in cancer research.

Creating a data resource: what will it take to build a medical information commons?

National and international public-private partnerships, consortia, and government initiatives are underway to collect and share genomic, personal, and healthcare data on a massive scale. Ideally, these efforts will contribute to the creation of a medical information commons (MIC), a comprehensive data resource that is widely available for both research and clinical uses. Stakeholder participation is essential in clarifying goals, deepening understanding of areas of complexity, and addressing long-standing policy concerns such as privacy and security and data ownership. This article describes eight core principles proposed by a diverse group of expert stakeholders to guide the formation of a successful, sustainable MIC. These principles promote formation of an ethically sound, inclusive, participant-centric MIC and provide a framework for advancing the policy response to data-sharing opportunities and challenges.

A high-throughput molecular data resource for cutaneous neurofibromas.

Neurofibromatosis type 1 (NF1) is a genetic disorder with a range of clinical manifestations such as widespread growth of benign tumours called neurofibromas, pain, learning disorders, bone deformities, vascular abnormalities and even malignant tumours. With the establishment of the Children's Tumour Foundation biobank, neurofibroma samples can now be collected directly from patients to be analysed by the larger scientific community. This work describes a pilot study to characterize one class of neurofibroma, cutaneous neurofibromas, by molecularly profiling of ~40 cutaneous neurofibromas collected from 11 individual patients. Data collected from each tumour includes (1) SNP Arrays, (2) Whole genome sequencing (WGS) and (3) RNA-Sequencing. These data are now freely available for further analysis at http://www.synapse.org/cutaneousNF.

Neurofibromatosis as a gateway to better treatment for a variety of malignancies.

The neurofibromatoses (NF) are a group of rare genetic disorders that can affect all races equally at an incidence from 1:3000 (NF1) to a log unit lower for NF2 and schwannomatosis. Since the research community is reporting an increasing number of malignant cancers that carry mutations in the NF genes, the general interest of both the research and pharma community is increasing and the authors saw an opportunity to present a novel, fresh approach to drug discovery in NF. The aim of the paper is to challenge the current drug discovery approach to NF, whereby existing targeted therapies that are either in the clinic or on the market for other disease indications are repurposed for NF. We offer a suggestion for an alternative drug discovery approach. In the new approach, selective and tolerable targeted therapies would be developed for NF and later expanded to patients with more complex diseases such as malignant cancer in which the NF downstream pathways are deregulated. The Children's Tumor Foundation, together with some other major NF funders, is playing a key role in funding critical initiatives that will accelerate the development of better targeted therapies for NF patients, while these novel, innovative treatments could potentially be beneficial to molecularly characterized cancer patients in which NF mutations have been identified.

Recombinant Adeno Associated Viral (AAV) vector type 9 delivery of Ex1-Q138-mutant huntingtin in the rat striatum as a short-time model for in vivo studies in drug discovery.

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by dyskinesia, cognitive impairment and emotional disturbances, presenting progressive neurodegeneration in the striatum and intracellular mutant Huntingtin (mHTT) aggregates in various areas of the brain. Recombinant Adeno Associated Viral (rAAV) vectors have been successfully used to transfer foreign genes to the brain of adult animals. In the present study we report a novel in vivo rat HD model obtained by stereotaxic injection of rAAV serotype2/9 containing Exon1-Q138 mHTT (Q138) and Exon1-Q17 wild type HTT (Q17; control), respectively in the right and in the left striatum, and expressed as C-terminal GFP fusions to facilitate detection of infected cells and aggregate production. Immunohistochemical analysis of brain slices from animals sacrificed twenty-one days after viral infection showed that Q138 injection resulted in robust formation of GFP-positive aggregates in the striatum, increased GFAP and microglial activation and neurodegeneration, with little evidence of any of these events in contralateral tissue infected with wild type (Q17) expressing construct. Differences in the relative metabolite concentrations (N-Acetyl Aspartate/Creatine and Myo-Inositol/Creatine) were observed by H1 MR Spectroscopy. By quantitative RT-PCR we also demonstrated that mHTT induced changes in the expression of genes previously shown to be altered in other rodent HD models. Importantly, administration of reference compounds previously shown to ameliorate the aggregation and neurodegeneration phenotypes in preclinical HD models was demonstrated to revert the mutant HTT-dependent effects in our model. In conclusion, the AAV2/9-Q138/Q17 exon 1 HTT stereotaxic injection represents a useful first-line in vivo preclinical model for studying the biology of mutant HTT exon 1 in the striatum and to provide early evidence of efficacy of therapeutic approaches.

Novel Hits in the Correction of ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Protein: Synthesis, Pharmacological, and ADME Evaluation of Tetrahydropyrido[4,3-d]pyrimidines for the Potential Treatment of Cystic Fibrosis.

Cystic fibrosis (CF) is a lethal genetic disease caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) with a prevalence of the ΔF508 mutation. Whereas the detailed mechanisms underlying disease have yet to be fully elucidated, recent breakthroughs in clinical trials have demonstrated that CFTR dysfunction can be corrected by drug-like molecules. On the basis of this success, a screening campaign was carried out, seeking new drug-like compounds able to rescue ΔF508-CFTR that led to the discovery of a novel series of correctors based on a tetrahydropyrido[4,3-d]pyrimidine core. These molecules proved to be soluble, cell-permeable, and active in a disease relevant functional-assay. The series was then further optimized with emphasis on biological data from multiple cell systems while keeping physicochemical properties under strict control. The pharmacological and ADME profile of this corrector series hold promise for the development of more efficacious compounds to be explored for therapeutic use in CF.

A phenotypic screening assay for modulators of huntingtin-induced transcriptional dysregulation.

Huntington's Disease is a rare neurodegenerative disease caused by an abnormal expansion of CAG repeats encoding polyglutamine in the first exon of the huntingtin gene. N-terminal fragments containing polyglutamine (polyQ) sequences aggregate and can bind to cellular proteins, resulting in several pathophysiological consequences for affected neurons such as changes in gene transcription. One transcriptional pathway that has been implicated in HD pathogenesis is the CREB binding protein (CBP)/cAMP responsive element binding (CREB) pathway. We developed a phenotypic assay to screen for compounds that can reverse the transcriptional dysregulation of the pathway caused by induced mutated huntingtin protein (µHtt). 293/T-REx cells were stably co-transfected with an inducible full-length mutated huntingtin gene containing 138 glutamine repeats and with a reporter gene under control of the cAMP responsive element (CRE). One clone, which showed reversible inhibition of µHtt-induced reporter activity upon treatment with the neuroprotective Rho kinase inhibitor Y27632, was used for the development of a high-throughput phenotypic assay suitable for a primary screening campaign, which was performed on a library of 24,000 compounds. Several hit compounds were identified and validated further in a cell viability adenosine triphosphate assay. The assay has the potential for finding new drug candidates for the treatment of HD.

Fused 3-Hydroxy-3-trifluoromethylpyrazoles Inhibit Mutant Huntingtin Toxicity.

Here, we describe the selection and optimization of a chemical series active in both a full-length and a fragment-based Huntington's disease (HD) assay. Twenty-four thousand small molecules were screened in a phenotypic HD assay, identifying a series of compounds bearing a 3-hydroxy-3-trifluoromethylpyrazole moiety as able to revert the toxicity induced by full-length mutant Htt by up to 50%. A chemical exploration around the series led to the identification of compound 4f, which demonstrated to be active in a Htt171-82Q rat primary striatal neuron assay and a PC12-Exon-1 based assay. This compound was selected for testing in R6/2 mice, in which it was well-tolerated and showed a positive effect on body weight and a positive trend in preventing ventricular volume enlargment. These studies provide strong rationale for further testing the potential benefits of 3-hydroxy-3-trifluoromethylpyrazoles in treating HD.