Operator versus material influence on film thickness using adhesive resin cement or pre-heated resin composite.

OBJECTIVE: There is a growing interest in using pre-heated composites instead of dual-cured cements when luting indirect restorations. This study evaluated the film thickness obtained from two pre-heated composites and two resin cements, by two different operators. The influence of the materials and the level of expertise of the operator were analyzed. MATERIALS AND METHODS: Forty specimens of human dentin and composite discs were prepared and divided into four groups depending on the luting process. Each group was randomly equally divided to be handled by two operators with different levels of experience. Two of the initial four groups were luted using dual-cured cements and the two remaining groups using light-cured pre-heated composites. Specimen discs were cut after luting, and film thickness was measured using a Digital microscope. Data were analyzed using a 2-way ANOVA with the Holm-Sidak pairwise multiple comparison procedure (p < 0.05). RESULTS: Mean film thickness ranged from 156.16 ± 4.7 to 33.82 ± 0.7 µm. Significant differences (p < 0.001) were noticed between expert and novice results with pre-heated composites. CONCLUSION: Within the limits of this study, using pre-heated composites as a luting cement requires a better level of expertise to achieve a clinically acceptable film thickness. CLINICAL SIGNIFICANCE: Using pre-heated composites as luting agent for indirect restorations requires an experimented skill level to achieve a clinically recommended film thickness.

Induction of Antimicrobial Protein S100A15 Expression by Oral Microbial Pathogens Is Toll-like Receptors-Dependent Activation of c-Jun-N-Terminal Kinase (JNK), p38, and NF-κB Pathways.

The antimicrobial protein S100A15 belongs to the S100 family, which is differentially expressed in a variety of normal and pathological tissues. Although the function of S100A15 protein has been discussed in several studies, its induction and regulation in oral mucosa, so far, are largely unknown. In this study, we demonstrate that S100A15 is induced by the stimulation of oral mucosa with gram- or gram+ bacterial pathogens, as well as with the purified membrane components, namely lipopolysaccharides (LPS) and lipoteichoic acid (LTA). The stimulation of the human gingival fibroblast (GF) and the human mouth epidermal carcinoma (KB) cell lines with either gram- or gram+ bacterial pathogens or their purified membrane components (LPS and LTA) results in the activation of NF-κB, apoptosis-regulating kinase1 (ASK1), and MAP kinase signaling pathways including, c-Jun N-terminal kinase (JNK) and p38 together with their physiological substrates AP-1 and ATF-2, respectively. Inhibition of S100A15 by antibodies-mediated Toll-like receptor 4 (TLR4) or Toll-like receptor 2 (TLR2) neutralization reveals the induction of S100A15 protein by LPS/gram- bacterial pathogens to be TLR4- dependent mechanism, whereas induction by LTA/gram+ bacterial pathogens to be TLR2- dependent mechanism. Pre-treatment of GF and KB cells with JNK (SP600125), p38 (SB-203580), or NF-κB (Bay11-7082) specific inhibitors further demonstrates the importance of JNK, p38 and NF-κB pathways in the regulation of gram-/gram+ bacterial pathogen-induced S100A15 expression. Our data provide evidence that S100A15 is induced in cancer and non-cancer oral mucosa-derived cell lines by gram-/gram+ bacterial pathogens and provide insight into the molecular mechanisms by which gram- and gram+ bacterial pathogens induce S100A15 expression in the oral mucosa.

The Catestatin-Derived Peptides Are New Actors to Fight the Development of Oral Candidosis.

Resistance to antifungal therapy of Candida albicans and non-albicans Candida strains, frequently associated with oral candidosis, is on the rise. In this context, host-defense peptides have emerged as new promising candidates to overcome antifungal resistance. Thus, the aim of this study was to assess the effectiveness against Candida species of different Catestatin-derived peptides, as well as the combined effect with serum albumin. Among Catestatin-derived peptides, the most active against sensitive and resistant strains of C. albicans, C. tropicalis and C. glabrata was the D-isomer of Cateslytin (D-bCtl) whereas the efficiency of the L-isomer (L-bCtl) significantly decreases against C. glabrata strains. Images obtained by transmission electron microscopy clearly demonstrated fungal membrane lysis and the leakage of the intracellular material induced by the L-bCtl and D-bCtl peptides. The possible synergistic effect of albumin on Catestatin-derived peptides activity was investigated too. Our finding showed that bovine serum albumin (BSA) when combined with the L- isomer of Catestatin (L-bCts) had a synergistic effect against Candida albicans especially at low concentrations of BSA; however, no synergistic effect was detected when BSA interacted with L-bCtl, suggesting the importance of the C-terminal end of L-bCts (GPGLQL) for the interaction with BSA. In this context in vitro D-bCtl, as well as the combination of BSA with L-bCts are potential candidates for the development of new antifungal drugs for the treatment of oral candidosis due to Candida and non-Candida albicans, without detrimental side effects.

The Effectiveness of Different Irrigation Techniques on Debris and Smear Layer Removal in Primary Mandibular Second Molars: An In Vitro Study.

AIMS: The aim of the present in vitro study was to compare the effectiveness of passive ultrasonic irrigation (PUI), sonic irrigation, and mechanic dynamic activation on the removal of debris and smear layer from primary mandibular second molars during pulpectomy. MATERIALS AND METHODS: Mesial roots of 48 primary mandibular second molars were prepared with an R-motion 21 mm file (30/0.04) (FKG Dentaire SA, La Chaux-de-Fonds, Switzerland), irrigated with 1% sodium hypochlorite (NaOCl) and 17% ethylenediaminetetraacetic acid (EDTA), and divided into four groups (n = 24 canals) according to the final irrigation activation technique: control group without activation, PUI with Ultra-X (Eighteeth, Changzhou, China), mechanical activation with XP-endo Finisher (FKG), and sonic irrigation with EQ-S (Meta Biomed, Chungcheongbuk-do, Korea). The roots were split longitudinally and analyzed using scanning electron microscopy (SEM). The presence of debris and smear layer was assessed using a 5-grade scoring scale with 200× and 1000× magnification, respectively. The Kruskal-Wallis and Friedman tests were used for data analysis. RESULTS: The activation of the irrigant significantly improved debris and smear layer removal (p < 0.001). There was no significant difference between Ultra-X, XP-endo Finisher, and EQ-S (p > 0.05). No activation technique was able to completely eliminate debris and smear layer from the root canals of primary mandibular second molars. CONCLUSIONS: During pediatric pulpectomy, the irrigation protocol must include activation of the irrigation solutions using either ultrasonic, sonic, or mechanical activation techniques to enhance the removal of debris and smear layer for a better prognosis. CLINICAL SIGNIFICANCE: During root canal treatment on primary teeth, the clinician must incorporate an activation technique in the irrigation protocol to enhance the removal of debris and smear layer and increase the success of the treatment.

Microscopic and chemical evaluation of the filling quality of five obturation techniques in oval-shaped root canals.

OBJECTIVES: The aim of this study was to assess the filling quality of five obturation techniques in oval-shaped root canals. MATERIALS AND METHODS: A total of 212 mandibular first molars with one distal oval canal were selected. Distal canals, shaped with WaveOne Gold Primary, were randomly divided in five groups (n = 40) for obturation: continuous wave condensation, GuttaCore, Thermafil, single cone with AH plus, and single cone with BioRoot RCS. The proportions of gutta-percha-filled areas (GPFA), sealer-filled areas (SFA), void areas (VA), and the sealer/gutta tags into dentinal tubules at 4 mm and 2 mm from the apex were analyzed by an optical numeric microscope, SEM, and energy-dispersive X-ray (EDX). Data were then compared by Kruskal-Wallis one-way ANOVA on ranks (α = 0.05). RESULTS: At 4 mm, a statistically significant higher GPFA and lower SFA were observed in the GuttaCore and Thermafil groups compared with the 3 other groups. A statistically significant lower VA was observed in the continuous wave condensation, GuttaCore, and Thermafil groups than in the two single-cone groups. At 2 mm, there were a statistically significant higher GPFA and lower SFA and VA in GuttaCore and Thermafil groups than in the 3 other groups. At the two levels investigated, the presence of gutta-percha tags was clearly demonstrated for GuttaCore and Thermafil groups; no tags were observed in the 3 other groups. CONCLUSIONS: Obturation quality was overall improved in GuttaCore and Thermafil groups. CLINICAL RELEVANCE: Carrier-based techniques may significantly improve the filling quality compared to continuous wave condensation and single-cone technique. The single-cone technique might have inherent limitations especially in oval root canals regardless of the sealer used.

COVID-19 and Alzheimer's Disease: A Literature Review.

There are a number of potential implications for the field of Alzheimer's disease (AD) stemming from the global spread of "SARS-COV-2". Many studies that were conducted by Cleveland Clinic researchers identified a link between COVID-19 infection and brain abnormalities seen in people with AD. This article explains the association between COVID-19 and AD and how people with AD are affected by COVID-19, whether directly or indirectly. First, this article begins by explaining AD and its types, then giving an overview about COVID-19, its symptoms and the associated complications. Then, direct and indirect consequences of COVID-19 on people experiencing AD are discussed briefly. Some management strategies are recommended at the end of this article in addition to a future perspective on this topic. This article concludes by summarizing the main points mentioned about the association between COVID-19 and AD.

Does Etching of the Enamel with the Rubbing Technique Promote the Bond Strength of a Universal Adhesive System?

AIM: The aim of this in vitro research was to study the effect of etching by phosphoric acid with rubbing technique on the shear bond strength (SBS) of adhesive universal to enamel. MATERIALS AND METHODS: Sixty extracted teeth were obtained. Three application methods (self-etch, etch-and-rinse, and etch-and-rinse with rubbing technique) were performed to bond the enamel surfaces by a universal adhesive. After 24 hours of immersion in water at 37°C, the specimens were prepared for the SBS test. Scanning electron microscopy was performed to observe the adhesive-enamel interfaces. Optical numeric microscope was used to observe the failure style. Statistical analyses were done with one-way analysis of variance test. RESULTS: Statistically significant higher bond strength values were observed for etch-and-rinse mode with rubbing technique (25.98 ± 5.70) MPa then for the etch-and-rinse without rubbing (22.07 ± 5.27) MPa and self-etch modes (9.96 ± 2.98) MPa. CONCLUSION: Enamel etched by 37% phosphoric acid with rubbing technique for 20 seconds showed an increase in the SBS of the universal adhesive to enamel surfaces. The tags of the adhesive can be presented more efficiently by rubbing the acid before the bonding process, consequently, an optimal interface for the bonding. CLINICAL SIGNIFICANCE: According to the results of this in vitro study, the selective enamel etching mode with rubbing technique is advisable when using the universal adhesive, as it significantly increased the bond strength of this adhesive to enamel surfaces. The clinician should etch the enamel using phosphoric acid with rubbing technique for 20 seconds to promote the bond strength of the universal adhesive system.

An In Vivo Study: Location and Instrumentation of the Second Mesiobuccal Canal of the Maxillary Second Molar.

AIM: The first purpose of this retrospective observational in vivo study was to determine the incidence of the second mesiobuccal canal (MB2) in maxillary second molars. The second purpose was to propose a modern shaping procedure able to transform a difficult canal, like MB2, into a normal canal. MATERIALS AND METHODS: This study was led from September 2016 to December 2017, for 15 months. It was conducted on fifty-seven successive cases of root canal therapy on maxillary second molars. All procedures were done in conformity with the current state of the art practices in endodontics. These included rigorous clinical and radiographic pre-access analysis, appropriate tooth restoration to ensure watertight rubber dam installation, surgical microscopic manipulations for precision, the systematic use of ultrasonic endodontic tips to manage the access cavity preparation, and a modern step down technique to shape MB2. RESULTS: Fifty-seven maxillary second molars were treated: 3.5% had one canal, 7.0% two canals, 24.6% three canals; 64.9% four canals (MB2 presence). Weine's method was used to classify mesiobuccal root canal morphology: 27.4% had a type I canal configuration, 35.3% type II, 37.2% type III canal configuration. CONCLUSION: The perfect knowledge of endodontic anatomy, a painstaking pre-access analysis of the preoperative radiographs, the systematic identification of the CEJ, using a periodontal probe, the use of surgical microscope coupled with the use of specific endodontic ultrasonic tips and the use of a modern step-down technique allows a high accuracy of the access cavity preparation, canal localization and instrumentation. CLINICAL SIGNIFICANCE: The rate of MB2 localization and instrumentation on maxillary second molars by our surgical protocol is high. The clinician should take the necessary time to locate and negotiate the MB2. The lack of its location can provoke the failure of endodontic treatment.

Effectiveness of Etching by Three Acids on the Morphological and Chemical Features of Dentin Tissue.

AIM: The purpose of this study was to evaluate the microscopic and chemical effects of phosphoric acid gel, phosphoric acid liquid, and polyacrylic acid application for 15 seconds (s) on coronal dentin. MATERIALS AND METHODS: Twelve extracted teeth were selected. Three etching acids were used to prepare the dentin surfaces. Scanning electron microscopy (SEM) and X-ray energy dispersive spectroscopy (EDX) were used to analyze the chemical and morphological changes of the dentinal surfaces, including the depth of demineralization. Collected data were statistically analyzed by the one-way analysis of variance test. RESULTS: Dentin etched with phosphoric acid gel or liquid showed greater peritubular dentin dissolution, including complete removal of the smear layer. In addition, there were many silica particles on the dentin etched by phosphoric acid gel 37%. The dentin that was etched with 25% polyacrylic acid for 15 seconds showed no smear layer removal. Chemical analysis (EDX) showed that dental surfaces etched with phosphoric acid liquid 37% for 15 seconds showed the strongest mineral dissolution at the calcium surface, with a calcium content of 5.25%. On the other hand, EDX analysis of the dental surface etched with 25% polyacrylic acid showed more surface enrichment in calcium (17.19%). CONCLUSION: Although phosphoric acid (gel or liquid) 37% cleans the dental surface, phosphoric acid gel precipitates silica particles on the etched dentin surface. These particles cannot be removed by rinsing off this acid. The application of polyacrylic acid for 15 seconds does not noticeably demineralized dentin, nor remove the smear layer. CLINICAL SIGNIFICANCE: The clinician should use phosphoric acid (gel or liquid) to clean dental surfaces to prepare them for the bonding process. The low demineralizing effects of the polyacrylic acid permits its use near the pulp.

Effectiveness of Sectioning Method and Filling Materials on Roughness and Cell Attachments in Root Resection Procedure.

OBJECTIVES: The purpose of the present study was to investigate the created roughness and cell attachment of intact teeth (C), obturated teeth with bioceramic (BR), or epoxy resin (AH) after root resection using piezoelectric ultrasonic and carbide bur. MATERIALS AND METHODS: Three groups of first mandibular premolars were used in the present study: control group (without any preparation or obturation) (C); second group was obturated with an epoxy resin sealer (AH, AH Plus Jet); and finally, the third one was obturated with a bioceramic sealer (BR, BioRoot RCS). All teeth were incubated for 4 months at 37°C. After that, the samples were sectioned using tungsten carbide bur or piezoelectric ultrasonic. Roughness and then cell attachment of periodontal ligament cells on the sectioned surfaces were investigated by profilometer and confocal microscope, respectively. STATISTICAL ANALYSIS: Data were statistically analyzed using one-way analysis of variance. RESULTS: After root resection, no significant difference was found between the roughness among the three groups sectioned using the piezoelectric technique (p > 0.05). In contrast, concerning the sectioned samples by burs, C demonstrated a rougher surface compared with BR (p < 0.05). There was a significant higher cell attachment in BR compared with AH in the piezoelectric groups (p = 0.047), while no statistically significant difference was found between the groups sectioned with bur (p > 0.05). CONCLUSION: Dentists are now focused on the use of calcium silicate-based sealers due to their bioactivity. The present study advises dentists to use bioceramic sealer which could improve the dentin characteristics which ameliorate the cell attachment.

Aesthetical and Functional Rehabilitation for an Ankylosed Maxillary Canine-A Case Report.

Background: As the functional and aesthetical importance of the canine cannot be overstated, the management of a missing canine is challenging. This case report describes the treatment of an infra-occluded ankylosed maxillary canine in a patient with previously failed orthodontic treatment. Case description: A 20-year-old patient sought a second opinion for orthodontic treatment failure. The patient presented with an impacted, ankylosed, and severely infra-occluded right maxillary canine, as well as an iatrogenic clockwise cant of the maxillary occlusal plane and several root resorptions. The treatment corrected the cant of the occlusal plane while avoiding further root resorption, partially extracted the upper right canine, improved the quality and quantity of the soft tissue in the newly edentulous area, and provided a prosthetic rehabilitation using a lithium disilicate ceramic resin-bonded cantilever bridge. Conclusions: The use of a cantilevered bridge resulted in an aesthetically pleasing and minimally invasive rehabilitation. This technique is reversible, does not affect pulp vitality, and is a viable solution for rehabilitating the smiles of young patients. Clinical significance: The smile rehabilitation for an ankylosed maxillary canine, especially in the case of a previously failed orthodontic treatment, is an important clinical challenge. A minimally invasive long-term restoration with a cantilever bridge is a viable solution. Functional and aesthetically pleasant results can be achieved with a multidisciplinary approach.

Organotypic 3D Cellular Models Mimicking the Epithelio-Ectomesenchymal Bilayer During Odontogenesis.

Odontogenesis, the intricate process of tooth development, involves complex interactions between oral ectoderm epithelial cells and ectomesenchymal cells derived from the cephalic neural crest, regulated by major signaling pathways. Dental developmental anomalies provide valuable insights for the clinical diagnosis of rare diseases. More than 30% of patients with rare diseases who undergo molecular analysis suffer from diagnostic errancy. In the search for up-to-date technologies and methods to study the pathophysiology of new candidate genetic variants, causing tooth mineralized tissue anomalies, we have developed an original model of tooth organoids with human or mouse cell lines of ameloblast-like cells and odontoblasts derived from the pulp. This in vitro 3D cellular model reproducing the two main compartments of the bell stage of tooth development between ameloblasts and odontoblasts, specific to enamel and dentin morphogenesis, respectively, mimics the epithelial-mesenchymal interactions during the dental bell stage of tooth morphogenesis and will facilitate the study of enamel and dentin genetic anomalies, allowing the functional validation of newly identified mutations (variants of uncertain significance or new candidate genes).

Mechanical and Physicochemical Characteristics of a Novel Premixed Calcium Silicate Sealer.

The aim of the present in vitro study was to evaluate specific mechanical and physicochemical properties of three calcium silicate-based sealers, BioRoot™ Flow (BRF), CeraSeal (CRS) and TotalFill® (TF). Samples were prepared to evaluate different physicochemical and mechanical properties of the tested sealers. These evaluations were accomplished by investigating the pH changes over time, porosity, roughness, flow properties, compressive strength and wettability. The results were statistically evaluated using one-way analysis of variance. All three sealers demonstrated an alkaline pH from 1 h of immersion in water to 168 h. A higher porosity and hydrophily were detected in BRF samples compared to CRS and TF. No significant difference was found between the tested materials in the flow properties. Lower compressive strength values were observed for BRF compared to TF and CRS. Differently shaped structures were detected on the three materials after 7 days of immersion in PBS. The three materials demonstrated a higher solubility than 3% after 24 h of immersion in water (CRS < BRF < TF). The novel premixed calcium silicate sealer (BRF) had comparable physicochemical properties to the existing sealers. The lower compressive strength values could facilitate the removal of these materials during retreatment procedures. Further studies should investigate the biological effects of the novel sealer.

Warm Air Delivery in Adhesive Application: Effect on Bonding Performance and Morphological Outcomes.

Solvent evaporation within an adhesive layer is a crucial step during a bonding process. The aim of this current research was to test whether the use of different air temperatures (20 °C, 40 °C, and 60 °C) for solvent evaporation improves the performance of four adhesive systems to dentin. Sixty non-carious human molar teeth were randomly prepared for micro-tensile bond strength (µTBS) tests. Four different adhesive systems, Prime&Bond Universal (PBU), OptiBond Universal (OBU), OptiBond FL (OBFL), and Clearfil SE (CSE), were applied following the manufacturer's instructions. Three groups based on the air-drying temperature were used: solvent evaporation was performed with either of warm (40 °C), (60 °C), and cold air as control group (20 °C) for 10 s at a distance of 5 cm. In all bonded surfaces, three resin composite (Reflectys, Itena Clinical, Paris, France) layers of 2 mm thickness were built up. The resin-dentin samples were kept in distilled water at 37 °C for 24 h and 6 months, respectively, before µTBS testing. Failure analysis, scanning electron microscopy of resin-dentin bonded interface, and solvent evaporation rate were tested as secondary variables. All analyses were conducted using a significance level of α = 0.05. Bond strength (BS) values were similar among all the adhesive systems used (p > 0.05). Also, the aging factor did not affect the BS (p > 0.05). Only the factor of temperature used for solvent evaporation resulted in a statistically significant effect (p < 0.05), with the temperature of 60 °C being the highest value (p < 0.05). A failure mode evaluation revealed mostly adhesive or mixed modes of failures in all the different temperatures of air used for the solvent evaporation of each adhesive system. The thickness of the adhesive layer and the creation of resin tags varied amongst the temperatures evaluated. For all adhesive systems tested, the use of 40 °C or 60 °C air for solvent evaporation led to an increased mass loss. Warmer temperatures for solvent evaporation contributed positively to bonding performance, enhancing both the quality of the adhesive layer and its interaction with the dentin tissue. Optimizing solvent evaporation with warmer air temperatures (40 °C and 60 °C) significantly improved µTBS, offering a practical means to enhance the quality and longevity of adhesive restorations in esthetic dentistry.

Is a White Diet Necessary for Tooth Bleaching Procedures? A Systematic Review and Meta-Analysis.

The aim of this investigation was to conduct a systematic review and meta-analysis to determine the necessity of a white diet during or following a bleaching procedure. This systematic review and meta-analysis followed the PRISMA guidelines meticulously. The research question was: Is a white diet necessary during and/or after a bleaching treatment? In vitro studies or clinical trials reporting the color change in bleached enamel after the use of a free-staining diet were considered for full-text review. For the analyses, a random-effects model was employed. Statistical significance was defined as a p-value < 0.05. A total of 17 documents were eligible for qualitative analysis: 5 clinical trials and 12 in vitro studies. Only data from the clinical trials were included in the meta-analysis. For at-home bleaching, differences in the color among the subjects were not statistically significant during the first (p = 0.64), second (p = 0.26) or third (p = 0.43) weeks of treatment. Also, the color difference one month after finishing the bleaching treatment were not statistically significant (p = 0.27). The color difference one month after finishing an in-office treatment showed that the restrictions on diet did not significantly improve the bleaching outcomes (p = 0.90). According to the findings of this review, dietary restrictions are not necessary during or after bleaching procedures.

Influence of Bioceramic Cements on the Quality of Obturation of the Immature Tooth: An In Vitro Microscopic and Tomographic Study.

The present in vitro study focuses on the filling ability of three different bioceramic cements with or without the addition of a bioceramic sealer in an open apex model on the marginal apical adaptation, tubule infiltrations, and void distributions as well as the interface between the cement and the sealer materials. To this end, sixty mandibular premolars were used. MTA-Biorep (BR), Biodentine (BD), and Well-Root Putty (WR) were used to obturate the open apex model with or without the addition of a bioceramic sealer, namely TotalFill® BC sealer™ (TF). A digital optical microscope and scanning electron microscope (SEM) were used to investigate the cement-dentin interface, marginal apical adaptation, and the material infiltration into the dentinal tubules. Micro-computed X-ray tomography and digital optical microscopy were used to investigate the cement-sealer interface. The results were analyzed by using the Kruskal-Wallis test. No significant difference was found between the groups for the marginal apical adaptation quality (p > 0.05). Good adaptation of the dentin-cement interface was found for all tested groups and the sealer was placed between the cement material and dentinal walls. All the groups demonstrated some infiltrations into the dentinal tubules at the coronal part except for the BR group. A good internal interface was found between the cement and the sealer with the presence of voids at the external interface. A larger number of voids were found in the case of the BD-TF group compared to each of the other two groups (p < 0.05). Within the limitations of the present in vitro study, all the groups demonstrated good marginal apical adaptation. The use of a sealer in an open apex does not guarantee good filling and, in addition, creates voids at the external interfaces with the dental walls when the premixed sealer is used with powder-liquid cement systems. The use of a premixed bioceramic cement could offer fewer complications than when a powder-liquid cement system is used.

Mechanisms of Melanoma Progression and Treatment Resistance: Role of Cancer Stem-like Cells.

Melanoma is the third most common type of skin cancer, characterized by its heterogeneity and propensity to metastasize to distant organs. Melanoma is a heterogeneous tumor, composed of genetically divergent subpopulations, including a small fraction of melanoma-initiating cancer stem-like cells (CSCs) and many non-cancer stem cells (non-CSCs). CSCs are characterized by their unique surface proteins associated with aberrant signaling pathways with a causal or consequential relationship with tumor progression, drug resistance, and recurrence. Melanomas also harbor significant alterations in functional genes (BRAF, CDKN2A, NRAS, TP53, and NF1). Of these, the most common are the BRAF and NRAS oncogenes, with 50% of melanomas demonstrating the BRAF mutation (BRAFV600E). While the successful targeting of BRAFV600E does improve overall survival, the long-term efficacy of available therapeutic options is limited due to adverse side effects and reduced clinical efficacy. Additionally, drug resistance develops rapidly via mechanisms involving fast feedback re-activation of MAPK signaling pathways. This article updates information relevant to the mechanisms of melanoma progression and resistance and particularly the mechanistic role of CSCs in melanoma progression, drug resistance, and recurrence.

The Rogdi knockout mouse is a model for Kohlschütter-Tönz syndrome.

Kohlschütter-Tönz syndrome (KTS) is a rare autosomal recessive disorder characterized by severe intellectual disability, early-onset epileptic seizures, and amelogenesis imperfecta. Here, we present a novel Rogdi mutant mouse deleting exons 6-11- a mutation found in KTS patients disabling ROGDI function. This Rogdi-/- mutant model recapitulates most KTS symptoms. Mutants displayed pentylenetetrazol-induced seizures, confirming epilepsy susceptibility. Spontaneous locomotion and circadian activity tests demonstrate Rogdi mutant hyperactivity mirroring patient spasticity. Object recognition impairment indicates memory deficits. Rogdi-/- mutant enamel was markedly less mature. Scanning electron microscopy confirmed its hypomineralized/hypomature crystallization, as well as its low mineral content. Transcriptomic RNA sequencing of postnatal day 5 lower incisors showed downregulated enamel matrix proteins Enam, Amelx, and Ambn. Enamel crystallization appears highly pH-dependent, cycling between an acidic and neutral pH during enamel maturation. Rogdi-/- teeth exhibit no signs of cyclic dental acidification. Additionally, expression changes in Wdr72, Slc9a3r2, and Atp6v0c were identified as potential contributors to these tooth acidification abnormalities. These proteins interact through the acidifying V-ATPase complex. Here, we present the Rogdi-/- mutant as a novel model to partially decipher KTS pathophysiology. Rogdi-/- mutant defects in acidification might explain the unusual combination of enamel and rare neurological disease symptoms.

CD133-Dependent Activation of Phosphoinositide 3-Kinase /AKT/Mammalian Target of Rapamycin Signaling in Melanoma Progression and Drug Resistance.

Melanoma frequently harbors genetic alterations in key molecules leading to the aberrant activation of PI3K and its downstream pathways. Although the role of PI3K/AKT/mTOR in melanoma progression and drug resistance is well documented, targeting the PI3K/AKT/mTOR pathway showed less efficiency in clinical trials than might have been expected, since the suppression of the PI3K/mTOR signaling pathway-induced feedback loops is mostly associated with the activation of compensatory pathways such as MAPK/MEK/ERK. Consequently, the development of intrinsic and acquired resistance can occur. As a solid tumor, melanoma is notorious for its heterogeneity. This can be expressed in the form of genetically divergent subpopulations including a small fraction of cancer stem-like cells (CSCs) and non-cancer stem cells (non-CSCs) that make the most of the tumor mass. Like other CSCs, melanoma stem-like cells (MSCs) are characterized by their unique cell surface proteins/stemness markers and aberrant signaling pathways. In addition to its function as a robust marker for stemness properties, CD133 is crucial for the maintenance of stemness properties and drug resistance. Herein, the role of CD133-dependent activation of PI3K/mTOR in the regulation of melanoma progression, drug resistance, and recurrence is reviewed.

Special Issue "Recent Advances in Biomaterials and Dental Disease" Part I.

Oral cavities provide an entry point for food and nutrients [...].