Potential Immunohistochemical Biomarkers for Grading Oral Dysplasia: A Literature Review.

Oral cancer is a prevalent global health issue, with significant morbidity and mortality rates. Despite available preventive measures, it remains one of the most common cancers, emphasising the need for improved diagnostic and prognostic tools. This review focuses on oral potentially malignant disorders (OPMDs), precursors to oral cancer, specifically emphasising oral epithelial dysplasia (OED). The World Health Organisation (WHO) provides a three-tier grading system for OED, and recent updates have expanded the criteria to enhance diagnostic precision. In the prognostic evaluation of OED, histological grading is presently regarded as the gold standard; however, its subjectivity and unreliability in anticipating malignant transformation or recurrence pose notable limitations. The primary objective is to investigate whether specific immunohistochemical biomarkers can enhance OED grading assessment according to the WHO classification. Biomarkers exhibit significant potential for comprehensive cancer risk evaluation, early detection, diagnosis, prognosis, and treatment optimisation. Technological advancements, including sequencing and nanotechnology, have expanded detection capabilities. Some analysed biomarkers are most frequently chosen, such as p53, Ki-67, cadherins/catenins, and other proteins used to differentiate OED grades. However, further research is needed to confirm these findings and discover new potential biomarkers for precise dysplasia grading and minimally invasive assessment of the risk of malignant transformation.

RACK1 release from the Ribosome Couples Translational Regulation with Starving Signaling and Possibly Depends on Phosphorylation of Key Serine and Threonine Residues.

The balance between protein anabolism and catabolism sets the foundations on which cells build their homeostasis. RACK1 is a ribosome-associated scaffold protein involved in signal transduction. On the ribosome, RACK1 enhances specific translation. Conversely, upon growth factor/nutrient starvation, RACK1 is present in a ribosome-free form and inhibits protein synthesis. However, the precise role of RACK1 when not bound to the ribosome still requires elucidation. Here, we show that extra-ribosomal RACK1 increases LC3-II accumulation, thereby mimicking an autophagy-like phenotype. Next, based on the ribosome-bound structure of RACK1, we suggest a possible mechanism for RACK1 release from the ribosome which relies on phosphorylation of precise amino acid residues, namely Thr39, Ser63, Thr86, Ser276, Thr277, Ser278, Ser279. Specifically, by performing an unbiased in silico screening using phospho-kinase prediction tools, we propose that, upon starving, AMPK1/2, ULK1/2 and PKR are the strongest candidate protein kinases to phosphorylate RACK1. This may be relevant in the context of caloric restriction and cancer therapy, where repressing translation of specific mRNAs would open important therapeutic avenues. Overall, our work provides novel insight into RACK1 function(s) by connecting its ribosomal and extra-ribosomal activities with translation and signaling.

Ozonized Hydrogels vs. 1% Chlorhexidine Gel for the Clinical and Domiciliary Management of Peri-Implant Mucositis: A Randomized Clinical Trial.

Peri-implant mucositis consists of a reversible inflammation of peri-implant tissues characterized by bleeding on gentle probing in the absence of bone loss. Ozone therapy is being extensively studied for its efficacy in treating different dental conditions. To date, few studies have evaluated ozone as an adjunct to the oral hygiene measures of peri-implant mucositis patients. The aim of the present study is to assess the efficacy of an ozonized gel (Trial group) compared to chlorhexidine (Control group) after a domiciliary protocol of oral hygiene in a 6-month study. According to a split-mouth study design, patients were divided into Group 1 for the application of chlorhexidine gel in peri-implant mucositis sites of quadrants Q1 and Q3, whereas in quadrants Q2 and Q4, the ozonized gel was in-office administered. For Group 2, the quadrants were inverted. At baseline (T0), and after 1 (T1), 2 (T2), and 3 (T3) months, Probing Depth (PD), Plaque Index (PI), SI Suppuration Index (SI), Bleeding Score (BS) and Marginal Mucosa Condition (MMC) were measured. A statistically significant decrease was found for all the variables assessed in each group (p < 0.05), whereas significant intergroup differences were found only for PI, BoP, and BS. Accordingly, both agents tested in this study showed an efficacy in treating peri-implant mucositis. The ozonized gel deserves particular attention, considering the better outcome than chlorhexidine on specific clinical periodontal parameters, as well as its lesser shortcomings.

Latest Findings of the Regenerative Materials Application in Periodontal and Peri-Implant Surgery: A Scoping Review.

Regenerative dentistry represents a therapeutic modern approach involving biomaterials and biologics such as mesenchymal stem cells. The role of regenerative dentistry is promising in all branches of dentistry, especially in periodontology and implantology for the treatment of bony defects around teeth and implants, respectively. Due to the number of different materials that can be used for this purpose, the aim of the present review is to evidence the regenerative properties of different materials both in periodontitis and peri-implantitis as well as to compare their efficacy. Clinical trials, case-control studies, cross-sectional studies, and cohort studies have been considered in this review. The outcome assessed is represented by the regenerative properties of bone grafts, barrier membranes, and biological materials in the treatment of intrabony and furcation defects, peri-implantitis sites, alveolar ridge preservation, and implant site development. Based on the studies included, it can be stated that in the last years regenerative materials in periodontal and peri-implant defects treatments have shown excellent results, thus providing valuable support to surgical therapy. To achieve optimal and predictable results, clinicians should always consider factors like occlusal load control, prevention of microbial contamination, and wound dehiscence. Further evidence is required about the use of enamel matrix derivative in alveolar ridge preservation, as well as of stem cells and bone morphogenetic proteins-2 in furcation defects and peri-implantitis sites. Considering the high amount of research being conducted in this field, further evidence is expected to be obtained soon.

Evaluation of Adjuvant Systems in Non-Surgical Peri-Implant Treatment: A Literature Review.

Can the use of lasers, ozone, probiotics, glycine and/or erythritol, and chlorhexidine in combination with non-surgical peri-implant treatment have additional beneficial effects on the clinical parameters? Objectives: The non-surgical treatment of peri-implant pathologies is based on mechanical debridement to eliminate bacterial biofilm and reduce tissue inflammation; some additional therapies have been studied to achieve more detailed clinical results. Materials and methods: A literature search for publications until January 2022 was conducted. The research question is formulated following the Problem, Intervention, Comparison/Control, and Outcome. Studies investigating adjunctive therapies were included. Results: In total, 29 articles were included. Most of the studies did not show any additional benefit of these therapies in the evaluation of bleeding on probing, probing pocket depth, or plaque index; among the proposed treatments, the use of laser was the one most studied in the literature, with the achievement of a reduction of bleeding and pocket depth. More studies would be needed to assess the benefit of other therapies. Conclusions: This review showed no significant improvements in the state of health in support of mechanical debridement therapy. However, the few benefits found would deserve to be considered in new clinical studies.

High levels of eukaryotic Initiation Factor 6 (eIF6) are required for immune system homeostasis and for steering the glycolytic flux of TCR-stimulated CD4+ T cells in both mice and humans.

Eukaryotic Initiation Factor 6 (eIF6) is required for 60S ribosomal subunit biogenesis and efficient initiation of translation. Intriguingly, in both mice and humans, endogenous levels of eIF6 are detrimental as they act as tumor and obesity facilitators, raising the question on the evolutionary pressure that maintains high eIF6 levels. Here we show that, in mice and humans, high levels of eIF6 are required for proper immune functions. First, eIF6 heterozygous (het) mice show an increased mortality during viral infection and a reduction of peripheral blood CD4+ Effector Memory T cells. In human CD4+ T cells, eIF6 levels rapidly increase upon T-cell receptor activation and drive the glycolytic switch and the acquisition of effector functions. Importantly, in CD4+ T cells, eIF6 levels control interferon-γ (IFN-γ) secretion without affecting proliferation. In conclusion, the immune system has a high evolutionary pressure for the maintenance of a dynamic and powerful regulation of the translational machinery.

The centrosomal OFD1 protein interacts with the translation machinery and regulates the synthesis of specific targets.

Protein synthesis is traditionally associated with specific cytoplasmic compartments. We now show that OFD1, a centrosomal/basal body protein, interacts with components of the Preinitiation complex of translation (PIC) and of the eukaryotic Initiation Factor (eIF)4F complex and modulates the translation of specific mRNA targets in the kidney. We demonstrate that OFD1 cooperates with the mRNA binding protein Bicc1 to functionally control the protein synthesis machinery at the centrosome where also the PIC and eIF4F components were shown to localize in mammalian cells. Interestingly, Ofd1 and Bicc1 are both involved in renal cystogenesis and selected targets were shown to accumulate in two models of inherited renal cystic disease. Our results suggest a possible role for the centrosome as a specialized station to modulate translation for specific functions of the nearby ciliary structures and may provide functional clues for the understanding of renal cystic disease.

Preclinical demonstration of synergistic Active Nutrients/Drug (AND) combination as a potential treatment for malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a poor prognosis disease lacking adequate therapy. We have previously shown that ascorbic acid administration is toxic to MPM cells. Here we evaluated a new combined therapy consisting of ascorbate/epigallocatechin-3-gallate/gemcitabine mixture (called AND, for Active Nutrients/Drug). In vitro effects of AND therapy on various MPM cell lines revealed a synergistic cytotoxic mechanism. In vivo experiments on a xenograft mouse model for MPM, obtained by REN cells injection in immunocompromised mice, showed that AND strongly reduced the size of primary tumor as well as the number and size of metastases, and prevented abdominal hemorrhage. Kaplan Meier curves and the log-rank test indicated a marked increase in the survival of AND-treated animals. Histochemical analysis of dissected tumors showed that AND induced a shift from cell proliferation to apoptosis in cancer cells. Lysates of tumors from AND-treated mice, analyzed with an antibody array, revealed decreased TIMP-1 and -2 expressions and no effects on angiogenesis regulating factors. Multiplex analysis for signaling protein phosphorylation exhibited inactivation of cell proliferation pathways. The complex of data showed that the AND treatment is synergistic in vitro on MPM cells, and blocks in vivo tumor progression and metastasization in REN-based xenografts. Hence, the AND combination is proposed as a new treatment for MPM.

RACK1 depletion in a mouse model causes lethality, pigmentation deficits and reduction in protein synthesis efficiency.

The receptor for activated C-kinase 1 (RACK1) is a conserved structural protein of 40S ribosomes. Strikingly, deletion of RACK1 in yeast homolog Asc1 is not lethal. Mammalian RACK1 also interacts with many nonribosomal proteins, hinting at several extraribosomal functions. A knockout mouse for RACK1 has not previously been described. We produced the first RACK1 mutant mouse, in which both alleles of RACK1 gene are defective in RACK1 expression (ΔF/ΔF), in a pure C57 Black/6 background. In a sample of 287 pups, we observed no ΔF/ΔF mice (72 expected). Dissection and genotyping of embryos at various stages showed that lethality occurs at gastrulation. Heterozygotes (ΔF/+) have skin pigmentation defects with a white belly spot and hypopigmented tail and paws. ΔF/+ have a transient growth deficit (shown by measuring pup size at P11). The pigmentation deficit is partly reverted by p53 deletion, whereas the lethality is not. ΔF/+ livers have mild accumulation of inactive 80S ribosomal subunits by polysomal profile analysis. In ΔF/+ fibroblasts, protein synthesis response to extracellular and pharmacological stimuli is reduced. These results highlight the role of RACK1 as a ribosomal protein converging signaling to the translational apparatus.