How safe is off-label use of imiquimod in oral lesions?

DATA SOURCES: A comprehensive search was conducted on PubMed and Embase, adhering to the principles outlined in the PRISMA Extension for Scoping Reviews (PRISMA-ScR). The search strategy was subsequently registered on PROSPERO. STUDY SELECTION: Articles were chosen based on an analysis of titles and abstracts, with no restrictions on publication date, language, or participant age. In vitro studies, animal studies, and literature reviews were excluded from consideration. DATA EXTRACTION AND SYNTHESIS: Clinical trials in humans, case reports, or case series that reported the use of imiquimod for treating conditions in the oral or labial mucosa were included in this study. Results from duplicate articles were excluded from the analysis. RESULTS: Out of a total of 601 references initially identified, only 28 studies were included in the review. These studies were classified based on the use of imiquimod into three groups: potentially malignant disorders and oral cancer, lesions related to HPV, and autoimmune conditions. In all cases presented in the article, there is an occurrence of both local and systemic side effects. CONCLUSIONS: The study elucidated the off-label use of imiquimod in oral pathologies, whether potentially malignant, cancerous, autoimmune, or associated with HPV infection. However, it was observed that further research is warranted for the development of a specific formulation for the oral mucosa, ensuring the drug's sustained presence at its active site of action without interference from saliva and minimizing potential side effects.

Would it really be necessary to use metronidazole as an adjunct in the surgical treatment of periodontitis?

DESIGN: Prospective, parallel, randomized, double-blind, clinical trial. CASE SELECTION: Participants were at least 30 years old, who were systemically healthy, with stages III-IV, grades B-C periodontitis. DATA ANALYSIS: Of the 50 eligible individuals for the study, 40 were divided into 2 equal groups. The test group received doses of 500 mg of metronidazole, while the control group received a placebo, both administered three times a day for 7 days, commencing immediately after periodontal surgery. All patients were followed up at 3-, 6-, 9-, and 12-months post-surgery. The study utilized probing depth, clinical attachment level, bleeding on probing, and plaque index as parameters for determining the outcomes at each assessment. Microbiological samples were collected for the detection and quantification of Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Tannerella forsythia DNA. In order to analyze quantitative variables in a comparison between the test and control groups, Student's t-tests or Mann-Whitney U tests were utilized. For categorical results, chi-square or Fisher tests were employed. For both probing depth and clinical attachment level, repeated measures ANOVA was used. The statistical significance level was set at p ≤ 0.05. RESULTS: The study found statistically significant differences for probing depth (mean difference, MD = 0.31 mm, 95% confidence interval, CI [0.13; 0.49]; p = 0.001) and clinical attachment level (MD = 0.64 mm, 95% CI [0.02; 1.27]; p = 0.044) only 3 months after surgery, with a reduction observed in the test group. However, despite being statistically significant, these results lack clinical relevance. CONCLUSIONS: Although the study found statistically significant results for clinical attachment level (MD = 0.66 mm, 95% CI [0.01; 1.31]; p = 0.045) and probing depth (MD = 0.28 mm, 95% CI [0.09; 0.46]; p = 0.004), these findings do not represent clinically significant gains. Therefore, no evidence was demonstrated to support the use of systemic metronidazole as adjunctive therapy to periodontal surgery.

What is the science underpinning the prescription of antibiotics in dentistry?

DESIGN: A critical review on the use of antimicrobials in dentistry. AIM: To provide a general overview of the use of antimicrobials in dentistry. METHODS: The paper was divided into different topics, starting with an approach to understanding both commensal and pathogenic oral microbiota. Subsequently, emphasis was placed on the main categories of antibiotics used in dentistry (ß-lactams, tetracyclines, macrolides, lincosamides, nitroimidazoles and quinolones), and the basis for their prescription. Finally, the implications between systemic diseases and the use of orally-administered antibiotics are presented. RESULTS: The study suggests that an adequate medical history can minimize the risk of systemic adverse effects, unwanted drug interactions, and allergies related to the use of antibiotics. In this regard, when facing a potential history of allergy to a particular group of antibiotics, the prescription of a different group is mandatory. In most indications, ß-lactam antibiotics represent the first-choice in dentistry. Moreover, a short-term prescription of antibiotics when treating acute oral infections is recommended. The use should be extended for 2 to 3 days following the resolution of the infection, with an average duration of 6 days in order to prevent the development of antibiotic resistance. CONCLUSIONS: Oral infections should be managed with interventions aiming at the elimination/reduction of the associated pathogens. Furthermore, inadequate prescription of antibiotics can lead to potential risks to the patient such as allergy, adverse effects, and development of microbial resistance.

Is there evidence that e-cigarettes promote an increased risk of dental caries?

DATA SOURCES: This study was conducted on a sample of patients who attended the dental clinic at Tufts University School of Dental Medicine, between January 1, 2019 and January 1, 2022. Ethical approval was obtained before commencing the research. STUDY SELECTION: This cross-sectional study was carried out through an electronic search of electronic records. It includes patients aged over 16 years, both electronic cigarette (e-cigarettes) users and non-users, with recorded caries risk assessments. Patients with a history of recreational drug use or lacking a caries diagnosis were excluded. The Caries Management by Risk Assessment (CAMBRA) was utilized to indicate and classify caries risk. DATA EXTRACTION AND SYNTHESIS: Descriptive statistics, multivariate and bivariate analyzes were used to assess the relationship between use of e-cigarettes and caries risk level. SPSS software, Version 26 (IBM) was used in the analysis with significance level set at α = 0.05. RESULTS: Out of a total of 13,216 patients included in the research, 13,080 (99.3%) self-declared as non-users of e-cigarettes, and 136 (0.69%) were e-cigarette users. There was a statistically significant difference (P < 0.001) in caries risk levels between e-cigarette users (6.6% low, 14.3% moderate, and 79.1% high caries risk level) and control group (14.5% low, 25.9% moderate, and 59.6% high caries risk level). CONCLUSIONS: The study provides evidence supporting the notion that e-cigarette users exhibit a high level of caries risk.

Impacts of smoking on oral health-what is the role of the dental team in smoking cessation?

DATA SOURCES: Electronic searches were conducted on databases (PubMed, EMBASE, and Google Scholar). In addition, websites of national organisations (US Food and Drug Administration, National Cancer Institute, Centres for Disease Control and Prevention, American Dental Association, Office of Disease Prevention and Health Promotion, National Institute on Drug Abuse, Agency for Healthcare Research and Quality) were also searched. STUDY SELECTION: To achieve the objectives of the study, systematic reviews, controlled clinical trials, and observational studies published between October 2021 and February 2022 were considered. DATA EXTRACTION AND SYNTHESIS: This narrative review included articles which investigated the role of Dentistry professionals and their impact on smoking cessation and the effects resulting from tobacco use on oral health. RESULTS: The review revealed that smokers have a significantly higher likelihood of developing oral cancer (95% CI: 3.19-6.77) compared to non-smokers. Passive smokers also have an increased risk (1.51 times) of developing oral cancer (95% CI: 1.20-1.91). Additionally, smokers have an 80% increased risk of periodontitis (RR = 1.82; 95% CI: 1.43-2.31), an 85% worsened periodontal condition (RR = 1.85; 95% CI: 1.5-2.2), and a 36.6% increase in caries prevalence (OR = 1.84; 95% CI: 1.64-2.07). Smoking is also associated with a higher potential for dental implant failure in a dose-dependent manner. Brief educational interventions by the dental team resulted in a smoking cessation rate of 74/1000 individuals versus 27/1000 individuals in the control group. When combined with pharmacological therapy, these interventions may lead to an additional 50 to 70% increase in long-term smoking abstinence. CONCLUSIONS: Smoking is strongly linked to an increased risk of oral cancer, dental caries, implant failure, and periodontal disease. Dental teams play a vital role in identifying and addressing oral pathologies related to smoking and providing necessary care for smoking cessation. Brief educational interventions, either alone or in combination with pharmacotherapy, offer valuable approaches for the dental team to support smoking cessation. However, establishing a comprehensive training and continuing education program is crucial to integrate dental professionals into a multidisciplinary smoking cessation program.

Electronic nicotine delivery systems (ENDS): a strategy for smoking cessation or a new risk factor for oral health?

DATA SOURCES: A search was conducted in PubMed and Cochrane Library databases for articles published in English between January 2012 and October 2022. STUDY SELECTION: Articles were selected using both the term "electronic nicotine delivery system" (ENDS), as per the Medical Subject Heading (MeSH), in conjunction with specific oral domains. In vitro studies, animal models, unregistered clinical trials, and articles with conflicts of interest were excluded. DATA EXTRACTION AND SYNTHESIS: Clinical and public health studies comparing ENDS users, smokers, and non-smokers in the context of oral-related diseases were included. Results from duplicate articles were not considered. RESULTS: The study indicates a potential carcinogenic effect due to cytogenotoxicity from intrinsic components of ENDS. However, this does not establish ENDS as an independent risk factor for oral cancer. ENDS use may alter the oral microbiome, leading to increased biofilm adhesion and potential associations with caries, periodontal disease, and peri-implantitis. The wide variety of flavors available in the ENDS market is a significant factor influencing initiation and long-term use by young people. CONCLUSIONS: ENDS users are susceptible to periodontal disease, caries, soft tissue injuries, and changes in tooth and prosthesis coloration. The chemical components in ENDS can induce cellular changes associated with a potential risk of oral cancer. However, more long-term studies are required to fully understand the impact of ENDS use on oral health.

Inhibition of CXCR2 plays a pivotal role in re-sensitizing ovarian cancer to cisplatin treatment.

cDNA microarray data conducted by our group revealed overexpression of CXCL2 and CXCL8 in ovarian cancer (OC) microenvironment. Herein, we have proven that the chemokine receptor, CXCR2, is a pivotal molecule in re-sensitizing OC to cisplatin, and its inhibition decreases cell proliferation, viability, tumor size in cisplatin-resistant cells, as well as reversed the overexpression of mesenchymal epithelium transition markers. Altogether, our study indicates a central effect of CXCR2 in preventing tumor progression, due to acquisition of cisplatin chemoresistant phenotype by tumor cells, and patients' high lethality rate. We found that the overexpression of CXCR2 by OC cells is persistent and anomalously confined to the cellular nuclei, thus pointing to an urge in developing highly lipophilic molecules that promptly permeate cells, bind to and inhibit nuclear CXCR2 to fight OC, instead of relying on the high-cost genetic engineered cells.

Prognostic significance of MUC2, CDX2 and SOX2 in stage II colorectal cancer patients.

BACKGROUND: Colorectal cancer (CRC) remains a serious health concern worldwide. Despite advances in diagnosis and treatment, about 15 to 30% of stage II CRC patients subjected to tumor resection with curative intent, develop disease relapse. Moreover, the therapeutic strategy adopted after surgery is not consensual for these patients. This supports the imperative need to find new prognostic and predictive biomarkers for stage II CRC. METHODS: For this purpose, we used a one-hospital series of 227 stage II CRC patient samples to assess the biomarker potential of the immunohistochemical expression of MUC2 mucin and CDX2 and SOX2 transcription factors. The Kaplan-Meier method was used to generate disease-free survival curves that were compared using the log-rank test, in order to determine prognosis of cases with different expression of these proteins, different mismatch repair (MMR) status and administration or not of adjuvant chemotherapy. RESULTS: In this stage II CRC series, none of the studied biomarkers showed prognostic value for patient outcome. However low expression of MUC2, in cases with high expression of CDX2, absence of SOX2 or MMR-proficiency, conferred a significantly worst prognosis. Moreover, cases with low expression of MUC2 showed a significantly clear benefit from treatment with adjuvant chemotherapy. CONCLUSION: In conclusion, we observe that patients with stage II CRC with low expression of MUC2 in the tumor respond better when treated with adjuvant chemotherapy. This observation supports that MUC2 is involved in resistance to fluorouracil-based adjuvant chemotherapy and might be a promising future predictive biomarker in stage II CRC patients.

Regulation of invasion and peritoneal dissemination of ovarian cancer by mesothelin manipulation.

Peritoneal dissemination is a particular form of metastasis typically observed in ovarian cancer and the major cause for poor patient's outcome. Identification of the molecular players involved in ovarian cancer dissemination can offer an approach to develop treatment strategies to improve clinical prognosis. Here, we identified mesothelin (MSLN) as a crucial protein in the multistep process of peritoneal dissemination of ovarian cancer. We demonstrated that MSLN is overexpressed in primary and matched peritoneal metastasis of high-grade serous carcinomas (HGSC). Using several genetically engineered ovarian cancer cell lines, resulting in loss or gain of function, we found that MSLN increased cell survival in suspension and invasion of tumor cells through the mesothelial cell layer in vitro. Intraperitoneal xenografts established with MSLNhigh ovarian cancer cell lines showed enhanced tumor burden and spread within the peritoneal cavity. These findings provide strong evidences that MSLN is a key player in ovarian cancer progression by triggering peritoneal dissemination and provide support for further clinical investigation of MSLN as a therapeutic target in HGSC.

A SOX2 Reporter System Identifies Gastric Cancer Stem-Like Cells Sensitive to Monensin.

Gastric cancer remains a serious health burden with few therapeutic options. Therefore, the recognition of cancer stem cells (CSCs) as seeds of the tumorigenic process makes them a prime therapeutic target. Knowing that the transcription factors SOX2 and OCT4 promote stemness, our approach was to isolate stem-like cells in human gastric cancer cell lines using a traceable reporter system based on SOX2/OCT4 activity (SORE6-GFP). Cells transduced with the SORE6-GFP reporter system were sorted into SORE6+ and SORE6- cell populations, and their biological behavior characterized. SORE6+ cells were enriched for SOX2 and exhibited CSC features, including a greater ability to proliferate and form gastrospheres in non-adherent conditions, a larger in vivo tumor initiating capability, and increased resistance to 5-fluorouracil (5-FU) treatment. The overexpression and knockdown of SOX2 revealed a crucial role of SOX2 in cell proliferation and drug resistance. By combining the reporter system with a high-throughput screening of pharmacologically active small molecules we identified monensin, an ionophore antibiotic, displaying selective toxicity to SORE6+ cells. The ability of SORE6-GFP reporter system to recognize cancer stem-like cells facilitates our understanding of gastric CSC biology and serves as a platform for the identification of powerful therapeutics for targeting gastric CSCs.

Differentiation reprogramming in gastric intestinal metaplasia and dysplasia: role of SOX2 and CDX2.

AIMS: Intestinal metaplasia (IM), which results from de-novo expression of CDX2, and dysplasia are precursor lesions of gastric cancer that are associated with an increased risk for cancer development. There is much evidence suggesting a role for the transcription factor SOX2 in gastric differentiation. The aim of this study was to attempt to establish the relationship of SOX2 with CDX2 and with the differentiation reprogramming that characterizes gastric carcinogenesis, to assess their involvement in IM and dysplasia. METHODS AND RESULTS: Characterization of gastric (SOX2, MUC5AC, and MUC6) and intestinal (CDX2 and MUC2) markers in normal gastric mucosa, in 55 foci of IM and in 26 foci of dysplasia, was performed by immunohistochemistry. SOX2 was expressed in the normal gastric mucosa, in the presumptive stem cell compartment, and was maintained in 7% of the complete (MUC5AC-negative) and 85% of the incomplete (MUC5AC-positive) IM subtypes. Twelve per cent of the dysplastic lesions expressed SOX2, and the association with MUC5AC was lost. CDX2 was present in all IMs and dysplastic lesions. CONCLUSIONS: SOX2 is associated with gastric differentiation in incomplete IM and is lost in the progression to dysplasia, whereas CDX2 is acquired de novo in IM and maintained in dysplasia. This suggests that the balance between gastric and intestinal differentiation programmes impacts on the gastric carcinogenesis cascade progression.

Fluoroquinolone-metal complexes: a route to counteract bacterial resistance?

Microbial resistance to antibiotics is one of the biggest public health threats of the modern world. Antibiotic resistance is an area of much clinical relevance and therefore research that has the potential to identify agents that may circumvent it or treat resistant infections is paramount. Solution behavior of various fluoroquinolone (FQ) complexes with copper(II) in the presence and absence of 1,10-phenanthroline (phen) was studied in aqueous solution, by potentiometry and/or spectrophotometry, and are herein described. The results obtained showed that under physiological conditions (micromolar concentration range and pH7.4) only copper(II):FQ:phen ternary complexes are stable. Hence, these complexes were synthesised and characterised by means of UV-visible and IR spectroscopy, elemental analysis and single-crystal X-ray diffraction. In these complexes, the FQ acts as a bidentate ligand that coordinates the metal cation through the carbonyl and carboxyl oxygen atoms and phen coordinates through two N-atoms forming the equatorial plane of a distorted square-pyramidal geometry. The fifth position of the penta-coordinated Cu(II) centre is generally occupied axially by an oxygen atom from a water molecule or from a nitrate ion. Minimum inhibitory concentration (MIC) determinations of the complexes and comparison with free FQ in various E. coli strains indicate that the Cu-complexes are as efficient antimicrobials as the free antibiotic. Moreover, results strongly suggest that the cell intake route of both species is different supporting, therefore, the complexes' suitability as candidates for further biological testing in FQ-resistant microorganisms.

Synthesis, characterization and antibacterial studies of a copper(II) levofloxacin ternary complex.

Solution behavior of levofloxacin (lvx) complexes with copper(II) in the presence and absence of phen was studied in aqueous solution, by potentiometry. The results obtained show that under physiological conditions (micromolar concentration range and pH 7.4) only copper(II):lvx:phen ternary complexes are stable. Hence, a novel copper(II) ternary complex of fluoroquinolone levofloxacin with nitrogen donor heterocyclic ligand phen was synthesized and characterized by means of UV-Visible and IR spectroscopy, elemental analysis and X-Ray crystallography. In the synthesized complex (1), [Cu(lvx)(phen)(H(2)O)](NO(3)).2H(2)O, levofloxacin acts as a bidentate ligand coordinating to the metal, in its anionic form, through the carbonyl and carboxyl oxygens and phen coordinates through two N-atoms forming the equatorial plane of a distorted square-pyramidal geometry. The fifth ligand of the penta-coordinated Cu(II) centre is occupied axially by an oxygen atom from a water molecule. Minimum inhibitory concentration (MIC) determinations of the complex and comparison with free levofloxacin in various E. coli strains indicated that the Cu-complex is as efficient an antimicrobial as the free antibiotic (both in the case of the dissolved synthesized complex and the complex formed following stoichiometric mixture of the individual components in solution). Moreover, results strongly suggest that the cell intake route of both species is different supporting, therefore, the complex's suitability as a candidate for further biological testing in fluoroquinolone-resistant microorganisms.