RESUMEN
Oral squamous cell carcinoma (OSCC) is a subtype of head and neck cancer that arises in the multilayered epithelia of the mouth and lips. Although inactivating mutations in CASP8 are frequently found in human OSCC their role in the disease is unknown. To investigate this, we deleted Casp8 in the oral epithelium of adult mice. Loss of Caspase-8 resulted in defects in the tongue epithelial barrier and triggered a neutrophil-rich immune infiltrate distinct from that observed on epidermal Casp8 deletion. Oral Casp8 deletion led to activation of autophagy. Inhibition of autophagy partially rescued epithelial integrity in Casp8-/- mice, while induction of autophagy in wild type mice resulted in oral barrier defects and excessive neutrophil infiltration. On treatment with the carcinogen 4-nitroquinoline-1-oxide Casp8-/- mice showed increased susceptibility to developing oral tumors. Depletion of neutrophils reduced tumor incidence, which correlated with a reduction in reactive oxygen species and decreased epithelial DNA damage. Our findings establish a functional link between epithelial integrity, autophagy, and the tumor immune microenvironment, placing Caspase-8 at the center of these processes.
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Autofagia , Carcinoma de Células Escamosas , Caspasa 8 , Ratones Noqueados , Neoplasias de la Boca , Infiltración Neutrófila , Caspasa 8/metabolismo , Caspasa 8/genética , Animales , Neoplasias de la Boca/patología , Neoplasias de la Boca/genética , Neoplasias de la Boca/inmunología , Neoplasias de la Boca/metabolismo , Ratones , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , 4-Nitroquinolina-1-Óxido/toxicidad , Humanos , Microambiente Tumoral/inmunología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Rapid and precise cancer subtype discrimination is essential for personalized oncology. Conventional diagnostic methods often lack sufficient accuracy and speed. Here, we introduce a multichannel fluorescence-encoded nanosystem based on erythrocyte-coated polydopamine nanoparticles (PDA@EM), functionalized with multiple resurfaced fluorescent proteins. The fluorescence of these proteins is initially quenched by PDA@EM and restored upon cell addition. This multichannel fluorescence-encoded nanosystem enables highly sensitive "turn-on" fluorescence profiling of cancer cells within 30 min, achieving 100% accuracy in distinguishing various proteins and classifying a wide range of cancer cell lines, including subtypes of oral squamous cell carcinoma (OSCC). Notably, it offers rapid, label-free diagnostics of OSCC malignancy from clinical samples postsurgery. This capability was validated through histopathological and proteomic analyses, which identified protein signatures associated with tumor progression and immune suppression. Overall, our multichannel nanosensor represents an advanced molecular diagnostics platform, paving the way for personalized cancer treatment in clinical oncology.
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Eritrocitos , Indoles , Nanopartículas , Polímeros , Humanos , Nanopartículas/química , Línea Celular Tumoral , Indoles/química , Polímeros/química , Neoplasias de la Boca/diagnóstico , Neoplasias de la Boca/patología , Fluorescencia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patologíaRESUMEN
OBJECTIVE: This systematic review and meta-analysis aims to assess the knowledge and awareness of oral cancer risk factors among medical and dental students. METHODS: This study followed the PRISMA guidelines and was registered in INPLASY (ID: 2024110035). Four databases were consulted (PubMed, Science Direct, Scopus, and Web of Science) from February 20th, 2005, to May 10th, 2024. The study selection and data extraction process was performed independently by 2 investigators. The risk of bias was assessed using the JBI tool, which can be found at: https://jbi.global/critical-appraisal-tools. A third investigator was consulted in case of disagreement. Meta-analysis results were systematically illustrated in a forest plot and expressed as odds ratio with 95% confidence interval. The I2 statistic assessed heterogeneity between studies. Funnel plot and Egger regression analysis were used for bias analysis. A P value <.05 was considered significant. All statistical analyses were performed using the STATA V.15 software. RESULTS: After the selection process, 41 studies met the eligibility criteria, comprising a total of 14,425 participants, 22% medical students and 78% dental students, primarily female (53%). The meta-analysis showed that 98% of students demonstrated relatively good knowledge about oral cancer risk factors. The most recognized risk factor was smoking (99%), followed by advanced age (68%), UV-rays exposure (64%), and alcoholism (57%). Knowledge of several other factors was comparatively lower, with less than 50% of students recognizing them. The studies indicated significant heterogeneity (I2 = 99.8%) and publication bias (P < .001). CONCLUSIONS: These findings suggest that while medical and dental students have a strong understanding of key risk factors for oral cancer, there are gaps in knowledge regarding other important factors. Addressing these gaps through enhanced education and training is essential to improving early detection and prevention efforts.
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Conocimientos, Actitudes y Práctica en Salud , Neoplasias de la Boca , Estudiantes de Odontología , Estudiantes de Medicina , Humanos , Estudiantes de Odontología/estadística & datos numéricos , Factores de Riesgo , Neoplasias de la Boca/epidemiología , Estudiantes de Medicina/estadística & datos numéricos , Estudiantes de Medicina/psicología , Femenino , MasculinoRESUMEN
The present study aimed to optimize a mouth-dissolving film (MDF) made from Pongamia pinnata stem bark extract to increase patient compliance and accelerate oral disease therapy. Several stem bark extracts were prepared, and karanjin was used as an herbal marker for the extracts. The ethanolic extract showed the maximum yield (12.10% ± 0.09%) and cytotoxic activity against human oral cancer (KB 3-1) and embryonic kidney cell lines. The MDF formulation was focused on incorporating a fixed amount of the extract and varying concentrations of HPMC E5 polymer, along with evaluating the performance of plasticizers like PEG 400 and propylene glycol (PG). An optimized formulation was determined based on disintegration time, wetting time, and folding endurance. The formulation consisted of HPMC E5 as a film-forming polymer, PG as a superior plasticizer, ascorbic acid as an antioxidant, and other ingredients contributing to solubility, dispersion, sweetening, and appearance. High-performance thin-layer chromatography-mass spectrometry analysis confirmed higher levels of karanjin in the optimized formulation, ensuring its successful incorporation and stability. Taste masking evaluations indicate a favorable taste profile and a high potential for patient compliance. The stability study displayed no significant changes in the physical characteristics of the film, affirming its stability and quality. In conclusion, the developed herbal-based optimized MDF presents a promising drug delivery system, offering enhanced patient compliance, taste masking, and stability. The MDF holds great potential for effective treatment and management of oral diseases, providing convenience and improved therapeutic outcomes.
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Extractos Vegetales , Humanos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Línea Celular Tumoral , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/patología , Neoplasias de la Boca/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Supervivencia Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , SolubilidadRESUMEN
OBJECTIVES: The presented study aimed to evaluate the effect of mandibular protrusion with a temporarily applied mandibular advancement device (MAD) on the posterior airway space and to determine a reliable metric constant based on a three-dimensional computed tomography (CT) evaluation. MATERIALS AND METHODS: The study population consisted of patients with oral squamous cell carcinoma who were treated at least six months prior to the follow-up CT in supine position. Each patient received an individually adjusted MAD that was temporarily applied with three different protrusion distances (P0 = 0 mm, P4 = 4 mm, and P8 = 8 mm) during follow-up CT. The open-source software Slicer was used to calculate three parameters: minimum cross-sectional area (minCSA), mean cross-sectional area (meanCSA), and volume. RESULTS: The results showed a significant increase for all three parameters. The minCSA increased as follows: P0 = 236.4 mm2 ± 192.2; P4 = 309.2 mm2 ± 235.4; and P8 = 430.6 mm2 ± 265.3. The meanCSA increased significantly (p < 0.001) in all protrusion steps and all parts of the pharynx. The volume changed as follows: P0 = 24.0 cm3 ± 5.0; P4 = 29.6 cm3 ± 18.1; and P8 = 33.6 cm3 ± 19.0. The minCSA increased by 24.9 mm2 ± 13.0 per millimeter mandibular protrusion. CONCLUSION AND CLINICAL RELEVANCE: The results are interesting for both conservative and surgical therapy and could find future application in dental, orthodontic, and combined oral surgical therapy. With the results of this study, surgeons and dentists may better predict the change of PAS parameter in order to better prepare for orthognathic surgery. They also could ensure the right protrusion distance for mandibular advancement devices in the case of obstructive sleep apnea.
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Carcinoma de Células Escamosas , Imagenología Tridimensional , Avance Mandibular , Neoplasias de la Boca , Faringe , Tomografía Computarizada por Rayos X , Humanos , Masculino , Estudios Prospectivos , Femenino , Persona de Mediana Edad , Carcinoma de Células Escamosas/diagnóstico por imagen , Faringe/diagnóstico por imagen , Imagenología Tridimensional/métodos , Tomografía Computarizada por Rayos X/métodos , Neoplasias de la Boca/diagnóstico por imagen , Avance Mandibular/métodos , Avance Mandibular/instrumentación , Anciano , Adulto , Resultado del TratamientoRESUMEN
BACKGROUND: Oral squamous cell carcinoma (OSCC) is one of the most prevalent oral cancers in the world. The major etiological factors are considered to be tobacco and alcohol. However, the etiological factors for non-habit associated oral squamous cell carcinoma (NHOSCC) remains an enigma. So we focused in assessing various etiological factors like genetic factor, microbial factor, dental factor and the biochemical factor of non-habit associated oral squamous cell carcinoma. The aim was to assess Harvey Rat Sarcoma Virus gene (HRAS) mutation, total bacterial count, Herpes Simplex Virus-1 (HSV-1), regressive changes of teeth, total antioxidant capacity and its association with NHOSCC. MATERIALS AND METHODS: A total of 564 (n = 564) patients with OSCC were included in the study. Out of 564 patients, 282 patients had NHOSCC and 282 patients had habit associated oral squamous cell carcinoma (HOSCC). The isolated DNA from the tissue was subjected to Sanger's sequencing analysis for mutation analysis of the HRAS gene. The isolated serum was subjected to HSV-1 ELISA analysis and TAC ELISA analysis. The dental cast used to analyze the presence of sharp teeth/ any other form of regressive changes of teeth. RESULTS: Firstly, we found 3 novel pathogenic mutations c.16C > A/p.L6M (missense mutation), c.359 T > C/p.L120P (point mutation), c.382C > T/p.R128W (missense mutation) of HRAS gene in NHOSCC samples by genetic analysis. No significant difference was noted in the total bacterial count between the non-habit associated and habit associated oral squamous cell carcinoma (HOSCC). The binary logistic regression showed patients with HSV1 infection have 2.667 odds (2.667 OR, CI, 1.589- 4.484) of getting NHOSCC and it was found to be statistically significant (p < 0.001).The dental analysis revealed that patients with regressive changes have 4.432 odds (4.432 OR, CI, 2.807- 6.998) of getting NHOSCC and it was found to be statistically significant (p < 0.001). The biochemical analysis revealed patients with lower total antioxidant capacity have 0.671 odds (0.671 OR, CI, 0.621-0.725) of getting NHOSCC and was found to be statistically significant (p < 0.001). Our results suggest that the frequency of HRAS mutation in NHOSCC is high. HSV1, oxidative stress and regressive changes of teeth are associated with NHOSCC. CONCLUSION: Our results suggest that the frequency of HRAS mutation in NHOSCC is high. HSV1, oxidative stress and regressive changes of teeth are associated with NHOSCC.
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Carcinoma de Células Escamosas , Herpesvirus Humano 1 , Neoplasias de la Boca , Humanos , Neoplasias de la Boca/genética , Neoplasias de la Boca/etiología , Neoplasias de la Boca/virología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/virología , Masculino , Femenino , Persona de Mediana Edad , Estudios de Casos y Controles , Estudios Transversales , Herpesvirus Humano 1/aislamiento & purificación , Herpesvirus Humano 1/genética , Mutación , Anciano , Adulto , Carga Bacteriana , Factores de RiesgoRESUMEN
BACKGROUND: Survival rate of patients with oral cancer (OC) remains to be very low despite advancements in therapy and surgical techniques. This is attributed to the fact that most OC cases are discovered at a late stage. Dentists play a vital role in early detection of OC through oral mucosal examination, and in informing the patients about avoidable risk factors of the disease, such as tobacco and excessive alcohol use. This study aimed at evaluating knowledge about OC among dental students in Moldova, Armenia and Belarus; three former soviet countries with high rates of tobacco use. METHODS: This was a cross-sectional, multi-country study based on self-administered questionnaire. Dental students in their clinical years at three dental faculties in Moldova, Armenia and Belarus were invited to participate in the study. Data collection took place during the period May to September 2019. Association between different categorical variables was investigated using Chi-squared test. A knowledge score ranging from 0-14 was constructed from the obtained data. Differences in the knowledge score between different groups of students was investigated using either student`s t-test whenever comparing two groups, or One-way ANOVA with Bonferroni`s correction for three or more groups. The level of significance was set to 0.05 for all statistical tests. RESULTS: A total of 642 dental students participated in the study. The mean knowledge score was found to be 6.62 ± 2.61, with 45% of the students scoring below the mean. Students from Belarus had the highest score (7.3 ± 2.14) in comparison to Armenia (6.66 ± 2.64) and Moldova (5.66 ± 2.81), as revealed by ANOVA test. However, we observed a significant increase (p-value < 0.001, ANOVA) in the students` knowledge score as they proceed through study years from third (6.07 ± 2.61) to fifth year (7.49 ± 2.48). In addition, we found that Students with current or previous cigarette smoking habits had significantly (p-value < 0.001, student`s t-test) lower mean knowledge score (5.96 ± 2.82) when compared to students who have never been smokers (6.98 ± 2.42). CONCLUSIONS: The present study reveals notable gaps in OC knowledge and concerning tobacco use behaviors among dental students in Moldova, Belarus, and Armenia. By providing comprehensive education on risk factors and addressing personal habits, dental schools can better prepare future professionals to play a critical role in OC prevention and management.
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Conocimientos, Actitudes y Práctica en Salud , Neoplasias de la Boca , Estudiantes de Odontología , Humanos , Estudios Transversales , Estudiantes de Odontología/psicología , República de Belarús , Armenia , Femenino , Masculino , Neoplasias de la Boca/prevención & control , Moldavia , Encuestas y Cuestionarios , Adulto , Adulto JovenRESUMEN
BACKGROUND: Proliferative Verrucous Leukoplakia (PVL) presents a unique manifestation of Oral Leukoplakia, characterized by its notable propensity for rapid advancement, dynamic clinical and histopathological alterations, and heightened risk of malignant transformation. AIM: The present systematic review explores the demographic characteristics, risk factors, progression patterns, treatment preferences, and outcomes for PVL lesions that undergo malignant transformation. MATERIALS AND METHODS: An electronic search was executed across various databases, such as PubMed, Scopus, Science Direct, Web of Science and Wiley Online Library from 1985 to December 2023, focusing on studies of PVL malignant transformation. Data on demographics, clinical features, treatment, and outcome data were synthesized, with bias assessed using Joanna Briggs Institute Criteria and outcomes evaluated using Comprehensive Meta-Analysis version (CMA) 3.0 software. RESULTS: Among 998 articles, 53 met inclusion criteria, covering 1159 PVL patients, with 48.4% experiencing malignant transformation over an average 6.28 ± 3.73-year follow-up. Most cases had low or moderate bias risk. In the malignant group, females comprised 74.3% of cases, with a mean age of 66.23 ± 7.76 years and had a 1.96 times greater risk of developing cancer (OR 1.96, 95% CI 1.38-2.782; p = 0.001). Gingiva (20%) and gingiva/buccal mucosa (17.4%) were commonly affected. Tobacco and alcohol showed weak associations, with most patients being non-smokers (59.54%) and non-drinkers (78.18%). HPV and candida infection positivity were tested in only a few studies and noted in a limited number of cases (33.3% and 38.46%, respectively). Malignant transformation mainly was invasive carcinoma (86.8%). Surgery was the primary treatment (58.33%), with 55.56% recurrence in 162 cases of data availability on recurrence. Of 228 patients with data availability, 33.77% succumbed to oral cancer from PVL-related oral cancer. CONCLUSIONS: PVL, a rare variant of leukoplakia, poses a significant risk of cancer, emphasizing the need for vigilant monitoring and proactive treatment. It mainly affects elderly females without typical cancer risk factors. Understanding its etiology could aid early detection and management.
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Transformación Celular Neoplásica , Leucoplasia Bucal , Humanos , Leucoplasia Bucal/patología , Transformación Celular Neoplásica/patología , Factores de Riesgo , Neoplasias de la Boca/patología , Femenino , Masculino , Anciano , Progresión de la EnfermedadRESUMEN
BACKGROUND: Given the suffering experienced by cancer patients, effective solutions must be found to prevent painful and debilitating side effects of anti-cancer treatment. This trial aims to study the effect of preconditioning with photobiomodulation in preventing oral mucositis and xerostomia in cancer patients undergoing chemotherapy alone for the first time, and to examine its role in improving patients' quality of life. MATERIALS AND METHODS: This is a prospective, randomized, double-blind clinical trial including 45 patients divided into three age- and sex-matched groups. Group 1 received basic oral care instructions before undergoing chemotherapy. Group 2 received basic oral care instructions plus photobiomodulation using an intraoral 650 nm diode laser. Group 3 received basic oral care instructions plus photobiomodulation using a 650 nm diode laser intraorally and a 980 nm diode laser extraorally. RESULTS: After one week of follow-up, 73.3% of patients in Group 2 and 80% in Group 3 did not develop oral mucositis. The remaining patients in both groups experienced only mild erythema. In contrast, all patients in Group 1 developed oral mucositis, ranging from mild erythema to ulceration greater than 3 cm². After two weeks of follow-up, 80% of patients in Group 2 and 86.7% in Group 3 remained free of oral mucositis. The remaining patients in both groups experienced only mild erythema. In contrast, 93.3% of patients in Group 1 developed oral mucositis, with cases ranging from mild erythema to ulcers larger than 3 cm². There were statistically significant differences between the three groups in oral mucositis assessment scale after one week and after two weeks (p < 0.001). Specifically, ulcerative mucositis was not observed in both laser groups, while it was observed in 13.3% of patients in Group 1. However, these differences were not statistically significant (p = 0.129). Regarding Late Effects in Normal Tissue (LENT-SOMA) scale, there was a statistically significant difference between the three groups studied (p = 0.037). There was also a statistically significant difference in the Oral Health Impact Profile (OHIP-14) between the three groups studied (p = 0.003 after one week, p = 0.023 after two weeks). CONCLUSION: Preconditioning before starting chemotherapy, whether with the intraoral red laser alone or in combination with the extraoral infrared laser, has shown significant results in preventing oral mucositis and dry mouth, and it has also played a major role in improving patients' quality of life. TRIAL REGISTRATION: This trial was registered in ISRCTN registry under no ISRCTN70634383 ( https://doi.org/10.1186/ISRCTN70634383 ) on 24/07/2023.
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Antineoplásicos , Láseres de Semiconductores , Terapia por Luz de Baja Intensidad , Calidad de Vida , Estomatitis , Xerostomía , Humanos , Femenino , Estomatitis/prevención & control , Estomatitis/etiología , Masculino , Terapia por Luz de Baja Intensidad/métodos , Estudios Prospectivos , Método Doble Ciego , Persona de Mediana Edad , Láseres de Semiconductores/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Xerostomía/prevención & control , Xerostomía/etiología , Adulto , Eritema/etiología , Eritema/prevención & control , Estudios de Seguimiento , Úlceras Bucales/prevención & control , Úlceras Bucales/etiología , Neoplasias/radioterapia , Neoplasias/complicaciones , Neoplasias/terapia , Higiene Bucal , AncianoRESUMEN
Diverse proteomics-based strategies have been applied to saliva to quantitatively identify diagnostic and prognostic targets for oral cancer. Considering that these targets may be regulated by events that do not imply variation in protein abundance levels, we hypothesized that changes in protein conformation can be associated with diagnosis and prognosis, revealing biological processes and novel targets of clinical relevance. For this, we employed limited proteolysis-mass spectrometry in saliva samples to explore structural alterations, comparing the proteome of healthy control and oral squamous cell carcinoma (OSCC) patients with and without lymph node metastasis. Thirty-six proteins with potential structural rearrangements were associated with clinical patient features including transketolase and its interacting partners. Moreover, N-glycosylated peptides contribute to structural rearrangements of potential diagnostic and prognostic markers. Altogether, this approach utilizes saliva proteins to search for targets for diagnosing and prognosing oral cancer and can guide the discovery of potential regulated sites beyond protein-level abundance.
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Neoplasias de la Boca , Proteoma , Saliva , Humanos , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Neoplasias de la Boca/diagnóstico , Saliva/química , Saliva/metabolismo , Proteoma/análisis , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/diagnóstico , Femenino , Biomarcadores de Tumor/metabolismo , Masculino , Metástasis Linfática , Conformación Proteica , Persona de Mediana Edad , Pronóstico , Proteómica/métodos , Transcetolasa/metabolismo , Anciano , Espectrometría de Masas , Proteínas y Péptidos Salivales/metabolismo , Proteínas y Péptidos Salivales/análisisRESUMEN
Oral squamous cell carcinoma (OSCC) is the prevalent type of oral cavity cancer, requiring precise, accurate, and affordable diagnosis to identify the disease in early stages, Comprehending the differences in lipid profiles between healthy and cancerous tissues encompasses great relevance in identifying biomarker candidates and enhancing the odds of successful cancer treatment. Therefore, the present study evaluates the analytical performance of simultaneous mRNA and lipid extraction in gingiva tissue from healthy patients and patients diagnosed with OSCC preserved in TRIzol reagent. The data was analyzed by partial least-squares discriminant analysis (PLS-DA) and confirmed via matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). The lipid extraction in TRIzol solution was linear in a range from 330 to 2000 ng mL-1, r2 > 0.99, intra and interday precision and accuracy <15%, and absolute recovery values ranging from 90 to 110%. The most important lipids for tumor classification were evaluated by MALDI-MSI, revealing that the lipids responsible for distinguishing the OSCC group are more prevalent in the cancerous tissue in contrast to the healthy group. The results exhibit the possibilities to do transcriptomic and lipidomic analyses in the same sample and point out important candidates related to the presence of OSCC.
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Carcinoma de Células Escamosas , Encía , Lipidómica , Lípidos , Neoplasias de la Boca , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Humanos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Neoplasias de la Boca/diagnóstico , Lipidómica/métodos , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patología , Lípidos/análisis , Lípidos/química , Encía/patología , Encía/química , Análisis Discriminante , Femenino , Masculino , Análisis de los Mínimos CuadradosRESUMEN
Oral streptococci, key players in oral biofilm formation, are implicated in oral dysbiosis and various clinical conditions, including dental caries, gingivitis, periodontal disease, and oral cancer. Specifically, Streptococcus anginosus is associated with esophageal, gastric, and pharyngeal cancers, while Streptococcus mitis is linked to oral cancer. However, no study has investigated the mechanistic links between these Streptococcus species and cancer-related inflammatory responses. As an initial step, we probed the innate immune response triggered by S. anginosus and S. mitis in RAW264.7 macrophages. These bacteria exerted time- and dose-dependent effects on macrophage morphology without affecting cell viability. Compared with untreated macrophages, macrophages infected with S. anginosus exhibited a robust proinflammatory response characterized by significantly increased levels of inflammatory cytokines and mediators, including TNF, IL-6, IL-1ß, NOS2, and COX2, accompanied by enhanced NF-κB activation. In contrast, S. mitis-infected macrophages failed to elicit a robust inflammatory response. Seahorse Xfe96 analysis revealed an increased extracellular acidification rate in macrophages infected with S. anginosus compared with S. mitis. At the 24-h time point, the presence of S. anginosus led to reduced extracellular itaconate, while S. mitis triggered increased itaconate levels, highlighting distinct metabolic profiles in macrophages during infection in contrast to aconitate decarboxylase expression observed at the 6-h time point. This initial investigation highlights how S. anginosus and S. mitis, two Gram-positive bacteria from the same genus, can prompt distinct immune responses and metabolic shifts in macrophages during infection.IMPORTANCEThe surge in head and neck cancer cases among individuals devoid of typical risk factors such as Human Papilloma Virus (HPV) infection and tobacco and alcohol use sparks an argumentative discussion around the emerging role of oral microbiota as a novel risk factor in oral squamous cell carcinoma (OSCC). While substantial research has dissected the gut microbiome's influence on physiology, the oral microbiome, notably oral streptococci, has been underappreciated during mucosal immunopathogenesis. Streptococcus anginosus, a viridans streptococci group, has been linked to abscess formation and an elevated presence in esophageal cancer and OSCC. The current study aims to probe the innate immune response to S. anginosus compared with the early colonizer Streptococcus mitis as an important first step toward understanding the impact of distinct oral Streptococcus species on the host immune response, which is an understudied determinant of OSCC development and progression.
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Carcinoma de Células Escamosas , Caries Dental , Neoplasias de la Boca , Succinatos , Humanos , Streptococcus anginosus , Carcinoma de Células Escamosas/microbiología , Streptococcus , MacrófagosRESUMEN
Leukoplakia, a potentially malignant oral condition, manifests as a nonremovable white lesion that is often linked to risk factors such as smoking, alcohol, and HPV. Pegylated liposomal doxorubicin (PLD), which is used in cancer treatment, has been associated with secondary oral cancers, particularly in patients with leukoplakia. A case study revealed the development of squamous cell carcinoma (SCC) on the tongue following PLD treatment, suggesting a potential link between the drug and malignant transformation. Despite the benefits of PLD in reducing cardiac toxicity, long-term oral monitoring is essential due to the persistent risk of oral cancer posttreatment.
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Carcinoma de Células Escamosas , Doxorrubicina , Neoplasias de la Boca , Polietilenglicoles , Humanos , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Polietilenglicoles/química , Polietilenglicoles/farmacología , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Masculino , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/uso terapéutico , Neoplasias de la Lengua/tratamiento farmacológico , Neoplasias de la Lengua/patología , Femenino , Persona de Mediana EdadRESUMEN
Oral squamous cell carcinoma (OSCC) has become a global health problem due to its increasing incidence and high mortality rate. Early intervention through monitoring of the diagnostic biomarker levels during OSCC treatment is critical. Extracellular vesicles (EVs) are emerging surrogates in intercellular communication through transporting biomolecule cargo and have recently been identified as a potential source of biomarkers such as phosphoproteins for many diseases. Here, we developed a multiple reaction monitoring cubed (MRM3) method coupled with a novel sample preparation strategy, extracellular vesicles to phosphoproteins (EVTOP), to quantify phosphoproteins using a minimal amount of saliva (50 µL) samples from OSCC patients with high specificity and sensitivity. Our results established differential patterns in the phosphopeptide content of healthy, presurgery, and postsurgery OSCC patient groups. Notably, we discovered significantly increased salivary phosphorylated alpha-amylase (AMY) in the postsurgery group compared to the presurgery group. We hereby present the first targeted MS method with extremely high sensitivity for measuring endogenous phosphoproteins in human saliva EVs.
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Carcinoma de Células Escamosas , Vesículas Extracelulares , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Carcinoma de Células Escamosas/diagnóstico , Biomarcadores de Tumor/análisis , Saliva/química , Neoplasias de la Boca/diagnóstico , Vesículas Extracelulares/patología , Carcinoma de Células Escamosas de Cabeza y Cuello , Fosfoproteínas/análisisRESUMEN
PD-L1-positive extracellular vesicles (PD-L1+ EVs) play a pivotal role as predictive biomarkers in cancer immunotherapy. These vesicles, originating from immune cells (I-PD-L1+ EVs) and tumor cells (T-PD-L1+ EVs), hold distinct clinical predictive values, emphasizing the importance of deeply differentiating the PD-L1+ EV subtypes for effective liquid biopsy analyses. However, current methods such as ELISA lack the ability to differentiate their cellular sources. In this study, a novel step-wedge microfluidic chip that combines magnetic microsphere separation with single-layer fluorescence counting is developed. This chip integrates magnetic microspheres modified with anti-PD-L1 antibodies and fluorescent nanoparticles targeting EpCAM (tumor cell marker) or CD45 (immunocyte marker), enabling simultaneous quantification and sensitive analysis of PD-L1+ EV subpopulations in oral squamous cell carcinoma (OSCC) patients' saliva without background interference. Analysis results indicate reduced levels of I-PD-L1+ EVs in OSCC patients compared to those in healthy individuals, with varying levels of heterogeneous PD-L1+ EVs observed among different patient groups. During immunotherapy, responders exhibit decreased levels of total PD-L1+ EVs and T-PD-L1+ EVs, accompanied by reduced levels of I-PD-L1+ EVs. Conversely, nonresponders show increased levels of I-PD-L1+ EVs. Utilizing the step-wedge microfluidic chip allows for simultaneous detection of PD-L1+ EV subtypes, facilitating the precise prediction of oral cancer immunotherapy outcomes.
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Antígeno B7-H1 , Vesículas Extracelulares , Inmunoterapia , Dispositivos Laboratorio en un Chip , Neoplasias de la Boca , Humanos , Vesículas Extracelulares/química , Vesículas Extracelulares/metabolismo , Antígeno B7-H1/metabolismo , Antígeno B7-H1/análisis , Neoplasias de la Boca/terapia , Neoplasias de la Boca/patología , Neoplasias de la Boca/metabolismo , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Molécula de Adhesión Celular Epitelial/metabolismo , Saliva/química , Saliva/metabolismoRESUMEN
BACKGROUND: Our study investigated the role of experimental periodontitis on tumor growth, local and systemic immunosuppressive status, and programmed death receptor 1 (PD-1) / programmed death ligand 1 (PD-L1) expression in oral squamous cell carcinoma (OSCC) and prostate cancer. METHODS: Mouse oral or prostate cancer xenograft models were divided into control, periodontitis and periodontitis + anti-PD-1 groups. Tumor volume and weight were recorded and the levels of relevant immune-suppressive cells and T cells were detected by flow cytometry or immunofluorescence. THP-1 cells were stimulated using conditioned media of LPS-stimulated Cal-27 cells and PD-L1 expression was measured by quantitative real-time PCR, western blotting and immunofluorescence. Tumor specimens from OSCC patients with or without periodontitis were also collected for immunofluorescence. RESULTS: Periodontitis significantly promoted tumor volume and weight. Compared to the control, the proportions of tumor-associated macrophages (TAMs), regulatory T cells (Tregs), PD-L1+TAMs and PD-1+CD8+T cells increased, while CD8+T cells decreased in the periodontitis group. Immunofluorescence demonstrated that there was an increase in PD-L1+TAMs and PD-1+CD8+T cells, but a decrease in IFN-γ+CD8+T cells in both xenografts and clinical OSCC samples with periodontitis. In vitro, LPS-stimulated Cal-27 cells had a stronger potential to induce PD-L1 expression in macrophages compared with unstimulated Cal-27 cells. And the promoting effect of periodontitis on tumor growth and immune evasion was significantly attenuated after anti-PD-1 therapy. CONCLUSION: Periodontitis may facilitate tumor growth and immune escape evidenced by the increased immune-suppressive cells and the decreased functional T cells, via enhancing PD-1/PD-L1 expression in the tumor microenvironment.
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Antígeno B7-H1 , Periodontitis , Receptor de Muerte Celular Programada 1 , Animales , Ratones , Antígeno B7-H1/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Humanos , Masculino , Periodontitis/inmunología , Periodontitis/metabolismo , Periodontitis/patología , Neoplasias de la Boca/inmunología , Neoplasias de la Boca/patología , Neoplasias de la Boca/metabolismo , Microambiente Tumoral/inmunología , Escape del Tumor , Ensayos Antitumor por Modelo de Xenoinjerto , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Evasión Inmune , Línea Celular Tumoral , Proliferación Celular , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , FemeninoRESUMEN
BACKGROUND: Oral cancer poses a significant health challenge due to limited treatment protocols and therapeutic targets. We aimed to investigate the invasive margins of gingivo-buccal oral squamous cell carcinoma (GB-OSCC) tumors in terms of the localization of genes and cell types within the margins at various distances that could lead to nodal metastasis. METHODS: We collected tumor tissues from 23 resected GB-OSCC samples for gene expression profiling using digital spatial transcriptomics. We monitored differential gene expression at varying distances between the tumor and its microenvironvent (TME), and performed a deconvulation study and immunohistochemistry to identify the cells and genes regulating the TME. RESULTS: We found that the tumor-stromal interface (a distance up to 200 µm between tumor and immune cells) is the most active region for disease progression in GB-OSCC. The most differentially expressed apex genes, such as FN1 and COL5A1, were located at the stromal ends of the margins, and together with enrichment of the extracellular matrix (ECM) and an immune-suppressed microenvironment, were associated with lymph node metastasis. Intermediate fibroblasts, myocytes, and neutrophils were enriched at the tumor ends, while cancer-associated fibroblasts (CAFs) were enriched at the stromal ends. The intermediate fibroblasts transformed into CAFs and relocated to the adjacent stromal ends where they participated in FN1-mediated ECM modulation. CONCLUSION: We have generated a functional organization of the tumor-stromal interface in GB-OSCC and identified spatially located genes that contribute to nodal metastasis and disease progression. Our dataset might now be mined to discover suitable molecular targets in oral cancer.
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Fibroblastos , Regulación Neoplásica de la Expresión Génica , Metástasis Linfática , Neoplasias de la Boca , Células Mieloides , Microambiente Tumoral , Humanos , Neoplasias de la Boca/patología , Neoplasias de la Boca/genética , Metástasis Linfática/patología , Fibroblastos/patología , Fibroblastos/metabolismo , Células Mieloides/patología , Células Mieloides/metabolismo , Fibroblastos Asociados al Cáncer/patología , Fibroblastos Asociados al Cáncer/metabolismo , Perfilación de la Expresión Génica , Femenino , Masculino , Persona de Mediana Edad , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/genéticaRESUMEN
INTRODUCTION: Saliva has gained increasing attention in the quest for disease biomarkers. Because it is a biological fluid that can be collected is an easy, painless, and safe way, it has been increasingly studied for the identification of oral cancer biomarkers. This is particularly important because oral cancer is often diagnosed at late stages with a poor prognosis. AREAS COVERED: The review addresses the evolution of the experimental approaches used in salivary proteomics studies of oral cancer over the years and outlines advantages and pitfalls related to each one. In addition, examines the current landscape of oral cancer biomarker discovery and translation focusing on salivary proteomic studies. This discussion is based on an extensive literature search (PubMed, Scopus and Google Scholar). EXPERT OPINION: The introduction of mass spectrometry has revolutionized the study of salivary proteomics. In the future, the focus will be on refining existing methods and introducing powerful experimental techniques such as mass spectrometry with selected reaction monitoring, which, despite their effectiveness, are still underutilized due to their high cost. In addition, conducting studies with larger cohorts and establishing standardized protocols for salivary proteomics are key challenges that need to be addressed in the coming years.
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Biomarcadores de Tumor , Neoplasias de la Boca , Proteómica , Saliva , Humanos , Neoplasias de la Boca/diagnóstico , Neoplasias de la Boca/metabolismo , Proteómica/métodos , Saliva/metabolismo , Saliva/química , Biomarcadores de Tumor/metabolismo , Espectrometría de Masas/métodosRESUMEN
INTRODUCTION: Oral squamous cell carcinoma (OSCC) represents the most prevalent form of oral cancer. Potentially malignant disorders of oral mucosa exhibit an elevated propensity for malignant progression. A substantial proportion of cases are discerned during advanced stages, significantly impacting overall survival. This investigation aims to ascertain salivary metabolites with potential utility in the early detection of OSCC. METHODS: A search encompassing PubMed, EMBASE, Scopus, Ovid, Science Direct, and Web of Science databases was conducted to identify eligible articles. The search strategy employed precise terms. The quality assessment of the included studies was executed using the QUADAS 2 ROB tool. This was registered with PROSPERO CRD42021278217. RESULTS: Upon removing duplicate articles and publications that didn't satisfy the inclusion criteria, seven articles were included in the current study. The Random Effects Maximum Likelihood (REML) model adopted for quantitative synthesis identified Nacetyl glucosamine as the sole metabolite in two studies included in this metaanalysis. The pathways significantly influenced by these identified metabolites were delineated. CONCLUSION: This study highlights Nacetyl glucosamine as a distinctive metabolite with the potential to serve as an early diagnostic marker for OSCC. Nevertheless, further research is warranted to validate its clinical utility.
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Carcinoma de Células Escamosas , Detección Precoz del Cáncer , Metabolómica , Neoplasias de la Boca , Saliva , Humanos , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/diagnóstico , Saliva/metabolismo , Saliva/química , Metabolómica/métodos , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Detección Precoz del Cáncer/métodos , Biomarcadores de Tumor/metabolismoRESUMEN
Head and neck squamous cell carcinoma (SCC) predisposing factors include smoking and alcohol consumption. However, other agents have been investigated, including viruses. We aimed to investigate the presence of DNA of four different types of human polyomavirus (HPyV) in the oral cavity and oropharyngeal SCC samples from an oncology center in Brazil and evaluate the association between HPyV detection and clinical and sociodemographic characteristics. Sixty fresh frozen samples from three different anatomical sites (tongue, floor of the mouth, and oropharynx, 20 samples for each region) were retrospectively selected. Data from medical records such as age, sex, alcohol consumption, smoking, tumor staging and death in less than 5 years of diagnosis were collected. DNA was extracted for the identification of MCPyV, BKPyV, JCPyV, and TSPyV using PCR followed by Sanger sequencing of positive samples. The identity of the generated DNA sequences was confirmed by alignment reference sequences. The investigation of the presence of HPyV DNA showed positivity of 5% for MCPyV (n = 3), 0% for both BKPyV or TSPyV, and 60% for JCPyV (n = 36). No association was found between the positivity of any HPyV in samples with any clinical or sociodemographic characteristics of the patients, nor with a certain anatomical site, except for the association between death in less than 5 years after diagnosis and positivity for JCPyV (p = 0.009). Positivity for HPyV in oral cavity and oropharyngeal SCC was low for MCPyV, high for JCPyV and null for BKPyV and TSPyV. Further studies should be carried out to better understand the high prevalence of JCPyV found in oral cavity and oropharyngeal SCC.