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Odontogenic tumors (OGTs), which originate from cells of odontogenic apparatus and their remnants, are rare entities. Primary intraosseous carcinoma NOS (PIOC), is one of the OGTs, but it is even rarer and has a worse prognosis. The precise characteristics of PIOC, especially in immunohistochemical features and its pathogenesis, remain unclear. We characterized a case of PIOC arising from the left mandible, in which histopathological findings showed a transition from the odontogenic keratocyst to the carcinoma. Remarkably, the tumor lesion of this PIOC prominently exhibits malignant attributes, including invasive growth of carcinoma cell infiltration into the bone tissue, an elevated Ki-67 index, and lower signal for CK13 and higher signal for CK17 compared with the non-tumor region, histopathologically and immunohistopathologically. Further immunohistochemical analyses demonstrated increased expression of ADP-ribosylation factor (ARF)-like 4c (ARL4C) (accompanying expression of ß-catenin in the nucleus) and yes-associated protein (YAP) in the tumor lesion. On the other hand, YAP was expressed and the expression of ARL4C was hardly detected in the non-tumor region. In addition, quantitative RT-PCR analysis using RNAs and dot blot analysis using genomic DNA showed the activation of Wnt/ß-catenin signaling and epigenetic alterations, such as an increase of 5mC levels and a decrease of 5hmC levels, in the tumor lesion. A DNA microarray and a gene set enrichment analysis demonstrated that various types of intracellular signaling would be activated and several kinds of cellular functions would be altered in the pathogenesis of PIOC. Experiments with the GSK-3 inhibitor revealed that ß-catenin pathway increased not only mRNA levels of ankyrin repeat domain1 (ANKRD1) but also protein levels of YAP and transcriptional co-activator with PDZ-binding motif (TAZ) in oral squamous cell carcinoma cell lines. These results suggested that further activation of YAP signaling by Wnt/ß-catenin signaling may be associated with the pathogenesis of PIOC deriving from odontogenic keratocyst in which YAP signaling is activated.
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Proteínas Adaptadoras Transductoras de Señales , Quistes Odontogénicos , Tumores Odontogénicos , Factores de Transcripción , Vía de Señalización Wnt , Humanos , Quistes Odontogénicos/patología , Quistes Odontogénicos/metabolismo , Tumores Odontogénicos/patología , Tumores Odontogénicos/metabolismo , Vía de Señalización Wnt/fisiología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Factores de Transcripción/metabolismo , beta Catenina/metabolismo , beta Catenina/genética , Proteínas Señalizadoras YAP , Neoplasias Mandibulares/patología , Neoplasias Mandibulares/metabolismo , Masculino , FemeninoRESUMEN
Interlocked compounds such as rotaxanes and catenanes exhibit unique kinetic properties in response to external chemical or physical stimuli and are therefore expected to be applied to molecular machines and molecular sensors. To develop a novel rotaxane for this application, an isophthalamide macrocycle and a neutral phenanthroline axle were used. Stable pseudorotaxanes are known to be formed using hydrogen bonds and π-π interactions. In this study, we designed a non-symmetric axial molecule and synthesized a [2]rotaxane with the aim of introducing two different stations; a phenanthroline and a secondary amine/ammonium unit. Furthermore, 1H NMR measurements demonstrated that the obtained rotaxane acts as a molecular switch upon application of external acid/base stimuli.
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Background: Diffusion-weighted imaging (DWI) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) are widely used in the orofacial region. Furthermore, quantitative analyses have proven useful. However, a few reports have described the correlation between DWI-derived parameters and DCE-MRI-derived parameters, and the results have been controversial. Purpose: To evaluate the correlation among parameters obtained by DWI and DCE-MRI and to compare them between benign and malignant lesions. Material and Methods: Fifty orofacial lesions were analysed. The apparent diffusion coefficient (ADC), true diffusion coefficient (D), pseudodiffusion coefficient (D*) and perfusion fraction (f) were estimated by DWI. For DCE-MRI, TK model analysis was performed to estimate physiological parameters, for example, the influx forward volume transfer constant into the extracellular-extravascular space (EES) (Ktrans) and fractional volumes of EES and plasma components (ve and vp). Results: Both ADC and D showed a moderate positive correlation with ve (ρ = 0.640 and 0.645, respectively). Ktrans showed a marginally weak correlation with f (ρ = 0.296), while vp was not correlated with f or D*; therefore, IVIM perfusion-related parameters and TK model perfusion-related parameters were not straightforward. Both D and ve yielded high diagnostic power between benign lesions and malignant tumours with areas under the curve (AUCs) of 0.830 and 0.782, respectively. Conclusion: Both D and ve were reliable parameters that were useful for the differential diagnosis. In addition, the true diffusion coefficient (D) was affected by the fractional volume of EES.
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AIM: Cyst formation of the jaws is frequently accompanied by the proliferation of odontogenic epithelial cells located in the periodontal ligament (PDL), which consists of heterozygous cells and includes the most fibroblasts. The lining epithelium of radicular cyst, an odontogenic cyst of inflammatory origin, is derived from the proliferation of the remnants of the Hertwig epithelial root sheath (odontogenic epithelial cell rests of Malassez; ERMs) in the PDL. ERMs are maintained at a lower proliferative state under physiological conditions, but the regulatory mechanisms underlying the inflammation-dependent enhanced-proliferative capabilities of ERMs are not fully understood. The aim of this study was to evaluate the effects of cytokine pathway association between TGF-ß signalling and IL-1ß signalling on the regulation of odontogenic epithelial cell proliferation using radicular cyst pathological specimens and odontogenic epithelial cell lines. METHODOLOGY: Immunofluorescence analyses were performed to clarify the expression levels of Smad2/3 and Ki-67 in ERMs of 8-week-old mouse molar specimens. In radicular cyst (n = 52) and dentigerous cysts (n = 6) specimens from human patients, the expression of p65 (a main subunit of NF-κB), Smad2/3 and Ki-67 were investigated using immunohistochemical analyses. Odontogenic epithelial cells and PDL fibroblastic cells were co-cultured with or without an inhibitor or siRNAs. Odontogenic epithelial cells were cultured with or without TGF-ß1 and IL-1ß. The proliferative capabilities and Smad2 phosphorylation levels of odontogenic epithelial cells were examined. RESULTS: Immunohistochemically, Smad2/3-positivity was increased, and p65-positivity and Ki-67-positivity were decreased both in ERMs and in the epithelial cells in dentigerous cysts, a non-inflammatory developmental cyst. In contrast, p65-positive cells, along with the expression of Ki-67, were increased and Smad2/3-positive cells were decreased in the lining epithelia of radicular cysts. Co-culture experiments with odontogenic epithelial cells and PDL fibroblastic cells revealed that PDL cells-derived TGF-ß1/2 and their downstream signalling suppressed odontogenic epithelial cell proliferation. Moreover, TGF-ß1 stimulation induced Smad2 phosphorylation and suppressed odontogenic epithelial cell proliferation, while IL-1ß stimulation reversed these phenotypes through p65 transactivation. CONCLUSIONS: These results suggest that IL-1ß-p65 signalling promotes odontogenic epithelial cell proliferation through suppressing TGF-ß-Smad2 signalling, which would be involved in the pathogenesis of radicular cysts.
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Quiste Dentígero , Quistes Odontogénicos , Quiste Radicular , Humanos , Animales , Ratones , Quiste Radicular/patología , Factor de Crecimiento Transformador beta1 , Quiste Dentígero/complicaciones , Quiste Dentígero/metabolismo , Quiste Dentígero/patología , Antígeno Ki-67 , Descanso , Quistes Odontogénicos/patología , Células Epiteliales , Epitelio/patología , Proliferación Celular , Factor de Crecimiento Transformador beta/metabolismo , Interleucina-1betaRESUMEN
Adenoid cystic carcinoma (ACC) is one of the most common malignant salivary gland tumors. ACC is composed of myoepithelial and epithelial neoplastic cells which grow slowly and have a tendency for neural invasion. The long term prognosis is still relatively poor. Although several gene abnormalities, such as fusions involving MYB or MYBL1 oncogenes and the transcription factor gene NFIB, and overexpression of KIT have been reported in ACC, their precise functions in the pathogenesis of ACC remain unclear. We recently demonstrated that the elevated expression of Semaphorin 3A (SEMA3A), specifically expressed in myoepithelial neoplastic cells, might function as a novel oncogene-related molecule to enhance cell proliferation through activated AKT signaling in 9/10 (90%) ACC cases. In the current study, the patient with ACC whose tumor was negative for SEMA3A in the previous study, revisited our hospital with late metastasis of ACC to the cervical lymph node eight years after surgical resection of the primary tumor. We characterized this recurrent ACC, and compared it with the primary ACC using immunohistochemical methods. In the recurrent ACC, the duct lining epithelial cells, not myoepithelial neoplastic cells, showed an elevated Ki-67 index and increased cell membrane expression of C-kit, along with the expression of phosphorylated ERK. Late metastasis ACC specimens were not positive for ß-catenin and lymphocyte enhancer binding factor 1 (LEF1), which were detected in the nuclei of perineural infiltrating cells in primary ACC cells. In addition, experiments with the GSK-3 inhibitor revealed that ß-catenin pathway suppressed not only KIT expression but also proliferation of ACC cells. Moreover, stem cell factor (SCF; also known as KIT ligand, KITL) induced ERK activation in ACC cells. These results suggest that inactivation of Wnt/ß-catenin signaling may promote C-kit-ERK signaling and cell proliferation of in metastatic ACC.
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Carcinoma Adenoide Quístico , Neoplasias de las Glándulas Salivales , Humanos , Carcinoma Adenoide Quístico/patología , beta Catenina/metabolismo , Cateninas/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Semaforina-3A , Recurrencia Local de Neoplasia , Neoplasias de las Glándulas Salivales/patología , Vía de Señalización Wnt , Proteínas Proto-Oncogénicas c-kit/metabolismoRESUMEN
BACKGROUND: IgG4-related disease (IgG4-RD), an example of a type I immune disease, is an immune-mediated fibrotic disorder characterized by dysregulated resolution of severe inflammation and wound healing. However, truly dominant or pathognomonic autoantibodies related to IgG4-RD are not identified. OBJECTIVE: We sought to perform single-cell RNA sequencing and T-cell receptor and B-cell receptor sequencing to obtain a comprehensive, unbiased view of tissue-infiltrating T and B cells. METHODS: We performed unbiased single-cell RNA-sequencing analysis for the transcriptome and T-cell receptor sequencing and B-cell receptor sequencing on sorted CD3+ T or CD19+ B cells from affected tissues of patients with IgG4-RD. We also conducted quantitative analyses of CD3+ T-cell and CD19+ B-cell subsets in 68 patients with IgG4-RD and 30 patients with Sjögren syndrome. RESULTS: Almost all clonally expanded T cells in these lesions were either Granzyme K (GZMK)-expressing CD4+ cytotoxic T cells or GZMK+CD8+ T cells. These GZMK-expressing cytotoxic T cells also expressed amphiregulin and TGF-ß but did not express immune checkpoints, and the tissue-infiltrating CD8+ T cells were phenotypically heterogeneous. MKI67+ B cells and IgD-CD27-CD11c-CXCR5- double-negative 3 B cells were clonally expanded and infiltrated affected tissue lesions. GZMK+CD4+ cytotoxic T cells colocalized with MKI67+ B cells in the extrafollicular area from affected tissue sites. CONCLUSIONS: The above-mentioned cells likely participate in T-B collaborative events, suggesting possible avenues for targeted therapies. Our findings were validated using orthogonal approaches, including multicolor immunofluorescence and the use of comparator disease groups, to support the central role of cytotoxic CD4+ and CD8+ T cells expressing GZMK, amphiregulin, and TGF-ß in the pathogenesis of inflammatory fibrotic disorders.
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Enfermedades del Sistema Inmune , Enfermedad Relacionada con Inmunoglobulina G4 , Humanos , Anfirregulina/genética , Linfocitos T CD8-positivos , Granzimas , Receptores de Antígenos de Linfocitos B , Receptores de Antígenos de Linfocitos T , Linfocitos T Citotóxicos , Factor de Crecimiento Transformador betaRESUMEN
BACKGROUND: Germinal center (GC) responses controlled by T follicular helper (Tfh) and T follicular regulatory (Tfr) cells are crucial for the generation of high-affinity antibodies. Acquired immune responses to tissue-released antigens might be mainly induced in tertiary lymphoid organs (TLOs) with GCs in affected tissues. IgG4-related disease (IgG4-RD) demonstrates polarized isotype switching and TLOs in affected tissues. We performed single-cell transcriptomics of tissue-infiltrating T cells from these TLOs to obtain a comprehensive, unbiased view of tissue-infiltrating GC-Tfh cells. OBJECTIVE: To identify GC-Tfh-cell subsets in TLOs in patients with IgG4-RD using single-cell transcriptomics. METHODS: Single-cell RNA sequencing of sorted CD3+ T cells and multicolor immunofluorescence analysis were used to investigate CD4+CXCR5+Bcl6+ GC-Tfh cells in affected lesions from patients with IgG4-RD. RESULTS: Infiltrating CD4+CXCR5+Bcl6+ Tfh cells were divided into 5 main clusters. We detected HLA+ granzyme K+ (GZMK+) Tfh cells with cytotoxicity-associated features in patients with IgG4-RD. We also observed abundant infiltrating Tfr cells with suppressor-associated features in patients with IgG4-RD. These GZMK+ Tfh cells and Tfr cells clustered together in affected tissues from patients with IgG4-RD. CONCLUSIONS: This single-cell data set revealed a novel subset of HLA+GZMK+ cytotoxic Tfh cells infiltrating affected organs in patients with IgG4-RD, suggesting that infiltrating Tfr cells might suppress cytotoxic Tfh cells.
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Antineoplásicos , Enfermedad Relacionada con Inmunoglobulina G4 , Estructuras Linfoides Terciarias , Humanos , Granzimas/genética , Células T Auxiliares Foliculares , Perfilación de la Expresión Génica , Linfocitos T Colaboradores-Inductores , Linfocitos T ReguladoresRESUMEN
Previous studies have demonstrated that extracellular vesicles (EVs) from dental pulp stem cells (DPSCs), which release abundant hepatocyte growth factor (HGF) and transforming growth factor-ß1 (TGF-ß1), contribute to the pathogenesis of Sjögren's syndrome (SS). However, depending on the condition of DPSCs, this effect is often not achieved. In this study, we established induced pluripotent stem (iPS) cells highly capable of releasing HGF and TGF-ß1 and iPS cells barely capable of releasing them, and administered each EV to SS model mice to see if there was a difference in therapeutic effect. EVs were collected from each iPS cell and their characteristics and shapes were examined. When they were administered to SS model mice, the EVs from iPS cells with higher concentrations of HGF and TGF-ß1 showed significantly reduced inflammatory cell infiltration in salivary gland tissues, increased saliva volume, and decreased anti-SS-A and anti-SS-B antibodies. A comprehensive search of microRNA arrays for differences among those EVs revealed that EVs from iPS cells with higher concentrations of HGF and TGF-ß1 contained more of the let-7 family. Thereafter, we examined the expression of toll-like receptors (TLRs), which are said to be regulated by the let-7 family, by qPCR, and found decreased TLR4 expression. Focusing on MAPK, a downstream signaling pathway, we examined cytokine concentrations in mouse macrophage culture supernatants and Western blotting of murine splenic tissues and found higher concentrations of anti-inflammatory cytokines in the EVs-treated group and decreased TLR4, NF-κB and phosphorylation (p)-p-38 MAPK expression by Western blotting. Alternatively, p-Smad2/3 was upregulated in the EVs-treated group. Our findings suggest that the let-7 family in EVs may suppress the expression of TLR4 and NF-κB, which may be involved in the suppression of MAPK-mediated pro-inflammatory cytokine production.
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Vesículas Extracelulares , Células Madre Pluripotentes Inducidas , Síndrome de Sjögren , Animales , Ratones , Vesículas Extracelulares/metabolismo , Factor de Crecimiento de Hepatocito/metabolismo , Inmunidad Innata , Células Madre Pluripotentes Inducidas/metabolismo , FN-kappa B/metabolismo , Síndrome de Sjögren/metabolismo , Síndrome de Sjögren/patología , Receptor Toll-Like 4/metabolismo , Factor de Crecimiento Transformador beta1RESUMEN
Background: Cancer immunotherapy targeting CD8+ T cells has made remarkable progress, even for oral squamous cell carcinoma (OSCC), a heterogeneous epithelial tumor without a substantial increase in the overall survival rate over the past decade. However, the therapeutic effects remain limited due to therapy resistance. Thus, a more comprehensive understanding of the roles of CD4+ T cells and B cells is crucial for more robust development of cancer immunotherapy. Methods: In this study, we examined immune responses and effector functions of CD4+ T cells, CD8+ T cells and B cells infiltrating in OSCC lesions using single-cell RNA sequencing analysis, T cell receptor (TCR) and B cell receptor (BCR) repertoire sequencing analysis, and multi-color immunofluorescence staining. Finally, two Kaplan-Meier curves and several Cox proportional hazards models were constructed for the survival analysis. Results: We observed expansion of CD4+ cytotoxic T lymphocytes (CTLs) expressing granzymes, which are reported to induce cell apoptosis, with a unique gene expression patterns. CD4+ CTLs also expressed CXCL13, which is a B cell chemoattractant. Cell-cell communication analysis and multi-color immunofluorescence staining demonstrated potential interactions between CD4+ CTLs and B cells, particularly IgD- CD27- double negative (DN) B cells. Expansion of CD4+ CTLs, DN B cells, and their contacts has been reported in T and B cell-activated diseases, including IgG4-related disease and COVID-19. Notably, we observed upregulation of several inhibitory receptor genes including CTLA-4 in CD4+ CTLs, which possibly dampened T and B cell activity. We next demonstrated comprehensive delineation of the potential for CD8+ T cell differentiation towards dysfunctional states. Furthermore, prognostic analysis revealed unfavorable outcomes of patients with a high proportion of CD4+ CTLs in OSCC lesions. Conclusion: Our study provides a dynamic landscape of lymphocytes and demonstrates a systemic investigation of CD4+ CTL effects infiltrating into OSCC lesions, which may share some pathogenesis reported in severe T and B cell-activated diseases such as autoimmune and infectious diseases.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Linfocitos T Citotóxicos , Linfocitos T CD8-positivos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Neoplasias de la Boca/genética , Neoplasias de la Boca/metabolismo , Linfocitos T CD4-Positivos , Neoplasias de Cabeza y Cuello/metabolismo , Análisis de la Célula Individual , Expresión GénicaRESUMEN
Oral lichen planus (OLP) is a chronic inflammatory disease associated with T cell infiltration. The crosstalk between oral epithelium and mucosal T cells was considered to be crucial in the pathogenesis of OLP. Here, we selectively extracted the normal epithelium (NE) and lesional epithelium (LE) of buccal mucosa specimens from three patients with OLP by laser capture microdissection due to identify the pathogenic factors. Cathepsin K (CTSK) was identified as one of common upregulated genes in the LE by DNA microarray. Immunohistochemically, CTSK was distinctly detected in and around the LE, while it was rarely seen in the NE. Recent studies showed that CTSK enhanced Toll-like receptor 9 (TLR9) signaling in antigen-presenting cells, leading to Th17 cell differentiation. TLR9 expression mainly co-localized with CD123+ plasmacytoid dendritic cells (pDCs). The number of RORγt-positive cells correlated with that of CTSK-positive cells in OLP tissues. CD123+ pDCs induced the production of Th17-related cytokines (IL-6, IL-23, and TGF-ß) upon stimulation with TLR9 agonist CpG DNA. Moreover, single cell RNA-sequencing analysis revealed that TLR9-positive pDCs enhanced in genes associated with Th17 cell differentiation in comparison with TLR9-negative pDCs. CTSK could induce Th17-related production of CD123+ pDCs via TLR9 signaling to promote the pathogenesis of OLP.
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Liquen Plano Oral , Humanos , Liquen Plano Oral/patología , Receptor Toll-Like 9/metabolismo , Subunidad alfa del Receptor de Interleucina-3/metabolismo , Catepsina K/genética , Catepsina K/metabolismo , Células Dendríticas , Epitelio/metabolismo , Inmunidad , Receptor Toll-Like 7/metabolismo , Células Th17/metabolismoRESUMEN
OBJECTIVES: To compare the delineation of mandibular cancer by 3D T1 turbo field echo with compressed SENSE (CS-3D-T1TFE) images and MDCT images, and to compare both sets of images with histopathological findings, as the gold standard, to validate the accuracy and clinical usefulness of CS-3D-T1TFE reconstruction. METHODS: Twenty-four patients with mandibular squamous cell carcinoma (SCC) who underwent MRI including CS-3D-T1TFE and MDCT examinations before surgery were retrospectively included. For both examinations, 0.5-mm-thick coronal plane images and 0.5-mm-thick plane images perpendicular and parallel to the dentition were constructed. Two radiologists rated bone invasion in three categories indexed by cortical bone, cancellous bone, and mandibular canal (MC), and inter-rater agreement was assessed by weighted kappa statistics. In 20 of the 24 patients who underwent surgery, the correlation of bone invasion with the histopathological evaluation by pathologists was assessed using Pearson's correlation coefficient. Soft-tissue invasion was assessed by diagnosing the presence of invasion into the mylohyoid muscle, gingivobuccal fold, and masticator space, and inter-rater agreement was assessed by kappa statistics. RESULTS: The interobserver agreement for bone invasion assessment was almost perfect with CS-3D-T1TFE and substantial with MDCT. The image evaluations by both observers agreed with the pathological evaluations in 15 of the 20 cases, showing high correlation (r > 0.8). CS-3D-T1TFE also showed higher inter-rater agreement than MDCT for all measures of soft-tissue invasion. CONCLUSIONS: CS-3D-T1TFE reconstructed images were clinically useful in accurately depicting the extent of mandibular cancer invasion and potentially solving the problem of lesion overestimation associated with conventional MRI. KEY POINTS: ⢠Reconstructed CS-3D-T1TFE images were useful for the diagnosis of mandibular cancer. ⢠CS-3D-T1TFE images showed higher inter-rater agreement than MDCT and high correlation with pathological findings. ⢠CS-3D-T1TFE images may solve the problem of overestimation of the tumor extent, which has been associated with MRI in the past.
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Carcinoma de Células Escamosas , Humanos , Estudios Retrospectivos , Sensibilidad y Especificidad , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/cirugía , Carcinoma de Células Escamosas/patología , Mandíbula/diagnóstico por imagen , Imagenología Tridimensional , Imagen por Resonancia Magnética/métodos , Tomografía Computarizada por Rayos XRESUMEN
An organometallic nickel complex containing thieno[3,2-b]thiophene units was designed and synthesized. Composite films of the resulting nickel complex and polyvinylidene difluoride, which can be fabricated via a simple solution process under atmospheric conditions, exhibit remarkably high n-type conductivity (>200 S cm-1). Moreover, the thermoelectric power factor of the n-type composite film was proven to be air stable. A grazing-incidence wide-angle X-ray diffraction analysis indicated a significant impact of introducing the thieno[3,2-b]thiophene core into the backbone of the nickel complex on the orientation within the composite films.
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Racemic 1-phenylethanols were converted into enantiopure (R)-1-phenylethanols via a chemoenzymatic process in which manganese oxide driven oxidation was coupled with enzymatic biotransformation by compartmentalization of the reactions, although the two reactions conducted under mixed conditions are not compatible due to enzyme deactivation by Mn ions. Achiral 1-phenylethanol is oxidized to produce acetophenone in the interior chamber of a polydimethylsiloxane thimble. The acetophenone passes through the membrane into the exterior chamber where enantioselective biotransformation takes place to produce (R)-1-phenylethanol with an enantioselectivity of >99% ee and with 96% yield. The developed sequential reaction could be applied to the deracemization of a wide range of methyl- and chloro-substituted 1-phenylethanols (up to 93%, >99% ee). In addition, this method was applied to the selective hydroxylation of ethylbenzene to afford chiral 1-phenylethanol.
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OBJECTIVES: To compare the gamma distribution (GD), intravoxel incoherent motion (IVIM), and monoexponential (ME) models in terms of their goodness-of-fit, correlations among the parameters, and the effectiveness in the differential diagnosis of various orofacial lesions. METHODS: A total of 85 patients underwent turbo spin-echo diffusion-weighted imaging with six b-values. The goodness-of-fit of three models was assessed using Akaike Information Criterion. We analysed the correlations and compared the effectiveness in the differential diagnosis among the parameters of GD model (κ, shape parameter; θ, scale parameter; fractions of diffusion: ƒ1, cellular component; ƒ2, extracellular diffusion; ƒ3, perfusion component), IVIM model (D, true diffusion coefficient; D*, pseudodiffusion coefficient; f, perfusion fraction), and ME model (apparent diffusion coefficient, ADC). RESULTS: The GD and IVIM models showed a better goodness-of-fit than the ME model (p < 0.05). ƒ1 had strong negative correlations with D and ADC (ρ = -0.901 and -0.937, respectively), while ƒ3 had a moderate positive correlation with f (ρ = 0.661). Malignant entity presented significantly higher ƒ1 and lower D and ADC than benign entity (p < 0.0001). Malignant lymphoma had significantly higher ƒ1 in comparison to squamous cell carcinoma (p = 0.0007) and granulation (p = 0.0075). The trend in ƒ1 was opposite to the trend in D. Malignant lymphoma had significant lower ƒ3 than squamous cell carcinoma (p = 0.005) or granulation (p = 0.0075). CONCLUSIONS: The strong correlations were found between the GD- and IVIM-derived parameters. Furthermore, the GD model's parameters were useful for characterising the pathological structure in orofacial lesions.
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Imagen de Difusión por Resonancia Magnética , Imagen por Resonancia Magnética , Diagnóstico Diferencial , Humanos , Movimiento (Física) , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Tumor-associated macrophages (TAMs) promote cancer cell proliferation and metastasis, as well as anti-tumor immune suppression. Recent studies have shown that tumors enhance the recruitment and differentiation of TAMs, but the detailed mechanisms have not been clarified. We thus examined the influence of cancer cells on the differentiation of monocytes to TAM subsets, including CD163+, CD204+, and CD206+ cells, in oral squamous cell carcinoma (OSCC) using immunohistochemistry, flow cytometry, and a cytokine array. Furthermore, we investigated the effect of OSCC cells (HSC-2, SQUU-A, and SQUU-B cells) on the differentiation of purified CD14+ cells to TAM subsets. The localization patterns of CD163+, CD204+, and CD206+ in OSCC sections were quite different. The expression of CD206 on CD14+ cells was significantly increased after the co-culture with OSCC cell lines, while the expressions of CD163 and CD204 on CD14+ cells showed no change. High concentrations of plasminogen activator inhibitor-1 (PAI-1) and interleukin-8 (IL-8) were detected in the conditioned medium of OSCC cell lines. PAI-1 and IL-8 stimulated CD14+ cells to express CD206. Moreover, there were positive correlations among the numbers of CD206+, PAI-1+, and IL-8+ cells in OSCC sections. These results suggest that PAI-1 and IL-8 produced by OSCC contribute to the differentiation of monocytes to CD206+ TAMs.
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Macrófagos/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas/patología , Diferenciación Celular/genética , Línea Celular Tumoral , Neoplasias de Cabeza y Cuello/patología , Humanos , Inmunohistoquímica , Interleucina-8/metabolismo , Interleucina-8/fisiología , Leucocitos Mononucleares/citología , Macrófagos/fisiología , Inhibidor 1 de Activador Plasminogénico/metabolismo , Inhibidor 1 de Activador Plasminogénico/fisiología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Microambiente Tumoral , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/fisiologíaRESUMEN
OBJECTIVES: This study evaluated the correlation among the diffusion-derived parameters obtained by monoexponential (ME), intravoxel incoherent motion (IVIM) and γ distribution (GD) models and compared these parameters among representative orofacial tumours. METHODS: Ninety-two patients who underwent 1.5 T MRI including diffusion-weighted imaging were included. The shape parameter (κ), scale parameter (θ), ratio of the intracellular diffusion (ƒ1), extracellular diffusion (ƒ2) and perfusion (ƒ3) were obtained by the GD model; the true diffusion coefficient (D) and perfusion fraction (f) were obtained by the IVIM model; and the apparent diffusion coefficient (ADC) was obtained by the ME model. RESULTS: ƒ1 had a strongly negative correlation with the ADC (ρ = -0.993) and D (ρ = -0.926). A strong positive correlation between f and ƒ3 (ρ = 0.709) was found. Malignant lymphoma (ML) had the highest ƒ1, followed by squamous cell carcinoma (SCC), malignant salivary gland tumours, pleomorphic adenoma (Pleo) and angioma. Both the IVIM and GD models suggested the highest perfusion in angioma and the lowest perfusion in ML. The GD model demonstrated a high extracellular component in Pleo and revealed that the T4a+T4b SCC group had a lower ƒ2 than the T2+T3 SCC group, and poor to moderately differentiated SCC had a higher ƒ1 than highly differentiated SCC. CONCLUSIONS: Given the correlation among the diffusion-derived parameters, the GD model might be a good alternative to the IVIM model. Furthermore, the GD model's parameters were useful for characterizing the pathological structure.
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Carcinoma de Células Escamosas , Imagen de Difusión por Resonancia Magnética , Carcinoma de Células Escamosas/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Movimiento (Física) , PerfusiónRESUMEN
RATIONALE: Kimura disease (KD) is a rare, chronic inflammatory disorder characterized by subcutaneous granuloma in the head and neck region, as well as increased eosinophil counts and high serum immunoglobulin E (IgE) levels. Kimura disease is suspected to be an IgE-mediated disease, associated with an allergic response, in which antigen-specific B cells are stimulated to undergo specific IgE class switching with disease-specific CD4+ T (Th) cells help. Thus, exploration of the Th cells in affected tissues with KD is a highly promising field of the investigation. However, there have been no reports with direct evidence to implicate Th cells in affected lesions with KD. Here we quantitatively demonstrate that CD4+ GATA3+ T cells and interleukin (IL)-4+ IgE+ c-kit+ mast cells prominently infiltrate in affected lesion with KD. PATIENT CONCERNS: A 56-year-old Japanese man who exhibited painless swelling in the left parotid region. DIAGNOSES: Diagnosis of KD was made based on characteristic histopathologic findings, in conjunction with peripheral eosinophilia and elevated serum IgE levels. INTERVENTIONS: The patient underwent corticosteroid therapy and had been followed for 2 years. OUTCOMES: We report a rare case of KD of the parotid region in a 56-year-old man, followed by corticosteroid therapy for 2 years. The mass decreased in size and skin itchiness decreased after therapy. He was discharged without any complications. Furthermore, we quantitatively demonstrate the dominance of CD4+ GATA3+ T cells in affected tissues of KD and detect IL-4+ IgE+ c-kit+ mast cells in lesions by multicolor staining approaches. LESSONS: The findings from this case suggest that peripheral blood eosinophilia might serve as a marker of recurrent disease, long-term follow-up is necessary due to the possibility of recurrent. Interactions among expanded IgE+ B cells, CD4+ GATA3+ T cells, eosinophils, and activated mast cells might play a critical role in the pathogenesis of KD.
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Hiperplasia Angiolinfoide con Eosinofilia/inmunología , Linfocitos B/inmunología , Eosinófilos/inmunología , Inmunoglobulina E/sangre , Mastocitos/inmunología , Hiperplasia Angiolinfoide con Eosinofilia/sangre , Hiperplasia Angiolinfoide con Eosinofilia/diagnóstico , Linfocitos B/patología , Biopsia , Eosinófilos/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Mastocitos/patología , Persona de Mediana EdadRESUMEN
Tumor-associated macrophages (TAMs) promote tumor progression and inhibit anti-tumor immune response by producing various mediators and preferentially express CD163, CD204, and CD206. However, the role of these TAM subsets in oral squamous cell carcinoma (OSCC) remains unclear. Here we investigated the expression and function of TAM subsets in OSCC, especially in cancer cell proliferation. Biopsy sample from 44 patients with OSCC were examined for the expression of TAM markers and EGF by immunohistochemistry. EGF production of TAM subsets isolated from OSCC patients was assessed by flow cytometry. We also examined the effect of conditioned medium from TAM subsets on the proliferation of OSCC cells. CD163+ cells were detected diffusely all over the tumor and connective tissue area, while CD204+ and CD206+ cells were mainly detected in/around the tumors. Flow cytometric analysis found that CD206+ TAMs strongly produced EGF compared with CD163+ and CD204+ TAMs. Cell proliferation and invasion of OSCC cells cultured with conditioned medium of CD206+ TAMs were strongly enhanced and inhibited by anti-EGFR. The number of CD206+ TAMs positively correlated with worse clinical prognosis. Our results revealed differences in localization and EGF production among these TAM subsets. CD206+ TAMs might play a critical role in the proliferation of OSCC via EGF production.
Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Factor de Crecimiento Epidérmico/metabolismo , Lectinas Tipo C/metabolismo , Macrófagos/citología , Lectinas de Unión a Manosa/metabolismo , Neoplasias de la Boca/metabolismo , Receptores de Superficie Celular/metabolismo , Microambiente Tumoral , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Biopsia , Carcinoma de Células Escamosas/patología , Proliferación Celular , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Receptor de Manosa , Persona de Mediana Edad , Neoplasias de la Boca/patología , Invasividad Neoplásica , Receptores Depuradores de Clase A/metabolismoRESUMEN
Low-grade myofibroblastic sarcoma (LGMS) is a rare intermediate tumor, which rarely metastasizes and has myofibroblastic differentiation in various sites. It is particularly associated with the tongue in the head and neck region. The lack of any pathological features means it is difficult to make a conclusive diagnosis of LGMS. The immunohistochemical features and genomic rearrangements, including SS18-SSXs and MYH9-USP6s and the genetic mutations of cancer-associated genes, including APC, CTNNB1, EGFR, KRAS, PIK3CA and p53 were examined in a case of LGMS arising in the tip of the tongue. Immunohistochemically, the tumor cells were positive for alpha-smooth muscle actin and vimentin, as in previous reports. They demonstrated neither genomic rearrangements nor point mutations of cancer-associated genes. Although several tumor cells demonstrated intravascular invasion, the MIB-l labeling index of the cells was the same as the original lesion. To the best of our knowledge, this is the first case report of LGMS arising in the tip of the tongue with intravascular invasion.
RESUMEN
Oral squamous cell carcinoma (OSCC) constitutes over 90% of all cancers in the oral cavity. The prognosis for patients with invasive OSCC is poor; therefore, it is important to understand the molecular mechanisms of invasion and subsequent metastasis not only to prevent cancer progression but also to detect new therapeutic targets against OSCC. Recently, extracellular vesicles-particularly exosomes-have been recognized as intercellular communicators in the tumor microenvironment. As exosomic cargo, deregulated microRNAs (miRNAs) can shape the surrounding microenvironment in a cancer-dependent manner. Previous studies have shown inconsistent results regarding miR-200c-3p expression levels in OSCC cell lines, tissues, or serum-likely because of the heterogeneous characters of the specimen materials. For this reason, single-cell clone analyses are necessary to effectively assess the role of exosome-derived miRNAs on cells within the tumor microenvironment. The present study utilized integrated microarray profiling to compare exosome-derived miRNA and exosome-treated cell-derived mRNA expression. Data were acquired from noninvasive SQUU-A and highly invasive SQUU-B tongue cancer cell clones derived from a single patient to determine candidate miRNAs that promote OSCC invasion. Matrigel invasion assays confirmed that hsa-miR-200c-3p was a key pro-invasion factor among six miRNA candidates. Consistently, silencing of the miR-200c-3p targets, CHD9 and WRN, significantly accelerated the invasive potential of SQUU-A cells. Thus, our data indicate that miR-200c-3p in exosomes derived from a highly invasive OSCC line can induce a similar phenotype in non-invasive counterparts.