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1.
Lancet Rheumatol ; 6(5): e279-e290, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38658114

RESUMO

BACKGROUND: Childhood Sjögren's disease is a rare, underdiagnosed, and poorly-understood condition. By integrating machine learning models on a paediatric cohort in the USA, we aimed to develop a novel system (the Florida Scoring System) for stratifying symptomatic paediatric patients with suspected Sjögren's disease. METHODS: This cross-sectional study was done in symptomatic patients who visited the Department of Pediatric Rheumatology at the University of Florida, FL, USA. Eligible patients were younger than 18 years or had symptom onset before 18 years of age. Patients with confirmed diagnosis of another autoimmune condition or infection with a clear aetiological microorganism were excluded. Eligible patients underwent comprehensive examinations to rule out or diagnose childhood Sjögren's disease. We used latent class analysis with clinical and laboratory variables to detect heterogeneous patient classes. Machine learning models, including random forest, gradient-boosted decision tree, partial least square discriminatory analysis, least absolute shrinkage and selection operator-penalised ordinal regression, artificial neural network, and super learner were used to predict patient classes and rank the importance of variables. Causal graph learning selected key features to build the final Florida Scoring System. The predictors for all models were the clinical and laboratory variables and the outcome was the definition of patient classes. FINDINGS: Between Jan 16, 2018, and April 28, 2022, we screened 448 patients for inclusion. After excluding 205 patients due to symptom onset later than 18 years of age, we recruited 243 patients into our cohort. 26 patients were excluded because of confirmed diagnosis of a disorder other than Sjögren's disease, and 217 patients were included in the final analysis. Median age at diagnosis was 15 years (IQR 11-17). 155 (72%) of 216 patients were female and 61 (28%) were male, 167 (79%) of 212 were White, and 20 (9%) of 213 were Hispanic, Latino, or Spanish. The latent class analysis identified three distinct patient classes: class I (dryness dominant with positive tests, n=27), class II (high symptoms with negative tests, n=98), and class III (low symptoms with negative tests, n=92). Machine learning models accurately predicted patient class and ranked variable importance consistently. The causal graphical model discovered key features for constructing the Florida Scoring System. INTERPRETATION: The Florida Scoring System is a paediatrician-friendly tool that can be used to assist classification and long-term monitoring of suspected childhood Sjögren's disease. The resulting stratification has important implications for clinical management, trial design, and pathobiological research. We found a highly symptomatic patient group with negative serology and diagnostic profiles, which warrants clinical attention. We further revealed that salivary gland ultrasonography can be a non-invasive alternative to minor salivary gland biopsy in children. The Florida Scoring System requires validation in larger prospective paediatric cohorts. FUNDING: National Institute of Dental and Craniofacial Research, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Heart, Lung, and Blood Institute, and Sjögren's Foundation.


Assuntos
Aprendizado de Máquina , Síndrome de Sjogren , Humanos , Estudos Transversais , Criança , Feminino , Masculino , Adolescente , Síndrome de Sjogren/diagnóstico , Índice de Gravidade de Doença , Florida/epidemiologia
2.
Oral Dis ; 29(2): 436-444, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34022097

RESUMO

OBJECTIVES: The role of Human papillomavirus (HPV) in the oral squamous cell carcinoma (OSCC) has not been completely elucidated. The purpose of the present study was to investigate the prevalence and localization of HPV-16 virus in OSCC and to correlate HPV-16 positivity and p16INK4A expression with the clinical and pathological features of OSCC. METHODS: The archives of Oral Pathology at the University of Florida, College of Dentistry were accessed for demographic, clinical, histopathological data, and slides of 114 OSCC patients. HPV-16 positivity of OSCC was evaluated by p16INK4A immunohistochemistry (IHC) and HPV-16 E6/E7mRNA by in situ hybridization (ISH). RESULTS: Out of 114 consecutive pathological slides of OSCC, 16 samples (14%) showed positivity for p16INK4A by IHC and 14 samples (12%) were positive for HPV-16 E6/E7mRNA ISH and the Positivity showed a significant correlation with the patients' age, alcohol consumption, and the degree of OSSC differentiation. The hard palate showed the highest positivity of p16INK4A IHC and HPV-16 mRNA ISH (38%, 36% respectively). CONCLUSION: HPV-16 is a significant factor in oral carcinogenesis. We recommend using p16INK4A as a surrogate marker for HPV detection in OSCC, which can be complemented by RNA ISH for the identification of HPV subtypes.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Infecções por Papillomavirus , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/patologia , Papillomavirus Humano , Papillomavirus Humano 16/genética , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/diagnóstico , Papillomaviridae/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo
3.
Oral Dis ; 29(8): 3313-3324, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36369668

RESUMO

OBJECTIVE: This study aims to determine the prevalence and risk factors associated with lymphoma in primary Sjögren's syndrome (pSS). METHODS: We conducted a cross-sectional study on pSS patients who were registered into the Integrated Data Repository (IDR) at the University of Florida (UF) Health Shands Hospital. The parameters, such as age, sex, race, and smoking status, were included. Lymphoma types in pSS were categorized. The clinical and laboratory features were compared between pSS patients with and those without lymphoma by utilizing the items in the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI). RESULTS: Among 1,211,343 patients, we found 6799 patients (0.56%) with lymphomas and 2562 patients (0.21%) with pSS. Out of the 2562 pSS patients, 67 patients (2.6%) were diagnosed with lymphoma. The difference in the clinical and laboratory features listed under the ESSDAI domains between pSS patients with lymphomas and pSS without it was significant (p < 0.05 or 0.01): fever, weight loss, lymphadenopathy, splenomegaly, lacrimal gland diseases, cough, shortness of breath, hematuria, cerebrovascular accident diseases, peripheral nerve involvement due to vasculitis, neutropenia, and thrombocytopenia. CONCLUSION: We report 2.6% of lymphoma prevalence in pSS, lower than previously reported in the literature.


Assuntos
Linfoma , Síndrome de Sjogren , Humanos , Síndrome de Sjogren/complicações , Síndrome de Sjogren/epidemiologia , Síndrome de Sjogren/diagnóstico , Estudos Transversais , Prevalência , Fatores de Risco , Linfoma/epidemiologia , Linfoma/complicações
4.
Purinergic Signal ; 19(2): 401-420, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36219327

RESUMO

G protein-coupled receptors are the target of more than 30% of all FDA-approved drug therapies. Though the purinergic P2 receptors have been an attractive target for therapeutic intervention with successes such as the P2Y12 receptor antagonist, clopidogrel, P2Y2 receptor (P2Y2R) antagonism remains relatively unexplored as a therapeutic strategy. Due to a lack of selective antagonists to modify P2Y2R activity, studies using primarily genetic manipulation have revealed roles for P2Y2R in a multitude of diseases. These include inflammatory and autoimmune diseases, fibrotic diseases, renal diseases, cancer, and pathogenic infections. With the advent of AR-C118925, a selective and potent P2Y2R antagonist that became commercially available only a few years ago, new opportunities exist to gain a more robust understanding of P2Y2R function and assess therapeutic effects of P2Y2R antagonism. This review discusses the characteristics of P2Y2R that make it unique among P2 receptors, namely its involvement in five distinct signaling pathways including canonical Gαq protein signaling. We also discuss the effects of other P2Y2R antagonists and the pivotal development of AR-C118925. The remainder of this review concerns the mounting evidence implicating P2Y2Rs in disease pathogenesis, focusing on those studies that have evaluated AR-C118925 in pre-clinical disease models.


Assuntos
Dibenzocicloeptenos , Transdução de Sinais , Humanos , Pirimidinonas , Fibrose , Receptores Purinérgicos P2Y2
5.
J Clin Med ; 11(21)2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36362587

RESUMO

Transurethral resection of bladder tumor (TURBT) is a standard treatment for non-muscle invasive bladder cancer. However, catheter-related bladder discomfort (CRBD) often occurs due to bladder irritation caused by indwelling large-diameter urinary catheters and delays patient recovery. We investigated the efficacy of the intraoperative administration of magnesium and ketorolac in preventing early CRBD after TURBT. One hundred patients scheduled for TURBT were enrolled in this prospective, randomized, double-blind study from December 2021 to June 2022. During surgery, the experimental group (n = 48) received intravenous magnesium and ketorolac, and the control group (n = 50) received only intravenous ketorolac. The primary outcome was CRBD incidence immediately after surgery. CRBD severity and the postoperative recovery profiles were also evaluated. Compared to the control group, the experimental group had significantly less CRBD until 1 h after surgery (0 h: 31.3% vs. 52.0%, p = 0.037; 1 h: 54.2% vs. 74.0%, p = 0.041). However, the two groups did not differ in other postoperative findings, including CRBD severity. Co-administration of magnesium and ketorolac during surgery significantly decreased the incidence of early CRBD after TURBT compared to the single use of ketorolac.

6.
J Int Med Res ; 50(8): 3000605221115163, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35929014

RESUMO

Endobronchial ablative therapy (EAT) in patients with preexisting obstructive airway disease can cause hypoxemia because bronchoscope insertion interferes with ventilation and a low fraction of inspired oxygen (FiO2) is essential to avoid airway fire. A man in his early 50s with moderately severe obstructive airway disease was scheduled for EAT for treatment of tracheal papillomatosis. Ventilation and oxygenation would have been difficult because of narrowing of the endotracheal tube by bronchoscopic insertion and a low FiO2; therefore, an i-gel supraglottic airway device with a larger inner diameter was inserted. All visible intratracheal papillomas were ablated by a potassium titanyl phosphate laser through the bronchoscopic port that passed through the lumen of the i-gel at an FiO2 of 0.3. During anesthesia for EAT, the i-gel supraglottic airway device provided a wider lumen for ventilation. We were thus able to provide stable ventilation at an FiO2 of 0.3 during EAT in this patient with obstructive airway disease, avoiding airway fire and hypoxemia.


Assuntos
Máscaras Laríngeas , Doença Pulmonar Obstrutiva Crônica , Manuseio das Vias Aéreas , Anestesia Geral , Humanos , Hipóxia/etiologia , Intubação Intratraqueal/efeitos adversos , Masculino , Doença Pulmonar Obstrutiva Crônica/cirurgia
7.
Medicine (Baltimore) ; 101(5): e28769, 2022 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-35119040

RESUMO

RATIONALE: Supraglottic stenosis is a rare cause of airway obstruction. It can be induced by radiation, trauma, autoimmune diseases, or caustic exposure, and is often misdiagnosed as asthma. Detailed airway information is necessary to re-establish the normal functioning of the airway. PATIENT CONCERNS: A 78-year-old woman with severe dyspnea and hypercarbia was scheduled for surgery to resolve airway obstruction, previously known as supraglottic stenosis. DIAGNOSES: To determine the exact internal shape of the stenotic lesion, we reconstructed three dimensional computed tomography (CT) images depicted a tubular supraglottic stenosis. INTERVENTIONS: The patient underwent tracheotomy under monitored anesthesia care and local anesthesia, followed by general anesthesia. For long-term management of the patient, the otorhinolaryngologist excised the supraglottic stricture via micro-laryngeal surgery using a CO2 laser and applied mitomycin to prevent further obstruction. OUTCOMES: The patient recovered uneventfully after anesthesia, and symptom due to supraglottic stenosis was improved. LESSONS: During airway management of patients with postlaryngectomy supraglottic stenosis, three-dimensional reconstructed computed tomography images facilitate airway configuration in addition to endoscopy and other radiological findings.


Assuntos
Obstrução das Vias Respiratórias , Laringoestenose , Idoso , Obstrução das Vias Respiratórias/diagnóstico por imagem , Obstrução das Vias Respiratórias/etiologia , Obstrução das Vias Respiratórias/cirurgia , Constrição Patológica/diagnóstico por imagem , Constrição Patológica/etiologia , Constrição Patológica/cirurgia , Feminino , Humanos , Laringoestenose/diagnóstico por imagem , Laringoestenose/etiologia , Laringoestenose/cirurgia , Tomografia Computadorizada por Raios X
8.
Front Immunol ; 12: 704193, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34249010

RESUMO

Objectives: The aim of this study was to evaluate the clinical validity of early Sjögren's syndrome (SS) autoantibodies (eSjA), which were originally marketed for early diagnosis of SS, for juvenile SS (JSS) in a recently identified pediatric cohort. Methods: A total of 105 symptomatic subjects with eSjA results available were evaluated at the Center for Orphaned Autoimmune Disorders at the University of Florida and enrolled for this study. JSS diagnosis was based on the 2016 ACR/EULAR SS criteria. Demographic/clinical/laboratory parameters were compared between JSS (n = 27) and non-JSS (n = 78) for % positivity, sensitivity, and specificity of eSjA (SP1, anti-salivary protein; CA6, anti-carbonic anhydrase VI; PSP, anti-parotid secretory protein) and classic SS-autoantibodies (cSjA; ANA, SSA/SSB, RF, and others) either alone or in combination. Associations between eSjA and diagnostic/glandular parameters were also determined by Fisher's exact test. Results: Compared to non-JSS, JSS patients exhibited sicca symptoms demonstrating reduced unstimulated salivary flow rate (USFR) and abnormal glandular features revealed by salivary gland ultrasound (SGUS). Among cSjA, ANA demonstrated the highest sensitivity of 69.2%, while SSA, SSB, and RF showed around 95% specificities for JSS diagnosis. The % positive-SSA was notably higher in JSS than non-JSS (56% vs. 5%). Of eSjA, anti-CA6 IgG was the most prevalent without differentiating JSS (37%) from non-JSS (32%). Sensitivity and specificity of eSjA were 55.6 and 26.9%, respectively. Autoantibodies with potentially applicable specificity/sensitivity for JSS were seen only in cSjA without a single eSjA included. There were no associations detected between eSjA and focus score (FS), USFR, SSA, SGUS, and parotitis/glandular swelling analyzed in the entire cohort, JSS, and non-JSS. However, a negative association between anti-PSP and parotitis/glandular swelling was found in a small group of positive-SSA (n = 19, p = 0.02) whereas no such association was found between anti-PSP-positive compared to anti-PSP-negative. JSS and non-JSS groups differed in FS, USFR, and EULAR SS Patient Reported Index Dryness/Mean in CA6/PSP/ANA, SP1, and SSA-positive groups, respectively. Additionally, a higher FS was found in RF-positive than RF-negative individuals. Conclusions: eSjA underperformed cSjS in differentiating JSS from non-JSS. The discovery of clinical impact of eSjA on early diagnosis of JSS necessitates a longitudinal study.


Assuntos
Autoanticorpos/imunologia , Glândulas Salivares/imunologia , Proteínas e Peptídeos Salivares/imunologia , Síndrome de Sjogren , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Florida , Humanos , Estudos Longitudinais , Masculino , Sensibilidade e Especificidade , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/imunologia
9.
Artigo em Inglês | MEDLINE | ID: mdl-34274288

RESUMO

OBJECTIVE: Patients with idiopathic pulmonary fibrosis (IPF) commonly present with sicca symptoms. This study aimed to assess labial minor salivary glands (LMSGs) in those patients to rule out Sjögren's syndrome (SS), in which sicca symptoms are the clinical hallmark. STUDY DESIGN: Cases of patients with IPF with sicca symptoms referred to the oral medicine clinic at the University of Florida within the last 13 years were selected with institutional review board approval. Demographic characteristics, clinical findings, laboratory results, and histomorphologic parameters were retrospectively analyzed. RESULTS: A total of 12 patients (9 men and 3 women, ages 55-76 years) were identified. History of exposure to asbestos or chemicals, smoking, and medication information was obtained. All patients reported sicca symptoms with 57% of those exhibiting objective or borderline dryness. Anti-SSA/Ro and anti-SSB/La were positive in 25% and 8% of the cases, respectively. Microscopically, 1 out of 12 patients was biopsy positive in the absence of anti-SSA/Ro, fulfilling the 2016 SS criteria with positive sialometry. CONCLUSIONS: A LMSG biopsy is critical to identify SS in patients with diagnosed IPF and present sicca symptoms, especially those with negative serology, as revealed in our study.


Assuntos
Fibrose Pulmonar Idiopática , Síndrome de Sjogren , Idoso , Biópsia , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Glândulas Salivares Menores , Síndrome de Sjogren/complicações , Síndrome de Sjogren/diagnóstico
10.
Clin Exp Rheumatol ; 39(4): 795-803, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33124573

RESUMO

OBJECTIVES: To elucidate the clinical values of anti-M3R in Sjögren's syndrome (SS) in the largest cohort for an anti-M3R study. METHODS: The plasma of 361 subjects (156 primary SS [pSS], 62 non-SS-sicca [SICCA], 40 systemic lupus erythematosus [SLE], 50 rheumatoid arthritis [RA], and 53 healthy controls [HC]) was screened using our modified On-Cell-Western assay. Saliva from pSS (n=37) compared to SICCA (n=26) was also analysed. The sensitivity and specificity of anti-M3R and its association with comprehensive clinical and laboratory features were determined. RESULTS: Plasma-anti-M3R was higher in pSS compared to other groups, differentiating pSS with good-to-excellent diagnostic power with a specificity of 85% and a sensitivity between 75% and 98%. pSS plasma-anti-M3R was positively correlated with ocular staining scores, anti-Ro/SSA, IgG, ß2-microglobulin, ESR, and ESSDAI. It was negatively correlated with WBC, C4, and salivary scintigraphic indices. Saliva-anti-M3R was 3.59 times higher in pSS than in SICCA. Interestingly, the agreement between the 2002 American European Consensus Group criteria and the criteria substituted with plasma-anti-M3R for the lip biopsy reached 92%, with a significant kappa of 0.824. CONCLUSIONS: Anti-M3R enhances sensitivity and specificity for SS diagnosis, correlating with ocular dryness and glandular hypofunction, and the haematological/biological domains of the ESSDAI. Our findings also highlight the clinical significance of anti-M3R in SS diagnosis, especially where clinical assessments, such as lip biopsy, sialometry, or ocular evaluation, by multi-disciplinary specialists are limited.


Assuntos
Artrite Reumatoide , Lúpus Eritematoso Sistêmico , Síndrome de Sjogren , Autoanticorpos , Humanos , Saliva , Síndrome de Sjogren/diagnóstico
11.
Int J Mol Sci ; 21(23)2020 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-33260559

RESUMO

Severe dry mouth in patients with Sjögren's Syndrome, or radiation therapy for patients with head and neck cancer, significantly compromises their oral health and quality of life. The current clinical management of xerostomia is limited to palliative care as there are no clinically-proven treatments available. Previously, our studies demonstrated that mouse bone marrow-derived mesenchymal stem cells (mMSCs) can differentiate into salivary progenitors when co-cultured with primary salivary epithelial cells. Transcription factors that were upregulated in co-cultured mMSCs were identified concomitantly with morphological changes and the expression of acinar cell markers, such as α-amylase (AMY1), muscarinic-type-3-receptor(M3R), aquaporin-5(AQP5), and a ductal cell marker known as cytokeratin 19(CK19). In the present study, we further explored inductive molecules in the conditioned media that led to mMSC reprogramming by high-throughput liquid chromatography with tandem mass spectrometry and systems biology. Our approach identified ten differentially expressed proteins based on their putative roles in salivary gland embryogenesis and development. Additionally, systems biology analysis revealed six candidate proteins, namely insulin-like growth factor binding protein-7 (IGFBP7), cysteine-rich, angiogenetic inducer, 61(CYR61), agrin(AGRN), laminin, beta 2 (LAMB2), follistatin-like 1(FSTL1), and fibronectin 1(FN1), for their potential contribution to mMSC transdifferentiation during co-culture. To our knowledge, our study is the first in the field to identify soluble inductive molecules that drive mMSC into salivary progenitors, which crosses lineage boundaries.


Assuntos
Transdiferenciação Celular , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Proteoma/metabolismo , Glândulas Salivares/citologia , Transdução de Sinais , Animais , Forma Celular/efeitos dos fármacos , Transdiferenciação Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Ontologia Genética , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos
12.
Int J Mol Sci ; 20(3)2019 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-30759717

RESUMO

Sjögren's syndrome (SjS) is an autoimmune disease that destroys the salivary glands and results in severe dry mouth. Mesenchymal stem cell (MSC) transplantation has been recently proposed as a promising therapy for restoring cells in multiple degenerative diseases. We have recently utilized advanced proteomics biochemical assays to identify the key molecules involved in the mesenchymal-epithelial transition (MET) of co-cultured mouse bone-marrow-derived MSCs mMSCs with primary salivary gland cells. Among the multiple transcription factors (TFs) that were differentially expressed, two major TFs were selected: muscle, intestine, and stomach expression-1 (MIST1) and transcription factor E2a (TCF3). These factors were assessed in the current study for their ability to drive the expression of acinar cell marker, alpha-salivary amylase 1 (AMY1), and ductal cell marker, cytokeratin19 (CK19), in vitro. Overexpression of MIST1-induced AMY1 expression while it had little effect on CK19 expression. In contrast, TCF3 induced neither of those cellular markers. Furthermore, we have identified that mMSCs express muscarinic-type 3 receptor (M3R) mainly in the cytoplasm and aquaporin 5 (AQP5) in the nucleus. While MIST1 did not alter M3R levels in mMSCs, a TCF3 overexpression downregulated M3R expressions in mMSCs. The mechanisms for such differential regulation of glandular markers by these TFs warrant further investigation.


Assuntos
Amilases/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Glândulas Salivares/metabolismo , Animais , Aquaporina 5/metabolismo , Biomarcadores/metabolismo , Células Cultivadas , Técnicas de Cocultura/métodos , Regulação para Baixo/fisiologia , Regulação da Expressão Gênica/fisiologia , Humanos , Queratina-19/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteômica/métodos , Síndrome de Sjogren/metabolismo , Fatores de Transcrição/metabolismo
13.
Mol Cells ; 42(1): 87-95, 2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30699287

RESUMO

Long interspersed element-1 (LINE-1 or L1) is an autonomous retrotransposon, which is capable of inserting into a new region of genome. Previous studies have reported that these elements lead to genomic variations and altered functions by affecting gene expression and genetic networks. Mounting evidence strongly indicates that genetic diseases or various cancers can occur as a result of retrotransposition events that involve L1s. Therefore, the development of methodologies to study the structural variations and interpersonal insertion polymorphisms by L1 element-associated changes in an individual genome is invaluable. In this study, we applied a systematic approach to identify human-specific L1s (i.e., L1Hs) through the bioinformatics analysis of high-throughput next-generation sequencing data. We identified 525 candidates that could be inferred to carry non-reference L1Hs in a Korean individual genome (KPGP9). Among them, we randomly selected 40 candidates and validated that approximately 92.5% of non-reference L1Hs were inserted into a KPGP9 genome. In addition, unlike conventional methods, our relatively simple and expedited approach was highly reproducible in confirming the L1 insertions. Taken together, our findings strongly support that the identification of non-reference L1Hs by our novel target enrichment method demonstrates its future application to genomic variation studies on the risk of cancer and genetic disorders.


Assuntos
Povo Asiático/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Elementos Nucleotídeos Longos e Dispersos/genética , Sequência de Bases , Biblioteca Gênica , Genoma Humano , Humanos , Mutagênese Insercional/genética , Reprodutibilidade dos Testes
14.
Spec Care Dentist ; 39(1): 51-55, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30431178

RESUMO

The development of dysplastic changes in oral epithelial lesions is a potential long-term complication after hematopoietic stem cell transplantation (HSCT). This may be related to mechanisms including radiation and chemotherapy regimens, chronic graft-versus-host disease (cGVHD), inflammation, and prolonged immunosuppression. The current case describes a 54-year-old male with multiple myeloma treated by autologous and allogenic HSCT followed by development of cGVHD (mouth, skin and the eyes) with the complaint of diffuse white lesions on the buccal mucosa, tongue, and palate. A biopsy performed with histopathological analysis revealed moderate to severe epithelial dysplasia with hyperkeratosis, positive for p16INK4A as a surrogate marker for human papillomavirus (HPV). Our finding suggests a possible association of oral dysplasia and HPV in patients after receiving allogenic HSCT with the necessity of more clinical follow-ups for those patients that may be at a higher risk for the development of oral dysplasia associated with HPV.


Assuntos
Doença Enxerto-Hospedeiro/etiologia , Mucosa Bucal/virologia , Mieloma Múltiplo/terapia , Papillomaviridae/isolamento & purificação , Transplante de Células-Tronco/efeitos adversos , Biópsia , Humanos , Masculino , Pessoa de Meia-Idade
15.
Clin Exp Rheumatol ; 36 Suppl 112(3): 31-40, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28421993

RESUMO

OBJECTIVES: To investigate the expressions of interferon (IFN)-λs and their receptor, IL28RA, in minor salivary glands (MSG) of pSS patients and their effects on the salivary gland cells. METHODS: The expressions of IFN-λs and IL28RA were evaluated in MSG by immunohistochemistry in 15 patients with pSS and in 5 patients with non-SS sicca. Poly(I:C)-induced IL-28A and IL-29 expressions were determined in immortalized human salivary gland acinar (NS-SV-AC) and ductal (NS-SV-DC) cell lines. We assessed the effect of IFN-λs on the expressions of typical interferon-inducible genes, B-cell activating factor (BAFF) and CXCL10, and the synergistic effect of IL-29 and type I or II IFN on their expressions. The serum IL-29 levels were measured in 44 patients with pSS and 22 healthy controls. RESULTS: IFN-λs expression was significantly higher in MSG from pSS than from non-SS sicca controls. Poly(I:C) treatment led to the induction of IL-28A and IL-29 in the salivary gland cell lines. In the NS-SV-DC cells, IFN-λ significantly increased the levels of BAFF and CXCL10 in a time and dose-dependent manner. Moreover, there was a synergistic effect between IL-29 and IFN-α in the induction of BAFF and CXCL10 expressions by prolonged STAT1 phosphorylation. However, the serum IL-29 levels were not significantly higher in pSS patients than in healthy controls. CONCLUSIONS: Our results suggest the possibility for IFN-λ to play a role by participating local inflammation in the salivary glands of pSS through direct and indirect regulations of the expressions of BAFF and CXCL10 in salivary gland epithelium.


Assuntos
Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Interferon-alfa/farmacologia , Interferon gama/metabolismo , Glândulas Salivares Menores/efeitos dos fármacos , Glândulas Salivares Menores/metabolismo , Síndrome de Sjogren/metabolismo , Adulto , Fator Ativador de Células B/metabolismo , Estudos de Casos e Controles , Linhagem Celular , Quimiocina CXCL10/metabolismo , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Células Epiteliais/imunologia , Feminino , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interferon gama/farmacologia , Interferons , Interleucinas/genética , Interleucinas/metabolismo , Masculino , Pessoa de Meia-Idade , Fosforilação , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Receptores de Interferon , Fator de Transcrição STAT1/metabolismo , Glândulas Salivares Menores/imunologia , Transdução de Sinais/efeitos dos fármacos , Síndrome de Sjogren/genética , Síndrome de Sjogren/imunologia , Fatores de Tempo , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/metabolismo , Regulação para Cima
16.
PLoS One ; 12(2): e0169677, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28158262

RESUMO

Severe xerostomia (dry mouth) compromises the quality of life in patients with Sjögren's syndrome or radiation therapy for head and neck cancer. A clinical management of xerostomia is often unsatisfactory as most interventions are palliative with limited efficacy. Following up our previous study demonstrating that mouse BM-MSCs are capable of differentiating into salivary epithelial cells in a co-culture system, we further explored the molecular basis that governs the MSC reprogramming by utilizing high-throughput iTRAQ-2D-LC-MS/MS-based proteomics. Our data revealed the novel induction of pancreas-specific transcription factor 1a (PTF1α), muscle, intestine and stomach expression-1 (MIST-1), and achaete-scute complex homolog 3 (ASCL3) in 7 day co-cultured MSCs but not in control MSCs. More importantly, a common notion of pancreatic-specific expression of PTF1 α was challenged for the first time by our verification of PTF1 α expression in the mouse salivary glands. Furthermore, a molecular network simulation of our selected putative MSC reprogramming factors demonstrated evidence for their perspective roles in salivary gland development. In conclusion, quantitative proteomics with extensive data analyses narrowed down a set of MSC reprograming factors potentially contributing to salivary gland regeneration. Identification of their differential/synergistic impact on MSC conversion warrants further investigation.


Assuntos
Diferenciação Celular/efeitos da radiação , Proteoma/metabolismo , Glândulas Salivares/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Western Blotting , Diferenciação Celular/genética , Células Cultivadas , Análise por Conglomerados , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteômica , Qualidade de Vida , Glândulas Salivares/fisiologia , Espectrometria de Massas em Tandem , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
17.
Biochem Biophys Res Commun ; 466(4): 704-10, 2015 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-26399685

RESUMO

Purinergic receptors, particularly type 7 (P2RX7), are involved in apoptotic cell death. However, the expression and function of P2RX7 are suppressed in HSG cells. In the present study, we explored whether P2RX7 function is regulated by epigenetic alteration of the receptors in two different cell lines, HSG cells derived from human submandibular ducts, and A253 cells, originated from human submandibular carcinoma. We discovered that HSG cells expressed all subtypes of purinergic receptors, excluding P2RX7, at the mRNA level. However, treatment of the cells with 5-Aza-CdR, a DNA demethylating agent, increased the mRNA expression levels of P2RX7 in a time-dependent manner. Furthermore, 5-Aza-CdR completely rescued the calcium response induced by P2RX7 agonist BzATP, a response that was absent in untreated HSG cells. In contrast, A253 cells showed a moderate methylation pattern in the P2RX7 CpG island. Most CG pairs from the first to the 21st were methylated in untreated HSG cells, but 5-Aza-CdR-treatment partially demethylated the methylated CG pairs. We obtained similar results when investigated human tissues; the CG pairs in the P2RX7 CpG islands showed hypermethylation and hypomethylation patterns in human normal and cancer tissues, respectively. Our results suggest that the expression level and function of P2RX7 are regulated by DNA methylation in epithelial cells.


Assuntos
Epigênese Genética , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/metabolismo , Glândulas Salivares/metabolismo , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/farmacologia , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Sequência de Bases , Linhagem Celular , Ilhas de CpG , Metilação de DNA , Decitabina , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Dados de Sequência Molecular , Agonistas do Receptor Purinérgico P2X/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Glândulas Salivares/citologia , Glândulas Salivares/efeitos dos fármacos
18.
PLoS One ; 9(11): e112158, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25402494

RESUMO

Patients with Sjögren's syndrome or head and neck cancer patients who have undergone radiation therapy suffer from severe dry mouth (xerostomia) due to salivary exocrine cell death. Regeneration of the salivary glands requires a better understanding of regulatory mechanisms by which stem cells differentiate into exocrine cells. In our study, bone marrow-derived mesenchymal stem cells were co-cultured with primary salivary epithelial cells from C57BL/6 mice. Co-cultured bone marrow-derived mesenchymal stem cells clearly resembled salivary epithelial cells, as confirmed by strong expression of salivary gland epithelial cell-specific markers, such as alpha-amylase, muscarinic type 3 receptor, aquaporin-5, and cytokeratin 19. To identify regulatory factors involved in this differentiation, transdifferentiated mesenchymal stem cells were analyzed temporarily by two-dimensional-gel-electrophoresis, which detected 58 protein spots (>1.5 fold change, p<0.05) that were further categorized into 12 temporal expression patterns. Of those proteins only induced in differentiated mesenchymal stem cells, ankryin-repeat-domain-containing-protein 56, high-mobility-group-protein 20B, and transcription factor E2a were selected as putative regulatory factors for mesenchymal stem cell transdifferentiation based on putative roles in salivary gland development. Induction of these molecules was confirmed by RT-PCR and western blotting on separate sets of co-cultured mesenchymal stem cells. In conclusion, our study is the first to identify differentially expressed proteins that are implicated in mesenchymal stem cell differentiation into salivary gland epithelial cells. Further investigation to elucidate regulatory roles of these three transcription factors in mesenchymal stem cell reprogramming will provide a critical foundation for a novel cell-based regenerative therapy for patients with xerostomia.


Assuntos
Células Epiteliais/metabolismo , Células-Tronco Mesenquimais/metabolismo , Glândulas Salivares/citologia , Animais , Biomarcadores/metabolismo , Transdiferenciação Celular , Técnicas de Cocultura , Biologia Computacional , Células Epiteliais/citologia , Masculino , Células-Tronco Mesenquimais/citologia , Camundongos , Proteoma , Proteômica/métodos , Fatores de Transcrição/metabolismo
19.
Immunotherapy ; 6(4): 377-80, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24815778

RESUMO

Evaluation of: Vergadi E, Vaporidi K, Theodorakis EE et al. Akt2 deficiency protects from acute lung injury via alternative macrophage activation and miR-146a induction in mice. J. Immunol. 192, 394-406 (2013). Acute respiratory distress syndrome currently has limited effective treatments; however, recent evidence suggests that modulation of alveolar macrophage responses may be an effective method for protection or repair of lung injury. Vergadi et al. are the first to demonstrate that depletion of Akt2 kinase and microRNA-146a induction in mice resulted in polarization of alveolar macrophages towards an M2 activation phenotype and resulted in less severe injury following acid-induced lung injury. However, this M2 polarization also resulted in increased lung bacterial load following infection with Pseudomonas aeruginosa.


Assuntos
Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/imunologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-akt/deficiência , Animais
20.
J Periodontol ; 85(6): e212-23, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24592909

RESUMO

BACKGROUND: Xylitol is a well-known anticaries agent and has been used for the prevention and treatment of dental caries. In this study, the anti-inflammatory effects of xylitol are evaluated for possible use in the prevention and treatment of periodontal infections. METHODS: Cytokine expression was stimulated in THP-1 (human monocyte cell line)-derived macrophages by live Porphyromonas gingivalis, and enzyme-linked immunosorbent assay and a commercial multiplex assay kit were used to determine the effects of xylitol on live P. gingivalis-induced production of cytokine. The effects of xylitol on phagocytosis and the production of nitric oxide were determined using phagocytosis assay, viable cell count, and Griess reagent. The effects of xylitol on P. gingivalis adhesion were determined by immunostaining, and costimulatory molecule expression was examined by flow cytometry. RESULTS: Live P. gingivalis infection increased the production of representative proinflammatory cytokines, such as tumor necrosis factor-α and interleukin (IL)-1ß, in a multiplicity of infection- and time-dependent manner. Live P. gingivalis also enhanced the release of cytokines and chemokines, such as IL-12 p40, eotaxin, interferon γ-induced protein 10, monocyte chemotactic protein-1, and macrophage inflammatory protein-1. The pretreatment of xylitol significantly inhibited the P. gingivalis-induced cytokines production and nitric oxide production. In addition, xylitol inhibited the attachment of live P. gingivalis on THP-1-derived macrophages. Furthermore, xylitol exerted antiphagocytic activity against both Escherichia coli and P. gingivalis. CONCLUSION: These findings suggest that xylitol acts as an anti-inflammatory agent in THP-1-derived macrophages infected with live P. gingivalis, which supports its use in periodontitis.


Assuntos
Anti-Inflamatórios/farmacologia , Macrófagos/efeitos dos fármacos , Porphyromonas gingivalis/efeitos dos fármacos , Xilitol/farmacologia , Aderência Bacteriana/efeitos dos fármacos , Contagem de Células , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CCL2/efeitos dos fármacos , Quimiocina CXCL10/efeitos dos fármacos , Quimiocinas CC/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Humanos , Epitopos Imunodominantes/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Interleucina-12/análise , Interleucina-1beta/efeitos dos fármacos , Proteínas Inflamatórias de Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Monócitos/imunologia , Óxido Nítrico/análise , Fragmentos de Peptídeos/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Porphyromonas gingivalis/imunologia , Fator de Necrose Tumoral alfa/efeitos dos fármacos
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