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1.
Cancers (Basel) ; 13(21)2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34771551

RESUMO

Matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) can determine the spatial distribution of analytes such as protein distributions in a tissue section according to their mass-to-charge ratio. Here, we explored the clinical potential of machine learning (ML) applied to MALDI MSI data for cancer diagnostic classification using tissue microarrays (TMAs) on 302 colorectal (CRC) and 257 endometrial cancer (EC)) patients. ML based on deep neural networks discriminated colorectal tumour from normal tissue with an overall accuracy of 98% in balanced cross-validation (98.2% sensitivity and 98.6% specificity). Moreover, our machine learning approach predicted the presence of lymph node metastasis (LNM) for primary tumours of EC with an accuracy of 80% (90% sensitivity and 69% specificity). Our results demonstrate the capability of MALDI MSI for complementing classic histopathological examination for cancer diagnostic applications.

2.
Commun Biol ; 4(1): 1067, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34518628

RESUMO

Cell embedment into a solid support matrix is considered essential for the culture of intestinal epithelial organoids and tumoroids, but this technique presents challenges that impede scalable culture expansion, experimental manipulation, high-throughput screening and diagnostic applications. We have developed a low-viscosity matrix (LVM) suspension culture method that enables efficient establishment and propagation of organoids and tumoroids from the human large intestine. Organoids and tumoroids cultured in LVM suspension recapitulate the morphological development observed in solid matrices, with tumoroids reflecting the histological features and genetic heterogeneity of primary colorectal cancers. We demonstrate the utility of LVM suspension culture for organoid and tumoroid bioreactor applications and biobanking, as well as tumoroid high-throughput drug sensitivity testing. These methods provide opportunities for the study and use of patient-derived organoids and tumoroids from the large intestine.

3.
Oral Dis ; 27(6): 1572-1579, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33085827

RESUMO

OBJECTIVES: To evaluate the oral shedding of herpesviruses in patients undergoing hematopoietic stem cell transplantation (HSCT) and correlate it with oral mucositis (OM). METHODS: Saliva samples were collected before the HSCT and on day D + 8. Multiplex Polymerse Chain Reaction (PCR) was performed to detect herpes simplex virus (HSV)-1 and HSV-2, Epstein-Barr virus (EBV), Cytomegalovirus (CMV), Variella-zoster virus (VZV), and human herpesvirus (HHV)-6, HHV-7, and HHV-8. OM was assessed according to WHO criteria. RESULTS: Thirty one patients were enrolled, in which 20 of 31 (64.5%) were males; median age was 50 (21-70) years; 16 of 31 (51.6%) underwent allo-HSCT; and 15 of 31 (48.4%) underwent auto-HSCT. On D + 8, OM grades III and IV were observed in 8 of 31 (25.8%) patients. In the first salivary collection, EBV was found in 24 of 31 (77.4%), followed by HHV-6 (7/31, 22.6%) and HHV-7 (8/31 25.8%). In the second collection, EBV was found in 24 of 27(89%), followed by HSV-1 (8/27, 30%) and CMV, HHV-6, and HHV-7 (5/27, 18.5%, each one). On D + 8, OM grades II and IV were associated with the presence of HSV-1. HSV-1 was also associated with worsening degrees of OM on D + 15. CONCLUSION: The presence of HSV-1 and CMV in oral samples was more frequent on day D + 8 after HSCT. HSV-1 detection was associated with severity and worsening of OM. HSV-1 and CMV seem to be associated with oral dysbiosis due to HSCT.


Assuntos
Infecções por Citomegalovirus , Infecções por Vírus Epstein-Barr , Transplante de Células-Tronco Hematopoéticas , Herpesvirus Humano 1 , Citomegalovirus/genética , DNA Viral , Infecções por Vírus Epstein-Barr/complicações , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 1/genética , Herpesvirus Humano 4/genética , Humanos , Masculino , Pessoa de Meia-Idade
4.
Heliyon ; 6(10): e05194, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33088959

RESUMO

Objective: This study aimed to investigate the use of texture analysis for characterization of radicular cysts and periapical granulomas and to assess its efficacy to differentiate between both lesions with histological diagnosis. Methods: Cone beam computed tomography (CBCT) images were obtained from 19 patients with 25 periapical lesions (14 radicular cysts and 11 periapical granulomas) confirmed by biopsy. Regions of interest were created in the lesions from which 11 texture parameters were calculated. Spearman's correlation analysis was performed and adjusted with Benjamini-Hochberg false discovery rate procedure (FDR <0.005). Results: The texture parameters used to differentiate the lesions were assessed by using a receiver operating characteristic analysis. Five texture parameters were predictive of lesion differentiation for eight positions: angular second moment; sum of squares; sum of average; contrast; correlation. Conclusion: Texture analysis of CBCT scans distinguishes radicular cysts from periapical granulomas and can be a promising diagnostic tool for periapical lesions. Clinical significance: Texture analysis can be used in diagnostic and treatment monitoring to provide supplementary information.

5.
Cell Death Dis ; 11(9): 735, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913182

RESUMO

Novel targets are required to improve the outcomes for patients with colorectal cancers. In this regard, the selective inhibitor of the pro-survival protein BCL2, venetoclax, has proven highly effective in several hematological malignancies. In addition to BCL2, potent and highly selective small molecule inhibitors of its relatives, BCLxL and MCL1, are now available, prompting us to investigate the susceptibility of colorectal cancers to the inhibition of one or more of these pro-survival proteins. While targeting BCLxL, but not BCL2 or MCL1, on its own had some impact, most (15/17) of the immortalized colorectal cancer cell lines studied were efficiently killed by the combined targeting of BCLxL and MCL1. Importantly, these in vitro findings were confirmed in a xenograft model and, interestingly, in all (5/5) patient derived tumor organoids evaluated. Our results lend strong support to the notion that BCLxL and MCL1 are highly promising targets for further evaluation in efforts to improve the treatment of colorectal cancers.


Assuntos
Neoplasias Colorretais/genética , Suscetibilidade a Doenças/metabolismo , Fragmentos de Peptídeos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Humanos , Camundongos
6.
Braz Oral Res ; 34: e108, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32876121

RESUMO

Asymptomatic Apical Periodontitis is essentially an inflammatory disease of microbial aetiology. Association and function of the cell components involved, or specific inductive factors and growth mediators associated with development, maintenance and resolution of the periapical lesions are still unknown. The objective of this study was to evaluate the concentration of Regulatory T cells (FoxP3+; Treg), Langerhans cells (CD1a+; LC) and mast cells in asymptomatic apical periodontitis. 73 cases were selected: 30 periapical granulomas, 29 radicular cysts and 14 residual cysts. All groups were submitted to morphological analysis for classification of inflammatory infiltrate and thickness of the epithelial lining as well as to immunohistochemical analysis for detection of LC and Treg cells. Toluidine blue staining was used for detecting mast cells. Analysis showed higher mean numbers of LC (8.2 cells/0.2mm2), and Treg cells in radicular cysts (5.910 cells/0.2mm2). As for mast cells, it was found that radicular cysts had a higher mean number of these cells compared to other periapical lesions (12.68 cells/0.2mm2). The association between thickness of the epithelial lining and inflammatory cells showed that the presence of hypertrophic epithelium in radicular cysts presented higher density of LC. The number of LC and Treg cells play an important role in the control of the inflammatory micro-environment in periapical granulomas and radicular cysts, respectively. The presence of mast cells in radicular cysts may be associated with progression of the lesion. Knowledge regarding the inflammatory cell profile is therefore essential for a better understanding of the pathogenesis of asymptomatic periapical periodontitis.


Assuntos
Periodontite Periapical , Humanos , Células de Langerhans , Mastócitos , Granuloma Periapical , Cisto Radicular , Linfócitos T Reguladores , Microambiente Tumoral
7.
Anal Bioanal Chem ; 412(10): 2339-2351, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32006064

RESUMO

Fatty acids are a major source of structural diversity within the lipidome due to variations in their acyl chain lengths, branching, and cyclization, as well as the number, position, and stereochemistry of double bonds within their mono- and poly-unsaturated species. Here, the utility of 193 nm UltraViolet PhotoDissociation tandem mass spectrometry (UVPD-MS/MS) has been evaluated for the detailed structural characterization of a series of unsaturated fatty acid lipid species. UVPD-MS/MS of unsaturated fatty acids is shown to yield pairs of unique diagnostic product ions resulting from cleavages adjacent to their C=C double bonds, enabling unambiguous localization of the site(s) of unsaturation within these lipids. The effect of several experimental variables on the observed fragmentation behaviour and UVPD-MS/MS efficiency, including the position and number of double bonds, the effect of conjugated versus non-conjugated double bonds, the number of laser pulses, and the influence of alkali metal cations (Li, Na, K) as the ionizing adducts, has been evaluated. Importantly, the abundance of the diagnostic ions is shown to enable relative quantitation of mixtures of fatty acid isomers across a range of molar ratios. Finally, the practical application of 193 nm UVPD-MS/MS is demonstrated via characterization of changes in the ratios of fatty acid double bond positional isomers in isogenic colorectal cancer cell lines. This study therefore demonstrates the practicality of UVPD-MS/MS for the structural characterization of fatty acid isomers in lipidome analysis workflows.


Assuntos
Ácidos Graxos Insaturados/química , Espectrometria de Massas em Tandem/métodos , Humanos , Isomerismo , Lipidômica , Estrutura Molecular , Espectrometria de Massas em Tandem/instrumentação
8.
J Periodontol ; 91(9): 1139-1147, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32012280

RESUMO

BACKGROUND: Patients with chronic kidney disease (CKD) have inability to maintain the normal levels of protein metabolism products, blood pressure and hematocrit. Periodontal disease involves an inflammatory destructive process. Identification of opportunistic viruses is extremely important as they are associated with co-morbidities. The objective of this study was to analyse the presence of human herpesviruses in saliva and gingival crevicular fluid (GCF) from patients with CKD. METHODS: One hundred and thirty one individuals were divided depending on the stage of CKD: Group 1 (clearance of creatinine > 75 mL/min) patients with no renal disease (n = 24); Group 2 (clearance of creatinine of 11-75 mL/min) patients with renal disease (n = 67); Group 3 (clearance of creatinine < 10 mL/min) patients on hemodialysis (n = 40). The parameters of periodontal disease were evaluated. The viral detection was assessed by PCR. RESULTS: considering the three groups, the prevalence of herpes simplex virus 1 (HSV-1) were 9% in saliva and 5% in GCF; Epstein-Barr virus 36% in saliva and 39% in GCF; human cytomegalovirus (HCMV) 11% in GCF; varicella zoster virus 6% in saliva and 3% in GCF; of human herpesvirus-6 (HHV-6) 6% in saliva and 2% in GCF; and HHV-7 44% in saliva and 8% in GCF. Of these patients, 46.48% presented with severe periodontitis. A statistically significant association between HSV-1 and HCMV was found in hemodialysis patients and severe periodontitis was also more frequent among them. CONCLUSION: These findings show the importance of evaluating the periodontal disease and detecting herpesviruses in patients with CKD as the inflammatory process observed in these clinical conditions may worsen the course of both periodontal disease and CKD.


Assuntos
Herpesviridae , Doenças Periodontais , Insuficiência Renal Crônica , Líquido do Sulco Gengival , Humanos , Insuficiência Renal Crônica/complicações , Saliva
9.
Mod Pathol ; 33(7): 1420-1432, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32047231

RESUMO

Mucinous colorectal adenocarcinoma (CRC) is conventionally defined by extracellular mucin comprising >50% of the tumour area, while tumours with ≤50% mucin are designated as having a mucinous component. However, these definitions are largely arbitrary and comparisons of clinico-molecular features and outcomes by proportion of mucinous component are limited. A cohort of 1643 patients with stage II/III cancer was examined for tumour mucinous component, DNA mismatch repair (MMR) status, BRAF mutation and tumour infiltrating lymphocytes (TILs). Tumours with ≤50% mucinous component exhibited similar characteristics as mucinous tumours, including association with female gender, proximal location, high grade, TIL-high, defective MMR (dMMR) and BRAF mutation. Proportion of mucinous component did not stratify disease-free survival (DFS). In univariate analysis dMMR status, but not histological grade, stratified survival for mucinous and mucinous component tumours; however, in multivariate analysis dMMR status was not an independent predictor. BRAF mutation prognostic value depended on mucinous differentiation and MMR status, with poor prognosis limited to non-mucinous pMMR tumours (HR 2.61, 95% CI 1.69-4.03; p < 0.001). TIL status was a strong independent predictor of DFS in mucinous/mucinous component tumours (HR 0.40, 95% CI 0.23-0.67; p < 0.001), and a superior predictor of prognosis compared with histological grade, MMR and BRAF mutation. Mucinous component and mucinous stage II/III CRCs exhibit clinico-molecular resemblances, with histological grade and BRAF mutation lacking prognostic value. Prognosis for these tumours was instead strongly associated with TIL status, with the most favourable outcomes in TIL-high dMMR tumours, whilst TIL-low tumours had poor outcomes irrespective of MMR status.


Assuntos
Adenocarcinoma Mucinoso/patologia , Biomarcadores Tumorais/análise , Neoplasias Colorretais/patologia , Linfócitos do Interstício Tumoral/patologia , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Reparo de Erro de Pareamento de DNA , Intervalo Livre de Doença , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética
10.
Clin Oral Investig ; 24(10): 3597-3608, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32036434

RESUMO

OBJECTIVES: This study was performed to characterise oral shedding of herpesviruses in patients who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) and to investigate its relationship with oral mucositis (OM). MATERIALS AND METHODS: PCR and enzymatic digestion were conducted to identify oral shedding of herpesviruses and its correlation with OM development in 31 patients. The samples were collected at three sites in the oral cavity and at 5 times during follow-up; two additional collections were made from patients who developed ulcerative OM. RESULTS: HSV-1, EBV, CMV, HHV-6A, HHV-6B, and HHV-7 were detected in 4.97%, 16.02%, 4.41%, 2.20%, 3.31%, and 68% of the oral mucosal samples, respectively; 4.41%, 16.57%, 5.52%, 2.20%, 5.52%, and 63.53% of supragingival samples, respectively, and 4.41%, 18.23%, 2.76%, 1.65%, 2.75%, and 35.91% of subgingival samples, respectively. OM was diagnosed in 13 patients. The presence of HHV-7 in C1 (oral mucosa: p = 0.032) and C2 (supragingival: p = 0.009; subgingival: p = 0.002) was significantly increased in patients who developed OM, and patients exhibiting HHV-7 shedding in the oral cavity were 3.32-fold more likely to develop OM. CONCLUSIONS: Patients who developed OM showed higher HHV-7 shedding in the oral cavity at nadir (immediately prior to OM development), suggesting modifications to the inflammatory microenvironment. CLINICAL RELEVANCE: HHV-7 may be involved in oral dysbiosis in HSCT-related OM; enhanced understanding of its role in the pathogenesis of OM may lead to the development of strategies for managing and preventing this common side effect of alloHSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Herpesvirus Humano 7 , Infecções por Roseolovirus/etiologia , Estomatite , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Mucosa Bucal
11.
Cell Death Differ ; 27(2): 742-757, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31296963

RESUMO

Gastrointestinal epithelial cells provide a selective barrier that segregates the host immune system from luminal microorganisms, thereby contributing directly to the regulation of homeostasis. We have shown that from early embryonic development Bcl-G, a Bcl-2 protein family member with unknown function, was highly expressed in gastrointestinal epithelial cells. While Bcl-G was dispensable for normal growth and development in mice, the loss of Bcl-G resulted in accelerated progression of colitis-associated cancer. A label-free quantitative proteomics approach revealed that Bcl-G may contribute to the stability of a mucin network, which when disrupted, is linked to colon tumorigenesis. Consistent with this, we observed a significant reduction in Bcl-G expression in human colorectal tumors. Our study identifies an unappreciated role for Bcl-G in colon cancer.


Assuntos
Neoplasias Colorretais/metabolismo , Inflamação/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Animais , Colite/metabolismo , Colite/patologia , Neoplasias Colorretais/patologia , Humanos , Inflamação/patologia , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-bcl-2/deficiência , Proteínas Proto-Oncogênicas c-bcl-2/genética
12.
Mod Pathol ; 33(3): 483-495, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31471586

RESUMO

TP53 mutations drive colorectal cancer development, with missense mutations frequently leading to accumulation of abnormal TP53 protein. TP53 alterations have been associated with poor prognosis and chemotherapy resistance, but data remain controversial. Here, we examined the predictive utility of TP53 overexpression in the context of current adjuvant treatment practice for patients with stage III colorectal cancer. A prospective cohort of 264 stage III patients was tested for association of TP53 expression with 5-year disease-free survival, grouped by adjuvant treatment. Findings were validated in an independent retrospective cohort of 274 stage III patients. Overexpression of TP53 protein (TP53+) was found in 53% and 52% of cases from the prospective and retrospective cohorts, respectively. Among patients receiving adjuvant chemotherapy, TP53+ status was associated with shorter disease-free survival (p ≤ 0.026 for both cohorts), while no difference in outcomes between TP53+ and TP53- cases was observed for patients treated with surgery alone. Considering patients with TP53- tumors, those receiving adjuvant treatment had better outcomes compared with those treated with surgery alone (p ≤ 0.018 for both cohorts), while no treatment benefit was apparent for patients with TP53+ tumors. Combined cohort-stratified analysis adjusted for clinicopathological variables and DNA mismatch repair status confirmed a significant interaction between TP53 expression and adjuvant treatment for disease-free survival (pinteraction = 0.030). For the combined cohort, the multivariate hazard ratio for TP53 overexpression among patients receiving adjuvant chemotherapy was 2.03 (95% confidence interval 1.41-2.95, p < 0.001), while the hazard ratio for adjuvant treatment among patients with TP53- tumors was 0.42 (95% confidence interval 0.24-0.71, p = 0.001). Findings were maintained irrespective of tumor location or when restricted to mismatch repair-proficient tumors. Our data suggest that adjuvant chemotherapy benefit in stage III colorectal cancer is restricted to cases with low-level TP53 protein expression. Identifying TP53+ tumors could highlight patients that may benefit from more aggressive treatment or follow-up.


Assuntos
Adenocarcinoma/química , Adenocarcinoma/terapia , Biomarcadores Tumorais/análise , Colectomia , Neoplasias Colorretais/química , Neoplasias Colorretais/terapia , Proteína Supressora de Tumor p53/análise , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Tomada de Decisão Clínica , Colectomia/efeitos adversos , Colectomia/mortalidade , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Regulação para Cima
13.
Ann Med Surg (Lond) ; 49: 33-36, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31871681

RESUMO

Introduction: Even though is rarely, mandibular fracture after the extraction of third molars can occur in almost 1% of the procedures. Gender, age, position of third molar, tooth volume, bone fragility, systemic disorders, associated lesions, and degree of mandibular atrophy are factors that contribute to increase the incidence of fracture. The installation of the titanium miniplate during exodontia is an important tool to prevent the fracture. Presentation of case: The objective of this study is to present a clinical case of extraction of inferior impacted third molar, in atrophic mandible, with posterior installation of titanium miniplate, to prevent mandibular fracture. Discussion and conclusion: preventive installation of titanium miniplate was effective and indeed prevented the mandibular fracture. No trans-operative or immediate post-operative complications were observed. Post-operative follow-up was of three years, with no complications, showing the success of the procedure.

14.
Braz. oral res. (Online) ; 34: e108, 2020. tab, graf
Artigo em Inglês | LILACS, BBO - Odontologia | ID: biblio-1132718

RESUMO

Abstract Asymptomatic Apical Periodontitis is essentially an inflammatory disease of microbial aetiology. Association and function of the cell components involved, or specific inductive factors and growth mediators associated with development, maintenance and resolution of the periapical lesions are still unknown. The objective of this study was to evaluate the concentration of Regulatory T cells (FoxP3+; Treg), Langerhans cells (CD1a+; LC) and mast cells in asymptomatic apical periodontitis. 73 cases were selected: 30 periapical granulomas, 29 radicular cysts and 14 residual cysts. All groups were submitted to morphological analysis for classification of inflammatory infiltrate and thickness of the epithelial lining as well as to immunohistochemical analysis for detection of LC and Treg cells. Toluidine blue staining was used for detecting mast cells. Analysis showed higher mean numbers of LC (8.2 cells/0.2mm2), and Treg cells in radicular cysts (5.910 cells/0.2mm2). As for mast cells, it was found that radicular cysts had a higher mean number of these cells compared to other periapical lesions (12.68 cells/0.2mm2). The association between thickness of the epithelial lining and inflammatory cells showed that the presence of hypertrophic epithelium in radicular cysts presented higher density of LC. The number of LC and Treg cells play an important role in the control of the inflammatory micro-environment in periapical granulomas and radicular cysts, respectively. The presence of mast cells in radicular cysts may be associated with progression of the lesion. Knowledge regarding the inflammatory cell profile is therefore essential for a better understanding of the pathogenesis of asymptomatic periapical periodontitis.


Assuntos
Humanos , Periodontite Periapical , Granuloma Periapical , Cisto Radicular , Células de Langerhans , Linfócitos T Reguladores , Microambiente Tumoral , Mastócitos
15.
Ear Nose Throat J ; : 145561319879245, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31619067

RESUMO

Despite its effectiveness, radiochemotherapy treatment in the head and neck region is accompanied by acute oral complications such as oral mucositis, dysphagia, xerostomia, and dysgeusia. The aim of this study was to analyze and prospectively assess the frequency and evolution of acute oral complications during radiochemotherapy in patients diagnosed with squamous cell carcinoma in the head and neck region. We have analyzed oral complications of 20 patients during 6 weeks of radiochemotherapy treatment for squamous cell carcinoma. Oral mucositis was evaluated according to the World Health Organization criteria, dysphagia, and dysgeusia according to the National Cancer Institute Common Toxicity Criteria, and xerostomia according to parameters set by the Seminars in Radiation Oncology. Mucositis was first observed in the second week and all patients presented some degree of mucositis in the fourth week of radiotherapy. Xerostomia and dysphagia were initially reported already in the first week of radiotherapy. All patients presented xerostomia in the fourth week; however, dysphagia was observed in all patients, only in the sixth week. Dysgeusia was first observed in the second week, becoming more severe in the third week. Acute oral complications can be observed throughout the treatment, but the third week of radiotherapy seems to represent a critical week, regardless of the grade of the complication. The sixth week presents the worst grades of these complications. Knowledge about the natural course of oral complications during radiotherapy is important to develop better strategies for treatment and improve the patients' quality of life.

16.
Medicine (Baltimore) ; 98(17): e15312, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31027098

RESUMO

INTRODUCTION: Pericoronitis is a common disease in the eruption phase of third molars, sometimes debilitating, with an impact on the quality of life. The most indicated treatment in the initial phase is the irrigation for cleanliness of the region. In order to reduce the chances of systemic dissemination of the infection and antibiotics use, it is mandatory to test effective treatments in the initial phase of pericoronitis avoiding the evolution of the infectious disease. Photodynamic therapy (PDT) is an interesting alternative because it is an effective antimicrobial treatment that is easy to perform and does not select bacterial resistance. The methylene blue (MB) used in PDT has been studied in an oral formulation, which optimizes the formation of monomers increasing its antimicrobial action. OBJECTIVE: The aim of this study is to evaluate the effectiveness of PDT with MB in an astringent vehicle in pericoronitis on the initial phase in healthy patients through microbiological, clinical, and immune response. The impact of pericoronitis on oral health-related quality of life (OHRQoL) of these patients will also be evaluated. METHOD: In this randomized, controlled, double-blind clinical bioequivalence protocol, 64 healthy patients with pericoronitis will be evaluated. Patients will be randomized into the positive control group (G1) (n = 32): irrigation with sterile saline and PDT (conventional MB at 0.005% concentration and irradiation with low intensity laser λ = 660 nm, 9J per point and radiant exposure of 318 J/cm), and the experimental group (G2) (n = 32): treatment identical to G1, however, MB will be delivered in a new formulation for oral use. Microbiological analysis will be performed by RT-PCR for the bacterium Tannerella forsythia. Gingival crevicular fluid and saliva will be collected to evaluate cytokines by Luminex assay (Luminex Corporation, Austin, TX). The pain (visual analogue scale), swelling and buccal opening (digital caliper), and OHRQoL will also be evaluated through the OHIP-14 questionnaire. The variables will be evaluated in T1 (baseline), T2 (immediately after PDT), and T3 (4th day after PDT). Registration: clinicaltrials.gov NCT03576105. Registered in July 2018.


Assuntos
Azul de Metileno/uso terapêutico , Pericoronite/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Adolescente , Adulto , Método Duplo-Cego , Feminino , Líquido do Sulco Gengival/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Qualidade de Vida , Saliva/imunologia , Adulto Jovem
17.
J Appl Oral Sci ; 27: e20180435, 2019 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-30673031

RESUMO

OBJECTIVES: This study aimed to verify the presence of polyomavirus BK (BKPyV) in the saliva of kidney transplant recipients and to correlate it with blood viremia. MATERIAL AND METHODS: We have conducted a cross-sectional study with a sample involving 126 renal transplant recipients. 126 samples of saliva and 52 samples of blood were collected from these patients. Detection and quantification of BKPyV were performed using a real-time PCR. To compare the presence of BKPyV in blood and saliva, the binomial proportion test was used. To verify associations between salivary shedding BKPyV and post-transplant periods (in months), the Mann-Whitney test was used. Spearman's correlation was used to correlate the viral load in the saliva with blood of kidney transplant recipients. RESULTS: The mean age of the study group was 51.11±12.45 years old, and 69 participants (54.8%) were female, with a mean post-transplantation time of 4.80±6.04 months. BKPyV was quantified in several samples of saliva and blood, with medians of 1,108 cp/mL and 1,255 cp/mL, respectively. Only 16/52 (30.8%) participants presented BKPyV in blood, and 59/126 (46.8%) excreted the virus in saliva (p=0.004). BKPyV shedding was found in patients at a shorter post-transplantation period (3.86±5.25, p=0.100). A weak correlation was observed between viral quantification in saliva and blood (Spearman's correlation coefficient=0.193). CONCLUSION: The results of this study suggested that, although saliva excretes more BKPyV than blood, there is no reliable correlation between salivary shedding and blood viremia, showing two independent compartments of viral replication.


Assuntos
Vírus BK/isolamento & purificação , Transplante de Rim/efeitos adversos , Saliva/virologia , Transplantados , Viremia/virologia , Eliminação de Partículas Virais , Adulto , Estudos Transversais , Feminino , Humanos , Imunocompetência , Imunossupressão/efeitos adversos , Masculino , Pessoa de Meia-Idade , Infecções por Polyomavirus/virologia , Reação em Cadeia da Polimerase em Tempo Real , Estatísticas não Paramétricas , Infecções Tumorais por Vírus/virologia , Carga Viral
18.
Gut ; 68(3): 465-474, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29382774

RESUMO

OBJECTIVE: Tumour-infiltrating lymphocyte (TIL) response and deficient DNA mismatch repair (dMMR) are determinants of prognosis in colorectal cancer. Although highly correlated, evidence suggests that these are independent predictors of outcome. However, the prognostic significance of combined TIL/MMR classification and how this compares to the major genomic and transcriptomic subtypes remain unclear. DESIGN: A prospective cohort of 1265 patients with stage II/III cancer was examined for TIL/MMR status and BRAF/KRAS mutations. Consensus molecular subtype (CMS) status was determined for 142 cases. Associations with 5-year disease-free survival (DFS) were evaluated and validated in an independent cohort of 602 patients. RESULTS: Tumours were categorised into four subtypes based on TIL and MMR status: TIL-low/proficient-MMR (pMMR) (61.3% of cases), TIL-high/pMMR (14.8%), TIL-low/dMMR (8.6%) and TIL-high/dMMR (15.2%). Compared with TIL-high/dMMR tumours with the most favourable prognosis, both TIL-low/dMMR (HR=3.53; 95% CI=1.88 to 6.64; Pmultivariate<0.001) and TIL-low/pMMR tumours (HR=2.67; 95% CI=1.47 to 4.84; Pmultivariate=0.001) showed poor DFS. Outcomes of patients with TIL-low/dMMR and TIL-low/pMMR tumours were similar. TIL-high/pMMR tumours showed intermediate survival rates. These findings were validated in an independent cohort. TIL/MMR status was a more significant predictor of prognosis than National Comprehensive Cancer Network high-risk features and was a superior predictor of prognosis compared with genomic (dMMR, pMMR/BRAFwt /KRASwt , pMMR/BRAFmut /KRASwt , pMMR/BRAFwt /KRASmut ) and transcriptomic (CMS 1-4) subtypes. CONCLUSION: TIL/MMR classification identified subtypes of stage II/III colorectal cancer associated with different outcomes. Although dMMR status is generally considered a marker of good prognosis, we found this to be dependent on the presence of TILs. Prognostication based on TIL/MMR subtypes was superior compared with histopathological, genomic and transcriptomic subtypes.


Assuntos
Adenocarcinoma/imunologia , Neoplasias Colorretais/imunologia , Reparo de Erro de Pareamento de DNA , Linfócitos do Interstício Tumoral/imunologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Genômica , Humanos , Estimativa de Kaplan-Meier , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Reprodutibilidade dos Testes , Transcriptoma
19.
J Investig Clin Dent ; 9(4): e12356, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30062730

RESUMO

AIM: The aim of the present study was to describe the salivary shedding of human herpesviruses (HHV) in renal transplant recipients and to observe the oral manifestations in this group. METHODS: A prospective case-control study was conducted with a study group of 20 renal transplant recipients and a control group of 20 non-transplanted, immunocompetent individuals. Clinical examination evaluated the presence of drug-induced gingival overgrowth (DIGO), salivary flow, and caries. Stimulated saliva was collected from both groups, with HHV being detected by using real-time polymerase chain reaction. RESULTS: The mean age of the study group was 45.90 ± 9.89 years, with 55% (11/20) being female, 60% (12/20) being Caucasian, 65% (13/20) having a deceased donor, and 70% (14/20) having used tacrolimus as the main immunosuppressive drug. Renal transplant recipients had shedding of more herpesviruses compared to the control group, with the exception of HHV-7. Statistical significance was found for herpes simplex virus-1 (HSV-1) (P = 0.017) and cytomegalovirus (P = 0.035). DIGO was observed in seven patients (35%), with 35% (7/20) presenting with decreased salivary flow and four (20%) reporting xerostomia. CONCLUSION: Renal transplant recipients excreted herpesviruses more often than control individuals, especially HSV-1. Decreased salivary flow and xerostomia were more frequent in patients who used tacrolimus, whereas those who used cyclosporine had more cases of DIGO.


Assuntos
Infecções por Herpesviridae/epidemiologia , Herpesviridae , Transplante de Rim/efeitos adversos , Saliva/virologia , Brasil/epidemiologia , Estudos de Casos e Controles , Ciclosporina/uso terapêutico , Citomegalovirus , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/virologia , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpes Simples/epidemiologia , Herpes Simples/virologia , Infecções por Herpesviridae/virologia , Herpesvirus Humano 1 , Herpesvirus Humano 4 , Herpesvirus Humano 6 , Herpesvirus Humano 7 , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real , Infecções por Roseolovirus/epidemiologia , Infecções por Roseolovirus/virologia , Tacrolimo/uso terapêutico , Eliminação de Partículas Virais/efeitos dos fármacos
20.
Lancet Gastroenterol Hepatol ; 3(9): 635-643, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30042065

RESUMO

BACKGROUND: Molecular indicators of colorectal cancer prognosis have been assessed in several studies, but most analyses have been restricted to a handful of markers. We aimed to identify prognostic biomarkers for colorectal cancer by sequencing panels of multiple driver genes. METHODS: In stage II or III colorectal cancers from the QUASAR 2 open-label randomised phase 3 clinical trial and an Australian community-based series, we used targeted next-generation sequencing of 82 and 113 genes, respectively, including the main colorectal cancer drivers. We investigated molecular pathways of tumorigenesis, and analysed individual driver gene mutations, combinations of mutations, or global measures such as microsatellite instability (MSI) and mutation burden (total number of non-synonymous mutations and coding indels) for associations with relapse-free survival in univariable and multivariable models, principally Cox proportional hazards models. FINDINGS: In QUASAR 2 (511 tumours), TP53, KRAS, BRAF, and GNAS mutations were independently associated with shorter relapse-free survival (p<0·035 in all cases), and total somatic mutation burden with longer survival (hazard ratio [HR] 0·81 [95% CI 0·68-0·96]; p=0·014). MSI was not independently associated with survival (HR 1·12 [95% CI 0·57-2·19]; p=0·75). We successfully validated these associations in the Australian sample set (296 tumours). In a combined analysis of both the QUASAR 2 and the Australian sample sets, mutation burden was also associated with longer survival (HR 0·84 [95% CI 0·74-0·94]; p=0·004) after exclusion of MSI-positive and POLE mutant tumours. In an extended analysis of 1732 QUASAR 2 and Australian colorectal cancers for which KRAS, BRAF, and MSI status were available, KRAS and BRAF mutations were specifically associated with poor prognosis in MSI-negative cancers. MSI-positive cancers with KRAS or BRAF mutations had better prognosis than MSI-negative cancers that were wild-type for KRAS or BRAF. Mutations in the genes NF1 and NRAS from the MAPK pathway co-occurred, and mutations in the DNA damage-response genes TP53 and ATM were mutually exclusive. We compared a prognostic model based on the gold standard of clinicopathological variables and MSI with our new model incorporating clinicopathological variables, mutation burden, and driver mutations in KRAS, BRAF, and TP53. In both QUASAR 2 and the Australian cohort, our new model was significantly better (p=0·00004 and p=0·0057, respectively, based on a likelihood ratio test). INTERPRETATION: Multigene panels identified two previously unreported prognostic associations in colorectal cancer involving TP53 mutation and total mutation burden, and confirmed associations with KRAS and BRAF. Even a modest-sized gene panel can provide important information for use in clinical practice and outperform MSI-based prognostic models. FUNDING: UK Technology Strategy Board, National Institute for Health Research Oxford Biomedical Research Centre, Cancer Australia Project, Cancer Council Victoria, Ludwig Institute for Cancer Research, Victorian Government.


Assuntos
Biomarcadores Tumorais , Neoplasias Colorretais/genética , Mutação , Austrália , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Tecnologia de Impulso Genético , Humanos , Estadiamento de Neoplasias , Prognóstico , Análise de Sequência de DNA
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