Inhibition of TGFβ signaling and its implications in anticancer treatments

The transforming growth factor-β (TGFβ) is a potent regulator of tumorigenesis. In cancer, two distinctive behaviors of TGFβ have been reported as a tumor suppressor at early stage of the disease, and as a tumor promoter at later stages. The past decades, the dualistic role of TGFβ has garnered a lot of attention. As a result, cancer researchers’ has been tasked to elucidate how TGFβ signaling may lead to metastatic dissemination, how to tackle carcinogenesis and which therapeutic strategies should be adopted. Consequently, TGFβ signaling pathways have been considered as appropriate targets for cancer therapy. The TGFβ therapeutic strategies have emerged at three levels: ligand, ligand-receptor interaction and intracellular signaling level. Promising inhibitors of TGFβ signaling have entered clinical trials and shown encouraging results. Here we review the three strategies of TGFβ signa­ling inhibition and theirs applications in treatment of cancer

Improved salinity tolerance in early growth stage of maize through salicylic acid foliar application

Soil salinity threatens agricultural production worldwide by constraining plant growth and final crop yield. The early stages are most sensitive to salinity, in response to which salicylic acid (SA) has demonstrated beneficial effects in various plant species. Based on this, a maize (Zea mays L.) pot experiment was set up combining three levels of soil salinity (0, 6 and 12 dS m–1), obtained through NaCl addition, with three levels of SA (0, 300 and 600 mM), applied by leaf spraying 20 days after seedling emergence. Fifteen days later, the following traits were assessed: morphology (plant height, leaf number), growth (root and shoot dry weight), leaf water status [relative water content (RWC), elec-trolyte leakage (EL)], pigments (chlorophyll a and b, carotenoids, anthocyanin), antioxidant enzymes (peroxidase, catalase, ascor-bate peroxidase, vitamin C), oxidative stress markers (H2O2, mal-ondialdehyde), osmo-regulating compounds (free amino acids, soluble proteins and sugars, proline), hormones [indole-3-acetic acid, gibberellic acid (GA), abscisic acid (ABA), ethylene], ele-ment (Na, K, Ca, Mg and Cl) concentration and content in roots, stem and leaves. Salinity severely affected maize growth (–26% total dry weight), impaired leaf water status (–31% RWC), reduced photosynthetic pigments, enhanced all antioxidant enzymes and oxidative stress markers, two osmo-regulating compounds (soluble sugars and proline) out of four, and all hormones except GA. SA was shown effective in containing most of the stress effects, while supporting plant defences by upgrading anti-oxidant activities (reduced oxidative stress markers), increasing cell membrane stability (–24% EL) and leaf water status (+20% RWC), and reducing plant stress signalling (–10% ABA and –20% ethylene). Above all, SA contrasted the massive entry of noxious ions (Na+ and Cl–), in favour of K+, Ca2+ and Mg2+ accumulation. Lastly, salicylic acid was shown beneficial for maize growth and physiology also under non-saline condition, suggesting a potential use in normal field conditions

Machine learning application for prediction of locoregional recurrences in early oral tongue cancer: a Web-based prognostic tool

Estimation of risk of recurrence in early-stage oral tongue squamous cell carcinoma (OTSCC) remains a challenge in the field of head and neck oncology. We examined the use of artificial neural networks (ANNs) to predict recurrences in early-stage OTSCC. A Web-based tool available for public use was also developed. A feedforward neural network was trained for prediction of locoregional recurrences in early OTSCC. The trained network was used to evaluate several prognostic parameters (age, gender, T stage, WHO histologic grade, depth of invasion, tumor budding, worst pattern of invasion, perineural invasion, and lymphocytic host response). Our neural network model identified tumor budding and depth of invasion as the most important prognosticators to predict locoregional recurrence. The accuracy of the neural network was 92.7%, which was higher than that of the logistic regression model (86.5%). Our online tool provided 88.2% accuracy, 71.2% sensitivity, and 98.9% specificity. In conclusion, ANN seems to offer a unique decision-making support predicting recurrences and thus adding value for the management of early OTSCC. To the best of our knowledge, this is the first study that applied ANN for prediction of recurrence in early OTSCC and provided a Web-based tool.</p

Tumour budding in oral squamous cell carcinoma : a meta-analysis

Background: Tumour budding has been reported as a promising prognostic marker in many cancers. This meta-analysis assessed the prognostic value of tumour budding in oral squamous cell carcinoma (OSCC). Methods: We searched OvidMedline, PubMed, Scopus and Web of Science for articles that studied tumour budding in OSCC. We used reporting recommendations for tumour marker (REMARK) criteria to evaluate the quality of studies eligible for meta-analysis. Results: A total of 16 studies evaluated the prognostic value of tumour budding in OSCC. The meta-analysis showed that tumour budding was significantly associated with lymph node metastasis (odds ratio = 7.08, 95% CI = 1.75-28.73), disease-free survival (hazard ratio = 1.83, 95% CI = 1.34-2.50) and overall survival (hazard ratio = 1.88, 95% CI = 1.25-2.82). Conclusions: Tumour budding is a simple and reliable prognostic marker for OSCC. Evaluation of tumour budding could facilitate personalised management of OSCC.Peer reviewe

The Prognostic Value Of Histopathological Grading Systems In Oral Squamous Cell Carcinomas

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)ObjectiveThis study evaluated the association of four histopathological grading systems (WHO grading system, malignancy grading of the deep invasive margins (MG), histological risk (HR) model, and tumor budding and depth of invasion (BD) model) with clinicopathological parameters and outcome of 113 oral squamous cell carcinomas to identify their roles in prognosis. MethodsDemographic and clinical features were obtained from patients' records. Sections from all paraffin-embedded blocks were evaluated according to the four grading systems. Demographic and clinical associations were analyzed using chi-square test, and correlations between the grading systems were established with the Spearman's rank correlation test. Survival curves were performed with Kaplan-Meier method, and multivariate analysis based on Cox proportional hazard model was calculated. ResultsSignificant associations with survival were observed for WHO grading system and BD model in the univariate analysis, but only the BD model was significantly associated with disease outcome as an independent prognostic marker. Age, tumor size, and presence of regional metastasis were also independent markers of reduced survival. ConclusionA significant association between the BD model and outcome of OSCC patients was observed, indicating this new histopathological grading system as a possible prognostic tool.216755761Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)FAPESP [2013/01607-6]CAPES [PVES 109/2012

The prognostic value of histopathological grading systems in oral squamous cell carcinomas

This study evaluated the association of four histopathological grading systems (WHO grading system, malignancy grading of the deep invasive margins (MG), histological risk (HR) model, and tumor budding and depth of invasion (BD) model) with clinicopathological parameters and outcome of 113 oral squamous cell carcinomas to identify their roles in prognosis. Demographic and clinical features were obtained from patients' records. Sections from all paraffin‐embedded blocks were evaluated according to the four grading systems. Demographic and clinical associations were analyzed using chi‐square test, and correlations between the grading systems were established with the Spearman's rank correlation test. Survival curves were performed with Kaplan–Meier method, and multivariate analysis based on Cox proportional hazard model was calculated. Significant associations with survival were observed for WHO grading system and BD model in the univariate analysis, but only the BD model was significantly associated with disease outcome as an independent prognostic marker. Age, tumor size, and presence of regional metastasis were also independent markers of reduced survival. A significant association between the BD model and outcome of OSCC patients was observed, indicating this new histopathological grading system as a possible prognostic tool216755761COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPPVES 109/20122013/01607‐

Clinicopathologic significance of ROCK2 expression in oral squamous cell carcinomas

Abstract Background: Rho-associated coiled-coil kinase 2 (ROCK2) is an oncoprotein that controls cytoskeleton organization and acts as prognostic marker in different types of solid tumors. ROCK2 overexpression is also observed in cancer-associated fibroblasts (CAF), which suggests its relevance within the tumor microenvironment. This study aimed to access the prognostic value of ROCK2 in oral squamous cell carcinomas (OSCCs) and its association with CAF density. Methods: Rho-associated coiled-coil kinase 2 immunohistochemical analysis was applied in 93 OSCC samples from 2 centers in Brazil and Finland. The samples were also stained for isoform α of smooth muscle actin (α-SMA) to characterize the presence of CAF in the tumor stroma. Clinicopathological associations were analyzed using Chi-squared test, survival curves were constructed according to the Kaplan-Meier method, and Cox proportional hazard model was applied for multivariate survival analysis. Results: Advanced clinical stage (P = .002) and increased density of CAF (P = .002) were significantly associated with high ROCK2 expression. The high expression of ROCK2 was also associated with shortened disease-specific survival (HR: 2.22, 95% CI: 1.15–4.38, P = .04), but the association did not withstand the Cox multivariate survival analysis. Conclusions: The findings suggest that high ROCK2 expression in OSCC is associated with advanced disease and follows the increase in CAF density, which may be important for tumor progression