Melanotic Neuroectodermal Tumour of Infancy.

Melanotic neuroectodermal tumour of infancy (MNTI) is a locally aggressive neoplasm of neural crest origin. It is primarily a paediatric tumour, and 95% of the cases occur in children below 1 year. The tumour mainly affects the head and neck region. It shows a predilection for the craniofacial sites and the most common site affected is anterior maxilla. Microscopically, it is characterized by a biphasic population of neuroblastic cells and pigmented epithelial cells. Although generally considered as a benign tumour, it can invade the adjacent muscle and bone, causing destruction of the involved site. The rapidity in growth and the aggressive clinical behaviour of the tumour can be deceptive and hence lack of familiarity with the clinical characteristics of the tumour may often lead to an erroneous diagnosis of malignancy. The treatment of choice for MNTI is excision, and it is usually curative. Extensive surgery in a child may interfere with the normal growth and development of the facial structures and reconstruction can be very challenging in infants. Hence, early diagnosis is critical for the effective management. Clinical findings, histopathological features, and differential diagnosis of a classic case of melanotic neuroectodermal tumour of infancy are discussed.

Minichromosome maintenance protein 5 - a promising prognostic marker of oral epithelial dysplasias and oral squamous cell carcinomas.

Background: Early diagnosis is the single most effective means of reducing the mortality rate of oral cancer. Aim: This study was undertaken to assess the expression of minichromosome maintenance protein 5 (MCM5) in oral epithelial dysplasias and oral squamous cell carcinomas (OSCCs) and to evaluate their possible role as a biomarker for early diagnosis and prognosis of OSCC. Design: A retrospective cross-sectional study. Materials and Methods: The study was conducted to assess the expression of MCM5 immunohistochemically in the tissue samples of oral epithelial dysplasias (n = 27) and OSCCs (n = 30) diagnosed between 2014 and 2019. Statistical Analysis: The difference in the mean nuclear labelling index (LI) between the groups and the subgroups was analysed statistically using the Kruskal-Wallis test and the post hoc test, and the Dunn-Bonferroni multiple comparison analysis was conducted for pairwise comparison between the four main groups and the subgroups. The association between mean MCM5 LI and clinicopathological parameters was analysed using Spearman's rank correlation coefficient. Results: A progressive increase in the nuclear expression of MCM5 protein (P-value <0.001) was noticed from normal oral mucosa through oral epithelial hyperplasia and oral epithelial dysplasia to OSCC. A significant correlation was also observed between the mean nuclear MCM5 LI of OSCC and TNM staging (R2 = 0.268, P = 0.029). Conclusion: Our findings suggest that MCM5 may be of great value in assessing the malignant potential of dysplastic lesions and may serve as biomarker of utility in the early diagnosis and prognosis of OSCC.

Comparative characterization of human induced pluripotent stem cells (hiPSC) derived from patients with schizophrenia and autism.

Human induced pluripotent stem cells (hiPSC) provide an attractive tool to study disease mechanisms of neurodevelopmental disorders such as schizophrenia. A pertinent problem is the development of hiPSC-based assays to discriminate schizophrenia (SZ) from autism spectrum disorder (ASD) models. Healthy control individuals as well as patients with SZ and ASD were examined by a panel of diagnostic tests. Subsequently, skin biopsies were taken for the generation, differentiation, and testing of hiPSC-derived neurons from all individuals. SZ and ASD neurons share a reduced capacity for cortical differentiation as shown by quantitative analysis of the synaptic marker PSD95 and neurite outgrowth. By contrast, pattern analysis of calcium signals turned out to discriminate among healthy control, schizophrenia, and autism samples. Schizophrenia neurons displayed decreased peak frequency accompanied by increased peak areas, while autism neurons showed a slight decrease in peak amplitudes. For further analysis of the schizophrenia phenotype, transcriptome analyses revealed a clear discrimination among schizophrenia, autism, and healthy controls based on differentially expressed genes. However, considerable differences were still evident among schizophrenia patients under inspection. For one individual with schizophrenia, expression analysis revealed deregulation of genes associated with the major histocompatibility complex class II (MHC class II) presentation pathway. Interestingly, antipsychotic treatment of healthy control neurons also increased MHC class II expression. In conclusion, transcriptome analysis combined with pattern analysis of calcium signals appeared as a tool to discriminate between SZ and ASD phenotypes in vitro.

An immunohistochemical evaluation of podoplanin expression in oral leukoplakia and oral squamous cell carcinoma to explore its potential to be used as a predictor for malignant transformation.

BACKGROUND: Oral leukoplakia (OL) is a potentially malignant disorder with increased risk for the development of oral squamous cell carcinoma (OSCC). Many cases of OSCC arise from the malignant transformation of preexisting OL. However, the risk of progression into OSCC and the possible prediction of malignant potential of OL remain inconclusive. Recent studies have shown that podoplanin, a mucin-like transmembrane glycoprotein specifically expressed in lymphatic endothelial cells, is expressed in various neoplasms including OSCC, indicating its possible biologic role in tumor cells. In this study, an evaluation of podoplanin expression in OL and OSCC has been carried out to assess its potential role as a biomarker to predict the possibility of malignant transformation in OL cases. AIMS AND OBJECTIVES: To assess the usefulness of podoplanin as a potential biomarker for predicting the risk of malignant transformation in OL, by comparing its immunohistochemical expression in OL and OSCC. MATERIALS AND METHODS: Archival paraffin-embedded blocks of 25 OL cases with varying grades of dysplasia and 30 OSCC cases showing its varying grades were selected. Sections were subjected to immunohistochemical staining for podoplanin and compared with the control group for evaluation of results in the three groups. RESULTS: A statistically significant increase in podoplanin expression was observed from normal mucosa through OL to OSCC. In the OL cases, the podoplanin staining score progressively increased from mild dysplasia to carcinoma in situ, whereas in OSCC, well-differentiated group showed the maximum expression of podoplanin. CONCLUSION: The progressive increase in podoplanin expression through the increasing grades of dysplasia in OL is suggestive of an increased risk for malignant transformation with increased expression of podoplanin in OL cases. A high podoplanin expression in the well-differentiated OSCC may indicate a vital role for podoplanin in the early stages of tumorigenesis.

Mucoepidermoid carcinoma of the posterior-lateral border of tongue: a rare presentation.

Mucoepidermoid carcinoma (MEC) is the most common malignant tumour of the major and minor salivary glands. Minor salivary glands are scattered in different areas of the oral cavity such as palate, retromolar area, floor of the mouth, buccal mucosa, lips and tongue, but so far, only a few lingual MEC cases have been documented in the literature and most of the studies have shown a predilection for base and dorsum of the tongue. We report a rare case of MEC involving the posterior-lateral border of the tongue.

The evolution of gene expression and binding specificity of the largest transcription factor family in primates.

The KRAB-containing zinc finger (KRAB-ZF) proteins represent the largest family of transcription factors (TFs) in humans, yet for the great majority, their function and specific genomic target remain unknown. However, it has been shown that a large fraction of these genes arose from segmental duplications, and that they have expanded in gene and zinc finger number throughout vertebrate evolution. To determine whether this expansion is linked to selective pressures acting on different domains, we have manually curated all KRAB-ZF genes present in the human genome together with their orthologous genes in three closely related species and assessed the evolutionary forces acting at the sequence level as well as on their expression profiles. We provide evidence that KRAB-ZFs can be separated into two categories according to the polymorphism present in their DNA-contacting residues. Those carrying a nonsynonymous single nucleotide polymorphism (SNP) in their DNA-contacting amino acids exhibit significantly reduced expression in all tissues, have emerged in a recent lineage, and seem to be less strongly constrained evolutionarily than those without such a polymorphism. This work provides evidence for a link between age of the TF, as well as polymorphism in their DNA-contacting residues and expression levels-both of which may be jointly affected by selection.

Evaluating the ability of the pairwise joint site frequency spectrum to co-estimate selection and demography.

The ability to infer the parameters of positive selection from genomic data has many important implications, from identifying drug-resistance mutations in viruses to increasing crop yield by genetically integrating favorable alleles. Although it has been well-described that selection and demography may result in similar patterns of diversity, the ability to jointly estimate these two processes has remained elusive. Here, we use simulation to explore the utility of the joint site frequency spectrum to estimate selection and demography simultaneously, including developing an extension of the previously proposed Jaatha program (Mathew et al., 2013). We evaluate both complete and incomplete selective sweeps under an isolation-with-migration model with and without population size change (both population growth and bottlenecks). Results suggest that while it may not be possible to precisely estimate the strength of selection, it is possible to infer the presence of selection while estimating accurate demographic parameters. We further demonstrate that the common assumption of selective neutrality when estimating demographic models may lead to severe biases. Finally, we apply the approach we have developed to better characterize the within-host demographic and selective history of human cytomegalovirus (HCMV) infection using published next generation sequencing data.

Why to account for finite sites in population genetic studies and how to do this with Jaatha 2.0.

With the advent of next-generation sequencing technologies, large data sets of several thousand loci from multiple conspecific individuals are available. Such data sets should make it possible to obtain accurate estimates of population genetic parameters, even for complex models of population history. In the analyses of large data sets, it is difficult to consider finite-sites mutation models (FSMs). Here, we use extensive simulations to demonstrate that the inclusion of FSMs is necessary to avoid severe biases in the estimation of the population mutation rate θ, population divergence times, and migration rates. We present a new version of Jaatha, an efficient composite-likelihood method for estimating demographic parameters from population genetic data and evaluate the usefulness of Jaatha in two biological examples. For the first application, we infer the speciation process of two wild tomato species, Solanum chilense and Solanum peruvianum. In our second application example, we demonstrate that Jaatha is readily applicable to NGS data by analyzing genome-wide data from two southern European populations of Arabidopsis thaliana. Jaatha is now freely available as an R package from the Comprehensive R Archive Network (CRAN).

Competing islands limit the rate of adaptation in structured populations.

Beneficial mutations can co-occur when population structure slows down adaptation. Here, we consider the process of adaptation in asexual populations distributed over several locations ("islands"). New beneficial mutations arise at constant rate ub, and each mutation has the same selective advantage s>0. We assume that populations evolve within islands according to the successional mutations regime of Desai and Fisher (2007), that is, the time to local fixation of a mutation is short compared to the expected waiting time until the next mutation occurs. To study the rate of adaptation, we introduce an approximate model, the successional mutations (SM) model, which can be simulated efficiently and yields accurate results for a wide range of parameters. In the SM model, mutations fix instantly within islands, and migrants can take over the destination island if they are fitter than the residents. For the special case of a population distributed equally across two islands with population size N, we approximate the model further for small and large migration rates in comparison to the mutation rate. These approximations lead to explicit formulas for the rate of adaptation which fit the original model for a large range of parameter values. For the d island case we provide some heuristics on how to extend the explicit formulas and check these with computer simulations. We conclude that the SM model is a good approximation of the adaptation process in a structured population, at least if mutation or migration is limited.