The growth pattern of transplanted normal and nodular hepatocytes

Overt neoplasia is often the end result of a long biological process beginning with the appearance of focal lesions of altered tissue morphology. While the putative clonal nature of focal lesions has often been emphasized, increasing attention is being devoted to the possible role of an altered growth pattern in the evolution of carcinogenesis. Here we compare the growth patterns of normal and nodular hepatocytes in a transplantation system that allows their selective clonal proliferation in vivo. Rats were pre-treated with retrorsine, which blocks the growth of resident hepatocytes, and were then transplanted with hepatocytes isolated from either normal liver or hepatocyte nodules. Both cell types were able to proliferate extensively in the recipient liver, as expected. However, their growth pattern was remarkably different. Clusters of normal hepatocytes integrated in the host liver, displaying a normal histology; however, transplanted nodular hepatocytes formed new hepatocyte nodules, with altered morphology and sharp demarcation from surrounding host liver. Both the expression and distribution of proteins involved in cell polarity, cell communication, and cell adhesion, including connexin 32, E-cadherin, and matrix metalloproteinase-2, were altered in clusters of nodular hepatocytes. Furthermore, we were able to show that down-regulation of connexin 32 and E-cadherin in nodular hepatocyte clusters was independent of growth rate. These results support the concept that a dominant pathway towards neoplastic disease in several organs involves defect(s) in tissue pattern formation

Cancer Biomarker Discovery: The Entropic Hallmark

Background: It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Methodology/Principal Findings: Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. Conclusions/Significance: We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases

VIDEOFLUOROSCOPIC SWALLOW STUDY IN CHILDREN WITH DYSPHAGIA

Introduction and Pourpose Infancy and childhood represent a time of unparalleled physical growth and cognitive development. In order for infants and children to reach their linear and neurological growth potential, they must be able to reliably and safely consume sufficient energy and nutrients. The prevalence of feeding problems has been estimated to be from 33% to 80% in children with developmental disorders. Approximately 37% to 40% of children assessed for feeding and swallowing disorders were born prematurely at less than 37 weeks of gestation. Increased survival rates of children with histories of prematurity, low birth weights, and complex medical conditions might explain the recent increase of pediatric dysphagia. Premature surviving patients, chronic illness, and psychological conditions are all possible causes of dysphagia in children. Swallowing difficulties in pediatric populations can have an adverse impact on pulmonary health. Dysphagia in pediatric populations can have a detrimental effect on dietary intake and, thus, growth and development. As a result, it is imperative to accurately identify and appropriately manage dysphagia in pediatric populations. These complex patients require a multidisciplinary approach that includes clinical and instrumental evaluations. The videofluoroscopic swallow study (VFSS) is a well established radiological technique largely used in adult population. VFSS in children of a referral center for dysphagia is herein reported. 288 patients, mean age 9 years (range: 2-18) underwent VFSS. In 185 cases (64%) macro silent aspiration (fig.1-2) or macro silent aspiration and GERD (Fig. 3-4), was evident and patients scheduled for gastro/ digiunostomy and, if necessary, fundoplication (fig. 9,10,11,12); in 45 (16%) only micro silent aspiration (Fig. 5-6) or micro silent aspiration and GERD (Fig. 7-8), was detected and patients directed to a rehabilitation trial, and in 58 cases (20%) no aspiration and patients sent to speech therapist. No complications occurred, although in 6 cases (0,74%) VFSS could not be completed due to demonstration of massive aspiration. Results VFSS swallowing study was performed with personal protocol. Dysphagic patients, aged <18 years, referred to our center underwent VFSS as part of a multidisciplinary program. The VFSS images were assessed according to structural and functional findings in the oral, pharyngeal and esophageal-phase of the swallowing process. Criteria for VFSS included: risk of aspiration, prior aspiration pneumonia, clinical suspicion of pharyngeal/laryngeal problem, and husky voice. VFSS started with nectar viscosity and boluses of 1-2mL. If no radiological aspiration was confirmed, patients received boluses of increased density. Materials and methods VFSS Protocol Three consistencies: ØSemiliquid, ØSemisolid ØLiquid üMixed with barium sulfate (PRONTOBARIO HD 250% weight-volume Bracco, Milan, Italy) To the volume 1-2 cc (teaspoon); bottled milk Step 1 Semiliquid bolus: yogurt, barium and barium sulfate Step 2 Semisolid bolus: pudding and barium sulfate Step 3 Liquid bolus: water and barium sulfate v Administer at least two pains for consistency v Examination suspended when aspiration occurred Swallowing, Nutrition And Imaging – 9 th European Society Swallowing Disordes Congress, 19 – 21 Sep, Vienna 2019 üSwallowing difficulties can have a detrimental effect on pulmonary health and can also impact nutritional intake. üDue to the heterogeneity of the pediatric dysphagia population, treatment and management of dysphagia must be tailored to the clinical characteristics of the individual patient. üCommon instrumental assessment for children suspected of dysphagia includes videofluoroscopic swallow study and esophagram contrast study. üCommon management strategies include for children with oral-phase swallowing problems are aimed at improving the sensory and motor skills needed for drinking and eating, for children with swallowing problems affecting the pharyngeal phase, therapy generally involves modifying the child’s swallowing strategy or modifying the food bolus, for children with severe dysphagia are subjected to surgery for a therapeutic surgical device (gastrostomy, jejunostomy or laparoscopic fundoplication ). Correspondence to: [email protected] Conclusions Like adults, infants and older children can present with swallowing difficulties. Unlike adults, children have rapidly developing body systems and even shortterm problems with swallowing can interrupt normal development and cause serious long-term sequelae. Therefore, accurate diagnosis and effective management of pediatric dysphagia is necessary due to its potential for significant morbidity and possible mortality in pediatric populations. VFSS is the gold standard for identifying inhalation episodes in dysphagic patients. It allows to evaluate the characteristic of swallowing, to determine the need of any nutritional devices and type of eating rehabilitation, and to monitor the progression of the underlying disease. VFSS must always be performed, even in children, before embarking on medical or surgical treatmen

Genetic isolates in Corsica (France): linkage disequilibrium extension analysis on the Xq13 region

Genetic isolates with a history of a small founder population, long-lasting isolation and population bottlenecks represent exceptional resources in the identification of genes involved in the pathogenesis of multifactorial diseases. In these populations, the disease allele reveals linkage disequilibrium (LD) with markers over significant genetic intervals, therefore facilitating disease locus identification. This study has been designed to examine the background LD extension in some subpopulations of Corsica. Our interest in the island of Corsica is due to its geographical and genetic proximity to the other Mediterranean island of Sardinia. Sardinian isolates in which the extension of the background LD is particularly high have been recently identified and are now the object of studies aimed at the mapping of genes involved in complex diseases. Recent evidence has highlighted that the genetic proximity between the populations of Corsica and Sardinia is particularly true for the internal conservative populations. Given these considerations, Sardinia and Corsica may represent a unique system to carry out parallel association studies whose results could be validated by comparison. In the present study, we have analyzed the LD extension on the Xq13 genomic region in three subpopulations of Corsica: Corte, Niolo and Bozio, all located in the mountainous north-center of the island. Our results show a strong degree of LD over long distance for the population of Bozio and to a less extent for the population of Niolo. Their LD extent is comparable to or higher than that reported for other isolates