Alagille Syndrome

Chromosome 20

Over the years, many scientists and doctors have been treating the deadly disease of cancer but are not able to find a permanent treatment for this disease. Also, sometimes it becomes very difficult to understand the mechanisms and causes of cancer as it is a very complex disease that involves many biological processes. Due to the redundancy in our biological system, cancer progression becomes very easy, thus making it difficult to cure. To find the root cause of this disease, we should know what genetic alterations are undergoing, which is causing cancer to progress, and know who is participating in these alterations, like proteins, signaling pathways, or genes. Cancer is caused due to various reasons; it can be due to genetics but mostly due to carcinogens, causing mutations in the genes, thereby making them an oncogene. The Proto-oncogenes are those genes that usually assist the growth of tumor cells. The alteration, mutation, or increased copy number of a particular gene may turn into a proto-oncogene which could end up completely activated or turned on. Many Tumor-causing alterations or mutations related to oncogenes are usually acquired and not inherited. These tumor-causing mutations often actuate oncogenes via chromosomal rearrangement, or alterations in the chromosome, which sequestrates one gene after another, thereby permitting the first gene to prompt the alternative. Search which genes are involved in different cancer types would help scientists proceed with new methods for finding a cure for this disease. This article will depict which genes and their location on which chromosomes, specifically on chromosome 20, are related to different types of cancer.

Transcription Factors in Cancer

Different types of signalling pathways have been approved to be involved in cancer imitation and progression. These signalling pathways include the JAK-STAT signalling, NF-κB signalling, Wnt, Notch and Hedgehog. STAT (Signal Transducer and Activator of Transcription) transports signals between proteins from the cell membrane into the nucleus to contribute to cancer progression. NF-κB signalling is essential for the survival of the B cell tumor types. The Wnt, Notch, and Hedgehog signalling pathways play a significant role in carcinogenesis by upregulating the genes associated with these pathways. Hence, pharmacological inhibitors of WNT, NOTCH, and HH pathways are required in clinical studies. Such inhibitors have features that make them important during the clinical trial since they offer great potential as novel therapeutics for cancer. They also have an antitumor response which should be taken into consideration. The three signalling pathways are also known to shape cell fate determination and differentiation. In case of depletion of a single molecular component within the three pathways, embryonic lethality will form.

Toward Induced Pluripotent Stem Cells for Clinical Use: Sources, Methods and Selection

Since their development by Yamanaka in 2007, much progress has been made in the last decade toward the use of human induced pluripotent stem cells (iPSCs) in clinical practice. In this review, we will focus on the various sources of somatic cells for human iPSC generation, the methods used for generating human iPSCs, their characterization, and the progress on directed differentiation toward several cell types. We will also describe current efforts to prevent culture-driven mutations and the selection of nontumorigenic cells for clinical use. A comprehensive comparison of such methods will aid in the establishment of standardized techniques and highlight areas in which further research is still needed.

Genetics of Structural Congenital Heart Defects

Epidemiological studies, clinical observations and recent advances in molecular genetics are shedding increasing light on the genetic origin of congenital heart disease (CHD). Chromosomal anomalies, Mendelian syndromes or associations account for nearly 30% of all congenital cardiac malformations. These developmental anomalies may be part of well-defined syndromes due to chromosomal or submicroscopic genomic anomalies or may be non-syndromic as a consequence of still unidentified genes with sporadic occurrence in families. This paper summarizes the available findings from literature on the inference of genetics on cardiac development by classifying the congenital heart diseases as cono-truncal defects, atrio-ventricular canal and septal defects, right-sided obstruction and left-sided obstruction.

Cono-truncal defects represent an anatomically heterogeneous group of CHDs affecting the outflow tract of the ventricles and the arterial pole of the heart. The most common malformations of this group are tetralogy of Fallot, pulmonary atresia with ventricular septal defect, truncus arteriosus and interrupted aortic arch. These CHDs are associated with genetic syndromes in 25-40% of cases and even in non-syndromic forms show a high incidence of mono-genic abnormalities.

Atrio-ventricular canal is a complex malformation due to abnormal septation of the “crux cordis” resulting in ostium primum atrial septal defect, inlet ventricular septal defect and common atrio-ventricular valve. It is almost always associated with genetic syndromes, being non-syndromic in only 25% of cases. However, septal defects other than atrio-ventricular canal are rarely due to genetic syndromes, ranging from 3% to 25% of cases, yet with a high rate of segregation in some families.

Valvular or vascular-elicited right sided obstructions, are due to genetic syndromes in about 10% of cases and this association results in difficult treatment due to the ineffectiveness of any percutaneous treatment and extent of the lesions along the pulmonary trunk.

Among left heart obstructions, supra-valvular stenosis is a well-know malformation due to disruption of the elastin gene associated with Williams syndrome in many cases.

Conversely, aortic coarctation and other left-sided heart stenosis or hypoplastic malformation are often non-syndromic, being associated with genetic syndromes in less than 10% of cases.

In conclusion, improved molecular genetic technologies has led to the discovery of several causes of syndromic and non-syndromic CHDs. Nevertheless, much work remains in identifying in etiology of non-syndromic CHDs, since the number of genes known to be involved is still limited.

Development of Mechanistic Model for Drug-Induced Cholestasis and its Applications for Drug Development

We describe construction of mechanistic model for drug-induced cholestasis using information available from ResNet and ChemEffect knowledge networks in Pathway Studio software. We first developed the mechanistic model using information about protein targets of the cholestasis-inducing drugs. We then expanded the model by incorporating knowledge about protein functional annotation, protein homology, canonical pathways and pathway reconstruction. The expanded model provides a toxicity mechanism for 81% of the drugs known to induce cholestasis vs. 58% of the drugs explained by the original model. Using the model we suggest that FGF19 secreted proteins are the biomarker for drug-induced cholestasis. In this discussion we suggest how the mechanistic model can be used for predicting cholestasic risk for new compounds, how it can be used for development of biomarker panel to monitor cholestasis risk in patient during drug therapy, and how the model can be used in personalized medicine for evaluating patient predisposition for cholestasis.

4D Study of Right Heart Anomalies

In this chapter, the 2D, color Doppler and four dimensional (4D) features of major right heart abnormalities are described. In particular, the echocardiographic views on which the various lesions are present are reported. The diagnostic role of 4D echocardiography in allowing a spatial demonstration of the defects with the possibility of getting new views into the heart is outlined. Videos of major diagnostic features are also provided, to facilitate the understanding of the text