K. Satyamoorthy, Ph.D.
Director, Life Sciences Centre, Manipal University, India
Epigenetic Changes due to DNA Methylation in Human Epithelial Tumors
Extensive global hypomethylation in the genome and hypermthylation of selective tumor specific suppressor genes appears to be a hallmark of human cancers. Data suggests that hypermethylation of promoter region in genes is more closely related to subsequent gene expression; contrary to gene-body DNA methylation. The intricate balance between these two may contribute to the progressive process of development, differentiation and carcinogenesis. Epigenetic changes encompass, apart from DNA methylation, chromatin modifications through post-translational changes in histones and control by miRNAs. At the genome level, effects from these are compounded by copy number variations (CNVs) which may ultimately influence protein functions. From clinical perspective, changes in DNA methylation occur very early which are reversible and are influenced by environmental factors. Therefore, these can be potential resource for identifying therapeutic targets as well as biomarkers for early screening of cancer. Our current efforts in profiling genome wide DNA methylation changes in oral, cervical and breast cancers through DNA methylation microarray analysis has revealed number of alterations critical for survival, progression and metastatic behavior of tumors. Bioinformatics and functional analysis revealed several key regulatory molecules controlled by DNA methylation and suggests that DNA methylation changes in several CpG islands appear to co-segregate in the regions of miRNAs as well as in the CNVs. We have validated the signatures for methylation of CpG islands through bisufite sequencing for essential genes in clinical samples and have undertaken transcriptional and functional analysis in tumor cell lines. These results will be presented.
Rohit Manchanda, Ph.D.
Professor, Biomedical Engineering Group, IIT-Bombay, India
Modelling the syncytial organization and neural control of smooth muscle: insights into autonomic physiology and pharmacology
We have been studying computationally the syncytial organization and neural control of smooth muscle in order to help explain certain puzzling findings thrown up by experimental work. This relates in particular to electrical signals generated in smooth muscles, such as synaptic potentials and spikes, and how these are explicable only if three-dimensional syncytial biophysics are taken fully into account. In this talk, I shall provide an illustration of outcomes and insights gleaned from such an approach. I shall first describe our work on the mammalian vas deferens, in which an analysis of the effects of syncytial coupling led us to conclude that the experimental effects of a presumptive gap junction uncoupler, heptanol, on synaptic potentials were incompatible with gap junctional block and could best be explained by a heptanol-induced inhibition of neurotransmitter release, thus compelling a reinterpretation of the mechanism of action of this agent. I shall outline the various lines of evidence, based on indices of syncytial function, that we adduced in order to reach this conclusion. We have now moved on to our current focus on urinary bladder biophysics, where the questions we aim to address are to do with mechanisms of spike generation. Smooth muscle cells in the bladder exhibit spontaneous spiking and spikes occur in a variety of distinct shapes, making their generation problematic to explain. We believe that the variety in shapes may owe less to intrinsic differences in spike mechanism (i.e., in the complement of ion channels participating in spike production) and more to features imposed by syncytial biophysics. We focus especially on the modulation of spike shape in a 3-D coupled network by such factors as innervation pattern, propagation in a syncytium, electrically finite bundles within and between which the spikes spread, and some degree of pacemaker activity by a sub-population of the cells. I shall report two streams of work that we have done, and the tentative conclusions these have enabled us to reach: (a) using the NEURON environment, to construct the smooth muscle syncytium and endow it with synaptic drive, and (b) using signal-processing approaches, towards sorting and classifying the experimentally recorded spikes.
Egidio D’Angelo, MD, Ph.D.
Full Professor of Physiology & Director, Brain Connectivity Center, University of Pavia, Italy
Realistic modeling: new insight into the functions of the cerebellar network
Realistic modeling is an approach based on the careful reconstruction of neurons synapses starting from biological details at the molecular and cellular level. This technique, combined with the connection topologies derived from histological measurements, allows the reconstruction of precise neuronal networks. Finally, the advent of specific software platforms (PYTHON-NEURON) and of super-computers allows large-scale network simulation to be performed in reasonable time. This approach inverts the logics of older theoretical models, which anticipated an intuition on how the network might work. In realistic modeling, network properties “emerge” from the numerous biological properties embedded into the model.
This approach is illustrated here through an outstanding application of realistic modeling to the cerebellar cortex network. The neurons (over 105) are reproduced at a high level of detail generating non-linear network effects like population oscillations and resonance, phase-reset, bursting, rebounds, short-term and long-term plasticity, spatiotemporal redistrbution of input patterns. The model is currently being used in the context of he HUMAN BRAIN PROJECT to investigate the cerebellar network function.
Correspondence should be addressed to
Dr. EgidioD’Angelo,
Laboratory of Neurophysiology
Via Forlanini 6, 27100 Pavia, Italy
Phone: 0039 (0) 382 987606
Fax: 0039 (0) 382 987527
dangelo@unipv.it
Acknowledgments
This work was supported by grants from European Union to ED (CEREBNET FP7-ITN238686, REALNET FP7-ICT270434) and by grants from the Italian Ministry of Health to ED (RF-2009-1475845).
Srisairam Achuthan, Ph.D.
Senior Scientific Programmer, Research Informatics Division, Department of Information Sciences, City of Hope, CA, USA
Applying Machine learning for Automated Identification of Patient Cohorts
Srisairam Achuthan, Mike Chang, Ajay Shah, Joyce Niland
Patient cohorts for a clinical study are typically identified based on specific selection criteria. In most cases considerable time and effort are spent in finding the most relevant criteria that could potentially lead to a successful study. For complex diseases, this process can be more difficult and error prone since relevant features may not be easily identifiable. Additionally, the information captured in clinical notes is in non-coded text format. Our goal is to discover patterns within the coded and non-coded fields and thereby reveal complex relationships between clinical characteristics across different patients that would be difficult to accomplish manually. Towards this, we have applied machine learning techniques such as artificial neural networks and decision trees to determine patients sharing similar characteristics from available medical records. For this proof of concept study, we used coded and non-coded (i.e., clinical notes) patient data from a clinical database. Coded clinical information such as diagnoses, labs, medications and demographics recorded within the database were pooled together with non-coded information from clinical notes including, smoking status, life style (active / inactive) status derived from clinical notes. The non-coded textual information was identified and interpreted using a Natural Language Processing (NLP) tool I2E from Linguamatics.
Rustom Mody, Ph.D.
Head R & D Lupin Ltd., Pune
Biosimilars are follow-on biologics also known as Similar Biologics – terms used to describe officially approved subsequent versions of innovator biopharmaceutical products made by rDNA technology when made by a different sponsor following patent expiry on the innovator product. These products are drawing global attention as a large number of block buster biopharmaceuticals have expired and many will soon seize to have patent protection in the coming years, opening the doors for the entry of biosimilars. However, the regulatory landscape is getting complex across the globe. The talk focuses on opportunities and challenges in the field of biosimilars and the future of biosimilar companies in India.