Combinatorial therapy for Metastatic cancers: A pharmaceutical mixture encompassing Docosahexaenoic acid (DHA) and Aspirin (ASA) increases the expression of tumor/metastatic suppressors BTG2 and INK4a, inhibits cell cycle progression, and suppresses migration, invasion and metastasis of cancer cells via up regulation of its target gene, 22/February/2018, 12.06 am
L-Arginine has been shown to increase nitric oxide (NO) levels; and improve blood flow. This study suggests, for the first time, an amino acid-based therapy for TIDM.
L-Arginine, by increasing the expression of its target gene, it may increase the expression of PD-L1. Thereby, it may: (1) increase Regulatory T-cells(Tregs) function; (2) decrease immune activation; (3) increase pancreatic-β-cell proliferation and regeneration; (4) increase expression of genes that promote insulin sensitivity and insulin secretion;(4) decrease metabolic stress; and (5) promote glucose homeostasis (Fig.1).Thus, pharmacological formulations encompassing “L-Arginine or its analogues, either alone or in combination with other drugs” may be used to treat TIDM (Fig.2.). Given that leucine and taurine may also aid in the treatment of autoimmune diabetes (published by us), a therapeutic mix encompassing L-Arginine, Taurine and Leucine may be used to reverse autoimmune diabetes.
Figure 1. Mechanistic insights into how L-Arginine inhibits the development of autoimmune diabetes (T1DM). L-Arginine, by increasing the expression of its target genes, it may increase the expression of PD-L1. Thereby, it may prevent immune activation and attenuate development of T1DM.
The research in my laboratory extends from basic science to translational research to technology development. My laboratory applies molecular and genomics approaches to do innovative studies concerning the regulation of gene expression in normal and cancer cells. The following paragraphs summarize our major research projects:
The c-Myb transcription factor is a key and essential regulator of hematopoiesis and plays important roles in epithelial and some neural cells. The two striking features of c-Myb are that it regulates different sets of genes in different situations and that relatively minor mutations can completely change its activity – even converting the normal regulator into an oncoprotein. One aspect of my research is to better understand how the activities of c-Myb are regulated and affected by protein-protein interactions and upstream regulatory and signal transduction pathways that lead to changes in post-translational modifications. We have developed novel and innovative approaches for following changes in c-Myb during the cell cycle and are mapping domains in the protein responsible for cell cycle-dependent changes in transcriptional activities. We are using whole genome techniques such as Chromatin Immunoprecipitation coupled with next-generation sequencing (ChIP-seq) to map global changes in the association of c-Myb with promoters during different stages of the cell cycle and to compare the activities of the wild type protein to the oncogenic alleles. The goals are to understand how signaling pathways lead to changes in c-Myb activity and how the activity of c-Myb becomes corrupted in cancer cells. A better understanding of the regulatory pathways that control c-Myb activity should lead to novel therapeutic approaches for treating cancer patients.
The c-Myb protein is a critical regulator of cell fate, controlling whether cells continue proliferating or differentiate. We found that the c-myb gene encodes at least 60 different splice variants, and that the expression of specific variants correlates with poor prognosis and poor survival in leukemia patients (manuscript in preparation). This provides a novel type of biomarker for analyzing and classifying leukemia patients, and we have developed high-throughput methods using next-generation sequencing technologies to take advantage of this approach. We have also found that the c-Myb protein is tightly regulated and that its specificity and targeting to specific genes is controlled by upstream signaling pathways that affect protein-protein interactions. This provides a novel approach for screening potential therapeutic agents that can lead to changes in c-Myb activities and determine whether cancer cells continue to proliferate or are triggered to differentiate. We have several projects designed to target the differentiation-promoting activity of c-Myb that could lead to new clinical trials.
As the Director of our genomics shared resource, I have made use of new types of genomics technologies for my own NCI- and NIDCR-funded research, and I have been involved in the development of new types of technologies for improving and lowering the cost of next-generation DNA sequencing. We are also working on novel ways of utilizing the amazing power of next-generation sequencing technologies and bioinformatics for the analysis of protein-protein interactions and post-translational modifications. These approaches could open new doors for the analysis and understanding of populations and sub-populations of proteins in the cell.