Abstract: Metabolic syndrome is a major risk factor for cardiovascular and metabolic diseases. Playing a central role in the development of metabolic syndrome and in its clinical consequences is visceral obesity. Adipose tissue is now considered to be an active endocrine organ that secretes various humoral factors (adipokines), and its shift to production of proinflammatory cytokines in obesity likely contributes to the low-level systemic inflammation that is seen in metabolic syndrome-associated chronic pathologies such as atherosclerosis. Recent studies have shown that obesity induces chronic local inflammation in adipose tissue, and that cells of the innate immune system, particularly macrophages, are crucially involved in adipose inflammation and systemic metabolic abnormalities. Moreover, we and others recently revealed that T cells are key regulators of adipose inflammation, and that the adaptive immune system is also crucially important. In mouse models modulation of T cell function ameliorated not only adipose inflammation but also systemic insulin resistance induced by obesity. Thus clarification of the inflammatory processes ongoing in obese adipose tissue would seem essential for the understanding of metabolic syndrome and for developing novel therapeutic strategies to treat it. ... Read more

A recent large clinical trial study concluded that cholesterol lowering statin drugs should be taken by diabetic patients to prevent heart disease complications regardless of their initial cholesterol levels (International Statin Study Group, Lancet 361:2005-2016, June 14, 2003). 5,963 UK adults with diabetes and 14,573 with occlusive arterial disease but no diagnosed diabetes were randomized into the treatment group who received Merck’s Zocor (simvastatin) 40 mg daily and the control group who received the placebo, for 5 years. In the three subgroups of patients evaluated: the diabetic patients with occlusive artery disease, diabetic patients who do not have occlusive artery ... Read more

Abstract: Despite billions of dollars allocated to cancer research, cancer remains the number 2 cause of death in the United States with less than 50% of advanced cancer patients living one year following standard treatment. Cancer is a complex disease both intrinsically and in relation to its host environment. From a molecular standpoint no two cancers are the same despite histotypic similarity. As evidenced by the recent advances in molecular biology, treatment for advanced cancer is headed towards specific targeting of vulnerable signaling nodes within the reconfigured pathways created by "omic" rewiring. With advancements in proteo-genomics and the capacity of bioinformatics, complex tumor biology can now be more effectively and rapidly analyzed to discover the vulnerable high information transfer nodes within individual tumors. RNA interference (RNAi) technology, with its capability to knock down the expression of targeted genes (the vulnerable nodes), is moving into the clinic to target these nodes, which are integral to tumor maintenance, with a low risk of side-effects and to block intrinsic immunosuppressors thereby priming the tumor for immune attack. An RNAi based sequential approach, a so called "one-two punch," is being advocated comprising tumor volume reduction (ideally to minimal residual disease status) effected by integrated multi-target knockdown followed by immune activation. Examples and recent developments are provided to illustrate this highly powerful approach heralding the future of personalized cancer therapy. ... Read more

Abstract: Controversial data are available about the relationship between Alzheimer's disease (AD) and rheumatoid arthritis (RA). An inverse relationship between AD and RA, due to different factors, was previously described. Similarly to RA, AD pathogenesis is multifactorial and different findings support the inflammatory pathogenetic hypothesis. Several inflammatory mediators are involved in the disease onset and progression regulated by genetic and epigenetic mechanisms. Among them, inteleukin-6 (IL-6) and interleukin-1 (IL-1) as pro-inflammatory soluble factors produced by monocytes-macrophages and tumor necrosis factor alpha (TNF-α) produced by activated macrophages and mononuclear cells represent key molecules in the induction and maintenance of chronic inflammation in RA. In particular a link with the T allele of the SNP 3953 T/C in the IL-1 gene and an overexpression of miR-146a appears to be common to both RA and AD. In this review we will discuss the genetic and epigenetic regulation of the inflammatory cascade in RA and AD to find out the possible links between RA and AD onset. ... Read more

Abstract: After the characterization of the sex-determining region of Y (SRY) in 1990, there have been an increasing number of genes recognized to play a role in sex development. The most common disorders of sex development (DSD) result from disruption of androgen levels and activity that affect later embryonal development, such as congenital adrenal hyperplasia and androgen insensitivity syndrome. However, genetic diagnosis of mutations affecting early gonadal development is becoming increasingly accessible to clinicians. More powerful genetic techniques are allowing for interrogation of the entire genome for causative changes and it is important to be able to critically assess the flood of genetic data for meaningful information. Recent discoveries have clarified the role of a variety of transcription factors in DSD such as SOX9, SF1, and WT1. Additionally, disruptions of signaling molecules such as hedgehog, WNT, cyclin-dependent kinase, and Ras/MAP kinase are now known to cause DSD. The dosage-dependence of genes involved in gonadal development is a recurrent theme, and genetic changes in promoter and repressor regions are being revealed by chromosomal microarray analysis and other techniques. In some cases, there are multiple different phenotypes caused by deletion, duplication, homozygous, heterozygous, and regulatory-region changes in the same gene. We aim to provide a concise and clinically-applicable overview of recent developments in the understanding of DSD caused by genetic changes affecting gonadal development. ... Read more

Abstract: The sodium/proton (Na/H) exchanger, Na,K-ATPase, and Ca²⁺-ATPase are membrane ion pumps whose basal activities may be regulated by local nongenomic actions of thyroid hormone and hormone analogues via a hormone receptor on plasma membrane integrin αvβ3. System A amino acid transport and the activity of P-glycoprotein (P-gp; ABCB1), a multidrug efflux pump, are also modulated by thyroid hormone and αvβ3. Where signal transduction has been studied, the presence of the hormone at the receptor is transduced by mitogen-activated protein kinase (MAPK) isoforms (ERK1/2; p38) or phosphatidylinositol 3-kinase into local actions. The existence of the cell surface receptor offers opportunities to pharmacologically modify actions of these important transport functions with nanoparticulate formulations of T₄ and T₃ that do not enter the cell. Such formulations may reverse complex intracellular accumulations of H⁺, Na⁺, and Ca²⁺ that occur in clinical settings such as ischemia. In addition, nanoparticulate tetraiodothyroacetic acid (tetrac), a thyroid hormone analogue that inhibits binding of T₄ and T₃ to integrin αvβ3 as well as certain other functions of the integrin, may reverse P-gp-dependent resistance to anti-cancer drugs in tumor cells. ... Read more

Abstract: Complex diseases are caused by perturbations of biological networks. Genetic analysis approaches focused on individual genetic determinants are unlikely to characterize the network architecture of complex diseases comprehensively. Network medicine, which applies systems biology and network science to complex molecular networks underlying human disease, focuses on identifying the interacting genes and proteins which lead to disease pathogenesis. The long biological path between a genetic risk variant and development of a complex disease involves a range of biochemical intermediates, including coding and non-coding RNA, proteins, and metabolites. Transcriptomics, proteomics, metabolomics, and other -omics technologies have the potential to provide insights into complex disease pathogenesis, especially if they are applied within a network biology framework. Most previous efforts to relate genetics to -omics data have focused on a single -omics platform; the next generation of complex disease genetics studies will require integration of multiple types of -omics data sets in a network context. Network medicine may also provide insight into complex disease heterogeneity, serve as the basis for new disease classifications that reflect underlying disease pathogenesis, and guide rational therapeutic and preventive strategies. ... Read more

Abstract: The purpose of this study was to explore epigenetic changes and functions of SOX17 in human lung cancer. Five lung cancer cell lines and 88 primary lung cancer samples were examined in this study. Methylation-specific polymerase chain reaction (MSP), semi-quantitative reverse-transcription PCR, immunohistochemistry, luciferase reporter assays, colony-formation assays, and western blotting were used to analyze methylation changes and functions of SOX17 in lung cancer. SOX17 methylation was found in 60.2% of primary human lung cancer samples, and promoter region methylation of SOX17 silenced its expression. SOX17 methylation was associated with female patients and lung cancer differentiation. Colony-formation assays revealed that SOX17 suppressed lung cancer cell proliferation. Re-expression of SOX17 inhibited Wnt signaling in H23 lung cancer cell line. SOX17 acts as a Wnt signaling inhibitor. ... Read more

Abstract: Aging is a progressive degenerative process tightly integrated with inflammation. Cause and effect are not clear. A number of theories have been developed that attempt to define the role of chronic inflammation in aging: redox stress, mitochondrial damage, immunosenescence, endocrinosenescence, epigenetic modifications, and age-related diseases. However, no single theory explains all aspects of aging; instead, it is likely that multiple processes contribute and that all are intertwined with inflammatory responses. Human immunodeficiency virus (HIV)-infected patients undergo a premature aging phenomenon which may provide clues to better elucidate the nature of inflammation in aging. Environmental and lifestyle effectors of inflammation may also contribute to modulation of both inflammation and age-related dysfunction. ... Read more

Abstract: Humans have been struggling with food and survival throughout a very large portion of Homo sapiens's long history. Genes are customarily programmed to prepare the fetus for harsh conditions and deprivation outside the womb of comfort. Today's affluence in certain parts of the world would surpass the wildest dreams of hunter-gatherers. The human genome might not have had enough time to adjust to the quantity of proteins and sugars ingested each day and the result may be an increase in disease. ... Read more