Discovery Medicine

Abstract: It is clear that micro-RNAs (miRNAs) are emerging as key players in the control of a multitude of biological processes, from plants to animals, alongside with coding genes. The regulation of miRNA expression is tightly controlled, and often the same rules and regulations that govern coding gene expression apply also to miRNAs. Similar to coding genes, altering the levels and the temporal expression of a specific miRNA clearly affects the proper development and function of the tissue where it is expressed. In this review we discuss seminal studies, which demonstrate the importance of miRNAs in the immune system and a possible link between dysregulated miRNA expression and diseases, such as systemic lupus erythematosus (SLE) and cancer. In addition, we summarize progresses towards targeting miRNAs as therapeutic agents. ... Read more

Abstract: Psoriatic arthritis (PsA) occurs in approximately 30% of psoriasis patients. Understanding the similarities and differences in the etiology of these related diseases may highlight pathways for intervention and allow risk prediction in the future. Both are complex diseases in which environmental susceptibility factors trigger disease in genetically susceptible individuals. In recent years, genome-wide association studies have been highly successful in identifying genetic susceptibility factors for psoriasis. Most of the psoriasis loci tested so far are also associated with PsA. For example, associations of HLA-Cw*06 and the IL12B and IL23R genes are well-established with both conditions. More recently, analysis of psoriasis genome-wide association studies in a PsA subgroup has also implicated IL23A, TNFAIP3, and TNIP1 genetic variants as conferring risk to PsA. One study has suggested that late cornified envelope (LCE) gene polymorphisms are associated with psoriasis but not PsA. However, this finding was not confirmed by a second study. Similarly, association of the 5q31 gene region encompassing the IL13 gene has been reported with PsA but not psoriasis by one group, but this awaits confirmation in other series. Dedicated genome-wide association studies of PsA are underway and are likely to reveal further insights into why some patients with psoriasis develop arthritis whilst the majority do not. ... Read more

Abstract: Systemic sclerosis (SSc) is a complex fibrosing autoimmune disease that has variable clinical manifestations and morbidity/mortality secondary to organ damage due to vasculopathy and/or fibrosis. Initial events in the pathogenesis are manifested by fibroproliferative vasculopathy that compromises delivery of blood to critical organs. There is evidence of autoimmunity early in the disease which persists and is accompanied by fibrotic processes that leave large accumulations of collagen and other matrix components in the intima of blood vessels and extracellularly in the connective tissue of organs affected by the disease. It has recently been realized that the lysophospholipids -- lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), which are elevated in sera of SSc patients, are capable of producing many of the abnormalities observed in the vasculature, immune system, and connective tissue of patients with this disease. This article reviews key abnormalities of the vasculature, immune system, and connective tissue in SSc that could be mediated by LPA/S1P. ... Read more

Abstract: Type 1 diabetes (T1D) is an autoimmune disease characterized by the disturbance of pancreatic insulin-producing cells, which results in hyperglycemia. The disease is associated with severe complications that impair the quality of life of individuals. The cause of T1D is unknown. Development of the disease is the result of interactions between immunological, genetic, and environmental factors. Viruses are thought to play an important role in the initiation or acceleration of the disease. This is an important issue since it opens the possibility to develop new preventive and therapeutic strategies to fight the disease. The role of enteroviruses in the development of T1D, in particular type B coxsackieviruses, is supported by epidemiological observations. It has been demonstrated that enterovirus infections were significantly more common in recently diagnosed diabetic patients, compared with control subjects. Enteroviral RNA and/or proteins can be detected in blood samples and intestine biopsies of patients with T1D. The hypothesis of a relationship between enteroviruses and the disease has been strengthened by the presence of enteroviral components or infectious particles in the pancreas of patients with T1D. In this review, arguments in favor of a relationship between enterovirus infections and T1D and the mechanisms of the enteroviral pathogenesis of the disease are presented. ... Read more

Abstract: There have been several publications recently that reported DNA sequence alterations in human tumors. There are gene deletions, amplifications, point mutations, translocations, and other genome changes in these samples compared to normal controls. There is also considerable variation in the number of such changes seen in different cancers. Some of the changes particularly those that are mutations in genes driving cellular proliferation will be useful clinically and could be used to monitor disease. At the present time, however, there are more cost effective ways than whole genome sequencing to derive "clinically actionable information" from the molecular analysis of patients and their tumors when they come into the clinic. The number of clinical options available for patients stratified by molecular diagnostics may actually be limited more by the specific treatments available rather than by the ability to stratify the patients in the first place. ... Read more

Abstract: Systemic sclerosis (SSc, scleroderma) is an autoimmune disease clinically characterized by progressive fibrosis in the skin and internal organs. While the pathogenesis of SSc is not completely understood, familial studies and genetic studies suggest that SSc is a complex polygenic disease. In the current review, we will discuss recent studies investigating genetic susceptibility to SSc. Candidate gene studies have identified critical immunoregulatory genes and gene regions including BANK1, FAM167A-BLK, IL23R, IRF5, STAT4, TBX21, and TNFSF4 as susceptibility genes for the development of SSc. More recently a genome-wide association study has been performed and identified CD247 (CD3-zeta) as a novel genetic risk factor for the susceptibility to SSc. Together these genetic association studies have substantially advanced our understanding of SSc pathogenesis and form the foundation for future studies seeking to understand the complexities of SSc. ... Read more

Abstract: Transplantation of cells, tissues, and organs from one individual to another can incite the production of antibodies specific for foreign antigens, especially major histocompatibility antigens, in the graft. Antibodies specific for a graft provide an index of immunity and a potential trigger for injury and rejection. However, the index of immunity can sometimes miss antibody-mediated rejection and besides causing injury the antibodies against a graft can also protect a graft from injury by blocking immune recognition, called enhancement, regulating activation of complement, and inducing changes in the graft that resist damage. Reviewed here are potential limitations in the use of antibodies as an index of immunity and the ways antibodies cause and/or prevent injury. ... Read more

Abstract: This review focuses on the most recent advances in the application of probiotics as potential therapeutics for the developing world, from the treatment of chronic and acute enteric infections and their associated diarrheal complexes to the development of designer probiotics for controlling HIV and as novel mucosal vaccine delivery vehicles. ... Read more

Abstract: The widespread use of antibiotics has markedly improved public health over the last 60 years. However, the efficacy of antibiotic treatment is rapidly decreasing as a result of the continual spread of antibiotic resistance in pathogen populations. The evolution of antibiotic resistance is an amazingly simple example of adaptation by natural selection, and there is growing interest among evolutionary biologists in using evolutionary principles to help understand and combat the spread of resistance in pathogen populations. In this article, we review recent progress in our understanding of the underlying evolutionary forces that drive antibiotic resistance. Recent work has shown that both the mechanisms of antibiotic action and resistance, as well as the treatment context in which resistance evolves, influence the evolution of resistance in predictable ways. We argue that developing predictive models of resistance evolution that can be used to prevent the spread of resistance in pathogen populations requires integrating the treatment context and the molecular biology of resistance into the same evolutionary framework. ... Read more

Abstract: Pituitary adenomas are benign tumors that can be either secreting (acromegaly, Cushing's disease, prolactinomas) or non-secreting. Transsphenoidal neurosurgery is the gold standard treatment; however, it is not always effective. Gamma Knife radiosurgery is a specific modality of stereotactic radiosurgery, a precise radiation technique. Several studies reported the efficacy and low risk of adverse effects induced by this technique: in secreting pituitary adenomas, hypersecretion is controlled in about 50% of cases and tumor volume is stabilized or decreased in 80-90% of cases, making Gamma Knife a valuable adjunctive or first-line treatment. As hormone levels decrease progressively, the main drawback is the longer time to remission (12-60 months), requiring an additional treatment during this period. Hypopituitarism is the main side effect, observed in 20-40% cases. Gamma Knife is thus useful in the therapeutic algorithms of pituitary adenomas in well-defined indications, mainly low secreting small lesions well identified on magnetic resonance imaging (MRI). ... Read more