Abstract: Cancer is a complex and heterogeneous disease which changes over time, and in the face of therapeutic intervention. Single tissue biomarkers, while partially successful in helping us understand which patients will respond to therapy, cannot hope to capture this amazing complexity. Systems pathology, which combines measurements made on tissues with new mathematical modelling approaches, permits the testing of new agents and biomarkers in silico through computational analysis. These approaches help us to refine pathological measurements and improve decision making about therapies for clinical trial planning and ultimately personalized therapy. ... Read more

Abstract: Prostate cancer is the most common cancer seen in aging males in the Western world, and is a major clinical challenge in uro-oncology due to biological heterogeneity. Recent advances in molecular medicine suggest that the genetic composition of a prostate tumor contributes significantly to the complexity of the disease. An important genetic mechanism underlying biological diversity is alternative pre-mRNA splicing, which is thought to affect ~95% of transcripts derived from protein-encoding genes. During alternative splicing, coding (exons) and non-coding (introns) regions of pre-messenger RNA (pre-mRNA) transcripts derived from a single gene are rearranged to generate several mRNAs species, which are translated into distinct protein isoforms with differing biological functions. Recent emerging evidence suggests that prostate cancer-specific aberrant and alternative splicing may contribute to the biological heterogeneity of the disease. Furthermore, identification of prostate cancer-specific splice variants may yield novel biomarkers and targets for therapy to improve patient care and clinical outcome. ... Read more

Abstract: Chronic infection with the bacterial pathogen Helicobacter pylori is closely linked to the development of gastric cancer. Experimental infection of the laboratory mouse strain C57Bl6 mimics the initiation and progression of the disease in humans. Using this model, we have identified a dual role for CD4⁺ IFN-γ-secreting T-cells in the control of Helicobacter infection as well as in the induction of preneoplastic gastric pathology. High gastric expression of IFN-γ was positively correlated with a low Helicobacter burden, and was essential for vaccine-induced protection; on the other hand, elevated levels of the cytokine also, either directly or indirectly, triggered the transformation of the normal gastric mucosa to atrophic, hyperplastic and metaplastic lesions. Based on similar patterns of gene expression changes induced by IFN-γ in vivo and in cultured gastric epithelial cells, we hypothesize that IFN-γ may act directly on epithelial cells to stimulate their hyperproliferation, and thus to predispose them to elevated mutation rates and an increased risk of malignant transformation. ... Read more

Abstract: Ghrelin is a recently identified gastric hormone that displays strong growth hormone (GH) releasing activity mediated by the GH secretagogue receptor (GHS-R). While this unique endogenous peptide participates in the regulation of energy homeostasis, increases food intake, and decreases energy expenditure, its ability to modulate immune regulation is another important feature. Here we discuss the effect of ghrelin on the immune system. Ghrelin was initially reported as an immune enhancing factor. More recently, however, the immunosuppressive effects of ghrelin have been found in several animal models including bowel disease, arthritis, and sepsis and endotoxemia. We recently demonstrated that exogenous administration of ghrelin suppressed experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis in association with the reduction of pro-inflammatory cytokines in microglia. These results shed light on the new role of ghrelin in the regulation of disorders that pro-inflammatory cytokines contribute to the pathogenesis such as neuroinflammatory and mental diseases. ... Read more

Abstract: The first descriptions of apoptosis were made over 150 years ago, although the implications for tumor development were not appreciated until the 1970s. Natural cell death is a critical part of development of multicellular organisms, and also counter-balances the cell generating effects of mitosis. Disruptions in the highly regulated apoptotic pathway can lead to disease, such as tumors, due to the accumulation of excessive numbers of cells. Restoring normal apoptosis in cancer cells is one of the current challenges of cancer research. ... Read more

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

Abstract: Despite the social stigma and manufacturing hurdles that come with using viruses as therapeutic tools, the molecular specificity offered by these bugs makes them too attractive to ignore. Still largely based on vaccines, viral vectors offer exciting tools to treat cancer or deliver specific genetic payloads to a desired tissue. Unfortunately, early clinical trials utilizing such vectors have been plagued with poor performance or even clinical toxicity most commonly associated with spurious genetic regulation and/or replication of the vector. Past efforts to control for unwanted toxicity have focused on modification of the receptor or use of tissue-specific genetic elements that added specificity to the transcriptional induction of the gene(s) of interest. While this has had some success, engineering receptors to control viral tropism often fails or results in a loss of replicative fitness. In addition, the use of tissue-specific promoter elements not only restricts the vector that can be used, bona fide small promoter elements are often not available for the desired target. With the caveats of viral vector-based therapeutics largely centered on a lack of in vivo control, the recent success of exploiting microRNA expression to limit viral tropism may breathe new life into the field. ... Read more

Abstract: The APOE ε4 allele is associated with risk of late-onset Alzheimer's disease (AD). Longitudinal memory decline in asymptomatic APOE ε4 carriers shows greater acceleration compared with non-carriers, with a possible allele-dose effect, and begins prior to age 60. These results correlate with imaging and neuropathological studies that show AD-like changes at this age and collectively support the existence of a presymptomatic stage of AD. ... Read more