Drug discovery today. Disease mechanisms最新文献

Viral infection in cancer is common. Although there is still debate whether viruses alone can cause tumors, the discovery of tumor viruses has enlightened many fields of tumor biology and viral oncogenesis. With the advances of biotechnology, the list of tumor viruses will grow in the coming decades. However, to determine if a candidate virus causes cancer, the key is to combine epidemiological and molecular biologic data. Recently, promising viral targeted therapies include anti-latent viral drugs and immunological therapies. In this article, we review the current knowledge of the role of human papillomavirus, human herpesvirus 8, and Merkel cell polyomavirus in skin cancer carcinogenesis, with a focus on recent literature.

Nephronophthisis is a recessive cystic kidney disorder that belongs to the group of ciliopathies. Most of the causal gene products localize at the primary cilium, as components of either the transition zone or the retrograde intraflagellar transport IFT-A complex, where they control ciliary protein trafficking and modulate responses to various signaling pathways. In this review, we summarize the current literature on nephronophthisis-related disease genetics and outline the essential pathophysiological mechanisms underlying these disorders.

Fluorescent in situ hybridization (FISH) and comparative genomic hybridization (CGH) are molecular techniques that have become valuable adjuncts in the diagnosis of histopathologically ambiguous melanocytic tumors. These techniques detect the presence of chromosomal gains or losses that are characteristic of malignant transformation in melanocytic neoplasms. CGH and FISH have been used to characterize distinct genomic characteristics of melanocytic tumors at various anatomic sites and tumors with certain histopathologic features (e.g. spitzoid, blue nevus-like, congenital nevi). Recent developments in this field include the transition of CGH from a research tool to a clinically available test and a new FISH probe set targeting chromosomal loci 11q13, 8q24, 6p25 and 9p21 that reportedly distinguishes melanoma from melanocytic nevi with a sensitivity and specificity of 94% and 98% respectively. Genomic analysis of melanocytic tumors also provides prognostic information. This review discusses these new advances in molecular diagnostics in melanoma and future directions in the field.

Mutations in the gene coding for the integral membrane protein polycystin-1 (PC1) are the cause of most cases of autosomal-dominant polycystic kidney disease (ADPKD), a very common disease that leads to kidney failure and currently lacks approved treatment. Recent work has revealed that PC1 can regulate the transcription factor STAT3, and that STAT3 is aberrantly activated in the kidneys of ADPKD patients and PKD mouse models. Recent approaches to directly inhibit STAT3 in PKD mouse models have been promising. Numerous signaling pathways are known to activate STAT3 and many have long been implicated in the pathogenesis of PKD – such as EGF/EGFR, HGF/c-Met, Src. However, a role of STAT3 in the pathogenesis of PKD had never been considered until now. Here, we review the current findings that suggest that STAT3 is a promising target for the treatment of PKD.

Itch is the most common symptom in dermatology. Understanding itch causation requires knowledge of cutaneous receptors, inciting factors, and behavioral influences. Studying itch can be done using both in vitro and in vivo methods. Understanding the molecular basis of itch may provide therapeutic targets for alleviating this most troubling dermatologic symptom.

Dysfunctional cilia cause kidney cysts. Most cilia are non-motile (primary) microtubular organelles expressed on epithelial cells that are thought to translate global positional cues into planar cell polarity (PCP), a pathway ascribed to non-canonical Wnt signaling. The PCP pathways then seem to ensure normal renal development by orienting the spindle axis of dividing epithelial cells along the axis of the developing kidney tubule (oriented cell division), and/or by orchestrating cell migration and intercalation, a morphogenetic program observed during vertebrate gastrulation (convergent extension). PCP signaling requires a set of proteins originally identified as PCP core proteins in Drosophila. Several observations now suggest that intact ciliogenesis and ciliary functions require the presence of PCP proteins, while the subcellular localization of core PCP proteins is not affected by ciliary defects. Furthermore, ciliary defects may be overcome by enhanced cell intercalation controlled by the PCP pathway, opening potentially exciting new avenues to prevent cyst formation.

Cystic kidney disease, one of the leading causes of end stage renal disease (ESRD), encompasses a group of genetic disorders defined by the presence and the expansion of cysts at various positions in the nephron. Recent studies in humans and model organisms have identified a direct relationship between cyst formation and dysfunctional ciliary proteins, and have suggested that ciliary dysfunction is a major driver of cystogenesis. However, the fact that the primary cilium is now understood to be a central coordinator for multiple cellular signaling pathways has complicated our mechanistic understanding of cystogenesis and has offered diverse and sometimes contradictory paths to therapeutic designs. Here, we will focus on the recent findings which underlie the molecular mechanisms of cyst formation in the kidney and we discuss how insights of these studies are beginning to offer routes toward the development of treatment paradigms and the promise of preclinical and clinical trials.

Autoimmune blistering diseases are classified by clinical, histological, and immunopathologic findings. As demonstrated by traditional immunofluorescence microscopy studies of patient skin and serum samples, these diseases develop as a consequence of loss of immunologic tolerance to self (i.e. skin) and are mediated by disease-specific autoantibodies. Subsequently, such autoantibodies were used to identify and characterize disease-specific target autoantigens in skin which interestingly are now recognized to be important structural proteins that mediate cell:cell or cell:matrix adhesion. In parallel with these advances, additional studies showed that patient autoantibodies are pathogenic in in vivo passive transfer animal models. Recent advances have explored pathomechanisms of disease and shown that autoantibodies disrupt cell:cell and cell:matrix adhesion by direct effects as well as secondary downstream events. Elucidation of variables that initiate loss of tolerance to skin, production of pathogenic (i.e. disease-causing) autoantibodies, and downstream disease pathomechanisms hold the potential to identify new target directed therapies that control these life threatening disorders without associated generalized immunosuppression, secondary infections, or drug toxicities.