Molekulare und genetische Medizin

The generation time of diplococcic viridans group streptococci, S. mitis is unusually prolonged when grown in rich broth containing xylitol (2% or higher concentrations). These xylitol-exposed streptococci predominantly grow in chains of varying lengths with heterogeneity of color: pink, purple and pink and purple combined. The pink portion of these bacterial chains appears to be thinner than the purple portion indicating a reduction in cell wall thickness. In support of optical microscopy, scanning electron microscopy of the same bacterial population demonstrates a considerable reduction of sizes but still in chains. In these chains, there is a variation in size indicating that all members of the diplococcic S. mitis population are not equally affected. Apparently, the partially affected viable population of S. mitis, becomes sensitive to colistin and nalidixic acid when grown in xylitol.

Telomeres are areas of heterochromatin composed of TTAGGG repeats located at the ends of linear chromosomes. They play a critical role in keeping genome stable and preventing premature aging diseases and the development of cancer. Characterizing mechanisms of telomere maintenance and understanding how their deregulation contributes to human diseases are therefore important for developing novel therapies. A key mechanism driving telomere maintenance and replicative immortality in cancer cells is telomere elongation by telomerase, and many emerging potential telomere-based therapies have focused on targeting telomerase components. By contrast, recent studies on telomere maintenance mechanism suggest that disrupting telomere stability by interfering with alternative mechanisms of telomere synthesis or protection may also yield new strategies for the treatment of cancer. This review will focus on emerging regulators of telomere synthesis or maintenance, such as G4 telomeric DNA, the CST complex, the t-loop, and shelterins, and discuss their potential as targets for anti-cancer chemotherapeutic intervention in the future.

Liver is one of the target organs for double-stranded DNA (dsDNA)-vector mediated gene delivery due to the highly efficient uptake of gene therapy vectors. Recently dsDNA was described as a pathogen associated molecular pattern that could be recognized by intracellular DNA sensors. Herein, we explored the possibility that dsDNA may change the intracellular innate immune responses of hepatocyte-derived cell and therefore regulate the replication of hepatitis B virus (HBV). A hepatoma cell line HepG2.2.15 which derived from HepG2 with integrated HBV genome, were treated with poly (dA-dT), a synthetic double-stranded DNA molecule. Unexpectedly, HBV replication was up-regulated after poly (dA-dT) transfection in HepG2.2.15 despite the delayed activation of ISGs. There was no nuclear-plasma translocation of IRF3 or NF-κB observed at a early stage. Treatment of HepG2.2.15 cells with supernatant harvested from the cells transfected with poly (dA-dT) indicating that poly (dA-dT) -enhanced HBV replication was predominantly mediated by not secreted cytokines, but intracellular factors. By blocking the cellular signal pathways with inhibitors, we found that U0126, an inhibitor of ERK1/2, could abolish the poly (dA-dT) enhanced HBV replication. Pathway-scan results also indicated that phosphorylated MEK1/2 was enhanced after poly (dA-dT) transfection. Whether this HBV replicating enhancement is good for HBV infection disease outcome needs to be further investigated.

Nanoparticles can occur naturally or be intentionally engineered. The field of nanotechnology has varied influence on industry and segments of our daily life. The health effects associated with human exposure to nanoparticles remains elusive and very little has been done with respect to investigate the genetic and epigenetic effects of nanomaterials. This is especially concerning given their wide spread applications in the modern world. We reviewed recent findings of genetic and epigenetic effects of several common nanoparticles that humans are commonly exposed to. Problems and concerns existing in current nano-toxic studies are addressed and discussed

Non Small Cell Lung Cancer (NSCLC) is often diagnosed in an advanced stage. In this setting the disease is associated with an unfavourable prognosis. Although recent therapeutic advances using molecularly targeted agents enable an improved prognosis, most patients still have a poor outcome. Many tumor antigens have been identified in NSCLC and the activation of tumour antigen-specific immunity mediated by vaccination strategies is widely accepted as an attractive new therapeutic strategy.
Different therapeutic cancer vaccines are currently under clinical development. In clinical studies vaccination protocols targeting tumour antigens like MAGE-A3, MUC1 and hTERT have resulted in favourable survival data. Mode of action as well as available clinical data in phase II and III studies are reviewed. The success of this ongoing tumour antigen-specific vaccination approaches is hampered by local immunosuppressive factors like TGF-β and PD-1. Promising data have been obtained by inhibition of these factors facilitating effective tumour specific immune responses. Also in this particular field we will give an update on the most promising approaches.

The term Cancer Stem Cells (CSCs) has been coined to refer to a subpopulation of tumor cells that has the ability to self-renew and to generate the diverse cell pool of a given tumor. In the last decade CSCs have been receiving a lot of interest due to their cancer initiating and maintaining capabilities making them the real driving force within a malignant mass that pushes towards more aggressive proliferation and more resistance against anticancer drugs. These cells have been linked to different specific markers in an attempt to achieve efficient isolation and characterization. Such markers include CD44, EpCAM and CD133 among others.
Aptamers are synthetic single stranded oligonucleotides selected from a huge pool of random sequences which can fold and bind to a wide range of targets with high affinity and specificity. They are not immunogenic or toxic and have good clearance rates, qualities that make aptamers a good rival to monoclonal antibodies in their diagnostic as well as therapeutic applications.
This review explores the potential applications of aptamers selected to target the main markers of CSCs. Such applications include diagnostic assays and analytical platforms where such aptamers can be utilized to detect and characterize the behavior of these cells in addition to predicting and monitoring disease course and response to different treatment regimens. The potential therapeutic applications are also discussed in details, where such anti- CSC aptamers can be used in a variety of formulations to efficiently target the initiating cores of tumors.

The immune stimulatory cytokine interleukin-15 was recognized as one of the most promising cancer cure drug in a NIH guided review and is currently in clinical trial alone or as an adjuvant for certain types of metastatic solid tumors. IL-15 is an essential survival factor for natural killer (NK), natural killer-like T (NKT), and CD44^hi memory CD8 T cells. The bioactivity of IL-15 in vivo is conferred mainly through a trans-presentation mechanism in which IL-15 is presented in complex with the α-subunit of soluble IL-15 receptor (IL-15R) to NK, NKT or T cells rather than directly interacts with membrane-bound IL-15R. With these understandings, recent studies have been focused on generating IL-15 agonists which consist of IL-15 and partial or whole of soluble IL-15R to improve its in vivo bioactivity. This mini review will summarize the key features of IL-15 as a potential cancer treatment cytokine and the most recent development of IL-15 agonists and preclinical studies. Critical milestones to translate the pre-clinical development to in-patients treatment are emphasized.

Mahvash disease is a novel pancreatic neuroendocrine tumor syndrome caused by inactivating glucagon receptor mutations. Its discovery was triggered by comparison of a patient with pancreatic neuroendocrine tumors, pancreatic α cell hyperplasia, extreme hyperglucagonemia but without glucagonoma syndrome, and occasional hypoglycemia, with the glucagon receptor knockout mice which exhibit similar phenotype and ultimately prove to be a model of Mahvash disease. So far 6 cases have been reported. The inheritance, prevalence, pathogenesis, natural history, diagnosis, treatment, and long-term follow-up of Mahvash disease are discussed in this article. Although rare, Mahvash disease provides important insights into the pathogenesis of pancreatic neuroendocrine tumors, pancreatic α cell fate regulation by glucagon signaling, and safety of glucagon signaling inhibition for diabetes treatment.

Gastric cancer has a dismal prognosis and remains one of the deadly diseases worldwide. It has increasingly been recognized that gastric cancer is heterogeneous disease, which may be subdivided into different groups based on histological, anatomical, and molecular classifications. New classifications combining histological features,anatomical locations, and molecular signatures will help improve our understanding of the biology and pathogenesis, and aid in finding novel therapeutic targets in gastric cancers.