Highlights Infection and Immunology

Antibodies administered subcutaneously are docking to cells and are delivered from a reservoir in the subcutaneous lymphnodes.
Antibodies administered subcutaneously are docking to cells and are delivered from a reservoir in the subcutaneous lymphnodes.

Gene Signature for Bone Cancer

In a study of 123 osteosarcomas regarding changes in the genome, 14 so-called driver genes were discovered. They are apparently crucial in driving tumor development. Further analyses revealed that more than 80 percent of the investigated osteosarcomas had a specific signature in these genes, which is also frequently observed in breast or ovarian tumors. Corresponding drugs for the treatment of BRCA1/2-deficient tumors already exist that could lead to new treatment options for patients with osteosarcoma.

Michal Kovac et al.:  Exome sequencing of Osteosarcoma Reveals Mutation Signatures Reminiscent of BRCA Deficiency. Nature Communications 6 (2015) | doi: 10.1038/ncomms9940

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Breeding Sites for Liver Cancer

Liver cancer develops in lymph node-like structures, which are a characteristic feature of chronic liver inflammation. Inside these "pseudo-nodes" scientists found high levels of signaling molecules of the immune system, particularly the so-called lymphotoxins. They drive the development of tumor progenitor cells that eventually migrate into the surrounding liver tissue and multiply there.

Shlomi Finkin et al.: Ectopic Lymphoid Structures Function as Microniches for Tumor Progenitor Cells in Hepatocellular Carcinoma. Nature Immunology 16 (2015) | doi: 10.1038/ni.3290

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Role of BMP7 in Adrenal Gland Tumors

In the development of adrenal gland tumors, the protein BMP7 plays a key role and could be a possible target for future treatments. This is the result of studies on pheochromocytomas (PCC), hormonally active tumors of the adrenal gland. Functional tests revealed that elevated BMP7 leads to increased cell division and to aggressive migration behavior of PCC cells, and an underlying signaling pathway was identified.

Ines Leinhäuser et al.: Oncogenic Features of the Bone Morphogenic Protein 7 (BMP7) in Pheochromocytoma. Oncotarget (2015) | doi: 10.18632/oncotarget.4912

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How Lymphomas Fend Off Immune Attacks

Natural killer cells of the immune system – they mediate an innate immunity against exogenous and altered endogenous structures – can fend off malignant lymphoma cells and thus are considered a promising therapeutic approach. However: In the in the immediate vicinity of the tumor they become functionally impaired and increasingly lose their effect. Scientists have now investigated which mechanisms block the killer cells and how to prevent this.

Lena Belting et al.: Critical Role of the NKG2D Receptor for NK Cell-mediated Control and Immune Escape of B-cell Lymphoma. European Journal of Immunology 45 (2015) | doi: 10.1002/eji.201445375

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Subcutaneous Treatment with Multispecific Antibodies

Tumor treatment with multispecific antibodies – artificially produced immunoglobulins that can deliver multiple different cell types simultaneously – is significantly more tolerable if administered subcutaneously rather than via the bloodstream, which was the standard procedure until now. The findings from this animal model study could lead to significantly shorter hospital stays for tumor patients.

Nina Deppisch et al.:  Efficacy and Tolerability of a GD2-Directed Trifunctional Bispecific Antibody in a Preclinical Model: Subcutaneous administration is superior to intravenous delivery. Molecular Cancer Therapeutics  14 (2015) | doi: 10.1158/1535-7163.MCT-15-0156

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Looking under the Camouflage of Epstein-Barr Virus

Most people are infected with Epstein-Barr virus (EBV) and carry it for life – yet as a rule they remain healthy. However, there are several types of cancer in which EBV is involved, e.g. Hodgkin’s disease. Now the enigma has been partially solved on how EBV conceals itself from the immune system. The culprit is the viral protein LMP2A, which helps infected cells to hide from the T cells. This could also play a role in the EBV-induced development of cancer.

Chiara Rancan et al.: Latent Membrane Protein LMP2A Impairs Recognition of EBV-Infected Cells by CD8+ T Cells. PLoS Pathog 11 (2015) | doi:10.1371/journal.ppat.1004906

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Ferroptosis: Cell Death with Therapeutic Potential

Ferroptosis is a newly discovered form of cell death believed to be involved in numerous pathological processes, such as renal failure, stroke and neurodegeneration. However, this particular form of cell death can be blocked pharmacologically by inhibitors such as liproxstatin-1. An international team of scientists has now elucidated the molecular mechanisms of ferroptosis, resulting in new approaches for drug discovery.

Jose Pedro Friedmann Angeli et al.: Inactivation of the Ferroptosis Regulator Gpx4  Triggers Acute Renal Failure in Mice. Nature Cell Biology 16 (2014) | doi:10.1038/ncb3064A

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Non-alcoholic Liver Diseases Caused by Immune Cells

Immune cells that migrate to the liver and interact there with liver cells can cause fatty liver, non-alcoholic steatohepatitis and liver cancer. Scientists have shown this based on an animal model and have thus identified a previously unknown pathogenic mechanism of these serious, widespread diseases. The activation and migration of T cells is apparently caused by a metabolic imbalance.

Monika Julia Wolf et al.: Metabolic Activation of Intrahepatic CD8+ and NKT-cells Causes Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma Via Cross-talk with Hepatocytes. Cancer Cell 26 | doi: 10.1016/j.ccell.2014.09.003

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How Roquin Prevents Autoimmunity

The Roquin protein controls T-cell activation and differentiation by regulating the expression of certain mRNAs. In doing so, it helps to ensure the immunological tolerance of the body and to prevent autoimmune responses. Now scientists have solved the three-dimensional structure of the Roquin protein when bound to messenger ribonucleic acid (mRNA) molecules. The results of the study reveal that there is a much larger spectrum of functionally important Roquin binding partners than previously assumed.

Andreas Schlundt et al.: Structural Basis for RNA Recognition in Roquin-mediated Post-transcriptional Gene Regulation. Nature Structural & Molecular Biology 21 (2014) | doi:10.1038/nsmb.2855

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New Insights into Transplant Tolerance

Chronic hepatitis C virus infections are among the most common reasons for liver transplants. Because existing viruses also infect the new liver, the immune system is highly active there. A clinical study provides evidence why in some patients the transplanted organ is tolerated and not rejected by the body's immune system. Thus, in the liver of tolerant patients, genes of the type I interferon system were active. They represent a potential marker for transplantation tolerance.

Felix Bohne et al.: HCV-induced Immune Responses Influence the Development of Operational Tolerance Following Liver Transplantation in Humans. Science Translational Medicine 6 (2014) | doi: 10.1126/scitranslmed.3008793

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Effect of T Cells on EBV-associated Tumors

Some T-cell subsets can inhibit the growth of tumors that are associated with the Epstein-Barr virus, while others promote such growth. In an analysis of tumor-specific T cells, the scientists found in the animal model that inhibition is mediated by T cells recognizing viral or cellular components of the tumor. These findings may lead to the development of more effective immunotherapies and vaccines.

Stefanie Linnerbauer et al.: Virus and Autoantigen-Specific CD4+ T Cells Are Key Effectors in a SCID Mouse Model of EBV-Associated Post-Transplant Lymphoproliferative Disorders. PLoS Pathog 10(5): e1004068 | doi:10.1371/journal.ppat.1004068

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CMV Defends Itself against Immune Attack

Cytomegalovirus (CMV) is widespread in the population and generally harmless. For people undergoing transplantation, however, it can cause serious illness. One therapy option is to transfer virus-specific immune cells that are obtained from healthy carriers of the virus. Now scientists have explored why the effectiveness of this method varies so much: inhibitors of the CM virus, immune-evasins, prevent the virus-infected cells from being recognized and killed off by the T cells. Some T cells, however, can overcome this inhibition.

Stefanie Ameres et al.: CD8 T Cell-Evasive Functions of Human Cytomegalovirus Display Pervasive MHC Allele Specificity, Complementarity, and Cooperativity. The Journal of Immunology (2014) | doi: 10.4049/jimmunol.1302281

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Hepatitis C Virus (HCV): The Interaction of Viral Proteins in Host Cells

Infections with HCV lead to inflammatory, usually chronic liver diseases. Hepatitis C is a risk factor for the development of liver cirrhosis and liver cancer. Now with a novel combination method, the interactions of hepatitis C virus proteins were investigated in human living cells. With this method, scientists hope to better elucidate the disease mechanisms and to identify new targets for effective treatments.

Nicole Hagen et al.: The Intra Viral Protein Interaction Network of Hepatitis C Virus. Molecular & Cellular Proteomics 13.7 (2014) | doi: 10.1074/mcp.M113.036301

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New Treatment Approach for Hepatitis B

Hepatitis B viruses (HBV) can persist in the liver by “hiding” their DNA in the cell nucleus. Later – e.g. after completion of an antiviral therapy – the DNAs can be reactivated and new viruses produced. A research team has now discovered that the activation of the lymphotoxin-β receptor or of the interferon receptor in the host cell induces certain proteins (deaminases) to chemically modulate and degrade the viral DNA. The result – the virus can no longer be reactivated. This is opening up new treatment possibilities for hepatitis B.

Julie Lucifora et al.: Specific and Non-Hepatotoxic Degradation of Nuclear Hepatitis B Virus cccDNA. Science 343 (2014) | doi: 10.1126/science.1243462

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Geranium Extracts Inhibit HIV-1

Extracts of the geranium plant prevent the replication of the human immunodeficiency virus type 1 (HIV-1) in cultured human cells. The plant extracts block the docking of the viruses to their host cells, thus preventing them from invading. Chemical analysis revealed that the antiviral effect is mediated by polyphenols. If the extracts should prove effective in the human organism as well, they represent a potential new class of anti-HIV-agents for the treatment of AIDS.

Markus Helfer et al.: The Root Extract of the Medicinal Plant Pelargonium sidoides is a Potent HIV-1 Attachment Inhibitor. PLOS ONE 9(1): e87487 (2014) | doi: 10.1371/journal.pone.0087487

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