Anti-MRC1 monoclonal antibody, clone FQS7939(C)

In both yeast and mammals, the topoisomerase poison camptothecin (CPT) induces fork reversal, which has been proposed to stabilize replication forks, thus providing time for the repair of CPT-induced lesions and supporting replication restart. We show that Tel1, the Saccharomyces cerevisiae orthologue of human ATM kinase, stabilizes CPT-induced reversed forks by counteracting their nucleolytic degradation by the MRX complex. Tel1-lacking cells are hypersensitive to CPT specifically and show less reversed forks in the presence of CPT. The lack of Mre11 nuclease activity restores wild-type levels of reversed forks in CPT-treated tel1 Delta cells without affecting fork reversal in wild-type cells. Moreover, Mrc1 inactivation prevents fork reversal in wild-type, tel1 Delta, and mre11 nuclease-deficient cells and relieves the hypersensitivity of tel1 Delta cells to CPT. Altogether, our data indicate that Tel1 counteracts Mre11 nucleolytic activity at replication forks that undergo Mrc1-mediated reversal in the presence of CPT.

Background:Craniofacial osteosarcomas (COS) and extracranial osteosarcomas (EOS) show distinct clinical differences. COS show a remarkably lower incidence of metastases and a better survival. However, in contrast to EOS, they show a poor response to neoadjuvant chemotherapy. Tumor-associated macrophages and their polarization as well as developmental biological signaling pathways are possible candidates for explaining the clinical differences between COS and EOS. The aim of the study was to analyze differential expression of macrophage markers and important regulators of these pathways. Methods:Twenty osteosarcoma cases (10 COS and 10 EOS) were immunohistochemically stained to assess CD68, CD11c, CD163, MRC1, Gli1, and Gli2 expression. Statistical differences between COS and EOS were tested using the Mann-WhitneyUtest. Additionally, the paper describes an example of multidisciplinary treatment of a patient suffering from COS and discusses the surgical challenges in treatment and rehabilitation of COS. Results:COS showed a significantly (p< 0.05) increased infiltration of CD11c-positive M1 macrophages and a shift toward M1 polarization compared to EOS. Additionally, COS revealed a significantly (p< 0.05) lower Gli1 expression than EOS. Conclusion:The reduced Gli1 expression in COS can be interpreted as reduced activation of the Hedgehog (Hh) signaling pathway. The increased M1 polarization and reduced Hh activation in COS could explain the low incidence of metastases in these osteosarcomas.