Distribution of Glutathione-Stabilized Gold Nanoparticles in Feline Fibrosarcomas and Their Role as a Drug Delivery System for Doxorubicin—Preclinical Studies in a Murine Model

Feline injection site sarcomas (FISS) are malignant skin tumors with high recurrence rates despite the primary treatment of radical surgical resections. Adjunctive radiotherapy or chemotherapy with doxorubicin is mostly ineffective. Cellular and molecular causes of multidrug resistance, specific physio-chemical properties of solid tumors impairing drug transport, and the tumor microenvironment have been indicated for causing standard chemotherapy failure. Gold nanoparticles are promising imaging tools, nanotherapeutics, and drug delivery systems (DDS) for chemotherapeutics, improving drug transport within solid tumors. This study was conducted to assess the distribution of 4-nm glutathione-stabilized gold nanoparticles in FISS and their influence on kidney and liver parameters in nude mice. The role of gold nanoparticles as a doxorubicin DDS in FISS was examined to determine the potential reasons for failure to translate results from in vitro to in vivo studies. Grade III tumors characterized by a large area of necrosis at their core displayed positive immuneexpression of tumor-associated macrophages (TAM) at both the periphery and within the tumor core near the area of necrosis. Gold nanoparticles did not cause necrosis at the injection site and had no negative effect on liver and kidney parameters in nude mice. Gold nanoparticles accumulated in the tumor core and at the periphery and co-internalized with TAM—an important observation and potential therapeutic target warranting further investigation. The large area of necrosis and high immunoexpression of TAM, indicating “pro-tumor macrophages”, may be responsible for FISS tumor progression and therapeutic failure. However, further studies are required to test this hypothesis

A New Inhibitor of Tubulin Polymerization Kills Multiple Cancer Cell Types and Reveals p21-Mediated Mechanism Determining Cell Death after Mitotic Catastrophe

Induction of mitotic catastrophe through the disruption of microtubules is an established target in cancer therapy. However, the molecular mechanisms determining the mitotic catastrophe and the following apoptotic or non-apoptotic cell death remain poorly understood. Moreover, many existing drugs targeting tubulin, such as vincristine, have reduced efficacy, resulting from poor solubility in physiological conditions. Here, we introduce a novel small molecule 2-aminoimidazoline derivative—OAT-449, a synthetic water-soluble tubulin inhibitor. OAT-449 in a concentration range from 6 to 30 nM causes cell death of eight different cancer cell lines in vitro, and significantly inhibits tumor development in such xenograft models as HT-29 (colorectal adenocarcinoma) and SK-N-MC (neuroepithelioma) in vivo. Mechanistic studies showed that OAT-449, like vincristine, inhibited tubulin polymerization and induced profound multi-nucleation and mitotic catastrophe in cancer cells. HeLa and HT-29 cells within 24 h of treatment arrested in G2/M cell cycle phase, presenting mitotic catastrophe features, and 24 h later died by non-apoptotic cell death. In HT-29 cells, both agents altered phosphorylation status of Cdk1 and of spindle assembly checkpoint proteins NuMa and Aurora B, while G2/M arrest and apoptosis blocking was consistent with p53-independent accumulation in the nucleus and largely in the cytoplasm of p21/waf1/cip1, a key determinant of cell fate programs. This is the first common mechanism for the two microtubule-dissociating agents, vincristine and OAT-449, determining the cell death pathway following mitotic catastrophe demonstrated in HT-29 cells

BMPR1B gene in brachydactyly type 2–A family with de novo R486W mutation and a disease phenotype

Abstract Background Brachydactylies are a group of inherited conditions, characterized mainly by the presence of shortened fingers and toes. Based on the patients’ phenotypes, brachydactylies have been subdivided into 10 subtypes. In this study, we have identified a family with two members affected by brachydactyly type A2 (BDA2). BDA2 is caused by mutations in three genes: BMPR1B, BMP2 or GDF5. So far only two studies have reported the BDA2 cases caused by mutations in the BMPR1B gene. Methods We employed next‐generation sequencing to identify mutations in culpable genes. Results and Conclusion In this paper, we report a case of BDA2 resulting from the presence of a heterozygous c.1456C>T, p.Arg486Trp variant in BMPR1B, which was previously associated with BDA2. The next generation sequencing analysis of the patients’ family revealed that the mutation occurred de novo in the proband and was transmitted to his 26‐month‐old son. Although the same variant was confirmed in both patients, their phenotypes were different with more severe manifestation of the disease in the adult