Most papillomaviruses (PVs) are oncogenic. There are at least 100 different human PVs and 65 nonhuman vertebrate hosts, including wild rodents, which have species-specific PV infections. Florid papillomatosis arose in a colony of NMRI-Foxn1 nu / Foxn1 nu (nude) mice at the Advanced Centre for Treatment Research and Education in Cancer in India. Lesions appeared at the mucocutaneous junctions of the nose and mouth. Histologically, lesions were classical papillomas with epidermal hyperplasia on thin fibrovascular stalks in a verrucous pattern. Koilocytotic cells were observed in the stratum granulosum of the papillomatous lesions. Immunohistochemically, these abnormal cells were positive for PV group-specific antigens. With transmission electron microscopy, virus particles were observed in crystalline intranuclear inclusions within keratinocytes. The presence of a mouse PV, designated MusPV, was confirmed by amplification of PV DNA with degenerative primers specific for PVs. This report is the first of a PV and its related disease in laboratory mice.

Plakophilin3 is a desmosomal plaque protein whose levels are reduced in poorly differentiated tumors of the oropharyngeal cavity and in invasive colon carcinomas. To test the hypothesis that plakophilin3 loss stimulates neoplastic progression, plakophilin3 expression was inhibited by DNA vector driven RNA interference in 3 epithelial cell lines, HCT116, HaCaT and fetal buccal mucosa. The plakophilin3-knockdown clones showed a decrease in cell-cell adhesion as assessed in a hanging drop assay, which was accompanied by an increase in cell migration. The HCT116 plakophilin3-knockdown clones showed a decrease in desmosome size as revealed by electron microscopy. These altered desmosomal properties were accompanied by colony formation in soft agar and growth to high density in culture. The HCT116-derived clones showed accelerated tumor formation in nude mice and increased metastasis to the lung, a phenotype consistent with the increased migration observed in vitro and is consistent with data from human tumors that suggests that plakophililn3 is lost in invasive and metastatic tumors. These data indicate that plakophilin3 loss leads to a decrease in cell-cell adhesion leading to the stimulation of neoplastic progression and metastasis. Plakophilins are desmosmal plaque proteins, which belong to the p120ctn subfamily of Armadillo repeat containing proteins (reviewed in Refs. 4 and 5). Unlike plakophilins 1 and 2, plakophilin3 is ubiquitously present in a wide range of epithelial cells and tissues with the exception of hepatocytes 6,7 and forms a complex with a number of desmosomal proteins. Plakophilin3 binds to the desmosomal cadherins desmoglein 1-3 and desmocollins 1 and 3, cytokeratin 18 and other desmosomal plaque proteins such as desmoplakin and plakoglobin.8 Therefore, plakophilin3 has been postulated to play a crucial role in the function of desmosomes and maintenance of the desmosomal structure.8 Immunofluorescence analysis followed by confocal microscopy has shown that in addition to being present at desmosomal plaques in epithelial tissues and in cell lines of epithelial origin, 6-8 plakophilin3 is also found in cytoplasmic stress granules in complex with RNA-binding proteins. 9 Furthermore, in epithelial cell lines, a speckled nuclear pattern of staining was also detected with antibodies to plakophilin3.6,7 Although plakophilin3 knockout mice are viable, they display severe defects in desmosome assembly in the basal membrane of the epidermis. The epidermis of the knockout mice show hyperplasia, and the mice are extremely susceptible to skin infections and inflammation. 10 These results suggest that in addition to regulating desmosome function and organization, plakophilin3 may play a role in integrating extra cellular signals with events occurring inside the cell.A number of reports have suggested that alterations in desmosome structure or composition could lead to neoplastic progression (reviewed in Ref. 11). To determine if plakophilin3 is required for desmosomal assembly and plays a role in inhibiting ep...

Despite phenomenal clinical success, the efficacy of platinum anticancer drugs is often compromised due to inherent and acquired drug resistant phenotypes in cancers. To circumvent this issue, we designed two heterobimetallic platinum (II)‐ferrocene hybrids that display multi‐pronged anticancer action. In cancer cells, our best compound, 2, platinates DNA, produces reactive oxygen species, and has nucleus, mitochondria, and endoplasmic reticulum as potential targets. The multi‐modal mechanism of action of these hybrid agents lead to non‐apoptotic cell death induction which enables circumventing apoptosis resistance and significant improvement in platinum cross resistance profile. Finally, in addition to describing detail mechanistic insights, we also assessed its stability in plasma and demonstrate anticancer efficacy in an in vivo A2780 xenograft model. Strikingly, compared to oxaliplatin, our compound displays better tolerability, safety profile and efficacy in vivo.