Aurora kinase A is overexpressed in human retinoblastoma and correlates with histopathological high-risk factors: implications for targeted therapy.

Retinoblastoma (RB) is an intraocular malignancy initiated by loss of RB1 function and/or dysregulation of MYCN oncogene. RB is primarily treated with chemotherapy; however, systemic toxicity and long-term side effects remain a significant challenge necessitating the identification of specific molecular targets. Aurora kinase A (AURKA), a critical cell cycle regulator, contributes to cancer pathogenesis especially in RB1-deficient and MYCN dysregulated tumors. Our immunohistochemistry study in patient specimens (n=67) discovered that AURKA is overexpressed in RB and elevated expression correlates with one or more histopathological high-risk factors such as tumor involvement of the optic nerve, choroid, sclera and/or anterior segment. More specifically, AURKA is ubiquitously expressed in majority of the advanced-stage RB tumors that show a sub-optimal response to chemotherapy. shRNA-mediated depletion/pharmacological inhibition studies in cell lines, patient-derived cells, in-vivo xenografts, and enucleated patient specimens confirm that RB cells are highly sensitive to a lack of functional AURKA. In addition, we deciphered that AURKA and MYCN associate with each other to regulate their levels in RB cells. Overall, our results demonstrate a previously unknown upregulation of AURKA in RB, facilitated by its crosstalk with MYCN, and elevated levels of this kinase may indicate unfavorable prognosis in tumors refractory to chemotherapy. This study provides a rationale and confirms that therapeutic targeting of elevated AURKA in RB could be a potential treatment approach.

Comprehensive Analysis of the Tegument Proteins Involved in Capsid Transport and Virion Morphogenesis of Alpha, Beta and Gamma Herpesviruses.

Herpesviruses are enveloped and have an amorphous protein layer surrounding the capsid, which is termed the tegument. Tegument proteins perform critical functions throughout the viral life cycle. This review provides a comprehensive and comparative analysis of the roles of specific tegument proteins in capsid transport and virion morphogenesis of selected, well-studied prototypes of each of the three subfamilies of Herpesviridae i.e., human herpesvirus-1/herpes simplex virus-1 (Alphaherpesvirinae), human herpesvirus-5/cytomegalovirus (Betaherpesvirinae) and human herpesvirus -8/Kaposi's sarcomavirus (Gammaherpesvirinae). Most of the current knowledge is based on alpha herpesviruses, in particular HSV-1. While some tegument proteins are released into the cytoplasm after virus entry, several tegument proteins remain associated with the capsid and are responsible for transport to and docking at the nucleus. After replication and capsid formation, the capsid is enveloped at the nuclear membrane, which is referred to as primary envelopment, followed by de-envelopment and release into the cytoplasm. This requires involvement of at least three tegument proteins. Subsequently, multiple interactions between tegument proteins and capsid proteins, other tegument proteins and glycoproteins are required for assembly of the virus particles and envelopment at the Golgi, with certain tegument proteins acting as the central hub for these interactions. Some redundancy in these interactions ensures appropriate morphogenesis.

Mammary not otherwise specified-type sarcoma with CD10 expression.

Although mammary carcinoma is one of the most common malignancies among women, sarcoma taking origin from the breast tissue is extremely rare. Most of the mammary sarcomas represent a specific entity such as malignant phyllodes tumor, liposarcoma, or angiosarcoma. However, some cases do not fit into any specific category of sarcoma. These cases are diagnosed with breast sarcoma-not otherwise specified (NOS) type. They constantly express CD10 and are called as NOS type sarcoma with CD10 expression. Herein, we report a case of primary mammary sarcoma-NOS type with CD10 expression in an 80-year-old male. It was misdiagnosed with carcinoma breast on fine-needle aspiration. However, on histology, it was a high-grade tumor without any specific differentiation. Immunohistochemical results showed diffuse strong expression of vimentin and CD10, whereas pancytokeratin, desmin, and CD34 were negative. These tumors are considered a variant of sarcoma with myoepithelial differentiation.

VP8, the Major Tegument Protein of Bovine Herpesvirus-1, Is Partially Packaged during Early Tegument Formation in a VP22-Dependent Manner.

Bovine herpesvirus-1 (BoHV-1) is a major cause of rhinotracheitis and vulvovaginitis in cattle. VP8, the major tegument protein of BoHV-1, is essential for viral replication in the host. VP8 is phosphorylated by the viral kinase US3, mediating its translocation to the cytoplasm. VP8 remains nuclear when not phosphorylated. Interestingly, VP8 has a significant presence in mature BoHV-1YmVP8, in which the VP8 phosphorylation sites are mutated. This suggests that VP8 might be packaged during primary envelopment of BoHV-1. This was investigated by mass spectrometry and Western blotting, which showed VP8, as well as VP22, to be constituents of the primary enveloped virions. VP8 and VP22 were shown to interact via co-immunoprecipitation experiments, in both BoHV-1-infected and VP8-transfected cells. VP8 and VP22 also co-localised with one another and with nuclear lamin-associated protein 2 in BoHV-1-infected cells, suggesting an interaction between VP8 and VP22 in the perinuclear region. In cells infected with VP22-deleted BoHV-1 (BoHV-1ΔUL49), VP8 was absent from the primary enveloped virions, implying that VP22 might be critical for the early packaging of VP8. In conclusion, a novel VP22-dependent mechanism for packaging of VP8 was identified, which may be responsible for a significant amount of VP8 in the viral particle.