Targeting nuclear transporters in cancer: Diagnostic, prognostic and therapeutic potential

The Karyopherin superfamily is a major class of soluble transport receptors consisting of both import and export proteins. The trafficking of proteins involved in transcription, cell signalling and cell cycle regulation among other functions across the nuclear membrane is essential for normal cellular functioning. However, in cancer cells, the altered expression or localization of nuclear transporters as well as the disruption of endogenous nuclear transport inhibitors are some ways in which the Karyopherin proteins are dysregulated. The value of nuclear transporters in the diagnosis, prognosis and treatment of cancer is currently being elucidated with recent studies highlighting their potential as biomarkers and therapeutic targets

Identification and characterization of a novel non-structural protein of bluetongue virus

Bluetongue virus (BTV) is the causative agent of a major disease of livestock (bluetongue). For over two decades, it has been widely accepted that the 10 segments of the dsRNA genome of BTV encode for 7 structural and 3 non-structural proteins. The non-structural proteins (NS1, NS2, NS3/NS3a) play different key roles during the viral replication cycle. In this study we show that BTV expresses a fourth non-structural protein (that we designated NS4) encoded by an open reading frame in segment 9 overlapping the open reading frame encoding VP6. NS4 is 77–79 amino acid residues in length and highly conserved among several BTV serotypes/strains. NS4 was expressed early post-infection and localized in the nucleoli of BTV infected cells. By reverse genetics, we showed that NS4 is dispensable for BTV replication in vitro, both in mammalian and insect cells, and does not affect viral virulence in murine models of bluetongue infection. Interestingly, NS4 conferred a replication advantage to BTV-8, but not to BTV-1, in cells in an interferon (IFN)-induced antiviral state. However, the BTV-1 NS4 conferred a replication advantage both to a BTV-8 reassortant containing the entire segment 9 of BTV-1 and to a BTV-8 mutant with the NS4 identical to the homologous BTV-1 protein. Collectively, this study suggests that NS4 plays an important role in virus-host interaction and is one of the mechanisms played, at least by BTV-8, to counteract the antiviral response of the host. In addition, the distinct nucleolar localization of NS4, being expressed by a virus that replicates exclusively in the cytoplasm, offers new avenues to investigate the multiple roles played by the nucleolus in the biology of the cell

Diversification of importin-α isoforms in cellular trafficking and disease states.

The human genome encodes seven isoforms of importin α which are grouped into three subfamilies known as α1, α2 and α3. All isoforms share a fundamentally conserved architecture that consists of an N-terminal, autoinhibitory, importin-β-binding (IBB) domain and a C-terminal Arm (Armadillo)-core that associates with nuclear localization signal (NLS) cargoes. Despite striking similarity in amino acid sequence and 3D structure, importin-α isoforms display remarkable substrate specificity in vivo. In the present review, we look at key differences among importin-α isoforms and provide a comprehensive inventory of known viral and cellular cargoes that have been shown to associate preferentially with specific isoforms. We illustrate how the diversification of the adaptor importin α into seven isoforms expands the dynamic range and regulatory control of nucleocytoplasmic transport, offering unexpected opportunities for pharmacological intervention. The emerging view of importin α is that of a key signalling molecule, with isoforms that confer preferential nuclear entry and spatiotemporal specificity on viral and cellular cargoes directly linked to human diseases

Broad targeting of resistance to apoptosis in cancer

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer

Is curettage and high-speed burring sufficient treatment for aneurysmal bone cysts?

© 2014, The Association of Bone and Joint Surgeons®. Background: To decrease the recurrence rate after intralesional curettage for aneurysmal bone cysts, different adjuvant treatments have been recommended. Liquid nitrogen spray and argon beam coagulation have provided the lowest recurrence rates, but unlike the high-speed burr, these adjuvants are not always available in operating rooms.Questions/purposes: We asked: (1) Is high-speed burring alone sufficient as an adjuvant to curettage with respect to recurrence rates? (2) What is the complication rate from this technique? (3) What are the risk factors for local recurrence?Methods: A retrospective review of the database of the University Musculoskeletal Tumor Unit and the private files of the senior author (EHW) for a period of 19 years (1993–2011) was performed to identify all patients histologically diagnosed with primary aneurysmal bone cyst. During that period, patients with aneurysmal bone cysts were treated with intralesional curettage, burring, and bone grafting if the lesions showed an adequate cortical wall or a wall with thinned out portions which could be reconstructed with bone grafting. Based on those indications, we treated 54 patients for this condition. Of those, 18 were treated using approaches other than burring because they did not meet the defined indications, and an additional five patients were lost to followup before 2 years, leaving 31 patients for analysis, all of whom were followed up for at least 2 years (mean, 7 years; range, 2–18 years).Results: Of these 31 patients, one had a recurrence (3.2%). Complications using this approach occurred in three patients (9.7%), and included growth plate deformity (1) and genu varus (2) secondary to collapse of the reconstructed condyle. With only one recurrence, we cannot answer what the risk factors might be for recurrence; however, the one patient with recurrence presented with a large lesion and a pathologic fracture.Conclusions: Curettage, burring, and bone grafting compare favorably in the literature with other approaches for aneurysmal bone cysts, such as cryotherapy and argon-beam coagulation. We conclude that high-speed burring alone as an adjuvant to intralesional curettage is a reasonable approach to achieving a low recurrence rate for aneurysmal bone cysts.Level of Evidence: Level IV, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence