A mortality event primarily affecting freshwater drum Aplodinotus grunniens was noted during April and May 2005 in the Bay of Quinte, Lake Ontario, Canada. A conservative estimate of the number of dead drum was approximately 100 metric tonnes. Large numbers of dead round goby Neogobius melanostomus were also seen, as well as a few muskellunge Esox masquinongy. In the drum, there was a consistent histological pattern of variably severe panvasculitis, a necrotising myocarditis, meningoencephalitis and a segmental enteritis. Moderate numbers of bullet-shaped viral particles consistent with a rhabdovirus were identified by transmission electron microscopy (TEM) in affected heart tissue. Following primary isolation from pooled tissues on fathead minnow (FHM) cells, a morphologically similar virus, ~165 × 60 nm in size, was visualised. Identification of the isolate as viral haemorrhagic septicemia virus (VHSV) was confirmed by enzyme immunoassay and by polymerase chain reaction. An appropriately sized product (468 bp) of the G-glycoprotein gene (nucleotides [nt] 340 to 807) was generated with RNA extracted from FHM cell supernatant. Analysis of a 360 nt partial glycoprotein gene sequence (nt 360 to 720) indicated a 96.4 to 97.2% nucleotide identity with known strains of North American (NA) VHSV. Analysis using Neighbour-joining distance methods assigned the isolate to the same lineage as the NA and Japanese isolates (Genogroup IV). However, there was sufficient sequence divergence from known NA VHSV isolates to suggest that this isolate may represent a distinct subgroup. The effects of ongoing mortality in freshwater drum and in multiple species during spring 2006 suggest that this newly recognised virus in the Great Lakes will have continued impact in the near future. KEY WORDS: Freshwater drum · Aplodinotus grunniens · Viral haemorrhagic septicemia virus · VHSV · Genogroup IV · Vasculitis · Meningoencephalitis · Necrotising myocarditis · EnteritisResale or republication not permitted without written consent of the publisher Dis Aquat Org 76: [99][100][101][102][103][104][105][106][107][108][109][110][111] 2007 Nishiziwa et al. 2002). In NA, a VHSV Genogroup IV was first isolated from returning Chinook Oncorhynchus tshawytscha and coho O. kisutch salmon (Brunson et al. 1989, Hopper 1989, Winton et al. 1989) and subsequently has been isolated on numerous occasions from a variety of apparently normal marine fish (Meyers & Winton 1995). Epizootics have been described in herring Clupea pallasi, hake Merluccius productus and pollock Theragra chalcogramma in Alaska (Meyers et al. 1999), as well as herring C. pallasi, pilchards Sardinops sagax and black cod Anoplopoma fimbria in British Columbia (Traxler et al. 1999). Subsequent surveillance has documented the species and geographical range extensions in healthy fish in Pacific coastal waters (Hedrick et al. 2003). It has been proposed that VHSV has likely been historically present in Pacific NA marine waters and may have been involved in epizootics in Pacifi...

IntroductionMetastases to the brain from breast cancer have a high mortality, and basal-like breast cancers have a propensity for brain metastases. However, the mechanisms that allow cells to colonize the brain are unclear.MethodsWe used morphology, immunohistochemistry, gene expression and somatic mutation profiling to analyze 39 matched pairs of primary breast cancers and brain metastases, 22 unmatched brain metastases of breast cancer, 11 non-breast brain metastases and 6 autopsy cases of patients with breast cancer metastases to multiple sites, including the brain.ResultsMost brain metastases were triple negative and basal-like. The brain metastases over-expressed one or more members of the HER family and in particular HER3 was significantly over-expressed relative to matched primary tumors. Brain metastases from breast and other primary sites, and metastases to multiple organs in the autopsied cases, also contained somatic mutations in EGFR, HRAS, KRAS, NRAS or PIK3CA. This paralleled the frequent activation of AKT and MAPK pathways. In particular, activation of the MAPK pathway was increased in the brain metastases compared to the primary tumors.ConclusionsDeregulated HER family receptors, particularly HER3, and their downstream pathways are implicated in colonization of brain metastasis. The need for HER family receptors to dimerize for activation suggests that tumors may be susceptible to combinations of anti-HER family inhibitors, and may even be effective in the absence of HER2 amplification (that is, in triple negative/basal cancers). However, the presence of activating mutations in PIK3CA, HRAS, KRAS and NRAS suggests the necessity for also specifically targeting downstream molecules.

The concept of cancer stem cells responsible for tumour origin, maintenance, and resistance to treatment has gained prominence in the field of breast cancer research. The therapeutic targeting of these cells has the potential to eliminate residual disease and may become an important component of a multimodality treatment. Recent improvements in immunotherapy targeting of tumourassociated antigens have advanced the prospect of targeting breast cancer stem cells, an approach that might lead to more meaningful clinical remissions. Here, we review the role of stem cells in the healthy breast, the role of breast cancer stem cells in disease, and the potential to target these cells. IntroductionThe past decades have seen advances in the diagnosis and treatment of breast cancer. Despite this progress, breast cancer is still a leading cause of cancer-related deaths among women, with as many as 40% relapsing with metastatic disease [1]. Breast cancer survival rates have been shown to plateau after 7 to 10 years, whereas most cancer survival curves take between 2 and 5 years to plateau [2]. The length of time for the survival rate to plateau in breast cancer might indicate the involvement of a cell type capable of disease recurrence which is able to withstand primary treatment and reside in the body, often undetected, for prolonged periods. Interestingly, it has been shown that, of the 40% of patients with lymph node involvement who did not undergo surgical removal, only 15% had recurrence of disease [3]. This raises the point that immune system surveillance of tumours or other protective mechanisms of the body might be capable of controlling breast cancer relapses.Prominent in the breast cancer field has been the notion of the existence of a transformed population of cells with many of the properties of stem cells that may be responsible for the origin and maintenance of tumours. These stem cell-like cells, designated as cancer stem cells, represent a minor subset of cells in the tumour and are distinct from the more differentiated tumour cells. It is thought that these cancer stem cells may play an important role in cancer establishment, progression, and resistance to current treatments. Traditional cancer therapies are effective at debulking some tumours but often fail to produce long-term clinical remissions, possibly due to their inability to eradicate the cancer stem cell population. Therefore, novel treatments aimed at targeting the cancer stem cell population could find use in treating both primary and metastatic tumours.