Low frequency of BK virus in prostatic adenocarcinomas

BK virus (BKV) exhibits many oncogenic properties and has been associated with a variety of tumors in humans. BKV has not been well studied in the context of prostate neoplasia; however, an association of BKV with prostatic adenocarcinoma has been suggested based on the detection of viral DNA sequences and expression of viral proteins in clinical samples. To further investigate the reported association of BKV with prostatic adenocarcinoma and the potential role of the virus in prostate tumorigenesis, 30 cases of adenocarcinoma of the prostate were analyzed for evidence of BKV infection by in situ hybridization and immunohistochemistry. In situ hybridization analysis detected BKV DNA in 2 of 30 (7%) prostatic adenocarcinomas, with positive signals focally identified in less than 1% of the neoplastic cells in both cases. However, none of the tumors evaluated demonstrated evidence of BKV large tumor antigen expression by immunohistochemistry. Among prostatic adenocarcinomas that showed no evidence of BKV infection, BKV DNA was focally observed in the adjacent non-neoplastic prostate tissue in four cases by in situ hybridization in the absence of BKV large tumor antigen immunoreactivity. The findings of the present study indicate rare cases of prostatic adenocarcinoma may be associated with BKV infection. However, lack of localization of BKV to a large population of the neoplastic cells and absence of BKV large tumor antigen expression suggest that the virus does not play a role in the pathogenesis of prostate cancer.     

Polyomavirus BK non-coding control region rearrangements in health and disease

BACKGROUND: BK virus is an increasingly recognized pathogen in transplanted patients. DNA sequencing of this virus shows considerable genomic variability. METHODS: To understand the clinical significance of rearrangements in the non-coding control region (NCCR) of BK virus (BKV), we report a meta-analysis of 507 sequences, including 40 sequences generated in our own laboratory, for associations between rearrangements and disease, tissue tropism, geographic origin, and viral genotype. RESULTS: NCCR rearrangements were less frequent in (a) asymptomatic BKV viruria compared to patients viral nephropathy (1.7% vs. 22.5%), and (b) viral genotype 1 compared to other genotypes (2.4% vs. 11.2%). Rearrangements were commoner in malignancy (78.6%), and Norwegians (45.7%), and less common in East Indians (0%), and Japanese (4.3%). A surprising number of rearranged sequences were reported from mononuclear cells of healthy subjects, whereas most plasma sequences were archetypal. This difference could not be related to potential recombinase activity in lymphocytes, as consensus recombination signal sequences could not be found in the NCCR region. CONCLUSIONS: NCCR rearrangements are neither required nor a sufficient condition to produce clinical disease. BKV nephropathy and hemorrhagic cystitis are not associated with any unique NCCR configuration or nucleotide sequence.     

An unusual pattern of peritubular capillary injury involving apoptosis in a renal transplant patient

Microvascular injury is an important factor in renal allograft survival. Repeated episodes of endothelial injury from chronic antibody-mediated rejection typically manifest at the ultrastructural level as circumferential multilayering of remodeled glomerular basement membrane material and peritubular capillary basal lamina. In contrast to this typical pattern of microvascular injury, a renal transplantation case is presented in which focally dilated and multilayered segments of peritubular capillary basal lamina bearing lipid droplets were interspersed with ultrastructurally normal unilayered segments of basal lamina devoid of lipid droplets. Glomerular basement membranes were not affected by this process. The peak incidence of lipid droplets within the peritubular capillary walls coincided with a peak in apoptotic activity within the allograft. Lesser amounts of the same lipidic material were identified in the mesangial matrix and an arteriolar wall. Mesangial electron-dense deposits were detected at two weeks posttransplantation and their appearance coincided with elevated immunological activity in the glomeruli, as determined by immunofluorescence microscopy. The unusual ultrastructure and immunological activity observed in this case may reflect a process of impaired apoptotic clearance within the allograft. The six biopsies from a single patient are discussed in the setting of a highly sensitized renal transplant recipient who received prophylactic terminal complement blockade by eculizumab. The findings may be relevant to the study of apoptosis, efferocytosis, microvascular injury, eculizumab, rejection, lupus, and drug-related disease.     

The large conductance calcium‐activated potassium channel affects extrinsic and intrinsic mechanisms of apoptosis

The large‐conductance calcium‐activated K⁺ or BK channel underlies electrical signals in a number of different cell types. Studies show that BK activity can also serve to regulate cellular homeostasis by protecting cells from apoptosis resulting from events such as ischemia. Recent coimmunoprecipitation studies, combined with mass spectrometry, suggest putative protein partners that interact with BK to regulate intrinsic and extrinsic apoptotic pathways. This study tests two of those partners to determine the effects on these two signaling pathways. Through reciprocal coimmunoprecipitation (coIP) experiments, we show that BK interacts with p53 and fas‐associated protein with death domain (FADD) in mouse brain and when overexpressed in a heterologous expression system, such as HEK293 cells. Moreover, coIP experiments with N‐ and C‐terminal fragments reveal that FADD interacts with the C‐terminus of BK, whereas p53 interacts with either the N‐ or the C‐terminus. Immunolocalization studies show that BK colocalizes with p53 and FADD in the mitochondrion and plasmalemma, respectively. HEK cells that stably express BK are more resistant to apoptosis when p53 or FADD is overexpressed or when their intrinsic and extrinsic pathways are stimulated via mitomycin C or tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL), respectively. Moreover, when stimulating with TRAIL, caspase‐8 activation decreases in BK‐expressing cells. These data suggest that BK is part of a larger complex of proteins that protects against apoptosis by interacting with proapoptotic proteins, such as p53 and FADD. © 2015 Wiley Periodicals, Inc.     

Antibody response to BK polyomavirus as a prognostic biomarker and potential therapeutic target in prostate cancer

Infectious agents, including the BK polyomavirus (BKPyV), have been proposed as important inflammatory pathogens in prostate cancer. Here, we evaluated whether the preoperative antibody response to BKPyV large T antigen (LTag) and viral capsid protein 1 (VP1) was associated with the risk of biochemical recurrence in 226 patients undergoing radical prostatectomy for primary prostate cancer. Essentially, the multivariate Cox regression analysis revealed that preoperative seropositivity to BKPyV LTag significantly reduced the risk of biochemical recurrence, independently of established predictors of biochemical recurrence such as tumor stage, Gleason score and surgical margin status. The predictive accuracy of the regression model was denotatively increased by the inclusion of the BKPyV LTag serostatus. In contrast, the VP1 serostatus was of no prognostic value. Finally, the BKPyV LTag serostatus was associated with a peculiar cytokine gene expression profile upon assessment of the cellular immune response elicited by LTag. Taken together, our findings suggest that the BKPyV LTag serology may serve as a prognostic factor in prostate cancer. If validated in additional studies, this biomarker may allow for better treatment decisions after radical prostatectomy. Finally, the favorable outcome of LTag seropositive patients may provide a potential opportunity for novel therapeutic approaches targeting a viral antigen.     

Bladder transitional cell carcinoma and BK virus in a young kidney transplant recipient

Kidney transplant recipients have a heightened risk of developing neoplasms. Immunosuppressive treatments decrease the incidence of transplant rejection but increase the risk of infections, including BK virus (BKV). This infection is acquired in childhood and remains latent in the renal and urinary epithelium. In cases of immunodeficiency, BKV has been implicated as a tumor virus, but the role of BKV in cancer is a controversial topic and is difficult to determine. In the tumor cells, it is possible to detect fragments of the viral genome that could alter the control mechanisms of the cell cycle and DNA repair. We report the case of a kidney transplant recipient who developed BKV nephropathy and carcinoma of the bladder, supporting a possible role for BKV in the oncogenic pathway in this clinical setting, but the role of BKV in cancer remains a controversial topic and difficult to determine.     

单克隆抗体BDI-I导向的阿霉素白蛋白毫微球对人膀胱癌细胞的特异杀伤活性

用化学偶联法将抗人膀胱癌单克隆抗体分子偶联到阿霉素白蛋白毫微球上,构建了一个有靶向杀伤性的免疫毫微球,即:阿霉素白蛋白载单克隆抗体毫微球(ADR-NP-Ab)。改变阿霉素毫微球和单克隆抗体的反应分子比,确定了制备该免疫毫微球的最佳条件。经免疫荧光检测及显微照像分析证明,免疫毫微球可有效地和人膀胱癌细胞结合。体外杀伤试验表明,此免疫毫微球对靶细胞EJ有高度特异杀伤活性,而对无关的人直肠癌Lovo细胞则无明显作用。