Human herpesvirus 6 major immediate early promoter has strong activity in T cells and is useful for heterologous gene expression

<p>Abstract</p> <p>Background</p> <p>Human herpesvirus-6 (HHV-6) is a beta-herpesvirus. HHV-6 infects and replicates in T cells. The HHV-6-encoded major immediate early gene (MIE) is expressed at the immediate-early infection phase. Human cytomegalovirus major immediate early promoter (CMV MIEp) is commercially available for the expression of various heterologous genes. Here we identified the HHV-6 MIE promoter (MIEp) and compared its activity with that of CMV MIEp in various cell lines.</p> <p>Methods</p> <p>The HHV-6 MIEp and some HHV-6 MIEp variants were amplified by PCR from HHV-6B strain HST. These fragments and CMV MIEp were subcloned into the pGL-3 luciferase reporter plasmid and subjected to luciferase reporter assay. In addition, to investigate whether the HHV-6 MIEp could be used as the promoter for expression of foreign genes in a recombinant varicella-zoster virus, we inserted HHV-6 MIEp-DsRed expression casette into the varicella-zoster virus genome.</p> <p>Results</p> <p>HHV-6 MIEp showed strong activity in T cells compared with CMV MIEp, and the presence of intron 1 of the MIE gene increased its activity. The NF-κB-binding site, which lies within the R3 repeat, was critical for this activity. Moreover, the HHV-6 MIEp drove heterologous gene expression in recombinant varicella-zoster virus-infected cells.</p> <p>Conclusions</p> <p>These data suggest that HHV-6 MIEp functions more strongly than CMV MIEp in various T-cell lines.</p

Analysis of Cancer Mortality among Atomic Bomb Survivors in Hiroshima Prefecture, 1968-1997

The Research Institute for Radiation Biology and Medicine has a cohort of atomic bomb survivors, residents of Hiroshima Prefecture, followed up since 1968. An epidemiological project on cancer mortality has been extended by the 5 years from 1992 to 1997. In this paper we aim to evaluate the relative risk pattern of specific cancers by radiation dose over time and during this recent 5 years. We obtained the late effects and temporary changes from cancer sites on mortal ity such as leukemia, all cancers except leukemia, and cancers of the lung, esophagus, liver, stomach, colon, pancreas, breast and uterus. Although results for the additional 5 years were not statistically significant due to the relatively small sample size, we observed decreasing trends for many cancer sites including all cancers except leukemia, esophagus, colon, stomach, liver and breast cancers. In particular the sharply increased excess relative risk for female breast cancer shown in 1988-1992 dramatically declined during the period 1993-1997

Varicella-zoster virus ORF 58 gene is dispensable for viral replication in cell culture

<p>Abstract</p> <p>Background</p> <p>Open reading frame 58 (ORF58) of varicella-zoster virus (VZV) lies at the 3'end of the Unique long (U_L) region and its functional is unknown. In order to clarify whether ORF58 is essential for the growth of VZV, we constructed a deletion mutant of ORF58 (pOka-BACΔ58) from the Oka parental genome cloned into a bacterial artificial chromosome (pOka-BAC).</p> <p>Results</p> <p>The ORF58-deleted virus (rpOkaΔ58) was reconstituted from the pOka-BACΔ58 genome in MRC-5 cells, indicating that the ORF58 gene is non-essential for virus growth. Comparison of the growth rate of rpOkaΔ58 and recombinant wild-type virus by assessing plaque sizes revealed no significant differences between them both in MRC-5 cells and malignant melanoma cells.</p> <p>Conclusion</p> <p>This study shows that the ORF58 gene is dispensable for viral replication and does not affect the virus' ability to form plaques <it>in vitro</it>.</p

A dominant-negative FGF1 mutant (the R50E mutant) suppresses tumorigenesis and angiogenesis.

Fibroblast growth factor-1 (FGF1) and FGF2 play a critical role in angiogenesis, a formation of new blood vessels from existing blood vessels. Integrins are critically involved in FGF signaling through crosstalk. We previously reported that FGF1 directly binds to integrin αvβ3 and induces FGF receptor-1 (FGFR1)-FGF1-integrin αvβ3 ternary complex. We previously generated an integrin binding defective FGF1 mutant (Arg-50 to Glu, R50E). R50E is defective in inducing ternary complex formation, cell proliferation, and cell migration, and suppresses FGF signaling induced by WT FGF1 (a dominant-negative effect) in vitro. These findings suggest that FGFR and αvβ3 crosstalk through direct integrin binding to FGF, and that R50E acts as an antagonist to FGFR. We studied if R50E suppresses tumorigenesis and angiogenesis. Here we describe that R50E suppressed tumor growth in vivo while WT FGF1 enhanced it using cancer cells that stably express WT FGF1 or R50E. Since R50E did not affect proliferation of cancer cells in vitro, we hypothesized that R50E suppressed tumorigenesis indirectly through suppressing angiogenesis. We thus studied the effect of R50E on angiogenesis in several angiogenesis models. We found that excess R50E suppressed FGF1-induced migration and tube formation of endothelial cells, FGF1-induced angiogenesis in matrigel plug assays, and the outgrowth of cells in aorta ring assays. Excess R50E suppressed FGF1-induced angiogenesis in chick embryo chorioallantoic membrane (CAM) assays. Interestingly, excess R50E suppressed FGF2-induced angiogenesis in CAM assays as well, suggesting that R50E may uniquely suppress signaling from other members of the FGF family. Taken together, our results suggest that R50E suppresses angiogenesis induced by FGF1 or FGF2, and thereby indirectly suppresses tumorigenesis, in addition to its possible direct effect on tumor cell proliferation in vivo. We propose that R50E has potential as an anti-cancer and anti-angiogenesis therapeutic agent ("FGF1 decoy")

Prediction of outcome of patients with oral squamous cell carcinoma using vascular invasion and the strongly positive expression of vascular endothelial growth factors.

Vascular invasion and lymph node metastasis have been used as histopathological prognosticators of cancers including oral squamous cell carcinoma (OSCC). In addition to metastatic potential via blood vessels, tumor-induced angiogenesis might also be associated with prognosis. However, the efficacy of combined evaluation of vascular invasion and angiogenesis-associated molecules for the prognosis of OSCC remains obscure. This is also the case in lymph node metastasis and lymphovasculogenesis-associated molecules. The aim of this study was to examine factors related to prognosis to improve the accuracy of prognostic prediction of OSCC using vasculogenesis-associated markers. Ninety specimens of patients from 1991 to 2002 with previously untreated OSCC, who underwent either biopsy or surgery, were histopathologically and immunohistochemically analyzed using antibodies for vascular endothelial growth factor (VEGF)-A, VEGF-C, cyclooxygenase (COX)-2 and Midkine. The ninety cases were composed of 72 well-differentiated, 12 moderately differentiated and 6 poorly differentiated OSCC. Efficient models of prognostic prediction were evaluated by extensive statistical analyses. The presence of vascular invasion or lymph node metastasis was confirmed to be significantly associated with poor prognosis in the univariate analysis. Multivariate logic regression analysis suggested that patients with the strongly positive expression of either VEGF-A or VEGF-C had a significant association with poor prognosis even in patients without vascular invasion and in early-stage patients. Neither COX-2 nor Midkine contributed to predict the prognosis of the patients. The strongly positive expression of VEGF-A or VEGF-C was suggested to reinforce the histopathological diagnosis of vascular invasion and improve the accuracy and efficacy of prognostic prediction of OSCC

Impact of phase angle on postoperative prognosis

Objective Phase angle (PhA), by bioelectrical impedance analysis, has been used in patients with several diseases; however, its prognostic value in patients with gastrointestinal and hepatobiliary–pancreatic (HBP) cancer is unclear. The present study aimed to investigate the impact of PhA on postoperative short-term outcomes and long-term survival in these patients. Research Methods & Procedures This retrospective study reviewed data of 501 patients with gastrointestinal and HBP cancers who underwent first resection surgery and divided the data into the following groups according to the preoperative PhA quartile values by sex: high-PhA group with the highest quartile (Q4), normal-PhA group with middle quartiles (Q3 and Q2), and low-PhA group with the lowest quartile (Q1). Preoperative nutritional statuses, postoperative short-term outcomes during hospitalization, and 5-year survival between three groups were compared. Cox proportional hazard models were used to evaluate the prognostic effect of PhA. Results PhA positively correlated with body weight, skeletal muscle mass, and handgrip strength, and negatively correlated with age and C-reactive protein levels. The low-PhA group showed a high prevalence of malnutrition (48%) than normal-PhA (25%), and high-PhA (9%) (P < 0.001). The incidence of postoperative severe complications was 10% in all patients [14% in low-PhA, 12% in normal-PhA, and 4% in high-PhA (P = 0.018)]. The incidence of prolonged postoperative high care unit or/and intensive care unit stays was 8% in all patients [16% in low-PhA, 8% in normal-PhA, and 2% in high-PhA (P < 0.001)]. The 5-year survival rate was 74% in all patients [68% in low-PhA, 74% in normal-PhA, and 79% in high-PhA (P < 0.001)]. The multivariate analysis demonstrated that a low-PhA group was an independent risk factor for mortality (hazard ratio, 1.99; 95% confidence interval 1.05–3.90; P = 0.034). Conclusion PhA is a useful short-term and long-term postoperative prognostic marker for patients with gastrointestinal and HBP cancers

Common Peak Approach Using Mass Spectrometry Data Sets for Predicting the Effects of Anticancer Drugs on Breast Cancer

We propose a method for biomarker discovery from mass spectrometry data, improving the common peak approach developed by Fushiki et al. (BMC Bioinformatics, 7:358, 2006). The common peak method is a simple way to select the sensible peaks that are shared with many subjects among all detected peaks by combining a standard spectrum alignment and kernel density estimates. The key idea of our proposed method is to apply the common peak approach to each class label separately. Hence, the proposed method gains more informative peaks for predicting class labels, while minor peaks associated with specific subjects are deleted correctly. We used a SELDI-TOF MS data set from laser microdissected cancer tissues for predicting the treatment effects of neoadjuvant therapy using an anticancer drug on breast cancer patients. The AdaBoost algorithm is adopted for pattern recognition, based on the set of candidate peaks selected by the proposed method. The analysis gives good performance in the sense of test errors for classifying the class labels for a given feature vector of selected peak values

Malnutrition by European Society for Clinical Nutrition and Metabolism criteria predicts prognosis in patients with gastrointestinal and hepatobiliary–pancreatic cancer

Background & Aims: The European Society for Clinical Nutrition and Metabolism (ESPEN) proposed the ESPEN diagnostic criteria (EDC) for malnutrition in 2015. There is no report on the association between the EDC and prognosis in patients with gastrointestinal (GI) and hepatobiliary–pancreatic (HBP) cancer. This study aimed to (1) determine the prevalence of EDC malnutrition, (2) investigate the validity of the EDC as a nutritional and prognostic indicator, and (3) examine which components of the EDC are most related to long-term prognosis in patients with GI and HBP cancers. Methods: A total of 634 patients with primary GI and HBP cancers who underwent their first resection surgery between July 2014 and March 2018 were retrospectively recruited. According to the EDC, patients were divided into malnourished and non-malnourished groups. Clinical parameters and survival between these two groups were compared. The prognostic effects of the EDC and the EDC components were analyzed using Cox proportional hazard models. Results: The prevalence of EDC malnutrition was 22%. Anthropometric data and biochemical data were associated with EDC malnutrition. The 5-year survival rate was lower in the malnourished group (72%) than in the non-malnourished group (73%; P = 0.007). The multivariate analysis demonstrated that the malnourished group was an independent risk factor for mortality (hazard ratio = 1.70 in the malnourished group; 95% confidence interval 1.08–2.63; P = 0.024). Among EDC components, body mass index (BMI) of <18.5 kg/m2 was an independent poor prognostic factor. Conclusions: EDC malnutrition is associated with poor postoperative long-term prognosis. Among the EDC components, BMI of <18.5 kg/m2 is most associated with prognosis in patients with preoperative GI and HBP cancers