The Effect of Epstein-Barr Virus Latent Membrane Protein 2 Expression on the Kinetics of Early B Cell Infection

Infection of human B cells with wild-type Epstein-Barr virus (EBV) in vitro leads to activation and proliferation that result in efficient production of lymphoblastoid cell lines (LCLs). Latent Membrane Protein 2 (LMP2) is expressed early after infection and previous research has suggested a possible role in this process. Therefore, we generated recombinant EBV with knockouts of either or both protein isoforms, LMP2A and LMP2B (Δ2A, Δ2B, Δ2A/Δ2B) to study the effect of LMP2 in early B cell infection. Infection of B cells with Δ2A and Δ2A/Δ2B viruses led to a marked decrease in activation and proliferation relative to wild-type (wt) viruses, and resulted in higher percentages of apoptotic B cells. Δ2B virus infection showed activation levels comparable to wt, but fewer numbers of proliferating B cells. Early B cell infection with wt, Δ2A and Δ2B viruses did not result in changes in latent gene expression, with the exception of elevated LMP2B transcript in Δ2A virus infection. Infection with Δ2A and Δ2B viruses did not affect viral latency, determined by changes in LMP1/Zebra expression following BCR stimulation. However, BCR stimulation of Δ2A/Δ2B cells resulted in decreased LMP1 expression, which suggests loss of stability in viral latency. Long-term outgrowth assays revealed that LMP2A, but not LMP2B, is critical for efficient long-term growth of B cells in vitro. The lowest levels of activation, proliferation, and LCL formation were observed when both isoforms were deleted. These results suggest that LMP2A appears to be critical for efficient activation, proliferation and survival of EBV-infected B cells at early times after infection, which impacts the efficient long-term growth of B cells in culture. In contrast, LMP2B did not appear to play a significant role in these processes, and long-term growth of infected B cells was not affected by the absence of this protein. © 2013 Wasil et al

TP53 status and taxane-platinum versus platinum-based therapy in ovarian cancer patients: A non-randomized retrospective study

<p>Abstract</p> <p>Background</p> <p>Taxane-platinum therapy (TP) has replaced platinum-based therapy (PC or PAC, DNA damaging chemotherapy) in the postoperative treatment of ovarian cancer patients; however, it is not always effective. TP53 protein plays a differential role in response to DNA-damaging agents and taxanes. We sought to define profiles of patients who benefit the most from TP and also of those who can be treated with PC.</p> <p>Methods</p> <p>We compared the effectiveness of PC/PAC (n = 253) and TP (n = 199) with respect to tumor TP53 accumulation in ovarian cancer patients with FIGO stage IIB-IV disease; this was a non-randomized retrospective study. Immunohistochemical analysis was performed on 452 archival tumors; univariate and multivariate analysis by the Cox's and logistic regression models was performed in all patients and in subgroups with [TP53(+)] and without TP53 accumulation [TP53(-)].</p> <p>Results</p> <p>The advantage of taxane-platinum therapy over platinum-based therapy was seen in the TP53(+), and not in the TP53(-) group. In the TP53(+) group taxane-platinum therapy enhanced the probability of complete remission (p = .018), platinum sensitivity (p = .014), platinum highly sensitive response (p = .038) and longer survival (OS, p = .008). Poor tumor differentiation diminished the advantage from taxane-platinum therapy in the TP53(+) group. In the TP53(-) group PC/PAC was at least equally efficient as taxane-platinum therapy and it enhanced the chance of platinum highly sensitive response (p = .010). However, in the TP53(-) group taxane-platinum therapy possibly diminished the risk of death in patients over 53 yrs (p = .077). Among factors that positively interacted with taxane-platinum therapy in some analyses were endometrioid and clear cell type, FIGO III stage, bulky residual tumor, more advanced age of patient and moderate tumor differentiation.</p> <p>Conclusion</p> <p>Our results suggest that taxane-platinum therapy is particularly justified in patients with TP53(+) tumors or older than 53 years. In the group of patients ≤53 yrs and with TP53(-) tumors platinum-based therapy is possibly equally efficient. We provide hints for planning randomized trials to verify these observations.</p

Modeling and solving the intersection inspection rural postman problem

Local governments inspect roads to decide which segments and intersections to repair. Videos are taken using a camera mounted on a vehicle. The vehicle taking the videos proceeds straight or takes a left turn to cover an intersection fully. We introduce the intersection inspection rural postman problem (IIRPP), which is a new variant of the rural postman problem (RPP) that involves turns. We develop integer programming formulations of the IIRPP based on two different graph transformations to generate least-cost vehicle routes. One formulation is based on a new idea of transforming a graph. A second formulation is based on a graph transformation idea from the literature. Computational experiments show that the formulation involving the new graph transformation idea performs much better than the other formulation. We also develop an RPP-based heuristic and a heuristic based on a modified RPP. Heuristic solutions are improved by solving integer programming formulations on an induced subgraph. Computational experiments show that the heuristics based on the modified RPP perform much better than the RPP-based heuristics. The best-performing heuristic generates very good quality IIRPP-feasible routes on large street networks quickly

MicroCT versus sTSLIM 3D imaging of the mouse cochlea

We made a qualitative and quantitative comparison between a state-of-the-art implementation of micro-Computed Tomography (microCT) and the scanning Thin-Sheet Laser Imaging Microscopy (sTSLIM) method, applied to mouse cochleae. Both imaging methods are non-destructive and perform optical sectioning, respectively, with X-rays and laser light. MicroCT can be used on fresh or fixed tissue samples and is primarily designed to image bone rather than soft tissues. It requires complex back-projection algorithms to produce a two-dimensional image, and it is an expensive instrument. sTSLIM requires that a specimen be chemically fixed, decalcified, and cleared; but it produces high-resolution images of soft and bony tissues with minimum image postprocessing and is less expensive than microCT. In this article, we discuss the merits and disadvantages of each method individually and when combined

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programming models for estimating weights in th

Atrial flutter and the risk of thromboembolism: a systematic review and meta-analysis

PURPOSE: We conducted a systematic review and meta-analysis of observational studies to assess the risk of thromboembolism associated with atrial flutter. METHODS: MEDLINE, EMBASE, bibliographies, and consultation with clinical experts were used to identify studies that report the risk of thromboembolism associated with attempted cardioversion and longer-term risk in chronic atrial flutter. The review process and data extraction were performed by two reviewers. Study event rates were assessed graphically, and a chi-squared test was used to assess heterogeneity across studies. Meta-regression with weighted logistic regression was used to assess the association between study-level clinical factors and reported thromboembolic event rates. RESULTS: We found 13 studies that reported the risk of thromboembolism associated with cardioversion of atrial flutter. Short-term event rates ranged from 0% to 7.3%. A chi-squared test for heterogeneity was significant (P &lt; 0.001), so results were not pooled. Instead, a meta-regression analysis was performed, which partly explained the heterogeneity across studies. Studies were more likely to report high event rates when they included patients with a prior history of thromboembolism, and to report lower event rates when at least some patients were anticoagulated or if patients underwent echocardiography before cardioversion. Four studies reported the longer-term risk of thromboembolism, and these suggest a yearly event rate of approximately 3% with sustained atrial flutter. CONCLUSION: These findings suggest that atrial flutter is indeed associated with an increased risk of thromboembolism, and that clinical factors account for the low event rates reported in some studies