The Oncolytic Adenovirus XVir-N-31, in Combination with the Blockade of the PD-1/PD-L1 Axis,Conveys Abscopal Effects in a Humanized Glioblastoma Mouse Model

Glioblastoma (GBM) is an obligatory lethal brain tumor with a median survival, even with the best standard of care therapy, of less than 20 months. In light of this fact, the evaluation of new GBM treatment approaches such as oncolytic virotherapy (OVT) is urgently needed. Based on our preliminary preclinical data, the YB-1 dependent oncolytic adenovirus (OAV) XVir-N-31 represents a promising therapeutic agent to treat, in particular, therapy resistant GBM. Preclinical studies have shown that XVir-N-31 prolonged the survival of GBM bearing mice. Now using an immunohumanized mouse model, we examined the immunostimulatory effects of XVir-N-31 in comparison to the wildtype adenovirus (Ad-WT). Additionally, we combined OVT with the inhibition of immune checkpoint proteins by using XVir-N-31 in combination with nivolumab, or by using a derivate of XVir-N-31 that expresses a PD-L1 neutralizing antibody. Although in vitro cell killing was higher for Ad-WT, XVir-N-31 induced a much stronger immunogenic cell death that was further elevated by blocking PD-1 or PD-L1. In vivo, an intratumoral injection of XVir-N-31 increased tumor infiltrating lymphocytes (TILs) and NK cells significantly more than Ad-WT not only in the virus-injected tumors, but also in the untreated tumors growing in the contralateral hemisphere. This suggests that for an effective treatment of GBM, immune activating properties by OAVs seem to be of greater importance than their oncolytic capacity. Furthermore, the addition of immune checkpoint inhibition (ICI) to OVT further induced lymphocyte infiltration. Consequently, a significant reduction in contralateral non-virus-injected tumors was only visible if OVT was combined with ICI. This strongly indicates that for an effective eradication of GBM cells that cannot be directly targeted by an intratumoral OV injection, additional ICI therapy is required.     

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Adjuvant whole body acupuncture in depression. A placebo-controlled study with standardized mianserin therapy

This article reports on the process undertaken to adapt the U.S. version of the SF-36 to an Australian setting. In addition, the results of psychometric testing, using the International Quality of Life Assessment (IQOLA) Project process and standards, is also reported. The adaptation process involved a number of steps including: a series of forward and backward translations; ratings of the difficulty of translating the SF-36 and the quality of the resulting translation. To assess the psychometric properties of the Australian form, a random sample of people residing in the Hunter region of New South Wales, Australia, were invited to complete the SF-36 with 855 respondents consenting to complete the measure. Principal components analyses supported the assumption of two factors underlying the measure with the percentage of variance explained by these factors ranging from between 0.66 and 0.77. Demonstrable internal consistency (both item and scale) and test-retest reliability were also found.     

The effects of disjunct sampling and averaging time on maximum mean wind speeds

Conventionally, the 50-year wind is calculated on basis of the annual maxima of consecutive 10-min averages. Very often, however, the averages are saved with a temporal spacing of several hours. We call it disjunct sampling. It may also happen that the wind speeds are averaged over a longer time period before being saved. In either case, the extreme wind will be underestimated. This paper investigates the effects of the disjunct sampling interval and the averaging time on the attenuation of the extreme wind estimation by means of a simple theoretical approach as well as measurements. The measurements include climates dominated by extratropical lows, as well as more complicated, wind climate types. For both, the investigations are done for omni-directional and sector-wise situations. The theory assumes the time series is a Gaussian Markov chain and it performs adequately for sites in the extratropical regions. The sector-wise situation is more complicated. The attenuation of the extreme mean winds for a sector shows a dependency on the frequency of occurrence from that sector.