Data Communication in Bulgaria - The Telecommunication Infrastructure and Relevant Administrative Procedures

In a small country with an open economy such as Bulgaria the potential role of transborder data flows is enormous. In what follows the present and future data communication infrastructure of Bulgaria will be described and the relevant administrative procedures outlined. Special emphasis will be given to the present transborder data flow applications of the country, which are characterized, in addition to the "classical" flow of data for civil aviation, information, news agencies' data, and meteorological data networks, by an emerging data base production and service industry

Nonlinear Circuits

Contains reports on four research projects

Immune cell profile of sentinel lymph nodes in patients with malignant melanoma - FOXP3+ cell density in cases with positive sentinel node status is associated with unfavorable clinical outcome

BACKGROUND: Besides being a preferential site of early metastasis, the sentinel lymph node (SLN) is also a privileged site of T-cell priming, and may thus be an appropriate target for investigating cell types involved in antitumor immune reactions. METHODS: In this retrospective study we determined the prevalence of OX40+ activated T lymphocytes, FOXP3+ (forkhead box P3) regulatory T cells, DC-LAMP+ (dendritic cell-lysosomal associated membrane protein) mature dendritic cells (DCs) and CD123+ plasmacytoid DCs by immunohistochemistry in 100 SLNs from 60 melanoma patients. Density values of each cell type in SLNs were compared to those in non-sentinel nodes obtained from block dissections (n = 37), and analyzed with regard to associations with clinicopathological parameters and disease outcome. RESULTS: Sentinel nodes showed elevated amount of all cell types studied in comparison to non-sentinel nodes. Metastatic SLNs had higher density of OX40+ lymphocytes compared to tumor-negative nodes, while no significant difference was observed in the case of the other cell types studied. In patients with positive sentinel node status, high amount of FOXP3+ cells in SLNs was associated with shorter progression-free (P = 0.0011) and overall survival (P = 0.0014), while no significant correlation was found in the case of sentinel-negative patients. The density of OX40+, CD123+ or DC-LAMP+ cells did not show significant association with the outcome of the disease. CONCLUSIONS: Taken together, our results are compatible with the hypothesis of functional competence of sentinel lymph nodes based on the prevalence of the studied immune cells. The density of FOXP3+ lymphocytes showed association with progression and survival in patients with positive SLN status, while the other immune markers studied did not prove of prognostic importance. These results, together with our previous findings on the prognostic value of activated T cells and mature DCs infiltrating primary melanomas, suggest that immune activation-associated markers in the primary tumor may have a higher impact than those in SLNs on the prognosis of the patients. On the other hand, FOXP3+ cell density in SLNs, but not in the primary tumor, was found predictive of disease outcome in melanoma patients

Nonlinear Circuits

Contains reports on four research projects

Using Heat to Characterize Streambed Water Flux Variability in Four Stream Reaches

Estimates of streambed water fl ux are needed for the interpretation of streambed chemistry and reactions. Continuous temperature and head monitoring in stream reaches within four agricultural watersheds (Leary Weber Ditch, IN; Maple Creek, NE; DR2 Drain, WA; and Merced River, CA) allowed heat to be used as a tracer to study the temporal and spatial variability of fluxes through the streambed. Synoptic methods (seepage meter and differential discharge measurements) were compared with estimates obtained by using heat as a tracer. Water flux was estimated by modeling one-dimensional vertical flow of water and heat using the model VS2DH. Flux was influenced by physical heterogeneity of the stream channel and temporal variability in stream and ground-water levels. During most of the study period (April–December 2004), flux was upward through the streambeds. At the IN, NE, and CA sites, high-stage events resulted in rapid reversal of flow direction inducing short-term surface-water flow into the streambed. During late summer at the IN site, regional ground-water levels dropped, leading to surface-water loss to ground water that resulted in drying of the ditch. Synoptic measurements of flux generally supported the model flux estimates. Water flow through the streambed was roughly an order of magnitude larger in the humid basins (IN and NE) than in the arid basins (WA and CA). Downward flux, in response to sudden high streamflows, and seasonal variability in flux was most pronounced in the humid basins and in high conductivity zones in the streambed

Changing forest water yields in response to climate warming: results from long-term experimental watershed sites across North America

Climate warming is projected to affect forest water yields but the effects are expected to vary. We investigated how forest type and age affect water yield resilience to climate warming. To answer this question, we examined the variability in historical water yields at long-term experimental catchments across Canada and the United States over 5-year cool and warm periods. Using the theoretical framework of the Budyko curve, we calculated the effects of climate warming on the annual partitioning of precipitation (P) into evapotranspiration (ET) and water yield. Deviation (d) was defined as a catchment’s change in actual ET divided by P [AET/P; evaporative index (EI)] coincident with a shift from a cool to a warm period – a positive d indicates an upward shift in EI and smaller than expected water yields, and a negative d indicates a downward shift in EI and larger than expected water yields. Elasticity was defined as the ratio of inter annual variation in potential ET divided by P (PET/P; dryness index) to inter annual variation in the EI – high elasticity indicates low d despite large range in drying index (i.e., resilient water yields), low elasticity indicates high d despite small range in drying index (i.e., non-resilient water yields). Although the data needed to fully evaluate ecosystems based on these metrics are limited, we were able to identify some characteristics of response among forest types. Alpine sites showed the greatest sensitivity to climate warming with any warming leading to increased water yields. Conifer forests included catchments with lowest elasticity and stable to larger water yields. Deciduous forests included catchments with intermediate elasticity and stable to smaller water yields. Mixed coniferous/deciduous forests included catchments with highest elasticity and stable water yields. Forest type appeared to influence the resilience of catchment water yields to climate warming, with conifer and deciduous catchments more susceptible to climate warming than the more diverse mixed forest catchments

Depletion of somatic mutations in splicing-associated sequences in cancer genomes

Abstract Background An important goal of cancer genomics is to identify systematically cancer-causing mutations. A common approach is to identify sites with high ratios of non-synonymous to synonymous mutations; however, if synonymous mutations are under purifying selection, this methodology leads to identification of false-positive mutations. Here, using synonymous somatic mutations (SSMs) identified in over 4000 tumours across 15 different cancer types, we sought to test this assumption by focusing on coding regions required for splicing. Results Exon flanks, which are enriched for sequences required for splicing fidelity, have ~ 17% lower SSM density compared to exonic cores, even after excluding canonical splice sites. While it is impossible to eliminate a mutation bias of unknown cause, multiple lines of evidence support a purifying selection model above a mutational bias explanation. The flank/core difference is not explained by skewed nucleotide content, replication timing, nucleosome occupancy or deficiency in mismatch repair. The depletion is not seen in tumour suppressors, consistent with their role in positive tumour selection, but is otherwise observed in cancer-associated and non-cancer genes, both essential and non-essential. Consistent with a role in splicing modulation, exonic splice enhancers have a lower SSM density before and after controlling for nucleotide composition; moreover, flanks at the 5’ end of the exons have significantly lower SSM density than at the 3’ end. Conclusions These results suggest that the observable mutational spectrum of cancer genomes is not simply a product of various mutational processes and positive selection, but might also be shaped by negative selection

Basics of advanced therapy medicinal product development in academic pharma and the role of a GMP simulation unit

Following successes of authorized chimeric antigen receptor T-cell products being commercially marketed in the United States and European Union, product development of T-cell-based cancer immunotherapy consisting of cell-based advanced therapy medicinal products (ATMPs) has gained further momentum. Due to their complex characteristics, pharmacological properties of living cell products are, in contrast to classical biological drugs such as small molecules, more difficult to define. Despite the availability of many new advanced technologies that facilitate ATMP manufacturing, translation from research-grade to clinical-grade manufacturing in accordance with Good Manufacturing Practices (cGMP) needs a thorough product development process in order to maintain the same product characteristics and activity of the therapeutic product after full-scale clinical GMP production as originally developed within a research setting. The same holds true for transferring a fully developed GMP-grade production process between different GMP facilities. Such product development from the research to GMP-grade manufacturing and technology transfer processes of established GMP-compliant procedures between facilities are challenging. In this review, we highlight some of the main obstacles related to the product development, manufacturing process, and product analysis, as well as how these hinder rapid access to ATMPs. We elaborate on the role of academia, also referred to as ‘academic pharma’, and the added value of GMP production and GMP simulation facilities to keep innovation moving by reducing the development time and to keep final production costs reasonable