Structural Changes in the Hungarian Economy and Foreign Trade in 1993–1998

In this article, the authors give a rich-in-data account of Hungary's structural transition to a market economy between 1993 and 1998. Although the availability of statistics also puts constraint on which period to study, these years may as well be later termed the first phase of post-socialist transition. The article has three main parts. In the first, structural changes of the whole economy are presented; the structural shifts in output, value added, and investments are analysed. The diffusion of private ownership and foreign capital and the process of decentralisation and concentration are also discussed. In the second part, the manufacturing industries are in focus. With an interesting analytical tool – the growth matrix – the authors present a possible approach of studying sectoral development. By distinguishing the factor needs of the manufacturing industries, the factor intensities of production are also easy to understand and yet reasonable for studying the adjustment to modernisation trends. In the third part, the structural changes of foreign trade are shown: export orientation, import dependency, the relationship between export and technology are the main concerns of analysis. The impact of FDI on the manufacturing industries' foreign trade and performance close the third part of the article

Therapy-induced antitumor vaccination in neuroblastomas by the combined targeting of IL-2 and TNF alpha

L19-IL2 and L19TNF are fusion proteins composed of L19(scFv), specific for the angiogenesis-associated ED-B containing fibronectin isoform and IL-2 or TNF. Because of the tumor targeting properties of L19, IL-2 and TNF concentrate at therapeutic doses at the tumor vascular level. To evaluate the therapeutic effects of L19-IL2 and L19mTNF in neuroblastoma (NB)-bearing mice, A/J mice bearing Neuro2A or NIE115 NB were systemically treated with L19-IL2 and L19mTNF, alone or in combination protocols. Seventy percent of Neuro2A- and 30% of NIE115-bearing mice were cured by the combined treatment with L19-IL2 and L19mTNF, and further rejected a homologous tumor challenge, indicating specific antitumor immune memory. The immunological bases of tumor cure and rejection were studied. A highly efficient priming of CD4+ T helper cells and CD8+ CTL effectors was generated, paralleled by massive infiltration in the tumor tissue of CD4+ and CD8+ T cells at day 16 after tumor cell implantation, when, after therapy, tumor volume was drastically reduced and tumor necrosis reached about 80%. The curative treatment resulted in a long-lasting antitumor immune memory, accompanied by a mixed Th1/Th2 type of response. Concluding, L19-IL2 and L19mTNF efficiently cooperate in determining a high percentage of NB cure that, in our experimental models, is strongly associated to the generation of adaptive immunity involving CD4+ and CD8+ T cells

vandetanib improves anti tumor effects of l19mtnfα in xenograft models of esophageal cancer

Purpose: Targeting the tumor vasculature by vascular disrupting agents (VDAs) has shown therapeutic activity in mouse models. In most cases, however, VDA efficacy is substantially compromised by the inability of these drugs to completely kill tumor cells located at the periphery of the tumor mass. In this study, we investigated anti-tumor effects of L19mTNFα, a fusion protein composed of L19 (scFv), specific for the angiogenesis-associated ED-B containing fibronectin isoform, and murine TNFα, in xenograft models of esophageal cancer. Experimental design: We evaluated ED-B expression in esophageal cancer samples. Subsequently, we generated subcutaneous xenografts from primary tumors, treated them with the L19mTNFα scFv, and determined effects on tumor vasculature, viability and proliferation, and VEGF expression and infiltration by hematopoietic cells. To overcome tumor resistance, L19mTNFα scFv was combined with vandetanib, a tyrosine kinase inhibitor of VEGF receptor, epidermal growth factor receptor, and RET signaling. Results: ED-B was broadly expressed by esophageal cancer cell lines, as well as xenografts and primary surgical samples of esophageal cancer. Administration of L19mTNFα acutely damaged tumor vasculature and increased necrosis, indicating a VDA-like activity of this immunoconjugate. This event was followed, however, by rapid tumor growth recovery associated with increased expression of VEGF and recruitment of CD11b+Gr1+ myeloid cells into tumors. Combination of L19mTNFα with vandetanib severely impaired vascular functions in tumors, leading to a reduction of cell proliferation and increased necrosis, without apparent signs of toxicity. Conclusion: These findings indicate that a combination of vascular damaging agents with anti-angiogenic drugs could represent a promising therapeutic strategy for esophageal cancer. Clin Cancer Res; 17(3); 447–58. ©2010 AACR

BoBafit: A copy number clustering tool designed to refit and recalibrate the baseline region of tumors’ profiles

Human cancer arises from a population of cells that have acquired a wide range of genetic alterations, most of which are targets of therapeutic treatments or are used as prognostic factors for patient's risk stratification. Among these, copy number alterations (CNAs) are quite frequent. Currently, several molecular biology technologies, such as microarrays, NGS and single-cell approaches are used to define the genomic profile of tumor samples. Output data need to be analyzed with bioinformatic approaches and particularly by employing computational algorithms. Molecular biology tools estimate the baseline region by comparing either the mean probe signals, or the number of reads to the reference genome. However, when tumors display complex karyotypes, this type of approach could fail the baseline region estimation and consequently cause errors in the CNAs call. To overcome this issue, we designed an R-package, BoBafit, able to check and, eventually, to adjust the baseline region, according to both the tumor-specific alterations’ context and the sample-specific clustered genomic lesions. Several databases have been chosen to set up and validate the designed package, thus demonstrating the potential of BoBafit to adjust copy number (CN) data from different tumors and analysis techniques. Relevantly, the analysis highlighted that up to 25% of samples need a baseline region adjustment and a redefinition of CNAs calls, thus causing a change in the prognostic risk classification of the patients. We support the implementation of BoBafit within CN analysis bioinformatics pipelines to ensure a correct patient's stratification in risk categories, regardless of the tumor type

Joining participatory approach and spatially-based modelling tools for groundwater resource management.

Although a lot of science has been produced on Water Resource Management (WRM) in the Information and Communication Technology (ICT) sector, WRM is still poorly addressed via scientific means. Some reasons for this may be: the underrated importance given to this topic at political and decision-making level; the low-capacity of the research environment to transfer results; and missing numerical modelling capacities at agencies and governing authorities. ICT may provide tools for water planning and management, as discussed within the ICT4WATER cluster initiative. Among these, GIS-integrated numerical modeling is a robust method to represent hydrological systems and to provide answers to problems of protection of groundwater resources. Because these tools require a high level of knowledge pertaining to various disciplines, they are often disregarded as complex “tricky games” providing unrealistic results. This is a barrier to the uptake of technologies for water management. To overcome this issue, the application of ICT tools has been combined with an innovative participatory approach, and large capacity building activities, in the framework of the H2020 FREEWAT project (FREE and open source software tools for WATer resource management; www.freewat.eu). The major result of the project consists in an open source and public domain, QGIS-integrated modeling platform for promoting WRM. FREEWAT capabilities have been demonstrated at 14 case studies in EU and non-EU Countries, where the effectiveness of few measures foreseen in River Basin Management Plans for achieving good status of water bodies was tested. At each case study, a Focus Group (FG) participated by local stakeholders (e.g., river basin authorities, research institutions, environmental protection agencies, environmental associations) was formed and seven meetings were organized. During these meetings, the objective of each case study, the methodology to be adopted, including definition of the conceptual model and of data needed, were discussed. The FG also took decisions on scenarios to be simulated for testing the feasibility of the foreseen measures. FGs aimed at demonstrating that WRM may be performed with open source and public domain software and participants’ perception on using ICT tools for WRM was discussed. Some of the implemented models are now being used for operational purposes: Vrbansky plato (Slovenia), where FREEWAT is used to monitor remediation of heating oil spillage and the water supply company intends to maintain and use developed groundwater flow model for managed groundwater recharge with induced riverbank filtration; the Bremerhaven case study (Germany), where the local water authority intends to use the developed groundwater flow model for predictions; the Scarlino-Follonica case study (Italy), where the model will be used by the regional authority to manage private groundwater remediation projects in a large industrial contaminated site; the Gozo case study (Malta), where the model is being developed to support the assessment of good groundwater quantitative status as part of the implementation of the Water Framework Directive

Identification of a Maturation Plasma Cell Index through a Highly Sensitive Droplet Digital PCR Assay Gene Expression Signature Validation in Newly Diagnosed Multiple Myeloma Patients

DNA microarrays and RNA-based sequencing approaches are considered important discovery tools in clinical medicine. However, cross-platform reproducibility studies undertaken so far have highlighted that microarrays are not able to accurately measure gene expression, particularly when they are expressed at low levels. Here, we consider the employment of a digital PCR assay (ddPCR) to validate a gene signature previously identified by gene expression profile. This signature included ten Hedgehog (HH) pathways' genes able to stratify multiple myeloma (MM) patients according to their self-renewal status. Results show that the designed assay is able to validate gene expression data, both in a retrospective as well as in a prospective cohort. In addition, the plasma cells' differentiation status determined by ddPCR was further confirmed by other techniques, such as flow cytometry, allowing the identification of patients with immature plasma cells' phenotype (i.e., expressing CD19+/CD81+ markers) upregulating HH genes, as compared to others, whose plasma cells lose the expression of these markers and were more differentiated. To our knowledge, this is the first technical report of gene expression data validation by ddPCR instead of classical qPCR. This approach permitted the identification of a Maturation Index through the integration of molecular and phenotypic data, able to possibly define upfront the differentiation status of MM patients that would be clinically relevant in the future

Long-term follow-up of patients with relapsing multiple sclerosis from the CLARITY/CLARITY Extension cohort of CLASSIC-MS : an ambispective study

Background: CLASSIC-MS evaluated the long-term efficacy of cladribine tablets in patients with relapsing multiple sclerosis. Objective: Report long-term mobility and disability beyond treatment courses received in CLARITY/CLARITY Extension. Methods: This analysis represents CLASSIC-MS patients who participated in CLARITY with/without participation in CLARITY Extension, and received ⩾1 course of cladribine tablets or placebo (N = 435). Primary objective includes evaluation of long-term mobility (no wheelchair use in the 3 months prior to first visit in CLASSIC-MS and not bedridden at any time since last parent study dose (LPSD), i.e. Expanded Disability Status Scale (EDSS) score <7). Secondary objective includes long-term disability status (no use of an ambulatory device (EDSS < 6) at any time since LPSD). Results: At CLASSIC-MS baseline, mean ± standard deviation EDSS score was 3.9 ± 2.1 and the median time since LPSD was 10.9 (range = 9.3-14.9) years. Cladribine tablets-exposed population: 90.6% (N = 394), including 160 patients who received a cumulative dose of 3.5 mg/kg over 2 years. Patients not using a wheelchair and not bedridden: exposed, 90.0%; unexposed, 77.8%. Patients with no use of an ambulatory device: exposed, 81.2%; unexposed, 75.6%. Conclusion: With a median 10.9 years' follow-up after CLARITY/CLARITY Extension, findings suggest the sustained long-term mobility and disability benefits of cladribine tablets

A nationwide real-world study on dynamic ustekinumab dosing and concomitant medication use among Crohn's disease patients in Finland

Background Real-world evidence to support optimal ustekinumab dosing for refractory Crohn's disease (CD) patients remains limited. Data from a retrospective nationwide chart review study was utilized to explore ustekinumab dosing dynamics and optimization, identify possible clinical predictors of dose intensification, and to evaluate ustekinumab trough concentrations (TCs) and concomitant medication use in Finland. Methods Information gathered from17 Finnish hospitals included clinical chart data from 155 adult CD patients who received intravenous ustekinumab induction during 2017-2018. Data on ustekinumab dosing and TCs, concomitant corticosteroid and immunosuppressant use, and antiustekinumab antibodies were analyzed in a two-year follow-up, subject to availability. Results Among 140 patients onustekinumab maintenance therapy, dose optimization was required in 55(39%) of the patients, and 41/47 dose-intensified patients (87%) persisted on ustekinumab. At baseline, dose-intensified patient group had significantly higher C-reactive protein (CRP) levels, and at week 16, significantly lower ustekinumab TCs than in patients without dose intensification. Irrespective of dose optimization, a statistically significant reduction in the use of corticosteroids was observed at both 16 weeks and one year, coupled with an increased proportion of patients on ustekinumab monotherapy. Antiustekinumab antibodies were undetectable in all 28 samples from 25 patients collected throughout the study period. Conclusions Nearly a third of all CD patients on ustekinumab maintenance therapy, with a history of treatment-refractory and long-standing disease, required dose intensification. These patients persisted on ustekinumab and had significant reduction of corticosteroid use. Increased baseline CRP was identified as the sole indicator of dose intensification.Peer reviewe

Digital realities & virtual ideals: Portraiture, idealism and the clash of subjectivities in the post-digital era

This is an accepted manuscript of an article published by Taylor and Francis in Photography and Culture on 26/02/2019, available online: https://doi.org/10.1080/17514517.2019.1565290 The accepted version of the publication may differ from the final published version.All portraits play host to a number of antithetical tensions, such as ‘private’ and ‘public’, ‘real’ and ‘ideal’, without which they would be reduced to a type of unassuming identification of subjects. Whereas in premodern times the artist was subject to the demands of the commissioner, after modernism the representational desires of the sitter began to clash with the creative intentions of the artist. Prior to the introduction of digital formats, this clash of subjectivities manifests itself in photography during the production of the work, the shooting of a portrait. Digital photography and post-production editing have expanded the methods for idealising external appearance; a desire stimulated by the recent technological acceleration of production and circulation of more ‘manipulated’ portraits than ever. In what ways, therefore, does the introduction of digital post-production editing and composite images affect this double-clash in portraiture, between the real and ideal, and the desires of the sitter against the intentions of the artist? Moreover, how does the evolution of self-portraiture in the ‘selfie’ affect the epistemological character of the genre? As such, is conceptual and aesthetic subservience a matter of technological possibility or creative determination