Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity

Primary immunodeficiency disorders enable identification of genes with crucial roles in the human immune system. Here we study patients suffering from recurrent bacterial, viral and Cryptosporidium infections, and identify a biallelic mutation in the MAP3K14 gene encoding NIK (NF- B-inducing kinase). Loss of kinase activity of mutant NIK, predicted by in silico analysis and confirmed by functional assays, leads to defective activation of both canonical and non-canonical NF- B signalling. Patients with mutated NIK exhibit B-cell lymphopenia, decreased frequencies of class-switched memory B cells and hypogammaglobulinemia due to impaired B-cell survival, and impaired ICOSL expression. Although overall T-cell numbers are normal, both follicular helper and memory T cells are perturbed. Natural killer (NK) cells are decreased and exhibit defective activation, leading to impaired formation of NK-cell immunological synapses. Collectively, our data illustrate the non-redundant role for NIK in human immune responses, demonstrating that loss-of-function mutations in NIK can cause multiple aberrations of lymphoid immunity

Busulfan/Fludarabine- or Treosulfan/Fludarabine-Based Conditioning Regimen for Patients with Wiskott-Aldrich Syndrome – an EBMT Inborn Errors Working Party and Scetide Study

Introduction Excellent survival rates have been reported after allogeneic haematopoietic stem cell transplantation (HSCT) for Wiskott-Aldrich syndrome (WAS) patients. Recipient age >5 years in MUD HSCT as well as MMFD as donor were negative predictors for outcome. However, the vast majority of HSCTs in previously published studies were performed with (oral) busulfan/cyclophosphamide-based conditioning and in the early 2000 years or before. Objectives To compare OS and EFS after HSCT with either busulfan/fludarabine (BuFlu) ± thiotepa (TT) or treosulfan/fludarabine (TreoFlu) ± TT as recommended for primary immunodeficiencies since 2005 by the inborn errors working party (IEWP) of EBMT and ESID. Methods We performed a retrospective analysis via the EBMT and SCETIDE registries of WAS patients transplanted between 20006 and 2016 with these two regimens. At the time of this interim analysis, 174 patients were included, 92 (53%) with BuFlu±TT and 82 (47%) with TreoFlu±TT conditioning, with a median age of 1.6 years (0.2-30) at HSCT and a median follow-up of 32.9 months (1.5-128.9). Donors were MSD in 30, other MRD in 5, MUD (9/10 or 10/10) in 105, MMUD ( Results Two year overall survival (OS) of the entire cohort was 88.6% (95% c.i. 83.5%-93.6%). There was no significant difference in OS between BuFlu±TT or TreoFlu±TT conditioning (2-year OS 88.1% vs. 89.5%; p=0.7). Patients aged >5 years had a worse OS as compared to those 5 years or younger at HSCT (74.9% vs. 90.8%; p=0.005). The type of donor had no influence on OS: 96.4% for MSD/MFD, 86.8% for MUD/MMUD and 87.7% for MMFD (p=0.4). The rate of complete (≥90%) donor chimerism at last follow-up or before a secondary procedure (if a patient had one) was 41/42 (98%) in the BuFlu±TT group and 21/35 (60%) in the TreoFlu±TT group (p=0.0001). Twenty-six patients required a second procedure: stem cell boost in 4, donor lymphocyte infusion in 9, 2nd HSCT in 15 and splenectomy in 1. The 2-year cumulative incidence (CI) of second procedures was higher at 33.9% in the TreoFlu±TT versus 12.8% in the BuFlu±TT group (p=0.017), and 2-year EFS (events: second procedure or death) was 61.4% in the TreoFlu±TT and 75.0% in the BuFlu±TT group (p=0.2). Grade II-IV acute GVHD had the same incidence in both groups (24.4% vs. 26.3%; p=0.849) and chronic GVHD of any grade was borderline more frequent in the TreoFlu±TT group (17.2% vs 6.7%; p=0.054). Conclusion HSCT with either BuFlu±TT or TreoFlu±TT conditioning reliably cures almost 90% of patients with WAS regardless of donor type. Age >5 years at HSCT remains a negative risk factor. More patients were mixed chimeras and required second procedures after TreoFlu±TT than after BuFlu±TT conditioning. These data confirm the feasibility and efficacy of the regimens currently recommended by the IEWP

Hematopoietic cell transplantation in severe combined immunodeficiency : The SCETIDE 2006-2014 European cohort

Publisher Copyright: © 2021 The AuthorsBackground: Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome. Objective: We performed a comprehensive multicenter analysis of genotype-specific HSCT outcome, including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome. Methods: HSCT outcome was studied in 338 patients with genetically confirmed SCID who underwent transplantation in 2006-2014 and who were registered in the SCETIDE registry. In a representative subgroup of 152 patients, data on IR and long-term clinical outcome were analyzed. Results: Two-year OS was similar with matched family and unrelated donors and better than mismatched donor HSCT (P 0.5 × 10e3/μL at +1 year were identified as independent predictors of favorable clinical and immunologic outcome. Conclusion: Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long-term outcome, treatment strategies should aim for optimal naive CD4 T lymphocyte regeneration.Peer reviewe

Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study.

peer reviewedAllogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT

Analysis of landscape changes as an indicator for environmental monitoring

PubMedID: 28000120Mediterranean coastal landscapes are complex systems that are subject to rapid and extensive changes due to unprecedented human interference. Changes in these landscapes are strong indications of anthropogenic disturbances that should be monitored carefully in order to make effective management decisions. Landscape changes can be analyzed using many qualitative and quantitative techniques. In this respect, the importance of land cover information arises from the fact that any change in the composition and/or configuration of land cover can be used as a landscape-level environmental indicator. Therefore, proper understanding of spatial and temporal characteristics of this environmental attribute is of vital importance as it enables decision-makers to reveal causes of environmental issues and to cope with consequences of mismanagement. The aims of this paper are to analyze landscape-level changes using the largest patch index (LPI) as a simple pattern indicator and provide guidelines for studying change phenomena that take place in the Mediterranean coastal areas. In this respect, changes in the LPI values for agricultural and built-up areas in three different sites were analyzed using georeferenced Ikonos and Quickbird images. The concepts of pattern and process were highlighted as important indicators for studying landscapes and understanding their change. © 2016, Springer International Publishing Switzerland

Analysis of landscape changes as a tool for monitoring ecosystem dynamics [Ekosistem dinamiklerinin i·zlenmesine bir araç olarak peyzaj degişimlerinin analizi]

This study aimed to provide a framework as a basis for determining qualitative and quantitative aspects of landscape changes. Special emphasis was placed on pixel-based comparison of satellite images and the advantages of this approach over traditional change detection based on a simple comparison of the area of a given land cover type at different dates was discussed. The results of this study showed that coastal landscape has high spatial heterogeneity. The results also suggested that rapid and complex changes in these areas resulting from human interference can be identified accurately by using spatially-referenced information. The use of "from one date to another" (-from ,-to) change categories was reported to provide more information on the movement, fragmentation, and consolidation components of landscape changes and the utility of the products of this approach for creating future secenarios was mentioned

Land-use change and urbanization of Adana, Turkey

This study analyses land-use/land-cover (LULC) changes in Adana city, Turkey, using satellite data of 1984 and 2000. Study of the expansion of the city over adjacent agricultural fields and semi-natural areas was the major focus. The satellite images were classified using supervised classification prior to comparison of LULC on two different dates. The change map was produced by pixel-to-pixel comparison of the classified images. Urban and built-up area increased by a factor of 2.07 during the 16 years; about 30 per cent on agricultural land and 70 per cent on previously semi-natural land. Permanent immigration and urban development strategies were the main driving forces. Some policy perspectives are also given. Copyright © 2003 John Wiley and Sons, Ltd

Comparing the utility of image algebra operations for characterizing landscape changes: The case of the Mediterranean coast

PubMedID: 21820236The aim of this study is to compare various image algebra procedures for their efficiency in locating and identifying different types of landscape changes on the margin of a Mediterranean coastal plain, Cukurova, Turkey. Image differencing and ratioing were applied to the reflective bands of Landsat TM datasets acquired in 1984 and 2006. Normalized Difference Vegetation index (NDVI) and Principal Component Analysis (PCA) differencing were also applied. The resulting images were tested for their capacity to detect nine change phenomena, which were a priori defined in a three-level classification scheme. These change phenomena included agricultural encroachment, sand dune afforestation, coastline changes and removal/expansion of reed beds. The percentage overall accuracies of different algebra products for each phenomenon were calculated and compared. The results showed that some of the changes such as sand dune afforestation and reed bed expansion were detected with accuracies varying between 85 and 97% by the majority of the algebra operations, while some other changes such as logging could only be detected by mid-infrared (MIR) ratioing. For optimizing change detection in similar coastal landscapes, underlying causes of these changes were discussed and the guidelines for selecting band and algebra operations were provided. © 2011 Elsevier Ltd

Assessing visibility of marble quarries from a scenic coastal Road

13th International MEDCOAST Congress on Coastal and Marine Sciences, Engineering, Management and Conservation, MEDCOAST 2017 --31 October 2017 through 4 November 2017 -- --Marble quarries have existed in Mediterranean coastal areas since ancient times. The numbers and extent of these quarries have substantially increased in the Mediterranean coastal zone of Turkey in recent decades. Marble quarries result with extensive scars on land surface. Landscape visibility is, therefore, negatively affected by this type of activity due to contrasting colours and altered topographical relief. Removal of vegetation and topsoil, disposal of tailings and new road constructions are responsible for these impacts. Since these extraction sites are generally located on hill slopes, they are highly visible from the roads and settlements in surrounding landscapes. Scenic quality is an important asset for coastal landscapes as far as tourism and recreation are concerned. To this end, visibility of quarries from the roads, settlements and potential development sites is critically important. This paper analysed visibility of marble extraction sites in Ta°ucu (Turkey) from a scenic state road. For this purpose, roads and land cover information were extracted from remotely sensed satellite imagery. Digital surface model (DSM) was used to quantify magnitude of visibility.TOVAG 214O391This project is supported by Turkish Scientific and Technological Council (TUBITAK) under the grant number TOVAG 214O391

Bi-temporal analysis of landscape changes in the easternmost mediterranean deltas using binary and classified change information

PubMedID: 23307139The aim of this study is (1) to quantify landscape changes in the easternmost Mediterranean deltas using bi-temporal binary change detection approach and (2) to analyze relationships between conservation/management designations and various categories of change that indicate type, degree and severity of human impact. For this purpose, image differencing and ratioing were applied to Landsat TM images of 1984 and 2006. A total of 136 candidate change images including normalized difference vegetation index (NDVI) and principal component analysis (PCA) difference images were tested to understand performance of bi-temporal pre-classification analysis procedures in the Mediterranean delta ecosystems. Results showed that visible image algebra provided high accuracies than did NDVI and PCA differencing. On the other hand, Band 5 differencing had one of the lowest change detection performances. Seven superclasses of change were identified using from/to change categories between the earlier and later dates. These classes were used to understand spatial character of anthropogenic impacts in the study area and derive qualitative and quantitative change information within and outside of the conservation/ management areas. Change analysis indicated that natural site and wildlife reserve designations fell short of protecting sand dunes from agricultural expansion in the west. East of the study area, however, was exposed to least human impact owing to the fact that nature conservation status kept human interference at a minimum. Implications of these changes were discussed and solutions were proposed to deal with management problems leading to environmental change. © 2013 Springer Science+Business Media New York