Economic impact of port activity : a disaggregate analysis. The case of Antwerp

The economic impact of the port sector is usually measured at an aggregate level by indicators such as value added, employment and investment. This paper tries to define the economic relevance for the regional as well as for the national economy at a disaggregate level. It attempts to identify, quantify and locate the mutual relationships between the various port players themselves and between them and other Belgian industries. Due to a lack of information foreign trade is only tackled very briefly but the method outlined in this paper can be used to measure the national effects of changes in port activity at a detailed level. A sector analysis is made by compiling a regional (regional as geographically opposed to national, not to be mistaken for the Belgian Regions Brussels, Flanders and Wallonia) input-output table, resorting to microeconomic data: a bottom-up approach. The main customers and suppliers of the port's key players or stakeholders are identified. A geographical analysis can also be carried out by using data at a disaggregate level. Each customer or supplier can be located by means of their postcode. In so doing, the economic impact of the port is quantified, both functionally and geographically. In the case of the port of Antwerp, the results show important links between freight forwarders and agents. The geographical analysis suggests the existence of major agglomerating effects in and around the port of Antwerp, referred to as a major transhipment location point. Key words: port economics, regional input-output table, sector analysis, geographical analysis.port economics, regional input-output table, sector analysis, geographical analysis

Describing complex interactions of social-ecological systems for tipping point assessments: an analytical framework

Humans play an interconnecting role in social-ecological systems (SES), they are part of these systems and act as agents of their destruction and regulation. This study aims to provide an analytical framework, which combines the concept of SES with the concept of tipping dynamics. As a result, we propose an analytical framework describing relevant dynamics and feedbacks within SES based on two matrixes: the “tipping matrix” and the “cross-impact matrix.” We take the Southwestern Amazon as an example for tropical regions at large and apply the proposed analytical framework to identify key underlying sub-systems within the study region: the soil ecosystem, the household livelihood system, the regional social system, and the regional climate system, which are interconnected through a network of feedbacks. We consider these sub-systems as tipping elements (TE), which when put under stress, can cross a tipping point (TP), resulting in a qualitative and potentially irreversible change of the respective TE. By systematically assessing linkages and feedbacks within and between TEs, our proposed analytical framework can provide an entry point for empirically assessing tipping point dynamics such as “tipping cascades,” which means that the crossing of a TP in one TE may force the tipping of another TE. Policy implications: The proposed joint description of the structure and dynamics within and across SES in respect to characteristics of tipping point dynamics promotes a better understanding of human-nature interactions and critical linkages within regional SES that may be used for effectively informing and directing empirical tipping point assessments, monitoring or intervention purposes. Thereby, the framework can inform policy-making for enhancing the resilience of regional SES

Describing complex interactions of social-ecological systems for tipping point assessments: an analytical framework

Humans play an interconnecting role in social-ecological systems (SES), they are part of these systems and act as agents of their destruction and regulation. This study aims to provide an analytical framework, which combines the concept of SES with the concept of tipping dynamics. As a result, we propose an analytical framework describing relevant dynamics and feedbacks within SES based on two matrixes: the “tipping matrix” and the “cross-impact matrix.” We take the Southwestern Amazon as an example for tropical regions at large and apply the proposed analytical framework to identify key underlying sub-systems within the study region: the soil ecosystem, the household livelihood system, the regional social system, and the regional climate system, which are interconnected through a network of feedbacks. We consider these sub-systems as tipping elements (TE), which when put under stress, can cross a tipping point (TP), resulting in a qualitative and potentially irreversible change of the respective TE. By systematically assessing linkages and feedbacks within and between TEs, our proposed analytical framework can provide an entry point for empirically assessing tipping point dynamics such as “tipping cascades,” which means that the crossing of a TP in one TE may force the tipping of another TE. Policy implications: The proposed joint description of the structure and dynamics within and across SES in respect to characteristics of tipping point dynamics promotes a better understanding of human-nature interactions and critical linkages within regional SES that may be used for effectively informing and directing empirical tipping point assessments, monitoring or intervention purposes. Thereby, the framework can inform policy-making for enhancing the resilience of regional SES

Role of stromal cell-mediated Notch signaling in CLL resistance to chemotherapy

Stromal cells are essential components of the bone marrow (BM) microenvironment that regulate and support the survival of different tumors, including chronic lymphocytic leukemia (CLL). In this study, we investigated the role of Notch signaling in the promotion of survival and chemoresistance of human CLL cells in coculture with human BM-mesenchymal stromal cells (hBM-MSCs) of both autologous and allogeneic origin. The presence of BM-MSCs rescued CLL cells from apoptosis both spontaneously and following induction with various drugs, including Fludarabine, Cyclophosphamide, Bendamustine, Prednisone and Hydrocortisone. The treatment with a combination of anti-Notch-1, Notch-2 and Notch-4 antibodies or γ-secretase inhibitor XII (GSI XII) reverted this protective effect by day 3, even in presence of the above-mentioned drugs. Overall, our findings show that stromal cell-mediated Notch-1, Notch-2 and Notch-4 signaling has a role in CLL survival and resistance to chemotherapy. Therefore, its blocking could be an additional tool to overcome drug resistance and improve the therapeutic strategies for CLL

The PI3-kinase delta inhibitor idelalisib (GS-1101) targets integrin-mediated adhesion of chronic lymphocytic leukemia (CLL) cell to endothelial and marrow stromal cells

CLL cell trafficking between blood and tissue compartments is an integral part of the disease process. Idelalisib, a phosphoinositide 3-kinase delta (PI3K\u3b4) inhibitor causes rapid lymph node shrinkage, along with an increase in lymphocytosis, prior to inducing objective responses in CLL patients. This characteristic activity presumably is due to CLL cell redistribution from tissues into the blood, but the underlying mechanisms are not fully understood. We therefore analyzed idelalisib effects on CLL cell adhesion to endothelial and bone marrow stromal cells (EC, BMSC). We found that idelalisib inhibited CLL cell adhesion to EC and BMSC under static and shear flow conditions. TNF\u3b1-induced VCAM-1 (CD106) expression in supporting layers increased CLL cell adhesion and accentuated the inhibitory effect of idelalisib. Co-culture with EC and BMSC also protected CLL from undergoing apoptosis, and this EC- and BMSC-mediated protection was antagonized by idelalisib. Furthermore, we demonstrate that CLL cell adhesion to EC and VLA-4 (CD49d) resulted in the phosphorylation of Akt, which was sensitive to inhibition by idelalisib. These findings demonstrate that idelalisib interferes with integrin-mediated CLL cell adhesion to EC and BMSC, providing a novel mechanism to explain idelalisib-induced redistribution of CLL cells from tissues into the blood

Bone Marrow Osteoblast Damage by Chemotherapeutic Agents

Hematopoietic reconstitution, following bone marrow or stem cell transplantation, requires a microenvironment niche capable of supporting both immature progenitors and stem cells with the capacity to differentiate and expand. Osteoblasts comprise one important component of this niche. We determined that treatment of human primary osteoblasts (HOB) with melphalan or VP-16 resulted in increased phospho-Smad2, consistent with increased TGF-β1 activity. This increase was coincident with reduced HOB capacity to support immature B lineage cell chemotaxis and adherence. The supportive deficit was not limited to committed progenitor cells, as human embryonic stem cells (hESC) or human CD34+ bone marrow cells co-cultured with HOB pre-exposed to melphalan, VP-16 or rTGF-β1 had profiles distinct from the same populations co-cultured with untreated HOB. Functional support deficits were downstream of changes in HOB gene expression profiles following chemotherapy exposure. Melphalan and VP-16 induced damage of HOB suggests vulnerability of this critical niche to therapeutic agents frequently utilized in pre-transplant regimens and suggests that dose escalated chemotherapy may contribute to post-transplantation hematopoietic deficits by damaging structural components of this supportive niche

Stereotypical Chronic Lymphocytic Leukemia B-Cell Receptors Recognize Survival Promoting Antigens on Stromal Cells

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Survival of CLL cells depends on their close contact with stromal cells in lymphatic tissues, bone marrow and blood. This microenvironmental regulation of CLL cell survival involves the stromal secretion of chemo- and cytokines as well as the expression of adhesion molecules. Since CLL survival may also be driven by antigenic stimulation through the B-cell antigen receptor (BCR), we explored the hypothesis that these processes may be linked to each other. We tested if stromal cells could serve as an antigen reservoir for CLL cells, thus promoting CLL cell survival by stimulation through the BCR. As a proof of principle, we found that two CLL BCRs with a common stereotyped heavy chain complementarity-determining region 3 (previously characterized as “subset 1”) recognize antigens highly expressed in stromal cells – vimentin and calreticulin. Both antigens are well-documented targets of autoantibodies in autoimmune disorders. We demonstrated that vimentin is displayed on the surface of viable stromal cells and that it is present and bound by the stereotyped CLL BCR in CLL-stroma co-culture supernatant. Blocking the vimentin antigen by recombinant soluble CLL BCR under CLL-stromal cell co-culture conditions reduces stroma-mediated anti-apoptotic effects by 20–45%. We therefore conclude that CLL BCR stimulation by stroma-derived antigens can contribute to the protective effect that the stroma exerts on CLL cells. This finding sheds a new light on the understanding of the pathobiology of this so far mostly incurable disease

The Novel Deacetylase Inhibitor AR-42 Demonstrates Pre-Clinical Activity in B-Cell Malignancies In Vitro and In Vivo

While deacetylase (DAC) inhibitors show promise for the treatment of B-cell malignancies, those introduced to date are weak inhibitors of class I and II DACs or potent inhibitors of class I DAC only, and have shown suboptimal activity or unacceptable toxicities. We therefore investigated the novel DAC inhibitor AR-42 to determine its efficacy in B-cell malignancies.In mantle cell lymphoma (JeKo-1), Burkitt's lymphoma (Raji), and acute lymphoblastic leukemia (697) cell lines, the 48-hr IC(50) (50% growth inhibitory concentration) of AR-42 is 0.61 microM or less. In chronic lymphocytic leukemia (CLL) patient cells, the 48-hr LC(50) (concentration lethal to 50%) of AR-42 is 0.76 microM. AR-42 produces dose- and time-dependent acetylation both of histones and tubulin, and induces caspase-dependent apoptosis that is not reduced in the presence of stromal cells. AR-42 also sensitizes CLL cells to TNF-Related Apoptosis Inducing Ligand (TRAIL), potentially through reduction of c-FLIP. AR-42 significantly reduced leukocyte counts and/or prolonged survival in three separate mouse models of B-cell malignancy without evidence of toxicity.Together, these data demonstrate that AR-42 has in vitro and in vivo efficacy at tolerable doses. These results strongly support upcoming phase I testing of AR-42 in B-cell malignancies

Autistic Disorder in Patients with Williams-Beuren Syndrome: A Reconsideration of the Williams-Beuren Syndrome Phenotype

International audienceBackground: Williams-Beuren syndrome (WBS), a rare developmental disorder caused by deletion of contiguous genes at 7q11.23, has been characterized by strengths in socialization (overfriendliness) and communication (excessive talkativeness). WBS has been often considered as the polar opposite behavioral phenotype to autism. Our objective was to better understand the range of phenotypic expression in WBS and the relationship between WBS and autistic disorder. Methodology: The study was conducted on 9 French individuals aged from 4 to 37 years old with autistic disorder associated with WBS. Behavioral assessments were performed using Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule (ADOS) scales. Molecular characterization of the WBS critical region was performed by FISH. Findings: FISH analysis indicated that all 9 patients displayed the common WBS deletion. All 9 patients met ADI-R and ADOS diagnostic criteria for autism, displaying stereotypies and severe impairments in social interaction and communication (including the absence of expressive language). Additionally, patients showed improvement in social communication over time. Conclusions: The results indicate that comorbid autism and WBS is more frequent than expected and suggest that the common WBS deletion can result in a continuum of social communication impairment, ranging from excessive talkativeness and overfriendliness to absence of verbal language and poor social relationships. Appreciation of the possible co-occurrence of WBS and autism challenges the common view that WBS represents the opposite behavioral phenotype of autism, and might lead to improved recognition of WBS in individuals diagnosed with autism