Vascular Wall-Resident Multipotent Stem Cells within the Process of Vascular Remodelling

Processes of new vessel formation are central events in tissue development and repair. Therein, sprouting endothelial cells and/or endothelial progenitor cells form immature blood vessels that lack coverage by pericytes and other mural cells. Subsequently, vascular remodelling takes place, in which association with mural cells (pericytes and smooth muscle cells, SMC) stabilizes these immature vessels resulting in normalization of the vascular structures. Vascular remodelling is a dynamic and strictly regulated process; an ordered remodelling seems to be critical for proper vascular development, maintenance and stability of the vessel wall. The molecular and cellular changes associated with this process and its importance for tumour growth remain elusive. Up to now, the origin of vascular wall cells in tumours and the molecular mechanisms that govern their recruitment and association with angiogenic endothelial cells (vascular stabilization) are not well understood. There is some evidence that pericytes and SMC might originate from multipotent mesenchymal stem cells. This chapter aims to explore the role of tissue-resident multipotent stem cells of mesenchymal nature (VW-MPSCs) which putatively reside in the adventitia of adult blood vessels within the process of vascular remodelling of tumour blood vessels as well as of molecular factors that regulate VW-MPSC differentiation into pericytes and SMC

Mainstreaming climate adaptation into development assistance in Mozambique: Institutional barriers and opportunities

Based on a literature review and expert interviews, this paper analyzes the most important climate impacts on development goals and explores relevant institutions in the context of mainstreaming climate adaptation into development assistance in Mozambique. Climate variability and change can significantly hinder progress toward attaining the Millennium Development Goals and poverty aggravates the country's climate vulnerability. Because Mozambique is one of the major recipients of official development assistance in the world, there is a clear interest in ensuring that the risks of climate impacts are incorporated into the country's development investments. A screening of donor activities at the sub-national level shows that a high share of development assistance is invested in climate-sensitive sectors, partly in areas that are particularly exposed to droughts, floods, and cyclones. The authors find that Mozambique has a supportive legislative environment and donors have a high awareness of climate risks. However, limited individual, organizational, networking, and financial capacity constrain mainstreaming initiatives. Given strong limitations at the national level, bilateral and multilateral donors can play a key role in fostering institutional capacity in Mozambique.Climate Change,Environmental Economics&Policies,Population Policies,Common Property Resource Development,Global Environment Facility

The Tumor Vascular Endothelium as Decision Maker in Cancer Therapy

Genetic and pathophysiologic criteria prearrange the uncontrolled growth of neoplastic cells that in turn initiates new vessel formation, which is prerequisite for further tumor growth and progression. This first endothelial lining is patchy, disordered in structure and thus, angiogenic tumor vessels were proven to be functionally inferior. As a result, tumors were characterized by areas with an apparent oversupply in addition to areas with an undersupply of vessels, which complicates an efficient administration of intravenous drugs in cancer therapy and might even lower the response e.g. of radiotherapy (RT) because of the inefficient oxygen supply. In addition to the vascular dysfunction, tumor blood vessels contribute to the tumor escape from immunity by the lack of response to inflammatory activation (endothelial anergy) and by repression of leukocyte adhesion molecule expression. However, tumor vessels can remodel by the association with and integration of pericytes and smooth muscle cells which stabilize these immature vessels resulting in normalization of the vascular structures. This normalization of the tumor vascular bed could improve the efficiency of previously established therapeutic approaches, such as chemo- or radiotherapy by a more homogenous drug and oxygen distribution, and/or by overcoming endothelial anergy. This review highlights the current investigations that take advantage of a proper vascular function for improving cancer therapy with a special focus on the endothelial-immune system interplay

Nestin(+) Tissue-Resident Multipotent Stem Cells Contribute to Tumor Progression by Differentiating into Pericytes and Smooth Muscle Cells Resulting in Blood Vessel Remodeling

Tumor vessels with resistance to anti-angiogenic therapy are characterized by the normalization of the vascular structures through integration of mature pericytes and smooth muscle cells (SMC) into the vessel wall, a process termed vessel stabilization. Unfortunately, stabilization-associated vascular remodeling can result in reduced sensitivity to subsequent anti-angiogenic therapy. We show here that blockade of VEGF by bevacizumab induces stabilization of angiogenic tumor blood vessels in human tumor specimen by recruiting Nestin-positive cells, whereas mature vessels down-regulated Nestin-expression. Using xenograft tumors growing on bone-marrow (BM) chimera of C57Bl/6 wildtype and Nestin-GFP transgenic mice, we show for first time that Nestin(+) cells inducing the maturation of tumor vessels do not originate from the BM but presumably reside within the adventitia of adult blood vessels. Complementary ex vivo experiments using explants of murine aortas revealed that Nestin(+) multipotent stem cells (MPSCs) are mobilized from their niche and differentiated into pericytes and SMC through the influence of tumor-cell-secreted factors. We conclude that tissue-resident Nestin(+) cells are more relevant than BM-derived cells for vessel stabilization and therefore have to be considered in future strategies for anti-angiogenic therapy. The identification of proteins mediating recruitment or differentiation of local Nestin(+) cells with potential stem cell character to angiogenic blood vessels may allow the definition of new therapeutic targets to reduce tumor resistance against anti-angiogenic drugs

GeneLink: a database to facilitate genetic studies of complex traits

BACKGROUND: In contrast to gene-mapping studies of simple Mendelian disorders, genetic analyses of complex traits are far more challenging, and high quality data management systems are often critical to the success of these projects. To minimize the difficulties inherent in complex trait studies, we have developed GeneLink, a Web-accessible, password-protected Sybase database. RESULTS: GeneLink is a powerful tool for complex trait mapping, enabling genotypic data to be easily merged with pedigree and extensive phenotypic data. Specifically designed to facilitate large-scale (multi-center) genetic linkage or association studies, GeneLink securely and efficiently handles large amounts of data and provides additional features to facilitate data analysis by existing software packages and quality control. These include the ability to download chromosome-specific data files containing marker data in map order in various formats appropriate for downstream analyses (e.g., GAS and LINKAGE). Furthermore, an unlimited number of phenotypes (either qualitative or quantitative) can be stored and analyzed. Finally, GeneLink generates several quality assurance reports, including genotyping success rates of specified DNA samples or success and heterozygosity rates for specified markers. CONCLUSIONS: GeneLink has already proven an invaluable tool for complex trait mapping studies and is discussed primarily in the context of our large, multi-center study of hereditary prostate cancer (HPC). GeneLink is freely available at

Working with children from substance-affected families: the community-based group intervention TRAMPOLINE.

[ES] : Introducción. Hijos de familias drogodependientes pone de manifiesto que existe un elevado riesgo de que los niños desarrollen sus propios trastornos relacionados con las drogas u otros problemas mentales. Sufren a menudo violencia, malos tratos y abandono en sus familias. Por ello constituyen un objetivo importante de los programas de prevención. En Alemania se calcula que aproximadamente 2,65 millones de niños y jóvenes se ven afectados por el consumo o dependencia de las drogas de sus padres. Tan sólo un 10% de ellos reciben tratamiento a la vez que sus padres. Hasta la fecha, no existe en Alemania ningún programa evaluado para hijos de familias afectadas por las drogas. Métodos: se desarrolló una nueva intervención grupal para hijos de familias con problemas de drogas y actualmente se está evaluando en un estudio aleatorio-controlado en múltiples centros financiado por el Ministerio de Sanidad alemán. El proceso de desarrollo se orientó simultáneamente en la teoría, los datos de investigación existentes y los informes de expertos. Uno de los objetivos clave del programa es fomentar la resiliancia en los hijos de padres drogodependientes. Resultados: el manual TRAMPOLINE expone un programa grupal modular de 9 sesiones, centrado en la adicción, para niños de 8 a 12 años con al menos un progenitor que consume drogas. Las sesiones semanales duran 90 minutos y combinan elementos psicopedagógicos con ejercicios y juegos de rol. Asimismo se integra en el programa un componente de intervención con los padres de dos sesiones. Se exponen el contenido, la estructura y los fundamentos teóricos de la intervención. Discusión: TRAMPOLINE es un nuevo planteamiento de intervención que se dirige a los hijos de familias drogodependientes. Se basa en la teoría y la práctica. Los resultados del estudio ofrecerán información crucial sobre la eficacia de un programa preventivo grupal estructurado para hijos alemanes de familias drogodependientes. De este modo, el estudio contribuirá a crear un sistema de ayuda preventiva más amplio y eficaz para este grupo de alto riesgo. [EN] : Introduction: Children from substance-affected families show an elevated risk for developing own substance-related or other mental disorders. Frequently, they experience violence, abuse and neglect in their families. Therefore, they are an important target group for preventive efforts. In Germany it is estimated that approx. 2.65 million children are affected by parental substance abuse or dependence. Only ten percent of them receive treatment when parents are treated. To date, no evaluated program for children from substance-affected families exists in Germany. Methods: A new group intervention for children from substance-affected families was developed and is currently being evaluated in a randomized-controlled multicenter study funded by the German Ministry of Health. The development process was simultaneously guided by theory, existing research knowledge and expert opinion. Promoting resilience in children affected by parental substance abuse is a key goal of the program. Results: The TRAMPOLINE manual describes a 9-session addiction-focused, modular group program for children aged 8 to 12 years with at least one substance-using parent. Weekly sessions last for 90 minutes and combine psychoeducational elements with exercises and role play. A two-session parent intervention component is also integrated in the program. Content, structure and theoretical background of the intervention are described. Discussion: TRAMPOLINE is a new interventive effort targeting children from substance-affected families. It is grounded in theory and practice. The results of the research in progress will provide fundamental information on the effectiveness of a structured group prevention program for German children from substance-abusing families. Thus, the study will contribute to creating a broader and more effective system of preventive help for this high-risk target group

Non-small cell lung cancer cells and concomitant cancer therapy induce a resistance-promoting phenotype of tumor-associated mesenchymal stem cells

IntroductionThe tumor microenvironment gained attraction over the last decades as stromal cells significantly impact on tumor development, progression and metastasis, and immune evasion as well as on cancer therapy resistance. We previously reported that lung-resident mesenchymal stem cells (MSCs) were mobilized and activated in non-small cell lung cancer (NSCLC) progression and could even mediate radiation resistance in co-cultured NSCLC cells.MethodsWe investigated how MSCs were affected by NSCLC cells in combination with cancer (radiation) therapy in indirect co-cultures using tumor-conditioned medium and Transwells or direct three-dimensional NSCLC–MSC spheroid co-cultures in order to unravel the resistance-mediating action of tumor-associated MSCs.ResultsAlthough no obvious phenotypic and functional alterations in MSCs following NSCLC co-culture could be observed, MSC senescence was induced following co-applied radiotherapy (RT). Global gene expression profiling, in combination with gene set enrichment analysis upon treatment, was used to confirm the senescent phenotype of irradiated MSC and to reveal relevant senescence-associated secretory phenotype (SASP) factors that could meditate NSCLC RT resistance. We identified senescent tumor-associated MSC-derived serine proteinase inhibitor (serpin) E1/PAI1 as potential SASP factor mediating NSCLC progression and RT resistance.DiscussionSpecified intra-tumor–stroma interactions and cell type-specific pro-tumorigenic functions could not only improve lung cancer classification but could even be used for a more precise profiling of individual patients, finally paving an additional way for the discovery of potential drug targets for NSCLC patients

Early and Highly Suppressive ART are Main Factors Associated with Low Viral Reservoir in European Perinatally HIV Infected Children

Abstract BACKGROUND: Future strategies aiming to achieve HIV-1 remission are likely to target individuals with small reservoir size. SETTING: We retrospectively investigated factors associated with HIV-1 DNA levels in European, perinatally HIV-infected children starting ART <6 months of age. METHODS: Total HIV-1 DNA was measured from 51 long-term suppressed children 6.3 years (median) after initial viral suppression. Factors associated with log10 total HIV-1 DNA were analyzed using linear regression. RESULTS: At ART initiation, children were aged median [IQR] 2.3 [1.2,4.1] months, CD4% 37 [24,45] %, CD8% 28 [18,36] %, log10 plasma viral load (VL) 5.4 [4.4,5.9] copies/ml. Time to viral suppression was 7.98 [4.6,19.3] months. Following suppression, 13 (25%) children had suboptimal response [ 652 consecutive VL50-400 followed by VL<50] and/or experienced periods of virological failure [ 652 consecutive VL 65400 followed by VL<50]. Median total HIV-1 DNA was 43 [6,195] copies/10 PBMC.Younger age at therapy initiation was associated with lower total HIV-1 DNA (adjusted coefficient [AC] 0.12 per month older, p=0.0091), with a month increase in age at ART start being associated with a 13% increase in HIV DNA. Similarly, a higher proportion of time spent virally suppressed (AC 0.10 per 10% higher, p=0.0022) and absence of viral failure/suboptimal response (AC 0.34 for those with fail/ suboptimal response, p=0.0483) were associated with lower total HIV-1 DNA. CONCLUSION: Early ART initiation and a higher proportion of time suppressed are linked with lower total HIV-1 DNA. Early ART start and improving adherence in perinatally HIV-1 infected children minimize the size of viral reservoir.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal