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Background: The chemokine and bone marrow-homing receptor CXCR4 has been implicated in metastatic dissemination of various cancers. We investigated CXCR4 expression in esophageal cancer specimens and its association with survival, lymph node microinvolvement, and bone marrow micrometastasis. Methods: We analyzed frozen tumor specimens from 136 patients with completely resected esophageal cancer for CXCR4 expression by immunohistochemistry. Lymph node microinvolvement and bone marrow micrometastasis were assessed by immunohistochemistry with monoclonal antibodies Ber-EP4 (against epithelial cell adhesion molecule) and pancytokeratin A45-B/B3 (against several cytokeratins), respectively. Associations between CXCR4 expression and clinicopathologic features, including tumor stage, histologic grade, lymph node metastasis and micro-involvement, bone marrow micrometastasis, and survival, were investigated with Fisher's test, log-rank test, and Cox multivariable analysis. All statistical tests were two-sided. Results: CXCR4 protein was expressed in 75 (55%) of 136 esophageal tumors examined. CXCR4 expression was statistically significantly associated with reduced median overall and disease-specific survival, compared with CXCR4 non-expression (P

Implementing digital learning approaches in fragile contexts offers opportunities and challenges at the same time. The article describes an ongoing project by the German development cooperation organization GIZ (Deutsche Gesellschaft für Internationale Zusammenarbeit GmbH) with the target to reforest areas of Afghanistan and conduct corresponding capacity building activities in the country. The international and Afghan stakeholders are facing a variety of challenges such as threats on personal safety and security, connectivity, and electricity breakdowns as well as working with a partwise illiterate and digital illiterate target group. The three steps of the capacity building process of the project will be described and explained – the training of trainers, the training of the NGOs, as well as the training of the final target group. Elements of the digital training are gamified and adapted to the Afghan culture, specifically focusing on storytelling, roleplay, as well as social learning.

The higher the share of components that are not related to an order (i.e. order-neutral) and therefore can be used across all product variants of a product family, the more internal costs and delivery times can be reduced. Due to low sales volumes and individual customer requirements, the identification and development of order-neutral components in the custom machine manufacturing sector is highly challenging. Accordingly, this paper presents a methodology that makes it possible to identify order-neutral components and increase their share by fixing individual operating parameters. Subsequently, the paper shows how to standardise variant components with long procurement lead times to optimise delivery time. The methodology is based on a product architecture determined for an existing product family, comprising an assessment of the order dependency of product functions and components using a novel classification matrix. A case study conducted on broaching machines demonstrates the applicability and validity of the methodology.

ABSTRACTMetastasis is a cancer-related systemic disease and is responsible for the greatest mortality rate among cancer patients. Interestingly, the interaction between the immune system and cancer cells seems to play a key role in metastasis formation in the target organ. However, this complex network is only partially understood. We previously found that IL-22 produced by tissue resident iNKT17 cells promotes cancer cell extravasation, the early step of metastasis. Based on these data, we aimed here to decipher the role of IL-22 in the last step of metastasis formation. We found that IL-22 levels were increased in established metastatic sites in both human and mouse. We also found that Th22 cells were the key source of IL-22 in established metastasis sites, and that deletion of IL-22 in CD4+ T cells was protective in liver metastasis formation. Accordingly, the administration of a murine IL-22 neutralizing antibody in the establishment of metastasis formation significantly reduced the metastatic burden in a mouse model. Mechanistically, IL-22-producing Th22 cells promoted angiogenesis in established metastasis sites. In conclusion, our findings highlight that IL-22 is equally as important in contributing to metastasis formation at late metastatic stages, and thus, identify it as a novel therapeutic target in established metastasis.

The transplantation model provides the opportunity to assess the relevance of a molecule of interest for tumor cell extravasation by using a respective genetically modified donor animal. Here, we present a protocol for orthotopic single-lung transplantation in mice as a tool for lung metastasis studies. We describe steps for animal preparation, lung transplantation, and tumor cell injection. We then detail procedures for the direct comparison of tumor cell spreading between the genetically modified left lung and the naive right lung parenchyma.

Reduced CD73 on T cells in HIV correlates with disease progression, as well as functional CD8+ T cell defects, and is partially reversible by ART. Recent studies indicate that murine Tregs highly express the ENTDP1, as well as the 5′‐NT and thereby, suppress Teff function by extracellular adenosine production. Furthermore, CD73 seems to play a role as costimulatory molecule for T cell differentiation. In this study, we analyzed the expression of CD73 on peripheral and lymph nodal Teffs and Tregs in a cohort of 95 HIV patients at different stages of disease, including LTNP and ECs. In contrast to murine Tregs, CD73 was only expressed on a small minority (∼10%) of peripheral Tregs. In contrast, we see high expression of CD73 on peripheral CD8+T cells. In HIV infection, CD73 is markedly reduced on all Teffs and Tregs, regardless of the memory subtype. On CD8+T cells, a positive correlation between CD73 expression and CD4 counts (P=0.0003) was detected. CD73 expression on CD8+T cells negatively correlated with HLA‐DR (<0.0001) and PD1 (P=0.0457) expression. The lower CD73 expression on CD8+T cells was partially reversible after initiation of ART (P=0.0016). Functionally, we observed that CD8+CD73+T cells produce more IL‐2 upon HIV‐specific and unspecific stimulation than their CD73−counterparts and show a higher proliferative capacity. These data indicate that down‐regulation of CD73 on CD8+T cells correlates with immune activation and leads to functional deficits in HIV infection.