Retinoic Acid Signaling Organizes Endodermal Organ Specification along the Entire Antero-Posterior Axis

Background: Endoderm organ primordia become specified between gastrulation and gut tube folding in Amniotes. Although the requirement for RA signaling for the development of a few individual endoderm organs has been established a systematic assessment of its activity along the entire antero-posterior axis has not been performed in this germ layer. Methodology/Principal Findings: RA is synthesized from gastrulation to somitogenesis in the mesoderm that is close to the developing gut tube. In the branchial arch region specific levels of RA signaling control organ boundaries. The most anterior endoderm forming the thyroid gland is specified in the absence of RA signaling. Increasing RA in anterior branchial arches results in thyroid primordium repression and the induction of more posterior markers such as branchial arch Hox genes. Conversely reducing RA signaling shifts Hox genes posteriorly in endoderm. These results imply that RA acts as a caudalizing factor in a graded manner in pharyngeal endoderm. Posterior foregut and midgut organ primordia also require RA, but exposing endoderm to additional RA is not sufficient to expand these primordia anteriorly. We show that in chick, in contrast to non-Amniotes, RA signaling is not only necessary during gastrulation, but also throughout gut tube folding during somitogenesis. Our results show that the induction of CdxA, a midgut marker, and pancreas induction require direct RA signaling in endoderm. Moreover, communication between CdxA + cells is necessary to maintain CdxA expression, therefore synchronizing the cells of the midgut primordium. We further show that the RA pathway acts synergistically wit

Meprinα transactivates the epidermal growth factor receptor (EGFR) via ligand shedding, thereby enhancing colorectal cancer cell proliferation and migration

Meprinα, an astacin-type metalloprotease is overexpressed in colorectal cancer cells and is secreted in a non-polarized fashion, leading to the accumulation of meprinα in the tumor stroma. The transition from normal colonocytes to colorectal cancer correlates with increased meprinα activity at primary tumor sites. A role for meprinα in invasion and metastatic dissemination is supported by its pro-angiogenic and pro-migratory activity. In the present study, we provide evidence for a meprinα-mediated transactivation of the EGFR signaling pathway and suggest that this mechanism is involved in colorectal cancer progression. Using alkaline phosphatase-tagged EGFR ligands and an ELISA assay, we demonstrate that meprinα is capable of shedding epidermal growth factor (EGF) and transforming growth factor-α (TGFα) from the plasma membrane. Shedding was abrogated using actinonin, an inhibitor for meprinα. The physiological effects of meprinα-mediated shedding of EGF and TGFα were investigated with human colorectal adenocarcinoma cells (Caco-2). Proteolytically active meprinα leads to an increase in EGFR and ERK1/2 phosphorylation and subsequently enhances cell proliferation and migration. In conclusion, the implication of meprinα in the EGFR/MAPK signaling pathway indicates a role of meprinα in colorectal cancer progression

Taking the Big Leap: A Case Study on Implementing Programmatic Assessment in an Undergraduate Medical Program

The concept of programmatic assessment (PA) is well described in the literature; however, studies on implementing and operationalizing this systemic assessment approach are lacking. The present case study developed a local instantiation of PA, referred to as Assessment System Fribourg (ASF), which was inspired by an existing program. ASF was utilized for a new competency-based undergraduate Master of Medicine program at the State University of Fribourg. ASF relies on the interplay of four key principles and nine main program elements based on concepts of PA, formative assessment, and evaluative judgment. We started our journey in 2019 with the first cohort of 40 students who graduated in 2022. This paper describes our journey implementing ASF, including the enabling factors and hindrances that we encountered, and reflects on our experience and the path that is still in front of us. This case illustrates one possibility for implementing PA

Taking the Big Leap: A Case Study on Implementing Programmatic Assessment in an Undergraduate Medical Program

The concept of programmatic assessment (PA) is well described in the literature; however, studies on implementing and operationalizing this systemic assessment approach are lacking. The present case study developed a local instantiation of PA, referred to as Assessment System Fribourg (ASF), which was inspired by an existing program. ASF was utilized for a new competency-based undergraduate Master of Medicine program at the State University of Fribourg. ASF relies on the interplay of four key principles and nine main program elements based on concepts of PA, formative assessment, and evaluative judgment. We started our journey in 2019 with the first cohort of 40 students who graduated in 2022. This paper describes our journey implementing ASF, including the enabling factors and hindrances that we encountered, and reflects on our experience and the path that is still in front of us. This case illustrates one possibility for implementing PA