Regeneration of the Exocrine Pancreas Is Delayed in Telomere-Dysfunctional Mice

INTRODUCTION: Telomere shortening is a cell-intrinsic mechanism that limits cell proliferation by induction of DNA damage responses resulting either in apoptosis or cellular senescence. Shortening of telomeres has been shown to occur during human aging and in chronic diseases that accelerate cell turnover, such as chronic hepatitis. Telomere shortening can limit organ homeostasis and regeneration in response to injury. Whether the same holds true for pancreas regeneration in response to injury is not known. METHODS: In the present study, pancreatic regeneration after acute cerulein-induced pancreatitis was studied in late generation telomerase knockout mice with short telomeres compared to telomerase wild-type mice with long telomeres. RESULTS: Late generation telomerase knockout mice exhibited impaired exocrine pancreatic regeneration after acute pancreatitis as seen by persistence of metaplastic acinar cells and markedly reduced proliferation. The expression levels of p53 and p21 were not significantly increased in regenerating pancreas of late generation telomerase knockout mice compared to wild-type mice. CONCLUSION: Our results indicate that pancreatic regeneration is limited in the context of telomere dysfunction without evidence for p53 checkpoint activation

Beneficial Endocrine but Adverse Exocrine Effects of Sitagliptin in the Human Islet Amyloid Polypeptide Transgenic Rat Model of Type 2 Diabetes: Interactions With Metformin

ObjectiveWe sought to establish the extent and mechanisms by which sitagliptin and metformin singly and in combination modify islet disease progression in human islet amyloid polypeptide transgenic (HIP) rats, a model for type 2 diabetes.Research design and methodsHIP rats were treated with sitagliptin, metformin, sitagliptin plus metformin, or no drug as controls for 12 weeks. Fasting blood glucose, insulin sensitivity, and beta-cell mass, function, and turnover were measured in each group.ResultsSitagliptin plus metformin had synergistic effects to preserve beta-cell mass in HIP rats. Metformin more than sitagliptin inhibited beta-cell apoptosis. Metformin enhanced hepatic insulin sensitivity; sitagliptin enhanced extrahepatic insulin sensitivity with a synergistic effect in combination. beta-Cell function was partially preserved by sitagliptin plus metformin. However, sitagliptin treatment was associated with increased pancreatic ductal turnover, ductal metaplasia, and, in one rat, pancreatitis.ConclusionsThe combination of metformin and sitagliptin had synergistic actions to preserve beta-cell mass and function and enhance insulin sensitivity in the HIP rat model of type 2 diabetes. However, adverse actions of sitagliptin treatment on exocrine pancreas raise concerns that require further evaluation

Recruitment and Activation of Pancreatic Stellate Cells from the Bone Marrow in Pancreatic Cancer: A Model of Tumor-Host Interaction

BACKGROUND AND AIMS: Chronic pancreatitis and pancreatic cancer are characterised by extensive stellate cell mediated fibrosis, and current therapeutic development includes targeting pancreatic cancer stroma and tumor-host interactions. Recent evidence has suggested that circulating bone marrow derived stem cells (BMDC) contribute to solid organs. We aimed to define the role of circulating haematopoietic cells in the normal and diseased pancreas. METHODS: Whole bone marrow was harvested from male β-actin-EGFP donor mice and transplanted into irradiated female recipient C57/BL6 mice. Chronic pancreatitis was induced with repeat injections of caerulein, while carcinogenesis was induced with an intrapancreatic injection of dimethylbenzanthracene (DMBA). Phenotype of engrafted donor-derived cells within the pancreas was assessed by immunohistochemistry, immunofluorescence and in situ hybridisation. RESULTS: GFP positive cells were visible in the exocrine pancreatic epithelia from 3 months post transplantation. These exhibited acinar morphology and were positive for amylase and peanut agglutinin. Mice administered caerulein developed chronic pancreatitis while DMBA mice exhibited precursor lesions and pancreatic cancer. No acinar cells were identified to be donor-derived upon cessation of cerulein treatment, however rare occurrences of bone marrow-derived acinar cells were observed during pancreatic regeneration. Increased recruitment of BMDC was observed within the desmoplastic stroma, contributing to the activated pancreatic stellate cell (PaSC) population in both diseases. Expression of stellate cell markers CELSR3, PBX1 and GFAP was observed in BMD cancer-associated PaSCs, however cancer-associated, but not pancreatitis-associated BMD PaSCs, expressed the cancer PaSC specific marker CELSR3. CONCLUSIONS: This study demonstrates that BMDC can incorporate into the pancreas and adopt the differentiated state of the exocrine compartment. BMDC that contribute to the activated PaSC population in chronic pancreatitis and pancreatic cancer have different phenotypes, and may play important roles in these diseases. Further, bone marrow transplantation may provide a useful model for the study of tumor-host interactions in cancer and pancreatitis

Praktische Lehre im Medizinstudium in Zeiten von COVID-19. Bericht über die COVID-19-bedingte Umgestaltung der peergestützten Lehre im Skills Lab mithilfe eines Inverted-Classroom-Formats

Objective: Drastic restrictions were imposed due to the COVID-19 pandemic, especially relating to the practical training part of the undergraduate human and dental medical training. During emergency mode teaching in the summer semester of 2020, a pilot project on practical classroom teaching under COVID-19 conditions was undertaken the Skills Lab Dresden, the Interprofessional Medical Training Centre (MITZ). Students were able to continue learning basic communication and manual skills. This project report presents the adaptations needed for this teaching concept and discusses their feasibility as well as selected evaluation results of the trial run.Description of the project: In normal teaching, students rotate to complete training sessions in small groups. Teaching is provided in a peer-teaching format. An Inverted Classroom Model was implemented as a teaching concept during emergency operation with preparation through digital learning and classroom teaching. Organisational and teaching adjustments were carried out for the concept and to comply with containment regulations. The concept was evaluated by the students using a standardised online questionnaire.Results: 1012 students completed their training during emergency operation at the university. The containment regulations meant that there were a higher number of training sessions and a higher workload. Only one of the alternative dates provided had to be used for COVID-19-related reasons. Infection chains could be tracked. The majority of students found the communication of information via Moodle to be sufficient and did not experience any technical problems. An analysis of the students' evaluation revealed a high level of overall satisfaction with the adapted teaching concept. Conclusion: The MITZ will once again use the concept in a modified form should there be renewed or continued emergency operation. The Inverted Classroom Model will also be established as an integral part of regular teaching. The findings may be of interest to other Skills Labs to develop concepts for emergency operation teaching to efficiently utilise site-specific resources.Zielsetzung: Bedingt durch die COVID-19-Pandemie entstanden insbesondere für die praktische Ausbildung des Human- und Zahnmedizinstudiums drastische Einschränkungen. Während der Notbetriebslehre im Sommersemester 2020 fand im Skills Lab Dresden, dem Medizinischen Interprofessionellen Trainingszentrum (MITZ), ein Pilotprojekt zur Umsetzung von praktischer Präsenzlehre unter COVID-19-Bedingungen statt. Studierende konnten weiterhin kommunikative und manuelle Basisfertigkeiten trainieren. Dieser Projektbericht stellt die nötigen Anpassungen für dieses Lehrkonzept vor und diskutiert deren Durchführbarkeit sowie ausgewählte Auswertungsergebnisse des Probedurchlaufs.Projektbeschreibung: In der regulären curricularen Lehre absolvieren die Studierenden in Kleingruppen Trainingsstationen im Rotationsprinzip. Die Lehre findet im Peer-Teaching-Format statt. Für den Notbetrieb wurde als Lehrkonzept ein Inverted-Classroom-Modell mit Vorbereitung durch digitales Lernen und Präsenzlehre implementiert. Für das Konzept und die Einhaltung der Eindämmungsbestimmungen wurden organisatorische und didaktische Anpassungen vorgenommen. Mit Hilfe eines standardisierten Online-Fragebogens wurde die Studierendenevaluation durchgeführt.Ergebnisse: Im Notbetrieb absolvierten 1012 Studierende die Trainings. Durch die Eindämmungsbestimmungen kam es zu einer höheren Anzahl an Trainingsterminen und einem erhöhten Arbeitsaufwand. Nur einer der bereitgestellten Ausweichtermine musste COVID-19-bedingt genutzt werden. Infektionsketten wären nachvollziehbar gewesen. Der Großteil der Studierenden empfand die Bereitstellung von Informationen über Moodle als ausreichend und sah keine technischen Probleme. Die Auswertung der Studierendenevaluation zeigte eine hohe Gesamtzufriedenheit mit dem angepassten Lehrkonzept. Schlussfolgerung: Im erneuten oder fortzusetzenden Notbetrieb wird das MITZ das Konzept modifiziert wieder nutzen. Zudem wird das Inverted-Classroom-Modell als fester Bestandteil der regulären Lehre etabliert. Die Erkenntnisse können für andere Skills Labs zur Erarbeitung von Konzepten für die Notbetriebslehre von Interesse sein, um die standortindividuellen Ressourcen effizient zu nutzen