Allogeneic islet transplantation is a standard of care treatment for patients with labile type 1 diabetes in many countries around the world, including Japan, the United Kingdom, Australia, much of... Show moreAllogeneic islet transplantation is a standard of care treatment for patients with labile type 1 diabetes in many countries around the world, including Japan, the United Kingdom, Australia, much of continental Europe, and parts of Canada. The United States is now endorsing islet cell treatment for type 1 diabetes, but the FDA has chosen to consider islets as a biologic that requires licensure, making the universal implementation of the procedure in the clinic very challenging and opening the manufacture of islet grafts to private companies. The commercialization of human tissues raises significant legal and ethical issues and ironically leads to a situation where treatments developed as a result of the scientific and economic efforts of academia over several decades become exploited exclusively by for-profit entities. Show less
Glanc, M.; Gelderen, K. van; Hoermayer, L.; Tan, S.; Naramoto, S.; Zhang, X.; ... ; Friml, J. 2021
Polar subcellular localization of the PIN exporters of the phytohormone auxin is a key determinant of directional, intercellular auxin transport and thus a central topic of both plant cell and... Show morePolar subcellular localization of the PIN exporters of the phytohormone auxin is a key determinant of directional, intercellular auxin transport and thus a central topic of both plant cell and developmental biology. Arabidopsis mutants lacking PID, a kinase that phosphorylates PINs, or the MAB4/MEL proteins of unknown molecular function display PIN polarity defects and phenocopy pin mutants, but mechanistic insights into howthese factors convey PIN polarity are missing. Here, by combining protein biochemistry with quantitative live-cell imaging, we demonstrate that PINs, MAB4/MELs, and AGC kinases interact in the same complex at the plasma membrane. MAB4/MELs are recruited to the plasma membrane by the PINs and in concert with the AGC kinases maintain PIN polarity through limiting lateral diffusion-based escape of PINs from the polar domain. The PIN-MAB4/MEL-PID protein complex has self-reinforcing properties thanks to positive feedback between AGC kinase-mediated PIN phosphorylation and MAB4/MEL recruitment. Wethus uncover the molecular mechanism by which AGC kinases and MAB4/MEL proteins regulate PIN localization and plant development. Show less
Hepatic, pancreatic, and biliary (HPB) organoids are powerful tools for studying development, disease, and regeneration. As organoid research expands, the need for clear definitions and... Show moreHepatic, pancreatic, and biliary (HPB) organoids are powerful tools for studying development, disease, and regeneration. As organoid research expands, the need for clear definitions and nomenclature describing these systems also grows. To facilitate scientific communication and consistent interpretation, we revisit the concept of an organoid and introduce an intuitive classification system and nomenclature for describing these 3D structures through the consensus of experts in the field. To promote the standardization and validation of HPB organoids, we propose guidelines for establishing, characterizing, and benchmarking future systems. Finally, we address some of the major challenges to the clinical application of organoids. Show less
Introduction Emergency department (ED) overcrowding is a major healthcare problem associated with worse patient outcomes and increased costs. Attempts to reduce ED overcrowding of patients with... Show moreIntroduction Emergency department (ED) overcrowding is a major healthcare problem associated with worse patient outcomes and increased costs. Attempts to reduce ED overcrowding of patients with cardiac complaints have so far focused on in-hospital triage and rapid risk stratification of patients with chest pain at the ED. The Hollands-Midden Acute Regional Triage-Cardiology (HART-c) study aimed to assess the amount of patients left at home in usual ambulance care as compared with the new prehospital triage method. This method combines paramedic assessment and expert cardiologist consultation using live monitoring, hospital data and real-time admission capacity. Methods and analysis Patients visited by the emergency medical services (EMS) for cardiac complaints are included. EMS consultation consists of medical history, physical examination and vital signs, and ECG measurements. All data are transferred to a newly developed platform for the triage cardiologist. Prehospital data, in-hospital medical records and real-time admission capacity are evaluated. Then a shared decision is made whether admission is necessary and, if so, which hospital is most appropriate. To evaluate safety, all patients left at home and their general practitioners (GPs) are contacted for 30-day adverse events. Ethics and dissemination The study is approved by the LUMC's Medical Ethics Committee. Patients are asked for consent for contacting their GPs. The main results of this trial will be disseminated in one paper. Discussion The HART-c study evaluates the efficacy and feasibility of a prehospital triage method that combines prehospital patient assessment and direct consultation of a cardiologist who has access to live-monitored data, hospital data and real-time hospital admission capacity. We expect this triage method to substantially reduce unnecessary ED visits. Show less
Trinanes, J.; Dijke, P. ten; Groen, N.; Hanegraaf, M.; Porrini, E.; Rodriguez-Rodriguez, A.E.; ... ; Vries, A.P.J. de 2020
Active maintenance of beta-cell identity through fine-tuned regulation of key transcription factors ensures beta-cell function. Tacrolimus, a widely used immunosuppressant, accelerates onset of... Show moreActive maintenance of beta-cell identity through fine-tuned regulation of key transcription factors ensures beta-cell function. Tacrolimus, a widely used immunosuppressant, accelerates onset of diabetes after organ transplantation, but underlying molecular mechanisms are unclear. Here we show that tacrolimus induces loss of human beta-cell maturity and beta-cell failure through activation of the BMP/SMAD signaling pathway when administered under mild metabolic stress conditions. Tacrolimus-induced phosphorylated SMAD1/5 acts in synergy with metabolic stress-activated FOXO1 through formation of a complex. This interaction is associated with reduced expression of the key beta-cell transcription factor MAFA and abolished insulin secretion, both in vitro in primary human islets and in vivo in human islets transplanted into high-fat diet-fed mice. Pharmacological inhibition of BMP signaling protects human beta-cells from tacrolimus-induced beta-cell dysfunction in vitro. Furthermore, we confirm that BMP/SMAD signaling is activated in protocol pancreas allograft biopsies from recipients on tacrolimus. To conclude, we propose a novel mechanism underlying the diabetogenicity of tacrolimus in primary human beta-cells. This insight could lead to new treatment strategies for new-onset diabetes and may have implications for other forms of diabetes. Show less
Nano, R.; Kerr-Conte, J.A.; Scholz, H.; Engelse, M.; Karlsson, M.; Saudek, F.; ... ; Piemonti, L. 2020
Background. Europe is currently the most active region in the field of pancreatic islet transplantation, and many of the leading groups are actually achieving similar good outcomes. Further... Show moreBackground. Europe is currently the most active region in the field of pancreatic islet transplantation, and many of the leading groups are actually achieving similar good outcomes. Further collaborative advances in the field require the standardization of islet cell product isolation processes, and this work aimed to identify differences in the human pancreatic islet isolation processes within European countries.Methods. A web-based questionnaire about critical steps, including donor selection, pancreas processing, pancreas perfusion and digestion, islet counting and culture, islet quality evaluation, microbiological evaluation, and release criteria of the product, was completed by isolation facilities participating at the Ninth International European Pancreas and Islet Transplant Association (EPITA) Workshop on Islet-Beta Cell Replacement in Milan.Results. Eleven islet isolation facilities completed the questionnaire. The facilities reported 445 and 53 islet isolations per year over the last 3 years from deceased organ donors and pancreatectomized patients, respectively. This activity resulted in 120 and 40 infusions per year in allograft and autograft recipients, respectively. Differences among facilities emerged in donor selection (age, cold ischemia time, intensive care unit length, amylase concentration), pancreas procurement, isolation procedures (brand and concentration of collagenase, additive, maximum acceptable digestion time), quality evaluation, and release criteria for transplantation (glucose-stimulated insulin secretion tests, islet numbers, and purity). Moreover, even when a high concordance about the relevance of one parameter was evident, thresholds for the acceptance were different among facilities.Conclusions. The result highlighted the presence of a heterogeneity in the islet cell product process and product release criteria. Show less
Rutten, G.E.H.M.; Vugt, H. van; Koning, E. de 2020
Introduction The American Diabetes Association and the European Association for the Study of Diabetes advocate a person-centered approach to enhance patient engagement in self-care activities. To... Show moreIntroduction The American Diabetes Association and the European Association for the Study of Diabetes advocate a person-centered approach to enhance patient engagement in self-care activities. To that purpose, people with diabetes need adequate diabetes knowledge, motivation, skills and confidence. These prerequisites are captured by the concept 'patient activation'. The Dutch Diabetes Federation implemented a person-centered consultation model for the annual diabetes review. To assess its relationship with patient activation, we measured the change in patient activation, and in person and disease-related factors in people with type 2 diabetes after their second person-centered annual review.Research design and methods Observational study in 47 primary care practices and six outpatient hospital clinics. Follow-up: 1 year. From 2.617 people with diabetes and capable of completing questionnaires (no additional exclusion criteria) 1.487 (56.8%) participated, 1366 with type 2 diabetes. Main outcome: patient activation (13-item Patient Activation Measure, score 0-100). Before the first and after the second review, participants completed questionnaires. Medical data were retrieved from electronic records. We performed a repeated measure analysis using a linear mixed model in 1299 participants, who completed the first set of questionnaires.Results In 1299 participants (41.6% female, mean age 66 years, median diabetes duration 10 years, median glycated hemoglobin (HbA1c) 6.8%/51 mmol/mol), the mean baseline activation level was 58.9 (SD 11.7). Independent of actual diabetes care, activation levels increased 1.53 units (95% CI 0.67 to 2.39, p=0.001). Several diabetes perceptions improved significantly; diabetes distress level decreased significantly. Body mass index (-0.22, 95% CI -0.33 to -0.10, p<0.001) and low-density lipoprotein cholesterol (-2.71 mg/dL, 95% CI -4.64 to -0.77, p=0.004) decreased, HbA1c increased 0.08% (95% CI 0.03 to 0.12) (p=0.001).Conclusions Person-centered diabetes care was associated with a slightly higher patient activation level, improved diabetes perception and small improvements in clinical outcomes. Person-centered care may enhance patient engagement, but one should not expect substantial improvement in patient outcomes in the short term. Show less
Hadavi, E.; Leijten, J.; Engelse, M.; Koning, E. de; Jonkheijm, P.; Karperien, M.; Apeldoorn, A. van 2019
Intrahepatic islet transplantation is a promising therapy for treatment of type 1 diabetes. During islet isolation, collagenase is used to extract islets from the pancreas, leading to loss of... Show moreIntrahepatic islet transplantation is a promising therapy for treatment of type 1 diabetes. During islet isolation, collagenase is used to extract islets from the pancreas, leading to loss of important cell-matrix interactions. Loss of the native pancreatic microenvironment is associated with apoptosis of islet cells, early graft failure, and poor islet function. The islet extracellular matrix (ECM) is composed of a specific combination of collagen (Col), laminin (LN), and fibronectin (FN) molecules. Reintroducing these molecules has been shown to boost the function, viability, morphology, and proliferation of beta-cells. In this research, the effect of combinatorial ECM on islet function and survival was investigated. Specifically, thin-film microwell array scaffolds made from two distinct biomaterials were coated with FN, collagen type IV (Col4), LN111, LN332, or a combination thereof. We found that coatings containing a single type of ECM molecule, for example, FN or Col, can improve short-term islet function. However, these single proteins do not prevent loss of morphology and subsequent loss of islet function afterward. In contrast, combining Col4 with LN111 at a ratio of 8:2 not only improved short-term islet function but also preserved islet structure and islet function on a longer term. This effect was reproducibly shown on poly(ester-urethane) and poly(ethylene-glycol-terephthalate-poly(butylene-terephthalate) microwell islet delivery devices as well as tissue culture polystyrene. We concluded that biofunctionalization of inert biomaterials regardless of their molecular composition with a specific combination of islet ECM molecules can support and improve islet function over longer time periods. Our data suggested that creating a biomimetic islet niche by biofunctionalization of biomaterials can significantly improve the endocrine function of beta-cells. The creation of islet mimicking niches in islet delivery devices leads to an improvement of islet function by restoring part of the islet's ECM in these devices. Impact Statement This research deals with finding a proper bioengineering strategy to improve the outcome of islets transplantation for treatment of type 1 diabetes. It is focused on the mimicking of islet extracellular matrix niche in microwell islet delivery devices to improve their endocrine function. Show less
Staels, W.; Verdonck, Y.; Heremans, Y.; Leuckx, G.; Groef, S. de; Heirman, C.; ... ; Leu, N. de 2018
