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3. Metformin impacts the differentiation of mouse bone marrow cells into macrophages affecting tumour immunity

Author

Andrea Scafidi, Frida Lind-Holm Mogensen, Eleonora Campus, Alexandros Pailas, Katrin Neumann, Nathalie Legrave, François Bernardin, Sandro L. Pereira, Paul M.A. Antony, Nathalie Nicot, Michel Mittelbronn, Anne Grünewald, Petr V. Nazarov, Aurélie Poli, Eric Van Dyck, and Alessandro Michelucci

Subjects
Metformin, Macrophages, Phagocytosis, Anti-tumour, HIF1α, Glycolysis, Science (General), Q1-390, Social sciences (General), H1-99
Abstract

Background: Epidemiological studies suggest that metformin reduces the risk of developing several types of cancer, including gliomas, and improves the overall survival in cancer patients. Nevertheless, while the effect of metformin on cancer cells has been extensively studied, its impact on other components of the tumour microenvironment, such as macrophages, is less understood. Results: Metformin-treated mouse bone marrow cells differentiate into spindle-shaped macrophages exhibiting increased phagocytic activity and tumour cell cytotoxicity coupled with modulated expression of co-stimulatory molecules displaying reduced sensitivity to inflammatory cues compared with untreated cells. Transcriptional analyses of metformin-treated mouse bone marrow-derived macrophages show decreased expression levels of pro-tumour genes, including Tgfbi and Il1β, related to enhanced mTOR/HIF1α signalling and metabolic rewiring towards glycolysis. Significance: Our study provides novel insights into the immunomodulatory properties of metformin in macrophages and its potential application in preventing tumour onset and in cancer immunotherapy.

Published
2024
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10. Bowel function and associated risk factors at preschool and early childhood age in children with anorectal malformation type rectovestibular fistula: An ARM-Net consortium study

Author

van der Steeg, Hendrik J.J., van Rooij, Iris A.L.M., Iacobelli, Barbara D., Sloots, Cornelius E.J., Morandi, Anna, Broens, Paul M.A., Makedonsky, Igor, Leon, Francesco Fascetti, Schmiedeke, Eberhard, Vázquez, Araceli García, Miserez, Marc, Lisi, Gabriele, Midrio, Paola, Amerstorfer, Eva E., Fanjul, Maria, Ludwiczek, Johanna, Stenström, Pernilla, van der Steeg, Alida F.W., and de Blaauw, Ivo

Published
2022
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11. Anatomical evaluation of deep-learning synthetic computed tomography images generated from male pelvis cone-beam computed tomography

Author

Yvonne J.M. de Hond, Camiel E.M. Kerckhaert, Maureen A.J.M. van Eijnatten, Paul M.A. van Haaren, Coen W. Hurkmans, and Rob H.N. Tijssen

Subjects
Deep-Learning, Synthetic computed tomography, Cone-beam computed tomography, Average surface distance, Anatomical comparison, Volume difference, Medical physics. Medical radiology. Nuclear medicine, R895-920, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background and purpose: To improve cone-beam computed tomography (CBCT), deep-learning (DL)-models are being explored to generate synthetic CTs (sCT). The sCT evaluation is mainly focused on image quality and CT number accuracy. However, correct representation of daily anatomy of the CBCT is also important for sCTs in adaptive radiotherapy. The aim of this study was to emphasize the importance of anatomical correctness by quantitatively assessing sCT scans generated from CBCT scans using different paired and unpaired dl-models. Materials and methods: Planning CTs (pCT) and CBCTs of 56 prostate cancer patients were included to generate sCTs. Three different dl-models, Dual-UNet, Single-UNet and Cycle-consistent Generative Adversarial Network (CycleGAN), were evaluated on image quality and anatomical correctness. The image quality was assessed using image metrics, such as Mean Absolute Error (MAE). The anatomical correctness between sCT and CBCT was quantified using organs-at-risk volumes and average surface distances (ASD). Results: MAE was 24 Hounsfield Unit (HU) [range:19-30 HU] for Dual-UNet, 40 HU [range:34-56 HU] for Single-UNet and 41HU [range:37-46 HU] for CycleGAN. Bladder ASD was 4.5 mm [range:1.6–12.3 mm] for Dual-UNet, 0.7 mm [range:0.4–1.2 mm] for Single-UNet and 0.9 mm [range:0.4–1.1 mm] CycleGAN. Conclusions: Although Dual-UNet performed best in standard image quality measures, such as MAE, the contour based anatomical feature comparison with the CBCT showed that Dual-UNet performed worst on anatomical comparison. This emphasizes the importance of adding anatomy based evaluation of sCTs generated by dl-models. For applications in the pelvic area, direct anatomical comparison with the CBCT may provide a useful method to assess the clinical applicability of dl-based sCT generation methods.

Published
2023
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15. The European Anorectal Malformation Network (ARM-Net) patient registry:10-year review of clinical and surgical characteristics

Author

Hageman, Isabel C., Midrio, Paola, van der Steeg, Hendrik J.J., Jenetzky, Ekkehart, Iacobelli, Barbara D., Morandi, Anna, Sloots, Cornelius E.J., Schmiedeke, Eberhard, Broens, Paul M.A., Fascetti Leon, Francesco, Çavuşoğlu, Yusuf H., Gorter, Ramon R., Trajanovska, Misel, King, Sebastian K., Aminoff, Dalia, Schwarzer, Nicole, Haanen, Michel, de Blaauw, Ivo, van Rooij, Iris A.L.M., Hageman, Isabel C., Midrio, Paola, van der Steeg, Hendrik J.J., Jenetzky, Ekkehart, Iacobelli, Barbara D., Morandi, Anna, Sloots, Cornelius E.J., Schmiedeke, Eberhard, Broens, Paul M.A., Fascetti Leon, Francesco, Çavuşoğlu, Yusuf H., Gorter, Ramon R., Trajanovska, Misel, King, Sebastian K., Aminoff, Dalia, Schwarzer, Nicole, Haanen, Michel, de Blaauw, Ivo, and van Rooij, Iris A.L.M.

Published
2024

19. The Parkinson’s-disease-associated mutation LRRK2-G2019S alters dopaminergic differentiation dynamics via NR2F1

Author

Jonas Walter, Silvia Bolognin, Suresh K. Poovathingal, Stefano Magni, Deborah Gérard, Paul M.A. Antony, Sarah L. Nickels, Luis Salamanca, Emanuel Berger, Lisa M. Smits, Kamil Grzyb, Rita Perfeito, Fredrik Hoel, Xiaobing Qing, Jochen Ohnmacht, Michele Bertacchi, Javier Jarazo, Tomasz Ignac, Anna S. Monzel, Laura Gonzalez-Cano, Rejko Krüger, Thomas Sauter, Michèle Studer, Luis Pereira de Almeida, Karl J. Tronstad, Lasse Sinkkonen, Alexander Skupin, and Jens C. Schwamborn

Subjects
LRRK2, Parkinson's disease, NR2F1, dopaminergic neurons, Biology (General), QH301-705.5
Abstract

Summary: Increasing evidence suggests that neurodevelopmental alterations might contribute to increase the susceptibility to develop neurodegenerative diseases. We investigate the occurrence of developmental abnormalities in dopaminergic neurons in a model of Parkinson’s disease (PD). We monitor the differentiation of human patient-specific neuroepithelial stem cells (NESCs) into dopaminergic neurons. Using high-throughput image analyses and single-cell RNA sequencing, we observe that the PD-associated LRRK2-G2019S mutation alters the initial phase of neuronal differentiation by accelerating cell-cycle exit with a concomitant increase in cell death. We identify the NESC-specific core regulatory circuit and a molecular mechanism underlying the observed phenotypes. The expression of NR2F1, a key transcription factor involved in neurogenesis, decreases in LRRK2-G2019S NESCs, neurons, and midbrain organoids compared to controls. We also observe accelerated dopaminergic differentiation in vivo in NR2F1-deficient mouse embryos. This suggests a pathogenic mechanism involving the LRRK2-G2019S mutation, where the dynamics of dopaminergic differentiation are modified via NR2F1.

Published
2021
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20. Impaired serine metabolism complements LRRK2-G2019S pathogenicity in PD patients

Author

Nickels, Sarah Louise, Walter, Jonas, Bolognin, Silvia, Gérard, Deborah, Jaeger, Christian, Qing, Xiaobing, Tisserand, Johan, Jarazo, Javier, Hemmer, Kathrin, Harms, Amy, Halder, Rashi, Lucarelli, Philippe, Berger, Emanuel, Antony, Paul M.A., Glaab, Enrico, Hankemeier, Thomas, Klein, Christine, Sauter, Thomas, Sinkkonen, Lasse, and Schwamborn, Jens Christian

Published
2019
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23. Neural Stem Cells of Parkinson's Disease Patients Exhibit Aberrant Mitochondrial Morphology and Functionality

Author

Jonas Walter, Silvia Bolognin, Paul M.A. Antony, Sarah L. Nickels, Suresh K. Poovathingal, Luis Salamanca, Stefano Magni, Rita Perfeito, Fredrik Hoel, Xiaobing Qing, Javier Jarazo, Jonathan Arias-Fuenzalida, Tomasz Ignac, Anna S. Monzel, Laura Gonzalez-Cano, Luis Pereira de Almeida, Alexander Skupin, Karl J. Tronstad, and Jens C. Schwamborn

Subjects
Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

Summary: Emerging evidence suggests that Parkinson's disease (PD), besides being an age-associated disorder, might also have a neurodevelopment component. Disruption of mitochondrial homeostasis has been highlighted as a crucial cofactor in its etiology. Here, we show that PD patient-specific human neuroepithelial stem cells (NESCs), carrying the LRRK2-G2019S mutation, recapitulate key mitochondrial defects previously described only in differentiated dopaminergic neurons. By combining high-content imaging approaches, 3D image analysis, and functional mitochondrial readouts we show that LRRK2-G2019S mutation causes aberrations in mitochondrial morphology and functionality compared with isogenic controls. LRRK2-G2019S NESCs display an increased number of mitochondria compared with isogenic control lines. However, these mitochondria are more fragmented and exhibit decreased membrane potential. Functional alterations in LRRK2-G2019S cultures are also accompanied by a reduced mitophagic clearance via lysosomes. These findings support the hypothesis that preceding mitochondrial developmental defects contribute to the manifestation of the PD pathology later in life. : Walter, Bolognin and colleagues show the detection of mitochondrial phenotypes in NESCs derived from Parkinson's disease (PD) patients carrying the LRRK2-G2019S mutation. This supports the use of stem cells as a relevant model to study PD-associated mitochondrial defects associated to PD. Keywords: Parkinson's disease, LRRK2, neurodevelopment, stem cells, mitochondria, autophagy, mitophagy

Published
2019
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24. Psychological Warfare

Author

Linebarger, Paul M.A.

Subjects
Psychological Warfare (Nonfiction work), Literature/writing
Abstract

LibriVox recording of Psychological Warfare by Paul M. A. Linebarger. Read in English by volunteer readers. Psychological warfare and propaganda have been used extensively in warfare since the earliest times.... [...]

Published
2021

25. Long-term Bowel Dysfunction and Decline in Quality of Life Following Surgery for Colon Cancer

Author

Sanne J. Verkuijl, Edgar J.B. Furnée, Wendy Kelder, Christiaan Hoff, Daniel A. Hess, Fennie Wit, Ronald J. Zijlstra, Monika Trzpis, and Paul M.A. Broens

Subjects
Cross-Sectional Studies, Colonic Neoplasms, Gastroenterology, Quality of Life, Humans, General Medicine, Constipation, Early Detection of Cancer, Fecal Incontinence, Retrospective Studies
Abstract

Differences in long-term outcomes regarding types of colon resections are inconclusive, precluding patient counseling, effective screening, and personalized treatment.This study aimed to compare long-term bowel function and quality of life in patients who underwent right or left hemicolectomy or sigmoid colon resection.This was a multicenter cross-sectional study.Seven Dutch hospitals participated in this study.This study included patients who underwent right or left hemicolectomy or sigmoid colon resection without construction of a permanent stoma between 2009 and 2015. Patients who were deceased, mentally impaired, or living abroad were excluded. Eligible patients were sent the validated Defecation and Fecal Continence and Short-Form 36 questionnaires.Constipation, fecal incontinence (both Rome IV criteria), separate bowel symptoms, and generic quality of life were the main outcomes assessed.This study included 673 patients who underwent right hemicolectomy, 167 who underwent left hemicolectomy, and 284 who underwent sigmoid colon resection. The median follow-up was 56 months. Sigmoid colon resection increased the likelihood of constipation compared to right and left hemicolectomy (OR, 2.92; 95% CI, 1.80-4.75; p0.001 and OR, 1.93; 95% CI, 1.12-3.35; p = 0.019). Liquid incontinence and fecal urgency increased after right hemicolectomy compared to sigmoid colon resection (OR, 2.15; 95% CI, 1.47-3.16; p0.001 and OR, 2.01; 95% CI, 1.47-2.74; p0.001). Scores on quality-of-life domains were found to be significantly lower after right hemicolectomy.Because of the cross-sectional design, longitudinal data are still lacking.Different long-term bowel function problems occur after right or left hemicolectomy or sigmoid colon resection. The latter seems to be associated with more constipation than right or left hemicolectomy. Liquid incontinence and fecal urgency seem to be associated with right hemicolectomy, which may explain the decline in physical and mental generic quality of life of these patients. See Video Abstract at http://links.lww.com/DCR/C13 .ANTECEDENTES:Las diferencias en los resultados a largo plazo con respecto a los tipos de resecciones de colon no son concluyentes, lo que impide el asesoramiento preoperatorio del paciente y la detección eficaz y el tratamiento personalizado de la disfunción intestinal postoperatoria durante el seguimiento.OBJETIVO:Comparar la función intestinal a largo plazo y la calidad de vida en pacientes sometidos a hemicolectomía derecha o izquierda, o resección de colon sigmoide.DISEÑO:Estudio transversal multicéntrico.AJUSTES:Participaron siete hospitales holandeses.PACIENTES:Se incluyeron pacientes sometidos a hemicolectomía derecha o izquierda, o resección de colon sigmoide sin construcción de estoma permanente entre 2009 y 2015. Se excluyeron pacientes fallecidos, con discapacidad mental o residentes en el extranjero. A los pacientes elegibles se les enviaron los cuestionarios validados de Defecación y Continencia Fecal y Short-Form 36.PRINCIPALES MEDIDAS DE RESULTADO:Se evaluaron el estreñimiento, la incontinencia fecal (ambos criterios de Roma IV), los síntomas intestinales separados y la calidad de vida genérica.RESULTADOS:Se incluyeron 673 pacientes con hemicolectomía derecha, 167 con hemicolectomía izquierda y 284 con resección de colon sigmoide. La mediana de seguimiento fue de 56 meses (RIC 41-80). La resección del colon sigmoide aumentó la probabilidad de estreñimiento en comparación con la hemicolectomía derecha e izquierda (OR, 2,92, IC 95%, 1,80-4,75, p0,001 y OR 1,93, IC 95%, 1,12-3,35, p = 0,019). La incontinencia de líquidos y la urgencia fecal aumentaron después de la hemicolectomía derecha en comparación con la resección del colon sigmoide (OR, 2,15, IC 95%, 1,47-3,16, p0,001 y OR 2,01, IC 95%, 1,47-2,74, p0,001). Las puntuaciones en los dominios de calidad de vida fueron significativamente más bajas después de la hemicolectomía derecha.LIMITACIONES:Debido al diseño transversal, aún faltan datos longitudinales.CONCLUSIONES:Se producen diferentes problemas de función intestinal a largo plazo después de la hemicolectomía derecha o izquierda, o la resección del colon sigmoide. Este último parece estar asociado con más estreñimiento que la hemicolectomía derecha o izquierda. La incontinencia de líquidos y la urgencia fecal parecen estar asociadas a la hemicolectomía derecha, lo que puede explicar el deterioro de la calidad de vida física y mental en general de estos pacientes. Consulte Video Resumen en http://links.lww.com/DCR/C13 . (Traducción-Dr. Yolanda Colorado ).

Published
2022

43. 35 Longen

Author

Paul, M.A., Gooszen, H.G., editor, Blankensteijn, J.D., editor, Borel Rinkes, I.H.M., editor, Dejong, C.H.C., editor, Gouma, D.J., editor, Heineman, E., editor, Lange, J.F., editor, and Schipper, I.B., editor

Published
2012
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44. 34 Mediastinum

Author

Paul, M.A., Gooszen, H.G., editor, Blankensteijn, J.D., editor, Borel Rinkes, I.H.M., editor, Dejong, C.H.C., editor, Gouma, D.J., editor, Heineman, E., editor, Lange, J.F., editor, and Schipper, I.B., editor

Published
2012
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46. Low frequency of defecation and hard stool are not reliable indicators of constipation in Chinese population

Author

Ge Sun, Monika Trzpis, Haibo Ding, Xianhua Gao, Paul M.A. Broens, and Wei Zhang

Abstract

Background: This study investigated the prevalence, characteristic symptoms and risk factors of constipation in the Chinese population. Methods: Data of 3450 respondents from the general Chinese population who completed the digital Groningen Defecation and Fecal Continence (DeFeC) questionnaire were analyzed. The non-comorbidity subgroup was defined as respondents without organic comorbidities known to influence defecation. Constipation and dyssynergic defecation prevalence and severity were evaluated using Rome IV criteria and the Renzi score (Obstruction Defecation Syndrome Score), respectively. A logistic regression analysis was used to identify factors contributing to constipation. Results: The prevalence of constipation was 20.4% in the total group and 18.7% in the non-comorbidity subgroup (n = 3145). Among the constipated non-comorbidity subgroup respondents, the median and interquartile range of Renzi score was 6 (5–8). The following symptoms related to dyssynergic defecation had the highest prevalence: straining during defecation, 86.4%; incomplete defecation, 75.1%; feeling of blockage, 63.4%; and anal pain, 46%. Women were more prone to constipation than men (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.53–2.28). Additionally, obese respondents (OR, 1.36; 95% CI,1–1.87), those who ate spicy food four to five times per week (OR, 5.33; 95% CI, 3.61–7.89), and those living in a metropolitan city (OR, 1.34; 95% CI, 1.08–1.68) were more prone to constipation. Conclusion: The Chinese population has a high prevalence of constipation. A significant proportion of constipated respondents reported symptoms typical for dyssynergic defecation. The low defecation frequency and hard stool seem not to be reliable indicators of constipation.

Published
2022

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