المؤلفون: Anthony C Keech, Yoon Hi Cho, Ryan J. Farr, Emma S. Scott, David N O'Neal, Anandwardhan A. Hardikar, Paul Z. Benitez-Aguirre, Mugdha V. Joglekar, Andrzej S. Januszewski, Luke M. Carroll, Alicia J. Jenkins, Maria E. Craig, Yik Wen Loh, Wilson K. M. Wong, Kim C. Donaghue

المصدر: Scientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
Scientific Reports

مصطلحات موضوعية: Blood Glucose, Male, 0301 basic medicine, Diabetes duration, medicine.medical_treatment, Autoimmunity, 0302 clinical medicine, Insulin-Secreting Cells, Insulin Secretion, Medicine, Child, Aged, 80 and over, Multidisciplinary, C-Peptide, Age Factors, Middle Aged, Type 1 diabetes, Female, Adult, medicine.medical_specialty, Adolescent, Science, 030209 endocrinology & metabolism, Article, Young Adult, 03 medical and health sciences, Diabetes mellitus, Internal medicine, microRNA, Humans, Secretion, Circulating MicroRNA, Insulin secretion, Aged, Autoantibodies, Glycated Hemoglobin, business.industry, Insulin, medicine.disease, MicroRNAs, Diabetes Mellitus, Type 1, 030104 developmental biology, Endocrinology, Gene Expression Regulation, Genetic markers, Age of onset, business, Biomarkers

الوصف: The aim of this cross-sectional study was to compare plasma C-peptide presence and levels in people without diabetes (CON) and with Type 1 diabetes and relate C-peptide status to clinical factors. In a subset we evaluated 50 microRNAs (miRs) previously implicated in beta-cell death and associations with clinical status and C-peptide levels. Diabetes age of onset was stratified as adult (≥ 18 y.o) or childhood ( 20 years. Plasma C-peptide was measured by ultrasensitive ELISA. Plasma miRs were quantified using TaqMan probe-primer mix on an OpenArray platform. C-peptide was detectable in 55.3% of (n = 349) people with diabetes, including 64.1% of adults and 34.0% of youth with diabetes, p p p = 0.02, respectively]. In the childhood-onset group more people with longer diabetes duration (> 20 years) had detectable C-peptide (60%) than in those with shorter diabetes duration (39%, p for trend

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cbd5b712c5082c4c879f559920494d80Test
https://doaj.orgTest/article/b1ec56fdb12a4c0cb5cb32be78d2f006

المؤلفون: Martin Haupt-Jorgensen, Karsten Buschard, Flemming Pociot, Kristina Pedersen, Knut Dahl-Jørgensen, Ivan C. Gerling, Simranjeet Kaur, Lars Krogvold

المصدر: Diabetologia
Pedersen, K, Haupt-Jorgensen, M, Krogvold, L, Kaur, S, Gerling, I C, Pociot, F, Dahl-Jørgensen, K & Buschard, K 2021, ' Genetic predisposition in the 2′-5′A pathway in the development of type 1 diabetes : potential contribution to dysregulation of innate antiviral immunity ', Diabetologia, vol. 64, no. 8, pp. 1805-1815 . https://doi.org/10.1007/s00125-021-05469-5Test

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Ribonuclease L, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Disease, Type 2 diabetes, Biology, Interferon α, RNase L, Type 1 interferon, Antiviral Agents, Polymorphism, Single Nucleotide, Article, Virus, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Immune system, Internal Medicine, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, RNA, Messenger, Gene, Type 1 diabetes, Oligoribonucleotides, Adenine Nucleotides, RNA-Binding Proteins, medicine.disease, Immunity, Innate, Toll-like receptor 7, Diabetes Mellitus, Type 1, 030104 developmental biology, Gene Expression Regulation, Virus Diseases, Immunology, 2′-5′A pathway, 2′-5′ Oligoadenylate synthetase, Female, Genome-Wide Association Study

الوصف: Aims/hypothesis The incidence of type 1 diabetes is increasing more rapidly than can be explained by genetic drift. Viruses may play an important role in the disease, as they seem to activate the 2′-5′-linked oligoadenylate (2′-5′A) pathway of the innate antiviral immune system. Our aim was to investigate this possibility. Methods Innate antiviral immune pathways were searched for type 1 diabetes-associated polymorphisms using genome-wide association study data. SNPs within ±250kb flanking regions of the transcription start site of 64 genes were examined. These pathways were also investigated for type 1 diabetes-associated RNA expression profiles using laser-dissected islets from two to five tissue sections per donor from the Diabetes Virus Detection (DiViD) study and the network of Pancreatic Organ Donors (nPOD). Results We found 27 novel SNPs in genes nominally associated with type 1 diabetes. Three of those SNPs were located upstream of the 2′-5′A pathway, namely SNP rs4767000 (p = 1.03 × 10−9, OR 1.123), rs1034687 (p = 2.16 × 10−7, OR 0.869) and rs739744 (p = 1.03 × 10−9, OR 1.123). We also identified a large group of dysregulated islet genes in relation to type 1 diabetes, of which two were novel. The most aberrant genes were a group of IFN-stimulated genes. Of those, the following distinct pathways were targeted by the dysregulation (compared with the non-diabetic control group): OAS1 increased by 111% (p < 1.00 × 10−4, 95% CI −0.43, −0.15); MX1 increased by 142% (p < 1.00 × 10−4, 95% CI −0.52, −0.22); and ISG15 increased by 197% (p = 2.00 × 10−4, 95% CI −0.68, −0.18). Conclusions/interpretation We identified a genetic predisposition in the 2′-5′A pathway that potentially contributes to dysregulation of the innate antiviral immune system in type 1 diabetes. This study describes a potential role for the 2′-5′A pathway and other components of the innate antiviral immune system in beta cell autoimmunity. Graphical abstract

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bc7c11e2de9bab5e6655271157f4e1c3Test
https://doi.org/10.1007/s00125-021-05469-5Test

المؤلفون: Carmella Evans-Molina, Clive Wasserfall, Megan T Legge, Eleni Beli, Craig A. Beam, Ryan Silk, Kieran M. Mcgrail, Linda A. DiMeglio, Mark A. Atkinson, Stephanie Woerner, Maria B. Grant

المصدر: Diabetologia
Beam, C A, Beli, E, Wasserfall, C H, Woerner, S E, Legge, M T, Evans-Molina, C, McGrail, K M, Silk, R, Grant, M B, Atkinson, M A & DiMeglio, L A 2021, ' Peripheral immune circadian variation, synchronisation and possible dysrhythmia in established type 1 diabetes ', Diabetologia . https://doi.org/10.1007/s00125-021-05468-6Test

مصطلحات موضوعية: 0301 basic medicine, CD4-Positive T-Lymphocytes, Male, type 1 diabetes, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Circadian clock, CD8-Positive T-Lymphocytes, T-Lymphocytes, Regulatory, Mice, 0302 clinical medicine, Cytotoxic T cell, education.field_of_study, B-Lymphocytes, Immune cells, Flow Cytometry, Circadian Rhythm, Cytokine, Type 1 diabetes, Female, Adult, Adolescent, Period (gene), Population, Biology, Chronobiology Disorders, circadian ryhtms, Article, 03 medical and health sciences, Clinical, Young Adult, Immune system, SDG 3 - Good Health and Well-being, Circadian Clocks, Internal Medicine, medicine, Animals, Humans, Circadian rhythms, Circadian rhythm, Lymphocyte Count, education, Interleukin-6, Dendritic Cells, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Diabetes Mellitus, Type 1, Immune System, Immunology, 030217 neurology & neurosurgery

الوصف: Aims/hypothesis The circadian clock influences both diabetes and immunity. Our goal in this study was to characterise more thoroughly the circadian patterns of immune cell populations and cytokines that are particularly relevant to the immune pathology of type 1 diabetes and thus fill in a current gap in our understanding of this disease. Methods Ten individuals with established type 1 diabetes (mean disease duration 11 years, age 18–40 years, six female) participated in a circadian sampling protocol, each providing six blood samples over a 24 h period. Results Daily ranges of population frequencies were sometimes large and possibly clinically significant. Several immune populations, such as dendritic cells, CD4 and CD8 T cells and their effector memory subpopulations, CD4 regulatory T cells, B cells and cytokine IL-6, exhibited statistically significant circadian rhythmicity. In a comparison with historical healthy control individuals, but using shipped samples, we observed that participants with type 1 diabetes had statistically significant phase shifts occurring in the time of peak occurrence of B cells (+4.8 h), CD4 and CD8 T cells (~ +5 h) and their naive and effector memory subsets (~ +3.3 to +4.5 h), and regulatory T cells (+4.1 h). An independent streptozotocin murine experiment confirmed the phase shifting of CD8 T cells and suggests that circadian dysrhythmia in type 1 diabetes might be an effect and not a cause of the disease. Conclusions/interpretation Future efforts investigating this newly described aspect of type 1 diabetes in human participants are warranted. Peripheral immune populations should be measured near the same time of day in order to reduce circadian-related variation. Graphical abstract

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5304384a2a7eb86434e13bd1acc63ddbTest
http://europepmc.org/articles/PMC8245361Test

المؤلفون: Jacqueline V. Schiesser, Thomas Loudovaris, Helen E. Thomas, Edouard G. Stanley, Andrew G. Elefanty

المصدر: Scientific Reports, Vol 11, Iss 1, Pp 1-8 (2021)
Scientific Reports

مصطلحات موضوعية: 0301 basic medicine, Adult, Male, Cell type, medicine.medical_treatment, Science, Cell, Integrin, Gene Expression, Biology, Immunofluorescence, Article, 03 medical and health sciences, 0302 clinical medicine, Insulin-Secreting Cells, medicine, Humans, Insulin, Receptors, Vitronectin, Beta (finance), geography, Multidisciplinary, geography.geographical_feature_category, medicine.diagnostic_test, Cluster of differentiation, Middle Aged, Islet, Gene expression profiling, Cell biology, 030104 developmental biology, medicine.anatomical_structure, Type 1 diabetes, Diabetes Mellitus, Type 1, biology.protein, Medicine, Female, 030217 neurology & neurosurgery, Biomarkers

الوصف: The identification of cell surface markers specific to pancreatic beta cells is important for both the study of islet biology and for investigating the pathophysiology of diseases in which this cell type is lost or damaged. Following analysis of publicly available RNAseq data, we identified specific integrin subunits, integrin αv and integrin β5, that were expressed in beta cells. This finding was further elaborated using immunofluorescence analysis of histological sections derived from donor human pancreas. Despite the broad expression of specific integrin subunits, we found that expression of integrin αvβ5 heterodimers was restricted to beta cells and that this complex persisted in islet remnants of some type 1 diabetic individuals from which insulin expression had been lost. This study identifies αvβ5 heterodimers as a novel cell surface marker of human pancreatic beta cells, a finding that will aid in the identification and characterisation of this important cell type.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::932b8419e0cfd10e677c6085465d5e16Test
https://doaj.orgTest/article/dcab1ff3fe334cd4b5b2b617cf023918

المؤلفون: Nadir Kadri, Sarah J. Richardson, Lydia Sorokin, Eva Korpos, Sophie Loismann, Clais R. Findeisen, Noel G. Morgan, Alberto Pugliese, Frank Arfuso, George W. Burke, Marika Bogdani

المصدر: Diabetologia

مصطلحات موضوعية: 0301 basic medicine, Male, Pathology, Endocrinology, Diabetes and Metabolism, Autoimmunity, medicine.disease_cause, Mice, 0302 clinical medicine, Tertiary lymphoid organs, Mice, Inbred NOD, Child, NOD mice, Aged, 80 and over, Middle Aged, medicine.anatomical_structure, Type 1 diabetes, Fibroblastic reticular cells, Child, Preschool, Lymph node, Female, Beta cell, Adult, medicine.medical_specialty, Basement membrane, Adolescent, T cell, High endothelial venules, 030209 endocrinology & metabolism, Biology, Article, 03 medical and health sciences, Islets of Langerhans, Young Adult, Internal Medicine, medicine, Animals, Humans, Pancreas, B cell, Aged, Autoantibodies, Transplantation, medicine.disease, 030104 developmental biology, Diabetes Mellitus, Type 1, Tertiary Lymphoid Structures, Microscopy, Fluorescence, Reticular fibres, Insulitis

الوصف: Aims/hypothesis We and others previously reported the presence of tertiary lymphoid organs (TLOs) in the pancreas of NOD mice, where they play a role in the development of type 1 diabetes. Our aims here are to investigate whether TLOs are present in the pancreas of individuals with type 1 diabetes and to characterise their distinctive features, in comparison with TLOs present in NOD mouse pancreases, in order to interpret their functional significance. Methods Using immunofluorescence confocal microscopy, we examined the extracellular matrix (ECM) and cellular constituents of pancreatic TLOs from individuals with ongoing islet autoimmunity in three distinct clinical settings of type 1 diabetes: at risk of diabetes; at/after diagnosis; and in the transplanted pancreas with recurrent diabetes. Comparisons were made with TLOs from 14-week-old NOD mice, which contain islets exhibiting mild to heavy leucocyte infiltration. We determined the frequency of the TLOs in human type 1diabetes with insulitis and investigated the presence of TLOs in relation to age of onset, disease duration and disease severity. Results TLOs were identified in preclinical and clinical settings of human type 1 diabetes. The main characteristics of these TLOs, including the cellular and ECM composition of reticular fibres (RFs), the presence of high endothelial venules and immune cell subtypes detected, were similar to those observed for TLOs from NOD mouse pancreases. Among 21 donors with clinical type 1 diabetes who exhibited insulitis, 12 had TLOs and had developed disease at younger age compared with those lacking TLOs. Compartmentalised TLOs with distinct T cell and B cell zones were detected in donors with short disease duration. Overall, TLOs were mainly associated with insulin-containing islets and their frequency decreased with increasing severity of beta cell loss. Parallel studies in NOD mice further revealed some differences in so far as regulatory T cells were essentially absent from human pancreatic TLOs and CCL21 was not associated with RFs. Conclusions/interpretation We demonstrate a novel feature of pancreas pathology in type 1 diabetes. TLOs represent a potential site of autoreactive effector T cell generation in islet autoimmunity and our data from mouse and human tissues suggest that they disappear once the destructive process has run its course. Thus, TLOs may be important for type 1 diabetes progression. Graphical abstract

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f333af12269efbba20d5e0fefe7a11dfTest
http://europepmc.org/articles/PMC8187221Test

المؤلفون: Amelia K. Linnemann, Charanya Muralidharan, Abass M. Conteh, Pascal de Boer, Jeroen Kuipers, Michelle Marasco, Justin J. Crowder

المصدر: Diabetologia, 64(4), 865-877. SPRINGER
Diabetologia

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Autophagosome, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, Autophagy-Related Proteins, Nod, Article, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Mice, Inbred NOD, Insulin-Secreting Cells, Internal medicine, Diabetes mellitus, Macroautophagy, Internal Medicine, medicine, Autophagy, Animals, Humans, NOD mice, Proinsulin, Type 1 diabetes, business.industry, Autoantibody-positive, medicine.disease, Lysosome, Disease Models, Animal, Diabetes Mellitus, Type 1, 030104 developmental biology, Endocrinology, Crinophagy, Case-Control Studies, Female, Beta cell, Lysosomes, business, 030217 neurology & neurosurgery, Signal Transduction

الوصف: Aims/hypothesis Pancreatic beta cells are subjected to exogenous damaging factors such as proinflammatory cytokines or excess glucose that can cause accumulation of damage-inducing reactive oxygen species during the pathogenesis of diabetes. We and others have shown that beta cell autophagy can reduce reactive oxygen species to protect against apoptosis. While impaired islet autophagy has been demonstrated in human type 2 diabetes, it is unknown if islet autophagy is perturbed in the pathogenesis of type 1 diabetes. We hypothesised that beta cell autophagy is dysfunctional in type 1 diabetes, and that there is a progressive loss during early diabetes development. Methods Pancreases were collected from chloroquine-injected and non-injected non-obese diabetes-resistant (NOR) and non-obese diabetic (NOD) mice. Age- and BMI-matched pancreas tissue sections from human organ donors (N = 34) were obtained from the Network for Pancreatic Organ Donors with Diabetes (nPOD). Tissue sections were stained with antibodies against proinsulin or insulin (beta cell markers), microtubule-associated protein 1 light chain 3 A/B (LC3A/B; autophagosome marker), lysosomal-associated membrane protein 1 (LAMP1; lysosome marker) and p62 (autophagy adaptor). Images collected on a scanning laser confocal microscope were analysed with CellProfiler and ImageJ. Secondary lysosomes and telolysosomes were assessed in electron micrographs of human pancreatic tissue sections (n = 12), and energy dispersive x-ray analysis was performed to assess distribution of elements (n = 5). Results We observed increased autophagosome numbers in islets of diabetic NOD mice (p = 0.008) and increased p62 in islets of both non-diabetic and diabetic NOD mice (p p p p = 0.003) and non-diabetic NOD mice (p p p p p = 0.002). Conclusions/interpretation We provide evidence of islet macroautophagy/crinophagy impairment in human type 1 diabetes. We also document accumulation of telolysosomes with peripheral nitrogen in beta cells of autoantibody-positive donors, demonstrating altered lysosome content that may be associated with lysosome dysfunction before clinical hyperglycaemia. Similar macroautophagy impairments are present in the NOD mouse model of type 1 diabetes. Graphical abstract

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::aca8a2e71e6e61e43eb7bea2f3d7a3e4Test
https://doi.org/10.1007/s00125-021-05387-6Test

المؤلفون: Sari Niinistö, Carin Andrén Aronsson, Nicole Frank, Roy N. Tamura, Anette-G. Ziegler, Randi K. Johnson, Jill M. Norris, Jorma Toppari, Ulla Uusitalo, Suvi M. Virtanen, Marian Rewers, William Hagopian, Jeffrey P. Krischer, Jimin Yang, Beena Akolkar

المصدر: Diabetologia

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Glutens, Offspring, Pregnancy Trimester, Third, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, The Environmental Determinants of Diabetes in the Young, Autoimmunity, 030209 endocrinology & metabolism, medicine.disease_cause, Diet Surveys, Article, Food group, Eating, Islets of Langerhans, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Risk Factors, Environmental health, Internal Medicine, medicine, Humans, Autoantibodies, Type 1 diabetes, Proportional hazards model, business.industry, Insulin, Postpartum Period, Infant, Newborn, Maternal Nutritional Physiological Phenomena, medicine.disease, Diet, Breast Feeding, Diabetes Mellitus, Type 1, 030104 developmental biology, Female, business

الوصف: AIMS/HYPOTHESIS: We aimed to investigate the association between maternal consumption of gluten-containing foods and other selected foods during late pregnancy and offspring risk of islet autoimmunity (IA) and type 1 diabetes in The Environmental Determinants of Diabetes in the Young (TEDDY) study. METHODS: The TEDDY study recruited children at high genetic risk for type 1 diabetes at birth, and prospectively follows them for the development of IA and type 1 diabetes (n=8556). A questionnaire on the mother’s diet in late pregnancy was completed by 3-4 months postpartum. The maternal daily intake was estimated from a food frequency questionnaire for eight food groups: gluten-containing foods, non-gluten cereals, fresh milk, sour milk, cheese products, soy products, lean/medium-fat fish and fatty fish. For each food, we described the distribution of maternal intake among the four participating countries in the TEDDY study and tested the association of tertile of maternal food consumption with risk of IA and type 1 diabetes using forward selection time-to-event Cox regression. RESULTS: By 28 February 2019, 791 cases of IA and 328 cases of type 1 diabetes developed in TEDDY. There was no association between maternal late-pregnancy consumption of gluten-containing foods or any of the other selected foods and risk of IA, type 1 diabetes, insulin autoantibody-first IA or GAD autoantibody-first IA (all p≥0.01). Maternal gluten-containing food consumption in late pregnancy was higher in Sweden (242 g/day), Germany (247 g/day) and Finland (221 g/day) than in the USA (199 g/day) (pairwise p

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8ec25b379f034a9ba74d821ec80bb705Test
https://doi.org/10.1007/s00125-021-05446-yTest

المؤلفون: Shu-Fen Chiang, Tao-Wei Ke, William Tzu-Liang Chen, Kevin Chih-Yang Huang, Pei-Chen Yang, Tsung-Wei Chen, K. S. Clifford Chao

المصدر: Scientific Reports, Vol 10, Iss 1, Pp 1-13 (2020)
Scientific Reports

مصطلحات موضوعية: Male, 0301 basic medicine, Oncology, Colorectal cancer, T-Lymphocytes, medicine.medical_treatment, Perineural invasion, Apoptosis, CD8-Positive T-Lymphocytes, Ligands, Tumour biomarkers, 0302 clinical medicine, Tumor Microenvironment, Cancer, Aged, 80 and over, Univariate analysis, education.field_of_study, Multidisciplinary, Hazard ratio, Gastroenterology, Middle Aged, Prognosis, Colon cancer, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, Tumour immunology, Immunohistochemistry, Medicine, Female, Programmed cell death 1 ligand 2, Colorectal Neoplasms, Cancer microenvironment, Adult, medicine.medical_specialty, Science, Article, Disease-Free Survival, 03 medical and health sciences, Internal medicine, Biomarkers, Tumor, medicine, Humans, education, Aged, Proportional Hazards Models, Chemotherapy, business.industry, Carcinoma, Programmed Cell Death 1 Ligand 2 Protein, medicine.disease, 030104 developmental biology, business, Biomarkers, CD8

الوصف: Colorectal cancer (CRC) is the leading cause of cancer-related mortality worldwide. Although the role of tumor programmed cell death 1 ligand 1 (PD-L1) in suppressing antitumor immunity has been validated in various malignances, the impact of PD-L2 (PD-L2/PDCD1LG2) within tumors remains elusive. Here, we examined tumor PD-L2 expression by immunohistochemical analysis and assessed its association with clinicopathological characteristics and the infiltration of intratumoral T lymphocytes in colon carcinoma patients (n = 1264). We found that tumor PD-L2 status was correlated with perineural invasion (PNI) and associated with survival outcome in colon carcinoma patients. The level of tumor PD-L2 was positively associated with tumor PD-L1 expression but inversely associated with the density of CD8+ tumor-infiltrating lymphocytes (TILs). Patients with elevated tumor PD-L2 levels had a favorable 5-year overall survival (OS) compared to patients with low PD-L2 levels (57% vs 40%, p p p = 0.001]. Moreover, tumor PD-L2 expression was inversely associated with the lymphocytic reaction in advanced stage colon carcinoma, suggesting that PD-L2 may be upregulated by a compensatory mechanism to inhibit T cell-mediated anticancer immunity. Taken together, these results show that tumor PD-L2 expression may be an independent prognostic factor for survival outcome in patients with advanced stage colon carcinoma.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::31308a0fea618ea45ff2e9e298e8da92Test
https://doaj.orgTest/article/e8eb68cf4800457a80ce9ce67aa48863

المؤلفون: Diana Babaevskaya, Andrey Proshin, Igor Pomytkin, Margarita Oplatchikova, Tatyana Strekalova, Johannes P.J.M. de Munter, D. A. Pavlov, Allan V. Kalueff, Klaus-Peter Lesch, Ekaterina Lysikova, Anna Gorlova, Erik Ch. Wolters, Aleksei Umriukhin

المساهمون: Psychiatrie & Neuropsychologie, RS: MHeNs - R3 - Neuroscience

المصدر: Journal of Cellular and Molecular Medicine, 24(17), 10251-10257. Wiley-Blackwell
Journal of Cellular and Molecular Medicine
J. Cell. Mol. Med.

مصطلحات موضوعية: Male, Pathology, amyotrophic lateral sclerosis, PROTEIN EXPRESSION, EXPERIMENTAL NEUROINFLAMMATION, REAL TIME POLYMERASE CHAIN REACTION, MOUSE, ANIMAL EXPERIMENT, stem cell therapy, FUS[1‐359]‐tg mice, Mice, 0302 clinical medicine, SUCROSE PREFERENCE TEST, CELECOXIB, BRAIN, MUTATION, FUS[1-359]-tg mice, Neurons, RNA BINDING PROTEIN FUS, Behavior, Animal, celecoxib, LOCOMOTION, Neurodegeneration, TRANSGENIC MOUSE, Brain, DEPRESSION, Riluzole, Spinal Cord, 030220 oncology & carcinogenesis, RNA ISOLATION, CALCIUM BINDING PROTEIN, DRUG EFFECT, medicine.medical_specialty, Short Communication, Short Communications, FUS PROTEIN, MOUSE, IONIZED CALCIUM BINDING ADAPTOR MOLECULE 1, BEHAVIOR, ANIMAL, INTERLEUKIN-1BETA, NEUROINFLAMMATION, 03 medical and health sciences, TAIL SUSPENSION TEST, NONHUMAN, Social Behavior, ELEVATED PLUS MAZE TEST, INTERLEUKIN 1BETA, FRONTOTEMPORAL LOBAR DEGENERATION, Glycogen Synthase Kinase 3 beta, animal model, ANIMALS, ANIMAL, medicine.disease, FUS[1-359]-TG MICE, Molecular medicine, 030104 developmental biology, Mutation, HIPPOCAMPUS, emotionality and cognition, CYCLOOXYGENASE 1, HOME-CAGE ACTIVITY TEST, ABNORMAL BEHAVIOR, SPINAL CORD, GELATINASE B, CYCLOOXYGENASE 2, 0301 basic medicine, MATRIX METALLOPROTEINASES, NERVE CELL, Interleukin-1beta, Anti-Inflammatory Agents, Hippocampus, PREFRONTAL CORTEX, ANIMAL MODEL, UNCLASSIFIED DRUG, neuroinflammation, MARBLE BURYING TEST, ANXIETY, COGNITIVE DEFECT, TISSUE INHIBITOR OF METALLOPROTEINASE 1, PLASTICITY, Amyotrophic lateral sclerosis, NEURONS, MOLECULAR MARKER, Frontotemporal lobar degeneration, STEM CELL, riluzole, Muscle atrophy, GENOTYPE, ANTIINFLAMMATORY ACTIVITY, frontotemporal lobar degeneration, BIOLOGICAL MARKER, GLYCOGEN SYNTHASE KINASE 3BETA, Molecular Medicine, AMYOTROPHIC LATERAL SCLEROSIS, RNA-BINDING PROTEIN FUS, medicine.symptom, ANTIINFLAMMATORY AGENT, medicine.drug, STEM CELL THERAPY, GLYCOGEN SYNTHASE KINASE 3 BETA, CAGE TEST, METABOLISM, ADULT, INFLAMMATION, WESTERN BLOTTING, ANIMAL TISSUE, GENE MUTATION, OPEN FIELD TEST, EMOTION, medicine, Animals, RESIDENT-INTRUDER TEST, ARTICLE, NERVE DEGENERATION, Neuroinflammation, Inflammation, MALE, TUMOR NECROSIS FACTOR, INTRACEREBROVENTRICULAR DRUG ADMINISTRATION, business.industry, SOCIAL BEHAVIOR, ANTI-INFLAMMATORY AGENTS, Cell Biology, FRONTOTEMPORAL DEMENTIA, ANIMAL BEHAVIOR, EMOTIONALITY AND COGNITION, CONTROLLED STUDY, MICE, GLYCOGEN SYNTHASE KINASE 3ALPHA, Cyclooxygenase 2, RILUZOLE, COGNITION, RNA-Binding Protein FUS, business

الوصف: Genetic mutations in FUS, a DNA/RNA-binding protein, are associated with inherited forms of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). A novel transgenic FUS[1-359]-tg mouse line recapitulates core hallmarks of human ALS in the spinal cord, including neuroinflammation and neurodegeneration, ensuing muscle atrophy and paralysis, as well as brain pathomorphological signs of FTLD. However, a question whether FUS[1-359]-tg mouse displays behavioural and brain pro-inflammatory changes characteristic for the FTLD syndrome was not addressed. Here, we studied emotional, social and cognitive behaviours, brain markers of inflammation and plasticity of pre-symptomatic FUS[1-359]-tg male mice, a potential FTLD model. These animals displayed aberrant behaviours and altered brain expression of inflammatory markers and related pathways that are reminiscent to the FTLD-like syndrome. FTLD-related behavioural and molecular Journal of Cellular and Molecular Medicine features were studied in the pre-symptomatic FUS[1-359]-tg mice that received standard or new ALS treatments, which have been reported to counteract the ALS-like syndrome in the mutants. We used anti-ALS drug riluzole (8 mg/kg/d), or anti-inflammatory drug, a selective blocker of cyclooxygenase-2 (celecoxib, 30 mg/kg/d) for 3 weeks, or a single intracerebroventricular (i.c.v.) infusion of human stem cells (Neuro-Cells, 500 000-CD34+), which showed anti-inflammatory properties. Signs of elevated anxiety, depressive-like behaviour, cognitive deficits and abnormal social behaviour were less marked in FUS-tg–treated animals. Applied treatments have normalized protein expression of interleukin-1β (IL-1β) in the prefrontal cortex and the hippocampus, and of Iba-1 and GSK-3β in the hippocampus. Thus, the pre-symptomatic FUS[1-359]-tg mice demonstrate FTLD-like abnormalities that are attenuated by standard and new ALS treatments, including Neuro-Cell preparation. © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd We thank Thomas Ricker and Alexander Trofimov for their valuable technical contribution, RSF-18-15-00357 and Neuroplast-BV (Maastricht, Netherlands) for a supply of FUS[1-359]-tg mice and ?Neuro-Cells', respectively, RFBR-18-015-00450 for a help with in vitro work and ?5-100' Russian Excellence Program for a support.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e06827f1ecd2f754817e6fe6568533e8Test
https://cris.maastrichtuniversity.nl/en/publications/0162d1c6-abc0-4610-83d0-566d46a45289Test

المؤلفون: Munisha Smalley, Mohammad Kohandel, Michelle Przedborski, Saravanan Thiyagarajan, Aaron Goldman

المصدر: Communications Biology, Vol 4, Iss 1, Pp 1-15 (2021)
Communications Biology

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, QH301-705.5, Systems biology, medicine.medical_treatment, Programmed Cell Death 1 Receptor, Medicine (miscellaneous), Cancer immunotherapy, Computational biology, Patient response, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Machine learning, Triple combination, medicine, Humans, Biology (General), Immune Checkpoint Inhibitors, Aged, Response rate (survey), Artificial neural network, Systems Biology, Immunotherapy, Middle Aged, Blockade, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Neural Networks, Computer, General Agricultural and Biological Sciences, Transfer of learning

الوصف: Anti-PD-1 immunotherapy has recently shown tremendous success for the treatment of several aggressive cancers. However, variability and unpredictability in treatment outcome have been observed, and are thought to be driven by patient-specific biology and interactions of the patient’s immune system with the tumor. Here we develop an integrative systems biology and machine learning approach, built around clinical data, to predict patient response to anti-PD-1 immunotherapy and to improve the response rate. Using this approach, we determine biomarkers of patient response and identify potential mechanisms of drug resistance. We develop systems biology informed neural networks (SBINN) to calculate patient-specific kinetic parameter values and to predict clinical outcome. We show how transfer learning can be leveraged with simulated clinical data to significantly improve the response prediction accuracy of the SBINN. Further, we identify novel drug combinations and optimize the treatment protocol for triple combination therapy consisting of IL-6 inhibition, recombinant IL-12, and anti-PD-1 immunotherapy in order to maximize patient response. We also find unexpected differences in protein expression levels between response phenotypes which complement recent clinical findings. Our approach has the potential to aid in the development of targeted experiments for patient drug screening as well as identify novel therapeutic targets.
Michelle Przedborski et al. report an integrative systems biology and machine learning method for predicting cancer patient responses to immunotherapy treatment. Using their method, they identify several new drug combinations that could potentially improve treatment protocols for immunotherapy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::637586ed76a4096271521c754b48ecb7Test
https://doaj.orgTest/article/44e3f66755784e83bdb6e51e9bad3437