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1.
The role of lamin A/C in mesenchymal stem cell differentiation.
Zhang, B, Yang, Y, Keyimu, R, Hao, J, Zhao, Z, Ye, R
Journal of physiology and biochemistry. 2019;(1):11-18
Abstract
Lamin A/C is the major architectural protein of cell nucleus in charge of the nuclear mechanosensing. By integrating extracellular mechanical and biochemical signals, lamin A/C regulates multiple intracellular events including mesenchymal stem cell (MSC) fate determination. Herein, we review the recent findings about the effects and mechanisms of lamin A/C in governing MSC lineage commitment, with a special focus on osteogenesis and adipogenesis. Better understanding of MSC differentiation regulated by lamin A/C could provide insights into pathogenesis of age-related osteoporosis.
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2.
Acute Promyelocytic Leukemia and HIV: Case Reports and a Review of the Literature.
Kunitomi, A, Hasegawa, Y, Lmamura, J, Yokomaku, Y, Tokunaga, T, Miyata, Y, Iida, H, Nagai, H
Internal medicine (Tokyo, Japan). 2019;(16):2387-2391
Abstract
Acute promyelocytic leukemia (APL) in human immunodeficiency virus (HIV)-infected individuals is very rare. There is currently no consensus regarding the use of anti-cancer drugs with highly active anti-retroviral therapy (ART) in these patients due to their small number. We herein report two cases of APL with HIV-infected patients. Both cases received all-trans-retinoic acid-containing chemotherapies and achieved complete remission. ART was continued throughout the treatment course. The clinical course of these cases suggests that it is preferable to perform standard chemotherapy for APL with ART if patients have an adequate performance status.
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3.
Retinoic Acid and the Gut Microbiota in Alzheimer's Disease: Fighting Back-to-Back?
Endres, K
Current Alzheimer research. 2019;(5):405-417
Abstract
BACKGROUND There is growing evidence that the gut microbiota may play an important role in neurodegenerative diseases such as Alzheimer's disease. However, how these commensals influence disease risk and progression still has to be deciphered. OBJECTIVE The objective of this review was to summarize current knowledge on the interplay between gut microbiota and retinoic acid. The latter one represents one of the important micronutrients, which have been correlated to Alzheimer's disease and are used in initial therapeutic intervention studies. METHODS A selective overview of the literature is given with the focus on the function of retinoic acid in the healthy and diseased brain, its metabolism in the gut, and the potential influence that the bioactive ligand may have on microbiota, gut physiology and, Alzheimer's disease. RESULTS Retinoic acid can influence neuronal functionality by means of plasticity but also by neurogenesis and modulating proteostasis. Impaired retinoid-signaling, therefore, might contribute to the development of diseases in the brain. Despite its rather direct impact, retinoic acid also influences other organ systems such as gut by regulating the residing immune cells but also factors such as permeability or commensal microbiota. These in turn can also interfere with retinoid-metabolism and via the gutbrain- axis furthermore with Alzheimer's disease pathology within the brain. CONCLUSION Potentially, it is yet too early to conclude from the few reports on changed microbiota in Alzheimer's disease to a dysfunctional role in retinoid-signaling. However, there are several routes how microbial commensals might affect and might be affected by vitamin A and its derivatives.
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4.
[Acute Promyelocytic Leukemia: New treatment strategies with ATRA and ATO - AML-BFM-Recommendations].
Creutzig, U, Dworzak, M, von Neuhoff, N, Rasche, M, Reinhardt, D
Klinische Padiatrie. 2018;(6):299-304
Abstract
The treatment of acute promyelocytic leukemia (APL) has changed significantly in recent years. Today, APL patients with standard risk (also known as low risk) can be treated chemotherapy-free only with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). For high-risk patients, induction chemotherapy should be added. The curative results are good and comparable to those achieved in the past with chemotherapy plus ATRA. However, toxicities, especially infectious complications, are reduced. The main risk remains early lethal bleeding. Timely diagnosis and early ATRA treatment can reduce this risk. This review presents and discusses current treatment strategies and recommendations for APL in children.
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5.
[Acute promyelocytic leukemia: state-of-the-art management].
Asou, N
[Rinsho ketsueki] The Japanese journal of clinical hematology. 2018;(6):725-734
Abstract
Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML) -retinoic acid receptor (RAR) α fusion protein generated by the chromosomal translocation t (15;17) which affects both nuclear receptor signaling and PML nuclear body (NB) assembly. The advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) as molecular targeted therapies directed against PML-RARα has been a major breakthrough in APL treatment. ATRA and ATO target RARα and PML, respectively, and elicit PML-RARα degradation, leading to the reformation of normal NBs and cell differentiation. In several multicenter trials, more than 90% of newly diagnosed APL patients treated with ATRA and chemotherapy achieved complete remission, of whom 20%-30% subsequently relapsed; the overall survival was approximately 80% in these studies. However, several major clinical problems continue to account for treatment failure including early death due to hemorrhage, infection during consolidation, disease relapse, and secondary malignancies. These issues are associated mainly with anticancer agents used in combination with ATRA. Combination therapy using ATRA and ATO is the current standard therapy for untreated patients with APL in Western countries. The current problems in patients with APL treated with ATRA and ATO are APL differentiation syndrome and high risk of relapse in patients with an initial leukocyte count of more than 10×109/l.
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6.
[Research advances in the protective effect of all-trans retinoic acid against podocyte injury].
Chen, XP, Qin, YH
Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics. 2017;(6):719-723
Abstract
All-trans retinoic acid (ATRA) is a vitamin A derivative and plays an important role in the regulation of cell aggregation, differentiation, apoptosis, proliferation, and inflammatory response. In recent years, some progress has been made in the role of ATRA in renal diseases, especially its protective effect on podocytes. This article reviews the research advances in podocyte injury, characteristics of ATRA, podocyte differentiation and regeneration induced by ATRA, and the protective effect of ATRA against proliferation, deposition of fibers, and apoptosis.
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7.
Reprogramming acute myeloid leukemia into sensitivity for retinoic-acid-driven differentiation.
van Gils, N, Verhagen, HJMP, Smit, L
Experimental hematology. 2017;:12-23
Abstract
The success of all-trans retinoic acid (ATRA) therapy for acute promyelocytic leukemia (APL) provides a rationale for using retinoic acid (RA)-based therapy for other subtypes of acute myeloid leukemia (AML). Recently, several studies showed that ATRA may drive leukemic cells efficiently into differentiation and/or apoptosis in a subset of AML patients with an NPM1 mutation, a FLT3-ITD, an IDH1 mutation, and patients overexpressing EVI-1. Because not all patients within these molecular subgroups respond to ATRA and clinical trials that tested ATRA response in non-APL AML patients have had disappointing results, the identification of additional biomarkers may help to identify patients who strongly respond to ATRA-based therapy. Searching for response biomarkers might also reveal novel RA-based combination therapies with an efficient differentiation/apoptosis-inducing effect in non-APL AML patients. Preliminary studies suggest that the epigenetic or transcriptional state of leukemia cells determines their susceptibility to ATRA. We hypothesize that reprogramming by inhibitors of epigenetic-modifying enzymes or by modulation of microRNA expression might sensitize non-APL AML cells for RA-based therapy. AML relapse is caused by a subpopulation of leukemia cells, named leukemic stem cells (LSCs), which are in a different epigenetic state than the total bulk of the AML. The survival of LSCs after therapy is the main cause of the poor prognosis of AML patients, and novel differentiation therapies should drive these LSCs into maturity. In this review, we summarize the current knowledge on the epigenetic aspects of susceptibility to RA-induced differentiation in APL and non-APL AML.
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8.
Retinoic acid, CYP26, and drug resistance in the stem cell niche.
Alonso, S, Jones, RJ, Ghiaur, G
Experimental hematology. 2017;:17-25
Abstract
The bone marrow niche is essential for hematopoietic stem cells to maintain lifelong blood production by balancing their self-renewal and differentiation. Hematologic malignancies have a similar hierarchical organization to their normal counterparts, with rare populations of cancer stem cells that rely on the microenvironment to survive and propagate their differentiated malignant progenitor cells. Cancer cells alter their microenvironment to create a supportive niche, where they endure chemotherapy, survive as minimal residual disease (MRD), and eventually prevail at relapse. Powerful morphogens, such as retinoids, Wnt/βcatenin, Notch, and Hedgehog, control stem cell fates across tissues, including normal and malignant hematopoiesis. The molecular conversations between these pathways and the mechanisms that control their activity and create gradients at cellular scale remain a mystery. Here, we discuss accumulating evidence suggesting that cytochrome P450 (CYP26), the primary retinoid-inactivating enzyme, plays a critical role in the integration of two of these molecular programs: the retinoid and Hedgehog pathways. Induction of stromal CYP26 by either one of these pathways limits retinoic acid concentration in the stem cell niche, with profound effects on tissue homeostasis and drug resistance. Bypassing this gatekeeping mechanism holds promise for overcoming drug resistance and improving clinical outcomes in hematological malignancies and cancer in general.
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9.
Senescence in hepatic stellate cells as a mechanism of liver fibrosis reversal: a putative synergy between retinoic acid and PPAR-gamma signalings.
Panebianco, C, Oben, JA, Vinciguerra, M, Pazienza, V
Clinical and experimental medicine. 2017;(3):269-280
Abstract
Hepatic stellate cells (HSCs), also known as perisinusoidal cells, are pericytes found in the perisinusoidal space of the liver. HSCs are the major cell type involved in liver fibrosis, which is the formation of scar tissue in response to liver damage. When the liver is damaged, stellate cells can shift into an activated state, characterized by proliferation, contractility and chemotaxis. The activated HSCs secrete collagen scar tissue, which can lead to cirrhosis. Recent studies have shown that in vivo activation of HSCs by fibrogenic agents can eventually lead to senescence of these cells, which would contribute to reversal of fibrosis although it may also favor the insurgence of liver cancer. HSCs in their non-active form store huge amounts of retinoic acid derivatives in lipid droplets, which are progressively depleted upon cell activation in injured liver. Retinoic acid is a metabolite of vitamin A (retinol) that mediates the functions of vitamin A, generally required for growth and development. The precise function of retinoic acid and its alterations in HSCs has yet to be elucidated, and nonetheless in various cell types retinoic acid and its receptors (RAR and RXR) are known to act synergistically with peroxisome proliferator-activated receptor gamma (PPAR-gamma) signaling through the activity of transcriptional heterodimers. Here, we review the recent advancements in the understanding of how retinoic acid signaling modulates the fibrogenic potential of HSCs and proposes a synergistic combined action with PPAR-gamma in the reversal of liver fibrosis.
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10.
Retinoic Acid for High-risk Neuroblastoma Patients after Autologous Stem Cell Transplantation - Cochrane Review.
Peinemann, F, van Dalen, EC, Berthold, F
Klinische Padiatrie. 2016;(3):124-9
Abstract
BACKGROUND Neuroblastoma is a rare malignant disease and patients with high-risk neuroblastoma have a poor prognosis. Retinoic acid has been shown to inhibit growth of human neuroblastoma cells and has been considered as a potential candidate for improving the outcome. METHODS The objective was to evaluate effects of retinoic acid after consolidation with high-dose chemotherapy and bone marrow transplantation as compared to placebo or no further treatment in patients with high-risk neuroblastoma. We searched the databases CENTRAL, MEDLINE, and EMBASE from inception to 01 October 2014 and included randomized controlled trials. RESULTS We identified one relevant randomized controlled trial with 50 participants receiving retinoic acid and 48 participants receiving no further therapy. There was no statistically significant difference between the treatment groups in overall survival (hazard ratio 0.87, 95% confidence interval 0.46-1.63, P=0.66) and event-free survival (hazard ratio 0.86, 95% confidence interval 0.50-1.49, P=0.59). We did not identify results for other outcomes, including toxicity. CONCLUSION The difference in overall and event-free survival between treatment alternatives was not statistically significantly different. Based on the currently available evidence, we are uncertain about the effects of retinoic acid after bone marrow transplantation in patients with high-risk neuroblastoma.