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Maja Theresa Dieterlen

Bio: Maja Theresa Dieterlen is an academic researcher from Leipzig University. The author has contributed to research in topics: Transplantation & P70-S6 Kinase 1. The author has an hindex of 5, co-authored 8 publications receiving 241 citations.

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Journal ArticleDOI
TL;DR: It is concluded that considerable advances in the different fields of tacrolimus monitoring have been achieved during this last decade, and the Expert Committee concludes that Continued efforts should focus on the opportunities to implement in clinical routine the combination of new standardized PK approaches with PG, and valid biomarkers to further personalize tacolimus therapy and to improve long-term outcomes for treated patients.
Abstract: Ten years ago, a consensus report on the optimization of tacrolimus was published in this journal. In 2017, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicity (IATDMCT) decided to issue an updated consensus report considering the most relevant advances in tacrolimus pharmacokinetics (PK), pharmacogenetics (PG), pharmacodynamics, and immunologic biomarkers, with the aim to provide analytical and drug-exposure recommendations to assist TDM professionals and clinicians to individualize tacrolimus TDM and treatment. The consensus is based on in-depth literature searches regarding each topic that is addressed in this document. Thirty-seven international experts in the field of TDM of tacrolimus as well as its PG and biomarkers contributed to the drafting of sections most relevant for their expertise. Whenever applicable, the quality of evidence and the strength of recommendations were graded according to a published grading guide. After iterated editing, the final version of the complete document was approved by all authors. For each category of solid organ and stem cell transplantation, the current state of PK monitoring is discussed and the specific targets of tacrolimus trough concentrations (predose sample C0) are presented for subgroups of patients along with the grading of these recommendations. In addition, tacrolimus area under the concentration-time curve determination is proposed as the best TDM option early after transplantation, at the time of immunosuppression minimization, for special populations, and specific clinical situations. For indications other than transplantation, the potentially effective tacrolimus concentrations in systemic treatment are discussed without formal grading. The importance of consistency, calibration, proficiency testing, and the requirement for standardization and need for traceability and reference materials is highlighted. The status for alternative approaches for tacrolimus TDM is presented including dried blood spots, volumetric absorptive microsampling, and the development of intracellular measurements of tacrolimus. The association between CYP3A5 genotype and tacrolimus dose requirement is consistent (Grading A I). So far, pharmacodynamic and immunologic biomarkers have not entered routine monitoring, but determination of residual nuclear factor of activated T cells-regulated gene expression supports the identification of renal transplant recipients at risk of rejection, infections, and malignancy (B II). In addition, monitoring intracellular T-cell IFN-g production can help to identify kidney and liver transplant recipients at high risk of acute rejection (B II) and select good candidates for immunosuppression minimization (B II). Although cell-free DNA seems a promising biomarker of acute donor injury and to assess the minimally effective C0 of tacrolimus, multicenter prospective interventional studies are required to better evaluate its clinical utility in solid organ transplantation. Population PK models including CYP3A5 and CYP3A4 genotypes will be considered to guide initial tacrolimus dosing. Future studies should investigate the clinical benefit of time-to-event models to better evaluate biomarkers as predictive of personal response, the risk of rejection, and graft outcome. The Expert Committee concludes that considerable advances in the different fields of tacrolimus monitoring have been achieved during this last decade. Continued efforts should focus on the opportunities to implement in clinical routine the combination of new standardized PK approaches with PG, and valid biomarkers to further personalize tacrolimus therapy and to improve long-term outcomes for treated patients.

338 citations

Journal ArticleDOI
TL;DR: In this article, the status of personalized treatment with mycophenolic acid (MPA) is discussed, including the criteria for analytics, methods to estimate exposure including pharmacometrics, potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention.
Abstract: When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted.

78 citations

Journal ArticleDOI
TL;DR: It is found that SDF1 stimulates proliferation and induces migration of C2C12 cells with a potency similar to that of FGF2 and HGF, which both represent prototypical extracellular regulators of myogenesis.
Abstract: Mice deficient in the SDF1-chemokine-receptor CXCR4, exhibit severe defects of secondary limb myogenesis. To further elucidate the role of SDF1 in muscle development, we have now analyzed putative effects of this chemokine on proliferation, migration and myogenic differentiation of mouse C2C12 myogenic progenitor/myoblast cells. In addition, we have characterized the signaling pathways employed by SDF1-CXCR4 to control myogenesis. We found that SDF1 stimulates proliferation and induces migration of C2C12 cells with a potency similar to that of FGF2 and HGF, which both represent prototypical extracellular regulators of myogenesis. In addition, SDF1 inhibits myogenic differentiation in both C2C12 cells and primary myoblasts, as assessed by MyoD, myosin heavy chain and/or myogenin expression. Regarding signaling pathways, C2C12 cells responded to SDF1 with activation (phosphorylation) of Erk and PKCζ, whereas even after prolonged SDF1 treatment for up to 120 minutes, levels of activated Akt, p38 and PKCα or PKCβ remained unaffected. Preventing activation of the classic MAP kinase cascade with the Erk inhibitor UO126 abolished SDF1-induced proliferation and migration of C2C12 cells but not the inhibitory action of SDF1 on myogenic differentiation. Moreover, the effects of SDF1 on proliferation, migration and differentiation of C2C12 cells were all abrogated in the presence of myristoylated PKCζ peptide pseudosubstrate and/or upon cellular depletion of PKCζ by RNA interference. In conclusion, our findings unravel a previously unknown role of CXCR4-PKCζ signaling in myogenesis. The potent inhibitory effects of SDF1 on myogenic differentiation point to a major function of CXCR4-PKCζ signaling in the control of secondary muscle growth.

53 citations

Journal ArticleDOI
TL;DR: Outcomes from this large single-center cohort at increased surgical risk demonstrate excellent long-term durability of the Trifecta valve for SAVR and feasibility of treating SVD by V-in-V TAVI.

27 citations

Journal ArticleDOI
TL;DR: Clinical relevance of monitoring the activity of inosine-5′-monophosphate dehydrogenase (IMPDH), the target enzyme of mycophenolic acid, and of the phosphorylation of mechanistic target of rapamycin (mTOR) molecules is discussed.
Abstract: Therapeutic drug monitoring of immunosuppressants in the clinic is based on the measurement of blood concentration (pharmacokinetics). However, pharmacokinetic monitoring of immunosuppressants does not allow prediction of individual differences in pharmacological effects on immune cells. Pharmacodynamic (PD) monitoring via direct determination of target enzyme activity and phosphorylation of pathway molecules may enhance therapeutic drug monitoring and allow prediction of individual responses to immunosuppressants. This review discusses the clinical relevance of monitoring the activity of inosine-5'-monophosphate dehydrogenase (IMPDH), the target enzyme of mycophenolic acid, and of the phosphorylation of mechanistic target of rapamycin (mTOR) molecules. Significant progress regarding a robust and practicable assay for the determination of IMPDH activity as a specific PD parameter of mycophenolic acid activity has been achieved. The development of a rapid and reliable IMPDH assay system suitable for use in clinical practice was an important step that allowed thorough pharmacokinetics-PD investigations in large numbers of mycophenolic acid-treated patients. A reproducible and validated IMPDH assay was used in a few clinical trials by different research groups and is based on the chromatographic determination of newly generated xanthine monophosphate in mononuclear cell lysates. This assay requires only small volumes of blood and can be reliably used in multicenter trials; however, more clinical data from larger cohorts are needed to determine its clinical utility. Regarding monitoring of mTOR inhibitors (mTORis), the results of the first study that provided data on measurement of mTOR pathway molecules [p70 ribosomal protein S6 kinase (p70S6 kinase) and phosphorylated ribosomal protein S6] suggest that they are suitable targets for individualized PD monitoring of sirolimus and everolimus after organ transplantation. At present, only the phospho-flow phosphorylated ribosomal protein S6 assay has been validated in vitro and evaluated for confounding factors in vivo. The reported specific biomarkers for IMPDH activity and phosphorylation of mTOR molecules must be validated in clinical settings and multicenter studies to prove their clinical validity.

7 citations


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Journal ArticleDOI
TL;DR: An overview of myoblast fusion in three model systems that have contributed much to understanding of these events: the Drosophila embryo; developing and regenerating mouse muscle; and cultured rodent muscle cells is provided.
Abstract: The fusion of myoblasts into multinucleate syncytia plays a fundamental role in muscle function, as it supports the formation of extended sarcomeric arrays, or myofibrils, within a large volume of cytoplasm. Principles learned from the study of myoblast fusion not only enhance our understanding of myogenesis, but also contribute to our perspectives on membrane fusion and cell-cell fusion in a wide array of model organisms and experimental systems. Recent studies have advanced our views of the cell biological processes and crucial proteins that drive myoblast fusion. Here, we provide an overview of myoblast fusion in three model systems that have contributed much to our understanding of these events: the Drosophila embryo; developing and regenerating mouse muscle; and cultured rodent muscle cells.

455 citations

Journal ArticleDOI
TL;DR: Current knowledge regarding the role of oxidative stress and systems of enzymatic antioxidant defence in muscular regeneration after both acute injury and persistent muscular degeneration are presented.
Abstract: Reactive oxygen species (ROS) are generated in skeletal muscle both during the rest and contractile activity. Myogenic cells are equipped with antioxidant enzymes, like superoxide dismutase, catalase, glutathione peroxidase, γ-glutamylcysteine synthetase and heme oxygenase-1. These enzymes not only neutralise excessive ROS, but also affect myogenic regeneration at several stages: influence post-injury inflammatory reaction, enhance viability and proliferation of muscle satellite cells and myoblasts and affect their differentiation. Finally, antioxidant enzymes regulate also processes accompanying muscle regeneration—induce angiogenesis and reduce fibrosis. Elevated ROS production was also observed in Duchenne muscular dystrophy (DMD), a disease characterised by degeneration of muscle tissue and therefore—increased rate of myogenic regeneration. Antioxidant enzymes are consequently considered as target for therapies counteracting dystrophic symptoms. In this review we present current knowledge regarding the role of oxidative stress and systems of enzymatic antioxidant defence in muscular regeneration after both acute injury and persistent muscular degeneration.

196 citations

Journal ArticleDOI
TL;DR: One receptor–ligand pair, CXCR4–SDF-1α (CXCL12), regulated migration of both proliferating and terminally differentiated muscle cells, and was necessary for proper fusion of muscle cells.
Abstract: Adult regenerative myogenesis is vital for restoring normal tissue structure after muscle injury. Muscle regeneration is dependent on progenitor satellite cells, which proliferate in response to injury, and their progeny differentiate and undergo cell–cell fusion to form regenerating myofibers. Myogenic progenitor cells must be precisely regulated and positioned for proper cell fusion to occur. Chemokines are secreted proteins that share both leukocyte chemoattractant and cytokine-like behavior and affect the physiology of a number of cell types. We investigated the steady-state mRNA levels of 84 chemokines, chemokine receptors and signaling molecules, to obtain a comprehensive view of chemokine expression by muscle cells during myogenesis in vitro. A large number of chemokines and chemokine receptors were expressed by primary mouse muscle cells, especially during times of extensive cell–cell fusion. Furthermore, muscle cells exhibited different migratory behavior throughout myogenesis in vitro. One receptor–ligand pair, CXCR4–SDF-1α (CXCL12), regulated migration of both proliferating and terminally differentiated muscle cells, and was necessary for proper fusion of muscle cells. Given the large number of chemokines and chemokine receptors directly expressed by muscle cells, these proteins might have a greater role in myogenesis than previously appreciated.

127 citations

Journal ArticleDOI
TL;DR: The positive effect of both hypoxic and acidic PC on progenitor cell therapeutic potential is reviewed, while stressing the role of the SDF-1/CXCR4 axis in this process.
Abstract: We review the pivotal role of the stromal derived factor (SDF)-1 chemokine in tissue ischaemia and how it orchestrates the rapid revascularization of injured, ischaemic, and regenerating tissues via the CXC chemokine receptors CXCR4 and CXCR7. Furthermore, we discuss the effects of preconditioning (PC), which is a well-known protective phenomenon for tissue ischaemia. The positive effect of both hypoxic and acidic PC on progenitor cell therapeutic potential is reviewed, while stressing the role of the SDF-1/CXCR4 axis in this process.

121 citations

Journal ArticleDOI
01 Mar 2012-Glia
TL;DR: Evidence is provided that CXCR7 affects astrocytic cell signaling and function through pertussis toxin‐sensitive Gi/o proteins inAstrocytes, and the demonstration that SDF‐1‐bound CX CR7 activates Gi/O proteins in astroCytes could help to explain some discrepancies previously observed for the function of CxCR4 and CXcr7 in other cell types.
Abstract: SDF-1/CXCL12 binds to the chemokine receptors, CXCR4 and CXCR7, and controls cell proliferation and migration during development, tumorigenesis, and inflammatory processes. It is currently assumed that CXCR7 would represent an atypical or scavenger chemokine receptor which modulates the function of CXCR4. Contrasting this view, we demonstrated recently that CXCR7 actively mediates SDF-1 signaling in primary astrocytes. Here, we provide evidence that CXCR7 affects astrocytic cell signaling and function through pertussis toxin-sensitive G(i/o) proteins. SDF-1-dependent activation of G(i/o) proteins and subsequent increases in intracellular Ca(2+) concentration persisted in primary rodent astrocytes with depleted expression of CXCR4, but were abolished in astrocytes with depleted expression of CXCR7. Moreover, CXCR7-mediated effects of SDF-1 on Erk and Akt signaling as well as on astrocytic proliferation and migration were all sensitive to pertussis toxin. Likewise, pertussis toxin abolished SDF-1-induced activation of Erk and Akt in CXCR7-only expressing human glioma cell lines. Finally, consistent with a ligand-biased function of CXCR7 in astrocytes, the alternate CXCR7 ligand, I-TAC/CXCL11, activated Erk and Akt through β-arrestin. The demonstration that SDF-1-bound CXCR7 activates G(i/o) proteins in astrocytes could help to explain some discrepancies previously observed for the function of CXCR4 and CXCR7 in other cell types.

115 citations