mTOR-Inhibitoren mit reduziertem CNI: Stellenwert der Kombinationstherapie (Sponsor: Novartis Pharma GmbH, Nürnberg)

2019 ◽  
Vol 07 (01) ◽  
pp. 4-12
Keyword(s):  
Mtor Inhibitor ◽  
De Novo

AbstractCalcineurinantagonisten (CNI) sind die „Basis“ der heutigen Immunsuppression, sind aber – vor allem in höherer Dosis – auch mit Nebenwirkungen assoziiert. Die Kombination mit dem mTOR-Inhibitor Everolimus bietet die Möglichkeit, die CNI-Dosis zu reduzieren. Dieses Regime zeigt gegenüber Mycophenolat (MPA) mit CNI-Volldosis eine vergleichbare immunsuppressive Wirksamkeit, eine ähnliche oder verbesserte Nierenfunktion sowie ein geringeres Infektions- und Tumorrisiko. In der bisher größten De-novo-Studie nach Nierentransplantation (TRANSFORM) war Everolimus mit reduziertem CNI der Kombination aus MPA und CNI nicht unterlegen.

Posttransplant CMV infection and the role of immunosuppression (Sponsor: Novartis Pharma GmbH, Nürnberg)

2016 ◽  
Vol 04 (01) ◽  
pp. 4-10
Keyword(s):  
Lower Incidence ◽  
Paradigm Shift ◽  
Mtor Inhibitor ◽  
De Novo ◽  
Expert Panel ◽  
Risk Of Infection ◽  
Cmv Infection ◽  
Expert Meeting ◽  
Selection Of

AbstractImmunosuppression permits graft survival after transplantation and consequently a longer and better life. On the other hand, it increases the risk of infection, for instance with cytomegalovirus (CMV). However, the various available immunosuppressive therapies differ in this regard. One of the first clinical trials using de novo everolimus after kidney transplantation [1] already revealed a considerably lower incidence of CMV infection in the everolimus arms than in the mycophenolate mofetil (MMF) arm. This result was repeatedly confirmed in later studies [2–4]. Everolimus is now considered a substance with antiviral properties. This article is based on the expert meeting “Posttransplant CMV infection and the role of immunosuppression”. The expert panel called for a paradigm shift: In a CMV prevention strategy the targeted selection of the immunosuppressive therapy is also a key element. For patients with elevated risk of CMV, mTOR inhibitor-based immunosuppression is advantageous as it is associated with a significantly lower incidence of CMV events.

mTOR Inhibitors as a New Therapeutic Strategy in Treatment Resistant Epilepsy in Hemimegalencephaly: A Case Report

2018 ◽  
Vol 34 (3) ◽  
pp. 132-138 ◽  
Author(s):  
Qi Xu ◽  
Shimrit Uliel-Sibony ◽  
Christopher Dunham ◽  
Harvey Sarnat ◽  
Laura Flores-Sarnat ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Mtor Inhibitor ◽  
De Novo ◽  
Mtor Inhibitors ◽  
Mtor Pathway ◽  
Definitive Treatment ◽  
Malformations Of Cortical Development ◽  
Treatment Resistant ◽  
Seizure Reduction ◽  
Functional Hemispherectomy

Hemimegalencephaly is a hamartomatous malformation of one hemisphere. Functional hemispherectomy, the definitive treatment, is associated with significant morbidity and mortality in early infancy. Dysregulation of the mTOR pathway can result in malformations of cortical development, and mTOR inhibitors can effectively reduce seizures in tuberous sclerosis complex. We report a 6-day-old female with hemimegalencephaly and frequent seizures despite 9 antiseizure medications. At 3 months of age, while awaiting hemispherectomy, an mTOR inhibitor, rapamycin, was initiated by the neurologist. After 1 week of treatment, there was >50% reduction in seizures and total seizure burden, and after 2 weeks, development improved, resulting in deferral of surgery by 2.5 months with an increased body weight. Pathology demonstrated cortical dysplasia with upregulation of the mTOR pathway. Deep-sequencing of brain tissue demonstrated 16% mosaicism for a pathogenic de novo MTOR gene mutation. This case exemplifies how mTOR inhibitors could be considered for seizure reduction in patients with hemimegalencephaly while awaiting surgery.

scholarly journals Everolimus and Malignancy after Solid Organ Transplantation: A Clinical Update

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Hallvard Holdaas ◽  
Paolo De Simone ◽  
Andreas Zuckermann
Keyword(s):  
Organ Transplantation ◽  
Mtor Inhibitor ◽  
De Novo ◽  
Case Reports ◽  
Meta Analysis ◽  
Mammalian Target Of Rapamycin ◽  
Solid Organ Transplantation ◽  
Population Data ◽  
Solid Organ ◽  
Mtor Inhibition

Malignancy after solid organ transplantation remains a major cause of posttransplant mortality. The mammalian target of rapamycin (mTOR) inhibitor class of immunosuppressants exerts various antioncogenic effects, and the mTOR inhibitor everolimus is licensed for the treatment of several solid cancers. In kidney transplantation, evidence from registry studies indicates a lower rate ofde novomalignancy under mTOR inhibition, with some potentially supportive data from randomized trials of everolimus. Case reports and small single-center series have suggested that switch to everolimus may be beneficial following diagnosis of posttransplant malignancy, particularly for Kaposi’s sarcoma and nonmelanoma skin cancer, but prospective studies are lacking. A systematic review has shown mTOR inhibition to be associated with a significantly lower rate of hepatocellular carcinoma (HCC) recurrence versus standard calcineurin inhibitor therapy. One meta-analysis has concluded that patients with nontransplant HCC experience a low but significant survival benefit under everolimus monotherapy, so far unconfirmed in a transplant population. Data are limited in heart transplantation, although observational data and case reports have indicated that introduction of everolimus is helpful in reducing the recurrence of skin cancers. Overall, it can be concluded that, in certain settings, everolimus appears a promising option to lessen the toll of posttransplant malignancy.

The mTOR-inhibitor rapamycin mediates proteinuria in nephrotoxic serum nephritis by activating the innate immune response

2012 ◽  
Vol 303 (4) ◽  
pp. F569-F575 ◽  
Author(s):  
A. H. Kirsch ◽  
V. Riegelbauer ◽  
A. Tagwerker ◽  
M. Rudnicki ◽  
A. R. Rosenkranz ◽  
...  
Keyword(s):  
Protein Level ◽  
Mtor Inhibitor ◽  
De Novo ◽  
Mammalian Target Of Rapamycin ◽  
Innate Immune ◽  
Cell Phenotype ◽  
Monocyte Chemoattractant Protein 1 ◽  
Nephrotoxic Serum Nephritis ◽  
Inflammatory Protein ◽  
Factor Α

Rapamycin (Rapa) is an immunosuppressant used to prevent rejection in recipients of renal transplants. Its clinical use is limited by de novo onset or exacerbation of preexisting proteinuria. In the present study, Rapa administration was started 14 days after induction of murine nephrotoxic serum nephritis (NTS) to study glomerular effects of this mammalian target of rapamycin (mTOR) inhibitor. Glomeruli were laser-microdissected, and real-time PCR was performed to assess effects on glomerular cells and the expression of inflammatory cytokines. Immunohistochemical stainings were performed to confirm mRNA data on the protein level. Compared with nephritic control animals, Rapa-treated mice developed significantly increased albuminuria. This was accompanied by a more prominent glomerular infiltration by CD4+ T cells and macrophages. Glomerular mRNA expression profiling revealed increased levels of the proinflammatory cytokines interleukin-6 and tumor necrosis factor-α, and the chemokines monocyte chemoattractant protein-1 and macrophage inflammatory protein-1β and their cognate macrophage-associated receptors CCR2 and CCR5 in the Rapa-treated animals. Furthermore, there were elevated glomerular transcription levels of the regulatory T cell phenotype transcription factor Foxp3. No differences in the glomerular expression of the podocyte marker nephrin or the endothelial cell marker CD31 were observed on the mRNA or protein level. In conclusion, our data indicate that Rapa-induced proteinuria in NTS is a result of the activation of the innate immune system rather than a direct toxicity to podocytes or glomerular endothelial cells.

DE NOVO USE OF MTOR INHIBITOR EVEROLIMUS IN COMBINATION WITH MYCOPHANOLATE SODIUM IN PATIENTS UNDERGONE ORTHOTOPIC LIVER TRANSPLANTATION

2008 ◽  
Vol 86 (Supplement) ◽  
pp. 424
Author(s):  
E Antoniou ◽  
D Dimitroulis ◽  
D Mantas ◽  
M Flessas ◽  
K Labathariou ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Orthotopic Liver Transplantation ◽  
Mtor Inhibitor ◽  
De Novo

Combination HDACi and mTOR inhibitor therapy in poor-risk de novo and refractory elderly patients with AML.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e18012-e18012
Author(s):  
Vijay Krishna Sandilya ◽  
Vikas Ghai ◽  
Kamal Sharma ◽  
Kamal Kant Singh Abbi ◽  
Elliot E Epner
Keyword(s):  
Bone Marrow ◽  
Combination Therapy ◽  
Histone Deacetylase Inhibitors ◽  
Mtor Inhibitor ◽  
De Novo ◽  
Retrospective Chart Review ◽  
Persistent Disease ◽  
Poor Risk ◽  
Elderly Aml

e18012 Background: Valproic acid (VPA, 2-propylpentanoic acid) is a histone deacetylase inhibitors (HDACi), which has in vitro activity against Acute Myeloid Leukemia (AML) blasts. HDACi produce epigenetic modifications, and may have antineoplastic effects in AML by activating transcriptional silenced genes. The mammalian target of rapamycin (mTOR) pathways constitutive activation has been involved in the pathogenesis of various cancers, including AML. We present a series of two cases of poor risk de novo and refractory elderly AML patients treated with a combination of HDACi VPA and mTOR inhibitor sirolimus (S). Methods: This is a retrospective chart review garnered data on two patients with de novo AML and refractory AML who were treated with a combination therapy of VPA 500 mg three times a day with sirolimus 1 mg by mouth daily. Patients continued to receive treatment until disease progression. Results: Patient 1 achieved transfusion independence and a 6 month CR with ECOG PS 1 without hospitalizations. Repeat BM demonstrated no morphologic or immunophenotypic evidence of AML. Persistent disease was still detectable by FISH. Patient 2 was started on the regimen after persistent disease was detected by day 14 bone marrow, post standard 7 + 3 induction. Repeat bone marrow after 23 days of treatment with VPA and Sirolimus showed no immunophenotypic, morphological or cytogenetic evidence of AML. The patient remained in remission for 9 months on therapy with normal blood counts. Conclusions: We postulate that the use of VPA with sirolimus, is an active combination therapy for elderly, poor risk AML patients who may not otherwise tolerate intensive chemotherapy. The mechanism of action may involve activation of the mTORC2 pathway by HDAC1. Given our observations, further studies are warranted to better define the activity of this or similar combination therapies in elderly AML patients. [Table: see text]

The Morphology of the Rat Kidney Following Folic Acid Administration

1970 ◽  
Vol 28 ◽  
pp. 200-201
Author(s):  
Aline Byrnes ◽  
Elsa E. Ramos ◽  
Minoru Suzuki ◽  
E.D. Mayfield
Keyword(s):  
Folic Acid ◽  
De Novo ◽  
Specific Activity ◽  
Rat Kidney ◽  
Present Report ◽  
Intracellular Localization ◽  
Male Rats ◽  
Renal Hypertrophy ◽  
Electron Microscopic ◽  
Biochemical Alterations

Renal hypertrophy was induced in 100 g male rats by the injection of 250 mg folic acid (FA) dissolved in 0.3 M NaHCO3/kg body weight (i.v.). Preliminary studies of the biochemical alterations in ribonucleic acid (RNA) metabolism of the renal tissue have been reported recently (1). They are: RNA content and concentration, orotic acid-c14 incorporation into RNA and acid soluble nucleotide pool, intracellular localization of the newly synthesized RNA, and the specific activity of enzymes of the de novo pyrimidine biosynthesis pathway. The present report describes the light and electron microscopic observations in these animals. For light microscopy, kidney slices were fixed in formalin, embedded, sectioned, and stained with H & E and PAS.

Early ossicle growth in the regenerating disc of a brittle star

1994 ◽  
Vol 52 ◽  
pp. 364-365
Author(s):  
M. Shlepr ◽  
R. L. Turner
Keyword(s):  
Cell Membrane ◽  
Light Microscopy ◽  
De Novo ◽  
Current Model ◽  
Syncytium Formation ◽  
Brittle Star ◽  
Intracellular Location ◽  
Limited Volume ◽  
Tissue Calcification

Calcification in the echinoderms occurs within a limited-volume cavity enclosed by cytoplasmic extensions of the mineral depositing cells, the sclerocytes. The current model of this process maintains that the sheath formed from these cytoplasmic extensions is syncytial. Prior studies indicate that syncytium formation might be dependent on sclerocyte density and not required for calcification. This model further envisions that ossicles formed de novo nucleate and grow intracellularly until the ossicle effectively outgrows the vacuole. Continued ossicle growth occurs within the sheath but external to the cell membrane. The initial intracellular location has been confirmed only for elements of the echinoid tooth.The regenerating aboral disc integument of ophiophragmus filograneus was used to test the current echinoderm calcification model. This tissue is free of calcite fragments, thus avoiding questions of cellular engulfment, and ossicles are formed de novo. The tissue calcification pattern was followed by light microscopy in both living and fixed preparations.

Arabidopsis 4-COUMAROYL-COA LIGASE 8 contributes to the biosynthesis of the benzenoid ring of coenzyme Q in peroxisomes

2019 ◽  
Vol 476 (22) ◽  
pp. 3521-3532
Author(s):  
Eric Soubeyrand ◽  
Megan Kelly ◽  
Shea A. Keene ◽  
Ann C. Bernert ◽  
Scott Latimer ◽  
...  
Keyword(s):  
Oxidative Metabolism ◽  
Time Course ◽  
Reverse Genetics ◽  
De Novo ◽  
Coenzyme Q ◽  
Control Level ◽  
Wild Type ◽  
Fluorescent Reporters ◽  
Coa Ligase ◽  
Peroxisomal Targeting

Plants have evolved the ability to derive the benzenoid moiety of the respiratory cofactor and antioxidant, ubiquinone (coenzyme Q), either from the β-oxidative metabolism of p-coumarate or from the peroxidative cleavage of kaempferol. Here, isotopic feeding assays, gene co-expression analysis and reverse genetics identified Arabidopsis 4-COUMARATE-COA LIGASE 8 (4-CL8; At5g38120) as a contributor to the β-oxidation of p-coumarate for ubiquinone biosynthesis. The enzyme is part of the same clade (V) of acyl-activating enzymes than At4g19010, a p-coumarate CoA ligase known to play a central role in the conversion of p-coumarate into 4-hydroxybenzoate. A 4-cl8 T-DNA knockout displayed a 20% decrease in ubiquinone content compared with wild-type plants, while 4-CL8 overexpression boosted ubiquinone content up to 150% of the control level. Similarly, the isotopic enrichment of ubiquinone's ring was decreased by 28% in the 4-cl8 knockout as compared with wild-type controls when Phe-[Ring-13C6] was fed to the plants. This metabolic blockage could be bypassed via the exogenous supply of 4-hydroxybenzoate, the product of p-coumarate β-oxidation. Arabidopsis 4-CL8 displays a canonical peroxisomal targeting sequence type 1, and confocal microscopy experiments using fused fluorescent reporters demonstrated that this enzyme is imported into peroxisomes. Time course feeding assays using Phe-[Ring-13C6] in a series of Arabidopsis single and double knockouts blocked in the β-oxidative metabolism of p-coumarate (4-cl8; at4g19010; at4g19010 × 4-cl8), flavonol biosynthesis (flavanone-3-hydroxylase), or both (at4g19010 × flavanone-3-hydroxylase) indicated that continuous high light treatments (500 µE m−2 s−1; 24 h) markedly stimulated the de novo biosynthesis of ubiquinone independently of kaempferol catabolism.

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