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1.
Arch Orthop Trauma Surg ; 143(3): 1499-1504, 2023 Mar.
Article in English | MEDLINE | ID: mdl-35224664

ABSTRACT

INTRODUCTION: Only 6.4-17% of the load is transmitted through the fibula when weight-bearing. Plate fixation of distal fibular fractures using minifragments (≤ 2.8 mm) could lead to similar reduction with less implant removal (IR) rates, compared to small-fragment plates (3.5 mm). We hypothesized that the use of minifragment plates is at least similar in unscheduled secondary surgery. MATERIALS AND METHODS: In this retrospective cohort study, all patients with surgically treated distal fibular fractures between October 2015 and March 2021 were included. Patients treated with plate fixation using minifragments and patients treated with small-fragment plates were compared regarding the following outcomes: secondary dislocation, malreduction, implant malposition, nonunion, surgical site infections (SSI) and IR. RESULTS: Sixty-five patients (54.2%) received a minifragment implant (≤ 2.8 mm) and 55 patients (45.8%) received a small-fragment implant (3.5 mm). There were no patients needing secondary surgery in the minifragment group compared to 9 patients following fixation using small-fragment implants (3 with secondary dislocation, 5 with malreduction and 1 with malposition, p = 0.001). SSI rates were 3.1% for minifragment and 9.1% for small-fragment implants (p = 0.161). Implant removal was performed significantly less often following use of minifragment implants (17.8% and 53.2%, p < 0.001). CONCLUSIONS: In this cohort, minifragment plate fixation for distal fibular fractures is an adequate fixation method offering stable fixation with significant lower need for implant removal and comparable complications to small-fragment plates, although an adequately powered randomized controlled study is needed for implementation in a clinical setting. LEVEL OF EVIDENCE: Therapeutic, III.


Subject(s)
Ankle Fractures , Humans , Ankle Fractures/surgery , Fibula/surgery , Retrospective Studies , Fracture Fixation, Internal/methods , Surgical Wound Infection/etiology , Bone Plates , Treatment Outcome
2.
Leukemia ; 30(9): 1832-43, 2016 09.
Article in English | MEDLINE | ID: mdl-27174491

ABSTRACT

We identified mutations in the IL7Ra gene or in genes encoding the downstream signaling molecules JAK1, JAK3, STAT5B, N-RAS, K-RAS, NF1, AKT and PTEN in 49% of patients with pediatric T-cell acute lymphoblastic leukemia (T-ALL). Strikingly, these mutations (except RAS/NF1) were mutually exclusive, suggesting that they each cause the aberrant activation of a common downstream target. Expressing these mutant signaling molecules-but not their wild-type counterparts-rendered Ba/F3 cells independent of IL3 by activating the RAS-MEK-ERK and PI3K-AKT pathways. Interestingly, cells expressing either IL7Ra or JAK mutants are sensitive to JAK inhibitors, but respond less robustly to inhibitors of the downstream RAS-MEK-ERK and PI3K-AKT-mTOR pathways, indicating that inhibiting only one downstream pathway is not sufficient. Here, we show that inhibiting both the MEK and PI3K-AKT pathways synergistically prevents the proliferation of BaF3 cells expressing mutant IL7Ra, JAK and RAS. Furthermore, combined inhibition of MEK and PI3K/AKT was cytotoxic to samples obtained from 6 out of 11 primary T-ALL patients, including 1 patient who had no mutations in the IL7R signaling pathway. Taken together, these results suggest that the potent cytotoxic effects of inhibiting both MEK and PI3K/AKT should be investigated further as a therapeutic option using leukemia xenograft models.


Subject(s)
Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Phosphoinositide-3 Kinase Inhibitors , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Receptors, Interleukin-7/metabolism , Signal Transduction/drug effects , Animals , Cell Proliferation/drug effects , Humans , Mice , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Protein Kinase Inhibitors/pharmacology , Receptors, Interleukin-7/antagonists & inhibitors , Transfection , Tumor Cells, Cultured
3.
Ann Oncol ; 26(10): 2180-92, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26153498

ABSTRACT

BACKGROUND: Triple-negative breast cancers (TNBC) are considered the most aggressive type of breast cancer, for which no targeted therapy exists at the moment. These tumors are characterized by having a high degree of chromosome instability and often overexpress the spindle assembly checkpoint kinase TTK. To explore the potential of TTK inhibition as a targeted therapy in TNBC, we developed a highly potent and selective small molecule inhibitor of TTK, NTRC 0066-0. RESULTS AND CONCLUSIONS: The compound is characterized by long residence time on the target and inhibits the proliferation of a wide variety of human cancer cell lines with potency in the same range as marketed cytotoxic agents. In cell lines and in mice, NTRC 0066-0 inhibits the phosphorylation of a TTK substrate and induces chromosome missegregation. NTRC 0066-0 inhibits tumor growth in MDA-MB-231 xenografts as a single agent after oral application. To address the effect of the inhibitor in breast cancer, we used a well-defined mouse model that spontaneously develops breast tumors that share key morphologic and molecular features with human TNBC. Our studies show that combination of NTRC 0066-0 with a therapeutic dose of docetaxel resulted in doubling of mouse survival and extended tumor remission, without toxicity. Furthermore, we observed that treatment efficacy is only achieved upon co-administration of the two compounds, which suggests a synergistic in vivo effect. Therefore, we propose TTK inhibition as a novel therapeutic target for neoadjuvant therapy in TNBC.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Cycle Proteins/antagonists & inhibitors , Cell Proliferation/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Taxoids/pharmacology , Triple Negative Breast Neoplasms/drug therapy , Animals , Disease Models, Animal , Docetaxel , Drug Therapy, Combination , Female , Flow Cytometry , HeLa Cells , Humans , Immunoenzyme Techniques , Mice , Molecular Structure , Survival Rate , Triple Negative Breast Neoplasms/mortality , Triple Negative Breast Neoplasms/pathology , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
4.
J Thromb Haemost ; 1(9): 1945-54, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12941035

ABSTRACT

Rebound thrombin generation after successful thrombolysis might be related to (i) too short-term anticoagulant therapy and to (ii) the inability of heparin derivatives to inhibit clot-bound thrombin. To meet these shortcomings, a compound was synthesized, which consists of a pentasaccharide conjugated to a direct thrombin inhibitor. This compound (Org 42675) has a 10 times longer half-life compared with the original half-life of the direct thrombin inhibitor, while the thrombin inhibitory activity is maintained. An extra advantage of this product is the inhibitory activity on thrombin generation via antithrombin III (AT)-mediated factor (F)Xa inhibition. Org 42675 inhibited in vitro clot-bound thrombin with similar activity to the direct thrombin inhibitor argatroban. In experimental models in rats, Org 42675 showed on a molar base similar antithrombotic activity to unfractionated heparin, was more active than argatroban and was more active than fondaparinux sodium (AT-mediated FXa inhibitor) in arterial thrombosis. Finally, Org 42675 was far more active than the three reference compounds in an experimental thrombolysis model in rabbits. These properties of Org 42675, with its FXa and (clot-bound) thrombin inhibitory activity in combination with its long half-life, make this compound a powerful drug that is likely to be effective in the prevention of re-occlusion after successful thrombolysis in man.


Subject(s)
Factor Xa Inhibitors , Fibrinolytic Agents/pharmacokinetics , Thrombin/antagonists & inhibitors , Thrombolytic Therapy/methods , Animals , Antithrombin III/physiology , Arginine/analogs & derivatives , Blood Coagulation Tests , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Fibrinolytic Agents/pharmacology , Fibrinolytic Agents/therapeutic use , Fondaparinux , Half-Life , Hemorrhage/chemically induced , Heparin/pharmacology , Male , Molecular Structure , Oligosaccharides/pharmacokinetics , Oligosaccharides/pharmacology , Oligosaccharides/therapeutic use , Pipecolic Acids/pharmacology , Polysaccharides/pharmacology , Rabbits , Rats , Rats, Wistar , Sulfonamides , Thrombosis/drug therapy
5.
Org Lett ; 3(23): 3785-7, 2001 Nov 15.
Article in English | MEDLINE | ID: mdl-11700138

ABSTRACT

[reaction--see text] Ionic liquid 1-butyl-3-methylimidazoliumhexafluorophosphate ([bmim]PF(6)) is described as an effective medium for ring-closing metathesis (RCM) using Grubbs catalysts. When [bmim]PF(6) was used as solvent, the RCM showed high conversions and a broad substrate tolerance. [bmim]PF(6) and the ruthenium catalyst were recycled after extraction of the product in the organic phase for at least three cycles.

6.
Bioorg Med Chem ; 7(9): 1881-90, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10530936

ABSTRACT

The synthesis of three heparin analogues (i.e. compounds VI-VIII) having perphosphorylated thrombin binding domains (TBDs) is reported. These compounds were tested in vitro for their antithrombin III (ATIII)-mediated anti-Xa and antithrombin activities. Conjugates VI and VIII show a remarkable increase in antithrombin activity compared to the structurally related conjugates with persulfated TBDs (i.e. compounds IV and V), whereas compound VII displays a diminished activity.


Subject(s)
Antithrombins/chemical synthesis , Heparin/analogs & derivatives , Thrombin/metabolism , Antithrombins/chemistry , Antithrombins/metabolism , Binding Sites , Carbohydrate Conformation , Carbohydrate Sequence , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Sequence Data , Phosphorylation
7.
Bioorg Med Chem Lett ; 9(14): 2013-8, 1999 Jul 19.
Article in English | MEDLINE | ID: mdl-10450972

ABSTRACT

The synthesis of a novel antithrombotic consisting of a heparin pentasaccharide conjugated to the active site inhibitor N-(2-naphtalenesulfonyl)-glycyl-(D)-4-aminophenyl-alanyl-piperidin e (NAPAP) (i.e. compound I) is reported. This conjugate shows a unique pharmacological profile both in vitro and in vivo having direct anti-thrombin and ATIII-mediated anti-Xa activity. Furthermore, conjugate I has a prolonged in vivo half-life compared to NAPAP (1.5 h vs 9 min.).


Subject(s)
Antithrombins/chemical synthesis , Antithrombins/pharmacology , Dipeptides/chemistry , Oligosaccharides/chemical synthesis , Piperidines/chemistry , Animals , Carbohydrate Sequence , Drug Design , Factor Xa Inhibitors , Half-Life , Heparin/chemistry , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Sequence Data , Rats , Solubility , Thrombin/antagonists & inhibitors
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