ABSTRACT
The altered metabolism of cancer cells is a treasure trove to discover new antitumoral strategies. The gene (SLC7A5) encoding system L amino-acid transporter 1 (LAT1) is overexpressed in murine lymphoma cells generated via T-cell deletion of the pten tumor suppressor, and also in human T-cell acute lymphoblastic leukemia (T-ALL)/lymphoma (T-LL) cells. We show here that a potent and LAT1 selective inhibitor (JPH203) decreased leukemic cell viability and proliferation, and induced transient autophagy followed by apoptosis. JPH203 could also alter the in vivo growth of luciferase-expressing-tPTEN-/- cells xenografted into nude mice. In contrast, JPH203 was nontoxic to normal murine thymocytes and human peripheral blood lymphocytes. JPH203 interfered with constitutive activation of mTORC1 and Akt, decreased expression of c-myc and triggered an unfolded protein response mediated by the C/EBP homologous protein (CHOP) transcription factor associated with cell death. A JPH203-resistant tPTEN-/-clone appeared CHOP induction deficient. We also demonstrate that targeting LAT1 may be an efficient broad spectrum adjuvant approach to treat deadly T-cell malignancies as the molecule synergized with rapamycin, dexamethasone, doxorubicin, velcade and l-asparaginase to alter leukemic cell viability.
Subject(s)
Breast Neoplasms/drug therapy , Animals , Apoptosis , Blotting, Western , Breast Neoplasms/enzymology , Breast Neoplasms/pathology , Cell Adhesion , Cell Cycle , Cell Movement , Cell Proliferation , Female , Flow Cytometry , Fluorescent Antibody Technique , Humans , Immunoenzyme Techniques , Mice , Mice, Inbred BALB C , Mice, Nude , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
UNLABELLED: The study of hemostasis often arises in paediatrics. Evidence of activated partial thromboplastin time (aPTT) prolongation sometime due to the presence of a circulating anticoagulant (antiphospholipid syndrome [APS]) may be embarrassing for the physician. AIM OF THE STUDY: To evaluate the prevalence of this situation, to identify the leading indicators and assess their impact. PATIENTS AND METHOD: All children aged 1 to 18 years old undergoing blood sample whatever was the reason, at the Nice University Hospital with existing isolated aPTT prolongation, were included. The assessment was completed by a mixing test, calculation of Rosner's index as well as the study of an APS and the measurement of factor VIII, IX, XI, XII. RESULTS: Between July 2006 and March 2008, 27 of 1845 children observed (1.5%) were selected for further study. Mean age was 6.17 years old. For 16 of the patients, aPTT prolongation was fortuitously discovered. Symptomatic subjects were older (9.8 vs. 5.2 years of age; P = 0.03). A significantly higher aPTT was indicative of an APS and predicted a positive Rosner Test outcome. A prolongated kaolin clotting time, observed among the younger subjects (3.45 vs. 8.88 years of age; P = 0.0011), was associated with a high aPTT prolongation (57.3 vs. 42.6s; P = 0.0009). CONCLUSION: In our study, the discovery of a prolongated aPTT is most often incidental and tends to occur during winter. The presence of a highly prolongated aPTT, abnormal kaolin clotting time and positive Rosner Test are strong predictors of the existence of an APS, especially in very young children. These antibodies are nonpathogenic and transitional.
Subject(s)
Blood Coagulation Disorders/blood , Blood Coagulation Disorders/diagnosis , Blood Coagulation Disorders/epidemiology , Pediatrics/statistics & numerical data , Adolescent , Child , Child, Preschool , Female , France , Hospitals, University , Humans , Incidental Findings , Infant , Male , Partial Thromboplastin Time/statistics & numerical data , Pediatrics/methods , Prevalence , Retrospective Studies , Time FactorsABSTRACT
NovoSeven (eptacog alfa [activated]) is a concentrate of recombinant activated factor VII currently indicated in 3 types of situation: (1) hemorrhagic syndromes in patients with acquired haemophilia or constitutional A or B haemophilia with inhibitor; (2) Glanzmann thrombasthenia in patients with ineffective platelet transfusion due to alloimmunization; (3) constitutional factor VII deficiency. NovoSeven is also used, off label, in a very large number of bleeding conditions or bleeding risk especially in adult's trauma; abdominal, cardiac or chest surgery; gastroenterology; gynaecology and obstetrics or haematology. In these situations and sometimes in the context of randomized trials, against placebo studies, a large number of publications are reported, with variable scientific value according to evidence-based proofs. Studies conducted in children are far fewer and most of them did not achieve a high-level of evidence. However, we wanted to write a synthesis of the paediatric experience reported in the literature. Whereas it is important to build on work done in adults published data, the conclusions drawn from them are not perfectly applicable in paediatric practice. This bibliographical work is not an accurate guide of recommendations but should allow everyone to get an idea of situations where the use of this drug should or might be considered.
