Research Spotlight

Mochel, F., E. Hainque, D. Gras, I. M. Adanyeguh, S. Caillet, B. Heron, A. Roubertie, E. Kaphan, R. Valabregue, D. Rinaldi, S. Vuillaumier, R. Schiffmann, C. Ottolenghi, J. Y. Hogrel, L. Servais and E. Roze (2016). “Triheptanoin dramatically reduces paroxysmal motor disorder in patients with glut1 deficiency.” J Neurol Neurosurg Psychiatry 87(5): 550-553.

Full text of this article.

OBJECTIVE: On the basis of our previous work with triheptanoin, which provides key substrates to the Krebs cycle in the brain, we wished to assess its therapeutic effect in patients with glucose transporter type 1 deficiency syndrome (GLUT1-DS) who objected to or did not tolerate ketogenic diets. METHODS: We performed an open-label pilot study with three phases of 2 months each (baseline, treatment and withdrawal) in eight patients with GLUT1-DS (7-47 years old) with non-epileptic paroxysmal manifestations. We used a comprehensive patient diary to record motor and non-motor paroxysmal events. Functional (31)P-NMR spectroscopy was performed to quantify phosphocreatine (PCr) and inorganic phosphate (Pi) within the occipital cortex during (activation) and after (recovery) a visual stimulus. RESULTS: Patients with GLUT1-DS experienced a mean of 30.8 (+/-27.7) paroxysmal manifestations (52% motor events) at baseline that dropped to 2.8 (+/-2.9, 76% motor events) during the treatment phase (p=0.028). After withdrawal, paroxysmal manifestations recurred with a mean of 24.2 (+/-21.9, 52% motor events; p=0.043). Furthermore, brain energy metabolism normalised with triheptanoin, that is, increased Pi/PCr ratio during brain activation compared to the recovery phase (p=0.021), and deteriorated when triheptanoin was withdrawn. CONCLUSIONS: Treatment with triheptanoin resulted in a 90% clinical improvement in non-epileptic paroxysmal manifestations and a normalised brain bioenergetics profile in patients with GLUT1-DS.

Fernandez, H. T., P. T. W. Kim, M. Cimo and R. M. Goldstein (2016). “A mass in the porta hepatis: A rare presentation of ectopic thyroid.” International Journal of Hepatobiliary and Pancreatic Diseases 6: 14-16.

Full text of this article.

Introduction: The neck and chest are the most common sites of ectopic thyroid tissues. Ectopic thyroid tissue is infrequently encountered in the liver or gallbladder. This is a rare presentation of an incidental portal hepatis mass consistent with ectopic thyroid. Case Report: A 69-year-old female with a medical history significant for hypothyroidism and multiple thyroid nodules, had undergone a total thyroidectomy. On subsequent ultrasound an incidental 3.6 cm porta hepatis mass was noted, with enlargement on Computed tomography (CT) scan and magnetic resonance imaging (MRI) scan to 4.6 cm. A complete resection of the porta hepatis mass was performed. Pathology of the porta hepatis mass was consistent with benign ectopic thyroid tissue with nodular hyperplasia. Conclusion: This case describes the rare presentation of a porta hepatis mass consistent with an ectopic thyroid. The presence of ectopic thyroid in the porta hepatis is especially rare, and required surgical resection due to increasing size.

Ghisoli, M., M. Barve, R. Mennel, C. Lenarsky, S. Horvath, G. Wallraven, B. O. Pappen, S. Whiting, D. Rao, N. Senzer and J. Nemunaitis (2016). “Three year follow up of gmcsf/bi-shrna DNA transfected autologous tumor immunotherapy (vigil) in metastatic advanced ewing’s sarcoma.” Mol Ther Apr 25 [Epub ahead of print].

Full text of this article.

Ewing’s sarcoma is a devastating rare pediatric cancer of the bone. Intense chemotherapy temporarily controls disease in most patients at presentation but has limited effect in patients with progressive or recurrent disease. We previously described preliminary results of a novel immunotherapy, FANGTM (VigilTM) vaccine, in which 12 advanced stage Ewing’s patients were safely treated and went on to achieve a predicted immune response (IFN? ELISPOT). We describe follow-up through year 3 of a prospective, non-randomized study comparing an expanded group of Vigil-treated advanced disease Ewing’s sarcoma patients (n=16) with a contemporaneous group of Ewing’s sarcoma patients (n=14) not treated with Vigil. Long-term follow up results show a survival benefit without evidence of significant toxicity (no = grade 3) to Vigil when administered once monthly by intradermal injection (1x10e6 cells/injection to 1x10e7 cells/injection). Specifically, we report a 1-year actual survival of 73% for Vigil treated patients compared to 23% in those not treated with Vigil. In addition, there was a 17.2 month difference in overall survival (OS; Kaplan-Meier) between the Vigil (median OS 731 days) and no Vigil patient groups (median OS 207 days). In conclusion, these results supply the rational for further testing of Vigil in advanced stage Ewing’s sarcoma.

Kim, T. W., S. Hong, A. H. Talukder, V. Pascual and Y.-J. Liu (2016). “Grancalcin (gca) modulates toll-like receptor 9 (tlr9) mediated signaling through its direct interaction with tlr9.” European Journal of Immunology 46(3): 712-724.

Full text of this article.

Toll-like receptors (TLRs) are playing important roles in stimulating the innate immune response and intensifying adaptive immune response against invading pathogens. Appropriate regulation of TLR activation is important to maintain a balance between preventing tumor activation and inhibiting autoimmunity. Toll-like receptor 9 (TLR9) senses microbial DNA in the endosomes of plasmacytoid dendritic cells and triggers myeloid differentiation primary response gene 88 (MyD88) dependent nuclear factor kappa B (NF-kappa B) pathways and type I interferon (IFN) responses. However, mechanisms of how TLR9 signals are mediated and which molecules are involved in controlling TLR9 functions remain poorly understood. Here, we report that penta EF-hand protein grancalcin (GCA) interacts and binds with TLR9 in a yeast two-hybrid system and an overexpression system. Using siRNA-mediated knockdown experiments, we also revealed that GCA positively regulates type I IFN production, cytokine/chemokine production through nuclear localization of interferon regulatory factor 7 (IRF7), NF-kappa B activation, and mitogen-activated protein kinase (MAPK) activation in plasmacytoid dendritic cells. Our results indicate that heterodimerization of GCA and TLR9 is important for TLR9-mediated downstream signaling and might serve to fine tune processes against viral infection.

Ohne, Y., J. S. Silver, L. Thompson-Snipes, M. A. Collet, J. P. Blanck, B. L. Cantarel, A. M. Copenhaver, A. A. Humbles and Y. J. Liu (2016). “Il-1 is a critical regulator of group 2 innate lymphoid cell function and plasticity.” Nat Immunol Apr 25 [Epub ahead of print].

Full text of this article.

Group 2 innate lymphoid cells (ILC2 cells) are important for type 2 immune responses and are activated by the epithelial cytokines interleukin 33 (IL-33), IL-25 and thymic stromal lymphopoietin (TSLP). Here we demonstrated that IL-1beta was a critical activator of ILC2 cells, inducing proliferation and cytokine production and regulating the expression of epithelial cytokine receptors. IL-1beta also governed ILC2 plasticity by inducing low expression of the transcription factor T-bet and the cytokine receptor chain IL-12Rbeta2, which enabled the conversion of these cells into an ILC1 phenotype in response to IL-12. This transition was marked by an atypical chromatin landscape characterized by the simultaneous transcriptional accessibility of the locus encoding interferon-alpha (IFN-alpha) and the loci encoding IL-5 and IL-13. Finally, IL-1beta potentiated ILC2 activation and plasticity in vivo, and IL-12 acted as the switch that determined an ILC2-versus-ILC1 response. Thus, we have identified a previously unknown role for IL-1beta in facilitating ILC2 maturation and plasticity.