Citations

Febrile infection‐related epilepsy syndrome (FIRES) is a devastating epileptic encephalopathy with limited treatment options and an unclear etiology. Anakinra is a recombinant version of the human interleukin‐1 receptor antagonist used to treat autoinflammatory disorders. This is the first report of anakinra for treatment of a child with super‐refractory status epilepticus secondary to FIRES. Anakinra was well tolerated and effective. Cerebral spinal fluid analysis revealed elevated levels of proinflammatory cytokines before treatment that normalized on anakinra, suggesting a potential pathogenic role for neuroinflammation in FIRES. Further studies are required to assess anakinra efficacy and dosing, and to further delineate disease etiology. Ann Neurol 2016;80:939–945

In June 2015, the National Institutes of Health (NIH) released a Guide notice (NOT‐OD‐15–102) that highlighted the expectation of the NIH that the possible role of sex as a biologic variable be factored into research design, analyses, and reporting of vertebrate animal and human studies. Anticipating these guidelines, the NIH Office of Research on Women's Health, in October 2014, convened key stakeholders to discuss methods and techniques for integrating sex as a biologic variable in preclinical research. The workshop focused on practical methods, experimental design, and approaches to statistical analyses in the use of both male and female animals, cells, and tissues in preclinical research. Workshop participants also considered gender as a modifier of biology. This article builds on the workshop and is meant as a guide to preclinical investigators as they consider methods and techniques for inclusion of both sexes in preclinical research and is not intended to prescribe exhaustive/specific approaches for compliance with the new NIH policy.—Miller, L. R., Marks, C., Becker, J.B., Hurn, P.D., Chen, W.‐J., Woodruff, T., McCarthy, M.M., Sohrabji, F., Schiebinger, L., Wetherington, C.L., Makris, S., Arnold, A. P., Einstein, G., Miller, V. M., Sandberg, K., Maier, S., Cornelison, T. L., Clayton, J. A. Considering sex as a biological variable in preclinical research. FASEB J. 31, 29–34 (2017) www.fasebj.org

Abstract Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive/protumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses. Methods: We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association Study and the admixture likelihood method were used to test gene and pathway associations with survival. Results: We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing (P < 3.5 × 10−5), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival. Conclusions: In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, individual genes, or the collective genetic pathway contributed to EOC survival outcomes. Impact: Common inherited variation in genes relevant to MDSCs was not associated with survival in women diagnosed with invasive EOC. Cancer Epidemiol Biomarkers Prev; 26(3); 420–4. ©2016 AACR.

Freely available software, derived from the past 2 decades of neuroimaging research, is significantly more flexible for research purposes than presently available clinical tools. Here, we describe and demonstrate the utility of rapidly deployable analysis software to facilitate trainee-driven translational neuroimaging research. A recipe and video tutorial were created to guide the creation of a NeuroDebian-based virtual computer that conforms to current neuroimaging research standards and can exist within a HIPAA-compliant system. This allows for retrieval of clinical imaging data, conversion to standard file formats, and rapid visualization and quantification of individual patients’ cortical and subcortical anatomy. As an example, we apply this pipeline to a pediatric patient’s data to illustrate the advantages of research-derived neuroimaging tools in asking quantitative questions “at the bedside.” Our goal is to provide a path of entry for trainees to become familiar with common neuroimaging tools and foster an increased interest in translational research.

ABSTRACT TGF‐β plays a central role in the pathogenesis of fibroproliferative disorders. Defining the exact underlying molecular basis is therefore critical for the development of viable therapeutic strategies. Here, we show that expression of the facilitative glucose transporter 1 (GLUT1) is induced by TGF‐β in fibroblast lines and primary cells and is required for the profibrotic effects of TGF‐β. In addition, enhanced GLUT1 expression is observed in fibrotic areas of lungs of both patients with idiopathic pulmonary fibrosis and mice that are subjected to a fibrosis‐inducing bleomycin treatment. By using pharmacologic and genetic approaches, we demonstrate that up‐regulation of GLUT1 occurs via the canonical Smad2/3 pathway and requires autocrine activation of the receptor tyrosine kinases, platelet‐derived and epidermal growth factor receptors. Engagement of the common downstream effector PI3K subsequently triggers activation of the MEK and mammalian target of rapamycin complex 2, which cooperate in regulating GLUT1 expression. Of note, inhibition of GLUT1 activity and/or expression is shown to impair TGFβ–driven fibrogenic processes, including cell proliferation and production of profibrotic mediators. These findings provide new perspectives on the interrelation of metabolism and profibrotic TGF‐β signaling and present opportunities for potential therapeutic intervention.—Andrianifahanana, M., Hernandez, D. M., Yin, X., Kang, J.‐H., Jung, M.‐Y., Wang, Y., Yi, E. S., Roden, A. C., Limper, A. H., Leof, E. B. Profibrotic up‐regulation of glucose transporter 1 by TGF‐β involves activation of MEK and mammalian target of rapamycin complex 2 pathways. FASEB J. 30, 3733–3744 (2016) www.fasebj.org

Purpose: Orbital vascular malformations are classified by their hemodynamic properties, either high or low flow. Low-flow lesions may be simple venous, lymphatic, or combined lymphaticovenous malformations. The authors report a series of cases in which predominantly low flow, venous lesions were unexpectedly noted to have arterial feeders. Methods: A retrospective chart review of patients identified by the authors as having orbital varices with arterial components was conducted. The authors identified 7 such cases. After careful review, 2 cases were excluded due to inconclusive neuroradiographic findings. The authors review the clinical, radiologic, histopathologic, and surgical information from the remaining 5 cases and discuss their clinical significance. Results: All 5 cases were most consistent with variceal lesions: 3 as clinically distensible lesions and 2 as thrombosed lesions. Additional arterial feeder vessels were noted by angiography (3) or intraoperative visualization (2). The arterial contribution varied from faint vessels to distinct branches of the ophthalmic artery. Ages ranged from 13 to 61 years without predilection for gender. Treatments consisted of excision, embolization, and observation. Two poignant cases are highlighted: the first illustrating that an angiogram in isolation of its clinical picture can be misleading and result in treatment intervention with undue risk, and the second illustrating that inadequate treatment of unrecognized arterial components may contribute to recurrences. Conclusions: Low-flow orbital variceal lesions may have less prominent, arterial components. This type of combined arterialized venous malformation is largely unrecognized in the ophthalmic literature. Correct identification of these lesions is critical in providing safe, effective, and durable treatment.