Citations

Background: The majority of patients with multiple sclerosis (MS) present with spinal cord pathology. Spinal cord atrophy is thought to be a marker of disease severity, but in long-disease duration its relation to brain pathology and clinical disability is largely unknown. Objective: Our aim was to investigate mean upper cervical cord area (MUCCA) in patients with long-standing MS and assess its relation to brain magnetic resonance imaging (MRI) measures and clinical disability. Methods: MUCCA was measured in 196 MS patients and 55 healthy controls using 3DT1-weighted cervical images obtained at 3T MRI. Clinical disability was measured using the Expanded Disability Status Scale (EDSS), Nine-Hole-Peg test (9-HPT), and 25 feet Timed Walk Test (TWT). Stepwise linear regression was performed to assess the association between MUCCA and MRI measures, and between MUCCA and clinical disability. Results: MUCCA was smaller (mean 11.7%) in MS patients compared with healthy controls (72.56±9.82 and 82.24±7.80 mm 2 respectively; p<0.001), most prominently in male patients. MUCCA was associated with normalized brain volume, and number of cervical cord lesions. MUCCA was independently associated with EDSS, TWT, and 9-HPT. Conclusion: MUCCA was reduced in MS patients compared with healthy controls. It provides a relevant marker for clinical disability in long-standing disease, independent of other MRI measures.

To understand the role of bone marrow mononuclear cells in the treatment of acute myocardial infarction, this overview offers a retrospective examination of strengths and limitations of 3 contemporaneous trials with attention to critical design features and provides an analysis of the combined data set and implications for future directions in cell therapy for acute myocardial infarction.

Ewing sarcoma is an aggressive pediatric small round cell tumor that predominantly occurs in bone. Approximately 85% of Ewing sarcomas harbor the EWS/FLI fusion protein, which arises from a chromosomal translocation, t(11:22)(q24:q12). EWS/FLI interacts with numerous lineage‐essential transcription factors to maintain mesenchymal progenitors in an undifferentiated state. We previously showed that EWS/FLI binds the osteogenic transcription factor RUNX2 and prevents osteoblast differentiation. In this study, we investigated the role of another Runt‐domain protein, RUNX3, in Ewing sarcoma. RUNX3 participates in mesenchymal‐derived bone formation and is a context dependent tumor suppressor and oncogene. RUNX3 was detected in all Ewing sarcoma cells examined, whereas RUNX2 was detected in only 73% of specimens. Like RUNX2, RUNX3 binds to EWS/FLI via its Runt domain. EWS/FLI prevented RUNX3 from activating the transcription of a RUNX‐responsive reporter, p6OSE2. Stable suppression of RUNX3 expression in the Ewing sarcoma cell line A673 delayed colony growth in anchorage independent soft agar assays and reversed expression of EWS/FLI‐responsive genes. These results demonstrate an important role for RUNX3 in Ewing sarcoma. J. Cell. Physiol. 229: 2049–2056, 2014. © 2014 Wiley Periodicals, Inc.

Abstract Purpose: This phase I, open-label, uncontrolled, ascending-dose study explored the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacology of the TLR8 agonist VTX-2337 in subjects with advanced solid tumors or lymphoma. Experimental Design: VTX-2337 doses (0.1–3.9 mg/m2) were administered subcutaneously on days 1, 8, and 15 of each 28-day cycle. Safety/tolerability assessments included adverse events (AE); physical, ophthalmologic, and laboratory evaluations; and electrocardiograms. Dose-limiting toxicities (DLT) were evaluated during the first cycle. Pharmacokinetics were evaluated after the first dose. Plasma samples were quantitatively assessed for chemokines, cytokines, and other inflammatory mediators. Antitumor activity was assessed. Results: Thirty-three subjects were enrolled in 8 cohorts and received an average of 2 treatment cycles (range, 1–8 cycles). Most AEs were grades 1 to 2; the most common drug-related AEs were injection site reactions, chills, pyrexia, and influenza-like illness. One DLT was reported: grade 3 hypotension (3.9 mg/m2). The MTD was considered the highest dose administered. Peak drug plasma levels and total systemic exposure were generally dose proportional. At doses ≥0.4 mg/m2, increases above baseline levels were observed for plasma levels of G-CSF, monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and TNFα. Eight subjects (24.2%) had a best response of stable disease (median duration, 54.5 days). Conclusions: VTX-2337 is clinically well tolerated and biologically active with a predictable pharmacokinetic profile. Suitable doses for testing in combination studies were identified. Phase II placebo-controlled studies of VTX-2337 in combination with doxorubicin in ovarian cancer, and in combination with platinum chemotherapy, 5 FU, and cetuximab in head and neck cancer have been initiated (NCT #01666444 and NCT#01836029). Clin Cancer Res; 20(14); 3683–91. ©2014 AACR.