Citations

Abstract Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of the uracil catabolic pathway, being critically important for inactivation of the commonly prescribed anti-cancer drug 5-fluorouracil (5-FU). DPD impairment leads to increased exposure to 5-FU and, in turn, increased anabolism of 5-FU to cytotoxic nucleotides, resulting in more severe clinical adverse effects. Numerous variants within the gene coding for DPD, DPYD, have been described, although only a few have been demonstrated to reduce DPD enzyme activity. To identify DPYD variants that alter enzyme function, we expressed 80 protein-coding variants in an isogenic mammalian system and measured their capacities to convert 5-FU to dihydro-fluorouracil, the product of DPD catabolism. The M166V, E828K, K861R, and P1023T variants exhibited significantly higher enzyme activity than wild-type DPD (120%, P = 0.025; 116%, P = 0.049; 130%, P = 0.0077; 138%, P = 0.048, respectively). Consistent with clinical association studies of 5-FU toxicity, the D949V substitution reduced enzyme activity by 41% (P = 0.0031). Enzyme activity was also significantly reduced for 30 additional variants, 19 of which had <25% activity. None of those 30 variants have been previously reported to associate with 5-FU toxicity in clinical association studies, which have been conducted primarily in populations of European ancestry. Using publicly available genotype databases, we confirmed the rarity of these variants in European populations but showed that they are detected at appreciable frequencies in other populations. These data strongly suggest that testing for the reported deficient DPYD variations could dramatically improve predictive genetic tests for 5-FU sensitivity, especially in individuals of non-European descent. Cancer Res; 74(9); 2545–54. ©2014 AACR.

ABSTRACT Because of its very low human seroprevalence, vesicular stomatitis virus (VSV) has promise as a systemic oncolytic agent for human cancer therapy. However, as demonstrated in this report, the VSV infectious titer drops by 4 log units during the first hour of exposure to nonimmune human serum. This neutralization occurs relatively slowly and is mediated by the concerted actions of natural IgM and complement. Maraba virus, whose G protein is about 80% homologous to that of VSV, is relatively resistant to the neutralizing activity of nonimmune human serum. We therefore constructed and rescued a recombinant VSV whose G gene was replaced by the corresponding gene from Maraba virus. Comparison of the parental VSV and VSV with Maraba G substituted revealed nearly identical host range properties and replication kinetics on a panel of tumor cell lines. Moreover, in contrast to the parental VSV, the VSV with Maraba G substituted was resistant to nonimmune human serum. Overall, our data suggest that VSV with Maraba G substituted should be further investigated as a candidate for human systemic oncolytic virotherapy applications. IMPORTANCE Oncolytic virotherapy is a promising approach for the treatment of disseminated cancers, but antibody neutralization of circulating oncolytic virus particles remains a formidable barrier. In this work, we developed a pseudotyped vesicular stomatitis virus (VSV) with a glycoprotein of Maraba virus, a closely related but serologically distinct member of the family Rhabdoviridae , which demonstrated greatly diminished susceptibility to both nonimmune and VSV-immune serum neutralization. VSV with Maraba G substituted or lentiviral vectors should therefore be further investigated as candidates for human systemic oncolytic virotherapy and gene therapy applications.

The founding and early development of the Southern Pediatric Neurology Society was in many ways parallel to that of the Child Neurology Society. The organization started out as the Southern Child Neurology Society but the name was changed at the time of incorporation so as to avoid confusion of identity and purpose with the larger Child Neurology Society. Although there are archives of early days and the later development of the Southern Pediatric Neurology Society, the details have never been set down in a narrative explaining the events that led to the development of the organization. In this paper, we try to produce a written record of the history of the founding and early development of the Southern Pediatric Neurology Society.

Abstract A recent randomized trial from the Finnish Degenerative Meniscal Lesion Study Group was published in the New England Journal of Medicine and attempted to determine the efficacy of partial meniscectomy without osteoarthritis. Patients were randomized to either arthroscopic partial meniscectomy or sham surgery. The authors concluded that the clinical outcomes after arthroscopic partial meniscectomy were no better than those after the sham surgical procedure. However, there are several important limitations of this trial that make it difficult to generalize to the 700,000 arthroscopic partial meniscectomies performed in the United States each year. In this small sample of 146 patients, patients with traumatic meniscal tears and locking symptoms—those most likely to benefit from a partial meniscectomy—were excluded. In addition, although patients with radiographic arthritis were excluded, most of the patients in the study had degenerative changes at the time of arthroscopy. Therefore it is difficult to determine whether the patients were symptomatic from their chondral degeneration or their degenerative meniscal tear. In our opinion this study does not change the role of surgery in current clinical practice. The primary indication for arthroscopic partial meniscectomy remains symptoms of well‐localized joint line pain with acute onset and mechanical symptoms such as catching or locking that have failed comprehensive nonoperative management.

ABSTRACTIntroductionThe Cl. NPhys Trial 3 showed that attributes of nerve conduction (NC) were without significant intraobserver differences, although there were significant interobserver differences. Methods: Trial 4 tested whether use of written instructions and pretrial agreement on techniques and use of standard reference values, diagnostic percentile values, or broader categorization of abnormality could reduce significant interobserver disagreement and improve agreement among clinical neurophysiologists. Results: The Trial 4 modifications markedly decreased, but did not eliminate, significant interobserver differences of measured attributes of NC. Use of standard reference values and defined percentile values of abnormality decreased interobserver disagreement and improved agreement of judgment of abnormality among evaluators. Therefore, the same clinical neurophysiologist should perform repeat NCs of therapeutic trial patients. Conclusions: Differences in interobserver judgment of abnormality decrease with use of common standard reference values and a defined percentile level of abnormality, providing a rationale for their use in therapeutic trials and medical practice. Muscle Nerve 50: 900–908, 2014