Citations

ABSTRACT Vesicular stomatitis virus (VSV) has long been regarded as a promising recombinant vaccine platform and oncolytic agent but has not yet been tested in humans because it causes encephalomyelitis in rodents and primates. Recent studies have shown that specific tropisms of several viruses could be eliminated by engineering microRNA target sequences into their genomes, thereby inhibiting spread in tissues expressing cognate microRNAs. We therefore sought to determine whether microRNA targets could be engineered into VSV to ameliorate its neuropathogenicity. Using a panel of recombinant VSVs incorporating microRNA target sequences corresponding to neuron-specific or control microRNAs (in forward and reverse orientations), we tested viral replication kinetics in cell lines treated with microRNA mimics, neurotoxicity after direct intracerebral inoculation in mice, and antitumor efficacy. Compared to picornaviruses and adenoviruses, the engineered VSVs were relatively resistant to microRNA-mediated inhibition, but neurotoxicity could nevertheless be ameliorated significantly using this approach, without compromise to antitumor efficacy. Neurotoxicity was most profoundly reduced in a virus carrying four tandem copies of a neuronal mir125 target sequence inserted in the 3′-untranslated region of the viral polymerase (L) gene.

PurposeThe purpose of this systematic review was to examine the current evidence for the use of oral motor exercises (OMEs) on speech (i.e., speech physiology, speech production, and functional speech outcomes) as a means of supporting further research and clinicians' use of evidence-based practice.MethodThe peer-reviewed literature from 1960 to 2007 was searched for articles examining the use of OMEs to affect speech physiology, production, or functional outcomes (i.e., intelligibility). Articles that met selection criteria were appraised by 2 reviewers and vetted by a 3rd for methodological quality, then characterized as efficacy or exploratory studies.ResultsFifteen studies met inclusion criteria; of these, 8 included data relevant to the effects of OMEs on speech physiology, 8 on speech production, and 8 on functional speech outcomes. Considerable variation was noted in the participants, interventions, and treatment schedules. The critical appraisals identified significant weaknesses in almost all studies.ConclusionsInsufficient evidence to support or refute the use of OMEs to produce effects on speech was found in the research literature. Discussion is largely confined to a consideration of the need for more well-designed studies using well-described participant groups and alternative bases for evidence-based practice.

Abstract Protein kinase Cι (PKCι) is an oncogene required for maintenance of the transformed phenotype of non–small cell lung cancer cells. However, the role of PKCι in lung tumor development has not been investigated. To address this question, we established a mouse model in which oncogenic KrasG12D is activated by Cre-mediated recombination in the lung with or without simultaneous genetic loss of the mouse PKCι gene, Prkci. Genetic loss of Prkci dramatically inhibits Kras-initiated hyperplasia and subsequent lung tumor formation in vivo. This effect correlates with a defect in the ability of Prkci-deficient bronchioalveolar stem cells to undergo Kras-mediated expansion and morphologic transformation in vitro and in vivo. Furthermore, the small molecule PKCι inhibitor aurothiomalate inhibits Kras-mediated bronchioalveolar stem cell expansion and lung tumor growth in vivo. Thus, Prkci is required for oncogene-induced expansion and transformation of tumor-initiating lung stem cells. Furthermore, aurothiomalate is an effective antitumor agent that targets the tumor-initiating stem cell niche in vivo. These data have important implications for PKCι as a therapeutic target and for the clinical use of aurothiomalate for lung cancer treatment. [Cancer Res 2009;69(19):7603–11]

Abstract The prognostic heterogeneity of the World Health Organization category of “systemic mastocytosis with associated clonal hematologic nonmast cell lineage disease” (SM-AHNMD) has not been systematically validated by primary data. Among 138 consecutive cases with SM-AHNMD, 123 (89%) had associated myeloid neoplasm: 55 (45%) myeloproliferative neoplasm (SM-MPN), 36 (29%) chronic myelomonocytic leukemia, 28 (23%) myelodysplastic syndrome (SM-MDS), and 4 (3%) acute leukemia. Of the myeloid subgroups, SM-MPN displayed a 2- to 3-fold better life expectancy (P = .003), whereas leukemic transformation was more frequent in SM-MDS (29%; P = .02). The presence of eosinophilia, although prevalent (34%), was prognostically neutral, and the overall results were not affected by exclusion of FIP1L1-PDGFRA-positive cases. We conclude that it is clinically more useful to consider specific entities, such as SM-MPN, systemic mastocytosis with chronic myelomonocytic leukemia, SM-MDS, and systemic mastocytosis with-acute leukemia, rather than their broad reference as SM-AHNMD.