No abstract

Lonafarnib is an orally bio-available farnesyltransferase inhibitor that prevents farnesylation of specific target proteins including Ras. In a multicenter study, 67 patients with advanced myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) were treated with a continuous oral dose of 200-300 mg of lonafarnib and were evaluated for hematologic, pathologic and pharmacodynamic response. The median age of patients was 70 years (range 44-86). There were 32 patients with MDS (RAEB-20 and RAEB-t-12) and 35 with CMML. Overall 16 (24%) of the patients responded with two patients achieving a complete remission and one a partial response. Responses were seen in 6/32 and 10/35 patients with MDS and CMML, respectively. Of the 19 patients who were platelet transfusiondependent prior to treatment, 5 (26%) became transfusion-free for a median duration of 185 days. A decrease in the farnesylation of the HDJ-2 protein measured in patient-derived cells was observed in the majority of patients during treatment with lonafarnib, but no clear correlation between changes in farnesylation and clinical effect could be made. Gastrointestinal toxicity was significant with 19% of patients discontinuing therapy due to diarrhea, nausea and/or anorexia. Lonafarnib has demonstrable activity in patients with advanced MDS and CMML.

Models of speech production typically assume that control over the timing of speech movements is governed by the selection of higher-level linguistic units, such as segments or syllables. This study used real-time magnetic resonance imaging of the vocal tract to investigate the anticipatory movements speakers make prior to producing a vocal response. Two factors were varied: preparation (whether or not speakers had foreknowledge of the target response) and pre-response constraint (whether or not speakers were required to maintain a specific vocal tract posture prior to the response). In prepared responses, many speakers were observed to produce pre-response anticipatory movements with a variety of articulators, showing that that speech movements can be readily dissociated from higher-level linguistic units. Substantial variation was observed across speakers with regard to the articulators used for anticipatory posturing and the contexts in which anticipatory movements occurred. The findings of this study have important consequences for models of speech production and for our understanding of the normal range of variation in anticipatory speech behaviors.

To evaluate the efficacy and tolerability of a high-dose mitoxanuniquely steep dose-response curve in clonogenic assays with trone-based induction regimen without consolidation therapy ovarian cancer and leukemic cells. 8,9 In a preliminary study had, for the most part, concluded that tolerance to dose-intenoccurred in 11 patients, three in the high-dose and eight in the sive induction therapy was poor in elderly patients, 11,12 our low-dose arm. Actuarial median survival was 6 months for the low-dose and 9 months for the high-dose group, and the experience suggested that the high-dose mitoxantrone inducrespective relapse-free survival is 3 and 5 months. The tion used in the study might be more acceptable to older indiobserved differences in outcome were not statistically signifividuals, while resulting in improved antileukemic activity. mg/m 2 ) mitoxantrone in combination with a fixed dose of

No abstract