19 research outputs found

    Safety and Pharmacokinetics of Motesanib in Combination with Panitumumab and Gemcitabine-Cisplatin in Patients with Advanced Cancer

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    Purpose. The aim of this study was to assess the safety and tolerability of motesanib (an orally administered small-molecule antagonist of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor, and Kit) when administered in combination with panitumumab, gemcitabine, and cisplatin. Methods. This was an open-label, multicenter phase 1b study in patients with advanced solid tumors with an ECOG performance status ≤1 and for whom a gemcitabine/cisplatin regimen was indicated. Patients received motesanib (0 mg [control], 50 mg once daily [QD], 75 mg QD, 100 mg QD, 125 mg QD, or 75 mg twice daily [BID]) with panitumumab (9 mg/kg), gemcitabine (1250 mg/m2) and cisplatin (75 mg/m2) in 21-day cycles. The primary endpoint was the incidence of dose-limiting toxicities (DLTs). Results. Forty-one patients were enrolled and received treatment (including 8 control patients). One of eight patients in the 50 mg QD cohort and 5/11 patients in the 125 mg QD cohort experienced DLTs. The maximum tolerated dose was established as 100 mg QD. Among patients who received motesanib (n = 33), 29 had motesanib-related adverse events. Fourteen patients had serious motesanib-related events. Ten patients had motesanib-related venous thromboembolic events and three had motesanib-related arterial thromboembolic events, two of which were considered serious. One patient had a complete response and nine had partial responses as their best objective response. Conclusions. The combination of motesanib, panitumumab, and gemcitabine/cisplatin could not be administered consistently and, at the described doses and schedule, may be intolerable. However, encouraging antitumor activity was noted in some cases

    The effect of different dosing regimens of motesanib on the gallbladder: a randomized phase 1b study in patients with advanced solid tumors

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    Extent: 11 p.BACKGROUND: Gallbladder toxicity, including cholecystitis, has been reported with motesanib, an orally administered small-molecule antagonist of VEGFRs 1, 2 and 3; PDGFR; and Kit. We assessed effects of motesanib on gallbladder size and function. METHODS: Patients with advanced metastatic solid tumors ineligible for or progressing on standard-of-care therapies with no history of cholecystitis or biliary disease were randomized 2:1:1 to receive motesanib 125 mg once daily (Arm A); 75 mg twice daily (BID), 14-days-on/7-days-off (Arm B); or 75 mg BID, 5-days-on/2-days-off (Arm C). Primary endpoints were mean change from baseline in gallbladder size (volume by ultrasound; independent review) and function (ejection fraction by CCK-HIDA; investigator assessment). RESULTS: Forty-nine patients received ≥1 dose of motesanib (Arms A/B/C, n = 25/12/12). Across all patients, gallbladder volume increased by a mean 22.2 cc (from 38.6 cc at baseline) and ejection fraction decreased by a mean 19.2% (from 61.3% at baseline) during treatment. Changes were similar across arms and appeared reversible after treatment discontinuation. Three patients had cholecystitis (grades 1, 2, 3, n = 1 each) that resolved after treatment discontinuation, one patient developed grade 3 acute cholecystitis requiring cholecystectomy, and two patients had other notable grade 1 gallbladder disorders (gallbladder wall thickening, gallbladder dysfunction) (all in Arm A). Two patients developed de novo gallstones during treatment. Twelve patients had right upper quadrant pain (Arms A/B/C, n = 8/1/3). The incidence of biliary “sludge” in Arms A/B/C was 39%/36%/27%. CONCLUSION: Motesanib treatment was associated with increased gallbladder volume, decreased ejection fraction, biliary sludge, gallstone formation, and infrequent cholecystitis. Trial registration: ClinicalTrials.gov NCT00448786Lee S. Rosen, Lara Lipton, Timothy J. Price, Neil D. Belman, Ralph V. Boccia, Herbert I. Hurwitz, Joe J. Stephenson Jr., Lori J. Wirth, Sheryl McCoy, Yong-jiang Hei, Cheng-Pang Hsu and Niall C. Tebbut

    Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

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    While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)—present in some but not all cells—remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk

    Some Factors Affecting Birth Weight and Gestation Length of Beef Cattle and Birth Weight of Milking Shorthorn Cattle

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    Information on the factors influencing the gestation and birth weight of calves is of importance to practical animal husbandry. The birth weight is of economic importance and a knowledge of factors influencing gestation length may be valuable in planning herd management. The purpose of this paper was to study the influence of some of the factors which may affect the gestation length and birth weight of calves of beef breeding and factors affecting birth weight in Milking Shorthorns. Some of the results of this study show: 1) The age of the cow at parturition had no significant effect on the length of gestation. 2) The interaction of breed and sex was not found to have any significant effect on gestation length. 3) Differences in birth weight averages for breeds were highly significant for all breeds except for theAngus-Shorthorn comparison which was not significant. Advisor: Cecil T. Blun

    Is This Within Reach? : Left but Not Right Brain Damage Affects Affordance Judgment Tendencies

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    The ability to judge accurately whether or not an action can be accomplished successfully is critical for selecting appropriate response options that enable adaptive behaviors. Such affordance judgments are thought to rely on the perceived fit between environmental properties and knowledge of one's current physical capabilities. Little, however, is currently known about the ability of individuals to judge their own affordances following a stroke, or about the underlying neural mechanisms involved. To address these issues, we employed a signal detection approach to investigate the impact of left or right hemisphere injuries on judgments of whether a visual object was located within reach while remaining still (i.e., reachability). Regarding perceptual sensitivity and accuracy in judging reachability, there were no significant group differences between healthy controls (N = 29), right brain damaged (RBD, N = 17) and left brain damaged stroke patients (LBD, N = 17). However, while healthy controls and RBD patients demonstrated a negative response criterion and thus overestimated their reach capability, LBD patients' average response criterion converged to zero, indicating no judgment tendency. Critically, the LBD group's judgment tendency pattern is consistent with previous findings in this same sample on an affordance judgment task that required estimating whether the hand can fit through apertures (Randerath et al., 2018). Lesion analysis suggests that this loss of judgment tendency may be associated with damage to the left insula, the left parietal and middle temporal lobe. Based on these results, we propose that damage to the left ventro-dorsal stream disrupts the retrieval and processing of a stable criterion, leading to stronger reliance on intact on-line body-perceptive processes computed within the preserved bilateral dorsal network.publishe

    Performing Arts Session

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    The music department is proud to present the research of its students through performance. Most of these students are majoring or minoring in music and spend considerable time developing their technique and mastering the art of expression. Each performance is informed by significant research on the composer and the composition. These performances will feature the following students and will include classical guitar, arias, art song, instrumental solo pieces and instrumental chamber music. The performances will appear in no particular order. Please stop by and enjoy this offering of classical music in the lively acoustic and glorious backdrop of the Weisman Museum of Art. The musicians will be performing in the upper gallery
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