Randomized phase II study of erlotinib in combination with placebo or R1507, a monoclonal antibody to insulin-like growth factor-1 receptor, for advanced-stage non-small-cell lung cancer.

PURPOSE: R1507 is a selective, fully human, recombinant monoclonal antibody (immunoglobulin G1 subclass) against insulin-like growth factor-1 receptor (IGF-1R). The strong preclinical evidence supporting coinhibition of IGF-1R and epidermal growth factor receptor (EGFR) as anticancer therapy prompted this study. PATIENTS AND METHODS: Patients with advanced-stage non–small-cell lung cancer (NSCLC) with progression following one or two prior regimens, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, and measurable disease were eligible. Patients were randomly assigned to receive erlotinib (150 mg orally once a day) in combination with either placebo, R1507 9 mg/kg weekly, or R1507 16 mg/kg intravenously once every 3 weeks. Treatment cycles were repeated every 3 weeks. The primary end point was comparison of the 12-week progression-free survival (PFS) rate. RESULTS: In all, 172 patients were enrolled: median age, 61 years; female, 33%; never-smokers, 12%; and performance status 0 or 1, 88%. The median number of R1507 doses was six for the weekly arm and 3.5 for the every-3-weeks arm. Grades 3 to 4 adverse events occurred in 37%, 44%, and 48% of patients with placebo, R1507 weekly, and R1507 every 3 weeks, respectively. The 12-week PFS rates were 39%, 37%, and 44%, and the median overall survival was 8.1, 8.1, and 12.1 months for the three groups, respectively, with statistically nonsignificant hazard ratios. The 12-week PFS rate in patients with KRAS mutation was 36% with R1507 compared with 0% with placebo. CONCLUSION: The combination of R1507 with erlotinib did not provide PFS or survival advantage over erlotinib alone in an unselected group of patients with advanced NSCLC. Predictive biomarkers are essential for further development of combined inhibition of IGF-1R and EGFR

An architectural framework for distributed naval ship systems

This paper introduces a framework for analyzing distributed ship systems. The increase in interconnected and interdependent systems aboard modern naval vessels has significantly increased their complexity, making them more vulnerable to cascading failures and emergent behavior that arise only once the system is complete and in operation. There is a need for a systematic approach to describe and analyze distributed systems at the conceptual stage for naval vessels. Understanding the relationships between various aspects of these distributed systems is crucial for uninterrupted naval operations and vessel survivability. The framework introduced in this paper decomposes information about an individual system into three views: the physical, logical, and operational architectural representations. These representations describe the spatial and functional relationships of the system, together with their temporal behavior characteristics. This paper defines how these primary architectural representations are used to describe a system, the interrelations between the architectural blocks, and how those blocks fit together. A list of defined terms is presented, and a preliminary set of requirements for specific design tools to model these architectures is discussed. A practical application is introduced to illustrate how the framework can be used to describe the delivery of power to a high energy weapon

United States Patent Application Publication: MAIZE CHLOROPLAST PROTEIN SYNTHESIS ELONGATION FACTORS AND METHODS OF USE FOR SAME

The invention discloses a novel heat shock protein with high homology to chloroplast elongation factor EF-Tu. Also disclosed is a transgenic method for enhancing tolerance to heat and drought in female reproductive organs. It involves the temporal and spatial expression of novel heat shock EF-Tu in a plant organ or plant tissue. The invention also includes expression constructs, and methods for the production of crop plants with heritable phenotypes which are useful in breeding programs designed to increase heat and drought tolerance

United States Patent Application Publication: MAIZE CHLOROPLAST PROTEIN SYNTHESIS ELONGATION FACTORS AND METHODS OF USE FOR SAME

The invention discloses a novel heat shock protein with high homology to chloroplast elongation factor EF-Tu. Also disclosed is a transgenic method for enhancing tolerance to heat and drought in female reproductive organs. It involves the temporal and spatial expression of novel heat shock EF-Tu in a plant organ or plant tissue. The invention also includes expression constructs, and methods for the production of crop plants with heritable phenotypes which are useful in breeding programs designed to increase heat and drought tolerance

The Design Knowledge Management Square - a Framework for Early Stage Complex Ship Design

This paper presents and demonstrates a new design thinking framework for early stage complex ship design, called the Design Knowledge Management Square (DKMS) framework. The DKMS framework provides a structure that explicitly incorporates the collaborative nature of complex ship design, contrary to other models or frameworks that primarily focus on the technical integration of tools and methods to describe early stage complex ship design. The DKMS framework is applied to three case studies: 1) multi-disciplinary early stage design of complex ships, 2) the integration of concept design generation and analysis methods, and 3) the application of design rationale to support collaborative design decision-making. The case studies show that the DKMS framework provides added value by explicitly describing both the collaborative and technical nature of complex ship design. Thereby the framework helps to analyse, support, and understand complex ship design.Green Open Access added to TU Delft Institutional Repository 'You share, we take care!' - Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Ship Design, Production and Operation

Phase 1 dose-escalation study of the antiplacental growth factor monoclonal antibody RO5323441 combined with bevacizumab in patients with recurrent glioblastoma

BACKGROUND We conducted a phase 1 dose-escalation study of RO5323441, a novel antiplacental growth factor (PlGF) monoclonal antibody, to establish the recommended dose for use with bevacizumab and to investigate the pharmacokinetics, pharmacodynamics, safety/tolerability, and preliminary clinical efficacy of the combination. METHODS Twenty-two participants with histologically confirmed glioblastoma in first relapse were treated every 2 weeks with RO5323441 (625 mg, 1250 mg, or 2500 mg) plus bevacizumab (10 mg/kg). A standard 3 + 3 dose-escalation trial design was used. RESULTS RO5323441 combined with bevacizumab was generally well tolerated, and the maximum tolerated dose was not reached. Two participants experienced dose-limiting toxicities (grade 3 meningitis associated with spinal fluid leak [1250 mg] and grade 3 cerebral infarction [2500 mg]). Common adverse events included hypertension (14 participants, 64%), headache (12 participants, 55%), dysphonia (11 participants, 50%) and fatigue (6 participants, 27%). The pharmacokinetics of RO5323441 were linear, over-the-dose range, and bevacizumab exposure was unaffected by RO5323441 coadministration. Modulation of plasmatic angiogenic proteins, with increases in VEGFA and decreases in FLT4, was observed. Dynamic contrast-enhanced/diffusion-weighted MRI revealed large decreases in vascular parameters that were maintained through the dosing period. Combination therapy achieved an overall response rate of 22.7%, including one complete response, and median progression-free and overall survival of 3.5 and 8.5 months, respectively. CONCLUSION The toxicity profile of RO5323441 plus bevacizumab was acceptable and manageable. The observed clinical activity of the combination does not appear to improve on that obtained with single-agent bevacizumab in patients with recurrent glioblastoma

KIL1 terminates fertility in maize by controlling silk senescence

Plant flowers have a functional life span during which pollination and fertilization occur to ensure seed and fruit development. Once flower senescence is initiated, the potential to set seed or fruit is irrevocably lost. In maize, silk strands are the elongated floral stigmas that emerge from the husk-enveloped inflorescence to intercept airborne pollen. Here we show that KIRA1-LIKE1 (KIL1), an ortholog of the Arabidopsis NAC (NAM (NO APICAL MERISTEM), ATAF1/2 (Arabidopsis thaliana Activation Factor1 and 2) and CUC (CUP-SHAPED COTYLEDON 2)) transcription factor KIRA1, promotes senescence and programmed cell death (PCD) in the silk strand base, ending the window of accessibility for fertilization of the ovary. Loss of KIL1 function extends silk receptivity and thus strongly increases kernel yield following late pollination. This phenotype offers new opportunities for possibly improving yield stability in cereal crops. Moreover, despite diverging flower morphologies and the substantial evolutionary distance between Arabidopsis and maize, our data indicate remarkably similar principles in terminating floral receptivity by PCD, whose modulation offers the potential to be widely used in agriculture. The maize NAC transcription factor KIL1 terminates the fertility of female flowers maize ears by promoting programmed cell death in senescing silk strands

Genetic contributions to agricultural sustainability

The current tools of enquiry into the structure and operation of the plant genome have provided us with an understanding of plant development and function far beyond the state of knowledge that we had previously. We know about key genetic controls repressing or stimulating the cascades of gene expression that move a plant through stages in its life cycle, facilitating the morphogenesis of vegetative and reproductive tissues and organs. The new technologies are enabling the identification of key gene activity responses to the range of biotic and abiotic challenges experienced by plants. In the past, plant breeders produced new varieties with changes in the phases of development, modifications of plant architecture and improved levels of tolerance and resistance to environmental and biotic challenges by identifying the required phenotypes in a few plants among the large numbers of plants in a breeding population. Now our increased knowledge and powerful gene sequence-based diagnostics provide plant breeders with more precise selection objectives and assays to operate in rationally planned crop improvement programmes. We can expect yield potential to increase and harvested product quality portfolios to better fit an increasing diversity of market requirements. The new genetics will connect agriculture to sectors beyond the food, feed and fibre industries; agri-business will contribute to public health and will provide high-value products to the pharmaceutical industry as well as to industries previously based on petroleum feedstocks and chemical modification processes

The US drought of 2012 in perspective: A call to action

The United States is the world's largest exporter of major grain and oilseed crops. In the three-year period from 2008-2010, it produced 39% of global maize and 35% of global soybean and accounted for 49% and 46%, respectively, of total global exports in these commodities. It also contributed 17% of total global exports in wheat and 11% of total rice exports. A large disruption to U.S. production of these crops, as occurred during the U.S. drought of 2012, can have a substantial impact on international grain markets. In this opinion piece, we consider the severity of this drought event and the impact on grain prices in relation to previous droughts of similar magnitude and use this information to highlight priorities for global research on drought and crop productivity to help buffer against future climatic shocks to global food supply. (C) 2013 Elsevier B.V. All rights reserved