Patritumab or Placebo Plus Cetuximab and Platinum-Based Therapy in Squamous Cell Carcinoma of the Head and Neck (SCCHN): a Phase 2 Study

BACKGROUND: P is a fully human monoclonal antibody against human epidermal growth factor receptor 3. P blocks activation by the ligand, heregulin (HRG), inducing receptor internalization. Evidence is growing that HRG presence determines disease progression and survival; in a phase 2 study in non–small-cell lung cancer, P + erlotinib increased progression-free survival (PFS) in high HRG mRNA expression (HRG-high) patients. A phase 1b study in SCCHN demonstrated safety, tolerability and tumor response of P + C + cisplatin or carboplatin and informed the P phase 2 dose. January 2016 (N = 15) response rate = 47%; best responses = 3 complete response (CR), 4 partial response (PR) and 8 stable disease (SD). This phase 2 study (NCT02633800) evaluates first-line P + C + platinum (P arm) vs. PBO + C + platinum (PBO arm) in recurrent and/or metastatic (R/M) SCCHN. The primary objective is to evaluate PFS in the HRG-high population (P vs. PBO arms). METHODS: This is arandomized, controlled, double-blind first-line study in Europe. Patients aged ≥ 18 years with confirmed R/M SCCHN, ECOG performance status ≤ 1 and documented HRG expression (per archived or fresh biopsies) are eligible. The primary efficacy endpoint is PFS. Secondary endpoints include overall survival, overall response rate, pharmacokinetics and safety (including human antihuman antibody incidence). Approximately 105 patients will be stratified 2:1 by HRG status (70 high; 35 low), and then randomized 1:1 to the P or PBO arm. All patients will receive either intravenous P (18mg/kg loading dose [LD]; 9mg/kg maintenance dose [MD] every 3 weeks [q3w]) or PBO, and C (400mg/m2 LD; 250mg/m2 MD weekly) + ≤ 6 cycles of cisplatin (100mg/m2 q3w) or carboplatin (area under the curve of 5). Patients demonstrating CR, PR or SD will be treated with P/PBO + C + ≤ 6 cycles platinum for the study duration (until all patients have died or ≥ 13 months postrandomization of last patient); those benefiting may continue treatment uninterrupted in an open-label extension phase until progressive disease, toxicity or withdrawal. Survival status will be obtained ≥ 13 months after discontinuation. The first patient was dosed December 2015 and enrollment is open. Clinical trial information: NCT0263380

Drug Screen Targeted at Plasmodium Liver Stages Identifies a Potent Multistage Antimalarial Drug

Plasmodium parasites undergo a clinically silent and obligatory developmental phase in the host's liver cells before they are able to infect erythrocytes and cause malaria symptoms. To overcome the scarcity of compounds targeting the liver stage of malaria, we screened a library of 1037 existing drugs for their ability to inhibit Plasmodium hepatic development. Decoquinate emerged as the strongest inhibitor of Plasmodium liver stages, both in vitro and in vivo. Furthermore, decoquinate kills the parasite's replicative blood stages and is active against developing gametocytes, the forms responsible for transmission. The drug acts by selectively and specifically inhibiting the parasite's mitochondrial bc1 complex, with little cross-resistance with the antimalarial drug atovaquone. Oral administration of a single dose of decoquinate effectively prevents the appearance of disease, warranting its exploitation as a potent antimalarial compoun

Collaborative environment for energy-efficient buildings at an early design stage

This paper provides an approach for creating a collaborative environment for energy efficient buildings highlighting the issues required to be addressed at an early design phase. The paper will discuss a design scenario for a new built and suggest system architecture for implementing such scenario through the use of advanced simulation tools and modelling techniques to improve current practice in an early design phase. The suggested system architecture will allow multi-disciplinary teams to collectively and individually explore various energy solutions in a 3D interactive workspace to achieve optimum energy efficiency at building level

A bone grease processing station at the Mitchell Prehistoric Indian Village: archaeological evidence for the exploitation of bone fats

© Association for Environmental Archaeology 2015. Author's accepted manuscript version deposited in accordance with SHERPA RoMEO guidelines. The definitive version is available at http://www.maneyonline.com/doi/abs/10.1179/1749631414Y.0000000035.Recent excavations at the Mitchell Prehistoric Indian Village, an Initial Middle Missouri site in Mitchell, South Dakota have revealed a large, clay-lined feature filled with fractured and fragmented bison bones. Fracture and fragmentation analysis, along with taphonomic evidence, suggests that the bones preserved within the feature represent evidence of prehistoric bone marrow and bone grease exploitation. Further, the character of the feature suggests that it served as a bone grease processing station. Bone fat exploitation is an activity that is frequently cited as a causal explanation for the nature of many fractured and fragmented bone assemblages in prehistory, and zooarchaeological assemblages have frequently been studied as evidence of bone fat exploitation. The Mitchell example provides some of the first direct, in-situ archaeological evidence of a bone grease processing feature, and this interpretation is sustained by substantial analytical evidence suggesting bone fat exploitation. This new evidence provides a clearer concept of the nature of bone fat exploitation in prehistory as well as an indication of the scale and degree to which bone grease exploitation occurred at the Mitchell site. Finally, this research demonstrates the importance of careful zooarchaeological and taphonomic analysis for the interpretation of both artifactual remains as well as archaeological features

Order and Stochastic Dynamics in Drosophila Planar Cell Polarity

Cells in the wing blade of Drosophila melanogaster exhibit an in-plane polarization causing distal orientation of hairs. Establishment of the Planar Cell Polarity (PCP) involves intercellular interactions as well as a global orienting signal. Many of the genetic and molecular components underlying this process have been experimentally identified and a recently advanced system-level model has suggested that the observed mutant phenotypes can be understood in terms of intercellular interactions involving asymmetric localization of membrane bound proteins. Among key open questions in understanding the emergence of ordered polarization is the effect of stochasticity and the role of the global orienting signal. These issues relate closely to our understanding of ferromagnetism in physical systems. Here we pursue this analogy to understand the emergence of PCP order. To this end we develop a semi-phenomenological representation of the underlying molecular processes and define a “phase diagram” of the model which provides a global view of the dependence of the phenotype on parameters. We show that the dynamics of PCP has two regimes: rapid growth in the amplitude of local polarization followed by a slower process of alignment which progresses from small to large scales. We discuss the response of the tissue to various types of orienting signals and show that global PCP order can be achieved with a weak orienting signal provided that it acts during the early phase of the process. Finally we define and discuss some of the experimental predictions of the model

RNAi screen for NRF2 inducers identifies targets that rescue primary lung epithelial cells from cigarette smoke induced radical stress

Chronic Obstructive Pulmonary Disease (COPD) is a highly prevalent condition characterized by inflammation and progressive obstruction of the airways. At present, there is no treatment that suppresses the chronic inflammation of the disease, and COPD patients often succumb to the condition. Excessive oxidative stress caused by smoke inhalation is a major driving force of the disease. The transcription factor NRF2 is a critical player in the battle against oxidative stress and its function is impaired in COPD. Increasing NRF2 activity may therefore be a viable therapeutic option for COPD treatment. We show that down regulation of KEAP1, a NRF2 inhibitor, protects primary human lung epithelial cells from cigarette-smoke-extract (CSE) induced cell death in an established in vitro model of radical stress. To identify new potential drug targets with a similar effect, we performed a siRNA screen of the 'druggable' genome using a NRF2 transcriptional reporter cell line. This screen identified multiple genes that when down regulated increased NRF2 transcriptional activity and provided a survival benefit in the in vitro model. Our results suggest that inhibiting components of the ubiquitin-proteasome system will have the strongest effects on NRF2 transcriptional activity by increasing NRF2 levels. We also find that down regulation of the small GTPase Rab28 or the Estrogen Receptor ESRRA provide a survival benefit. Rab28 knockdown increased NRF2 protein levels, indicating that Rab28 may regulate NRF2 proteolysis. Conversely ESRRA down regulation increased NRF2 transcriptional activity without affecting NRF2 levels, suggesting a proteasome-independent mechanism

Implementation of Object Oriented Product Model Applications

The paper describes implementation aspects of object oriented applications using different software tools such as a CAD- system, a relational data base management system and an object oriented programming language. The different implementations are based on a common generic product model and are integrated by means of neutral file transfer. The modules make up a toolbox from which various specific applications can be derived by adding application specific subclasses. The described development aims to provide steps along an evolutionary path from the dominating design tools of today towards the envisioned object oriented systems of tomorro