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This TRAIL intends to describe the current heterogeneous state of data generation and archiving. This will create the basis for coordinated and practical optimisation and standardisation of procedures.

Archiving of digital research data based on established standards and methods is an important part of the research data lifecycle. It guarantees the long-term transparency and reusability of research results. In the case of archaeological data, this is of particular importance for the preservation of unique and irreplaceable cultural heritage. To gain insight into the current state of affairs regarding long-term archiving in Germany, the SEADDA (Saving European Archaeology from the Digital Dark Age) COST Action (1) and the Commission on Archaeology and Information Systems in the Association of German State Archaeologists (2), with the support of the IANUS Research Data Center of the DAI (3), conducted a survey in spring/summer 2021. This article presents the results of the survey together with recommendations for further and supporting measures targeted at improving the long-term archiving of digital archaeological data in Germany.

Serious Injuries and fatalities (SIFs) occurring in the workplace have become a significant focus in the field of safety. Over the past 20 years there has been a steady decline in the prevalence of all injuries, however the rates of SIFs has plateaued in recent years, contrary to Heinrich's Triangle. In one of the largest studies of its kind, we set out to identify trends and common factors of SIF incidents in order to identify strategies to reduce the risk of SIF incidents occurring. We have studied OSHA log records and OSHA recorded fatalities of over 50,000 companies over multiple years, broken down by numerous different indices including industry, age, day of the week, body part affected, type of incident and severity of incident, to give a picture of SIF prevalence and trends. This data has also been cross referenced against qualitative information of these companies to identify trends, commonalities and disparities in order to identify causes and opportunities for improvement. The data reported on has shown different risk groups for SIF incidents occurring, that 60% of companies are at low risk of SIF incidents occurring, and identifying the highest risk injuries for SIF events occurring (drilling and construction work). In addition, seemingly random factors such as day of the week and month of the year are actually found to statistically vary, presenting opportunities for targeted outreach based on this data in order to reduce risk. Furthermore, the study reveals that companies who work with chemicals, performing welding work and work at heights should be the top targets for DIF prevention intervention, whilst the impact of heavily regulated industries (e.g. PSM facilities) and ensuring organization have good safety procedures are linked to lower risks of SIF events occurring. This information is of valuable use for all organizations who are interested in truly understanding the root causes of incidents and learning techniques to achieve a Vision Zero of a reduction of incidents, particularly serious injuries and fatalities, to the lowest possible level. A no-blame culture to the accurate reporting of incidents is also vital to a deeper understanding of causation and prevention.

Since 2005, the Landesamt für Denkmalpflege Baden-Württemberg has been collecting semi-structured archaeological digital project data with the aim of one day turning that data into a real long-term digital archive. This process is still ongoing. In the last 15 years appropriate data formats have been defined, and the transition from CAD to GIS as the mainstay of project recording in Baden-Württemberg has been made. The research-driven development of the Software Survey2GIS (GNU GPL), initiated by the Landesamt für Denkmalpflege Baden-Württemberg, facilitates on the one hand an easy-to-use transition of field data into GIS and on the other better control of data formats. We are learning to cope with increasingly more complex data - laser scan, LIDAR and sfm data. The recent advent of commercial archaeology in the state of Baden Württemberg is another factor with which we are confronted. We have experimented with the best methods of convincing archaeologists, technicians and ancillary staff of the necessity of saving their data in a central repository - for example friendliness, even occasional coercion, as well as the guarantee of recoverable data if the deposition rules are followed. The boundary of each saved excavation or survey project is uploaded to the State's own cultural heritage GIS-Application - ADAB - where it can be accessed by researchers. A simple click within the polygon will invoke metadata about the project as well as a selection of quintessential photos. The excavation archive in Baden-Württemberg is, as yet, by no means a fully accessible, usable 'real' digital archive. But we are succeeding in saving the data in a structured manner for future transition into that 'real' archive - hopefully as a pilot project within the framework of the federally financed NFDI infrastructure.

The paper provides the overview of the evolution of the Copernicus Sentinel-l Space Segment and the Spacecraft development status. Following the successful launch and in-orbit Commissioning of Sentinel-1A in 2014 and Sentinel-1B in 2016, ESA is currently developing the Sentinel-1C and −1D models. The paper addresses the improvements in system robustness and performance. In addition, it discusses the main characteristics of the Automatic Identification System (AIS) instrument to augment the SAR payload data for ship marine traffic applications and the Optical Communication Payload (OCP) for payload data downlink via inter-satellite laser-link with the European Data Relay System (EDRS). Finally, it will address the novel solutions to make Sentinel-lC and Sentinel-lD design fully compliant with the latest Space Debris code-of-conduct and the required casualty risks at re-entry.

Sentinel-1 C&D SAR instruments are designed to continue the observations beyond the lifetime of Sentinel-1 A & B. They are to a high degree rebuilds of S-lA&B and will have the same imaging modes and interfaces to ground. Changes have been implemented within the SAR antenna by using a new Tile Amplifier design, which will contribute to improved radiometric stability and accuracy. The new tile amplifiers simplify the internal calibration approach by reducing the number of internal measurements from five to three. Another improvement is the introduction of interleaved noise measurements during image acquisition in addition to noise acquisitions in preamble and postamble. This is important as the surface brightness temperature have a significant impact on the acquired noise and can change the measured levels by up to 1 dB. A first tile for S-lC with the new design has been successfully tested. Results confirm the updated design and indicate improved measurement accuracy.

BACKGROUND About 10% of new diagnoses of subtype B human immunodeficiency virus type 1 (HIV-1) in the United Kingdom are with viruses showing transmitted drug resistance (TDR). However, there is discordance between the mutation patterns observed in HIV-infected patients failing therapy and those seen in TDR. METHODS We extracted all subtype B HIV-1 pol gene sequences from treatment-naive patients within the United Kingdom HIV Drug Resistance Database sampled between 1997 and 2011 and carrying the most common protease inhibitors, nonnucleoside and nucleotide reverse transcriptase inhibitors TDR mutations, namely, L90M, K103N, and T215Y/F/rev, respectively (n = 1140). Transmission clusters (n ≥ 2 sequences) were identified by maximum-likelihood phylogeny using a genetic distance cutoff of ≤ 1.5%. The time of origin and the basic reproductive number (R0) of clusters were estimated by Bayesian methods. RESULTS T215rev was present alone in 47% of the sequences (n = 540), K103N in 31% (n = 359), and L90M in 10% (n = 109). The remaining sequences contained T215Y or combinations of L90M, K103N, and T215rev. Fifty-five percent (n = 624) of the sequences formed highly supported transmission clusters (n = 193) containing between 2 and 15 sequences. The time of origin of 10 large clusters (≥ 8 sequences) was estimated to be between 2000 (1999-2002; 95% highest posterior density [HPD]) and 2006 (2005-2007; 95% HPD). The oldest cluster had persisted for nearly 8 years. All 10 clusters had R0s ranging from 1.3 (0.4-2.5; 95% HPD) to 2.8 (0.6-6.5; 95% HPD). CONCLUSIONS A high proportion of the most common TDR in subtype B infections in the United Kingdom is derived by onward transmission from treatment-naive patients.

The paper provides an overview of the evolution of the Copernicus Sentinel-1 mission, which is part of the Copernicus European Earth Observation program. Following the successful launch and in-orbit Commissioning of Sentinel-1A in 2014 and Sentinel-1B in 2016, ESA is currently developing the Sentinel-1 C and D models. The paper addresses the expected improvements in system robustness and performance. In addition, it discusses the main characteristics of the Automatic Identification System (AIS) instrument to augment the SAR payload data for ship marine traffic applications and the Optical Communication Payload (OCP) for payload data downlink via inter-satellite laser-link with the European Data Relay System (EDRS). Finally, the design of Sentinel-1C and Sentinel-1D incorporates novel solutions that will make both satellites fully compliant with the latest Space Debris code-of-conduct and the required casualty risks at re-entry.

The paper provides an overview of the Copernicus Sentinel-1 mission, which includes Sentinel-1A (S-1A) and Sentinel-1B (S-1B) satellites, and the characteristics of its SAR system. Sentinel-1 uses pre-programmed SAR mode operations to provide a high revisit frequency and systematic global SAR image coverage. This is mainly based upon the operational use of the novel TOPS (Terrain Observation with Progressive Scans in azimuth) SAR imaging mode. In particular, we present results of the SAR system performance analysis focusing on the instrument stability and the achieved radiometric accuracy, as well as the Noise Equivalent Sigma Zero (NESZ). In addition, we discuss the cross-S-1A/S-1B SAR Interferometry (InSAR) performance considering the effects of burst synchronization and SAR antenna pointing on the achievable common Doppler bandwidth. Results of differential cross interferograms are presented showing the coseismic surface displacement caused by the central Italy earthquake.

This short article illustrates the growth in the use of Free and Open Source Software (FOSS) GIS tools in European archaeology. It draws mainly on the experience gained using the programs gvSIG CE and Survey2GIS. It demonstrates the advantages of open source software for archaeological research and fieldwork, while not ignoring the pitfalls and hazards to be avoided in the FOSS world.

Decision system analysis (DSA) is a conceptually simple technique that maps the process of group decisions over time. The data are gathered in a variety of ways, but most often some form of protocol analysis is the foremost tool. The data are then condensed and depicted as a flow chart for a specific decision. If several such flow charts can be assembled within an industry, they can be melded together to form a generic guide that is very useful to practitioners and very interesting to theorists. Here, a brief history of the development of the technique leads to a description of the process. This is followed by a comparison to cognitive mapping, a similar technique applied to mapping thought processes rather than physical processes, and an illustrative longitudinal example of DSA.

Statistics show what gets measured gets done. Measuring and benchmarking contractor performance is a key driver of continual health and safety efforts in the oil and gas industry. Our research, drawn from 15 years of global experience with 450+ Clients and 60,000+ contractors, highlights the key leading and lagging performance indicators used in the oil and gas industry and introduces leading edge methods to identify vital Key Performance Indicators. Monitoring and benchmarking tools such as collection and tracking of contractor work hours, incident rates, action items, evaluations and written health and safety procedures are all crucial to effective ongoing management of contractor performance. In addition, having a system for contractors to be able to identify potential safety system gaps that may need their attention, can further drive improvements. Our paper demonstrates some basic data trending and analysis methods plus leading edge methods, including regression and correlation statistical analysis approaches being used in the industry to identify factors that are positively or negatively associated with increased or decreased health and safety performance. Such methods are useful in identifying vital Key Performance Indicators (KPI's) to measure and monitor. Real world analytical examples will be presented and discussed. Using data driven hiring decisions is a vital part of any prevention plan. Through use of a system for managing and evaluating contractor safety data, Clients have seen significant improvement in their contractors' performance. Case studies of clients who have seen improvement of more than 90% for their contractors' incident rates will be discussed.

In the frame of the Global Monitoring for Environment and Security (GMES) Space Component programme, the European Space Agency (ESA) undertook the development of a European Radar Observatory (Sentinel-1), a polar orbiting two-satellite constellation for the continuation and improvement of SAR operational services and applications. Satellite and payload are being built to provide routine, day-and-night, all-weather medium (typically 10 m) resolution observation capability. Ground infrastructure is provided for planning, mission control, data processing, dissemination and archiving. Free and open data access is provided. Data quality of the Sentinel-1 data products is shown along with uncertainty estimation of retrieved information products confirming specified performance and indicating application growth potential. The unique data availability performance of the Sentinel-1 routine operations makes the mission particularly suitable for emergency response support, marine surveillance, ice monitoring and interferometric applications such as detection of subsidence and landslides.

OBJECTIVES To describe the frequency and risk factors of non-B HIV-1 subtypes in men who have sex with men (MSM) in the UK. DESIGN Observational study. METHODS MSM diagnosed with HIV-1 infection from 1980-2007, with HIV genotype held in the UK HIV Drug Resistance Database were identified. Protease and reverse transcriptase sequences were collected and viral clade determined using the REGA algorithm. Associations between demographic variables and subtype were analysed using logistic regression. RESULTS The prevalence of non-B HIV-1 infection amongst MSM in the UK was 5.4% (437/8058). In the UK this increased with year of diagnosis from pre1996 to 2002, and has subsequently remained relatively stable at around 7-9% after 2002, with a recent increase in 2007 to 13%. Multivariate analysis showed that acquisition of non-B HIV-1 infection was independently associated with later year of HIV diagnosis (P < 0.001), black ethnicity (P < 0.001) and non-European country of birth (P = 0.01). Age was also associated with subtype with individuals aged 25-39 years being less likely to have non-B virus than those aged less than 25 years (P = 0.01). Restricting the analysis to white men born in the UK, the association between subtype and year of diagnosis remained statistically significant (P < 0.001), as did the association with age (P < 0.001). DISCUSSION The number of MSM in the UK infected with non-B clade HIV-1 is increasing, suggesting that the sociodemographic boundaries between HIV-1 viral subtypes globally are diminishing. Should viral subtypes be relevant to clinical disease progression or vaccine design, the changing pattern of distribution will need to be taken into account.

The progress of the Crown Research Institutes (CRIs) since their formation in 1992 from the dismantling of the centralised Department of Scientific and Industrial Research (DSIR) is charted. Particular attention is paid to the funding environment, characterised by the concept of contestability, in which the CRIs have operated. In recent years, the CRIs have lobbied for more funding stability arguing that contestability has resulted in fickle funding decisions, eroding their ability to plan for the long-term and build human capital. Certainly recent changes in policy reflect a greater concern with CRI capability. When the Government moved to increase the amount of core funding for CRIs, however, the universities, concerned that this would reduce their access to funding, argued that this 'stability' would result in ossification and less than excellent science. The paper concludes with some reflections on the contrast between the CSIRO and CRI cousins, and on the future for CRIs.

This paper concerns the performance of the Flexible Dynamic Block Adaptive Quantizer (FDBAQ), the on-board data compression scheme used by Sentinel-1A (S-1), the C-band Synthetic Aperture Radar (SAR) system for Earth Observation launched on 3rd April 2014. FDBAQ has been designed to deal with the high instrument data rate due to the high spatial resolution and large swath width. S-1 SAR is able to acquire long data take, corresponding to large volumes of data stored on-board. Since FD-BAQ has been implemented for the first time on S-1, the capabilities of such a compression scheme have not been tested on real data before. The purpose of this paper is to present the results of the analysis of real acquisitions acquired after the end of the Commissioning Phase, so in its full efficiency. FDBAQ is compared with the traditional Block Adaptive Quantizer (BAQ) compression scheme in terms of quantization noise level, average bit rate and signal to noise ratio.

This essay discusses Chien, Cornwell, and Pappu's (forthcoming) paper, “Sponsorship portfolio as brand image creation strategy.” Although Chien et al. (forthcoming) seek to enhance understanding of the impact of a brand's sponsorship portfolio on its brand image they are not completely successful in this endeavor. One of their key constructs, the event personality fit (EPF) construct, has no significant effect on brand meaning. This essay suggests that this finding is because of limitations in the brand personality metrics in the study and because of the tautological nature of the hypotheses proposals. Their sponsorship category relatedness (SCR) construct, however, is a useful construct for those seeking to assemble a portfolio of sponsored products that builds positive brand meaning for the sponsor's brand.

With an ever-growing global trend of outsourcing non-core business activities to third-party contractors across all industries, the challenge and opportunity lies in establishing a robust contractor management process. Drawing from experience from over 370 Hiring Clients and 55,000+ contractor companies, mostly from the oil and gas industry, several key elements have been identified that are strategic attributes of leading edge contractor management practices. These are communication, consequences, guidelines, integration, and technology. This paper demonstrates how these elements can foster an improved culture of prevention in the ever-growing sector of outsourced operations. These findings highlight the importance of consistent expectations and requirements tailored to local operating conditions in order to drive safety performance. Through use of a system for managing and evaluating contractor safety data, client companies have seen significant improvement in their contractors' performance. For companies that hire contractors, the elements discussed will assist by providing ideas for benchmarking and give useful and actionable takeaways for enhancing contractor management processes.

Decision system analysis is a conceptually simple technique that maps the process of group decisions over time. The data is gathered in a variety of ways, but most often some form of protocol analysis is the foremost tool. The data is then condensed and depicted as a flowchart for a specific decision. If several such flowcharts can be assembled within an industry, they can be melded together to form a generic guide that is very useful to practitioners and very interesting to theorists. Here, a brief history of the development of the technique leads to a description of the process. This is followed by a comparison to cognitive mapping (a similar technique applied to mapping thought processes rather than physical processes), and an illustrative longitudinal example of DSA.

Objective: HIV-1 is typically categorized by genetically distinct viral subtypes. Viral subtypes are usually compartmentalized by ethnicity and transmission group and, thus, convey important epidemiological information, as well as possibly influencing the rate of disease progression. We aim to describe the prevalence and time trends of subtypes observed among key populations living with HIV-1 in the UK. Design: Analyses of reverse transcriptase and protease sequences generated from HIV-1-positive antiretroviral-naive patients as part of routine resistance testing between 2002 and 2010 in all public health and NHS laboratories in the UK. Methods: Subtype was assigned centrally using the SCUEAL algorithm. Subtyping results were combined with data from the UK Collaborative HIV Cohort Study and the UK HIV and AIDS Reporting System. Analyses adjusted for the number of national HIV-1 diagnoses made each year within demographic subgroups. Viral subtypes were described overall, over time and by demographic subgroup. Results: Subtype B diagnoses (39.9%) have remained stable since 2005, whereas subtype C diagnoses (34.3%) were found to decline in prevalence from 2004. Across most demographic subgroups, the prevalence of non-B non-C subtypes has increased over time, in particular novel recombinant forms (9.9%), subtype G (2.7%), and CRF01 AE (2.0%). Conclusion: HIV-1 subtypes are increasingly represented across all demographic subgroups and this could be evidence of sexual mixing. Between 2002 and 2010, the prevalence of novel recombinant forms has increased in all demographic subgroups. This increasing genetic diversity and the effect of subtype on disease progression may impact future HIV-1 treatment and prevention.

Most debates and discussions regarding trends towards globalization and localization, occur in the over-arching context of the knowledge economy, and focus on the impact of these trends on innovation and competitiveness in the 'Triad' of Europe, Japan and the USA. However, in the knowledge economy, competitiveness is increasingly based upon access to knowledge, in the form of skills and capabilities, wherever it is located in the world including the smaller industrialized countries. This paper extends the discussion of the impacts of globalization and localization to encompass other nations and their 'national innovation systems'. Policy underpinning national systems to encourage innovation is increasingly being called into question by the general move towards globalization and localization. Multi-national enterprises (MNEs) and localized clusters in the emerging technologies determine and control technological paths beyond and through national borders. Small industrialized nations which have neither a br...

This study explores the relationship between brand image and brand equity in the context of sports sponsorship. Keller's (1993, 2003) customer-based brand equity models are the conceptual inspiration for the research, with Faircloth, Capella, and Alford's (2001) conceptual model – adapted from the work of Aaker (1991) and Keller (1993) – the primary conceptual model. The study focuses on the sponsorship relationship between the New Zealand All Blacks and their major sponsor and co-branding partner, adidas. The sporting context for the study was the 2003 Rugby World Cup held in Australia. Data were collected from two independent samples of 200 respondents, utilizing simple random sampling procedures. A bivariate correlation analysis was undertaken to test whether there was any correlation between changes in adidas' brand image and adidas' brand equity as a result of the All Blacks' performance in the 2003 Rugby World Cup. Results support the view that Keller (1993, 2003) proposes that brand image is antecedent to the brand equity construct. Results are also consistent with the findings of Faircloth et al. (2001) that brand image directly impacts brand equity.

TPS5612 Background: BNC105P is a tubulin polymerization inhibitor and a vascular disrupting agent (VDA). In vivo exposure to BNC105P leads to selective damage of tumor vasculature in both primary and metastatic lesions, causing disruption of blood flow to tumors, hypoxia, and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells, including ovarian cancer cell lines. Pre-clinical data has demonstrated synergistic activity of BNC105P when combined with platinum or with gemcitabine, supporting the proposed study design. This study will determine the safety and efficacy of BNC105P in ovarian cancer when used in combination with gemcitabine-carboplatin. The target population is women with ovarian or primary peritoneal cancers who progressed 4 to 9 months after first-line platinum based chemotherapy, or 4 to 12 months after second line platinum based chemotherapy. Methods: A single arm phase I will be used to determine the phase II dose for the triplet combination (3-6 subjects per dose level, maximum of 24 subjects). Four dose levels of BNC105P (12-16 mg/m2) and gemcitabine (800-1000 mg/m2) will be assessed. The dose of carboplatin will be set at AUC 4. Enrolment to cohort 2 started in January 2013. The phase II component will consist of a 2-arm, randomized (1:1) study of BNC105P, gemcitabine and carboplatin versus gemcitabine and carboplatin alone. The primary endpoint for the phase II trial is objective response rate (ORR, according to RECIST 1.1 and/or GCIG CA125 criteria. An ORR of 40% or more with the experimental regimen would be considered worthy of further investigation, assuming an ORR of 20% with the control regimen. 110 phase II participants are planned (N = 55/arm). Treatment allocation will be balanced using minimization for the study site, target lesions according to RECIST (present vs. absent), progression free interval from last platinum based chemotherapy regimen (

7079^ Background: BNC105P is a tubulin polymerization inhibitor that acts as a Vascular Disrupting Agent (VDA), has direct cytotoxic effects, and had preclinical and phase I activity in MPM. This aim of this study was to determine activity and safety of BNC105P as second-line therapy after pemetrexed and a platin in MPM. Methods: Eligible patients had progressive MPM, prior pemetrexed and platinum, measurable disease by modified RECIST, ECOG 0-1, and adequate organ and cardiovascular function. Important exclusions included recent thromboembolic, cardiovascular or cerebrovascular disease, or therapeutic anticoagulation. Pts received BNC105P (16 mg/m2 IV) Day 1 + 8 q21d until progression or toxicity. The primary endpoint was centrally reviewed objective tumour response rate (RR); the Simon 2-stage design assumed a RR of interest of 20% and a RR of no interest of 5%, with α = β = 0.05. Continuation past first stage accrual required >1 objective response in 24 patients. Results: 30 subjects were accrued over 10 months (90% male; median age 65 (range 41-83); 77% ECOG PS 1; histology epithelioid (67%), biphasic (10%), sarcomatoid (7%), other/unspecified (17%)). All pts received at least one dose of study drug; pts received a median of 2 cycles and median dose intensity was 100%. No significant haematologic, biochemical, peripheral neurotoxic or cardiac adverse events (AEs) including hypertension were observed. Grade 3 or 4 AEs occurred in 10 pts (33%). There were 2 deaths on study: 1 due to stroke, the other due to pneumonia and respiratory failure. We observed 1 partial response (3%) and 13 pts with SD as their best response (43%). Median progression free survival was 1.5 mo (95% CI 1.4-2.4); median overall survival was 8.7 mo (95% CI 3.8-NR). Lung function and QOL data was collected. Biomarker analyses correlating to pharmacological changes induced by BNC105P are ongoing and will be presented. Conclusions: BNC105P was safe and tolerable but its single agent response rate failed to meet the pre-specified primary endpoint of interest.

BNC105 is a small molecule that exerts anti-cancer activity through disruption of tubulin polymerization. BNC105 is unique in its ability to selectively block tumor blood flow resulting in hypoxia and cancer cell necrosis. A prodrug formulation, BNC105P, is under evaluation in a phase I/II clinical trial for metastatic renal cell carcinoma in combination with the mTOR inhibitor Everolimus. With the aim of expanding the development of BNC105 in the clinic, we investigated its activity in preclinical models of ovarian cancer. Despite modest improvements in patient outcomes as a result of surgery or platinum based chemotherapy, the majority of ovarian cancer patients relapse and die of their disease. There is a clear unmet medical need for more effective systemic therapy. The activity of BNC105 on the human ovarian carcinoma cell line A2780 and a derived cisplatin-resistant sub-line, A2780cis, was investigated using in vitro proliferation assays. BNC105 was a potent inhibitor of proliferation in both the A2780 and A2780cis cell lines with an IC50 of 0.3 and 0.1 nM respectively. In comparison, cisplatin and carboplatin were considerably less potent against A2780 with an IC50 of 330 nM and 7822 nM respectively. Both cisplatin and carboplatin were inactive against the sub-line A2780cis (IC50 >5 uM). BNC105 was also a potent disruptor of tumoral blood flow in A2780cis solid tumors grown subcutaneously in Balbc nu/nu mice. Tumors in mice treated with BNC105P exhibited a clear pattern of cavitation, with the center being completely deprived of blood perfusion. A small amount of blood perfusion was evident in the periphery of these tumors. In contrast, tumors obtained from animals treated with the vehicle control displayed dense blood perfusion throughout. Based on the observation of direct proliferative activity against A2780cis cells and the disruption of blood circulation in A2780cis tumors, it was reasoned that BNC105P treatment should induce tumor growth inhibition and increase survival in animals bearing A2780cis tumors. Mice bearing A2780cis solid tumors were treated with two weekly doses of BNC105P at 24mg/kg. For comparison purposes, separate animal groups bearing A2780cis tumors were treated with either cisplatin at 4mg/kg or carboplatin at 50mg/kg. Consistent with the lack of activity exhibited by platinum agents for these cells in vitro, there was no therapeutic benefit seen in animals treated with either platinum agent. In contrast, BNC105P treatment resulted in a robust inhibition of tumor growth (81% reduction compared to control) and improved overall survival. Our data demonstrate the potential therapeutic utility of BNC105 in suppressing the growth of ovarian tumors that respond poorly to platinum based therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2774. doi:1538-7445.AM2012-2774

TPS194 Background: Treatment options remain limited in progressive metastatic renal cell carcinoma (mRCC) for patients who are refractory to tyrosine kinase inhibitors (TKI). Treatment with everoli...

3054 Background: BNC105P is a novel agent which inhibits tubulin polymerization and acts as a VDA. BNC105P is a phosphorylated parent compound which rapidly converts to the active agent BNC105. BNC...

The novel agent, BNC105, is a tubulin polymerization inhibitor which acts as a vascular disruption agent (VDA). BNC105 exhibits 100-fold selectivity for activated endothelial cells compared to quiescent endothelial cells, providing a large differential between effects on cancer vasculature and normal vasculature. We developed a tubulin fractionation assay that enables evaluation of tubulin polymerisation changes in peripheral blood mononuclear cell samples (PBMCs) obtained from patients treated with BNC105. The assay capitalizes on the mass differences between polymerized and depolymerised tubulin to separate each fraction in a density gradient by ultracentrifugation. Experimental conditions during the extraction process were optimised to maintain the polymerisation state of tubulin. This optimisation was carried out in cell lines and PBMCs from healthy volunteers. Critical parameters include temperature, GTP concentration, DMSO concentration, pH, and buffer density. Tubulin monomer and polymer extracts were resolved using SDS-PAGE and transferred onto nitrocellulose membranes followed by detection using βI tubulin specific antibodies. The tubulin bands were analysed by densitometry and normalized to an actin loading control. Following exposure of cell lines or PBMCs to tubulin polymerisation inhibitors for a period of 60 minutes, the depolymerised tubulin fraction increased, while the polymerised tubulin fraction decreased. Conversely, exposure to tubulin polymerizing agents caused a greater proportion of tubulin to appear in the polymerized fraction. We used this method to evaluate the tubulin polymerisation status in PBMC samples obtained from cancer patients treated with BNC105. Samples were obtained prior to dosing and at 1, 2, 3-5, 7, and 24 hours post-dosing. Based on the data obtained, BNC105 treatment caused an 80% reduction in the polymerised tubulin fraction at the 1, 2 and 3-5 hour sampling time points. The amount of tubulin in the polymerised fraction returned to pre-dose levels by the 7 hour post-dose time point. The pharmacokinetic profile of BNC105 shows a steep curve reaching Cmax at around 20 minutes post-administration, followed by plasma clearance with no BNC105 detectable after the 7 hour time point. The pharmacokinetics of BNC105 supports our tubulin depolymerisation data with respect to response time and the subsequent recovery period. These results were reproducible, and have shown a similar pattern in all patients tested to date. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2768.

e14512 Background: BNC105P is a novel anticancer agent that inhibits tubulin polymerization and acts as a VDA. BNC105P is a phosphorylated parent compound which rapidly becomes the active agent BNC105. BNC105 exhibits 100-fold specificity for activated endothelial cells compared to quiescent endothelial cells. Methods: BNC105P (2.1 to 18.9 mg/m2) was given IV over 10 min on day 1 and 8 every 21 days to patients (pts) with advanced solid tumors (ECOG 0–2) and adequate organ function. The objectives were to determine safety, tolerability, MTD and pharmacokinetics (PK). A pharmacodynamic response was evaluated using DCE-MRI with two baseline and two post dose assessments (3–6, 24 h). DLTs were determined during the first 21 days. Results: 9 pts (7 M; 2 F), median age 60 years have been enrolled with one pt each at 2.1 and 4.2 mg/m2. At 8.4 mg/m2, one pt experienced Grade 2 (Gr 2) mucositis and a switch to a ‘3+3’ design occurred. No DLTs have been observed in 3 pts at 12.6 mg/m2 and 1 pt at 18.9 mg/m2. Notable toxicity includes one episode of Gr 1 febrile episode possibly related to infusion, two episodes of Gr 1 fatigue and one Gr 1 rash. PK data of BNC105 indicates a linear increase in plasma AUC levels (Table) and plasma half life of < 0.5 h. Best observed responses were SD in 2/9 pts including one pt with mesothelioma (progression at entry) with SD up to week 22 (8.4 mg/m2). At doses ≥ 8.4 mg/m2, DCE-MRI images indicate changes in tumor perfusion post-dose. Two pts at 12.6 mg/m2 had a decrease in Ktrans values of 6 and 15 % compared to baseline. Conclusions: Pharmacodynamically active doses have been achieved with plasma drug levels correlating with active preclinical plasma exposure. To date, no excess toxicity has been observed at doses up to 18.9 mg/m2. [Table: see text] [Table: see text]