Background:Compared with normal cells, tumour cells contain elevated levels of reactive oxygen species (ROS). Increased levels of the antioxidant protein NAD(P)H:quinone oxidoreductase 1 (NQO1) and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) correlate negatively with the survival of patients with pancreatic cancer. Napabucasin is an investigational, orally administered ROS generator bioactivated by NQO1. Methods:In the open-label, phase 3 CanStem111P study (NCT02993731), adults with previously untreated metastatic pancreatic adenocarcinoma (mPDAC) were randomised (1:1) to napabucasin plus nab-paclitaxel with gemcitabine or nab-paclitaxel with gemcitabine alone. The primary endpoint was overall survival (OS). In exploratory analyses, OS was evaluated in the subgroup of patients with tumours positive for pSTAT3 (biomarker-positive). Findings:Between 30 January 2017 and 20 February 2019, a total of 1779 patients were screened across 165 study sites in Austria, Australia, Belgium, Canada, China, Czech Republic, France, Germany, Italy, Japan, Korea, Netherlands, Poland, Portugal, Russia, Singapore, Spain, Taiwan, Ukraine, and the US. Of the 565 and 569 patients randomised to the napabucasin and control treatment arms, respectively, 206 and 176 were biomarker-positive. Median (95% confidence interval [CI]) OS in the napabucasin and control treatment arms was 11.4 (10.5-12.2) and 11.7 (10.7-12.7) months, respectively (hazard ratio, 1.07; 95% CI, 0.93-1.23). Due to the lack of OS improvement in the napabucasin arm, CanStem111P was terminated due to futility. In the biomarker-positive subgroup, no difference between treatment arms was found for OS. Grade ≥3 adverse events were reported in 85.4% and 83.9% of napabucasin-treated and control-treated patients, respectively. The incidence of gastrointestinal-related grade ≥3 events was higher with napabucasin (diarrhoea: 11.6% vs 4.9%; abdominal pain: 10.0% vs 4.8%). Interpretation:Our findings suggested that although the addition of napabucasin to nab-paclitaxel with gemcitabine did not improve efficacy in patients with previously untreated mPDAC, the safety profile of napabucasin was consistent with previous reports. CanStem111P represents the largest cohort of patients with mPDAC administered nab-paclitaxel with gemcitabine in the clinical trial setting. Our data reinforce the value of nab-paclitaxel plus gemcitabine as a platform for novel therapeutics approaches in mPDAC. Funding:The Sumitomo Pharma Oncology, Inc.

Supplementary Figure 10 from Fusion between Intestinal Epithelial Cells and Macrophages in a Cancer Context Results in Nuclear Reprogramming

697 Background: Pre-operative therapy for resectable pancreatic ductal adenocarcinoma (PDAC) may eliminate micro-metastatic disease early and help achieve negative surgical margins. The present study is based on the hypothesis that gemcitabine/nab-paclitaxel chemotherapy followed by chemo-radiation with fluoropyrimidine is a feasible and efficacious pre-operative treatment for borderline resectable or node-positive PDAC. Methods: This is a single-arm phase II trial to evaluate pre-operative treatment with 2 cycles of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on days 1, 8, 15 every 28 days followed by 50.4 Gy of intensity-modulated radiation therapy over 28 fractions with concurrent 5-fluorouracil or capecitabine prior to pancreatic resection. Patients were eligible if they met borderline resectable criteria or had abnormal regional nodes visible on contrast CT. After surgery, they were eligible to receive up to 4 additional cycles of gemcitabine/nab-paclitaxel. The primary endpoint was the R0 resection rate. Secondary endpoints included response to pre-operative therapy, overall toxicities, relapse-free survival, and overall survival. Results: Nineteen of 24 screened patients have been enrolled. Median age was 68, 10 (53%) were female, and 4 (21%) were non-Caucasian. Eleven (78%) had head of pancreas cancers, 13 (68%) exhibited both arterial and venous involvement, and 12 (63%) had positive clinical nodes. All 19 patients received 2 months of gemcitabine/nab-paclitaxel, of which 17 patients continued to chemo-radiation (1 developed metastatic disease and 1 moved out of state). In the interval between chemo-radiation and surgery, 3 developed metastatic disease, 1 became unresectable, 1 withdrew from study, and 1 was deemed too frail for surgery. Nine have undergone successful pancreatic resection, and 2 are pending resection. Conclusions: Pre-operative gemcitabine/nab-paclitaxel followed by chemo-radiation with fluoropyrimidine is feasible in patients with borderline resectable PDAC and represents another strategy to FOLFIRINOX-based therapy. A planned interim analysis is ongoing. Clinical trial information: NCT02427841.

Supplementary Movie 2 from Fusion between Intestinal Epithelial Cells and Macrophages in a Cancer Context Results in Nuclear Reprogramming

Supplementary Movie 1 from Fusion between Intestinal Epithelial Cells and Macrophages in a Cancer Context Results in Nuclear Reprogramming

Supplementary Figure 9 from Fusion between Intestinal Epithelial Cells and Macrophages in a Cancer Context Results in Nuclear Reprogramming

Supplementary Tables 1-3 from Fusion between Intestinal Epithelial Cells and Macrophages in a Cancer Context Results in Nuclear Reprogramming

Supplementary Figures 1-8 from Fusion between Intestinal Epithelial Cells and Macrophages in a Cancer Context Results in Nuclear Reprogramming

Abstract. This paper seeks to identify opportunities to integrate Earth observations (EO) into flood forecast-based early action and propose future directions for research and collaboration between EO and humanitarian communities. Forecast-based early action (FbA) is an approach to shift disaster response toward anticipation to mitigate impacts to at-risk communities; however, timely and accurate information is needed in the development of data-based triggers and thresholds for action. Therefore, this paper considers the readiness of a wide range of EO for flood monitoring and forecasting in the design, operations, and evaluation phases of FbA. The most significant opportunities for EO to inform FbA efforts lie in the design and evaluation phases, as EO can aid in the development of impact-based triggers. The EO products most readily applicable include precipitation, streamflow estimates, and exposure mapping, and those requiring the greatest amount of further research include vulnerability and impact assessments. This paper identifies collaboration opportunities for the EO and humanitarian communities to create tailored products, such as overlays combining flood extents with exposure maps. Such collaboration opportunities can be fostered by open data sharing, data verification efforts, and incentives for supporting boundary organizations capable of enabling the use of EO for FbA.

AbstractIn the first phase, SERVIR-HKH placed high importance on developing application products and tools to demonstrate the usefulness of earth observation (EO) and geospatial information in supporting decision-making on various thematic areas including land cover mapping, forest fire monitoring, agriculture and food security, disasters, and air quality monitoring (Chap. 1).

Background Smoking has significant negative impact on periodontal health and treatment outcomes. The molecular effects of smoking on oral immune homeostasis have not been fully elucidated. The present study aimed to provide a comprehensive assessment of smoking-associated gene expression changes in healthy palatal mucosa and to identify potentially implicated immunologic pathways. Methods Palatal biopsies, in the form of connective tissue grafts, were obtained from periodontally healthy smokers and non-smokers. Smoking status was biochemically verified (exhaled air CO and serum cotinine). Tissue samples were processed for next generation sequencing, quantitative real-time polymerase chain reaction (qPCR), and immunohistochemistry. Gene set enrichment/pathway analysis and correlation analysis between gene expression and serum cotinine levels were also performed. Results Analysis of palatal tissues from 12 non-smokers and 10 smokers identified 830 significantly (P <0.05) differentially expressed genes (DEGs), 249 with fold change (FC) >2. Most increased in expression (>= 5-FC) were CYP1A1, CYP1B1, and USP17L9P; most decreased (>= 6-FC) were IL36A, DEFB4A, DEFB4B, SPRR2F, CCL20, KLK6, and ADH4. 203 DEGs (FC >2) were significantly correlated with serum cotinine levels. Significant enrichment pathways for cotinine-associated genes include antimicrobial humoral response, regulation of humoral response and various metabolic processes. qPCR and immunohistochemistry confirmed gene and protein expression of selected DEGs. Conclusions Smoking has a significant effect on the transcriptome of normal human palatal mucosa and seems to target genes important for innate immune defenses, which may prove to be one of the key mechanisms by which tobacco smoking leads to increased periodontitis susceptibility.

Dam construction in mainland Southeast Asia has increased substantially in recent years. Most dams have the potential to generate value, however, potential and existing impacts include alterations in water regimes, loss and degradation of natural forests and bio-diversity. For mapping impacts, we have developed the Reservoir Mapping Tool for the greater Mekong region designed in ArcGIS Desktop 10.5 ModelBuilder, with dam point location and digital elevation model SRTM-30 m on a publicly available web interface which provides inundated area and dam volume based on user inputs. We validate our results and find excellent agreement with ground data from the Lanh Ra dam located in Vietnam. Further validation and error quantification are done comparing results of three different DEMS's and compared with reported values. We also illustrate various application areas using this information in combination with other geospatial layers, which could provide key inputs towards assessing overall social impacts of dams.

Land cover maps are a critical component to make informed policy, development, planning, and resource management decisions. However, technical, capacity, and institutional challenges inhibit the creation of consistent and relevant land cover maps for use in developing regions. Many developing regions lack coordinated capacity, infrastructure, and technologies to produce a robust land cover monitoring system that meets land management needs. Local capacity may be replaced by external consultants or methods which lack long-term sustainability. In this study, we characterize and respond to the key land cover mapping gaps and challenges encountered in the Lower Mekong (LMR) and Hindu Kush-Himalaya (HKH) region through a needs assessment exercise and a collaborative system design. Needs were assessed using multiple approaches, including focus groups, user engagement workshops, and online surveys. Efforts to understand existing limitations and stakeholder needs resulted in a co-developed and modular land cover monitoring system which utilizes state-of-the-art cloud computing and machine learning which leverages freely available Earth observations. This approach meets the needs of diverse actors and is a model for transnational cooperation.

People, livelihoods, and infrastructure in Myanmar suffer from devastating monsoonal flooding on a frequent basis. Quick and effective management of flood risk relies on planning and preparedness to ensure the availability of supplies, shelters and emergency response personnel. The mandated government agency Department of Disaster Management (DDM) as well as local and international organizations play roles in producing, disseminating, and using accurate and timely information on flood risk. Currently, systematic flood risk maps are lacking, which leaves DDM to rely on inconsistent historic reports and local knowledge to inform their emergency planning. Although these types of knowledge are critical, they can be complemented to reduce bias and human error to planning processes and decisions. As such, the present situation has led to ineffective distribution of emergency response resources prior to flooding, leaving vulnerable populations less-than-prepared for inevitable flood events. Given these issues, we have developed a flood risk decision-support tool in collaboration with DDM. The tool uses surface water maps developed by the Joint Research Center (JRC), which were derived from more than 30 years of Landsat imagery. We have also incorporated population data, land cover data, and other information on flood exposure and vulnerability to create the first scalable and replicable Flood Risk Index (FRI) for flood risk reduction in Myanmar.