RAF1 kinase activity is dispensable for KRAS/p53 mutant lung tumor progression.

We thank Dr. Shiva Malek and her colleagues (Genentech Inc.) for sharing their results with us before publication. We also thank M. San Roman, R. Villar, M.C. Gonzalez, A. Lopez, N. Cabrera, P. Villanueva, J. Condo, O. Dominguez, and S. Ortega for excellent technical support. This work was supported by grants from the European Research Council (ERC-2015-AdG/695566, THERACAN); the Spanish Ministry of Science, Innovation, and Universities (RTC-2017-6576-1 and RTI2018094664-B-I00) and the Autonomous Community of Madrid (B2017/BMD-3884 iLUNG-CM) to M.B., as well as by a grant from the Spanish Ministry of Science, Innovation and Universities (RTI2018-094664-B-I00) to M.B. and M.M. M.B. is a recipient of an Endowed Chair from the AXA Research Fund. M.S., P.N., and F.F.-G. were supported by FPU fellowships from the Spanish Ministry of Education. L.E.-B. was a recipient of an FPI fellowship from the Spanish Ministry of Economy and Competitiveness. S.G.-A. is a recipient of a postdoctoral fellowship from the Asociacion Espanola Contra el Cancer (AECC).S

Toxicity results after treatment with Electronic Brachytherapy in patients with endometrial cancer

Poster Session [EP-2226] Purpose or Objective To analyse the toxicity outcomes after treatment with Electronic Brachytherapy (XB) in postsurgical endometrial cancer patients treated at our medical centre. Material and Methods Prospective study in which we selected 94 patients, between September/2015 and September/2017, that received treatment with XB administered twice a week after endometrial cancer surgery, with IMRT planificati on. The patients were divided in two groups: Group 1 (57/94) considered high risk received external beam radiotherapy (46Gy) followed by XB (15Gy in 5Gy fractions) and group 2 (37/94) considered intermediate risk received exclusive XB (25Gy in 5Gy fraction s). We analysed the median dose in bladder, rectum and sigmoid D2cc, V50, V35 with XB comparing the doses with Ir192. The vaginal mucosa, gastrointestinal (GI) and genitourinary (GU) toxicities were analysed with the Common Terminology Criteria for Adverse Events (CTCAE 4.0) scale. Results The median dose in bladder with XB vs. Ir192 was: 2cc 62.9 vs. 69.9%, V50 7.1 vs. 12.6Gy, V35 15 vs. 28.1. In rectum XB vs. Ir192 was: D 2cc 64.01% vs. 67.7%, V50 7.8 vs. 10.9Gy, V35 16.5 vs. 31.8Gy. In sigmoid XB vs. Ir 192 was: D 50.37%vs. 58.0%, V50 8.8 vs. 16.2Gy, V35 21.2 vs. 37.5Gy. The median follow- up was 11 months (range 1 - 23, 9 months). In group 1, acute vaginal mucositis (G1) was observed in 35.08% of the patients, GI toxicity (G1) in 5.26% and GU toxicity (G1) in 10.52%. In group 2, we observed acute vaginal mucositis G1 in 45% of the patients and G2 in 10.81%, GI toxicity (G1) occurred in 2.7% and GU toxicity (G1) was present in 16.21%. There was no grade 3 or greater toxicity in any of the groups. Late toxici ty was observed in only 4 patients: Mucositis (G1) in 3 patients and GU toxicity (G1) in 1 patient. Conclusion The dose received by the organs at risk with the XB is less compared to Ir192, with a good coverage of the PTV. The greater toxicity was observe d immediately after the treatment was finished with an important reduction of the symptoms after 6 months. This technique shows excellent results as for toxicity

Utility of a Short Neuropsychological Protocol for Detecting HIV-Associated Neurocognitive Disorders in Patients with Asymptomatic HIV-1 Infection

Human Immunodeficiency Virus type 1 (HIV-1) infection is a chronic disease that affects ~40 million people worldwide. HIV-associated neurocognitive disorders (HAND) are common in individuals with HIV-1 Infection, and represent a recent public health problem. Here we evaluate the performance of a recently proposed short protocol for detecting HAND by studying 60 individuals with HIV-1-Infection and 60 seronegative controls from a Caribbean community in Barranquilla, Colombia. The short evaluation protocol used significant neuropsychological tests from a previous study of asymptomatic HIV-1 infected patients and a group of seronegative controls. Brief screening instruments, i.e., the Mini-mental State Examination (MMSE) and the International HIV Dementia Scale (IHDS), were also applied. Using machine-learning techniques, we derived predictive models of HAND status, and evaluated their performance with the ROC curves. The proposed short protocol performs exceptionally well yielding sensitivity, specificity, and overall prediction values >90%, and better predictive capacity than that of the MMSE and IHDS. Community-specific cut-off values for HAND diagnosis, based on the MMSE and IHDS, make this protocol suitable for HAND screening in individuals from this Caribbean community. This study shows the effectivity of a recently proposed short protocol to detect HAND in individuals with asymptomatic HIV-1-Infection. The application of community-specific cut-off values for HAND diagnosis in the clinical setting may improve HAND screening accuracy and facilitate patients’ treatment and follow-up. Further studies are needed to assess the performance of this protocol in other Latin American populations

Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas.

KRAS mutant lung adenocarcinomas remain intractable for targeted therapies. Genetic interrogation of KRAS downstream effectors, including the MAPK pathway and the interphase CDKs, identified CDK4 and RAF1 as the only targets whose genetic inactivation induces therapeutic responses without causing unacceptable toxicities. Concomitant CDK4 inactivation and RAF1 ablation prevented tumor progression and induced complete regression in 25% of KRAS/p53-driven advanced lung tumors, yet a significant percentage of those tumors that underwent partial regression retained a population of CDK4/RAF1-resistant cells. Characterization of these cells revealed two independent resistance mechanisms implicating hypermethylation of several tumor suppressors and increased PI3K activity. Importantly, these CDK4/RAF1-resistant cells can be pharmacologically controlled. These studies open the door to new therapeutic strategies to treat KRAS mutant lung cancer, including resistant tumors.We thank S. Ortega for the generation of the Cdk4FxKD mouse model; and M. San Roman, R. Villar, M. C. Gonzalez, A. Lopez, N. Cabrera, P. Villanueva, J. Condo, J. Klett, A. Cebria, A. Otero, O. Dominguez, G. Luengo, G. Garaulet, F. Mulero, and D. Megias for excellent technical support. This work was supported by European Research Council Grant ERC-2015-AdG/695566, THERACAN, Spanish Ministry of Science, Innovation, and Universities Grant RTC-2017-6576-1, and the Autonomous Community of Madrid Grant B2017/BMD-3884 iLUNG-CM (to M.B.); Spanish Ministry of Science, Innovation, and Universities Grant RTI2018-094664B-I00 (to M.B. and M.M.); and National Natural Science Foundation of China Grant 31771469 (to H.W.). M.B. is a recipient of an Endowed Chair from the AXA Research Fund. L.E.-B. is the recipient of an FPI fellowship from the Spanish Ministry of Economy and Competitiveness. F.F.-G., M.S., and P.N. were supported by an FPU fellowships from the Spanish Ministry of Education.S

The ROSAT International X-ray/Optical Survey (RIXOS): source catalogue

We describe the ROSAT International X-ray/Optical Survey (RIXOS), a medium-sensitivity survey and optical identification of X-ray sources discovered in ROSAT high Galactic latitude fields (|b|>28°) and observed with the Position Sensitive Proportional Counter (PSPC) detector. The survey made use of the central 17 arcmin of each ROSAT field. A flux limit of 3×10−14 erg cm−2 s−1 (0.5–2 keV) was adopted for the survey, and a minimum exposure time of 8000 s was required for qualifying ROSAT observations. X-ray sources in the survey are therefore substantially above the detection threshold of each field used, and many contain enough counts to allow the X-ray spectral slope to be estimated. Spectroscopic observations of potential counterparts were obtained of all sources down to the survey limit in 64 fields, totalling a sky area of 15.77 deg2. Positive optical identifications are made for 94 per cent of the 296 sources thus examined. A further 18 fields (4.44 deg2), containing 105 sources above the 3×10−14 erg cm−2 s−1 survey limit, are completely optically identified to a higher flux of 8×10−14 erg cm−2 s−1 (0.5–2 keV). Optical spectroscopic data are supplemented by deep CCD imaging of many sources to reveal the morphology of the optical counterparts, and objects too faint to register on Sky Survey plates. The faintest optical counterparts have R∼22. This paper describes the survey method, and presents a catalogue of the RIXOS sources and their optical identifications. Finding charts based on Sky Survey data are given for each source, supplemented by CCD imaging where necessary

A GHEP-ISFG collaborative study on the genetic variation of 38 autosomal indels for human identification in different continental populations

A collaborative effort was carried out by the Spanish and Portuguese Speaking Working Group of the International Society for Forensic Genetics (GHEP-ISFG) to promote knowledge exchange between associate laboratories interested in the implementation of indel-based methodologies and build allele frequency databases of 38 indels for forensic applications. These databases include populations from different countries that are relevant for identification and kinship investigations undertaken by the participating laboratories. Before compiling population data, participants were asked to type the 38 indels in blind samples from annual GHEP-ISFG proficiency tests, using an amplification protocol previously described. Only laboratories that reported correct results contributed with population data to this study. A total of 5839 samples were genotyped from 45 different populations from Africa, America, East Asia, Europe and Middle East. Population differentiation analysis showed significant differences between most populations studied from Africa and America, as well as between two Asian populations from China and East Timor. Low FST values were detected among most European populations. Overall diversities and parameters of forensic efficiency were high in populations from all continents.RP is supported by a postdoctoral fellowship (SFRH/BPD/81986/2011) awarded by the Portuguese Foundation for Science and Technology (FCT) and co-financed by the European Social Fund (Human Potential Thematic Operational Programme – POPH

The Center for Environmental Kinetics Analysis: an NSF- and DOE-funded Environmental Molecular Science Institute (EMSI) at Penn State

Physicochemical and microbiological processes taking place at environmental interfaces influence natural processes as well as the transport and fate of environmental contaminants, the remediation of toxic chemicals, and the sequestration of anthropogenic CO2. A team of scientists and engineers has been assembled to develop and apply new experimental and computational techniques to expand our knowledge of environmental kinetics. We are also training a cohort of talented and diverse students to work on these complex problems at multiple length scales and to compile and synthesize the kinetic data. Development of the human resources capable of translating molecular-scale information into parameters that are applicable in real world, field-scale problems of environmental kinetics is a major and relatively unique objective of the Institute's efforts. The EMSI team is a partnership among 10 faculty at The Pennsylvania State University (funded by the National Science Foundation Divisions of Chemistry and Earth Sciences), one faculty member at Juniata College, one faculty member at the University of Florida, and four researchers drawn from Los Alamos National Laboratory, Pacific Northwest National Laboratory, and Lawrence Berkeley National Laboratory (funded by the Department of Energy Division of Environmental Remediation Sciences). Interactions among the applied and academic scientists drives research approaches aimed toward solving important problems of national interest. The Institute is organized into three interest groups (IGs) focusing on the processes of dissolution (DIG), precipitation (PIG), and microbial reactions at surfaces (BIG). Some of the research activity from each IG is highlighted to the right. The IGs interact with each other as each interest group studies reactions across the molecular, microscopic, mesoscopic and, in most cases, field scales. For example, abiotic dissolution and precipitation reactions of Fe oxides as studied in the Dissolution IG provides the baseline for kinetic behavior as the BIG researches the interaction of microorganisms with these same minerals. The attachment of bacteria and redox chemistry that occurs between microorganisms and minerals are critical factors in maintaining groundwater quality and remediation of many toxic waste sites and is one of the main thrusts of research within our EMSI. The IGs also participate in using visualization tools to promote greater understanding of complex environmental data. As a whole, CEKA is also working to compile environmental kinetics data into a cyberinfrastructure and database. The database can be accessed at: http://keystone.ist.psu.edu/

Performance and Operation of the CMS Electromagnetic Calorimeter

The operation and general performance of the CMS electromagnetic calorimeter using cosmic-ray muons are described. These muons were recorded after the closure of the CMS detector in late 2008. The calorimeter is made of lead tungstate crystals and the overall status of the 75848 channels corresponding to the barrel and endcap detectors is reported. The stability of crucial operational parameters, such as high voltage, temperature and electronic noise, is summarised and the performance of the light monitoring system is presented

A live dengue virus vaccine carrying a chimeric envelope glycoprotein elicits dual DENV2-DENV4 serotype-specific immunity

The four dengue virus serotypes co-circulate globally and cause significant human disease. Dengue vaccine development is challenging because some virus-specific antibodies are protective, while others are implicated in enhanced viral replication and more severe disease. Current dengue tetravalent vaccines contain four live attenuated serotypes formulated to theoretically induce balanced protective immunity. Among the number of vaccine candidates in clinical trials, only Dengvaxia is licensed for use in DENV seropositive individuals. To simplify live-virus vaccine design, we identify co-evolutionary constraints inherent in flavivirus virion assembly and design chimeric viruses to replace domain II (EDII) of the DENV2 envelope (E) glycoprotein with EDII from DENV4. The chimeric DENV2/4EDII virus replicates efficiently in vitro and in vivo. In male macaques, a single inoculation of DENV2/4EDII induces type-specific neutralizing antibodies to both DENV2 and DENV4, thereby providing a strategy to simplify DENV vaccine design by utilizing a single bivalent E glycoprotein immunogen for two DENV serotypes

The CoDiNOS trial protocol: an international randomised controlled trial of intravenous sildenafil versus inhaled nitric oxide for the treatment of pulmonary hypertension in neonates with congenital diaphragmatic hernia

INTRODUCTION: Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that impairs normal lung development, causing pulmonary hypertension (PH). PH in CDH newborns is the main determinant for morbidity and mortality. Different therapies are still mainly based on 'trial and error'. Inhaled nitric oxide (iNO) is often the drug of first choice. However, iNO does not seem to improve mortality. Intravenous sildenafil has reduced mortality in newborns with PH without CDH, but prospective data in CDH patients are lacking. METHODS AND ANALYSIS: In an open label, multicentre, international randomised controlled trial in Europe, Canada and Australia, 330 newborns with CDH and PH are recruited over a 4-year period (2018-2022). Patients are randomised for intravenous sildenafil or iNO. Sildenafil is given in a loading dose of 0.4 mg/kg in 3 hours; followed by continuous infusion of 1.6 mg/kg/day, iNO is dosed at 20 ppm. Primary outcome is absence of PH on day 14 without pulmonary vasodilator therapy and/or absence of death within the first 28 days of life. Secondary outcome measures include clinical and echocardiographic markers of PH in the first year of life. We hypothesise that sildenafil gives a 25% reduction in the primary outcome from 68% to 48% on day 14, for which a sample size of 330 patients is needed. An intention-to-treat analysis will be performed. A p-value (two-sided) <0.05 is considered significant in all analyses. ETHICS AND DISSEMINATION: Ethics approval has been granted by the ethics committee in Rotterdam (MEC-2017-324) and the central Committee on Research Involving Human Subjects (NL60229.078.17) in the Netherlands. The principles of the Declaration of Helsinki, the Medical Research Involving Human Subjects Act and the national rules and regulations on personal data protection will be used. Parental informed consent will be obtained. TRIAL REGISTRATION NUMBER: NTR6982; Pre-results