Efficacy and epigenetic interactions of novel DNA hypomethylating agent guadecitabine (SGI-110) in preclinical models of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a deadly malignancy characterized at the epigenetic level by global DNA hypomethylation and focal hypermethylation on the promoter of tumor suppressor genes. In most cases it develops on a background of liver steatohepatitis, fibrosis, and cirrhosis. Guadecitabine (SGI-110) is a second-generation hypomethylating agent, which inhibits DNA methyltransferases. Guadecitabine is formulated as a dinucleotide of decitabine and deoxyguanosine that is resistant to cytidine deaminase (CDA) degradation and results in prolonged in vivo exposure to decitabine following small volume subcutaneous administration of guadecitabine. Here we found that guadecitabine is an effective demethylating agent and is able to prevent HCC progression in pre-clinical models. In a xenograft HCC HepG2 model, guadecitabine impeded tumor growth and inhibited angiogenesis, while it could not prevent liver fibrosis and inflammation in a mouse model of steatohepatitis. Demethylating efficacy of guadecitabine on LINE-1 elements was found to be the highest 8 d post-infusion in blood samples of mice. Analysis of a panel of human HCC vs. normal tissue revealed a signature of hypermethylated tumor suppressor genes (CDKN1A, CDKN2A, DLEC1, E2F1, GSTP1, OPCML, E2F1, RASSF1, RUNX3, and SOCS1) as detected by methylation-specific PCR. A pronounced demethylating effect of guadecitabine was obtained also in the promoters of a subset of tumor suppressors genes (CDKN2A, DLEC1, and RUNX3) in HepG2 and Huh-7 HCC cells. Finally, we analyzed the role of macroH2A1, a variant of histone H2A, an oncogene upregulated in human cirrhosis/HCC that synergizes with DNA methylation in suppressing tumor suppressor genes, and it prevents the inhibition of cell growth triggered by decitabine in HCC cells. Guadecitabine, in contrast to decitabine, blocked growth in HCC cells overexpressing macroH2A1 histones and with high CDA levels, despite being unable to fully demethylate CDKN2A, RUNX3, and DLEC1 promoters altered by macroH2A1. Collectively, our findings in human and mice models reveal novel epigenetic anti-HCC effects of guadecitabine, which might be effective specifically in advanced states of the disease

Biosafety Studies of a Clinically Applicable Lentiviral Vector for the Gene Therapy of Artemis-SCID

Genetic deficiency of the nuclease DCLRE1C/Artemis causes radiosensitive severe combined immunodeficiency (RS-SCID) with lack of peripheral T and B cells and increased sensitivity to ionizing radiations. Gene therapy based on transplanting autologous gene-modified hematopoietic stem cells could significantly improve the health of patients with RS-SCID by correcting their immune system. A lentiviral vector expressing physiological levels of human ARTEMIS mRNA from an EF1a promoter without post-transcriptional regulation was developed as a safe clinically applicable candidate for RS-SCID gene therapy. The vector was purified in GMP-comparable conditions and was not toxic in vitro or in vivo. Long-term engraftment of vector-transduced hematopoietic cells was achieved in irradiated Artemis-deficient mice following primary and secondary transplantation (6 months each). Vector-treated mice displayed T and B lymphopoiesis and polyclonal T cells, had structured lymphoid tissues, and produced immunoglobulins. Benign signs of inflammation were noted following secondary transplants, likely a feature of the model. There was no evidence of transgene toxicity and no induction of hematopoietic malignancy. In vitro, the vector had low genotoxic potential on murine hematopoietic progenitor cells using an immortalization assay. Altogether, these preclinical data show safety and efficacy, and support further development of the vector for the gene therapy of RS-SCID

Prospects for SIMPLE 2000: A large-mass, low-background Superheated Droplet Detector for WIMP searches

SIMPLE 2000 (Superheated Instrument for Massive ParticLE searches) will consist of an array of eight to sixteen large active mass ($\sim15$ g) Superheated Droplet Detectors(SDDs) to be installed in the new underground laboratory of Rustrel-Pays d'Apt. Several factors make of SDDs an attractive approach for the detection of Weakly Interacting Massive Particles (WIMPs), namely their intrinsic insensitivity to minimum ionizing particles, high fluorine content, low cost and operation near ambient pressure and temperature. We comment here on the fabrication, calibration and already-competitive first limits from SIMPLE prototype SDDs, as well as on the expected immediate increase in sensitivity of the program, which aims at an exposure of $>$25 kg-day during the year 2000. The ability of modest-mass fluorine-rich detectors to explore regions of neutralino parameter space beyond the reach of the most ambitious cryogenic projects is pointed out.Comment: 19 pages, 10 figures included. New Journal of Physics, in pres

First Dark Matter Limits from a Large-Mass, Low-Background Superheated Droplet Detector

We report on the fabrication aspects and calibration of the first large active mass ($\sim15$ g) modules of SIMPLE, a search for particle dark matter using Superheated Droplet Detectors (SDDs). While still limited by the statistical uncertainty of the small data sample on hand, the first weeks of operation in the new underground laboratory of Rustrel-Pays d'Apt already provide a sensitivity to axially-coupled Weakly Interacting Massive Particles (WIMPs) competitive with leading experiments, confirming SDDs as a convenient, low-cost alternative for WIMP detection.Comment: Final version, Phys. Rev. Lett. (in press

Data-driven modeling of electron recoil nucleation in PICO C3F8 bubble chambers

[EN] The primary advantage of moderately superheated bubble chamber detectors is their simultaneous sensitivity to nuclear recoils from weakly interacting massive particle (WIMP) dark matter and insensitivity to electron recoil backgrounds. A comprehensive analysis of PICO gamma calibration data demonstrates for the first time that electron recoils in C3F8 scale in accordance with a new nucleation mechanism, rather than one driven by a hot spike as previously supposed. Using this semiempirical model, bubble chamber nucleation thresholds may be tuned to be sensitive to lower energy nuclear recoils while maintaining excellent electron recoil rejection. The PICO-40L detector will exploit this model to achieve thermodynamic thresholds as low as 2.8 keV while being dominated by single-scatter events from coherent elastic neutrino-nucleus scattering of solar neutrinos. In one year of operation, PICO-401, can improve existing leading limits from PICO on spin-dependent WIMP-proton coupling by nearly an order of magnitude for WIMP masses greater than 3 GeV c(-2) and will have the ability to surpass all existing non-xenon bounds on spin-independent WIMP-nucleon coupling for WIMP masses from 3 to 40 GeV c(-2).The PICO Collaboration wishes to thank SNOLAB and its staff for support through underground space, logistical and technical services. SNOLAB operations are supported by the Canada Foundation for Innovation and the Province of Ontario Ministry of Research and Innovation, with underground access provided by Vale at the Creighton mine site. We wish to acknowledge the support of the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Canada Foundation for Innovation (CFI) for funding. We acknowledge the support from National Science Foundation (NSF) (Grants No. 0919526, No. 1506337, No. 1242637, No. 1205987, and No. 1806722). We acknowledge that this work is supported by the U.S. Department of Energy (DOE) Office of Science, Office of High Energy Physics (under Award No. DE-SC-0012161), by DGAPA-UNAM (PAPIIT No. IA100118) and Consejo Nacional de Ciencia y Tecnología (CONACyT, M¿exico, Grants No. 252167 and No. A1-S-8960), by the Department of Atomic Energy (DAE), Government of India, under the Centre for AstroParticle Physics II project (CAPP-II) at the Saha Institute of Nuclear Physics (SINP), European Regional Development Fund¿Project ¿Engineering Applications of Microworld Physics¿ (Project No. CZ.02.1.01/0.0/0.0/ 16_019/0000766), and the Spanish Ministerio de Ciencia, Innovación y Universidades (Red Consolider MultiDark, Grant No. FPA2017-90566-REDC). This work is partially supported by the Kavli Institute for Cosmological Physics at the University of Chicago through NSF Grant No. 1125897, and an endowment from the Kavli Foundation and its founder Fred Kavli. We also wish to acknowledge the support from Fermi National Accelerator Laboratory under Contract No. DE-AC02-07CH11359, and Pacific Northwest National Laboratory, which is operated by Battelle for the U.S. Department of Energy under Contract No. DE-AC05- 76RL01830. We also thank Compute Canada [75] and the Center for Advanced Computing, ACENET, Calcul Qu¿ebec, Compute Ontario, and WestGrid for computational support.Amole, C.; Ardid Ramírez, M.; Arnquist, I.; Asner, DM.; Baxter, D.; Behnke, E.; Bressler, M.... (2019). Data-driven modeling of electron recoil nucleation in PICO C3F8 bubble chambers. Physical Review D: covering particles, fields, gravitation, and cosmology. 100(8):1-18. https://doi.org/10.1103/PhysRevD.100.082006S1181008Amole, C., Ardid, M., Arnquist, I. J., Asner, D. M., Baxter, D., Behnke, E., … Chen, C. J. (2019). Dark matter search results from the complete exposure of the PICO-60 C3F8 bubble chamber. 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Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 513(3), 550-558. doi:10.1016/j.nima.2003.06.012Archambault, S., Aubin, F., Auger, M., Beleshi, M., Behnke, E., … Behnke, J. (2011). New insights into particle detection with superheated liquids. New Journal of Physics, 13(4), 043006. doi:10.1088/1367-2630/13/4/043006Glaser, D. A. (1954). Progress report on the development of bubble chambers. Il Nuovo Cimento, 11(S2), 361-368. doi:10.1007/bf02781098Fabian, B. N., Place, R. L., Riley, W. A., Sims, W. H., & Kenney, V. P. (1963). Density of Particle Tracks in the Hydrogen Bubble Chamber. Review of Scientific Instruments, 34(5), 484-495. doi:10.1063/1.1718415Willis, W. J., Fowler, E. C., & Rahm, D. C. (1957). Bubble Density in a Propane Bubble Chamber. Physical Review, 108(4), 1046-1047. doi:10.1103/physrev.108.1046Hahn, B., & Hugentobler, E. (1960). 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Physical Review Letters, 114(14). doi:10.1103/physrevlett.114.141301Ruppin, F., Billard, J., Figueroa-Feliciano, E., & Strigari, L. (2014). Complementarity of dark matter detectors in light of the neutrino background. Physical Review D, 90(8). doi:10.1103/physrevd.90.083510Felizardo, M., Girard, T. A., Morlat, T., Fernandes, A. C., Ramos, A. R., Marques, J. G., … Marques, R. (2014). The SIMPLE Phase II dark matter search. Physical Review D, 89(7). doi:10.1103/physrevd.89.072013Adrián-Martínez, S., Albert, A., André, M., Anton, G., Ardid, M., Aubert, J.-J., … Basa, S. (2016). Limits on dark matter annihilation in the sun using the ANTARES neutrino telescope. Physics Letters B, 759, 69-74. doi:10.1016/j.physletb.2016.05.019Adrián-Martínez, S., Albert, A., André, M., Anton, G., Ardid, M., Aubert, J.-J., … Basa, S. (2016). A search for Secluded Dark Matter in the Sun with the ANTARES neutrino telescope. Journal of Cosmology and Astroparticle Physics, 2016(05), 016-016. doi:10.1088/1475-7516/2016/05/016Aprile, E., Aalbers, J., Agostini, F., Alfonsi, M., Althueser, L., Amaro, F. D., … Bauermeister, B. (2018). Dark Matter Search Results from a One Ton-Year Exposure of XENON1T. Physical Review Letters, 121(11). doi:10.1103/physrevlett.121.111302Akerib, D. S., Alsum, S., Araújo, H. M., Bai, X., Bailey, A. J., Balajthy, J., … Biesiadzinski, T. P. (2017). Results from a Search for Dark Matter in the Complete LUX Exposure. Physical Review Letters, 118(2). doi:10.1103/physrevlett.118.021303Agnes, P., Albuquerque, I. F. M., Alexander, T., Alton, A. K., Araujo, G. R., Asner, D. M., … Batignani, G. (2018). Low-Mass Dark Matter Search with the DarkSide-50 Experiment. Physical Review Letters, 121(8). doi:10.1103/physrevlett.121.081307Agnes, P., Albuquerque, I. F. M., Alexander, T., Alton, A. K., Araujo, G. R., Ave, M., … Biery, K. (2018). DarkSide-50 532-day dark matter search with low-radioactivity argon. Physical Review D, 98(10). doi:10.1103/physrevd.98.102006Agnese, R., Anderson, A. J., Aralis, T., Aramaki, T., Arnquist, I. J., Baker, W., … Bauer, D. A. (2018). Low-mass dark matter search with CDMSlite. Physical Review D, 97(2). doi:10.1103/physrevd.97.022002Agnese, R., Aramaki, T., Arnquist, I. J., Baker, W., Balakishiyeva, D., Banik, S., … Binder, T. (2018). Results from the Super Cryogenic Dark Matter Search Experiment at Soudan. Physical Review Letters, 120(6). doi:10.1103/physrevlett.120.061802Hehn, L., Armengaud, E., Arnaud, Q., Augier, C., Benoît, A., Bergé, L., … Yakushev, E. (2016). Improved EDELWEISS-III sensitivity for low-mass WIMPs using a profile likelihood approach. The European Physical Journal C, 76(10). doi:10.1140/epjc/s10052-016-4388-yTolman, R. C. (1949). The Effect of Droplet Size on Surface Tension. The Journal of Chemical Physics, 17(3), 333-337. doi:10.1063/1.1747247Kirkwood, J. G., & Buff, F. P. (1949). The Statistical Mechanical Theory of Surface Tension. The Journal of Chemical Physics, 17(3), 338-343. doi:10.1063/1.1747248Xue, Y.-Q., Yang, X.-C., Cui, Z.-X., & Lai, W.-P. (2010). The Effect of Microdroplet Size on the Surface Tension and Tolman Length. The Journal of Physical Chemistry B, 115(1), 109-112. doi:10.1021/jp108431

Worldwide comparison of survival from childhood leukaemia for 1995–2009, by subtype, age, and sex (CONCORD-2): a population-based study of individual data for 89 828 children from 198 registries in 53 countries

Background Global inequalities in access to health care are reflected in differences in cancer survival. The CONCORD programme was designed to assess worldwide differences and trends in population-based cancer survival. In this population-based study, we aimed to estimate survival inequalities globally for several subtypes of childhood leukaemia. Methods Cancer registries participating in CONCORD were asked to submit tumour registrations for all children aged 0-14 years who were diagnosed with leukaemia between Jan 1, 1995, and Dec 31, 2009, and followed up until Dec 31, 2009. Haematological malignancies were defined by morphology codes in the International Classification of Diseases for Oncology, third revision. We excluded data from registries from which the data were judged to be less reliable, or included only lymphomas, and data from countries in which data for fewer than ten children were available for analysis. We also excluded records because of a missing date of birth, diagnosis, or last known vital status. We estimated 5-year net survival (ie, the probability of surviving at least 5 years after diagnosis, after controlling for deaths from other causes [background mortality]) for children by calendar period of diagnosis (1995-99, 2000-04, and 2005-09), sex, and age at diagnosis (< 1, 1-4, 5-9, and 10-14 years, inclusive) using appropriate life tables. We estimated age-standardised net survival for international comparison of survival trends for precursor-cell acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). Findings We analysed data from 89 828 children from 198 registries in 53 countries. During 1995-99, 5-year agestandardised net survival for all lymphoid leukaemias combined ranged from 10.6% (95% CI 3.1-18.2) in the Chinese registries to 86.8% (81.6-92.0) in Austria. International differences in 5-year survival for childhood leukaemia were still large as recently as 2005-09, when age-standardised survival for lymphoid leukaemias ranged from 52.4% (95% CI 42.8-61.9) in Cali, Colombia, to 91.6% (89.5-93.6) in the German registries, and for AML ranged from 33.3% (18.9-47.7) in Bulgaria to 78.2% (72.0-84.3) in German registries. Survival from precursor-cell ALL was very close to that of all lymphoid leukaemias combined, with similar variation. In most countries, survival from AML improved more than survival from ALL between 2000-04 and 2005-09. Survival for each type of leukaemia varied markedly with age: survival was highest for children aged 1-4 and 5-9 years, and lowest for infants (younger than 1 year). There was no systematic difference in survival between boys and girls. Interpretation Global inequalities in survival from childhood leukaemia have narrowed with time but remain very wide for both ALL and AML. These results provide useful information for health policy makers on the effectiveness of health-care systems and for cancer policy makers to reduce inequalities in childhood survival

Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2)

BACKGROUND: Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control. METHODS: Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75,000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease. INTERPRETATION: International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems

The histology of ovarian cancer: worldwide distribution and implications for international survival comparisons (CONCORD-2)

Objective Ovarian cancers comprise several histologically distinct tumour groups with widely different prognosis. We aimed to describe the worldwide distribution of ovarian cancer histology and to understand what role this may play in international variation in survival. Methods The CONCORD programme is the largest population-based study of global trends in cancer survival. Data on 681,759 women diagnosed during 1995â\u80\u932009 with cancer of the ovary, fallopian tube, peritoneum and retroperitonum in 51 countries were included. We categorised ovarian tumours into six histological groups, and explored the worldwide distribution of histology. Results During 2005â\u80\u932009, type II epithelial tumours were the most common. The proportion was much higher in Oceania (73.1%), North America (73.0%) and Europe (72.6%) than in Central and South America (65.7%) and Asia (56.1%). By contrast, type I epithelial tumours were more common in Asia (32.5%), compared with only 19.4% in North America. From 1995 to 2009, the proportion of type II epithelial tumours increased from 68.6% to 71.1%, while the proportion of type I epithelial tumours fell from 23.8% to 21.2%. The proportions of germ cell tumours, sex cord-stromal tumours, other specific non-epithelial tumours and tumours of non-specific morphology all remained stable over time. Conclusions The distribution of ovarian cancer histology varies widely worldwide. Type I epithelial, germ cell and sex cord-stromal tumours are generally associated with higher survival than type II tumours, so the proportion of these tumours may influence survival estimates for all ovarian cancers combined. The distribution of histological groups should be considered when comparing survival between countries and regions