Search

HE 0107$-$5240 is a hyper metal-poor star with $\rm [Fe/H]=-5.39$. We performed high-res observations with the ESPRESSO spectrograph at the VLT to constrain the kinematical properties of the binary system HE 0107$-$5240 and to probe the binarity of the sample of 8 most metal-poor stars with $\rm [Fe/H], 15 pages, 7 Figures. Accepted for publication in A&A

Full list of authors: Chaturvedi, P.; Bluhm, P.; Nagel, E.; Hatzes, A. P.; Morello, G.; Brady, M.; Korth, J.; Molaverdikhani, K.; Kossakowski, D.; Caballero, J. A.; Guenther, E. W.; Palle, E.; Espinoza, N.; Seifahrt, A.; Lodieu, N.; Cifuentes, C.; Furlan, E.; Amado, P. J.; Barclay, T.; Bean, J.; Bejar, V. J. S.; Bergond, G.; Boyle, A. W.; Ciardi, D.; Collins, K. A.; Collins, K., I; Esparza-Borges, E.; Fukui, A.; Gnilka, C. L.; Goeke, R.; Guerra, P.; Henning, Th; Herrero, E.; Howell, S. B.; Jeffers, S., V; Jenkins, J. M.; Jensen, E. L. N.; Kasper, D.; Kodama, T.; Latham, D. W.; Lopez-Gonzalez, M. J.; Luque, R.; Montes, D.; Morales, J. C.; Mori, M.; Murgas, F.; Narita, N.; Nowak, G.; Parviainen, H.; Passegger, V. M.; Quirrenbach, A.; Reffert, S.; Reiners, A.; Ribas, I; Ricker, G. R.; Rodriguez, E.; Rodriguez-Lopez, C.; Schlecker, M.; Schwarz, R. P.; Schweitzer, A.; Seager, S.; Stefansson, G.; Stockdale, C.; Tal-Or, L.; Twicken, J. D.; Vanaverbeke, S.; Wang, G.; Watanabe, D.; Winn, J. N.; Zechmeister, M.--This is an Open Access article, published by EDP Sciences, under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited., We report the discovery and characterization of two small transiting planets orbiting the bright M3.0V star TOI-1468 (LSPM J0106+1913), whose transit signals were detected in the photometric time series in three sectors of the TESS mission. We confirm the planetary nature of both of them using precise radial velocity measurements from the CARMENES and MAROON-X spectrographs, and supplement them with ground-based transit photometry. A joint analysis of all these data reveals that the shorter-period planet, TOI-1468 b (Pb = 1.88 d), has a planetary mass of Mb = 3.21 ± 0.24M⊕ and a radius of Rb = 1.280−0.039+0.038 R⊕, resulting in a density of ρb = 8.39−0.92+1.05 g cm−3, which is consistent with a mostly rocky composition. For the outer planet, TOI-1468 c (Pc = 15.53 d), we derive a mass of Mc = 6.64−0.68+0.67 M⊕,aradius of Rc = 2.06 ± 0.04 R⊕, and a bulk density of ρc = 2.00−0.19+0.21 g cm−3, which corresponds to a rocky core composition with a H/He gas envelope. These planets are located on opposite sides of the radius valley, making our system an interesting discovery as there are only a handful of other systems with the same properties. This discovery can further help determine a more precise location of the radius valley for small planets around M dwarfs and, therefore, shed more light on planet formation and evolution scenarios. © P. Chaturvedi et al. 2022., CARMENES is an instrument at the Centro Astronómico Hispano en Andalucía (CAHA) at Calar Alto (Almería, Spain), operated jointly by the Junta de Andalucía and the Instituto de Astrofísica de Andalucía (CSIC). CARMENES was funded by the Max-Planck-Gesellschaft (MPG), the Consejo Superior de Investigaciones Científicas (CSIC), the Ministerio de Economía y Competitividad (MINECO) and the European Regional Development Fund (ERDF) through projects FICTS-2011-02, ICTS-2017-07-CAHA-4, and CAHA16-CE-3978, and the members of the CARMENES Consortium (Max-Planck-Institut für Astronomie, Instituto de Astrofísica de Andalucía, Landessternwarte Königstuhl, Institut de Ciències de l’Espai, Institut für Astrophysik Göttingen, Universidad Complutense de Madrid, Thüringer Landessternwarte Tautenburg, Instituto de Astrofísica de Canarias, Hamburger Sternwarte, Centro de Astrobiología and Centro Astronómico Hispano-Alemán), with additional contributions by the MINECO, the Deutsche Forschungsgemeinschaft (DFG) through the Major Research Instrumentation Programme and Research Unit FOR2544 “Blue Planets around Red Stars”, the Klaus Tschira Stiftung, the states of Baden-Württemberg and Niedersachsen, and by the Junta de Andalucía. This work was based on data from the CARMENES data archive at CAB (CSIC-INTA). Funding for the TESS mission is provided by NASA’s Science Mission Directorate. We acknowledge the use of public TESS data from pipelines at the TESS Science Office and at the TESS Science Processing Operations Center. This research has made use of the Exoplanet Follow-up Observation Program website, which is operated by the California Institute of Technology, under contract with the National Aeronautics and Space Administration under the Exo-planet Exploration Program. Resources supporting this work were provided by the NASA High-End Computing (HEC) Program through the NASA Advanced Supercomputing (NAS) Division at Ames Research Center for the production of the SPOC data products. This paper includes data collected by the TESS mission that are publicly available from the Mikulski Archive for Space Telescopes (MAST). The development of the MAROON-X spectrograph was funded by the David and Lucile Packard Foundation, the Heising-Simons Foundation, the Gemini Observatory, and the University of Chicago. The MAROON-X team acknowledges support for this work from the NSF (award number 2108465) and NASA (through the TESS Cycle 4 GI program, grant number 80NSSC22K0117). This work was enabled by observations made from the Gemini North telescope, located within the Maunakea Science Reserve and adjacent to the summit of Maunakea. We are grateful for the privilege of observing the Universe from a place that is unique in both its astronomical quality and its cultural significance. Data were partly collected with the 150-cm telescope at Observatorio de Sierra Nevada (OSN), operated by the Instituto de Astrofífica de Andalucía (IAA, CSIC), with the MuSCAT2 instrument, developed by ABC, at Telescopio Carlos Sánchez operated on the island of Tenerife by the IAC in the Spanish Observatorio del Teide, with the Telescopi Joan Oró (TJO) of the Observatori Astronómic del Montsed (OdM), which is owned by the Generalitat de Catalunya and operated by the Institute for Space Studies of Catalonia (IEEC), and with the LCOFT network (part of the LCOGT telescope time was granted by NOIRLab through the Mid-Scale Innovations Program (MSIP), which is funded by the National Science Foundation). Some of the Observations in the paper made use of the High-Resolution Imaging instrument. ‘Alopeke. ‘Alopeke was funded by the NASA Exoplanet Exploration Program and built at the NASA Ames Research Center by Steve B. Howell, Nic Scott, Elliott P. Horch, and Emmett Quigley. Data were reduced using a software pipeline originally written by Elliott Horch and Mark Everett. ‘Alopeke was mounted on the Gemini North telescope of the international Gemini Observatory, a program of NSF s OIR Lab, which is managed by the Association of Universities for Research in Astronomy (AURA) under a cooperative agreement with the National Science Foundation. on behalf of the Gemini partnership: the National Science Foundation (United States), National Research Council (Canada), Agencia Nacional de Investigación y Desarrollo (Chile), Ministerio de Ciencia, Tecnología e Innovación (Argentina), Ministério da Ciência, Tecnologia, Inovações e Comunicações (Brazil), and Korea Astronomy and Space Science Institute (Republic of Korea). We acknowledge financial support from: the Thüringer Ministerium für Wirtschaft, Wissenschaft und Digitale Gesellschaft; the Spanish Agencia Estatal de Investigación of the Ministerio de Ciencia e Innovación and the ERDF “A way of making Europe” through projects PID2019-109522GB-C5[1:4], PID2019-107061GB-C64, PID2019-110689RB-100, PGC2018-098153-B-C31, and the Centre of Excellence “Severo Ochoa” and “María de Maeztu” awards to the Instituto de Astrofísica de Canarias (CEX2019-000920-S), Instituto de Astrofísica de Andalucía (SEV-2017-0709), and Centro de Astrobiología (MDM-2017-0737); the Generalitat de Catalunya/CERCA programme; the European Union s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement no. 895525; the DFG through grant CH 2636/1-1, the Excellence Cluster ORIGINS under Germany’s Excellence Strategy (EXC-2094 – 390783311), and priority programme SPP 1992 “Exploring the Diversity of Extrasolar Planets” (JE 701/5-1); the Swedish National Space Agency (SNSA; DNR 2020-00104); the JSPS KAKENHI grants JP17H04574, JP18H05439, JP21K13975, Grant-in-Aid for JSPS fellows grant JP20J21872, JST CREST Grant Number JPMJCR1761, and the Astrobiology Center of National Institutes of Natural Sciences (NINS) through grants AB031010 and AB031014; and the program “Alien Earths” (supported by the National Aeronautics and Space Administration under agreement No. 80NSSC21K0593) for NASA’s Nexus for Exoplanet System Science (NExSS) research coordination network sponsored by NASA’s Science Mission Directorate.

N.S., R.W. and B.-O.D. acknowledge support from the Swiss National Science Foundation (PP00P2-163967 and PP00P2-190080). M.N.G. acknowledges support from MIT's Kavli Institute as a Juan Carlos Torres Fellow and from the European Space Agency (ESA) as an ESA Research Fellow. A.A.B., B.S.S.and I.A.S. acknowledge the support of the Ministry of Science and Higher Education of the Russian Federation under the grant 075-15-2020-780 (N13.1902.21.0039). L.D. is an F.R.S.-FNRS Postdoctoral Researcher. B.V.R. thanks the Heising-Simons Foundation for support. This publication benefits from the support of the French Community of Belgium in the context of the FRIA Doctoral Grant awarded to M.T. and E.J. acknowledges DGAPA for his postdoctoral fellowship. Y.G.M.C. acknowledges support from UNAM-DGAPA PAPIIT BG-101321. D.D. acknowledges support from the TESS Guest Investigator Program grant 80NSSC19K1727 and NASA Exoplanet Research Program grant 18-2XRP18_2-0136. We acknowledge support from the Centre for Space and Habitability (CSH) of the University of Bern. Part of this work received support from the National Centre for Competence in Research PlanetS, supported by the Swiss National Science Foundation (SNSF). Funding for the TESS mission is provided by NASA's Science Mission Directorate. We acknowledge the use of public TESS data from pipelines at the TESS Science Office and at the TESS Science Processing Operations Center. This research has made use of the Exoplanet Follow-up Observation Program website, which is operated by the California Institute of Technology, under contract with the National Aeronautics and Space Administration under the Exoplanet Exploration Program. Resources supporting this work were provided by the NASA High-End Computing (HEC) Program through the NASA Advanced Supercomputing (NAS) Division at Ames Research Center for the production of the SPOC data products. This paper includes data collected by the TESS mission that are publicly available from the Mikulski Archive for Space Telescopes (MAST). This work is based upon observations carried out at the Observatorio Astronomico Nacional on the Sierra de San Pedro Martir (OAN-SPM), Baja California, Mexico. We warmly thank the entire technical staff of the Observatorio Astronomico Nacional at San Pedro Martir in Mexico for their unfailing support to SAINT-EX operations, namely: E. Cadena, T. Calvario, E. Colorado, F. Diaz, A. Franco, B. Garcia, C. Guerrero, G. Guisa, F. Guillen, A. Landa, L. Figueroa, B. Hernandez, J. Herrera, E. Lopez, E. Lugo, B. Martinez, G. Melgoza, F. Montalvo, J.M. Nunez, J.L. Ochoa, I. Plauchu, F. Quiroz, H. Riesgo, H. Serrano, T. Verdugo, I. Zavala. The research leading to these results has received funding from the European Research Council (ERC) under the FP/2007-2013 ERC grant agreement nffi 336480, and under the European Union's Horizon 2020 research and innovation programme (grants agreements nffi 679030 and 803193/BEBOP); from an Actions de Recherche Concertee (ARC) grant, financed by the Wallonia-Brussels Federation, from the Balzan Prize Foundation, from the BEL-SPO/BRAIN2.0 research program (PORTAL project), from the Science and Technology Facilities Council (STFC; grant nffi ST/S00193X/1), and from F.R.S-FNRS (Research Project ID T010920F). This work was also partially supported by a grant from the Simons Foundation (PI: Queloz, grant number 327127), as well as by the MERAC foundation (PI: Triaud). PI: Gillon is F.R.S.-FNRS Senior Research Associate. TRAPPIST is funded by the Belgian Fund for Scientific Research (Fond National de la Recherche Scientifique, FNRS) under the grant PDR T.0120.21, with the participation of the Swiss National Science Fundation (SNF). M.G. and E.J. are F.R.S.-FNRS Senior Research Associate. This work makes use of observations from the LCOGT network. Part of the LCOGT telescope time was granted by NOIRLab through the Mid-Scale Innovations Program (MSIP). M.S.I.P. is funded by NSF. Some of the observations in the paper made use of the High-Resolution Imaging instrument(s) `Alopeke (and/or Zorro). `Alopeke (and/or Zorro) was funded by the NASA Exoplanet Exploration Program and built at the NASA Ames Research Center by Steve B. Howell, Nic Scott, Elliott P. Horch, and Emmett Quigley. Data were reduced using a software pipeline originally written by Elliott Horch and Mark Everett. `Alopeke (and/or Zorro) was mounted on the Gemini North (and/or South) telescope of the international Gemini Observatory, a program of NSF's OIR Lab, which is managed by the Association of Universities for Research in Astronomy (AURA) under a cooperative agreement with the National Science Foundation, on behalf of the Gemini partnership: the National Science Foundation (United States), National Research Council (Canada), Agencia Nacional de Investigacion y Desarrollo (Chile), Ministerio de Ciencia, Tecnologia e Innovacion (Argentina), Ministerio da Ciencia, Tecnologia, Inovacoes e Comunicacoes (Brazil), and Korea Astronomy and Space Science Institute (Republic of Korea). This research has made use of the NASA Exoplanet Archive, which is operated by the California Institute of Technology, under contract with the National Aeronautics and Space Administration under the Exoplanet Exploration Program. This research made use of exoplanet (Foreman-Mackey et al. 2021a,b) and its dependencies (Agol et al. 2020; Kumar et al. 2019; Astropy Collaboration 2013, 2018; Kipping 2013; Luger et al. 2019; Salvatier et al. 2016; Theano Development Team 2016). Additional use of software packages AstroImageJ (Collins et al. 2017) and TAPIR (Jensen 2013)., Context. Thanks to the relative ease of finding and characterizing small planets around M-dwarf stars, these objects have become cornerstones in the field of exoplanet studies. The current paucity of planets in long-period orbits around M dwarfs makes such objects particularly compelling as they provide clues about the formation and evolution of these systems. Aims. In this study we present the discovery of TOI-2257 b (TIC 198485881), a long-period (35 d) sub-Neptune orbiting an M3 star at 57.8 pc. Its transit depth is about 0.4%, large enough to be detected with medium-size, ground-based telescopes. The long transit duration suggests the planet is in a highly eccentric orbit (e similar to 0.5), which would make it the most eccentric planet known to be transiting an M-dwarf star. Methods. We combined TESS and ground-based data obtained with the 1.0-meter SAINT-EX, 0.60-meter TRAPPIST-North, and 1.2-meter FLWO telescopes to find a planetary size of 2.2 R-circle plus and an orbital period of 35.19 days. In addition, we make use of archival data, high-resolution imaging, and vetting packages to support our planetary interpretation. Results. With its long period and high eccentricity, TOI-2257 b falls into a novel slice of parameter space. Despite the planet's low equilibrium temperature (similar to 256 K), its host star's small size (R-* = 0.311 +/- 0.015) and relative infrared brightness (K-mag = 10.7) make it a suitable candidate for atmospheric exploration via transmission spectroscopy., Swiss National Science Foundation (SNSF), European Commission PP00P2-163967 PP00P2-190080, MIT's Kavli Institute, European Space Agency European Commission, Ministry of Science and Higher Education of the Russian Federation 075-15-2020-780 (N13.1902.21.0039), Heising-Simons Foundation, French Community of Belgium, DGAPA, Programa de Apoyo a Proyectos de Investigacion e Innovacion Tecnologica (PAPIIT) Universidad Nacional Autonoma de Mexico BG-101321, TESS Guest Investigator Program 80NSSC19K1727, NASA Exoplanet Research Program 18-2XRP18_2-0136, Centre for Space and Habitability (CSH) of the University of Bern, European Research Council (ERC) 336480, Actions de Recherche Concertee (ARC) grant - Wallonia-Brussels Federation, UK Research & Innovation (UKRI), Science & Technology Facilities Council (STFC), Science and Technology Development Fund (STDF) ST/S00193X/1, Fonds de la Recherche Scientifique - FNRS T010920F, Simons Foundation 327127, MERAC foundation, Fonds de la Recherche Scientifique - FNRS PDR T.0120.21, National Science Foundation (NSF), NASA Exoplanet Exploration Program NASA's Science Mission Directorate, European Research Council (ERC) 679030 803193/BEBOP, Balzan Prize Foundation BEL-SPO/BRAIN2.0 research program (PORTAL project)

Full list of authors: Kawauchi, K.; Murgas, F.; Palle, E.; Narita, N.; Fukui, A.; Hirano, T.; Parviainen, H.; Ishikawa, H. T.; Watanabe, N.; Esparaza-Borges, E.; Kuzuhara, M.; Orell-Miquel, J.; Krishnamurthy, V; Mori, M.; Kagetani, T.; Zou, Y.; Isogai, K.; Livingston, J. H.; Howell, S. B.; Crouzet, N.; de Leon, J. P.; Kimura, T.; Kodama, T.; Korth, J.; Kurita, S.; Laza-Ramos, A.; Luque, R.; Madrigal-Aguado, A.; Miyakawa, K.; Morello, G.; Nishiumi, T.; Rodriguez, G. E. F.; Sanchez-Benavente, M.; Stangret, M.; Teng, H.; Terada, Y.; Gnilka, C. L.; Guerrero, N.; Harakawa, H.; Hodapp, K.; Hori, Y.; Ikoma, M.; Jacobson, S.; Konishi, M.; Kotani, T.; Kudo, T.; Kurokowa, T.; Kusakabe, N.; Nishikawa, J.; Omiya, M.; Serizawa, T.; Tamura, M.; Ueda, A.; Vievard, S.--This is an Open Access article, published by EDP Sciences, under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited., Context. The NASA space telescope TESS is currently in the extended mission of its all-sky search for new transiting planets. Of the thousands of candidates that TESS is expected to deliver, transiting planets orbiting nearby M dwarfs are particularly interesting targets since they provide a great opportunity to characterize their atmospheres by transmission spectroscopy. Aims. We aim to validate and characterize the new sub-Neptune-sized planet candidate TOI-2136.01 orbiting a nearby M dwarf (d = 33.36 ± 0.02pc, Teff = 3373 ± 108 K) with an orbital period of 7.852 days. Methods. We use TESS data, ground-based multicolor photometry, and radial velocity measurements with the InfraRed Doppler (IRD) instrument on the Subaru Telescope to validate the planetary nature of TOI-2136.01, and estimate the stellar and planetary parameters. We also conduct high-resolution transmission spectroscopy to search for helium in its atmosphere. Results. We confirm that TOI-2136.01 (now named TOI-2136b) is a bona fide planet with a planetary radius of Rp = 2.20 ± 0.07R⊕ and a mass of Mp = 4.7−2.6+3.1 M⊕. We also search for helium 10830 Å absorption lines and place an upper limit on the equivalent width of, The MEarth Project acknowledges funding from the David and Lucile Packard Fellowship for Science and Engineering, the National Science Foundation under grants AST-0807690, AST-1109468, AST-1616624 and AST-1004488 (Alan T. Waterman Award), the National Aeronautics and Space Administration under Grant No. 80NSSC18K0476 issued through the XRP Program, and the John Templeton Foundation. Based on observations obtained with the Samuel Oschin 48-inch Telescope at the Palomar Observatory as part of the Zwicky Transient Facility project. Z.T.F. is supported by the National Science Foundation under Grant No. AST-1440341 and a collaboration including Caltech, IPAC, the Weizmann Institute for Science, the Oskar Klein Center at Stockholm University, the University of Maryland, the University of Washington, Deutsches Elektronen-Synchrotron and Humboldt University, Los Alamos National Laboratories, the TANGO Consortium of Taiwan, the University of Wisconsin at Milwaukee, and Lawrence Berkeley National Laboratories. Operations are conducted by COO, IPAC, and UW. Our data reductions benefited from PyRAF and PyFITS that are the products of the Space Telescope Science Institute, which is operated by AURA for NASA. G.M. has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 895525. R.L. acknowledges financial support from the Spanish Ministerio de Ciencia e Innovación, through project PID2019-109522GB-C52, and the Centre of Excellence “Severo Ochoa” award to the Instituto de Astrofísica de Andalucía (SEV-2017-0709). J.K. gratefully acknowledge the support of the Swedish National Space Agency (SNSA; DNR 2020-00104). This work is partly supported by JSPS KAKENHI Grant Numbers JP21K20376, JP21K13975, JP21H00035, JP21K20388, JP20K14518, JP20K14521, JP19K14783, JP18H05439, JP17H04574, by Grant-in-Aid for JSPS Fellows Grant Number JP20J21872, by JST CREST Grant Number JPMJCR1761, by Astrobiology Center PROJECT Research AB031014, by Astrobiology Center SATELLITE Research project AB022006, and the Astrobiology Center of National Institutes of Natural Sciences (NINS) (Grant Number AB031010). M.T. is supported by MEXT/JSPS KAKENHI grant Nos. 18H05442, 15H02063, and 22000005. Some of the observations in the paper made use of the High-Resolution Imaging instrument Alopeke obtained under Gemini LLP Proposal Number: GN/S-2021A-LP-105. Alopeke was funded by the NASA Exoplanet Exploration Program and built at the NASA Ames Research Center by Steve B. Howell, Nic Scott, Elliott P. Horch, and Emmett Quigley. Alopeke was mounted on the Gemini North (and/or South) telescope of the international Gemini Observatory, a program of NSF’s OIR Lab, which is managed by the Association of Universities for Research in Astronomy (AURA) under a cooperative agreement with the National Science Foundation, on behalf of the Gemini partnership: the National Science Foundation (United States), National Research Council (Canada), Agencia Nacional de Investigación y Desarrollo (Chile), Mnisterio de Ciencia, Tecnología e Innovación (Argentina), Ministério da Ciência, Tecnologia, Inovações e Comunicações (Brazil), and Korea Astronomy and Space Science Institute (Republic of Korea).

Context. The number of super-Earth and Earth-mass planet discoveries has increased significantly in the last two decades thanks to the Doppler radial velocity and planetary transit observing techniques. Either technique can detect planet candidates on its own, but the power of a combined photometric and spectroscopic analysis is unique for an insightful characterization of the planets, which in turn has repercussions for our understanding of the architecture of planetary systems and, therefore, their formation and evolution. Aims. Two transiting planet candidates with super-Earth radii around the nearby (d = 70.64 ± 0.06 pc) K7–M0 dwarf star TOI-1238 were announced by NASA’s Transiting Exoplanet Survey Satellite (TESS), which observed the field of TOI-1238 in four different sectors. We aim to validate their planetary nature using precise radial velocities taken with the CARMENES spectrograph. Methods. We obtained 55 CARMENES radial velocity measurements that span the 11 months between 9 May 2020 and 5 April 2021. For a better characterization of the parent star’s activity, we also collected contemporaneous optical photometric observations at the Joan Oró and Sierra Nevada observatories and retrieved archival photometry from the literature. We performed a combined TESS+CARMENES photometric and spectroscopic analysis by including Gaussian processes and Keplerian orbits to account for the stellar activity and planetary signals simultaneously. Results. We estimate that TOI-1238 has a rotation period of 40 ± 5 d based on photometric and spectroscopic data. The combined analysis confirms the discovery of two transiting planets, TOI-1238 b and c, with orbital periods of 0.764597−0.000011+0.000013 d and 3.294736−0.000036+0.000034 d, masses of 3.76−1.07+1.15 M⊕ and 8.32−1.88+1.90 M⊕, and radii of 1.21−0.10+0.11 R⊕ and 2.11−0.14+0.14 R⊕. They orbit their parent star at semimajor axes of 0.0137 ± 0.0004 au and 0.036 ± 0.001 au, respectively.The two planets are placed on opposite sides of the radius valley for M dwarfs and lie between the star and the inner border of TOI-1238’s habitable zone. The inner super-Earth TOI-1238 b is one of the densest ultra-short-period planets ever discovered (ρ = 11.7−3.4+4.2 g cm−3). The CARMENES data also reveal the presence of an outer, non-transiting, more massive companion with an orbital period and radial velocity amplitude of ≥600 d and ≥70 m s−1, which implies a likely mass of M ≥ 2 √(1− e2) MJup and a separation ≥1.1 au from its parent star. © ESO 2022., CARMENES is an instrument for the Centro Astronómico Hispano-Alemán de Calar Alto (CAHA, Almería, Spain). CARMENES is funded by the German Max-Planck- Gesellschaft (MPG), the Spanish Consejo Superior de Investigaciones Científicas (CSIC), the European Union through FEDER/ERF funds, and the members of the CARMENES Consortium (Max-Planck-Institut für Astronomie, Instituto de Astrofísica de Andalucía, Landessternwarte Koönigstuhl, Institut de Ciències de l’Espai, Insitut für Astrophysik Göttingen, Universidad, Complutense de Madrid, Thüringer Landessternwarte Tautenburg, Instituto de Astrofísica de Canarias, Hamburger Sternwarte, Centro de Astrobiología and Centro Astronómico Hispano-Alemán), with additional contributions by the Spanish Ministry of Economy, the state of Baden-Wüttemberg, the German Science Foundation (DFG), the Klaus Tschira Foundation (KTS), and by the Junta de Andalucía. This work was based on data from the CARMENES data archive at CAB (CSIC-INTA). This research has made use of the NASA Exoplanet Archive, which is operated by the California Institute of Technology, under contract with the National Aeronautics and Space Administration under the Exoplanet Exploration Program. Funding for the TESS mission is provided by NASA’s Science Mission Directorate. This paper includes data collected by the TESS mission that are publicly available from the Mikulski Archive for Space Telescopes. We acknowledge the use of public TESS data from pipelines at the TESS Science Office and at the TESS Science Processing Operations Center. Resources supporting this work were provided by the NASA High-End Computing (HEC) Program through the NASA Advanced Supercomputing (NAS) Division at Ames Research Center for the production of the SPOC data products. Some of the observations in the paper made use of the High-Resolution Imaging instrument ‘Alopeke obtained under Gemini LLP Proposal Number: GN/S-2021A-LP-105. ‘Alopeke was funded by the NASA Exoplanet Exploration Program and built at the NASA Ames Research Center by Steve B. Howell, Nic Scott, Elliott P. Horch, and Emmett Quigley. ‘Alopeke was mounted on the Gemini North (and/or South) telescope of the international Gemini Observatory, a program of NSF’s OIR Lab, which is managed bythe Association of Universities for Research in Astronomy (AURA) under a cooperative agreement with the National Science Foundation. on behalf of the Gemini partnership: the National Science Foundation (United States), National Research Council (Canada), Agencia Nacional de Investigación y Desarrollo (Chile), Ministerio de Ciencia, Tecnología e Innovación (Argentina), Ministério da Ciência, Tecnologia, Inovações e Comunicações (Brazil), and Korea Astronomy and Space Science Institute (Republic of Korea). Data were partly collected with the 90 cm telescope at the Sierra Nevada Observatory (SNO) operated by the Instituto de Astrofí fica de Andalucí a (IAA-CSIC). We acknowledge the telescope operators from Observatori Astronómic del Montsec, Sierra Nevada Observatory, and Centro Astronómico Hispano-Alemán de Calar Alto (CAHA). E.G.A., M.R.Z.O., J.A.C., J.S.F, and D.M. acknowledge financial support from the Spanish Ministry of Science and Innovation through project PID2019-109522GBC5[1:4]. E.G.A also acknowledges support from AEI Project No. MDM-2017-0737 Unidad de Excelencia “María de Maeztu” – Centro de Astrobiología (CSIC-INTA). V.M.P. acknowledges financial support from NASA through grant NNX17AG24G. S.V.J. acknowledges the support of the DFG priority program SPP 1992 “Exploring the Diversity of Extrasolar Planets (JE 701/5-1)”. M.J.L.-G., E.R., C.R.-L., and P.J.A. acknowledge financial support from the Agencia Estatal de Investigación of the Ministerio de Ciencia e Innovación through projects PID2019-109522GB-C52, PID2019-107061GB-C64, PID2019-110689RB-100 and the Centre of Excellence Severo Ochoa Instituto de Astrofísica de Andalucía (SEV-2017-0709). G.M. received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 895525. S.S. and S.R. acknowledgesupport by the DFG Research Unit FOR 2544 Blue Planets around Red Stars, project no. RE 2694/4-1.

Full list of authors: Luque, R.; Fulton, B. J.; Kunimoto, M.; Amado, P. J.; Gorrini, P.; Dreizler, S.; Hellier, C.; Henry, G. W.; Molaverdikhani, K.; Morello, G.; Pena-Monino, L.; Perez-Torres, M.; Pozuelos, F. J.; Shan, Y.; Anglada-Escude, G.; Bejar, V. J. S.; Bergond, G.; Boyle, A. W.; Caballero, J. A.; Charbonneau, D.; Ciardi, D. R.; Dufoer, S.; Espinoza, N.; Everett, M.; Fischer, D.; Hatzes, A. P.; Henning, Th; Hesse, K.; Howard, A. W.; Howell, S. B.; Isaacson, H.; Jeffers, S., V; Jenkins, J. M.; Kane, S. R.; Kemmer, J.; Khalafinejad, S.; Kidwell, R. C., Jr.; Kossakowski, D.; Latham, D. W.; Lillo-Box, J.; Lissauer, J. J.; Montes, D.; Orell-Miquel, J.; Palle, E.; Pollacco, D.; Quirrenbach, A.; Reffert, S.; Reiners, A.; Ribas, I; Ricker, G. R.; Rogers, L. A.; Sanz-Forcada, J.; Schlecker, M.; Schweitzer, A.; Seager, S.; Shporer, A.; Stassun, K. G.; Stock, S.; Tal-Or, L.; Ting, E. B.; Trifonov, T.; Vanaverbeke, S.; Vanderspek, R.; Villasenor, J.; Winn, J. N.; Winters, J. G.; Osorio, M. R. Zapatero.-- This is an Open Access article, published by EDP Sciences, under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited., We report the discovery of a multiplanetary system transiting the M0 V dwarf HD 260655 (GJ 239, TOI-4599). The system consists of at least two transiting planets, namely HD 260655 b, with a period of 2.77 d, a radius of Rb = 1.240 ± 0.023 R⊕, a mass of Mb = 2.14 ± 0.34 M⊕, and a bulk density of ρb = 6.2 ± 1.0 g cm−3, and HD 260655 c, with a period of 5.71 d, a radius of , a mass of Mc = 3.09 ± 0.48 M⊕, and a bulk density of g cm−3. The planets have been detected in transit by the Transiting Exoplanet Survey Satellite (TESS) mission and confirmed independently with archival and new precise radial velocities obtained with the HIRES and CARMENES instruments since 1998 and 2016, respectively. At a distance of 10 pc, HD 260655 has become the fourth closest known multitransiting planet system after HD 219134, LTT 1445 A, and AU Mic. Due to the apparent brightness of the host star (J = 6.7 mag), both planets are among the most suitable rocky worlds known today for atmospheric studies with the James Webb Space Telescope, both in transmission and emission. © R. Luque et al. 2022., This paper includes data collected by the TESS mission. Funding for the TESS mission is provided by the NASA Explorer Program. We acknowledge the use of public TESS data from pipelines at the TESS Science Office and at the TESS Science Processing Operations Center. Resources supporting this work were provided by the NASA High-End Computing (HEC) Program through the NASA Advanced Supercomputing (NAS) Division at Ames Research Center for the production of the SPOC data products. This research has made use of the Exoplanet Follow-up Observation Program website, which is operated by the California Institute of Technology, under contract with the National Aeronautics and Space Administration under the Exoplanet Exploration Program. CARMENES is an instrument at the Centro Astronómico Hispano-Alemán (CAHA) at Calar Alto (Almería, Spain), operated jointly by the Junta de Andalucía and the Instituto de Astrofísica de Andalucía (CSlC). CARMENES was funded by the Max-Planck-Gesellschaft (MPG), the Consejo Superior de Investigaciones Científicas (CSIC), the Ministerio de Economía y Competitividad (MINECO) and the European Regional Development Fund (ERDF) through projects FICTS-2011-02, ICTS-2017-07-CAHA-4, and CAHA16-CE-3978, and the members of the CARMENES Consortium with additional contributions. Some of the observations in this paper made use of the NN-EXPLORE Exoplanet and Stellar Speckle Imager (NESSI). NESSI was funded by the NASA Exoplanet Exploration Program and the NASA Ames Research Center. NESSI was built at the Ames Research Center by Steve B. Howell, Nic Scott, Elliott P. Horch, and Emmett Quigley. R.L. acknowledges funding from University of La Laguna through the Margarita Salas Fellowship from the Spanish Ministry of Universities ref. UNI/551/2021-May 26, and under the EU Next Generation funds. We acknowledge financial support from the Agencia Estatal de Investigación of the Ministerio de Ciencia e Innovación and the ERDF “A way of making Europe” through projects PID2019-109522GB-C5[1:4]/AEI/10.13039/501100011033 and the Centre of Excellence “Severo Ochoa” and “María de Maeztu” awards to the Instituto de Astrofísica de Canarias (CEX2019-000920-S), Instituto de Astrofísica de Andalucía (SEV-2017-0709), and Centro de Astrobiología (MDM-2017-0737); the Generalitat de Catalunya/CERCA programme; the Deutsche Forschungsgemeinschaft (DFG) through the Major Research Instrumentation Programme and Research Unit FOR2544 “Blue Planets around Red Stars” (RE 2694/8-1, KU 3625/2-1), the Excellence Cluster ORIGINS (EXC-2094 – 390783311) and the Priority Programme “Exploring the Diversity of Extrasolar Planets” (JE 701/5-1); the National Aeronautics and Space Administration under grants 80NSSC21K0367 and 80NSSC22K0165 in support of Cycles 3 and 4 of the TESS Guest Investigator program; the National Science Foundation, Tennessee State University, and the State of Tennessee through its Centers of Excellence Program; and the Bulgarian BNSF program “VIHREN-2021” project No. KP-06-DV/5. The results reported herein benefited from collaborations and/or information exchange within the program “Alien Earths” (supported by the National Aeronautics and Space Administration under agreement No. 80NSSC21K0593) for NASA’s Nexus for Exoplanet System Science (NExSS) research coordination network sponsored by NASA’s Science Mission Directorate. The authors wish to recognize and acknowledge the very significant cultural role and reverence that the summit of Maunakea has always had within the indigenous Hawaiian community. We are most fortunate to have the opportunity to conduct observations from this mountain. We thank VeraM. Passegger for a helpful discussion on the photospheric parameters of HD 260655.

We report the detection and characterization of the transiting sub-Neptune TOI-1759 b, using photometric time-series from TESS and near infrared spectropolarimetric data from SPIRou on the CFHT. TOI-1759 b orbits a moderately active M0V star with an orbital period of $18.849975\pm0.000006$ d, and we measure a planetary radius and mass of $3.06\pm0.22$ R$_\oplus$ and $6.8\pm2.0$ M$_\oplus$. Radial velocities were extracted from the SPIRou spectra using both the CCF and the LBL methods, optimizing the velocity measurements in the near infrared domain. We analyzed the broadband SED of the star and the high-resolution SPIRou spectra to constrain the stellar parameters and thus improve the accuracy of the derived planet parameters. A LSD analysis of the SPIRou Stokes $V$ polarized spectra detects Zeeman signatures in TOI-1759. We model the rotational modulation of the magnetic stellar activity using a GP regression with a quasi-periodic covariance function, and find a rotation period of $35.65^{+0.17}_{-0.15}$ d. We reconstruct the large-scale surface magnetic field of the star using ZDI, which gives a predominantly poloidal field with a mean strength of $18\pm4$ G. Finally, we perform a joint Bayesian MCMC analysis of the TESS photometry and SPIRou RVs to optimally constrain the system parameters. At $0.1176\pm0.0013$ au from the star, the planet receives $6.4$ times the bolometric flux incident on Earth, and its equilibrium temperature is estimated at $433\pm14$ K. TOI-1759 b is a likely gas-dominated sub-Neptune with an expected high rate of photoevaporation. Therefore, it is an interesting target to search for neutral hydrogen escape, which may provide important constraints on the planetary formation mechanisms responsible for the observed sub-Neptune radius desert., Accepted for publication in the 10. Planets and planetary systems section of Astronomy & Astrophysics

Full list of authors: Lillo-Box, J.; Gandolfi, D.; Armstrong, D. J.; Collins, K. A.; Nielsen, L. D.; Luque, R.; Korth, J.; Sousa, S. G.; Quinn, S. N.; Acuña, L.; Howell, S. B.; Morello, G.; Hellier, C.; Giacalone, S.; Hoyer, S.; Stassun, K.; Palle, E.; Aguichine, A.; Mousis, O.; Adibekyan, V.; Azevedo Silva, T.; Barrado, D.; Deleuil, M.; Eastman, J. D.; Fukui, A.; Hawthorn, F.; Irwin, J. M.; Jenkins, J. M.; Latham, D. W.; Muresan, A.; Narita, N.; Persson, C. M.; Santerne, A.; Santos, N. C.; Savel, A. B.; Osborn, H. P.; Teske, J.; Wheatley, P. J.; Winn, J. N.; Barros, S. C. C.; Butler, R. P.; Caldwell, D. A.; Charbonneau, D.; Cloutier, R.; Crane, J. D.; Demangeon, O. D. S.; Díaz, R. F.; Dumusque, X.; Esposito, M.; Falk, B.; Gill, H.; Hojjatpanah, S.; Kreidberg, L.; Mireles, I.; Osborn, A.; Ricker, G. R.; Rodriguez, J. E.; Schwarz, R. P.; Seager, S.; Serrano Bell, J.; Shectman, S. A.; Shporer, A.; Vezie, M.; Wang, S. X.; Zhou, G.--This is an Open Access article, published by EDP Sciences, under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited., Context. The current architecture of a given multi-planetary system is a key fingerprint of its past formation and dynamical evolution history. Long-term follow-up observations are key to complete their picture. Aims. In this paper, we focus on the confirmation and characterization of the components of the TOI-969 planetary system, where TESS detected a Neptune-size planet candidate in a very close-in orbit around a late K-dwarf star. Methods. We use a set of precise radial velocity observations from HARPS, PFS, and CORALIE instruments covering more than two years in combination with the TESS photometric light curve and other ground-based follow-up observations to confirm and characterize the components of this planetary system. Results. We find that TOI-969 b is a transiting close-in (Pb ~ 1.82 days) mini-Neptune planet (mb = 9.1−1.0+1.1 M⊕, Rb = 2.765−0.097+0.088 R⊕), placing it on the lower boundary of the hot-Neptune desert (Teq,b = 941 ± 31 K). The analysis of its internal structure shows that TOI-969 b is a volatile-rich planet, suggesting it underwent an inward migration. The radial velocity model also favors the presence of a second massive body in the system, TOI-969 c, with a long period of Pc = 1700−280+290 days, a minimum mass of mc sin ic = 11.3−0.9+1.1 MJup, and a highly eccentric orbit of ec = 0.628−0.036+0.043. Conclusions. The TOI-969 planetary system is one of the few around K-dwarfs known to have this extended configuration going from a very close-in planet to a wide-separation gaseous giant. TOI-969 b has a transmission spectroscopy metric of 93 and orbits a moderately bright (G = 11.3 mag) star, making it an excellent target for atmospheric studies. The architecture of this planetary system can also provide valuable information about migration and formation of planetary systems. © The Authors 2023., J.L-B. acknowledges financial support received from “la Caixa” Foundation (ID 100010434) and from the European Unions Horizon 2020 research and innovation programme under the Marie Slodowska-Curie grant agreement No 847648, with fellowship code LCF/BQ/PI20/11760023. This research has also been partly funded by the Spanish State Research Agency (AEI) Projects No.PID2019-107061GB-C6l and No. MDM-2017-0737 Unidad de Excelencia “Maria de Maeztu” – Centro de Astrobiología (INTA-CSIC). R.L. acknowledges financial support from the Spanish Ministerio de Ciencia e Innovación, through project PID2019-109522GB-C52, and the Centre of Excellence “Severo Ochoa” award to the Instituto de Astrofísica de Andalucía (SEV-2017-0709). DJ.A. acknowledges support from the STFC via an Ernest Rutherford Fellowship (ST/R00384X/1). S.G.S acknowledges the support from FCT through Estimulo FCT contract nr.CEECIND/00826/2018 and POPH/FSE (EC). G.M. has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 895525. S.H. acknowledges CNES funding through the grant 837319. The French group acknowledges financial support from the French Programme National de Planétologie (PNP, INSU). This work is partly financed by the Spanish Mnistry of Economics and Competitiveness through grants PGC2018-098153-B-C31. We acknowledge the support by FCT – Fundação para a Ciência e a Tecnologia through national funds and by FEDER through COMPETE2020 – Programa Operacional Competitividade e Internacionalização by these grants: UID/FIS/04434/2019; UIDB/04434/2020; UIDP/04434/2020; PTDC/FIS-AST/32113/2017 & POCI-01-0145-FEDER-032113; PTDC/FISAST/28953/2017 & POCI-01-0145-FEDER-028953. P.J.W is supported by an STFC consolidated grant (ST/T000406/1). F.H. is funded by an STFC studentship. T.A.S acknowledges support from the Fundação para a Ciência e a Tecnologia (FCT) through the Fellowship PD/BD/150416/2019 and POCH/FSE (EC). C.M.P. acknowledges support from the SNSA (dnr 65/19P). This work has been carried out within the framework of the National Centre of Competence in Research (NCCR) PlanetS supported by the Swiss National Science Foundation. This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement SCORE No 851555). O.D.S.D. is supported in the form of work contract (DL 57/2016/CP1364/CT0004) funded by national funds through Fundação para a Ciência e a Tecnologia (FCT). M.E. acknowledges the support of the DFG priority programSPP 1992 “Exploring the Diversity of Extrasolar Planets” (HA 3279/12-1). A.O. is funded by an STFC studentship. J.K. gratefully acknowledge the support of the Swedish National Space Agency (SNSA; DNR 2020-00104). This work makes use of observations from the LCOGT network. This paper is based on observations made with the MuSCAT3 instrument, developed by the Astrobiology Center and under financial supports by ISPS KAKENHI (IP18H05439) and 1ST PRESTO (IPMIPR1775), at Faulkes Telescope North on Maui, HI, operated by the Las Cumbres Observatory. Some of the observations in the paper made use of the High-Resolution Imaging instrument Zorro obtained under Gemini LLP Proposal Number: GN/S-2021A-LP-105. Zorro was funded by the NASA Exoplanet Exploration Program and built at the NASA Ames Research Center by Steve B. Howell, Nie Scott, Elliott P. Horch, and Emmett Quigley. Zorro was mounted on the Gemini North (and/or South) telescope of the international Gemini Observatory, a program of NSF’s OIR Lab, which is managed by the Association of Universities for Research in Astronomy (AURA) under a cooperative agreement with the National Science Foundation. on behalf of the Gemini partnership: the National Science Foundation (United States), National Research Council (Canada), Agencia Nacional de Investigación y Desarrollo (Chile), Ministerio de Ciencia, Tecnología e Innovación (Argentina), Ministério da Ciência, Tecnologia, Inovações e Comunicações (Brazil), and Korea Astronomy and Space Science Institute (Republic of Korea). We acknowledge the use of public TESS data from pipelines at the TESS Science Office and at the TESS Science Processing Operations Center. Resources supporting this work were provided by the NASA High-End Computing (HEC) Program through the NASA Advanced Supercomputing (NAS) Division at Ames Research Center for the production of the SPOC data products. The MEarth Team gratefully acknowledges funding from the David and Lucile Packard Fellowship for Science and Engineering (awarded to D.C.). This material is based upon work supported by the National Science Foundation under grants AST-0807690, AST-1109468, AST-1004488 (Alan T. Waterman Award), and AST-1616624, and upon work supported by the National Aeronautics and Space Administration under Grant No. 80NSSC18K0476 issued through the XRP Program. This work is made possible by a grant from the John Templeton Foundation. The opinions expressed in this publication are those of the authors and do not necessarily reflect the views of the John Templeton Foundation. This research made use of Astropy, (a community-developed core Python package for Astronomy, Astropy Collaboration 2013, 2018), SciPy (Virtanen et al. 2020), matplotlib (a Python library for publication quality graphics Hunter 2007), and numpy (Harris et al. 2020). This research has made use of NASA’s Astrophysics Data System Bibliographic Services. This research has made use of the SIMBAD database, operated at CDS, Strasbourg, France., With funding from the Spanish government through the "Severo Ochoa Centre of Excellence" accreditation (CEX2021-001131-S).

In this work we quantify the effect of an unresolved companion star on the derived stellar parameters of the primary star if a blended spectrum is fit assuming the star is single. Fitting tools that determine stellar parameters from spectra typically fit for a single star, but we know that up to half of all exoplanet host stars may have one or more companion stars. We use high-resolution spectra of planet host stars in the Kepler field from the California-Kepler Survey to create simulated binaries; we select 8 stellar pairs and vary the contribution of the secondary star, then determine stellar parameters with SpecMatch-Emp and compare them to the parameters derived for the primary star alone. We find that in most cases the effective temperature, surface gravity, metallicity, and stellar radius derived from the composite spectrum are within 2-3 $\sigma$ of the values determined from the unblended spectrum, but the deviations depend on the properties of the two stars. Relatively bright companion stars that are similar to the primary star have the largest effect on the derived parameters; in these cases the stellar radii can be overestimated by up to 60%. We find that metallicities are generally underestimated, with values up to 8 times smaller than the typical uncertainty in [Fe/H]. Our study shows that follow-up observations are necessary to detect or set limits on stellar companions of planetary host stars so that stellar (and planet) parameters are as accurate as possible., Comment: Accepted by ApJ; 20 pages

Intraperitoneal therapy has now been demonstrated in multiple randomized trials to improve the outcome of chemotherapy for patients with optimally debulked or small volume ovarian carcinoma. This article reviews the basic pharmacologic principles that underlie the use of intraperitoneal therapy and identifies the key factors that determine the pharmacologic advantage of this route of administration. These include the relative peritoneal and plasma clearances and elements of tumor vascular permeability and blood flow that limit the penetration of drug entering tumor nodules by free-surface diffusion. New information about how cisplatin and carboplatin are transported into ovarian carcinoma cells points to novel strategies for further improving the therapeutic effectiveness of intraperitoneal chemotherapy

We present the first detections by the NASA K2 mission of oscillations in solar-type stars, using short-cadence data collected during K2 Campaign 1 (C1). We understand the asteroseismic detection thresholds for C1-like levels of photometric performance, and we can detect oscillations in subgiants having dominant oscillation frequencies around 1000 μHz. Changes to the operation of the fine-guidance sensors are expected to give significant improvements in the high-frequency performance from C3 onwards. A reduction in the excess high-frequency noise by a factor of 2.5 in amplitude would bring main-sequence stars with dominant oscillation frequencies as high as ≃2500 μHz into play as potential asteroseismic targets for K2.

The Faint Sky Variability Survey is aimed at finding photometric and/or astrometric variable objects in the brightness range between 16, Comment: Accepted by MNRAS, 8 pages, 6 figure + 3 as JPEGs

Down-regulation of protein kinase C (PKC) by 12- O -tetradecanoylphorbol-13-acetate (TPA) enhances the sensitivity of human ovarian carcinoma 2008 cells to various types of platinum compounds such as cisplatin (DDP), carboplatin and (–)-(R)-2-aminomethylpyrrolidine (1,1-cyclobutanedicarboxylato)-platinum(II) monohydrate (DWA) by a factor of two- to threefold. TPA enhanced the sensitivity of the DDP-resistant 2008/C13*5.25 subline to each of these three drugs to the same extent as for the 2008 cells. The extent of PKC down-regulation and drug sensitization depended on the duration of TPA exposure; maximum effect was achieved with a 48 h pretreatment. Sensitization was TPA concentration-dependent and was maximal at 0.05 μM TPA. 2008 cells expressed only the PKCα and PKCζ isoforms. Western blot analysis revealed that whereas the expression of PKCα was reduced by TPA the level of PKCζ was not affected. These results suggest that PKCα is the isotype responsive to TPA in these cells and that platinum drug sensitivity can be modulated by this isoform alone. In parallel to its effect on PKCα, TPA decreased cellular glutathione content by 30 ± 3 (standard deviation (s.d.) % in 2008 cells and by 41 ± 3 (s.d.) % in 2008/C13*5.25 cells. TPA also increased accumulation of DDP and DWA by 70%, although this effect was limited to the 2008/C13*5.25 cells. TPA rendered 2008 and 2008/C13*5.25 cells resistant to cadmium chloride by a factor of 3.7 and 3.6-fold respectively, suggesting a significant increase in cellular metallothionein content. Although the mechanism of TPA induced sensitization is not yet fully understood, this study points to a central role for PKCα in modulating platinum drug sensitivity. © 2000 Cancer Research Campaign

We present an atlas of extreme ultraviolet (EUV) spectra of 95 bright stellar sources observed between 1992 July and 1996 June with the Extreme Ultraviolet Explorer (EUVE) spectrometers. These data are taken in the short- (SW; 70-190 A), medium- (MW; 140-380 A), and long-wavelength bandpasses (LW; 280-760 A) at roughly 0.5, 1, and 2 A resolution, respectively. We describe the spectrometers and detail the procedure used to reduce the observational data to spectra. The atlas is grouped by the type of source: O-A stars, F-M stars, white dwarfs, and cataclysmic variables. We present a brief overview of the general nature and EUV spectral distribution of each group and present accompanying notes and individual spectra for each source. We show selected F-M sources in more detail with identifications of the brightest spectral lines illustrating the characteristics of the EUV spectra of stars of various temperatures. The current study is the most complete compilation to date of aggregate spectra of bright EUV stellar sources.

In an attempt to improve the dismal prognosis for patients with advanced cancer involving the temporal bone, a regional chemotherapy technique was piloted as part of the multimodality therapy for such patients. Rapid supradose cisplatin infusions selectively delivered to the lesion were given to 14 patients with carcinoma involving the temporal bone. Concurrent systemic cisplatin neutralization was achieved with sodium thiosulfate which permitted the use of cisplatin dose intensity regimens equivalent to fivefold the conventional amount. Four patients received chemotherapy alone, four had concomitant irradiation, and six had subsequent irradiation and/or temporal bone surgery. All patients tolerated the chemotherapy without significant complications or toxicity. All three of the patients with previously untreated disease responded to chemotherapy (2 Crs, 1 PR); three of the seven patients with recurrent disease responded to chemotherapy; and all four patients treated with chemoradiation had a complete response (including one patient with recurrent disease). The median follow-up time was 19 months (range, 5 to 63 months). Nine of the 14 patients are alive, including the 4 who were treated with targeted chemoradiation. The use of targeted high-dose chemotherapy for patients with malignant skull base lesions offers hope for improved outcome, particularly when this regimen is given simultaneously with radiation.

We present near infra-red light curves of supernova (SN) 2011fe in M101, including 34 epochs in H band starting fourteen days before maximum brightness in the B-band. The light curve data were obtained with the WIYN High-Resolution Infrared Camera (WHIRC). When the data are calibrated using templates of other Type Ia SNe, we derive an apparent H-band magnitude at the epoch of B-band maximum of 10.85 \pm 0.04. This implies a distance modulus for M101 that ranges from 28.86 to 29.17 mag, depending on which absolute calibration for Type Ia SNe is used., 9 pages, 3 figures, emulateapj style, accepted for publication in The Astrophysical Journal

Metallothionein (MT) is a low-molecular-weight protein (6800 Da) and one-third of its amino acids are cysteine residues. The 20 cysteines coordinate 7 metal atoms (zinc, copper, and/or cadmium). This protein is extremely inducible by metals as well as a number of organic compounds. MT is though to be an important intracellular storage site for zinc and possibly other essential trace elements. In addition, tolerance to cadmium toxicity is often due to the induction of MT, which sequesters cadmium and lowers its concentration at critical intracellular sites. Recently it has been proposed that MT might play important roles in several aspects of the carcinogenic process. In this context a symposium was held recently on this topic at the 1993 Annual Society of Toxicology Meeting. At this symposium Dr. Cherian discussed the expression of MT in various human tumors and its use as a potential marker of tumor differentiation or cell proliferation. Dr. Imura provided data illustrating that induction of MT can be used as an adjunct in cancer chemotherapy, in preventing toxicity caused by gamma-irradiation or cisplatin (CDDP) and other chemotherapeutics. Induction of MT has been suggested to be an important mechanism of resistance of tumor cells to chemotherapeutic agents, such as CDDP. This is controversial, and various views on this topic were presented by Drs. Howell, Lazo, and Koropatnick. Dr. Waalkes then discussed the role of MT in the carcinogenic and anticarcinogenic effects of metals.

Here we present Spitzer 4.5 μm light curves of two intermediate polars (IPs)—DQ Her and EX Hya—obtained with Cycle 6 observations. Our initial evaluation of the light curves of DQ Her and EX Hya shows that these two IPs exhibit similar behavior as that seen in non‐magnetic systems (specifically WZ Sge). The binary eclipses seen in the Spitzer light curves of DQ Her and EX Hya are about three times longer than their optical counterparts, indicating that a reservoir of dust extends beyond the outer edge of the optically visible accretion disk.

We have studied several aspects of DNA damage formation and repair in human ovarian cancer cell lines which have become resistant to cisplatin through continued exposure to the anticancer drug. The resistant cell lines A2780/cp70 and 2008/c13*5.25 were compared with their respective parental cell lines, A2780 and 2008. Cells in culture were treated with cisplatin, and the two main DNA lesions formed, intrastrand adducts and interstrand cross-links, were quantitated before and after repair incubation. This quantitation was done for total genomic lesions and at the level of individual genes. In the overall genome, the initial frequency of both cisplatin lesions assayed was higher in the parental than in the derivative resistant cell lines. Nonetheless, the total genomic repair of each of these lesions was not increased in the resistant cells. These differences in initial lesion frequency between parental and resistant cell lines were not observed at the gene level. Resistant and parental cells had similar initial frequencies of intrastrand adducts and interstrand cross-links in the dihydrofolate reductase (DHFR) gene and in several other genes after cisplatin treatment of the cells. There was no increase in the repair efficiency of intrastrand adducts in the DHFR gene in resistant cell lines compared with the parental partners. However, a marked and consistent repair difference between parental and resistant cells was observed for the gene-specific repair of cisplatin interstrand cross-links. DNA interstrand cross-links were removed from three genes, the DHFR, multidrug resistance (MDR1), and delta-globin genes, much more efficiently in the resistant cell lines than in the parental cell lines. Our findings suggest that acquired cellular resistance to cisplatin may be associated with increased gene-specific DNA repair efficiency of a specific lesion, the interstrand cross-link.

We have studied several aspects of DNA damage formation and repair in human ovarian cancer cell lines which have become resistant to cisplatin through continued exposure to the anticancer drug. The resistant cell lines A2780/cp70 and 2008/c13*5.25 were compared with their respective parental cell lines, A2780 and 2008. Cells in culture were treated with cisplatin, and the two main DNA lesions formed, intrastrand adducts and interstrand cross-links, were quantitated before and after repair incubation. This quantitation was done for total genomic lesions and at the level of individual genes. In the overall genome, the initial frequency of both cisplatin lesions assayed was higher in the parental than in the derivative resistant cell lines. Nonetheless, the total genomic repair of each of these lesions was not increased in the resistant cells. These differences in initial lesion frequency between parental and resistant cell lines were not observed at the gene level. Resistant and parental cells had similar initial frequencies of intrastrand adducts and interstrand cross-links in the dihydrofolate reductase (DHFR) gene and in several other genes after cisplatin treatment of the cells. There was no increase in the repair efficiency of intrastrand adducts in the DHFR gene in resistant cell lines compared with the parental partners. However, a marked and consistent repair difference between parental and resistant cells was observed for the gene-specific repair of cisplatin interstrand cross-links. DNA interstrand cross-links were removed from three genes, the DHFR, multidrug resistance (MDR1), and delta-globin genes, much more efficiently in the resistant cell lines than in the parental cell lines. Our findings suggest that acquired cellular resistance to cisplatin may be associated with increased gene-specific DNA repair efficiency of a specific lesion, the interstrand cross-link.

Basic pharmacologic principles support the concept that more drugs can be delivered to the tumor when it is delivered through the intraperitoneal route. Pharmacokinetic studies have confirmed that for many chemotherapeutic agents a substantial pharmacologic advantage can be achieved using this approach. Preliminary studies have suggested that intraperitoneal chemotherapy may be especially advantageous in patients with small-volume disease or in patients who have a negative second-look laparotomy. Clinical studies are ongoing to further define the role intraperitoneal therapy will play in the management of patients with ovarian cancer.

Cataclysmic variables have been extensively observed at optical, ultraviolet, and Xray wavelengths, where their white dwarf primary stars and bright accretion disks dominate their emitted luminosity. Comparatively little is known about the infrared properties of cataclysmic variables. The assumption that infrared observations would reveal only the “uninteresting” secondary star has been shown to be false: recent infrared observations of cataclysmic variables have instead shown that cool dust in these interacting binaries is possibly the most important contributor to their spectral energy distributions at long wavelengths. We present recent results from infrared observations of the cataclysmic variable EF Eridani obtained with the Spitzer Space Telescope.

AP5280 is a novel N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-bound platinum (Pt) therapeutic designed to increase the therapeutic index relative to conventional, small-molecule platinum agents. The platinum-polymer construct accumulates in solid tumours on the basis of increased capillary permeability. The bound platinum moiety is present as an N,O-Pt chelate at the distal end of a tetrapeptide linker, glycine-phenylalanine-leucine-glycine, and the weight-average molecular weight (Mw) of the construct is 22 kDa. The antitumour activity and toxicity of AP5280 were assessed in the syngeneic murine B16F10 and Lewis lung tumour models, and in the human ovarian carcinoma 2008 and head and neck squamous carcinoma UMSCC10b xenograft models. The maximum tolerated dose (MTD) of AP5280 was 6-fold greater than that of carboplatin (CBDCA) in vivo. AP5280 was active in all four tumour models, and it displayed a higher therapeutic index than CBDCA in each of these tumour models. The antitumour effect of AP5280 given at 16% of its MTD was equivalent to that produced by a MTD of CBDCA. Thus, consistent with the design goal for this drug, and despite being less potent than CBDCA, AP5280 produced less systemic toxicity relative to its antitumour activity and thus has a greater therapeutic index. On the basis of the improved therapeutic index evidenced in these models, AP5280 has been advanced into clinical trials.

Cisplatin (cDDP) is effective against some human tumors, but many are intrinsically resistant and, even among initially sensitive tumors, acquired resistance develops commonly during treatment. It has not been possible to prove which biochemical mechanisms control sensitivity to cDDP. Gene knockout studies in yeast, Dictyostelium discoideum, and mammalian cells have begun to unambiguously identify genes whose products function to modulate the cytotoxicity of cDDP. This review summarizes information currently available about the function of these genes. This comprehensive compilation points to the involvement of regulatory pathways known to mediate apoptosis, cell cycle checkpoint activation, and transcriptional rescue as regulators of cDDP sensitivity. Elucidation of the molecular mechanisms that mediate cDDP resistance holds promise for the design of pharmacological strategies for preventing, overcoming, or reversing this form of drug resistance.

Loss of DNA mismatch repair (MMR) increases the risk of spontaneous mutations. We sought to determine whether there was an interaction between hypoxia and MMR deficiency that might contribute to the phenomenon of tumor progression. Human colon carcinoma HCT116+ch2 (MMR-deficient) and HCT116+ch3 (MMR-proficient) sublines were exposed for varying periods of time to an environment of0.1% O2 and pH as low as 6.1. When a population containing 5% MMR-deficient cells and 95% MMR-proficient cells was subjected to hypoxia for 72 h, the MMR-deficient cells were enriched by a factor of 2-fold in the surviving population, whereas no enrichment was detected in cells maintained under aerobic conditions. The potential of hypoxia to destabilize the genome was determined by measuring the frequency of clones in the surviving population resistant to very high concentrations of 6-thioguanine or cisplatin. A 72-h exposure to hypoxia did not increase the frequency of resistant clones in the MMR-proficient cells but produced a 7.8-fold increase in 6-thioguanine-resistant clones and a 2.5-fold increase in cisplatin-resistant clones in the MMR-deficient cells. Loss of MMR increased the frequency of mutations in a reporter vector sensitive to frameshift mutations in a microsatellite sequence. Exposure to hypoxia for a time period as short as 48 h further increased the number of mutations in both cell types, but the absolute number of mutants was higher in the MMR-deficient cells. These results indicate that hypoxia and its accompanying low pH enrich for MMR-deficient cells and that loss of MMR renders human colon carcinoma cells hypersensitive to the ability of hypoxia to induce microsatellite instability and generate highly drug-resistant clones in the surviving population.

The therapeutic effectiveness of drugs is often limited by the inability to sustain therapeutic levels at the target site. Encapsulation of drugs in multivesicular lipid-based particles for sustained release is a novel approach to improving the pharmacokinetics of drug therapy. This paper reviews the preclinical and clinical literature on the applications and potential therapeutic benefits of DepoFoam technology, a novel sustained-release, injectable drug delivery system. DepoFoam formulations of drugs, including anticancer agents (cytarabine, methotrexate, bleomycin, recombinant interferon alfa, 5-fluorouridine-5'-monophosphate, and others), anti-infective agents (dideoxycytidine, 2'-norcyclic guanosine monophosphate, cidofovir, tobramycin, gentamicin, amikacin), analgesics (morphine, bupivacaine), and macromolecules (insulin, interleukin-2), delivered intrathecally, subcutaneously, intraperitoneally, or intralesionally, provide sustained therapeutic levels of drug at the intended target site and reduce systemic exposure and toxicity. Pharmacokinetic studies have demonstrated that DepoFoam particle encapsulation effectively extends the half-life of drugs, thus prolonging the duration of therapeutic drug concentrations in local tissues or in body spaces into which the encapsulated drug is injected. In the case of cell-cycle phase-specific chemotherapeutic agents, such formulations can improve efficacy and therapeutic ratio. DepoFoam is a promising drug delivery system for sustained release of hydrophilic injectable drugs that has a wide range of potential applications in oncology, infectious disease, analgesia, and other therapeutic areas.

The GADD153 gene is strongly transcriptionally activated by many types of cellular injury and the magnitude of the change in GADD153 expression is proportional to the extent of damage. We developed a novel reporter system in which a chimeric gene containing the GADD153 promoter linked to the coding region of an enhanced green fluorescent protein (EGFP) gene was stably integrated into the genome of a clone of UMSCC10b head and neck carcinoma cells. Activation of the exogenous GADD153 promoter was quantified using flow cytometric measurement of EGFP expression following drug exposure. The exogenous GADD153 promoter in this clone was activated by N-methl-N'-nitro-N-nitrosoguanidine (MNNG) in a concentration-dependent manner with kinetics that closely paralleled perturbation of cell cycle phase distribution. EGFP expression was strongly activated by a variety of genotoxic agents including DNA cross-linking and methylating agents, oxygen free radicals, DNA intercalator, UV and gamma-radiation and hypoxia. When grown as a xenograft in nude mice, the stably transfected clone also demonstrated dose-dependent EGFP expression when measured 4 days after cisplatin treatment. The reporter system accurately categorized the relative potency of adducts produced by 6 related platinum-containing drugs. In conclusion, this reporter system can facilitate in vitro and in vivo screening for agents capable of producing cytotoxicity via a wide variety of different mechanisms, and can be utilized to investigate the relative potency of structurally related DNA adducts.

This study examined how the DNA mismatch repair (MMR) system and p53 interact to maintain genomic integrity in the presence of the mutagenic stress induced by cisplatin (DDP). Sensitivity to the cytotoxic and mutagenic effect of DDP was assessed using a panel of sublines of the MMR-deficient HCT116 colon carcinoma cells in which MMR function had been restored by transfer of a copy of MLH1 on chromosome 3 or in which p53 function had been disabled by expression of HPV-16 E6. Loss of p53 function by expression of E6 in MMR-proficient HCT116+ ch3 cells conferred only 1.1-2.0-fold resistance to a panel of commonly used chemotherapeutic agents, whereas disruption of p53 in MMR-deficient HCT116 cells resulted in substantial levels of resistance to some agents (paclitaxel, 1.9-fold; gemcitabine, 2.7-fold; 6-thioguanine, 3.3-fold; and etoposide, 4.4-fold) but sensitization to other agents (topotecan, 2.5-fold; and DDP, 3.3-fold). Loss of MMR or p53 alone had only a minor effect on sensitivity to the mutagenic effect of DDP as measured by the appearance of variants resistant to 6-thioguanine, etoposide, topotecan, gemcitabine, and paclitaxel in the population 10 days later (1.0-2.4-fold), whereas loss of both p53 and MMR had a more profound effect (1.7-6.5-fold). Loss of both p53 and MMR increased the basal frequency insertion/deletion mutations detected by a shuttle vector-based assay to a greater extent than loss of either alone. In association with DDP-induced injury, loss of p53 or MMR alone resulted in 1.2- and 1.7-fold more mutations, whereas loss of both resulted in a 5.1-fold increase in mutant frequency. Examination of the impact of loss of p53 and/or MMR on the DDP-induced cell cycle checkpoint activation, p53 induction, ability of the cell to tolerate adducts in its DNA, and the rate of disappearance of platinum from genomic DNA indicated the effects of the loss of p53 and/or MMR on all of these parameters, suggesting a multifactorial etiology for the changes in sensitivity to the cytotoxic and mutagenic effects of DDP. These results indicate that p53 and MMR can cooperate to control sensitivity to the cytotoxic effect of DDP and to limit its mutagenic potential in the colon cancer cells.

Androgen-independent prostate cancer cells are remarkably resistant to therapeutic agents that work by triggering apoptosis via the caspase cascade. The recent sequencing of the entire genome of one of the most radiation-resistant organisms known, Deinococcus radiodurans, yields some insight into how prostate cancer cells might mount such resistance to apoptosis. Rather than being attributable to any one mechanism, the extreme radiation resistance of D. radiodurans appears to reflect the expression of a large number of different systems capable of preventing, repairing, or tolerating DNA damage and a very high degree of redundancy in these systems. Many molecular alterations that may influence the threshold for apoptosis have already been described in advanced prostate cancer; changes in bcl-2, p53, and the androgen receptor have been the most extensively studied. Current information is consistent with the concept that individual prostate cancer cells express multiple antiapoptotic mechanisms. This conclusion implies that it will not be possible to enhance cellular sensitivity to therapeutics that activate apoptosis by disabling just one target in a pathway, because other proteins are likely to be available to assume its function. Likewise, even elimination of a whole pathway may have little effect on sensitivity because cellular viability is protected by so many different mechanisms. However, where molecular changes have a phenotypic consequence, they offer a window of opportunity for the development of novel therapeutic strategies. One such example is a recently identified small organic compound that can inhibit p53 function and thus protect normal tissues against radiation-induced apoptosis without impairing killing of p53-deficient tumor cells.

To determine the survival results, patterns of relapse, and organ preservation effects of a targeted chemoradiation protocol for patients with advanced (stage III-IV) carcinoma of the head and neck.Analysis of 213 patients with stage III-IV squamous cell carcinoma treated at UT Memphis between June 1993 and March 1998. Treatment included weekly intra-arterial infusions of cisplatin (150 mg/m(2)/ week x 4) rapidly delivered to the tumor bulk, simultaneous intravenous thiosulfate for systemic drug neutralization, and conventional external-beam irradiation (180-200 cGy/fraction) to a total dose of 68-72 Gy.Tumor response, toxicity, disease control above the clavicle, pattern of relapse, and survival. There were 89 events of grade III-IV toxicity and 6 treatment-related deaths (grade V). Complete response in the primary and regional sites was obtained in 171 of 213 (80%) and 92 of 151 (61%), respectively. The rate of clearance of regional disease after neck dissection was 98%. There were 51 of 195 recurrences (26%): 11 local (5.6%), 5 regional (2.6%), and 35 distant (17.9%). The Kaplan Meier plot projections for overall and cancer-related 5-year survival was 38.8% and 53.6%, respectively, whereas disease control above the clavicle was 74.3%.We believe this chemoradiation protocol represents an effective management scheme for patients with advanced head and neck cancer with a high rate of organ preservation and possibly improved survival.

Preclinical studies have demonstrated a relationship between DNA mismatch repair (MMR) status and sensitivity to cisplatin and carboplatin. MMR-deficient cells are resistant to both drugs, and selection for cisplatin resistance in vitro is sometimes accompanied by loss of MMR protein expression. We used immunohistochemical staining techniques to investigate hMLH1 and hMSH2 expression in paired ovarian tumor sections from 54 ovarian cancer patients before and after platinum-based therapy. We sought associations between hMLH1 and hMSH2 protein expression and clinical parameters known to be of prognostic significance as well as response to treatment and overall survival. hMLH1 and hMSH2 staining decreased significantly after platinum-based therapy. The percent of malignant cells that stained positive correlated with the intensity of nuclear staining for both proteins; staining for hMLH1 correlated well with staining for hMSH2. Unexpectedly, expression of nuclear hMLH1 correlated negatively with response to treatment. Expression of nuclear hMLH1 and hMSH2 was positively correlated with pretreatment CA125 level, and expression of nuclear hMSH2 was positively correlated with change in CA125 level after treatment. Tumor stage was associated with expression of nuclear hMSH2, and tumor histological subtype was associated with both hMLH1 and hMSH2 staining. No association was found between expression of either protein and overall survival. These results indicate that the tumor is biologically altered after chemotherapy consistent with treatment-induced selection for cells expressing lower hMLH1 and hMSH2 levels. However, immunohistochemical staining for either hMLH1 or hMSH2 was not highly predictive of drug sensitivity as measured by response or survival.

Standard treatment for neoplastic meningitis requires frequent intrathecal (IT) injections of chemotherapy and is only modestly effective. DepoCyt is a sustained-release formulation of cytarabine that maintains cytotoxic concentrations of the drug in the cerebrospinal fluid (CSF) for more than 14 days after a single 50-mg injection. We conducted a randomized, controlled trial of DepoCyt versus methotrexate in patients with solid tumor neoplastic meningitis. Sixty-one patients with histologically proven cancer and positive CSF cytologies were randomized to receive IT DepoCyt (31 patients) or IT methotrexate (30 patients). Patients received up to six 50-mg doses of DepoCyt or up to sixteen 10-mg doses of methotrexate over 3 months. Treatment arms were well balanced with respect to demographic and disease-related characteristics. Responses occurred in 26% of DepoCyt-treated and 20% of methotrexate-treated patients (P = 0.76). Median survival was 105 days in the DepoCyt arm and 78 days in the methotrexate arm (log-rank P = 0.15). The DepoCyt group experienced a greater median time to neurological progression (58 versus 30 days; log-rank P = 0.007) and longer neoplastic meningitis-specific survival (log-rank P = 0.074; median meningitis-specific survival, 343 versus 98 days). Factors predictive of longer progression-free survival included absence of visible central nervous system disease on neuroimaging studies (P0.001), longer pretreatment duration of CSF disease (P0.001), history of intraparenchymal tumor (P0.001), and treatment with DepoCyt (P = 0.002). The frequency and grade of adverse events were comparable between treatment arms. In patients with solid tumor neoplastic meningitis, DepoCyt produced a response rate comparable to that of methotrexate and significantly increased the time to neurological progression while offering the benefit of a less demanding dose schedule.

Intrastrand DNA adducts formed by cisplatin and oxaliplatin were modeled with molecular mechanics minimization and restrained molecular dynamics simulations in a comparative study. A reasonable set of force field parameters for the Pt atom were refined by using the available cisplatinated DNA crystal structure as a guide. This crystal structure was also used as the starting structure for the simulations. Analysis of the resulting structures indicated that the covalent effects of oxaliplatin coordination on DNA structure were very similar to those of cisplatin. The most prominent difference between the two structures resulted from the presence of the 1,2-diaminocyclohexane ring in the oxaliplatin adduct. The modeling indicated that this ring protrudes directly outward into, and fills much of, the narrowed major groove of the bound DNA, forming a markedly altered and less polar major groove in the area of the adduct. The differences in the structure of the adducts produced by cisplatin and oxaliplatin are consistent with the observation that they are differentially recognized by the DNA mismatch repair system.

Cells injured by exposure to cisplatin (cDDP) undergo a cellular injury response that shares characteristics with responses produced by many other injurious agents. We sought to determine whether the increase of the message of the "growth arrest and DNA damage-inducible" gene, GADD153, could be used to assess the extent of the cellular injury response in model systems and in patients with head and neck cancer after treatment with cDDP. The mRNA levels of GADD153, a gene highly transcriptionally activated by cDDP damage, were increased in a transient, concentration-dependent manner by cDDP when human UMSCC10b head and neck carcinoma cells were treated with cDDP both in vitro and when grown as tumor xenografts in nude mice. There was a good correlation between the change in level of GADD153 mRNA and UMSCC10b cell kill by cDDP in vitro (r = 0.98). The magnitude of the increase was proportionally reduced in UMSCC10b sublines that were 3- or 6-fold resistant to cDDP. GADD153 mRNA levels were measured in biopsies obtained before and 24 h after treatment with cDDP from 32 patients with stage III/IV head and neck cancer. There was a relationship between the increase in GADD153 mRNA levels and the response rate. Seven of the 32 patients had no response and no increase in GADD153 mRNA level. Among the eight patients who attained a partial response, the increase in GADD153 message ranged from 0.7-2.5-fold. In contrast, 17 of 32 patients had a complete response, and this was accompanied by a 2-9-fold induction of GADD153. The mean increase in the complete responders (3.8+/-2.2-fold) differed significantly from that for the partial responders (1.6+/-0.9) and nonresponders (0.8+/-0.5; P0.05); the difference between the partial responders and nonresponders was also significant (P0.05). An increase of GADD153 mRNA of 1.75-fold or higher predicted a complete response, with a sensitivity of 94% and a specificity of 87%. We conclude that the magnitude of the increase in GADD153 mRNA is a promising candidate for service as an intermediate marker of head and neck tumor response to cDDP. The fact that the change in GADD153 mRNA reflects the actual extent of injury sustained by the tumor makes it particularly attractive as a potential marker. One strength of this approach is that it can provide a measure of the effectiveness of therapy as early as 24-48 h after the first dose of treatment.

Loss of DNA mismatch repair is a common finding in many types of sporadic human cancers as well as in tumors arising in patients with hereditary nonpolyposis colon cancer. The effect of the loss of DNA mismatch repair activity on sensitivity to a panel of commonly used chemotherapeutic agents was tested using one pair of cell lines proficient or deficient in mismatch repair due to loss of hMSH2 function and another due to loss of hMLH1 function. 6-Thioguanine and N-methyl-N'-nitro-N-nitrosoguanidine, to which these cells are known to be resistant, were included in the panel as controls. The results were concordant in both pairs of cells. Loss of either hMSH2 or hMLH1 function was associated with low level resistance to cisplatin, carboplatin, and etoposide, but there was no resistance to melphalan, perfosfamide, 5-fluorouracil, doxorubicin, or paclitaxel. The results are consistent with the concept that the DNA mismatch repair proteins function as a detector for adducts produced by 6-thioguanine, N-methyl-N'-nitro-N-nitrosoguanidine, cisplatin, and carboplatin but not for melphalan and perfosfamide. They also suggest that these proteins play a role in detecting the DNA damage produced by the binding of etoposide to topoisomerase II and propagating signals that contribute to activation of apoptosis.

Cisplatin exerts its cytotoxicity by inducing apoptosis. Similarly, all-trans retinoic acid (ATRA) causes apoptosis in certain cells. We studied the interaction of cisplatin and ATRA in human ovarian adenocarcinoma cells 2008, in human head and neck squamous carcinoma cells UMSCC10b, and in their respective cisplatin-resistant sub-lines. ATRA enhanced the cytotoxicity of cisplatin. The interaction of the drugs was synergistic in combination index-isobologram analyses (combination index0.5 at 50% cell survival) in all of the cell lines tested. ATRA inhibited the cellular accumulation of the cisplatin analogue [3H] cis-dichloroethylenediamineplatinum(II) by 22-33% in three of four cell lines tested but did not alter the cellular content of reduced glutathione. The expression of Bcl-2 relative to Bax decreased more after combined treatment with cisplatin and ATRA than after either drug alone. The apoptotic mechanism of cell death was confirmed by demonstrating cleavage of poly(ADP-ribose)polymerase and by morphological analysis. The combined treatment with ATRA and cisplatin induced apoptosis in significantly more cells than either drug alone. We conclude that ATRA enhances the cytotoxicity of cisplatin by facilitating apoptosis in ovarian and head and neck carcinoma cells.

The arsenite-stimulated human ATPase (hASNA-I) protein is a distinct human ATPase whose cDNA was cloned by sequence homology to the Escherichia coli ATPase arsA. Its subcellular localization in human malignant melanoma T289 cells was examined to gain insight into the role of hASNA-I in the physiology of human cells. Immunocytochemical staining using the specific anti-hASNA-I monoclonal antibody 5G8 showed a cytoplasmic, perinuclear, and nucleolar distribution. Subcellular fractionation indicated that the cytoplasmic hASNA-I was soluble and that the perinuclear distribution was due to association with the nuclear membrane rather than with the endoplasmic reticulum. Its presence in the nucleolus was confirmed by showing colocalization with an antibody of known nucleolar specificity. Further immunocytochemical analysis showed that the hASNA-I at the nuclear membrane was associated with invaginations into the nucleus in interphase cells. These results indicate that hASNA-I is a paralogue of the bacterial ArsA protein and suggest that it plays a role in the nucleocytoplasmic transport of a nucleolar component.

In addition to playing a role in tumorigenesis, loss of DNA mismatch repair results in low-level intrinsic resistance to cisplatin and carboplatin. We used a mismatch repair-deficient (clone B) and -proficient (clone B/rev) pair of Chinese hamster ovary sublines to determine the ability of cisplatin to enrich for repair-deficient cells during growth in vitro and in vivo. Clone B cells were 1.8-fold resistant to cisplatin as measured by a clonogenic assay. These cells were molecularly engineered to express constitutively the green fluorescent protein, and changes in the fraction of these repair-deficient cells were monitored by flow cytometric analysis. A single 1-hr exposure to cisplatin at an IC50 concentration enriched populations initially containing either 5 or 10% clone B cells by 81 and 75%, respectively, when measured at 5 days. Enrichment increased as a function of drug concentration to 158 and 169%, respectively, following an IC90 exposure. When grown as a xenograft, a single LD10 dose of cisplatin enriched the tumors by 48% from 4.6 to 6.8% repair-deficient cells (p = 0.04). To determine whether similar enrichment occurs during the treatment of human ovarian cancer patients, paired tumor samples were obtained from 38 patients before and after treatment with a minimum of 3 cycles of platinum drug-based primary chemotherapy and analyzed immunohistochemically for changes in the fraction of tumor cells expressing hMHL1. Following treatment there was a reduction in hMLH1 staining in 66% of the cases (p = 0.0005). Our results demonstrate that, despite the fact that loss of mismatch repair yields only modest levels of cisplatin resistance, even a single exposure to cisplatin produces quite a marked enrichment for repair-deficient cells in vitro and in vivo. Our results are consistent with the concept that treatment with cisplatin or carboplatin selects for preexisting mismatch repair-deficient cells, and that this contributes to the frequent development of clinical resistance.

Loss of DNA mismatch repair (MMR) has been observed in a variety of human cancers. In addition to predisposing to oncogenesis, loss of MMR activity is of concern with respect to the use of chemotherapeutic agents to treat established tumors. Loss of MMR results in drug resistance directly by impairing the ability of the cell to detect DNA damage and activate apoptosis and indirectly by increasing the mutation rate throughout the genome. The MMR proteins are involved in mediating the activation of cell cycle checkpoints and apoptosis in response to DNA damage. MMR-deficient cells have been reported to be resistant to the methylating agents procarbazine and temozolomide, the alkylating agent busulfan, the platinum-containing drugs cisplatin and carboplatin, the antimetabolite 6-thioguanine, and the topoisomerase II inhibitors etoposide and doxorubicin. In the case of cisplatin, busulfan, temozolomide, and procarbazine, the degree of resistance has been shown to be sufficient to produce a large difference in clinical responsiveness in vivo in tumor model systems. The available preclinical data suggest that tumors that contain a significant fraction of cells deficient in MMR will demonstrate reduced responsiveness to specific drugs. The challenge now is to assess the clinical significance of the presence of deficient cells in tumors and to discover drugs that retain activity against MMR-deficient cells.

The c-Abl nonreceptor tyrosine kinase and the c-Jun NH2-terminal kinase (JNK/stress-activated protein kinase) are activated during the injury response to the DNA-damaging agent cisplatin. Loss of DNA mismatch repair activity results in resistance to cisplatin in human cancer cells, suggesting that the mismatch repair proteins function as a detector for cisplatin DNA adducts. To identify signaling pathways activated by this detector, we investigated the effect of the loss of DNA mismatch repair function on the ability of cisplatin to activate the JNK and c-Abl kinases. The results demonstrate that cisplatin activates JNK kinase 3.8 +/- 0.2-fold more efficiently in DNA mismatch repair-proficient than repair-deficient cells, and that activation of c-Abl is completely absent in the DNA mismatch repair-deficient cells. Furthermore, the results show that cisplatin-induced activation of JNK occurs through a stress-activated protein kinase/extracellular signal-regulated kinase kinase 1-independent mechanism. We conclude that activation of JNK and c-Abl by cisplatin is in part dependent upon the integrity of DNA mismatch repair function, suggesting that these kinases are part of the signal transduction pathway activated when mismatch repair proteins recognize cisplatin adducts in DNA.