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  • 1
    Publication Date: 2018-01-04
    Description: Purpose: The objectives of the study were to evaluate the safety of daily oral PX-866 in combination with twice daily vemurafenib and to identify potential predictive biomarkers for this novel combination. Experimental Design: We conducted a phase I, open-label, dose-escalation study in patients with advanced BRAF V600–mutant solid tumors. PX-866 was administered on a continuous schedule in combination with vemurafenib. Patients underwent a baseline and on-treatment biopsy after 1-week of PX-866 monotherapy for biomarker assessment. Results: Twenty-four patients were enrolled. The most common treatment-related adverse events were gastrointestinal side effects. One dose-limiting toxicity (DLT) of grade 3 rash and one DLT of grade 3 pancreatitis were observed in cohort 2 (PX-866 6 mg daily; vemurafenib 960 mg twice daily) and cohort 3 (PX-866 8 mg daily; vemurafenib 960 mg twice daily), respectively. Of 23 response-evaluable patients, seven had confirmed partial responses (PR), 10 had stable disease, and six had disease progression. Decreases in intratumoral pAKT expression were observed following treatment with PX-866. Patients who achieved PRs had higher rates of PTEN loss by IHC (80% vs. 58%) and pathogenic PTEN mutations and/or deletions (57% vs. 25%). Two patients with durable PRs had an increase in intratumoral CD8 + T-cell infiltration following treatment with PX-866. Conclusions: PX-866 was well tolerated at its maximum tolerated single-agent dose when given in combination with a modified dose of vemurafenib (720 mg twice daily). Response to treatment appeared to be associated with PTEN loss and treatment with PX-866 seemed to increase CD8 + T-cell infiltration in some patients. Clin Cancer Res; 24(1); 22–32. ©2017 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 2
    Publication Date: 2016-01-14
    Description: How ecosystem productivity and species richness are interrelated is one of the most debated subjects in the history of ecology. Decades of intensive study have yet to discern the actual mechanisms behind observed global patterns. Here, by integrating the predictions from multiple theories into a single model and using data from 1,126 grassland plots spanning five continents, we detect the clear signals of numerous underlying mechanisms linking productivity and richness. We find that an integrative model has substantially higher explanatory power than traditional bivariate analyses. In addition, the specific results unveil several surprising findings that conflict with classical models. These include the isolation of a strong and consistent enhancement of productivity by richness, an effect in striking contrast with superficial data patterns. Also revealed is a consistent importance of competition across the full range of productivity values, in direct conflict with some (but not all) proposed models. The promotion of local richness by macroecological gradients in climatic favourability, generally seen as a competing hypothesis, is also found to be important in our analysis. The results demonstrate that an integrative modelling approach leads to a major advance in our ability to discern the underlying processes operating in ecological systems.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grace, James B -- Anderson, T Michael -- Seabloom, Eric W -- Borer, Elizabeth T -- Adler, Peter B -- Harpole, W Stanley -- Hautier, Yann -- Hillebrand, Helmut -- Lind, Eric M -- Partel, Meelis -- Bakker, Jonathan D -- Buckley, Yvonne M -- Crawley, Michael J -- Damschen, Ellen I -- Davies, Kendi F -- Fay, Philip A -- Firn, Jennifer -- Gruner, Daniel S -- Hector, Andy -- Knops, Johannes M H -- MacDougall, Andrew S -- Melbourne, Brett A -- Morgan, John W -- Orrock, John L -- Prober, Suzanne M -- Smith, Melinda D -- England -- Nature. 2016 Jan 21;529(7586):390-3. doi: 10.1038/nature16524. Epub 2016 Jan 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉US Geological Survey, Wetland and Aquatic Research Center, 700 Cajundome Boulevard, Lafayette, Louisiana 70506, USA. ; Department of Biology, 206 Winston Hall, Wake Forest University, Box 7325 Reynolda Station, Winston-Salem, North Carolina 27109, USA. ; Ecology, Evolution, and Behavior, University of Minnesota, 1987 Upper Buford Circle, St Paul, Minnesota 55108, USA. ; Department of Wildland Resources and the Ecology Center, Utah State University, 5230 Old Main, Logan, Utah 84322, USA. ; Department of Physiological Diversity, Helmholtz Center for Environmental Research - UFZ, Permoserstrasse 15, 04318 Leipzig, Germany. ; German Centre for Integrative Biodiversity Research (iDiv), Deutscher Platz 5e, D-04103 Leipzig, Germany. ; Martin Luther University Halle-Wittenberg, Am Kirchtor 1, 06108 Halle (Saale), Germany. ; Ecology and Biodiversity Group, Department of Biology, Utrecht University, Padualaan 8, Utrecht 3584 CH, The Netherlands. ; Institute for Chemistry and Biology of the Marine Environment, University of Oldenburg, Schleusenstrasse 1, Wilhelmshaven D-26381, Germany. ; Institute of Ecology and Earth Sciences, University of Tartu, Lai 40, Tartu 51005, Estonia. ; School of Environmental and Forest Sciences, University of Washington, Box 354115, Seattle, Washington 98195-4115, USA. ; School of Natural Sciences, Zoology, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland. ; Department of Biological Sciences, Imperial College London, Silwood Park, Ascot, Berkshire SL5 7PY, UK. ; Department of Zoology, University of Wisconsin, 430 Lincoln Drive, Madison, Wisconsin 53706, USA. ; Department of Ecology and Evolutionary Biology, UCB 334, University of Colorado, Boulder, Colorado 80309, USA. ; Grassland Soil and Water Research Laboratory, United States Department of Agriculture Agricultural Research Service, 808 East Blackland Road, Temple, Texas 76502, USA. ; #15 Queensland University of Technology, School of Earth, Environment and Biological Sciences, Brisbane, Queensland 4001, Australia. ; Department of Entomology, University of Maryland, College Park, 4112 Plant Sciences, College Park, Maryland 20742, USA. ; Department of Plant Sciences, University of Oxford, South Parks Road, Oxford OX1 3RB, UK. ; School of Biological Sciences, 348 Manter Hall, University of Nebraska, Lincoln, Nebraska 68588, USA. ; Department of Integrative Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada. ; Department of Ecology, Environment, and Evolution, La Trobe University, Bundoora, Victoria 3083, Australia. ; CSIRO Land and Water, Private Bag 5, Wembley, Western Australia, 6913, Australia. ; Department of Biology, Colorado State University, 1878 Campus Delivery, Fort Collins, Colorado 80526, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26760203" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2018-10-26
    Description: The Primary Immune Deficiency Treatment Consortium (PIDTC) performed a retrospective analysis of 662 patients with severe combined immunodeficiency (SCID) who received a hematopoietic cell transplantation (HCT) as first-line treatment between 1982 and 2012 in 33 North American institutions. Overall survival was higher after HCT from matched-sibling donors (MSDs). Among recipients of non-MSD HCT, multivariate analysis showed that the SCID genotype strongly influenced survival and immune reconstitution. Overall survival was similar for patients with RAG , IL2RG , or JAK3 defects and was significantly better compared with patients with ADA or DCLRE1C mutations. Patients with RAG or DCLRE1C mutations had poorer immune reconstitution than other genotypes. Although survival did not correlate with the type of conditioning regimen, recipients of reduced-intensity or myeloablative conditioning had a lower incidence of treatment failure and better T- and B-cell reconstitution, but a higher risk for graft-versus-host disease, compared with those receiving no conditioning or immunosuppression only. Infection-free status and younger age at HCT were associated with improved survival. Typical SCID, leaky SCID, and Omenn syndrome had similar outcomes. Landmark analysis identified CD4 + and CD4 + CD45RA + cell counts at 6 and 12 months post-HCT as biomarkers predictive of overall survival and long-term T-cell reconstitution. Our data emphasize the need for patient-tailored treatment strategies depending upon the underlying SCID genotype. The prognostic significance of CD4 + cell counts as early as 6 months after HCT emphasizes the importance of close follow-up of immune reconstitution to identify patients who may need additional intervention to prevent poor long-term outcome.
    Keywords: Pediatric Hematology, Immunobiology and Immunotherapy, Transplantation, Plenary Papers
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 4
    Publication Date: 2018-05-17
    Description: AID/APOBEC-like cytidine deaminases are ancient innate immune mediators in invertebrates AID/APOBEC-like cytidine deaminases are ancient innate immune mediators in invertebrates, Published online: 16 May 2018; doi:10.1038/s41467-018-04273-x The AID/APOBEC cytidine deaminase family are nucleic acid editors, important for antigen receptor expression and thought to have evolved along with vertebrate adaptive immunity. Here the authors show this family may have evolved prior to adaptive immunity as members with cytidine deaminase activity are present and functional in invertebrate sea urchins and brachiopods.
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2016-01-30
    Description: Fraser et al. (Reports, 17 July 2015, p. 302) report a unimodal relationship between productivity and species richness at regional and global scales, which they contrast with the results of Adler et al. (Reports, 23 September 2011, p. 1750). However, both data sets, when analyzed correctly, show clearly and consistently that productivity is a poor predictor of local species richness.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tredennick, Andrew T -- Adler, Peter B -- Grace, James B -- Harpole, W Stanley -- Borer, Elizabeth T -- Seabloom, Eric W -- Anderson, T Michael -- Bakker, Jonathan D -- Biederman, Lori A -- Brown, Cynthia S -- Buckley, Yvonne M -- Chu, Chengjin -- Collins, Scott L -- Crawley, Michael J -- Fay, Philip A -- Firn, Jennifer -- Gruner, Daniel S -- Hagenah, Nicole -- Hautier, Yann -- Hector, Andy -- Hillebrand, Helmut -- Kirkman, Kevin -- Knops, Johannes M H -- Laungani, Ramesh -- Lind, Eric M -- MacDougall, Andrew S -- McCulley, Rebecca L -- Mitchell, Charles E -- Moore, Joslin L -- Morgan, John W -- Orrock, John L -- Peri, Pablo L -- Prober, Suzanne M -- Risch, Anita C -- Schutz, Martin -- Speziale, Karina L -- Standish, Rachel J -- Sullivan, Lauren L -- Wardle, Glenda M -- Williams, Ryan J -- Yang, Louie H -- New York, N.Y. -- Science. 2016 Jan 29;351(6272):457. doi: 10.1126/science.aad6236.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Wildland Resources and the Ecology Center, Utah State University, 5230 Old Main, Logan, UT 84322, USA. atredenn@gmail.com. ; Department of Wildland Resources and the Ecology Center, Utah State University, 5230 Old Main, Logan, UT 84322, USA. ; U.S. Geological Survey, Wetland and Aquatic Research Center, 700 Cajundome Boulevard, Lafayette, LA 70506, USA. ; Department of Physiological Diversity, Helmholtz Center for Environmental Research - UFZ, Permoserstrasse 15, 04318 Leipzig, Germany. ; Department of Ecology, Evolution, and Behavior, University of Minnesota, St. Paul, MN 55108, USA. ; Department of Biology, Wake Forest University, Box 7325 Reynolda Station, Winston-Salem, NC 27109, USA. ; School of Environmental and Forest Sciences, University of Washington, 3501 NE 41st Street, Box 354115, Seattle, WA 98195, USA. ; Ecology, Evolution and Organismal Biology, Iowa State University, 251 Bessey Hall, Ames, IA 50010, USA. ; Department of Bioagricultural Sciences and Pest Management, Colorado State University, 307 University Avenue, Fort Collins, CO 80523, USA. ; School of Natural Sciences, Trinity College Dublin, University of Dublin, Zoology, Dublin 2, Ireland. ; School of Life Sciences, Sun Yat-sen University, Xingang Xi Road 135, Guangzhou, 510275, China. ; Department of Biology, University of New Mexico, Albuquerque, NM 87131, USA. ; Department of Biology, Imperial College London, Silwood Park, Ascot, SL5 7PY, UK. ; Grassland, Soil, and Water Research Laboratory, USDA-ARS, 808 East Blackland Road, Temple, TX 76502, USA. ; School of Earth, Environmental and Biological 42 Sciences, Queensland University of Technology (QUT), Gardens Point, Brisbane, Queensland, Australia, 4001. ; Department of Entomology, University of Maryland, 4112 Plant Sciences, College Park, MD 20742, USA. ; School of Life Sciences, University of KwaZulu-Natal, 1 Carbis Road, Pietermaritzburg, 3201, South Africa. ; Department of Biology, Ecology and Biodiversity group, Utrecht University, Padualaan 8, 3584 CH Utrecht, Netherlands. ; Department of Plant Sciences, University of Oxford, South Parks Road, Oxford, OX1 3RB, UK. ; Institute for Chemistry and Biology of the Marine Environment, Carl-von-Ossietzky University Oldenburg, Schleusenstrasse 1, 26382 Wihlhemshaven, Germany. ; School of Biological Sciences, University of Nebraska, 211 Manter Hall, Lincoln, NE 68588, USA. ; Biology Department, Doane College, 1014 Boswell Avenue, Crete, NE 68333, USA. ; Department of Integrative Biology, University of Guelph, 50 Stone Road, Guelph, Ontario, Canada N1G 2W1. ; Department of Plant and Soil Science, University of Kentucky, N-222D Ag Science North, Lexington, KY 40546-0091, USA. ; Department of Biology, University of North Carolina at Chapel Hill, CB#3280, Chapel Hill, NC 27599, USA. ; School of Biological Sciences, Monash University, Clayton Campus, Wellington Road, Clayton 3800, Victoria, Australia. ; Department of Ecology, Environment and Evolution, La Trobe University, Kingsbury Drive, Bundoora 3086, Victoria, Australia. ; Department of Zoology, University of Wisconsin, 430 Lincoln Drive, Madison, WI 53706, USA. ; Department of Forestry, Agriculture and Water, Southern Patagonia National University-INTA-CONICET, CC 332 (CP 9400), Rio Gallegos, Santa Cruz, Patagonia, Argentina. ; Commonwealth Scientific and Industrial Research Organisation Land and Water, Private Bag 5, Wembley, WA 6913, Australia. ; Community Ecology, Swiss Federal Institute for Forest, Snow and Landscape Research, Zuercherstrasse 111, 8903 Birmensdorf, Switzerland. ; Department of Ecology, INIBIOMA (CONICET-UNCO), Quintral 1250, Bariloche (8400), Rio Negro, Argentina. ; School of Veterinary and Life Sciences, Murdoch University, Perth, Western Australia, 90 South Street, Murdoch, Western Australia 6150. ; School of Biological Sciences, University of Sydney, Heydon-Laurence Building, A08, University of Sydney, Sydney, NSW, 2006, Australia. ; Agricultural and Biosystems Engineering, Iowa State University, Ames, IA, USA. ; Department of Entomology and Nematology, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26823418" target="_blank"〉PubMed〈/a〉
    Keywords: *Biodiversity ; *Grassland ; *Plant Development
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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