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Jennings, Maggie. "Proceedings of Animals in Science Conference: Perspectives on Their Use, Care and Welfare Edited by N E Johnston (1995). Monash University: Clayton. 262 pp. Paperback. Obtainable from the Research Ethics Unit, Monash University, Clayton, Victoria 3168, Australia (ISBN 0 7326 0636 5). Price AUS$30." Animal Welfare 5, no. 4 (November 1996): 460–61. http://dx.doi.org/10.1017/s096272860001931x.
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Richardson, James K. "Percy Rollo Brett OBE (1923–2022)." Journal of Telecommunications and the Digital Economy 10, no. 3 (September 26, 2022): 165–70. http://dx.doi.org/10.18080/jtde.v10n3.628.
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Percy Rollo Brett OBE (11 November 1923 to 8 August 2022) was a highly respected head of the PMG/APO (later Telecom Australia/Telstra) Research Laboratories between 1964 and 1975. He was promoted to Head of Planning for Telecom Australia in July 1975, and then State Manager, Victoria for that organization in 1980–1983. Rollo’s achievements as Director of the Research Laboratories included building links with Australian universities to strengthen the Laboratories’ expertise in longer term research, and masterminding the Laboratories’ move from six different sites in central Melbourne to a single site, in purpose-designed buildings in Clayton, opposite Monash University’s main campus. In the early 1970s, he used the expertise he gained as Chairman of the Telecommunications and Electronics Standards Committee of the Standards Association of Australia to lead the Australian Post Office’s conversion of all its standards to metric. Upon retirement in 1983 he was awarded the OBE.
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Barnes, R. H., Janet Hoskins, Peter Boomgaard, Ann Kumar, Peter Boomgaard, Lenore Manderson, Matthew Isaac Cohen, et al. "Book Reviews." Bijdragen tot de taal-, land- en volkenkunde / Journal of the Humanities and Social Sciences of Southeast Asia 155, no. 2 (1999): 264–303. http://dx.doi.org/10.1163/22134379-90003877.
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- R.H. Barnes, Janet Hoskins, Biographical objects; How things tell the stories of people’s lives. London: Routledge, 1998, x + 213 pp. - Peter Boomgaard, Ann Kumar, Java and modern Europe; Ambiguous encounters. Richmond, Surrey: Curzon, 1997, vii + 472 pp. - Peter Boomgaard, Lenore Manderson, Sickness and the state; Health and illness in colonial Malaya, 1870-1940. Cambridge: Cambridge University Press, 1996, xix + 315 pp. - Matthew Isaac Cohen, Bambang Widoyo, Gapit; 4 naskah drama berbahasa Jawa: Rol, Leng, Tuk dan Dom. Yogyakarta: Yayasan Benteng Budaya, 1998, xiv + 302 pp. - James T. Collins, Bernd Nothofer, Reconstruction, classification, description; Festschrift in honor of Isidore Dyen. Hamburg: Abera, 1996, xiv + 259 pp. - J.R. Flenley, Kristina R.M. Beuning, Modern pollen rain, vegetation and climate in lowland East Java, Indonesia. Rotterdam: Balkema, 1996, 51 pp. + 49 plates. [Modern Quaternary Research in Southeast Asia 14.] - Gregory Forth, Karl-Heinze Kohl, Der Tod der Riesjungfrau; Mythen, Kulte und Allianzen in einer ostindonesischen Lokalkultur. Stuttgart: Kohlhammer, 1998, 304 pp. [Religionsethnologische Studien des Frobenius-Instituts Frankfurt am Main, Band I.] - J. van Goor, Brook Barrington, Empires, imperialism and Southeast Asia; Essays in honour of Nicholas Tarling. Clayton, Victoria: Monash Asia Institute, 1997, v + 250 pp. [Monash Papers on Southeast Asia 43.] - Mies Grijns, Penny van Esterik, Women of Southeast Asia. DeKalb: Center for Southeast Asian Studies, Northern Illinois University, 1996, xiv + 229 pp. ‘Monographs on Southeast Asia, Occasional Paper 17; Second, revised edition.] - Hans Hagerdal, Alfons van der Kraan, Bali at war; A history of the Dutch-Balinese conflict of 1846-49. Clayton, Victoria: Centre of Southeast Asian Studies, Monash University, 1995, x + 240 pp. [Monash Papers on Southeast Asia 34]. - Volker Heeschen, Jurg Wassmann, Das Ideal des leicht gebeugten Menschen; Eine ethnokognitive Analyse der Yupno in Papua New Guinea. Berlin: Reimer, 1993, xiii + 246 pp. - Nico Kaptein, Masykuri Abdillah, Responses of Indonesian Muslim intellectuals to the concept of democracy (1966-1993). Hamburg: Abera, 1997, iv + 304 pp. - Niels Mulder, Ivan A. Hadar, Bildung in Indonesia; Krise und kontinuitat; Das Beispiel Pesantren. Frankfurt: IKO-Verlag fur Interkulturelle Kommunikation, 1999, 207 pp. - Niels Mulder, Jim Schiller, Imagining Indonesia: Cultural politics and political culture. Athens: Ohio University, 1997, xxiii + 351 pp. [Monographs in International Studies, Southeast Asia Series 97.], Barbara Martin-Schiller (eds.) - J.W. Nibbering, Raymond L. Bryant, The political ecology of forestry in Burma 1824-1994. London: Hurst, 1997, xiii + 257 pp. - Hetty Nooy-Palm, Douglas W. Hollan, Contentment and suffering; Culture and experience in Toraja. New York: Columbia University Press, 1994, xiii + 276 pp., Jane C. Wellenkamp (eds.) - Anton Ploeg, Bill Gammage, The sky travellers; Journeys in New Guinea, 1938-1939. Carlton South, Victoria: Melbourne University Press, 1998. x + 292 pp. - Anton Ploeg, Jurg Wassmann, Pacific answers to Western hegemony; Cultural practices of identity construction. Oxford: Berg, 1998, vii + 449 pp. - John Villiers, Abdul Kohar Rony, Bibliography; The Portugese in Southeast Asia: Malacca, Moluccas, East Timor. Hamburg: Abera Verlag, 1997, 138 pp. [Abera Bibliographies 1.], Ieda Siqueira Wiarda (eds.) - Lourens de Vries, Ulrike Mosel, Saliba. Munchen/Newcastle: Lincom Europa, 1994, 48 pp. [Languages of the World/Materials 31.]
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Reckelhoff, Jane F., and Licy L. Yanes Cordozo. "As precision medicine becomes more important, is it finally time for increased emphasis on gender medicine?" Biochemist 39, no. 1 (February 1, 2017): 4–5. http://dx.doi.org/10.1042/bio03901004.
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Gender medicine is the topic of this issue of The Biochemist. In 2014, Francis Collins, Director of the National Institutes of Health (NIH), and Janine Clayton, Director of the Office of Research on Women's Health (ORWH) at NIH, announced that NIH would begin requiring all preclinical grant proposals to address sex as a biological variable1. The ORWH was set up in 1990 with the specific mandate to promote the inclusion of women and minority individuals in all clinical trials going forward2. Similar guidelines are imposed by the European Commission and the Canadian Institutes of Health Research.
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Amster, Matthew, Jérôme Rousseau, Atsushi Ota, Johan Talens, Wanda Avé, Johannes Salilah, Peter Boomgaard, et al. "Book Reviews." Bijdragen tot de taal-, land- en volkenkunde / Journal of the Humanities and Social Sciences of Southeast Asia 156, no. 2 (2000): 303–45. http://dx.doi.org/10.1163/22134379-90003850.
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- Matthew Amster, Jérôme Rousseau, Kayan religion; Ritual life and religious reform in Central Borneo. Leiden: KITLV Press, 1998, 352 pp. [VKI 180.] - Atsushi Ota, Johan Talens, Een feodale samenleving in koloniaal vaarwater; Staatsvorming, koloniale expansie en economische onderontwikkeling in Banten, West-Java, 1600-1750. Hilversum: Verloren, 1999, 253 pp. - Wanda Avé, Johannes Salilah, Traditional medicine among the Ngaju Dayak in Central Kalimantan; The 1935 writings of a former Ngaju Dayak Priest, edited and translated by A.H. Klokke. Phillips, Maine: Borneo Research Council, 1998, xxi + 314 pp. [Borneo Research Council Monograph 3.] - Peter Boomgaard, Sandra Pannell, Old world places, new world problems; Exploring issues of resource management in eastern Indonesia. Canberra: Centre for Resource and Environmental Studies, Australian National University, 1998, xiv + 387 pp., Franz von Benda-Beckmann (eds.) - H.J.M. Claessen, Geoffrey M. White, Chiefs today; Traditional Pacific leadership and the postcolonial state. Stanford, California: Stanford University Press, 1997, xiv + 343 pp., Lamont Lindstrom (eds.) - H.J.M. Claessen, Judith Huntsman, Tokelau; A historical ethnography. Auckland: Auckland University Press, 1996, xii + 355 pp., Antony Hooper (eds.) - Hans Gooszen, Gavin W. Jones, Indonesia assessment; Population and human resources. Canberra: Research School of Pacific and Asian Studies, Australian National University, 1997, 73 pp., Terence Hull (eds.) - Rens Heringa, John Guy, Woven cargoes; Indian textiles in the East. London: Thames and Hudson, 1998, 192 pp., with 241 illustrations (145 in colour). - Rens Heringa, Ruth Barnes, Indian block-printed textiles in Egypt; The Newberry collection in the Ashmolean Museum, Oxford. Oxford: Clarendon Press, 1997. Volume 1 (text): xiv + 138 pp., with 32 b/w illustrations and 43 colour plates; Volume 2 (catalogue): 379 pp., with 1226 b/w illustrations. - H.M.J. Maier, David T. Hill, Beyond the horizon; Short stories from contemporary Indonesia. Clayton, Victoria: Monash Asia Institute, 1998, xxxviii + 201 pp. - John N. Miksic, Helena A. van Bemmel, Dvarapalas in Indonesia; Temple guardians and acculturation, 1994, xvii + 249 pp. Rotterdam: Balkema. [Modern Quarternary Research in Southeast Asia 13.] - Remco Raben, Paul van Beckum, Adoe Den Haag; Getuigessen uit Indisch Den Haag. Den Haag: SeaPress, 1998, 200 pp. - Cornelia M.J. van der Sluys, Colin Nicholas, Pathway to dependence; Commodity relations and the dissolution of Semai society. Clayton: Centre of Southeast Asian Studies, Monash University, 1994, vii + 130 pp. [Monash Papers on Southeast Asia 33.] - David Stuart-Fox, Herman C. Kemp, Bibliographies on Southeast Asia. Leiden: KITLV Press, 1998, xvii + 1128 pp. - Sikko Visscher, Lynn Pan, The encyclopedia of the Chinese overseas. Richmond, Surrey: Curzon, 1999, 399 pp. - Sikko Visscher, Jurgen Rudolph, Reconstructing identities; A social history of the Babas in Singapore. Aldershot: Ashgate, 1998, 507 pp. - Edwin Wieringa, Perry Moree, ‘Met vriend die God geleide’; Het Nederlands-Aziatisch postvervoer ten tijde van de Verenigde Oost-Indische Compagnie. Zutphen: Walburg Pers, 1998, 287 pp. - Edwin Wieringa, Monique Zaini-Lajoubert, L’image de la femme dans les littératures modernes indonésienne et malaise. Paris: Association Archipel, 1994, ix + 221 pp. [Cahiers d‘Archipel 24.]
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Burger, Henry G. "Diagnostic role of follicle-stimulating hormone (FSH) measurements during the menopausal transition—an analysis of FSH, oestradiol and inhibin." European Journal of Endocrinology 130, no. 1 (January 1994): 38–42. http://dx.doi.org/10.1530/eje.0.1300038.
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Burger HG. Diagnostic role of follicle-stimulating hormone (FSH) measurements during the menopausal transition—an analysis of FSH, oestradiol and inhibin. Eur J Endocrinol 1994;130:38–42. ISSN 0804–4643 This review examines the role of follicle-stimulating hormone (FSH) measurement in assessing the significance of symptoms and possible continuing fertility during the menopausal transition. Follicle-stimulating hormone measurement is advocated frequently as a useful diagnostic tool in perimenopausal patients. Several investigators have shown that the serum FSH level increases in the early—midfollicular and early postovulatory phases in women over the age of 40 years who continue to experience regular menstrual cycles. The serum oestradiol level may fall (although this is controversial) and the immunoreactive inhibin level falls, being inversely correlated with the rising FSH level. When alterations in menstrual cyclicity or flow commence, signalling the onset of the menopausal transition, FSH levels may change abruptly, rising into the normal postmenopausal range and falling again into the range normally seen in young fertile women. Oestradiol and inhibin generally fluctuate in parallel with each other but inversely to FSH, although at times oestradiol in particular may be increased markedly. Postmenopausal FSH levels may be followed by endocrine evidence compatible with normal ovulation. After the menopause, FSH levels rise 10–1 5-fold, with low oestradiol and undetectable inhibin levels. It is concluded that FSH measurement is of little value, if any in the assessment of women during the menopausal transition because it cannot be interpreted reliably and because, apparently, ovulatory (and, presumably, potentially fertile) cycles may occur subsequent to the observation of postmenopausal FSH levels. Both oestradiol and inhibin are important negative feedback regulators of circulating FSH. Henry G Burger, Prince Henry's Institute of Medical Research, PO Box 152, Clayton, Victoria 3168, Australia
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DAVID, Monica, Cristina-Magdalena CIOBOTEA, Mădălina F. BĂNUȚĂ, Gina NEDELEA, Ramona STAN, Andrei TIŢA, and Ionela D. SĂRDĂRESCU. "Genetic differences as estimators of osmotic adjustment and source-sink balance in grapevine hybrid elites." Notulae Scientia Biologicae 14, no. 2 (June 28, 2022): 11250. http://dx.doi.org/10.55779/nsb14211250.
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This study deals with the best responses of a diverse collection of grapevine genotypes to osmotic stress associated with source-sink balance responses given by an estimator such as leaf area to fruit ratio. ‘Centennial Seedless’, a drought tolerant cultivar, was selected as control. The cultivars, ‘Victoria’ and ‘Argessis’, were chosen as a repetition from previous research dealing with pollen grain test, two years ago. Ten genotypes were hybrid elites in first and second hybrid generations. Three cultivars ‘Victoria’, ‘Centennial Seedless’, and ‘Argessis’ were grown under field conditions in containers, and in the soil under greenhouse conditions. Significant differences were found between genotypes for both responses to osmotic stress and source-sink balance. ‘Centennial Seedless’ and ‘BP9’ hybrid showed the best responses of induced osmotic adjustment; results confirmed the compensatory potassium uptake theory. ‘Victoria’ and ‘Argessis’ had almost the same average values as ‘Centennial Seedless’ osmotic estimator for induced osmotic adjustment. ‘Victoria’ and ‘HR7’ hybrid showed an increase in osmotic stress in the cell, after application of polyethylene glycol solutions without potassium cation and a lower source-sink ratio, which could be associated with higher photosynthesis rates. No correlations were identified between the mechanisms expressed by the analyzed estimators, indicating that they are activated and functional separately from each other, sometimes only compensatory.
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Burns, Linda J., Charles P. Clayton, James N. George, Beverly S. Mitchell, and Scott D. Gitlin. "The ASH Clinical Research Training Institute (CRTI) Positively Impacts The Success Of Early Career Hematologists In Patient-Oriented Clinical Research." Blood 122, no. 21 (November 15, 2013): 1679. http://dx.doi.org/10.1182/blood.v122.21.1679.1679.
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Abstract There is a recognized need to translate scientific discoveries to patient-oriented clinical research (POCR) in order to improve human health. To overcome obstacles that interfere with the recruitment and retention of physicians for POCR careers, in 2003 the American Society of Hematology (ASH) developed the Clinical Research Training Institute (CRTI), an enhanced and extensive mentored experience for early career POCR investigators. The ASH CRTI is limited to 20 trainees/year (senior fellows or junior faculty) with an equivalent number of faculty mentors. The year-long Institute includes a 1 week workshop with didactic sessions on a variety of POCR and career development topics, disease-specific small group sessions focusing on research protocol development with biostatistician participation, and one-on-one interactions with faculty and representatives with expertise in career-development awards from the U.S. National Institutes of Health. Trainees have additional interactions with their small groups and CRTI mentors throughout the ensuing year to promote career development and research collaborations. Communications between the trainees’ CRTI and home institution mentors are a vital component of the program. Evaluation of the POCR career development successes of the first 7 CRTI classes (140 trainees) was performed by reviewing trainees’ curriculum vitaes and their responses to an electronically distributed survey. Gender, racial and ethnic distributions were similar to that of U.S. Hematology/Oncology fellowship programs. The majority (66%) of trainees were senior fellows or graduates of adult hematology/oncology training programs, 31% of pediatric hematology/oncology programs and the remainder of other hematology-related programs. Eighty-six percent of trainees had self-described success establishing a POCR study and 85% considered themselves clinical investigators. Nearly half of trainees had positions that were primarily research focused. CRTI trainees received at least 144 external grant awards plus additional internal awards, and had published 1035 peer-reviewed manuscripts,173 chapters and 115 review articles. Over 95% of trainees were satisfied with their CRTI experience and testimonials supported their impression that CRTI had a significant impact on their career success. Enhancements introduced into the CRTI program, as a result of ongoing program evaluations, include broadening participant eligibility to include up to 5 international trainees per class to enhance global research collaborations and further enhancements to the trainee-mentor interactions. The outcomes of the ASH CRTI support the hypothesis that enhanced mentoring experiences contribute to the successful career development of physicians pursuing POCR careers. Disclosures: Clayton: American Society of Hematology: Employment.
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Kell, Professor Douglas, and Richard Reece. "Q&A." Biochemist 30, no. 6 (December 1, 2008): 31–32. http://dx.doi.org/10.1042/bio03006031.
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Douglas Kell was Professor of Bioanalytical Science at the University of Manchester and Director of the BBSRC-funded Manchester Centre for Integrative Systems Biology before taking over as Chief Executive of the BBSRC in October 2008. He studied at the University of Oxford and then did research at Aberystwyth University. He joined UMIST (University of Manchester Institute of Science and Technology) in 2002. (UMIST merged with the Victoria University of Manchester to form The University of Manchester in 2004.)
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Chepinoga, I. S. "Introduction and studying of the species polymorphism in the almond genetic diversity preserved at Krymsk Experiment Breeding Station of VIR in the prebreeding stage." Proceedings on applied botany, genetics and breeding 183, no. 2 (June 24, 2022): 103–12. http://dx.doi.org/10.30901/2227-8834-2022-2-103-112.
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Modern trends and ways of resuming and increasing the production of domestic almond kernels based on the development of cultivars that have advantages in adaptability, productivity, and kernel quality, and are distinguished for a quick payback are discussed. The results of VIR’s expeditions that collected almond species and varieties in Southern Russia, the Transcaucasus, and Central Asia are presented. Almonds introduced from foreign research institutions are also described.Analytical selection helped to identify complex sources of resistance to abiotic factors: ‘Victoria’ (k-42684), ‘Meteor’ (k-42683), ‘Dessertny’ (k-43550), Ai-Dere No.4 (k-42676), Ai-Dere No.5 (k-42677), Kolod 6 (k-42709), Podvoyny 205 (k-42678), ‘Tuono’ (k-49598), and Ferraduel × Tuono (k-43561). Promising source material is recommended for targeted development of new competitive almond cultivars for intensive horticulture, including sources of restrained growth type, compact crown, and earliness: Ferraduel × Tuono, ‘Monterey’(k-49538), elite 1-18-2 (k-42679), elite 2-40 (k-42680), and Kalmykov’s almond seedling 1-1 (k-42711); of productivity and almond kernel quality: Ferraduel × Tuono, ‘Monterey’, ‘Victoria’, ‘Meteor’, ‘Mindalny’ (k-42682), ‘Ferragness’ (k-42696), ‘Tuono’, ‘Karmeil’ (k-49540), elite 1-18-2, and Kalmykov’s almond seedling 1-1; of high oil content in kernels: elite 13-37 (k-42681); and of valuable fatty acid composition (according to the content of unsaturated fatty acids): cv. ‘Victoria’, elites 1-18-2 and 2-40, and Kolod 5 (k-42708).
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TRIVEDI, Devanshi, Vishal M. MAKWANA, Ashish H. SHUKLA, and Pravinsang P. DODIA. "Diversity of butterflies in Victoria Park Reserve Forest, Bhavnagar, Gujarat, India." Notulae Scientia Biologicae 14, no. 3 (September 23, 2022): 11293. http://dx.doi.org/10.55779/nsb14311293.
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Documentation of biodiversity is crucial for examining the health of ecosystems. Many species act as an ecological indicator due to their susceptibility to changes in a particular environment. Butterflies, providing vital ecosystem services, respond uniquely to urbanization and can be a good tool for the assessment of the well-being of the habitat. The present study, one of its first kind in the particular habitat, provides a comprehensive outlook on the species diversity and abundance of butterflies at Victoria Park Reserve Forest, an urban forest area in Bhavnagar, Gujarat, India. The survey was conducted from March 2018 to February 2019 across all seasons. A total of 69 species belonging to 45 genera and five different families were recorded. The most diverse family was Lycaenidae (33.33%), followed by Nymphalidae (31.88%), Pieridae (21.74%), Papilionidae (7.25%), and Hesperiidae (5.80%). Junonia , was the dominant genus with six species. Out of the total recorded species,12 species are listed under the Least Concern category of the IUCN red list and 57 species are Not Evaluated. Seasonal variation in the number of species was observed, which shows the highest number of species in September (n=63) and the lowest in May (n=22). The abundance of the butterfly community was found to be highest during August (26.37%) and the lowest during February (1.85%). This study provided an understanding of the butterfly community in the habitat and would encourage further research for habitat restoration in the reserve forest.
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Batra, Mehak, Bircan Erbas, and Don Vicendese. "Asthma Hospital Admission and Readmission Spikes, Advancing Accurate Classification to Advance Understanding of Causes." Diagnostics 12, no. 10 (October 10, 2022): 2445. http://dx.doi.org/10.3390/diagnostics12102445.
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Background: An important component of asthma care is understanding potential causes of high asthma admissions (HAADs) or readmissions (HARDs) with potential of risk mitigation. Crucial to this research is accurately distinguishing these events from background seasonal changes and time trends. To date, classification methods have been based on ad hoc and untested definitions which may hamper understanding causes of HAADs and HARDs due to misclassification. The aim of this article is to introduce an easily applied robust statistical approach, with high classification accuracy in other settings—the Seasonal Hybrid Extreme Studentized Deviate (S-H-ESD) method. Methods: We demonstrate S-H-ESD on a time series between 1996 and 2009 of all daily paediatric asthma hospital admissions in Victoria, Australia. Results: S-H-ESD clearly identified HAADs and HARDs without applying ad hoc classification definitions, while appropriately accounting for seasonality and time trend. Importantly, it was done with statistical testing, providing evidence in support of their identification. Conclusion: S-H-ESD is useful and statistically appropriate for accurate classification of HAADs and HARDS. It obviates ad hoc approaches and presents as a means of systemizing their accurate classification and detection. This will strengthen synthesis and efficacy of research toward understanding causes of HAADs and HARDs for their risk mitigation.
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Gibbs, L., K. Block, C. MacDougall, L. Harms, E. Baker, J. Richardson, G. Ireton, et al. "Ethical Use and Impact of Participatory Approaches to Research in Post-Disaster Environments: An Australian Bushfire Case Study." BioMed Research International 2018 (June 11, 2018): 1–11. http://dx.doi.org/10.1155/2018/5621609.
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This paper presents a case study of Beyond Bushfires, a large, multisite, mixed method study of the psychosocial impacts of major bushfires in Victoria, Australia. A participatory approach was employed throughout the study which was led by a team of academic investigators in partnership with service providers and government representatives and used on-site visits and multiple methods of communication with communities across the state to inform decision-making throughout the study. The ethics and impacts of conducting and adapting the approach within a post-disaster context will be discussed in reference to theories and models of participatory health research. The challenges of balancing local interests with state-wide implications will also be explored in the description of the methods of engagement and the study processes and outcomes. Beyond Bushfires demonstrates the feasibility of incorporating participatory methods in large, post-disaster research studies and achieving rigorous findings and multilevel impacts, while recognising the potential for some of the empowering aspects of the participatory experience to be reduced by the scaled-up approach.
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Yeo, Geoffrey. "Research in the Archival MultiverseEdited by Anne J. Gilliland, Sue McKemmish, and Andrew J. Lau . Clayton, Victoria, Australia: Monash University Publishing, 2017. viii, 1,064 pp. Softcover and Open Access PDF. $99.95. Softcover ISBN 978-1-876924-67-6; Open Access PDF ISBN 978-1-925377-69-9." American Archivist 81, no. 1 (March 2018): 249–53. http://dx.doi.org/10.17723/0360-9081-81.1.249.
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Clayton, Nicholas P., Eric J. J. Charpentier, Emily R. LaCasse, Richard C. Khan-Malek, and Joan M. Keutzer. "Sargramostim Accelerates Leukocyte Recovery and Improves Mortality Rate at Day 60 in a Non-Human Primate Model of Hematopoietic Acute Radiation Syndrome When Administered 48 h after Total Body Irradiation." Blood 128, no. 22 (December 2, 2016): 2512. http://dx.doi.org/10.1182/blood.v128.22.2512.2512.
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Abstract Background: Hematopoietic acute radiation syndrome (H-ARS) occurs in individuals that are exposed to high levels of radiation over a short period of time. The destruction of bone marrow leads to pancytopenia, which increases the incidence of infections and accounts for the majority of morbidity and mortality. Sargramostim (yeast-derived rhGM-CSF) is a leukocyte growth factor that promotes differentiation, maturation and activation of granulocytes, monocytes and macrophages. Methods: We evaluated the efficacy of repeat administrations of sargramostim (7 μg/kg/day) in a blinded, GLP study in total body irradiated non-human primates (NHPs) when administered 48 h post-irradiation with minimal supportive care (e.g., no blood products or individualized antibiotics). The primary objective was to assess the efficacy of sargramostim versus vehicle on mortality rate at Day 60 in irradiated male and female NHPs at LD50-60/60 (n=36/group). Secondary objectives included the efficacy of sargramostim on overall survival and its effect on hematology parameters. The study included an exploratory arm of male and female NHPs that were irradiated at a LD70-80/60(n= 18/group) and received the same treatments. Results: Sargramostim decreased the mortality rate at Day 60 by 36% in the LD50-60/60 group (p=0.0018) and by 44% in the LD70-80/60 group (p=0.0076). Additionally, neutrophil, platelet, lymphocyte, and white blood cell levels in survivors demonstrated accelerated recovery in the sargramostim-treated NHPs in the LD50-60/60 and LD70-80/60 groups. Conclusion: Treatment with sargramostim (7 μg/kg/day) beginning at 48 h, in the absence of blood products and individualized antibiotics, suggests that the use of sargramostim is a viable therapeutic strategy for H-ARS in a mass casualty event. Funding: This project has been funded in whole or in part with Federal funds from the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under Contract No. HHSO100201300005I. Disclosures Clayton: Sanofi Genzyme: Employment. Charpentier:Sanofi: Employment. LaCasse:Sanofi Genzyme: Employment. Khan-Malek:Sanofi: Employment. Keutzer:Sanofi Genzyme: Employment.
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Arnold, Donald M., Julie Carruthers, Julie DiTomasso, Thea Gagliardi, Ralph M. Meyer, Mark A. Crowther, and John G. Kelton. "Passive Transfer of Hepatitis B Core Antibody by Intravenous Immune Globulin in Patients with Immune Thrombocytopenic Purpura." Blood 114, no. 22 (November 20, 2009): 2418. http://dx.doi.org/10.1182/blood.v114.22.2418.2418.
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Abstract Abstract 2418 Poster Board II-395 Background: Rituximab may reactivate remote hepatitis B infection. Thus, hepatitis B core antibody (HBcAb) seropositivity was an exclusion for a randomized trial of rituximab in patients with immune thrombocytopenic purpura (ITP) in Canada. During screening for this trial, we observed a high rate of HBcAb seropositivity at our centre. We investigated passive antibody transfer by intravenous immune globulin (IVIg) as a potential explanation. Methods: We performed a case-control study of consecutive ITP patients screened for eligibility for a randomized trial of rituximab. We compared the frequency of prior IVIg use and the IVIg product administered to patients who tested positive (n=11) and negative (n=13) for HBcAb. Total (IgG and IgM) HBcAb was tested using a microparticle enzyme immunoassay (MEIA) that measures the rate of inhibition compared with an internal cut-off value (AxSYM®, Abbott Laboratories, IL, USA). We calculated the odds ratio (OR) and 95% confidence interval (CI) for IVIg exposure. We also tested different lots of 2 IVIg products directly for HBcAb in the MEIA. Results: Of 24 consecutive patients with ITP screened, 11 (45.8%) were positive for HBcAb and thus were excluded from the randomized trial. The observed rate of HBcAb seropositivity in this cohort was 35 times higher than the expected seroprevalence in Canada of 1.3% (O'Brien Transfusion 2009). Of 11 HBcAb-positive patients, 10 (90.9%) had received prior IVIg [OR, 16 (95% CI, 1.54, 166.05)]. Of the 10 patients who received IVIg, 8 (80.0%) received Gamunex (10% human immune globulin, Talecris Biotherapeutics, Clayton, NC). HBcAb was repeated in 8 seropositive patients, of whom 4 were negative on repeat testing 7 to 104 weeks after the last dose of IVIg. Of the 13 HBcAb-negative patients, 5 (38.5%) had received prior IVIg; none were Gamunex. Seroconversion was documented in one patient serially tested after receiving Gamunex; MEIA rates decreased (became positive) rapidly, then gradually increased to normal after 7 weeks. Samples from 4 lots of Gamunex were reactive in the MEIA; whereas 3 lots of IGIVnex (Talecris Biotherapeutics) were non-reactive. Conclusions: False positive HBcAb results may occur due to the passive transfer of HBcAb from Gamunex, an IVIg product manufactured from donors who are not screened for HBcAb. HBcAb should be interpreted cautiously in any patient who received IVIg. We recommend HBcAb testing before IVIg administration so that treatments such as rituximab are not withheld unnecessarily. Disclosures: Arnold: Hoffman-LaRoche: Research Funding; Amgen: Consultancy, Honoraria. Meyer:The NCIC CTG is a clinical trials cooperative group. It receives its base grant support from the Canadian Cancer Society Research Institute. Many of its clinical trials include research support from industry. : Research Funding.
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F Jelinek, Herbert, Clare Wilding, and Paul Tinely. "An innovative Multi-disciplinary Diabetes Complications Screening Program in a Rural Community: A Description and Preliminary Results of the Screening." Australian Journal of Primary Health 12, no. 1 (2006): 14. http://dx.doi.org/10.1071/py06003.
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This paper describes an innovative multi-disciplinary pilot project for people living in rural north-east Victoria and southern New South Wales that focused on screening for diabetes complications. Participants enrolled for the diabetes screening through media announcements. A total of 91 participants were screened, 14 with diabetes. Screening tests included 12-lead ECG, ankle-brachial index, monofilament sensitivity, retinal photography as well as blood biochemistry. Twenty-six participants were referred to their general practitioners with cardiovascular anomalies, eight had retinal vasculature changes indicating diabetes, and 26 had foot problems that warranted podiatric assessment. This project illustrates that a university-based screening clinic is feasible, can be operated in conjunction with major research projects and results in significant community benefit. Serious health issues were identified in 31% of the study population. Without involvement in the screening, these people?s medical conditions may have otherwise remained hidden, potentially leading to significant health problems.
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KITLV, Redactie. "Book Reviews." Bijdragen tot de taal-, land- en volkenkunde / Journal of the Humanities and Social Sciences of Southeast Asia 158, no. 3 (2002): 535–92. http://dx.doi.org/10.1163/22134379-90003776.
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-Martin Baier, Han Knapen, Forests of fortune?; The environmental history of Southeast Borneo, 1600-1880. Leiden: The KITLV Press, 2001, xiv + 487 pp. [Verhandelingen 189] -Jean-Pascal Bassino, Per Ronnas ,Entrepreneurship in Vietnam; Transformations and dynamics. Copenhagen: Nordic Institute of Asian Studies (NIAS) and Singapore: Institute of Southeast Asian Studies, 2001, xii + 354 pp., Bhargavi Ramamurty (eds) -Adriaan Bedner, Renske Biezeveld, Between individualism and mutual help; Social security and natural resources in a Minangkabau village. Delft: Eburon, 2001, xi + 307 pp. -Linda Rae Bennett, Alison Murray, Pink fits; Sex, subcultures and discourses in the Asia-Pacific. Clayton, Victoria: Monash Asia Institute, 2001, xii + 198 pp. [Monash Papers on Southeast Asia 53.] -Peter Boomgaard, Laurence Monnais-Rousselot, Médecine et colonisation; L'aventure indochinoise 1860-1939. Paris: CNRS Editions, 1999, 489 pp. -Ian Coxhead, Yujiro Hayami ,A rice village saga; Three decades of Green revolution in the Philippines. Houndmills, Basingstoke: MacMillan, 2000, xviii + 274 pp., Masao Kikuchi (eds) -Robert Cribb, Frans Hüsken ,Violence and vengeance; Discontent and conflict in New Order Indonesia. Saarbrücken: Verlag für Entwicklungspolitik, 2002, 163 pp. [Nijmegen Studies in Development and Cultural Change 37.], Huub de Jonge (eds) -Frank Dhont, Michael Leifer, Asian nationalism. London: Routledge, 2000, x + 210 pp. -David van Duuren, Joseph Fischer ,The folk art of Bali; The narrative tradition. Kuala Lumpur: Oxford University Press, 1998, xx + 116 pp., Thomas Cooper (eds) -Cassandra Green, David J. Stuart-Fox, Pura Besakih; Temple, religion and society in Bali. Leiden: KITLV Press, xvii + 470 pp. [Verhandelingen 193.] -Hans Hägerdal, Vladimir I. Braginsky ,Images of Nusantara in Russian literature. Leiden: KITLV Press, 1999, xxvi + 516 pp., Elena M. Diakonova (eds) -Hans Hägerdal, David Chandler, A history of Cambodia (third edition). Boulder, Colorado: Westview, 2000, xvi + 296 pp. -Robert W. Hefner, Leo Howe, Hinduism and hierarchy in Bali. Oxford: James Currey, Santa Fe: School of American Research Press, 2001, xviii + 228 pp. -Russell Jones, Margaret Shennan, Out in the midday sun; The British in Malaya, 1880-1960. London: John Murray, 2000, xviii + 426 pp. -Russell Jones, T.N. Harper, The end of empire and the making of Malaya. Cambridge: Cambridge University Press, 1999, xviii + 417 pp. -Sirtjo Koolhof, Christian Pelras, The Bugis. Oxford: Blackwell, 1996, xvii + 386 pp. [The People of South-East Asia and the Pacific.] -Tania Li, Lily Zubaidah Rahim, The Singapore dilemma; The political and educational marginality of the Malay community. Kuala Lumpur: Oxford University Press, 1998, xviii + 302 pp. -Yasser Mattar, Vincent J.H. Houben ,Coolie labour in colonial Indonesia; A study of labour relations in the Outer Islands, c. 1900-1940. Wiesbaden: Harrassowitz, 1999, xvi + 268 pp., J. Thomas Lindblad et al. (eds) -Yasser Mattar, Zawawi Ibrahim, The Malay labourer; By the window of capitalism. Singapore: Institute of Southeast Asian Studies, 1998, xvi + 348 PP. -Kees Mesman Schultz, Leo J.T. van der Kamp, C.L.M. Penders, The West Guinea debacle; Dutch decolonisation and Indonesia 1945-1962. Leiden: KITLV Press, 2002, viii + 490 pp. -S. Morshidi, Beng-Lan Goh, Modern dreams; An inquiry into power, cultural production, and the cityscape in contemporary urban Penang, Malaysia. Ithaca, New York: Cornell University Southeast Asia Program, 2002, 224 pp. [Studies on Southeast Asia 31.] -Richard Scaglion, Gert-Jan Bartstra, Bird's Head approaches; Irian Jaya studies - a programme for interdisciplinary research. Rotterdam: Balkema, 1998, ix + 275 pp. [Modern Quarternary Research in Southeast Asia 15.] -Simon C. Smith, R.S. Milne ,Malaysian politics under Mahathir. London: Routledge, 1999, xix + 225 pp., Diane K. Mauzy (eds) -Reed L. Wadley, Christine Helliwell, 'Never stand alone'; A study of Borneo sociality. Phillips, Maine: Borneo Research Council, 2001, xiv + 279 pp. [BRC Monograph Series 5.] -Nicholas J. White, Francis Loh Kok Wah ,Democracy in Malaysia; Discourses and practices. Richmond, Surrey: Curzon Press, 2002, xiii + 274 pp. [Nordic Institute of Asian Studies Democracy in Asia Series 5.], Khoo Boo Teik (eds)
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de Brito Fontana, H., J. Lourdes Rios, R. A. Seerattan, V. Joumaa, D. A. Hart, R. A. Reimer, and W. Herzog. "AB0045 EFFECTS OF AEROBIC EXERCISE AND PREBIOTIC FIBRE SUPPLEMENTATION ON THE VASTUS LATERALIS AND SOLEUS MUSCLES IN A RAT MODEL OF DIET-INDUCED OBESITY." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1157.1–1158. http://dx.doi.org/10.1136/annrheumdis-2022-eular.409.
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BackgroundA high-fat/high-sucrose (HFS) diet leads to osteoarthritis-like damage in the knee and shoulder (Collins et al., 2018), and to a low-level systemic inflammation that is accompanied by a decrease in insulin sensitivity. Recently, we demonstrated in a rat model, that when prebiotic fibre supplementation, aerobic exercise, or their combination is started at the onset of the HFS diet exposure, the development of the osteoarthritis-like lesions in the knee joints and the metabolic dysfunction is prevented (Rios et al., 2019).A central role in the altered metabolic state of rats fed a HFS diet is thought to be played by skeletal muscle (Collins et al., 2018). Besides the detrimental effect on metabolic and inflammatory regulation, muscular dysfunction might be a contributor to the decline in running endurance and coordination observed with prolonged exposure to a low quality diet (Clayton et al., 2022).ObjectivesTo evaluate the changes in insulin sensitivity and vastus lateralis and soleus muscle composition in a HFS diet rat model and determine whether the expected muscle alterations can be prevented with a prebiotic fibre supplementation, aerobic exercise, or their combination.MethodsTwelve-week-old male Sprague Dawley rats fed a high-fat/high-sucrose diet (HFS, Diet #102412, Dyets) were randomized into a sedentary (HFS, n=12), moderate aerobic exercise (HFS+E, n=12), prebiotic fibre supplementation (HFS+F, n=12), or moderate aerobic exercise combined with prebiotic fibre supplementation (HFS+F+E, n=12) group for 12 weeks. Eight chow-fed (Diet #5001) age- and sex-matched animals were used as controls.Whole body insulin sensitivity (composite insulin sensitivity index – CISI) was determined at the end of the intervention period and, after sacrifice, the VL and soleus muscle composition was evaluated through a triglyceride colorimetric assay and histological analysis of collagen with picrosirius red staining. Non-parametric Kruskal-Wallis testing with pairwise comparisons was used to compare groups.ResultsHFS group rats had less than half (40%, p = 0.001) of the whole-body insulin sensitivity of control rats while rats in the HFS+E, HFS+F and HFS+F+E groups were similar to control.Rats that were fed the HFS diet showed increased VL (p = 0.033) but not soleus (p = 0.644) triglycerides content compared to control (Figure 1 A). Both VL and soleus showed increased collagen content in the groups fed the HFS diet compared to the control group (p<0.001 for VL and soleus) (Figure 1 B). Moderate aerobic exercise, prebiotic fibre supplementation, or their combination did not prevent the observed alterations in muscle composition in the groups fed the HFS diet.ConclusionWhile a positive effect of prebiotic fibre and exercise in managing metabolic disturbance was present with a clear recovery of insulin sensitivity to control levels in the groups that were fed the HFS diet, the protective effect of exercise and prebiotic fibre that has been previously described for knee joints in this model was not observed for the VL and soleus muscles. The HFS diet led to alterations in muscle composition that seem to be muscle-specific and cannot be prevented by combining prebiotic fibre or exercise with the HFS diet.References[1]Clayton, Z.S.et al.. 2022. Lifelong physical activity attenuates age- and Western-style diet-related declines in physical function and adverse changes in skeletal muscle mass and inflammation. Exp. Gerontol. 157, 111632.[2]Collins, K. H. et al.. 2018. Obesity, Metabolic Syndrome, and Musculoskeletal Disease: Common Inflammatory Pathways Suggest a Central Role for Loss of Muscle Integrity. Front. Physiol. 9.[3]Rios, J.L., Bomhof, M.R., Reimer, R.A., Hart, D.A., Collins, K.H., Herzog, W., 2019. Protective effect of prebiotic and exercise intervention on knee health in a rat model of diet-induced obesity. Sci. Rep. 9, 3893.AcknowledgementsThis work was supported by the Canadian Institutes of Health Research # RT736475 (WH) and MOP 115076, the Canada Research Chair Programme (WH), the Alberta Innovates Health Solutions Osteoarthritis Team Grant (DAH, WH), Alberta Innovates Health Solutions, Killam Foundation (WH), Alberta Innovates (JLR), and theCoordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.Disclosure of InterestsNone declared
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Walters, Judi, Kate Light, and Nathan Robinson. "Using agricultural metadata: a novel investigation of trends in sowing date in on-farm research trials using the Online Farm Trials database." F1000Research 9 (May 26, 2021): 1305. http://dx.doi.org/10.12688/f1000research.26903.2.
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Background: A growing ability to collect data, together with the development and adoption of the FAIR guiding principles, has increased the amount of data available in many disciplines. This has given rise to an urgent need for robust metadata. Within the Australian grains industry, data from thousands of on-farm research trials (Trial Projects) have been made available via the Online Farm Trials (OFT) website. OFT Trial Project metadata were developed as filters to refine front-end database searches, but could also be used as a dataset to investigate trends in metadata elements. Australian grains crops are being sown earlier, but whether on-farm research trials reflect this change is currently unknown. Methods: We investigated whether OFT Trial Project metadata could be used to detect trends in sowing dates of on-farm crop research trials across Australia, testing the hypothesis that research trials are being sown earlier in line with local farming practices. The investigation included 15 autumn-sown, winter crop species listed in the database, with trial records from 1993 to 2019. Results: Our analyses showed that (i) OFT Trial Project metadata can be used as a dataset to detect trends in sowing date; and (ii) cropping research trials are being sown earlier in Victoria and Western Australia, but no trend exists within the other states. Discussion/Conclusion: Our findings show that OFT Trial Project metadata can be used to detect trends in crop sowing date, suggesting that metadata could also be used to detect trends in other elements such as harvest date. Because OFT is a national database of research trials, further assessment of metadata may uncover important agronomic, cultural or economic trends within or across the Australian cropping regions. New information could then be used to lead practice change and increase productivity within the Australian grains industry.
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Mo, Allison, Jake Shortt, Erica M. Wood, and Zoe K. McQuilten. "Large Population Dataset Linkage to Understand Evolving Practice in Red Cell and Platelet Transfusion and Clinical Outcomes in Patients with Myelodysplastic Syndromes (MDS): A 15-Year Study." Blood 138, Supplement 1 (November 5, 2021): 3255. http://dx.doi.org/10.1182/blood-2021-147132.
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Abstract Aim: Transfusions are frequently administered for anemia and thrombocytopenia in MDS. However, evidence to guide transfusion remains sparse, along with data about real-world MDS transfusion practices, transfusion-related outcomes and changes over time with increasing access to disease-modifying therapies. In Australia, from 2011, 5-azacitidine was funded through the Pharmaceutical Benefit Scheme (PBS) for patients with IPSS classification intermediate-2 or high-risk MDS, or Chronic Myelomonocytic Leukemia-2 (CMML-2). Australian Patient Blood Management (PBM) guidelines were also first published in 2011. We aimed to characterise red blood cell (RBC) and platelet transfusion practices, and transfusion-related outcomes of MDS and CMML patients over a 15 year period, and explore whether access to disease-modifying therapies or the introduction of PBM guidelines impacted on transfusion requirements. Methods: Retrospective longitudinal cohort study including all patients with MDS/CMML admitted to hospitals in Victoria, Australia's second most populous state, from 2002-2017. Data linkage from the Victorian Admissions Episode Dataset (VAED) (contains data from all public and private hospital admissions in Victoria, including all transfusion episodes), the Victorian Cancer Registry and the Victorian Death Index was performed. We analysed transfusion episodes and outcome events (cardiac ischemia/failure, transfusion reactions, bleeding). Results: 6771 patients with a diagnosis of MDS/CMML reported to the Cancer Registry were included (5970 MDS; 801 CMML). The cohort was elderly (>50% aged 70y and over) and predominantly male (male 61%; female 39%). The majority of patients had a low number of comorbidities (Charlson Comorbidity Score: 60% low (0-2); 32% moderate (3-5); 8% high (≥6)). Of the 179 patients on 5-azacitidine, 38 (21.2%) commenced prior to 2011 and 141 (78.8%) from 2011 onwards. Patients on 5-azacitidine were more likely to be RBC transfusion dependent (TD) (defined as 2 or more RBC transfusions within 16 weeks) (77.7.1% vs 49.9%, p<0.001) and receive platelet transfusions (54.2% vs 28.6%, p<0.001). During the study period, the patients had a total of 142,765 hospital admissions. 66,068 (46.3%) admissions involved RBC transfusion, with median 3 admissions (IQR 1-10) per patient and median 14 days (IQR 14-33) between transfusions. 3433 (50.7%) of patients were RBC transfusion-dependent (TD). Comparing pre-and post-2011, the proportion of admissions involving RBC transfusion, median number of RBC transfusion admissions per patient, and rates of RBC-TD decreased (table 1). Cardiac events were common, and more frequent in RBC-TD patients (acute cardiac ischemia 14.6% vs 10.3%, p<0.001; acute cardiac failure 27.3% vs 14.1%,p<0.001). 10,049 (7.0%) admissions involved platelet transfusion. Platelet transfusion admissions increased over time (table 1). Median time between platelet transfusions was 7 days (IQR 4-16). 2436 patients (36.0%) experienced bleeding, including 51.3% of platelet-transfused patients. The commonest bleeding site was gastrointestinal (n=1388, 20.5%). Intracranial bleeding occurred in 175 patients (2.6%). 300 patients (4.4%) died from bleeding complications, with higher bleeding-related mortality in platelet-transfused patients (7.0% vs 3.4%, p<0.001) and RBC-TD patients (5.2% vs 4.0%, p=0.001). Conclusion: This study highlights the high transfusion burden in MDS patients, and related adverse cardiac and bleeding outcomes and mortality. RBC transfusion requirements reduced over time but platelet transfusions increased. This may be related to changing availability or use of MDS therapies, or clinical transfusion decision-making practices, or both - although national PBM guidelines do not specify a particular hemoglobin threshold for chronically transfused MDS patients, clinicians may be extrapolating from recommendations for restrictive transfusion thresholds in other settings (e.g. critical care, perioperative transfusion). These data will help design future MDS transfusion trials, which should include quality-of-life and health economics outcomes, given the burden of transfusion on these elderly patients. Figure 1 Figure 1. Disclosures Shortt: Amgen: Research Funding; Astex: Research Funding; BMS: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Wood: Amgen, Celgene, Gilead, Janssen, Novartis, Sanofi, Takeda: Research Funding; Abbvie, Amgen, Antengene, Bristol-Myers Squibb, Celgene, Gilead, GSK, Janssen, Novartis, Sanofi, and Takeda.: Other: The Australian and New Zealand Myeloma and Related Diseases Registry (MRDR) has received funding from Abbvie, Amgen, Antengene, Bristol-Myers Squibb, Celgene, Gilead, GSK, Janssen, Novartis, Sanofi, and Takeda. .
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Andel, Joan D., H. E. Coomans, Rene Berg, James N. Sneddon, Thomas Crump, H. Beukers, M. Heins, et al. "Book Reviews." Bijdragen tot de taal-, land- en volkenkunde / Journal of the Humanities and Social Sciences of Southeast Asia 147, no. 4 (1991): 516–46. http://dx.doi.org/10.1163/22134379-90003185.
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- Joan D. van Andel, H.E. Coomans, Building up the the future from the past; Studies on the architecture and historic monuments in the Dutch Caribbean, Zutphen: De Walburg Pers, 1990, 268 pp., M.A. Newton, M. Coomans-Eustatia (eds.) - Rene van den Berg, James N. Sneddon, Studies in Sulawesi linguistics, Part I, 1989. NUSA, Linguistic studies of Indonesian and other languages in Indonesia, volume 31. Jakarta: Badan Penyelenggara Seri Nusa, Universitas Katolik Indonesia Atma Jaya. - Thomas Crump, H. Beukers, Red-hair medicine: Dutch-Japanese medical relations. Amsterdam/Atlanta, GA: Rodopi, Publications for the Netherlands Association of Japanese studies No. 5, 1991., A.M. Luyendijk-Elshout, M.E. van Opstall (eds.) - M. Heins, Kees P. Epskamp, Theatre in search of social change; The relative significance of different theatrical approaches. Den Haag: CESO Paperback no. 7, 1989. - Rudy De Iongh, Rainer Carle, Opera Batak; Das Wandertheater der Toba-Batak in Nord Sumatra. Schauspiele zur Währung kultureller Identität im nationalen Indonesischen Kontext. Veröffentlichungen des Seminars fur Indonesische und Südseesprachen der Universität Hamburg, Band 15/1 & 15/2 (2 Volumes), Berlin: Dietrich Reimer Verlag, 1990. - P.E. de Josselin de Jong, Birgit Rottger-Rossler, Rang und Ansehen bei den Makassar von Gowa (Süd-Sulawesi, Indonesien), Kölner Ethnologische Studien, Band 15. Dietrich Reimar Verlag, Berlin, 1989. 332 pp. text, notes, glossary, literature. - John Kleinen, Vo Nhan Tri, Vietnam’s economic policy since 1975. Singapore: ASEAN Economic research unit, Institute of Southeast Asian studies, 1990. xii + 295 pp. - H.M.J. Maier, David Banks, From class to culture; Social conscience in Malay novels since independence, Yale, 1987. - Th. C. van der Meij, Robyn Maxwell, Textiles of Southeast Asia; Tradition, trade and transformation. Melbourne/Oxford/Auckland/New York: Australian National Gallery/Oxford University Press. - A.E. Mills, Elinor Ochs, Culture and language development, Studies in the social and cultural foundations of language No. 6, Cambridge University Press, 227 + 10 pp. - Denis Monnerie, Frederick H. Damon, Death rituals and life in the societies of the Kula Ring, Dekalb: Northern Illinois University Press, 1989. 280 pp., maps, figs., bibliogr., Roy Wagner (eds.) - Denis Monnerie, Frederick H. Damon, From Muyuw to the Trobriands; Transformations along the northern side of the Kula ring, Tucson: The University of Arizona Press, 1990. xvi + 285 pp., maps, figs., illus., apps., bibliogr., index. - David S. Moyer, Jeremy Boissevain, Dutch dilemmas; Anthropologists look at the Netherlands, Assen/Maastricht: Van Gorcum, 1989, v + 186 pp., Jojada Verrips (eds.) - Gert Oostindie, B.H. Slicher van Bath, Indianen en Spanjaarden; Een ontmoeting tussen twee werelden, Latijns Amerika 1500-1800. Amsterdam: Bert Bakker, 1989. 301 pp. - Parakitri, C.A.M. de Jong, Kompas 1965-1985; Een algemene krant met een katholieke achtergrond binnen het religieus pluralisme van Indonesie, Kampen: Kok, 1990. - C.A. van Peursen, J. van Baal, Mysterie als openbaring. Utrecht: ISOR, 1990. - Harry A. Poeze, R.A. Longmire, Soviet relations with South-East Asia; An historical survey. London-New York: Kegan Paul International, 1989, x + 176 pp. - Harry A. Poeze, Ann Swift, The road to Madiun; The Indonesian communist uprising of 1948. Ithaca, N.Y.: Cornell Modern Indonesia Project (Monograph series 69), 1989, xii + 116 pp. - Alex van Stipriaan, Cornelis Ch. Goslinga, The Dutch in the Caribbean and in Surinam 1791/5 - 1942, Assen/Maastricht: Van Gorcum, 1990. xii + 812 pp. - A. Teeuw, Keith Foulcher, Social commitment in literature and the arts: The Indonesian ‘Institute of People’s culture’ 1950-1965, Clayton, Victoria: Southeast Asian studies, Monash University (Centre of Southeast Asian studies), 1986, vii + 234 pp. - Elly Touwen-Bouwsma, T. Friend, The blue-eyed enemy; Japan against the West in Java and Luzon, 1942-1945. New Jersey: Princeton University press, 1988, 325 pp.
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McQuilten, Zoe K., Vijaya Sundararajan, Erica M. Wood, David J. Curtis, Mark N. Polizzotto, Lynda J. Campbell, and Meaghan Wall. "Monosomal Karyotype Is Associated With Worse Survival Independent Of Complex Karyotype In Patients With Myelodysplastic Syndrome." Blood 122, no. 21 (November 15, 2013): 1523. http://dx.doi.org/10.1182/blood.v122.21.1523.1523.
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Abstract Background There are conflicting data on the impact of monosomal karyotype (MK) on overall survival (OS) in patients with myelodysplastic syndrome (MDS) and in particular whether MK is an independent predictor of survival in the subset of MDS patients with a complex karyotype (CK). We aimed to determine whether MK was associated with inferior survival independent of number of cytogenetic abnormalities. Methods Patients and data sources: A retrospective cohort study was performed using three population-based datasets from the Australian state of Victoria (population approximately 5.3 million). All incident cases of MDS notified to the Victorian Cancer Registry (VCR) from 2000 to 2010 were included. VCR data was linked with cytogenetic testing results performed by The Victorian Cancer Cytogenetic Service, the single provider of cytogenetic services for hematological malignancies in Victoria, and with hospital admission records held within the Victorian Admission Episode Database (VAED), a database of all hospital admissions within the state of Victoria. Cytogenetics: Metaphase cytogenetic analysis was performed according to standard techniques and karyotypes were described using the International System for Cytogenetic Nomenclature (ISCN). Statistical analysis: MK was defined as the presence of 2 or more autosomal monosomies or one monosomy with at least one additional structural abnormality. CK was defined as 3 or more cytogenetic abnormalities (CA). Overall survival (OS) was defined from date of diagnosis until death, censoring surviving patients at study end. OS was estimated using Kaplan-Meier curves, with survival between groups compared with the log rank test. Multivariable analysis was performed using the Cox proportional regression method, including all those variables associated with OS with a p-value less than 0.2 on univariate analysis. Results 1476 incident MDS cases notified to the VCR had cytogenetic testing performed. Metaphase cytogenetic testing was successful in 1407 cases (95%). The median age at diagnosis was 77 (interquartile range [IQR] 69-83) and 866 (62%) were male. The most common MDS subtypes were refractory anemia (RA) with multi-lineage dysplasia (n=482; 34%), RA with excess blasts (RAEB, n=243, 17%), RA (n=136, 9%), RA with ring sideroblasts (n=127, 9%) and not specified in 334 (24%). Hospital admission records were available for 1197 (85%), of whom 676 (56%) had one or more co-morbidity and 150 (12%) were red cell transfusion dependent (RC-TD) at diagnosis. 908 (65%) had a normal karyotype and 499 (34%) had at least one cytogenetic abnormality. CK was present in 129 (9%) and more than 5 CA in 96 (7%). MK was present in 90 (6%), of whom 82 (91%) also had CK and 74 (82%) also had 5 or more CA. Patients with a MK had worse overall survival compared to patients who did not have a MK (non-MK) (median OS 7 months vs. 41 months, Figure 1, p<0.001). Strikingly, MK was associated with worse survival than non-MK in patients with CK (median OS 6 months vs. 18 months, Figure 2, p<0.001) and in those with 5 or more CA (median OS 5 months vs. 9 months, p=0.0091, Figure 3). Variables included in the multivariable analysis were MDS subtype, age, sex, RC-TD, comorbidities, bone marrow blasts, MK, 5 or more CA, presence of monosomal 7 and/or monosomal 5, marker chromosomes and ring chromosomes. In multivariable analysis, stratified by MDS subtype, factors associated with worse survival were MK (hazard ratio [HR] 2.3, 95% CI 1.3 – 4.2, p=0.006), 5 or more CA (HR 2.4, 95% CI 1.4 – 3.9, p=0.001), aged 75 years or older (HR 2.1, 95% CI 1.6 – 2.7, p<0.001), RC-TD (HR 1.9, 95% CI 1.5 – 2.4, p<0.001), co-morbidity at diagnosis (HR 1.5, 95% CI 1.3 – 1.8, p <0.001) and bone marrow blasts more than 10% (HR 2.0, 95% CI 1.4 – 2.9, p<0.001). Conclusion In our representative cohort of MDS patients identified through population-level data sets from a large and well-defined population, MK is associated with worse OS in patients with MDS independent of the number of cytogenetic abnormalities. MK was one of the strongest predictors of survival in multivariable analysis and retained prognostic utility even in patients with CK where it was associated with an approximately 50% reduction in median survival. Thus, our data supports the clinical utility of MK as a predictor of adverse outcome in MDS. Disclosures: Wood: CSL Behring: Research Funding.
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Moser, Florian N., Jacco C. van Rijssel, Salome Mwaiko, Joana I. Meier, Benjamin Ngatunga, and Ole Seehausen. "The onset of ecological diversification 50 years after colonization of a crater lake by haplochromine cichlid fishes." Proceedings of the Royal Society B: Biological Sciences 285, no. 1884 (August 15, 2018): 20180171. http://dx.doi.org/10.1098/rspb.2018.0171.
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Adaptive radiation research typically relies on the study of evolution in retrospective, leaving the predictive value of the concept hard to evaluate. Several radiations, including the cichlid fishes in the East African Great Lakes, have been studied extensively, yet no study has investigated the onset of the intraspecific processes of niche expansion and differentiation shortly after colonization of an adaptive zone by cichlids. Haplochromine cichlids of one of the two lineages that seeded the Lake Victoria radiation recently arrived in Lake Chala, a lake perfectly suited for within-lake cichlid speciation. Here, we infer the colonization and demographic history, quantify phenotypic, ecological and genomic diversity and diversification, and investigate the selection regime to ask if the population shows signs of diversification resembling the onset of adaptive radiation. We find that since their arrival in the lake, haplochromines have colonized a wide range of depth habitats associated with ecological and morphological expansion and the beginning of phenotypic differentiation and potentially nascent speciation, consistent with the very early onset of an adaptive radiation process. Moreover, we demonstrate evidence of rugged phenotypic fitness surfaces, indicating that current ecological selection may contribute to the phenotypic diversification.
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Ahi, Ehsan P., Anna Duenser, Pooja Singh, Wolfgang Gessl, and Christian Sturmbauer. "Appetite regulating genes may contribute to herbivory versus carnivory trophic divergence in haplochromine cichlids." PeerJ 8 (January 20, 2020): e8375. http://dx.doi.org/10.7717/peerj.8375.
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Feeding is a complex behaviour comprised of satiety control, foraging, ingestion and subsequent digestion. Cichlids from the East African Great Lakes are renowned for their diverse trophic specializations, largely predicated on highly variable jaw morphologies. Thus, most research has focused on dissecting the genetic, morphological and regulatory basis of jaw and teeth development in these species. Here for the first time we explore another aspect of feeding, the regulation of appetite related genes that are expressed in the brain and control satiety in cichlid fishes. Using qPCR analysis, we first validate stably expressed reference genes in the brain of six haplochromine cichlid species at the end of larval development prior to foraging. We next evaluate the expression of 16 appetite related genes in herbivorous and carnivorous species from the parallel radiations of Lake Tanganyika, Malawi and Victoria. Interestingly, we find increased expression of two appetite-regulating genes (anorexigenic genes), cart and npy2r, in the brain of carnivorous species in all the three lakes. This supports the notion that appetite gene regulation might play a part in determining trophic niche specialization in divergent cichlid species, already prior to exposure to different diets. Our study contributes to the limited body of knowledge on the neurological circuitry that controls feeding transitions and adaptations in cichlids and other teleosts.
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Song, Madeline, Michael J. Kovacs, and Mark A. Crowther. "A Cohort Study of Warfarin Administered to Achieve An INR of 2.0 to 3.0 for the Prevention of Recurrent Venous Thrombosis in Patients with An Antiphospholipid Antibody." Blood 114, no. 22 (November 20, 2009): 3123. http://dx.doi.org/10.1182/blood.v114.22.3123.3123.
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Abstract Abstract 3123 Poster Board III-60 Introduction Despite recent evidence, controversy remains regarding the optimal method of recurrent thrombosis prevention in patients with antiphospholipid antibodies (APLA) and prior thrombosis. Specifically, although two randomized trials have supported the efficacy of “usual intensity warfarin” (administered to a target INR of 2.0 to 3.0) there remains a dearth of prospective data examining this treatment. The aim of our study was to confirm that patients with prior thrombosis and an APLA had a low risk of recurrent thrombosis while being treated with warfarin administered to achieve an INR of 2.0 to 3.0. Methods We examined the annual rate of recurrent thrombosis in patients with prior thrombosis and APLA who had all been treated with OAT (oral anticoagulant therapy) to achieve a target INR of 2.0 to 3.0. Eligible patients had to have had at least one prior objectively confirmed arterial or venous thrombosis and at least one positive standardized test for an APLA. Patients were selected from the Victoria Hospital, and follow up appointments were conducted through the hospital's thrombosis clinic. Consenting patients underwent a baseline clinical examination with the intent to be followed every six months for evidence of recurrent thrombosis, adverse consequences of anticoagulation therapy, or until death. Results Eighty three patients (mean age 50.5 years; 50 females) were enrolled; one patient was lost to follow up and did not contribute data to the analyses. Median follow up was 12 months (Range 5-18 months). No patients experienced a recurrent thrombotic event. 10 patients (12.2%) had a minor bleeding event (5 had significant ecchymosis, two had rectal bleeding, two had vaginal bleeding, and one had hematuria). No major bleeding events occurred. One patient had a presumed transient ischemic attack (TIA). One patient (1.2%) died during follow up due to multi-system organ failure in the context of a failing hepatic allograft. Conclusion Patients with previous thrombosis and an APLA have a low risk of recurrent thrombosis while having a target INR of 2.0 to 3.0. “Usual intensity warfarin” therapy appears to be an adequate method of thromboprophylaxis in these patients. Disclosures Crowther: BI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Leo Pharma: Consultancy, Honoraria, Research Funding; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Artisan Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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Pucino, V., M. Nefla, V. Gauthier, S. A. Clayton, A. Filer, A. R. Clark, K. Raza, and C. D. Buckley. "OP0075 FIBROBLAST/MACROPHAGE CROSSTALK VIA LACTATE: NEW THERAPEUTIC TARGET IN RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 51–52. http://dx.doi.org/10.1136/annrheumdis-2022-eular.2323.
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BackgroundThe synovial membrane is the principal site of inflammation in rheumatoid arthritis (RA) and distinct subsets of fibroblasts and macrophages, with different effector functions, have been described within it1,2,3. Inflammation renders the RA synovial microenvironment hypoxic and acidic, with increased levels of lactate, the end product of glycolysis. Lactate acts as an immunomodulatory molecule within the synovium4, interacting with lactate transporters present on fibroblasts and macrophages to regulate their function, movement and metabolism.ObjectivesTo test whether dysfunctional crosstalk between fibroblasts and macrophages, driven by lactate, promotes the persistence of synovial inflammation.MethodsSynovial tissues (n = 8) from patients fulfilling the 2010 ACR/EULAR RA criteria were obtained by ultrasound-guided synovial biopsy. Osteoarthritis (OA) synovial tissues of subjects undergoing joint replacement were used as control group. Monocarboxylate transporter 1 (MCT)1 and MCT4 expression on fibroblasts and macrophages was assessed via confocal microscopy. We used RA synovial fibroblasts and monocyte-derived macrophages to test the effect of lactate in vitro. Migration was assessed in trans-well plates or via scratch test assays. Seahorse was used to evaluate metabolic pathways. IL6 production was measured by ELISA. Bioinformatic data were confirmed on publicly available scRNAseq datasets.ResultsWe showed that: i) The expression of MCT1 and MCT4 which regulate lactate import and export respectively, is up-regulated upon inflammation. ii) Fibroblasts preferentially express MCT1, while MCT4 is more highly expressed by macrophages. iii) Lactate, at the concentration found in RA synovial fluid (10 mM), has divergent effects on the effector functions of these two cell types. In fibroblasts, lactate promotes IL6 production and cell motility; these effects are reduced by pre-treatment with a pan-lactate transporter inhibitor. In contrast macrophages respond to lactate by reducing migration, IL6 secretion and glycolysis.ConclusionThe contrasting effects of lactate on macrophage and fibroblast migration, IL6 production and metabolism suggest that lactate represents a key metabolite ensuring linked choreography between fibroblast and macrophage movement in the synovium which may become uncoupled in disease. We propose that dysfunctional crosstalk between these two cell types due to high lactate levels, promotes inflammation and the establishment of persistent disease in RA. Targeting lactate/MCTs pathway may provide a novel therapeutic strategy, to restore cellular crosstalk and to reduce inflammation in RA patients.References[1]Croft et al, Nature 2019;570:246-251[2]Culemann et al, Nature 2019;572:670-675[3]Alivernini et al, Nat Med 2020;26:1295-1306[4]Pucino et al, Cell Metab 2019;30:1055-1074.e8Disclosure of InterestsValentina Pucino: None declared, Meriam Nefla: None declared, Vincent Gauthier: None declared, Sally A Clayton: None declared, Andrew Filer Consultant of: Abbvie, Roche, Janssen, Grant/research support from: Roche, UCB, Nascient, Mestag, GSK, Janssen, Andy R Clark: None declared, Karim Raza: None declared, Christopher D Buckley Consultant of: GSK, Astra-Zenica, Roche, Pfizer, Lilly, Janssen Mestag, Grant/research support from: GSK, Roche, Pfizer, Janssen Mestag.
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Fuentes, Sigfredo, Claudia Gonzalez Viejo, Chelsea Hall, Yidan Tang, and Eden Tongson. "Berry Cell Vitality Assessment and the Effect on Wine Sensory Traits Based on Chemical Fingerprinting, Canopy Architecture and Machine Learning Modelling." Sensors 21, no. 21 (November 3, 2021): 7312. http://dx.doi.org/10.3390/s21217312.
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Berry cell death assessment can become one of the most objective parameters to assess important berry quality traits, such as aroma profiles that can be passed to the wine in the winemaking process. At the moment, the only practical tool to assess berry cell death in the field is using portable near-infrared spectroscopy (NIR) and machine learning (ML) models. This research tested the NIR and ML approach and developed supervised regression ML models using Shiraz and Chardonnay berries and wines from a vineyard located in Yarra Valley, Victoria, Australia. An ML model was developed using NIR measurements from intact berries as inputs to estimate berry cell death (BCD), living tissue (LT) (Model 1). Furthermore, canopy architecture parameters obtained from cover photography of grapevine canopies and computer vision analysis were also tested as inputs to develop ML models to assess BCD and LT (Model 2) and the intensity of sensory descriptors based on visual and aroma profiles of wines for Chardonnay (Model 3) and Shiraz (Model 4). The results showed high accuracy and performance of models developed based on correlation coefficient (R) and slope (b) (M1: R = 0.87; b = 0.82; M2: R = 0.98; b = 0.93; M3: R = 0.99; b = 0.99; M4: R = 0.99; b = 1.00). Models developed based on canopy architecture, and computer vision can be used to automatically estimate the vigor and berry and wine quality traits using proximal remote sensing and with visible cameras as the payload of unmanned aerial vehicles (UAV).
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Tse, K., Y. Peña, K. Arntsen, S. C. Bae, L. Bloch, I. N. Bruce, K. Costenbader, et al. "AB1338-HPR GLOBAL PATIENT PERSPECTIVE ON TOP CHALLENGES IN LUPUS CARE AND RESEARCH PARTICIPATION." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1957.1–1957. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2871.
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Background:The Addressing Lupus Pillars for Health Advancement (ALPHA) Project is a global consensus initiative to identify, prioritize and address top barriers in lupus drug development, clinical care and access to care. The Lupus Foundation of America convenes ALPHA with Tufts Center for the Study of Drug Development and a Global Advisory Committee of lupus experts representing clinician-scientists, industry and patients.Objectives:Collect global patient input to determine alignment with the lupus clinician-scientist community on prior published consensus of top lupus barriers.Methods:A 23-question online Qualtrics survey was developed to identify challenges across lupus diagnosis, clinical care and research participation. The survey, available in English, Spanish, Korean and simplified Chinese, was fielded in November 2019 to people with lupus and caregivers of children <18 with lupus. SPSS 26 and SAS 9.4 were used for descriptive statistics and sub-analysis.Results:Analysis included only consented responses with ≥ 68% survey completion (n=3,447) received across 83 countries. 95% were female with a mean age of 45. Respondents reported being White (57%), Black or of African descent (14%), Hispanic or Latino (18%) and Asian (10%). 65% resided in the US while 35% resided in countries outside of the US. 97% were people with lupus while 3% were caregivers to children <18 with lupus.Highest ranked challenges were similar globally and across children and adults: medication side effects, lack of treatment options and high out-of-pocket costs. Managing side effects ranked significantly higher (p<.05) outside of the US (48%) compared to US (40%). 50% of caregivers reported managing side effects as the top challenge for children compared to 43% of adults (p<.05). Research participation was low (24%) and lower among children (16%). The top reason for not participating in a clinical trial was not being asked by their doctor.Conclusion:This global survey revealed that medication side effects and lack of effective treatments are top challenges for people with lupus, including children. Most respondents were never asked by their doctors to participate in a clinical trial, which may explain difficulties in trial recruitment. These barriers are consistent with prior published barriers identified by the clinician-scientist community.Acknowledgments:ALPHA sponsors: EMD Serono, GSK, Aurinia, MallinckrodtDisclosure of Interests:Karin Tse: None declared, Yaritza Peña: None declared, Kathleen Arntsen: None declared, Sang-Cheol Bae: None declared, Lauren Bloch Consultant of: Faegre Drinker Consulting is a division of Faegre Drinker Biddle & Reath, a law and consulting firm that represents patient advocacy organizations and sponsors developing drugs, Ian N. Bruce Grant/research support from: Genzyme Sanofi, GSK, and UCB, Consultant of: Eli Lilly, AstraZeneca, UCB, Iltoo, and Merck Serono, Speakers bureau: UCB, Karen Costenbader Grant/research support from: Merck, Consultant of: Astra-Zeneca, Bradley Dickerson Employee of: Aurinia, Thomas Dörner Grant/research support from: Janssen, Novartis, Roche, UCB, Consultant of: Abbvie, Celgene, Eli Lilly, Roche, Janssen, EMD, Speakers bureau: Eli Lilly, Roche, Samsung, Janssen, Kenneth Getz: None declared, Amy Kao Employee of: EMD Serono, Susan Manzi: None declared, Eric F. Morand Grant/research support from: AstraZeneca, Consultant of: AstraZeneca, Speakers bureau: AstraZeneca, Sandra Raymond: None declared, Brad H Rovin Grant/research support from: GSK, Consultant of: GSK, Laura Schanberg Grant/research support from: Sobi, BMS, Consultant of: Aurinia, UCB, Sanofi, Victoria Werth Grant/research support from: Biogen, Celgene, Gilead, Janssen, Viela, Consultant of: Biogen, Gilead, Janssen, Abbvie, GSK, Resolve, AstraZeneca, Amgen, Eli Lilly, EMD Serono, BMS, Viela, Kyowa Kirin, Joan Von Feldt Shareholder of: GSK, Employee of: GSK, David Zook Consultant of: Faegre Drinker Consulting is a division of Faegre Drinker Biddle & Reath, a law and consulting firm that represents patient advocacy organizations and sponsors developing drugs, Leslie Hanrahan: None declared
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El Rassi, Fuad, Martha Arellano, Leonard T. Heffner, Edmund K. Waller, Elliott F. Winton, Kevin Ward, and H. Jean Khoury. "Incidence and Geographic Distribution of Adult Acute Lymphoblastic Leukemia in the State of Georgia." Blood 120, no. 21 (November 16, 2012): 4309. http://dx.doi.org/10.1182/blood.v120.21.4309.4309.
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Abstract Abstract 4309 We investigated an apparent increase in acute lymphoblastic leukemia (ALL) referral from north Georgia to Emory University Hospital, a tertiary care center located in Atlanta, Georgia. Cases reported between 1999 and 2008 to the Georgia Comprehensive Cancer Registry (GCCR) and the national Surveillance Epidemiology and End Results (SEER) cancer registry were analyzed. Age-adjusted incidence rates were calculated for all counties and public health regions within the state of Georgia and compared to national rates calculated using SEER 17 data for those ages 20 and above. Cases of adult acute myeloid leukemia (AML) served as control for health referral patterns, completeness of data collection and healthcare availability. The associations between geographic residence and acute leukemia were analyzed using Poisson regression analysis, and additional models were created to control for the effects of race and ethnicity. The age-adjusted incidence rate of adult ALL (0.8/100,000) and AML (4.6/100,000) for the state of Georgia were comparable to the national rates (0.9/100,000 and 5.2/100,000 respectively). Overall, the rate of ALL observed in parts of the North Georgia region (1.1 (95% CI 0.8, 1.5) were similar when compared to the rest of the state; and not affected after adjusting for race. We conclude that the higher number of cases of ALL cases referred from North Georgia is likely related to a physician-related referral pattern rather than an increased incidence. Age-adjusted incidence rate of ALL by state and public health region and rate ratios comparing the rate of ALL within each region to the pooled rates demonstrated in all other Georgia public health regions. Region of Georgia (GA) Rate SE Lower CI Upper CI Count Pop GA: Clayton (Jonesboro) 1.1 0.3 0.6 1.8 17 1,715,865 GA: DeKalb 0.8 0.1 0.5 1.1 37 5,111,685 GA: Fulton 0.6 0.1 0.4 0.8 37 6,565,834 GA: Northwest (Rome) 0.9 0.1 0.6 1.2 35 3,962,399 GA: North Georgia (Dalton) 0.9 0.2 0.6 1.4 23 2,632,276 GA: North (Gainesville) 1.1 0.2 0.8 1.5 41 3,723,276 GA: Cobb-Douglas 0.8 0.1 0.5 1.1 38 5,357,377 GA: Gwinnett 0.7 0.1 0.5 1 38 5,712,772 GA: LaGrange 0.8 0.1 0.5 1.1 37 4,818,090 GA: South Central (Dublin) 0.3 0.2 0.1 0.9 4 1,009,356 GA: North Central (Macon) 0.7 0.1 0.4 1 24 3,476,472 GA: East Central (Augusta) 0.7 0.2 0.4 1.1 20 3,017,677 GA: West Central (Columbus) 0.6 0.2 0.3 1 14 2,492,172 GA: South (Valdosta) 0.3 0.1 0.1 0.8 5 1,638,741 GA: Southwest (Albany) 0.9 0.2 0.5 1.3 22 2,500,405 GA: Coastal (Savannah) 0.8 0.2 0.6 1.2 29 3,568,163 GA: Northeast (Athens) 0.9 0.2 0.6 1.3 26 2,903,745 GA: All Georgia 0.8 0 0.7 0.8 463 62,540,286 Rates are per 100,000 and age-adjusted to the 2000 US Std Population (19 age groups - Census P25–1130) standard; Confidence intervals (Tiwari mod) are 95% for rates. Disclosures: Waller: Outsuka: Research Funding.
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Merrill, J. T., V. Werth, R. Furie, E. F. Morand, J. M. Kahlenberg, G. Abreu, and R. Tummala. "OP0131 ANIFROLUMAB EFFECTS ON RASH AND ARTHRITIS IN PATIENTS WITH SLE AND IMPACT OF INTERFERON SIGNAL IN POOLED DATA FROM PHASE 3 TRIALS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 75–76. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1471.
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Background:Treatment with the type I interferon (IFN) receptor antibody anifrolumab was associated with clinical improvements in mucocutaneous and musculoskeletal disease activity in patients with systemic lupus erythematosus (SLE) in the phase 2 MUSE trial (NCT01438489) and phase 3 TULIP trials.1–4 Because rash and arthritis are the most common manifestations of SLE, the effect of anifrolumab on these symptoms can be examined in biomarker-defined subsets, as previously reported for the MUSE trial.2Objectives:To evaluate the effect of anifrolumab on rash and arthritis in patients with SLE, and the impact of IFN gene signature (IFNGS) on treatment response, using disease measures of different stringency in pooled data from the phase 3 TULIP trials.Methods:TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) were placebo-controlled, 52-week trials of intravenous anifrolumab administered every 4 weeks in patients with moderate to severe SLE.3,4 In this post hoc analysis, outcomes of rash and arthritis were evaluated using mucocutaneous and musculoskeletal domains of the SLE Disease Activity Index 2000 (SLEDAI-2K) and the British Isles Lupus Assessment Group (BILAG) index. In addition, the modified Cutaneous Lupus Erythematosus Disease Area and Severity Index (mCLASI) score was used to evaluate rash, and tender and swollen joint counts were used to assess arthritis.Results:360 patients received anifrolumab 300 mg (IFNGS test–high, n=298; IFNGS test–low, n=62) and 366 patients were given placebo (IFNGS test–high, n=302; IFNGS test–low, n=64). Change from baseline to Week 52 compared with placebo was measured by outcomes, ordered by their stringency. More anifrolumab-treated patients achieved rash improvement using SLEDAI-2K (complete resolution: difference 13.5%, nominal P<0.001), BILAG (at least 1 severity grade lowering: difference 15.5%, nominal P<0.001), and mCLASI (≥50% improvement, if baseline score >0: difference 15.6%, nominal P<0.001). Results were comparable in the IFNGS test–high subset (SLEDAI-2K: difference 17.0%, nominal P<0.001, BILAG: difference 16.1%, nominal P<0.001; mCLASI: difference 18.1%, nominal P<0.001). There was a trend toward anifrolumab-associated rash improvement in IFNGS test–low patients using BILAG (Figure). More patients receiving anifrolumab had SLEDAI-2K–defined resolution in arthritis (difference 8.2%, nominal P=0.029), BILAG severity lessening (difference 11.8%, nominal P=0.002), and ≥50% decrease in tender/swollen joint counts, when ≥6 at baseline (difference 12.6%, nominal P=0.016). Results were comparable in the IFNGS test–high subset (SLEDAI-2K: difference 11.7%, nominal P=0.005; BILAG: difference 12.9%, nominal P=0.003; joint counts: difference 11.3%, nominal P=0.054). In IFNGS test–low patients, there was a trend toward anifrolumab-associated arthritis improvement when measured using BILAG, and the effect of anifrolumab on the number of swollen/tender joint counts was similar to the IFNGS test–high group, although the IFNGS test–low sample size in this analysis was very small (Figure).Conclusion:In pooled data from the TULIP trials, anifrolumab treatment was associated with improvements in rash and arthritis using measures of different stringency. The SLEDAI-2K findings were largely driven by the subset of patients who were IFNGS test–high. However, using measures that were more sensitive to change, despite small sample sizes, IFNGS test–low patients may also have benefit.References:[1]Furie R, et al. Arthritis Rheumatol. 2017;69:376–86.[2]Merrill JT, et al. Lupus Sci Med. 2018;5:e000284.[3]Furie RA, et al. Lancet Rheumatol. 2019;1:e208–19.[4]Morand EF, et al. N Engl J Med. 2020;382:211–21.Acknowledgements:Writing assistance by Victoria Alikhan, PhD, of JK Associates Inc., part of Fishawack Health. This study was sponsored by AstraZeneca.Disclosure of Interests:Joan T Merrill Consultant of: AstraZeneca, AbbVie, Amgen, Aurinia, BMS, EMD Serono, GSK, Remegen, Janssen, Provention, and UCB, Grant/research support from: BMS and GSK, Victoria Werth Speakers bureau: University of Pennsylvania, who own the copyright for the CLASI and SDASI, Consultant of: AbbVie, Amgen, Argenx, AstraZeneca, Biogen, BMS, Celgene, Chrysalis, CSL Behring, Cugene, Eli Lilly, EMD Serono, Genentech, GSK, Incyte, Idera, Janssen, Kirin, Medimmune, Medscape, Nektar, Octapharma, Pfizer, Principa, Regeneron, Resolve, and Viela Bio, Grant/research support from: AstraZeneca, Biogen, Celgene, Corbus Pharmaceuticals, Genentech, Gilead, Janssen, Pfizer, Syntimmune, and Viela Bio, Richard Furie Consultant of: AstraZeneca, Grant/research support from: AstraZeneca, Eric F. Morand Speakers bureau: AstraZeneca, Consultant of: AstraZeneca, Grant/research support from: AstraZeneca, J Michelle Kahlenberg Consultant of: Admirex Pharmaceuticals, AstraZeneca, Aurinia Pharmaceuticals, BMS, Boehringer Ingelheim, Eli Lilly, and Ventus Therapeutics, Grant/research support from: BMS/Celgene and Q32 Bio, Gabriel Abreu Employee of: AstraZeneca, Raj Tummala Employee of: AstraZeneca
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Pang, Alexis, Melissa W. L. Chang, and Yang Chen. "Evaluation of Random Forests (RF) for Regional and Local-Scale Wheat Yield Prediction in Southeast Australia." Sensors 22, no. 3 (January 18, 2022): 717. http://dx.doi.org/10.3390/s22030717.
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Wheat accounts for more than 50% of Australia’s total grain production. The capability to generate accurate in-season yield predictions is important across all components of the agricultural value chain. The literature on wheat yield prediction has motivated the need for more novel works evaluating machine learning techniques such as random forests (RF) at multiple scales. This research applied a Random Forest Regression (RFR) technique to build regional and local-scale yield prediction models at the pixel level for three southeast Australian wheat-growing paddocks, each located in Victoria (VIC), New South Wales (NSW) and South Australia (SA) using 2018 yield maps from data supplied by collaborating farmers. Time-series Normalized Difference Vegetation Index (NDVI) data derived from Planet’s high spatio-temporal resolution imagery, meteorological variables and yield data were used to train, test and validate the models at pixel level using Python libraries for (a) regional-scale three-paddock composite and (b) individual paddocks. The composite region-wide RF model prediction for the three paddocks performed well (R2 = 0.86, RMSE = 0.18 t ha−1). RF models for individual paddocks in VIC (R2 = 0.89, RMSE = 0.15 t ha−1) and NSW (R2 = 0.87, RMSE = 0.07 t ha−1) performed well, but moderate performance was seen for SA (R2 = 0.45, RMSE = 0.25 t ha−1). Generally, high values were underpredicted and low values overpredicted. This study demonstrated the feasibility of applying RF modeling on satellite imagery and yielded ‘big data’ for regional as well as local-scale yield prediction.
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Peiris, Sujanie, Stuart Newstead, Janneke Berecki-Gisolf, and Brian Fildes. "Quantifying the Foregone Benefits of Intelligent Speed Assist Due to the Limited Availability of Speed Signs across Three Australian States." Sensors 22, no. 20 (October 13, 2022): 7765. http://dx.doi.org/10.3390/s22207765.
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By being able to communicate the speed limit to drivers using speed sign recognition cameras, Intelligent Speed Assist (ISA) is expected to bring significant road safety gains through increased speed compliance. In the absence of complete digital speed maps and due to limited cellular connectivity throughout Australia, this study estimated the forgone savings of ISA in the event that speed signs are solely relied upon for optimal advisory ISA function. First, speed-related fatalities and serious injuries (FSI) in the Australian states of Victoria, South Australia, and Queensland (2013–2018) were identified, and published effectiveness estimates of ISA were applied to determine the potential benefits of ISA. Subsequently, taking into account speed sign presence across the three states, the forgone savings of ISA were estimated as FSI that would not be prevented due to absent speed signage. Annually, 27–35% of speed-related FSI in each state are unlikely to be prevented by ISA because speed sign infrastructure is absent, equating to economic losses of between AUD 62 and 153 million. Despite a number of assumptions being made regarding ISA fitment and driver acceptance of the technology, conservative estimates suggest that the benefits of speed signs placed consistently across road classes and remoteness levels would far outweigh the costs expected from the absence of speed signs. The development and utilisation of a methodology for estimating the foregone benefits of ISA due to suboptimal road infrastructure constitutes a novel contribution to research. This work provides a means of identifying where infrastructure investments should be targeted to capitalise on benefits offered by advanced driver assist technologies.
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Swain, S., C. Coupland, V. Strauss, C. Mallen, C. F. Kuo, A. Sarmanova, M. Doherty, and W. Zhang. "OP0074 MULTIMORBIDITY CLUSTERS, DETERMINANTS AND TRAJECTORIES IN OSTEOARTHRITIS IN THE UK: FINDINGS FROM THE CLINICAL PRACTICE RESEARCH DATALINK." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 49.1–50. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1488.
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Background:Multimorbidity (≥2 chronic conditions) escalates the risk of adverse health outcomes. However, its burden in people with osteoarthritis (OA) remains largely unknown.Objectives:To identify the clusters of patients with multimorbidity and associated factors in OA and non-OA populations and to estimate the risk of developing multimorbidity clusters after the index date (after diagnosis).Methods:The study used the Clinical Practice Research Datalink – a primary care database from the UK. Firstly, age, sex and practice matched OA and non-OA people aged 20+ were identified to explore patterns and associations of clusters of multimorbidity within each group. Non-OA controls were assigned with same index date as that of matched OA cases. Secondly, multimorbidity trajectories for 20 years after the index date were examined in people without any comorbidities at baseline in both OA and non-OA groups. Latent class analysis was used to identify clusters and latent class growth modelling was used for cluster trajectories. The associations between clusters and age, sex, body mass index (BMI), alcohol use, smoking habits at baseline were quantified through multinomial logistic regression.Results:In total, 47 long-term conditions were studied in 443,822 people (OA- 221922; non-OA- 221900), with a mean age of 62 years (standard deviation ± 13 years), and 58% being women. The prevalence of multimorbidity was 76.6% and 68.9% in the OA and non-OA groups, respectively. In the OA group five clusters were identified including relatively healthy (18%), ‘cardiovascular (CVD) and musculoskeletal (MSK)’ (12.3%), metabolic syndrome (28.2%), ‘pain and psychological (9.1%), and ‘musculoskeletal’ (32.4%). The non-OA group had similar patterns except that the ‘pain+ psychological’ cluster was replaced by ‘thyroid and psychological’. (Figure 1) Among people with OA, ‘CVD+MSK’ and metabolic syndrome clusters were strongly associated with obesity with a relative risk ratio (RRR) of 2.04 (95% CI 1.95-2.13) and 2.10 (95% CI 2.03-2.17), respectively. Women had four times higher risk of being in the ‘pain+ psychological’ cluster than men when compared to the gender ratio in the healthy cluster, (RRR 4.28; 95% CI 4.09-4.48). In the non-OA group, obesity was significantly associated with all the clusters.Figure 1: Posterior probability distribution of chronic conditions across the clusters in Osteoarthritis (OA, n=221922) and Non-Osteoarthritis (Non-OA, n=221900) group. COPD- Chronic Obstructive Pulmonary Disease; CVD- Cardiovascular; MSK- MusculoskeletalOA (n=24139) and non-OA (n=24144) groups had five and four multimorbidity trajectory clusters, respectively. Among the OA population, 2.7% had rapid onset of multimorbidity, 9.5% had gradual onset and 11.6% had slow onset, whereas among the non-OA population, there was no rapid onset cluster, 4.6% had gradual onset and 14.3% had slow onset of multimorbidity. (Figure 2)Figure 2: Clusters of multimorbidity trajectories after index date in OA (n=24139) and Non-OA (n=24144)Conclusion:Distinct identified groups in OA and non-OA suggests further research for possible biological linkage within each cluster. The rapid onset of multimorbidity in OA should be considered for chronic disease management.Supported by:Acknowledgments:We would like to thank the University of Nottingham, UK, Beijing Joint Care Foundation, China and Foundation for Research in Rheumatology (FOREUM) for supporting the study.Disclosure of Interests:Subhashisa Swain: None declared, Carol Coupland: None declared, Victoria Strauss: None declared, Christian Mallen Grant/research support from: My department has received financial grants from BMS for a cardiology trial., Chang-Fu Kuo: None declared, Aliya Sarmanova: None declared, Michael Doherty Grant/research support from: AstraZeneca funded the Nottingham Sons of Gout study, Consultant of: Advisory borads on gout for Grunenthal and Mallinckrodt, Weiya Zhang Consultant of: Grunenthal for advice on gout management, Speakers bureau: Bioiberica as an invited speaker for EULAR 2016 satellite symposium
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Karras, Nicole, Wendy Sessions, Bruce R. Blazar, John E. Wagner, and Michael R. Verneris. "A Randomized Trial of One Vs. Two Doses of Influenza Vaccine Following Allogeneic Transplantation." Blood 120, no. 21 (November 16, 2012): 1896. http://dx.doi.org/10.1182/blood.v120.21.1896.1896.
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Abstract Abstract 1896 Following hematopoietic stem cell transplantation (HSCT) influenza infections can be potentially life threatening. Prior studies demonstrate that following HSCT, the influenza vaccine is relatively ineffective at inducing influenza specific immunity—especially early after transplant. Additionally, the effectiveness of the annual vaccine depends on recipient age, immune competence and antigenic potential of the three strains included. We hypothesized that a second vaccine dose, as is standard of care in vaccine naïve pediatric patients, might improve vaccine specific immune responses in patients following allogeneic HSCT. During the 2010 influenza season, we conducted a clinical trial where patients who were >60 days post HSCT were stratified by age and steroid use, and randomized to receive either 1 (n=33) or 2 (n=32) influenza vaccinations separated by one month. Blood samples were obtained pre-vaccination, 4 weeks and 8 weeks after the first vaccine. Vaccine specific B and T cell responses were assessed using hemagglutination inhibition (HAI) and IFN-g ELISPOT, respectively. Of the 65 patients, 73% (n=48) were >18 yrs old, 40% (n=26) received non-myeloablative conditioning and 35% (n=23) were umbilical cord blood (UCB) transplant recipients. HAI responses to the 2010/2011 vaccine components (H3N2, H1N1 and B/Victoria) were significantly greater for patients vaccinated >1 year post transplant (p<=0.005 for all 3 strains) compared to those vaccinated at earlier time points. Testing of T cell specific responses (IFN-g ELISPOT at week 8) showed 29/65 (45%) patients had IFN-g vaccine specific responses (defined as >5x increase in the number of spots over baseline). Recipients of 2 vaccines did not show a significant improvement in either HAI or in IFN-g ELISPOT responses. The HAI results were similar to the T cell specific responses in that patients >1 year after HSCT were more likely to develop positive responses compared to those vaccinated <1 yr (p=0.03). UCB recipients were less likely to have an influenza specific T cell response (p=<0.001). Flow cytometry was performed to determine whether the numbers of pre-vaccination naïve, effector memory or central memory T and or similar B cell populations were associated with responses. There was a positive correlation between the total number of CD19+ cells prior to vaccination and seroconversion (p=0.01) and an inverse correlation for IFN-g responses (p=0.05). No correlation with CD4+ subsets were found for either seroconversion or IFN-g positivity. In multivariate analysis for HAI responses, time from transplant to vaccination, and greater numbers of prevaccination CD19+ cells were significantly associated with responses (p<0.001 and p=0.01 respectively). Multivariate analysis for vaccine specific ELISPOT responses demonstrated significance for stem cell source (PB/BM > UCB, p=0.005) and CD19+ unswitched memory cells (p=0.008). Our study illustrates that time from transplantation was the strongest predictor of vaccine associated responses, and that vaccine specific T cell responses can be elicited prior to antibody responses. Furthermore, UCB recipients had significantly fewer IFN-g vaccine specific responses. Surprisingly steroid use did not negatively impact vaccine responses. In summary an additional influenza vaccine dose, separated by 1 month, did not increase vaccine responses. Disclosures: Blazar: Tarix Pharmaceuticals: Research Funding; Boehringer Ingelheim: Research Funding; Acetylon Pharmaceuticals, Inc.: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; University of Minnesota/University of Pennsylvania: Licensing Agreement, Licensing Agreement Other; Athelos-NeoStem, Inc.: Consultancy.
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Coombes, Caitlin, Keisuke Horikawa, Sanjiv Jain, Jun Hee Lim, Sewa Rijal, Kartik Saxena, and Dipti Talaulikar. "Somatic Mutations Associated with IgVH4-34 FR1 Region Unmutated QW and Avy Motifs in DLBCL Patients." Blood 136, Supplement 1 (November 5, 2020): 20–21. http://dx.doi.org/10.1182/blood-2020-142486.
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There is increasing evidence for antigen-driven B-cell receptor (BCR) signalling in diffuse large B-cell lymphoma (DLBCL) and other lymphoid malignancies. This includes antigens from infections e.g.Helicobacter pyloriand Hepatitis C virus, but it is theorised that self-antigens may play a major role in some cases of lymphoid malignancy. IgVH4-34 demonstrates intrinsic autoreactivity to self-antigens on red cells, which appears to be largely mediated by two motifs within the first framework region (FR1); Q6W7 and A24V25Y26. These motifs work together to for a hydrophobic patch which determines red cell antigen binding and are frequently mutated away from self-reactivity in normal B cells. IgVH4-34 has been reported to be over-represented in DLBCL compared with expression in normal B cells. We therefore sought to identify IgVH4-34 DLBCL cases from a local cohort and to screen them for Q6W7 and A24V25Y26 motifs expecting them to be less frequently mutated in DLBCL compared with normal B cells.We also aimed to screen V4-34 cases for associated somatic mutations in other genes using high-throughput sequencing. DLBCL patient samples were obtained via the Haematology Research Tissue Bank (HRTB) in Canberra, Australia, and the Victoria Cancer BioBank. Forty-eight Formalin-Fixed, Paraffin-Embedded (FFPE) samples and 26 fresh frozen samples were screened. All samples were collected at the time of diagnosis. Patients were treated with standard chemoimmunotherapy approaches. IgVH 4-34 gene sequences were determined using an IgVH4 family-specific leader primer in combination with a JH consensus reverse primer. The IgVH region was then sequenced using Sanger sequencing. Sequences were analyzed using the IgBLAST database (National Centre for Biotechnology Information). DNA extracted from FFPE samples generally proved to have low concentration and fragmented DNA. Only 1 IgVH4-34 sequence was obtained from FFPE tissue. Five samples sequenced from fresh tissue were identified as using IgVH4-34. Using Hans criteria, it was possible to classify 3 of the 6 cases as germinal center (GC) and 1 as non-GC origin. Using fresh samples, we estimated the frequency of IgVH4-34 cases at 23%. Within FR1, Q6W7 was unmutated in all 6 samples. One sample had mutations in the A24V25Y26 motif resulting in a change to A24V25F26. The other 5 samples (83.3%) had unmutated AVY motifs. We extracted genomic DNA from and performed next generation sequencing on the 5 samples with unmutated Q6W7 and A24V25Y26 motifs using a customized capture library (SureSelectXT Target Enrichment System, Aqilent Technologies) covering genes involved in lymphomagenesis. The purified libraries were sequenced on the Illumina NextSeq500 platform at AGRF (Australian Genome Research Facility, Australia). Several genes (FCGR3A,NOTCH2andNOTCH2NLR) had mutations in all 5 samples.FCGR3Ais an IgG Fc receptor gene, and mutations inFCGR3Ahave previously been linked to systemic lupus erythematosus (SLE).NOTCH2pathway genes are frequently mutated in DLBCL.CREBBPwas mutated in four of the five samples. Mutations inCREBBPhave previously been linked with DLBCL development and regulation of immune responses. We identified high rates of IgVH4-34 (23%) in our cohort of fresh samples as previously reported. Further, we noted preservation of the Q6W7 and A24V25Y26 motifs in IgVH4-34-expressing DLBCL. This over-representation of unmutated FR1 motifs suggests that the ability to recognise self-antigens likely provides important ongoing BCR signalling that promotes survival in DLBCL. This study also highlights the difficulties in conducting DNA-based research on FFPE clinical samples which have not been collected for research purposes and the importance of tissue banking fresh samples. Studies are currently being conducted into the efficacy of BCR pathway inhibitors e.g. ibrutinib in the treatment of DLBCL and testing for unmutated IgVH4-34 FR1 motifs may present a method to predict patients who are more likely to respond. Mutations in genes such as FCGR3A,NOTCH2andCREBBPmay work in conjunction with the preserved QW and AVY motifs to promote lymphomagenesis in IgVH4-34-expressing B cells and may present targets for future research into treatment therapies. Figure Disclosures Talaulikar: Roche:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Amgen:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda:Research Funding.
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Hawkes, Eliza A., Kate Manos, Geoff Chong, Jodie Palmer, Michael MacManus, Colm Keane, Andrew Scott, et al. "Phase I Dose Escalation Study of Radiotherapy and Durvalumab (MEDI4736) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL): The RaDD Study." Blood 134, Supplement_1 (November 13, 2019): 5328. http://dx.doi.org/10.1182/blood-2019-122635.
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Background: Although ~60% of patients with DLBCL are cured with frontline therapy, outcomes for those with relapsed/refractory disease remain poor. Tumour cells exploit immune checkpoint pathways, including the PD1/PDL1 axis, to evade and inhibit host anti-tumour immune responses. PD1/PDL1 expression and cytogenetic 9p24 alterations in some DLBCL subtypes provide additional rationale for PDL1 inhibition (PD-L1i) in DLBCL. Though single agent PD1i yields a disappointing ORR of 10-30% in heavily pre-treated DLBCL, some responses are durable.1 Radiotherapy (RT) is an established mechanism of stimulating anti-tumour immunity via increased circulating tumour antigen, immunogenic cell death and T-cell recruitment and activation in the tumour microenvironment. Synergy between concomitant immune checkpoint inhibition (ICI) and RT has been demonstrated in preclinical studies2 and solid tumours; a recent study in non-small cell lung cancer demonstrated an ORR of 36% with pembrolizumab + RT compared with 18% with pembrolizumab alone.3 RT hypofractionation appears critical to the abscopal effect when used with ICI,4 and concurrent RT and PD-L1i is more successful than sequential treatment.5 RT to multiple sites may broaden the spectrum of tumour antigen released and overcome clonal variation between disease sites; a dose-response relationship between RT and antigen release has yet to be established. This phase I study aims to determine the safety profile of escalating dose and number of sites of RT in combination with Durvalumab (MEDI4736), an anti-PD-L1 monoclonal antibody, in relapsed/refractory DLBCL, including primary refractory DLBCL and transformed follicular lymphoma. Study Design and Methods: RaDD (NCT03610061) includes eligible pts who have received ≥1 prior line of therapy and are ineligible for or relapsed after autologous stem cell transplantation (SCT). Pts with active autoimmune disease, CNS involvement, prior allogeneic SCT or chronic steroid use are excluded. Treatment comprises external beam RT to target site(s) daily for 5 days (Fig 1). Durvalumab 1500mg IV commences on day 2 of RT and continues 4-weekly until disease progression. Pts can continue until a second radiological progression if clinical benefit is ongoing. The primary endpoint is the toxicity, drug pharmacokinetics, maximum tolerated dose (MTD) and recommended phase two dose (RP2D) of simultaneous RT plus durvalumab. Secondary endpoints are response rates; progression free survival; and overall survival. An exploratory PET substudy will employ novel tracers to characterise the local and systemic immune response via assessment of the biodistribution of durvalumab (with 89Zr-Durvalumab) and CD8+ T cells (with 89Zr -Df-IAB22M2C). Biomarker sample collection is synchronised with PET response assessment. A comprehensive translational substudy will apply high throughput technologies to tissue and sequential blood samples to characterise the tumour-immune system interaction and correlate novel host, tumour and tumour microenvironment factors with treatment responses and toxicity. Findings may inform the RP2D. RT dose and site escalation will proceed according to a 3+3 design with 5 dose levels (cohorts 1-5, Fig 2). The dose limiting toxicity assessment window is the first 28 days. Projected enrolment for determination of MTD and RP2D is 6-30 pts pending toxicity. Recruitment will continue to a total of 36 pts to allow for secondary endpoint analysis. 5 pts have been enrolled to date. Acknowledgements: Victorian Cancer Agency (funding), Astra Zeneca (durvalumab and funding), Celgene (funding), Imaginab (89Zr -Df-IAB22M2C) References: 1. Ansell SM et al. Nivolumab for Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Patients Ineligible for or Having Failed Autologous Transplantation. J Clin Oncol. 2. Deng L et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 3. Theelen W et al. Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs Pembrolizumab Alone on Tumor Response in Patients With Advanced Non-Small Cell Lung Cancer. JAMA oncology. 4. Golden EB et al. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res. 5. Sharabi AB et al. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncology. Disclosures Hawkes: Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Roche: Research Funding; Takeda: Speakers Bureau; Astra Zeneca: Research Funding; Merck KgA: Research Funding; Mundi pharma: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau. Manos:Janssen: Honoraria; Novo Nordisk Pharmaceuticals: Other: Travel. Chong:Merck Serono: Research Funding; Hutchison Medipharma: Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; Bayer: Research Funding; BMS: Research Funding. MacManus:National Health and Medical Research Council Australia: Research Funding. Keane:MSD: Consultancy; Celgene: Consultancy; Gilead: Consultancy; BMS: Research Funding; Roche: Consultancy, Other: Travel Grant. Scott:Cancer Council Victoria: Research Funding; Cancer Australia: Research Funding; Avipep: Consultancy; IBA: Consultancy; Paracrine Therapeutics: Equity Ownership, Patents & Royalties; Life Science Pharmaceuticals: Equity Ownership; NHMRC: Research Funding; Abbvie: Consultancy, Patents & Royalties; Cure Brain Cancer: Research Funding; Medimmune: Consultancy; Humanigen: Patents & Royalties. Shortt:Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Astex: Research Funding; Amgen: Research Funding; Gilead: Speakers Bureau; Takeda: Speakers Bureau. Ritchie:Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Takeda: Research Funding; Beigene: Research Funding; Imago: Research Funding; Novartis: Honoraria; Sanofi: Honoraria. Lee:Australian Nuclear Science and Technology Organisation: Membership on an entity's Board of Directors or advisory committees. Koldej:NanoString Technologies: Other: Travel grant. OffLabel Disclosure: Durvalumab is an anti-PD-L1 monoclonal antibody.
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Xie, J., A. Turkiewicz, G. Collins, M. Englund, V. Y. Strauss, C. Reyes, and D. Prieto-Alhambra. "OP0280 TEMPORAL TRENDS OF OPIOID USE AMONG INCIDENT OSTEOARTHRITIS PATIENTS IN CATALONIA, 2007-2016: A POPULATION-BASED COHORT STUDY." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 174.1–175. http://dx.doi.org/10.1136/annrheumdis-2020-eular.3070.
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Background:Opioids are not recommended as first-line treatments for chronic pain management in osteoarthritis (OA), but recent data suggest they are commonly used in routine practice in North America and northern Europe.Objectives:To characterise the secular trends of opioid and strong opioids use in patients with incident OA from 2007 to 2016, and to explore the impact of patient characteristics on the use of opioid/s for OA.Methods:Data was obtained from the SIDIAP (The System for the Development of Research in Primary Care) database, which contains primary care records and pharmacy dispensing data for 80 % of the population in Catalonia (~ 6 million people). All persons aged 18 or older at the beginning of each calendar year with an incident OA diagnosis (including both peripheral and central joints) in the study period were included. Index date was the date of first OA diagnosis, and the observation period of opioid use was 1-year after index date. Opioids considered included codeine, tramadol, fentanyl, and morphine, with the latter three classified as strong opioids. The period prevalence of any opioid use was estimated in whole and sub-population stratified by sex, age, socio-economic status (U1 – U5, higher values of the indicator equivalent to deprivation) and residence area (rural/urban).Results:The 1-year prevalence of any opioid use among incident OA patients was around 15% from 2007 to 2012. After that, this figure grew by 10% approaching 25% in 2016. However, strong opioid use increased continuously to nearly triple, from 8% in 2007 to 20% in 2016. The different subgroups followed similar trends over time, with women 4% higher than men, oldest 10% higher than youngest, most deprived 6% higher than least deprived, and rural 1% higher than urban.Conclusion:The use of opioids (and especially strong opioids) has substantially increased in recent years among newly diagnosed OA patients in Catalonia. Our findings call for urgent action for safe opioid prescribing to avoid opioid abuse in OA patients especially amongst older women living in deprived areas.Figure 1.Trends of 1-year prevalence of opioid/s use among incident OA patients, whole and subgroup population.Disclosure of Interests:Junqing Xie: None declared, Aleksandra Turkiewicz: None declared, Gary Collins: None declared, Martin Englund Consultant of: Advisory Board 1 day (2019) Pfizer (Tanezumab)., Victoria Y Strauss: None declared, Carlen Reyes: None declared, Daniel Prieto-Alhambra Grant/research support from: Professor Prieto-Alhambra has received research Grants from AMGEN, UCB Biopharma and Les Laboratoires Servier, Consultant of: DPA’s department has received fees for consultancy services from UCB Biopharma, Speakers bureau: DPA’s department has received fees for speaker and advisory board membership services from Amgen
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Garcia-Delgado, Regina, Donal P. McLornan, László Rejtő, Eric Jourdan, Haifa Kathrin Al-Ali, Andrzej Pluta, Marek Hus, et al. "An Open-Label, Phase 2 Study of KRT-232, a First-in-Class, Oral Small Molecule Inhibitor of MDM2, for the Treatment of Patients with Myelofibrosis (MF) Who Have Previously Received Treatment with a JAK Inhibitor." Blood 134, Supplement_1 (November 13, 2019): 2945. http://dx.doi.org/10.1182/blood-2019-123836.
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Background: Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by progressive bone marrow fibrosis, ineffective erythropoiesis, dysplastic megakaryocyte hyperplasia, and extramedullary hematopoiesis. MF includes primary MF (PMF), post-polycythemia vera MF (post-PV-MF), and post-essential thrombocythemia MF (post-ET-MF). Clinical presentation is heterogeneous, marked by splenomegaly, progressive anemia, and constitutional symptoms. The median survival in patients with high-risk disease is approximately 2 years. Hematopoietic Stem Cell Transplant (HSCT) is a potentially curative therapy, however due to considerable morbidity and mortality rates, HSCT is not appropriate for most patients, including elderly patients with intermediate-II and high-risk disease. The Janus kinase (JAK) inhibitor ruxolitinib is approved in the US and EU for the treatment of patients with intermediate or high-risk MF, including PMF, post-PV-MF, and post-ET-MF. In clinical studies, treatment with ruxolitinib has been shown to reduce spleen volume by International Working Group (IWG) criteria in approximately 28% to 42% of patients and improve constitutional symptoms of MF in approximately 46% of patients (Verstovsek, J Hematol Oncol. 2017). Ruxolitinib provides symptomatic improvement, however, does not target the malignant clone or appreciably reduce the degree of fibrosis; some patients experience disease progression and leukemic transformation while on therapy (Versotvsek, NEJM. 2010; Harrison, NEJM. 2012; Kremyanskaya, Br J Hem. 2014). Moreover, ruxolitinib is associated with AEs including anemia and thrombocytopenia, which can lead to discontinuation. Approximately 50% of patients treated with ruxolitinib discontinued treatment within 3 years and 73% at 5 years (Verstovsek, Haematologica. 2015; Verstovsek, J Hematol Oncol. 2017; Cervantes, Blood. 2013; Harrison, Leukemia. 2016). Median overall survival in patients who discontinue ruxolitinib is 14-16 months, highlighting the need for novel therapies targeting alternative pathways in the setting of failure or intolerance of JAK inhibitor therapy (Newberry, Blood. 2017). The tumor suppressor protein p53 is the master regulator of cell-cycle arrest and apoptosis in response to cellular stress or DNA damage. Murine double minute 2 (MDM2) is a key regulator of p53, inhibiting its activity via ubiquitination, nuclear export, and direct inhibition of transcriptional activity. Increased MDM2 protein expression has been observed in MF CD34+ cells, suggesting that MF might be sensitive to MDM2 inhibition (Lu M, Blood. 2017). KRT-232 is a potent and selective, oral, small molecule drug that targets MDM2 and prevents MDM2-mediated p53 inhibition, allowing p53 to mediate tumor cell-cycle arrest and apoptosis. In MF, TP53 is observed to be wild-type in 96% of MF patients, suggesting MDM2 inhibition could be a successful therapeutic strategy in this disease (Raza, Am J Hematol. 2012). KRT-232 has been investigated as monotherapy and in combination with trametinib or dabrafenib in phase I studies of AML and melanoma; the most common treatment-related adverse events (TRAEs) observed were nausea, diarrhea, vomiting, decreased appetite, anemia, leukopenia, thrombocytopenia, and fatigue. The majority of TRAEs were grade 1 or 2. Methods: KRT-232 is being evaluated in an open-label phase 2 study in patients with MF who relapsed on or are refractory to JAK inhibitors (Figure). Up to 247 patients ≥ 18 years of age, with ECOG performance status ≤ 2, with high-, intermediate-2, or intermediate-1 risk disease by Dynamic International Prognostic System (DIPSS), and failure of prior treatment with JAK inhibitors will be enrolled. The study will be conducted in 2 parts. Part A will identify the recommended dose and schedule by testing varying doses and schedules across 7 treatment cohorts. Part B will evaluate safety and efficacy using the recommended dose and schedule from Part A. The primary endpoint of the study is to determine spleen response at week 24; secondary endpoints include improvement in MPN-SAF Total Symptom Score (weeks 24 and 48), red blood cell (RBC) transfusion independence, and rates of complete remission and partial remission (IWG-ERT and ELN) at week 24. This trial is enrolling at multiple sites in the United States and Europe (NCT03662126, EudraCT: 2018-001671-21). Disclosures Garcia-Delgado: Hospital Virgen De La Victoria Malaga: Employment; Novartis: Consultancy, Speakers Bureau; Celgene: Speakers Bureau. McLornan:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Novartis: Honoraria. Jourdan:Novartis: Honoraria; Astellas: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Al-Ali:Celgene: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CTI: Honoraria. Pluta:Freelight Poland: Honoraria; Sandoz: Honoraria; Servier: Honoraria; Jansen-Cilag: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Roche: Honoraria; Specialistic Hospital in Brzozow,Dept of Haematooncology Ks.Bielawskiego 18 36-200 Brzozow, Poland: Employment; Teva: Honoraria; Roche Poland: Membership on an entity's Board of Directors or advisory committees; Jansen Cilag Poland: Membership on an entity's Board of Directors or advisory committees. Ewing:Novartis: Honoraria, Other: Meeting attendance sponsorship ; Bristol Myers-Squibb: Other: Meeting attendance sponsorship . Khan:Amgen: Consultancy; Celgene: Consultancy; Incyte: Honoraria; Pfizer: Consultancy; Takeda: Research Funding. Jost:Novartis: Research Funding; Celgene: Other: Travel Support; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Abbvie: Consultancy, Patents & Royalties: Royalty payments for the drug compound ABT-199, Research Funding; Bohringer: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau. Rothbaum:Kartos Therapeutics: Employment, Patents & Royalties: Pending; Quogue Bioventures LLC: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. McGreivy:Kartos Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Verstovsek:Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. OffLabel Disclosure: Yes, KRT-232 is an investigational small molecule MDM2 inhibitor. This trial-in-progress abstract describes a registered clinical trial that will evaluate the safety and efficacy of KRT-232 for patients with myelofibrosis.
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Campbell, Lynda J., Stephen J. Farish, and Joanne S. White. "Seasonal Variation in New Adult Acute Myeloid Leukemia." Blood 104, no. 11 (November 16, 2004): 3017. http://dx.doi.org/10.1182/blood.v104.11.3017.3017.
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Abstract Investigations into seasonal trends for the onset of leukemia have produced conflicting results. The majority of studies demonstrating seasonal variation have done so for childhood ALL and have suggested a role for an infectious agent. Few investigations have studied adult AML and none have looked at the potential differences between various AML subtypes. An infectious etiology for adult AML will more likely be reflected by cases that are truly de novo and that have not arisen by transformation from a pre-leukemic phase or from prior exposure to a carcinogenic agent. The Victorian Cancer Cytogenetics Service is the central reference laboratory for cytogenetic analysis of all new adult leukemias in the state of Victoria. We have investigated seasonal trends in the diagnosis of 635 cases of new adult AML (≥15 yrs) received for cytogenetic analysis during a five-year period, March 1999 – Feb 2004. Cases of new AML that were secondary in nature were excluded. Cases were subdivided into three recognised prognostic risk groups (favourable, intermediate and adverse) based on cytogenetic findings according to the published criteria of the UK Medical Research Council. The favourable risk group (FR) consisted of t(15;17), inv(16)/t(16;16) and t(8;21) (n = 95). The adverse risk group (AR) included complex karyotypes, abnormalities of 3q, monosomy 7 and loss of chromosome 5 or part of 5q (n = 118). The intermediate risk group (IR) consisted of all other cytogenetic findings including normal results (n = 422). The cytogenetic abnormalities comprising the FR group are rarely associated with secondary AML whereas the converse is true of the AR group. Initial descriptive statistics demonstrated that the greatest trend towards seasonal variation was in the FR group with a peak occurrence in Spring. Spectral analysis was subsequently performed on the data in order to detect if any underlying pattern was genuinely present for the three prognostic groups. The outcome of this analysis supported the possibility of an approximately 12 month cycle for the FR group with the potential peak around the month of October, the middle month of a southern hemisphere Spring. The relatively short time frame of only 5 years limited the interpretation of the analysis. However, these results suggest a possible seasonal trend in the incidence of new adult AML presenting with cytogenetic abnormalities associated with a favourable prognosis. Analysis of data covering a greater time period is proposed to further investigate these preliminary findings.
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White, Matt A., and Nicolás E. Campione. "A three-dimensional approach to visualize pairwise morphological variation and its application to fragmentary palaeontological specimens." PeerJ 9 (January 19, 2021): e10545. http://dx.doi.org/10.7717/peerj.10545.
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Classifying isolated vertebrate bones to a high level of taxonomic precision can be difficult. Many of Australia’s Cretaceous terrestrial vertebrate fossil-bearing deposits, for example, produce large numbers of isolated bones and very few associated or articulated skeletons. Identifying these often fragmentary remains beyond high-level taxonomic ranks, such as Ornithopoda or Theropoda, is difficult and those classified to lower taxonomic levels are often debated. The ever-increasing accessibility to 3D-based comparative techniques has allowed palaeontologists to undertake a variety of shape analyses, such as geometric morphometrics, that although powerful and often ideal, require the recognition of diagnostic landmarks and the generation of sufficiently large data sets to detect clusters and accurately describe major components of morphological variation. As a result, such approaches are often outside the scope of basic palaeontological research that aims to simply identify fragmentary specimens. Herein we present a workflow in which pairwise comparisons between fragmentary fossils and better known exemplars are digitally achieved through three-dimensional mapping of their surface profiles and the iterative closest point (ICP) algorithm. To showcase this methodology, we compared a fragmentary theropod ungual (NMV P186153) from Victoria, Australia, identified as a neovenatorid, with the manual unguals of the megaraptoran Australovenator wintonensis (AODF604). We discovered that NMV P186153 was a near identical match to AODF604 manual ungual II-3, differing only in size, which, given their 10–15Ma age difference, suggests stasis in megaraptoran ungual morphology throughout this interval. Although useful, our approach is not free of subjectivity; care must be taken to eliminate the effects of broken and incomplete surfaces and identify the human errors incurred during scaling, such as through replication. Nevertheless, this approach will help to evaluate and identify fragmentary remains, adding a quantitative perspective to an otherwise qualitative endeavour.
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Qi, Jiangjiao, Xue Yu, Xuzhe Wang, Fanfan Zhang, and Chunhui Ma. "Differentially expressed genes related to plant height and yield in two alfalfa cultivars based on RNA-seq." PeerJ 10 (October 10, 2022): e14096. http://dx.doi.org/10.7717/peerj.14096.
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Background Alfalfa (Medicago sativa L.) is a kind of forage with high relative feeding value in farming and livestock breeding, and is of great significance to the development of animal husbandry. The growth of the aboveground part of alfalfa is an important factor that limits crop yield. Clarifying the molecular mechanisms that maintain vigorous growth in alfalfa may contribute to the development of molecular breeding for this crop. Methods Here, we evaluated the growth phenotypes of five cultivars of alfalfa (WL 712, WL 525HQ, Victoria, Knight 2, and Aohan). Then RNA-seq was performed on the stems of WL 712, chosen as a fast growing cultivar, and Aohan, chosen as a slow growing cultivar. GO enrichment analysis was conducted on all differentially expressed genes (DEGs). Result Among the differentially expressed genes that were up-regulated in the fast growing cultivar, GO analysis revealed enrichment in the following seven categories: formation of water-conducting tissue in vascular plants, biosynthesis and degradation of lignin, formation of the primary or secondary cell wall, cell enlargement and plant growth, cell division and shoot initiation, stem growth and induced germination, and cell elongation. KEGG analysis showed that differentially expressed genes were annotated as being involved in plant hormone signal transduction, photosynthesis, and phenylpropanoid biosynthesis. KEGG analysis also showed that up-regulated in the fast growing cultivar were members of the WRKY family of transcription factors related to plant growth and development, members of the NAC and MYB gene families related to the synthesis of cellulose and hemicellulose, and the development of secondary cell wall fibres, and finally, MYB family members that are involved in plant growth regulation. Our research results not only enrich the transcriptome database of alfalfa, but also provide valuable information for explaining the molecular mechanism of fast growth, and can provide reference for the production of alfalfa.
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Hawkes, Eliza A., Kate Manos, Charmaine Smith, Joanne Hawking, Stephanie O'Brien, Leonid Churilov, Joseph McKendrick, et al. "AvR-CHOP: Feasibility Study of Induction and Maintenance Avelumab Plus R-CHOP in Patients with Diffuse Large B-Cell Lymphoma (DLBCL)." Blood 134, Supplement_1 (November 13, 2019): 5332. http://dx.doi.org/10.1182/blood-2019-127858.
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Background: Whilst up to 60% of DLBCL patients (pts) are cured with frontline R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), outcomes remain poor for those with relapsed or refractory disease. 1 New strategies to improve frontline cure rates are needed. Tumour cells exploit immune checkpoint pathways, including the PD1/PDL1 axis, to evade the host immune system. PD1/PDL1 over-expression and cytogenetic 9p24 alterations in some DLBCL subtypes provide additional rationale for immune checkpoint inhibition (ICI) in this disease. Although single agent PD1 inhibition yields an overall response rate (ORR) of only 10%-30% in heavily pre-treated unselected DLBCL, many responses are durable.2 Immunosuppressive effects of prior therapy may contribute to the modest response to ICI in relapsed disease. A number of considerations influence the incorporation of ICI into upfront DLBCL treatment. Although concurrent PD1/PDL1 inhibition and R-CHOP is safe,3 corticosteroid-related immunosuppression may negate PDL1-inhibitor efficacy. Evidence supporting host immune priming with ICI prior to chemotherapy is promising,4 and maintenance ICI post chemotherapy may assist with immune reconstitution and enhance the anti-tumour immune response. Additionally, avelumab (Av, an anti-PDL1 monoclonal antibody with antibody dependent cellular cytotoxicity activity) acts synergistically with rituximab (R) in vitro (unpublished data, Pfizer 2016). Thus, we present our phase II study assessing the safety of sequential Av+R induction, R-CHOP and Av maintenance as upfront therapy for DLBCL. Methods: AvR-CHOP (NCT03244176) is a phase II multicentre single-arm trial of Av induction + maintenance with R-CHOP in newly-diagnosed adult pts with DLBCL. Pts aged >18 years, ECOG 0-2, stage II-IV and with no active autoimmune disease are eligible. Exclusion criteria include the necessity for urgent cytoreduction, grade 3B or transformed follicular lymphoma, CNS involvement, chronic steroid use, prior transplantation or pneumonitis. Treatment (Fig 1) comprises R (375mg/m2 IV) + Av (10mg/kg IV) x 2 cycles q2-weekly, followed by R-CHOP21 x 6 cycles. Maintenance Av x 6 cycles q2-weekly is given to patients achieving a complete metabolic response by PET/CT at the end of R-CHOP. PET/CT is performed after R+Av 2 cycles, cycle 2 R-CHOP, end of R-CHOP and end of Av maintenance. The primary endpoint is immune-related toxicity within 30 days post-treatment. Secondary endpoints include ORR, failure free survival (FFS), overall survival (OS) and toxicity of treatment. Complete metabolic response rates by PET-CT after R-Av induction and after C2 R-CHOP are exploratory endpoints. Biomarker sample collection is synchronised with PET response assessment. A comprehensive translational substudy will apply high throughput technologies to tissue and sequential blood samples to characterise the tumour-immune system interaction and correlate novel host, tumour and tumour microenvironment factors with treatment responses and toxicity. Planned enrolment is 28 pts across 3 sites in Australia. The study follows a Simon 1 stage design, with an 80% power and a 1-sided alpha of 0.05 to rule out an Av-related toxicity rate of 30% (p0=70%), assuming an expected immune related toxicity rate of 10% [p1=90%]. 23 pts are enrolled to date. Acknowledgements: Merck KgA (avelumab and funding) References: 1. Cunningham D et al. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet (London, England). 2013;381(9880):1817-26. 2. Ansell SM et al. Nivolumab for Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Patients Ineligible for or Having Failed Autologous Transplantation: A Single-Arm, Phase II Study. J Clin Oncol. 2019;37(6):481-9. 3. Nowakowski GS et al. Safety and efficacy of PD-L1 inhibitor durvalumab with R-CHOP or R2-CHOP in subjects with previously untreated, high-risk DLBCL. Journal of Clinical Oncology. 2019;37(15_suppl):7520-. 4. Park SE et al. Increased Response Rates to Salvage Chemotherapy Administered after PD-1/PD-L1 Inhibitors in Patients with Non-Small Cell Lung Cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2018;13(1):106-11. Disclosures Hawkes: Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Astra Zeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck KgA: Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Mundi pharma: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Takeda: Speakers Bureau; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees. Manos:NovoNordisk Pharmaceuticals: Other: Travel; Janssen: Honoraria. Renwick:Celgene: Consultancy; Roche: Honoraria. Grigg:MSD: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel. Scott:Medimmune: Consultancy; Abbvie: Consultancy, Patents & Royalties; IBA: Consultancy; Avipep: Consultancy; Life Science Pharmaceuticals: Equity Ownership; Paracrine Therapeutics: Equity Ownership, Patents & Royalties; NHMRC: Research Funding; Cancer Australia: Research Funding; Cancer Council Victoria: Research Funding; Cure Brain Cancer: Research Funding; Humanigen: Patents & Royalties. Lee:Australian Nuclear Science and Technology Organisation: Membership on an entity's Board of Directors or advisory committees. Fong:Astellas: Consultancy; Amgen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Rooney:GenesisCare: Employment. Wight:Janssen: Honoraria; Takeda: Honoraria; Abbvie: Honoraria; BMS: Other: Travel; Amgen: Other: Travel. Chong:BMS: Research Funding; Merck Serono: Research Funding; Bayer: Research Funding; Novartis: Research Funding; Hutchison Medipharma: Research Funding; Pharmacyclics: Research Funding. OffLabel Disclosure: Avelumab is an anti-PDL1 monoclonal antibody.
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Ryland, Georgina L., Lucy C. Fox, Ella Thompson, Graham John Lieschke, David Hughes, Francoise Marie Mechinaud, Anthea Louise Greenway, et al. "Providing Diagnoses in Bone Marrow Failure Syndromes through Multimodal Comprehensive Genomic Evaluation and Multidisciplinary Care: The Melbourne Genomics Health Alliance Bone Marrow Failure Flagship." Blood 132, Supplement 1 (November 29, 2018): 3867. http://dx.doi.org/10.1182/blood-2018-99-114410.
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Abstract Background and Aims The detection of sequence variants and copy number changes can improve diagnosis, inform prognosis and guide treatment in patients with bone marrow failure syndromes (BMFS). We aimed to establish and prospectively assess the impact of comprehensive genomic evaluation on diagnostic categorisation and clinical outcomes in patients with genomically uncharacterised BMFS. Methods Eligible patients were recruited from four participating institutions across Victoria, Australia. Inclusion criteria were (i) age >3 months (ii) clinicopathological diagnosis or suspicion of either acquired aplastic anaemia (AA), inherited BMFS, hypoplastic myelodysplastic syndrome (hMDS) or a BMFS with marrow hypoplasia/aplasia not able to be definitively categorised. Patients initially underwent 90-gene targeted sequencing (Peter MacCallum Cancer Centre PanHaem and Myeloid Amplicon next generation sequencing [NGS] panels) for rapid turnaround of accredited results for clinical decision-making. In addition, whole exome sequencing (WES), whole genome copy number analysis, NGS T-cell receptor β (TRB) repertoire assessment and longitudinal monitoring of selected mutations by digital droplet PCR (ddPCR) were performed. All patients received pre-test counselling and assessment. Genomic results were reviewed in centralised multidisciplinary case conferences including the treating clinician, molecular haematopathologists, medical scientists, clinical geneticists and genetic counsellors. Results 100 patients were enrolled. Median age was 25 years (range 3 months - 80 years); 39% were under 18 years. Detection of sequence variants or copy number abnormalities led to or confirmed a diagnosis of either an inherited or acquired BMFS in 36 patients. In 17 patients a diagnosis of an inherited BMFS was positively made by detection of pathogenic sequence variants or copy number changes in FANCA(1 patient [pt]), FANCM(1 pt), FANCI(1 pt), RAD51C(1 pt), HAX1(1 pt), SBDS(1 pt), DNAJC21(1 pt), RPS19(5 pts), RPL35A(1 pt), TERT(1 pt), TINF2(1 pt) and SAMD9L(1 pt). In five patients the clinical BMFS was considered undifferentiated without a clear candidate gene suspected on phenotypic features prior to genomic evaluation. Importantly, an established diagnosis of AA was altered to an inherited BMFS by genomic characterisation in two patients (SAMD9L, FANCA). In 19 patients pathogenic sequence variants or copy number changes were detected either leading to or confirming a diagnosis of an acquired BMFS (paroxysmal nocturnal haemoglobinuria, hMDS or AA). Pathogenic sequence variants were detected in TET2(n=5), RUNX1(n=4), ASXL1(n=3), PIGA(n=3), DNMT3A(n=3),CBL(n=2), and BCOR/IDH2/SF3B1/SRSF2/TP53/U2AF1(n=1 each). Sequencing-detected copy number abnormalities included loss of chromosome 7 (n=6), losses on chromosome 5q (n=2) and copy number loss of ETV6(n=2). Longitudinal monitoring of an acquired truncating RUNX1 mutation by ddPCR resulted in one patient undergoing allogeneic bone marrow transplant for a progressively rising allelic burden. There was a trend towards more restricted TRB diversity in patients with genomically-defined acquired BMFS versus inherited BMFS (normalised Shannon index ≤0.85, 36.4% vs 0%, p=0.09). Conclusion We have established and evaluated a model of comprehensive multimodal genomic characterisation and multidisciplinary care for 100 patients with BMFS. Our results demonstrate a significant contribution to diagnostic categorisation and patient care in this area of clinical need. Disclosures Lieschke: CSL Behring Australia: Consultancy. Tam:Janssen: Honoraria, Research Funding; Gilead: Honoraria; AbbVie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Travel funding; Pharmacyclics: Honoraria; Beigene: Honoraria, Other: Travel funding; Roche: Honoraria; Beigene: Honoraria, Other: Travel funding; Gilead: Honoraria; Roche: Honoraria; AbbVie: Honoraria, Research Funding.
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Van Vollenhoven, R., R. Furie, K. Kalunian, S. Navarra, J. Romero-Diaz, V. Werth, X. Huang, et al. "POS0698 BIIB059 DEMONSTRATED A CONSISTENT THERAPEUTIC EFFECT ON SRI-4 RESPONSE ACROSS SUBGROUPS OF PARTICIPANTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS IN THE LILAC PHASE 2 STUDY." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 597–98. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2570.
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Background:Type I interferons and other inflammatory mediators derived from plasmacytoid dendritic cells (pDCs) are implicated in systemic lupus erythematous (SLE) pathology. BIIB059 is a humanized monoclonal antibody that targets blood dendritic cell antigen 2 (BDCA2), a pDC-specific receptor. The binding of BIIB059 to BDCA2 leads to rapid internalization of BDCA2 from the surface of pDCs and subsequent inhibition of interferon, cytokine, and chemokine production. In Part A of the 2-part, phase 2 LILAC study (NCT02847598), BIIB059 significantly reduced SLE activity, as evidenced by reduced total active joint count (primary endpoint) and higher SLE Responder Index (SRI-4)1 response (a secondary endpoint) versus placebo.2Objectives:To evaluate SRI-4 response for BIIB059 versus placebo at Week 24 in SLE participant subgroups.Methods:Enrollment in LILAC Part A was open to adults fulfilling ≥ 4 of 11 revised 1997 ACR criteria for classification of SLE, with ≥ 4 tender and ≥ 4 swollen joints, active skin disease, and positive lupus antibodies. Participants were randomized to receive either BIIB059 450 mg or placebo subcutaneously every 4 weeks for 20 weeks (with an additional dose at Week 2). SRI-4 response at Week 24 was analyzed in subgroups, though analyses were limited by small sample sizes and were not powered for statistical testing.Results:In LILAC Part A, 64 and 56 participants were dosed with BIIB059 450 mg and placebo, respectively. At week 24, SRI-4 response rate was observed in favor of BIIB059 regardless of the baseline disease activity, such as SLEDAI-2K <10 versus ≥10, presence of BILAG-2004 grade A or B arthritis, oral corticosteroid usage, positivity for anti-ds DNA autoantibody and/or complement status, with point estimates for least-squares mean differences as well as corresponding 95% CIs consistently favoring BIIB059 (Figure 1). The incidence of adverse events in the overall study population was similar between the placebo and BIIB059 groups.2Conclusion:BIIB059 treatment was associated with greater SRI-4 response rate, consistent among different subgroups of baseline disease activity as measured by SLEDAI-2K and BILAG-2004, glucocorticoid dosage, and serology. These findings provide additional evidence of the potential benefit of BIIB059 for the treatment of patients with active SLE.References:[1]Furie RA, et al. Arthritis Rheum. 2009;61(9):1143-1151. 2. Furie RA, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 0935.Acknowledgements:This study was sponsored by Biogen (Cambridge, MA, USA). Writing and editorial support was provided by Excel Scientific Solutions (Fairfield, CT, USA); funding was provided by Biogen.Disclosure of Interests:Ronald van Vollenhoven Consultant of: AbbVie, AstraZeneca, Biotest, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Lilly, Medac, Merck, Novartis, Pfizer, Roche, UCB, Grant/research support from: AbbVie, Arthrogen, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Pfizer, UCB, Richard Furie Consultant of: Biogen, Grant/research support from: Biogen, Kenneth Kalunian Consultant of: AbbVie, Amgen, AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, Equillium, Genentech, Gilead, ILTOO, Janssen, Nektar, Roche, Viela, Grant/research support from: Lupus Research Alliance, Pfizer, Sanford Consortium, Sandra Navarra Speakers bureau: Astellas, Johnson & Johnson, Novartis, Pfizer, Consultant of: Biogen, Grant/research support from: Biogen, Juanita Romero-Diaz Consultant of: Biogen, Boehringer Ingelheim, Victoria Werth Consultant of: AbbVie, Amgen, AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, EMD Serono, Gilead, GlaxoSmithKline, Janssen, Kyowa Kirin, Resolve, Viela, Grant/research support from: Biogen, Celgene, Gilead, Janssen, Viela, XIAOBI HUANG Shareholder of: Biogen, Employee of: Biogen, HUA CARROLL Shareholder of: Biogen, Employee of: Biogen, Cristina Musselli Shareholder of: Biogen, Employee of: Biogen, Catherine Barbey Shareholder of: Biogen, Employee of: Biogen, NATHALIE FRANCHIMONT Shareholder of: Biogen, OMass Therapeutics, Employee of: Biogen
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Traianos, E., B. Dibnah, D. Lendrem, Y. Clark, V. Macrae, V. Slater, K. Wood, et al. "AB0051 THE EFFECTS OF NON-INVASIVE VAGUS NERVE STIMULATION ON IMMUNOLOGICAL RESPONSES AND PATIENT REPORTED OUTCOME MEASURES OF FATIGUE IN PATIENTS WITH CHRONIC FATIGUE SYNDROME, FIBROMYALGIA, AND RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1057.3–1058. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1999.
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Background:Fatigue is reported as a common symptom among autoimmune and other chronic diseases such as fibromyalgia (FM), a long-term condition with uncertain pathophysiology. Previous studies from our group suggest that non-invasive vagus nerve stimulation (nVNS) may contribute to the improvement of patient reported outcome measures (PROMs) of fatigue in patients with primary Sjögren’s Syndrome (1).Objectives:This follow-up study uses the gammaCore device (electroCore) to assess the effect of nVNS on PROMs of fatigue and immune responses in chronic fatigue syndrome (CFS), FM and rheumatoid arthritis (RA).Methods:The study included thirteen CFS, fourteen FM and fifteen RA patients who used the gammaCore nVNS device twice daily over a 26-day period. Pre- and post- nVNS bloods were drawn at baseline and final visits. Whole blood samples were stimulated with 2 ng/mL lipopolysaccharide (LPS) and the IL-6 and TNF-α cytokine concentrations were quantified at 24 hours. In addition, the epidermal growth factor (EGF), IFN-γ, IL-6, IP-10, MIP-1α, and TNF-α levels were measured in ‘pre-nVNS’ serum and flow cytometric profiles of whole blood immune cells were analysed. The patient reported outcome measures (PROMs) recorded at each visit were the Visual Analogue Scale (VAS) (0-100 cm) of abnormal fatigue, Hospital Anxiety and Depression (HAD) Scale, Orthostatic Grading Scale, Epworth Sleepiness Scale (daytime sleepiness), and Profile of fatigue (PRO-F) for Physical and Mental fatigue. Paired t-tests were performed to assess for changes in PROMs, cytokine levels, and cell subset distribution and associations of cytokine response with PROMs were investigated by correlation analyses.Results:Eleven CFS, twelve FM and fourteen RA patients completed the study. There was a significant reduction in daytime sleepiness in CFS (p =0.0321) and FM (p =0.0294) patients between the final and baseline visits and a significant reduction in HAD depression (p =0.0413) in FM (Fig.1). Improvement in VAS for abnormal fatigue, HAD-Anxiety, HAD-Depression, PRO-F Physical and Mental fatigue was observed in all three groups over the study period with a reduction in VAS fatigue in 64% of CFS, 67% of FM and 62% of RA patients. There were no significant changes in the immune cell subsets or in cytokine response. Finally, higher baseline pre-nVNS supernatant IL-6 levels were predictive of an improvement in VAS fatigue (p =0.0006), Daytime Sleepiness (p =0.0466) and PRO-F Physical fatigue (p =0.0196) in RA, while higher baseline TNF-α levels were predictive of an improvement in VAS fatigue (p =0.0003), Daytime Sleepiness (p =0.0380), Orthostatic (p =0.0281) and PRO-F Physical fatigue (p =0.0007) in FM.Conclusion:Our findings suggest that nVNS may contribute to the improvement of PROMs of fatigue in CFS, FM and RA. NVNS led to significant reductions in daytime sleepiness in CFS and FM, and depression in FM. Further studies and a larger sample size are needed to investigate the potential effects of nVNS on diseases characterised by persistent fatigue.References:[1]Tarn J, Legg S, Mitchell S, Simon B, Ng WF. The Effects of Noninvasive Vagus Nerve Stimulation on Fatigue and Immune Responses in Patients With Primary Sjögren’s Syndrome. Neuromodulation Technol Neural Interface. 2018;22(5):580–5.Figure 1.VAS for abnormal fatigue and PROMs recorded at baseline and final visits in patients with chronic fatigue syndrome (CFS), fibromyalgia (FM) and rheumatoid arthritis (RA). Boxplots show the median, upper, and lower quartiles for PROMs at visit 1 and visit 3 in each disease group. Paired-t tests revealed a significant reduction in daytime sleepiness in CFS and FM (B), and a significant reduction in HAD depression in FM (E). Improvement trends were observed in VAS for abnormal fatigue, HAD-Anxiety, HAD-Depression, PRO-F Physical fatigue and PRO-F Mental fatigue in all three groups over the 26-day study period.Acknowledgements:This study received infrastructural support from the National Institute of Health Research (NIHR) Newcastle Biomedical Research Centre at Newcastle Hospitals Foundation Trust and Newcastle University.Disclosure of Interests:Emmanuella Traianos: None declared, Bethany Dibnah: None declared, Dennis Lendrem: None declared, Yasmin Clark: None declared, Victoria Macrae: None declared, Victoria Slater: None declared, Karl Wood: None declared, David Storey: None declared, Bruce Simon Shareholder of: Bruce Simon is an employee and shareholder of electroCore., Employee of: electroCore, Inc., Justyna Blake Shareholder of: Justyna Blake is an employee of electroCore, and receives stock ownership., Employee of: electroCore, Inc., Jessica Tarn: None declared, Wan Fai Ng: None declared
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Quintana, R., L. Garcia, P. Alba, S. Roverano, A. Alvarez, C. Graf, C. Pisoni, et al. "POS0707 POTENTIAL USE OF BELIMUMAB IN LUPUS PATIENTS FROM ARGENTINE COHORT ACCORDING DISEASE ACTIVITY STATE." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 634.1–634. http://dx.doi.org/10.1136/annrheumdis-2022-eular.789.
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BackgroundThe goal of targeted treatment in patients with Systemic Lupus Erythematosus (SLE) is to achieve clinical remission or low disease activity, with the best quality of life, low damage rates and better survival 1-4. RELESSAR is a multicenter, cross-sectional study registry of ≥18 years SLE (ACR 97) patients 5.ObjectivesTo describe demographic, clinical characteristics and treatments in SLE patients according to disease activity state. To evaluate the proportion of SLE and refractory SLE patients that are potentially candidates for Belimumab treatment (Active SLE despite standard treatment including increased acDNA autoantibodies and low complement).MethodsWe evaluated demographic and clinical data, treatments, score of damage (SLICC), activity (SLEDAI) and comorbidity (Charlson), hospital admissions and severe infections. The patients were compared according to disease activity: remission (SLEDAI = 0 and without corticosteroids), low disease activity (LDA, SLEDAI> 0 and ≤4 and without corticosteroids) and non-optimal control (SLEDAI> 4 and any dose of corticosteroids). Refractory SLE was defined according to Rituximab (RTX) use, non-response to cyclophosphamide or two or more immunosuppressant or splenectomized patients. Potential use of Belimumab according approved prescription in Argentina was analyzed.ResultsOverall, 1277 patients were analyzed: 299 (23.4%) were in remission, 162 (12.7%) in LDA and 816 (63.9%) with non-optimal control of the disease.Patients in non-optimal control group were younger, less frequently female and they showed less time of disease and lower socioeconomic status (p < 0.001). They were also more prevalent mestizos (p= 0.004), had higher SLEDAI and SLICC indexes (p <0.001) and higher use of immunosuppressant therapy (p <0.001). There was no difference regarding biologic treatment (RTX p= 0.547 and Belimumab p= 0.08). This group had higher proportion of hospital admissions and severe infections (p<0.001, respectively).Two hundred and one SLE patients fulfilled the use of Belimumab prescription criteria but only 45/201 patients (22,3%) received it in the last visit. Malar rash was the only clinical variable associated with the use of Belimumab (72.7% vs 29.8% p= 0.005).Seventy-six patients classified as refractory SLE (15.7%) and 56/76 (75.7%) never received Belimumab. Patients on Belimumab therapy were associated to treatment with lower doses of corticoids (p= 0.018) and lower rate of hospital admission caused by SLE flare (p= 0.027).ConclusionA high percentage of patients had uncontrolled disease upon entry into the registry and were potential candidates for treatment with Belimumab. The patients who received biologic treatment showed the benefit of requiring fewer doses of corticosteroids and having a lower rate of hospitalizations.References[1]Mok CC. Treat-to-target in systemic lupus erythematosus: Are we there yet? Expert Rev Clin Pharmacol. 2016;9(5).[2]Morand EF, Mosca M. Treat to target, remission and low disease activity in SLE. Vol. 31, Best Practice and Research: Clinical Rheumatology. 2017.[3]Golder V, Tsang-A-Sjoe MWP. Treatment targets in SLE: Remission and low disease activity state. Rheumatol (United Kingdom). 2020;59.[4]Ruiz-Irastorza G, Bertsias G. Treating systemic lupus erythematosus in the 21st century: new drugs and new perspectives on old drugs. Vol. 59, Rheumatology (United Kingdom). 2021.[5]Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum [Internet]. 1997;40(9):1725. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9324032Disclosure of InterestsRosana Quintana: None declared, Lucila Garcia: None declared, Paula Alba: None declared, Susana Roverano: None declared, Analia Alvarez: None declared, Cesar Graf: None declared, Cecilia Pisoni: None declared, Alberto Spindler: None declared, Catalina Gomez: None declared, Heber Matias Figueredo: None declared, Silvia Papasidero: None declared, Raul Horacio Paniego: None declared, Maria DeLaVega: None declared, Emma Estela Civit De Garignani: None declared, Luciana Gonzalez Lucero: None declared, Victoria Martire: None declared, Rodrigo Águila Maldonado: None declared, Sergio Gordon: None declared, Carla Gobbi: None declared, Romina Nieto: None declared, Gretel Rausch: None declared, Vanina Góngora: None declared, Maria Agustina D´Amico: None declared, Diana Dubinsky: None declared, Alberto Omar Orden: None declared, Johana Zacariaz: None declared, Julia Romero: None declared, Mariana Alejandra Pera: None declared, Oscar Rillo: None declared, Roberto Baez: None declared, Valeria Arturi: None declared, Andrea Gonzalez: None declared, Florencia Vivero: None declared, Marcela Schmid: None declared, Victor Caputo: None declared, Maria Silvia Larroude: None declared, Graciela Gomez: None declared, Graciela Rodriguez: None declared, Josefina Marin: None declared, Maria Victoria Collado: None declared, Marisa Jorfen: None declared, Zaida Bedran: None declared, Judith Sarano: None declared, David Zelaya: None declared, MONICA SACNUN: None declared, Pablo Finucci: None declared, Romina Rojas Tessel: None declared, Maria Emilia Sattler: None declared, MAXIMILIANO MACHADO ESCOBAR: None declared, Pablo Astesana: None declared, Ursula Vanesa Paris: None declared, Alberto Allievi: None declared, Juan Manuel Vandale: None declared, Bernardo Pons-Estel: None declared, Guillermo Pons-Estel: None declared, Mercedes García Grant/research support from: GSK grant
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Najeeb, Muhammad Naveed, Sadiq Hussain Malik, Sheikh Khurram Salam Sehgal, Ameer Ahmad Malik, and Saqib Mehmood. "46 XY DISORDER." Professional Medical Journal 23, no. 10 (October 10, 2016): 1202–8. http://dx.doi.org/10.29309/tpmj/2016.23.10.1723.
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Objectives: The Disorders of Sex Development are classified as 46, XY DSD,46, XX DSD and Chromosomal DSD according to the chromosomal constitution of the affectedpersons. 46, XY DSD is further classified into Androgen Synthetic Defect, Androgen InsensitivitySyndrome Gonadal Dysgenesis, 5-Alpha Reductase Deficiency, Persistent Mullerian DuctSyndrome and Isolated Hypospadias according to the pathophysiology of the disease. Theaim of present study was to classify 46, XY patients into their subclasses on the basis of theirhormonal profile and physical examination. Study Design: Observational descriptive study.Setting: Biochemistry Department University of Health Sciences for Karyotyping and Geneticassessment, and its allied institution Biochemistry Department Quaid-e-Azam Medical CollegeBahawalpur for hormonal analysis, along with Pediatric Medicine Departments of Quaid-e-AzamMedical College / Bahawal Victoria Hospital Bahawalpur for collection of Sample and clinicalassessments. Period: June 2015 to December 2015. Study Design: Observational descriptivestudy. Material and Methods: 53 patients with 46, XY DSD were recruited. Complete clinicalhistory and data of each patient was recorded in the research proforma. Genitals examinedfor the phallus length and size, position of urinary meatus, palpation of gonads and shape ofthe labioscrotal folds. Ultrasonography examination of each patient was performed to look forundescended testes and for the presence of either male or female internal reproductive organs.Results: Base line levels of serum Testosterone Dihydrotestosterone Luteinizing hormone,Follicle stimulating hormone, 17-OH-Progesteron and Anti-mullerian hormones were measuredby ELISA technique. Testosterone and DHT were measured again after hCG stimulation. Onthe basis of physical examination, ultrasonographic findings and hormonal profile diagnosisof the types of 46, XY DSD was possible in 27 (51%) of patients. Androgen synthesis defect asa cause of 46, XY DSD was diagnosed in 7(13%) patients, Androgen insensitivity syndrome in6(11%) patients, 5-Alpha reductase deficiency in 3(6%) patients, Gonadal Dysgenesis in 3 (6%),Persistent Mullerian Duct Syndrome in 3(6%) and Isolated Hypospadias in 2 (4%) patients.There were 26 (49%) patients which remain undiagnosed with the algorithm of diagnosis usedin the present study.
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Gotlib, Jason, Nashat Gabrail, Casey L. O'Connell, Regina Garcia-Delgado, Timothy Sbardellati, Wayne M. Rothbaum, Jesse McGreivy, Claire N. Harrison, and Jean-Jacques Kiladjian. "A Randomized, Open-Label, Multicenter, Phase 2 Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of KRT-232 Compared with Ruxolitinib in Patients with Phlebotomy-Dependent Polycythemia Vera." Blood 134, Supplement_1 (November 13, 2019): 4168. http://dx.doi.org/10.1182/blood-2019-123546.
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Background: Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) characterized by clonal stem cell proliferation of the erythroid, myeloid, and megakaryocytic lines. The predominant clinical characteristic is an increase in red cell mass, resulting in hyperviscosity of the blood, which is responsible for most symptoms during early stages of disease. Disease progression typically results in symptomatic splenomegaly and severe constitutional symptoms, causing significant morbidity and a shortened life expectancy. Patients with PV may develop cardiovascular complications, myelofibrosis (MF), myelodysplasia, or acute myeloid leukemia (AML). Long-term (20-year) survival for PV is 18%, highlighting the poor long-term prognosis and need for additional therapies. Phlebotomy and low-dose aspirin are the standard of care for initial treatment; hydroxyurea (HU) remains the myelosuppressive agent of choice, despite the increased potential for leukemic transformation, estimated at 10% after 13 years of exposure. The Janus kinase (JAK) inhibitor ruxolitinib is approved in the US and Europe for the treatment of patients who have had an inadequate response to or are intolerant of HU. In clinical trials, ruxolitinib produced responses in 23% of patients, compared with <1% in patients receiving best available therapy (Verstovsek, et al. Haematologica. 2016). Despite this significant improvement, there remains a substantial unmet need for patients with PV who are resistant to or intolerant of HU. The tumor suppressor protein p53 is the master regulator of cell-cycle arrest and apoptosis in response to cellular stress or DNA damage. Murine double minute 2 (MDM2) is a key regulator of p53, inhibiting its activity via ubiquitination, nuclear export, and direct inhibition of transcriptional activity. MDM2 is upregulated in PV CD43+ stem/progenitor cells, making the p53-MDM2 axis an attractive target in PV. In PV, TP53 is observed to be wild-type in 94% of patients, suggesting MDM2 inhibition as a potentially successful strategy (Raza, et al. Am. J. Hematol. 2012). KRT-232 is a potent and selective oral small-molecule drug that targets MDM2 and prevents MDM2-mediated p53 inhibition, allowing p53 to mediate tumor cell-cycle arrest and apoptosis. In a phase 1 dose-finding study, clinical responses were observed in 7/12 (58%) of PV patients treated with an alternative MDM2 inhibitor (Mascarenhas, et al. Blood, 2019). KRT-232 has been investigated as monotherapy and in combination with trametinib or dabrafenib in phase I studies of AML and melanoma; the most common treatment-related adverse events (TRAEs) observed in these studies were nausea, diarrhea, vomiting, decreased appetite, anemia, leukopenia, thrombocytopenia, and fatigue. The majority of TRAEs were grade 1 or 2. Methods: This randomized, open-label study aims to evaluate the efficacy, safety, and pharmacokinetics of KRT-232 compared with ruxolitinib in up to 320 patients with phlebotomy-dependent PV (Figure). The study will be conducted in 2 parts. Part A will identify the recommended dose and schedule by testing 4 treatment cohorts. In Part B, patients will be randomized 1:1 to either KRT-232 or ruxolitinib in order to evaluate safety and efficacy using the recommended dose/schedule for KRT-232 from part A. This study will enroll patients ≥ 18 years of age with PV and an ECOG performance status ≤ 2. In Part A, patients who are phlebotomy dependent with and without splenomegaly are eligible and patients must be resistant to or intolerant of HU or have undergone treatment with interferon. In Part B, only phlebotomy-dependent patients with splenomegaly are eligible, and patients must be resistant or intolerant to HU. The primary endpoint is proportion of patients with splenomegaly achieving a response at Week 32, defined as having achieved both of the following: 1) the absence of phlebotomy eligibility from Week 8 through Week 32, with no more than one phlebotomy eligibility occurring after randomization and before the Week 8 visit and 2) a reduction in spleen volume as assessed by MRI (or CT) ≥ 35% from baseline at Week 32. Secondary endpoints include response rate, duration of response and improvement in patient-reported outcomes. Exploratory endpoints include molecular and biomarker analysis including TP53 mutational status. This trial is enrolling at multiple sites in the United States and Europe (NCT03669965, EduraCT: 2018-001672-38). Figure Disclosures Gotlib: Deceiphera: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Promedior: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Allakos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. O'Connell:Pfizer: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding. Garcia-Delgado:Celgene: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Hospital Virgen De La Victoria Malaga: Employment. Sbardellati:Kartos Therapeutics: Employment, Equity Ownership. Rothbaum:Kartos Therapeutics: Employment, Patents & Royalties: Pending; Quogue Bioventures LLC: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. McGreivy:Kartos Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Harrison:Janssen: Speakers Bureau; Gilead: Speakers Bureau; CTI: Speakers Bureau; Roche: Honoraria; Sierra Oncology: Honoraria; AOP: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Promedior: Honoraria; Shire: Speakers Bureau; Incyte: Speakers Bureau. Kiladjian:AOP Orphan: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Consultancy. OffLabel Disclosure: Yes, KRT-232 is an investigational small molecule MDM2 inhibitor. This trial-in-progress abstract describes a registered clinical trial that will evaluate the safety and efficacy of KRT-232 for patients with polycythemia vera.
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Minkley, Michael, Nancy Sweeters, Shiva Kasravi, Jennifer Ferguson, Annie Higa, Angela Jackson, Derek Smith, et al. "Systemic Biomarkers Show Elevated Oxidative Stress and Chronic Inflammation in Two Disorders of Neurodegeneration with Brain Iron Accumulation (NBIA)." Blood 130, Suppl_1 (December 7, 2017): 943. http://dx.doi.org/10.1182/blood.v130.suppl_1.943.943.
Full textAbstract:
Abstract Background: Neurodegeneration with Brain Iron Accumulation (NBIA) is a group of rare genetic disorders characterized by progressive degenerative motor symptoms and the accumulation of iron in the basal ganglia. Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a form of NBIA caused by a mutation in the PANK2 gene leading to a deficiency in pantothenate kinase. Phospholipase A2G6-Associated Neurodegeneration (PLAN) is caused by a mutation in the PLA2G6 gene resulting in impaired phospholipase activity. Current understanding of systemic changes in NBIA disorders is limited, leaving no clear diagnostic biomarkers. Monitoring the systemic changes could identify candidate biomarkers for assessing disease severity and evaluating the efficacy of new therapies. Previous studies of Parkinson's disease (PD) have found a systemic burden of increased oxidative stress and chronic inflammation accompanies the neurological symptoms of the disease. Similarly, abnormal systemic iron regulation associated with brain iron accumulation as well as damage associated with neuromuscular degeneration could lead to increased oxidative stress and a state of chronic inflammation in NBIA. Our initial investigation of a patient with PLAN1, revealed elevated levels of systemic oxidative stress. We investigated a group of PKAN patients as well as continued our investigation of a patient with PLAN to evaluate the possibility of abnormal iron trafficking, increased oxidative stress and chronic inflammation in NBIA. Our aim was to expand our investigation of circulating levels of inflammatory cytokines, oxidative stress markers and iron regulatory and metabolic proteins in NBIA patients to include a group of patients with PKAN. Methods: Plasma samples from 15 PKAN patients were collected at the UCSF Benioff Children's Hospital in Oakland, California. Similarly, a plasma sample from a patient with PLAN was collected in Campbell River, British Columbia. Plasma samples from a matched group of 15 healthy controls were also collected at the University of Victoria. All patients provided informed consent to the study. The pro-inflammatory cytokines IL-6 and TNFα as well as the anti-inflammatory cytokine IL-10 were measured by ELISA. Total levels of the lipid peroxidation product malondialdehyde (MDA) were measured using N-Methyl-Phenyl-Indole (NMPI). Free, acutely generated, MDA not bound to proteins, was measured by removing plasma proteins via a 10KD spin filtration then measuring the MDA content of resulting filtrate using NMPI. Results: The levels of MDA and Free MDA were significantly elevated in PKAN patients at baseline in comparison to controls (p = 0.05, p = 0.03). IL-6 and TNFα were slightly, but not significantly elevated at baseline compared to controls. We previously demonstrated, similar elevations of oxidative stress in our case study of an NBIA patient with PLAN1. Additionally, all three inflammatory cytokines measured for this study expansion in PLAN were higher than average levels observed in the PKAN and control groups (S ee Table 1). Further analysis of systemic biomarkers in NBIA including proteomic analysis of 30 systemic blood proteins, including iron trafficking proteins is ongoing. Conclusions: We expand previous findings of elevated levels of systemic oxidative stress in other neurodegenerative diseases such as PD to include NBIA patients with PKAN and PLAN. We provide novel evidence of elevated levels of Free MDA; representative of an acute oxidative stress burden in NBIA in addition to the previously noted elevation in total MDA levels. We provide preliminary signs that of an accompanying inflammatory burden in NBIA, but a larger sample group may be needed to determine its significance. References M. Minkley, A. Jackson, D. Smith, C. Borchers, E. Vichinsky, R. Nashmi, P.B. Walter and P. M. Macloed. (2017). Neurodegeneration with Brain Iron Accumulation: PLA2G6-Associated Dystonia-Parkinsonism: Clinical and Animal Studies. Presented at the 2017 European Human Genetics Conference, Copenhagen, Denmark . Disclosures Minkley: Apopharma: Research Funding. Neumayr: Apopharma: Research Funding. Walter: Apopharma: Research Funding.