Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Palaeontology from Australasia and beyond: Abstracts from Palaeo Down Under 3 Perth, Western Australia, July 2023

Palaeo Down Under 3 (PDU3), the now quadrennial conference of the Australasian Palaeontologists (AAP) association, was held in Perth, Western Australia, from the 10th-14th of July 2023. PDU3 showcased innovative research, outreach and education initiatives being conducted across Australasia and beyond by both local and international scientists. A total of 78 talks, 17 posters and 6 plenaries were presented across the five days, and covered a wide range of topics, geological timeframes, and fossil groups. AAP is proud to publish this compilation of PDU3 abstracts to illustrate the current and ongoing strength of Australasian palaeontology. Sarah K. Martin [ [email protected] ], Geological Survey of Western Australia, Department of Energy, Mines, Industry Regulation and Safety, 100 Plain St, East Perth, Western Australia 6004, Australia; Michael Archer [ [email protected] ], School of Biological, Earth & Environmental Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia; Heidi J. Allen [ [email protected] ], Geological Survey of Western Australia, Department of Energy, Mines, Industry Regulation and Safety, 100 Plain St, East Perth, Western Australia 6004, Australia; Daniel D. Badea [ [email protected] ], Faculty of Geography and Geology, "Alexandru Ioan Cuza" University, Bulevard "Carol I", Nr.11, 707006, Iași, Romania; Eleanor Beidatsch [ [email protected] ], Palaeoscience Research Centre, University of New England, Armidale, New South Wales 2351, Australia; Marissa J. Betts [ [email protected] ], Palaeoscience Research Centre/LLUNE, University of New England, Armidale, New South Wales 2351, Australia; Maria Blake [ [email protected] ], School of Earth, Atmosphere and Environment, Monash University, 9 Rainforest Walk, Clayton, Victoria 3800, Australia; Phillip C. Boan [ [email protected] ], University of California, Riverside, Geology 1242, 900 University Ave, Riverside, CA 92521, U.S.A.; Tory Botha [ [email protected] ], School of Biological Sciences, Molecular Life Sciences Building, North Terrace Campus, The University of Adelaide, Adelaide, South Australia 5005, Australia; Glenn A. Brock [ [email protected] ], School of Natural Sciences, Macquarie University, New South Wales 2109, Australia; Luke Brosnan [ [email protected] ], WA Organic and Isotope Geochemistry Centre, The Institute for Geoscience Research, School of Earth and Planetary Sciences, Building 500, Curtin University, Kent St, Bentley, Western Australia 6102, Australia; Jack Castle-Jones [ [email protected] ], School of Natural Sciences, Macquarie University, New South Wales 2109, Australia; Jonathan Cramb [ [email protected] ], Queensland Museum, PO Box 3300, South Brisbane BC, Queensland 4101, Australia; Vanesa L. De Pietri [ [email protected] ], School of Earth and Environment, University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand; Sherri Donaldson [ [email protected] ], School of Geosciences, University of Edinburgh, Grant Institute, The King's Buildings, James Hutton Road, Edinburgh, EH9 3FE, Scotland, U.K.; Elizabeth M. Dowding [ [email protected] ], Friedrich-Alexander-Universität Erlangen-Nürnberg, Loewenichstraße 28 91054 Erlangen, Germany; Ruairidh Duncan [ [email protected] ], Evans EvoMorph Lab, Room 226, 18 Innovation Walk, School of Biological Sciences, Monash University, Clayton, Victoria 3800, Australia; Amy L. Elson [ [email protected] ], WA Organic and Isotope Geochemistry Centre, The Institute for Geoscience Research, School of Earth and Planetary Sciences, Building 500, Curtin University, Kent St, Bentley, Western Australia 6102, Australia; Roy M. Farman [ [email protected] ], School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia; Mahala A. Fergusen [ [email protected] ], School of Biological Sciences, Benham Building, North Terrace Campus, The University of Adelaide, Adelaide, South Australia 5005, Australia; Alyssa Fjeld [ [email protected] ], School of Biological Sciences, 18 Innovation Walk, Monash University, Clayton, Victoria 3800, and School of Natural Sciences, Macquarie University, New South Wales 2109, Australia; David Flannery [ [email protected] ], School of Earth and Atmospheric Sciences, Queensland University of Technology, 2 George St, Brisbane, Queensland 4000, Australia; Timothy G. Frauenfelder [ [email protected] ], University of New England, Armidale, New South Wales 2351, Australia; John D. Gorter [ [email protected] ], PO Box 711, Claremont, Western Australia 6910, Australia; Michelle Gray [ [email protected] ], School of Life and Environmental Sciences, Deakin University, Geelong, Victoria 3216, Australia; Nigel Gray [ [email protected] ], GPO Box 2902, Brisbane, Queensland 4001, Australia; Peter Haines [ [email protected] ], Geological Survey of Western Australia, Department of Energy, Mines, Industry Regulation and Safety, 100 Plain St, East Perth, Western Australia 6004, Australia; Lachlan J. Hart [ [email protected] ], Australian Museum Research Institute, 1 William Street, Sydney, New South Wales 2010, Australia; Brooke E. Holland [ [email protected] ], School of Biological Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia; James D. Holmes [ [email protected] ], Department of Earth Sciences, Palaeobiology, Uppsala University, Villavägen 16, Uppsala 752 36, Sweden; Lars Holmer [ [email protected] ], Department of Earth Sciences, Palaeobiology, Uppsala University, Villavägen 16, Uppsala 752 36, Sweden; Ashleigh V.S. Hood [ [email protected] ], School of Geography, Earth and Atmospheric Sciences, University of Melbourne, Parkville, Victoria 3010, Australia; Alexey P. Ippolitov [ [email protected]] , School of Geography, Environment and Earth Sciences, Victoria University of Wellington | Te Herenga Waka, 21 Kelburn Parade, Wellington 6012, New Zealand; Christine M. Janis [ [email protected] ], Bristol Palaeobiology Group, School of Earth Sciences, University of Bristol, Wills Memorial Building, Bristol, BS8 1RJ, U.K.; Benjamin P. Kear [ [email protected] ], The Museum of Evolution, Uppsala University, Norbyvägen 16, SE-752 36 Uppsala, Sweden; Sophie Kelly [ [email protected] ], School of Earth and Environment, University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand; Justin L. Kitchener [ [email protected] ], School of Environmental and Rural Science, University of New England, Armidale, New South Wales 2351, Australia; John R. Laurie [ [email protected] ], Geoscience Australia, Symonston, Australian Capital Territory 2601, and School of Natural Sciences, Macquarie University, North Ryde, New South Wales 2109, Australia; Lucy G. Leahey [ [email protected] ], The University of Queensland, Brisbane, Queensland 4072, Australia; John A. Long [ [email protected] ], College of Science and Engineering, Flinders University, PO Box 2100, Adelaide, South Australia 5001, Australia; Daniel Mantle [ [email protected] ], MGPalaeo, Unit 1, 5 Arvida Street, Malaga, Western Australia 6090, Australia; David McB. Martin [ [email protected] ], Geological Survey of Western Australia, Department of Energy, Mines, Industry Regulation and Safety, 100 Plain St, East Perth, Western Australia 6004, Australia; Chris Mays [ [email protected] ], School of Biological, Earth and Environmental Sciences, Environmental Research Institute, University College Cork, Distillery Fields, Cork T23 N73K, Ireland; Matthew R. McCurry [ [email protected] ], Australian Museum, 1 William St, Sydney, New South Wales 2010, Australia; Peter McGoldrick [ [email protected] ], CODES, University of Tasmania, Locked Bag 66, Hobart, Tasmania 7001, Australia; Corinne L. Mensforth [ [email protected] ], Flinders University, GPO Box 2100, Adelaide, South Australia 5001, Australia; Rhys D. Meyerkort [ [email protected] ], University of Western Australia, 35 Stirling Hwy, Crawley, Western Australia 6009, Australia; Christina Nielsen-Smith [ [email protected] ], School of Biological Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia; Ryan Nel [ [email protected] ], Geology Department, Rhodes University, Grahamstown, South Africa; Jake Newman-Martin [ [email protected] ], Curtin University, Kent St, Bentley, Western Australia 6102, Australia; Yeongju Oh [ [email protected] ], Division of Earth Sciences, Korea Polar Research Institute, 26 Songdomirae-ro, Yeonsu-gu, 21990 Incheon, Republic of Korea, and Polar Science, University of Science and Technology, Daejeon, 34113, Republic of Korea; John R. Paterson [ [email protected] ], Palaeoscience Research Centre, School of Environmental and Rural Science, University of New England, Armidale, New South Wales 2351, Australia; Jacob Pears [ [email protected] ], School of Molecular and Life Sciences, Curtin University, Kent St, Bentley, Western Australia 6102, Australia; Stephen F. Poropat [ [email protected] ], Western Australian Organic and Isotope Geochemistry Centre, School of Earth and Planetary Science, Curtin University, Kent St, Bentley, Western Australia 6102, and Australian Age of Dinosaurs Museum of Natural History, Winton, Queensland 4735, Australia; Catherine M. Reid [ [email protected] ], School of Earth and Environment, University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand; R. Pamela Reid [ [email protected] ], Department of Marine Geosciences, Rosenstiel School of Marine, Atmospheric, and Earth Science, University of Miami, Miami, FL 33149, U.S.A., and Bahamas Marine EcoCentre, Miami, FL 3315

Complications Occurring Through 5 Years Following Primary Intraocular Lens Implantation for Pediatric Cataract

Importance Lensectomy with primary intraocular lens (IOL) implantation is often used in the management of nontraumatic pediatric cataract, but long-term data evaluating the association of age and IOL location with the incidence of complications are limited. Objective To describe the incidence of complications and additional eye surgeries through 5 years following pediatric lensectomy with primary IOL implantation and association with age at surgery and IOL location. Design, Setting, and Participants This prospective cohort study used Pediatric Eye Disease Investigator Group cataract registry data from 61 institution- and community-based practices over 3 years (June 2012 to July 2015). Participants were children younger than 13 years without baseline glaucoma who had primary IOL implantation (345 bilateral and 264 unilateral) for nontraumatic cataract. Data analysis was performed between September 2021 and January 2023. Exposures Lensectomy with primary IOL implantation. Main Outcome and Measures Five-year cumulative incidence of complications by age at surgery (<2 years, 2 to <4 years, 4 to <7 years, and 7 to <13 years) and by IOL location (sulcus vs capsular bag) were estimated using Cox proportional hazards models. Results The cohort included 609 eyes from 491 children (mean [SD] age, 5.6 [3.3] years; 261 [53%] male and 230 [47%] female). Following cataract extraction with primary IOL implantation, a frequent complication was surgery for visual axis opacification (VAO) (cumulative incidence, 32%; 95% CI, 27%-36%). Cumulative incidence was lower with anterior vitrectomy at the time of IOL placement (12%; 95% CI, 8%-16%) vs without (58%; 95% CI, 50%-65%), and the risk of undergoing surgery for VAO was associated with not performing anterior vitrectomy (hazard ratio [HR], 6.19; 95% CI, 3.70-10.34; P < .001). After adjusting for anterior vitrectomy at lens surgery, there were no differences in incidence of surgery for VAO by age at surgery (<2 years, HR, 1.35 [95% CI, 0.63-2.87], 2 to <4 years, HR, 0.86 [95% CI, 0.44-1.68], 4 to <7 years, HR, 1.06 [95% CI, 0.72-1.56]; P = .74) or by capsular bag vs sulcus IOL fixation (HR, 1.22; 95% CI, 0.36-4.17; P = .75). Cumulative incidence of glaucoma plus glaucoma suspect by 5 years was 7% (95% CI, 4%-9%), which did not differ by age after controlling for IOL location and laterality. Conclusions and Relevance In this cohort study, a frequent complication following pediatric lensectomy with primary IOL was surgery for VAO, which was associated with primary anterior vitrectomy not being performed but was not associated with age at surgery or IOL location. The risk of glaucoma development across all ages at surgery suggests a need for long-term monitoring

Whole genomes redefine the mutational landscape of pancreatic cancer

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded