John Rose Research Articles

Abstract 4503: Preclinical characterization of PRT7732: A highly potent, selective, and orally bioavailable targeted protein degrader of SMARCA2

Abstract SWI/SNF (BAF) complexes play an important role in controlling gene expression by remodeling chromatin. SMARCA2 (BRM) and SMARCA4 (BRG1) are the core catalytic subunits of the SWI/SNF complexes, containing an ATPase domain and a bromodomain. SMARCA4 protein expression is lost in some cancers due to loss-of-function (LOF) mutations and homozygous deletions, and SMARCA4-deleted cancer cells are highly dependent on its paralog gene SMARCA2 for their survival. Therefore, targeting SMARCA2 in SMARCA4-deficient cancers using selective SMARCA2 degraders induces synthetic lethality while sparing SMARCA4 wild type (WT) normal cells. We have recently identified a series of orally bioavailable SMARCA2 selective degraders that demonstrate robust efficacy in pre-clinical animal models with favorable pharmacokinetic properties and safety profiles. Our nomination candidate PRT7732 exhibits >1000x selectivity for SMARCA2 over SMARCA4 in cell-based assays, with DC50 values in cancer cell lines in the low nanomolar range. The PRT7732-induced SMARCA2 degradation was rescued by a proteasome inhibitor and neddylation inhibitor, indicating ubiquitin-proteasome dependent degradation. Furthermore, PRT7732 does not change levels of known CRBN ligand neo-substrates such as IKZF2/3, GSPT1 and SALL4. PRT7732 inhibits only SMARCA4-deficient cancer cell proliferation with IC50 values ranging from 5.0-50 nM, but not SMARCA4 WT cells in vitro. Oral administration of PRT7732 resulted in near-total degradation of SMARCA2 protein with complete selectivity over SMARCA4 protein in a SMARCA4 WT lung cancer model in mice, consistent with the SMARCA2 degradation kinetics-based pharmacodynamic prediction model. PRT7732 oral daily administration showed significant tumor growth inhibition of SMARCA4-deficient lung cancer xenograft models at well tolerated doses. The treated tumor tissues show robust SMARCA2 protein reduction for 24h post dosing. In summary, our orally bioavailable SMARCA2 degraders induce synthetic lethality in SMARCA4-deficient cancers in vitro and in vivo. Efforts to further evaluate these compounds in additional models and in combination with other agents are ongoing. Citation Format: Artem Shvartsbart, Koichi Ito, Joseph Rager, Michael Hulse, Anjana Agarwal, Komali Vykuntam, Jessica Burtell, Min Wang, Justin Kurian, Miles Cowart, Joy Cote, Nick Stahl, Monisha Sivakumar, Anthony Reichelderfer, Jack Carter, Alexander Grego, Andrew Moore, Neha Bhagwat, Ross Kuskovsky, Shanthi Ganesan, Stefan Ruepp, Tom Emm, Philip Pitis, Corey Basch, Klare Bersch, Yongchun Pan, Song Mei, Raul Leal, John Rose, Dani Roth, Chaoyi Xu, Ganfeng Cao, Kris Vaddi, Sang Hyun Lee, Sandy Geeganage, Andrew Combs, Peggy Scherle. Preclinical characterization of PRT7732: A highly potent, selective, and orally bioavailable targeted protein degrader of SMARCA2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4503.

FRII-09 CONSERVATIVE KIDNEY TRAUMA MANAGEMENT AND CONSERVATIVE POLITICS: HOW SIR WINSTON CHURCHILL'S PHYSICIANS MAY HAVE SAVED THE WESTERN WORLD

You have accessJournal of UrologyHistory of Urology: History Forum1 Apr 2017FRII-09 CONSERVATIVE KIDNEY TRAUMA MANAGEMENT AND CONSERVATIVE POLITICS: HOW SIR WINSTON CHURCHILL'S PHYSICIANS MAY HAVE SAVED THE WESTERN WORLD Alan Carnes, Zach Klaassen, Michael Kemper, Arthur Smith, and Durwood Neal Alan CarnesAlan Carnes More articles by this author , Zach KlaassenZach Klaassen More articles by this author , Michael KemperMichael Kemper More articles by this author , Arthur SmithArthur Smith More articles by this author , and Durwood NealDurwood Neal More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2458AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The exquisite leadership and unmatched resolve of Sir Winston Churchill during the Second World War are known well beyond the borders of Britain. The adversities he overcame in the 1930's and 1940's have been extensively explored. However, one lesser known misfortune he faced earlier in life had a profound impact upon Mr. Churchill. The details surrounding this urologic traumatic event are herein examined, specifically with respect to the management his physicians selected. These medical decisions early in Mr. Churchill's life were important for shaping the future of the Western World and the emergence of the ‘British Bulldog’. METHODS A review of the literature was performed with Google Scholar to assess secondary sources pertinent to the early life of Sir Winston Churchill. Specifically, to further examine the urologic traumatic event that took place during Churchill's late adolescence and how this clinical situation was managed. RESULTS In the early winter of 1892, an 18 year old Winston Churchill was on holiday at the estate of his aunt in Bournemouth, England. While accompanied by his younger brother and a young cousin, the boys took up a game of chasing the older Churchill. Churchill found himself in the middle of a bridge straddling a ravine with a boy on either side. In the spirit of the game, he climbed over the railing of the bridge and pondered, “to plunge or not to plunge, that was the question!” He chose to plunge, and the slender firs he hoped would break his 29-foot fall did little to mitigate the traumatic results. It was 3 days before he regained consciousness and several weeks before he could climb from bed. He was diagnosed with a 'kidney rupture' as well as a concussion and right shoulder injury. The Churchill's family physician, Dr. Robson Roose, as well as a London surgeon, Dr. John Rose, recommended 3 months of bed rest. Churchill's recovery was prolonged and he stated, “for a year I looked at life round a corner.” CONCLUSIONS Kidneys are the 3rd most common solid organ to be damaged following blunt trauma, and renal lacerations are a common result of rapid deceleration. These injuries need operative intervention in less than 10% of cases, but those numbers are bolstered by 21st century imaging. In late 19th century Britain, without the use of modern imaging technology, these physicians selected the appropriate conservative treatment modality. If young Winston Churchill would have met an early demise, the fight against Nazi Germany may have ultimately had a different outcome. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1069-e1070 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Alan Carnes More articles by this author Zach Klaassen More articles by this author Michael Kemper More articles by this author Arthur Smith More articles by this author Durwood Neal More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

The Many Transformations of Albert Facey

In the last months of his life, 86-year-old Albert Facey became a best-selling author and revered cultural figure following the publication of his autobiography, A Fortunate Life. Released on Anzac Day 1981, it was praised for its "plain, unembellished, utterly sincere and un-self-pitying account of the privations of childhood and youth" (Semmler) and "extremely powerful description of Gallipoli" (Dutton 16). Within weeks, critic Nancy Keesing declared it an "Enduring Classic." Within six months, it was announced as the winner of two prestigious non-fiction awards, with judges acknowledging Facey's "extraordinary memory" and "ability to describe scenes and characters with great precision" ("NBC" 4). A Fortunate Life also transformed the fortunes of its publisher. Founded in 1976 as an independent, not-for-profit publishing house, Fremantle Arts Centre Press (FACP) might have been expected, given the Australian average, to survive for just a few years. Former managing editor Ray Coffey attributes the Press's ongoing viability, in no small measure, to Facey's success (King 29). Along with Wendy Jenkins, Coffey edited Facey's manuscript through to publication; only five months after its release, with demand outstripping the capabilities, FACP licensed Penguin to take over the book's production and distribution. Adaptations soon followed. In 1984, Kerry Packer's PBL launched a prospectus for a mini-series, which raised a record $6.3 million (PBL 7–8). Aired in 1986 with a high-rating documentary called The Facey Phenomenon, the series became the most watched television event of the year (Lucas). Syndication of chapters to national and regional newspapers, stage and radio productions, audio- and e-books, abridged editions for young readers, and inclusion on secondary school curricula extended the range and influence of Facey's life writing. Recently, an option was taken out for a new television series (Fraser).

Technology in community practice - part 1

At last year's Optrafair, Heidelberg Engineering invited optometrists to speak about their introduction of the latest technology into their practices and to share case studies and experiences. In the first of four articles based upon these presentations, John Rose explains how modern image tracking technology has significantly improved his ability to detect progressive conditions such as glaucoma.

John Y. Moossy, MD (1925–2012)

A distinguished member of the Academy, John Y. Moossy, MD, died on June 12, 2012. He was born in Shreveport, Louisiana, in 1925, and was the oldest of 4 siblings (Louis Emile, Marie, and Selma) of Lebanese immigrant parents John Yazbeck Moossy and Rose (Ferris) Moossy. Dr. Moossy attended Fordham University in New York, New York, served in the US Navy during World War II, and, after the war, received his MD from Tulane University in New Orleans in 1950. Following his internship and neurology residency in New Orleans, he trained in neuropathology with Abner Wolf, MD, and David Cowen, MD, at Columbia University. He was board-certified in neurology, anatomic pathology, and neuropathology. From 1960 to 1961 he was the director of the Cerebrovascular Disease Study of the World Federation of Neurology at the Bunge Institute, Antwerp, Belgium. He served on the faculties of Tulane, Louisiana …

Strict adherence to bsg guidelines required forcholecystectomy following pancreatitis toprevent high readmission rates

Strict adherence to bsg guidelines required forcholecystectomy following pancreatitis toprevent high readmission rates

Reminiscences and reflections

PurposeThe purpose of this paper is to present a personal view of Professor John Rose. The organisational skill of the late Professor John Rose is illustrated by reminiscences, and his choice of Thales Press as the name of his publishing house is shown to be apposite. An aspect of his “statement of mission” for World Organisation of Systems and Cybernetics and Kybernetes is considered in detail.Design/methodology/approachThe presentation is partly anecdotal but also serious concerns are expressed about current developments in cybernetics.FindingsThe drive and organisational skill of John Rose will be sadly missed.Practical implicationsRose's insistence on soundness of approach is important though arguably slightly misdirected. Attention is drawn to an important development in psychophysics of vision.Originality/valueThe reminiscences and views are the author's own.

John Rose and the early years of sociocybernetics

PurposeThe purpose of this paper is to sketch the most valuable contribution of Dr Rose to the development of social cybernetics over the period 1975‐1995.Design/methodology/approachThe paper is based on an analysis of the proceedings of the sections on “Social Systems” or “Social Cybernetics” of the WOSC conferences from 1978 through 1991, and on an analysis of the entries of the Bibliography on Social Cybernetics (1998).FindingsThe sections on “Social Systems” of the International Congresses on Systems and Cybernetics, initiated by Dr Rose, provided in the period 1978‐1995 the most important meeting point for social scientists aiming at the application of the cybernetic approach to social systems and social processes, and for cyberneticians wanting to use the principles of cybernetics for the analysis and solution of social problems.Originality/valueThe paper shows how the journal Kybernetes, founded by Dr Rose, became the most frequently used publication medium of social cyberneticians: of the 184 papers on social cybernetics mentioned in this bibliography 76 (41 per cent) were published in Kybernetes, more than in any other journal in the domain of cybernetics or social science.

Special double issue – memoriam: Professor John Rose

Special double issue – memoriam: Professor John Rose

Tributes to Professor John Rose 6 February 1917 – 3 August 2007

Tributes to Professor John Rose 6 February 1917 – 3 August 2007

The personality of Professor John Rose, famous scientist

The personality of Professor John Rose, famous scientist

Crystal structure solution of a ParB‐like nuclease at atomic resolution

Crystal structure solution of a ParB-like nuclease at atomic resolution Neil Shaw, Wolfram Tempel, Jessie Chang, Hua Yang, Chongyun Cheng, Joseph Ng, John Rose, Zihe Rao, Bi-Cheng Wang, and Zhi-Jie Liu* 1National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China 2 Southeast Collaboratory for Structural Genomics, Department of Biochemistry and Molecular Biology, University of Georgia, Georgia 30602 3 Laboratory of Structural Biology and Department of Biological Sciences, University of Alabama in Huntsville, Huntsville, Alabama 35899

Offenders with learning disabilities

Two papers related to sex offenders with learning disabilities have recently been published in the Journal of Sexual Aggression. The first, by Daniel Wilcox, suggests that in comparison with mainstream sex offender treatment services, the development of services for offenders with disabilities has been slow. The main reason for this appears to be a lack of expertise in the area. The second paper, by Jude Courtney and John Rose, is a review of studies considering the efficacy of interventions for sex offenders with learning disabilities. The authors suggest that there is still a lack of a rigorous evidence base for practitioners in this area and call for further research.

Family Diplomacy: Canada and the Commonwealth Office of High Commissioner

THE OFFICE OF HIGH COMMISSIONER emerged because Britain and fully self-governing dominions-Canada, Australia, South Africa, New Zealand, Newfoundland (until 1934) and Ireland-were engaging in diplomacy well before dominions had become separate international units. Such development did not fit into diplomatic system. Diplomacy was, and usually still is, understood to be [t]he conduct of relations between sovereign and is therefore restricted to states enjoying constitutional independence.1 Yet not only did non-independent parts of British empire engage in what was recognizably diplomacy with mother country, but they also developed between themselves distinctive diplomatic practices long before 1931 statute of Westminster (which gave them right to obtain sovereign statehood).Canada's attitude to office reflected its relationship with Britain as well as nature of evolving empire and Commonwealth.2 One of hangovers of colonialism was considerable touchiness in some dominions about slightest suggestion of dominion subordination to Britain. It rubbed off on office of high commissioner inasmuch as distinctions between high commissioners and ambassadors were interpreted as indications that high commissioners (and by implication states they represented) were second-rate. Once, however, dominions could fully stand on their own international feet and decolonisation was under way, Commonwealth was swiftly transformed, and in 1948 high commissioners gained equal status with ambassadors. At this point, high commissioners began appreciating their exclusivity and their very real advantages over foreign agents. The obvious benefits of office did not long outlast heyday of new Commonwealth, which was over by early 1960s. Yet office survives.I INTRA-IMPERIAL ASSERTION: THE ESTABLISHMENT OF THE OFFICE OF HIGH COMMISSIONERIntra-imperial contacts of diplomatic kind began when overseas colonies of settlement needed representatives in London to encourage and supervise emigration. Nova Scotia, for example, was at least intermittently represented from 1762. Other appointments followed, and by time of Canada's Confederation (in 1867), most self-governing colonies had appointed part-time agents to speak for them in London and to promote their interests, especially in respect of immigration and economic matters.In 1868, Canada took intra-imperial diplomacy step further by appointing Sir John Rose as a quasi-official representative3 to Britain. Then, in 1878, Canada's recently re-elected prime minister, Sir John A. MacDonald, claimed his country was now an auxiliary kingdom, whose relations with Britain were political and diplomatic rather than colonial. Accordingly, it needed full-time resident to London with diplomatic or semi-diplomatic status, someone who could engage in the fullest and most frank interchange of views with British government.4 Macdonald accepted that such an official would have to have title other than one of those customarily used in diplomacy, but he wanted it to sound important and to be easily recognized by foreign courts. He therefore suggested resident minister.This was at time when Canada's constitutional subordination to Britain meant that it had to conduct all its official business with Whitehall through Colonial Office, to which Macdonald had addressed his request. The Colonial Office accepted idea of highranking official, but thought that Canada's membership in British empire meant that its representative could neither have diplomatic status nor be called minister (since is recognized diplomatic title). Commissioner was suggested as more suitable. Macdonald wanted it prefixed by high, partly to ensure that foreign governments appreciated stature of his representative. After some grumbling about Canadian grandiloquence, Britain agreed, and first appointment was made in 1880 in person of Sir Alexander Gait (who served until 1883). …

A rose by any other name: a geochemical comparison of Caughley (c. 1772–99), Coalport (John Rose & Co.; c. 1799–1837), and rival porcelains based on sherds from the factory sites

Compositional data for sherds from various Shropshire factory sites show that at the Coalport works, John Rose and colleagues produced two types of true porcelain that differed in their phosphate content, and bone-ash porcelain. The low-phosphate true porcelain is compositionally similar to its Caughley counterpart; there is, however, no knwn analogue to the relatively phosphatic (0.7–2.7 wt.% P2O5) true porcelain, which appears to have been produced between c. 1795 and the 1830s. All of the analysed Coalport true porcelain sherds are in biscuit, indicating an ‘artificial-porcelain type’ firing sequence. Had they been glazed, the glaze would likely have been lead-rich, as is the case of the glazed true porcelain sherds from the Caughley factory.Soapstone (magnesian) porcelains from the Caughley site resemble Flight-period Worcester porcelain in terms of the concentration of their plastic ingredients (soapstone and clay), but they can have small amounts of fluxing components (lead, alkalis). This indicates that Turner sought to produce a paste with a similar degree of plasticity as Worcester, but he either could achieve and control higher kiln temperatures, or at times was satisfied with a somewhat less vitrified ware. The latter inference is supported by mineralogical and modal melt data, and the rather crude character of some of Turner’s mass-produced wares.Analysed Coalport phosphatic porcelain produced during the decade (1820s) when Nantgarw’s former proprietor (William Billingsley) worked at Coalport has a similar bone-ash/clay ratio (∼ 1.3) but a significantly lower K2O/Na2O ratio (∼ 1.9 versus 5.2) than Nantgarw porcelain. Another Billingsley-related ware, Swansea ‘duck egg’ porcelain (c. 1815–17) has an even more divergent composition, with lower phosphate contents and up to half again as much alumina as Nantgarw and c. 1820s Coalport. The data support the traditional view that Billingsley had little influence on Rose during his tenure at Coalport.

New structure, new programmes, bright future

On 4 July 2000, the European Association of Aerospace Industries (AECMA) published its statistical data for 1999 during a press conference in London, As an introduction, John Rose commented on the situation of the aerospace industry in Europe. The text of his speech is reproduced here.

CONFERENCE PROCEEDINGS OF THE 11TH INTERNATIONAL CONGRESS OF CYBERNETICS AND SYSTEMS, edited by Robert Vallée and John Rose. World Organisation of Systems and Cybernetics, Paris, France, 1999, XII+398 pp. (Pbk: £50)

<i>CONFERENCE PROCEEDINGS OF THE 11TH INTERNATIONAL CONGRESS OF CYBERNETICS AND SYSTEMS, </i>edited by Robert Vallée and John Rose. World Organisation of Systems and Cybernetics, Paris, France, 1999, XII+398 pp. (Pbk: £50)

Industrial Organic Chemistry Klaus Weissermel and Hans‐Jurgen Arpe 3rd edn. VCH, Weinheim, 1997 xvii + 464 pages. £70 ISBN 3‐527‐28838‐4

Applied Organometallic ChemistryVolume 13, Issue 11 p. 857-858 Book Review Industrial Organic Chemistry Klaus Weissermel and Hans-Jurgen Arpe 3rd edn. VCH, Weinheim, 1997 xvii + 464 pages. £70 ISBN 3-527-28838-4 John Rose, John Rose ICI and University of Surrey (Retired)Search for more papers by this author John Rose, John Rose ICI and University of Surrey (Retired)Search for more papers by this author First published: 26 October 1999 https://doi.org/10.1002/(SICI)1099-0739(199911)13:11<857::AID-AOC879>3.0.CO;2-GCitations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume13, Issue11November 1999Pages 857-858 RelatedInformation

The development of the Coalport Chinaworks: analysis of ceramic finds

Recent stratigraphically recorded excavations at Coalport have uncovered features and waster dumps from the early years of earthenware and porcelain manufacture. The assemblage has strong similarities with wares retrieved in the 1970s, and appears to have been made at William Reynolds’ pottery (later Reynolds, Horton & Rose) from c. 1795. The vessel types suggest that earthenware production had stopped by 1810. Most of the porcelains are known wares of Reynolds/Anstice, Horton and Rose; limited excavation further north revealed porcelain wasters produced by John Rose and partners. For a time, early porcelains are found in the same archaeological contexts as earthenwares, strongly suggesting contemporary production by the same factory. This has repercussions on the layout of the factory and the historical, archaeological and ceramic evidence is discussed. It is possible that some kilns were incorporated within buildings and were not of the hovel type. An excavated structure is interpreted as an enamelling kiln belonging to Anstice, Horton and Rose. Geochemical analysis of sherds from the Coalport factory (see Appendix), shows a progression from hard paste to bone-ash porcelains. The potential for further study of Coalport bodies and glazes is made clear.

The State of Shame: Australian Multiculturalism and the Crisis of Indigenous Citizenship

I know I have hurt you. But I want to make (it) up to you, repair the rupture, bridge the rift between us, heal the pain that I have caused. I want us to imagine a place where the possibility of our hurting each other does not exist. Where we can each be our different selves without shame, without fear, without alienation. True partners in peace. A world of brothers and sisters. A world of recognition and enhancement. This is the right thing to do: to heal, to move on, to found and enter a New Society.