tbuckley/cabot-search huggingface dataset:
DNMT3A Harboring Leukemia-Associated Mutations Directs Sensitivity to DNA Damage at Replication Forks
Authors: Kartika Venugopal, Yang Feng, Pawel Nowialis, Huanzhou Xu, Daniil E. Shabashvili, Cassandra M. Berntsen, Prabhjot Kaur, Kathryn I. Krajcik, Christina Taragjini, Zachary Zaroogian, Heidi L. Casellas Román, Luisa M. Posada, Chamara Gunaratne, Jianping Li, Daphné Dupéré-Richer, Richard L. Bennett, Santhi Pondugula, Alberto Riva, Christopher R. Cogle, Rene Opavsky, Brian K. Law, Sumita Bhaduri-McIntosh, Stefan Kubicek, Philipp B. Staber, Jonathan D. Licht, Jonathan E. Bird, Olga A. Guryanova
Journal: Clinical Cancer Research (2021)

In acute myeloid leukemia (AML), recurrent DNA methyltransferase 3A (DNMT3A) mutations are associated with chemoresistance and poor prognosis, especially in advanced-age patients. Gene-expression studies in DNMT3A-mutated cells identified signatures implicated in deregulated DNA damage response and replication fork integrity, suggesting sensitivity to replication stress. Here, we tested whether pharmacologically induced replication fork stalling, such as with cytarabine, creates a therapeutic vulnerability in cells with DNMT3A(R882) mutations.Leukemia cell lines, genetic mouse models, and isogenic cells with and without DNMT3A(mut) were used to evaluate sensitivity to nucleoside analogues such as cytarabine in vitro and in vivo, followed by analysis of DNA damage and signaling, replication restart, and cell-cycle progression on treatment and after drug removal. Transcriptome profiling identified pathways deregulated by DNMT3A(mut) expression.We found increased sensitivity to pharmacologically induced replication stress in cells expressing DNMT3A(R882)-mutant, with persistent intra-S-phase checkpoint activation, impaired PARP1 recruitment, and elevated DNA damage, which was incompletely resolved after drug removal and carried through mitosis. Pulse-chase double-labeling experiments with EdU and BrdU after cytarabine washout demonstrated a higher rate of fork collapse in DNMT3A(mut)-expressing cells. RNA-seq studies supported deregulated cell-cycle progression and p53 activation, along with splicing, ribosome biogenesis, and metabolism.Together, our studies show that DNMT3A mutations underlie a defect in recovery from replication fork arrest with subsequent accumulation of unresolved DNA damage, which may have therapeutic tractability. These results demonstrate that, in addition to its role in epigenetic control, DNMT3A contributes to preserving genome integrity during replication stress. See related commentary by Viny, p. 573.
TCT-47 Valvosoft Noninvasive Ultrasound Therapy (NIUT) in Low-Flow, Low-Gradient Severe Aortic Stenosis
Authors: A.J.J. IJsselmuiden, Jonathan Halim, Guillaume Goudot, Bas Schőlzel, Jeroen Vos, Martijn Meuwissen, Ben Van Den Branden, Samuel Zarka, Christian Spaulding, Etienne Puymirat, Olga Petrovic, Danijela Trifunovic, Peter Den Heijer, Emmanuel Messas
Journal: Journal of the American College of Cardiology (2021)
TCT-101 Long-Term Outcomes Following Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting for Treating In-Stent Restenosis in Unprotected Left Main Coronary Artery: Multicenter LM-DRAGON Registry
Authors: Wojciech Wańha, Jacek Bil, Michalina Kołodziejczak, Adam Kowalowka, Damian Hudziak, Radoslaw Gocol, Mariusz Kowalewski, Rafal Januszek, Tomasz Figatowski, Marek Milewski, Brunon Tomasiewicz, Piotr Kubler, Piotr Desperak, Łukasz Kuźma, Krzysztof Milewski, Bartlomiej Gora, Andrzej Los, Jan Kulczycki, Adrian Wlodarczak, Marek Grygier, Maciej Lesiak, Pawel Kleczynski, Radoslaw Litwinowicz, Andrea Borin, Grzegorz Smolka, Krzysztof Reczuch, Marcin Gruchała, Robert Gil, Miłosz Jaguszewski, Krzysztof Bartus, Piotr Suwalski, Slawomir Dobrzycki, Dariusz Dudek, Stanislaw Bartus, Mariusz Gasior, Jacek Legutko, Andrzej Ochała, Alexandra Lansky, Marek Deja, Elvin Kedhi, Wojciech Wojakowski
Journal: Journal of the American College of Cardiology (2021)
Alexander McNeish: paediatric gastroenterologist, clinical researcher, and academic administrator
Authors: Rebecca Wallersteiner
Journal: BMJ (2021)

An only child, Alexander Stewart McNeish (“Sandy”) was born in Glasgow to Angus Stewart McNeish, a general practitioner, and Minnie (nee Howieson), a housewife. His father’s medical practice was part of the family house and run by his mother. Educated at Glasgow Academy, he was an all rounder, good at academic subjects and at sports. An excellent swimmer, his 100 m backstroke was fast enough for McNeish to be considered for the Empire Games. He also developed a lifelong passion for golf. His parents imbued him with a strong Protestant work ethic, manifest as a commitment to hard work and to punctuality. He originally wanted to read classics at university but changed his mind and decided to become a doctor, like his father.

McNeish first trained in cardiology but found that he enjoyed working with children and switched to paediatric gastroenterology.

He moved to Birmingham in 1970 to work with the formidable Charlotte Anderson, who encouraged him at …
Abstract 12891: Cardiovascular Outcomes in Patients With Ankylosing Spondylitis in a Population Based-Study
Authors: John B Kostis, Davit Sargsyan, Javier Cabrera, Mohammed Fahim, Traymon Beavers, Stavros Zinonos, William J Kostis
Journal: Circulation (2019)

Introduction: Numerous studies have shown that ankylosing spondylitis (AS) is associated with cardiovascular disease (CVD) including acute myocardial infarction (AMI), heart failure (HF), transient...
効果的な標的イメージングと治療のためのポルフィリンに基づくナノ複合材料の最近の進歩【JST・京大機械翻訳】
Authors: Rabiee Navid, Yaraki Mohammad Tavakkoli, Garakani Soha Mokhtari, Garakani Shima Mokhtari, Ahmadi Sepideh, Lajevardi Aseman, Bagherzadeh Mojtaba, Rabiee Mohammad, Tayebi Lobat, Tahriri Mohammadreza, R Hamblin Michael
Journal: Biomaterials (2020)
BNT162b2 and mRNA-1273 COVID-19 vaccine effectiveness against the SARS-CoV-2 Delta variant in Qatar
Authors: Patrick Tang, Mohammad R. Hasan, Hiam Chemaitelly, Hadi M. Yassine, Fatiha M. Benslimane, Hebah A. Al Khatib, Sawsan AlMukdad, Peter Coyle, Houssein H. Ayoub, Zaina Al Kanaani, Einas Al Kuwari, Andrew Jeremijenko, Anvar Hassan Kaleeckal, Ali Nizar Latif, Riyazuddin Mohammad Shaik, Hanan F. Abdul Rahim, Gheyath K. Nasrallah, Mohamed Ghaith Al Kuwari, Hamad Eid Al Romaihi, Adeel A. Butt, Mohamed H. Al-Thani, Abdullatif Al Khal, Roberto Bertollini, Laith J. Abu-Raddad
Journal: Nature Medicine (2021)
A modular ROS-responsive platform co-delivered by 10-hydroxycamptothecin and dexamethasone for cancer treatment
Authors: Qingye Meng, Hao Hu, Xiaodong Jing, Ying Sun, Liping Zhou, Yaowei Zhu, Bing Yu, Hailin Cong, Youqing Shen
Journal: Journal of Controlled Release (2021)
Carcinoma of the Breast
Authors: Andrew G. Jessiman, Francis D. Moore
Journal: New England Journal of Medicine (1956)

IV–The Role of Breast SurgeryBiopsyThe folly of undertaking or withholding treatment of the small breast lump without histologic study has been emphasized and re-emphasized for years. It remains folly; but this should not blind us to two facts: Excision is safer than incision. If one cannot circumincise the lesion freely in normal tissue, a simple mastectomy may in itself provide the best biopsy. One should not knowingly cut across disease in this initial approach. When cancer is obvious by all physical signs, and characteristic metastases are present, one should not endanger the patient by a compulsive desire . . .
De Novo IgA Vasculitis Following Exposure to SARS-CoV-2 Immunization
Authors: Terrance Wickman, Muner Mohamed, Agnes B. Fogo, Juan Carlos Q. Velez
Journal: Journal of the American Society of Nephrology (2021)

Introduction: Immunizations have been previously described as potential triggering events for the development of certain glomerular diseases. However, there is paucity of reports of occurrence of glomerular diseases developing after exposure to a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. Case Description: A 50-yearl-old man presented to a nephrology clinic for evaluation of persistent proteinuria. Six weeks prior to evaluation, the patient had reported developing a new rash approximately 2 weeks after receiving the first dose of a SARS-CoV-2 vaccine (Pfizer®). The rash was treated by his primary care provider with topical and oral corticosteroids, leading to partial improvement of the skin lesions. Three weeks after the first vaccine injection, the patient received his scheduled second vaccine injection. Within 2 days, the rash reappeared. This time, the lesions were more severe in nature, with a violaceous papular rash involving his lower legs and with some areas progressing to blisters. He also reported myalgias and arthralgias. A skin biopsy was performed and revealed IgA-dominant leukocytoclastic vasculitis. After completion of 2 weeks of oral corticosteroids, a urinalysis revealed proteinuria and a consultation to nephrology was requested. On examination, healing papules were noted on his legs but otherwise exam was normal. Serum creatinine was 0.9 mg/dL. Microscopic examination of the urinary sediment revealed acanthocytes. A urine protein-to-creatinine ratio (UPCR) was 1.1 g/g. Serum complements were normal and all pertinent serology was negative. A kidney biopsy was performed and light and immunofluorescence microscopy findings showed an IgA nephropathy. UPCR decreased to 0.7 g/g and rash completely subsided. Discussion: The clinical presentation and pathological findings in this case strongly suggest that SARS-CoV-2 vaccine (Pfizer®) can trigger a clinical syndrome compatible with Henoch-Schonlein purpura. The recurrence of the rash following re-exposure to the vaccine injection (second dose) argues for a definite causal association by Naranjo criteria.
Mouse inbred strain variation in docetaxel pharmacokinetics and hematopoietic toxicity
Authors: Shi-Rong Cai, Vicky Hou, Jim Watters, Howard McLeod
Journal: Cancer Research (2005)

4163  Most pharmacogenomic studies to date have relied on the identification of candidate genes and associating variants in these genes to predict drug response. However, drug response is most often a complex trait, with multiple genes and environmental factors determining treatment outcome. The mapping of individual genes contributing to complex phenotypes like drug response in humans is made difficulty by issues such as the extent of linkage disequilbrium, the availability of relevant populations, and the difficulty of controlling the influence of environment on a trait. The laboratory mouse provides an ideal model system for the study of pharmacogenomics. The mouse has many properties that are advantageous for genetic studies, the similarities in physiology and anatomy with human; it is possible to create large “family pedigrees”; the content and structure of the human and mouse genomes are very closely related; most importantly, well-defined inbred mouse strains, in which genetic factors have segregated and become fixed during inbreeding, facilitate the analysis of complex traits by reducing genetic complexity. Docetaxel, a taxane chemotherapy agent commonly used to treat breast, lung, and prostate cancer was used for this study. 21 different inbred strains mice (20 mice/strain) were injected I.P. with 20mg/kg docetaxel. Plasma was obtained at 5 different time points (0, 30min, 1h, 2h, 5h; n=3) and analyzed for docetaxel pharmacokinetics parameters. In addition, neutrophil toxicity (n=5) was determined on day 0, 1, 3, 4, 5, 6, 7, 8, 11, and 14 after I.P. injection of 20mg/kg docetaxel. The pharmacokinetic results demonstrated that metabolism varied widely among strains (AUC median 3259, range 6936-1189). In addition, neutrophil toxicity after docetaxel treatment also showed significant interstrain variation among strains (2 strains/grade=0, 2 strains/grade=1, 10 strains/grade=2, 4 strains/grade=3, 2 strains/grade=4, and 1strain/grade=5). The docetaxel-induced neutrophil nadir was just 87% of baseline in DBA/2J, but 10% of baseline in NZB/BINJ. Genetic mapping and candidate gene analysis is currently being conducted as an approach to discover genes influencing docetaxel activity.
Visualization of Lesions of Metaphyses and Epiphyses of Bones in Newborns and Young Children
Authors: N. A. Sholokhova
Journal: Radiology - Practice (2021)

The aim of this study was to determine the diagnostic capabilities of various methods of radiological diagnostics for lesions of the metaphyses and epiphyses of bones in newborns and young children. The study involved 108 children in the age group 5 days – 12 months with pathological changes in the pineal gland and bone metaphysis. The possibilities and advantages of standard radiography (СR), ultrasound examination (US) and magnetic resonance imaging (MRI) in the early and differential diagnosis of the osteomyelitis process and epiphyseolysis have been determined. High sensitivity (98 %), specificity (99 %) and accuracy (98 %) for ultrasound and sensitivity (94 %), specificity (89 %) and accuracy (95 %) of MRI in diagnosing osteomyelitis in patients of this age groups. At the same time, the possibilities of standard radiography at the stages of early diagnosis of inflammatory processes in the distal parts of the bones were limited due to a number of factors. The use of diagnostic algorithms greatly facilitates the work of a radiologist and reduces the number of false negative results during the initial treatment of patients.
TCT-38 Ticagrelor With and Without Aspirin in Patients With Previous Coronary Artery Bypass Graft Undergoing Percutaneous Coronary Intervention: The TWILIGHT-CABG Subanalysis
Authors: Frans Beerkens, Davide Cao, George Dangas, Samantha Sartori, Zhongjie Zhang, Johny Nicolas, Anton Camaj, Bimmer Claessen, Carlo Andrea Pivato, David Power, Victor Razuk, Davis Jones, Dominick Angiolillo, Shamir Mehta, C. Michael Gibson, Gennaro Sardella, Samin Sharma, Richard Shlofmitz, Timothy Collier, Stuart Pocock, Roxana Mehran
Journal: Journal of the American College of Cardiology (2021)
BT7480, a novel fully synthetic <i>Bicycle</i> tumor-targeted immune cell agonist™ (<i>Bicycle</i> TICA™) induces tumor localized CD137 agonism
Authors: Kristen Hurov, Johanna Lahdenranta, Punit Upadhyaya, Eric Haines, Heather Cohen, Elizabeth Repash, Drasti Kanakia, Jun Ma, Julia Kristensson, Fanglei You, Carly Campbell, David Witty, Mike Kelly, Stephen Blakemore, Phil Jeffrey, Kevin McDonnell, Philip Brandish, Nicholas Keen
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background CD137 (4-1BB) is an immune costimulatory receptor with high therapeutic potential in cancer. We are creating tumor target-dependent CD137 agonists using a novel chemical approach based on fully synthetic constrained bicyclic peptide ( Bicycle® ) technology. Nectin-4 is overexpressed in multiple human cancers that may benefit from CD137 agonism. To this end, we have developed BT7480, a novel, first-in-class, Nectin-4/CD137 Bicycle tumor-targeted immune cell agonist™ ( Bicycle TICA™). Methods Nectin-4 and CD137 co-expression analyses in primary human cancer samples was performed. Chemical conjugation of two CD137 Bicycles to a Nectin-4 Bicycle led to BT7480, which was then evaluated using a suite of in vitro and in vivo assays to characterize its pharmacology and mechanism of action. Results Transcriptional profiling revealed that Nectin-4 and CD137 were co-expressed in a variety of human cancers with high unmet need and spatial proteomic imaging found CD137-expressing immune cells were deeply penetrant within the tumor near Nectin-4-expressing cancer cells. BT7480 binds potently, specifically, and simultaneously to Nectin-4 and CD137. In co-cultures of human peripheral blood mononuclear cells and tumor cells, this co-ligation causes robust Nectin-4-dependent CD137 agonism that is more potent than an anti-CD137 antibody agonist. Treatment of immunocompetent mice bearing Nectin-4-expressing tumors with BT7480 elicited a profound reprogramming of the tumor immune microenvironment including an early and rapid myeloid cell activation that precedes T cell infiltration and upregulation of cytotoxicity-related genes. BT7480 induces complete tumor regressions and resistance to tumor re-challenge. Importantly, antitumor activity is not dependent on continuous high drug levels in the plasma since a once weekly dosing cycle provides maximum antitumor activity despite minimal drug remaining in the plasma after day 2. BT7480 appears well tolerated in both rats and non-human primates at doses far greater than those expected to be clinically relevant, including absence of the hepatic toxicity observed with non-targeted CD137 agonists. Conclusion BT7480 is a highly potent Nectin-4-dependent CD137 agonist that produces complete regressions and antitumor immunity with only intermittent drug exposure in syngeneic mouse tumor models and is well tolerated in preclinical safety species. This work supports the clinical investigation of BT7480 for the treatment of cancer in humans.
TCT-259 The Impact of Stent Rotational Angle on Leaflet Thrombosis After Transcatheter Valve Replacement
Authors: Fateme Esmailie, Hoda Hatoum, Shelly Singh-Gryzbon, Sri Krishna Sivakumar, Sanchita Bhat, Philipp Ruile, Franz-Josef Neumann, Philipp Blanke, Vinod Thourani, Ajit Yoganathan
Journal: Journal of the American College of Cardiology (2021)
Adverse Cardiovascular and Pulmonary Events Associated With Chimeric Antigen Receptor T-Cell Therapy
Authors: Adam Goldman, Elad Maor, David Bomze, Jennifer E Liu, Joerg Herrmann, Joshua Fein, Richard M Steingart, Syed S Mahmood, Wendy L Schaffer, Miguel-Angel Perales, Roni Shouval
Journal: Journal of the American College of Cardiology (2021)
TCT-149 Risk Stratification in Acute Coronary Syndrome by Comprehensive Morphofunctional Assessment With Optical Coherence Tomography
Authors: Huihong Hong, Haibo Jia, Ming Zeng, Juan Luis Gutiérrez-Chico, Yini Wang, Xiaoling Zeng, Yuhan Qin, Chen Zhao, Miao Chu, Jiayue Huang, Lili Liu, Sining Hu, Luping He, Chen Lianglong, William Wijns, Bo Yu, Shengxian Tu
Journal: Journal of the American College of Cardiology (2021)
p21 ubiquitination by SCF-Skp2 and APC/C
Authors: Bipin Chandra Dash, Wafik S. El-Deiry
Journal: Cancer Research (2005)

5404  Progress through mitosis is controlled by the sequential destruction of key regulators including geminin, mitotic cyclins, Emi-I, securin, Plk-I, and Aurora kinases. One key to understanding the regulation of mitosis is to determine how the right protein is degraded at the right time. Here, we have described the destruction of p21 WAF1, which we found act as an activator following its phosphorylation by cyclinA-CdK2 at the S-G2 boundary. CyclinA-CDK2 phosphorylation of p21 changes the p21 protein into an assembly factor and an activator of cyclin B1-Cdc2 in G2/M progression. However, GSK3 phosphorylation at the Serine 27 and Serine 31 targets the p21 protein for its destruction by ubiquitination through Skp1-Cul1 and F-box protein Skp2. The presence of hyper-phosphorylated p21 protein stabilizes cyclin B1 and cyclin A complexes and delays exit from anaphase. p21 interacts with the APC/C complex, which degrades the F-box protein Skp2 at the mitotic/G1 phase. Thus, hyper-phosphorylated p21 gets degraded by GSK3-SCF, while hypo-phosphorylated p21 protein is degraded through APC/C CdhI.
TCT-269 Five-Year Outcomes After Valve-in-Valve Transcatheter Aortic Valve Replacement: Excellent Valve-Specific Outcomes but Poor Overall Survival
Authors: Andrew Vekstein, Krunal Amin, Sydney Record, Adam Williams, Ryan Plichta, Andrew Wang, Todd Kiefer, J. Kevin Harrison, Jeffrey G. Gaca, G. Chad Hughes
Journal: Journal of the American College of Cardiology (2021)
Practice patterns and outcomes of direct oral anticoagulant use in myeloproliferative neoplasm patients
Authors: Joan How, Charlotte Story, Siyang Ren, Donna Neuberg, Rachel P. Rosovsky, Gabriela S. Hobbs, Jean M. Connors
Journal: Blood Cancer Journal (2021)

Myeloproliferative neoplasms (MPNs) are characterized by an increased risk of thrombosis and bleeding. Vitamin K antagonists (VKAs) are the historic anticoagulant recommended for use in MPNs. Direct oral anticoagulants (DOACs) are being increasingly used in general and cancer populations. However, DOAC safety and efficacy in MPN patients remains unclear. We characterized real-world practice patterns of DOAC use in MPN patients and evaluated thrombosis and bleeding risk. We conducted a retrospective cohort study of 133 MPN patients prescribed DOACs for venous thromboembolism (VTE), atrial fibrillation, or arterial thromboembolism (ATE). Practice patterns including duration of anticoagulation, dosing, and concomitant use of antiplatelet/cytoreductive agents, were heterogeneous among MPN patients. The 1-year cumulative incidence of thrombosis and bleeding on DOAC was 5.5% (1.5-9.5%) and 12.3% (6.4-18.2%) respectively. In comparison, reported bleeding rates in MPN patients on DOAC and VKAs are 1-3%. On multivariable analysis, prior history of thrombosis, use of dabigatran or edoxaban, and younger age were significantly associated with a higher risk of recurrent thrombosis, while leukocytosis was associated with a higher risk of bleeding on DOAC. The higher-than-expected bleeding rate found in our study indicates the continued need for rigorous evaluation of DOACs in this population.
Micro-ultrasound imaging for bladder cancer in a murine model
Authors: Amit Patel, William Larchian, Warren Heston
Journal: Cancer Research (2008)

4534  A validated mouse model for superficial bladder cancer is warranted to enable preclinical studies on intravesical anticancer agents. We sought to improve upon our previously described orthotopic superficial bladder cancer mouse model with validation using in vivo ultrasound imaging.  Using the murine bladder tumor (MBT-2) cell line, 11 C3H/HeJ female mice were inoculated with 5 x 105 MBT-2 cells in 50 uL serum-free RPMI via transurethral catheterization without electrocautery. Using the VisualSonicsTM Vevo 770® ultrasound device, we performed transabdominal micro-ultrasound imaging 3, 6, and 15 days after tumor instillation. Imaging was also performed in all mice prior to tumor cell instillation. Tumors were measured using linear 2-dimensional measurements using sagittal and transverse imaging planes. Mouse bladders were subsequently harvested, formalin-fixed, embedded in paraffin, sectioned and stained with hematoxylin and eosin for confirmation of bladder tumors.  Superficial bladder tumors were evident on micro-ultrasound imaging starting on day 3 post-MBT-2 cell instillation in all mice. Multifocal tumors were seen in 27% of mice on day 3, 91% on day 6, and 100% on day 15. Average number of tumors found on days 3, 6, and 15 was 1.3, 2.4, and 3.5. Mean tumor size (max dimension of largest tumor) on days 3, 6, and 15 was 0.7mm, 1.1mm, 1.3mm. Histology sections on all mice confirmed presence of bladder tumors in all mice.  Using abdominal micro-ultrasound, we validate the presence of superficial bladder tumors in our MBT-2 mouse orthotopic bladder cancer model. Our model is reproducible and can be used to evaluate the efficacy of various intravesical anti-cancer agents. Tumors can be followed longitudinally for progression or regression with micro-ultrasound imaging.
TCT-384 Incidence, Treatment, and Outcomes of Coronary Artery Perforation During Percutaneous Coronary Intervention: Insights From the PROGRESS-COMPLICATIONS Registry
Authors: Vennela Avula, Judit Karacsonyi, Spyridon Kostantinis, Bavana Rangan, Alessandra Gutierrez, Emmanouil Brilakis, M. Nicholas Burke, Santiago Garcia, Michael Mooney, Paul Sorajja, Jay Traverse, Anil Poulose, Ivan Chavez, Yale Wang, Mario Goessl
Journal: Journal of the American College of Cardiology (2021)