tbuckley/cabot-search huggingface dataset:
DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition
Authors: Elisa Izquierdo, Diana M. Carvalho, Alan Mackay, Sara Temelso, Jessica K.R. Boult, Giulia Pericoli, Elisabet Fernandez, Molina Das, Valeria Molinari, Yura Grabovska, Rebecca F. Rogers, Maria Antonietta Ajmone-Cat, Paula Z. Proszek, Mark Stubbs, Sarita Depani, Patricia O'Hare, Lu Yu, Georgia Roumelioti, Jyoti S. Choudhary, Matthew Clarke, Amy R. Fairchild, Thomas S. Jacques, Richard G. Grundy, Lisa Howell, Susan Picton, Jenny Adamski, Shaun Wilson, Juliet C. Gray, Bassel Zebian, Lynley V. Marshall, Fernando Carceller, Jacques Grill, Maria Vinci, Simon P. Robinson, Michael Hubank, Darren Hargrave, Chris Jones
Journal: Cancer Discovery (2021)

The survival of children with diffuse intrinsic pontine glioma (DIPG) remains dismal, with new treatments desperately needed. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling and drug screening in newly established patient-derived models in vitro and in vivo. We identified in vitro sensitivity to MEK inhibitors in DIPGs harboring MAPK pathway alterations, but treatment of patient-derived xenograft models and a patient at relapse failed to elicit a significant response. We generated trametinib-resistant clones in a BRAFG469V model through continuous drug exposure and identified acquired mutations in MEK1/2 with sustained pathway upregulation. These cells showed hallmarks of mesenchymal transition and expression signatures overlapping with inherently trametinib-insensitive patient-derived cells, predicting sensitivity to dasatinib. Combined trametinib and dasatinib showed highly synergistic effects in vitro and on ex vivo brain slices. We highlight the MAPK pathway as a therapeutic target in DIPG and show the importance of parallel resistance modeling and combinatorial treatments for meaningful clinical translation. We report alterations in the MAPK pathway in DIPGs to confer initial sensitivity to targeted MEK inhibition. We further identify for the first time the mechanism of resistance to single-agent targeted therapy in these tumors and suggest a novel combinatorial treatment strategy to overcome it in the clinic. This article is highlighted in the In This Issue feature, p. 587.
TCT-239 Efficacy and Safety of Short-Infusion Tirofiban in Patients Undergoing Percutaneous Coronary Intervention: The SAVI-PCI Trial
Authors: Jorge Saucedo, Matthew Price, Peter Berger, Mazen Abu-Fadel, Brian Jefferson, Michael Arcarese, Bill Matthai, Hector Picon, Varinder Singh, Wissam Jaber, B. Clay Sizemore, Joseph McGarvey, Kyle Brown, Albert Friesen, Steven Manoukian
Journal: Journal of the American College of Cardiology (2021)
Macrophage Regulation of the Development of Castration-Resistant Prostate Cancer
Authors: Haider Al-Janabi, Claire E. Lewis
Journal: Cancer Research (2021)

Abstract Androgen deprivation therapy (ADT) is the front-line treatment for early and metastatic prostate cancer, and the development of tumor resistance to it has major clinical consequences. Cancer cells start to proliferate and tumors begin to regrow, requiring the administration of more generic anticancer treatments like surgery, radiotherapy, and/or chemotherapy. Tumor-associated macrophages are known to drive tumor resistance to a number of anti-cancer therapies. El-Kenawi and colleagues now demonstrate a novel mechanism underpinning their ability to do so in prostate tumors during ADT. This involves the accumulation of cholesterol by macrophages in tumors and its transfer to cancer cells, where it acts as a precursor for androgen biosynthesis and results in the activation of androgen receptors. See related article by El-Kenawi and colleagues, p. 5477
Preparing anti-SARS-CoV-2 agent EIDD-2801 by a practical and scalable approach, and quick evaluation via machine learning
Authors: Zhen Qin, Bin Dong, Renbing Wang, Dechun Huang, Jubo Wang, Xi Feng, Jinlei Bian, Zhiyu Li
Journal: Acta Pharmaceutica Sinica B (2021)

EIDD-2801 is an orally bioavailable prodrug, which will be applied for emergency use authorization from the U.S. Food and Drug Administration for the treatment of COVID-19. To investigate the optimal parameters, EIDD-2801 was optimized
特発性肺線維症の診断基準:Fleischner社会白書【JST・京大機械翻訳】
Authors: Lynch David A, Sverzellati Nicola, Travis William D, Brown Kevin K, Colby Thomas, Galvin Jeffrey R, Goldin Jonathan G, Hansell David M, Inoue Yoshikazu, Johkoh Takeshi, Nicholson Andrew G, Knight Shandra L, Raoof Suhail, Richeldi Luca, Ryerson Christopher J, Ryu Jay H, Wells Athol U
Journal: The Lancet Respiratory Medicine (2018)
The impact of public health interventions in the Nordic countries during the first year of SARS-CoV-2 transmission and evolution
Authors: Sebastian Duchene, Leo Featherstone, Birgitte Freiesleben de Blasio, Edward C Holmes, Jon Bohlin, John H-O Pettersson
Journal: Eurosurveillance (2021)

BackgroundMany countries have attempted to mitigate and control COVID-19 through non-pharmaceutical interventions, particularly with the aim of reducing population movement and contact. However, it remains unclear how the different control strategies impacted the local phylodynamics of the causative SARS-CoV-2 virus.AimWe aimed to assess the duration of chains of virus transmission within individual countries and the extent to which countries exported viruses to their geographical neighbours.MethodsWe analysed complete SARS-CoV-2 genomes to infer the relative frequencies of virus importation and exportation, as well as virus transmission dynamics, in countries of northern Europe. We examined virus evolution and phylodynamics in Denmark, Finland, Iceland, Norway and Sweden during the first year of the COVID-19 pandemic.ResultsThe Nordic countries differed markedly in the invasiveness of control strategies, which we found reflected in transmission chain dynamics. For example, Sweden, which compared with the other Nordic countries relied more on recommendation-based rather than legislation-based mitigation interventions, had transmission chains that were more numerous and tended to have more cases. This trend increased over the first 8 months of 2020. Together with Denmark, Sweden was a net exporter of SARS-CoV-2. Norway and Finland implemented legislation-based interventions; their transmission chain dynamics were in stark contrast to their neighbouring country Sweden.ConclusionSweden constituted an epidemiological and evolutionary refugium that enabled the virus to maintain active transmission and spread to other geographical locations. Our analysis reveals the utility of genomic surveillance where monitoring of active transmission chains is a key metric.
Association of Sun-Protective Behaviors With Bone Mineral Density and Osteoporotic Bone Fractures in US Adults
Authors: Mohsen Afarideh, Julio C. Sartori-Valinotti, Megha M. Tollefson
Journal: JAMA Dermatology (2021)

Despite the reassuring emerging evidence on the lack of a causal relationship between sun protection and vitamin D deficiency, there is scarce data on whether multimodal sun protection is associated with reduced bone mineral density (BMD) and/or increased prevalence of osteoporotic bone fractures. This lack of data may lead to worry and decreased sun-protective behaviors on the part of patients.To investigate the association of sun-protective behaviors with BMD z scores and the prevalence of osteoporotic fractures.This population-based cross-sectional study included data from US adults who participated in the 2017 to 2018 cycle of the National Health and Nutrition Examination Survey (NHANES). Data were analyzed between September and November 2020.Definition of sun-protective behaviors (staying in the shade, wearing long sleeves, and sunscreen use), site-specific and total BMD, and osteoporotic fractures (hip, wrist, and spine) in the NHANES data.Data from 3418 adults 20 years and older (average age, 39.5 [95% CI, 38.6-40.4] years; 1612 [47.2%] men and 1806 [52.9%] women) who completed the NHANES dermatology questionnaire were included in this study. The prevalence of frequent staying in the shade, wearing of long sleeves, and sunscreen use were 31.6% (95% CI, 27.8%-35.7%), 11.8% (95% CI, 10.6%-13.1%), and 26.1% (95% CI, 23.5%-28.8%), respectively. The use of individual sun-protective behaviors was not associated with diminished site-specific and total BMD z scores in the multivariate models (estimate, -0.23 [95% CI, -0.47 to 0.02], P = .18; -0.08 [-0.27 to 0.12], P = .72; and -0.10 [-0.32 to 0.13], P = .15 for frequent staying in the shade, wearing of long sleeves, and sunscreen use, respectively). Moderate to frequent staying in the shade was associated with reduced prevalence of spine fractures in the multivariate model (odds ratio, 0.19 [95% CI, 0.04-0.86], P = 0.02).In this cross-sectional study, routine use of sun-protective behaviors among the US adult population was not associated with decreased BMD or increased risk of osteoporotic fracture. Sun protection may be associated with a modest decrease in the prevalence of osteoporotic fractures, possibly owing to risk-averse behaviors. These reassuring findings add to the growing body of evidence on the safety of sun protection, with no considerable negative association with bone health.
Fewer ESKD Dialysis Patients (pts) Reach Antibody (AB) Levels Consistent with Neutralizing Titers When Vaccinated with Ad26.COV2.S Compared with mRNA COVID-19 Vaccines
Authors: Jeffrey Mulhern, Amit Fadia, Ruchir S. Patel, Linda Ficociello, Joanna Willetts, Ines Dahne-Steuber, Claudy Mullon, Josephine Delisi, Curtis D. Johnson, Chance Mysayphonh, Robert J. Kossmann, Michael S. Anger, Jeffrey L. Hymes
Journal: Journal of the American Society of Nephrology (2021)

Background: The COVID-19 viral vector (VV) vaccine's single dose and routine storage requirements may be preferred to the mRNA-based vaccine's 2 doses and low temperature storage requirements. We report an interim analysis of a quality improvement project performed at 2 Arizona dialysis clinics comparing the AB response to VV vaccine with mRNA vaccine in ESKD pts. Methods: Pts received either the VV vaccine (Ad26.COV2.S) administered in the dialysis clinic or mRNA vaccines (BNT162b2, mRNA-1273) administered in the community. AB response was assessed with remnant blood and a semi-quantitative chemiluminescent assay for IgG directed against the receptor binding domain of the SARS-CoV-2 spike antigen. Values >7.0 Index produce plaque reduction neutralization test (PRNT50) titers greater than 1:80 dilution recommended by the FDA standard for measuring neutralizing titer. Results: AB response was evaluated at an average of 22 days post vaccination (≥14 days post Ad26.COV2.S or post 2nd mRNA vaccine). 36/45 pts (80%) who received the VV vaccine failed to develop an AB index >7 after ≥14 days post vaccine compared to 5/31 pts (16%) who received an mRNA vaccine (84% achieved AB index >7);all 5 pts had no prior COVID-19 history. Of pts receiving the VV vaccine with prior history of COVID-19, 22% of pts had AB index  7 in the recent sample and had previously been   7 from 2 to 5 (15%). AB levels remained unchanged in pts with a prior history of COVID-19 (n=9). No demographic or laboratory differences were observed. Conclusions: Our data support the contention that the available VV-based vaccine against the SARS-CoV-2 virus is not effective in producing AB response in most ESKD pts especially when compared to an mRNA counterpart. If AB indices predict immunity and other studies support our findings, alternative vaccination strategies in ESKD pts vaccinated with VV vaccines is needed.
TCT-133 New-Onset Atrial Fibrillation After Patent Foramen Ovale Closure in Patients Over the Age of 60
Authors: Hoang Nguyen, Benita Tjoe, Sri Mandava, Jessica Quintos, Ahmed Gul, Maha Gul, David Lerner, Michael Shenoda, Philip Delio, Joseph Aragon
Journal: Journal of the American College of Cardiology (2021)
Subcutaneous Teclistamab in Combination with Daratumumab for the Treatment of Patients with Relapsed/Refractory Multiple Myeloma: Results from a Phase 1b Multicohort Study
Authors: Paula Rodriguez-Otero, Bhagirathbhai Dholaria, Elham Askari, Donna E. Reece, Niels W.C.J. van de Donk, Ajai Chari, Hartmut Goldschmidt, Amrita Y. Krishnan, Thomas Martin, Maria-Victoria Mateos, Daniel Morillo Giles, Cesar Rodriguez, Laura Rosinol, Jesús F. San-Miguel, Anna Sureda, Ralph Wäsch, Katja Weisel, Raluca I. Verona, Shun Xin Wang Lin, Thomas J. Prior, Brendan M. Weiss, Mark Wade, Jenna D. Goldberg, Albert Oriol, Parameswaran Hari
Journal: Blood (2021)
Topography and Permeability Analyses of Vasculature‐on‐a‐Chip Using Scanning Probe Microscopies (Adv. Healthcare Mater. 21/2021)
Authors: Yuji Nashimoto, Minori Abe, Ryota Fujii, Noriko Taira, Hiroki Ida, Yasufumi Takahashi, Kosuke Ino, Javier Ramon‐Azcon, Hitoshi Shiku
Journal: Advanced Healthcare Materials (2021)

Microphysiological Systems In article number 2101186 by Yuji Nashimoto, Javier Ramon-Azcon, Hitoshi Shiku, and co-workers, endothelial functions (permeability and topography) in a microphysiological system (MPS) are electrochemically visualized using scanning probe microscopies. The analytical system is a new option to evaluate MPS or organ-on-a-chip which are promising tools for nextgeneration in vitro models.
Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection
Authors: Martina Patone, Lahiru Handunnetthi, Defne Saatci, Jiafeng Pan, Srinivasa Vittal Katikireddi, Saif Razvi, David Hunt, Xue W. Mei, Sharon Dixon, Francesco Zaccardi, Kamlesh Khunti, Peter Watkinson, Carol A. C. Coupland, James Doidge, David A. Harrison, Rommel Ravanan, Aziz Sheikh, Chris Robertson, Julia Hippisley-Cox
Journal: Nature Medicine (2021)

Abstract Emerging reports of rare neurological complications associated with COVID-19 infection and vaccinations are leading to regulatory, clinical and public health concerns. We undertook a self-controlled case series study to investigate hospital admissions from neurological complications in the 28 days after a first dose of ChAdOx1nCoV-19 ( n = 20,417,752) or BNT162b2 ( n = 12,134,782), and after a SARS-CoV-2-positive test ( n = 2,005,280). There was an increased risk of Guillain–Barré syndrome (incidence rate ratio (IRR), 2.90; 95% confidence interval (CI): 2.15–3.92 at 15–21 days after vaccination) and Bell’s palsy (IRR, 1.29; 95% CI: 1.08–1.56 at 15–21 days) with ChAdOx1nCoV-19. There was an increased risk of hemorrhagic stroke (IRR, 1.38; 95% CI: 1.12–1.71 at 15–21 days) with BNT162b2. An independent Scottish cohort provided further support for the association between ChAdOx1nCoV and Guillain–Barré syndrome (IRR, 2.32; 95% CI: 1.08–5.02 at 1–28 days). There was a substantially higher risk of all neurological outcomes in the 28 days after a positive SARS-CoV-2 test including Guillain–Barré syndrome (IRR, 5.25; 95% CI: 3.00–9.18). Overall, we estimated 38 excess cases of Guillain–Barré syndrome per 10 million people receiving ChAdOx1nCoV-19 and 145 excess cases per 10 million people after a positive SARS-CoV-2 test. In summary, although we find an increased risk of neurological complications in those who received COVID-19 vaccines, the risk of these complications is greater following a positive SARS-CoV-2 test.
The Frailty of Disability: A Controversial Triage Criterion
Authors: Joaquín Hortal-Carmona, Belén Liedo, Jon Rueda, Rosana Triviño-Caballero
Journal: The American Journal of Bioethics (2021)

Disability has been traditionally understood as a medical condition. However, people with disabilities have claimed in recent decades for a dephatologized social model of disability—i.e. the functi...
Simultaneous stent placement for biliary and afferent loop obstruction due to tumor recurrence after pancreatoduodenectomy
Authors: Tatsunori Satoh, Hirotoshi Ishiwatari, Kazuma Ishikawa, Hidenori Kimura, Hiroyuki Matsubayashi, Hiroyuki Ono
Journal: Endoscopy (2021)

After pancreaticoduodenectomy, patients experiencing tumor recurrence involving the Roux limb can suffer from afferent loop syndrome, cholangitis, and jaundice [1]. Placement of expandable metal stents at the site of enteral obstruction is considered a reasonable treatment option [2] [3] [4]. However, when the tumor recurs near the choledochojejunostomy, biliary and enteral stent placements would be required to decompress the dilated bile duct and afferent loop. Herein we report the first case of afferent loop syndrome with cholangitis and liver abscess treated by simultaneous metal stent placement using the stent-in-stent technique.
Multi-center validation of a lymph node metastasis gene-expression signature for head and neck squamous cell carcinomas
Authors: E.J.M. Speel, F.K.J. Leusink, S.R. van Hooff, J.A. Kummer, P.J. van Diest, R. Koole, P. Roepman, M.W.M. van den Brekel, T.A. Merkx, J.C. Jansen, E.M.D. Schuuring, R.H. Brakenhoff, R.J.B. de Jong, P.J. Slootweg, F.C.R. Holstege, R.P. Takes
Journal: Cancer Research (2011)
Daratumumab (DARA) with Bortezomib, Thalidomide, and Dexamethasone (VTd) in Transplant-Eligible Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM): Analysis of Minimal Residual Disease (MRD) Negativity in Cassiopeia Part 1 and Part 2
Authors: Herve Avet Loiseau, Pieter Sonneveld, Philippe Moreau, Fritz Offner, Vincent H.J. van der Velden, Denis Caillot, Cyrille Hulin, Bertrand Arnulf, Jill Corre, Mohamad Mohty, Lionel Karlin, Jérôme Lambert, Margaret Macro, Aurore Perrot, Mark-David Levin, Saskia K. Klein, Anne-Marie Stoppa, Michel Delforge, Sonja Zweegman, Kon-Siong Jie, Niels W.C.J. Van De Donk, Maria Krevvata, Fabio Rigat, Shiyi Yang, Veronique Vanquickelberghe, Carla de Boer, Tobias Kampfenkel, Jessica Vermeulen, Soraya Wuillème, Annemiek Broyl, Marie C Bene
Journal: Blood (2021)
Prognostic significance of acquired 1q22 gain in multiple myeloma
Authors: Hadiyah Y. Audil, Joselle M. Cook, Patricia T. Greipp, Prashant Kapoor, Linda B. Baughn, Angela Dispenzieri, Morie A. Gertz, Francis K. Buadi, Martha Q. Lacy, David Dingli, Amie L. Fonder, Suzanne R. Hayman, Miriam A. Hobbs, Eli Muchtar, Mustaqeem Siddiqui, Wilson I. Gonsalves, Yi Lisa Hwa, Nelson Leung, Yi Lin, Taxiarchis V. Kourelis, Rahma Warsame, Robert A. Kyle, Rhett P. Ketterling, S. Vincent Rajkumar, Shaji K. Kumar
Journal: American Journal of Hematology (2021)

Abstract Gain of 1q22 at diagnosis portends poorer outcomes in multiple myeloma (MM), but the prognostic significance of acquired 1q22 gain is unknown. We identified 63 MM patients seen at Mayo Clinic from 1/2004 to 12/2019 without 1q22 gain at diagnosis who acquired it during follow up and compared them to 63 control patients who did not acquire 1q22 gain with similar follow up. We also compared outcomes in the acquired 1q22 gain group with outcomes in 126 patients with 1q22 gain present at diagnosis. The incidence of acquired 1q22 gain was 6.1% (median follow‐up 6.8 years); median time to acquisition was 5.0 years (range: 0.7–11.5 years). Abnormalities on baseline fluorescence in situ hybridization (FISH) included trisomies (54%) and monosomy 13 (39%); 16 (25%) had high‐risk (HR) translocations or del(17p). Median progression‐free survival with front line therapy was 29.5 months in patients with acquired 1q22 gain, versus 31.4 months in control patients ( p = .34) and 31.2 months in patients with de novo 1q22 gain ( p = .04). Median overall survival (OS) from diagnosis was 10.9 years in patients with acquired 1q22 gain, versus 13.0 years in control patients ( p = .03) and 6.3 years in patients with de novo 1q22 gain ( p = .01). Presence of HR FISH at baseline increased risk of 1q22 gain acquisition. We demonstrate that acquisition of 1q22 gain is a significant molecular event in MM, associated with reduced OS. Among HR patients for whom this clonal evolution is determined, a risk‐adapted approach and/or clinical trial should be considered.
Mesothelioma among vehicle mechanics: a controversy?
Authors: Patrick A Hessel
Journal: Thorax (2021)

The paper by Thomsen et al 1 is a significant contribution to the now-substantial body of literature on the relationship between asbestos-related diseases and vehicle repair work. It is a large study, inclusive of all registered vehicle mechanics in the country for the designated years, with a mean follow-up time of 20 years and a maximum of 45 years. Several comprehensive administrative databases were linked for exposure and disease outcomes. The numbers of outcomes for the three main diseases of interest produced relatively narrow CIs.

The authors present data indicating that reliance on administrative databases for health outcomes was unlikely to be a problem for mesothelioma and lung cancer; however, it is reasonable to question the validity of the diagnoses of asbestosis based on administrative data alone. As the authors point out, the statistically significant elevation in asbestosis mortality and morbidity is somewhat puzzling given the relatively high exposures required for asbestosis and the relatively low asbestos exposures experienced by vehicle mechanics. The existing literature does not support a positive relationship between asbestosis and vehicle repair work.2–5 The authors suggested that diagnostic bias may have played a role, but this is speculative.

The result warrants further examination, possibly a nested case–control study with documentation of the diagnostic criteria supporting the database entries, blinded re-evaluation of the available diagnostic material, and further exploration of complete occupational histories.

The investigators observed a slight elevation in lung cancer risk. The results are consistent with those from an earlier meta-analysis6 and are unremarkable.

Studies of potential asbestos-related diseases among vehicle mechanics have focused primarily on risk of …
TCT-337 Multicenter Propensity-Matched Comparison of Latest-Generation Self-Expanding and Balloon-Expandable Transcatheter Heart Valves
Authors: Won-Keun Kim, Tobias Rheude, Alexander Wolf, Oliver Dörr, Holger Nef, Christian Hamm, Michael Joner, Costanza Pellegrini
Journal: Journal of the American College of Cardiology (2021)
TCT-470 Incidence and Clinical Characteristics of Stroke in Patients Presenting With STEMI: Insights From the Midwest STEMI Consortium
Authors: Michael Megaly, Edward Tannenbaum, Brynn Okeson, Marshall Dworak, Ross Garberich, Scott Sharkey, Mark Tannenbaum, Timothy Smith, Timothy Henry, Santiago Garcia
Journal: Journal of the American College of Cardiology (2021)