tbuckley/cabot-search huggingface dataset:
Abstract 15: Imputing a more targeted therapy for triple-negative breast cancers
Authors: Robert F. Gruener, Geoffrey L. Greene, R. Stephanie Huang
Journal: Clinical Cancer Research (2020)

Abstract Triple-negative breast cancer (TNBC) is a clinically defined subset of breast cancers that are inherently difficult to treat since, unlike the other breast cancer subtypes, they are defined by their lack of a distinct molecular target. Previously our lab developed a computational framework to impute drug response in patients that accurately mirrored the observed patient response. In short, this methodology involves building unsupervised linear regression models between cell line baseline gene expression values and the respective drug sensitivity metric (EC50 or AUC), which allows us to generate imputed sensitivity scores for cell line or patient tumor samples for which we have gene expression data. For this study, we applied this methodology to prospectively identify agents that are predicted to be more effective specifically in triple-negative breast cancer. We began by expanding the drug imputation training dataset to the Broad’s Cell Therapeutics Response Portal, which contains 545 drugs and over 1,000 cancer cell lines (CCLs) and imputed sensitivity in The Cancer Genome Atlas’s (TCGA’s) breast cancer cohort. Our imputation data indicated that TNBC tumors were expected to be comparatively sensitive to cell cycle pathway inhibitors. Among these compounds, the Wee1 inhibitor MK1775 (aka adavosertib and AZD1775) was identified for having the most significant predicted effect in TNBC patients compared to the receptor-positive patients. We were able to validate the accuracy of the MK1775 imputation model using traditional cross-validation approaches as well as in independent cell line dataset and showed that the measured and our predicted response to Wee1 inhibition strongly correlated. Additionally, we were able to uses our predicted MK1775 response scores to recapitulate the significant association between MK1775 response and p53 mutation status. We then looked to validate the efficacy of MK1775’s efficacy in TNBC cell line and xenograft experiments. We observed strong inhibition of cancer growth by MK1775 alone but also identified a combination effect between MK1775 and the TNBC standard-of-care agent paclitaxel as assayed by both in vitro viability experiments as well as in vivo tumor growth assays. We believe these results indicate that this methodology could generally be applied as a hypothesis-generating tool for identifying targeted agents for other disease subtypes as well as supporting the use of MK1775, especially in combination with paclitaxel, for TNBC. Citation Format: Robert F. Gruener, Geoffrey L. Greene, R. Stephanie Huang. Imputing a more targeted therapy for triple-negative breast cancers [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 15.
Pharmacologic Prehabilitation—What About “the Polypill”?
Authors: Katherine M. Reitz, Christopher W. Seymour, Matthew D. Neal
Journal: JAMA Surgery (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Identification of whole blood gene expressions correlated with responsiveness to benralizumab
Authors: Masayuki Nakajima, Masashi Matsuyama, Naoki Arai, Hideyasu Yamada, Kentaro Hyodo, Mizu Nonaka, Haruna Kitazawa, Kazufumi Yoshida, Rie Shigemasa, Yuko Morishima, Takumi Kiwamoto, Hironori Masuko, Yukio Ishii, Masafumi Muratani, Takefumi Saito, Nobuyuki Hizawa
Journal: Journal of Allergy and Clinical Immunology (2020)
Heterogeneous Landscape of RUNX1 Related Disorder: Four Families with Inherited Thrombocytopenias and Novel Genetic Variants in RUNX1 Associated to Relevant Clinical Complications
Authors: Jose Maria Bastida, Rocio Benito, Jesus M Hernández-Sánchez, Maria L Lozano, Kamila Janusz, Eva Lumbreras, Alvaro Lassaletta, Susana Riesco, Jorge Huerta, Veronica Palma-Barqueros, Ana Hortal, Maria Díez-Campelo, Maria Isabel Prieto-Conde, Maria Carmen Chillon, Consuelo Del Cañizo, Jesús M Hernández-Rivas, Jose Rivera, Jose Ramon González-Porras
Journal: Blood (2017)
In-hospital use of ACEI/ARB is associated with lower risk of mortality and critic illness in COVID-19 patients with hypertension
Authors: Yuan Yuan, Dan Liu, Shaoqing Zeng, Siyuan Wang, Sen Xu, Ya Wang, Ruidi Yu, Yue Gao, Huayi Li, Xinxia Feng, Ning Zhou, Chunxia Zhao, Qinglei Gao
Journal: Journal of Infection (2020)
Refining our understanding of the “elephant in the room”
Authors: Andrew Whiten
Journal: Behavioral and Brain Sciences (2020)

Abstract The authors do the field of cultural evolution a service by exploring the role of non-social cognition in human cumulative technological culture, truly neglected in comparison with socio-cognitive abilities frequently assumed to be the primary drivers. Some specifics of their delineation of the critical factors are problematic, however. I highlight recent chimpanzee–human comparative findings that should help refine such analyses.
Clinical and laboratory evaluation of SARS-CoV-2 lateral flow assays for use in a national COVID-19 seroprevalence survey
Authors: Barnaby Flower, Jonathan C Brown, Bryony Simmons, Maya Moshe, Rebecca Frise, Rebecca Penn, Ruthiran Kugathasan, Claire Petersen, Anna Daunt, Deborah Ashby, Steven Riley, Christina Joanne Atchison, Graham P Taylor, Sutha Satkunarajah, Lenny Naar, Robert Klaber, Anjna Badhan, Carolina Rosadas, Maryam Khan, Natalia Fernandez, Macià Sureda-Vives, Hannah M Cheeseman, Jessica O'Hara, Gianluca Fontana, Scott J C Pallett, Michael Rayment, Rachael Jones, Luke S P Moore, Myra O McClure, Peter Cherepanov, Richard Tedder, Hutan Ashrafian, Robin Shattock, Helen Ward, Ara Darzi, Paul Elliot, Wendy S Barclay, Graham S Cooke
Journal: Thorax (2020)

Accurate antibody tests are essential to monitor the SARS-CoV-2 pandemic. Lateral flow immunoassays (LFIAs) can deliver testing at scale. However, reported performance varies, and sensitivity analyses have generally been conducted on serum from hospitalised patients. For use in community testing, evaluation of finger-prick self-tests, in non-hospitalised individuals, is required.Sensitivity analysis was conducted on 276 non-hospitalised participants. All had tested positive for SARS-CoV-2 by reverse transcription PCR and were ≥21 days from symptom onset. In phase I, we evaluated five LFIAs in clinic (with finger prick) and laboratory (with blood and sera) in comparison to (1) PCR-confirmed infection and (2) presence of SARS-CoV-2 antibodies on two 'in-house' ELISAs. Specificity analysis was performed on 500 prepandemic sera. In phase II, six additional LFIAs were assessed with serum.95% (95% CI 92.2% to 97.3%) of the infected cohort had detectable antibodies on at least one ELISA. LFIA sensitivity was variable, but significantly inferior to ELISA in 8 out of 11 assessed. Of LFIAs assessed in both clinic and laboratory, finger-prick self-test sensitivity varied from 21% to 92% versus PCR-confirmed cases and from 22% to 96% versus composite ELISA positives. Concordance between finger-prick and serum testing was at best moderate (kappa 0.56) and, at worst, slight (kappa 0.13). All LFIAs had high specificity (97.2%-99.8%).LFIA sensitivity and sample concordance is variable, highlighting the importance of evaluations in setting of intended use. This rigorous approach to LFIA evaluation identified a test with high specificity (98.6% (95%CI 97.1% to 99.4%)), moderate sensitivity (84.4% with finger prick (95% CI 70.5% to 93.5%)) and moderate concordance, suitable for seroprevalence surveys.
High-Sensitivity Cardiac Troponin Concentrations at Presentation in Patients With ST-Segment Elevation Myocardial Infarction
Authors: Ryan Wereski, Andrew R. Chapman, Kuan Ken Lee, Stephen W. Smith, David J. Lowe, Alasdair Gray, Nicholas L. Mills
Journal: JAMA Cardiology (2020)

This secondary analysis of a randomized clinical trial evaluates the testing of high-sensitivity cardiac troponin in clinical practice.
Recognition of Research Participants’ Need for Autonomy
Authors: Carrie D. Wolinetz, Francis S. Collins
Journal: JAMA (2020)

August 1, 2020, marked what would have been the 100th birthday of Henrietta Lacks, the Black woman whose cervical cancer cells gave rise to the immortal HeLa cell line.HeLa cells have played an extraordinary role in scientific research, underlying multiple Nobel Prize-winning discoveries and enabling medical advances for polio, cancer, Ebola virus disease, sickle cell disease, and countless other conditions.However, the bright biomedical legacy of HeLa cells is tarnished by the injustice of this biospecimen being preserved without the consent of Lacks or her family, whose identity was revealed decades ago. 1 This failure, while permitted by the ethical norms of the time, has affected the Lacks family in profound ways, including limiting the comfort, pride, and satisfaction that comes with knowing a deceased loved one made an important contribution to science.Today's current events provide an opportune time to reflect on the experiences of Lacks and other African Americans in the context of biomedical research, and to look ahead to what can be done to make that future far more just and equitable.In the wake of the killing of George Floyd and other similar events, the US may have reached an inflection point in challenging systemic racism and a long history of injustices against Black individuals.
Brainwide Genetic Sparse Cell Labeling to Illuminate the Morphology of Neurons and Glia with Cre-Dependent MORF Mice
Authors: Matthew B. Veldman, Chang Sin Park, Charles M. Eyermann, Jason Y. Zhang, Elizabeth Zuniga-Sanchez, Arlene A. Hirano, Tanya L. Daigle, Nicholas N. Foster, Muye Zhu, Peter Langfelder, Ivan A. Lopez, Nicholas C. Brecha, S. Lawrence Zipursky, Hongkui Zeng, Hong-Wei Dong, X. William Yang
Journal: Neuron (2020)
Continuous Glucose Monitoring and Use of Alternative Markers To Assess Glycemia in Chronic Kidney Disease
Authors: Leila R. Zelnick, Zona O. Batacchi, Iram Ahmad, Ashveena Dighe, Randie R. Little, Dace L. Trence, Irl B. Hirsch, Ian H. de Boer
Journal: Diabetes Care (2020)

OBJECTIVE In chronic kidney disease, glycated albumin and fructosamine have been postulated to be better biomarkers of glycemic control than HbA1c. We evaluated the accuracy, variability, and covariate bias of three biomarkers (HbA1c, glycated albumin, and fructosamine) compared with continuous glucose monitoring (CGM)–derived measurement of glycemia across estimated glomerular filtration rate (eGFR) in type 2 diabetes. RESEARCH DESIGN AND METHODS A prospective cohort study was conducted of 104 participants with type 2 diabetes, 80 with eGFR &amp;lt;60 mL/min/1.73 m2 (not treated with dialysis) and 24 frequency-matched control subjects with eGFR ≥60 mL/min/1.73 m2. Participants wore a blinded CGM for two 6-day periods separated by 2 weeks, with blood and urine collected at the end of each CGM period. HbA1c, glycated albumin, and fructosamine were measured by high-performance liquid chromatographic, enzymatic, and colorimetric nitroblue tetrazolium methods, respectively. RESULTS Within-person biomarker values were strongly correlated between the two CGM periods (r = 0.92–0.95), although no marker fully captured the within-person variability of mean CGM glucose. All markers were similarly correlated with mean CGM glucose (r = 0.71–77). Compared with mean CGM glucose, glycated albumin and fructosamine were significantly biased by age, BMI, serum iron concentration, transferrin saturation, and albuminuria; HbA1c was underestimated in those with albuminuria. CONCLUSIONS Glycated albumin and fructosamine were not less variable than HbA1c at a given mean CGM glucose level, with several additional sources of bias. These results support measuring HbA1c to monitor trends in glycemia among patients with eGFR &amp;lt;60 mL/min/1.73 m2. Direct measurements of glucose are necessary to capture short-term variability.
Reduced risk of mortality associated with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment and Registry (PSOLAR): A nested case-control analysis
Authors: Richard G. Langley, Yves Poulin, Bhaskar Srivastava, Kimberly Parnell Lafferty, Steven Fakharzadeh, Wayne Langholff, Matthias Augustin
Journal: Journal of the American Academy of Dermatology (2020)

The effects of systemic therapy on mortality risk among patients with psoriasis are not fully understood.To evaluate the impact of systemic treatment on mortality risk in patients enrolled in the Psoriasis Longitudinal Assessment and Registry.Nested case-control analyses were performed to estimate mortality risk. Cases were defined as patients who died while participating in the Psoriasis Longitudinal Assessment and Registry. Cases were matched (1:4) with controls by age, race, sex, and geographic region. Evaluated treatments included methotrexate, ustekinumab, and tumor necrosis factor α inhibitors. Exposure was defined as at least 1 dose of treatment within 3 months before death and was stratified by duration of therapy.Among 12,090 patients, 341 deaths occurred, matched to 1364 controls. Biologic treatment within the preceding 3 months was protective against mortality versus no exposure: odds ratio (OR) for exposure of less than 1 year, 0.08 (95% confidence interval [CI], 0.03-0.23); OR for exposure of 1 year or longer, 0.09 (95% CI, 0.06-0.13). Methotrexate was protective against mortality only with exposure for 1 year or longer (OR, 0.08; 95% CI, 0.02-0.28).Observational studies are subject to unmeasured confounding.Biologic therapy was associated with reduced mortality risk in patients with moderate to severe psoriasis, regardless of treatment duration; methotrexate reduced risk only with exposure for 1 year or longer.
Efficacy and Safety of Sacubitril/Valsartan by Dose Level Achieved in the PIONEER-HF Trial
Authors: David D. Berg, Eugene Braunwald, Adam D. DeVore, Anuradha Lala, Sean P. Pinney, Carol I. Duffy, Yared Gurmu, Eric J. Velazquez, David A. Morrow
Journal: JACC Heart Failure (2020)
Progression of Stage 2 and 3 Acute Kidney Injury in Patients With Decompensated Cirrhosis and Ascites
Authors: Florence Wong, K. Rajender Reddy, Puneeta Tandon, Jacqueline G. O’Leary, Guadalupe Garcia-Tsao, Hugo E. Vargas, Jennifer C. Lai, Scott W. Biggins, Benedict Maliakkal, Michael Fallon, Ram Subramanian, Paul Thuluvath, Patrick S. Kamath, Leroy Thacker, Jasmohan S. Bajaj
Journal: Clinical Gastroenterology and Hepatology (2020)
Abstract 20836: Prevalence of Fragmented QRS Complexes in Non-Ischemic Dilated Cardiomyopathy Patients and Long Term Prognosis
Authors: Subba Reddy Vanga, Scott Koerber, Luigi DiBiase, Atul Verma, Sudharani Bommana, Vijay Swarup, Andrea Natale, Buddhadeb Dawn, Dhanunjaya Lakkireddy
Journal: Circulation (2010)

Objectives: Fragmented QRS complexes (fQRS), which include various RSR' patterns without a typical bundle-branch block pattern, are thought to represent myocardial scarring. Presence of fQRS is ass...
Abstract IA23: ctDNA as predictive biomarkers for response and toxicity with immunotherapy
Authors: Lillian L. Siu
Journal: Clinical Cancer Research (2020)

Abstract Immune checkpoint blockade (ICB) with anti-PD1/PD-L1 antibodies provides clinical benefit to a subset of cancer patients. However, existing biomarkers do not reliably predict treatment response across diverse cancer types. Limited data exist to show how serial circulating tumor (ct)DNA testing may perform as a predictive biomarker in patients receiving immune checkpoint blockade. In an investigator-initiated phase II study of the anti-PD1 antibody pembrolizumab in patients with advanced solid tumors (INSPIRE; NCT02644369), we collected plasma samples at baseline and prior to every third cycle. These samples were retrospectively analyzed using a validated patient-specific, amplicon-based sequencing assay to detect and quantify ctDNA levels at each plasma time point. In total, 94 patients with serial ctDNA collections in five cohorts of solid tumors received single-agent pembrolizumab 200 mg IV ever 3 weeks. Levels of ctDNA at serial time points and the change from baseline were correlated with overall survival (OS), progression-free survival (PFS), objective response rate (ORR by RECIST v1.1), and clinical benefit rate (CBR, CR + PR + SD &amp;gt; 6 cycles). Response was measured by RECIST v1.1. Across the five cancer cohorts, median number of pembrolizumab cycles received was 3 and median follow-up was 13.8 months. Baseline ctDNA concentration correlated with multiple efficacy measures. This association became stronger across the cohorts when considering ctDNA kinetics after treatment initiation. An early reduction in ctDNA levels (at about 6-7 weeks) was strongly correlated with OS, PFS, ORR, and CBR. Sustained ctDNA clearance during treatment preceded durable clinical response. Strikingly, all 14 patients with ctDNA clearance during treatment were alive with a median of 27.5 months follow-up. These results demonstrate the potential for broad clinical utility of ctDNA-based surveillance in patients treated with ICB for advanced solid tumors of diverse histologies. Limited by the number of patients with grade 2 or higher immune-related adverse events (irAEs, 23/94 patients, 24%), no correlation was seen between irAE and cell-free DNA levels in the INSPIRE cohort. Currently we are planning interventional ICB studies using early ctDNA dynamics as predictive biomarkers. Citation Format: Lillian L. Siu. ctDNA as predictive biomarkers for response and toxicity with immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr IA23.
Disabled doctors are not getting the workplace adjustments they need, research finds
Authors: Abi Rimmer
Journal: BMJ (2020)

Disabled doctors and medical students are too afraid to discuss their disability at work for fear of prejudice, and only half have the workplace adjustments that they need, research by the BMA has found.

An online survey of disabled doctors and medical students, conducted by the BMA from November 2019 to January 2020, received 705 responses from around the UK.1

Over three quarters of respondents (77%) were worried about being treated unfavourably if they disclosed a disability or long term health condition. Only two in five (41%) said that telling their workplace or medical school had led to …
Outcomes of patients with end-stage kidney disease hospitalized with COVID-19
Authors: Jia H. Ng, Jamie S. Hirsch, Rimda Wanchoo, Mala Sachdeva, Vipulbhai Sakhiya, Susana Hong, Kenar D. Jhaveri, Steven Fishbane, Mersema Abate, Hugo Paz Andrade, Richard L. Barnett, Alessandro Bellucci, Madhu C. Bhaskaran, Antonio G. Corona, Bessy Suyin Flores Chang, Mark Finger, Steven Fishbane, Michael Gitman, Candice Halinski, Shamir Hasan, Azzour D. Hazzan, Susana Hong, Yuriy Khanin, Aireen Kuan, Varun Madireddy, Deepa Malieckal, Abdulrahman Muzib, Gayatri Nair, Jia Hwei Ng, Rushang Parikh, Daniel W. Ross, Vipulbhai Sakhiya, Mala Sachdeva, Richard Schwarz, Hitesh H. Shah, Purva Sharma, Pravin C. Singhal, Nupur N. Uppal, Rimda Wanchoo, Jamie S. Hirsch, Kenar D. Jhaveri, Vinay V. Nair
Journal: Kidney International (2020)
Mental Pain and Suffering: The “Universal Currencies” of the Illness Experience?
Authors: Tom Sensky
Journal: Psychotherapy and Psychosomatics (2020)

Fava et al. [1] have recently proposed mental pain as a transdiagnostic patient-reported outcome measure.A similar claim has been made for suffering [2].The main aims of this paper are: (a) to briefly outline the requirements of an optimal person-centred outcome measure; (b) to compare the features characteristic of mental pain and suffering; and (c) to consider mental pain and suffering as candidates for an optimal person-centred outcome measure.The conceptualisation and measurement of mental pain have been reviewed previously [1,3], and before comparing this with suffering, a brief review will be presented of the conceptualisation and measurement of suffering.
Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study
Authors: Emma Barron, Chirag Bakhai, Partha Kar, Andy Weaver, Dominique Bradley, Hassan Ismail, Peter Knighton, Naomi Holman, Kamlesh Khunti, Naveed Sattar, Nicholas J Wareham, Bob Young, Jonathan Valabhji
Journal: The Lancet Diabetes & Endocrinology (2020)