tbuckley/cabot-search huggingface dataset:
Multiomic Profiling of Central Nervous System Leukemia Identifies mRNA Translation as a Therapeutic Target
Authors: Robert J. Vanner, Stephanie M. Dobson, Olga I. Gan, Jessica McLeod, Erwin M. Schoof, Ildiko Grandal, Jeff A. Wintersinger, Laura Garcia-Prat, Mohsen Hosseini, Stephanie Z. Xie, Liqing Jin, Nathan Mbong, Veronique Voisin, Michelle Chan-Seng-Yue, James A. Kennedy, Esmé Waanders, Quaid Morris, Bo Porse, Steven M. Chan, Cynthia J. Guidos, Jayne S. Danska, Mark D. Minden, Charles G. Mullighan, John E. Dick
Journal: Blood Cancer Discovery (2021)

Abstract Central nervous system (CNS) dissemination of B-precursor acute lymphoblastic leukemia (B-ALL) has poor prognosis and remains a therapeutic challenge. Here we performed targeted DNA sequencing as well as transcriptional and proteomic profiling of paired leukemia-infiltrating cells in the bone marrow (BM) and CNS of xenografts. Genes governing mRNA translation were upregulated in CNS leukemia, and subclonal genetic profiling confirmed this in both BM-concordant and BM-discordant CNS mutational populations. CNS leukemia cells were exquisitely sensitive to the translation inhibitor omacetaxine mepesuccinate, which reduced xenograft leptomeningeal disease burden. Proteomics demonstrated greater abundance of secreted proteins in CNS-infiltrating cells, including complement component 3 (C3), and drug targeting of C3 influenced CNS disease in xenografts. CNS-infiltrating cells also exhibited selection for stemness traits and metabolic reprogramming. Overall, our study identifies targeting of mRNA translation as a potential therapeutic approach for B-ALL leptomeningeal disease. Significance: Cancer metastases are often driven by distinct subclones with unique biological properties. Here we show that in B-ALL CNS disease, the leptomeningeal environment selects for cells with unique functional dependencies. Pharmacologic inhibition of mRNA translation signaling treats CNS disease and offers a new therapeutic approach for this condition. This article is highlighted in the In This Issue feature, p. 1
P31.02 Impact of COVID-19 Pandemic in Spanish and Portuguese Lung Cancer Patients
Authors: A. Araujo, A. Mendes, R. Pinheiro, V. Calvo, N. Núñez, D. Corbacho, A. Figueiredo, H. Magalhães, P. Fidalgo, C. Benito, B. Balea, S. Azevedo, A. Vaz, S. Vázquez-Estévez, F. Estevinho, M. Quintela, F. Barata, M. Provencio
Journal: Journal of Thoracic Oncology (2021)
The effects of exercise training on antitumor efficacy of doxorubicin in MDA-MB-231 breast cancer xenografts
Authors: Lee W. Jones, Neil Eves, Kerry S. Courneya, Brian Chiu, Vickie E. Baracos, Hanson John, John Mackey
Journal: Cancer Research (2005)

1092  In recent years a growing number of reports have examined the role of exercise as a supportive intervention for cancer patients during adjuvant chemotherapy. All studies to date have focused exclusively on the ability of exercise to improve physical functioning or help patients cope with side-effects of treatment in order to improve quality of life. However, a critical and previously unexplored question is whether exercise training influences the efficacy of chemotherapy. To address this question, MDA-MB-231 breast carcinoma cells (5 X 106) were subcutaneously injected into the right flank of female athymic mice (age 3-4 weeks). Following tumor establishment (14 days), mice were stratified by tumor volume and randomly assigned to one of four groups (n=21 per group): (i) control (CO), (ii) exercise only (EX), (iii) chemotherapy only (CT), or (iv) exercise + chemotherapy (EX+CT). Doxorubicin was administered through weekly intravenous lateral tail vein injections at 4mg/kg for 8 weeks. Exercise groups performed progressive treadmill running up to 18m/min at 0% grade for 45mins, 5 days/wk for 8 weeks. Mice were sacrificed when tumor volume reached 1100mm3 as required by institutional guidelines or 48 hours following the final exercise training session. Tumor volume was measured twice weekly. The primary endpoint was tumor growth delay, calculated as the median number of days for tumor burden to reach 1100mm3. Survival times were compared using the log-rank test and all tests were two-sided. Median tumor growth delay was significantly longer in the CT and EX+CT groups compared with the CO (42 days vs. 25 days, RR 0.38, p=0.0084; 36 days vs. 25 days, RR 0.46, p=0.029, respectively) and EX groups (42 days vs. 25 days, RR 0.45, p=0.029; 36 days vs. 25 days, RR 0.54, p=0.080, respectively). There was no significant difference between CT and EX+CT groups (42 days vs. 36 days, RR 1.44, p=0.33). At 56 days, Kaplan-Meier estimates indicated a 35% (95% CI=17% to 54%) survival rate for the CT mice compared with 20% (95% CI=7% to 33 %) in the EX+CT group, 16% (95% CI=2% to 31%) in the EX group and 0% in the CO group. This data suggests that moderate intensity endurance exercise does not significantly influence doxorubicin-induced tumor growth delay in athymic mice implanted with breast carcinoma cell line MDA-MB 231. However, the trend for longer survival with doxorubicin only, suggests that exercise training during chemotherapy may inhibit the efficacy of this therapy. Future studies are underway to explore mechanisms of this potential interaction. This study was supported by a grant from the United States Department of Defense Breast Cancer Research Program - Concept Award.
P70.08 Allelic Frequencies of Population Markers Correlate with KRAS G12C Prevalence: Considerations for Ancestries and Molecular Epidemiology
Authors: A. Ruiz-Patiño, J.K. Rodriguez, J. Avila Coy, P. Archila, A. Cardona Zorrilla, C. Sotelo, H. Carranza, C. Vargas, J. Otero, M. Bermudez, T. Gamez, O. Arrieta, L Zatarain Barron, L.L. Rojas Puentes, L. Corrales, C. Martin, J.E. Garcia-Robledo, N.D. Santoyo Sarmiento, C. Rolfo, R. Rosell
Journal: Journal of Thoracic Oncology (2021)
Variations in Quality of Care by Sex and Social Determinants of Health Among Younger Adults With Acute Myocardial Infarction in the US and Canada
Authors: Valeria Raparelli, Louise Pilote, Brian Dang, Hassan Behlouli, James D. Dziura, Hector Bueno, Gail D’Onofrio, Harlan M. Krumholz, Rachel P. Dreyer
Journal: JAMA Network Open (2021)

Quality of care of young adults with acute myocardial infarction (AMI) may depend on health care systems in addition to individual-level factors such as biological sex and social determinants of health (SDOH).To examine whether the quality of in-hospital and postacute care among young adults with AMI differs between the US and Canada and whether female sex and adverse SDOH are associated with a low quality of care.This retrospective cohort analysis used data from 2 large cohorts of young adults (aged ≤55 years) receiving in-hospital and outpatient care for AMI at 127 centers in the US and Canada. Data were collected from August 21, 2008, to April 30, 2013, and analyzed from July 12, 2019, to March 10, 2021.Sex, SDOH, and health care system.Opportunity-based quality-of-care score (QCS), determined by dividing the total number of quality indicators of care received by the total number for which the patient was eligible, with low quality of care defined as the lowest tertile of the QCS.A total of 4048 adults with AMI (2345 women [57.9%]; median age, 49 [interquartile range, 44-52] years; 3004 [74.2%] in the US) were included in the analysis. Of 3416 patients with in-hospital QCS available, 1061 (31.1%) received a low QCS, including more women compared with men (725 of 2007 [36.1%] vs 336 of 1409 [23.8%]; P < .001) and more patients treated in the US vs Canada (962 of 2646 [36.4%] vs 99 of 770 [12.9%]; P < .001). Conversely, low quality of post-AMI care (748 of 2938 [25.5%]) was similarly observed for both sexes, with a higher prevalence in the US (678 of 2346 [28.9%] vs 70 of 592 [11.8%]). In adjusted analyses, female sex was not associated with low QCS for in-hospital (odds ratio [OR], 1.05; 95% CI, 0.87-1.28) and post-AMI (OR, 1.07; 95% CI, 0.88-1.30) care. Conversely, being treated in the US was associated with low in-hospital (OR, 2.93; 95% CI, 2.16-3.99) and post-AMI (OR, 2.67; 95% CI, 1.97-3.63) QCS, regardless of sex. Of all SDOH, only employment was associated with higher quality of in-hospital care (OR, 0.72; 95% CI, 0.59-0.88). Finally, only in the US, low quality of in-hospital care was associated with a higher 1-year cardiac readmissions rate (234 of 962 [24.3%]).These findings suggest that beyond sex, health care systems and SDOH that depict social vulnerability are associated with quality of AMI care. Taking into account SDOH among young adults with AMI may improve quality of care and reduce readmissions, especially in the US.
Automated dander dispersal in a cat Naturalistic Exposure Chamber (NEC)
Authors: Laura Kilford Haya, Rym Mehri, Shawn Somers‐Neal, Stefan Van de Mosselaer, Ashley Spence, Suzanne Marie Kelly, Edgar Akio Matida, William H. Yang
Journal: Allergy (2021)

Laura Haya is an employee of Red Maple Trials, Inc. Rym Mehri and Shawn Somers-Neal received grant contributions from Mitacs and Red Maple Trials, Inc. Stefan Van de Mosselaer and Ashley Spence are employees of Red Maple Trials, Inc, and Red Maple Trials received wage subsidies for their positions through the Biotalent Student Work Placement Program. Suzanne Kelly is a stockholder and employee of Red Maple Trials, Inc. Edgar Matida was the academic supervisor for Rym Mehri and Shawn Somers-Neal. William H. Yang is a stockholder and employee of Red Maple Trials, Inc. He has received consultant and speaker fees from CSL Behring, Shire/Takeda, Novartis, Sanofi, Merck. Also, he has received research grants from CSL Behring, Shire/Takeda, BioCryst, Pharvaris, Sanofi, Regeneron, GSK, AstraZeneca, Amgen, Genentec/Roche, Pfizer, ALK, Stallergenes, Providence, Galderma, Glenmark, Dermira/Eli Lilly, AnaptysBio, Celgene, Johnson & Johnson, and Pharming. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Fatal enhanced respiratory syncytial virus disease in toddlers
Authors: Fernando P. Polack, Damián Alvarez-Paggi, Romina Libster, Mauricio T. Caballero, Robert V. Blair, Diego R. Hijano, Paola X. de la Iglesia Niveyro, Daniel R. Menendez, Wes Gladwell, Luis M. Avendano, Luis Velozo, Alanna Wanek, Eduardo Bergel, Gregory A. Prince, Steven R. Kleeberger, Joyce Johnson, Derek Pociask, Jay K. Kolls
Journal: Science Translational Medicine (2021)

In 1967, two toddlers immunized with a formalin-inactivated vaccine against respiratory syncytial virus (FIRSV) in the United States died from enhanced RSV disease (ERD), a severe form of illness resulting from aberrant priming of the antiviral immune response during vaccination. Up to 80% of immunized children subsequently exposed to wild-type virus were hospitalized. These events hampered RSV vaccine development for decades. Here, we provide a characterization of the clinical, immunopathological, and transcriptional signature of fatal human ERD, outlining evidence for safety evaluation of RSV vaccines and a framework for understanding disease enhancement for pathogens in general.
Improving Longitudinal Outcomes, Efficiency, and Equity in the Care of Patients With Congenital Heart Disease
Authors: Brett R. Anderson, Kacie Dragan, Sarah Crook, Joyce L. Woo, Stephen Cook, Edward L. Hannan, Jane W. Newburger, Marshall Jacobs, Emile A. Bacha, Robert Vincent, Khanh Nguyen, Kathleen Walsh-Spoonhower, Ralph Mosca, Neil Devejian, Steven A. Kamenir, George M. Alfieris, Michael F. Swartz, David Meyer, Erin A. Paul, John Billings
Journal: Journal of the American College of Cardiology (2021)
Rate of Pediatrician Recommendations for Behavioral Treatment for Preschoolers With Attention-Deficit/Hyperactivity Disorder Diagnosis or Related Symptoms
Authors: Yair Bannett, Rebecca M. Gardner, Jose Posada, Lynne C. Huffman, Heidi M. Feldman
Journal: JAMA Pediatrics (2021)

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
Effects of sequence motifs in the yeast 3′ untranslated region determined from massively parallel assays of random sequences
Authors: Andrew Savinov, Benjamin M. Brandsen, Brooke E. Angell, Josh T. Cuperus, Stanley Fields
Journal: Genome biology (2021)

Abstract Background The 3′ untranslated region (UTR) plays critical roles in determining the level of gene expression through effects on activities such as mRNA stability and translation. Functional elements within this region have largely been identified through analyses of native genes, which contain multiple co-evolved sequence features. Results To explore the effects of 3′ UTR sequence elements outside of native sequence contexts, we analyze hundreds of thousands of random 50-mers inserted into the 3′ UTR of a reporter gene in the yeast Saccharomyces cerevisiae . We determine relative protein expression levels from the fitness of transformants in a growth selection. We find that the consensus 3′ UTR efficiency element significantly boosts expression, independent of sequence context; on the other hand, the consensus positioning element has only a small effect on expression. Some sequence motifs that are binding sites for Puf proteins substantially increase expression in the library, despite these proteins generally being associated with post-transcriptional downregulation of native mRNAs. Our measurements also allow a systematic examination of the effects of point mutations within efficiency element motifs across diverse sequence backgrounds. These mutational scans reveal the relative in vivo importance of individual bases in the efficiency element, which likely reflects their roles in binding the Hrp1 protein involved in cleavage and polyadenylation. Conclusions The regulatory effects of some 3′ UTR sequence features, like the efficiency element, are consistent regardless of sequence context. In contrast, the consequences of other 3′ UTR features appear to be strongly dependent on their evolved context within native genes.
MA02.06 Phase 1b Study of Pelcitoclax (APG-1252) in Combination With Osimertinib in Patients With EGFR TKI-Resistant NSCLC
Authors: L. Zhang, H. Zhao, Y. Ma, Y. Cheng, Y. Zhao, J. Cui, C. Yang, J. Zhang, P. Wang, L. Xu, J. Yu, L. Men, E. Liang, D. Yang, Y. Zhai
Journal: Journal of Thoracic Oncology (2021)
The effect of cisplatin adducts on double strand break repair by non-homologous end joining
Authors: Christine P. Diggle, Johanne Bentley, Margaret A. Knowles, Anne E. Kiltie
Journal: Cancer Research (2004)

2664  Chemoradiation is the combined treatment of patients with chemotherapy agents, such as cisplatin, and radiotherapy. It is now the standard treatment in several cancer types, and the subject of clinical trials in others. Radiotherapy treatment alone causes many types of DNA damage, the most lethal is the double strand break (DSB). If not repaired a single DSB can produce cellular death. The presence of a cisplatin adduct close to a DSB could physically hinder the cisplatin removal and repair by the nucleotide excision repair pathway, or the cisplatin adduct could hinder the DSB repair pathways. Repair of DSBs can occur via several pathways, one of which is the non-homologous end joining (NHEJ) pathway. In the basic NHEJ pathway a Ku heterodimer binds to the free ends of the broken DNA. DNA-PKcs is then recruited to the Ku heterodimer to form the DNA-PK holoenzyme. The Ku heterodimer translocates along the DNA strand as the DNA passes through its ring-like shape. The DNA-PK holoenzyme has kinase activity, which may be important in phosphorylating proteins in this pathway. Finally, XRCC4 stimulates DNA ligase IV to join the broken ends. Previous work has shown that cisplatinated DNA may decrease the rate of multiple exogenous Ku heterodimers translocating along the DNA strand and lowers the DNA-PK kinase activity. The objective of the present work was to examine the effect cisplatin adduct formation has on NHEJ proficiency in a more physiological environment, using cellular extracts and much larger DNA fragments of 3 kb in size. Double strand breaks were created by restriction enzyme digestion of plasmid DNA. This linearised DNA was treated with cisplatin and incubated with cellular extracts that have NHEJ activity. The presence of cisplatin dramatically reduced the level of NHEJ in a cisplatin dose dependent manner. As the cisplatin molecule interacts with the G bases of the DNA, we designed a new DNA substrate, where surrounding the restriction enzyme site there were minimal G bases for 25 base pairs. A second substrate was produced which in addition had a single GTG motif 10 bases from the DSB. A cisplatin adduct binding to this sequence produces an intra strand cisplatin adduct which can distort the local DNA structure. The DNA from the two new substrates was linearised with restriction enzyme, treated with cisplatin and subject to NHEJ. Once again a dose dependent effect was seen in the ability of cisplatin treated DNA to perform NHEJ. However, the presence of a GTG adduct had relatively little effect on NHEJ. To conclude, we have shown that the ability to perform NHEJ in a physiological environment was reduced if the DNA was cisplatinated. However the presence of a single additional adduct had minimal impact on NHEJ levels.
P59.21 Impact of Reflex Testing on Pathology Based Molecular Testing in Patients With Advanced Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
Authors: M. Marmarelis, A. Berman, D. Scholes, J. Thompson, A. Doucette, P. Gabriel, J. Bauml, A. Singh, R. Cohen, L. Litzky, C. Mcgrath, M. Feldman, C. Langer, E. Carpenter, C. Aggarwal
Journal: Journal of Thoracic Oncology (2021)
Analysis of Suicide After Cancer Diagnosis by US County-Level Income and Rural vs Urban Designation, 2000-2016
Authors: Ryan Suk, Young-Rock Hong, Rachel M. Wasserman, J. Michael Swint, N. Belinda Azenui, Kalyani B. Sonawane, Alexander C. Tsai, Ashish A. Deshmukh
Journal: JAMA Network Open (2021)

Studies suggest the risk of suicide among people with cancer diagnosis is higher compared with the general population. However, little is known about how suicide risk among people diagnosed with cancer might vary according to area-level income and rurality.To examine whether the risks and patterns of suicide mortality among people with a cancer diagnosis differ by US county-level median income and rural or urban status.A retrospective, population-based cohort study following up individuals who were diagnosed with cancer between January 1, 2000, and December 31, 2016, was conducted. The Surveillance, Epidemiology, and End Results Program 18 registries (SEER 18) database was used to obtain data on persons diagnosed with a first primary malignant tumor. Comparisons with the general US population were based on mortality data collected by the National Center for Health Statistics. Analyses were conducted from February 22 to October 14, 2020.County-level median household income and urban or rural status.Standardized mortality ratios (SMRs) of suicide deaths and annual percentage changes (APCs) of SMRs.The SEER 18 database included 5 362 782 persons with cancer diagnoses living in 635 counties. Most study participants were men (51.2%), White (72.2%), and older than 65 years (49.7%). Among them, 6357 persons died of suicide (SMR, 1.41; 95% CI, 1.38-1.44). People with cancer living in the lowest-income counties had a significantly higher risk (SMR, 1.94; 95% CI, 1.76-2.13) than those in the highest-income counties (SMR, 1.30; 95% CI, 1.26-1.34). Those living in rural counties also had significantly higher SMR than those in urban counties (SMR, 1.81; 95% CI, 1.70-1.92 vs SMR, 1.35; 95% CI, 1.32-1.39). For all county groups, the SMRs were the highest within the first year following cancer diagnosis. However, among people living in the lowest-income counties, the risk remained significantly high even after 10 or more years following cancer diagnosis (SMR, 1.83; 95% CI, 1.31-2.48). The comparative risk of suicide mortality within 1 year following cancer diagnosis significantly decreased over the years but then plateaued in the highest-income (2005-2015: APC, 2.03%; 95% CI, -0.97% to 5.13%), lowest-income (2010-2015: APC, 4.80%; 95% CI, -19.97% to 37.24%), and rural (2004-2015: APC, 1.83; 95% CI, -1.98% to 5.79%) counties.This cohort study showed disparities in suicide risks and their patterns among people diagnosed with cancer by county-level income and rural or urban status. The findings suggest that additional research and effort to provide psychological services addressing these disparities among people with cancer may be beneficial.
Interoception of breathing and its relationship with anxiety
Authors: Olivia K. Harrison, Laura Köchli, Stephanie Marino, Roger Luechinger, Franciszek Hennel, Katja Brand, Alexander J. Hess, Stefan Frässle, Sandra Iglesias, Fabien Vinckier, Frederike H. Petzschner, Samuel J. Harrison, Klaas E. Stephan
Journal: Neuron (2021)

Interoception, the perception of internal bodily states, is thought to be inextricably linked to affective qualities such as anxiety. Although interoception spans sensory to metacognitive processing, it is not clear whether anxiety is differentially related to these processing levels. Here we investigated this question in the domain of breathing, using computational modeling and high-field (7 T) fMRI to assess brain activity relating to dynamic changes in inspiratory resistance of varying predictability. Notably, the anterior insula was associated with both breathing-related prediction certainty and prediction errors, suggesting an important role in representing and updating models of the body. Individuals with low versus moderate anxiety traits showed differential anterior insula activity for prediction certainty. Multi-modal analyses of data from fMRI, computational assessments of breathing-related metacognition, and questionnaires demonstrated that anxiety-interoception links span all levels from perceptual sensitivity to metacognition, with strong effects seen at higher levels of interoceptive processes.
MA15.02 Association of Healthcare System Resources With Lung Cancer Screening Utilization
Authors: J. Lewis, L. Samuels, J. Denton, M. Matheny, A. Maiga, C. Slatore, E. Grogan, J. Kim, R. Sherrier, R. Dittus, P. Massion, L. Keohane, C. Roumie, S. Nikpay
Journal: Journal of Thoracic Oncology (2021)
P45.11 Co-occurring CDKN2A/B Alteration Is Associated With Worse Survival Outcomes in Advanced ALK-Positive Non-Small Cell Lung Cancer
Authors: L. Lara-Mejía, D. Heredia, N. Hernández-Pedro, E. Varela-Santoyo, G. Cruz-Rico, A. Cardona Zorrilla, L. Cabrera Miranda, M. Ramos, F. Barrón, O. Arrieta
Journal: Journal of Thoracic Oncology (2021)
Decompensation in Advanced Nonalcoholic Fatty Liver Disease May Occur at Lower Hepatic Venous Pressure Gradient Levels Than in Patients With Viral Disease
Authors: Octavi Bassegoda, Pol Olivas, Laura Turco, Mattias Mandorfer, Miquel Serra-Burriel, Luis Tellez, Wilhelmus Kwanten, Alexia Laroyenne, Oana Farcau, Edilmar Alvarado, Lucile Moga, Elise Vuille-Lessard, Jose Ignacio Fortea, Luis Ibañez, Giulia Tosetti, Thomas Vanwolleghem, Hélène Larrue, Diego Burgos-Santamaría, Horia Stefanescu, Rafael Paternostro, Annalisa Cippitelli, Sabela Lens, Salvador Augustin, Elba Llop, Wim Laleman, Jonel Trebicka, Johannes Chang, Helena Masnou, Alexander Zipprich, Francesca Miceli, Georg Semmler, Xavier Forns, Massimo Primignani, Rafael Bañares, Angela Puente, Annalisa Berzigotti, Pierre Emmanuel Rautou, Candid Villanueva, Pere Ginès, J.C. Garcia-Pagan, Bogdan Procopet, Cristophe Bureau, Agustin Albillos, Sven Francque, Thomas Reiberger, Filippo Schepis, Isabel Graupera, Virginia Hernandez-Gea
Journal: Clinical Gastroenterology and Hepatology (2021)