tbuckley/cabot-search huggingface dataset:
Long-Term Survival After Surgical or Percutaneous Revascularization in Patients With Diabetes and Multivessel Coronary Disease
Authors: Derrick Y. Tam, Christoffer Dharma, Rodolfo Rocha, Michael E. Farkouh, Husam Abdel-Qadir, Louise Y. Sun, Harindra C. Wijeysundera, Peter C. Austin, Jacob A. Udell, Mario Gaudino, Stephen E. Fremes, Douglas S. Lee
Journal: Journal of the American College of Cardiology (2020)

There remains a paucity of real-world observational evidence comparing percutaneous coronary intervention (PCI) with coronary artery bypass grafting (CABG) in patients with diabetes and multivessel coronary artery disease (CAD). This study compared early and long-term outcomes of PCI versus CABG in patients with diabetes. Clinical and administrative databases in Ontario, Canada were linked to obtain records of all patients with diabetes with angiographic evidence of 2- or 3-vessel CAD who were treated with either PCI or isolated CABG from 2008 to 2017. A 1:1 propensity score match was performed to account for baseline differences. All-cause mortality and the composite of myocardial infarction, repeat revascularization, stroke, or death (termed major cardiovascular and cerebrovascular events [MACCEs]) were compared between the matched groups using a stratified log-rank test and Cox proportional hazards model. A total of 4,519 and 9,716 patients underwent PCI and CABG, respectively. Before matching, patients who underwent CABG were significantly younger (age 65.7 years vs. 68.3 years), were more likely to be men (78% vs. 73%) and had more severe CAD. Propensity score matching based on 23 baseline covariates yielded 4,301 well-balanced pairs. There was no difference in early mortality between PCI and CABG (2.4% vs. 2.3%; p = 0.721) after matching. The median and maximum follow-ups were 5.5 and 11.5 years, respectively. All-cause mortality (hazard ratio [HR]: 1.39; 95% CI: 1.28 to 1.51) and overall MACCEs (HR: 1.99; 95% CI: 1.86 to 2.12) were significantly higher with PCI compared with CABG. In patients with multivessel CAD and diabetes, CABG was associated with improved long-term mortality and freedom from MACCEs compared with PCI.
This synopsis summarizes key features of a joint VA/DoD guideline on diagnosis and management of hypertension in the primary care setting.
Authors: CDR Mark P. Tschanz, William C. Cushman, CDR Travis E. Harrell, Dan R. Berlowitz, James L. Sall
Journal: Annals of Internal Medicine (2020)

Description: In January 2020, the U.S. Department of Veterans Affairs (VA) and the U.S. Department of Defense (DoD) approved a joint clinical practice guideline for the diagnosis and management of hypertension in the primary care setting. Methods: The VA/DoD Evidence-Based Practice Work Group convened a joint VA/DoD guideline development effort that included a multidisciplinary panel of practicing clinician stakeholders and conformed to the Institute of Medicine's tenets for trustworthy clinical practice guidelines. The guideline panel developed key questions in collaboration with the ECRI Institute, which systematically searched and evaluated the literature from 15 December 2013 to 25 March 2019 and developed and rated recommendations by using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. Recommendations: This synopsis summarizes key features of the guideline in several key areas: the measurement of blood pressure, the definition of hypertension, target treatment goals, and nonpharmacologic and pharmacologic treatment of essential and resistant hypertension.
Abstract 4085: Blocking Fra-1 sensitises triple-negative breast cancer to olaparib
Authors: Dandan Song, Huan He, Indranil Sinha, Linnea Pettersson, Feifei Yan, Lars-Arne Haldosen, Chunyan Zhao, Cecilia Williams
Journal: Cancer Research (2020)

Abstract Fra-1 (FOSL1), a member of the activator protein 1 (AP-1) transcription factor complex, is overexpressed in triple-negative breast cancer (TNBC) and plays crucial roles in tumor progression and treatment resistance. We have previously identified 118 proteins that interact with endogenous chromatin-bound Fra-1 in TNBC cells in a large screen, and this included PARP1 (Poly (ADP-ribose) polymerase 1). PARP1 inhibitor olaparib is currently in use for treatment of BRCA-mutated TNBC breast cancer. Here, we corroborate that PARP1 interacts with Fra-1, and we also find that PARP1 downregulates Fra-1 and reduces AP-1 transcriptional activity. Inhibition of PARP1, on the other hand, increases Fra-1 levels and enhances AP-1 transcriptional activity. Further, we find that upon inhibition of Fra-1, TNBC cells become sensitized to olaparib treatment. By comparing the Fra-1 and PARP1 regulated transcriptomes with Fra-1 chromatin binding site, we determine that a large fraction of PARP1-regulated genes is dependent on Fra-1. Finally, we show that PARP1 protein levels significantly correlate with Fra-1 in clinical breast cancer tumors, and we identify that while high PARP1 expression is indicative of a poor clinical outcome in breast cancer patients overall, it is not in basal-like tumors. In conclusion, by exploring the functionality of the Fra-1 and PARP-1 interaction, we propose that targeting Fra-1 could serve as a therapeutic approach to improve olaparib treatment outcome for TNBC patients. Citation Format: Dandan Song, Huan He, Indranil Sinha, Linnea Pettersson, Feifei Yan, Lars-Arne Haldosen, Chunyan Zhao, Cecilia Williams. Blocking Fra-1 sensitises triple-negative breast cancer to olaparib [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4085.
Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19
Authors: Pierre-François Dequin, Nicholas Heming, Ferhat Meziani, Gaëtan Plantefève, Guillaume Voiriot, Julio Badié, Bruno François, Cécile Aubron, Jean-Damien Ricard, Stephan Ehrmann, Youenn Jouan, Antoine Guillon, Marie Leclerc, Carine Coffre, Hélène Bourgoin, Céline Lengellé, Caroline Caille-Fénérol, Elsa Tavernier, Sarah Zohar, Bruno Giraudeau, Djillali Annane, Amélie Le Gouge
Journal: JAMA (2020)

Coronavirus disease 2019 (COVID-19) is associated with severe lung damage. Corticosteroids are a possible therapeutic option.
FOXA1 Mutations Reveal Distinct Chromatin Profiles and Influence Therapeutic Response in Breast Cancer
Authors: Amaia Arruabarrena-Aristorena, Jesper L.V. Maag, Srushti Kittane, Yanyan Cai, Wouter R. Karthaus, Erik Ladewig, Jane Park, Srinivasaraghavan Kannan, Lorenzo Ferrando, Emiliano Cocco, Sik Y. Ho, Daisylyn S. Tan, Mirna Sallaku, Fan Wu, Barbara Acevedo, Pier Selenica, Dara S. Ross, Matthew Witkin, Charles L. Sawyers, Jorge S. Reis-Filho, Chandra S. Verma, Ralf Jauch, Richard Koche, José Baselga, Pedram Razavi, Eneda Toska, Maurizio Scaltriti
Journal: Cancer Cell (2020)
Abstract 5182: Examining the effects of honokiol on EGFR-positive glioblastoma multiforme
Authors: Keller Smith, Blake Johnson
Journal: Cancer Research (2020)

Abstract Glioblastoma (GBM) is a highly aggressive and lethal form of primary brain tumor. Systemic suppression of the immune system, specifically T-cell impairment, significantly contributes to GBM development and progression. Recent advances in cancer immunotherapies have shown great promise in alleviating such tumor-associated immunosuppression, namely programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) checkpoint inhibitors. Regrettably, early clinical studies evaluating the efficacy of checkpoint inhibition in recurrent GBM have rendered only modest improvements in overall survival rates, due partially to insufficient inhibition of AKT-STAT3 pathways which are often dysregulated downstream of hyperactive epidermal growth factor receptors (EGFR) in GBM. In the current study, we aim to evaluate a newly discovered small molecule inhibitor of AKT-STAT3, honokiol, and its ability to suppress AKT-STAT3 activity in the context of hyperactive EGFR in GBM. Using U87-MG cells that stably overexpress a common hyperactivating mutation of EGFR, EGFRvIII, we have preliminary evidence that honokiol is an effective inhibitor of U87-EGFRvIII cellular migration as a result of its robust AKT-STAT3 pathway suppression. Thus, honokiol may provide a novel means of pharmacological inhibition of AKT-STAT3 hyperactivity in GBM and therefore greater clinical efficacy of immune checkpoint inhibitors in this deadly disease. Citation Format: Keller Smith, Blake Johnson. Examining the effects of honokiol on EGFR-positive glioblastoma multiforme [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5182.
Abstract 3553: Three-dimensional (3D) telomere signatures of sporadic pediatric papillary thyroid carcinoma (PTC)
Authors: Luiza Sisdelli, Maria Isabel Cordioli, Fernanda Vaisman, Osmar Monte, Carlos Longui, Adriano N. Cury, Monique O. Freitas, Aline Rangel-Pozzo, Sabine Mai, Janete Cerutti
Journal: Cancer Research (2020)

Abstract The incidence of thyroid carcinoma has increased worldwide, including in pediatric patients. Papillary thyroid carcinoma (PTC) is the most common subtype. Previous studies have suggested that clinical presentation and outcome diverge between pediatric and adult PTC and that this difference is likely due to distinct genetic alterations. BRAF V600E point mutation is highly prevalent in adults, while genetic fusions (RET/PTC, AGK-BRAF, ETV6-NTRK3) are the most prevalent events in the pediatric population. As telomere loss or dysfunction results in aneuploidy and chromosomal rearrangements, which can promote carcinogenesis, we investigated the three-dimensional (3D) structure of the telomeres in the nuclei from 21 pediatric patients (≤18 y.o), representing 16 PTC cases (with paired normal and tumor tissues for five of them) and five normal thyroid tissues from patients undergoing thyroidectomy for reasons other than cancer. We performed quantitative fluorescence in situ hybridization (FISH), 3D imaging, and 3D telomere analysis using TeloView® software to examine telomere dysfunction. The parameters examined included total number of signals (numbers of telomeres), total number of telomere aggregates, a/c ratio (indicating the phase of the cell cycle), total intensity (telomere length) and nuclear volume. Thyroid cancer cells showed lower average intensity of signals (p&amp;lt;0.0001) and lower intensity signals (p&amp;lt;0.0001), as well as higher nuclear volume (p&amp;lt;0.0001), compared to normal thyroid cells. In addition, tumour cells showed a higher a/c ratio (p&amp;lt;0.0001), indicating that they are more actively dividing than normal cells, which correlates with the high proliferation rate of cancer cells. We did not observe any alterations related to the total number of telomere signals and total number of aggregates, which suggests no significant aneuploidies occurring with these samples. The 3D nuclear telomere signature was able to detect differences in telomere architecture in tumours, compared to normal. Further analysis is necessary to define whether nuclear telomere architecture and specific genetic alterations observed in pediatric thyroid cancer are associated. Citation Format: Luiza Sisdelli, Maria Isabel Cordioli, Fernanda Vaisman, Osmar Monte, Carlos Longui, Adriano N. Cury, Monique O. Freitas, Aline Rangel-Pozzo, Sabine Mai, Janete Cerutti. Three-dimensional (3D) telomere signatures of sporadic pediatric papillary thyroid carcinoma (PTC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3553.
Abstract 99: Phenotypic characterization of knockdown of CDKs in the intestinal epithelial cells
Authors: Shuyan Lu, Wenyue Hu, Tae Sung, Brad Hirakawa, Marina Amaro, Bart Jessen
Journal: Cancer Research (2020)

Abstract Cyclin-dependent kinases (CDKs) are serine/threonine kinases that bind to cyclins and together act as regulators of cell cycle progression. CDK inhibitors have various therapeutic potentials including cancer (e.g. CDK4/6 inhibitors). Intestinal epithelial cells are highly proliferative; however, the impact of individual CDK inhibition on intestinal cell proliferation has not been well studied. The IEC6 cell line, a non-transformed rat small intestinal epithelial cell line with characteristics of crypt epithelial cells, was utilized in the current study to understand the role of CDKs in the proliferation and survival of intestinal cells. In the initial experiment CDK4/6 inhibitor palbociclib treatment demonstrated a lack of potent toxicity in the IEC6 in comparison with MCF7 (breast cancer cell line), indicating the absence of intestinal cell reliance on CDK4 or CDK6 for cell cycle progression. To further illustrate the role of CDKs in intestinal cells, targeted gene knockdown experiments using CDK1, 2, 4, and 6 siRNA and lipofectamine-mediated transfection were conducted. Surprisingly, only CDK1 knockdown causes profound cell death. CDK2, 4, or 6 knockdowns, whether single, double or triple combinations, did not have significant impact on IEC6 cells, as measured by multiple endpoints including impedance, ATP viability, and caspase activity. To further understand the role of CDK1 in cell cycle, various seeding densities of IEC6 cells were used with CDK1 siRNA. Although the impact of CDK1 knockdown on IEC6 cells decreased at the initial proliferation phase with the higher seeding density, there was still a decrease of viability observed at the later time point (when cells reached proliferation plateau), indicating a non-canonical role of CDK1 that is not related to cell cycle. This research supports the concept that CDK1, but not CDKs 2, 4, or 6, is essential for intestinal cell cycle progression and explains the lack of GI toxicity observed with palbociclib. Citation Format: Shuyan Lu, Wenyue Hu, Tae Sung, Brad Hirakawa, Marina Amaro, Bart Jessen. Phenotypic characterization of knockdown of CDKs in the intestinal epithelial cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 99.
Abstract 1811: Sorafenib-mediated apoptotic and autophagic cell death is increased by carnosic acid and a vitamin D2 analog in hepatocellular carcinoma (HCC)
Authors: Xuening Wang, Qunfeng Wu, Kien Pham, Aesis Luna, Michael Danilenko, Chen Liu, George P. Studzinski
Journal: Cancer Research (2020)

Abstract Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality worldwide. Its incidence is increasing, and currently there is no curative therapy for it in advanced cases. Sorafenib (Sf), a multikinase inhibitor, is an FDA approved drug for the treatment of unresectable hepatomas, but the improvement in patient survival is very short, so new approaches are needed to supplement the existing regimens. In this study we show that the addition of a plant antioxidant Carnosic acid (CA) and a vitamin D2 derivative Doxercalciferol (D2) to Sf can markedly enhance its cytotoxic effect on HCC cell lines Huh7 (Sf-sensitive) and HCO2 (partially Sf-resistant). In contrast, similar combinatorial treatment of Hu1545 cells (immortalized human hepatocytes) results in only a minimal increase in cell death (CD). The combination Sf-CA/D2 increases HCC cell death by enhancing both apoptosis and cytotoxic autophagy (AuPh). Apoptosis was shown by Annexin V binding analysis and by the increased levels of apoptosis-related proteins BIM, cleaved caspases 9 and 3. AuPh was demonstrated by increased cytoplasmic vacuolation and elevated protein levels of Beclin1, Atg3, and LC3-II. Individually, both CA and D2 enhance Sf-induced CD, but CA produces the predominant effect. These effects were significantly reduced by the addition of the Caspase 3 inhibitor Z-DEVD-fmk or the AuPh inhibitor Chloroquine, and by Beclin1 depletion. A pilot experiment with mice bearing a Huh7 HCC cell xenograft showed markedly increased survival of the animals when CA was added to Sf. These results suggest that CA alone or with D2 may increase the survival of Sf-treated HCC patients. Supported by NIH grants 1R01DK110024 (to CL) and 5R01 44722-27 (to GPS). Citation Format: Xuening Wang, Qunfeng Wu, Kien Pham, Aesis Luna, Michael Danilenko, Chen Liu, George P. Studzinski. Sorafenib-mediated apoptotic and autophagic cell death is increased by carnosic acid and a vitamin D2 analog in hepatocellular carcinoma (HCC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1811.
Abstract B23: CDK4/6 and MEK inhibitor combination in low-grade serous ovarian cancer cell lines
Authors: Joshua Hoenisch, Hannah Kim, Amy Dawson, Nicole Lam, Dane A. Cheasley, Kylie Gorringe, Ian Campbell, David G. Huntsman, Gabriel DiMattia, Martin Kobel, Marta Llaurado Fernandez, Mark S. Carey
Journal: Clinical Cancer Research (2020)

Abstract Background: Low-grade serous ovarian cancer (LGSC) is a rare tumor type that requires effective therapies. CDKN2A/B (p16/p15) loss and oncogenic mutations in MAPK genes are common genetic aberrations found in these tumors. We aimed to evaluate CDK4/6 inhibitor (palbociclib) activity, with and without MEK inhibitor (trametinib) treatment, in LGSC cell lines. Methods: Nine LGSC cell lines (from advanced/recurrent cases) were used to evaluate the effects of palbociclib treatment, with and without trametinib, on cell proliferation (Incucyte) and viability (MTS). Cell cycle gene and protein expression status (p16, CDK4, CDK6, Rb, p-Rb, CCDN1 and E2F) were characterized using whole-exome sequencing and Western blot analysis. CDKN2A and RB1 gene copy-number (CN) data and P16 immunohistochemistry staining were obtained from 70 LGSC FFPE tumors and correlated with patient overall survival (OS). Results: Palbociclib treatment had cytotoxic effects on one LGSC cell line (11%). Presence of CDK4/CDK6 protein expression was observed in 100% of the lines. Absence of p16 and Rb1 expression was detected in 78% (7/9) and 44% (4/9) of lines, respectively, and did not correlate with gene copy number status. Interestingly, none of the lines had detectable mutations in the cell cycle genes screened. Trametinib-resistant lines expressed total and phosphorylated Rb1 but palbociclib treatment did not result in drug synergistic effects. CDKN2A and RB1 copy number loss was detected in 21% and 7% LGSC tumors (all stages), respectively. The prognostic value of CDKN2A/RB1 expression in LGSC tumors is under evaluation. Conclusions: Palbociclib (with and without trametinib) showed poor activity in LGSC in vitro, and its activity did not correlate with either p16 or Rb1 expression. Our data suggest that other factors in addition to Rb-proficiency determine palbociclib efficacy in LGSC. Therefore, future translational research to define predictive biomarkers of palbociclib efficacy is needed. Citation Format: Joshua Hoenisch, Hannah Kim, Amy Dawson, Nicole Lam, Dane A. Cheasley, Kylie Gorringe, Ian Campbell, David G. Huntsman, Gabriel DiMattia, Martin Kobel, Marta Llaurado Fernandez, Mark S. Carey. CDK4/6 and MEK inhibitor combination in low-grade serous ovarian cancer cell lines [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B23.
Safety assessment of extended adjuvant endocrine therapy with letrozole; results of the randomized phase III IDEAL trial (BOOG 2006-05)
Authors: E.J. Blok, J.R. Kroep, E.M.M.K. Kranenbarg, M.D.D. Carpentier, H. Putter, J. van den Bosch, E. Maartense, A.E. van Leeuwen-Stok, G.J. Liefers, J.W.R. Nortier, E.J.T. Rutgers, C.J.H. van de Velde
Journal: Cancer Research (2017)
Abstract PO-016: Seeing glycolysis on PDAC: Applying deep learning convolutional neural network model
Authors: Peiling Tsou, Chang-Jiun Wu
Journal: Clinical Cancer Research (2021)

Abstract The reprogramming of cellular metabolism to support continuous proliferation is a hallmark of cancer. Accumulating evidence indicates that the reprogramming of tumor metabolism is under the control of various oncogenic signals. The KRAS oncogene is known to induce aerobic glycolysis, and pancreatic adenocarcinoma (PDAC) cells have been shown previously to have metabolism consistent with elevated aerobic glycolysis. Survival analysis showed that higher glycolysis activity was associated with worse clinical outcome in TCGA PDAC. Several glycolytic inhibitors are currently in preclinical and clinical development. It had been reported that cancer metabolic status could play a role in the interaction with tumor microenvironment. We hypothesized that cancer glycolysis activity could affect tumor histopathological architecture in PDAC. As a proof-of-concept study, we trained a deep learning convolutional neural network (CNN) model (Google Inception v3) on histopathological images obtained from TCGA PAAD cohort to classify tumors with high and low glycolysis pathway activity. We aimed to answer whether CNNs can predict PDAC glycolysis status using images as the only input. Our model was tested on separate tissue samples from the same cohort. Aggregated accuracy was 75% on 48 cases with area under ROC curve as 0.751. Prediction scores significantly correlated with transcriptome-based glycolysis signature (Pearson correlation = 0.352, p=0.007). The current study demonstrates the potential of deep learning approaches for histopathologically classifying cancer based on metabolic status. This information could be of value in assisting clinical decisions on targeting cancer metabolism. Citation Format: Peiling Tsou, Chang-Jiun Wu. Seeing glycolysis on PDAC: Applying deep learning convolutional neural network model [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-016.
Blood eosinophils do not predict inhaled budesonide response in bronchiectasis
Authors: Stefano Aliberti, Giovanni Sotgiu, Miguel-Angel Martinez Garcia
Journal: European Respiratory Journal (2020)

We would like to thank B. Lipworth and co-workers for their feedback on our study, which showed that 6-month treatment with inhaled fluticasone proprionate (FP) significantly improved quality of life in bronchiectasis patients with neither asthma nor COPD, and with blood eosinophil counts either ≥3% or≥150 cells·μL−1 [1, 2]. We agree with B. Lipworth and co-workers on the higher dose-dependent suppression of blood eosinophils due to the systemic absorption of FP. We re-analysed previously published data on bronchiectasis patients treated with budesonide, which has less systemic potency than FP [3]. Blood eosinophils do not predict inhaled budesonide response in bronchiectasis <https://bit.ly/2Yr1b11>
Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial
Authors: Ravi Savarirayan, Louise Tofts, Melita Irving, William Wilcox, Carlos A Bacino, Julie Hoover-Fong, Rosendo Ullot Font, Paul Harmatz, Frank Rutsch, Michael B Bober, Lynda E Polgreen, Ignacio Ginebreda, Klaus Mohnike, Joel Charrow, Daniel Hoernschemeyer, Keiichi Ozono, Yasemin Alanay, Paul Arundel, Shoji Kagami, Natsuo Yasui, Klane K White, Howard M Saal, Antonio Leiva-Gea, Felipe Luna-González, Hiroshi Mochizuki, Donald Basel, Dania M Porco, Kala Jayaram, Elena Fisheleva, Alice Huntsman-Labed, Jonathan Day
Journal: The Lancet (2020)