tbuckley/cabot-search huggingface dataset:
Abstract PR11: Investigating lung cancer cells-of-origin using three-dimensional organoid cultures
Authors: Kwok-Kin Wong, Carla Kim, Christine Fillmore Brainson
Journal: Cancer Research (2018)

Abstract There are many distinct epithelial cell types in the adult lung that could give rise to non-small cell lung cancer. These cell types include tracheal basal stem cells, tracheal club cells, distal lung bronchioalveolar stem cells (BASCs), and distal lung alveolar type 2 cells (AT2). My laboratory is using mouse models to test directly which lung stem and progenitor cells are most fit to serve as cells-of-origin of lung adenocarcinoma and lung squamous cell carcinoma. Previously, we demonstrated that tracheal club cells and BASCs are the likely cells-of-origin for KRASG12D; Lkb1-null adenosquamous tumors. The same strategy is now being used to test which cells can give rise to adenocarcinomas using the LSL:EGFRT90M/L858R (LSL=lox-stop-lox) mouse strain, or squamous cell carcinoma using the Lkb1flox/flox; Ptenflox/flox mouse strain. Briefly, tracheas and lungs from Cre-naïve mice are enzymatically dissociated, and fluorescence activated cell sorting (FACS) is used to enrich for four distinct populations: NGFR+/Sca1+ tracheal basal cells, NGFR-/Sca1+ tracheal club cells, Sca1+ distal lung BASCs, and Sca1- distal lung AT2 cells. Each population is then incubated with either adeno-GFP control virus or adeno-Cre virus to induce EGFR T790M/L858R expression or delete both alleles of Lkb1 and Pten. Three dimensional air-liquid-interface cultures are then used to expand the populations as organoids. For EGFR organoids, both basal and club cells give rise to larger, faster-growing bronchiolar organoids after EGFR is induced. AT2 cells similarly give rise to much larger alveolar organoids after EGFR induction, and BASCs change from giving rise to both bronchiolar and alveolar organoids to nearly exclusively alveolar. For Lkb1/Pten organoids, all four populations can tolerate deletion of the two genes, but it is only the basal cell and club cell organoids that progress to a squamous morphology in vitro. While both BASC and AT2 organoids continue to grow, they appear phenotypically normal. Transplant assays to assess malignancy and RNA-seq and ChIP-seq studies to explore gene transcription and epigenetic changes are under way. These experiments will shed light on the cells of the adult lung that give rise to genotype-specific tumors, and will aid us to better classify lung cancer heterogeneity from a cell-of-origin perspective. Citation Format: Kwok-Kin Wong, Carla Kim, Christine Fillmore Brainson. Investigating lung cancer cells-of-origin using three-dimensional organoid cultures [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr PR11.
The oncogenic fusion protein CBFB-SMMHC downregulates CD48 to evade NK cell recognition
Authors: Shira Kahlon, Dorin Shreibman, Tamar Unger, Dina Ben-Yehuda, Shlomo Elias
Journal: Blood Cancer Journal (2018)

Chromosomal translocations are often found in acute leukemia and frequently result in the generation of fusion proteins with oncogenic properties 1 .We recently studied the immune evasion properties of PML-RARA and AML1-ETO, two common oncogenic fusion proteins in acute myeloid leukemia (AML).We found that both of these fusion proteins downregulate the expression of CD48, a ligand of the NK cell-activating receptor 2B4, thus leading to impaired NK cell cytotoxicity 2 .However, it remained unclear whether other leukemic fusion proteins can manipulate NK cell ligands.To explore this issue, here we tested the effects of several leukemic fusion proteins on the expression of NK cell ligands.To examine whether NK cell ligands are downregulated by oncogenic fusion proteins other than PML-RARA and AML1-ETO 2 , we cloned several oncogenic fusion proteins associated with acute leukemia into lentiviral vectors.The oncogenic fusion proteins we examined were MLL-AF4, NUP98-HOXA9, DEK-NUP214, and CBFB-SMMHC.MLL-AF4 is associated with acute lymphoblastic lymphoma, whereas the other three fusion proteins are associated with AML.We expressed these fusion proteins in U937 cells (since this is the only cell line that could be transduced and this cell line is commonly used to express leukemic fusion proteins 3,4 ).We confirmed the expression of each of these fusion proteins in U937 cells by qPCR (data not shown).Expression of MLL-AF4, NUP98-HOXA9, and DEK-NUP214 did not affect the level of several NK cell ligands including the NKG2D
Comment on Suissa. Lower Risk of Death With SGLT2 Inhibitors in Observational Studies: Real or Bias? Diabetes Care 2018;41:6–10
Authors: Thomas Nyström, Johan Bodegård, David Nathanson, Marcus Thuresson, Anna Norhammar, Jan W. Eriksson
Journal: Diabetes Care (2018)

Comment on Suissa. Lower Risk of Death With SGLT2 Inhibitors in Observational Studies : Real or Bias? Diabetes Care 2018;41:6–10
Diversity of Participants in the 340B Drug Pricing Program for US Hospitals
Authors: Sayeh Nikpay, Melinda Buntin, Rena M. Conti
Journal: JAMA Internal Medicine (2018)

cessful.However, most interventions have focused on increasing overall rates of prophylaxis rather than overall appropriateness.Although overall rates have improved, the unintended consequence may be excess administration of VTE prophylaxis among low-risk patients.The major drawback to pharmacologic overprophylaxis is major bleeding. 5Patient discomfort, potential risk of falls and impaired mobility with mechanical prophylaxis, medication cost, and risk for heparin-induced thrombocytopenia are additional concerns.Limitations of this study include its observational design subject to inherent biases.Furthermore, this analysis did not incorporate VTE events, so it is unknown whether 1 specific VTE prophylaxis strategy was superior to another.After years of promoting aggressive VTE prophylaxis strategies for hospitalized patients, renewed effort to scale back-or "deimplement"-this practice in low-risk patients may be necessary. 6Discontinuing conventional practices, however, can be difficult, even in the presence of newer compelling data.
Experimental vaccine ready for use in Congo’s Ebola outbreak
Authors: Owen Dyer
Journal: BMJ (2018)

An experimental vaccine that arrived too late to stem the 2014 Ebola outbreak could be used within hours in the Democratic Republic of the Congo (DRC), WHO director-general Tedros Adhanom Ghebreyesus, said from the capital Kinshasa.

Cold chain equipment arrived in the country on 13 May and has since been set up throughout the affected zone. WHO and the DRC’s health ministry have agreed to use a ring vaccination approach, in which all suspected contacts of infected people are vaccinated, in addition to health workers. So far, 382 contacts have been identified, …
Trained Memory of Human Uterine NK Cells Enhances Their Function in Subsequent Pregnancies
Authors: Moriya Gamliel, Debra Goldman-Wohl, Batya Isaacson, Chamutal Gur, Natan Stein, Rachel Yamin, Michael Berger, Myriam Grunewald, Eli Keshet, Yoach Rais, Chamutal Bornstein, Eyal David, Adam Jelinski, Iris Eisenberg, Caryn Greenfield, Arbel Ben-David, Tal Imbar, Ronit Gilad, Ronit Haimov-Kochman, David Mankuta, Matan Elami-Suzin, Ido Amit, Jacob H. Hanna, Simcha Yagel, Ofer Mandelboim
Journal: Immunity (2018)
Cost-utility of proton therapy in the treatment of localized prostate cancer.
Authors: Ravi K. Goyal, Anne-Marie Meyer, Nathan Christopher Sheets, Jerome J Federspiel, William Ruffin Carpenter, Ronald C. Chen, Andrea K Biddle
Journal: Journal of Clinical Oncology (2012)

e15184 Background: Proton therapy (PT) has received much public attention due to its higher costs and lack of evidence of clinical benefit compared to intensity modulated radiation therapy (IMRT) for prostate cancer treatment. In this economic study, we performed a threshold analysis to assess the reduction in toxicity that PT would need to achieve compared with IMRT to be considered cost-effective for the treatment of localized prostate cancer. Methods: SEER-Medicare data was used to identify a cohort, aged 66 years or older, receiving IMRT as definitive radiation therapy (n=4,540). We assumed equal disease control efficacy between IMRT and PT and simulated toxicity outcomes and costs using an incidence-based Markov model. The relative risk of composite toxicity, comparing PT to IMRT, was the efficacy parameter studied. Rates of therapy-induced toxicity associated with IMRT were obtained from SEER-Medicare data. Utility values to calculate quality-adjusted life-years (QALY) and costs (in 2011 US dollars) were obtained from the literature and claims data, respectively. Deterministic threshold analysis using a payer perspective and analytic horizon of 4 years post radiation was performed to determine the relative risk thresholds that would result in incremental cost-effectiveness ratios (ICER) of $50,000 and $100,000/QALY for PT versus IMRT. One-way sensitivity analyses were performed with the lowest and highest treatment costs of PT and IMRT. Results: ComparingPT against IMRT, the threshold values for the relative risk of composite toxicity were 0.318 and 0.588 at cost-effectiveness levels of $50,000/QALY and $100,000/QALY, respectively. Sensitivity analyses showed that the relative risk needed to achieve an ICER of 100,000/QALY ranged from 0.79 and 0.40 for the low and high cost estimates of PT, and from 0.47 to 0.72, for the low and high cost estimates of IMRT. Conclusions: Assuming equal disease control, PT would need to result in a 41% reduction in composite toxicity to be considered cost-effective in the treatment of Medicare beneficiaries with localized prostate cancer at a cost-effectiveness threshold of $100,000/QALY.
ERK Mutations and Amplification Confer Resistance to ERK-Inhibitor Therapy.
Authors: Bijay S. Jaiswal, Steffen Durinck, Eric W. Stawiski, Jianping Yin, Weiru Wang, Eva Lin, John Moffat, Scott E. Martin, Zora Modrusan, Somasekar Seshagiri
Journal: Clinical Cancer Research (2018)

Purpose: MAPK pathway inhibitors targeting BRAF and MEK have shown clinical efficacy in patients with RAF- and/or RAS-mutated tumors. However, acquired resistance to these agents has been an impediment to improved long-term survival in the clinic. In such cases, targeting ERK downstream of BRAF/MEK has been proposed as a potential strategy for overcoming acquired resistance. Preclinical studies suggest that ERK inhibitors are effective at inhibiting BRAF/RAS-mutated tumor growth and overcome BRAF or/and MEK inhibitor resistance. However, as observed with other MAPK pathway inhibitors, treatment with ERK inhibitors is likely to cause resistance in the clinic. Here, we aimed to model the mechanism of resistance to ERK inhibitors.Experimental Design: We tested five structurally different ATP-competitive ERK inhibitors representing three different scaffolds on BRAF/RAS-mutant cancer cell lines of different tissue types to generate resistant lines. We have used in vitro modeling, structural biology, and genomic analysis to understand the development of resistance to ERK inhibitors and the mechanisms leading to it.Results: We have identified mutations in ERK1/2, amplification and overexpression of ERK2, and overexpression of EGFR/ERBB2 as mechanisms of acquired resistance. Structural analysis of ERK showed that specific compounds that induced on-target ERK mutations were impaired in their ability to bind mutant ERK. We show that in addition to MEK inhibitors, ERBB receptor and PI3K/mTOR pathway inhibitors are effective in overcoming ERK-inhibitor resistance.Conclusions: These findings suggest that combination therapy with MEK or ERBB receptor or PI3K/mTOR and ERK inhibitors may be an effective strategy for managing the emergence of resistance in the clinic. Clin Cancer Res; 24(16); 4044-55. ©2018 AACR.
Striatal dopamine regulates systemic glucose metabolism in humans and mice
Authors: Kasper W. ter Horst, Nicolette M. Lammers, Richard Trinko, Darren M. Opland, Martijn Figee, Mariette T. Ackermans, Jan Booij, Pepijn van den Munckhof, P. Richard Schuurman, Eric Fliers, Damiaan Denys, Ralph J. DiLeone, Susanne E. la Fleur, Mireille J. Serlie
Journal: Science Translational Medicine (2018)

Modulation of the striatal dopamine system affects glucose metabolism in humans and mice.
Use of Venous Thromboembolism Prophylaxis in Hospitalized Patients
Authors: Paul J. Grant, Anna Conlon, Vineet Chopra, Scott A. Flanders
Journal: JAMA Internal Medicine (2018)

National guidelines1 recommend objective risk stratification for venous thromboembolism (VTE) in hospitalized medical patients. The Padua Prediction Score risk assessment model2 is recommended to categorize patients as high or low risk. The Michigan Hospital Medicine Safety Consortium (HMS), a statewide quality collaborative aimed at preventing adverse events in hospitalized medical patients, collects detailed data on VTE risk factors, prophylactic treatment, and outcomes. Using data from the HMS,3 we sought to determine whether patients in this cohort were receiving appropriate VTE prophylaxis.
Premature endothelial cell (EC) senescence (SEN) and macrovasculopathy in obesity-induced diabetes are preventable by chronic treatment with a peroxynitrite scavenger ebselen.
Authors: S V Brodsky, O Gealikman, J Chen, F Zhang, N Togashi, M Crabtree, S S Gross, A Nasjletti, M S Goligorsky
Journal: Journal of the American Society of Nephrology (2003)
In vitro effects of erlotinib and gemcitabine in erlotinib-resistant cells
Authors: Naoto T. Ueno, Mary J. Johansen, Hsiao-Ling Huang, Kaoru Kurisu, Gabriel N. Hortobagyi, Fumiyuki Yamasaki
Journal: Cancer Research (2006)

2147   Erlotinib (Tarceva) inhibits the epidermal growth factor receptor (EGFR) tyrosine kinase by competing with ATP to inhibit phosphorylation of the kinase. Erlotinib was recently approved for use in combination with gemcitabine for advanced pancreatic cancer. However, in vitro evidence to support the use of erlotinib with gemcitabine as anticancer therapy is lacking. To address this gap, we created 2 erlotinib-resistant pools of A-431 cells, an EGFR-overexpressing, erlotinib-sensitive epidermoid cancer cell line, and assessed them for dose-response and cell cycling in response to erlotinib and gemcitabine. The resistant pools were developed by continuously exposing A-431 cells to erlotinib (pool 1, 3 μM for 1 mo, 5 μM for 1 mo, and 10 μM for 4 mo; pool 2, 3 μM for 1 mo and 5 μM for 5 mo). Basal expression of EGFR was no different among the 3 cell types, and erlotinib blocked EGF signaling in both resistant pools (as evidenced by EGFR phosphorylation after EGF stimulation). Intracellular concentrations of erlotinib (measured by LC/MS/MS) after a 24-h exposure were 0.98 ± 0.04 ng/ml for parental cells, 3.03 ± 0.97 ng/ml for pool 1, and 1.88 ± 0.47 ng/ml for pool 2, confirming that erlotinib penetrated the cell membrane in both pools. Next, parental cells (IC50 1.67 μM) and erlotinib-resistant cells (IC50 17.6 or 13.2 μM) were treated with 2-fold serial dilutions of erlotinib (0.125-16 μM), gemcitabine (0.000436-0.056 μM), or both. Combination indices (CI) for the 2 drugs were derived by using Calcusyn (Biosoft, Cambridge, UK). Drug synergy is indicated by a CI   1.0. In the parental cells, synergy between erlotinib and gemcitabine was noted (CI = 0.68 at IC50); strong synergy was also maintained in the erlotinib-resistant pools (CI = 0.69 for pool 1 and 0.56 for pool 2 at their respective IC50s) despite their being resistant to erlotinib. This synergism was confirmed by trypan blue exclusion. Flow cytometric cell-cycle analysis showed substantial increases in proportions of subdiploid (apoptotic) cells. These results suggest that synergistic effects between erlotinib and gemcitabine in cancer cells may not require sensitivity to erlotinib as a single agent at the concentration used as long as EGFR phosphorylation is blocked by erlotinib. Further studies are warranted to explore the use of erlotinib as a gemcitabine chemosensitizer in cancer cells that overexpress EGFR.
Genetic Targeting of Organ-Specific Blood Vessels
Authors: Wenjuan Pu, Lingjuan He, Ximeng Han, Xueying Tian, Yan Li, Hui Zhang, Qiaozhen Liu, Xiuzhen Huang, Libo Zhang, Qing-Dong Wang, Zhenyang Yu, Xiao Yang, Nicola Smart, Bin Zhou
Journal: Circulation Research (2018)

Organs of the body require vascular networks to supply oxygen and nutrients and maintain physiological function. The blood vessels of different organs are structurally and functionally heterogeneous in nature. To more precisely dissect their distinct in vivo function in individual organs, without potential interference from off-site targets, it is necessary to genetically target them in an organ-specific manner.The objective of this study was to generate a genetic system that targets vascular endothelial cells in an organ- or tissue-specific manner and to exemplify the potential application of intersectional genetics for precise, target-specific gene manipulation in vivo.We took advantage of 2 orthogonal recombination systems, Dre-rox and Cre-loxP, to create a genetic targeting system based on intersectional genetics. Using this approach, Cre activity was only detectable in cells that had expressed both Dre and Cre. Applying this new system, we generated a coronary endothelial cell-specific Cre (CoEC-Cre) and a brain endothelial cell-specific Cre (BEC-Cre). Through lineage tracing, gene knockout and overexpression experiments, we demonstrated that CoEC-Cre and BEC-Cre efficiently and specifically target blood vessels in the heart and brain, respectively. By deletion of vascular endothelial growth factor receptor 2 using BEC-Cre, we showed that vascular endothelial growth factor signaling regulates angiogenesis in the central nervous system and also controls the integrity of the blood-brain barrier.We provide 2 examples to illustrate the use of intersectional genetics for more precise gene targeting in vivo, namely manipulation of genes in blood vessels of the heart and brain. More broadly, this system provides a valuable strategy for tissue-specific gene manipulation that can be widely applied to other fields of biomedical research.
Abstract 13424: Prospective Trial of Adenosine on Atrioventricular Nodal Conduction in the Pediatric Transplanted Heart
Authors: Jonathan N Flyer, Warren A Zuckerman, Marc E Richmond, Brett R Anderson, Tamar G Mendelsberg, Jennie M McAllister, Leonardo Liberman, Linda J Addonizio, Eric S Silver
Journal: Circulation (2016)

Introduction: Supraventricular tachycardia (SVT) is common after heart transplant. Adenosine is the standard of care for SVT treatment in children and adults, but is relatively contraindicated post-transplant due to presumed risk of prolonged atrioventricular (AV) block in denervated hearts. This is the first trial of adenosine use in pediatric and young adult heart transplant patients. Hypothesis: Adenosine use after heart transplant does not cause prolonged asystole and is effective in blocking AV nodal conduction. Methods: This was a single center prospective clinical trial including healthy heart transplant recipients ages 6 months - 25 years presenting for routine cardiac catheterization from July 2015 to April 2016. After catheterization, a pacing catheter was placed in the right ventricle and adenosine was given according to a stepwise protocol (12.5mcg/kg, 25mcg/kg, 50mcg/kg, 100mcg/kg and 200mcg/kg, with maximum doses of 0.8mg, 1.5mg, 3mg, 6mg and 12mg for patients ≥ 60kg) until AV block was achieved. The primary outcome was clinically significant asystole ≥ 12 seconds following adenosine that required rescue ventricular pacing. The effects of patient characteristics on adenosine dose and total adenosine effect were tested. Results: Eighty patients completed adenosine testing. No patient (0%, 95% CI 0-3%) required rescue ventricular pacing. AV block was observed in 77 patients (96%, 95% CI 89-99%) at different doses (Figure 1). The median longest AV block was 1.9 seconds (IQR 1.4-3.2) and the mean total adenosine effect was 4.3 seconds (±2.0). No patient characteristics were significant predictors of adenosine dose and total adenosine effect. Results were similar when patients were stratified by weight ≥60kg. Conclusion: Adenosine is a safe medical therapy for the induction of AV block in pediatric and young adult heart transplant patients when using low initial doses (25mcg/kg; 1.5mg if ≥60kg) and gradually escalating therapy.
Abstract 13877: 5-Year Impact of Catheter Ablation for Atrial Fibrillation in Patients With a Prior History of Stroke
Authors: Thomas J Bunch, Heidi T May, Tami L Bair, Michael J Cutler, Brian G Crandall, Victoria Jacobs, Charles Mallender, Jeffrey S Osborn, J. P Weiss, John D Day
Journal: Circulation (2016)

Background: Catheter ablation of atrial fibrillation (AF) is an established therapeutic rhythm approach. Patients with a prior history of a stroke (CVA) represent a unique high-risk population for recurrent thromboembolic events. The role of antiarrhythmic treatment on the long-term natural history of stroke recurrence in these high patients is not fully understood. Hypothesis: The process of AF ablation will impact the long-term history of disease progression in high risk CVA patients. Methods: 3 patient groups with a prior CVA and 5 years of follow-up were matched 1:3:3 by propensity score (±0.01): AF ablation patients receiving their first ablation (n=139), AF patients that did not receive an ablation (n=416), and CVA patients without clinical AF (n=416). Prior CVA was determined by medical chart review using ICD 9/10 codes. Patients were followed for 5-year outcomes of recurrent CVA, heart failure, death. Results: The average age of the population was 69±11 years and 51% male. The AF was paroxysmal in 25%, persistent in 34.7%, and longstanding persistent in 41%. AF ablation patients had higher rates of hypertension (p&lt;0.0001), but diabetes prevalence was similar between the groups (p=0.50). Propensity-matched 5-year risk of CVA (HR=2.26, p&lt;0.0001, Figure) and death (HR=2.43, p&lt;0.0001) were higher in the AF, no ablation group compared those that were ablated. When comparing AF, ablation to no AF patients, there was not a significant difference in 5-year risk of for CVA (HR=0.82, p=0.39) and death (HR=0.92, p=0.70), however heart failure risk was increased (HR=3.08, p=0.001). Conclusion: In patients with a prior CVA, the system and approach towards the management of AF in patients that undergo ablation is associated with lower rates of recurrent stroke compared to AF patients that do not undergo ablation. The CVA rates are similar to a non AF population to suggest the potential of altering the natural history of disease progression.
Cavity LeadのST上昇(Cal‐STE)を示す急性心不全患者の半数は虚血性心疾患の進行と関連する
Authors: Itakura Kiho, Dote Keigo, Kato Masaya, Sasaki Syota, Kagawa Eisuke, Nakano Yoshinori, Takiguchi Yu, Ochiumi Yusuke
Journal: Circulation (2012)
The Chaperone UNC93B1 Regulates Toll-like Receptor Stability Independently of Endosomal TLR Transport
Authors: Karin Pelka, Damien Bertheloot, Elisa Reimer, Kshiti Phulphagar, Susanne V. Schmidt, Anette Christ, Rainer Stahl, Nicki Watson, Kensuke Miyake, Nir Hacohen, Albert Haas, Melanie M. Brinkmann, Ann Marshak-Rothstein, Felix Meissner, Eicke Latz
Journal: Immunity (2018)