tbuckley/cabot-search huggingface dataset:
Abstract 3496: Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors
Authors: Manasi Ratnaparkhe, John K. Wong, Pei-Chi Wei, Mario Hlevnjak, Thorsten Kolb, Milena Simovic, Daniel Haag, Yashna Paul, Frauke Devens, Paul Northcott, David T. Jones, Marcel Kool, Anna Jauch, Agata Pastorczak, Wojciech Mlynarski, Andrey Korshunov, Rajiv Kumar, Susanna M. Downing, Stefan M. Pfister, Marc Zapatka, Peter J. McKinnon, Frederick W. Alt, Peter Lichter, Aurelie Ernst
Journal: Cancer Research (2019)

Abstract Chromothripsis and chromoanasynthesis are catastrophic events leading to clustered genomic rearrangements. Whole-genome sequencing revealed frequent complex genomic rearrangements (n= 16/26) in brain tumors developing in mice deficient for factors involved in homologous recombination repair or non-homologous end-joining. Catastrophic events were tightly linked to Myc/Mycn amplification, with increased DNA damage and inefficient apoptotic response already observable at early postnatal stages. Inhibition of repair processes and comparison of the mouse tumors with human medulloblastomas (n=68) and glioblastomas (n=32) identified chromothripsis as associated with MYC/MYCN gains and with DNA repair deficiencies, pointing towards therapeutic opportunities to target DNA repair defects in tumors with complex genomic rearrangements. Citation Format: Manasi Ratnaparkhe, John K. Wong, Pei-Chi Wei, Mario Hlevnjak, Thorsten Kolb, Milena Simovic, Daniel Haag, Yashna Paul, Frauke Devens, Paul Northcott, David T. Jones, Marcel Kool, Anna Jauch, Agata Pastorczak, Wojciech Mlynarski, Andrey Korshunov, Rajiv Kumar, Susanna M. Downing, Stefan M. Pfister, Marc Zapatka, Peter J. McKinnon, Frederick W. Alt, Peter Lichter, Aurelie Ernst. Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3496.
Abstract 4759: Antitumor activity of eribulin after fulvestrant plus palbociclib treatments in the HR(+) human breast PDx model
Authors: Makoto Asano, Takayuki Nakagawa, Taro Semba, Akira Yokoi, Junji Matsui, Yasuhiro Funahashi
Journal: Cancer Research (2019)

Abstract Fulvestrant (FLV) and Palbociclib (Palb), which have an effect on degradation of estrogen receptor (ER) and inhibition of cyclin dependent kinases 4 and 6 (CDK4/6), respectively are used for treatments to postmenopausal breast cancer patients. However, there is not a clinical rationale to define a standard treatment regimen against breast cancer patients who are resistant to endocrine therapy plus Palb. Eribulin is a fully synthetic analog of the marine sponge natural product halichondrin B. Its clinical formulation is currently approved for advanced breast cancer (BC) and advanced liposarcoma in numerous countries. We examined the antitumor activity of eribulin after endocrine therapy (combination of FLV and Palb) compared with that of Capecitabine (Cape) in the luminal type breast cancer PDx model (OD-BRE-0438). OD-BRE-0438 is a patient derived xenograft (PDx) model developed from patient with luminal B breast cancer. Gene expression analysis by RNA-Seq showed that OD-BRE-0438 highly expressed ER and PR, but not ERBB2. OD-BRE-0438 tumor bearing mice were treated for 2 weeks of FLV (5mg/ head, Q7Dx2, sc) and Palb (10mg/kg, Q1Dx14, po), and treated mice were randomly divided using tumor volume around 350 mm3 as an index (day1). After that, mice were treated with eribulin (0.5 or 1 mg/kg, which are 1/4 MTD or 1/2 MTD in this model, Q7Dx2, iv) or Cape (125 or 250 mg/kg, which are 1/2 MTD or MTD in this model, Q1Dx14, po for 2 weeks). We measured tumor volume of each mouse after treatments (day 15) and analyzed the ratio of tumor volume at day 15 divided by that at day 1 (RTV: relative tumor volume). Treatments of FLV and Palb nearly completely inhibited in vivo growth of OD-BRE-0438 tumors, but didn’t cause tumor shrinkage. After two weeks of combination treatment with endocrine therapy, we started treatments with either eribulin or Cape, and compared the antitumor activity. Both drug showed strong antitumor activity with tumor shrinkage. In comparison of antitumor activity with either eribulin or Cape, that of eribulin was significantly greater than Cape. [eribulin 0.5mg/kg (RTV=0.42) vs Cape 125mg/kg (RTV=0.62, p=0.0068), eribulin 1.0mg/kg (RTV=0.32) vs Cape 250mg/kg (RTV=0.59, p=0.0008)]. Further investigation for mechanism of action of eribulin to show clear antitumor activity after treatments of FLV and Palb in the luminal type breast cancer PDx model are warranted. Citation Format: Makoto Asano, Takayuki Nakagawa, Taro Semba, Akira Yokoi, Junji Matsui, Yasuhiro Funahashi. Antitumor activity of eribulin after fulvestrant plus palbociclib treatments in the HR(+) human breast PDx model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4759.
Randomized, open-label, perioperative phase II study evaluating nivolumab alone versus nivolumab plus ipilimumab in patients with resectable HCC
Authors: A. Kaseb, L. Vence, J. Blando, S. Yadav, N. Ikoma, R. Pestana, J. Vauthey, H. Cao, Y. Chun, D. Sakamura, R. Wolff, J. Yao, J. Allison, P. Sharma
Journal: Annals of Oncology (2019)
Novel concept using a plastic stent for endoscopic ultrasound-guided hepaticogastrostomy adjusting the length according to the patient’s anatomy
Authors: Mamoru Takenaka, Kosuke Minaga, Tomoe Yoshikawa, Ayana Okamoto, Atsushi Nakai, Shunsuke Omoto, Masatoshi Kudo
Journal: Endoscopy (2019)

Recently, the usefulness of plastic stents for creation of an endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) was reported [1] [2] [3]. Re-intervention using a plastic stent is easy owing to the ability to remove it, which may be difficult with a metal stent [4] [5]. However, as there are few different types of plastic stent dedicated to creation of an EUS-HGS, in some patients it may be difficult to insert the plastic stent in a proper position.
Abstract 4186: Aggressive prostate cancer among men in Pennsylvania: Differences between Appalachian and non-Appalachian counties
Authors: Alicia C. McDonald, Emily Wasserman, Eugene J. Lengerich, Jay D. Raman, Nathaniel Geyer, Raymond Hohl, Ming Wang
Journal: Cancer Research (2019)

Abstract Introduction: The incidence of prostate cancer (PC) is known to vary within Appalachia, with Northern Appalachia and Southern Appalachia having higher and lower rates, respectively. However, the geographical disparity for aggressive PC has not been investigated. The objective of this study was to determine whether having more aggressive PC was associated with residing in an Appalachian/non-Appalachian county and rural/urban community. Methods: A cross-sectional study was conducted among men, aged &amp;gt = 40 years, who had a primary, clinical PC diagnosis identified in the Pennsylvania Cancer Registry between 2004 and 2014. PC aggressiveness was defined as less aggressive (Gleason score 6 or 7 [3+4] and clinical/pathologic tumor stage T1-T2) and more aggressive (Gleason score &amp;gt = 7 [4+3], clinical/pathologic tumor stage T3-T4, or distant metastasis) PC. Logistic regression analysis was used to examine the association between having aggressive PC (less vs more aggressive PC - dependent variable) and residing in a geographical region (Appalachian versus non-Appalachian county - independent variable), stratified by rural/urban, after adjusting for age, race, ethnicity, insurance status, marital status, serum PSA, positive lymph node status, and cancer treatment. Results: There were 94,264 PC cases, aged 40 to 105 years, included in the study. The majority of the PC cases were white (83.9%) followed by black race (10.7%). PC cases from urban Appalachian counties (35.42%) had the highest frequency of aggressive PC followed by rural non-Appalachian (34.18%), rural Appalachian (32.12%), and urban non-Appalachian counties (32.08%). In urban areas, Appalachian PC cases were more likely to be aggressive compared to non-Appalachian PC cases, after adjusting for confounders (odds ratio [O.R.] =1.16; 95% confidence interval [C.I.], 1.13-1.21). Conversely, in rural areas, Appalachian PC cases were less likely to be aggressive compared to non-Appalachian PC cases, after adjusting for confounders (O.R. =0.91; 95% C.I., 0.85-0.98). Conclusion: Differences in having more aggressive PC was observed for Appalachian populations by rural/urban status, with urban Appalachian PC cases more likely and rural Appalachian PC cases less likely to have more aggressive disease, compared to their non-Appalachian counterparts. Further investigation on the underlying mechanisms of aggressive PC in urban Appalachia in PA is warranted. Citation Format: Alicia C. McDonald, Emily Wasserman, Eugene J. Lengerich, Jay D. Raman, Nathaniel Geyer, Raymond Hohl, Ming Wang. Aggressive prostate cancer among men in Pennsylvania: Differences between Appalachian and non-Appalachian counties [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4186.
Abstract 19574: Adenosine Deaminase Acting on RNA-1 is Indispensable for Vascular Development and Homeostasis in vivo
Authors: Federica Francesca Lunella, Aikaterini Gatsiou, Phillip Grote, Carolin Amrhein, Anuradha Doddaballapur, Emmanouil Chavakis, Thomas Braun, Andreas Zeiher, Stefanie Dimmeler, Konstantinos Stellos
Journal: Circulation (2016)

Introduction: Adenosine deaminase acting on RNA-1 (ADAR1) binds to double-stranded RNAs and mediates adenosine to inosine RNA editing, which is a widespread post-transcriptional mechanism in mammal...
Abstract 3849: Structure-based PROTAC design demonstrates BAF complex ATPase vulnerabilities in cancer
Authors: Manfred Koegl, William Farnaby, Claire Whitworth, Michael Roy, Emelyne Diers, Nicole Trainor, Steffen Steurer, Carina Riedmueller, Teresa Gmaschitz, Johannes Wachter, Christian Dank, Michael Gallant, Bernadette Sharps, Klaus Rumpel, Elisabeth Traxler, Romario Lorenz, Oliver Petermann, Peter Greb, Harald Weinstabl, Gerd Bader, Andreas Zoephel, Alexander Weiss-Puxbaum, Joerg Rinnenthal, Heribert Arnnhof, Nicola Wiechens, Meng-Ying Wu, Tom Owen-Hughes, Peter Ettmayer, Mark Pearson, Darryl B. McConnell, Alessio Ciulli
Journal: Cancer Research (2019)

Abstract Targeting subunits of BAF/PBAF complexes has been proposed as an approach to exploit cancer vulnerabilities, yet small molecules developed to date have remained largely ineffectual. Here we develop PROTAC degraders of the BAF ATPase subunits SMARCA2 and SMARCA4 using a bromodomain ligand and recruitment of the E3 ubiquitin ligase VHL. High-resolution ternary complex crystal structures and biophysical investigation guided the rational optimization of ACBI1, a potent cooperative SMARCA2/4 degrader. ACBI1 induced antiproliferative effects and cell death caused by SMARCA2 depletion in SMARCA4 mutant cancer cells, and in acute myeloid leukemia cells dependent on SMARCA4 ATPase activity. These findings exemplify a successful biophysics and structure driven campaign to degrade targets previously considered undruggable, and pave the way towards new therapeutics for the treatment of tumors sensitive to the loss of BAF complex ATPases. Citation Format: Manfred Koegl, William Farnaby, Claire Whitworth, Michael Roy, Emelyne Diers, Nicole Trainor, Steffen Steurer, Carina Riedmueller, Teresa Gmaschitz, Johannes Wachter, Christian Dank, Michael Gallant, Bernadette Sharps, Klaus Rumpel, Elisabeth Traxler, Romario Lorenz, Oliver Petermann, Peter Greb, Harald Weinstabl, Gerd Bader, Andreas Zoephel, Alexander Weiss-Puxbaum, Joerg Rinnenthal, Heribert Arnnhof, Nicola Wiechens, Meng-Ying Wu, Tom Owen-Hughes, Peter Ettmayer, Mark Pearson, Darryl B. McConnell, Alessio Ciulli. Structure-based PROTAC design demonstrates BAF complex ATPase vulnerabilities in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3849.
Abstract 2129: CPTAC: Biospecimen accrual for proteogenomics
Authors: Mathangi Thiagarajan
Journal: Cancer Research (2019)

Abstract The Clinical Proteomics Tumor Analysis Consortium (CPTAC) is a National Cancer Institute initiative that seeks to uncover the molecular basis of cancer using a proteogenomic approach to study prospective cancer specimens from treatment naïve patients. Leidos Biomed provides an infrastructure for supporting the collection of high quality biospecimens specific to proteogenomics and the corresponding clinical data, in addition to project and subcontract management for the program. The proportion of biospecimens so far from racial and ethnic minority patients are underrepresented, which preclude equitable research across all patient groups for cancer treatment. CPTAC program seeks diversity in the accrual cohort and an effort is ongoing to encourage the participation of tissue source sites serving racial and ethnic minorities that can contribute high quality biospecimens towards the collection. CPTAC applies the understanding of the molecular basis of cancer to identify biomarker candidates. CPTAC Phase II completed in 2016, collecting over 350 cases from breast, colon and ovarian patients. CPTAC Phase III that is in progress began to collect and analyze 200 cases from each of ten additional cancers. Analysis is close to completion for uterine corpus endometrial carcinoma, kidney clear cell renal cell carcinoma and lung adenocarcinoma while accruals are ongoing for 7 other cancer types. The study entails collection and pathology evaluation of biospecimens, high-quality clinical data and images from clinical sites from around the world. A biorepository evaluates and processes the biospecimens, sending nucleic acids to a sequencing center and tissues to proteomics groups. Data are combined and analyzed by analysis and translational centers. Genomic data are made available to the research community through the NCI Genomic Data Commons(GDC). Proteomic data are made available through CPTAC’s Data Coordinating Center(DCC). Imaging data are made available through The Cancer Imaging Archive (TCIA). The program is expanding and initiating biospecimen collection for proteogenomic analysis of ten additional rare tumor types. Citation Format: Mathangi Thiagarajan. CPTAC: Biospecimen accrual for proteogenomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2129.
Abstract 12171: Elevated Pulmonary Artery Pressure is Associated With Diffuse Myocardial Fibrosis in Adolescents and Young Adults With Fontan Circulation: Results of a Prospective Investigation of Invasive Hemodynamics and Cardiac Magnetic Resonance Imaging
Authors: Ryan A Moore, Vien Truong, Sean M Lang, Konstantin Averin, Mantosh Rattan, Gruschen R Veldtman, Elaine M Urbina, Phil Khoury, Andrew N Redington, Wojciech Mazur, James F Cnota, MIchael D Taylor, Bryan Goldstein
Journal: Circulation (2018)

Introduction: Diastolic dysfunction is increasingly recognized as a contributor to failing Fontan circulation. The relationship between invasive hemodynamics (IHD) and diffuse myocardial fibrosis (...
Organic and inorganic arsenic compounds sensitize human bronchial epithelial cells to hydrogen peroxide-induced DNA damage
Authors: Alejandro R. Molinelli, Miroslav Styblo, Jun Nakamura, James A. Swenberg, Michael C. Madden
Journal: Cancer Research (2005)

3054  The lungs are a target organ for arsenic carcinogenesis, however, its mechanism of action remains unclear. Furthermore, it has been suggested that inorganic arsenic (iAs) can potentiate DNA damage induced by other agents. Once inside the human body iAs generally undergoes two different metabolic changes. Pentavalent forms of the semi-metal can be reduced to their trivalent forms; and the inorganic forms can undergo a sequence of methylation reactions. Recent studies suggest that methylated forms of trivalent arsenic can be more cytotoxic and genotoxic than the inorganic forms. To study the possible mechanistic link between arsenic and lung carcinogenesis we examined the induction of DNA breaks in human bronchial epithelial cells by organic and inorganic arsenicals. We also investigated whether these arsenicals could modify DNA damage caused by hydrogen peroxide, a potent oxidant. To assess DNA single-strand breaks (SSBs) we utilized the alkaline single cell gel electrophoresis technique (comet assay). The human bronchial epithelial cell line (BEAS-2B) was exposed to iAs (as sodium arsenite) or dimethylarsine iodide (DMAs), a dimethylated form of trivalent arsenic, at non-cytotoxic concentrations as determined by the neutral red assay. We did not find any statistically significant increases in SSBs between the control and iAs-treated cells (1 nM - 10 μM) after a 4h exposure. However, we found that DMAs increased DNA SSBs at 1-10 μM after 4h. To test if arsenic compounds have any effect on hydrogen peroxide-induced DNA SSBs we pre-treated the BEAS-2B cells with iAs or DMAs for 4h. After pre-treatment the cells were rinsed and exposed to 20 μM hydrogen peroxide for 30 min. at 4°C. We found that hydrogen peroxide-exposed cells that were pre-treated with iAs (at 10 μM) and DMAs (at 1 and 10 μM) had a statistically significant increase (p
Rivaroxaban Plus Aspirin Versus Aspirin in Relation to Vascular Risk in the COMPASS Trial
Authors: Sonia S. Anand, John W. Eikelboom, Leanne Dyal, Jackie Bosch, Christoph Neumann, Petr Widimsky, Alvaro A. Avezum, Jeffrey Probstfield, Nancy Cook Bruns, Keith A.A. Fox, Deepak L. Bhatt, Stuart J. Connolly, Salim Yusuf
Journal: Journal of the American College of Cardiology (2019)

The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial showed that the combination of low-dose rivaroxaban and aspirin reduced major vascular events in patients with stable vascular disease.The purpose of this study was to identify subsets of patients at higher risk of recurrent vascular events, which may help focus the use of rivaroxaban and aspirin therapy.COMPASS patients with vascular disease were risk stratified using 2 methods: the REACH (REduction of Atherothrombosis for Continued Health) atherothrombosis risk score and CART (Classification and Regression Tree) analysis. The absolute risk differences for rivaroxaban with aspirin were compared to aspirin alone over 30 months for the composite of cardiovascular death, myocardial infarction, stroke, acute limb ischemia, or vascular amputation; for severe bleeding; and for the net clinical benefit.High-risk patients using the REACH score were those with 2 or more vascular beds affected, history of heart failure (HF), or renal insufficiency, and by CART analysis were those with ≥2 vascular beds affected, history of HF, or diabetes. Rivaroxaban and aspirin combination reduced the serious vascular event incidence by 25% (4.48% vs. 5.95%, hazard ratio: 0.75; 95% confidence interval: 0.66 to 0.85), equivalent to 23 events prevented per 1,000 patients treated for 30 months, at the cost of a nonsignificant 34% increase in severe bleeding (1.34; 95% confidence interval: 0.95 to 1.88), or 2 events caused per 1,000 patients treated. Among patients with ≥1 high-risk feature identified from the CART analysis, rivaroxaban and aspirin prevented 33 serious vascular events, whereas in lower-risk patients, rivaroxaban and aspirin treatment led to the avoidance of 10 events per 1,000 patients treated for 30 months.In patients with vascular disease, further risk stratification can identify higher-risk patients (≥2 vascular beds affected, HF, renal insufficiency, or diabetes). The net clinical benefit remains favorable for most patients treated with rivaroxaban and aspirin compared with aspirin.
Abstract 835: Altered DNA modifications in Barrett’s oesophagus and oesophageal adenocarcinoma
Authors: Skirmantas Kriaucionis, Marketa Tomova, Sophie Kirschner, Pijus Brazauskas, Mankgopo Kgatle, Richard Owen, Michael White, Benjamin Schuster-Boeckler, Xin Lu
Journal: Cancer Research (2019)

Abstract Cytosine in human DNA can be modified by DNA methyltransferases (DNMTs) and the Ten-Eleven Translocation (TET) family of oxygenases. Activity of these enzymes results in four modifications, among which 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are the major ones. Different patterns of localisation of both these modifications relate to gene transcription and the developmental origin of different cell types. Cancers have been shown to have globally altered DNA modifications, however it is poorly understood when in carcinogenesis the shift in DNA modifications happens and how it influences tumour growth. Here we mapped 5mC and 5hmC genome-wide at single nucleotide resolution in Barrett’s oesophagus, a well-known pre-malignant precursor of oesophageal adenocarcinoma (OAC). To get better insight into alterations in Barrett’s oesophagus (BO), we also analysed samples from OAC, adjacent normal oesophagus and gastric and duodenal epithelia. We found substantial global hypomethylation outside genic regions in Barrett’s oesophagus. Specific hypermethylation was evident in gene regulatory regions as defined by DNAseI hypersensitive sites. Moreover, we observed elevated methylation at CpG islands in a fraction of genes, which have reduced expression in Barrett’s oesophagus. While we find 5hmC depleted both in BO and OAC, distribution of the modification in CpG islands is different. Overall our results demonstrate that cancer-specific epigenetic alterations can already be found in benign Barrett’s oesophagus, suggesting early redistribution of DNA modifications in the process of transformation. Citation Format: Skirmantas Kriaucionis, Marketa Tomova, Sophie Kirschner, Pijus Brazauskas, Mankgopo Kgatle, Richard Owen, Michael White, Benjamin Schuster-Boeckler, Xin Lu. Altered DNA modifications in Barrett’s oesophagus and oesophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 835.
Abstract 18075: Long and Short-Term Outcomes of Alcohol Septal Ablation at Tertiary Care Center
Authors: Prakriti Gaba, Jeffrey Geske, Mackram Eleid, Rick Nishimura
Journal: Circulation (2017)

Background: In hypertrophic obstructive cardiomyopathy (HOCM) with medically-refractory symptoms, septal reduction therapy is indicated. Considerable debate exists regarding short- and long-term ou...