tbuckley/cabot-search huggingface dataset:
Abstract PD7-01: Bromodomain protein 3 is a novel therapeutic target in invasive lobular carcinoma
Authors: K Haley, L Walsh, B Moran, S Das, F Tarrant, C Caldas, R Bernards, W Gallagher, D O'Connor, T Ni Chonghaile
Journal: Cancer Research (2019)

Abstract Invasive lobular carcinoma (ILC) is a subtype of breast cancer comprising 10% of breast tumours. ILC is characterised by a loss of E-cadherin, and is generally estrogen receptor (ER) positive. The majority of ILC breast cancers are treated with endocrine therapy, although approximately one in three women are de novo resistant to therapy. To identify novel therapeutic targets for the treatment of ILC, we carried out RNA sequencing on 61 primary ILC samples. We found that high expression of the epigenetic reader, bromodomain protein 3 (BRD3) was associated with poor recurrence free survival. We also validated this finding in a separate cohort of 99 ILC patient samples using the METABRIC cohort. Next, we assessed ILC cell lines for sensitivity to JQ1, an inhibitor of BET family proteins. We found that JQ1 inhibited cell growth in all the cell lines tested. Interesting, two of the ILC cell lines were sensitive to JQ1-induced apoptosis, whereas two of the cell lines were inherently resistant to JQ1-induced apoptosis. Using dynamic BH3 profiling we showed that the JQ1 resistant cell lines were dependent on anti-apoptotic protein BCL-XL following JQ1 treatment. Interestingly, we show both in 2D and 3D cultures that JQ1 is synergistic when combined with the BH3 mimetic, ABT-263. Highlighting that combination treatment with JQ1 and ABT-263 may be a novel potential therapeutic option for ILC. To unveil the mechanism underlying resistance to JQ1-induced apoptosis, we performed paired-end RNA sequencing and compared differentially expressed genes in JQ1 sensitive and JQ1 resistant ILC cell lines. DAVID gene ontology analysis identified 6 pathways differentially upregulated in the JQ1 resistant ILC cell line including MAPK, Wnt, and insulin resistance signaling. Interestingly, we found that ILC cell lines, which were resistant to BET inhibition with JQ1, demonstrated high levels of FGFR1-4 both at the mRNA level and the protein level. Combination treatment with JQ1 and the FGFR1 inhibitor PD173074 or following knockdown of FGFR with siRNA, resulted in increased cell death in JQ1 resistant cells. Currently, we are assessing how FGFR signaling enables survival of ILC cells following JQ1 treatment and determining the exact function of BRD3 in ILC. In conclusion, we have identified a novel therapeutic target, BRD3, which may be inhibited using JQ1 in combination with BH3 mimetic ABT-263 or FGFR1 inhibitor for a more effective treatment strategy for ILC. Citation Format: Haley K, Walsh L, Moran B, Das S, Tarrant F, Caldas C, Bernards R, Gallagher W, O'Connor D, Ni Chonghaile T. Bromodomain protein 3 is a novel therapeutic target in invasive lobular carcinoma [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD7-01.
An Active Inference Approach to Interoceptive Psychopathology
Authors: Martin P. Paulus, Justin S. Feinstein, Sahib S. Khalsa
Journal: Annual Review of Clinical Psychology (2019)

Interoception refers to the process by which the nervous system senses and integrates signals originating from within the body, providing a momentary mapping of the body's internal landscape and its relationship to the outside world. Active inference is based on the premise that afferent sensory input to the brain is constantly shaped and modified by prior expectations. In this review we propose that interoceptive psychopathology results from two primary interoceptive dysfunctions: First, individuals have abnormally strong expectations of the situations that elicit bodily change (i.e., hyperprecise priors), and second, they have great difficulty adjusting these expectations when the environment changes (i.e., context rigidity). Here we discuss how these dysfunctions potentially manifest in mental illness and how interventions aimed at altering interoceptive processing can help the brain create a more realistic model of its internal state.
Hepatocellular carcinoma: killing one bird with two stones
Authors: Marina Ruiz de Galarreta, Amaia Lujambio
Journal: Gut (2019)

Hepatocellular carcinoma (HCC) is a very aggressive disease and represents the most frequent form of liver cancer. Although treatment of HCC has greatly improved over the last decade, most patients with HCC diagnosed at advanced stages are ineligible for curative ablative therapies such as liver resection or liver transplantation.1 Several multikinase inhibitors, including sorafenib, regorafenib, lenvatinib and cabozantinib, are approved by the Food and Drug Administration for the treatment of patients with advanced HCC, providing limited survival benefits.1 In the last 2 years, the programmed cell death receptor 1 (PD-1) immune checkpoint inhibitors (ICIs) nivolumab and pembrolizumab have also been approved for the treatment of patients with advanced HCC. While immunotherapies have aroused tremendous enthusiasm among clinicians and scientists,2 only a small percentage of patients respond with clinical benefit. One strategy to improve clinical outcomes would be to select those patients who are most likely to respond to ICIs by defining accurate and validated biomarkers of response. A second approach, which is somehow bolder, is to combine two drugs that synergise at killing the tumour cells. In fact, combination immunotherapies have proven effective in melanoma,3 where the first immunotherapy sensitises the tumour cells to the second one.

Activation …
Abstract A30: The role of neutrophil extracellular traps in promoting metastatic cancer following surgical stress
Authors: Samer Tohme, Hai Huang, Alexis Chidi, Richard Simmons, Allan Tsung
Journal: Cancer Research (2016)

Abstract Background: Surgical removal of malignancies may enhance the risk of recurrence but mechanisms remain poorly understood. Neutrophils, first line responders after surgical stress, can facilitate cancer progression. Neutrophils can expel nuclear DNA studded with proteins to form web-like structures known as Neutrophil Extracellular Traps (NETs) in response to stress. Here we aim to characterize the role of NETs in promoting metastatic cancer growth after surgical stress that is currently entirely unknown. Methods: We used a standardized mouse model of partial hepatic ischemia reperfusion, to stimulate surgical stress, directly or five days after splenic injection of MC38 colon carcinoma cells. Results: We found that NET formation is significantly increased in the immediate post-operative period in humans undergoing curative liver resection for colorectal cancer metastases. The risk of liver metastases recurrence was 4.22 times higher in patients with increased post-operative NET formation. In the murine model, we demonstrated increased NET deposition after surgical stress and this was associated with both increased formation of metastases and growth of already established micrometastatic disease. In vitro, NETs increase growth, invasion, migration and adhesion in multiple cancer cell lines. All the above effects were abrogated by NET inhibition with DNAse. NETs exert their pro-tumorigenic effects by releasing HMGB1 and activating TLR-9 dependent pathways in the cancer cells. In addition, as metastatic tumors continue to grow, hypoxia within the tumor microenvironment induces further neutrophil recruitment and NET formation that further accelerates tumor growth. Conclusions: These findings implicate NETs in the process of cancer metastasis progression and recurrence after surgery and identifies NETs as potential therapeutic targets. Citation Format: Samer Tohme, Hai Huang, Alexis Chidi, Richard Simmons, Allan Tsung. The role of neutrophil extracellular traps in promoting metastatic cancer following surgical stress. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A30.
A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy
Authors: Arri Coomarasamy, Adam J. Devall, Versha Cheed, Hoda Harb, Lee J. Middleton, Ioannis D. Gallos, Helen Williams, Abey K. Eapen, Tracy Roberts, Chriscasimir C. Ogwulu, Ilias Goranitis, Jane P. Daniels, Amna Ahmed, Ruth Bender-Atik, Kalsang Bhatia, Cecilia Bottomley, Jane Brewin, Meenakshi Choudhary, Fiona Crosfill, Shilpa Deb, W. Colin Duncan, Andrew Ewer, Kim Hinshaw, Tom Holland, Feras Izzat, Jemma Johns, Kathiuska Kriedt, Mary-Ann Lumsden, Padma Manda, Jane E. Norman, Natalie Nunes, Caroline E. Overton, Siobhan Quenby, Sandhya Rao, Jackie Ross, Anupama Shahid, Martyn Underwood, Nirmala Vaithilingam, Linda Watkins, Catherine Wykes, Andrew Horne, Davor Jurkovic
Journal: New England Journal of Medicine (2019)

Bleeding in early pregnancy is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may improve pregnancy outcomes in women who have bleeding in early pregnancy.We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data.A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P = 0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P = 0.08). The incidence of adverse events did not differ significantly between the groups.Among women with bleeding in early pregnancy, progesterone therapy administered during the first trimester did not result in a significantly higher incidence of live births than placebo. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment program; PRISM Current Controlled Trials number, ISRCTN14163439.).
Antibacterial Activity of Ticagrelor in Conventional Antiplatelet Dosages Against Antibiotic-Resistant Gram-Positive Bacteria
Authors: Patrizio Lancellotti, Lucia Musumeci, Nicolas Jacques, Laurence Servais, Eric Goffin, Bernard Pirotte, Cécile Oury
Journal: JAMA Cardiology (2019)

Antibacterial Activity of Ticagrelor in Conventional Antiplatelet Dosages Against Antibiotic-Resistant Gram-Positive BacteriaTicagrelor reversibly inhibits the platelet adenosine diphosphate P2Y 12 receptor (P2Y 12 ). 1 It is approved for prevention of cardiovascular events in patients with atherosclerotic cardiovascular disease and shows evidence of superior clinical performance compared with other P2Y 12 inhibitors.A post hoc analysis of the Comparison of Ticagrelor (AZD6140) and Clopidogrel in Patients With Acute Coronary Syndrome (PLATO) trial 2 revealed that patients treated with ticagrelor had a lower risk of infection-related death than those treated with clopidogrel bisulfate. 3More recently, in the Targeting Platelet-Leukocyte Aggregates in Pneumonia With Ticagrelor (XANTHIPPE) study, ticagrelor was associated with improved lung function in patients hospitalized for pneumonia. 4We therefore questioned whether ticagrelor or its metabolites could possess antimicrobial properties.Methods | Tic agrelor and its major metabolites (M5 AR-C133913, M7, M8 AR-C124910) 5 were synthetized and tested in time-kill assays against gram-positive methicillinresistant Staphylococcus epidermidis RP62A (MRSE) (ATCC 35984); methicillin-sensitive Staphylococcus aureus (MSSA) (ATCC 25904, ATCC 6538); glycopeptide intermediate S aureus (GISA) Mu-50 (ATCC 700699); methicillin-resistant S aureus (MRSA) (ATCC BAA-1556); Enterococcus faecalis (ATCC 29212); vancomycin-resistant E faecalis (VRE) (ATCC BAA-2365); and Streptococcus agalactiae (ATCC 12386) and against gram-negative Escherichia coli (ATCC 8739) and Pseudomonas aeruginosa (PAK laboratory strain).Biofilm formation was assessed in vitro with crystal violet staining and in a mouse model of S aureus polyurethane-implant infection using Xen-29 bacteria (Perkin Elmer).Infected disks were implanted in specific pathogen-free BALB/cAnCrl mice (Charles River).The mouse protocol was approved by the ethical committee of Liège University.
Abstract LB-201: Updated results from a Phase I study of AV-951 (KRN951), a potent and selective VEGFR-1, -2 and -3 tyrosine kinase inhibitor, in patients with advanced solid tumors
Authors: Ferry A.l.m. Eskens, Maja J.a. de Jonge, Brooke Esteves, Monette Cotreau, Pankaj Bhargava, John Ryan, Leny van Doorn, Toshiyuki Isoe, Kunihiko Hayashi, Lena Ekman, Herman Burger, Jaap Verweij
Journal: Cancer Research (2008)

Abstract Background: AV-951 inhibits phosphorylation of VEGF receptors (VEGFR)-1, -2, and -3 at picomolar concentrations (IC50 of 0.21, 0.16, and 0.24 nM, respectively) and inhibits c-Kit and PDGFR at 10-times higher concentrations (IC50 of 1.63 and 1.72 nM, respectively). In a dose-escalation study of AV-951 given orally on a 4 week on, 2 week off schedule, the maximum tolerated dose (MTD) was determined to be 1.5 mg/day and clinical activity was observed in renal (RCC), colon, and lung cancers [Proc ASCO 2006;24(18S):2034]. Thereafter, the study was amended to enroll an additional 10 patients at 1.0 mg/day in order to compare the safety profile, pharmacokinetics (PK), effects on tumor blood flow, and antitumor activity across all dose levels. Results: 40 patients (26M/14F), were enrolled at AV-951 doses of 1 (n=16), 1.5 (n=16), and 2.0 mg (n=8). At 2 mg DLTs consisting of grade 3 proteinuria, grade 3 ataxia, and grade 4 intracranial hemorrhage were seen in one patient each. The primary toxicity across all dose levels was hypertension (HTN), as listed in Table 1. HTN was dose-dependent, and could be controlled with standard anti-hypertensive agents. Only two patients, both at 1.5 mg, required dose reduction to 1.0 mg for control of HTN. PK analysis revealed dose dependent drug exposure and peak plasma concentrations. DCE-MRI analysis indicated a decrease in tumor perfusion in selected patients. Among 9 patients with RCC, there were 2 confirmed partial responses at 2.0 mg (n=1) and 1.5 mg (n=1) lasting 128 weeks and 42 weeks, respectively, and 7 patients with stable disease (lasting &amp;gt;12 wks) at 1.0 mg (n=5), 1.5 mg (n=1), and 2.0 mg (n=1). Clinical activity was observed in multiple tumor types. Conclusions: AV-951 could be safely administered at 1.0 and 1.5 mg doses. The primary toxicity was dose-dependent HTN, a biomarker of VEGFR inhibition. Clinical activity was observed across all dose levels. In future combination studies, AV-951 may be administered at a dose of either 1.0 mg or 1.5 mg. Table 1.Primary toxicity of AV-951 across all dose levelsHypertensionAV-951 DoseGrade 1-2Grade 3Grade 4All Grades1.0 mg (n=16)6% (n=1)31% (n=5)0%37% (n=6)1.5 mg (n=16)0% (n=0)56% (n=9)0%56% (n=9)2.0 mg (n=8)25% (n=2)75% (n=6)0%100% (n=8)
Post-conflict zones: an explosive area of research
Authors: Ewan Barron
Journal: BMJ (2010)

Leeds 

Most post-conflict zones are seen as limited access areas for research, and few robust papers have been published. This is an overview of my research experience in the post-conflict environment of Liberia. It demonstrates some of the challenges faced when researching in this volatile area and addresses methods and strategies for overcoming these barriers. I hope to encourage individuals who are passionate about a subject to strive for their research and not to shy away from any challenge. Research in post-conflict zones has the potential for helping target important healthcare initiatives.

#### Summary points

Fifty yards (55m) to my right, children play football with the shells of old hand grenades. From far in the distance, the rumble of an unexpected explosion shakes the ground where I stand, closely followed by the smell of discharged explosives sweeping by in the afternoon heat of Lofa county, Liberia. With the dangers of unexploded ordnance lying throughout this lush green country, I ask myself whether my research will in some small way help protect these children and improve their understanding of the hidden dangers of unexploded remnants of war (this phrase refers to an array of explosive weapons, including artillery shells, grenades, mortars, rockets, bombs, and explosive submunitions). I have never been one to take the easy path, and embarking on research into …
Abstract 15785: Prognostic Value of Silent Myocardial Infarction in End-stage Renal Disease
Authors: Ayman Farag, John Neill, Harish Doppalapudi, Vineeta Kumar, Dana Rizk, Ami Iskandrian, Fadi G Hage
Journal: Circulation (2016)

Introduction: Patients with end-stage renal disease (ESRD) have an increased risk of cardiac events including myocardial infarction (MI). Silent MIs (SMIs) have been shown to be more common in pati...
Abstract P1-20-06: Association of circulating tumor DNA with clinical outcomes in metastatic breast cancer patients
Authors: AR Tan, J Symanowski, EN Kim, M Hosking, CD Morris, V Plagnol, CJ Farhangfar, JL Ersek
Journal: Cancer Research (2019)

Abstract Background: Circulating tumor DNA (ctDNA) can be used as a non-invasive method to detect and quantify genomic alterations (GA) in blood. We evaluated the relationship between ctDNA features, radiographic disease progression (RDP) and progression-free survival (PFS) in patients (pts) with metastatic breast cancer (MBC). Methods: A retrospective analysis of 32 female MBC pts with plasma ctDNA tested prior to a radiology scan was performed. Plasma ctDNA tests were run by Inivata using a 36-gene panel for detecting point mutations, short insertions/deletions, and copy number variations. ctDNA features were tabulated for each pt and included number of genomic alterations (numGA), maximum mutant allele frequency (maxMAF), and sum of mutant allele frequency (sumMAF). Univariate and multivariable logistic regression (LR) models were used to explore ctDNA features associated with RDP. Univariate and multivariable Cox proportional hazards models were used to identify ctDNA features that were associated with PFS. All models included ctDNA features as continuous variables. Results: Frequency of subtypes were 38% HR+HER2-, 28% HR+HER2+, 28% triple-negative, and 6% HR-HER2+. 97% had prior chemotherapy; 92% of HR+HER2-negative pts had prior endocrine therapy. 20 of 32 samples (69%) had GAs. The most common GAs were TP53 (50%), ESR1 (25%), PIK3CA (19%), and GATA3 (9.4%). Median numGA was 1 (0-12); median maxMAF was 1.9 (0-65.5); median sumMAF was 2.2 (0-157.2). Univariate LR analysis identified numGA (p=0.025), maxMAF (p=0.034), and sumMAF (p=0.049) to be significantly associated with RDP; numGA (p=0.056) and maxMAF (p=0.109) were retained in the final multivariable LR model. Univariate Cox regression analysis showed that numGA (HR=1.32, p&amp;lt;0.001), maxMAF (HR=1.03, p=0.011), and sumMAF (HR=1.02, p=0.002) were significantly associated with PFS; numGA (HR= 1.30, p=0.001) and maxMAF (HR= 1.02, p=0.045) were retained in the final multivariable Cox model. Conclusions: Blood ctDNA profiling contributes to the prediction of RDP and PFS in MBC pts. High number of alterations and high allele fraction of these alterations were associated with worse clinical outcomes. These data provide an overview of the ctDNA dynamics in treated MBC pts. Citation Format: Tan AR, Symanowski J, Kim EN, Hosking M, Morris CD, Plagnol V, Farhangfar CJ, Ersek JL. Association of circulating tumor DNA with clinical outcomes in metastatic breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-20-06.
The Importance of Incorporating Frailty Screening Into Surgical Clinical Workflow
Authors: Elizabeth L. George, Shipra Arya
Journal: JAMA Network Open (2019)

Armin Shahrokni, MD, MPH; Amy Tin, MA; Koshy Alexander, MD; Saman Sarraf, MD; Anoushka Afonso, MD; Olga Filippova, MD; Jennifer Harris, MD; Robert J. Downey, MD; Andrew J. Vickers, PhD; Beatriz Korc-Grodzicki, MD, PhD
Abstract 4314: Exclusive delivery of <i>mazF</i> in cancer cells by <i>Listeria monocytogenes</i>
Authors: Maryam Saffarian, Jeremy Tzeng
Journal: Cancer Research (2017)

Abstract Programmed cell death (PCD), an active process that leads to cell suicide, is a critical mechanism in every organism. MazF, a bacterial ribonuclease protein, can trigger PCD in bacterial cells and also induce Bak-dependent apoptosis in mammalian cells. This bacterial ribonuclease cleaves mRNAs at ACA sequences leading to inhibition of protein synthesis in cells. Hence, we hypothesized that the overexpression of MazF proteins in cancer cells could result in the induction of apoptosis. In the present study, the ACA-less mazF gene was inserted downstream of the Internal Ribosome Entry Site (IRES) and under the control of T7 promoter. The plasmid was electroporated into Listeria monocytogenes harboring pCSA1 that encodes T7 RNA polymerase under the control of the listeria actA promoter. Subsequently, the bacteria were functionalized with Trastuzumab (Herceptin®) to deliver the mazF mRNA into HER2/neu breast cancer cells. The results showed that MazF protein has an ability to induce apoptosis in HER2/neu breast cancer cells. This finding is the first report of the application and delivery of MazF as an anti-cancer agent for the induction of apoptosis in HER2/neu breast cancer cell line. This research suggests cancer therapy that targets only cancer cells but not healthy cells and offers more advantages, e.g., inexpensiveness, target tissue specificity, easy and safe delivery, in comparison to other gene therapy vectors or direct protein administration. Citation Format: Maryam Saffarian, Jeremy Tzeng. Exclusive delivery of mazF in cancer cells by Listeria monocytogenes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4314. doi:10.1158/1538-7445.AM2017-4314
Abstract 14787: Repeated Psychosocial Stress Enhances Neutrophil Elastase Activity in Adipose Tissue: Possible Mechanisms of Highly Vulnerable to Diet-induced Insulin Resistance
Authors: Shinichiro Motoyama, Hiroyuki Yamada, Keita Yamamoto, Naotoshi Wada, Makoto Saburi, Takeshi Sugimoto, Kensuke Terada, Masakazu Kikai, Noriyuki Wakana, Satoaki Matoba
Journal: Circulation (2017)

Background: Psychosocial stress is closely associated with the development of insulin resistance; however, the underlying mechanisms remain undefined. Method and Result: Eight-week-old male wild-ty...