tbuckley/cabot-search huggingface dataset:
Abstract 4200: New potential therapeutic applications of WX-UK1, as a specific and potent inhibitor of human trypsin-like proteases
Authors: Emil Oldenburg, Christine R. Schar, Eva Lange, Terry F. Plasse, Danielle T. Abramson, Reza Fathi, Eric M. Towler, Mark Levitt, Jan K. Jensen
Journal: Cancer Research (2018)

Abstract WX-UK1 (the active metabolite of upamostat) was originally developed as an inhibitor of the serine protease urokinase (uPA) with a Ki ~1 uM. To identify more sensitive targets, we performed a bioinformatic analysis of the ~200 human trypsin-like serine proteases, many of which play crucial roles in homeostasis and disease. Among these we selected a subset for biochemical analysis based on an inspection of modelled 3D structures of WX-UK1:protease complexes and sequence alignment of binding site residues. Samples of the selected proteases were prepared and characterized for their binding to WX-UK1; enzymatically with respect to inhibition constant (Ki) and by surface plasmon resonance with respect to dissociation constant (kd). We now report that WX-UK1 is a potent and specific inhibitor of five human serine proteases (trypsin-3, trypsin-2, trypsin-1 and matriptase-1 and trypsin-6), with Ki's down to the low nanomolar range, 19 nM for trypsin-3. Several of these serine proteases are known to be associated with cancer progression and metastasis. As a compound with an established clinical safety profile, targeted use of upamostat in oncology and extension to non-oncology indications may be assessed. Citation Format: Emil Oldenburg, Christine R. Schar, Eva Lange, Terry F. Plasse, Danielle T. Abramson, Reza Fathi, Eric M. Towler, Mark Levitt, Jan K. Jensen. New potential therapeutic applications of WX-UK1, as a specific and potent inhibitor of human trypsin-like proteases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4200.
YES1 amplification as a mechanism of acquired resistance (AR) to EGFR tyrosine kinase inhibitors (TKIs) identified by a transposon mutagenesis screen and clinical genomic testing.
Authors: Pang-Dian Fan, Giuseppe Narzisi, Anitha Jayaprakash, Elisa Venturini, Nicolas Robine, Peter Smibert, Soren Germer, Emmet Jordan, Lu Wang, Achim A Jungbluth, Lee Spraggon, Christine Marie Lovly, Mark G. Kris, Helena Alexandra Yu, Gregory J. Riely, Harold Varmus, Katerina A. Politi, Marc Ladanyi
Journal: Journal of Clinical Oncology (2017)

9043 Background: Overcoming AR to EGFR TKIs remains challenging, and in many cases the mechanisms are still unclear. To identify novel mechanisms of resistance to EGFR TKIs, we performed a forward genetic screen using transposon mutagenesis in EGFR-mutant lung adenocarcinoma cells. Methods: EGFR TKI-sensitive PC9 cells were co-transfected with plasmids encoding a mutagenic piggyBactransposon and hyperactive piggyBac transposase. Transposon-tagged, afatinib-resistant clones were generated by sequential selection of transfected cells with puromycin and 1µM afatinib. Transposon insertion sites were mapped using a modified TraDIS-type method and next-generation sequencing (NGS). Selected clones were characterized using Western blots, receptor tyrosine kinase (RTK) arrays, and viability assays following treatment with TKIs or siRNA-mediated gene knockdowns. We reviewed MSK-IMPACT™ NGS data on 100 patient tumors with EGFR TKI AR. Available tumor samples were analyzed by fluorescence in situ hybridization (FISH). Results: In 187/188 afatinib-resistant clones, transposon insertion sites consistent predominantly with gene upregulation were found in MET, the Src family kinase (SFK) member YES1, or both. Clones with activating YES1 insertions exhibited resistance to all three generations of EGFR TKIs; high levels of expression of tyrosine-phosphorylated YES1; sensitivity to the SFK TKI dasatinib and to siRNA-mediated knockdown of YES1; and tyrosine phosphorylation of YAP1 and ERBB3. A query of the MSK-IMPACT™ data on EGFR TKI AR patients revealed amplification of YES1 and no alteration of MET, ERBB2 or BRAF in 3/54 T790M-negative (95% CI 1 to 16%) and 1/46 (95% CI 1 to 12%) T790M-positive cases. Amplification of YES1was confirmed by FISH in 2/2 cases, and was absent in matched pre-TKI samples in 2/2 cases. Conclusions: YES1 amplification is found in 4% of patients with acquired resistance to EGFR TKIs and is potentially targetable by Src family kinase inhibitors. Forward genetic screens using transposon mutagenesis and routine clinical NGS of patient samples can identify novel mechanisms of resistance to targeted therapies.
Abstract 115: Crosstalk between breast cancer cells and macrophages in tumor microenvironment induces inflammasome activation
Authors: Jeong-Hoon Jang, Do-Hee Kim, Sin-Aye Park, Su-Jung Kim, Young-Joon Surh
Journal: Cancer Research (2018)

Abstract The inflammasome is a multiprotein complex that is composed of NOD-like receptor, ASC and caspase-1. During the activation of the inflammasome, pro-interleukin (IL)-1β is cleaved by active caspase-1 to produce mature IL-1β. Although the inflammasome plays a controversial role in many types of tumor, emerging evidence indicates that the inflammasome functions as a negative regulator of breast cancer progression. Notably, high levels of IL-1β in breast cancer tissues are associated with a more virulent tumor phenotype and poor prognosis. However, it remains unresolved how IL-1β is accumulated in breast tumor microenvironment. In the present study, we have found that various human breast cancer cells (MDA-MB-231, MDA-MB-468, SKBr3, MCF-7 and T47D) retain cleaved-IL-1β whereas secretion of IL-1β into the culture medium was not observed. However, IL-1β was detected in the medium when human breast cancer cells were co-cultured with human monocytic (THP-1) cells. Among the various human breast cancer cells, triple-negative breast cancer cells (MDA-MB-231 and MDA-MB-468) effectively stimulated secretion of IL-1β. When co-cultured with MDA-MB-231 cells, THP-1 cells exhibited the elevated levels of pro- and cleaved-IL-1β. Consistent with this result, there was a marked increase in the secretion of IL-1β from THP-1 cells treated with the conditioned media of triple-negative breast cancer cells. Both triple-negative MDA-MB-231 and MDA-MB-468 breast cancer cells induced ASC oligomerization, which is a hallmark of inflammasome activation. Thus, it is likely that soluble factors from breast cancer cells promote IL-1β secretion from macrophages through activation of inflammasomes. In conclusion, breast cancer cells drive inflammasome activation in macrophages, thereby stimulating the accumulation of IL-1β in the tumor microenvironment. The secreted-IL-1β, in turn, promotes breast cancer progression. Citation Format: Jeong-Hoon Jang, Do-Hee Kim, Sin-Aye Park, Su-Jung Kim, Young-Joon Surh. Crosstalk between breast cancer cells and macrophages in tumor microenvironment induces inflammasome activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 115.
Abstract 16551: Efficacy and Safety of Oral Anticoagulation in 21105 Patients With Atrial Fibrillation Stratified by Diabetic Status in the ENGAGE AF-TIMI 48 Trial
Authors: Anna Plitt, Christian Ruff, Assen Goudev, Joao Morais, Jeong-Gun Park, Elliott M Antman, Eugene Braunwald, Robert P Giugliano
Journal: Circulation (2016)

Introduction: AF is twice as prevalent in patients with diabetes mellitus (DM) and DM is associated with increased risk of stroke, morbidity, and mortality in patients with AF. We explored outcomes by DM status and randomized anticoagulant in a large AF trial. Methods: 21,105 patients in ENGAGE AF-TIMI 48 trial were stratified into pre-specified categories: no-DM (n=13481); non-insulin dependent DM (NIDDM, n=6354); and IDDM (n=1270). We compared efficacy, safety, and net outcomes adjusted for baseline differences across the 3 groups. We assessed for effect modification by DM status on the relative efficacy and safety of edoxaban vs warfarin. The primary endpoints were stroke/SEE and ISTH major bleeding. Results: Patients with IDDM were younger (mean age 68.8 vs 69.5 vs 71.3 yrs) and had higher BMIs (32.9 vs 31.0 vs 28.4kg/m2) and CHA2DS2-VASc scores (mean 4.8 vs 4.6 vs 4.2) as compared to those with NIDDM or no-DM (each P<0.001). Patients with IDDM (adj HR 1.46, p=0.004), but not those with NIDDM (adj HR ...
Abstract 2356: Prioritizing cancer gene drivers defined in large-scale cancer genome analyses using the SBCDDB
Authors: Justin Y. Newberg, Michael B. Mann, Karen M. Mann
Journal: Cancer Research (2018)

Abstract Next-generation sequencing approaches to identify molecular signatures of cancer have uncovered few frequently altered genes, many infrequently altered genes, and various transcriptional changes associated with cancer initiation/progression. Prioritization of genetic and epigentic alterations in various contexts is therefore important for biological discovery and therapy development. Comparative oncogenomics is a powerful approach to identify drivers that impact cancer development. Importantly, data integration across different experimental systems and data types is imperative to the success of these oncogenomics approaches. Sleeping Beauty (SB) insertional mutagenesis coupled with next generation sequencing forms a powerful cancer gene discovery framework widely used to identify and prioritize candidate drivers in mouse models of human cancers. SB has been used to model over 20 different human cancers and identify cooperating drivers underlying tumor development. Integration of SB data with human cancer genomic and transcriptomic data from The Cancer Genome Atlas (TCGA) / Genomic Data Commons (GDC) is one way to identify and prioritize genes for biological validation and targeted therapies. Our group has built a resource, the Sleeping Beauty Cancer Driver Database (SBCDDB), to identify sets of cancer driver genes associated with specific tumor types or genetic aberrations underling cancer initiation. Using the SBCDDB, in combination with human mutation, copy-number alteration, and mRNA-seq datasets from the Broad Firehose, we have prioritized infrequently mutated driver genes in human tumors that are recurrently altered in SB tumors. Cancer drivers defined in both human tumors and in related mouse models of cancer, using distinct but complimentary methods to discover and catalog mutations, provide strong evidence for a causal role of detectable alteration in tumor initiation and/or progression. This work is an important step in a larger, comparative pan-cancer approach to better define molecular signatures that make up the tumor landscape. Citation Format: Justin Y. Newberg, Michael B. Mann, Karen M. Mann. Prioritizing cancer gene drivers defined in large-scale cancer genome analyses using the SBCDDB [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2356.
Clinical and Genetic Complexities of Left Ventricular Noncompaction
Authors: Samantha Barratt Ross, Christopher Semsarian
Journal: JAMA Cardiology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
Downregulation of TMEM16A Calcium-Activated Chloride Channel Contributes to Cerebrovascular Remodeling During Hypertension by Promoting Basilar Smooth Muscle Cell Proliferation
Authors: MiWang, HuiYang, Ling-YunZheng, ZhengZhang, Yong-BoTang, Guan-LeiWang, Yan-HuaDu, Xiao-FeiLv, JieLiu, Jia-GuoZhou, Yong-YuanGuan
Journal: Circulation (2012)

Background—The Ca2+-activated chloride channel (CaCC) plays an important role in a variety of physiological functions. In vascular smooth muscle cells, CaCC is involved in the regulation of agonist-stimulated contraction and myogenic tone. The physiological functions of CaCC in blood vessels are not fully revealed because of the lack of specific channel blockers and the uncertainty concerning its molecular identity. Methods and Results—Whole-cell patch-clamp studies showed that knockdown of TMEM16A but not bestrophin-3 attenuated CaCC currents in rat basilar smooth muscle cells. The activity of CaCC in basilar smooth muscle cells isolated from 2-kidney, 2-clip renohypertensive rats was decreased, and CaCC activity was negatively correlated with blood pressure (n=25; P<0.0001) and medial cross-sectional area (n=24; P<0.0001) in basilar artery during hypertension. Both upregulation of CaMKII activity and downregulation of TMEM16A expression contributed to the reduction of CaCC in the hypertensive basilar ar...
Ultrasonographic and Biochemical Markers of Human Fetal Cardiac Dysfunction in Placental Insufficiency
Authors: KaarinMäkikallio, OlliVuolteenaho, PenttiJouppila, JuhaRäsänen
Journal: Circulation (2002)

Background— Placental insufficiency may lead to fetal cardiovascular compromise. We sought to determine whether ultrasonographic parameters of fetal cardiovascular function correlate with umbilical arterial levels of biochemical markers of myocardial dysfunction and damage in placental insufficiency. Methods and Results— In 48 fetuses with placental insufficiency, umbilical artery blood was obtained at delivery for assessment of N-terminal peptide of proatrial natriuretic peptide (NT-proANP) and cardiac troponin-T (cTnT). Group 1 fetuses (n=12) had normal NT-proANP and cTnT serum concentrations. Group 2 fetuses (n=25) showed increased NT-proANP (>1145 pmol/L) and normal cTnT values. Group 3 fetuses (n=11) had increased NT-proANP and cTnT (>0.10 ng/mL) levels. The ultrasonographic parameters of fetal cardiovascular function were compared between the groups. Pulsatility indices for veins of the ductus venosus, left hepatic vein, and inferior vena cava correlated significantly with NT-proANP levels. In group...
Association Between SAH, an Acyl-CoA Synthetase Gene, and Hypertriglyceridemia, Obesity, and Hypertension
Authors: NaoharuIwai, TomohiroKatsuya, ToshifumiMannami, JitsuoHigaki, ToshioOgihara, KoichiKokame, JunOgata, ShunrokuBaba
Journal: Circulation (2002)

Background— The SA gene (SAH) has been isolated by differential screening from a genetically hypertensive rat strain as a candidate gene that may contribute to hypertension. Recently, the SA protein has been reported to be highly homologous to bovine xenobiotic–metabolizing medium-chain fatty acid:CoA ligase. Methods and Results— To clarify the pathophysiological significance of SAH, we searched for polymorphisms of human SAH and performed association studies using a large cohort (4000 subjects) representing the general population in Japan. We found 2 polymorphisms in the promoter region and single-nucleotide polymorphisms in introns 5, 7, and 12 and exon 8. One of the variants, an A/G polymorphism in intron 12, just 7 bp upstream from exon 13, strongly affected plasma triglyceride, plasma cholesterol, body mass index (BMI), waist-to-hip ratio (W/H), and blood pressure status. The effect of this genotype on blood pressure seems to be conveyed through its effects on BMI and W/H. Transient expression of the...
Abstract 13439: Arteriogenesis is Impaired in CSEKO Mouse Hind Limb Ischemia Due to Attenuated Expression of Chemokines and Cytokines
Authors: Shyamal C Bir, Rui Wang, Christopher Kevil
Journal: Circulation (2012)

Introduction Collateral growth due to arteriogenesis is a major mechanism to restore blood flow during chronic tissue ischemia. Arteriogenesis involves outward vascular remodeling of collateral art...
Abstract 1834: Src inhibition overcomes neratinib resistance in HER2-positive breast cancer
Authors: Neil Conlon, Michelle Lowry, Susan Breslin, Lorraine O'Driscoll, Alexander J. Eustace, John Crown, Norma O'Donovan, Denis M. Collins
Journal: Cancer Research (2018)

Abstract Introduction: Despite the recent successes of HER2-targeted therapies, drug resistance still represents a significant clinical problem. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has been recently FDA approved for the extended adjuvant treatment of early-stage HER2-positive breast cancer and little is known of its mechanism of resistance in breast cancer. Using a neratinib-resistant cell line model of HER2-positive breast cancer, HCC1954-N, the aim of this study was to characterise cross-resistance to other HER-targeting tyrosine kinase inhibitors (TKIs) and investigate the role of Src in acquired neratinib resistance. Methods: The effect of HER-family targeting TKIs neratinib, lapatinib, afatinib and, the Src inhibitor, dasatinib on proliferation of HCC1954-N and HCC1954-Par cells was assessed by acid phosphatase assays and three-dimensional Matrigel assays. Cell cycle progression was examined by flow cytometry using a propidium iodide assay. Caspase 3/7-Glo assay was used to assess apoptosis induction. To assess the prevention of the development of neratinib resistance, HCC1954 cells were treated twice weekly with neratinib, dasatinib, or the combination and stained with crystal violet when confluent. Results: The HCC1954-N cell line was resistant to neratinib and to afatinib and lapatinib compared to parental HCC1954, but neratinib was still the most potent of the three anti-proliferative agents. The combination of neratinib and dasatinib was synergistic in the neratinib-resistant HCC1954-N cell line in both adherent (CI value = 0.1 ± 0.03) and three-dimensional (CI value = 0.36 ± 0.02) conditions. Neratinib plus dasatinib did not result in cell cycle arrest; however, the combination caused a significant increase in the sub-G1 cell cycle population (p value = 0.018), indicating induction of apoptosis. This was further validated by increased activation of caspase 3 and 7 (p value = 0.015) in HCC1954-N cells treated with neratinib plus dasatinib. The addition of dasatinib to neratinib treatment prevented the development of neratinib resistance in parental HCC1954 cells. Conclusions: Further pre-clinical investigation of the combination of neratinib plus dasatinib is warranted as a potential therapeutic intervention for patients with neratinib-resistant HER2-positive breast cancer. Citation Format: Neil Conlon, Michelle Lowry, Susan Breslin, Lorraine O'Driscoll, Alexander J. Eustace, John Crown, Norma O'Donovan, Denis M. Collins. Src inhibition overcomes neratinib resistance in HER2-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1834.
Abstract 4252: Antihypertensive medication use and ovarian cancer survival
Authors: Tianyi Huang, Anil K. Sood, Shelley S. Tworoger
Journal: Cancer Research (2018)

Abstract Background: Both experimental and clinical studies suggest that beta-blockers, a common antihypertensive agent, may reduce ovarian tumor aggressiveness, inhibit angiogenesis and metastasis, and improve survival. However, no study has considered the potential role of other antihypertensive medications in conjunction with beta-blockers in ovarian cancer survival. Methods: We evaluated the associations of pre-diagnostic (n=899) and post-diagnostic (n=683) use of individual antihypertensive medications with ovarian cancer survival in the Nurses' Health Study (NHS; diagnosed between 1994-2012) and NHSII (diagnosed between 2001-2013), with at least 4 years of follow-up for death. Cox proportional hazards models were used to estimate hazard ratios (HR) for ovarian cancer mortality according to antihypertensive medication use. Results: In analyses of individual drugs adjusted for age, BMI and tumor characteristics, pre-diagnostic use of calcium-channel blockers (CCB) was associated with higher ovarian cancer mortality (HR: 1.52; 95% CI: 1.15, 2.00), whereas lower mortality was observed for post-diagnostic use of beta-blockers (HR: 0.76; 95% CI: 0.58, 1.01) and angiotensin-converting enzyme (ACE) inhibitors (HR: 0.64; 95% CI: 0.44, 0.93). While hypertension itself was not associated with ovarian cancer mortality (HR: 0.99; 95% CI: 0.83, 1.17), the associations between antihypertensive medications and ovarian cancer mortality were suggestively stronger among women with history of hypertension. Conclusion: Our findings suggest that post-diagnosis use of beta-blockers and ACE inhibitors is associated with lower ovarian cancer mortality and pre-diagnosis use of CCBs may be associated with higher mortality. These results warrant further investigation, and ongoing work is exploring whether the observed associations may be explained by changes in antihypertensive medication prescription after ovarian cancer diagnosis or changes in overall prescription patterns over time. Citation Format: Tianyi Huang, Anil K. Sood, Shelley S. Tworoger. Antihypertensive medication use and ovarian cancer survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4252.