tbuckley/cabot-search huggingface dataset:
Abstract 4577: ESR1 methylation: A liquid biopsy-based epigenetic assay for the follow up of patients with metastatic breast cancer receiving endocrine treatment
Authors: Sofia Mastoraki, Areti Strati, Eleni Tzanikou, Maria Chimonidou, Eleni Politaki, Alexandra Voutsina, Amanda Psyrri, Vassilis Georgoulias, Evi S. Lianidou
Journal: Cancer Research (2018)

Abstract Introduction: Liquid biopsy provides real-time monitoring of tumor evolution and response to therapy through analysis of CTCs and plasma-ctDNA. ESR1 epigenetic silencing potentially affects response to endocrine treatment. We evaluated ESR1 methylation in CTCs and paired plasma-ctDNA. We evaluated ESR1 methylation in CTCs and paired plasma-ctDNA as a potential biomarker for response to everolimus/exemestane treatment. Materials and methods: A highly sensitive and specific real-time MSP assay for ESR1 methylation was developed and validated in: a) 65 primary breast tumors (FFPEs), b) EpCAM+ CTC-fractions (122 patients and 30 healthy donors; HD), c) plasma-ctDNA (108 patients and 30HD), d) in CTCs (CellSearch®) and in paired plasma-ctDNA for 58 BrCa patients. ESR1 methylation status was investigated in CTCs isolated from serial peripheral blood samples of 19 patients with ER+/ HER2- advanced BrCa receiving everolimus/exemestane. Results: ESR1 methylation was detected in: a) 25/65(38.5%) FFPEs, b) EpCAM+ CTC-fractions: 26/112(23.3%) patients and 1/30(3.3%) HD, c) plasma-ctDNA: 8/108(7.4%) patients and 1/30(3.3%) HD. ESR1 methylation was highly concordant in 58 paired DNA samples, isolated from CTCs (CellSearch®) and corresponding plasma. In serial peripheral blood samples of patients treated with everolimus/exemestane, ESR1 methylation was observed in 10/36(27.8%) CTC-positive samples, and was associated with lack of response to treatment (p=0.023 Fisher's Exact Test). Conclusions: We report for the first time the detection of ESR1 methylation in CTCs and a high concordance with paired plasma-ctDNA. ESR1 methylation in CTCs was associated with lack of response to everolimus/exemestane regimen. ESR1 methylation should be further evaluated as a potential liquid biopsy-based biomarker. Citation Format: Sofia Mastoraki, Areti Strati, Eleni Tzanikou, Maria Chimonidou, Eleni Politaki, Alexandra Voutsina, Amanda Psyrri, Vassilis Georgoulias, Evi S. Lianidou. ESR1 methylation: A liquid biopsy-based epigenetic assay for the follow up of patients with metastatic breast cancer receiving endocrine treatment [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 4577.
Abstract 16150: Desmoplakin Missense vs Non-missense Mutations: Genotype-phenotype Correlations in Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Silvia Castelletti, Annina S Vischer, Petros Syrris, Lia Crotti, Carla Spazzolini, Alice Ghidoni, Gianfranco Parati, Franco Cecchi, Sharon Jenkins, Maria-Christina Kotta, William J McKenna, Peter J Schwartz, Antonis Pantazis
Journal: Circulation (2016)

Introduction: Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited disease characterized by risk for sudden cardiac death (SCD) and fibro-fatty replacement primarily of the right ...
Mechanical Device–Based Methods of Managing and Treating Heart Failure
Authors: DonnaMancini, DanielBurkhoff
Journal: Circulation (2005)

Despite advances in pharmacological treatments aimed at neurohormonal blockade for heart failure in the setting of left ventricular pump dysfunction, there is still a growing number of patients with advanced symptoms who suffer significant morbidity and mortality. Mechanical stresses and chronic neurohormonal activation conspire to propagate maladaptive ventricular remodeling responsible for the insidious nature of this disease. Recent studies suggest that further pharmacological neurohormonal blockade may not be safe or effective, which has driven development of devices for this patient population. Furthermore, such devices may target fundamental pathophysiological abnormalities that are largely hemodynamic and mechanical in nature that are not addressed by available pharmacological agents. The profound reverse remodeling routinely associated with left ventricular assist device use, reviewed in detail, further validates device-based approaches and should inspire research to find ways to make this recover...
Effect of the oxLDL Binding Protein Fc-CD68 on Plaque Extension and Vulnerability in Atherosclerosis
Authors: StephanZeibig, ZhongminLi, SilviaWagner, Hans-PeterHolthoff, MartinUngerer, AndreasBültmann, KerstinUhland, JasminVogelmann, ThomasSimmet, MeinradGawaz, GötzMünch
Journal: Circulation Research (2011)

Rationale:There is strong evidence that oxidative modification of low-density lipoprotein (oxLDL) plays a critical role in atherogenesis and that oxLDL may profoundly influence the mechanical stability of atherosclerotic plaques. Objective:To block oxLDL, we designed, expressed, and tested Fc-CD68, a soluble oxLDL binding protein consisting of human Fc and the extracellular domain of the human oxLDL-binding receptor CD68. Methods and Results:Fc-CD68 bound with high specific affinity to oxLDL and strongly bound and colocalized with oxLDL in plaques. To study the effects of repeated administrations of Fc-CD68 on the progression of atherosclerosis and plaque vulnerability, 12- and 16-week old cholesterol-fed ApoE−/− mice received either Fc-CD68 (n=6) or Fc control protein (n=6 to 8) thrice weekly for 4 weeks. Macroscopic and histological analysis of Sudan red lipid staining showed strong and significant reduction of plaque extension in the aorta and in the aortic root, respectively. Histological analysis of ...
Administration of Hematopoietic Cytokines in the Subacute Phase After Cerebral Infarction Is Effective for Functional Recovery Facilitating Proliferation of Intrinsic Neural Stem/Progenitor Cells and Transition of Bone Marrow-Derived Neuronal Cells
Authors: HiroshiKawada, ShunyaTakizawa, TomomiTakanashi, YukoMorita, JunFujita, KeiichiFukuda, ShigeharuTakagi, HideyukiOkano, KiyoshiAndo, TomomitsuHotta
Journal: Circulation (2006)

Background— Hematopoietic cytokines, granulocyte colony-stimulating factor (G-CSF), and stem cell factor (SCF) were reported to show a neuroprotective effect or to support neurogenesis. These cytokines also mobilize bone marrow (BM) cells into the brain, and the BM-derived cells differentiate into neuronal cells. We administered these hematopoietic cytokines after focal cerebral ischemia and assessed their effects and the therapeutic time window for neuronal regeneration. Methods and Results— We induced permanent middle cerebral artery occlusion in mice whose BM had been replaced with BM cells from green fluorescent protein (GFP)-transgenic mice. The occluded mice were treated with G-CSF and SCF in the acute phase (days 1 to 10) or subacute phase (days 11 to 20), and the brain functions and histological changes were evaluated. Separately, we injected bromodeoxyuridine during cytokine treatment to assess cell kinetics in the brain. Six mice were prepared for each experimental group. Administration of G-CSF...
Differences in Vascular Bed Disease Susceptibility Reflect Differences in Gene Expression Response to Atherogenic Stimuli
Authors: David Xing-FeiDeng, AnyaTsalenko, AdityaVailaya, AmirBen-Dor, RamendraKundu, IvetteEstay, RaymondTabibiazar, RobertKincaid, ZoharYakhini, LaurakayBruhn, ThomasQuertermous
Journal: Circulation Research (2006)

Atherosclerosis occurs predominantly in arteries and only rarely in veins. The goal of this study was to test whether differences in the molecular responses of venous and arterial endothelial cells (ECs) to atherosclerotic stimuli might contribute to vascular bed differences in susceptibility to atherosclerosis. We compared gene expression profiles of primary cultured ECs from human saphenous vein (SVEC) and coronary artery (CAEC) exposed to atherogenic stimuli. In addition to identifying differentially expressed genes, we applied statistical analysis of gene ontology and pathway annotation terms to identify signaling differences related to cell type and stimulus. Differential gene expression of untreated venous and arterial endothelial cells yielded 285 genes more highly expressed in untreated SVEC (P 1.5). These genes represented various atherosclerosis-related pathways including responses to proliferation, oxidoreductase activity, antiinflammatory responses, cell growth, and hemo...
Abstract 709: Anti-PD-1 therapy reduces bone lesion growth in a novel syngeneic bladder cancer bone metastasis model
Authors: Tiina E. Kähkönen, Mari I. Suominen, Jussi M. Halleen, Jenni Bernoulli, Arne Scholz
Journal: Cancer Research (2018)

Abstract Bladder cancer is a common and aggressive type of cancer occurring both in women and in men. At diagnosis, lymph node involvement is frequently observed and in some cases metastatic spread can already be seen at early stage. With advanced stages, the metastatic incidence increases and the most common metastatic sites are bones, lung, liver and peritoneum. Bone metastases count about 50% of all metastases and the 5-year survival rate in metastatic disease is only 15%. Bone metastases are incurable but can be treated to reduce tumor burden in bone, and new therapies such as immunotherapies hold the potential to treat patients with bone metastatic bladder cancer. The aim of the study was to establish a novel syngeneic model for bladder cancer bone metastasis that could be used to study efficacy of new immunotherapies, and to test efficacy of anti-PD-1 therapy in the model. In the model establishment study, an intratibial injection of varying number of murine MBT-2 bladder cancer cells was given to 5-6 weeks old female C3H/HeN mice. Tumor-induced bone changes were followed by X-ray imaging once a week. At sacrifice, tumor-bearing tibias were collected and evaluated by histology. In the efficacy study, 5x105 MBT-2 cells were used. The mice were stratified to treatment groups based on similar bone lesion areas at 10 days after cancer cell inoculations and treated with anti-PD-1 therapy (RMP1-14) or isotype control (rat IgG2a, 200 µg per dose) at Q3D schedule. Bone lesion growth was followed by X-ray imaging one week after start of treatment and at sacrifice after three weeks on treatment. In the model establishment study, tumor take rate of 50% was observed. MBT-2 cells induced an osteolytic bone reaction resulting in substantial bone loss in the mice. The osteolytic bone lesions started to be visible between 7-14 days and the maximum duration of the study was 4 weeks from the cancer cell inoculations. Histology confirmed a large tumor and decreased bone mass in the inoculated tibia. In the efficacy study, treatment with anti-PD-1 reduced bone lesion growth. A trend towards decreased bone lesion area was seen already at one week on treatment and a significant reduction of bone lesion area was seen at sacrifice. A novel syngeneic bladder cancer bone metastasis model was established. According to the observed significant effects on bone lesion growth by anti-PD-1 treatment this model can be used in preclinical efficacy assessment of new immunotherapies as monotherapy or in combination with other therapies. Citation Format: Tiina E. Kähkönen, Mari I. Suominen, Jussi M. Halleen, Jenni Bernoulli, Arne Scholz. Anti-PD-1 therapy reduces bone lesion growth in a novel syngeneic bladder cancer bone metastasis model [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 709.
Abstract 132: Role of IL-17-CXCR2 axis in neutrophil recruitment facilitating breast cancer metastasis and therapy resistance
Authors: Lingyun Wu, Bhawna Sharma, Rakesh K. Singh
Journal: Cancer Research (2018)

Abstract The major challenges for breast cancer includes therapy resistance and metastasis to distant organs. Chronic inflammation has been intimately linked with these processes. We have observed increased level of CXCR2 ligands, inflammatory immunosuppressive microenvironment, and increased metastasis in chemotherapy resistant cells. CXCR2 and its ligands have been shown to be the primary mechanism for neutrophils recruitment to the sites of primary tumors and metastases. However, their precise roles in therapy resistance and metastasis remains unclear. The aim of this project is to investigate the role of neutrophils in chemotherapy resistance and metastasis in breast cancer. In this report, we investigated the mechanisms and putative role of neutrophils in chemotherapy resistance and metastasis. We evaluated the expression level of the factors critical for neutrophil recruitments, such as interleukin (IL)-17 and its receptors (IL-17R), granulocyte colony stimulating factor (GCSF), CXCR2 and its ligands in primary tumors and metastases established from parents and chemotherapy resistant cells. The frequency of neutrophils and T-helper 17 (Th17) cells were analyzed using immunohistochemistry. Chemotherapy-resistant cell lines express higher levels of GCSF, IL-17, and IL-17R compared to Cl66 parent cells. We observed higher expression of IL-17R, CXCR2, and CXCR2 ligands in metastatic lesions compared to primary tumors. Furthermore, there were more recruitments of neutrophils and Th17 cells in resistant tumors than parent tumors. In addition, treatment of tumor cells with IL-17 significantly increased cellular proliferation together with CXCL1 and CXCL5 expression in a concentration-dependent manner. Moreover, we observed higher expression of TGFβ 2 and Th17 cell priming factors, IL-6 and IL-23, in neutrophils co-cultured with therapy resistant cells compared to the control suggesting a feed forward loop. In addition, we observed that IL17 treatment of tumor cells did not increase their tolerance to chemotherapy drug, indicating its role in establishing immune suppressive microenvironments. Together our data demonstrate an IL17-CXCR2 ligands axis induces protumorigenic inflammation, facilitating therapy resistance and metastasis through recruited neutrophils. Citation Format: Lingyun Wu, Bhawna Sharma, Rakesh K. Singh. Role of IL-17-CXCR2 axis in neutrophil recruitment facilitating breast cancer metastasis and therapy resistance [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 132.
Liver Complications Following Treatment of Hematologic Malignancy With Anti‐CD22‐Calicheamicin (Inotuzumab Ozogamicin)
Authors: George B. McDonald, James W. Freston, James L. Boyer, Laurie D. DeLeve
Journal: Hepatology (2018)

Treatment of hematological malignancy with antibody-drug conjugates (ADCs) may cause liver injury. ADCs deliver a toxic moiety into antigen-expressing tumor cells, but may also injure hepatic sinusoids (sinusoidal obstruction syndrome; SOS). We studied patients who received an anti-CD22/calicheamicin conjugate (inotuzumab ozogamicin; InO) to gain insight into mechanisms of sinusoidal injury, given that there are no CD22+ cells in the normal liver, but nonspecific uptake of ADCs by liver sinusoidal endothelial cells (LSECs). Six hundred thirty-eight patients (307 with acute lymphocytic leukemia [ALL], 311 with non-Hodgkin's lymphoma [NHL]) were randomized to either InO or standard chemotherapy (controls). While blinded to treatment assignment, we reviewed all cases with hepatobiliary complications to adjudicate the causes. Frequency of SOS among patients who received InO was 5 of 328 (1.5%), compared to no cases among 310 control patients. Drug-induced liver injury (DILI) developed in 26 (7.9%) InO recipients and 3 (1%) controls. Intrahepatic cholestasis (IHC) was observed in 4.9% of InO recipients and in 5.5% of controls. Subsequent to the randomization study, 113 patients with ALL underwent allogeneic hematopoietic cell transplantation (HCT); frequency of SOS in those previously exposed to InO was 21 of 79 (27%) versus 3 of 34 (9%) in controls. An exploratory multivariate model identified a past history of liver disease and thrombocytopenia before conditioning therapy as dominant risk factors for SOS after transplant. Conclusion: Frequencies of SOS and DILI after inotuzumab ozogamicin treatment were 1.5% and 7.9%, respectively, compared to none and 1% among controls who received standard chemotherapy. These data suggest that ADCs that do not target antigens present in the normal liver have a relatively low frequency of SOS, but a relatively high frequency of DILI.
Abstract 3151: Novel regulation of cancer cell migration by ABCG2-enhanced autophagy
Authors: Kalkal Anil Trivedi, Rui Ding, Kathleen W. Scotto
Journal: Cancer Research (2018)

Abstract ABCG2 is an ABC multidrug transporter best known for its ability to efflux a wide variety of chemotherapeutic agents, resulting in tumor drug resistance. More recently, our laboratory has shown that ABCG2 plays an additional role in tumor cell survival by enhancing the rate of autophagy, a conserved, catabolic recycling process that breaks down damaged proteins and cellular organelles to form cellular building blocks (Ding et al., Autophagy, 2016). Sporadic studies over the decades have led to somewhat conflicting reports about the impact of ABCG2 expression on migration. Likewise, autophagy can play either a pro-metastatic or anti-metastatic role depending on the context. In the present study, we confirm that ABCG2 enhances tumor cell migration in vitro, and provide novel data to suggest that this enhancement is due to the ability of ABCG2 to augment autophagy flux. Two cell line pairs were used for these studies: the NSCLC line H460 and its drug-selected ABCG2-overexpressing subline H460/MX20, and the embryonic kidney HEK293 cells stably-transfected either with ABCG2 or an empty vector. Transwell assays were used to study in vitro migration and invasion. ABCG2-overexpressing cells exhibited a marked increase in both cell migration and invasion relative to their parental counterparts. Using gelatin zymography, we also showed that ABCG2 over-expressing cells had enhanced MMP-2 activity, consistent with increased invasion. Both siRNA-mediated knockdown of ABCG2 expression and pharmacological inhibition of ABCG2 transport reduced the migration of ABCG2-overexpressing cells. Moreover, blocking autophagy using either a pharmacological or genetic approach also inhibited migration. Further supporting the hypothesis that ABCG2-enhanced autophagy influenced tumor cell migration, wild-type (WT) and MEFs in which the autophagy essential gene ATG5 was knocked out (ATG5-/-) were transiently transfected with either an empty vector or ABCG2. The ABCG2-transfected WT MEFs showed significantly enhanced migration compared to the empty vector transfected WT MEFs. The autophagy compromised ATG5-/- MEFs, however, did not display a statistically significant difference in the migration of the ABCG2 and empty-vector transfected cells, supporting the hypothesis that ABCG2 requires functional autophagy to enhance cell migration. Taken together, our results demonstrate a novel role for ABCG2 in enhancing cell migration by augmenting autophagy flux. Studies to determine whether ABCG2-regulated autophagy enhances migration and metastasis in vivo are underway. Citation Format: Kalkal Anil Trivedi, Rui Ding, Kathleen W. Scotto. Novel regulation of cancer cell migration by ABCG2-enhanced autophagy [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 3151.
Oxygen Free Radical Release in Human Failing Myocardium Is Associated With Increased Activity of Rac1-GTPase and Represents a Target for Statin Treatment
Authors: ChristophMaack, TanjaKartes, HeikoKilter, Hans-JoachimSchäfers, GeorgNickenig, MichaelBöhm, UlrichLaufs
Journal: Circulation (2003)

Background— Reactive oxygen species (ROS) contribute to the development of heart failure. A potential source of myocardial ROS is the NADPH oxidase, which is regulated by the small GTP-binding protein rac1. Isoprenylation of rac1 can be inhibited by statin therapy. Thus, we examined ROS and rac1 in human failing myocardium and tested their regulation by statins in vivo. Methods and Results— In human left ventricular myocardium from patients with ischemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM), NADPH oxidase activity was increased 1.5-fold compared with nonfailing controls (P<0.05, n=8). In failing myocardium, increased oxidative stress determined by measurements of lipid peroxidation and aconitase activity was associated with increased translocation of rac1 from the cytosol to the membrane. Pull-down assays revealed a 3-fold increase of rac1-GTPase activity in ICM and DCM. In parallel, membrane expression of the NADPH oxidase subunit p47phox, but not p67phox, was upregulated in failing compa...
Evidence for Primary Genetic Determination of Heart Rate Regulation
Authors: ReinholdKreutz, BertholdStruk, PhillippeStock, NorbertHübner, DetlevGanten, KlausLindpaintner
Journal: Circulation (1997)

Background We investigated whether an accelerated heart rate (HR), observed in the stroke-prone spontaneously hypertensive rat (SHRSPHD), is a primary, genetically determined trait and whether it contributes to blood pressure (BP) regulation in this model of polygenic hypertension. Methods and Results We measured BP and HR in SHRSPHD and normotensive Wistar-Kyoto rats (WKY), as well as in F2 hybrids bred from crossing the two strains, at baseline and after 12 days of dietary NaCl loading. Random marker genome screening and cosegregation analysis were performed on F2 hybrids derived from SHRSPHD/WKY-0HD (n=115) and SHRSPHD/WKY-1HD (n=139) crosses (WKY-0HD and WKY-1HD are two congenic WKY strains). HR in SHRSPHD was significantly higher than in WKY-0HD both at baseline (404±30 versus 375±46 bpm; P=.0034) and after NaCl (437±23 versus 364±40 bpm; P=10−9). BP in F2 hybrids showed no significant correlation with HR either at baseline or after NaCl loading. HR after NaCl loading but not at baseline was signific...