tbuckley/cabot-search huggingface dataset:
Abstract LB-292: p95HER2-T cell bispecific antibody for breast cancer treatment
Authors: Rocío Vicario, Irene Rius Ruiz, Beatriz Morancho, Cristina Bernadó Morales, Sylvia Herter, Anne Freimoser-Grundscholber, Jitka Somandin, Johannes Sam, Oliver Ast, Águeda Martinez Barriocanal, Antonio Luque, Marta Escorihuela, Ismael Varela, Paolo Nuciforo, Roberta Fasani, Vicente Peg, Isabel Rubio, Javier Cortés, Violeta Serra, Santiago Escrivá, Jeff Sperinde, Ahmed Chenna, Weidong Huang, John Winslow, Maurizio Scaltriti, Josep Baselga, Josep Tabernero, Pablo Umaña, Marina Bacac, Cristina Saura, Christian Klein, Joaquín Arribas
Journal: Cancer Research (2018)

Abstract T cell bispecific antibodies (TCBs) are engineered molecules that include, within a single entity, binding sites to the T cell receptor and to a tumor-specific or a tumor-associated antigen. The receptor tyrosine kinase HER2 is a tumor-associated antigen in ~25% of breast cancers. Clinical evidence shows that TCBs targeting HER2 may result in severe toxicities, likely due to the physiologic levels of HER2 in normal epithelia. Approximately 40% of HER2-positive tumors express detectable levels of p95HER2, a carboxy-terminal fragment of HER2. We previously developed different antibodies that specifically recognize p95HER2 but not full-length HER2 and hypothesized that a TCB antibody recognizing p95HER2 would be exquisitely specific for tumor cells. Here, we describe the development of such p95HER2-TCB and show that it has a potent anti-tumor effect on p95HER2-expressing breast cancers. Since p95HER2 is not expressed in normal tissues, in contrast with HER2-TCB, it has no effect on non-transformed cells expressing physiological levels of HER2. These data paves the way for the safe targeting of a subtype of HER2-positive tumors with a novel tumor-specific TCB. Citation Format: Rocío Vicario, Irene Rius Ruiz, Beatriz Morancho, Cristina Bernadó Morales, Sylvia Herter, Anne Freimoser-Grundscholber, Jitka Somandin, Johannes Sam, Oliver Ast, Águeda Martinez Barriocanal, Antonio Luque, Marta Escorihuela, Ismael Varela, Paolo Nuciforo, Roberta Fasani, Vicente Peg, Isabel Rubio, Javier Cortés, Violeta Serra, Santiago Escrivá, Jeff Sperinde, Ahmed Chenna, Weidong Huang, John Winslow, Maurizio Scaltriti, Josep Baselga, Josep Tabernero, Pablo Umaña, Marina Bacac, Cristina Saura, Christian Klein, Joaquín Arribas. p95HER2-T cell bispecific antibody for breast cancer 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 LB-292.
Abstract 5894: Snail reduces the antitumor efficacy of mTOR kinase inhibitors by transcriptional repression of 4E-BP1
Authors: Qing Ye, Jun Wang, Yanan Cao, Yubin Guo, Xiuping Huang, Wenting Mi, Side Liu, Chi Wang, Hsin-Sheng Yang, Binhua Zhou, Bernard M. Evers, Qing-Bai She
Journal: Cancer Research (2018)

Abstract The mTOR inhibitors, including the second generation of mTOR kinase inhibitors, for cancer treatment have been evaluated in clinical trials, but their overall activity as monotherapy is limited. The cap-dependent translation repressor, 4E-BP1, is an important downstream effector of the mTOR kinase in controlling cell proliferation and tumor growth. Loss of 4E-BP1 expression has been linked to cancer progression and resistance to mTOR inhibitors. However, the molecular mechanism underlying 4E-BP1 downregulation in tumors remains unclear. Here, we identify Snail as a strong transcriptional repressor of 4E-BP1. We find that 4E-BP1 expression inversely correlates with Snail level in cancer cell lines and clinical specimens. Snail binds to three E-boxes present in the human 4E-BP1 promoter to block the transcription of the 4E-BP1 gene. Ectopic expression of Snail in cancer cell lines lacking Snail profoundly represses 4E-BP1 expression, promotes the formation of the eIF4F translation initiation complex for active translation in polysomes, and reduces the antiproliferative effect of mTOR kinase inhibitors. Conversely, genetic disruption of Snail or pharmacologic inhibition of Snail activity using the Snail co-repressor HDAC inhibitors restores 4E-BP1 expression and sensitizes cancer cells to mTOR kinase inhibitors by enhancing 4E-BP1-mediated translation-repressive effect on cell proliferation and tumor growth. Together, our findings reveal a novel oncogenic function of Snail in mTOR/4E-BP1-mediated translational control of tumorigenesis, and provide a rationale for targeting Snail to improve mTOR-targeted therapies. Citation Format: Qing Ye, Jun Wang, Yanan Cao, Yubin Guo, Xiuping Huang, Wenting Mi, Side Liu, Chi Wang, Hsin-Sheng Yang, Binhua Zhou, Bernard M. Evers, Qing-Bai She. Snail reduces the antitumor efficacy of mTOR kinase inhibitors by transcriptional repression of 4E-BP1 [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 5894.
Desensitization of Platelet-Derived Growth Factor Receptor-β by Oxidized Lipids in Vascular Cells and Atherosclerotic Lesions
Authors: CecileVindis, IsabelleEscargueil-Blanc, MeyerElbaz, BertrandMarcheix, Marie-HeleneGrazide, KojiUchida, RobertSalvayre, AnneNègre-Salvayre
Journal: Circulation Research (2006)

The platelet-derived growth factor receptor-β (PDGFRβ) signaling pathway regulates smooth muscle cell (SMC) migration and proliferation and plays a role in the vascular wall response to injury. Oxidized low-density lipoprotein (oxLDL) in atherosclerotic lesions can activate the PDGFRβ pathway, but the long-term effects of oxLDL on PDGFRβ function are not well understood. We found that oxLDL induced a dual effect on PDGFRβ signaling. Initial activation of the PDGFR was followed by desensitization of the receptor. PDGFRβ desensitization was not attributable to PDGFRβ degradation or changes in localization to the caveolae but instead resulted from decreased PDGF binding and inhibition of PDGFRβ tyrosine kinase activity. This inhibition was associated with formation of (4HNE)– and acrolein–PDGFRβ adducts and was mimicked by preincubation of cells with 4HNE. These PDGFRβ adducts were also detected in aortae of apolipoprotein-deficient mice and hypercholesterolemic rabbits and in human carotid plaques. The alde...
Randomized, Controlled Trial of Long-Term Moderate Exercise Training in Chronic Heart Failure
Authors: RomualdoBelardinelli, DemetriosGeorgiou, GiovanniCianci, AugustoPurcaro
Journal: Circulation (1999)

Background—It is still a matter of debate whether exercise training (ET) is a beneficial treatment in chronic heart failure (CHF). Methods and Results—To determine whether long-term moderate ET improves functional capacity and quality of life in patients with CHF and whether these effects translate into a favorable outcome, 110 patients with stable CHF were initially recruited, and 99 (59±14 years of age; 88 men and 11 women) were randomized into 2 groups. One group (group T, n=50) underwent ET at 60% of peak Vo2, initially 3 times a week for 8 weeks, then twice a week for 1 year. Another group (group NT, n=49) did not exercise. At baseline and at months 2 and 14, all patients underwent a cardiopulmonary exercise test, while 74 patients (37 in group T and 37 in group NT) with ischemic heart disease underwent myocardial scintigraphy. Quality of life was assessed by questionnaire. Ninety-four patients completed the protocol (48 in group T and 46 in group NT). Changes were observed only in patients in group...
Abstract 16611: Impact of Mechanical Unloading on Structural and Non-structural Components of the Extracellular Matrix in Patients With Dilated Cardiomyopathy
Authors: Siva S Sakamuri, Abhijit Takawale, Ratnadeep Bas, Xiuhua Wang, Paul W Fedak, Darren H Freed, Gavin Y Oudit, Zamaneh Kassiri
Journal: Circulation (2015)

Introduction: Extracellular matrix (ECM) is the non-cellular component of the myocardium and its remodeling in cardiomyopathy is a major contributor to disease outcomes. While the impact of left ventricular assist device (LVAD) on remodeling of fibrillar ECM has been studied, its effects on the non-fibrillar ECM and matricellular proteins within the ECM that can influence cardiac structure and function are unknown. Hypothesis: Mechanical unloading preserves the non-fibrillar ECM composition, thereby contributing to reversal of adverse myocardial remodeling. Methods: Hearts were obtained from heart failure patients with idiopathic dilated cardiomyopathy (DCM) with LVAD support (&gt;3mths; LVAD), without LVAD (no-LVAD), and non-failing control hearts (NFC) (n=10/group). LV free wall were fixed or flash-frozen for molecular and IHC evaluations. Results: Assessment of fibrillar ECM showed greater total and insoluble collagen content in no-LVAD hearts, consistent with an increase in collagen type I mRNA, and collagen type I-to-type III ratio. Proteolytic activities (collagenase &amp; gelatinase) were significantly higher in no-LVAD (by 45% and 40%) suggesting greater ECM turnover in these hearts. TIMP1 mRNA decreased in both DCM groups (by 60%), but its protein decreased only in no-LVAD hearts (by 30%). TIMP3 and TIMP4 mRNA (by 30% and 55%) and protein (by 60% and 55%) decreased in both LVAD and no-LVAD hearts. ADAM-TS2, the N-terminal endopeptidase for collagen, was markedly lower in no-LVAD, while LOX1, the cross-linking enzyme showed a small increase in no-LVAD hearts. Evaluation of the basement membrane revealed that laminin arrangements were dispersed in no-LVAD hearts. Integrin β1, a cardiomyocyte cell-surface receptor for laminin, was reduced in no-LVAD but preserved in LVAD hearts. Other basement membrane proteins (fibronectin-1, collagen IV) showed similar trends, whereas differences in matricellular proteins (osteopontin, SPARC) were less striking between LVAD and no-LVAD hearts. Conclusions: Mechanical unloading positively impacts multiple aspects of myocardial ECM, the fibrillar ECM network and the less explored basement membrane, although the matricellular proteins residing within the ECM seem to be less affected.
Abstract 13327: Prediction of Upcoming Therapeutic Episodes of ICD Through Routine Data in Routine Device Clinic of ICD Patients
Authors: TamamiFujiishi, ShinichiNiwano, MasamiMurakami, HironoriNakamura, TazuruIgarashi, NaruyaIshizue, JunOikawa, JunKishihara, HidehiraFukaya, HiroeNiwano, JunyaAko
Journal: Circulation (2015)

Background: Although implantable cardioverter-defibrillator (ICD) prevents sudden death of patients with life-threatening arrhythmia, prediction of upcoming ICD therapy, if possible, would be an important issue in device management. In the present study, the relationship between ICD therapeutic episodes and preceding routine device data was evaluated to clarify the predictors for ICD actuation in near future. Methods: The study population consisted of 100 consecutive ICD patients. All patients were followed up in the device clinic in every 4-month period, and their total follow-up periods of 22.8±4.1 months were divided into 734 4-month observation windows. The common data in device clinic including 12-lead ECG, chest X-ray, and interrogated device data were compared between patients with and without ICD therapeutic episodes during upcoming 4-month windows. To avoid inappropriate weighting on data of specific cases, such as unusual data in cases with frequent shock therapy, sampling number was limited 4-8...
Abstract 5401: Dysregulated microRNAs in aflatoxin-induced hepatocellular carcinoma: Serum miR-182 as a potential predictive biomarker
Authors: Merricka C. Livingstone, Natalie M. Johnson, Bill D. Roebuck, Thomas W. Kensler, John D. Groopman
Journal: Cancer Research (2018)

Abstract Hepatocellular carcinoma (HCC) continues to be a major cause of cancer death globally, with aflatoxin B1 (AFB1) as a prevalent risk factor in low- and middle-income countries. MicroRNAs have been shown to be differentially expressed in HCC and may serve as predictive biomarkers. In this study, we analyzed tumor and non-tumor tissue from rats dosed with AFB1 (200 µg/kg BW) for 28 consecutive days that received vehicle only or AFB1 plus the chemopreventive agent CDDO-Im (30 µmol), and control animals (Johnson et al., CaPR, 2014). Total RNA was isolated from tumor or non-tumor tissue at the time of sacrifice and sequenced. MicroRNA transcriptomic analysis revealed 17 miRNAs significantly upregulated (&amp;gt; 5 fold) in tumors compared to non-tumor tissue. The top ten dysregulated miRNAs determined by fold change and biological significance were selected for further investigation: rno-miR- 205, 200b-3p, 182, 429, 31a-5p, 10b-5p, 141-3p, 132-3p, 802-5p. Validation of sequencing results by quantitative PCR (qPCR) confirmed the upregulation of the majority of candidate miRNAs in tumors and rno-miR-224-5p as the most dysregulated miRNA (over 400 fold). We also examined the levels of these candidates in terminal sera of the same animals by qPCR. Circulating miRs-224-5p, 182, and 122-5p were increased (&amp;gt; 1.5 fold) in animals diagnosed with HCC compared to untreated animals and those previously dosed with AFB1 plus CDDO-Im. Analysis of tracking of serum miR-182 by generalized estimating equations (GEE) revealed significantly increased levels (5 fold; CI: 2.17- 2.50) in animals that developed HCC. This sustained increase in serum miR-182 is seen months before any tumors or other symptoms are present, and highlights this miRNA as a potential predictive biomarker in AFB1-induced HCC. Supported by T32ES007141-31A1 and CA197222. Citation Format: Merricka C. Livingstone, Natalie M. Johnson, Bill D. Roebuck, Thomas W. Kensler, John D. Groopman. Dysregulated microRNAs in aflatoxin-induced hepatocellular carcinoma: Serum miR-182 as a potential predictive biomarker [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 5401.
Abstract IA07: Targeting micrometastasis for the treatment of ovarian cancer
Authors: Ahmed Ashour Ahmed
Journal: Clinical Cancer Research (2018)

Abstract Unlike many other solid tumors, high-grade serous ovarian cancer seldom spreads outside the abdominal cavity. The most common cause of death is malnutrition secondary to intestinal obstruction because of abdominal metastasis. Understanding the key mechanisms involved in driving abdominal metastases is important for the development of novel strategies to prevent metastasis. In this talk, I will present our recent work on preventing ovarian cancer metastasis by targeting Salt Inducible Kinase 2 (SIK2). Citation Format: Ahmed Ashour Ahmed. Targeting micrometastasis for the treatment of ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA07.
Abstract 3597: Xenobiotic detoxification enzymes and cancer risk: A multiplex immunofluorescence detection of AE1/AE3, GSTA1 and GSTA3 in the tissue microarrays of gastrointestinal tract
Authors: Victor Wan-San Ma, Goretti Hoi-Yan Cheung, Eunice Yuen-Ting Lau, William Chi-Shing Cho
Journal: Cancer Research (2018)

Abstract Background: Glutathione S-transferases (GSTs) are an enzyme family responsible for the metabolism of toxins and carcinogens in the phase II detoxification pathway. Among the 5 alpha class isoforms, GSTA1 and GSTA3 are involved in metabolizing several active carcinogenic substrates generated from benzo-[a]-pyrene mainly found in grilled meats and burnt coal. The expression of GSTA1 and GSTA3 in gastrointestinal (GI) tract may be implicated with cancer development associated with the intake of xenobiotic substances. Methods: Formalin-fixed and paraffin-embedded tissue cores of esophagus (190), stomach (180), small intestine (372), colon (120) and rectum (142) were stained with a multiplex tyramide-immunofluorescence (T-IMF) technique for the simultaneous demonstration of cytokeratin AE1/AE3, GSTA1 and GSTA3. The tissue types range from normal to cancer progression spectrum. All tissue cores were screened for AE1/AE3 expression to confirm the epithelial cell lineage before scoring for GSTA1 and GSTA3 positivity. A p-value &amp;lt;0.05 by Chi-squared test is considered significant. Results: T-IMF is useful in studying the interaction of multi-markers in a single slide. This technique is superior to chromogenic immunohistochemical application in multi-color presentation. This highly sensitive and handy technique will save multiple sectionings and precious tissues. We found a significant down-regulation of two alpha class GSTs in the malignancies of GI tract (Table 1). Table 1. Positive percentages of glutathione S-transferases markersMarkerEsophagusStomachSmall intestineColonRectumNMNMNMNMNMGSTA141%24%99%40%90%15%22%3%43%21%p-value0.0603&amp;lt;0.0001&amp;lt;0.00010.0010.0194GSTA378%35%99%54%96%64%100%39%88%40%p-value&amp;lt;0.0001&amp;lt;0.0001&amp;lt;0.0001&amp;lt;0.0001&amp;lt;0.0001Abbreviation: N= normal; M= malignant Conclusion: The differential expression of these detoxification enzymes in normal epithelium vs GI cancer may shed some light on their role in protecting normal tissue from cancer development. This finding may provide a potential target for the development of intervention strategies against GI cancer. Further investigations will be conducted to decipher the mechanism underlying this observation. Citation Format: Victor Wan-San Ma, Goretti Hoi-Yan Cheung, Eunice Yuen-Ting Lau, William Chi-Shing Cho. Xenobiotic detoxification enzymes and cancer risk: A multiplex immunofluorescence detection of AE1/AE3, GSTA1 and GSTA3 in the tissue microarrays of gastrointestinal tract [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 3597.
Role of NAD(P)H Oxidase in Angiotensin II–Induced JAK/STAT Signaling and Cytokine Induction
Authors: BernhardSchieffer, MarenLuchtefeld, SabineBraun, AndresHilfiker, DeniseHilfiker-Kleiner, HelmutDrexler
Journal: Circulation Research (2000)

Abstract—Inflammatory processes involve both synthesis of inflammatory cytokines, such as interleukin-6 (IL-6), and the activation of their distinct signaling pathways, eg, the janus kinases (JAKs) and signal transducers and activators of transcription (STAT). Superoxide (O2−) anions activate this signaling cascade, and the vasoconstrictor angiotensin II (Ang II) enhances the formation of O2− anions via the NAD(P)H oxidase system in rat aortic smooth muscle cells. Ang II activates the JAK/STAT cascade via its type 1 (AT1) receptor and induces synthesis and release of IL-6. Therefore, we investigated the role of O2− anions generated by the NAD(P)H oxidase system on the Ang II activation of the JAK/STAT cascade and its impact on IL-6 synthesis. Ang II stimulation of rat aortic smooth muscle cells induced a rapid increase in O2− anions determined by laser fluoroscopy, which can be abolished by DPI, a flavoprotein inhibitor. Ang II–induced phosphorylation of JAK2, STAT1α/β, STAT3, and IL-6-synthesis can be ab...
Abstract 4863: Targeting the NFAT1-MDM2-MDMX network for prostate cancer therapy
Authors: Jiang-Jiang Qin, Xin Li, Wei Wang, Ruiwen Zhang
Journal: Cancer Research (2018)

Abstract The MDM2 and MDMX oncogenes are overexpressed in human prostate cancer, promoting tumor growth and metastasis. We recently demonstrate that the transcription factor NFAT1 activates MDM2 oncogene, independent of p53. The present study was designed to examine the effectiveness of targeting the NFAT1-MDM2-MDMX network for prostate cancer therapy. We identified a natural product NFAT1-MDM2 inhibitor, Inulanolide A (InuA) in the present study. The anticancer activity of InuA and its effects on the expression and stability of NFAT1, MDM2, and MDMX were examined in human prostate cancer cell lines with different genetic background, including LNCaP (p53 wild-type, AR positive), PC3 (p53 null, AR negative) and DU145 (p53 mutant, AR negative) cells. Our molecular docking studies predicted the binding ability and binding sites of InuA on NFAT1, MDM2, and MDMX. Its binding affinity and specificity were investigated using recombinant proteins and biotinylated InuA. To further demonstrate the specificity of InuA in targeting NFAT1-MDM2-MDMX network and the importance of NFAT1-MDM2-MDMX network in InuA's anticancer activity, the transient overexpression (OE) and knockdown (KD) experiments of these genes, as well as the pharmacological activators and inhibitors of NFAT1 signaling, were used. Our results indicated that InuA directly bound to the DNA binding domain of NFAT1, leading to a marked inhibition of MDM2 transcription. The compound also bound to the RING domains of MDM2 and MDMX with high affinity, inhibited the MDM2-MDMX binding, and enhanced MDM2 protein degradation. InuA inhibited the proliferation, migration, and invasion of prostate cancer cells, regardless of their p53 status and AR responsiveness. The expression of NFAT1, MDM2, and MDMX were important for InuA's anticancer activity, as demonstrated using the cancer cell lines with transient OE and KD of these genes. In conclusion, InuA represents a novel class of NFAT1-MDM2-MDMX inhibitor, and inhibiting the NFAT1-MDM2-MDMX network may be a promising strategy for prostate cancer therapy. (Supported by NIH R01 CA186662 and R01CA214019 and ACS RSG-15-009-01-CDD.) Citation Format: Jiang-Jiang Qin, Xin Li, Wei Wang, Ruiwen Zhang. Targeting the NFAT1-MDM2-MDMX network for prostate cancer therapy [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 4863.
Mercury Exposure, Blood Pressure, and Hypertension: A Systematic Review and Dose–response Meta-analysis
Authors: Xue Feng Hu, Kavita Singh, Hing Man Chan
Journal: Environmental Health Perspectives (2018)

Background: Body burden of mercury has been linked to hypertension in populations exposed to high mercury levels. Objectives: We summarized, extracted, and pooled the results of published studies that investigated mercury biomarkers and hypertension or blood pressure (BP) measurements to examine this potential relationship. Methods: We searched PubMed, Embase, and TOXLINE and selected studies according to a priori defined inclusion criteria. Study quality was assessed by the Newcastle-Ottawa scale for cohort and case–control studies and the Quality Assessment Tool for cross-sectional studies. Study estimates were pooled using inverse-variance weighted random-effects models. Dose–response meta-analysis was performed with studies reporting hypertension and systolic BP for at least three mercury categories. Results: A total of 29 studies were included in the meta-analysis. The pooled odds ratio (OR) for hypertension, comparing the highest and lowest mercury exposure categories, was 1.35 [95% confidence interval (CI): 0.99, 1.83] for populations with hair mercury ≥2μg/g in comparison with the OR of 1.12 (95% CI: 0.82, 1.52) for populations with hair mercury &lt;2μg/g. Positive associations were also observed for highest versus lowest mercury exposure categories on systolic and diastolic BP. Heterogeneity was observed for mercury species and exposure groups across different studies. Associations estimated using different mercury biomarkers generally agree with each other in the same study. A nonlinear dose–response relationship with an inflection point at 3μg/g was identified, for both hypertension and systolic BP. Conclusions: A significant positive association between mercury and hypertension and between mercury and BP was identified. The exposure dose is an important factor in determining the toxic effects of mercury on hypertension. https://doi.org/10.1289/EHP2863