tbuckley/cabot-search huggingface dataset:
Abstract 16344: LMO2 Modulates SPHK1 and Promotes Endothelial Cell Migration
Authors: Gianfranco Matrone, Shu Meng, John P Cooke
Journal: Circulation (2016)

Introduction: Lim-domain only (LMO) 2 is a transcription factor that regulates hematopoiesis and angiogenesis. Only a few LMO2 modulated genes have been described. In ChIP-Seq analysis we identifie...
Dopamine as a Novel Antioxidative Agent for Rat Vascular Smooth Muscle Cells Through Dopamine D1-Like Receptors
Authors: KenichiYasunari, MasakazuKohno, HiroakiKano, MiekoMinami, JunichiYoshikawa
Journal: Circulation (2000)

Background—To elucidate the roles of vascular D1-like receptors in atherosclerosis, the effects of the specific D1-like agonists on platelet-derived growth factor (PDGF)-BB–mediated oxidative stress in vascular smooth muscle cells (VSMCs) were studied. Methods and Results—Immunohistochemical studies demonstrated the coexistence of D1A and D1B dopamine receptors in VSMCs. Western blotting revealed a band of ≈70 kDa for D1A and D1B dopamine receptors. VSMCs stimulated by PDGF-BB exhibited increased oxidative stress directly measured by flow cytometry. These effects were prevented by dopamine, SKF 38393, or YM 435, and this prevention was reversed by Sch 23390. These effects were blocked by a specific protein kinase A (PKA) inhibitor, N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide (H 89). The PDGF-BB–mediated increase in oxidative stress of VSMCs was significantly suppressed by the indirect phospholipase D (PLD) inhibitor suramin or the specific protein kinase C (PKC) inhibitor calphostin C. Bot...
Abstract 1497: A PRC2 independent role of EZH2 in androgen receptor signaling in prostate cancer
Authors: Yongik Lee, Jung a Kim, Zhao Changsheng, Xiadong Lu, Ka Wing Fong, Jindan Yu
Journal: Cancer Research (2018)

Abstract Prostate cancer is the most frequently diagnosed cancer and third most frequent cause of cancer deaths in US males. Prostate cancer patients have benefitted from androgen deprivation therapy and small molecular inhibitors targeting androgen receptor (AR). However, 30% of patients have primary resistance to both forms of treatment with a majority of patients eventually developing resistance to these therapies and progressing from androgen dependent prostate cancer (ADPC) to castration resistant prostate cancer (CRPC). Unfortunately, there are no effective therapeutic options available for CRPC patients, so novel and more effective therapeutic strategies for CRPC are urgently needed. Enhancer of Zeste 2 (EZH2) is a well-characterized oncogene that is one of the most highly upregulated genes in aggressive PCa and suggested as a prognostic biomarker. EZH2 is a part of polycomb repressive complex2 (PRC2) with embryonic ectoderm development (EED) and suppressor of zeste 12 (SUZ12) to function as a repressor through the SET domain, especially Histidine 689 to methylate H3K27. Recently, some studies suggest a context-dependent or PRC2 independent function of EZH2, but new functional role of EZH2 in cancer that are yet to be delineated. In the present study, we demonstrated EZH2 enhances AR signaling through direct AR promoter occupancy at exon1, independent of histone methyltransferase activity. EZH2 has a dual role as a transcriptional activator mediated by AR and an epigenetic silencer mediated by H3K27me3. Therefore, simultaneously targeting EZH2 and AR by drug inhibitors, EPZ and enzalutamide (Enz), respectively, leads to synergistic cell growth inhibition. Taken together, our data reveal a dual function of EZH2 in PCa as a transcriptional activator and an epigenetic silencer. We believe that this study provide not only a novel function of EZH2 in the regulating AR signaling pathway but also provide novel therapeutic strategies for advanced prostate cancer which currently has no therapeutic options available. Citation Format: Yongik Lee, Jung a Kim, Zhao Changsheng, Xiadong Lu, Ka Wing Fong, Jindan Yu. A PRC2 independent role of EZH2 in androgen receptor signaling in prostate 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 1497.
Methylene blue‐induced <scp>H</scp>einz body hemolytic anemia in a premature neonate
Authors: Lewis Vanhinsbergh, Sabita Uthaya, Barbara J. Bain
Journal: American Journal of Hematology (2018)

A baby of Northern European ancestry, was born by uncomplicated vaginal delivery at 33 weeks gestation following induction because of abnormal umbilical artery Dopplers. He was known to have trisomy 21, complicated by duodenal atresia, but was otherwise healthy at birth. At day 2 of life he underwent a duodeno-duodenostomy utilizing methylene blue for intraoperative confirmation of anastomotic integrity. A higher than recommended dose was used leading to classical green/blue urine and inability to detect oxygen saturation on pulse oximetry as a result of skin discoloration. He became significantly jaundiced over the next few days (bilirubin 404 μmol/L) with a mixed hyperbilirubinemia (unconjugated 197 μmol/L). His blood film showed marked oxidative hemolytic changes including irregularly contracted cells, blister cells, and ghost cells (Images). Heinz bodies were visible within ghost cells and blister cells (top left and right Images), this being confirmed on supravital staining. His hemoglobin concentration dropped from 192 g/L to 67 g/L necessitating top-up blood transfusion. Phototherapy was initially commenced but stopped due to the risk of bronzing in the presence of conjugated hyperbilirubinaemia. The baby recovered fully from the hemolytic crisis without skin blistering or desquamation. Glucose-6-phosphate dehydrogenase (G6PD), checked on a pretransfusion sample, was normal. Methylene blue has many uses including checking anastomotic integrity, determining tissue dysplasia (chromoendoscopy), and treatment of ifosfamide neurotoxicity and methemoglobinemia.1 At therapeutic doses it activates the nicotinamide adenine dinucleotide phosphate (NADPH) pathway facilitating reduction of the ferric iron of methemoglobin to the ferrous form. However, at high doses it behaves as an oxidant and is therefore contraindicated in patients with G6PD deficiency. Oxidative hemolytic effects of methylene blue at high doses in patients without G6PD deficiency have been previously reported.2, 3 Toxicity includes skin and urine discoloration, phototoxicity, and respiratory distress. Additionally, methylene blue at toxic doses can precipitate serotonin syndrome due to it monoamine oxidase inhibition.1 This case highlights the diagnostic utility of the blood film when combined with appropriate clinical information. It also demonstrates the risks of methylene blue usage, particularly in the susceptible neonate.
Abstract 754: Unique pharmacologic properties of Dolaflexin-based ADCs—a controlled bystander effect
Authors: Susan M. Clardy, Alex Yurkovetskiy, Mao Yin, Dmitry Gumerov, Ling Xu, Elena Ter-Ovanesyan, Charlie Bu, Alex Johnson, Marina Protopopova, Qingxiu Zhang, Natalya Bodyak, Marc Damelin, David H. Lee, Donald Bergstrom, Timothy B. Lowinger
Journal: Cancer Research (2018)

Abstract Antibody-drug conjugates (ADCs) are designed to bind tumor-associated antigens and deliver conjugated cytotoxic payloads to antigen-positive cells. Some ADCs also kill neighboring cells (including antigen-negative cells) by a mechanism referred to as the bystander effect. This effect can be beneficial when the antigen has heterogeneous expression among cells in a solid tumor, but it can also increase off-target toxicity of ADCs. Herein, we report on a unique pharmacologic property of the Dolaflexin platform, which provides a controlled bystander effect that retains the benefits of the bystander effect with respect to antitumor cytotoxicity but reduces the off-target toxicity. The controlled bystander effect, termed “Dolalock,” was achieved through design of a payload, auristatin F-hydroxypropylamide (AF-HPA), that is membrane-permeable and capable of bystander killing but is further catabolized to membrane-impermeable auristatin F (AF). This catabolism of the payload “locks” the highly potent AF in the cell. Using Dolaflexin-based ADCs, we investigated the extent of intracellular AF-HPA and AF release, tumor cell retention and bystander activities in vitro and in vivo. We observed both auristatin species within cells. Co-culture assays with HER2-positive and HER2-negative cells confirmed the cell permeability and bystander-killing capabilities of AF-HPA released from a Dolaflexin-based ADC. Biodistribution studies of Dolaflexin-based ADCs revealed time-dependent concentrations of AF-HPA and AF as well as significant accumulation of AF in xenografted tumor cells, consistent with the Dolalock mechanism. An additional benefit of AF formation was seen in multidrug-resistant transporter studies, which demonstrate that AF, in contrast to AF-HPA, is not a P-glycoprotein 1 (Pgp) substrate. This property may offer additional benefit in Pgp-expressing tumors. In summary, we have shown that the novel AF-HPA payload used in the Dolaflexin platform allows for a controlled bystander effect that likely contributes to the enhanced efficacy and lack of neutropenia we have observed with Dolaflexin-based ADCs. Citation Format: Susan M. Clardy, Alex Yurkovetskiy, Mao Yin, Dmitry Gumerov, Ling Xu, Elena Ter-Ovanesyan, Charlie Bu, Alex Johnson, Marina Protopopova, Qingxiu Zhang, Natalya Bodyak, Marc Damelin, David H. Lee, Donald Bergstrom, Timothy B. Lowinger. Unique pharmacologic properties of Dolaflexin-based ADCs—a controlled bystander effect [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 754.
Abstract 1974: Inhibition of the P-glycoprotein with a novel agent in overexpressing P-glycoprotein chemotherapy resistant colorectal cancer cells
Authors: Christopher L. Farrell, Rebecca Mahan, Catherine Blauvelt, Taylor Kaye Servais, Jessica Lane
Journal: Cancer Research (2018)

Abstract Multidrug resistance (MDR) plays a key role in chemotherapy failure and poor patient outcome. One of the ways multidrug resistance occurs is through the efflux of chemotherapeutic agents using the P-glycoprotein transporter protein on the surface of the tumor cell. There are several medications that work through P-glycoprotein (Pgp), which can either induce or inhibit the activity of the transporter. The purpose of this study was to evaluate known P-glycoprotein inhibitors and their effects on chemotherapy resistance in Caco2 cells, a colorectal cancer cell line. The experiments consisted of feeding the colorectal cancer cells with commonly known drugs that are Pgp substrates such as vinblastine for 4-8 months to establish an overexpressing Pgp transporter. An untreated negative control was used to show that Pgp was not overly expressed. Once the treated cells were overexpressing Pgp, the cells were seeded into a 96 well plate with a matrix of increasing chemotherapy and bergamottin, a known P-glycoprotein inhibitor. A cell proliferation assay was performed according to manufacturer protocol, with a Presto-Blue Cell Proliferation Assay kit to assess the effects of the chemotherapy agent, vinblastine and the bergamottin. Absorbance was recorded at 595 nanometers. This assay was tested on several multidrug resistant colorectal cell with different substrates and normal P-glycoprotein expressing cancer cells. The overexpressing Pgp cell lines required higher doses of vinblastine to exhibit cell death compared to the negative cells. The positive cells treated with bergamottin only showed change in cell death with increasing bergamottin concentration. From these results, it was determined that the use of the novel P-glycoprotein inhibitor was able to reverse the chemotherapy induced multidrug resistance in the cells with high Pgp expression. Patients whose tumor cells develop MDR have a poor prognosis compared to patients whose cells are responsive to chemotherapy. Because the chemotherapy agents are ineffective in killing the all of the tumor cells including cells which have become metastatic, the overall survival rate for patients with MDR-positive tumors is markedly decreased. Identify these patients as potential candidates for the Pgp inhibitor could significant increase their chances of survival with this aggressive form of cancer. Citation Format: Christopher L. Farrell, Rebecca Mahan, Catherine Blauvelt, Taylor Kaye Servais, Jessica Lane. Inhibition of the P-glycoprotein with a novel agent in overexpressing P-glycoprotein chemotherapy resistant colorectal cancer cells [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 1974.
Abstract 642: Comparison between in situ hybridization and digital polymerase chain reaction methods for detecting <i>c-MYC</i> gene copy number gain in tissue and cell-free plasma samples of colorectal cancer patients
Authors: Soo Hyun Seo, Kyu Sang Lee, Soo Kyung Nam, Kyoung Un Park, Heung-Kwon Oh, Duck-Woo Kim, Sung-Bum Kang, Hye Seung Lee
Journal: Cancer Research (2018)

Abstract Introduction: We focused on the utility of the droplet digital polymerase chain reaction (ddPCR) for detecting c-MYC gene copy number (GCN) gain in cell-free plasma and tumor tissue of CRC patients. Methods: c-MYC GCN was determined by using dual-color silver in situ hybridization (SISH) and ddPCR in retrospective cohort of 193 CRC patients (cohort 1) and prospective cohort of 64 CRC patients (cohort 2). Additionally, c-MYC GCN was analyzed by ddPCR method in cell-free plasma samples of cohort 2. Results: In cohort 1, c-MYC GCN gain, defined as mean c-MYC copies/nucleus ≥ 4.0 in SISH analysis, was observed in 34 (17.5%), and c-MYC GCN gain by ddPCR method in 7 (3.6%). c-MYC GCN by SISH was significantly correlated with ddPCR results (ρ= 0.532, P &amp;lt; 0.001). Forty cases (20.7%) showed intratumoral genetic heterogeneity, but it did not affect the concordance between SISH and ddPCR results (P &amp;gt; 0.05). c-MYC GCN gain by both SISH and ddPCR methods had the worst prognosis (P = 0.001). In cohort 2, c-MYC GCN by SISH was significantly associated with tissue ddPCR (ρ=0.349, P = 0.005), but not with plasma ddPCR (P = 0.620). Intratumoral genetic and regional heterogeneity of c-MYC status have been found in 29 (45.3%) and 8 (12.7%). c-MYC status in plasma was associated with tissue ddPCR, but borderline statistical significance (ρ= 0.246, P = 0.050). Conclusions: Our findings suggested that results by SISH and ddPCR methods were discordant. Therefore, detecting method should be carefully selected to determine c-MYC GCN status. Citation Format: Soo Hyun Seo, Kyu Sang Lee, Soo Kyung Nam, Kyoung Un Park, Heung-Kwon Oh, Duck-Woo Kim, Sung-Bum Kang, Hye Seung Lee. Comparison between in situ hybridization and digital polymerase chain reaction methods for detecting c-MYC gene copy number gain in tissue and cell-free plasma samples of colorectal cancer patients [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 642.
Characterization of Left Ventricular Activation in Patients With Heart Failure and Left Bundle-Branch Block
Authors: AngeloAuricchio, CeciliaFantoni, FrancoisRegoli, CorradoCarbucicchio, AndreasGoette, ChristophGeller, MichaelKloss, HelmutKlein
Journal: Circulation (2004)

Background— Conventional activation mapping in the dilated human left ventricle (LV) with left bundle-branch block (LBBB) morphology is incomplete given the limited number of recording sites that may be collected in a reasonable time and given the lack of precision in marking specific anatomic locations. Methods and Results— We studied LV activation sequences in 24 patients with heart failure and LBBB QRS morphology with simultaneous application of 3D contact and noncontact mapping during intrinsic rhythm and asynchronous pacing. Approximately one third of the patients with typical LBBB QRS morphology had normal transseptal activation time and a slightly prolonged or near-normal LV endocardial activation time. A “U-shaped” activation wave front was present in 23 patients because of a line of block that was located anteriorly (n=12), laterally (n=8), and inferiorly (n=3). Patients with a lateral line of block had significantly shorter QRS (P<0.003) and transseptal durations (P<0.001) and a longer distance ...
Abstract 5646: Serum functional biomarker discovery with PEP technology
Authors: Xing Wang, Michael Davies
Journal: Cancer Research (2018)

Abstract Proteins play essential roles in numerous biological processes and being able to pinpoint functional differences between cell or tissue samples can greatly aid in understanding disease processes and metabolic changes. The PEP technology allows systematic analysis of protein functions within a proteome. Hundreds of functional proteins can be separated and functionally assayed to generate a comprehensive three-dimensional landscape of protein families such as protein kinases, phosphatases, proteinases and oxido-reductases. This information can then be integrated into other genomic and proteomic knowledge bases to provide further insight of important biological processes such as cancer development and aging. Using the PEP technology, functional biomarker candidates have been identified from liver, lung and breast cancer patient serum. Both qualitative and quantitative differences of metabolic enzymes and proteases were observed when comparing the cancer patient serum and normal serum. Some of the active enzymes were identified by mass spectrometry and validated in selected bioassays. Deep mass spectrometry analysis revealed that some of the functional biomarkers are protein variants of important biological function. It is believed that this functional proteomics technology will provide a unique approach in the discovery of potential cancer biomarkers for diagnostic and prognostic applications. Further efforts are ongoing to develop a prototype of diagnosis kit for cancer detection based on the current discoveries. Citation Format: Xing Wang, Michael Davies. Serum functional biomarker discovery with PEP technology [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 5646.
Abstract 5285: Evaluation of a postpartum human papillomavirus vaccination program
Authors: Abbey B. Berenson, Jacqueline M. Hirth, Yong-Fang Kuo, Richard E. Rupp
Journal: Cancer Research (2018)

Abstract Evaluation of a postpartum human papillomavirus vaccination program Berenson AB, Hirth JM, Kuo YF, Rupp RE Purpose: To evaluate the effectiveness of a large vaccination program which offers the human papillomavirus (HPV) vaccine to women during their postpartum hospitalization. Methods: Based on the success of a pilot which offered the HPV vaccine to a select group of women, a postpartum HPV vaccination program was expanded in 2016 to include all eligible mothers who gave birth in a large Texas hospital serving low income women. Women from 23 different counties were included. With funding from the Cancer Prevention Research Institute of Texas (CPRIT), patient navigators were hired to identify and personally counsel all eligible women who met catch-up recommendation guidelines prior to their hospital discharge. Women were informed about the need and availability of the HPV vaccine during their hospitalization and offered it free of charge. Follow-up doses are coordinated with postpartum visits as well as well-baby visits in collaboration with the Department of Pediatrics. With Institutional Review Board approval, records of women who were approached during the first 11 months of the expanded program were reviewed to determine the number who chose to participate. Results: Baseline HPV vaccination rates were low. A total of 1,782 postpartum women were counseled about the HPV vaccine of which 168 (9.4%) were already vaccinated and 5 others were ineligible. Of the remaining 1,609 women, 71.2% received a dose of the HPV vaccine during their hospitalization. The refusal rate among eligible women was 24%. Another 4.3% (n-76) agreed to get vaccinated, but were released from the hospital before the injection was given. Of these, 48 (63.2%) received the dose at a later clinic visit. Conclusions: Offering the HPV vaccine as part of postpartum care can increase catch-up vaccination of young women who did not have the opportunity to be vaccinated at a younger age. Citation Format: Abbey B. Berenson, Jacqueline M. Hirth, Yong-Fang Kuo, Richard E. Rupp. Evaluation of a postpartum human papillomavirus vaccination program [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 5285.
Abstract 1838: A pre-existing rare PIK3CAE545Ksubpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling
Authors: Gabriele Romano, Pei-Ling Chen, Ping Song, Jennifer McQuade, Roger Liang, Mingguang Liu, Whijae Roh, Dzifa Duose, Fernando Carapeto, Jun Li, Jessica Teh, Andrew Aplin, Merry Chen, Jianhua Zhang, Alexander Lazar, P Andrew Futreal, Rodabe Amaria, David Zhang, Jennifer Wargo, Lawrence N. Kwong
Journal: Cancer Research (2018)

Abstract Combined MEK and CDK4/6 inhibition (MEKi+CDK4i) has shown promising clinical outcomes in NRAS mutant melanoma patients. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi+CDK4i therapy but subsequently developed resistance. Whole exome sequencing and functional validation identified an acquired PIK3CAE545K mutation as conferring drug resistance. We demonstrate that PIK3CAE545K pre-existed in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multi-region sampling due to PIK3CAE545K being non-uniformly distributed. This resistant population rapidly expanded after the initiation of MEKi+CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy. Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CAE545K-induced resistance. These results demonstrate that comprehensive analysis of pre-treatment samples can reveal rare pre-existing resistant subpopulations and posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways. Citation Format: Gabriele Romano, Pei-Ling Chen, Ping Song, Jennifer McQuade, Roger Liang, Mingguang Liu, Whijae Roh, Dzifa Duose, Fernando Carapeto, Jun Li, Jessica Teh, Andrew Aplin, Merry Chen, Jianhua Zhang, Alexander Lazar, P Andrew Futreal, Rodabe Amaria, David Zhang, Jennifer Wargo, Lawrence N. Kwong. A pre-existing rare PIK3CAE545K subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling [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 1838.