tbuckley/cabot-search huggingface dataset:
Abstract 360: Leveraging a novel ITIM motif in GPCRs for targeted antibody design
Authors: Lili T. Belcastro, Anastasia Jancina, Christina Adams, Ryan D. Paulukinas, Catherine C. Moore
Journal: Cancer Research (2017)

Abstract CXCR4, a chemokine GPCR, is essential for migration of neuronal, hematopoietic, and breast cancer cells during metastasis whereby CXCR4 dysregulation promotes migration and invasion. Following SDF stimulation, CXCR4 is phosphorylated on Ser/Thr residues which initiates adaptor recruitment, receptor desensitization, and trafficking to endocytic sites. Here we show that stimulation with gradient SDF, delays receptor phosphorylation and trafficking, leading to sustained signaling to a novel CXCR4-SHP2-ERK pathway. SHP2 is a tyrosine phosphatase implicated in HER2(+) and triple-negative breast cancers, whereby it transduces mitogenic and migratory signals driving hyperproliferation and invasion. SHP2 is recruited to tyrosine phosphorylated ITIM motifs (immmunoreceptor tyrosine-based inhibitory consensus motifs), a hallmark found in inhibitory immune receptors with little evidence in GPCRs. Here we identify an ITIM motif in CXCR4 that regulates both SHP2 binding and signaling. Specifically, we assessed if gradient SDF stimulation of CXCR4 1) delays receptor phosphorylation and trafficking, 2) sustains signaling to SHP2-ERK, 3) induces SHP2-dependent migration; and if CXCR4 Tyr mutation within the ITIM motif 4) maintains SDF gradient sensing ability, and 5) disrupts interaction with and signaling to SHP2. Our data demonstrate that gradient SDF delays receptor Ser/Thr phosphorylation and internalization thereby sustaining signaling to SHP2-ERK and driving SHP2-dependent migration. Furthermore, the ITIM mutant maintains SDF gradient sensing ability, but disrupts interaction with and signaling to SHP2. Our data support a working model that CXCR4 contains a functional ITIM motif which we are currently leveraging for targeted antibody design for use in migration studies of aggressive breast cancer cells with dysregulated CXCR4. These studies were supported by NIH grant GM-097718, PA Department of Health grant SAP4100057688, and the Milton Lev Memorial Faculty Research Fund. Citation Format: Lili T. Belcastro, Anastasia Jancina, Christina Adams, Ryan D. Paulukinas, Catherine C. Moore. Leveraging a novel ITIM motif in GPCRs for targeted antibody design [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 360. doi:10.1158/1538-7445.AM2017-360
Abstract 5068: A novel dual action inhibitor of histone deacetylase and demethylase in melanoma
Authors: Muzhou WU, Jay Kalin, Byungwoo Ryu, Philip Cole, Rhoda Alani
Journal: Cancer Research (2017)

Abstract Epigenetic agents have drawn great attention as anti-cancer therapies, with several HDAC inhibitors approved for a subset of hematologic malignancies. One of the biggest challenges in targeting epigenetic mechanisms of tumorigenesis is the wide spectrum of effects which restrict the therapeutic window for these compounds. We have developed a series of potent small molecule inhibitors with specificity towards the CoREST epigenetic corepressor complex through a dual-action mechanism targeting LSD1 and HDAC1. These compounds show a unique profile of pharmacologic action with an improved therapeutic window in a variety of cell types. Screening of tumor cell lines for growth inhibitory effects revealed variable efficacy in a broad spectrum of cancers with the most consistent and potent effects seen in human melanomas. The growth of a number of melanoma cell lines was found to be potently inhibited by one of these compounds, Corin 2; however, primary human melanocytes were relatively resistant to this agent. Transcriptomic analysis revealed that Corin2 was a more potent inducer of tumor suppressor genes compared to the parent HDAC and LSD1 compounds. Genetic knockdown of CoREST or LSD1 in cancer cell lines abolished the differences in potency of Corin2 vs. the parent HDAC inhibitor, Entinostat, suggesting that Corin2's favorable pharmacologic effects rely on an intact CoREST complex. Corin2 was also effective in slowing tumor growth in a melanoma mouse xenograft model. These dual action inhibitors demonstrate a novel, potent, and specific therapeutic approach to targeting epigenetic pathways in human melanomas which may lead to improved therapeutic benefits in patients with advanced disease. Note: This abstract was not presented at the meeting. Citation Format: Muzhou WU, Jay Kalin, Byungwoo Ryu, Philip Cole, Rhoda Alani. A novel dual action inhibitor of histone deacetylase and demethylase in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5068. doi:10.1158/1538-7445.AM2017-5068
The Symbol of Modern Medicine
Authors: Meyer D. Lifschitz
Journal: Annals of Internal Medicine (2004)

Letters17 February 2004The Symbol of Modern MedicineMeyer D. Lifschitz, MDMeyer D. Lifschitz, MDFrom Veterans Affairs Hospital and University of Texas Health Science Center at San Antonio; San Antonio, TX 78229-4404.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-140-4-200402170-00020 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:Drs. Wilcox and Whitham (1) trace the origin of the healing imagery of a snake on a staff to the Greek tradition of Asklepios. However, an earlier reference to Moses in the Hebrew Bible describes the healing power of this symbol centuries before the Greeks: “Hashem said to Moses, ‘Make yourself a burning one and place it on a pole, and it will be that anyone who has been bitten will look at it and live.’ Moses made a snake of copper and placed it on the pole; so it was that if the snake bit a ...References1. Wilcox RA, Whitham EM. The symbol of modern medicine: why one snake is more than two. Ann Intern Med. 2003;138:673-7. [PMID: 12693891] LinkGoogle Scholar2. Numbers 21:8-9. Google Scholar Author, Article, and Disclosure InformationAuthors: Meyer D. Lifschitz, MDAffiliations: From Veterans Affairs Hospital and University of Texas Health Science Center at San Antonio; San Antonio, TX 78229-4404. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoThe Symbol of Modern Medicine: Why One Snake Is More Than Two* Robert A. Wilcox and Emma M. Whitham The Symbol of Modern Medicine Sarkis J. Chobanian The Symbol of Modern Medicine David P. Steensma The Symbol of Modern Medicine Konstantinos Paparounas The Symbol of Modern Medicine Jamie Newman The Symbol of Modern Medicine Robert A. Wilcox and Emma M. Whitham The Symbol of Modern Medicine Michael E. Toedt and Dominique M. Gooby Toedt The Symbol of Modern Medicine Neni Prasad The Symbol of Modern Medicine Adrian G. Letz The Symbol of Modern Medicine Drew Hause Metrics 17 February 2004Volume 140, Issue 4Page: 310 ePublished: 17 February 2004 Issue Published: 17 February 2004 Copyright & PermissionsCopyright © 2004 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Abstract 2470: Compromised BRCA1-PALB2 interaction is associated with breast cancer risk
Authors: Tzeh Keong Foo, Marc Tischkowitz, Srilatha Simhadri, Talia Boshari, Kathleen A. Burke, Samuel H. Berman, Nadia Zayed, Yuan Chun Ding, Susan L. Neuhausen, Britta Weigelt, Jorge S. Reis-Filho, William D. Foulkes, Bing Xia
Journal: Cancer Research (2017)

Abstract The major breast cancer suppressor proteins BRCA1 and BRCA2 play essential roles in homologous recombination (HR)-mediated DNA repair, which is thought to be critical for tumor suppression. The two BRCA proteins are physically and functionally linked by a third tumor suppressor, PALB2 (partner and localizer of BRCA2), in the HR pathway. Heterozygous PALB2 mutation carriers have increased risk of breast, ovarian and pancreatic cancer. While truncating mutations in BRCA genes are generally pathogenic, interpretations of missense variants remains a challenge. To date, patient-derived missense variants that disrupt PALB2 binding have been identified in BRCA1 and BRCA2; however, there has not been sufficient evidence to establish their pathogenicity in humans. Variants in PALB2 that disrupt either its BRCA1 or BRCA2 binding have not been reported. Here, we report on the identification of a novel PALB2 variant, c.104T&amp;gt;C [p.L35P], that segregated in a family with a strong history of breast cancer. Functional analyses showed that L35P abrogates the PALB2-BRCA1 interaction, resulting in impaired HR and sensitivity to platinum salts and PARP inhibitors. Whole-exome sequencing of breast tumor from a c.104T&amp;gt;C carrier revealed a somatic, truncating mutation in the second allele of PALB2, with the tumor displays hallmark genomic features of tumors with BRCA mutations and HR defects. Using a combination of traditional clinical genetics, tumor whole-exome sequencing and in-depth functional analyses, we have provided direct evidence to cement the pathogenicity of L35P. Parallel analyses of other germline variants in the PALB2 N-terminal BRCA1-binding domain also identified multiple variants that affect HR function to varying degrees, suggesting their possible contribution to cancer development. Our findings establish p.L35P as the first pathogenic missense mutation in PALB2 identified to date and directly demonstrate the requirement of the PALB2-BRCA1 interaction for breast cancer suppression. Citation Format: Tzeh Keong Foo, Marc Tischkowitz, Srilatha Simhadri, Talia Boshari, Kathleen A. Burke, Samuel H. Berman, Nadia Zayed, Yuan Chun Ding, Susan L. Neuhausen, Britta Weigelt, Jorge S. Reis-Filho, William D. Foulkes, Bing Xia. Compromised BRCA1-PALB2 interaction is associated with breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2470. doi:10.1158/1538-7445.AM2017-2470
Abstract 2697: A role for the membrane type-1 matrix metalloproteinase in the transcriptional regulation of carcinogen-induced inflammasome components
Authors: Samuel Sheehy, Borhane Annabi
Journal: Cancer Research (2017)

Abstract BACKGROUND : Signal transducing functions driven by the cytoplasmic domain of membrane type-1 matrix metalloproteinase (MT1-MMP) are believed to regulate many inflammation-mediated cancer cell functions including migration, proliferation, and survival. Besides the upregulation of the inflammation biomarker cyclooxygenase (COX)-2 expression, MT1-MMP’s role in relaying the signals triggered from pro-inflammatory cues remain poorly understood. METHODS : Here, we treated HT1080 fibrosarcoma cells with phorbol-12-myristate-13-acetate (PMA), a well-known carcinogen and inducer of COX-2 and of MT1-MMP. In order to assess the global transcriptional regulatory role that MT1-MMP may exert on inflammation biomarkers, we combined gene array screens to transiant MT1-MMP gene silencing strategy. RESULTS : We found that MT1-MMP expression exerted both stimulatory and repressive transcriptional control of several inflammasome-related biomarkers such as IL-1B, IL-6, IL-12A, and IL-33, as well as of transcription factors such as EGR1, ELK1, and ETS1/2 in PMA-treated cells. Among the signal transducing pathways explored, silencing of MT1-MMP prevented PMA from phosphorylating Erk, IκB, and p105 KF-κB intermediates. We also highlight a signaling axis linking MT1-MMP to MMP-9 transcriptional regulation. CONCLUSIONS : Altogether, our data evidence an important involvement of MT1-MMP in the transcriptional regulation of inflammatory biomarkers consolidating its contribution in signal transducing functions, in addition to its classical hydrolytic activity. Citation Format: Samuel Sheehy, Borhane Annabi. A role for the membrane type-1 matrix metalloproteinase in the transcriptional regulation of carcinogen-induced inflammasome components [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2697. doi:10.1158/1538-7445.AM2017-2697
Abstract 16275: Out-of-Hospital Cardiac Arrest and Short-Term Exposure to Air Pollutants: A Case-Crossover Study
Authors: Bing Zhao, Farhad Salimi, Fay Johnston, Kiyohiro Oshima, Masahiko Kurabayashi, Kazuaki Negishi
Journal: Circulation (2016)

Introduction: Over the past decade, particulate matter (PM), such as fine particles  3 million premature deaths occur per year and 76 million disability-adjusted life-years are lost annually due to ambient PM exposure. However, the evidence regarding the association between air pollution and acute cardiac events, such as out-of-hospital cardiac arrest (OHCA), is inconsistent. This study aimed to identify the associations between incidence of OHCA with air pollutants including PM2.5, Ox and NOX. Methods: The association between air quality and OHCA was evaluated using a case-crossover design in Gunma Prefecture (population ~2million; area 6,363km2), Japan. OHCA cases were identified through the Gunma Prefectural Ambulance Activity Database in 2015. Our exclusion criteria were: arrests...
Abstract 2531: Regulation of androgen signaling axis and tumor suppressive function of miR-149-5p in prostate cancer
Authors: Savita Singh, Jey Sabith Ebron, Eswar Shankar, Sanjay Gupta, Daniel Lindner, Girish Shukla
Journal: Cancer Research (2017)

Abstract Prostate cancer growth and proliferation depends on androgen signaling mediated by transactivation of Androgen Receptor (AR). Androgen ablation remains the mainstay therapy for treatment of the disease. However, despite androgen ablation, the disease relapses to more aggressive form known as castration-resistant prostate cancer (CRPC). Androgen Signaling Inhibitor such as Abiraterone Acetate and Enzalutamide are the most effective treatment methods currently being used to treat CRPC. However, more than one-third of CRPC patients develop resistance to these treatments, mostly due to the gain of function in the AR protein and increase in intratumoral dihydrotestosterone (DHT) synthesis. Intratumoral DHT synthesis from steroid precursors in tumors is augmented by up-regulation of enzymes of cholestrogenesis and steroidogenesis, such as HMG-CoA reductase, SCARB1, and 17βHSD respectively. Tumor-specific downregulation of microRNAs which regulate the AR and steroid biosynthesis has been implicated in tumor growth and resistance to therapeutics in CRPC. We are focusing on tumor suppressive role of miR-149-5p in PCa. We discovered that miR-149-5p expression was significantly lower in prostate cancer tissues compared to normal tissues. The mechanistic investigation revealed that miR-149-5p downregulates wild type and alternatively spliced variant of AR. It also down regulates the expression of SCARB1, HMGCS and HMG-CoA reductase, the proteins known to facilitate intratumoral DHT synthesis. Ectopic expression of miR-149-5p negatively regulated the expression of prostate-specific antigen, a downstream target of androgen signaling and it also inhibited invasion and proliferation of CRPC cells. Our findings indicate a significant role of miR-149-5p in regulating androgen signaling and possibly DHT synthesis in CRPC. This provides a strong rationale for further investigating the significance of miR-149-5p for generation of new therapeutic for CRPC. Citation Format: Savita Singh, Jey Sabith Ebron, Eswar Shankar, Sanjay Gupta, Daniel Lindner, Girish Shukla. Regulation of androgen signaling axis and tumor suppressive function of miR-149-5p in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2531. doi:10.1158/1538-7445.AM2017-2531
Abstract 1276: Gene-environment interaction relevant to estrogen and risk of breast cancer
Authors: JooYong Park, Ji-Yeob Choi, Seokang Chung, Nan Song, Sue K Park, Wonshik Han, Dong-Young Noh, Sei-Hyun Ahn, Mi-Kyung Kim, Keun-Young Yoo, Wei Zheng, Daehee Kang
Journal: Cancer Research (2017)

Abstract Introduction: Many established reproductive risk factors for breast cancer are mediated by hormonal mechanisms, and most parts are involved in estrogens. In addition, the estrogen level controlled by genetic factors might be a sort of determinants to breast cancer risk involving estrogen metabolism. This study aims to examine gene and environment interaction (GxE) between candidate genes which are involved in estrogen metabolism and environmental factors which are related to estrogen exposure. Methods: GxE analyses were conducted in the Korean 1,970 breast cancer cases and 2,052 controls which were recruited in the Seoul Breast Cancer Study (SEBCS), a multicenter case control study. 137 candidate genes involved in estrogen metabolism were searched from couple of databases and 11,555 SNPs (2,472 typed SNPs and 9,083 imputed SNPs) from the range of candidate genes were included in GxE analyses with 8 established environmental factors. Statistical analyses were performed by using GxEScan (ver. Beta 0.4.0; http://biostats.usc.edu/software) for GxE test. Results: There were three significant interaction between 11,555 SNPs and 8 environmental factors. Firstly, interaction rs851998 nearby ESR1 with height was shown in the GE|2df model (p-2df = 1.1x10-4) This SNP had protective effect marginally (ORG = 0.82, 95% CI: 0.75-0.90) and further protective effect for women whose height is smaller than 160cm (OR G | height ≥ 160cm = 0.78, 95% CI: 0.70-0.87, p = 1.09x10-5). Second interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2x10-3). This SNP also had protective effect marginally (ORG = 0.85, 95% CI: 0.77-0.97) and more protective effect when age at menarche is 14 years and over (OR G | age at menarche ≥ 14years = 0.82, 95% CI: 0.73-0.97, p=3.6x10-4). Lastly, there was marginally significant interaction between rs4140979 of FSHR and age at first full term pregnancy (FFTP) in the EDGxE model. Although this SNP had no marginal effect, qualitative interaction was shown with FFTP (OR G | FFTP &amp;lt; 27years = 0.88, 95% CI: 0.78-1.00, p=0.0482; OR G | Nulliparity or FFTP ≥ 27 years = 1.30, 95% CI: 1.10-1.53, p=0.002). Conclusion: Three significant interactions were identified by focusing two step methods. Replication should be performed in the independent and larger population due to statistical limitation. Citation Format: JooYong Park, Ji-Yeob Choi, Seokang Chung, Nan Song, Sue K Park, Wonshik Han, Dong-Young Noh, Sei-Hyun Ahn, Mi-Kyung Kim, Keun-Young Yoo, Wei Zheng, Daehee Kang. Gene-environment interaction relevant to estrogen and risk of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1276. doi:10.1158/1538-7445.AM2017-1276
Abstract 1285: Analysis of esophageal cancer SNPs and gene expression to predict ESCC risk
Authors: Lilly A. Ding, Molly P. Ding, Xin Song, Lidong Wang, Liang Wang
Journal: Cancer Research (2017)

Abstract Esophageal cancer is one of most common cancers worldwide and its incidence has increased rapidly over the past decades. The majority of esophageal cancers is the esophageal squamous cell carcinoma (ESCC), which is particularly prevalent in Asian and South African areas. Most cases of ESCC are diagnosed at advanced stages, with an overall 5-year survival rate of 10–20%. Currently, genome-wide association studies (GWAS) are used to identify high risk individuals for the development of ESCC. Many SNPs have been identified to associate with a risk of ESCC. However, the effect size attributable to individual SNPs was typically modest, suggesting that genetic variants may only account for a very small amount of genetic risk and heritability of ESCC. The combined effect of multi genetic variants with altered mRNA expression play critical roles in ESCC. In this study, we used several existing bioinformatics databases (HaploReg, GTEx Portal and cBio Portal). We first selected 450 potential ESCC risk SNPs from HaploReg and then defined which SNPs caused gene expression alterations in the esophagus through expression quantitative trait loci (eQTL). Nine SNPs in eight genes (MUC1, ALS2CR12, ADHB1, TMEM173, XBP1, PLCE1, HEATR3 and SMG6) were identified as having altered mRNA expression. The altered mRNA expression of these seventeen genes are: MUC1, THBS3, GBAP1, EFNA1, SCAMP3, CASP8, CASP10, ALS2CR12, STRADB, ADH4, TMEM173, CYCTM1, DNAJC18, DNAJC20, NOC3L, HEATR3 and SRR. These altered gene expressions in the mucosal layer of the esophagus metabolize enzymes, repair DNA, and prevent cell death and inflammation, all of which may indicate that the existing altered esophageal mRNA levels plus the predisposition of normal esophageal epithelial cells can lead to harmful environmental carcinogens, thus attributing to ESCC development. In order to validate these gene alterations related to ESCC SNPs in screening and early detection of high risk individuals, DNA genotyping of this group of SNPs with a prospective cohort (n=5451) in a high risk area of ESCC will be tested in future studies. Citation Format: Lilly A. Ding, Molly P. Ding, Xin Song, Lidong Wang, Liang Wang. Analysis of esophageal cancer SNPs and gene expression to predict ESCC risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1285. doi:10.1158/1538-7445.AM2017-1285