tbuckley/cabot-search huggingface dataset:
Abstract 3854: Antizyme inhibitor editing modulates nuclear localization but not antizyme binding: Implications for prostate cancer
Authors: James M. Rice, Aram Ghalali, Liangzhe Wang, Amanda Kusztos, Finith Jernigan, Chin Lee Wu, Bruce Zetter, Michael S. Rogers
Journal: Cancer Research (2018)

Abstract The endogenous antizyme inhibitor (AZIN) binds to, and is a key regulator of, the cell cycle suppressor antizyme. Antizyme itself is a key regulator of ornithine decarboxylase (ODC), the rate-limiting enzyme in the polyamine synthesis. We have measured the expression and localization of AZIN in 202 prostate cancer specimens, along with 26 adjacent benign samples, and found that nuclear localization of AZIN is dramatically associated with worse outcome. Upregulation and nuclear localization of AZIN have been observed in several cancers, as has editing of the AZIN1 mRNA. Other have hypothesized that the RNA- edited AZIN (edAZIN) may have an increased affinity to antizyme and that could explain the association of edAZIN to the various cancers. We have studied the mechanism behind the nuclear localization of AZIN and found the single base pair substitution caused by RNA editing is sufficient to result in nuclear localization of the protein in all cell types tested. To determine if the nuclear localization might result from increased antizyme-edAZIN affinity, we developed fluorescent protein FRET sensor for protein-protein interaction using Clover-AZIN and antizyme-mRuby2 fusion proteins. Unexpectedly, we found that the editing event decreases edAZIN affinity for antizyme, notwithstanding increased interaction in vivo. Thus, the data indicate that the change in protein localization to the nucleus may be more important to oncogenic function than the actual degree of binding to antizyme. Other functional differences between edAZIN and AZIN might be explained by altered kinetics of binding, by the contribution of an additional adapter protein that modulates the intracellular antizyme:AZIN complex, or by competition for AZIN binding by other partners whose interaction is affected by the editing event. Therefore, we plan to identify AZIN and edAZIN interacting proteins by using proteomic analysis and later study the interaction between AZIN or edAZIN with their binding partners in more detail. Furthermore, our validated FRET assays can be used to identify antagonists of AZIN-antizyme binding (no antagonists are currently known). Given the important role of AZIN in tumor growth, discovery of small-molecule inhibitors of AZIN should lead to antitumor therapies. Citation Format: James M. Rice, Aram Ghalali, Liangzhe Wang, Amanda Kusztos, Finith Jernigan, Chin Lee Wu, Bruce Zetter, Michael S. Rogers. Antizyme inhibitor editing modulates nuclear localization but not antizyme binding: Implications for 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 3854.
Monocyte adhesion with platelet satellitism and phagocytosis in Hodgkin lymphoma
Authors: Barbara J. Bain, Branislav Czako
Journal: American Journal of Hematology (2018)

Platelet satellitism is an in vitro phenomenon usually involving neutrophils and occasionally followed by phagocytosis of platelets. It is quite uncommon for lineages other than neutrophils, to be involved. Here, we report the occurrence of monocyte-monocyte adhesion, satellitism and phagocytosis of platelets by monocytes without neutrophils being involved. The patient was a 37-year-old man with β-thalassemia heterozygosity and stage IVB Hodgkin lymphoma. His blood count showed: white cell count 10.2 × 109/L; monocyte count 1.3 × 109/L; hemoglobin concentration 75 g/L; mean cell volume 73 fL; and platelet count 174 × 109/L. His blood film confirmed monocytosis and showed monocytes that were adherent to each other, satellitism of platelets around monocytes, and phagocytosis of platelets (Images). In addition, there was microcytosis and hypochromia (attributable to β-thalassemia) and increased rouleaux formation. Other blood tests showed evidence of a marked inflammatory response with C-reactive protein of 253 mg/L (normal range 0-10), serum ferritin of 1306 μg/L (22-322), reduced serum iron, transferrin at the lower limit of normal and reduced serum albumin of 22 g/L (35-50). The patient responded well to treatment and on follow-up, when he was clinically well, the phenomenon was no longer present. We postulate that the abnormalities observed were part of the marked inflammatory response to Hodgkin lymphoma. None.
Stromelysin Promoter 5A/6A Polymorphism Is Associated With Acute Myocardial Infarction
Authors: MasahiroTerashima, HozukaAkita, KenjiKanazawa, NobutakaInoue, ShinichiroYamada, KeiichiIto, YasuakiMatsuda, EijiTakai, ChikaoIwai, HiroyukiKurogane, YutakaYoshida, MitsuhiroYokoyama
Journal: Circulation (1999)

Background—Rupture of the fibrous cap of an atherosclerotic plaque is a key event that predisposes to acute myocardial infarction (AMI). Matrix metalloproteinases (MMPs) may contribute to weakening of the cap, which favors rupture. Stromelysin, a member of MMP family, is identified extensively in human coronary atherosclerotic lesions. It can degrade most of the constituents of extracellular matrix as well as activating other MMPs, which suggests that it may play an important role in plaque rupture. Recently, a common variant (5A/6A) in the promoter of the stromelysin gene has been identified. The 5A/6A polymorphism could regulate the transcription of the stromelysin gene in an allele-specific manner. Methods and Results—To investigate the relation between the 5A/6A polymorphism in the promoter of the stromelysin gene and AMI, we conducted a case-control study of 330 AMI patients and 330 control subjects. The prevalence of the 5A/6A+5A/5A genotype was significantly more frequent in the patients with AMI t...
Abstract 100: Interleukin 1 receptor type II upregulates MMP1 expression and increases motility of keratinocytes cells
Authors: Hsiu-Hua Wang, Te-Chang Lee
Journal: Cancer Research (2018)

Abstract We have shown that long-term exposure to low doses of inorganic arsenite (iAs) induced malignant transformation of non-tumorigenic human keratinocytes, HaCaT cells. We further demonstrated that enhanced expression of a decoy type II receptor of interleukin-1 (IL1R2) in transformed keratinocytes mediated through IL-6 and VEGFR to increase the migration and invasion activities, indicating the oncogenic potential of IL1R2. In this present study, we further explored how IL1R2 enhances the cell motility in human keratinocytes. As described earlier, long-term and low dose iAs (0, 0.5 and 1 μM) exposed HaCaT cells were designated as HaCaT A0, A1 and A2 cells, respectively. The tumorigenic cell line, T4R2, was derived from the tumor in mice implanted with HaCaT A2 cells. By growing HaCaT A0, A1, A2 and T4R2 cells on an organotypic culture system using basal medium, we found that T4R2 cells formed multilayered morphology. By aid of siRNA and ectopic expression techniques, we further demonstrated that increased expression of IL1R2 in T4R2 cells was associated with increased matrix metalloproteinase-1 (MMP1) and enhanced cell motility. The roles of MMP1 on supporting the organotypic growth of T4R2 cells were confirmed by using the stably MMP1-silenced T4R2 cells (T4R2-shMMP1). The cell motility of T4R2-shMMP1 cells was also significantly reduced. Furthermore, IL1R2-induced MMP1 upregulation was remarkably inhibited by inhibitors of MAPK/ERK signaling. Our present results revealed that MMP1 was one of downstream targets of IL1R2 which plays a crucial role on the progression of malignancy. Therefore, IL1R2 may be a target for cancer intervention. Citation Format: Hsiu-Hua Wang, Te-Chang Lee. Interleukin 1 receptor type II upregulates MMP1 expression and increases motility of keratinocytes 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 100.
Abstract 3393: Characterizing recurrent high-grade serous ovarian cancer through whole-genome sequencing
Authors: Elizabeth L. Christie, Swetansu Pattnaik, Sian Fereday, Australian Ovarian Cancer Study, Heather Thorne, Andrea Bild, David D. Bowtell
Journal: Cancer Research (2018)

Abstract Acquired drug resistance is the major obstacle in controlling high-grade serous ovarian cancer (HGSC) and leads to poor overall survival. Comparatively little massively parallel sequencing data exist from HGSC patients with recurrent disease who have been extensively treated with chemotherapy or newer targeted agents, such as anti-angiogenics or PARP inhibitors (PARPi). We previously identified four mechanisms of acquired resistance from whole-genome sequencing (WGS) of 23 HGSC patients with recurrent disease; a resistance mechanism of any kind was only identified in half of the patients. Since 2012, we have collected tumor samples from 16 HGSC patients through our rapid-autopsy program. On average, we collect 17 tumor sites per patient during the autopsy, and to date we have performed WGS on 28 autopsy samples from 8 patients. These data are allowing us to understand HGSC at end-stage, by examining the complete catalog of resistance mechanisms within an individual patient and reconstructing the natural history of HGSC. One acquired resistance mechanism we identified in HGSC involves transcriptional fusion of the drug efflux pump ABCB1 to an upstream gene that causes its overexpression. ABCB1 encodes the multidrug resistance transporter MDR1, also known as P-glycoprotein. Through WGS and targeted RNA sequencing on end-stage tumor samples as well as recurrent ascites samples, we identified multiple fusion partners to ABCB1, with more than 15% of recurrent HGSC patients harboring ABCB1 transcriptional fusions. A number of HGSC patients carry multiple ABCB1 fusions, demonstrating convergent evolution within patients and the strong selective advantage of ABCB1 overexpression by gene fusion. Extending our analysis to recurrent and autopsy samples from breast and prostate cancer patients also identified ABCB1 transcriptional fusions as a resistance mechanism in these cancers. Our findings suggest that ABCB1 transcriptional fusions are a common mechanism of acquired chemotherapy resistance in ovarian, breast and prostate cancer patients, and that characterizing end-stage disease is particularly informative for understanding resistance mechanisms. Citation Format: Elizabeth L. Christie, Swetansu Pattnaik, Sian Fereday, Australian Ovarian Cancer Study, Heather Thorne, Andrea Bild, David D. Bowtell. Characterizing recurrent high-grade serous ovarian cancer through whole-genome sequencing [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 3393.
Abstract 5783: Strong antitumor activity of ASN007, an oral ERK1/2 inhibitor, in PDX tumor models with MAP kinase pathway alterations including KRAS mutations
Authors: Sanjeeva P. Reddy, Niranjan S. Rao, Roger A. Smith, Scott K. Thompson, Sarper Toker
Journal: Cancer Research (2018)

Abstract The RAS/RAF/MEK pathway is frequently dysregulated in a broad range of cancers through mutations in several targets such as KRAS, NRAS, HRAS, BRAF, NF1 and receptor tyrosine kinases. Although MEK and BRAF inhibitors improve the outcome for patients with BRAF mutant melanoma and lung cancers, the duration of response is limited due to reactivation of the pathway. The extracellular-signal-regulated kinases, ERK1 and ERK2 (ERK1/2), which are downstream of MEK and BRAF kinases, serve as a key node in this crucial signaling pathway. Targeting ERK1/2 offers a promising therapeutic strategy for a broad range of cancers, particularly the ones driven by RAS mutations, and in overcoming resistance to MEK/BRAF inhibitors. Here, we present discovery and characterization of a novel orally bioavailable compound, ASN007, that showed inhibition of ERK1/2 kinases in a biochemical assay with IC50 = 2 nM for both targets. Interestingly, ASN007 displayed a much slower dissociation rate (longer target residence time) as compared to other ERK inhibitors. ASN007 inhibited the phosphorylation of ERK1/2 substrates such as RSK1, FRA1 and Elk1 in various cell lines with low nM IC50 values. ASN007 showed potent anti-proliferative activity that was selective for MAPK-pathway dependent cancer cell lines. Indeed, ASN007 showed much more robust activity against RAS mutant cell lines as compared to other ERK1/2 inhibitors. In a daily oral dosing regimen, ASN007 demonstrated strong tumor growth inhibition in BRAF, KRAS and NRAS mutant xenograft models in mice and was well tolerated at efficacious doses. Of note, ASN007 showed strong efficacy using various intermittent dosing regimens. It also showed a strong anti-tumor activity in colorectal PDX models with various KRAS mutations. Furthermore, ASN007 showed regression of tumor growth in a melanoma PDX model that was resistant to both MEK and BRAF inhibitors. In addition to the single agent activity, greater efficacy was observed when ASN007 was combined with immunotherapeutic agents such as an anti-PD-1 antibody or an IDO-1 inhibitor. ASN007 does not exhibit significant inhibition of CYP enzymes or the hERG channel. A Phase 1 trial with ASN007 in patients with BRAF and K-, H- and N-RAS mutant melanoma, colorectal, non-small lung and pancreatic cancers is being planned. Citation Format: Sanjeeva P. Reddy, Niranjan S. Rao, Roger A. Smith, Scott K. Thompson, Sarper Toker. Strong antitumor activity of ASN007, an oral ERK1/2 inhibitor, in PDX tumor models with MAP kinase pathway alterations including KRAS mutations [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 5783.
Abstract 2115: An authenticated in vitro model for prostate microenvironment studies utilizing prostate epithelial cells and stromal-derived cells
Authors: Luis G. Rodriguez, Russell E. McDaniel, Xiangshan Zhao, Chaozhong Zou
Journal: Cancer Research (2018)

Abstract Prostate cancer remains one of the most common cancers diagnosed in men and one of the leading causes of cancer death in men. Tumor development and progression have been shown to be highly influenced not simply by the genetic makeup of a cell, but by its surrounding stroma, particularly fibroblasts. It has been demonstrated that prostate cancer-associated fibroblasts (CAFs, which are located marginal to the prostate tumor), differ from prostate normal-associated fibroblast (NAFs, which are located distal to the prostate tumor), on their contribution to tumor progression. However, human prostate cancer in-vitro model systems have focused largely on prostate cancer epithelial cells exclusively. A need exists for a more physiologically relevant human cell model system to study prostate cancer progression within the context of its tumor microenvironment. In this study, we utilized prostate cancer-associated fibroblasts (CAFs), prostate normal-associated fibroblasts (NAFs) and normal prostate epithelial (PrE) cells; all three lines were immortalized by hTERT (human telomerase reverse transcriptase) alone and they were continuously passaged for at least 15 passages without any indications of a decrease in growth rate. All cell lines express appropriate specific cell lineage markers for either fibroblasts or epithelial cells. Fibroblasts expressed TE7 and alpha smooth muscle actin (a-SMA), while prostate epithelial cells expressed cytokeratin 5, low levels of prostate specific antigen (PSA) and high levels of p63 throughout their continuous passage; all characteristics in accord with their primary cell counterparts. Next, cell proliferation was measured for various prostate-derived epithelial cells under the influence of CAFs and NAFs cells. Normal prostate epithelial cell proliferation was inhibited and produced a visible morphological change in the cells in the presence of CAFs or CAF-conditioned medium. Meanwhile, the effects of stromal cells on prostate cancer cells was cell line dependent, demonstrating both promotion and inhibition of growth of selected cancer cells. Surprisingly, both CAFs and NAFs promoted cancer cell growth, but CAFs promoted a greater increase in cell proliferation than NAFs in some cancer cell lines. This study demonstrates that these three hTERT immortalized cells from human prostate are a valuable model system for the study of prostate cancer cell progression and tumor micro environment studies. Citation Format: Luis G. Rodriguez, Russell E. McDaniel, Xiangshan Zhao, Chaozhong Zou. An authenticated in vitro model for prostate microenvironment studies utilizing prostate epithelial cells and stromal-derived 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 2115.
Abstract 1346: Lycorine Promotes Autophagy and Apoptosis via TCRP1/Akt/mTOR Axis Inactivation in Human Hepatocellular Carcinoma
Authors: Yuhaiyang Yuhaiyang Yuhaiyang
Journal: Cancer Research (2018)

Abstract Lycorine is a multi-functional bioactive compound, and it possesses potential anti-cancer activities. However, little is known about the underlying mechanism. In this research we have found that lycorine significantly induces the apoptotic and autophagic capacities of hepatocellular carcinoma (HCC) cells in vitro and in vivo. Treatment with specific autophagy inhibitor (3-methyladenine/Bafilomycin A1) or knockdown of LC-3B/Atg5 by siRNA drastically enhances the apoptotic cell death effect by facilitating the switch from autophagy to apoptosis. Molecular validation mechanistically demonstrates that lycorine-induced apoptosis and autophagy in HCC cells is associated with decreased protein levels of tongue cancer resistance-associated protein 1 (TCRP1), and we further find that inhibition of TCRP1 decreases phosphorylation level of Akt and represses Akt/mTOR signaling. Finally, lycorine-induced apoptosis and autophagy suppress the growth of xenograft hepatocellular tumors without remarkable toxicity. Our results elucidate a novel molecular mechanism whereby lycorine promotes apoptosis and autophagy through TCRP1/Akt/mTOR pathway in HCC. Our results reveal that lycorine might be a potential therapeutic agent for the treatment of HCC. Citation Format: Yuhaiyang Yuhaiyang Yuhaiyang. Lycorine Promotes Autophagy and Apoptosis via TCRP1/Akt/mTOR Axis Inactivation in Human Hepatocellular Carcinoma [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 1346.
Immune system-mediated atherosclerosis caused by deficiency of long non-coding RNA<i>MALAT1</i>in ApoE−/−<b>mice</b>
Authors: Martina Gast, Bernhard H Rauch, Shinichi Nakagawa, Arash Haghikia, Andrzej Jasina, Jan Haas, Neetika Nath, Lars Jensen, Andrea Stroux, Andreas Böhm, Julian Friebel, Ursula Rauch, Carsten Skurk, Stefan Blankenberg, Tanja Zeller, Kannanganattu V Prasanth, Benjamin Meder, Andreas Kuss, Ulf Landmesser, Wolfgang Poller
Journal: Cardiovascular Research (2018)

The immune system is considered a key driver of atherosclerosis, and beyond proteins and microRNAs (miRs), long non-coding RNAs (lncRNAs) are implicated in immune control. We previously described that lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is involved in cardiac innate immunity in a myocarditis model. Here, we investigated the impact of MALAT1 deficiency upon atherosclerosis development. Heterozygous MALAT1-deficient ApoE−/− mice displayed massive immune system dysregulation and atherosclerosis within 2 months even when kept on normal diet. Aortic plaque area (P < 0.05) and aortic root plaque size (P < 0.001) were increased in MALAT1-deficient vs. MALAT1-wildtype ApoE−/− mice. Serum levels of interferon-γ (IFN-γ), tumour necrosis factor (TNF), and interleukin 6 (IL6) were elevated (P < 0.001) in MALAT1-deficient animals. MALAT1-deficient bone marrow-derived macrophages showed enhanced expression of TNF (P = 0.001) and inducible NO synthase (NOS2) (P = 0.002), suppressed MMP9 (P < 0.001), and impaired phagocytic activity (P < 0.001) upon lipopolysaccharide stimulation. RNA-sequencing revealed grossly altered transcriptomes of MALAT1-deficient splenocytes already at baseline, with massive induction of IFN- γ, TNF, NOS2, and granzyme B; CC and CXC chemokines and CCR8; and innate immunity genes interferon-induced protein with tetratricopeptide repeats (IFIT)1/3, interferon-induced transmembrane protein (IFITM)1/3, ISG15. Multiple miRs were up to 45-fold upregulated. Further, selective ablation of the cytosolic part of the MALAT1 system only, the enzymatically MALAT1-derived mascRNA, resulted in massive induction of TNF (P = 0.004) and IL6 (P = 0.028) in macrophages. Northern analysis of post-myocardial infarction patient vs. control peripheral blood mononuclear cells showed reduced (P = 0.005) mascRNA in the patients. CHART-enriched RNA-sequencing reads at the genomic loci of MALAT1 and neighbouring nuclear enriched abundant transcript (NEAT1) documented direct interaction between these lncRNA transcripts. The data suggest a molecular circuit involving the MALAT1-mascRNA system, interactions between MALAT1 and NEAT1, and key immune effector molecules, cumulatively impacting upon the development of atherosclerosis. It appears reasonable to look for therapeutic targets in this circuit and to screen for anomalies in the NEAT1–MALAT1 region in humans, too, as possible novel disease risk factors.
Spectrum of interstitial lung disease in China from 2000 to 2012
Authors: Chengjun Ban, Wei Yan, Bingbing Xie, Min Zhu, Yan Liu, Shu Zhang, Qiao Ye, Yanhong Ren, Dingyuan Jiang, Jing Geng, Huaping Dai, Chen Wang
Journal: European Respiratory Journal (2018)

<b>Hospital admissions of patients for ILD increased in China from 2000 to 2012 and IPF was the most frequent type. This suggests an increasing recognition of ILD and/or increased burden of disease.</b>http://ow.ly/WC6t30kWlje
Abstract 13175: Impaired Activity of The Thioredoxin Reducing System Contributes to Diabetic Cardiac Disease: Evidence from Human and Experimental Studies
Authors: Andrew Advani, Richard E Gilbert, kabir Golam, Yanling Zhang, Suzanne L Advani, Kim A Connelly
Journal: Circulation (2012)

Background: Excessive reactive oxygen species (ROS) are implicated in the pathogenesis of diabetes induced vascular complications, including diabetic cardiomyopathy. While increased ROS are traditionally viewed as arising from the metabolic flux of diabetes, we explored the possibility that altered activity of anti-oxidant systems may also contribute, focusing upon the activity of the thioredoxin (TRX) reducing system, and expression of its endogenous inhibitor thioredoxin interacting protein (TxnIP). Methods: TRX activity, mRNA expression and protein content of its endogenous inhibitor, TxnIP, were examined in human right atrial biopsy specimens from diabetic and non-diabetic individuals obtained during coronary artery bypass surgery (CABG) and in cardiac tissue derived from a hemodynamically validated animal model of diastolic heart failure, the streptozotocin TGR(mRen)2-27 rat. ROS were assessed using 3-nitrotyosine staining. Results: Right atrial tissue from individuals with diabetes demonstrated a si...