tbuckley/cabot-search huggingface dataset:
Abstract 352: DNA replication licensing factor MCM5 is a target for SETD8 mediated methylation
Authors: Fabio Pittella, Gil Blum, Yongxia Zhu, Chamara Senevirathne, Minkui Luo
Journal: Cancer Research (2018)

Abstract SETD8 methyltransferase activity is implicated in several fundamental cellular processes such as transcriptional regulation and heterochromatin formation as well as processes that ensures genomic stability including DNA replication and the DNA damage response. It has been proposed that SETD8 affects DNA replication as a positive regulator of origin licensing through H4K20 methylation and by supporting Okazaki fragment processing through PCNA methylation. However, there is no evidence whether other key element in the replication machinery is directly modified by SETD8. To address this question, we used a combination of SILAC-based BPPM (Bioorthogonal Profiling of Protein Methylation) to profile new substrates for SETD8. We genetically engineered SETD8 and identified mutants amenable to accommodate non-native SAM analogues containing a terminal alkyne moiety for click chemistry. The engineered SETD8 can transfer this unique chemical moiety into target proteins for subsequent identification of the modified substrates. Stable cell lines expressing catalytically active or catalytically dead SETD8 mutants were systematically cultured with distinct stable isotope labeled amino acids allowing quantitative proteomic analysis of the identified substrates. With this method we could validate previously known substrates of SETD8 and identify novel targets, including MCM5, a subunit of the hexameric minichromosome maintenance (MCM) DNA helicase complex. MCM5 directly interacts with MCM2 and 3 to form the MCM2-7 hexamer which associates with the origins of DNA replication to form part of the pre-replicative complex (preRC), playing a major role during replication initiation and elongation. We found that SETD8 mediated methylation of MCM5 directly affects its binding affinity to MCM2 and 3. Amino acid substitutions at the methylated lysine further evidenced a stronger binding to its interacting partners contributing to the formation of the MCM hexamer. In addition, CRISPR based modifications on MCM5 methylated lysine affected the replication process resulting in defective cell cycle progression. Taken together our results indicate that MCM5 methylation contributes to the assembly of the MCM complex revealing a novel role for SETD8 in replication initiation. Our findings brings new perspectives on the biological importance of SETD8 during DNA replication. Citation Format: Fabio Pittella, Gil Blum, Yongxia Zhu, Chamara Senevirathne, Minkui Luo. DNA replication licensing factor MCM5 is a target for SETD8 mediated methylation [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 352.
Abstract 2924: Preclinical analysis of synergistic antitumor effect of eribulin and HDAC inhibitor for triple-negative breast cancer cells
Authors: Takaaki Oba, Hiroto Izumi, Ken-ichi Ito
Journal: Cancer Research (2018)

Abstract Eribulin (ERI), an inhibitor of microtubule dynamics, is a key drug for metastatic breast cancer. While HDAC inhibitors have been shown to presents antitumor effect for various malignancies. Among HDAC family, HDAC6 is known as a deacetylase of tubulin. To develop a novel therapeutic strategy for triple negative breast cancer (TNBC), we tested the combinational effect of ERI and HDAC inhibitor for TNBC cells in vitro. Two TNBC cell lines (MDA-MB-231, Hs578T) and their ERI-resistant cells (MDA-MB-231/E, Hs578T/E) established in our laboratory were used in the study. Vorinostat (VOR), a pan-HDAC inhibitor, and ricolinostat (RICO), a selective HDAC6 inhibitor were used. The sensitivity to VOR or RICO was not different between the parental and the ERI-resistant cells. In the protein expression analysis, HDAC6 expression was not altered between parental and ERI-resistant cells. Prior treatment with VOR or RICO increased the expression of acetylatedα-tubulin in both parental and ERI-resistant TNBC cell lines. When low concentration of VOR (0.5 μM) or RICO (0.5 μM) was added simultaneously with ERI, the sensitivity to ERI was enhanced significantly in both parental MDA-MB-231 and Hs578T cell lines. Furthermore, when both parental cell lines were treated with VOR (5 μM) or RICO (5 μM) for 48 hrs prior to addition of ERI, the sensitivity to ERI was significantly enhanced. The enhancement of sensitivity to ERI both by the simultaneous addition with low concentration of VOR or RICO and by the prior treatment with VOR or RICO was observed in the ERI-resistant cells as well. Moreover, inhibition of HDAC6 by small interfering RNA partially enhanced the sensitivity to ERI in the both parental cell lines. Our study demonstrated the possibility that the combination of ERI with HDAC inhibitor might enhance the antitumor effect of ERI and overcome ERI resistance through acetylation of α-tubulin by HDAC6 inhibition in TNBC cells. Citation Format: Takaaki Oba, Hiroto Izumi, Ken-ichi Ito. Preclinical analysis of synergistic antitumor effect of eribulin and HDAC inhibitor for triple-negative breast 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 2924.
Thyroid cancers of follicular origin in a genomic light: in-depth overview of common and unique molecular marker candidates
Authors: Natalia Pstrąg, Katarzyna Ziemnicka, Hans Bluyssen, Joanna Wesoły
Journal: Molecular Cancer (2018)

In recent years, thyroid malignances have become more prevalent, especially among women. The most common sporadic types of thyroid tumors of follicular origin include papillary, follicular and anaplastic thyroid carcinomas. Although modern diagnosis methods enable the identification of tumors of small diameter, tumor subtype differentiation, which is imperative for the correct choice of treatment, is still troublesome. This review discusses the recent advances in the field of molecular marker identification via next-generation sequencing and microarrays. The potential use of these biomarkers to distinguish among the most commonly occurring sporadic thyroid cancers is presented and compared. Geographical heterogeneity might be a differentiator, although not necessarily a limiting factor, in biomarker selection. The available data advocate for a subset of mutations common for the three subtypes as well as mutations that are unique for a particular tumor subtype. Tumor heterogeneity, a known issue occurring within solid malignancies, is also discussed where applicable. Public databases with datasets derived from high-throughput experiments are a valuable source of information that aid biomarker research in general, including the identification of molecular hallmarks of thyroid cancer.
Abstract 103: Role of miRNA-7 in Cardiac Function
Authors: Manveen K Gupta, Wang Xi, Elizabeth Martelli, Sathyamangla V Naga Prasad
Journal: Circulation Research (2017)

Studies in cancer have established clearly the role of epidermal growth factors receptors as targets of microRNA-7 (miR-7) but there are no studies so far to elucidate the role and function of miR-7 in human heart. Our studies show that ERBB2 (a member of epidermal growth factors receptor family) is targeted by miR-7 in human heart failure as well as in mice hearts undergoing stress. In order to understand the role of miR-7 in the heart, we generated miR-7 transgenic (Tg) mice with cardiac myocyte-specific overexpression of miR-7. miR-7 Tg mice have age dependent deterioration in cardiac dysfunction associated with cardiac dilation as measured by echocardiography (3 months - 60% FS, 6 month -52% FS and 12 months - 24%FS) and yet, they survive well for more than a year. To investigate whether pathological stress would accelerate the deterioration in cardiac function, miR-7 Tg mice were subjected to transverse aortic constriction (TAC) for two weeks. In contrast to the wild type littermates which undergo hypertrophic response following TAC, miR-7 Tg mice have accelerated cardiac dysfunction and dilation within two weeks. Histological analysis shows increased fibrosis in miR-7 Tg mice hearts as shown by Picro Sirius red and Meson Trichome staining which is further accelerated after TAC stress in hearts of the miR-7 Tg mice as compared to their sham controls. We also find that there is a difference in the mitochondrial morphology and structure in miR-7 Tg mice as compared to Wildtype controls as seen by transmission Electron Microscopy (TEM) explaining the reason for deteriorated cardiac function in terms of energy generation. Our study will discuss the mechanism underlying the deteriorated cardiac function in the miR-7 Tg mice after pathological stress as compared to wildtype littermates.
Abstract 3286: A prototype Cancer Publication Portal (CPP) for summarizing and accessing cancer genomic publications
Authors: Andrew Johnson, Roland DePratti, Garrett M. Dancik
Journal: Cancer Research (2018)

Abstract A search of PubMed finds more than 71,000 publications with the keywords “cancer” and “gene” published since the beginning of 2015. This increasingly large volume of publications necessitates the development of text-mining tools to help cancer researchers navigate and summarize articles efficiently. Here, we present a prototype Cancer Publication Portal (CPP) that allows a user to search and summarize the biomedical literature for a gene of interest. CPP leverages the data generated by PubTator, a tool that uses robust text-mining methods and associates articles with gene names and Medical Subject Heading (MeSH) terms. Additionally, CPP associates articles with therapeutic agents and selected cancer-related terms from the NCI Thesaurus. To use CPP, the user selects a gene of interest, and is presented with a summary of MeSH terms, therapeutic agents, and cancer-related terms that are associated with the selected gene. Cancer-related terms are highlighted, so that, for example, a user can quickly ascertain the frequency of publications per cancer type, or how many articles are associated with “mutations” in the gene. The summaries are interactive, so that the user can click on a term of interest to filter the results, and update the summaries. The user can repeat this process to narrow in on a specific topic of interest. Following all searches and filters, relevant articles are listed and are linked back their PubMed entries so that the reference article can be accessed. CPP currently includes information for ~4 million publications associated with &amp;gt;10,000 human genes. The underlying data is stored in an Oracle database while R/Shiny is used to implement the web interface. CPP is available from the following link: https://gdancik.github.io/bioinformatics/ Citation Format: Andrew Johnson, Roland DePratti, Garrett M. Dancik. A prototype Cancer Publication Portal (CPP) for summarizing and accessing cancer genomic publications [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 3286.
Abstract 4776: Antitumor activity of pan-HER inhibitors in HER2-positive gastric cancer
Authors: Takahiro Yoshioka, Kazuhiko Shien, Yuta Takahashi, Eisuke Kurihara, Kei Namba, Yusuke Ogoshi, Hidejiro Torigoe, Hiroki Sato, Hiromasa Yamamoto, Junichi Soh, Toshiyoshi Fujiwara, Shinichi Toyooka
Journal: Cancer Research (2018)

Abstract Purpose: Molecularly targeted therapy has enabled outstanding advances in cancer treatment. Whereas various anti-HER2 drugs have been developed, trastuzumab is still the only anti-HER2 drug presently available for gastric cancer. Among HER2 targeting drug, afatinib and neratinib inhibit the activation of all HER family protein, and are called pan-HER inhibitors. In this study, we examined the effect of these pan-HER inhibitors to gastric cancer cells. Materials and Methods: We determined the molecular profiles of 12 gastric cancer cell lines. Protein level of HER2 and down-signal pathway molecules were analyzed by Western blotting, and copy number assay or gene expression assay were performed using qPCR. To detect HER2 mutation, we also performed direct-sequence of these cell lines. And next, we examined the antitumor effect of the pan-HER inhibitors afatinib and neratinib in those cell lines, in vitro and in vivo. In addition, we analyzed HER2 alteration in 123 primary gastric cancers resected from Japanese patients to clarify possible candidates with the potential to respond to these drugs. Results: HER2 was amplified in 5 out of 12 gastric cancer cell lines. Gene expression or protein level of HER2 were generally correlated with the copy number of HER2. HER2 mutation was found in one cell line, ECC10, at kinase domain (L755S). In the drug sensitivity analysis, both afatinib and neratinib showed an anti-tumor effect in all the HER2 amplified cell lines both in vitro and in vivo except MKN7 cell line. When the molecular profiles of the cells were compared based on the drug sensitivities, we found that cancer cells with lower mRNA expression levels of IGFBP7, a tumor suppressor gene by inhibiting the activation of IGF-1R, were less sensitive to pan-HER inhibitors. A combination therapy consisting of pan-HER inhibitors and an IGF-1R inhibitor, picropodophyllin, demonstrated a notable synergistic effect. Regarding HER2 alteration in 123 clinical samples, we found 19 cases of HER2 amplification and 3 cases of oncogenic mutations. Conclusion: Afatinib and neratinib are promising therapeutic options for the treatment of HER2-amplified gastric cancer. In addition to HER2 amplification, IGFBP7 might be a biomarker of sensitivity to these drugs, and IGF-1R-targeting therapy can overcome drug insensitiveness in HER2-amplified gastric cancer. Citation Format: Takahiro Yoshioka, Kazuhiko Shien, Yuta Takahashi, Eisuke Kurihara, Kei Namba, Yusuke Ogoshi, Hidejiro Torigoe, Hiroki Sato, Hiromasa Yamamoto, Junichi Soh, Toshiyoshi Fujiwara, Shinichi Toyooka. Antitumor activity of pan-HER inhibitors in HER2-positive gastric 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 4776.
Clinical Tests of the Simple Method of Estimating Cardiac Stroke Volume from Blood Pressure and Age
Authors: Isaacstarr
Journal: Circulation (1954)

The results secured by the simple method of estimating cardiac output, described in the previous paper, have been applied to data already in the literature. Hundreds of comparisons are possible between estimates of cardiac output made by our blood pressure method from values given by the authors, and the results of estimates of cardiac output by some other well known method employed at the same time. The correlations between the results secured by our method and those obtained by Fick, acetylene, ethyl iodide, and nitrous oxide methods are often surprisingly good. There is an unexplained difference in level between the Fick and blood pressure estimates, but not between the blood pressure estimates and those of the three older methods.
Diazoxide Opens the Mitochondrial Permeability Transition Pore and Alters Ca2+ Transients in Rat Ventricular Myocytes
Authors: HidekiKatoh, NobuhiroNishigaki, HideharuHayashi
Journal: Circulation (2002)

Background— The mitochondrial KATP channel (mitoKATP) has been implicated as an end effector or trigger of ischemic preconditioning (IP). Although a mitoKATP opener, diazoxide, mimics IP, mechanisms for the cardioprotective action remain unclear. Methods and Results— We measured Ca2+ transients (CaTs) and mitochondrial inner membrane potential (Δψm) with confocal microscopy and the fluorescent probes fluo-4 and tetramethylrhodamine ethyl ester perchlorate in rat ventricular myocytes. Diazoxide increased the amplitudes and diastolic levels of CaTs dose dependently. The effects of diazoxide on CaTs were inhibited by the mitoKATP antagonist sodium 5-hydroxydecanoic acid (100 μmol/L), whereas application of diazoxide caused little change in Δψm. After sarcoplasmic reticulum function was disabled with ryanodine and thapsigargin, the effects of diazoxide on CaTs were still observed. The opening of the mitochondrial permeability transition pore was monitored with fluorescent calcein. Diazoxide accelerated the le...
Multipotent Vasculogenic Pericytes From Human Pluripotent Stem Cells Promote Recovery of Murine Ischemic Limb
Authors: AyeletDar, HagitDomev, OrenBen-Yosef, MatyTzukerman, NaamaZeevi-Levin, AtaraNovak, IgalGermanguz, MichalAmit, JosephItskovitz-Eldor
Journal: Circulation (2012)

Background—Pericytes represent a unique subtype of microvessel-residing perivascular cells with diverse angiogenic functions and multilineage developmental features of mesenchymal stem cells. Although various protocols for derivation of endothelial and/or smooth muscle cells from human pluripotent stem cells (hPSC, either embryonic or induced) have been described, the emergence of pericytes in the course of hPSC maturation has not yet been elucidated. Methods and Results—We found that during hPSC development, spontaneously differentiating embryoid bodies give rise to CD105+CD90+CD73+CD31− multipotent clonogenic mesodermal precursors, which can be isolated and efficiently expanded. Isolated and propagated cells expressed characteristic pericytic markers, including CD146, NG2, and platelet-derived growth factor receptor β, but not the smooth muscle cell marker α-smooth muscle actin. Coimplantation of hPSC-derived endothelial cells with pericytes resulted in functional and rapid anastomosis to the murine vas...
Vesnarinone Limits Infarct Size via Adenosine-Dependent Mechanisms in the Canine Heart
Authors: MasafumiKitakaze, TetsuoMinamino, HiroharuFunaya, KoichiNode, YoshiroShinozaki, HidezoMori, MasatsuguHori
Journal: Circulation (1997)

Background Recently, vesnarinone, a synthetic inotropic agent, was reported to inhibit adenosine transport into cells, which may increase adenosine levels in the heart and in turn mediate cardioprotection. Thus, vesnarinone may also have protective effects in sustained ischemia-reperfusion, because adenosine limits infarct size. Methods and Results In open-chest dogs, the left anterior descending coronary arteries were occluded for 90 minutes followed by 6 hours of reperfusion. Vesnarinone limited infarct size compared with controls (6.8±2.2% versus 44.7±3.9%), which was completely reversed by a nonselective adenosine receptor antagonist, 8-sulfophenyltheophylline (44.1±6.8%), and partially blunted by an inhibitor of ecto-5′-nucleotidase, α,β-methyleneadenosine 5′-diphosphate (AMP-CP, 28.9±4.7%). Dipyridamole, an inhibitor of adenosine uptake into cells, only modestly limited infarct size (27.4±5.5%). Furthermore, vesnarinone increased adenosine release during coronary hypoperfusion, which was attenuated ...
Impact of Human Immunodeficiency Virus Infection on Cardiovascular Disease in Africa
Authors: MpikoNtsekhe, JamesHakim
Journal: Circulation (2005)

Background— Human immunodeficiency virus (HIV) infection is the single greatest health challenge facing Africa today. However, the impact of the HIV epidemic on the cardiovascular system in Africans has received scant attention in the world literature. Methods and Results— We searched MEDLINE (January 1, 1980, to December 31, 2004) and reference lists of literature on HIV and the heart in Africa and contacted experts in the field. The search for this review yielded 22 articles involving HIV and the cardiovascular system from 8 countries in Africa. Conclusions— The available information suggests that there are unique features in the etiology, presentation, and spectrum of HIV-associated cardiovascular disorders in people living in Africa. First, pericardial disease may be the initial manifestation of HIV infection in the early stages of the illness. Second, the etiology of cardiac disease tends to reflect the prevalent infectious diseases, such as tuberculosis. Third, unique cardiovascular disorders such a...
HPV: CIB1 is for EVER and EVER
Authors: Luigi D. Notarangelo
Journal: The Journal of Experimental Medicine (2018)

In this issue, de Jong et al. (https://doi.org/10.1084/jem.20170308) identify bi-allelic loss-of-expression, loss-of-function mutations of the calcium- and integrin-binding protein 1 (CIB1) gene as a new cause of epidermodysplasia verruciformis (EV) and demonstrate that the CIB1 interacts with the EVER1 and EVER2 proteins to form a complex involved in keratinocyte-intrinsic immune response to human β-papillomaviruses (β-HPVs).
Abstract 14662: Temperature Significantly Alters Capillary Refill Time: A Major Confounder in the Bedside Evaluation of Shock
Authors: Koichiro Shinozaki, Kota Saeki, Joshua W Lampe, Lance B Becker
Journal: Circulation (2017)

Objective: Capillary refill time (CRT) measured at the bedside is widely promulgated as an acceptable method to identify patients in hemorrhagic shock. Recently temperature has been reported to int...
Anticoagulation Therapy in Atrial Fibrillation in Combination With Acute Myocardial Infarction Influences Long-Term Outcome
Authors: UlfStenestrand, JohanLindbäck, LarsWallentin
Journal: Circulation (2005)

Background— The American and European guidelines do not agree with regard to antithrombotic treatment in patients with atrial fibrillation (AF) and acute myocardial infarction (AMI), thus causing uncertainty among physicians. We investigated the prescription of oral anticoagulation (OAC) in patients discharged alive with AF after an AMI and the influence of OAC treatment on 1-year mortality. Methods and Results— This was a prospective cohort study using data from the Register of Information and Knowledge about Swedish Heart Intensive care Admissions (RIKS-HIA) on patients admitted to the coronary care units of 72 Swedish hospitals from 1995 to 2002. A total of 6182 patients discharged alive with first registry-recorded AMI and AF on discharge ECG were included. One-year mortality data were obtained from the Swedish National Cause of Death Register. Only 30% (n=1848) of the 6182 patients with AF were prescribed OAC. At 1 year, the unadjusted mortality was 31% (1183 deaths) in the platelet-inhibitors only g...
Evaluation of the predictive accuracy of MRI-detected erosions in hand and foot joints in patients with undifferentiated arthritis
Authors: Debbie M Boeters, Aleid C Boer, Annette H M van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2018)

Radiographic erosions are a clear hallmark of rheumatoid arthritis (RA). The European League Against Rheumatism (EULAR) definition of radiographic erosive disease has a high specificity, and its fulfilment alone is sufficient to classify RA.1 However, the sensitivity of radiography to detect erosions early in the disease is low. Other imaging techniques, such as MRI, are more sensitive to detect erosions than radiography and are therefore recommended by a EULAR imaging task force.2 To determine the specificity of MRI-detected erosions, we recently compared erosions in the metacarpophalangeal (MCP) and metatarsophalangeal (MTP) joints (scored according to the RA MRI Scoring System (RAMRIS)3) of patients presenting with RA with those of symptom-free persons and patients presenting with arthritides other than RA.4 MRI-detected erosions were present in all groups; therefore, the specificity of the presence of any MRI-detected erosions was low. By evaluating different erosion features, a few features were identified as specific for RA; these were severe erosions (grade ≥2, defined as >10% of bone eroded), erosions in MTP5 and erosions in MTP1 in persons aged <40. A subsequent and clinically relevant question is whether MRI-detected erosions in patients presenting with undifferentiated arthritis (UA) are valuable in predicting future progression to RA. This was explored to a limited extent in our previous study but as the number of patients with UA was limited (n=192), the predictive value of the different ‘RA-specific …