tbuckley/cabot-search huggingface dataset:
Secretory form of rheumatoid arthritis–associated autoantibodies in serum are mainly of the IgM isotype, suggesting a continuous reactivation of autoantibody responses at mucosal surfaces
Authors: Myrthe A M van Delft, Diane van der Woude, René E M Toes, Leendert A Trouw
Journal: Annals of the Rheumatic Diseases (2018)

Several lines of evidence obtained in recent years indicate a role of mucosal surfaces in the development of autoimmune responses associated with rheumatoid arthritis (RA). Therefore, more attention is going to the influence of the microbiome in RA development. Secretory antibodies are typically produced at mucosal surfaces and transported through epithelial cells for secretion at the luminal site. Importantly, secretory antibodies comprise both IgM and IgA, and both isotypes can harbour a J-chain that binds to the polymeric Ig receptor (pIgR).1 Following transport through epithelial cells, the antibodies are enzymatically released at the luminal site by cleavage of the pIgR leaving a fragment of the receptor, the secretory component (SC) bound to the immunoglobulin. SC-containing antibodies can however also be detected systemically in the circulation, although the mechanism by which these SC-containing antibodies arise in serum is still unclear.2 Interestingly, antigen-specific secretory antibodies are present in serum after mucosal immunisation,3 indicating that the presence of secretory antibodies may provide information about their origin: the mucosa. Well-known autoantibodies in RA are rheumatoid factor (RF), ACPA (against citrullinated proteins) and anti-CarP (against carbamylated proteins).4 Secretory RF (SC-RF) and secretory ACPA (SC-ACPA) have been detected in RA sera,5 6 indicating a mucosal origin. Although it is often postulated that SC-containing autoantibodies are of the IgA isotype, this is unknown as both IgM and IgA can harbour SC. Nonetheless, it is important to define the isotype of SC-containing autoantibodies as this provides relevant information on the type of B cell (re)activated at …
Abstract 5549: Antitumor efficacy of the oncolytic peptide LTX-315 in genetic mouse models that resist conventional chemo- and immunotherapeutic treatments
Authors: Mikael J. Pittet, Hsin-Wei Liao, Baldur Sveinbjørnsson, Øystein Rekdal
Journal: Cancer Research (2018)

Abstract LTX-315 is an oncolytic peptide that induces immunogenic cancer cell death and is currently evaluated in phase 1 clinical trials for its ability to trigger recruitment of tumor-specific T cells to tumors. Previous experimental studies identified LTX-315's ability to control cancer in mice grafted with various tumor cell lines. Here we extend our analyses to conditional genetic mouse models of both melanoma (driven by Braf and Pten alterations) and soft tissue sarcoma (driven by Kras and P53 alterations). In these genetic models, cancer cells are derived from somatic cells that are transformed in their normal tissue microenvironment and progress to high-grade tumors that are poorly infiltrated by T cells and typically resist prescribed chemo- and immunotherapeutic treatments. We report that LTX-315 not only delays tumor progression substantially in both models, but also profoundly alters the tumor microenvironment, most notably characterized with CD8+ T cell, NK cell and dendritic cell infiltration. Transition from a ‘cold' to a ‘hot' tumor microenvironment was also observed in patients with melanoma, sarcoma and breast cancer. Furthermore, CD8+ T cell depletion in mice abrogated long-term antitumor efficacy of LTX-315, indicating that these cells are required for drug-induced tumor control. Importantly, the ability to convert non-T-cell-infiltrated tumors into ones that display antitumor T cell immunity opens the possibility to prime and make unresponsive tumors sensitive for systemic immune treatments. Citation Format: Mikael J. Pittet, Hsin-Wei Liao, Baldur Sveinbjørnsson, Øystein Rekdal. Antitumor efficacy of the oncolytic peptide LTX-315 in genetic mouse models that resist conventional chemo- and immunotherapeutic treatments [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 5549.
Abstract 5865: Gartanin, a 4-prenylated xanthone in the mangosteen fruit, inhibits the growth of prostate cancer cells associated with Skp2 degradation via neddylation inhibition and FBXW2 induction
Authors: Victor Pham, Michelle Bui, Raymond Rendon, Ericka Agredano, Thanh Le, Liankun Song, Xiaolin Zi
Journal: Cancer Research (2018)

Abstract The S-phase kinase-associated protein 2 (Skp2) is overexpressed in prostate cancer and associated with tumor stage, disease recurrence, and worse patient survival. Studies also have demonstrated that Skp2 overexpression plays a critical role in development and progression of prostate cancer in several prostate cancer models, including PTEN knockout and TRAMP carcinogenesis and CWR22 xenograft models. Therefore, Skp2 is a promising target for developing new therapeutic and preventive approaches for prostate cancer. Here, we have found that gartanin, 4-prenylated xanthone from the Garcinia mangostana fruit (mangosteen), promoted Skp2 degradation in a proteasome-dependent manner in prostate cancer cells. In addition, gartanin induced the expression of FBXW2, a novel E3 ligase of SKP2 for targeted degradation, and downregulated the expression of NEDD8, leading to reduced neddylation levels of UBC12 and Cullin1. Molecular modelling analysis predicts that gartanin reasonably docks onto the regulatory subunit of NEDD8 activating enzyme E1 (NAE1) and next to the NEDD8 binding complex. More interestingly, gartanin selectively inhibits the growth of Skp2 overexpressing PC3 cells compared to parental PC cells (IC50 values for PC3/Skp2 vs. PC3 cells are approximately 4 μM vs. 14 μM). Together, our data indicate that gartanin is a novel natural agent for targeting Skp2 degradation via induction of FBXW2 expression and inhibition of neddylation. Gartanin deserves further investigation for its usefulness in prostate cancer prevention and treatment. Citation Format: Victor Pham, Michelle Bui, Raymond Rendon, Ericka Agredano, Thanh Le, Liankun Song, Xiaolin Zi. Gartanin, a 4-prenylated xanthone in the mangosteen fruit, inhibits the growth of prostate cancer cells associated with Skp2 degradation via neddylation inhibition and FBXW2 induction [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 5865.
Abstract A52: Potassium channel activator minoxidil (Rogaine) as a novel single-agent or combination therapy in ovarian cancer
Authors: Daniela Fukushiro-Lopes, Megan Jain, Maryam Khalid, Alexandra Hegel, Saverio Gentile
Journal: Clinical Cancer Research (2018)

Abstract Recent advances in cancer therapy treatments for ovarian cancer have been severely hindered by limited drug availability, excessive side effects, and drug resistance and the difficulty in finding and targeting proteins governing important events in ovarian cancer cells. Novel therapeutic agents targeting specific molecular pathways involved in ovarian cancer are urgently needed. During our investigation to identify new and critical targets in cancer, we found a novel role for the potassium ion channel Kir6.2 in ovarian cancer cells. Our bioinformatics investigation showed that Kir6.2 is expressed in ovarian cancers. We discovered that stimulation of the Kir6.2 channel activity with the small molecule minoxidil (Rogaine®) produces a strong inhibition on ovarian cancer cells’ growth. However, minoxidil had no significant effects on cells that do not express Kir6.2. We describe a biochemical signaling linking activation of Kir6.2 potassium channel to the tumor suppressor mechanism, which includes a Ca2+-dependent production of superoxide species (ROS), which leads to a significant increase of DNA damage. Consequently, cells die upon activation of apoptosis via caspase-3. Minoxidil is an FDA-approved drug that presents very limited side effects. Therefore, our data are important because for the first time they reveal that use of the Kir6.2 potassium channel activator, e.g., Rogaine®, could be considered as a potential single-agent novel treatment for ovarian cancer. Clinicians’ approaches for treating advanced ovarian cancer patients are strongly limited by the concern that current chemotherapeutic agent will raise toxicity. For example, although genotoxic chemotherapeutic agents such as doxorubicin or platinum-containing molecules of carboplatin are among the most effective drug classes in ovarian cancer, dose-dependent toxicity of these agents is often the cause for interrupting the treatment. Our experiments demonstrated that the Kir6.2 activator minoxidil potentiates the antineoplastic effects of doxorubicin as well as of carboplatin by exacerbating their DNA-damaging effects. This discovery is important because it offers the opportunity to design a clinically effective therapeutic strategy in which minoxidil could be administered in combination with genotoxic agents to limit their toxicity in ovarian cancer patients. Citation Format: Daniela Fukushiro-Lopes, Megan Jain, Maryam Khalid, Alexandra Hegel, Saverio Gentile. Potassium channel activator minoxidil (Rogaine) as a novel single-agent or combination therapy in ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A52.
Abstract 5753: Cancer stem cell markers allow for immune evasion in triple-negative breast cancer
Authors: Andrew D. Hoffmann
Journal: Cancer Research (2018)

Abstract Triple-negative breast cancer tumor-initiating cells, or cancer stem cells (CSCs) are identified as a population that is CD44+ and CD24low. These cells are important drivers of distant metastasis and recurrence. An important component of both the recurrence and metastasis functions of CSCs is the capacity to evade immune detection. Our work has identified key members of the antigen presentation machinery required for proper immunosurveillance as being differentially expressed in tumor cells expressing CD44 compared to cells lacking CD44, including a differential response to important immune system cytokines. We are currently working to identify functional differences related to the altered protein levels in these cells. Citation Format: Andrew D. Hoffmann. Cancer stem cell markers allow for immune evasion in triple-negative breast 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 5753.
Abstract 3800: Inhibition of Polycomb Repressive Complex 2 EZH2 lysine methyltransferase improves tumoricidal activity of macrophages towards mesothelioma cells
Authors: Malik Hamaidia, Clotilde Hoyos, Luc L. Willems
Journal: Cancer Research (2018)

Abstract Rationale: Clinical evidence indicates that tumor infiltration by tumor associated macrophages (TAMs) correlates with poor prognosis in malignant mesothelioma (MM). By attenuating the immune response, TAMs indeed promote survival of MM cells. TAMs share properties with alternative macrophages (M2) that are activated by anti-inflammatory (e.g. IL-10) or Th2-associated (i.e. IL-4, IL-13) cytokines. Objectives: We hypothesized that macrophage activation is mediated by a transcriptional program tightly regulated by epigenetic modifications. We focused on the Polycomb Repressive Complex 2 (PRC2) EZH2 lysine methyltransferase responsible for trimethylation of histone H3 at lysine 27 (H3K27me3). We investigated the effect of a selective EZH2 inhibitor (EPZ005687) on tumoricidal activity of primary human monocyte-derived macrophages. Results: Our data show that inhibition of EZH2 reduces CD206 expression and phagocytic activity of macrophages conditioned in MM pleural effusions (PE-macrophages). Moreover, EZH2 inhibition enhances the cytotoxic potential of PE-macrophages towards MM cells. Inhibition of EZH2 also increases the ability of macrophages to support proliferation of autologous T-cells. Conclusion: Induction of cytotoxic activity of PE-macrophages via PRC2 EZH2 lysine methyltransferase could be of therapeutic value in MM. Citation Format: Malik Hamaidia, Clotilde Hoyos, Luc L. Willems. Inhibition of Polycomb Repressive Complex 2 EZH2 lysine methyltransferase improves tumoricidal activity of macrophages towards mesothelioma 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 3800.
Vagal Nerve Stimulation Markedly Improves Long-Term Survival After Chronic Heart Failure in Rats
Authors: MeihuaLi, CanZheng, TakayukiSato, ToruKawada, MasaruSugimachi, KenjiSunagawa
Journal: Circulation (2004)

Background— Diminished cardiac vagal activity and higher heart rate predict a high mortality rate of chronic heart failure (CHF) after myocardial infarction. We investigated the effects of chronic electrical stimulation of the vagus nerve on cardiac remodeling and long-term survival in an animal model of CHF after large myocardial infarction. Methods and Results— Two weeks after the ligation of the left coronary artery, surviving rats were randomized to vagal- and sham-stimulated groups. Using an implantable miniature radio-controlled electrical stimulator, we stimulated the right vagal nerve of CHF rats for 6 weeks. The intensity of electrical stimulation was adjusted for each rat, so that the heart rate was lowered by 20 to 30 beats per minute. The treated rats had significantly lower left ventricular end-diastolic pressure (17.1±5.9 versus 23.5±4.2 mm Hg, P<0.05) and higher maximum dp/dt of left ventricular pressure (4152±237 versus 2987±192 mm Hg/s, P<0.05) than the untreated rats. Improvement of card...
Dermatoglyphics in Congenital Heart Disease
Authors: Miltonalter, Robertschulenberg
Journal: Circulation (1970)

Dermatoglyphics form in utero during early gestation and may be influenced by genetic or environmental factors operating at that time. Since cardiac embryogenesis also occurs during early gestation, an analysis of dermatoglyphics in congenital heart disease (CHD) might reveal some types which are associated with aberrant dermatoglyphics. Ten dermatoglyphic traits were analyzed in 225 individuals with CHD proved, in most instances, by extensive radiologic studies and at surgery. These traits were compared with dermatoglyphics in 200 normal control subjects. The analysis revealed that the atd angle was significantly increased in CHD. Except for endocardial fibroelastosis and atrioventricular canal, all subtypes of CHD had a wider atd angle than controls. In ventricular septal defect, patent ductus arteriosus, tetralogy of Fallot, and multiple cardiac defects, the increase was statistically significant. The present study confirms previous reports that the atd angle may be increased in CHD.
Abstract SY14-01: Determinants of neoantigen immunogenicity
Authors: Lelia Delamarre
Journal: Cancer Research (2018)

Abstract Genetic instability is a hallmark of cancer, and can lead to accumulation of hundreds of somatic mutations. These mutations, which are unique to each patient, have the potential to be immunogenic if presented on major histocompatibility complex (MHC) molecules and recognized as “non-self” neoantigens by the immune system. There is now compelling evidence that neoantigens have an important role in driving antitumor immunity. Mutational load correlates with clinical response to immune checkpoint blockade therapy in cancer patients. In addition, neoantigen-directed tumor-infiltrating lymphocyte therapy was shown to lead to regression of metastatic lesions in patients. The recent advent of next-generation sequencing technologies has enabled rapid and comprehensive discovery of cancer mutations in individual patients and provides the opportunity to develop novel approaches to selectively target neoantigens. A major challenge, however, is that only a small fraction of the mutations generate T-cell responses. Currently, MHCI binding prediction is used as the major criterion for prioritizing neoantigens. Although this approach enriches for immunogenic neoantigens, a high frequency of false positive remains. For a mutant peptide to be immunogenic, the source protein has to be processed, the resulting mutant peptide needs to bind MHCI, and finally T cells must recognize the MHCI/peptide complex. To investigate the determinants of neoantigen immunogenicity, we performed profiling of the immunopeptidome by mass spectrometry and generated a dataset of immunogenic and nonimmunogenic mutant peptides identified in mouse tumor models by vaccination. Citation Format: Lelia Delamarre. Determinants of neoantigen immunogenicity [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 SY14-01.
Aortic Root Dilatation in Patients With Spontaneous Cervical Artery Dissection
Authors: ChristopheTzourio, ArielCohen, NathalieLamisse, ValérieBiousse, Marie-GermaineBousser
Journal: Circulation (1997)

Background Spontaneous cervical artery dissections are a relatively common cause of ischemic stroke in young adults. Their mechanism is unknown, though it is generally assumed that an underlying minor form of extracellular matrix defect could exist. The present study tested the hypothesis that aortic and cardiac morphological abnormalities usually seen in patients with heritable connective diseases are more frequent in patients with spontaneous cervical artery dissections than in patients without such dissections. Methods and Results We performed a case-control study of 28 case patients with spontaneous cervical artery dissection and 84 control subjects with an ischemic stroke not due to cervical artery dissection. Control subjects were matched to case patients for age (±5 years), sex, and year of hospitalization. The aortic root was more frequently enlarged (ie, diameter >34 mm) in case patients (56%) than in control subjects (15%). Mitral valve prolapse, mitral valve dystrophy, and aortic valve dystroph...
Impact of monovalent rotavirus vaccine on diarrhoea-associated post-neonatal infant mortality in rural communities in Malawi: a population-based birth cohort study
Authors: Naor Bar-Zeev, Carina King, Tambosi Phiri, James Beard, Hazzie Mvula, Amelia C Crampin, Ellen Heinsbroek, Sonia Lewycka, Jacqueline E Tate, Umesh D Parashar, Anthony Costello, Charles Mwansambo, Robert S Heyderman, Neil French, Nigel A Cunliffe, Osamu Nakagomi, Jennifer R Verani, Cynthia G Whitney
Journal: The Lancet Global Health (2018)

Rotavirus is a major contributor to child mortality. The effect of rotavirus vaccine on diarrhoea mortality has been estimated in middle-income but not low-income settings, where mortality is high and vaccine effectiveness in reducing admissions to hospital is lower. Empirical population-based mortality studies have not been done in any setting. Malawi introduced monovalent rotavirus vaccine (RV1) in October, 2012. We aimed to investigate the impact and effectiveness of the RV1 vaccine in reducing diarrhoea-associated mortality in infants aged 10-51 weeks.
Abstract 1429: MYH8 R1292X: A novel mutation in relapsed AML induces EMT features and poor prognosis
Authors: Hyejoo Park, Daeyoon Kim, Dongchan Kim, Yungyeong Park, Youngil Koh, Sung-Soo Yoon
Journal: Cancer Research (2018)

Abstract Introduction: Recent advances in tumor genomic analysis have led to the discovery of NPM1, FLT3, CEBPA, MLL, NRAS, and RUNX1 alterations as the cause of AML. Nevertheless, there is a limit to the treatment and clarification of AML, and research for the identification of novel genetic alterations that cause AML is actively underway. Materials and methods: In this study, we performed Whole exome sequencing (WES) with 53 AML patient's samples and conducted targeted re-sequencing using 391 AML patient's samples based on locus of somatic mutation that were found by WES. For functional validation of novel oncogenic mutations, we used CRISPR-Cas9 system to generate knock-in (KI) cell line. For characterization of mutant cells, we performed proliferation assay, cell cycle assay, adhesion assay, and wound healing assay. Epithelial to mesenchymal transition (EMT) markers were checked by western blotting. Results: Using WES and targeted resequencing, we could identify MYH8 R1292X novel mutation as recurrent potentially oncogenic mutation. Additional validation using separate AML cohort revealed MYH8 R1292X variants in four AML patients, suggesting that MYH8 R1292X is potential oncogenic mutation. In functional validation using KI cell line, we could not find change in morphology of KI cells. However, there was a difference in proliferation – the rate of proliferation was faster in KI cells than in cells without mutation. In the cell cycle assay, the mutant cells showed more S phase DNA than the non-mutant cells. Wound healing assay showed that the mutant cells had higher migration ability and lowered the ability of adhesion in comparison. PCR and western blot showed that EMT markers except vimentin increased in mutant cells.Survival analysis based on TCGA data showed that both the overall survival and the disease-free survival curves were significantly different according to MYH8 alterations. Conclusion: Taken together, we conclude that the novel alteration MYH8 R1292X is associated with recurrent AML and poor prognosis by increasing migration, and inducing an increase in EMT markers. Citation Format: Hyejoo Park, Daeyoon Kim, Dongchan Kim, Yungyeong Park, Youngil Koh, Sung-Soo Yoon. MYH8 R1292X: A novel mutation in relapsed AML induces EMT features and poor prognosis [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 1429.
Abstract 16028: Sustained Increase in the Incidence of Acute Cardiovascular Events After the 2011 Northeast Japan Tsunami: A Population Based Study
Authors: MotoyukiNakamura, FumitakaTanaka, MihoHonma, RyosukeKomi
Journal: Circulation (2014)

BACKGROUD: No population based studies to date have reported the long-term effects on the incidence of acute myocardial infarction (AMI) and acute decompensated heart failure (DHF) after a devastating tsunami. METHODS: A population based AMI and DHF registration study was conducted in the Iwate prefecture 2 years before and 2 years after the 2011 Japan earthquake and tsunami. Clinical records were reviewed at all hospitals within the district and at nearby teaching hospitals. AMI including sudden cardiac death and DHF were then registered according to the MONICA criteria, and the Framingham definition, respectively. RESULTS: During the 4 year survey period, a total of 1,223 AMI cases (mean age = 74.5) and 1,416 DHF cases (mean age = 80.1) were identified. The standardized incidence ratio (SIR) and 95% CI for AMI and DHF during the disaster year of 2011 and the post disaster year of 2012 were determined respectively from the number of observed cases relative to the number of expected cases calculated by ag...