tbuckley/cabot-search huggingface dataset:
P119 Epigenetic regulation of wnt signaling in systemic sclerosis via sFRP1
Authors: S O’reilly
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Young investigator. <h3>Introduction</h3> Systemic sclerosis is an autoimmune connective tissue disease. The disease is characterised by inflammation and fibrosis. The main cell type is an activated fibroblast called a myofibroblast that secretes a panopoly of extracellular matrix molecules lieading to the skin and lung fibrosis. The mechanism(s) that lead to the myofibroblast generation are unknown. In recent times epigenetic regulation has been shown to play a major role in generation of myofiibroblasts in systemic sclerosis and other fibrotic diseases. Epigenetics is defined as a change in gene expression without a change in the DNA bases. This is mainly facilitated by DNA methylatedl the addition of a methyl group onto cytosine and microRNAs. Wnt is a conserved signaling pathway that is needed for organ formation and is known to be elevated in systemic sclerosis. Enhanced Wnt can lead to fibrosis through beta catenin and extracelluar antagonists regulate the threshold of Wnt signalling. sFRP1 is an extracellular Wnt inhibitor that we have previously demonstrated to be involved in systemic sclerosis. <h3>Objectives</h3> To determine the epigenetic regulation of sFRP1 in systemic sclerosis. <h3>Methods</h3> Diffuse systemic sclerosis and healthy control serum was collected from 10 patients and controls. sFRP1 was measured with a standard ELISA method using a commercial ELISA. qPCR was perfromed with SSc fibroblasts or control fibroblasts using Taqman specific kits for miR27a3p and RNU44. Data was normalised to RNU44 and shown as fold change to controls. Transfection of microRNA mimics was performed using 100 nM of miR27 mimics or matched concentration of scramble after 48 hours post transfection media was collected and the cells lysed in RIPA buffer and lysates subjected to western blotting. <h3>Results</h3> We found reduced levels of sFRP1 in systemic sclerosis sera compared to healthy controls (n=10). Using taqman PCR we also found elevated levels of microRNA27a3p in systemic sclerosis fibroblasts. Using software to predict targets it was identified that sFRP1 is a direct target of microRNA27a3p. We could demonstrate after transfection of microRNA27a3p into healthy dermal fibroblasts compared to scramble controls that the levels of the target sFRP1 was reduced and elevated levels of collagen1 and beta catenin was present. This suggest that sFRP1 is a direct target leading to upregulation of Wnt signaling. We also found reuced levels of anti-fibrotic PPAR-gamma also after transfection. siRNA knockdown of sFRP1 using small interfering RNA leads to upregulation of collagen and Axin2 and lactate elevation. <h3>Conclusions</h3> sFRP1 is regulated by miR27a2p in systemic sclerosis. MiR27a3p can also regulate PPAR gamma. Enhanced Wnt signaling is associated with metabolic alterations. <h3>Disclosure of Interest</h3> None declared.
TMIC-08. CHD7 IS SUPPRESSED IN THE PERINECROTIC/ISCHEMIC MICROENVIRONMENT AND IS A NOVEL REGULATOR OF ANGIOGENESIS
Authors: Nathaniel Boyd, Adetokunbo Ayokanmbi, Kiera Walker, Julia Whetsel, Juan Gordillo, Cynthia Smith, Emily Gordon, Cameron Herting, Dolores Hambardzumyan, Yancey Gillespie, James Hackney, Sara Cooper, Kai Jiao, Anita Hjelmeland
Journal: Neuro-Oncology (2018)

A pathologic hallmark of glioblastoma (GBM), the most common and deadly primary brain tumor in adults, is pseudopalisading necrotic regions in which ischemic conditions are found. Ischemic microenvironments characterized by low oxygen, restricted glucose, and acidic pH due to poor blood supply occurs in both solid tumors and non-neoplastic tissue injury. Modeling these physiologically relevant ischemic conditions within glioblastoma in vitro, we identified chromodomain helicase DNA binding protein 7 (CHD7) as a novel ischemia-regulated gene. CHD7 is an epigenetic reader that controls neural stem cell maintenance and is mutated in CHARGE syndrome, a developmental disorder associated with cranial nerve abnormalities. CHD7 mRNA expression was consistently suppressed in multiple patient-derived xenograft brain tumor lines in response to ischemic conditions, and lower expression of CHD7 correlates with poor GBM patient survival. These microenvironment-mediated decreases in CHD7 protein and mRNA levels observed in glioblastoma were also mirrored in neural progenitor cells in vitro, and CHD7 levels were reduced in the perinecrotic niche of GBM patient and xenograft tissue sections. Genetic targeting of CHD7 increased angiogenesis in vitro in association with differential regulation of angiogenesis associated genes as determined in RNA sequencing analysis. Although targeting CHD7 in orthotopically implanted xenograft brain tumor models did not affect survival outcomes in mice, we observed marked differences in blood vessel architecture and organization, suggesting a major role for CHD7 in regulating vessel formation within these tumors. Together, our data provide insight into the molecular responses to ischemia that regulate angiogenesis.
Pertussis (whooping cough)
Authors: Dipesh P Gopal, John Barber, Daniel Toeg
Journal: BMJ (2019)

### What you need to know

Pertussis, also known as whooping cough, is caused by the Gram negative bacterium Bordetella pertussis .1 It is transmitted via airborne droplets and is highly infectious.2 Diagnosis is often delayed or missed,3 as pertussis mimics the presentation of a viral upper respiratory tract infection and can sometimes present atypically.2 In this article, we review the management of pertussis and present recent evidence and guidance on prevention through vaccination.

### Sources and selection criteria

We performed a Medline search from January 2007 to December 2018 using the search terms ‘whooping cough’ and ‘pertussis.’ We included journal papers that we encountered from references of the papers from the initial search. We performed a similar search in the Cochrane database. We consulted the Public Health England website and the Centers for Disease Control and Prevention for guidelines on pertussis. We have referred to recent systematic reviews, meta-analyses and literature reviews in writing this manuscript but have cited individual clinical studies where there is no higher quality of evidence.

Pertussis affects nearly 24 million children under the age of …
Abstract IA15: Overcoming drug resistance and tumor heterogeneity in gastrointestinal cancers
Authors: Ryan B. Corcoran
Journal: Clinical Cancer Research (2018)

Abstract Personalized cancer medicine approaches, inhibiting kinases in tumors driven by defined genomic alterations, have demonstrated striking efficacy in many cancer types. However, the development of drug resistance is a major limitation to the efficacy of targeted therapies in oncology. Identifying and understanding the molecular mechanisms driving resistance may foster opportunities to develop therapeutic strategies to overcome resistance. For example, in the ~10% of colorectal cancer patients whose tumors harbor BRAF V600 mutations, we have found that feedback reactivation of MAPK signaling, often mediated by EGFR, underlies the relative insensitivity of these cancers to RAF inhibitors. The development of targeted therapy combination strategies to block feedback reactivation of MAPK signaling has led to marked improvements in response rates for these patients from ~5% to &amp;gt;30% over the past few years. However, in patients who respond to these targeted combinations, the rapid development of acquired resistance still limits clinical benefit. Acquired resistance in BRAF mutant colorectal cancer and in other molecularly defined tumor types can be marked by the development of extensive molecular heterogeneity due to the selection of sub-clonal tumor cell populations, capable of growing under drug pressures, which poses significant diagnostic and therapeutic challenges. We will present data demonstrating how a single-lesion biopsy at disease progression to diagnose the mechanism of acquired resistance can vastly underrepresent the molecular heterogeneity of resistant tumor clones in an individual patient, and may fail to detect the existence of distinct but important resistance mechanisms that can drive mixed or lesion-specific responses and treatment failure to subsequent targeted therapy. By contrast, liquid biopsy approaches analyzing circulating tumor DNA have the potential to detect the presence of simultaneous resistance mechanisms residing in separate metastases in a single patient and to monitor the effects of subsequent therapies on specific sub-clonal tumor cell populations. These findings highlight the critical role of tumor heterogeneity in driving therapeutic resistance and how convergent targeted therapy strategies blocking common signaling nodes capable of overcoming multiple resistance mechanisms may be needed. Citation Format: Ryan B. Corcoran. Overcoming drug resistance and tumor heterogeneity in gastrointestinal cancers [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr IA15.
Genetic Load and Potential Mutational Meltdown in Cancer Cell Populations
Authors: Yuezheng Zhang, Yawei Li, Tao Li, Xu Shen, Tianqi Zhu, Yong Tao, Xueying Li, Di Wang, Qin Ma, Zheng Hu, Jialin Liu, Jue Ruan, Jun Cai, Hurng-Yi Wang, Xuemei Lu
Journal: Molecular Biology and Evolution (2018)

Large genomes with elevated mutation rates are prone to accumulating deleterious mutations more rapidly than natural selection can purge (Muller's ratchet). As a consequence, it may lead to the extinction of small populations. Relative to most unicellular organisms, cancer cells, with large and nonrecombining genome and high mutation rate, could be particularly susceptible to such "mutational meltdown." However, the most common type of mutation in organismal evolution, namely, deleterious mutation, has received relatively little attention in the cancer biology literature. Here, by monitoring single-cell clones from HeLa cell lines, we characterize deleterious mutations that retard the rate of cell proliferation. The main mutation events are copy number variations (CNVs), which, estimated from fitness data, happen at a rate of 0.29 event per cell division on average. The mean fitness reduction, estimated reaching 18% per mutation, is very high. HeLa cell populations therefore have very substantial genetic load and, at this level, natural population would likely face mutational meltdown. We suspect that HeLa cell populations may avoid extinction only after the population size becomes large enough. Because CNVs are common in most cell lines and tumor tissues, the observations hint at cancer cells' vulnerability, which could be exploited by therapeutic strategies.
RetroNectin® Reagent: A novel method to increase gene transduction efficiency
Authors: Jasmin Gibson, Julie Kramer
Journal: Cancer Research (2007)

1194  A variety of both viral (adenovirus, retroviral, lentiviral, adeno-associated virus (AAV)) and non-viral (liposomes, injection, gene gun) methods are currently available for the transfer of exogenous genes to mammalian cells. Non-viral, adenovirus, and AAV based methods offer ease-of-use and high efficiency, but these vectors are generally only transiently maintained and/or expressed. Retroviral and lentiviral vectors offer targeted delivery via binding to cell surface receptors and stable integration of a construct into the cell genome. However, the weakness of retroviral techniques has historically been relatively low efficiency of gene transfer. Takara created RetroNectin® Reagent in an effort to improve transduction efficiency.  Several regions of the fibronectin molecule are known to bind cells and retrovirus. Performing transduction in the presence of fibronectin has been observed to improve transduction efficiency. RetroNectin® is a recombinant peptide consisting of a selection of fibronectin fragments which is pre-coated onto plates prior to transduction. RetroNectin® allows easy and efficient gene transduction into a variety of target cells, including difficult-to-transduce cells such as hematopoietic stem cells. Here we describe the use of Takara’s RetroNectin® Reagent for retrovirus-mediated gene transfer and its ability to dramatically increase retroviral transduction efficiency with a variety of target cells.
Antibody-Mediated Endocytosis of Polysialic Acid Enables Intracellular Delivery and Cytotoxicity of a Glycan-Directed Antibody–Drug Conjugate
Authors: Emily C. Cox, Dana N. Thornlow, Michaela A. Jones, Jordan L. Fuller, Judith H. Merritt, Matthew J. Paszek, Christopher A. Alabi, Matthew P. DeLisa
Journal: Cancer Research (2019)

Abstract The specific targeting of differentially expressed glycans in malignant cells has emerged as an attractive anticancer strategy. One such target is the oncodevelopmental antigen polysialic acid (polySia), a polymer of α2,8-linked sialic acid residues that is largely absent during postnatal development but is re-expressed during progression of several malignant human tumors, including small-cell and non–small cell lung carcinomas, glioma, neuroblastoma, and pancreatic carcinoma. In these cancers, expression of polySia correlates with tumor progression and poor prognosis and appears to modulate cancer cell adhesion, invasiveness, and metastasis. To evaluate the potential of PolySia as a target for anticancer therapy, we developed a chimeric human polySia-specific mAb that retained low nanomolar (nmol/L) target affinity and exhibited exquisite selectivity for polySia structures. The engineered chimeric mAb recognized several polySia-positive tumor cell lines in vitro and induced rapid endocytosis of polySia antigens. To determine whether this internalization could be exploited for delivery of conjugated cytotoxic drugs, we generated an antibody–drug conjugate (ADC) by covalently linking the chimeric human mAb to the tubulin-binding maytansinoid DM1 using a bioorthogonal chemical reaction scheme. The resulting polySia-directed ADC demonstrated potent target-dependent cytotoxicity against polySia-positive tumor cells in vitro. Collectively, these results establish polySia as a valid cell-surface, cancer-specific target for glycan-directed ADC and contribute to a growing body of evidence that the tumor glycocalyx is a promising target for synthetic immunotherapies. Significance: These findings describe a glycan-specific antibody-drug conjugate that establishes polySia as a viable cell surface target within the tumor glycocalyx.
P087 The anti-inflammatory cytokine interleukin 37 is an endogenous inhibitor of trained immunity
Authors: G Cavalli, M Gresnigt, T Nemkov, R Arts, A D’Alessandro, S Giugliano, E Eisenmensser, L Dagna, L Joosten, M Netea, C Dinarello
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Assistant. <h3>Introduction</h3> Trained immunity (TI) is a <i>de-facto</i> innate immune memory program induced in monocytes/macrophages by exposure to pathogens or vaccines, which evolved as a protective mechanism against infections. TI is characterized by rewiring of functional, epigenetic and metabolic programs of innate immune cells such as monocytes and macrophages, which sustain enhanced production of pro-inflammatory cytokines. Since aberrant activation of TI is implicated in inflammatory diseases, tight regulatory mechanisms are likely in place, but the mechanisms responsible for this modulation remain elusive. <h3>Objectives</h3> Scope of this study was to evaluated the role of IL-37, an anti-inflammatory cytokine that curbs inflammation as well as modulates metabolic pathways, as an endogenous regulator of trained immunity. <h3>Methods</h3> The effects of recombinant IL-37 were evaluated in a mouse model of TI induced by the administration of beta-glucan <i>in vivo</i> (survival to a lethal inoculum of infectious agents, production of inflammatory cytokines, recruitment of inflammatory cells at the sites of infection). Subsequently, the effects of IL-37 were evaluated <i>ex vivo</i> on splenic and bone marrow monocytes (production of inflammatory cytokines, metabolomic analysis of the activation status of the main pathways of cellular energy metabolism). Finally, we evaluated the association between IL-37 gene polymorphisms and the induction of TI in monocytes of healthy donors with <i>in vitro</i> functional studies. <h3>Results</h3> The exogenous administration of IL-37 abrogates the pro-inflammatory effects of TI, significantly reducing the production of pro-inflammatory cytokines and the survival of experimental animals subjected to a disseminated infection model. The inhibitory effects of IL-37 on TI are also associated with reduced recruitment of neutrophils at sites of inflammation. IL-37 and TI programs have differential and opposite effects on the modulation of cellular energy metabolism of monocytes. In humans, polymorphisms in the IL-37 gene are associated with reduced activation of TI programs and reduced production of inflammatory cytokines by healthy donor monocytes. <h3>Conclusions</h3> In conclusion, IL-37 emerges as an endogenous regulator of TI, which makes this cytokine a potential therapeutic target in immune-mediated pathologies. <h3>Disclosure of Interest</h3> None declared.
The discovery of AZD0530: a novel, oral, highly selective and dual-specific inhibitor of the Src and Abl family kinases
Authors: Laurent F. Hennequin, J. Allen, G. F. Costello, M. Fennell, T. P. Green, V. Jacobs, R. Morgentin, A. Olivier, Patrick A. Ple
Journal: Cancer Research (2005)

2537  Normal cell growth, activity and function are coordinated and regulated by a complex network of signaling pathways. Aberrations in these signaling pathways are a hallmark of tumor development. Src kinase, a non-receptor tyrosine kinase, is a signal transduction modulator and is a critical component of many of the key signaling pathways currently thought to be pivotal in carcinogenesis. In contrast to its highly regulated role in normal cells, Src kinase has been shown to be de-regulated and its activity significantly increased in many human tumors. Recent publications have highlighted the critical role of Src kinase in tumor cell migration and invasion. Inhibition of Src kinase has the potential to have a significant impact as a treatment for cancer. AZD0530, a novel anilino quinazoline, is a potent dual-specific inhibitor of cSrc kinase (IC50: 2.7 nM) and the related Abl kinase (IC50: 30 nm). AZD0530 is highly selective for Src and Abl kinases against a large range of tyrosine and serine-threonine kinases (VEGFR2, FGFR, c-Kit, Aur-3 etc. >5 μM). AZD0530 exerts its activity through ATP competitive and reversible inhibition of the target enzyme. Structure-activity analyses that led to the discovery of AZD0530 are presented, focusing in particular on the critical role played by the aniline substitution pattern and the effect of the C5-C7 quinazoline substitution pattern. AZD0530 possesses excellent properties for a small molecule inhibitor of Src kinase that translate into excellent ADME properties in preclinical animal species. AZD0530 is orally available and is suitable for once-daily administration to humans. AZD0530 causes dramatic inhibition of human breast cancer cell (MDA-MB231) migration in vitro. Following oral administration at single daily doses of 6 mg/kg, AZD0530 completely prevents the growth of c-Src-NIH 3T3 xenografts grown in nude rats, and at 25 mg/kg/d significantly increases survival in an orthotopic model of human pancreatic cancer (BxPC-3). AZD0530 is a highly selective, orally available, dual-specific Src/Abl kinase inhibitor. It has the potential for activity in a wide range of tumors. AZD0530 is currently in early clinical development.
Interim Estimates of 2018–19 Seasonal Influenza Vaccine Effectiveness — United States, February 2019
Authors: Joshua D. Doyle, Jessie R. Chung, Sara S. Kim, Manjusha Gaglani, Chandni Raiyani, Richard K. Zimmerman, Mary Patricia Nowalk, Michael L. Jackson, Lisa A. Jackson, Arnold S. Monto, Emily T. Martin, Edward A. Belongia, Huong Q. McLean, Angie Foust, Wendy Sessions, LaShondra Berman, Rebecca J. Garten, John R. Barnes, David E. Wentworth, Alicia M. Fry, Manish M. Patel, Brendan Flannery
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

In the United States, annual vaccination against seasonal influenza is recommended for all persons aged ≥6 months (https://www.cdc.gov/flu/protect/whoshouldvax.htm). Effectiveness of seasonal influenza vaccine varies by season. During each influenza season since 2004-05, CDC has estimated the effectiveness of seasonal influenza vaccine to prevent laboratory-confirmed influenza associated with medically attended acute respiratory illness (ARI). This interim report uses data from 3,254 children and adults enrolled in the U.S. Influenza Vaccine Effectiveness Network (U.S. Flu VE Network) during November 23, 2018-February 2, 2019. During this period, overall adjusted vaccine effectiveness against all influenza virus infection associated with medically attended ARI was 47% (95% confidence interval [CI] = 34%-57%). For children aged 6 months-17 years, overall vaccine effectiveness was 61% (44%-73%). Seventy-four percent of influenza A infections for which subtype information was available were caused by A(H1N1)pdm09 viruses. Vaccine effectiveness was estimated to be 46% (30%-58%) against illness caused by influenza A(H1N1)pdm09 viruses. CDC recommends that health care providers continue to administer influenza vaccine because influenza activity is ongoing and the vaccine can still prevent illness, hospitalization, and death associated with currently circulating influenza viruses, or other influenza viruses that might circulate later in the season. During the 2017-18 influenza season, in which influenza A(H3N2) predominated, vaccination was estimated to prevent 7.1 million illnesses, 3.7 million medical visits, 109,000 hospitalizations, and 8,000 deaths (1). Vaccination can also reduce the severity of influenza-associated illness (2). Persons aged ≥6 months who have not yet been vaccinated this season should be vaccinated.
Predictors and outcomes of disseminated tuberculosis in an intermediate burden setting
Authors: L. Meira, C. Chaves, D. Araújo, L. Almeida, R. Boaventura, A. Ramos, T. Carvalho, N.S. Osório, A.G. Castro, F. Rodrigues, J.T. Guimarães, M. Saraiva, H.N. Bastos
Journal: Pulmonology (2019)

University-affiliated hospital located in Porto, North Portugal, an area with a low to intermediate incidence of tuberculosis (TB). To identify predictors and outcomes of disseminated TB (dTB). A cohort of patients diagnosed with TB between 2007 and 2013 was retrospectively analysed. Patients with dTB criteria were characterized and compared to single organ TB cases. Factors independently associated with dTB were determined by multivariate logistic regression analysis. A total of 744 patients were analysed, including 145 with dTB. Independent risk factors for dTB were pharmacological immunosuppression (OR 5.6, 95% CI 2.8–11.3), HIV infection (OR 5.1, 95% CI 3.1–8.3), chronic liver failure or cirrhosis (OR 2.3, 95% CI 1.4–4.1) and duration of symptoms (OR 2.3, 95% CI 1.4–3.8). Compared to single organ TB, the clinical presentation of dTB patients differed by the absence of haemoptysis (OR 3.2, 95% CI 1.3–8.4) and of dyspnoea (OR 1.9, 95% CI 1.2–3.1), presence of weight loss (OR 1.8, 95% CI 1.1–2.9), night sweats (OR 1.7, 95% CI 1.1–2.7) and bilateral lung involvement (OR 4.4, 95% CI 2.8–7.1). Mortality and time until culture conversion were higher for dTB patients, although not reaching statistical significance. Immunosuppressive conditions and chronic liver failure or cirrhosis were associated with increased risk of dTB. The haematogenous spread may be dependent on longer symptomatic disease and usually progresses with bilateral lung involvement.