tbuckley/cabot-search huggingface dataset:
The Evolutionary History of Nebraska Deer Mice: Local Adaptation in the Face of Strong Gene Flow
Authors: Susanne P Pfeifer, Stefan Laurent, Vitor C Sousa, Catherine R Linnen, Matthieu Foll, Laurent Excoffier, Hopi E Hoekstra, Jeffrey D Jensen
Journal: Molecular Biology and Evolution (2018)

The interplay of gene flow, genetic drift, and local selective pressure is a dynamic process that has been well studied from a theoretical perspective over the last century. Wright and Haldane laid the foundation for expectations under an island-continent model, demonstrating that an island-specific beneficial allele may be maintained locally if the selection coefficient is larger than the rate of migration of the ancestral allele from the continent. Subsequent extensions of this model have provided considerably more insight. Yet, connecting theoretical results with empirical data has proven challenging, owing to a lack of information on the relationship between genotype, phenotype, and fitness. Here, we examine the demographic and selective history of deer mice in and around the Nebraska Sand Hills, a system in which variation at the Agouti locus affects cryptic coloration that in turn affects the survival of mice in their local habitat. We first genotyped 250 individuals from 11 sites along a transect spanning the Sand Hills at 660,000 single nucleotide polymorphisms across the genome. Using these genomic data, we found that deer mice first colonized the Sand Hills following the last glacial period. Subsequent high rates of gene flow have served to homogenize the majority of the genome between populations on and off the Sand Hills, with the exception of the Agouti pigmentation locus. Furthermore, mutations at this locus are strongly associated with the pigment traits that are strongly correlated with local soil coloration and thus responsible for cryptic coloration.
OP0242 SAFETY PROFILE OF NINTEDANIB IN PATIENTS WITH SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE AND IDIOPATHIC PULMONARY FIBROSIS
Authors: Kristin Highland, Oliver Distler, Martina Gahlemann, Arata Azuma, Aryeh Fischer, Maureen Mayes, Ganesh Raghu, Wiebke Sauter, Mannaig Girard, Veronika Kohlbrenner, Emmanuelle Clerisme-Beaty, Susanne Stowasser, Masataka Kuwana, Toby M Maher
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Nintedanib has been investigated in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) in the SENSCIS trial and idiopathic pulmonary fibrosis (IPF) in the two INPULSIS trials. These patient populations differ in age, sex, disease characteristics and comorbidities. <h3>Objectives</h3> To compare the safety and tolerability of nintedanib in patients with SSc-ILD and IPF. <h3>Methods</h3> Adverse events that occurred over 52 weeks of treatment in the SENSCIS and INPULSIS trials were assessed descriptively in subjects who received ≥1 dose of trial drug. <h3>Results</h3> A total of 576 subjects were treated in the SENSCIS trial (288 nintedanib; 288 placebo) and 1061 in the INPULSIS trials (638 nintedanib; 423 placebo). At baseline, mean (SD) age was 54.0 (12.2) and 66.8 (8.0) years in SENSCIS and INPULSIS, respectively. The proportion of males was 24.8% and 79.3%, respectively. Over 52 weeks, 19.4% and 10.8% of patients treated with nintedanib and placebo discontinued treatment in SENSCIS, compared with 24.5% and 18.9% of patients treated with nintedanib and placebo in INPULSIS. Gastrointestinal adverse events were the most frequently reported adverse events with nintedanib and, as expected based on the underlying disease, were more frequent in patients with SSc-ILD than IPF in both treatment groups (Table). Diarrhoea adverse events were reported in 75.7% and 31.6% of patients treated with nintedanib and placebo in SENSCIS, and 62.4% and 18.4% of patients treated with nintedanib and placebo in INPULSIS, respectively. <h3>Conclusion</h3> The safety and tolerability profile of nintedanib in patients with SSc-ILD is similar to that observed in patients with IPF. <h3>Disclosure of Interests</h3>
Integration of metabolomics and expression of enolase-phosphatase 1 links to hepatocellular carcinoma progression
Authors: Hao Zhuang, Zhaoyan Qiang, Xiaowen Shao, Huan Wang, Yamei Dang, Zun Wang, Fei Wu, Wen Wei, Yongmei Li
Journal: Theranostics (2019)

Reprogramming of cellular metabolism is one of the hallmarks for cancer, in which tumor cells rewire their metabolic fluxes to generate sufficient energy and biosynthetic intermediates. Therefore, elucidating the correlation between cellular metabolism and hepatocellular carcinoma (HCC) progression may provide insights into novel approaches to cancer therapy.
TRANSFORMING ACTIVITIES OF THE NUP98-KMT2A FUSION GENE ASSOCIATED WITH MYELODYSPLASIA AND ACUTE MYELOID LEUKEMIA
Authors: J. N. Fisher, A. Thanasopoulou, S. Juge, A. Tzankov, F. O. Bagger, M. Mendez, A. H. Peters, J. Schwaller
Journal: HemaSphere (2019)
SAT0308 CLUSTER-BASED SPONDYLOARTHRITIS PHENOTYPES DEFINED AT BASELINE ARE PREDICTIVE OF 5-YEAR SEVERITY OUTCOME IN THE DESIR COHORT
Authors: Felicie Costantino, Philippe Aegerter, Anna Moltó, Maxime Breban, Maria-Antonietta D’agostino
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> The course of axial spondyloarthritis (SpA) is heterogeneous, varying from mild to severe and remains to be better defined. DESIR is a French cohort of early undifferentiated axial SpA that are longitudinally followed-up, offering such opportunity. We recently performed a cluster analysis in the DESIR cohort, according to baseline characteristics and identified 2 clusters: one characterized by an isolated axial disorder (A for axial) and one by additional high frequency of peripheral manifestations (B for both)<sup>1</sup>. Those cluster-based SpA phenotypes could correspond to different levels of disease severity. <h3>Objectives</h3> To assess whether cluster-based SpA phenotypes defined at baseline are conserved over time and might predict disease outcome at follow-up. <h3>Methods</h3> We analysed longitudinal data from the 586 patients who completed all follow-up visits until 5-year (mo 6, 12, 18, 24, 36, 48 and 60) out of the 679 patients included in the DESIR cohort used to define clusters at baseline. We performed a linear mixed-effect analysis for quantitative variables (using lme4 R package) and a generalized linear mixed-effect analysis for qualitative variables (using glmer R package) with cluster and follow-up visits as fixed effects and subjects as random effect. <i>P</i>-values were obtained by likelihood ratio tests of the full model with cluster against the model without cluster as fixed effects. <h3>Results</h3> Over the time, both clusters continued to show sustainable consistent differences characterized by higher frequency of peripheral involvement, higher disease activity, worse patient-reported outcome, higher frequency of conventional DMARDs and TNF blockers usage in cluster B, and higher frequency of radiographic and MRI sacroiliitis at 2 and 5 years in cluster A (Table). <h3>Conclusion</h3> Cluster-based SpA phenotypes defined at baseline in the DESIR cohort were predictive of severity outcome after 5 years. Patients from cluster A were more prone to develop sacroiliitis despite lower disease activity over the time, whereas those from cluster B had poorer clinical outcome and higher need for conventional DMARDs and TNF blockers. <h3>Reference</h3> [1] Costantino F, Aegerter P, Dougados M, Breban M, D'Agostino M-A. Two Phenotypes Are Identified by Cluster Analysis in Early Inflammatory Back Pain Suggestive of Spondyloarthritis: Results From the DESIR Cohort. Arthritis &amp; Rheumatology (Hoboken, NJ). 2016;68(7):1660–8. <h3>Disclosure of Interests</h3> Felicie Costantino: None declared, Philippe Aegerter: None declared, Anna Moltó: None declared, Maxime Breban Grant/research support from: Pfizer, UCB, Novartis, MSD, Consultant for: UCB, Maria-Antonietta d'Agostino: None declared
PS1491 PLATELET KINETICS IN PATIENTS WITH CHRONIC IMMUNE THROMBOCYTOPENIA TREATED WITH THROMBOPOIETIN RECEPTOR AGONISTS
Authors: Z. Pravdic, M. Mitrovic, M. Todorovic‐Tirnanic, M. Virijevic, N. Sabljic, N. Suvajdzic‐Vukovic
Journal: HemaSphere (2019)

Background: Chronic immune thrombocytopenia (ITP) is characterised by antibody‐mediated platelet destruction, shortened platelet survival (PS) and impaired platelets production. Platelet kinetic study (PKS) assesses in vivo the mean PS, platelet production and the platelet sequestration site. Thrombopoietin receptor agonists (TPO‐RA) increase platelets counts (PC) in majority of chronic ITP patients. Moreover, some patients could retain stabile response after TPO‐RA discontinuation, which is attributed to the immunomodulatory effects of the drugs. Addressing this issue only a few studies have been done assessing the effect of TPO‐RA on PKS parameters. Aims: To evaluate the effects of TPO‐RA on PKS parameters. Methods: Ten patients with chronic ITP, median age 55.3 years (range 12–72), gender (f: n = 7, m: n = 3), splenectomised 6/10, were treated with TPO‐RA (eltrombopag, n = 7, romiplostim, n = 3). Response was assessed according to the criteria of the International Working Group ( IWG) on ITP . Autologous 111 Induim‐oxinate‐labeled PKS were performed in all patients before and 5 months after TPO‐RA therapy initiation. Results: A good treatment response was achieved in 8/10 of patients (eltrombopag, n = 6, romiplostim, n = 2). Two refractory patients were treated with TPO‐RA and low dose prednisolone. Baseline median parameters were as follows: PC 6.5x10 9 /L (range 1–17), PS 0.5 days (range 0.1–1.6, normal: 7–10), platelet production ratio 0.65 (range 0.01–3.2, normal 1 ± 0.2), platelet turnover 30875 Plt/μL/day (range 1731–103500). The post−treatment PKS showed significantly higher median PC of 62.5x10 9 /L (range 5–501) (p = 0.013) and median platelet production ratio of 1.8 (range 0.5–37.9) (p = 0.05). However, median PS of 0.7 days (range 0.1–2.9) (p = 0.09), as well as platelet turnover of 58471.5 Plt/μL/day (range 2800–462236) (p = 0.086) and platelet destruction site remained unaltered. It is of note that two refractory patients (N 0 8 and N 0 10 in table) increased their platelet production (platelet production ratio and platelet turnover), while their PS remained reduced. It is of note that there was no clear correlation between PC and PS. Nevertheless, PC correlated only with platelet turnover prior (p = 0.006) and after TPO‐RA therapy (p = 0.029). Summary/Conclusion: Our prospective study in which PKS was performed initially and during TPO‐RA therapy suggests that TPO‐RA could increase PC by augmented production. Further studies on larger cohorts are needed to confirm this idea. image
Abstract 19053: Left Atrial Appendage Strain and New-onset Postoperative Atrial Fibrillation After Cardiac Surgery
Authors: Fawaz Alenezi, Miklos Kerati, John Hunting, Tara Holder, Yi Ju Li, Madhav Swaminathan, Jennifer Rymer, Eric Velazquez, Zainab Samad, Alina Nicoara
Journal: Circulation (2017)

Introduction: Postoperative atrial fibrillation (PoAF) is a well- described complication after cardiac surgery. Left atrium strain by speckle tracking (ST) has been associated with the occurrence o...
PEGylated immunoliposome-loaded endoglin single-chain antibody enhances anti-tumor capacity of porcine α1,3GT gene
Authors: Yingying Huang, Yong Huang, Jian He, Huiling Wang, Yiqun Luo, Yanmei Li, Junjie Liu, Liping Zhong, Yongxiang Zhao
Journal: Biomaterials (2019)
SP0012 THE HYGIENE HYPOTHESIS IN AUTOIMMUNITY
Authors: Jean-Francois Bach
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background and Aims:</h3> The frequency of autoimmune diseases has increased significantly in recent decades in developed countries. The hygiene hypothesis provides a possible explanation for this increase. The hypothesis is based on the observation of a concomitant decrease in the frequency of infectious diseases and an increase in the frequency of autoimmune diseases. It is also based on the geographical disparity in the frequency of autoimmune diseases, much more frequent in the north than in the south of the northern hemisphere, a disparity that is not explained by genetics. <h3>Method:</h3> The disease frequency which is very low in southern countries increases from the first generation among subjects migrating northward. The causal relationship between the decline in infections and the increase in autoimmune diseases remains to be proven. Most of the evidence is based on spontaneous experimental models of autoimmune diseases that show the higher frequency of these diseases in a clean sanitary environment and their prevention through the administration of various bacteria, viruses or parasites. <h3>Results:</h3> The underlying mechanisms are beginning to be revealed. An important place is given to pathogens and more particularly to their TLR ligands. Some arguments suggest that commensal bacteria in the intestinal microbiota also play a role. At the cellular level, the stimulation of certain regulatory cells and more particularly those producing TGF beta is well documented. <h3>Conclusion:</h3> These considerations are important for understanding the epidemiology and pathophysiology of autoimmune diseases but can also provide new guidance on their treatment and especially their prevention. The problem is, however, complicated by the fact that the theory applies to varying degrees depending on the disease, for instance more in systemic lupus erythematosus than rheumatoid arthritis. <h3>Disclosure of Interests:</h3> None declared
THU0503 ICONOGRAPHIC STUDY OF ACUTE MECHANICAL HIP PAIN IN YOUNG PATIENTS: CLINICAL-ULTRASONOGRAPHIC CORRELATE AND PROPOSAL OF DIAGNOSTIC-THERAPEUTIC ALGORITHM
Authors: Carlos Guillén-Astete, Lourdes Villalobos-Sánchez
Journal: Annals of the Rheumatic Diseases (2019)

THU0502 -Figure 1. A. Hypo intense mass lesion in the left knee of the first case and on the in the suprapatellar and intraarticular areas (T-1-weighted MRI image).B. Intraoperative image of open approach total synovectomy (second case).C. Suprapatellar and intraarticular lesions compatible with PVNS right knee of second case (T-2 weighed image).D. Suprapatellar and intraarticular focal hyper intense lesions (T-2-weighted MRI image).Case-3: An eleven-year-old female was referred to our clinic with recurrent swelling and pain on her right knee.Attacks lasted for 2-3 days and resolved spontaneously, accompanied by abdominal pain and vomiting.FMF attack was suspected, for she had signs of peritonitis with knee arthritis, and elevated acute phase reactants.A744S/R202Q compound heterozygote mutations were detected in the MEFV analysis.Colchicine was started 1 mg/kg/ per day.Abdominal pain attacks were resolved with colchicine, but articular symptoms persisted.MRI of the right knee detected focal hyper intense lesions in T2 weighted images compatible with PVNS.Total synovectomy was performed and confirmed PVNS.Conclusion: PVNS is a rare but serious reason for joint effusion, presented as chronic arthritis.It should be considered in the differential diagnosis of mono-arthritis, especially when the patient is unresponsive to specific treatment for JIA.MRI is the best diagnostic tool in imaging, and histopathological evaluation should be performed to confirm the diagnosis.
NmeCas9 is an intrinsically high-fidelity genome-editing platform
Authors: Nadia Amrani, Xin D. Gao, Pengpeng Liu, Alireza Edraki, Aamir Mir, Raed Ibraheim, Ankit Gupta, Kanae E. Sasaki, Tong Wu, Paul D. Donohoue, Alexander H. Settle, Alexandra M. Lied, Kyle McGovern, Chris K. Fuller, Peter Cameron, Thomas G. Fazzio, Lihua Julie Zhu, Scot A. Wolfe, Erik J. Sontheimer
Journal: Genome biology (2018)

The development of CRISPR genome editing has transformed biomedical research. Most applications reported thus far rely upon the Cas9 protein from Streptococcus pyogenes SF370 (SpyCas9). With many RNA guides, wildtype SpyCas9 can induce significant levels of unintended mutations at near-cognate sites, necessitating substantial efforts toward the development of strategies to minimize off-target activity. Although the genome-editing potential of thousands of other Cas9 orthologs remains largely untapped, it is not known how many will require similarly extensive engineering to achieve single-site accuracy within large genomes. In addition to its off-targeting propensity, SpyCas9 is encoded by a relatively large open reading frame, limiting its utility in applications that require size-restricted delivery strategies such as adeno-associated virus vectors. In contrast, some genome-editing-validated Cas9 orthologs are considerably smaller and therefore better suited for viral delivery.Here we show that wildtype NmeCas9, when programmed with guide sequences of the natural length of 24 nucleotides, exhibits a nearly complete absence of unintended editing in human cells, even when targeting sites that are prone to off-target activity with wildtype SpyCas9. We also validate at least six variant protospacer adjacent motifs (PAMs), in addition to the preferred consensus PAM (5'-N4GATT-3'), for NmeCas9 genome editing in human cells.Our results show that NmeCas9 is a naturally high-fidelity genome-editing enzyme and suggest that additional Cas9 orthologs may prove to exhibit similarly high accuracy, even without extensive engineering.
Gene expression markers of Tumor Infiltrating Leukocytes
Authors: Patrick Danaher, Sarah Warren, Lucas Dennis, Leonard D’Amico, Andrew White, Mary L. Disis, Melissa A. Geller, Kunle Odunsi, Joseph Beechem, Steven P. Fling
Journal: Journal for ImmunoTherapy of Cancer (2017)

Assays of the abundance of immune cell populations in the tumor microenvironment promise to inform immune oncology research and the choice of immunotherapy for individual patients. We propose to measure the intratumoral abundance of various immune cell populations with gene expression. In contrast to IHC and flow cytometry, gene expression assays yield high information content from a clinically practical workflow. Previous studies of gene expression in purified immune cells have reported hundreds of genes showing enrichment in a single cell type, but the utility of these genes in tumor samples is unknown. We use co-expression patterns in large tumor gene expression datasets to evaluate previously reported candidate cell type marker genes lists, eliminate numerous false positives and identify a subset of high confidence marker genes.Using a novel statistical tool, we use co-expression patterns in 9986 samples from The Cancer Genome Atlas (TCGA) to evaluate previously reported cell type marker genes. We compare immune cell scores derived from these genes to measurements from flow cytometry and immunohistochemistry. We characterize the reproducibility of our cell scores in replicate runs of RNA extracted from FFPE tumor tissue.We identify a list of 60 marker genes whose expression levels measure 14 immune cell populations. Cell type scores calculated from these genes are concordant with flow cytometry and IHC readings, show high reproducibility in replicate RNA samples from FFPE tissue and enable detailed analyses of the anti-tumor immune response in TCGA. In an immunotherapy dataset, they separate responders and non-responders early on therapy and provide an intricate picture of the effects of checkpoint inhibition. Most genes previously reported to be enriched in a single cell type have co-expression patterns inconsistent with cell type specificity.Due to their concise gene set, computational simplicity and utility in tumor samples, these cell type gene signatures may be useful in future discovery research and clinical trials to understand how tumors and therapeutic intervention shape the immune response.
Involvement of p53 in senescence arrest and caspase 3 activity in the cell death response to methotrexate in the breast tumor cell
Authors: Deepali K. Hattangadi, Gerald A. Demasters, Kara R. Jones, Xu Di, David A. Gewirtz
Journal: Cancer Research (2004)

4629  It has recently been reported (Devarajan et al, Oncogene, 21:8443, 2002) that breast tumors frequently fail to express caspase 3, an executioner caspase strongly implicated in the final stages of apoptotic cell death. In view of the fact that the antifolate drug, methotrexate, is utilized in the standard CMF regimen for the treatment of breast cancer, studies were performed to evaluate the promotion of apoptosis in breast tumor cells differing in caspase 3 activity as well as functional p53 status. We were further interested in whether senescence arrest might represent an alternative response in cells which failed to undergo apoptosis. In p53 wild-type MCF-7 breast tumor cells that do not express functional caspase 3, death of approximately 40% of the cell population was observed immediately after acute exposure to 10 μM methotrexate (the IC90 value for a 2 hour drug exposure). Cell death appeared to occur via a pathway other than apoptosis based on the absence of DNA fragmentation or alterations in cell morphology. Cell death was succeeded by growth arrest for at least 72 hours - where arrest was characterized by a marked reduction of the G2/M population, an increase in the cell population in G1 and expression of the senescence marker, beta galactosidase. The primary response to methotrexate in MCF-7/E6 cells with attenuated p53 function was also growth arrest - but lacking characteristics of senescence. In contrast, MCF-7 cells which expressed caspase 3 demonstrated a gradual and continuous loss of viable cells and unequivocal morphological evidence of apoptosis. Apoptosis was also detected after exposure to methotrexate in p53 mutant MDA-MB231 breast tumor cells. Methotrexate induced both p53 and p21 waf1/cip1 in MCF-7 cells within 6 hours; however, no significant strand breakage was evident before 18 hours, suggesting that the induction of p53 could reflect a response to cellular stresses other than DNA damage such as nucleotide depletion. Overall, these studies suggest that the nature of the cellular response to methotrexate depends, in large part, on p53 and caspase function. Apoptosis appears to be independent of p53 while the senescence phenotype can apparently be induced in the breast tumor cell through p53 (and possibly p21 waf1/cip1) in the absence of direct DNA damage. Our current work is focused on the question of whether senescence arrest is permissive for recovery of proliferative function.
Abstract IA04: Lgr5 stem cell-based organoids in human disease
Authors: Hans Clevers
Journal: Clinical Cancer Research (2016)

Abstract The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We originally defined Lgr5 as a Wnt target gene, transcribed in colon cancer cells. Two knock-in alleles revealed exclusive expression of Lgr5 in cycling, columnar cells at the crypt base. Using lineage tracing experiments in adult mice, we found that these Lgr5+ve crypt base columnar cells (CBC) generated all epithelial lineages throughout life, implying that they represent the stem cell of the small intestine and colon. Lgr5 was subsequently found to represent an exquisitely specific and almost ‘generic’ marker for stem cells, including in hair follicles, kidney, liver, mammary gland, inner ear tongue and stomach epithelium. Single sorted Lgr5+ve stem cells can initiate ever-expanding crypt-villus organoids, or so called ‘mini-guts’ in 3D culture. The technology is based on the observation that Lgr5 is the receptor for a potent stem cell growth factor, R-spondin. Similar 3D cultures systems have been developed for the Lgr5+ve stem cells of human stomach, liver, pancreas, prostate and kidney. Using CRISPR/Cas9 technology, genes can be efficiently modified in organoids of various origins. Citation Format: Hans Clevers. Lgr5 stem cell-based organoids in human disease. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA04.