tbuckley/cabot-search huggingface dataset:
MetaLnc9 Facilitates Lung Cancer Metastasis via a PGK1-Activated AKT/mTOR Pathway
Authors: Tao Yu, Yingjun Zhao, Zhixiang Hu, Jing Li, Dandan Chu, Jiwei Zhang, Zhe Li, Bing Chen, Xiao Zhang, Hongyu Pan, Shengli Li, Hechun Lin, Lei Liu, Mingxia Yan, Xianghuo He, Ming Yao
Journal: Cancer Research (2017)

Long noncoding RNAs (lncRNA) participate in carcinogenesis and tumor progression in lung cancer. Here, we report the identification of a lncRNA signature associated with metastasis of non-small cell lung cancer (NSCLC). In particular, elevated expression of LINC00963 (MetaLnc9) in human NSCLC specimens correlated with poor prognosis, promoted migration and invasion of NSCLC cells in vitro, and enhanced lung metastasis formation in vivo Mechanistic investigations showed that MetaLnc9 interacted with the glycolytic kinase PGK1 and prevented its ubiquitination in NSCLC cells, leading to activation of the oncogenic AKT/mTOR signaling pathway. MetaLnc9 also interacted with P54nrb/NonO (NONO) to help mediate the activity of CRTC, a coactivator for the transcription factor CREB, reinforcing a positive feedback loop for metastasis. Taken together, our results establish MetaLnc9 as a driver of metastasis and a candidate therapeutic target for treating advanced NSCLC. Cancer Res; 77(21); 5782-94. ©2017 AACR.
SAT0413 Infectious profile in a tuberculosis-endemic population with spondyloarthropathies
Authors: MA Alzate, F Ramirez, F Vargas, D Hernandez-Parra, JC Salazar-Uribe, P Ortiz-Salazar, R Pineda
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Screening latent tuberculosis (TB) and other opportunistic infections in patients with spondyloarthropathies (SpA) with biologic or immunosuppression therapy is important in highly endemic population (1). <h3>Objectives</h3> To assess the prevalence of latent and active TB, hepatitis B, hepatitis C, HIV and Syphilis in a colombian cohort with SpA, as well as evaluate differences between treatments. <h3>Methods</h3> A cross-sectional study was conducted in 621 patients with SpAs, in whom TB, hepatitis B, hepatitis C, HIV and syphilis screening was analyzed based on type of diagnosis. Differences among immunomodulatory therapies were assessed. Statistical association was examined by means of Chi-square tests, Mann-Whitney test, and logistic regression analyses. <h3>Results</h3> The prevalence of latent and active TB in this cohort were 63,1%, and 2,9%, respectively. Significant differences were found in proportions of latent and active TB among types of SpAs, indicating a positive association with AS. A high proportion of TST conversion during immunotherapy was found. According to the immunomodulatory therapy, no differences were found among latent TB patients, active TB disease and no infection with the use of conventional DMARD therapy, but a positive association between latent TB and the use of biologic therapy was recognized. Low prevalences of opportunistic infections (i.e., Hepatitis B and C, syphilis and HIV) were found in this cohort, dispite the frequent use of biologic therapy. <h3>Conclusions</h3> In a TB-endemic population, higher prevalences of latent and active TB were found in patients with SpAs, when compared to the general population. Complete infectious screening is mandatory in patients under consideration of biologic agents, and close follow-up must be done to recognize TST conversion. <h3>References</h3> Pérez-Díaz CE, Uribe-Pardo E, Calixto OJ, Faccini-Martínez ΆA, Rodriguez-Morales AJ. Infections with biological therapy: strategies for risk minimization in tropical and developing countries. J Infect Dev Ctries. 2016;10(12). <h3>Disclosure of Interest</h3> None declared
The Road Less Traveled
Authors: Keith Romano, Valeria Pazo, Xiaohua Qian, Anand Vaidya, James H. Maguire
Journal: New England Journal of Medicine (2017)

A 26-year-old woman presented to the emergency department with a 1-week history of worsening pleuritic chest pain. She recalled the development of a dull, substernal ache several days after a 5-hour flight home from Puerto Rico, where she had spent 3 weeks hiking in national parks and exploring several caves. The ache progressed . . .
Occupational Animal Exposure Among Persons with Campylobacteriosis and Cryptosporidiosis — Nebraska, 2005–2015
Authors: Chia-ping Su, Derry T. Stover, Bryan F. Buss, Anna V. Carlson, Sara E. Luckhaupt
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Campylobacter and Cryptosporidium are two common causes of gastroenteritis in the United States. National incidence rates measured for these pathogens in 2015 were 17.7 and 3.0 per 100,000 population, respectively; Nebraska was among the states with the highest incidence for both campylobacteriosis (26.6) and cryptosporidiosis (≥6.01) (1). Although campylobacteriosis and cryptosporidiosis are primarily transmitted via consumption of contaminated food or water, they can also be acquired through contact with live animals or animal products, including through occupational exposure (2). This exposure route is of particular interest in Nebraska, where animal agriculture and associated industries are an important part of the state's economy. To estimate the percentage of disease that might be related to occupational animal exposure in Nebraska, the Nebraska Department of Health and Human Services (NDHHS) and CDC reviewed deidentified investigation reports from 2005 to 2015 of cases of campylobacteriosis and cryptosporidiosis among Nebraska residents aged ≥14 years. Case investigation notes were searched for evidence of occupational animal exposures, which were classified into discrete categories based on industry, animal/meat, and specific work activity/exposure. Occupational animal exposure was identified in 16.6% of 3,352 campylobacteriosis and 8.7% of 1,070 cryptosporidiosis cases, among which animal production (e.g., farming or ranching) was the most commonly mentioned industry type (68.2% and 78.5%, respectively), followed by employment in animal slaughter and processing facilities (16.3% and 5.4%, respectively). Among animal/meat occupational exposures, cattle/beef was most commonly mentioned, with exposure to feedlots (concentrated animal feeding operations in which animals are fed on stored feeds) reported in 29.9% of campylobacteriosis and 7.9% of cryptosporidiosis cases. Close contact with animals and manure in feedlots and other farm settings might place workers in these areas at increased risk for infection. It is important to educate workers with occupational animal exposure about the symptoms of enteric diseases and prevention measures. Targeting prevention strategies to high-risk workplaces and activities could help reduce disease.
Association of biomarkers of insulin resistance and inflammation with PET CT SUV values in stage IV non-small cell lung cancer (NSCLC).
Authors: Benjamin Avi Derman, Jeffrey Allen Borgia, Cristina L. Fhied, Sanjib Basu, Marta Batus, Philip Bonomi, Mary J. Fidler
Journal: Journal of Clinical Oncology (2016)

e20589 Background: PET CT is the imaging technique of choice for staging nodal and metastatic disease in NSCLC. Standardized Uptake Value (SUV) on PET CT is a quantification of FDG uptake and a surrogate of glycolysis. The aim of this project was to correlate pretreatment levels of circulating biomarkers of insulin resistance and inflammation with SUV on FDG PETs performed as part of routine care in stage IV NSCLC patients receiving platinum doublet chemotherapy. Methods: Pretreatment serum from 137 patients with frontline stage IV NSCLC were evaluated with the Bio-Plex Pro Human Diabetes Assay Panel and the Milliplex Human High Sensitivity T Cell Panel. All patients were treated with standard platinum doublet based chemotherapy. 80 patients had PET CT scans available to record maximal SUV (SUVmax). Associations of biomarkers with SUVmax were assessed using a Spearman’s Rank Correlation Coefficient. Results: SUVmax levels ranged from 2.2 to 41.9, mean 10.2, median 9.1. High levels of endocrine markers glucagon, visfatin, glucagon like peptide-1, ghrelin, resistin, C-peptide, and adipsin, and high levels of inflammatory markers ITAC, MIP-3α, IL-12, and IL-13 were associated with shortened overall survival (OS). Low levels of adiponectin (low values associated with obesity) were associated with shortened OS. High levels of some of these markers including MIP-1α, C-peptide, resistin, IL-8, and glucagon were significantly associated with high SUVmax, and low levels of adiponectin were significantly associated with high SUVmax (see table). Conclusions: High values of several biomarkers of insulin resistance and inflammation were associated with shortened survival in frontline NSCLC patients receiving platinum double therapy. Despite the lower number of patients with PETs, we found several biomarkers associated with high SUVmax. This study suggests that patients with high FDG uptake on PET may benefit from agents which modulate insulin resistance and/or inflammation. Biomarkers SUVmax (n = 80) Spearman Correlation p-value Adiponectin -0.258 0.021 MIP-1α 0.239 0.033 C-Peptide 0.242 0.030 Resistin 0.250 0.025 IL-8 0.263 0.018 Glucagon 0.268 0.016
Galectin-3, a Druggable Vulnerability for KRAS-Addicted Cancers
Authors: Laetitia Seguin, Maria F. Camargo, Hiromi I. Wettersten, Shumei Kato, Jay S. Desgrosellier, Tami von Schalscha, Kathryn C. Elliott, Erika Cosset, Jacqueline Lesperance, Sara M. Weis, David A. Cheresh
Journal: Cancer Discovery (2017)

Identifying the molecular basis for cancer cell dependence on oncogenes such as KRAS can provide new opportunities to target these addictions. Here, we identify a novel role for the carbohydrate-binding protein galectin-3 as a lynchpin for KRAS dependence. By directly binding to the cell surface receptor integrin αvβ3, galectin-3 gives rise to KRAS addiction by enabling multiple functions of KRAS in anchorage-independent cells, including formation of macropinosomes that facilitate nutrient uptake and ability to maintain redox balance. Disrupting αvβ3/galectin-3 binding with a clinically active drug prevents their association with mutant KRAS, thereby suppressing macropinocytosis while increasing reactive oxygen species to eradicate αvβ3-expressing KRAS-mutant lung and pancreatic cancer patient-derived xenografts and spontaneous tumors in mice. Our work reveals galectin-3 as a druggable target for KRAS-addicted lung and pancreas cancers, and indicates integrin αvβ3 as a biomarker to identify susceptible tumors.Significance: There is a significant unmet need for therapies targeting KRAS-mutant cancers. Here, we identify integrin αvβ3 as a biomarker to identify mutant KRAS-addicted tumors that are highly sensitive to inhibition of galectin-3, a glycoprotein that binds to integrin αvβ3 to promote KRAS-mediated activation of AKT. Cancer Discov; 7(12); 1464-79. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1355.
FRI0666 Increased prevalence of subclinical atherosclerosis in moderate-severe plaque psoriatic patients
Authors: N Vegas-Revenga, J Martín-Varillas, S Armesto, M Drake, V Portilla, P Fuentevilla, J Rueda-Gotor, B Atienza, L Domínguez-Casas, C Fernández-Díaz, R Blanco, M González-Gay, A Corrales
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Recent studies suggest that plaque psoriasis may be a risk factor for major adverse cardiac events. This has important therapeutic implications for cardiovascular (CV) risk stratification and prevention in patients with severe psoriasis. For that reason surrogate markers of subclinical atherosclerosis and CV mortality such as carotid plaques (CP) have been studied by carotid US examination. In most studies of psoriasis done before, the results have shown an increased prevalence of carotid plaques, but it is not always the rule. <h3>Objectives</h3> To compare the prevalence of CP between patients with moderate-severe psoriasis and the general population. <h3>Methods</h3> A cross-sectional study that included 40 patients with moderate- severe psoriasis (PASI&gt;10, BAS&gt;10%), that fulfilled definitions for initiating treatment with a biological agent and 40 age-, sex- and traditional CV risk factors- matched healthy control subjects. Patients with history of CV events, diabetes mellitus, and chronic kidney disease or body max index (BMI)&gt;35 were excluded. Carotid ultrasonography was performed by a MyLab 70 scanner (Esaote; Genoa, Italy), then carotid plaque was defined according to the Manheim Consensus Conference criteria. Statistical analysis: Qualitative data were expressed as number and percentages and quantitative data as mean (SD). Student9s t test or Mann-Whitney U were used to compare continuous variables, as appropriate. Chi2 test or Fisher test were used for qualitative variables. <h3>Results</h3> The main data of the patients are summarized in the Table. It is important to highlight that it is based on a young population (mean age&lt;40 years). The two groups did not present significant differences except for high sensitivity C-reactive protein (hsCRP) As expected given the age of the group, CV risk measured by SCORE was low (0%) with a mean of 0.2 us 0.15. No patient had a high-very high CV risk as measured by SCORE (≥5%). Patients with psoriasis had a long-standing disease (17.05±11.63 years). The presence of carotid plaques was found in a total of 10 patients with plaque psoriasis (25%), 5 of them had bilateral plaques) and one in the control group (2.5%) without bilateral plaques), p&lt;0.003. <h3>Conclusions</h3> Moderate-severe psoriasis is associated with increased prevalence of carotid plaques. <h3>Disclosure of Interest</h3> None declared
AB0971 Characterisation of the patients at the time of the transition into the adult rheumatology. 63% of the patients are in remission at the time of the transition
Authors: S Tatsis, I Foeldvari
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The issue of transition from pediatric to adult rheumatology service is an emerging important topic. In 2012 a transition clinic was established according to the "Berliner Transitionsprogramm" [1] in cooperation of the Hamburger Zentrum für Kinder-und Jugendrheumatologie and the Rheumatology Unit of the Marien Hospital in Hamburg. The Berliner programm suggests three visits of the patient in transitionprocess, in the presence of the pedriatic and an adult rheumatologist together, and the fourth visit conducted by the adult rheumatologist alone. We present the characteristics of the patients at the time of the 4th visit. <h3>Objectives</h3> To characterize the patient population at the time of enrollment into the adult service in the frame of our transition programm. <h3>Methods</h3> We collected patient data starting 8/2012 to 11/2016. We summarized the patient population, who succesfully transitioned from pediatric to adult rheumatologic service, concerning diagnosis, sex, age at the time of diagnosis, disease duration at the time of transition, JADAS, HAQ, VAS globular assessment, VAS pain, medication and disease activity. <h3>Results</h3> 73 patients were transitioned. 65% of them female. Mean age at diagnosis of the patients was 12.5 years. Mean disease duration at time of transition ws 10.8 years. The mean JADAS Score was 3.18 and the mean HAQ Score was 0.136. The patients global activity score was, on a VAS of 0 to 100, 14.03 and the global pain score, on a VAS of 0 to 100, 12.33. 39.7% of the patients received synthetic DMARDS and 34% biologic DMARDS: Only 1 patient received steroids. 24.6% of the patients were off medication. 63% of the patients were in remission, 61% of them on medication and 39% off medication in remission. <h3>Conclusions</h3> In this monocenter cohort 63% of patients were in remission, and with the mean JADAS Score of 3.18 most of them have low disease activity under the current treatment. The mean HAQ Score with 0.136 reflects a score, which is expected in healthy controls. But 75.4% of the patients needed medication to achieve this good condition. The amount of patients on medication emphasize the need of the structured transition. <h3>References</h3> Minden K, Niewerth M, Muther S: [Berlin transition program: from adolescents to adults in rheumatology treatment]. Z Rheumatol 2014, 73(6):526–531. <h3>Disclosure of Interest</h3> None declared
Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke
Authors: Lars Søndergaard, Scott E. Kasner, John F. Rhodes, Grethe Andersen, Helle K. Iversen, Jens E. Nielsen-Kudsk, Magnus Settergren, Christina Sjöstrand, Risto O. Roine, David Hildick-Smith, J. David Spence, Lars Thomassen
Journal: New England Journal of Medicine (2017)

The efficacy of closure of a patent foramen ovale (PFO) in the prevention of recurrent stroke after cryptogenic stroke is uncertain. We investigated the effect of PFO closure combined with antiplatelet therapy versus antiplatelet therapy alone on the risks of recurrent stroke and new brain infarctions.In this multinational trial involving patients with a PFO who had had a cryptogenic stroke, we randomly assigned patients, in a 2:1 ratio, to undergo PFO closure plus antiplatelet therapy (PFO closure group) or to receive antiplatelet therapy alone (antiplatelet-only group). Imaging of the brain was performed at the baseline screening and at 24 months. The coprimary end points were freedom from clinical evidence of ischemic stroke (reported here as the percentage of patients who had a recurrence of stroke) through at least 24 months after randomization and the 24-month incidence of new brain infarction, which was a composite of clinical ischemic stroke or silent brain infarction detected on imaging.We enrolled 664 patients (mean age, 45.2 years), of whom 81% had moderate or large interatrial shunts. During a median follow-up of 3.2 years, clinical ischemic stroke occurred in 6 of 441 patients (1.4%) in the PFO closure group and in 12 of 223 patients (5.4%) in the antiplatelet-only group (hazard ratio, 0.23; 95% confidence interval [CI], 0.09 to 0.62; P=0.002). The incidence of new brain infarctions was significantly lower in the PFO closure group than in the antiplatelet-only group (22 patients [5.7%] vs. 20 patients [11.3%]; relative risk, 0.51; 95% CI, 0.29 to 0.91; P=0.04), but the incidence of silent brain infarction did not differ significantly between the study groups (P=0.97). Serious adverse events occurred in 23.1% of the patients in the PFO closure group and in 27.8% of the patients in the antiplatelet-only group (P=0.22). Serious device-related adverse events occurred in 6 patients (1.4%) in the PFO closure group, and atrial fibrillation occurred in 29 patients (6.6%) after PFO closure.Among patients with a PFO who had had a cryptogenic stroke, the risk of subsequent ischemic stroke was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone; however, PFO closure was associated with higher rates of device complications and atrial fibrillation. (Funded by W.L. Gore and Associates; Gore REDUCE ClinicalTrials.gov number, NCT00738894 .).
Cysteine 277 as a putative site of p53 for covalent modification with 15-deoxy-Δ12,14-prostaglandin J2 : implications for functional inactivation of p53
Authors: Do-Hee Kim, Hye-Kyung Na, Yi Sun, Young-Joon Surh
Journal: Cancer Research (2007)

2423  Cyclopentenone prostaglandins (cyPGs) exert diverse cellular functions, such as anti-inflammatory and cytoprotective effects, via multiple mechanisms. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a representative cyPG of the J series, has been reported to directly inhibit the activity of the transcription factors, such as AP-1 and NF-κB. In the present study, we found that human breast cancer (MCF-7) cells treated with 15d-PGJ2 rapidly accumulated the tumor suppressor gene p53 protein in both cytosolic and nuclear fractions. Under the same experimental conditions, however, the mRNA level of p53 remained unchanged. In addition, 15d-PGJ2 significantly decreased p53 DNA binding as well as activity of p21WAF1 promoter containing a p53-binding site in MCF-7 cells. We observed that the majority of accumulated p53 in 15d-PGJ2-treated MCF-7 cells represents the changed mutant form of p53 and ubiquitinated p53 as assessed by immunoprecipitation and immunofluorscence assays. Murine double-minute 2 (MDM2), a zinc finger protein, is known to negatively regulate p53. 15d-PGJ2 treatment caused failure of proper p53-MDM2 interaction in MCF-7 cells which could stabilize the abnormal p53 protein by blocking MDM2-mediated degradation. We hypothesized that 15d-PGJ2 could covalently modify p53, which may hamper DNA binding of this redox-sensitive transcription factor. In support of this assumption, 15d-PGJ2 treated to both recombinant p53 and MCF-7 nuclear extracts diminished the DNA binding ability of p53 in a concentration-dependent manner. In addition, covalent binding of 15d-PGJ2 to p53 occurred upon incubation of recombinant p53 with biotinylated 15d-PGJ2. The incorporation of biotinylated 15d-PGJ2 into p53 was abolished by excess 15d-PGJ2 and restored in the presence of dithiothreitol. By using 35S-labeled translated p53, we could identify to cysteine 277 as a putative site of modification of p53 by 15d-PGJ2. The DNA binding ability of a mutant p53 in which Cys-277 was substituted by Ala was virtually unaffected by 15d-PGJ2. It is anticipated that the electrophilic carbon center located in the α,β-unsaturated carbonyl moiety of the cyclopentenone ring might be critical for the 15d-PGJ2-induced covalent modification of p53 at Cys-277 which hampered its degradation as well as DNA binding. MCF-7 cells treated with 9,10-dihydro-15-deoxy-Δ12,14-prostaglandin J2 that lacks the electrophilic α,β-unsaturated functionality failed to inhibit p53 DNA binding activity, lending further support to the above assumption. In conclusion, 15d-PGJ2, by covalently modifying cysteine 277 of p53, abrogates p53 DNA binding, leading to functional inactivation of this tumor suppressor.