tbuckley/cabot-search huggingface dataset:
Abstract 4760: Inhibition of c-myc by the triterpenoid celastrol
Authors: Angela Hu, Huabo Wang, Kelsey Pendleton, Edward V. Prochownik
Journal: Cancer Research (2012)

Abstract c-Myc is a bHLH-ZIP transcription factor that is deregulated in a variety of human cancers. More specifically, c-Myc heterodimerizes with another bHLH-ZIP partner protein, Max, to bind to specific sequences (E-Boxes: CAC/TGTG) located near the transcriptional start sites of its numerous target genes. Because c-Myc's highly variable downstream effects are difficult to attack individually, directly inhibiting the association between c-Myc and Max association by interfering with their bHLH-ZIP-mediated heterodimerization has emerged as an attractive therapeutic strategy. Thus far, high throughput screens of chemical libraries have identified a number of small molecules that specifically inhibit the c-Myc-Max association. However, these synthetic compounds and their analogs are generally of low potency and therefore have limited clinical utility. Here we report identification of celastrol, a naturally occurring triterpenoid, as a potent c-Myc inhibitor. We sought to further assess celastrol's ability to inhibit c-Myc-Max interaction and cell growth, and determine its structure activity relationship. Surface plasmon resonance and electrophoretic mobility shift studies revealed that celastrol specifically binds to c-Myc and prevents both its interaction with Max, and subsequent DNA binding with a Kd in the low micromolar range. Co-immunoprecipitation studies confirmed that the dose-dependent disruption of c-Myc-Max heterodimers by celastrol could also be achieved in c-Myc-overexpressing human HL60 promyelocytic leukemia cells. Moreover, in vitro data demonstrated that celastrol significantly inhibited both HL60 and Burkitt's lymphoma cell growth with IC50s in the nanomolar range. However, modifications to the C-28 carboxylic acid group of celastrol eliminated c-Myc binding, suggesting that celastrol binds to c-Myc via this functional group. This structure activity relationship may provide a basis for the development of more pharmacologically suitable analogs. Together these results suggest that celastrol is among the most potent Myc-Max disruptors yet identified, and suggest a mechanism of action. Celastrol thus represents a promising new agent with which to target c-Myc and provides a new structural chemical platform for further pharmaceutical development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4760. doi:1538-7445.AM2012-4760
Is enthesitis the primary immunopathological lesion in HLA-B27-associated experimental and human spondyloarthritis?
Authors: Jacqueline E Paramarta, Christiaan van der Leij, Ioana Gofita, Nataliya Yeremenko, Marleen G van de Sande, Maria J de Hair, Paul P Tak, Joel D Taurog, Mario Maas, Dominique L Baeten, Leonie M van Duivenvoorde
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Backgroundand objectives</h3> A MRI study of knee arthritis demonstrated that enthesitis was more frequently observed in established SpAthan RA, leading to the hypothesis that enthesitis rather than synovitis is the primary lesion in SpA.12 Although this hypothesis provides a useful conceptual framework to investigate the pathophysiology of SpA, very few studies have confirmed these findings. Here, the authors investigated the presence of enthesitis in the HLA-B27/Huβ2m tg rats.3 and in early untreated human SpA. <h3>Material and methods</h3> Histological samples were obtained at different stages of spontaneous tail spondylitis (n=10) and peripheral arthritis (n=9) in HLA-B27/Huβ2m tg rats. Paraffin sections were stained with H&amp;E or toluidine blue and evaluated by two independent observers. Synovial biopsies and MRI were performed in 41 patients with early (less than 1 year) untreated knee or ankle arthritis, who were diagnosed with SpA (n=13), RA (n=20) or crystal arthropathy (n=8) at follow-up. MRI evaluation of enthesitis, synovitis and osteitis and immunohistochemical characterisation of synovitis (CD3, CD22, CD68, CD163 and von Willebrand Factor) were performed by two observers blinded to diagnosis. <h3>Results</h3> Experimental HLA-B27-related spondylitis and peripheral arthritis were characterised by a progressive inflammatory infiltration of the stromal tissues with mono and polymorphonuclear cells. In moderate to severe inflammation, this was associated with progressive destruction of bone and cartilage, inflammatory infiltration of the underlying bone, and enchondral bone formation. The entheseal sites of the axial and peripheral joints were not affected as they did neither display signs of inflammation nor osteoproliferation. In human early untreated arthritis immunohistochemical analysis revealed a similar degree of synovitis in SpA and RA, with a significant increase of sublining CD163 in SpA. On MRI, the synovitis score was even higher in SpA (1.3; SD 0.7) than RA (0.7; SD 0.6). In contrast, there were no differences in prevalence of enthesitis as assessed by peri-entheseal focal tissue oedema (67% vs 75%), peri-entheseal focal bone marrow oedema (0% vs 10%) and entheseal enhancement (46% vs 47%). Also the number of peri-entheseal lesions did not differ between SpA and RA. <h3>Conclusions</h3> This combined histological and imaging evaluation of experimental and early human disease show that enthesitis is not a specific feature of SpA, which challenges the concept that enthesitis would be the primary immunopathological lesion.
P664 POST-PARTUM REACTIVATION OF CHRONIC HBV INFECTION AMONG HBeAg-NEGATIVE WOMEN: 5-YEARS FOLLOW UP DATA. A SINGLE-CENTER, PROSPECTIVE STUDY
Authors: I. Elefsiniotis, E. Vezali, D. Vrachatis, S. Hatzianastasiou, S. Pappas, G. Farmakidis, G. Vrioni, A. Tsakris
Journal: Journal of Hepatology (2014)
P255 Defining a circadian pattern of presentation of pulmonary embolism on CT/VQ imaging
Authors: N. Shah, A. S. Jubber, I. Syed
Journal: Thorax (2010)

<h3>Purpose</h3> To evaluate whether there is an association between the chronological occurrence of pulmonary emboli, anatomical site, radiological extent and associated clinical risk factors. <h3>Materials and Methods</h3> 1410 consecutive CTPA and VQ scans performed between December 2005 and October 2008 were retrospectively reviewed independently by 2 thoracic radiologists (kc=0.78). A third observer was used in equivocal cases. 270 cases of pulmonary emboli were identified. Records were available for 180 patients. 40 were excluded on the basis of incomplete presenting details. All diagnosed cases of pulmonary emboli were risk stratified according to the Wells score, underlying co-morbidities including diabetes, DVT, malignancy and cardiomyopathy. Morbidity, mortality and survival data were recorded. For 140 (Age 67 y SD ±17, 61 male), the occurrence of the pulmonary emboli based on onset of symptoms was defined by four time intervals. Each group was subdivided according to extent of clot. The average Wells score was calculated for each 6 h period. <h3>Results</h3> 11% (n=16) patients presented between 00:00 and 06:00 h, 36% (n=50) between 06:00 and 12:00 hours, 30% (n=43) between 12:00 and 18:00, and 22% (n=31) between 18:00 and 24:00(χ<sup>2</sup> =18.3, p&lt;0.05). Average Wells Scores were 4 (SD±2), 6 (SD±1), 4 (SD±2) and 5 (SD±2) for the respective times. Patients with bilateral emboli affecting the main pulmonary arteries were distributed as follows: 00:00–06:00 (n=2), 06:00–12:00 (n=17), 12:00–18:00 (n=10), 18:00–24:00 (n=9) (χ<sup>2</sup> =10.7, p&lt;0.05). Patients with unilateral emboli affecting the main pulmonary arteries were found to present as follows: 00:00–06:00 (n=3), 06:00–12:00 (n=11), 12:00–18:00 (n=10), 18:00–24:00 (n=7) (χ<sup>2</sup> =5.00, p=0.17). Patients with bilateral emboli affecting the segmental arteries presented at: 00:00–06:00 (n=4), 06:00–12:00 (n=12), 12:00–18:00 (n=8), 18:00–24:00 (n=3) (χ<sup>2</sup> =7.52, p=0.05). Patients with unilateral emboli affecting the segmental arteries presented at: 00:00–06:00 (n=5), 06:00–12:00 (n=5), 12:00–18:00(n=8), 18:00–24:00 (n=5). (χ<sup>2</sup> =1.17, p=0.76) In the 4 time intervals, patients with &gt;2 symptoms of chest pain, dyspnoea, or haemoptysis were found to be distributed as: 00:00–06:00 (n=8), 06:00–12:00 (n=26), 12:00–18:00 (n=16), 18:00–24:00 (n=17) (χ<sup>2</sup> =9.72, p&lt;0.05). <h3>Conclusion</h3> Pulmonary Emboli were most frequent between 06:00 and 12:00 h during which there was more extensive radiographical findings, associated with a higher Wells score, and more profound symptoms. This suggests a circadian pattern of the presentation of pulmonary emboli, correlating with the clinical and radiological severity of disease.
Metabolomics of basal breast carcinomas: a potential target for treatment intervention.
Authors: AD Thor, SM Edgerton, Z Fan, SE Lind, B Liu
Journal: Cancer Research (2009)

Abstract Abstract #6026 Breast cancers of the basal subtype (ER, PR and HER2 negative; EGFR and/or CK5/6 positive) are typically high grade, rapidly proliferative, associated with a poor outcome and are resistant to many chemotherapeutic regimens. They occur more frequently in women with BRCA-1 mutations, African Americans and obese individuals. At the molecular level, basal cancers have impairment of BRCA-1 and p53 signaling and are driven, in part, through EGFR which activates the PI3K/AKT/mTOR pathways. Treatment of basal carcinoma cell lines with the FDA approved anti-diabetic drug metformin significantly reduces cellular proliferation, induces cell cycle arrest (late G1/S phase) and apoptosis in vivo and in vitro. Similar effects were not observed in breast cancer cells of the luminal A, B or HER2 subtypes. Metformin induces a wide spectrum of metabolic and molecular changes in basal carcinoma cell lines in vitro, including: a reduction in glucose uptake, enhanced lactate release, a decrease in cellular proliferation and colony formation, a decrease in EGFR, phospho-EGFR and downstream signaling including pAKT, pMAPK and psrc, inhibition of cyclins D1 and E, reduced E2F1, PARP cleavage and activation of caspases 3, 8 and 9 in a dose and time dependent manner. Nude mice with basal cell line MDA-MB-231 xenografts treated with metformin showed significantly reduced tumor growth and prolonged survival as compared to control untreated mice. Pre-treatment with metformin prior to xenograft inoculation reduced both tumor formation and growth as compared to mice treated with metformin after implantation or untreated control mice, suggesting that metformin may have some use in basal cancer prevention. Epidemiologic data has shown that women treated with metformin have a reduced rate of breast cancer and, for those patients with breast cancer, an improved disease free and overall survival. In aggregate, these data suggest that further study of metformin to prevent or treat breast cancer in some patient subgroups may be indicated. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6026.
Abstract 4402: Triple negative breast cancer progression is impacted by NR4A orphan nuclear receptor signaling
Authors: Shawn D. Llopis, Brittany Singleton, Christopher Williams
Journal: Cancer Research (2011)

Abstract PURPOSE: Despite the lack of an increased rate of breast cancer occurrence among African-American women, African-American women suffer greater mortality due to breast cancer as compared with other ethnic groups. A key factor in decreased survival among African American women may be the elevated occurrence of triple negative (ER-/PR-/HER2-) breast cancers. The negative response makes these patients ineligible for hormonal therapy or Her2 targeted therapies, often leaving cytotoxic chemotherapeutic strategies. The NR4A subfamily of orphan nuclear receptors have the potential to serve as distinct, specific pharmacological targets which can directly affect apoptosis and be exploited to design highly selective, less toxic regimens in triple negative breast cancer phenotypes. DESIGN METHOD: Using cell lines derived from MB468 cells, crystal violet staining and Alamar blue assays for cell viability, Western blot for protein expression, PCR for gene expression, and fluorescence microscopy for immunohistochemical staining and xenograft studies were performed. RESULTS: Breast tumor microarrays demonstrate that NR4A2 is highly expressed in the nucleus of normal, but not malignant breast epithelial cells. shRNA-mediated silencing of NR4A2 in triple negative breast cancer cells leads to increased proliferation. Studies also reveal shRNA-silencing of NR4A2 expression mediated partial resistance to doxorubicin, while overexpression leads to cell cycle arrest. Additionally, gene expression arrays show that overexpression of NR4A2 induces expression of angiogenic factors, and suppresses markers associated with epithelial-mesenchymal transition. CONCLUSION: These studies suggest that NR4A2 is a viable pharmacological target in triple negative breast cancer and may prove an effective means to address the disparity in survival rates of African-American women as compared to other ethnicities. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4402. doi:10.1158/1538-7445.AM2011-4402
A2.29 Association of<i>REL</i>locus with rheumatoid arthritis susceptibility in Tunisian and French populations
Authors: O Khalifa, B M'Madi, N Balandraud, N Lambert, M Martin, A Senechal, D Genevieve, C Picard, G Lefranc, E Pardoux, T Mahjoub, F Apparailly
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background and objectives</h3> Rheumatoid arthritis (RA) is a systemic autoimmune disease characterised by a chronic destructive inflammation in synovial joints. Genetic and environmental factors are likely to contribute etiologically to RA pathogenesis. Genome-wide association studies have identified dozen genes associated with RA among which REL, a member of the NF-kB family of transcription factors. A strong association at the <i>REL</i> locus was found in North American population. The present study aimed at investigating the association between 2 critical polymorphisms in the REL locus (rs13031237 and rs13017599) and RA susceptibility in two novel populations: Tunisian and French. In addition, the present study aimed at comparing the differences in genotypic distribution in both populations. <h3>Material and methods</h3> A case–control study of 493 RA patients and 507 healthy controls age and sex matched was conducted in both Tunisian and French. All RA patients were ACPA positive. DNA was isolated from total blood using standard phenol chloroform method. All subjects were genotyped for both polymorphisms using a direct sequencing with the BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems). The genotype distribution, haplotype analysis, and the linkage disequilibrium (LD) were analysed using the Bayesian method, and PLINK 1.07 and Haploview 4.2 softwares, respectively. <h3>Results</h3> Only the genotype distribution of the rs13031237 polymorphism respected Hardy-Weinberg equilibrium, both in Tunisian and French populations. The association between REL rs13031237 polymorphism and RA susceptibility was found (p = 0.014), the genotype GG representing a protective factor for RA (OR = 0.46, 95% CI = 0.25–0.86). Linkage disequilibrium between both SNPs was strong (D = 53). There were 4 haplotypes with a frequency higher than 5%, constructed from the <i>REL</i> locus polymorphism. Haplotype H1 (TT), H3 (TC) and H4 (GC) were associated with increased risk for RA, whereas the haplotype H2 (GT) was significantly associated with a decreased risk for RA (p &lt; 0.001). Analysis of the genotypic distribution of the rs13017599 polymorphism was however inconclusive. Finally correlation analyses with clinical and biological parameters are in progress. <h3>Conclusion</h3> Our case-control study replicated for the first time the association of the rs13031237 at the REL locus with RA risk, in an independent cohort from Tunisia and France. We also identified haplotypes closely associated with disease risk.
Genetic evolution of Human Enterovirus A71 subgenotype C4 in Shenzhen, China, 1998–2013
Authors: Yaqing He, Linjie Zou, Marc Ka Chun Chong, Ruoting Men, Wenbo Xu, Hong Yang, Xiangjie Yao, Long Chen, Huixia Xian, Hailong Zhang, Min Luo, Jinquan Cheng, Hanwu Ma, Qianjin Feng, Yun Huang, Yujie Wang, Eng-kiong Yeoh, Benny Chung-Ying Zee, Yuanping Zhou, Ming-Liang He, Maggie Haitian Wang
Journal: Journal of Infection (2016)
AB0426 Calcium intake in algerian rheumatoid arthritis patients. A multicenter study
Authors: S. Slimani, A. Abbas, A. Ben Ammar, D. Kebaili, E.H. Ali, F. Rahal, C. Dahou-Makhloufi, N. Brahimi, S. Abtroun-Benmadi, A. Ladjouze-Rezig
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> To determine the adequacy of calcium intake in an Algerian cohort of rheumatoid arthritis (RA) patients. <h3>Methods</h3> Of 249 RA patients followed in 11 centres, 139 patients accepted to participate in an evaluation of calcium intake at inclusion (22 men, 117 women, mean age 52.7±14.4 years). All patients satisfied the 2010 ACR/EULAR criteria for the diagnosis of RA. Their calcium intake was evaluated by Fardellone questionnaire and compared with recommended calcium intake guidelines of the Institute of Medicine (1000mg/d for adults &lt;50 years and men &lt;71 years, 1200mg for women ≥51 years and men ≥71 years). Information on disease activity, functional status and drug therapy has been recorded at baseline. Statistical analysis has been realised, mainly ANOVA tests and tests of correlation. <h3>Results</h3> Mean calcium intake was 408±141mg/d. No patient had an intake of calcium &gt;1000mg/d, and only one person received &gt;800mg/d. The percentage of patients who were supplemented with calcium and vitamin D (1000mg + 800IU) was 52.5%. Male patients had significantly reduced intake of calcium compared with females (350mg/d vs 418mg/d, <i>p</i>=0.038). Other identified risk factors for low calcium intake were higher age (<i>r</i>=0.208, <i>p</i>=0.015), lower education level (<i>r</i>=0.264, <i>p</i>=0.002), higher CRP (<i>r</i>=0.328, <i>p</i>&lt;0.0001). However, there was no variation in calcium intake according to the current DMARD, the type of housing, DAS28, hypertension and diabetes, erosions and HAQ. <h3>Conclusions</h3> 100% of our patients do not receive the recommended calcium intake. Only 52.5% are calcium/vitamin D supplemented. Risk factors are male sex, higher age, low education levels and high CRP. Patients with RA should receive dietary education associated with supplementation to bring their intake of calcium to the recommended guidelines. <h3>Disclosure of Interest</h3> None Declared
P285 FATTY ACID AVAILABILITY INDUCES CHROMATIN MODIFICATIONS BY INCREASING THE EXPRESSION OF HISTONE VARIANT macroH2A1.2 MODULATING GENES INVOLVED IN LIPID METABOLISM
Authors: C. Podrini, S. Chokshi, E. Palma, K. Moutasim, R. Williams, A. Greco
Journal: Journal of Hepatology (2014)
Value of FDG PET in the Evaluation of Therapy Response in Nerve Root Neurolymphomatosis
Authors: Roland Talanow, Sankaran Shrikanthan
Journal: Clinical Nuclear Medicine (2011)

A 45-year-old man with history of B-cell lymphoma and new back pain underwent PET/CT that showed tracer uptake in multiple lumbosacral nerve roots, concerning for neurolymphomatosis. Histology after lumbar puncture revealed lymphoma involvement in the central nervous system. After cycle 3 of chemotherapy (RICE), restaging PET/CT (2 months after initial PET/CT) showed resolution of all abnormalities including nerve root uptake. Maximum standardized uptake value was 2.4 (equivalent to background level; prechemotherapy max SUV was 7.2; both SUVs were measured after time of flight (TOF) reconstruction). A subsequent cerebrospinal fluid analysis was negative for malignant cells consistent with response to treatment. This case is of particular interest, because we can demonstrate the utility of PET/CT imaging in nerve root neurolymphomatosis and are able to evaluate the therapy response by comparing tracer uptake on pre- with postchemotherapy imaging.
INTRACARDIAC ECHOCARDIOGRAPHY GUIDED TRANSFEMORAL TRANSCATHETER AORTIC VALVE REPLACEMENT WITHOUT ENDOTRACHEAL INTUBATION
Authors: Mamoo Nakamura, Abhijeet Dhoble, Jorge Castellanos, Hasan Jilaihawi, Wen Cheng, Raj Makkar
Journal: Journal of the American College of Cardiology (2015)
Increasing glioma-associated monocytes leads to increased intratumoral and systemic myeloid-derived suppressor cells in a murine model
Authors: Michael Chae, Timothy E. Peterson, Alexis Balgeman, Selby Chen, Lei Zhang, Danielle N. Renner, Aaron J. Johnson, Ian F. Parney
Journal: Neuro-Oncology (2014)

Patients with glioblastoma multiforme (GBM) exhibit marked intratumoral and systemic immunosuppression. GBM is heavily infiltrated with monocytic cells. Monocytes contacting GBM cells develop features of immunosuppressive myeloid-derived suppressor cells (MDSCs), which are elevated in GBM patients. Therefore, we hypothesized that circulating MDSC levels could be raised in vivo by increasing glioma-associated macrophages. GL261-luciferase glioma was implanted intracranially in C57BL/6 mice with or without additional normal syngeneic CD11b+ monocytes. Tumor growth and intratumoral and systemic MDSC (CD11b+/Gr-1+) levels were determined. Green fluorescent protein (GFP)–transgenic monocytes were coinjected intracranially with GL261-luciferase cells. GFP+ cell frequency among splenic and bone marrow MDSCs was determined. Impact of increased MDSC's on spontaneous immune responses to tumor cells expressing a model antigen (ovalbumin [OVA]) was determined. Tumors grew faster and MDSC's were increased in tumor, spleen, and bone marrow in mice receiving GL261-Luc plus monocytes. Many (30%–50%) systemic MDSC's were GFP+ in mice receiving intracranial tumor plus GFP-transgenic monocytes, suggesting that they originated from glioma-associated monocytes. Tumor-infiltrating OVA-specific CD8+ T cells were markedly reduced in mice receiving GL261-OVA and monocytes compared with mice receiving GL261-OVA alone. Increasing glioma-associated macrophages in intracranial GL261 glioma decreases survival and markedly increases intratumoral and systemic MDSC's, many of which originate directly from glioma-associated macrophages. This is associated with decreased spontaneous immune responses to a model antigen. To our knowledge, this is the first evidence in cancer that systemic MDSC's can arise directly from normal monocytes that have undergone intratumoral immunosuppressive education.
How and where does nitric oxide affect cerebellar synaptic plasticity? New methods for investigating its action
Authors: Lynn J. Bindman
Journal: Behavioral and Brain Sciences (1996)

The role of nitric oxide in cerebellar synaptic plasticity is controversial. Two recent papers on nitric oxide-(NO) and synaptic plasticity are discussed which use new methods for investigating the actions of NO and suggest that under certain conditions it is an essential anterograde messenger. In the light of current thinking about the diversity of expression of hippocampal LTP, should a presynaptic contribution to cerebellar LTD be re-examined? If NO acts orthogradely, might its product cGMP have a retrograde action? [CRÉPEL et al.; LINDEN; VINCENT]