tbuckley/cabot-search huggingface dataset:
Activity of highly selective LSD1 inhibitors in HCT-116 xenograft mice.
Authors: T. Maes, J. Castro, A. Ortega, N. Guibourt
Journal: Journal of Clinical Oncology (2010)

e13663 Background: One hallmark of many cancers is aberrant gene expression. The methylation status of histone lysines was recently shown to be important in the dynamic regulation of gene expression. Lysine Specific Demethylase-1 (LSD1) is involved in histone modification (Shi et al. Cell 2004) and can demethylate mono and dimethylated H3K4 and H3K9. LSD1 expression was shown to be up-regulated in prostate, brain and ER negative breast cancers with aggressive biology (Kahl, P. et al. Cancer Res. 2006, Schulte et al., Cancer Res. 2009. Lim et al., Carcinogenesis 2009). LSD1 belongs to the family of FAD-dependent amine oxidases, was shown to be weakly inhibited by inhibitors of monoamine oxidases (MAOs). So far no selective, potent inhibitors of LSD1 have been reported in the literature. Methods: LSD1, MAO-A and MAO-B activities were evaluated. Cytotoxic activity was measured in Alamar blue and hexoaminidase assays. Athymic Nude-Foxn1nu mice were inoculated with 2.5 ×106 HCT-116 cells and treatments were started when average tumor size reached 125 mm3. Tumor growth was assessed during four weeks following the initiation of treatment. Results: Here we report several families of compounds which show high selectivity and inhibit LSD1 in the low nanomolar range. We have identified several lead compounds that show excellent physicochemical properties with good aqueous solubility and possibility of salt formation. They have good in vitro ADME properties, are clean in hERG and in CYP assays and stable in microsomes. They have good PK parameters and show dose and time dependent cytotoxic effects in different cancer cell lines. Cytotoxic activity on HCT-116 cells ranges from 1 to 50 μM. In a HCT-116 xenograft mice model, administration of the LSD1 inhibitors, alone or in combination with other epigenetic drugs, showed clear effects on tumor growth. Conclusions: Selective, potent, and pharmacologically refined LSD1 inhibitors can constitute a powerful approach in the treatment of some cancers, alone or in combination with established drugs. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Oryzon Genomics, S.A. Oryzon Genomics, S.A. Oryzon Genomics, S.A.
Case 31-1976
Authors: Richard C. Cabot, Robert E. Scully, James J. Galdabini, Betty U. McNeely, Edwin P. Maynard, Robert E. Scully
Journal: New England Journal of Medicine (1976)

Presentation of CaseA 42-year-old woman was admitted to the hospital because of abdominal pain.She was well until three weeks previously, when she began to have a constant, sharp pain in the right upper abdominal quadrant that was aggravated by movement or by local pressure and unaffected by food intake or bowel movements. She entered another hospital, where a mass in the right upper abdominal quadrant was found on physical examination. An intravenous pyelographic examination, an oral cholecystographic study, a barium-enema examination and an upper gastrointestinal study were reported to be negative. The pain disappeared spontaneously, and the mass . . .
Monoclonal Origin of Multicentric Kaposi's Sarcoma Lesions
Authors: Charles S. Rabkin, Siegfried Janz, Alex Lash, Allen E. Coleman, Elizabeth Musaba, Lance Liotta, Robert J. Biggar, Zhengping Zhuang
Journal: New England Journal of Medicine (1997)

Kaposi's sarcoma has features of both hyperplastic proliferation and neoplastic growth. Multiple lesions, in which spindle cells are prominent, often arise synchronously over widely dispersed areas. We tested the hypothesis that the spindle cells in these multicentric lesions originate from a single clone of precursor cells.
AB0967 Determinants of Aortic Wall Thickness in Patients without Aortitis: A Computed Tomography-Based Study: Table 1
Authors: A. Nakhleh, D. Rimar, I. Rukhkyan, V. Wolfson, I. Rosner, M. Odeh, G. Slobodin
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Thickening of the aortic wall, probably the earliest computed tomography (CT)-seen sign of aortitis, is frequently missed as there are no accepted criteria for normal aortic wall thickness (AWT). As aortitis can affect patients in a wide range of ages and with different co-morbidities, information on the normal values for AWT for various age groups, as well as for the presence of co-morbid background, may be essential. <h3>Objectives</h3> The present study was conducted to assess the relationship of CT-measured AWT with patient-related and disease-related variables in a large cohort of patients without aortitis. <h3>Methods</h3> CT scans of 250 consecutive patients without known aortitis, hospitalized at Bnai Zion Medical Center were reviewed and AWT manually measured at three levels: 1. thoracic descending aorta at the level of the bifurcation of the pulmonary artery; 2. abdominal aorta at the level of celiac artery origin; 3. abdominal aorta one slice below the level of the origin of renal arteries. Patients9 charts were analyzed and demographic data and data on co-morbidities extracted. Correlations with measured AWT were calculated. <h3>Results</h3> By multivariate regression analysis, AWT had significant positive correlation with patient age (p&lt;0.000), gender (p&lt;0.03) and the presence of calcifications of the aortic wall (p&lt;0.000). Arterial hypertension, hyperlipidemia, coronary artery disease and diabetes mellitus, when present, affected AWT upon univariate analysis only, with correlation lost upon applying multivariate regression. The calculated age-dependent reference values of CT-measured AWT in patients without aortitis are presented in Table 1. <h3>Conclusions</h3> The "normal" range of AWT varies with age, gender and may also vary with co-morbidities. The data presented may serve as a reference and should be considered in the interpretation of the CT-appearance of the aortic wall when assessing for aortitis. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1116
P66 Oxygen, too much of a good thing - Can we save lives using a novel simulation?
Authors: H Whitehouse, E Lombard, H Blakey
Journal: Thorax (2013)

<h3>Introduction</h3> Delivery of high-flow oxygen therapy (OT) to patients experiencing acute exacerbations of COPD can result in respiratory acidosis and hypercapnic respiratory failure, significantly increasing morbidity and mortality rates. <sup>[1] </sup>BTS guidelines recommend that severe AECOPD should be managed with OT delivered at 4L/min using a 28% Venturi mask with target oxygen saturations of 88–92%. Literature suggests these guidelines are poorly adhered to due to long-standing routines and desire to rapidly correct hypoxia.<sup> [1]</sup> <h3>Aim</h3> Develop a model of AECOPD using the Human Patient Simulator (HPS) demonstrating the dangers of high-flow OT and the advantages of titrated OT. This could be used in the education of healthcare professionals promoting awareness of the risks and improving adherence to BTS guidelines ultimately reducing unnecessary morbidity and mortality. <h3>Methods</h3> Creation of the AECOPD model was achieved through parameter manipulation within the HPS software. Target values for P<sub>a</sub>O<sub>2</sub>, P<sub>a</sub>CO<sub>2</sub>, respiratory rate and pH were sourced from average recorded measurements of 405 patients experiencing AECOPD found in the literature. <sup>[1]</sup> On administration of high-flow oxygen additional parameters were altered to model the resultant hypercapnic respiratory failure. <h3>Results</h3> An accurate model of AECOPD was achieved producing values reflective of literature: P<sub>a</sub>O<sub>2</sub> 53 mmHg, P<sub>a</sub>CO<sub>2 </sub>54 mmHg, S<sub>p</sub>O<sub>2</sub> 84% and pH 7.34. Manipulation of additional software parameters on administration of high-flow oxygen demonstrated the rapid onset of hypercapnic respiratory failure, with P<sub>a</sub>CO<sub>2</sub> increasing to 102 mmHg and pH falling to 6.98. In comparison, on 28% oxygen administration P<sub>a</sub>CO<sub>2</sub> rose only to 50.6 mmHg and pH to 7.39, whilst P<sub>a</sub>O<sub>2 </sub>increased to levels seen in stable COPD (61 mmHg). <h3>Conclusion</h3> These findings demonstrate that the HPS can be used to accurately demonstrate the risks of high flow OT in AECOPD. The model created here has the potential to be an excellent educational tool, which could be used to improve adherence to the evidence based guidelines and potentially reduce patient morbidity and mortality in the future. <h3>References</h3> 1. Austin <i>et al. BMJ</i> 2010;341:c5462
Proposed new definition of exercise pulmonary hypertension decreases false-positive cases
Authors: Gabor Kovacs, Alexander Avian, Horst Olschewski
Journal: European Respiratory Journal (2016)

The exercise part of the haemodynamic definition of pulmonary hypertension (PH) was used between the first (1973) [1] and fourth (2008) [2] world conferences on PH for patients with a mean pulmonary arterial pressure (mPAP) >30 mmHg during exercise. However, at the World Symposium on Pulmonary Hypertension in Dana Point in 2008, this part of the PH definition was abandoned, mainly due to the fact that pulmonary arterial pressure (PAP) values during exercise are strongly dependent on age and exercise level [3], and a definition based on a single parameter such as PAP may not be reliable. The analysis of historical studies [3, 4] and the generation of novel data [5–8] have led to a better understanding of exercise haemodynamics. Herve et al . [7] suggest a new definition of exercise-PH that includes not only PAP, but also total pulmonary resistance (TPR), calculated as mPAP/cardiac output, representing the steepness of PAP increase during exercise. According to this definition, exercise-PH may be diagnosed if during maximal exercise mPAP >30 mmHg and TPR >3 Wood units (WU). This may reduce the number of false positive exercise-PH diagnoses in healthy subjects who develop high mPAP values at excessive exercise levels. The proposed novel definition for exercise-PH reduces numbers of false positives and may be an important step forward <http://ow.ly/U2z7n>
Neural reuse: A polysemous and redundant biological system subserving niche-construction
Authors: Atsushi Iriki
Journal: Behavioral and Brain Sciences (2010)

Abstract Novel functions, which emerge by reusing existing resources formerly adapted to other original usages, cannot be anticipated before the need eventually arises. Simple reuse must be accidental. However, to survive the evolutionary race, one cannot merely keep hoping for a string of good fortune. So, successful species might be gifted with “rational” and “purposeful” biological mechanisms to prepare for future reuse. Neural reuse must be extrapolated from such mechanisms.
OP0267 The influence of latent cytomegalovirus (CMV) infection on T-cell-phenotype in children with juvenile idiopathic arthritis (JIA)
Authors: R.D. Trippen, G. Almanzar, K. Sustal, K. Höfner, M. Prelog
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Life-long latent CMVinfection seems to diminish the size of the naive and the early memory T-cell pool and to drive Th1 polarization within the immune system. Previous studies in patients with Juvenile idiopathic arthritis (JIA) have shown that CMV-positive patients did not show an increase of CD28<sup>–</sup> effector T-cells compared to CMV-positive controls <h3>Objectives</h3> The aim of this study was to determine the influence of latent CMV infection on the phenotype and cytokine profile of T-cell populations in children with JIA. <h3>Methods</h3> Peripheral blood mononuclear cells (PBMC) and serum samples were obtained from 16 JIA patients in clinical remission on medication and 18 age-matched healthy donors (HD). Serum CMV-IgG concentration was determined by ELISA. So far, phenotypical characterization of peripheral T-cells was performed in CMV-positive (n=9) and CMV-negative (n=7) patients by flowcytometry. <h3>Results</h3> The proportion of memory T-cells (CD45RA<sup>–</sup>CD28<sup>+</sup>CCR7<sup>+/–</sup>) within the CD4<sup>+</sup> T-cell pool was significantly increased in CMV-positive patients (mean 47.4±16.6%) compared to CMV-negative patients (mean 32.9±7.4%) (p&lt;0.05). In contrast, the proportion of naive T-cells (CD45RA<sup>+</sup>CD28<sup>+</sup>CCR7<sup>+</sup>) (CMV+: 37.3±18%; CMV-: 46.1±10.9%) within the CD4+ T-cell pool, the proportion of effector-memory T-cells (CD45RA<sup>–</sup>CD28-CCR7<sup>+/–</sup>) andterminal differentiated effector T-cells (CD45RA<sup>+</sup>CD28<sup>–</sup>CCR7<sup>+/–</sup>) did not show a significant differences depending on the CMV-status. So far, no difference in the CMVpp65-specific IFN-gamma response could be found between JIA patients in remission and healthy controls. <h3>Conclusions</h3> Our preliminary findings indicate a different T-cell response in CMV-positive JIA patients as found in CMV-positive healthy controls, possibly suggesting a disturbed peripheral T-cell response to latent CMV infection. So far it is unclear, whether these findings are primarily caused by the disease itself or secondarily to treatment and whether CMV may accelerate T-cell differentiation in JIA patients as described for healthy individuals. This may be of relevance for immune reconstitution of the immune system under T-cell-depleting therapies or during aging of JIA patients. <h3>Disclosure of Interest</h3> None Declared
THU0145 Association of Mean Changes in Laboratory Safety Parameters with C-Reactive Protein at Baseline and Week 12 in Rheumatoid Arthritis Patients Treated with Tofacitinib
Authors: V. Strand, J. Isaacs, J. Beal, C. Nduaka, S. Krishnaswami, R. Riese, M. Boy, S. Menon
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Tofacitinib is a novel, oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Changes in laboratory parameters observed during tofacitinib treatment included mean increases in low (LDL) and high (HDL) density lipoproteins, serum creatinine (SCr) and mean decreases in neutrophils (ANC). It was of interest to understand the inter-relationship between drug and disease effects on these parameters [1]. <h3>Objectives</h3> To investigate potential explanatory mechanisms for these changes in laboratory parameters. <h3>Methods</h3> Baseline and Week 12 data from five Phase 3 (P3) nonbiologic or biologic disease-modifying anti-rheumatic drug-inadequate responder trials were pooled for each treatment arm: placebo, tofacitinib 5 mg and 10 mg twice daily (BID), and adalimumab 40 mg every other week (EOW). The defined laboratory parameters were explored with C-reactive protein (CRP) as a marker of inflammation. Mean changes at Week 12 were compared with quartile levels of CRP at baseline and quartiles of change in CRP at Week 12. <h3>Results</h3> Across the defined laboratory parameters, the smallest mean changes from baseline were observed in the quartile of patients with the smallest reductions in CRP (Figure, 1st quartile) and the greatest changes were observed with the greatest reductions in CRP (Figure, 4th quartile). A similar pattern of association was evident with baseline CRP, where the greatest mean changes in laboratory parameters occurred in patients with highest levels of baseline CRP. Numerical differences in the magnitude of changes across the treatment arms were observed, but no statistical comparisons were performed. <h3>Conclusions</h3> A consistent pattern of association between mean changes in each of the laboratory parameters and CRP was observed. The precise mechanism behind these laboratory changes is unknown. Based upon these analyses, the lowering of inflammation, as measured by CRP, may partly explain some of the observed mean changes in laboratory parameters during clinical studies. <h3>References</h3> Genovese MC et al. Arthritis and Rheumatism 2013; 65: S193 <h3>Acknowledgements</h3> Editorial support was provided by AM Reid, PhD, of CMC and funded by Pfizer Inc. <h3>Disclosure of Interest</h3> : V. Strand Consultant for: Pfizer Inc, J. Isaacs Consultant for: Pfizer Inc, J. Beal Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Nduaka Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Krishnaswami Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Riese Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, M. Boy Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Menon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4361
Abstract 2326: Antiangiogenic effects associated with the inhibition of HSP90 in colorectal cancer
Authors: Hemchandra Mahaseth, Ganji Purnachandra Nagaraju, Roberto Diaz, LaTonia D. Taliaferro-Smith, Jerome C. Landry, Nabil F. Saba, Bassel F. El-Rayes
Journal: Cancer Research (2012)

Abstract Purpose/Objectives: Angiogenesis has a central role in tumor growth and metastasis. Inhibition of angiogenesis has been shown to improve outcomes of patients with advanced stage colorectal cancer receiving standard chemotherapy regimens. HSP90 has a central role in the regulation of transcription factors that modulate the expression of angiogenic cytokines. Ganetespib is a small molecule functional inhibitor of HSP90. We tested the hypothesis that HSP90 inhibition by ganetespib can inhibit angiogenesis in colorectal cell lines. Methods: Two colorectal cancer (CRC) cell lines were used, HCT-116 and HT-29. Cells were either untreated (control) or treated with ganetespib at 50 nM for 24 hours. Western blot and RT-PCR analyses were carried out to determine the effect of ganetespib on HIF-1alpha and vascular endothelial growth factor (VEGF) expression. ELISA for VEGF expression was performed on the medium of CRC cells to evaluate the effects of ganetespib on VEGF secretion. Tube formation assays and chicken egg chorioallantoic membrane (Egg CAM) assay were also performed. Results: Western blot analyses demonstrated significant (p&amp;lt;0.001) inhibition of HIF-1alpha and VEGF expression in both cell lines treated with ganetespib. RT-PCR demonstrated significant (p&amp;lt;0.0001) downregulation of VEGF transcription. Similarly, ELISA assay demonstrated significant inhibition of VEGF expression in the culture medium in both CRC cell lines. The HUVEC tube formation and the egg CAM assays further confirmed that treatment of the cell lines with ganetespib inhibited angiogenesis. Conclusions: HSP90 inhibition has significant antiangiogenic effects in preclinical models. Evaluating HSP90 inhibitors in conjugation with chemotherapy in colorectal cancer is a rational approach that could have a significant impact on the outcome of this deadly and common disease. 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 2326. doi:1538-7445.AM2012-2326
AB0149 Activation of indoleamine 2,3-dioxygenase 1 (ido1) in patients with systemic sclerosis
Authors: N. Del Papa, P. Filippini, R. De Cristofaro, D. Sambataro, F. Rovelli, C. Vitali, F. Locatelli, S. Rutella
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> IDO1 degrades tryptophan (TRP) into intermediates with immune-modulating activities and endothelium-relaxing properties, collectively referred to as kynurenines (KYN). A contributory effect of IDO1 to inflammatory autoimmune pathologies, such as rheumatoid arthritis and systemic lupus erythematosus, has been recently described. Systemic sclerosis (SSc) is an autoimmune systemic disease characterized by vascular abnormalities and diffuse fibrosis in skin and internal organs. <h3>Objectives</h3> We aimed to address whether IDO1-driven kynurenine (KYN) production correlates with degree of inflammation and clinical features in SSc patients. <h3>Methods</h3> Peripheral blood was obtained from 70 consecutive adult patients with SSc. Serum KYN and TRP levels were measured with RP-HPLC. Pro-angiogenic hepatocyte growth factor (HGF) and placental growth factor (PlGF) were quantitated with ELISA. <h3>Results</h3> Serum KYN levels were higher in SSc compared with healthy controls (2.55±1.47 μM versus 1.74±0.30 μM; p=0.018) and positively correlated with serum C-reactive protein (r=0.35, p=0.0042) and erythrocyte sedimentation rate (r=0.26, p=0.037), but not with HGF or PlGF levels, complement C3 or C4 levels, presence of skin ulcers, modified Rodnan skin score (MRSS) or disease activity score. Interestingly, KYN levels positively correlated with pulmonary arterial pressure (r=0.38; p=0.017). However, KYN levels were superimposable in patients with normal chest CT findings and in those with clinical and radiographic evidence of alveolitis or lung fibrosis. <h3>Conclusions</h3> The generation of KYN is heightened in SSc patients and it could be related to the activation of counter-regulatory mechanisms of both inflammation (related to the production of pro-inflammatory cytokines) and vasoconstriction. The role played by KYN in promoting autoimmune circuits in SSc remains to be elucidated. <h3>Disclosure of Interest</h3> None Declared
Abstract 4869: p27kip1 is a metastasis-associated antigen that promotes cell migration in osteosarcoma
Authors: Yiting Li, Ricardo Flores, John Hicks, Murali Chintagumpala, Ching Lau, Tsz Kwong Man
Journal: Cancer Research (2011)

Abstract Metastasis is the leading cause of death in osteosarcoma (OS). Despite the advent of cancer therapy, patients with metastasis still have a dismal outcome. Hence, identification and characterization of new cellular targets that are critical to the metastatic process are urgently needed in order to improve both the treatment and detection of metastatic patients. Previous evidence has indicated that cancer patients produce autoantibodies. Many of these tumor-associated autoantibodies target cellular proteins that are essential for tumor formation. In this study, we used a high-density Human Protein Array (HPA) that contains over 8,000 purified proteins, to identify tumor-associated antigens that are associated with metastatic OS at the time of diagnosis. Plasma samples from patients with metastatic (n=10) or localized (n=16) OS, as well as hospitalized children with non-cancerous diseases (n=21) were pooled separately and analyzed using HPA. Totally, 16 autoantibodies were found to be reactive in metastatic OS. Of those, 6 of them showed higher prevalence in the metastatic cases relative to the localized cases and the control cases (p&amp;lt;0.01). One of these autoantibodies targets a cell cycle inhibitor protein, p27kip1, which is involved in tumor suppression and invasion. The higher prevalence of p27kip1 autoantibody in metastatic OS was subsequently validated using a novel HaloLink assay and individual plasma samples. To test if p27kip1 plays a role in metastatic OS, immunohistochemistry was performed on three pairs of metastatic OS cell lines and their parental, non-metastatic cell lines. We found that the p27kip1 protein, which is normally localized in the nucleus, was mislocalized in the cytoplasm in all three metastatic OS cell lines. Functional studies demonstrated that the wild type or CDK- mutant of p27kip1 harboring a nuclear export signal significantly induced OS cell migration in vitro. In summary, our results indicate that mislocalization of p27kip1 can promote metastatic potential of OS. Further characterization of p27kip1 and its related pathways may lead to the development of a novel therapeutic strategy for treating metastatic OS and other sarcomas. 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 4869. doi:10.1158/1538-7445.AM2011-4869