tbuckley/cabot-search huggingface dataset:
Abstract 4885: mTOR complex 2 is involved in regulation of c-FLIP stability and sensitization of TRAIL-induced apoptosis
Authors: Liqun Zhao, Ping Yue, Fadlo R. Khuri, Shi-Yong Sun
Journal: Cancer Research (2012)

Abstract The mammalian target of rapamycin (mTOR), a serine-threonine kinase related tightly to the phosphoinositide 3-kinase family, acts as a central molecule in regulation of cell proliferation and survival through forming two complexes primarily with raptor (mTOR complex 1; mTORC1) or rictor (mTOR complex 2; mTORC2). Compared with the mTORC1, relatively little is known about the biological functions of mTORC2. However, it is clear that both of the mTOR signaling pathways are dysregulated in human cancers, including lung cancer. Accordingly, novel ATP-competitive mTOR kinase inhibitors such as PP242 that inhibit both mTORC1 and mTORC2 have been developed for cancer therapy. In this study, we focus on addressing whether mTORC2 regulates apoptosis, particularly induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a potential cancer therapeutic protein tested in clinical trials. We found that PP242 synergized with TRAIL to augment apoptosis in human lung cancer cells. PP242 reduced the level of the short form of c-FLIP (FLIPS) and survivin with minimal effects on the expression of DR4 and DR5. Enforced expression of FLIPS, but not survivin, attenuated PP242/TRAIL-induced apoptosis; this suggests that FLIPS downregulation contributes to synergistic induction of apoptosis by the PP242 and TRAIL combination. Mechanistic studies revealed that PP242 decreased FLIPS stability, increased FLIPS ubiqutination and facilitated FLIPS degradation, suggesting that PP242 decreases FLIPS levels through promoting its degradation via an ubiqutination and proteasome-dependent mechanism. Interestingly, knockdown of rictor, but not raptor, mimicked PP242 in decreasing FLIPS levels and sensitizing cells to TRAIL. Moreover, rictor knockdown decreased the stability of FLIPS. These data together suggest that it is mTORC2 inhibition that mediates FLIPS downregulation and subsequent sensitization of TRAIL-induced apoptosis. Our findings hence provide the first evidence showing that mTORC2 positively regulates FLIPS expression, thereby, connecting mTORC2 signaling to regulation of the death receptor-mediated apoptosis pathway. (This study was supported by the Georgia Cancer Coalition Distinguished Cancer Scholar award and NIH/NCI R01 CA118450. FR Khuri and SY Sun are Georgia Cancer Coalition Distinguished Cancer Scholars) 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 4885. doi:1538-7445.AM2012-4885
AB0874 Outcomes of Fluoroscopic Sacroiliac Joint Injections (Patients Views)
Authors: R. Al-Rubae, C. Chattopadhyay
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> The sacroiliac joint has been shown to be a source of pain in 10% to 27% of suspected cases with chronic low back pain utilizing controlled comparative local anesthetic blocks. Sacroiliac joint steroid injection is a well-known treatment option, yet it is not that widely used. We are trying to show its benefits from patients9 perspective and emphasize its importance as a treatment option. <h3>Methods</h3> We audited one hundred patients who had Sacroiliac joint injections under X-RAY guidance between 2007 and 2012 in Wrightington hospital by sending patient questionnaire with reply envelope. We have received thirty-nine replies. <h3>Results</h3> Results showed that 26 out of 39 patients (66.6%) found the injection very useful. Among those 26 patients (12.8%) reported that the pain completely resolved while (46.1%) reported more than 50% of pain improvement post injection,(10.2%) reported 25% of improvement while (15.3%) reported no improvement and 6 patients didn9t comment. Among the 39 patients audited 32.5% reported pain improvement lasted for more than 6 months and 41% experienced pain improvement between 1-3 months, only one patient reported no improvement and the rest didn9t comment. Finally 23 out of 39 patients (58.9%) reported reduction in long-term usage of painkillers after having the injection. <h3>Conclusions</h3> The study shows encouraging results that the fluoroscopic sacroiliac injection should be considered more often and be available to a wider range of patients. It is hoped that this procedure will be considered as an adjunct management of back pain. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1243
Case 8-2004
Authors: William R. Brugge, Peter R. Mueller, Joseph Misdraji
Journal: New England Journal of Medicine (2004)

A 28-year-old Moroccan man was admitted to the hospital because of a 10-day history of epigastric pain and a 2-day history of right-upper-quadrant pain and fever. On examination, there was right-upper-quadrant tenderness with guarding and rebound. Imaging studies disclosed a complex, cystic mass in or adjacent to the neck of the pancreas.
Hematologic Toxicity after the Use of Desacetylmethylcolchicine in the Treatment of Gouty Arthritis
Authors: Israeli A. Jaffe, George A. Hyman
Journal: New England Journal of Medicine (1957)

DESACETYLMETHYLCOLCHICINE (Colcemide) is a natural alkaloid which differs from colchicine in that a methyl group replaces an acetyl group at the N position.1 It is a potent antimitotic agent, and over 30 papers have appeared in the foreign literature between 1953 and 1956 reporting its use in the treatment of chronic myelogenous leukemia.2 3 4 5 6 Recent reports have indicated that because of the rarity of gastrointestinal toxicity, it might be a more useful agent than colchicine and indeed might even replace it in the management of acute gouty arthritis.7 8 9 The case reported below illustrates an unusual and profound toxicity to the hematopoietic . . .
A4.9 Effect of different doses of Rituximab on the progression of bone destruction in rheumatoid arthritis (RA)
Authors: AV Pivanova, GV Lukina, YA Sigidin, AV Smirnov, KH Kuzikyants, AY Kuznetsova, EL Nasonov
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Objective</h3> Comparison of clinical and antidestructive effect of different Rituximab (RTX) doses. <h3>Methods</h3> Clinical and radiological study of 60 patients (pts) with RA (mean disease duration 9+7.3 years, mean DAS28 6.4+0.95, RF-positive 89%, ACCP-positive 92%) treated with different RTX doses (1000 mg x2 or 500 mg x2). Clinical effect was assessed by EULAR criteria; radiological progression by SVH method. <h3>Results</h3> Pronounced therapeutic effect of RTX was noted. By the 24-th week after the first course good results were registered in 23.5%; good and satisfactory results in 82.9%. After the 2-nd course of treatment the corresponding figures were 29.7% and 85.3%. Antidestructive effect of RTX was also significant. After 48 weeks of treatment progression of articular destruction was absent in all pts in clinical remission, in 83% of pts with low disease activity, and in 43% of pts with moderate activity. Noteworthy, clinical and antidestructive effects often did not coincide. Thus RTX treatment slowed joint damage in 54% of pts without clinical improvement. There were no significant correlations between clinical outcomes and doses of RTX (after both the 1-st and the 2-nd courses). The inhibition of radiological progression was more pronounced in pts treated with higher doses of RTX. <h3>Conclusion</h3> The therapeutic effect of different doses of RTX (1000 mg x2 or 500 mg x2) was practically the same but the antidestructive effect of higher doses was significantly greater. Clinical and antidestructive results did not always coincide which suggests different mechanisms of clinical and antidestructive effects of anti-B-cell therapy.
AB0061 Reconstituted hdl ameliorates nod1 ligand induced kawasaki arteritis in mice
Authors: H. Kono, T. Yanagida, K. Asako, H. Kikuchi, Y. Kimura
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Atherosclerosis is a chronic metabolic disease of inflammatory processes. Immune cells including monocytes are recruited to the subintimal lesion of the vascular wall and store lipids to transform themselves to the foam cells. The cholesterol crystal formed inside of the foam cells stimulates NLRP3 inflammaosme to secrete IL-1 and further inflammation. The lipid profiles in the serum are shown to be risk factors for developing atherosclerosis, such as high LDL (low density lipoprotein) or low HDL (high density lipoprotein) concentration. In addition to deliver cholesterol from vascular wall to liver, HDL is supposed to exert antiinflammatory properties which are not well characterized. <h3>Objectives</h3> To investigate the antiinflammatory function of reconstituted HDL (rHDL) in the Kawasaki arteritis murine model in vivo. <h3>Methods</h3> Coronary arteritis mimicking Kawasaki disease was induced by administrating 20 microgram of lipopolysaccharide followed by weekly injection of 500 microgram of the nucleotide-binding oligomerization domain 1 (NOD1) ligand FK-565 for 4 times. 2 mg of rHDL or control PBS was injected 4 times along with FK-565 administration. After a week of the last injection of FK-565 or control PBS, the severity of coronary arteritis was quantified by measuring the inflammation area surrounding the coronary arteries. <h3>Results</h3> The rHDL treatment reduced the inflammatory area of coronary arteries compared with the control PBS treated groups, showing statistically significance (P&lt;0.05 with Student <i>t-</i>test, 0.31±0.29 mm<sup>2</sup> (PBS control group) and 0.14±0.08 mm<sup>2</sup> (rHDL group)). <h3>Conclusions</h3> The data indicate that rHDL exerts an antiinflammatory activity in the NOD1 ligand induced Kawasaki arteritis model in vivo. <h3>References</h3> Nishio H et al. Arterioscler Thromb Vasc Biol. 2011, 31: 1093-9 Duewell P, Kono H, et al. Nature 2010, 464: 1357-61. <h3>Disclosure of Interest</h3> None Declared
Massive Pulmonary Embolism Without Symptoms Demonstrated By Radionuclide Imaging With Thromboemboli in Both Main Pulmonary Arteries
Authors: WEI-JEN SHIH, CALIXTO PULMANO
Journal: Clinical Nuclear Medicine (1996)

Massive pulmonary embolism is defined as an anatomic obstruction of 50% or more of the pulmonary artery. A reduction of at least 50% of the cross-sectional area of the pulmonary artery causes significant hemodynamic instability and marked hypoxia exhibiting syncope, apprehension, hypotension, diaphoresis, chest pain, altered mental status, and shortness of breath. A patient, who had no definite clinical signs and symptoms, was demonstrated to have massive pulmonary embolism by extensive mismatched ventilation-perfusion defects scintigraphically and confirmed as thromboemboli in the main pulmonary arteries on a standard CT of the thorax. The lack of clinical manifestations of massive pulmonary embolism might be related to the insidious onset and progressive formation of thromboembolism. The patient gradually adapted to and/or compensated for hemodynamic changes.
SAT0066 NF-κB signaling in rheumatoid arthritis drives inflammation and joint destruction in part through inactivation of forkhead box class O transcription factors
Authors: L.M. Hartkamp, A.M. Grabiec, J. Ludikhuize, I.E. van Es, P.P. Tak, K.A. Reedquist
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Rheumatoid arthritis (RA) stromal fibroblast-like synoviocytes (FLS) are key effector cells in the pathology of RA, and share many phenotypic characteristics with transformed cancer cells. In many cancer models, inflammatory NF-κB signaling promotes transformation via inactivation of forkhead box class O (FoxO) transcription factors, classically regulated by phosphatidylinositol 3-kinase (PI3-K). <h3>Objectives</h3> As both NF-κB and PI3-K pathways are activated in RA synovial tissue, we examined potential functional interactions between these pathways. <h3>Methods</h3> Expression and/or phosphorylation of IKKβ, IκBα, PTEN, a negative regulator of PI3-K, protein kinase B (PKB) and FoxO1, downstream targets of PI3-K, was detected by immunohistochemistry combined with digital image analysis in synovial tissue from 15 disease-modifying antirheumatic drug (DMARD)-naive RA patients. Biopsies were obtained at baseline, and x-rays made of hands and feet at baseline and at 2 years follow-up. At 2 years, patients were classified as having non-erosive or erosive disease (Sharp van der Heijde score &gt;2). Effects of PI3-K isoform specific inhibitors on RA FLS IL-1β- induced IκBα phosphorylation and NF-κB p65 activation were assessed by immunoblotting and ELISA, respectively. Furthermore, effects of NF-κB inhibition on LPS induced FoxO nuclear export was assessed by immunoblotting. RA FLS were transduced with adenovirus encoding control GFP or constitutively active FoxO1ADA to examine the effects on RA FLS NF-κB dependent gene sets using low density qPCR arrays. <h3>Results</h3> In vivo we observed a strong correlation between expression of IKKβ and phosphorylation of its target IκBα (R=0.70, p&lt;0.01). Similarly, activation of PKB correlated with phosphorylation of FoxO1 (R=0.66, p&lt;0.01). Reciprocal positive correlations were also observed between activation of NF-κB and PI3-K pathways. In vitro, pan-PI3-K inhibitor LY294002 and inhibitors specific for α/β, γ and δ isoforms of PI3-K failed to influence IL-1β and LPS-induced activation of NF-κB transcriptional activity and cytokine production. However, inhibitors of IKKβ significantly reduced nuclear exclusion of FoxO proteins in FLS and macrophages, and increased FoxO DNA-binding activity. qPCR array analysis of NF-κB-dependent gene sets induced by IL-1β in RA FLS identified several genes, including CCL2, ICAM1 and BCL2A1, which were suppressed by introduction of constitutively active FoxO1. <h3>Conclusions</h3> Our data suggest that NF-κB signaling drives inflammation and joint destruction in RA at least in part via inactivation of FoxO transcription factors. <h3>Disclosure of Interest</h3> None Declared
P16.15 * DEVELOPING ROLE OF ADVANCED MRI TECHNIQUES FOR DIAGNOSIS OF HIGH-GRADE GLIOMA RELAPSE AFTER COMPLEX ONCOLOGY TREATMENT
Authors: R. Jancalek, M. Bulik, T. Kazda, P. Pospisil, P. Slampa, M. Smrcka
Journal: Neuro-Oncology (2014)

PURPOSE/OBJECTIVES: High-grade gliomas (HGG) are the most common primary brain tumors of adults. Despite a multidisciplinary approach, HGGs frequently recur as a new gadolinium-enhanced MRI lesion at or near the site of the original tumor; thus, at the site of high-dose target volume for radiotherapy. An early differentiation between HGG relapse and changes in connection with oncology treatment (pseudoprogression or radionecrosis) is still problematic by commonly used diagnostic imaging techniques. The goal of our project is to verify whether a combination of diffusion-weighted MR imaging (DWI) and proton magnetic resonance spectroscopy (MRS) increase specificity of the conventional structural MRI with gadolinium for early non-invasive differentiation between of HGG relapse and pseudoprogression or radionecrosis. MATERIALS/METHODS: Patients (n= 26) with HGG and structural progression on MRI after neurosurgical resection and radiotherapy with concurrent administration of temozolomide underwent DWI expressed as ADC map and MRS focused on concentration of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), lactate (Lac), and lipids (Lip). An etiology of the lesion was then established by a finding on a subsequent MRI or by a biopsy and correlated with results of the investigated MR techniques. RESULTS: Compared to the pseudoprogression or radionecrosis, the relapse of HGG was characterized by significantly lower ADC values, lower NAA concentration, appearance of Lac+Lip spectra, as well as by non-significant increase in Cho. We found very high sensitivity and specificity of ADC median value (≤1220 × 10−6 mm2/sec) and Cho/NAA ratio (≥1.7) to designate the MRI lesion with gadolinium uptake as the HGG relapse. CONCLUSION: It can be concluded that DWI (ADC value) and MRS (mainly Cho/NAA ratio) have the ability for early non-invasive differentiation of the HGG relapse from the pseudoprogression or radionecrosis after the oncology treatment. The project is supported by grants IGA MZC R NT/14120 and NT/14600 and the European Regional Development Fund Project FNUSA-IC RC (No. CZ.1.05/1.1.00/02.0123).
Progressive Systemic Sclerosis (Scleroderma)
Authors: Paul M. Beigelman, Fred Goldner, Theodore B. Bayles
Journal: New England Journal of Medicine (1953)

THE skin manifestations of scleroderma have long been recognized and adequately described. These features are usually identified readily, particularly in the later phases of the disease when the spectacular, hardened, bound-down, wrinkleless appearance of the skin is so characteristic as to supply a descriptive name for the illness. This term refers to the most apparent manifestation of scleroderma and may, in part, explain the lack of emphasis on involvement of other body systems in the course of the disease.As early as 1897, Hektoen1 indicated that the disease was not limited to the skin. In a single case, he reported . . .
Abstract 4844: A novel mechanism of immune escape in cancer and its regulation by nitric oxide
Authors: Ivraym B. Barsoum, Thomas K. Hamilton, Ellen Miles, Robert Siemens, Charles H. Graham
Journal: Cancer Research (2012)

Abstract One key to malignant progression is the acquired ability of tumor cells to escape immune-mediated lysis. Whereas tumor hypoxia is known to play a causal role in cancer metastasis and resistance to therapy, the link between hypoxia and immune escape in cancer remains poorly understood. Previously, we showed that hypoxia induces resistance to natural killer (NK) cell-mediated lysis in tumour cells through a mechanism that involves the shedding of the NK cell-activating ligand, MHC Class I Chain Related molecule A (MICA), from the cell surface. Additionally, we reported that activation of NO signalling in the tumour cells was able to block this hypoxia-induced shedding of MICA, as well as resistance to NK-mediated lysis. Here, we show that hypoxia-induced tumor resistance to lysis is mediated by a HIF-1-dependent increased expression of the metalloproteinase ADAM10, which is required for the hypoxia-induced shedding of MICA. Our findings demonstrate that HIF-1α knock down attenuated the hypoxia-induced expression of ADAM10 and MICA in tumour cells. Also, siRNA-mediated knockdown of HIF-1α or ADAM10 prevented the hypoxia-induced resistance of DU145 cells to innate immune effector cell-mediated lysis. Treatment with nitric oxide mimetic agents interfered with the hypoxia-induced accumulation of HIF-1α, and with the hypoxia-induced up-regulation of ADAM10 expression required for decreased surface MICA expression and resistance to lysis. To validate the in vitro results, we adopted a model in which human DU145 cells were injected subcutaneously into Swiss nude mice (T and B cell-deficient). Continuous transdermal delivery of nitroglycerine (1.8 µg/h for up to 62 days) significantly attenuated attenuated the tumor growth (P &amp;lt; 0.05). This tumor growth-inhibitory effect of nitroglycerine was absent in mice depleted of innate immune effector cells. Within the tumours, areas of hypoxia co-localized with the metalloproteinase ADAM10 expression. Our results demonstrate a novel mechanism by which hypoxia contributes to immune escape in tumor cells and provide evidence that activation of nitric oxide signalling interferes with this mechanism. The findings described here are important because they indicate that nitric oxide mimetics could potentially be used as immunosensitizers in the treatment and/or prevention of cancer. 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 4844. doi:1538-7445.AM2012-4844
A10.10 Pain -the main index of treatment effectiveness in early rheumatoid arthritis (RA) patients: Comparative efficacy of four treatment regimens
Authors: E Fedorenko
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Pain is one of the major complaints of patients (pts) suffering from RA and the most common motivation for seeking medical help. The most robust quantitative pain measure appears to be a simple 10 cm visual analogue scale (VAS), which can be completed by the patient and scored by a physician very quickly. <h3>Objectives</h3> To compare the dynamics of pain in 4 different treatment regimens in early (&lt;2 years duration) RA: methotrexate (MTX), leflunomide (LEF) and combinations of MTX with glucocorticoids (GC). <h3>Methods</h3> One hundred forty-one pts with early RA (122 women, mean age 51 years, mean disease duration 24 weeks, mean DAS28 5,9; 64% RF-positive, 59% ACCP-positive) were randomised to receive one of the following treatment regimens: methotrexate (MTX, up to 20 mg/week, 35 pts); MTX plus prednisolone (P) 10 mg daily (MTX-P,&nbsp;34 pts); MTX-P plus methylprednisolone (MP) 1000 mg intravenously on the first day of treatment (MTX-P-MP, 35 pts); leflunomide 20 mg daily (LEF, 37 pts). Duration of the therapy was one year. Pain was assessed by VAS at the day 0 and after the completion of one-year treatment. <h3>Results</h3> At baseline all groups were comparable in their demographic, clinical and radiographic characteristics, including pain scores. At the end of the treatment the pain scores of pts were decreased in all groupssignificantly (p &lt; 0.05). In the MTX group pain score was reduced by 49%, in MTX-P group by 52.4%, in MTX-P-MP group by 60.1% and LEF group by 62.8%. <h3>Conclusion</h3> In pts with early RA treated by all 4 regimens pain score was decreased significantly. The most pronounced analgesic effect was noted in MTX-P-MP and LEF groups.
Modeling ALS with motor neurons derived from human induced pluripotent stem cells
Authors: Samuel Sances, Lucie I Bruijn, Siddharthan Chandran, Kevin Eggan, Ritchie Ho, Joseph R Klim, Matt R Livesey, Emily Lowry, Jeffrey D Macklis, David Rushton, Cameron Sadegh, Dhruv Sareen, Hynek Wichterle, Su-Chun Zhang, Clive N Svendsen
Journal: Nature Neuroscience (2016)