tbuckley/cabot-search huggingface dataset:
AB0172 The relationship between the different types of cell death in systemic connective tissue diseases
Authors: V. Shishkin, G.V. Kudriavtseva, Y.A. Malenkov, V.V. Shishkin
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> To study the basic mechanism of cell death (autophagy, apoptosis and necrosis) typical of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic scleroderma (SSD). During systemic connective tissue diseases and especially in SLE, a close relationship between various types of cellular death is observed. <h3>Methods</h3> 7 SLE-, 10 RA-, 10 SSD patients' and 5 donors' sera were studied. The level of Ca ions was registered by the method of <b>atomic absorption spectrometry.</b> Adenosine monophosphate-activated protein kinase (AMPK) was estimated by the Western blotting method. The activity of ATP-ase was measured spectrophotometrically. In order to find out the level of p53 protein, the immune-enzyme "Human p53 Platinum ELISA" method was employed. The quantity of hemoprotein (Cyt c) and the level of 8-hydroxy-2'-deoxyguanosine (8-OH-dG) was measured by employing the immune-enzyme method. <h3>Results</h3> Assessing the functional activity of AMPK is an specific marker and a strategic biopower regulator of autophagy, as well as a specific indicator of red-ox cellular potential. In systemic connective tissue diseases, the oxidative stress is matched by urinary calcium and a decrease in the level of calcium in the blood. It reflects the level of seriousness of osteoporosis especially in case of RA. Molecular chaperones (HSP) play a key role in the changing of the way of cellular death. The family of chaperones HSP60 – HSP 100 shows ATPase activity which is most distinct during SLE and RA. The de-energisation of cells during systemic connective tissue diseases and the disappearing of the link between respiration and oxidative phosphorylation lead to proapoptotic protein – Cyt c is being released from mitochondria. High levels of Cyt c reflect cellular mitochondrial apoptosis and show the growing of hypoxia in SLE and RA. The level of protein p53 – a biological marker of apoptosis – is expressed when the DNA is destroyed. It reflects a higher level of the oxidative damage done to the DNA and the extent of the oxidative stress in SLE. This is also evidenced by the data collected by finding out the level of 8-OH-dG which is a biological marker of the free-radical damage of the DNA. Comparison of markers of autophagy, apoptosis and necrosis in sera in SLE, RA and SSD: AMPK activity (units·mg of protein), the total level of ATP-ase active of HSP-60 – HSP-100 (nmol Pi/min·mg protein), (mM/l), quantity of (ng/ml): Cyt c, p53-protein, 8-OH-dG <h3>Conclusions</h3> Chaperone-mediated induction of the immune response by autophagy, an evolutionary enshrined only in mammals, perhaps, is the central link in the pathogenesis of systemic connective tissue diseases. <h3>Reference</h3> [1] Shishkin VI, et al. Ann Rheum Dis2017;76:6–507. <h3>Disclosure of Interest</h3> None declared
AB1318 Practical aspects of biological-drug monitoring in rheumatoid arthritis and spondyloarthritis
Authors: J. Rosas-Gómez de Salazar, M. Martín-López, T. Oton, L. Carmona, A. Balsa, J. Calvo-Alén, R. Sanmarti, J. Tornero
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> To prepare recommendations on practical aspects of biological-drug monitoring that may be useful for rheumatologist <h3>Methods</h3> A systematic review of the literature was carried out to determine in which patients and in what clinical circumstances may be most beneficial to monitor the levels of biological drugs and their antibodies in patients suffering Rheumatoid Arthritis (RA) and/or Spondyloarthritis (SpA). With the results of the review, a group of experts produced a series of clinical questions, to be answered through the available scientific evidence, and then, subsequently, to make the recommendations and clinical algorithms for instructing the decision-making process. <h3>Results</h3> Results from the systematic review showed that the biological-drug monitoring might be especially useful in two clinical situations; in case of a treatment failure (primary or secondary) and in sustained remission (see figure 1). It was also reviewed which laboratory technique might be better and the optimal time for blood withdrawal. Specific recommendations are given on the interpretation of drug levels and on factors that should be taken into account are given (i.e. body mass index and concomitant medication). <h3>Conclusions</h3> Informed algorithms have been developed regarding the optimal time for requesting drug levels and anti- drug antibodies in patients with RA and SpA. This recommendations may help in the decision-making process and could be useful as part of future guidelines in the field. <h3>Acknowledgements</h3> This study was funded by Grifols through the Asociación para la Investigación en Reumatología de la Marina Baixa (AIRE-MB). The content is solely the responsibility of the authors and does not necessarily represent the official views of Grifols. <h3>Disclosure of Interest</h3> None declared
A novel small-molecule HIF-1 inhibitor that increases HIF-1 alpha degradation
Authors: Mark Creighton-Gutteridge, Annamaria Rapisarda, Badarch Uranchimeg, John H. Cardellina, William A. Denny, Robert H. Shoemaker, Giovanni Melillo
Journal: Cancer Research (2005)

6154  The hypoxia-inducible factor (HIF) is a transcription factor that regulates a variety of genes enabling cells to adapt to a low-oxygen environment. In recent years HIFs have become a very attractive target for cancer therapy, since HIF-1 activates the transcription of genes that are involved in critical aspects of cancer biology, including but not limited to angiogenesis, cell survival, glucose metabolism, invasion and metastasis. A cell-based high-throughput screen of the National Cancer Institute library of synthetic compounds sought to uncover inhibitors of the aforementioned pathway by utilizing a genetically engineered U251 human glioma cell line to stably express a recombinant vector in which the luciferase reporter gene is under the control of three copies of a canonical hypoxia-responsive element (U251-HRE) (Rapisarda et al Cancer Res. 2002). This screen yielded many novel and distinct small-molecule inhibitors of HIF-1 transactivation, one such small molecule inhibitor was a tricyclic carboxamide: NSC 644221. In addition to inhibiting HRE-luciferase activity, a subsequent decrease in vascular endothelial growth factor (VEGF) and glucose transporter-3 (GLUT-3) mRNA expression was also observed in U251 cells. Further studies using an effective and non-cytotoxic dose of NSC 644221, between 1-5 microM, demonstrated that NSC 644221 had the capacity to accelerate the degradation of HIF-1 alpha when cells were exposed to hypoxia. Analysis of protein half-life, using cyclohexamide, demonstrated that the half-life of HIF-1 alpha was decreased in the presence of NSC 644221. However, this inhibition was not observed in the presence of the proteosome inhibitors MG132, ALLNL and PS-341. NSC 644221 appears to be a specific and potent inhibitor of HIF-1 alpha in several different cancer cell lines and has no effect on the expression of a variety of other short-lived proteins. Interestingly, the mode of action of NSC 644221 was found to be independent of the Von-Hippel Lindau (VHL) tumor suppressor protein, which is used by cells for the endogenous degradation of HIF-1 alpha in the presence of oxygen. The inhibition of HIF-1 alpha expression by NSC644221 was not mediated by heat-shock protein-90 (HSP90), AKT or histone deacetylation. Unlike other previously described non-selective HIF-1 inhibitors, NSC 644221 is a compound that targets the cellular degradative pathway of HIF-1 alpha in what appears to be a novel and selective manner. This compound has potential both as a useful analytical tool and as a potential anticancer therapy. Contract No. NO1-CO-12400
Genetics and Epigenetics of Gastroenteropancreatic Neuroendocrine Neoplasms
Authors: Andrea Mafficini, Aldo Scarpa
Journal: Endocrine Reviews (2019)

Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are heterogeneous regarding site of origin, biological behavior, and malignant potential. There has been a rapid increase in data publication during the last 10 years, mainly driven by high-throughput studies on pancreatic and small intestinal neuroendocrine tumors (NETs). This review summarizes the present knowledge on genetic and epigenetic alterations. We integrated the available information from each compartment to give a pathway-based overview. This provided a summary of the critical alterations sustaining neoplastic cells. It also highlighted similarities and differences across anatomical locations and points that need further investigation. GEP-NENs include well-differentiated NETs and poorly differentiated neuroendocrine carcinomas (NECs). NENs are graded as G1, G2, or G3 based on mitotic count and/or Ki-67 labeling index, NECs are G3 by definition. The distinction between NETs and NECs is also linked to their genetic background, as TP53 and RB1 inactivation in NECs set them apart from NETs. A large number of genetic and epigenetic alterations have been reported. Recurrent changes have been traced back to a reduced number of core pathways, including DNA damage repair, cell cycle regulation, and phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling. In pancreatic tumors, chromatin remodeling/histone methylation and telomere alteration are also affected. However, also owing to the paucity of disease models, further research is necessary to fully integrate and functionalize data on deregulated pathways to recapitulate the large heterogeneity of behaviors displayed by these tumors. This is expected to impact diagnostics, prognostic stratification, and planning of personalized therapy.
AB0177 Toll-like receptor 7(TLR7) is upregulated on peripheral b cells and associated with disease activity and damage in primary sjogren syndrome
Authors: Y. Xue, T. Wang, X. Song, M. Li, X. Zeng
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> Primary Sjogren Syndrom(pSS) is characterised by activitition of B cells, increased production of RNA-associated antibodies and elevated proportion of transitonal B cell. Toll-like receptors 7(TLR7) have been reported promoting the effects above in some murine models of SS. We took up this study to identify if TLR7 expression is associated with disease activity and the role of TLR7 in pSS. <h3>Methods</h3> 21 pSS patients and 12 healthy controls(HCs) were selected. The mRNA expression of TLR7 was determined by real-time PCR on peripheral B cells of both pSS patients and HCs. We measured BAFF serum concentrations by ELISA, and the BAFF-R, TACI and BCMA expression was analysed on each B cell subset (CD27<sup>-</sup>CD24<sup>hi</sup>CD38<sup>hi</sup>/transitional B cell; CD27<sup>-</sup>CD24<sup>lo</sup>CD38<sup>lo</sup>/naive B cell;) by flow cytometry. The results were compared among patients with diversed degree of disease activity and damage to HCs. <h3>Results</h3> The expression level of TLR7 mRNA were elevated in pSS patients compared with HCs(p=0.004), and correlated with the SSDAI (SS disease activity index) (r=0.803; p=0.009) and the SSDI(SS damage index)(r=0.881;p=0.002). Serum BAFF concentrations increased in pSS patients compared with HCs(p=0.041), but not corrleted with TLR7 expression. TACI expression in pSS patients in total B cells and traditional B cells compared to HCs were elevated and are both associated with TLR7 expression (r=0.763,p=0.048,r=0.820,p=0.004, respectively). A lower BAFFR expression was seen in transitional B cell compared with HCs(p=0.018). BCMA expression was of no significance. <h3>Conclusions</h3> Increased TLR7 expression on peripheral B cells were associated with disease activity and damage, suggesting that TLR7 may play a role in the development in pSS. Increased serum BAFF concentrition and TACI expression were associated with TLR7 expression, indicating that BAFF may regulate TLR7 expression through TACI according to previous studies.TLR7 may be a potential treatment target of pSS and worth of further study. <h3>Disclosure of Interest</h3> None declared
A Clinical, Genomic and Proteomic Approach for the Characterization of Fanconi Anemia in Adolescent and Young Adult (AYA) Patients : A Single Center Study of 55 Patients from a National Bone Marrow Failure Referral Center
Authors: Taimoor Hussain, Ayodele Alaiya, Majed Dasouki, Hazzaa Alzahrani, Afnan Al-Sabbagh, Raghad Al Ammari, Emad Ghabashi, Abdullah Faruk Demirkaya, Moheeb Alawwami, Naeem A. Chaudhri, Fahad Z. Alsharif, Walid Rasheed, Amr Suleiman Hanbali, Marwan Shaheen, Feras Al Fraih, Riad Elfakih, Shahrukh Hashmi, Saud Alhayli, Shad Ahmed, Abdul Mannan, Mostafa Saleh, Ahmed Abdrabou, Husam Alsaadi, Ahmed Bin Salman, Haroon Alfadhil, Mona Hassanein, Ahmed Al Sagheir, Tom Morris, Ahmad Alhuraiji, Almohareb Fahad, Mahmoud Aljurf, Syed Osman Ahmed
Journal: Blood (2018)
IL-17F, rather than IL-17A, underlies airway inflammation in a steroid-insensitive toluene diisocyanate-induced asthma model
Authors: Rongchang Chen, Qingling Zhang, Shuyu Chen, Haixiong Tang, Peikai Huang, Shushan Wei, Zhenyu Liang, Xin Chen, Ailin Tao, Lihong Yao
Journal: European Respiratory Journal (2019)

Steroid insensitivity constitutes a major problem for asthma management. Toluene diisocyanate (TDI) is one of the leading allergens of asthma that induces both T-helper Th2 and Th17 responses, and is often associated with poor responsiveness to steroid treatment in the clinic. We sought to evaluate the effects of inhaled and systemic steroids on a TDI-induced asthma model and to find how interleukin (IL)-17A and IL-17F function in this model. BALB/c mice were exposed to TDI for generating an asthma model and were treated with inhaled fluticasone propionate, systemic prednisone, anti-IL-17A, anti-IL-17F, recombinant IL-17A or IL-17F. Both fluticasone propionate and prednisone showed no effects on TDI-induced airway hyperresponsiveness (AHR), bronchial neutrophilia and eosinophilia, and epithelial goblet cell metaplasia. TDI-induced Th2 and Th17 signatures were not suppressed by fluticasone propionate or prednisone. Treatment with anti-IL-17A after TDI exposure led to increased AHR, aggravated mucus production and airway eosinophil recruitment, accompanied by amplified Th2 responses, whereas anti-IL-17F ameliorated TDI-induced AHR and airway neutrophilia, with decreased Th17 responses. Recombinant IL-17A and IL-17F showed opposite effects to the monoclonal antibodies. IL-17A and IL-17F exert distinct biological effects during airway inflammation of a TDI-induced asthma model, which is unresponsive to both inhaled and systemic steroids.
AB0657 Cyclophosphamide-sparing role of an intensified b-cell depletion protocol in anca-associated vasculitis: a case-control study
Authors: D. Roccatello, R. Fenoglio, D. Rossi, M. Radin, I. Cecchi, S. Murgia, S. Baldovino, E. Rubini, S. Sciascia
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background:</h3> The management of ANCA-associated-vasculitis (AAV) requires the use of immunosuppressive drugs with potential toxicity. Recently, two trials demonstrated the efficacy of Rituximab (RTX) for the therapy of AAV. <h3>Objectives:</h3> this case-control study aims to evaluate the immunosuppressive-sparing effect of a RTX-based protocol compared to the standard CYC treatment. <h3>Methods:</h3> 26 patients with AAV and extracapillary glomerulonephritis were prospectively enrolled. Thirteen patients received an intensified protocol of B-cell depletion therapy (IBCDT) consisting of 4-weekly infusions of 375 mg/sm RTX followed by 2 infusions after 1 and 2 months, 3 pulses of methylprednisolone followed by prednisone tapered to 5 mg/day in three months and 2 pulses of 10 mg/kg CYC, without further maintenance therapy. Thirteen patients treated with 2 mg/kg/day CYC followed by azathioprine as a maintenance therapy served as controls. <h3>Results:</h3> A significant improvement (p&lt;0.05) of B-VAS, ESR, CRP and ANCA was observed in the IBCDT-group at 3, 6 and 12 months, with decrease of mean creatinine values from 4.81±6.4 mg/dl to 2.21±3.8 mg/dl. When compared to controls, no difference was observed in terms of complete and partial response. However, the IBCDT regimen achieved a 1 g/month reduction of CYC cumulative dose (p&lt;0.001). <h3>Conclusions:</h3> in the treatment of this sample of severe AAV patients, the IBCT protocol appeared to be noninferior to CYC-based regimen. Notably, the IBCDT regimen allowed a significant reduction of CYC cumulative dose. <h3>Disclosure of Interest:</h3> None declared
<i>Notes from the Field</i>: Tuberculosis Control in the Aftermath of Hurricane Maria — Puerto Rico, 2017
Authors: Mahmoud K. Aboukheir, Francisco Alvarado-Ramy, Miguel Fernandez Vazquez, Olga Joglar
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

On September 20, 2017, Hurricane Maria made landfall in Puerto Rico as a Category 4 storm. The unprecedented destruction in Puerto Rico caused by Hurricane Maria challenged tuberculosis (TB) control, but the Puerto Rico Department of Health Tuberculosis Control Programâs limited personnel, in collaboration with partners, was able to maintain treatment and access to TB laboratory services.
FRI0496 Polyarteritis nodosa: over 20 years’ clinical experience
Authors: H.E. Sönmez, B. Armağan, G. Ayan, K. Barut, E.D. Batu, A. Erden, S. Uğurlu, Y. Bilginer, Ö. Kasapçopur, Ö. Karadağ, S.A. Bilgen, H. Özdoğan, S. Özen
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Polyarteritis nodosa (PAN) is a necrotizing vasculitis of predominantly medium size vessels. <h3>Objectives</h3> The present study aimed to summarise the characteristics of PAN patients, and also analyse the trend of decreasing PAN frequency in the last 25 years, in Turkey <h3>Methods</h3> Paediatric and adult PAN patients followed up in Hacettepe University and Istanbul University Cerrahpasa Faculty of Medicine between 1990 and 2015, were included. The demographics, clinical findings and outcomes were evaluated retrospectively. <h3>Results</h3> One hundred thirty-three patients, including 66 children, were enrolled in the study. The mean follow-up duration was 13<sup>2–27</sup> years. Among 133 patients, 86 (64.7%) had fever, 108 (81.2%) had skin involvement, 54 (40.6%) had renal involvement, 43 (32.3%) had neurological involvement, 32 (24.1%) had gastrointestinal involvement, 10 (7.5%) had cardiac involvement, 6 (4.5%) had pulmonary involvement. The median (minimum-maximum) leukocyte count, erythrocyte sedimentation rate and C-reactive protein levels at the time of diagnosis were 10400 (6100–32000)/mm<sup>3</sup>, 58(2–132) mm/h and 5.22 (0–46) mg/dL, respectively. All patients were ANCA negative. Hepatitis serology was analysed in 121 patients and found positive in 13 of them. <i>MEFV</i> mutations were screened among 65 patients, 24 of them had mutations in at least one allele. Myalgia and skin involvement were significantly more frequent in children whereas neurologic involvement was much more common among adults (table 1). The number of PAN patients declined significantly after 2010 (figure 1). 9 patients were re-categorised as DADA2 after 2014 and no patient were diagnosed with FMF+. PAN after 2008 <h3>Conclusions</h3> Our results suggest a decrease in PAN in our country which may be due to improved healthcare and dissecting mimicking diseases. Further prospective studies with prolonged follow-up could help us to better understand the disease characteristics. <h3>Reference</h3> [1] Ozen S, et al. Childhood vasculitides in Turkey: a nationwide survey. Clin Rheumatol2007;26(2):196–200. <h3>Acknowledgements</h3> None <h3>Disclosure of Interest</h3> None declared
Analysis of RBC Properties in Patients with SCD Treated with Lentiglobin Gene Therapy
Authors: Nicolas Hebert, Elisa Magrin, Annarita Miccio, Kiger Laurent, Nguyen-Peyre Kim-Anh, Laure Joseph, Alessandra Magnani, Chloé Couzin, Wassim El Nemer, France Pirenne, Olivier Negre, Jean-Antoine Ribeil, Isabelle André-Schmutz, Pablo Bartolucci, Marina Cavazzana
Journal: Blood (2018)
Combination Therapy with BTK Inhibitor Plus Anti-PD-1 Antibody Results in a Hyperprogressor Phenotype in a Mouse Model of CLL
Authors: Aidi Gu, Huaxian Ma, Xiaorui Zhang, Prerna Malaney, Miguel Gallardo, Jingwei Liu, Sattva S. Neelapu, Sean M Post
Journal: Blood (2018)
FRI0694 Twitter: a new platform for public health campaigns: systemic lupus erythematosus and rheumatoid arthritis as examples
Authors: M. Mohameden, B. Alkhairi, C. Yuvienco
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background:</h3> Social media is widely used these days and has the capacity to distribute information widely and rapidly to a large audience. Twitter is a popular social network site with hundreds of millions of users and over 500 million Tweets being sent each day. Patients commonly receive information about their condition from social media sites including Twitter. Patient education plays an important role in the management of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). The role of Twitter and its present application in SLE and RA patients' education was analyzed. <h3>Methods:</h3> Twitter advanced search function was used to retrieve all tweets (English language only) containing the words systemic lupus erythematosus, lupus and/or SLE, as well as rheumatoid arthritis over one week (October 23, 2017 to October 29, 2017). Contents of collected tweets were analyzed, and tweets were categorized into 2 groups: general public (editorial/blogging, social/conversational, and advertisement tweets) and professional sources (tweets from physicians, rheumatologists, including hyperlinks to academic publications and websites of professional organizations, and educational tweets by awareness groups). <h3>Results:</h3> Over the one-week timeframe, a total of 618 tweets mentioned lupus, systemic lupus erythematosus and/or SLE, and a total of 178 tweets mentioned rheumatoid arthritis. In the respective disease groups, tweets assigned to the professional sources category were 32% of the total tweets for SLE (200/618) and 51% for RA (92/178). Tweets sent by physicians constituted 2.6% (21/796) and by rheumatologists 1 % (8/796) of the total tweets. Tweets with links to reliable sources (defined as hyperlinks to academic publications, professional organizations and awareness groups) were 23% of the total tweets. Finally, educational tweets by patient advocate groups were 10% of the total tweets. <h3>Conclusions:</h3> Twitter has the capability of engaging a wide audience in a topic-specific conversation. Thus, it can be used as cost-effective platform for public health campaigns and to distribute evidence-based knowledge to educate patients. At this time, disease-specific search revealed a smaller percentage of content is employed for public health education and awareness. Links to reliable sources were 23% of the total tweets, indicating shortage of contribution from healthcare organizations and professionals. Majority of tweets were in the general public category (including tweets by patients) indicating an audience waiting for professional input. Health advocates should use Twitter to construct public health campaigns. Further research should be conducted to examine approaches to target specific Twitter users that engage in SLE and RA conversations. <h3>Disclosure of Interest:</h3> None declared