tbuckley/cabot-search huggingface dataset:
AB0443 GAYET WERNICKE’S ENCEPHALOPATHY SECONDARY TO METHOTREXATE INTOLERANCE: A SERIOUS COMPLICATION OF CHRONIC VOMITING
Authors: Houda Sahraoui, Imane El Bouchti
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Gayet-Wernicke's encephalopathy is a serious complication of thiamine deficiency. Chronic alcoholism is recognized as the most commun cause of Gayet-Wernicke's encephalopathy, but other causes including malnutrition, chronic vomiting, prolonged fasting, and exclusive artificial feeding have been documented. <h3>Objectives:</h3> We report a case of Gayet-Wernicke's encephalopathy complicating uncontrollable vomiting secondary to severe Methotrexate intolerance. <h3>Methods:</h3> Case report <h3>Results:</h3> A 47-year-old women with rheumatoid arthritis. She was put under methotrexate at the dose of 15 mg/week, 1 month prior to admission into our department for the management of an acute febrile polyarthritis associated to severe and uncontrollable gastrointestinal intolerance to Methotrexate. There was no abdominal pain or transit problem. One month later, she experienced temporo-spatial disorientation, somnolence, horizontal nystagmus, and vertigo attacks with visual hallucinations and memory problems. The muscular forces at the four limbs were decreased to 3/5 with abolished osteotendinous reflexes at the two lower limbs. MRI showed hyperintense signals on T2 and FLAIR image in thalamus, periaqueducal area and mamillary bodies. Electroneuromyography (ENMG) showed axonal motor neuropathy in all 4 limbs. The hemogram showed normochromic normocytic anemia. Laboratory testing for Vitamin B12, vitamin D, folate and minerals showed multiple deficiencies. A multivitamin supplementation was introduced with good evolution. <h3>Conclusion:</h3> This is the first case of severe digestive intolerance to methotrexate leading to a serious neurological complication. Although digestive intolerance to methotrexate is considered benign, it can be daunting. Thorough knowledge of complications and close monitoring of patients must be imperative. Gayet Wernicke encephalopathy is a rare and serious pathology. We should keep it in mind and prevent it in risky situations. <h3>References</h3> [1] Seci G, Sera A. Wernicke's encephalopathy: new clinical settings and recent advances in diagnosis and management. Lancet Neurol. 2007;6(5):442-55. [2] osiezagha K, ali s, freeman c, et al. thiamine deficiency and delirium. Innov clin neurosci 2013;10:26-32. [3] manzo g, de gennaro a, cozzolino a, et al. mr imaging findings in alcoholic and nonalcoholic acute wernicke's encphalopathy : a review. Biomed res Intern 2014; 2014:503596. <h3>Disclosure of Interests:</h3> None declared
PF370 SIGNAL-OMICS ANALYSIS OF THE IMPACT OF THERAPY ON BCR SIGNALLING IN CHRONIC LYMPHOCYTIC LEUKAEMIA
Authors: A. Linley, N. Kalakonda, D. MacEwan, I. Prior, J. Slupsky
Journal: HemaSphere (2019)

Background: Induction of signalling via cell surface receptor activation is a critical driver of chronic lymphocytic leukaemia (CLL) pathobiology, especially via the B-cell receptor (BCR), which promotes tumour survival and progression. The vital nature of BCR signalling has been recognized through the development of kinase inhibitors (KI), most notably ibrutinib, that target key nodes within this pathway. Current efforts to monitor signalling investigate expression of a highly confined series of kinases and phosphoproteins. While generating key insights, full appreciation of their wider significance to malignant pathology and therapy response remains an unresolved issue. Here, we describe a ‘signal-omics’ approach, involving a kinobead-based protocol used in conjunction with mass-spectrometry (MS) or immunoblotting. Kinobead binding is related to the availability of a kinase's active site and thus can be used to determine signalling within cells. We have employed this approach characterise surface-IgM (sIgM) signalling within primary CLL cells. Aims: Validate signal-omic profiling for investigating BCR signalling in primary CLL. Methods: Kinobead Signalling Analysis of BCR Signalling Response Whole cell lysates from anti-IgM and control F(ab’)2-treated primary CLL cells underwent kinobead isolation. Elutions from these were processed and were tested using mass-spectrometry (MS). MaxQuant software analysis of MS- data was used to identify kinases and relative binding to kinobeads. Immunoblotting Immunoblotting was used to screen whole cell lysates and kinobead elutions for kinase expression and activation change in all conditions. Results: Employing this approach, it was possible to isolate over 100 kinases from primary CLL cells and identified a ‘fingerprint’ of over 50 kinases which displayed unique, patient-specific response to sIgM stimulation. Signal strength was correlated to sIgM expression but not IGHV mutation status, calcium flux, karyotype or staging. Interestingly, our analysis recognised greater activation change in patients who had undergone prior chemoimmunotherapy compared to those from untreated/treatment-naïve patients. Comparison of matched samples was also able to illustrate kinomic changes in patients who have failed chemoimmunotherapy or have developed resistance to ongoing ibrutinib treatment. Summary/Conclusion: These data represent the first comprehensive, high-resolution investigation into BCR signalling response within CLL, where our probing of kinase active sites reveals unique evidence of adaptive reprogramming in response to therapy.
Quinine enhances the apoptotic and antiproliferative effects of Seocalcitol in breast cancer cell lines
Authors: Melhem Solh, Joel Appel, Linda Dubay, Catherine Lobocki, Vijay Mittal
Journal: Cancer Research (2008)

4028  Objectives: Vitamin D3 and quinine have been considered modulators of cell differentiation and proliferation, as well as inducers of apoptosis. In vivo studies investigating Vitamin D3 and its analogues for breast cancer treatment have been faced with the side effect of hypercalcemia. The purpose of this study was to examine the growth inhibitory and cellular differentiation effects of 1,25-dihydroxyvitamin D3 and Seocalcitol (a Vitamin D3 analog) alone and in combination with quinine on four breast cancer cell lines (MCF7, T-47D, SKBR3 and BT474), as well as in nude mice model.  Methods: Growth inhibition was determined using the colorimetric MTT assay after 4 and 7 days of drug treatment. Lipid visualization using the Oil Red O stain was used to assess cellular differentiation. Two ER positive cell lines(MCF-7,T-47D), ER negative SKBR3 and weak ER positive BT474 were treated with Vitamin D3, Seocalcitol alone or in combination with quinine. Cells were decanted using MTT reagent and absorbance was measured using Bio-Tek microplate reader.  In Vivo: mammary cell lines were tested for vitamin D3 receptor expression, and then transplanted under the axillae of nude mice. 40 mice divided into four groups (control, Seocalcitol, quinine and combination) will be treated for 6 weeks, then tumors were harvested for expression of vitamin D3 receptor, ER, PR, apoptosis and differentiation. Mice were monitored for hypercalcemia on a every three days.  Results: Both time and dose dependent effects were demonstrated. The IC50’s for MCF7, T-47D and SKBR3 were: 3 - 5 x 10-8 M and 14 - 29μMfor 1,25-D3 and quinine, respectively.Seocalcitol was significantly more potent with an IC50 of 2 - 3 x 10-9 M. The BT474 cell line was relatively resistant to all drugs tested. The combination of drugs showed a significant decrease in growth (p
THU0183 UPADACITINIB PHARMACOKINETICS IN JAPANESE SUBJECTS WITH RHEUMATOID ARTHRITIS WITH THE EXTENDED-RELEASE FORMULATION AND COMPARABILITY TO NON-JAPANESE SUBJECTS
Authors: Mohamed-Eslam Mohamed, Ben Kluender, Sebastian Meerwein, Ahmed Othman
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Upadacitinib (UPA), an oral selective JAK1 inhibitor, is being developed for treatment of patients with moderate to severely active rheumatoid arthritis (RA). UPA efficacy was demonstrated in subjects with moderate to severe RA in five global Phase 3 studies and a regional Phase 2b/3 study in Japanese subjects. <h3>Objectives:</h3> To characterize the pharmacokinetics of UPA after administration of the extended-release formulation in Japanese subjects with RA and to compare UPA plasma exposures between Japanese and non-Japanese subjects. <h3>Methods:</h3> Population pharmacokinetic analyses were conducted using UPA data across Phase 1 to 3 studies including Japanese and non-Japanese subjects. The population pharmacokinetic model was used to estimate UPA plasma exposures from the extended-release formulation regimens in non-Japanese and Japanese subjects with RA in Phase 3 trials. Additionally, a total of 29 Japanese subjects with RA who were enrolled in SELECT-SUNRISE Phase 2b/3 study participated in a pharmacokinetics substudy in which serial blood samples were collected from each subject over a 24 hour period after UPA dosing. UPA was administered in the study at doses of 7.5 mg, 15 mg, and 30 mg QD using the extended-release formulation. Pharmacokinetic parameters were calculated in the pharmacokinetic substudy using noncompartmental methods. <h3>Results:</h3> UPA maximum plasma concentration was reached within 2 hours of dosing under fasting condition. UPA plasma exposures were approximately dose proportional over the evaluated dose range in Japanese subjects with RA. UPA model estimated plasma exposures (based on population pharmacokinetic analyses) were comparable (within 20%) between Japanese and non-Japanese subjects with RA (Table 1). Results from the pharmacokinetic substudy using noncompartmental methods were consistent with the population pharmacokinetic analyses. Cmax: maximum plasma concentration; Cavg: average plasma concentration during a dosing interval; Ctrough: trough plasma concentration <h3>Conclusion:</h3> No clinically relevant difference was observed in UPA plasma exposures between Japanese and non-Japanese subjects with RA. <h3>References:</h3> [1] Mohamed, et al. Clin Pharmacol Drug Dev. 2018Apr24. [2] Genovese et al. Lancet. 2018;391(10139):2513-2524. [3] Burmester et al. Lancet. 2018;391(10139):2503-2512. <h3>Disclosure of Interests:</h3> Mohamed-Eslam Mohamed Shareholder of: AbbVie, Employee of: AbbVie, Ben Kluender Shareholder of: AbbVie, Employee of: AbbVie Deutschland GmbH &amp; Co. KG, Sebastian Meerwein Shareholder of: AbbVie, Employee of: AbbVie Deutschland GmbH &amp; Co. KG, Ahmed Othman Shareholder of: AbbVie, Employee of: AbbVie
Forkhead box K2 promotes human colorectal cancer metastasis by upregulating ZEB1 and EGFR
Authors: Feng Du, Chenyang Qiao, Xiaowei Li, Zhangqian Chen, Hao Liu, Shengda Wu, Sijun Hu, Zhaoyan Qiu, Meirui Qian, Dean Tian, Kaichun Wu, Daiming Fan, Yongzhan Nie, Limin Xia
Journal: Theranostics (2019)

Background: Metastasis is the major reason for high recurrence rates and poor survival among patients with colorectal cancer (CRC). However, the underlying molecular mechanism of CRC metastasis is unclear. This study aimed to investigate the role of forkhead box K2 (FOXK2), one of the most markedly increased FOX genes in CRC, and the mechanism by which it is deregulated in CRC metastasis. Methods: FOXK2 levels were analyzed in two independent human CRC cohorts (cohort I, n = 363; cohort II, n = 390). In vitro Transwell assays and in vivo lung and liver metastasis models were used to examine CRC cell migration, invasion and metastasis. Chromatin immunoprecipitation and luciferase reporter assays were used to measure the binding of transcription factors to the promoters of FOXK2, zinc finger E-box binding homeobox 1 (ZEB1) and epidermal growth factor receptor (EGFR). Cetuximab was utilized to treat FOXK2-mediated metastatic CRC. Results: FOXK2 was significantly upregulated in human CRC tissues, was correlated with more aggressive features and indicated a poor prognosis. FOXK2 overexpression promoted CRC migration, invasion and metastasis, while FOXK2 downregulation had the opposite effects. ZEB1 and EGFR were determined to be direct transcriptional targets of FOXK2 and were essential for FOXK2-mediated CRC metastasis. Moreover, activation of EGFR signaling by EGF enhanced FOXK2 expression via the extracellular regulated protein kinase (ERK) and nuclear factor (NF)-κB pathways. The EGFR monoclonal antibody cetuximab significantly inhibited FOXK2-promoted CRC metastasis. In clinical CRC tissues, FOXK2 expression was positively correlated with the expression of p65, ZEB1 and EGFR. CRC patients who coexpressed p65/FOXK2, FOXK2/ZEB1 and FOXK2/EGFR had poorer prognosis. Conclusions: FOXK2 serves as a prognostic biomarker in CRC. Cetuximab can block the EGF-NF-κB-FOXK2-EGFR feedback loop and suppress CRC metastasis.
AB1143 SUBCLINICAL MICROVASCULAR INVOLVEMENT IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS
Authors: Alberto Sulli, Carmen Pizzorni, Barbara Ruaro, Sabrina Paolino, Veronica Tomatis, Emanuele Gotelli, Vanessa Smith, Maurizio Cutolo
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Peripheral microcirculation is well studied in primary Raynaud's phenomenon (RP), but poorly investigated in systemic lupus erythematosus (SLE) (1-3). <h3>Objectives</h3> To investigate morphological and functional aspects of microcirculation in different skin areas of the hands in SLE patients in comparison with primary RP (PRP) patients and healthy subjects (CNT). <h3>Methods</h3> 15 SLE patients without RP (ACR 2013 criteria) (mean age 52±13 SD years, mean disease duration 6±3 years), 15 PRP patients (LeRoy 2001 criteria) (mean age 52±16 years, mean RP duration 6±4 years) and 15 sex-matched controls (CNT) (mean age 51±16 years) were enrolled during the winter period. Nailfold videocapillaroscopy (NVC) and laser speckle contrast analysis (LASCA) have been performed in the three groups of patients. The absolute nailfold capillary number (CN) per linear millimeter at first distal row was assessed by NVC (4). Blood perfusion (BP) was detected by LASCA at the level of fingertips, periungual areas, dorsum and palm of both hands (2). Patients were not taking vasoactive drugs since at least one month before study entry. Statistical analysis was performed by non parametric tests. <h3>Results</h3> SLE patients showed a statistically significant lower nailfold absolute CN than both PRP and CNT (median 9.2 vs 10.2 vs 11.1, respectively, p&lt;0.0006). Conversely, no statistically significant difference of nailfold CN was observed between PRP and CNT. PRP patients showed a statistically significant lower BP than SLE and CNT, and SLE than CNT, at the level of fingertips (median 90, 113, 186 PU, respectively; p&lt;0.0001), periungual (median 75, 100, 142 PU, respectively, p&lt;0.0001), dorsal (median 63, 73, 126 PU, respectively, p&lt;0.0001), and palm areas (median 76, 95, 124 PU, respectively, p&lt;0.0001). A positive correlation between nailfold CN and BP was observed in all areas of hands in SLE patients (p&lt;0.0001). On the contrary, no statistically significant correlation was observed in both PRP and CNT, between nailfold CN and BP in all examined areas (p=0.74 and p=0.23, respectively). <h3>Conclusion</h3> SLE patients, without RP, show a subclinical microvascular impairment, having lower nailfold CN and lower BP than CNT. Conversely, PRP patients show only a functional dysfunction, having lower peripheral skin BP than both SLE patients and CNT. A correlation between morphological and functional microvascular features was also found in SLE patients. These findings seem to suggest interesting microvascular insights in active SLE patients. <h3>References</h3> [1] Ruaro B, et al. Ann Rheum Dis 2014;73:1181-5. 2. Cutolo M, et al. J Rheumatol 2010;37:1174-80. 3. Cutolo M, et al. Autoimmun Rev. 2018;17:344-352. 4. Cutolo M, et al. Arthritis Rheumatol. 2016;68:2527-39. <h3>Disclosure of Interests</h3> None declared
Miro’s Dots and Lines
Authors: Shaurya Taran, Allan S. Detsky
Journal: JAMA Internal Medicine (2019)

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David Oliver: Doctors with drink problems deserve help
Authors: David Oliver
Journal: BMJ (2019)

On Victoria Derbyshire’s BBC Radio 5 show in 2011, a report on alcoholism featured a live on-air conversation with an anaesthetic trainee using the pseudonym of Rachel, who had contacted the show.1 She was in great distress, brought to her knees by alcohol addiction. While awaiting a taxi to residential rehabilitation she opened another can on air, hoping to stave off withdrawal.

Doctors are more susceptible to substance misuse and addiction than the general population,2 and in the NHS increasing numbers have been seeking help from specialist services.3 Workload, working conditions, staffing gaps, emotional demands, and perfectionism leave doctors at high risk of mental health problems and burnout. A 2019 BMJ Open study of 417 NHS doctors found 44% resorting to binge drinking, 5% meeting the criteria for alcohol dependence, and others using food or recreational drugs as coping strategies for occupational stress.45 Our medical knowledge of the problems of addiction seems to be no defence.

When “Rachel” appeared on the …
FRI0535 COMPARISON OF SERUM BIOMARKERS FOR THE DIAGNOSIS OF MACROPHAGE ACTIVATION SYNDROME COMPLICATING SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS: CLINICAL SIGNIFICANCE OF SERUM NEOPTERIN LEVELS
Authors: Hitoshi Irabu, Masaki Shimizu, Maiko Takakuwa, Naoto Sakumura, Natsumi Inoue, Mao Mizuta, Yasuo Nakagishi, Akihiro Yachie
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Macrophage activation syndrome (MAS) is a severe life-threatening condition that complicates systemic juvenile idiopathic arthritis (s-JIA). Differentiating MAS from these conditions is essential for selecting appropriate therapeutic interventions in a timely manner. However, there is no definite biomarkers that can effectively diagnose MAS. <h3>Objectives</h3> Our study aimed to compare the accuracy of serum biomarkers for the diagnosis of MAS complicating s-JIA and to investigate the clinical significance of serum neopterin levels as an indicator of disease activity and diagnosis of MAS complicating s-JIA. <h3>Methods</h3> Serum cytokine levels (neopterin, IL-18, and CXCL9 and soluble tumor necrosis factor receptor type I (sTNFR-I) and II were determined by enzyme-linked immunosorbent assay in 78 patients with s-JIA, including 21 with MAS. The accuracy of these levels for the diagnosis of MAS were compared. Next, serum neopterin levels, in total 125 patients with s-JIA, including 30 with MAS, 15 with Epstein–Barr virus-induced hemophagocytic lymphohistiocytosis (EBV-HLH), and 15 with Kawasaki disease (KD), as well as 28 healthy controls (HCs) were analysed. Results were compared with the clinical features of MAS. <h3>Results</h3> Receiver operating characteristic curve analysis revealed area under the curve values and cut off values of neopterin, IL-18, CXCL9, sTNFR-II/I ratio and ferritin were 0.9465/19.5nmol/l, 0.8895/69250ng/ml, 0.9333/3130pg/ml, 0.9395/3.796 and 0.8671/2560ng/ml, respectively. Serum neopterin levels were significantly elevated in patients with MAS and EBV-HLH compared with those in patients with acute-phase s-JIA and KD. Serum neopterin levels profoundly and rapidly increased as MAS developed and correlated positively with disease activity. <h3>Conclusion</h3> Serum neopterin levels may be used as a promising indicator of disease activity in s-JIA and MAS and for evaluating it. It may also be a useful marker to diagnose the transition to MAS from active-phase s-JIA. <h3>References</h3> [1] Huber C, et al. J Exp Med1984;160:310-6. [2] Bracaglia C, et al. Ann Rheum Dis2017;76:166-72. [3] Shimizu M, et al. Clin Exp Immunol2018;191:349-355. <h3>Disclosure of Interests</h3> None declared
AB0734 CHANGES IN HEIGHT AND BODY MASS INDEX OVER TIME IN PATIENTS WITH AXIAL SPONDYLOARTHITIS, TREATED WITH TUMOR NECROSIS FACTOR-A INHIBITORS
Authors: Elizaveta Vasilenko, Olga Nikolaeva, Anna Dadalova, Ekaterina Gaydukova, V Mazurov, Inna Gaydukova
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Monitoring of height and body mass index (BMI) is an important for patients with axial spondyloarthritis (axSpA). Reduction of height not only reflects spine remodeling, but affects various indexes, such as BMI (fig.1). However, BMI calculations assume that the adult patient's height is a constant. Therefore these calculations may be inaccurate in patients whose height is susceptible to decrease. <h3>Objectives:</h3> To evaluate changes in height and BMI over time in patients with axSpA, treated with tumor necrosis factor-α inhibitors (iTNF-α). <h3>Methods:</h3> The study included 51 patients with axSpA (ASAS criteria 2009). All the patients were treated with iTNF-α for one and &gt; years. The patient's height and weight measured before the beginning TNF-α inhibitors and during the treatment. Only patients with stable weight (variability ± 2.0 kg from baseline) were included in the study. <h3>Results:</h3> Mean age of axSpA patients at baseline was 40.22±13.51, 38 (74.5%) were male, disease duration 12.77±6.82, duration of TNF-α inhibitors treatment 5.64±2.21 years, all the patients had inactive disease. In 19 patients with axSpA diagnostic delay was 8 years. Patients' height varied between 1.55 – 1.92 m (average height 1.73±0.07 m). Male's mean height was 1.78±0.05 m, women's – 1.63±0.05 m. Height decrease over time in patients with axSpa was 3.74±1.83 cm (from 1.0 to 15.0 cm). Maximal decrease in height was shown in patients with 10 years after the first symptoms emerged. Mean weight in patients who had height loss was 79.75±12.7 kg. Among patients who had decrease of height and stable body mass the difference between BMI at subsequent measurement and the time of treatment initiation (<b>Δ</b>BMI) was 1.15 kg/m<sup>2</sup>: BMI at baseline = 26.25±3.34 kg/m<sup>2</sup>, over time of observation BMI = 27.39±3.38 kg/m<sup>2</sup>). <h3>Conclusion:</h3> Height loss in axSpA is significant even in patients with inactive disease. Height loss affects BMI calculation that could lead to overestimation of cardiovascular risk, obesity and could change all of the BMI-dependent areas. Correction of BMI calculation for the patients with unstable height is needed. <h3> Disclosure of interests:</h3> Elizaveta Vasilenko: None declared, Olga Nikolaeva: None declared, anna Dadalova: None declared, Ekaterina Gaydukova: None declared, V Mazurov Grant/research support from: JSC BIOCAD, inna Gaydukova Grant/research support from: JSC BIOCAD, Speakers bureau: paiment from Pfizer, Novartis, abbvie, Biocad, Selgene, MSD, Sanofy not exceed 10 000 euros