tbuckley/cabot-search huggingface dataset:
The sTRA Plasma Biomarker: Blinded Validation of Improved Accuracy Over CA19-9 in Pancreatic Cancer Diagnosis
Authors: Ben Staal, Ying Liu, Daniel Barnett, Peter Hsueh, Zonglin He, ChongFeng Gao, Katie Partyka, Mark W. Hurd, Aatur D. Singhi, Richard R. Drake, Ying Huang, Anirban Maitra, Randall E. Brand, Brian B. Haab
Journal: Clinical Cancer Research (2019)

The CA19-9 biomarker is elevated in a substantial group of patients with pancreatic ductal adenocarcinoma (PDAC), but not enough to be reliable for the detection or diagnosis of the disease. We hypothesized that a glycan called sTRA (sialylated tumor-related antigen) is a biomarker for PDAC that improves upon CA19-9.We examined sTRA and CA19-9 expression and secretion in panels of cell lines, patient-derived xenografts, and primary tumors. We developed candidate biomarkers from sTRA and CA19-9 in a training set of 147 plasma samples and used the panels to make case-control calls, based on predetermined thresholds, in a 50-sample validation set and a blinded, 147-sample test set.The sTRA glycan was produced and secreted by pancreatic tumors and models that did not produce and secrete CA19-9. Two biomarker panels improved upon CA19-9 in the training set, one optimized for specificity, which included CA19-9 and 2 versions of the sTRA assay, and another optimized for sensitivity, which included 2 sTRA assays. Both panels achieved statistical improvement (P < 0.001) over CA19-9 in the validation set, and the specificity-optimized panel achieved statistical improvement (P < 0.001) in the blinded set: 95% specificity and 54% sensitivity (75% accuracy), compared with 97%/30% (65% accuracy). Unblinding produced further improvements and revealed independent, complementary contributions from each marker.sTRA is a validated serological biomarker of PDAC that yields improved performance over CA19-9. The new panels may enable surveillance for PDAC among people with elevated risk, or improved differential diagnosis among patients with suspected pancreatic cancer.
AB0590 A validation study of the pregnancy morbidity questionnaire(PMQ) in women with antiphospholipid antibodies and pregnancy morbidity
Authors: K. Schreiber, S. Koder, C. Ay, I. Pabinger, S. Jacobsen
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> The presence of antiphospholipid antibodies (aPL) are associated with pregnancy complications. There is a lack of validated pregnancy questionnaires to assess previous pregnancy morbidity reliably in aPL positive patients. We therefore designed the pregnancy morbidity questionnaire (PMQ). <h3>Objectives</h3> To validate the pregnancy morbidity questionnaire (PMQ) in the prospective Vienna Lupus Anticoagulant and Thrombosis Study (LATS) cohort. <h3>Methods</h3> The Vienna Lupus Anticoagulant and Thrombosis Study (LATS) is an ongoing, single-centre, biobank-based, prospective observational cohort study enrolling patients (age &gt;18 years) who are persistently positive for lupus anticoagulant (LA) (two positive tests at least 12 weeks apart) with or without a history of thrombosis or pregnancy complications<sup>1</sup>. The cohort currently consists of 150 patients (mean age: 41.3 years, female gender: n = 122 (81.3%), history of thrombosis or pregnancy complications: n = 111 (74.0%)). Of these 150 women, 15 were approached at their follow up visit and invited to fill out the PMQ. The PMQ consists eight questions outlined in table 2. <h3>Results</h3> Twelve women agreed to participate, of whom nine had a previous history of pregnancy and/or pregnancy complications. Patient characteristics are shown in table 2. PMQ results are outlined in table 2. <h3>Conclusions</h3> Our aim was to validate the PMQ in the prospective Vienna Lupus Anticoagulant and Thrombosis Study (LATS) cohort. Patients were able to recall their pregnancy history in great detail over a period of more than three decades. Our PMQ may provide a tool to assess previous pregnancy morbidity in patients with antiphospholipid antibodies. <h3>References</h3> [1] Gebhart, J. P., F.; Koder, S.; Perkmann, T.; Quehenberger, P.; Zoghlami, C.; Ay, C.; Pabinger, I. Increased mortality in patients with the lupus anticoagulant: the Vienna Lupus Anticoagulant and Thrombosis Study (LATS). Blood125, 3477–3483. http://dx.doi.org/10.1182/blood-2014-11-611129 (2015). <h3>Disclosure of Interest</h3> None declared
Gene Therapy for Thalassemia and Sickle Cell Anemia Poses Acceptable Toxicity and Efficacy: Clinical Outcomes in Forty-Seven Cases
Authors: Hafiz Muhammad Fazeel, Muhammad Abu Zar, Saad Ullah Malik, Ahmad Kamal, Mustafa Nadeem Malik, Syed Shabee Hassan, Syeda Sabeeka Batool, Ceren Durer, Seren Durer, Shehroz Aslam, Madeeha Shafqat, Faiqa Ijaz, Faiz Anwer, Shahrukh K. Hashmi
Journal: Blood (2018)
Abstract 13839: Differences in Prevalence, Incidence, and Progression of Coronary Artery Calcium among Participants With Chronic Kidney Disease With and Without Diabetes Mellitus: Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Gautam R Shroff, Otto A Sanchez, Michael D Miedema, Holly Kramer, Joachim H Ix, Daniel A Duprez, David R Jacobs
Journal: Circulation (2016)

Introduction: Chronic kidney disease (CKD) is associated with elevated coronary artery calcium (CAC) scores, presumed from altered calcium/phosphorus metabolism. However, differences in prevalence/progression of CAC in CKD with (CKD-DM) and without (CKD-non-DM) diabetes are not known. Methods: The MESA cohort (6780 individuals aged 45-84 yr, with no clinical cardiovascular disease enrolled 2000-02) were followed until 2010-12. Baseline CKD was identified (eGFR&lt;60 ml/min/1.73 m 2 using CKD-EPI creatinine and cystatin C-based eGFR or spot urine albumin/creatinine ≥ 17 mg/g in men; 25 mg/g in women). Prevalent CAC was defined by baseline Agatston score &gt;0, incident CAC by any follow-up Agatston score &gt; 0 in those with baseline CAC=0, and CAC progression by any CAC score increase vs. baseline. CAC progression was adjusted for demographic, clinical and inflammatory biomarker variables using linear regression. Results: 1308 (19.3%) MESA participants had CKD, while 853 (12.5%) had DM. CAC &gt; 0 at baseline was lowest (44.3%) in non-CKD, non-DM, intermediate in those with either condition, and highest (67.1%) in CKD-DM participants (table). CAC incidence (among those with CAC=0 at baseline) was highest in CKD-DM, lowest in non-CKD-non-DM (39.3% vs 18.3%, p&lt;0.0001) &amp; intermediate with either CKD or DM alone (27%). About 90% of those with CAC &gt; 0 at baseline had an increase in Agatston score in follow-up; Agatston score increased 37.0/yr in non-CKD-non-DM, 57.6/yr in CKD-non-DM, 68.3/yr in non-CKD-DM, and 107.6/yr in CKD-DM (all pairwise p&lt;0.001). Extensive adjustment (table) attenuated to similar increases between non-CKD-non-DM and CKD-non-DM (40.6 vs 47.2/yr, p=0.09). Greater increases remained in non-CKD-DM (65.7/yr) and in CKD-DM (95.8/yr, p&lt;0.002). Conclusion: CKD-non-DM participants had slower CAC incidence/progression compared to CKD-DM participants. CAC differences among CKD participants may help identify subgroups at higher risk of future events.
Sixty seconds on . . . Peter Boghossian
Authors: Jacqui Wise
Journal: BMJ (2019)

No, he’s assistant professor of philosophy at Portland State University in Oregon in the US, but he faces losing his job after helping to create a number of spoof academic papers which were published in peer reviewed journals.

He says he was trying to expose politically correct “nonsense” in social sciences. He, along with two colleagues, wrote “intentionally broken” papers on gender, …
Protein Phosphatase 2A Reduces Cigarette Smoke–induced Cathepsin S and Loss of Lung Function
Authors: Declan F. Doherty, Sridesh Nath, Justin Poon, Robert F. Foronjy, Michael Ohlmeyer, Abdoulaye J. Dabo, Matthias Salathe, Mark Birrell, Maria Belvisi, Nathalie Baumlin, Michael D. Kim, Sinéad Weldon, Clifford Taggart, Patrick Geraghty
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: CTSS (cathepsin S) is a cysteine protease that is observed at higher concentrations in BAL fluid and plasma of subjects with chronic obstructive pulmonary disease (COPD). Objectives: To investigate whether CTSS is involved in the pathogenesis of cigarette smoke-induced COPD and determine whether targeting upstream signaling could prevent the disease. Methods: CTSS expression was investigated in animal and human tissue and cell models of COPD. Ctss-/- mice were exposed to long-term cigarette smoke and forced oscillation and expiratory measurements were recorded. Animals were administered chemical modulators of PP2A (protein phosphatase 2A) activity. Measurements and Main Results: Here we observed enhanced CTSS expression and activity in mouse lungs after exposure to cigarette smoke. Ctss-/- mice were resistant to cigarette smoke-induced inflammation, airway hyperresponsiveness, airspace enlargements, and loss of lung function. CTSS expression was negatively regulated by PP2A in human bronchial epithelial cells isolated from healthy nonsmokers and COPD donors and in monocyte-derived macrophages. Modulating PP2A expression or activity, with silencer siRNA or a chemical inhibitor or activator, during acute smoke exposure in mice altered inflammatory responses and CTSS expression and activity in the lung. Enhancement of PP2A activity prevented chronic smoke-induced COPD in mice. Conclusions: Our study indicates that the decrease in PP2A activity that occurs in COPD contributes to elevated CTSS expression in the lungs and results in impaired lung function. Enhancing PP2A activity represents a feasible therapeutic approach to reduce CTSS activity and counter smoke-induced lung disease.
SAT0518 The role of leflunomide in the treatment of giant cell arteritis
Authors: A. Hocevar, R. Ješe, Ž. Rotar, M. Tomšič
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Glucocorticoids (GC) have been the mainstay treatment in giant cell arteritis (GCA) for decades. Recently tocilizumab and abatacept have been proven to be effective alternatives to glucocortiocids. However, not all GCA patients are eligible for a biologics. <h3>Objectives</h3> We aimed to evaluate the role of leflunomide (LEF) as a steroid sparing agent in GCA. <h3>Methods</h3> This prospective observational study included newly diagnosed GCA patients followed at least 48 weeks at a single secondary/tertiary rheumatology centre. Patients were treated with GC in line with the EULAR recommendations.<sup>1</sup> In short, patients with uncomplicated GCA initially received oral methylprednisolone (MP) 32–48 mg qd, while those with ischaemic complications or large vessel disease first received MP 250 mg on 3 consecutive days intravenously, followed by oral MP. MP tapering was started 2–4 weeks after treatment initiation slowly to 4 mg qd which was continued for at least 6 months. At week 12, LEF 10 mg qd was recommended as an add-on therapy to those GCA patients without contraindications for it. The final decision to add LEF was patient dependent. Follow-up visits with predetermined clinical and laboratory tests were performed 4, 12, 24, 48, 96 and 144 weeks after diagnosis. In patients who relapsed during the MP tapering unscheduled visits were arranged and treatment was adjusted (GC dose was increased and LEF 10 mg or LEF dose increase to 20 mg or alternative steroid sparing agent in case of LEF ineffectiveness recommended). The number of relapses and a cumulative GC dose during follow-up were recorded. <h3>Results</h3> Between July 2014 and December 2016 we identified 76 (65.8% female, median (IQR) age 73.7 (66.1–78.8) years) new GCA cases with a follow-up of at least 48 weeks (median (IQR) 75<sup>51–104</sup> weeks). 30/76 patients (39.5%) received LEF at W12 ("LEF" group), the others continued with GC only. During the follow-up 22 patients relapsed, 4 in "LEF" group (13.3%) and 18 (39.1%) in "GC only" group. The difference was statistically significant (p=0.02; NNT 3.9 (95%CI 2.2–17.4)). Furthermore, 17/30 GCA cases (56.7%) in "LEF" group managed to stop GC at W48 (with 1 relapse (5.9%) shortly afterwards), but none in GC only group. Patients tolerated LEF relatively well. Adverse events (AEs) were usually mild. 8/30 patients (26.7%) discontinued LEF (1 due to ineffectiveness and 7 due to one/more AEs – hair loss developed in 4/7 cases, diarrhoea in 2/7 patients, weight loss in 2/7 cases, and elevated transaminases in 1/7). The occurrence of infections requiring antibiotics and/or hospital admission was lower in LEF group compared to "GC only" group (10% vs. 26.5%). <h3>Conclusions</h3> We found in our prospective observational study in GCA a steroid sparing action and a rather good tolerability of LEF. <h3>Disclosure of Interest</h3> None declared
THU0098 Combination therapy of rapamycin and a glutamine antagonist facilitates the expansion of myeloid-derived suppressor cells and ameliorates arthritis in skg mice
Authors: Y. Ueda, J. Saegusa, T. Okano, S. Sendo, H. Yamada, Y. Ichise, I. Naka, S. Takahashi, K. Akashi, A. Onishi, A. Morinobu
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature cells that increase in the pathological state such as tumour or inflammation and have the immunosuppressive ability. MDSCs have been reported to ameliorate arthritis in several mice models. Mechanistic target of rapamycin (mTOR) pathway and glutaminolysis activate cooperatively in the differentiation from myeloid progenitors to mature myeloid cells such as dendritic cells, macrophages, or osteoclasts as well as the activation of effector T cells and the differentiation of Th1 and Th17 cells. Although rapamycin has reported to facilitate the expansion of MDSCs and their immunosuppressive ability, the effect of the inhibitor of glutaminolysis on MDSCs is still unknown. <h3>Objectives</h3> The aim of this study is to evaluate the facilitative effects of the inhibition of mTOR pathway and glutaminolysis on MDSCs in a mouse model of rheumatoid arthritis. <h3>Methods</h3> Bone marrow (BM) cells from untreated Balb/c mice were cultured for 5 days under granulocyte–macrophage colony-stimulating factor (GM-CSF) stimulation with four patterns of drugs; 1) DMSO (control), 2) rapamycin (Rapa), 3) 6-Diazo-5-oxo-l-norleucine (DON; a glutamine antagonist), or 4) the combination of rapamycin and DON (Rapa +DON). Cultured BM cells were analysed by flow cytometry. Cultured MDSCs were isolated by manual MACS and analysed their immunosuppressive characters by co-culture with CFSE-dyed CD4<sup>+</sup> T cells. Rapa or Rapa +DON were administered intraperitoneally to arthritic SKG mice induced by Zymosan A injection. <h3>Results</h3> We found that DON suppressed the differentiation of dendritic cells (DC) in a dose-dependent manner and the addition of Rapa on DON inhibited the differentiation of macrophages <i>in vitro.</i> The proportions of the phenotype of MDSCs were increased with administrations of Rapa or DON, and large part of them were Ly6G<sup>+</sup> cells (the phenotype of polymorphonuclear MDSCs; PMN-MDSCs). Rapa ±DON significantly increased the expressions of TGF-β and PD-L1 and the inhibitory capacity of Ly6G<sup>+</sup> PMN-MDSCs. Rapa +DON significantly suppressed arthritis more efficiently in SKG mice than Rapa <i>in vivo</i>. (see figure 1) <h3>Conclusions</h3> The combination of rapamycin and a glutamine antagonist facilitates the expansion of PMN-MDSCs <i>in vitro</i> and ameliorates arthritis in SKG mice <i>in vivo</i>. <h3>Disclosure of Interest</h3> None declared
IL-34–Dependent Intrarenal and Systemic Mechanisms Promote Lupus Nephritis in MRL-Faslpr Mice
Authors: Yukihiro Wada, Hilda M. Gonzalez-Sanchez, Julia Weinmann-Menke, Yasunori Iwata, Amrendra K. Ajay, Myriam Meineck, Vicki R. Kelley
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Macrophages and autoantibodies play a central role in the pathology of lupus nephritis in patients with lupus and in the MRL- Faslpr mouse model. The authors demonstrate that IL-34 and its two receptors, cFMS and PTPRZ, are upregulated in the kidney with advancing nephritis in MRL- Faslpr mice. Genetically deleting IL-34 in these mice suppresses nephritis and the systemic illness via macrophage- and autoantibody-mediated mechanisms within and outside of the kidney. The authors also found that patients with lupus nephritis have elevated IL-34 in serum and urine; intrarenal and systemic expression of IL-34, cFMS, and PTPRZ similar to that displayed in MRL- Faslpr mice; and IL-34 expression that correlates with histopathologic index of disease activity. These findings suggest that IL-34 is a promising novel therapeutic target for patients with lupus nephritis. Background In people with SLE and in the MRL- Faslpr lupus mouse model, macrophages and autoantibodies are central to lupus nephritis. IL-34 mediates macrophage survival and proliferation, is expressed by tubular epithelial cells (TECs), and binds to the cFMS receptor on macrophages and to a newly identified second receptor, PTPRZ. Methods To investigate whether IL-34–dependent intrarenal and systemic mechanisms promote lupus nephritis, we compared lupus nephritis and systemic illness in MRL- Faslpr mice expressing IL-34 and IL-34 knockout (KO) MRL- Faslpr mice. We also assessed expression of IL-34 and the cFMS and PTPRZ receptors in patients with lupus nephritis. Results Intrarenal IL-34 and its two receptors increase during lupus nephritis in MRL- Faslpr mice. In knockout mice lacking IL-34, nephritis and systemic illness are suppressed. IL-34 fosters intrarenal macrophage accumulation via monocyte proliferation in bone marrow (which increases circulating monocytes that are recruited by chemokines into the kidney) and via intrarenal macrophage proliferation. This accumulation leads to macrophage-mediated TEC apoptosis. We also found suppression of circulating autoantibodies and glomerular antibody deposits in the knockout mice. This is consistent with fewer activated and proliferating intrarenal and splenic B cells in mice lacking IL-34, and with our novel discovery that PTPRZ is expressed by macrophages, B and T cells. These findings appear translatable to human patients with lupus nephritis, whose expression of IL-34, cFMS, and PTPRZ is similar to that seen in the MRL- Faslpr lupus mouse model. Moreover, expression of IL-34 in TECs correlates with disease activity. Conclusions IL-34 is a promising novel therapeutic target for patients with lupus nephritis.
SAT0553 Chondrocalcinosis of the knee and the risk for knee or hip osteoarthritis progression: data from the khoala cohort
Authors: A. Latourte, A.C. Rat, W. Ngueyon Sime, C. Roux, F. Guillemin, P. Richette
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Cross-sectional studies repeatedly found that chondrocalcinosis (CC) is associated with osteoarthritis (OA). However, whether CC worsens preexisting knee or hip OA is unclear. <h3>Objectives</h3> We conducted this study to assess the impact of knee CC on the risk of 1) incident joint replacement surgery, 2) worsening of pain or function and 3) radiographic progression in patients with symptomatic knee OA. <h3>Methods</h3> The KHOALA cohort is a French multicenter population-based cohort of 878 patients with symptomatic knee and/or hip OA (ACR criteria), aged 40–75 years. Patients were followed annually by self-reported questionnaires and by clinical examination and radiography at baseline (year 0), years 3 and 5. Only patients with knee OA were kept for this analysis. CC, defined by the presence of calcium deposits within hyaline or fibro-cartilage on knee radiograph (anteroposterior view), was recorded as present or absent. We used Cox proportional-hazard regression modelling to estimate the local or systemic impact of CC at one knee (index knee) on the 5 year risk of incident total knee replacement (TKR) at the index knee or incident total hip or knee joint replacement (TJR), respectively. In the subgroup of patients without incident TJR during follow-up, logistic regression was performed to assess whether CC was associated with the worsening of Western Ontario and McMaster Universities Arthritis Index (WOMAC) for OA pain or function, or with radiographic progression as defined by a change in Kellgren and Lawrence (KL) grade, between years 0 and 5. <h3>Results</h3> Among the 656 patients included (mean ±SD age 62.2±8.5 years; 70.3% females), 93 (14.2%) had CC in at least one knee at baseline. As compared with patients without CC, those with CC were older (64.3±9.6 vs 61.9±8.2 years; p=0.009), had longer disease duration (16.4±10.5 vs 13.0±7.6 years; p&lt;0.001) and lower body mass index (29.1±5.3 vs 30.5±6.3 kg/m²; p=0.047). Patients with/without CC did not differ in baseline pain (7.1±4.3 vs 6.6±3.8; p=0.26) and function (22.2±14.7 vs 20.7±13.5; p=0.32) scores, or KL grade (p=0.69). Overall, 105 (16.0%) and 91 (13.9%) patients underwent TJR and TKR of the index knee, respectively, during follow-up. The presence of CC at one knee did not affect the risk of TKR in the same index knee (HR=1.0; 95% CI 0.6 to 1.8), or risk of TJR (HR=0.9; 95% CI 0.5 to 1.6). In patients without incident TJR surgery (n=551), the presence of CC did not affect the risk of worsened WOMAC pain/function scores or KL grade at year 5. <h3>Conclusions</h3> In a population-based cohort of symptomatic knee OA, the presence of CC in the knee did not affect the risk of subsequent TKR or TJR, nor clinical or radiographic outcomes at 5 years. These results suggest that CC is not a risk factor for worsening clinical or structural outcomes in knee OA. <h3>Disclosure of Interest</h3> None declared
Integration of A Deep Learning Classifier with A Random Forest Approach for Predicting Malonylation Sites
Authors: Zhen Chen, Ningning He, Yu Huang, Wen Tao Qin, Xuhan Liu, Lei Li
Journal: Genomics Proteomics & Bioinformatics (2018)

As a newly-identified protein post-translational modification, malonylation is involved in a variety of biological functions. Recognizing malonylation sites in substrates represents an initial but crucial step in elucidating the molecular mechanisms underlying protein malonylation. In this study, we constructed a deep learning (DL) network classifier based on long short-term memory (LSTM) with word embedding (LSTMWE) for the prediction of mammalian malonylation sites. LSTMWE performs better than traditional classifiers developed with common pre-defined feature encodings or a DL classifier based on LSTM with a one-hot vector. The performance of LSTMWE is sensitive to the size of the training set, but this limitation can be overcome by integration with a traditional machine learning (ML) classifier. Accordingly, an integrated approach called LEMP was developed, which includes LSTMWE and the random forest classifier with a novel encoding of enhanced amino acid content. LEMP performs not only better than the individual classifiers but also superior to the currently-available malonylation predictors. Additionally, it demonstrates a promising performance with a low false positive rate, which is highly useful in the prediction application. Overall, LEMP is a useful tool for easily identifying malonylation sites with high confidence. LEMP is available at http://www.bioinfogo.org/lemp.