tbuckley/cabot-search huggingface dataset:
A phase I trial of intratumoral administration of HF10 in patients with refractory superficial cancer: Immune correlates of virus injection.
Authors: Neil Gildener-Leapman, Robert L. Ferris, James Ohr, Athanassios Argiris, John J. Nemunaitis, Neil N. Senzer, Cindi Bedell, Neil D. Gross, John T. Vetto, Maki Tanaka, Yukihiro Nishiyama, Richard S. Ungerleider
Journal: Journal of Clinical Oncology (2013)

3099 Background: HF10 is a spontaneously occurring, oncolytic, mutant Herpes Simplex Virus type 1 (HSV-1). Several deletions/insertions in its genome render it nonpathogenic. HF10 has been tested in solid tumors accessible for injection. Methods: We report correlative studies from an open label, non-randomized, multicenter, single dose escalation phase I study in patients with refractory superficial cancer. The study was a “3 + 3” design with 4-dose cohorts at escalating doses of HF10 (1 x 10 5 TCID 50 /dose with incremental dose escalations up to 1 x 10 7 TCID 50 /dose), which has been completed. Body fluids (qPCR), peripheral blood (flow cytometry) and serum (30-plex cytokine assay) were examined for viral levels, quantitative immune cell variation, and cytokines, respectively. Results: Seventeen patients were enrolled and 15 treated (9 H/N; 4 melanoma; 1 colon; 1 sarcoma). Best response was stable disease in six patients and progressive disease in nine patients. Three of the 15 patients had an adverse event possibly related to the study therapy. These AEs were grade 1 hypotension (1) and flu-like symptoms (2): typical of treatment with oncolytic viruses. qPCR analysis transiently revealed virus in the saliva of two patients (day 2 and day 22); viral clearance was achieved after 1 and 7 days respectively. Comparing the two highest and two lowest dose HF10 cohorts, CD8+PD1+ cells were decreased with increasing HF10 dose (p=0.023). Increased monocyte population (CD14+CD11c+) appeared to correlate with increased HF10 dose (p=0.063). IL-8 increased in all samples (p=0.0078 Wilcoxon Signed rank test) post injection. Conclusions: Single dose intratumoral injection was well tolerated with mild-drug related AEs and rapid viral clearance. Six patients achieved stable disease during the study period. There appears to be a generalized IL-8 related inflammatory response coincident with increased peripheral blood monocytes after HF10 administration. Decreased CD8+PD1+ cells may indicate a shift towards a non-exhausted, functional CTL phenotype. These results justify the currently accruing study of multiple administrations of HF10 at the highest administered dose. Clinical trial information: NCT01017185.
Effect of arsenic trioxide on radiation response in Chinese hamster cells
Authors: Shung-Jun Yang, Mingliang Jiang, Pamela Ross, Mark Ashamalla, Sameer Rafla
Journal: Cancer Research (2006)

585   Recent success on the use of arsenic trioxide (ATO) in treating acute promyelocytic leukemia has stimulated renewed interest in the compound. Arsenicals are well known carcinogens, capable of inducing a wide array of molecular alterations and cellular abnormalities. Prominent among others are disturbances in signal transduction, caspases and apoptosis, heat shock proteins, cell cycle progression, cell differentiation, cellular redox status, stress response, and angiogenesis. Precise mechanisms in causing various cytotoxic and physiological effects are not well understood. Arsenic evidently perturbs many cellular pathways that it may well influence the effect of radiation and chemicals used in cancer treatment. Radiation is known to kill cells primarily by producing double strand DNA breaks, the repair of which depends more on the process of non-homologous end joining (NHEJ) than homologous recombination. This study compares ATO effect on radiation response in Chinese hamster CHO-K1 cells and its radiosensitive derivative xrs-5 cells that are deficient in ku80. The latter is a member of DNA-PK, the function of which is required for NHEJ. Culture growth as measured by the colorimetric method MTT and by cell counts with a hemacytometer showed more inhibition by ATO to xrs-5 cells than the repair-proficient CHO-K1 cells. Clonogenic assay also revealed a more sensitive response in the mutant. Consistent with the characteristic deficiency of ku80, xrs-5 cells were distinctively more sensitive to x-rays. Pretreatment with ATO for 2 h enhanced radiation response in both cell lines, though to a different extent. Clonogenic survival of CHO-K1 cells to 3Gy of x-rays with and without combined exposure to ATO were 18% and 52% respectively, resulting in an enhancement ratio of approximately 2.9. Corresponding survivals in xrs-5 cells were 1.2% and 1.9% respectively, providing a ratio of 1.6. The diminished level of modification in cells without normal ku 80 indicates a role for NHEJ in ATO interaction with radiation. Further effort is warranted in revealing the mechanisms of interaction and exploring the potential of arsenic radiosensitization in cancer therapy.
AB0761 The biologic therapy use for enthesitis as a predictor of psoriatic arthritis in psoriatic patients
Authors: I Litovchenko, O Golovchenko
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> According to ACR data 15–20% patients (PTN) with psoriasis are developed with psoriatic arthritis (PsA). Herewith the enthesitis (ETS) as usual is the first signs of PsA manifestations. It is usually asymptomatic at the beginning of the disease, however it is successfully diagnosed with Doppler ultrasound (DU). In average, it takes about 2 years from beginning of the disease till diagnosis PsA is established. PsA treatment is low effective with DMARD, and middle effective with biologic therapy. Wherein no treatment restores the articular changes that have occurred. Thus the actual is to find some resolution to the effective therapy for PTN with psoriasis and also to identify the factors preceding the development of the PsA. <h3>Objectives</h3> Consider the application of biologic therapy before the articular changes in PTN with psoriasis and predictors of psoriatic arthritis. <h3>Methods</h3> Observed 82 PTN with pustural psoriasis without clinical manifestations of PsA. A physical examination (including PASI), a series of laboratory tests (hematology, CRP, RF, anti -ccp, HLA-B27, uric acid), DU to identify the PsA, its activity, as well as to the exclusion of other types of arthritis were used. <h3>Results</h3> 3,7% PTN were diagnosed with PsA with articular changes. 23,1% PTN were founded with enthesitis. The remaining 73,2% PTN had no signs of enthesitis during physical examination and DU. PTN with enthesitis were divided into 2 groups. I – 47% PTN (22% of them had clinical manifestations of enthesitis; the average group PASI– 42,4±8,2) received a 52-weeks course of ustekinumab (45 mg administered subcutaneously initially and 4 weeks later, followed by 45 mg administered subcutaneously every 12 weeks). II group – 53% people (20% PTN had clinical manifestations of enthesitis; the average group PASI– 43,6±9,0) did not receive biological therapy, but only standart treatment for psoriasis. After 1 year follow-up after completion of the treatment course – 11% PTN from group I developed PsA with articular changes. From the group II in 80% PTN developed PsA with articular changes. The average group I PASI– 7,6±1,5; the average group PASI– 6,2±1,3. (p &lt;0,05) <h3>Conclusions</h3> Thus, the ustekinumab use in psoriatic PTN with enthesitis possibly may be reasonable and will hinder the development of PsA. Ustekinumab is also high effective for the improving of the psoriasis skin symptoms. DU is the high effective diagnostic method for detecting enthesitis without clinical manifestations. Frequency of screening DU in PTN with psoriasis, for the early detection of enthesitis is the perspective for further study. <h3>Disclosure of Interest</h3> None declared
SAT0753-HPR Awareness of possible side effects of nsaids among the albanian patient population
Authors: E Pistja, A Themeli
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> No official published figures are available regarding the annual use of NSAIDs in Albania. Nonsteroidal anti-inflammatory drugs are used primarily to manage different pain conditions, less commonly they are used for their antipyretic effect. Although generally well tolerated, conventional NSAIDs have been associated with a wide range of adverse effects. The most common of which are gastrointestinal tract (GIT) side effects like: dyspepsia, abdominal pain, heartburn, and the most serious life–threatening gastrointestinal (GI) ulceration. <h3>Objectives</h3> To investigate patient awareness of the proper use and frequency of side effects in nonsteroidal anti-inflammatory drugs (NSAIDs) patients in Albania. <h3>Methods</h3> This study was a prospective 15 question interview of patients purchasing medications, during randomized 1 hour/day pharmacy visits over a one month study period (May 2015). The study was conducted in 4 community pharmacies located in the city of Tirana (capital of Albania). Two hundred and ten patients were included in this study. <h3>Results</h3> Overall NSAIDs use during last year was 63%: Ibuprofene and diclofenac was the most used NSAIDs. The majority of patients (58%) reported having side effects upon NSAIDs-use; gastrointestinal upset was the most frequently reported side effect. Patients9 awareness regarding proper NSAIDs use was poor, and pharmacist role in counseling was inadequate. However, user ability to discover the most common side effect to the drug seemed not to be affected. <h3>Conclusions</h3> Nonsteroidal anti-inflammatory drugs use awareness and knowledge of probable serious side effects and how to handle them was not adequate. This probably reflected on high incidence of side effects. Nonsteroidal anti-inflammatory drugs are available on prescription as well as over the counter drugs. Pharmacist involvement in education of patients using them is highly recommended and much needed to help decrease frequency of side effects. However this is a small scale study and further studies need to be done. <h3>References</h3> Langman MJ. Risks of anti-inflammatory drug-associated damage. Inflamm Res 1999; 48: 236–238. Garcia Rodriquez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994; 343: 769–772. Kay EA, Barker AR. Rheumatoid arthritis andosteoarthritis. In: Walker R, Edward C, editor. Clinicalpharmacy and therapeutics. Edinburgh (UK): Churchill Livingstone; 2002. p. 779–795. <h3>Disclosure of Interest</h3> None declared
FRI0351 Papulopustular lesions according to age, sex and localization in behcet's syndrome patients compared healthy and diseased controls
Authors: Z Kutlubay, Y Ozguler, G Hatemi, K Tascilar, C Mat, H Yazici
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Papulopustular lesions (PPL) are the most common skin lesions in Behçet9s syndrome (BS). <h3>Objectives</h3> To assess whether PPL are different in BS according to localization, age, sex and medications used when compared to rheumatoid arthritis patients (RA) and apparently healthy subjects (HS). <h3>Methods</h3> 209 consecutive BS patients who were routinely followed in our dedicated BS center were studied. Patients with RA (n=146) who were followed up in the rheumatology outpatient clinic of the same unit and HS (n=149) were used as controls. All subjects were clinically evaluated by the same dermatologist and all skin lesions (papules, pustules, comedones, folliculitis, cysts, nodules) on the face, trunk and legs were separately counted. Information regarding the demographic and clinical features of primary disease and medications used were obtained from patients9 charts. <h3>Results</h3> Subjects without PPL were excluded before analyses. Demographic features and mean number of PPL according to site of body were summarized in Table-1. Mean number of total PPL were similar between BS and HS and significantly higher than in RA (p&lt;0.001). Mean number of total PPL according to sex were similar in RA and HS but higher in male BS patients compared to female BS patients (p=0.04). When we analyzed the number of PPL according to different body sites, we observed that BS patients had significantly more lesions on the legs when compared to the RA patients and HS (p&lt;0.0001). Number of PPL lesions tend to decrease as the patient ages in BS similar to RA and HS. When leg lesions were analyzed according to age, this difference remained in the age groups 31–50 and &gt;50 but not in the age group ≤30. Corticosteroid use did not impact the results. <h3>Conclusions</h3> BS patients have significantly more PPL on the legs when compared to HS and RA. Number of PPL tend to decrease as the patient ages in BS similar to RA and HS however BS patients still have more PPL on the legs after the age of 50 suggesting that these lesions somehow differ from acne vulgaris, in pathogenesis. <h3>Disclosure of Interest</h3> None declared
A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles
Authors: Vito W. Rebecca, Michael C. Nicastri, Noel McLaughlin, Colin Fennelly, Quentin McAfee, Amruta Ronghe, Michel Nofal, Chun-Yan Lim, Eric Witze, Cynthia I. Chude, Gao Zhang, Gretchen M. Alicea, Shengfu Piao, Sengottuvelan Murugan, Rani Ojha, Samuel M. Levi, Zhi Wei, Julie S. Barber-Rotenberg, Maureen E. Murphy, Gordon B. Mills, Yiling Lu, Joshua Rabinowitz, Ronen Marmorstein, Qin Liu, Shujing Liu, Xiaowei Xu, Meenhard Herlyn, Roberto Zoncu, Donita C. Brady, David W. Speicher, Jeffrey D. Winkler, Ravi K. Amaravadi
Journal: Cancer Discovery (2017)

Lysosomes serve dual roles in cancer metabolism, executing catabolic programs (i.e., autophagy and macropinocytosis) while promoting mTORC1-dependent anabolism. Antimalarial compounds such as chloroquine or quinacrine have been used as lysosomal inhibitors, but fail to inhibit mTOR signaling. Further, the molecular target of these agents has not been identified. We report a screen of novel dimeric antimalarials that identifies dimeric quinacrines (DQ) as potent anticancer compounds, which concurrently inhibit mTOR and autophagy. Central nitrogen methylation of the DQ linker enhances lysosomal localization and potency. An
FRI0123 Does the body mass index have any influence in the characteristics of early arthritis patients?
Authors: P Moreno Fresneda, L Martínez-Quintanilla, AM Ortiz, E Tomero, R Vicuña García, I Άlvaro González
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Obesity has been proposed as a risk factor to develop rheumatoid arthritis (RA) and it has been associated with a worse response to several disease modifying anti-rheumatic drugs (DMARDs). <h3>Objectives</h3> To study the differences in baseline characteristics according to the body mass index (BMI) of patients in the PEARL (Princesa Early Arthritis Register Longitudinal) study. <h3>Methods</h3> A total of 432 patients (69.1% female) of the PEARL cohort were included for this study. The register protocol comprises the collection of sociodemographic, disease-related and treatment data in five visits (baseline, 6, 12, 24 and 60 months). The local ethics and clinical research committee approved the protocol and all patients sign an informed consent prior to their inclusion. For this study it was analyzed the baseline visit data from the 304 (70.37%) patients that met ACR 1987 criteria for RA after 2 years of follow-up, as well as those considered undifferentiated arthritis (UA) since other diagnoses were excluded. The WHO definition for low, normal weight, overweight and obesity (BMI &lt;18.5, 18.5–25, 25–30 or ≥30 kg/m<sup>2</sup> respectively) was applied. ACPA (anticitrullinated peptide antibodies) were assessed by enzyme immunoassay (CCP2 Eurodiagnostica). HLA-DRB1 genotype was determined in 219 patients using specific HLADRB1 typing kits (Dynal RELI SSO). The presence of shared epitope (SE) was determined based on this genotyping. The statistical analysis was performed by using Stata 12.1. Chi-Square and Kruskal-Wallis tests were used for the bivariate analysis. A multivariate logistic regression was performed to determine which factors may be related to ACPA positivity, including BMI, age, sex, smoking habit, number of SE alleles and study level as independent variables. <h3>Results</h3> Patients were 54.9 years old [44.2–67.5] (median [p25-p75]); disease duration was 5.3 months [3–8.4]. Table 1 shows the main variables significantly associated to BMI. In addition, we observed less ACPA positivity with increasing BMI (57% low weight vs. 43% in obese [p =0.08]), as well as a lower frequency of SE in patients with a higher BMI. The multivariate analysis confirmed that being smoker (ever or current) and carrying SE alleles is associated with the presence of ACPA. Adjusted by these variables, overweight and obesity were associated with lower probability of suffering an ACPA positive disease (OR 0.49, p=0.027 and OR 0.39, p=0.019 respectively). <h3>Conclusions</h3> In our early arthritis register, patients with a higher BMI have predominantly ACPA negative disease, a more intense perception of pain and higher disability. These findings should be validated in other populations. <h3>Disclosure of Interest</h3> None declared
SAT0709 Mortality prediction in mixed connective tissue disease
Authors: S Reiseter, R Gunnarsson, TM Aaløkken, MB Lund, J Corander, Ø Molberg
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Mixed Connective Tissue Disease (MCTD) is a chronic, immune-mediated disorder defined by the combined presence of serum anti-ribonucleoprotein (RNP) antibodies and selected clinical features of Systemic Sclerosis, Systemic Lupus Erythematosus, Rheumatoid Arthritis and Polymyositis. Several clinical manifestations and laboratory findings have been found to be associated to increased risk of mortality in univariable analyses (1). <h3>Objectives</h3> Here we present a mortality predicting model in a long-term observational unselected nationwide cohort aiming to enhance the knowledge of long-term prognosis in MCTD. <h3>Methods</h3> 135 patients were included from our nationwide MCTD cohort. Abnormal high resolution computed tomography (CT) findings of ground glass attenuation and reticular patterns were defined as Interstitial Lung Disease (ILD) and expressed as percentage of Total Lung Volume (TLV). Pulmonary function tests and laboratory tests were performed within 2 months of the HRCT examination. Pleuritis was defined as typical pleurisity for more than one day, pleural effusions or pleural rub present at or before baseline. Pericarditis was defined as typical pericardial pain for more than one day, pericardial effusion, pericardial rub or pericarditis by electrocardiography at or before baseline. Myositis was confirmed by muscle biopsy and/or electromyogram and CK elevation at or before baseline. Cox regression analyses were used to find the predictive factors of mortality. Variables at a significant level of <i>P</i>&lt;.25 where considered a candidate in the prediction model by manual backward elimination procedure. <h3>Results</h3> 21 patients died after a mean (standard deviation) observation of 9 (2) years. The predictive model is shown in Table 1. According to the Harrell9s C index, patient outcomes were accurately predicted by this model 85% of the time. <h3>Conclusions</h3> The strongest predicting factors of mortality in MCTD is increasing % ILD of TLV, pericarditis, male gender, DLCO less than 60% of predicted and increasing age at diagnosis. <h3>References</h3> Hajas A, Szodoray P, Nakken B, Gaal J, Zold E, Laczik R, et al. Clinical course, prognosis, and causes of death in mixed connective tissue disease. The Journal of rheumatology. 2013;40(7):1134–42. <h3>Disclosure of Interest</h3> None declared
Plexiform Vasculopathy in Chronic Thromboembolic Pulmonary Hypertension
Authors: Maximilian Ackermann, Andreas Gaumann, Steven J. Mentzer, Jan B. Hinrichs, Gregor Warnecke, Marius M. Hoeper, Peter Braubach, Mark Kuehnel, Lavinia Maegel, Danny Jonigk
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
The IRF4 Gene Regulatory Module Functions as a Read-Write Integrator to Dynamically Coordinate T Helper Cell Fate
Authors: Veena Krishnamoorthy, Sunil Kannanganat, Mark Maienschein-Cline, Sarah L. Cook, Jianjun Chen, Neil Bahroos, Evelyn Sievert, Emily Corse, Anita Chong, Roger Sciammas
Journal: Immunity (2017)
FRI0263 Systemic disease activity progression in a large cohort of primary sjÖgren's syndrome: a long-term follow-up data based on the essdai score
Authors: L Quartuccio, S Zandonella Callegher, S Gandolfo, C Fabro, S De Vita
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Primary Sjögren9s syndrome (pSS) is a chronic slowly progressive autoimmune disease, which mainly affects the salivary and lachrymal gland function. However, it is an autoimmune systemic disease with a widespread spectrum of systemic manifestations, which are now captured by validated scores (1). <h3>Objectives</h3> The aim of this restrospective study is to evaluate the disease course in a long-term follow-up, by focusing on the accrual of the systemic activity of the disease over time. <h3>Methods</h3> 254 patients suffering from pSS were studied. Mean (standard deviation) age at diagnosis was 52 (13) years. They were 235/254 (92,5%) females. Patients9 chart were reviewed in order to compare the baseline ESSDAI score, ie calculated at the diagnosis, with the total ESSDAI accrual, by verifying the new onset ESSDAI domain and/or the worsening in already active ESSDAI domains in the whole available follow-up. <h3>Results</h3> The observation covered 9,1 (6,9) years of follow-up from the diagnosis to the last follow-up visit. The median (range) baseline ESSDAI was 4 (0–31), while the total ESSDAI score accrual up to the last visit was 7 (0–43) (p&lt;0,0001, by Wilcoxon). The onset of new ESSDAI domains and/or worsening of already active ESSDAI domains was shown in 136/254 (53,5%) patients, accounting for a total amount of 210 onsets of new domains or worsening in the already active domains [9,1 (95% CI 5,2–27,7) events/100 patients/year]. There was no difference between patients with baseline ESSDAI score &lt;5 and patients with baseline ESSDAI score ≥5 (56/103, 54,4% vs 66/121, 54,5%). In only 15/135 (11,1%), the biologic domain was the sole ESSDAI domain, which was worsened or newly recorded. Finally, the ESSDAI domains, which more frequently raised or worsened in the follow-up were haematological (42/210, 20%), biological (37/210, 17,6%), articular (37/210, 17,6%), lymphadenopathy (28/210, 13,3%), and peripheral nervous system (15/210, 7,1%). <h3>Conclusions</h3> Primary Sjögren9s syndrome is not a benign disease, a half of patients showing an increasing disease activity, and probably damage, in terms of new onset or worsening of already existing manifestations, even when the disease activity is low at the onset. Importantly, clinically relevant changes over time are much more frequently observed than only biological changes, thus suggesting the need of a careful follow-up by experts, as well as the unmet need of effective treatments, according to disease activity and damage. <h3>References</h3> Seror R, et al. Outcome measures for primary Sjögren9s syndrome: a comprehensive review. J Autoimmun. 2014;51:51–6. <h3>Disclosure of Interest</h3> None declared