tbuckley/cabot-search huggingface dataset:
Trypsin/chymotrypsin and their respective zymogens inhibit tumor growth in vitro and in vivo
Authors: Josef F. Novak, Frantisek Trnka, Mitchell I. Chernin
Journal: Cancer Research (2006)

4359   Elevated protease activities are commonly found at the growing front of primary tumors and their metastastic sites. This led to the search for specific and global protease inhibitors, particularly the inhibitors of metalloproteases. None of the many such inhibitors have yet been identified as potential first-line antineoplastic drugs. We hypothesize that increased pericellular proteolytic activity is a necessity for tumor expansion but that it also must be in balance with many other processes occurring at the tumor-host interface. These include bidirectional interactions between normal and tumor cells and the extracellular matrix. We raised the possibility that induction of excessive proteolytic activity at the tumor-host or tumor-ECM interfaces could lead to a new tumor treatment modality. This approach was first incorporated into animal and clinical tests conducted nearly 100 years ago by John Beard with some surprisingly positive results. The preliminary results in support of our hypothesis (Anticancer Research 25:1157–1178, 2005) demonstrate that a mixture of purified pancreatic zymogens trypsinogen/chymotrypsinogen (TG/CG) can indeed invoke pronounced tumor and metastatic inhibitory effects at the cellular, preclinical and clinical level. Treatment with trypsin and chymotrypsin (TR/CH) inhibits tumor cell migration, increases cell-cell adhesion, cell clustering, and induces apoptosis in solitary but not clustered tumor cells in vitro. In vivo, in addition to the clearance of the metastatic disease, the treatment with TG/CG causes pronounced increase of angiostatin and endostatin blood levels. In contrast, the same treatments of normal cells in vitro promote cell migration and limited cell aggregation. The treatment of tumor-free animals produce no adverse effects. We found that Y–27632, an inhibitor of Rho kinases, allows MG63 osteosarcoma cell migration and inhibits migration of non-transformed NRK52E cells. Surpsisingly, the tumor cell migration inhibitory effect of TR/CH was abrogated in the presence of Y–27632 while the migration of normal cells was accelerated. The effect of TR/CH was not contradicted by U–73122, an inhibitor of phospholipase C (PLC). These results could be duplicated with several other tumor and normal cells. We conclude that the effect of TR/CH on the tumor cell shape, cell-cell interactions and the ability to migrate is mediated by a pathway involving Rho kinase. Whereas, PAR1-activating peptide was inactive in reproducing effects of TR/CH on migration and aggregation of tumor cells, the PAR2-activating peptide led to analogous results but only at high concentrations. Combination of PAR2-peptide and TR/CH was additive. Further studies will focus on confirmation of these preliminary results as well as the extent to which the treatment with exogenous TG/CG and TR/CH may have modified total pericellular proteolytic systems in vivo and in vitro, respectively.
Nintedanib Plus Pemetrexed/Cisplatin in Patients With Malignant Pleural Mesothelioma: Phase II Results From the Randomized, Placebo-Controlled LUME-Meso Trial
Authors: Federica Grosso, Nicola Steele, Silvia Novello, Anna K. Nowak, Sanjay Popat, Laurent Greillier, Thomas John, Natasha B. Leighl, Martin Reck, Paul Taylor, David Planchard, Jens Benn Sørensen, Mark A. Socinski, Ute von Wangenheim, Arsène Bienvenu Loembé, José Barrueco, Nassim Morsli, Giorgio Scagliotti
Journal: Journal of Clinical Oncology (2017)

Purpose LUME-Meso is a phase II/III randomized, double-blind trial designed to assess efficacy and safety of nintedanib plus chemotherapy as first-line treatment of malignant pleural mesothelioma (MPM). Phase II results are reported here. Patients and Methods Chemotherapy-naïve patients with unresectable, nonsarcomatoid MPM (Eastern Cooperative Oncology Group performance status 0 to 1), stratified by histology (epithelioid or biphasic), were randomly assigned in a 1:1 ratio to up to six cycles of pemetrexed and cisplatin plus nintedanib (200 mg twice daily) or placebo followed by nintedanib plus placebo monotherapy until progression. The primary end point was progression-free survival (PFS). Results Eighty-seven patients were randomly assigned. The median number of pemetrexed and cisplatin cycles was six; the median treatment duration for nintedanib was 7.8 months and 5.3 months for placebo. Primary PFS favored nintedanib (hazard ratio [HR], 0.56; 95% CI, 0.34 to 0.91; P = .017), which was confirmed in updated PFS analyses (HR, 0.54; 95% CI, 0.33 to 0.87; P = .010). A trend toward improved overall survival also favored nintedanib (HR, 0.77; 95% CI, 0.46 to 1.29; P = .319). Benefit was evident in epithelioid histology, with a median overall survival gain of 5.4 months (HR, 0.70; 95% CI, 0.40 to 1.21; P = .197; median [nintedanib v placebo], 20.6 months v 15.2 months) and median PFS gain of 4.0 months (HR, 0.49; 95% CI, 0.30 to 0.82; P = .006; median [nintedanib v placebo], 9.7 v 5.7 months). Neutropenia was the most frequent grade ≥ 3 adverse event (AE; nintedanib 43.2% v placebo 12.2%); rates of febrile neutropenia were low (4.5% in nintedanib group v 0% in placebo group). AEs leading to discontinuation were reported in 6.8% of those receiving nintedanib versus 17.1% of those in the placebo group. Conclusion Addition of nintedanib to pemetrexed plus cisplatin resulted in PFS improvement. AEs were manageable. The clinical benefit was evident in patients with epithelioid histology. The confirmatory phase III part of the study is ongoing.
FRI0524 Carotid atherosclerosis is associated with compromised volumetric bone mineral density and microstructures in patients with inflammatory arthritis
Authors: TH Cheng, Q Shang, EKM Li, PCH Wong, EWL Kun, M Li, TKY Li, TY Zhu, APW Lee, L Qin, LS Tam
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Carotid Atherosclerosis is associated with compromised volumetric bone mineral density and microstructures in patients with inflammatory arthritis <h3>Objectives</h3> The aim of this study was to explore the relationship between volumetric bone mineral density (vBMD)/microstructural features and presence of carotid plaque (CP) in patients with inflammatory arthritis. <h3>Methods</h3> 175 inflammatory arthritis patients (81 [46%] PsA, 94 [54%] RA; 70 [40%] males; age: 53±12 years) were recruited into an ongoing prospective study assessing the relationship between inflammation, osteoporosis and carotid atherosclerosis. Carotid plaque and intima-media thickness (IMT) were measured by carotid ultrasound. Areal BMD (aBMD) was measured by dual energy X-ray absorptiometry (DXA). Microstructure features and vBMD of distal radius were measured using high-resolution peripheral quantitative computed tomography (HR-pQCT). <h3>Results</h3> No patients had established cardiovascular disease (CVD). Data from 172 patients at baseline were analyzed for this cross-sectional study. Patients were sub grouped according to the presence or absence of carotid plaque (CP+ group, n=68 [40%]) and CP- group, n=132 [60%]). CP+ group were older (59±10 vs 49±11, <i>p</i>&lt;0.001), more likely to be male (54% vs 31%, <i>p=</i>0.002), had higher systolic blood pressure (130±19 vs 124±17 mmHg, <i>p</i>=0.034) and CVD risk (15.7±14.2 vs 7.9±8.6, <i>p</i>&lt;0.001) according to the Framingham Risk Score (FRS) then the CP- group. aBMD, vBMD and microstructure were significantly compromised in the CP+ group. Distal radius aBMD, distal radius total vBMD, trabecular (Tb) vBMD, Tb thickness, cortical (Ct.) vBMD, Ct. thickness and bone volume fraction were 5% (<i>p</i>=0.004), 12% (<i>p</i>&lt;0.001), 8% (<i>p</i>=0.007), 8% (<i>p</i>=0.004), 4% (<i>p</i>=0.007), 10% (<i>p</i>=0.001) and 8% (<i>p</i>=0.007) lower in the CP+ group. The differences remained significant after adjustment for gender, disease type and FRS (Table 1). <h3>Conclusions</h3> Inflammatory arthritis patients with carotid plaque had lower aBMD, vBMD and compromised bone microstructure in the distal radius even after adjustment for gender, disease type and FRS, suggesting that inflammation may be the common link for both conditions. <h3>Disclosure of Interest</h3> None declared
FRI0515 Classic cardiovascular risk factors and minimal disease activity in psoriatic arthritis: results of a spanish multicenter study
Authors: R Queiro, JD Cañete, C Montilla, MA Abad, M Montoro, S Gόmez, A Cábez, JC Torre Alonso, JA Román Ivorra, J Sanz, J Salvatierra, J Alén Calvo, A Sellas, FJ Rodriguez, A Bermúdez, M Romero, M Riesco, JC Cobeta, F Medina, A Aragόn, ML García, A Urruticoechea
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Some cardiovascular risk factors (CVRF) have been related to poorer responses to biological therapy<sup>1</sup>. We aimed to evaluate the potential link between the MDA response and the presence of CVRF in patients treated with traditional and/or biological DMARDs. <h3>Objectives</h3> The objective has been to evaluate the potential association beetween classic CVRF and the probability of reaching an MDA response in PsA patients. <h3>Methods</h3> Cross-sectional study carried out at 25 rheumatology outpatient clinics in patients who fulfilled the Classification for Psoriatic Arthritis (CASPAR) criteria with at least one year disease duration, and treated with biological or conventional synthetic (cs) DMARDs according to routine clinical practice in Spain. Patients were considered in MDA if they met at least 5/7 of the MDA criteria<sup>2</sup>. The relationship between MDA and CVRF was evaluated by uni and multivariate analyses. <h3>Results</h3> 227 patients were included, 133 (58.6%) were in MDA state (52% on anti-TNFα monotherapy, 24% on csDMARD monotherapy, 24% on anti-TNFα in combination with csDMARD). Among the classic CVRF, tobacco (crude OR: 0.54), sedentary lifestyle (crude OR: 1.95), hyperuricemia (crude OR: 2.01) and obesity (crude OR: 1.54) were related to the likelihood of MDA in the univariate model (p&lt;0.25). The only CVRF related to the MDA response in the multivariate analysis was a sedentary lifestyle (OR 3.13, 95% CI: 1.50–6.53; p=0.002). We did not find any association between the number of CVRF and the MDA response. <h3>Conclusions</h3> Contrary to what has been found in other studies, in this cross-sectional multicenter study we could not find any relationship between traditional CVRF (except for sedentary lifestyle) and MDA. In any case, patients with psoriatic disease should be encouraged to maintain healthy lifestyle habits. <h3>References</h3> Ogdie A, Eder L. Improving cardiovascular health and metabolic comorbidities in patients with psoriatic arthritis. Int J Clin Rheumatol 2015; 10(6):451–459. Coates LC, Fransen J, Helliwell PS. Defining minimal disease activity in psoriatic arthritis: a proposed objective target for treatment. Ann Rheum Dis 2010; 69(1):48–53. <h3>Acknowledgements</h3> This study was funded by Pfizer. <h3>Disclosure of Interest</h3> None declared
Mbd3/NuRD controls lymphoid cell fate and inhibits tumorigenesis by repressing a B cell transcriptional program
Authors: Stephen J. Loughran, Federico Comoglio, Fiona K. Hamey, Alice Giustacchini, Youssef Errami, Eleanor Earp, Berthold Göttgens, Sten Eirik W. Jacobsen, Adam J. Mead, Brian Hendrich, Anthony R. Green
Journal: The Journal of Experimental Medicine (2017)

Differentiation of lineage-committed cells from multipotent progenitors requires the establishment of accessible chromatin at lineage-specific transcriptional enhancers and promoters, which is mediated by pioneer transcription factors that recruit activating chromatin remodeling complexes. Here we show that the Mbd3/nucleosome remodeling and deacetylation (NuRD) chromatin remodeling complex opposes this transcriptional pioneering during B cell programming of multipotent lymphoid progenitors by restricting chromatin accessibility at B cell enhancers and promoters. Mbd3/NuRD-deficient lymphoid progenitors therefore prematurely activate a B cell transcriptional program and are biased toward overproduction of pro–B cells at the expense of T cell progenitors. The striking reduction in early thymic T cell progenitors results in compensatory hyperproliferation of immature thymocytes and development of T cell lymphoma. Our results reveal that Mbd3/NuRD can regulate multilineage differentiation by constraining the activation of dormant lineage-specific enhancers and promoters. In this way, Mbd3/NuRD protects the multipotency of lymphoid progenitors, preventing B cell–programming transcription factors from prematurely enacting lineage commitment. Mbd3/NuRD therefore controls the fate of lymphoid progenitors, ensuring appropriate production of lineage-committed progeny and suppressing tumor formation.
FRI0752-HPR Computer podometric measuring system in assessment of flat feet and lower limbs deformities in patients with systemic sclerosis
Authors: R Michalik, AJ Owczarek, P Kotyla, J Chudek, P Antończak, E Kucharz
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Systemic sclerosis (SSc) is a connective tissue disease characterized by an excessive collagen production, fibrotic changes in the skin, internal organs, and vascular involvement. Patients with SSc may have pathological changes in their joints, especially in feet that enclosed: flat feet, valgus or varus foot, hallux valgus, tendinopathy, foot ulcers, joint space narrowing, joint subluxation and degenerative changes [1, 2]. <h3>Objectives</h3> The aim of the study was to assess occurrence and the severity of lesions and deformities of spine and joints of lower limbs, especially of feet, in patients with SSc, in comparison to the healthy volunteers. <h3>Methods</h3> All subject have anamnesis, anthropometric tests, and feet assessment with the computer podometric measuring system. <h3>Results</h3> The study enclosed 53 patients with SSc (69.8% female) in mean age 55±12 and 65 healthy volunteers (53.8% female) in mean age 45±15. Disease duration median was 3 years (IQR =6). In comparison to healthy volunteers, patients with SSc have more frequent flat feet and pes valgus (p&lt;0.001) – Figure 1. No significant differences (p=0.96) were observed in round back (8% both groups) and round-concave back (28% vs. 30%) occurrence. Patients with SSc have diminished spine mobility (15.06±5.52 vs. 26.09±6.52 [cm]; p&lt;0.001), to small knee-joint and ankle flexion/extension regardless of body side, more often hallux valgus and longitudinal flat foot. No differences were observed in transverse flat foot and heel varus/valgus occurrence. <h3>Conclusions</h3> Patients with SSc have a relatively high prevalence of feet pathological deformities and a smaller range of flexion of the joints than the lowest normal range, but mostly normal curvature of the spine. <h3>References</h3> La Montagna G, Baruffo A, Tirri R, Buono G, Valentini G: Foot involvement in systemic sclerosis: A longitudinal study of 100 patients. Semin Arthritis Rheum 2002, 31(4): 248–255. Sari-Kouzel H, Hutchinson CE, Middleton A, Webb F, Moore T, Griffin K, Herrick AL: Foot problems in patients with systemic sclerosis. Br Soc for Rheumatol 2001, 40: 410–413. <h3>Disclosure of Interest</h3> None declared
OP0143-HPR Disability in the feet related to participation in daily life in patients with early ra – an interview study in the swedish tira project
Authors: M Björk, I Thyberg, E Valtersson, G Östlund, B Stenström, A Sverker
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Pain, stiffness and deformity of the feet are related to reduced mobility and participation restrictions in daily activities in patients with established rheumatoid arthritis (RA). The new biological medications are effective and reduce disease activity, but not disability to the same extent. Foot problems are assumed to be related to participation restrictions also in patients with early RA, diagnosed after the introduction of biological medications, hindering for example physical activity. Hence, there is a need for more knowledge about foot problems in order to identify possible needs for rehabilitative interventions. <h3>Objectives</h3> To explore disability related to foot problems in women and men with early rheumatoid arthritis and its relation to participation in daily life. <h3>Methods</h3> 59 patients (58% women, 20–63 years) with early RA were interviewed about participation dilemmas in daily life related to RA, using Critical Incident Technique. The interviews were audio-recorded and transcribed. Data related to foot problems were extracted and analysed thematically. A research partner with RA validated the retrieved categories. The study was approved by the Regional Ethics Committee. <h3>Results</h3> More than 2/3 of the patients mentioned that they had participation restrictions related to foot problems. The analysis revealed 5 categories concerning foot problems and the relation to participation restrictions: 1) foot problems as an early indicator of the disease, 2) hindrance in managing the daily routine and house hold activities, 3) struggling to be mobile, 4) difficulties in doing a god job at work and 5) difficulties in participating in recreation and leisure activities. Both women and men shared many experiences, as difficulties to be physically active. Several women expressed difficulties to use the shoes they wanted. Being able to move on uneven ground in, for example, the forest was something that many men expressed as difficult. <h3>Conclusions</h3> Patients with early RA with access to effective medications and multi professional interventions based on their individual needs still experience a wide range of foot related disability in major life arenas as work, in the household and during leisure time. This indicates a need to pay attention also in today9s early RA patients to foot problems in the multi professional rehabilitation to prevent further disabilities and enable physical activity for men and women with RA. <h3>Disclosure of Interest</h3> None declared
OP0052 Cortical bone loss is an early feature of axial spondyloarthritis
Authors: J Haschka, A Neumann, A Kleyer, L Schuster, M Englbrecht, CP Figueiredo, C Muschitz, R Kocijan, H Resch, J Rech, G Schett
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Systemic bone loss is a well-known and severe consequence in axial spondyloarthritis (axSpA). To date deterioration of bone microstructure has only been described in patients with long-standing ankylosing spondylitis while bone microstructure has not been assessed in axSpA. <h3>Objectives</h3> The aim of the present study was to investigate bone microstructure, geometry and volumetric bone mineral density (vBMD) using high resolution peripheral quantitative CT (HR-pQCT) in a cohort of axSpA patients at an early stage of disease and to search for potential factors for deterioration of bone microstructure. <h3>Methods</h3> An inception cohort of 101 axSpA patients and 50 healthy controls of similar age and sex was assessed for geometric, volumetric and microstructural parameters of bone using HR-pQCT scanning of the radius. Additionally, demographic and disease specific characteristics of SpA patients were recorded. <h3>Results</h3> SpA patients and controls were comparable in age (median (IQR) 45.0 (15.0) vs. 44.76 (26.0) years, p=0.917), sex (female 41.6% vs. 40%, p=0.852) and BMI (median (IQR) 26.3 (6.5) vs. 23.8 (5.2), p=0.118). 75% of patients showed HLA-B27 positivity. Median disease duration was 6.5 (9.0) years, 58.4% of patients were on biological treatment and 14.9% of patients in disease remission according to ASDAS-CRP. Geometric and microstructural analysis by HR-pQCT revealed a significantly reduced cortical area (p=0.022) and cortical thickness (p=0.006) in SpA patients compared to controls. No differences in cortical porosity (p=0.685), trabecular geometry or microstructure were detected. Total and cortical vBMD were significantly reduced in SpA patients (p=0.042 and p=0.007), while there was no difference in trabecular vBMD (p=0.376). Patients with a short disease duration &lt;2 years (n=46) showed a significant reduction of cortical thickness and cortical area (p=0.050 and p=0.032) compared to controls. Patients with a disease duration &gt;2 years (n=55) additionally developed a decrease of cortical and total vBMD (p=0.004 and p=0.036). Multivariate regression models identified male sex to be associated with lower cortical vBMD and female sex with lower trabecular vBMD. History of prednisolone treatment (&gt;5mg &gt;3months) was associated with lower trabecular vBMD, and disease duration with higher trabecular vBMD. Remission status, treatment with TNF inhibitors, HLA-B27 status and presence of peripheral arthritis did not influence bone microstructure independently. <h3>Conclusions</h3> Bone microstructure in SpA patients is primarily characterized by deterioration of cortical bone. Cortical bone loss starts early and is evident within the first 2 years of disease. <h3>Disclosure of Interest</h3> None declared
SAT0431 The relationship of seasonal variation, the onset and the symptoms of ankylosing spondylitis measured by self-administrated questionnaires in chinese patients
Authors: Y Jiang, M Yang, Z Lin, Q Wei, S Cao, J Gu
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Ankylosing spondylitis (AS) is a chronic inflammatory disease which mainly involves sacroiliac joints, resulting in pain, functionally limitation and even less life expectancy. Seasonal variation was found in rheumatoid arthritis and gout [1,2]. No reports had been focused on seasonal variation of AS onset or symptoms in AS patients. <h3>Objectives</h3> Our study was to investigate the relationship of seasonal variation and the onset and symptoms of AS in Chinese patients. <h3>Methods</h3> Adult AS patients diagnosed with the modified New York criteria for AS whose disease duration was over 2 years were enrolled from several provinces all over China. Participants were required to complete a set of questionnaires and examinations, including demographic and clinical information. Questions included "in which season(s) did you have the initial symptoms of AS", and "in which season(s) were the symptoms aggravated/improved". The Statistical Package for Social Sciences (SPSS) software version 21 was used for all data management and analysis. <h3>Results</h3> Of all the 859 AS patients, 75.1% were male patients. 47.8% were married. Mean age was 30.60±9.50 years. Mean disease duration was 7.43±6.92 years. 27.7% of the patients had an onset of the disease in summer, while the lowest incidence happened in autumn (12.5%, p&lt;0.05). 29.6% of the patients could not recall the exact season. 29.5% of the patients9 symptoms got worse in winter, while only 2.6% of the patients felt worse in autumn, in comparison of 10.3% in spring and 6.0% in summer. 24.4% of the patients felt relieved in summer, while surprising, only 2.7% felt better in spring, with a lowest rate in the four season. However, 48.1% of the patients believed there were no seasonal differences. <h3>Conclusions</h3> More patients had an onset of AS in summer, compared to other seasons. More patients felt worse in winter and better in summer. Nearly half of AS patients considered that there were no seasonal differences in the deterioration or improvement of the symptoms. <h3>References</h3> Karmacharya P, Pathak R, Aryal MR, Giri S, Donato AA (2016) Seasonal variation in acute gouty arthritis: data from Nationwide Inpatient Sample. Clin Rheumatol 35: 523–525. Feldthusen C, Grimby-Ekman A, Forsblad-d9Elia H, Jacobsson L, Mannerkorpi K (2016) Seasonal variations in fatigue in persons with rheumatoid arthritis: a longitudinal study. BMC Musculoskelet Disord 17: 59. <h3>Disclosure of Interest</h3> Y. Jiang: None declared, M. Yang: None declared, Z. Lin: None declared, Q. Wei: None declared, S. Cao: None declared, J. Gu Grant/research support from: Guangzhou Science and Technology Plan Projects [grant number 2006Z2-E0221] and 5010 Subject of Sun Yat-sen University (2009–2010)