tbuckley/cabot-search huggingface dataset:
08.34 Ra synovial recombinant monoclonal antibodies from single b cells target citrullinated calreticulin
Authors: Elisa Corsiero, Lucas Jagemann, Edoardo Prediletto, Costantino Pitzalis, Michele Bombardieri
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Fibroblast-like synoviocytes (FLS) play a crucial role in the pathogenesis of rheumatoid arthritis (RA) directly contributing to local cartilage destruction and synovial inflammation.<sup>1</sup> Autophagy, a mechanism whereby damaged proteins are removed from the cells, has been implicated in the pathogenesis of RA by activating the citrullination process in RA-FLS.<sup>2</sup> The protein expression pattern of FLS has been also characterised with the identification of &gt;200 proteins which have been involved in the normal or pathological FLS function.<sup>3</sup> Among all the proteins identified in the RA-FLS, calreticulin (CRT) has been implicated in the pathogenesis of RA.<sup>4,5</sup> In particular, citrullinated-(cit)-CRT has been shown to better recognise the RA 'share epitope' HLA domain compared to native CRT.<sup>4</sup> Therefore, here we tested the immunoreactivity of RA synovial recombinant monoclonal antibodies (RA-syn-rmAbs) towards RA-FLS and towards cit-CRT. <h3>Materials and methods</h3> 82 RA-syn-rmAbs were generated from single CD19+B cells FACS-sorted from fresh synovial cell suspensions following IgV<sub>H</sub>+V<sub>L</sub> genes cloning (6). RA-syn-rmAbs were tested by means of i) cell-based immunofluorescence assays with FLS of RA patients and controls (osteoarthritis (OA)/healthy donors (HD)-FLS and dermal fibroblast (DF)) and ii) immunoenzymatic tests using native/cit-CRT. Control rmAbs were also used (Sjögren's syndrome/HD-IgG rmAbs). <h3>Results</h3> Immunofluoresce on RA-FLS demonstrated reactivity of 21% of RA-syn-rmAbs (14/67 mAbs) towards cytoplasmic/nuclear components of FLS. This reactivity was not exclusively directed against RA-FLS since it was also observed for OA/HD-FLS and DF. When tested in ELISA for native vs cit-CRT, 50% (7/14 mAbs) of the FLS+ RA clones showed to be reactive towards CRT. Interestingly, 4 out of 7 rmAbs displayed an increased reactivity towards cit-CRT. Controls mAbs showed no reactivity towards FLS and CRT. <h3>Conclusions</h3> Here, we provided evidence that locally differentiated B cells within RA synovial germinal center-like structures can react towards native/cit-CRT likely expressed in RA-FLS. Importantly, this reactivity was disease-specific. The identification of additional cit-antigens such as cit-CRT may provide further insight into the RA pathogenesis. Thus, they might be used as potential new biomarkers in RA diagnosis. <h3>References</h3> I McInnes and G Schett. <i>N Engl J Med</i>, 2011. M Sorice, et al. <i>Rheumatology</i>, 2016. K Dasuri, et al. <i>Arthritis Res Ther</i>, 2004. J Holoshitz, et al. <i>Ann N Y Acad Sci</i>, 2010. M Ni, et al. <i>J Clin Immunol</i>, 2013. E Corsiero, et al. <i>Ann Rheum Disease</i>, 2015.
SAT0076 Serum level of syndecan-4 and its correlation with clinical parameters in rheumatoid arthritis patients
Authors: X Ye, J Zhao, Z Zhang
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Heparan sulfate proteoglycan syndecan-4 plays an important role in inflammation. However, the role of syndecan-4 in rheumatoid arthritis (RA) has not yet been elucidated. <h3>Objectives</h3> To detect serum level of syndecan-4 in RA patients and investigate its correlation with RA clinical parameters. <h3>Methods</h3> The concentration of serum syndecan-4 was assayed by enzyme-linked immunosorbent assay (ELISA). 43 patients9 serum samples from our RA cohort study between 2014 and 2016, and 20 age- and gender-matched osteoarthritis (OA) patients9 serum samples were collected and analyzed. Compared the serum syndecan-4 levels in RA patients with DAS28≥3.2 and DAS28&lt;3.2 by Wilcoxon signed rank test. The relationships between serum syndecan-4 levels and RA clinical parameters (DAS28, rheumatoid factor (RF), erythrocyte sedimentation rate, C-reactive protein, etc.) were analyzed. <h3>Results</h3> Baseline serum syndecan-4 levels of RA patients were significantly higher than the matched OA patients (1101.56 pg/mL vs 281.41 pg/mL, p&lt;0.001). In RA patients who had sera both at the point of DAS28≥3.2 and DAS28&lt;3.2 (n=13), we found that the former syndecan-4 levels were higher than the latter (1666.22 pg/mL vs 1378.34 pg/mL, p=0.65). The levels of serum syndecan-4 and RF were significantly and positively correlated in RA patients (r=0.696, p=0.008). Furthermore, there is a tendency that serum syndecan-4 levels were higher in the RF-positive (n=31) than in the RF-negative (n=12) RA patients (1344.43 pg/mL vs 971.27 pg/mL, p=0.078). <h3>Conclusions</h3> Compared with age- and gender- matched OA patients, serum syndecan-4 concentration is significantly higher in RA patients. Serum syndecan-4 level is positively correlated with RF. Syndecan-4 may play an important role in thes pathogenesis of RA. Further investigation is required to study the mechanism of syndecan-4 in RA. <h3>References</h3> Zhao J, Guo J, Wang L, et al. The role of a proliferation-inducing ligand (APRIL) in the pathogenesis of rheumatoid arthritis. Scand J Rheumatol 2014;43(6):462–9. Patterson AM, Cartwright A, David G, et al. Differential expression of syndecans and glypicans in chronically inflamed synovium. Ann Rheum Dis 2008 May;67(5):592–601. Endo T, Ito K, Morimoto J, et al. Syndecan 4 Regulation of the Development of Autoimmune Arthritis in Mice by Modulating B Cell Migration and Germinal Center Formation. Arthritis Rheumatol 2015 Sep;67(9):2512–22. <h3>Acknowledgements</h3> We are indebted to all the patients who kindly participated in this study. This study was partly supported by Peking University Clinical Research Institute. <h3>Disclosure of Interest</h3> None declared
A first in human experience of the anti-CD37 antibody-drug conjugate AGS67E in lymphoid malignancies.
Authors: Ahmed Sawas, Kerry J. Savage, Raymond P. Perez, Ranjana H. Advani, Amal Melhem-Bertrandt, Jacqueline Lackey, Fabio Trave, Banmeet Anand, Yao Huang, Martha Vincent, Leonard M. Reyno, Owen A. O'Connor
Journal: Journal of Clinical Oncology (2016)

7549 Background: CD37 is a tetraspanin expressed in most B- and T- cell malignancies in previous tumor profiling studies (Pereira et al, Mol Cancer Ther; 2015). AGS67E, is an antibody drug conjugate (ADC) composed of a fully human IgG2 antibody targeting CD37 that is conjugated to the microtubule-disrupting agent MMAE through a cleavable linker. CD37 expression is found in: > 80% of B and T-cell lymphomas as well as in 100% of Chronic lymphocytic leukemia (CLL) samples tested. Patient-derived xenograft studies demonstrated the efficacy of AGS67E in non-Hodgkin lymphomas (NHLs) and CLL models. Methods: The first in human, ongoing, multicenter, phase 1 dose-escalation study is currently evaluating the safety, PK and anticancer activity of AGS67E given as monotherapy to subjects with relapsed / refractory NHLs and CLL. AGS67E is administered IV Q3 weeks until disease progression or unacceptable toxicity. The dose escalation will first determine the maximum tolerated dose (MTD) without growth factor (GF), followed by the MTD with GF support. Results: As of January 18, 2016, 30 subjects have been treated in 7 dose level cohorts. Median age was 65 years (range 25 - 85). Subjects received a median number of 2 (1 - 11) prior therapies. The MTD was exceeded at 1.2 mg/kg without GF; the dose limiting toxicity (DLT) was Gr 4 neutropenia 8 - 15 days after 1st dose. No major non-hematological toxicities have been observed. No ≥ Gr 3 neuropathy reported; Gr1 neuropathy (N = 3) and 1 subject with preexisting Gr 1 developed Gr 2 neuropathy after long term exposure. Dose escalation with GF is currently ongoing and started at 1.2 mg/kg. Responses were noted in subjects dosed at 0.9 and 1.2 mg/kg; Specifically, 2 subjects with Diffuse Large B-Cell Lymphoma (DLBCL) experienced a complete remission (CR) and 2 subjects (Mycosis Fungoides and DLBCL) experienced a partial remission (PR). The serum AGS67E concentrations indicated a non-linear PK at ≤ 0.6 mg/kg dose levels. At 1.2 mg/kg, the half-life of AGS67E and free MMAE ranged from 1.59-2.25 and 2.34-3.64 days, respectively. Conclusions: AGS67E has a favorable safety profile and has demonstrated signs of activity. Expansion cohorts are ongoing at the MTD without GF and are planned at the MTD with GF. Clinical trial information: NCT02175433.
An essential role of high-molecular-weight kininogen in endotoxemia
Authors: Aizhen Yang, Zhanli Xie, Bo Wang, Robert W. Colman, Jihong Dai, Yi Wu
Journal: The Journal of Experimental Medicine (2017)

In this study, we show that mice lacking high-molecular-weight kininogen (HK) were resistant to lipopolysaccharide (LPS)-induced mortality and had significantly reduced circulating LPS levels. Replenishment of HK-deficient mice with human HK recovered the LPS levels and rendered the mice susceptible to LPS-induced mortality. Binding of HK to LPS occurred through the O-polysaccharide/core oligosaccharide, consistent with the ability to bind LPS from K. pneumoniae, P. aeruginosa, S. minnesota, and different E. coli strains. Binding of LPS induced plasma HK cleavage to the two-chain form (HKa, containing a heavy chain [HC] and a light chain [LC]) and bradykinin. Both HKa and the LC, but not the HC, could disaggregate LPS. The light chain bound LPS with high affinity (Kd = 1.52 × 10-9 M) through a binding site in domain 5 (DHG15). A monoclonal antibody against D5 significantly reduced LPS-induced mortality and circulating LPS levels in wild-type mice. Thus, HK, as a major LPS carrier in circulation, plays an essential role in endotoxemia.
Clinical Features and Outcomes in the Elderly Following Percutaneous Coronary Intervention between 1985 and 2010
Authors: Naito Ryo, Miyauchi Katsumi, Shitara Jun, Endo Hirohisa, Wasa Hideki, Doi Shinichiro, Konishi Hirokazu, Tsuboi Shuta, Ogita Manabu, Dohi Tomotaka, Kasai Takatoshi, Tamura Hiroshi, Okazaki Shinya, Isoda Kikuo, Daida Hiroyuki
Journal: Circulation (2016)
THE IMPACT OF HEAVY MENSTRUAL BLEEDING (MENORRHAGIA) AND IRON STATUS IN EXERCISING FEMALES
Authors: Georgie Bruinvels, Richard J Burden, Timothy Cushway, Nicola Brown, Charles Pedlar, Toby Richards
Journal: British Journal of Sports Medicine (2017)

Background The effects of the menstrual cycle on exercise participation and performance are poorly researched. Menstrual blood loss is a leading cause of iron deficiency (ID) and ultimately iron deficiency anaemia (IDA). Furthermore, iron losses are increased in those who exercise. The menstrual cycle, ID and IDA may affect the ability to exercise, mood state, productivity and quality of life while also increasing fatigue and anxiety. Objective To determine the impact of heavy menstrual bleeding (HMB) on iron status; to identify the association between HMB, ID and IDA with self-reported exercise training and performance. Design A cross-sectional study design was used. Setting Routine healthcare assessments in Singapore. Participants Healthy females (n=271; mean age 36.3±9.6 years, body mass 58.3±12.5 kg, height 1.59±0.12 m). Inclusion criteria: regularly menstruating and reporting &gt;60 minutes exercise participation per week or ‘taking part in races, in a relatively non-competitive manner’. Interventions No interventions were applied. Main Outcome Measurements Participants completed a ‘Female Health Questionnaire’ capturing: a 4-part diagnostic criteria for HMB; aspects of exercise training habits and performance; exercise volume; and competition level. Haemoglobin concentration ([Hb]) and serum ferritin were measured in all participants. Results 22.4% reported HMB, 18.8% had IDA ([Hb]&lt;12 g/dL), 30.0% severe ID (ferritin&lt;16 ug/L), and 48.0% had moderate ID (ferritin &lt;30 ug/L). Those with HMB were twice as likely to suffer IDA or have moderate ID, while they were nearly three times as likely to have severe ID ( p&lt;0.05 ). When controlling for IDA those with HMB were 3.9 times more likely to cite negative impacts on training and performance as a result of the menstrual cycle ( p&lt;0.05 ). Conclusions Heavy menstrual bleeding is common in exercising women. Regular screening should be encouraged to check iron status as this has potential to cause IDA in addition to compromising exercise training behaviours and performance.
COGNITION IN FORMER RUGBY UNION PLAYERS AND IMPACT OF CONCUSSION HISTORY
Authors: Patria Hume, Alice Theadom, Gwyn N Lewis, Kenneth L Quarrie, Scott R Brown, Rosamund Hill, Stephen W. Marshall
Journal: British Journal of Sports Medicine (2017)

Background Information is needed on the effects on health after retirement from participating in sport and any effects of sustaining concussions. Objective To investigate differences in cognitive function between former rugby and non-contact sport players, and any association between concussion history and cognitive function. Design Cross sectional descriptive study. Comparisons across player groups, concussion groups (one or more self-reported concussions versus no concussions) and between these groups with CNS-vital signs age-matched norms (US norms). Setting On-line data collection. Participants 366 former players (mean ±SD age 43.3±8.2 years); 103 elite rugby, 193 community rugby, 65 non-contact sport. Assessment of Risk Factors Concussion history was obtained from an on-line self-report questionnaire. Cognitive functioning was assessed using the online CNS-vital signs neuropsychological test battery. Main Outcome Measurements CNS-vital signs test scores and concussion counts. Results The former elite rugby union player group had deficits in cognitive functioning relative to the non-contact sport player group as indicated by complex attention, cognitive flexibility, processing speed and executive functioning scores using the CNS-vital signs test. The former community rugby group performed worse than non-contact sports players on cognitive flexibility and executive functioning tests. Community and elite former rugby union players reported a substantially higher number of concussions than non-contact sport players. The player group who had experienced one or more concussions, had deficits in cognitive flexibility, complex attention, and executive function relative to the player group with no history of concussion. Conclusions Past participation in rugby, or history of concussion, were associated with small to moderate neurocognitive deficits, as indicated by worse CNS-vital signs scores. A greater proportion of former rugby players than expected showed deficits in composite memory, verbal memory, and reaction time, in addition to processing speed and complex attention for elite rugby, and psychomotor speed and motor speed for community rugby.
Cortical Functional Connectivity Evident After Birth and Behavioral Inhibition at Age 2
Authors: Chad M. Sylvester, Christopher D. Smyser, Tara Smyser, Jeanette Kenley, Joseph J. Ackerman, Joshua S. Shimony, Steve E. Petersen, Cynthia E. Rogers
Journal: American Journal of Psychiatry (2017)

Objective: The infant temperament behavioral inhibition is a potent risk factor for development of an anxiety disorder. It is difficult to predict risk for behavioral inhibition at birth, however, and the neural underpinnings are poorly understood. The authors hypothesized that neonatal functional connectivity of the ventral attention network is related to behavioral inhibition at age 2 years beyond sociodemographic and familial factors. This hypothesis is supported by the ventral attention network's role in attention to novelty, a key feature of behavioral inhibition. Method: Using a longitudinal design (N=45), the authors measured functional connectivity using MRI in neonates and behavioral inhibition at age 2 using the Infant-Toddler Social and Emotional Assessment. Whole-brain connectivity maps were computed for regions from the ventral attention, default mode, and salience networks. Regression analyses related these maps to behavioral inhibition at age 2, covarying for sex, social risk, and motion during scanning. Results: Decreased neonatal functional connectivity of three connections was associated with increased behavioral inhibition at age 2. One connection (between the right ventrolateral prefrontal cortex and the right temporal-parietal junction) included the ventral attention network seed, and two connections (between the medial prefrontal cortex and both the right superior parietal lobule and the left lateral occipital cortex) included the default mode network seed. Conclusions: Neonatal functional connectivity of the ventral attention and default mode networks is associated with behavioral inhibition at age 2. These results inform the developmental neurobiology of behavioral inhibition and anxiety disorders and may aid in early risk assessment and intervention.
Development of autoimmune pancreatitis is independent of CDKN1A/p21-mediated pancreatic inflammation
Authors: Gitta M Seleznik, Theresia Reding, Lukas Peter, Anurag Gupta, Sabrina G Steiner, Sabrina Sonda, Caroline S Verbeke, Emmanuel Dejardin, Igor Khatkov, Stephan Segerer, Mathias Heikenwalder, Rolf Graf
Journal: Gut (2017)

Objective Chronic pancreatitis (CP) and autoimmune pancreatitis (AIP) are characterised by different inflammatory processes. If pancreatic inflammation is a prerequisite for autoimmunity is still unclear. AIP is considered mostly a T cell-mediated disease; however, in induction of CP, macrophages play a pivotal role. p21—a member of cyclin-dependent kinase inhibitors—can influence inflammatory processes, in particular can regulate T cell activation and promote macrophage development. We therefore examined the role of p21-mediated inflammation in AIP. Design We intercrossed lymphotoxin (LT) overexpressing mice (Tg(Ela1-LTa,b))—a model to study AIP development—with p21-deficient mice. Furthermore, we characterised p21 expression in human AIP and non-AIP specimens. Results p21 deficiency in LT mice (LTp21 −/− ) prevented early pancreatic injury and reduced inflammation. In acinar cells, diminished proliferation and abrogated activation of non-canonical nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathway was observed. In contrast, 12-month-old LT mice with and without p21 had similar inflammatory signatures and T–B cell infiltration. Interestingly, LT and LTp21 −/− mice had comparable tertiary lymphoid organs (TLOs), autoantibodies and elevated IgG levels. However, acinar cell proliferation, acinar-to-ductal metaplasia and acinar non-canonical NF-κB pathway activation remained impaired in LTp21 −/− pancreata. Conclusions Our findings indicate that p21 is crucial for pancreatic inflammation in LT-driven pancreatic injury. p21 is involved in early acinar secretion of inflammatory mediators that attract innate immune cells. However, p21 is not essential for humoral immune response, accountable for autoimmunity. Remarkably, p21 renders acinar cells less susceptible to proliferation and transdifferentiation. We therefore suggest that AIP can also develop independent of chronic inflammatory processes.
Integrating genomics and genetics into clinical trials for patient stratification
Authors: Charles Perou
Journal: Clinical Cancer Research (2008)

ED02-03   	The use of gene expression microarrays in clinical medicine is a goal that is being realized because the technology is maturing, and a handful of prognostic and predictive profiles have been validated across multiple patient sets. Our gene expression profiling studies have focused on identifying the dominant biological subtypes of breast cancer. These studies identified five major molecular intrinsic subtypes of breast cancer (Luminal A, Luminal B, Basal-like, HER2-enriched, and Normal-like), which show significant differences in patient survival and metastatic potential. Mounting evidence also suggests that these subtypes vary in their responsiveness to chemotherapeutics and biologic agents. In fact, the expression of drug targets like ER, HER2, and HER1 within selected subtypes strongly suggests that the use of specific biologic agents will be subtype-specific; therefore, I will discuss the development of improved predictors for the intrinsic subtypes and how this information can be used to help predict the benefits of endocrine-therapy, and neoadjuvant chemotherapy.  For breast cancer patients, clinical trials are increasing being run within biologically-defined classes (i.e. ER+, HER2+ and Triple-negatives), and many of these trials have embedded correlative sciences studies that utilize genomic analyses. For example, many new trials are focused on “Triple-negative” breast tumors (i.e. ER-, PgR-, HER2-), which is an immunohistochemical based assay for the stratification of patients for inclusion into clinical trials. The Triple-negative phenotype is not, however, a validated biomarker and data will be presented that compares and contrasts the genomic distinction of Basal-like versus Triple-negative.  Lastly, despite the prognostic and predictive abilities of the intrinsic subtype classification of Basal-like, the treatment options for these patients is still limited to combination chemotherapeutics. Our results suggest, however, that the HER1-RAS-MAPK pathway is critical to this subtype. We have initiated a clinical trial where pre-selected Triple-negative patients received a HER1 inhibitor alone (cetuximab) and in combination with carboplatin (NCT00232505), with genomic endpoints performed. Analyses of these data again highlight the importance of the HER1-RAS-MAPK pathway, but suggest that this pathway is being activated via non-HER1-ligand mediated methods. In addition, these data identify and confirm the importance of a new potential subtype of breast tumor called the “Claudin-low” group; this subtype appears enriched for potential tumor initiating cell markers, is related to Basal-like tumors, and is also classified as Triple-negative. These findings highlight that genomics can sometimes provide further subdivisions within clinically defined groups, which is valuable additional information that might change treatment decisions.