tbuckley/cabot-search huggingface dataset:
08.24 Monoclonal acpa antibodies recognising a common citrulline motif are mainly dependent on light chain hypermutations for antigen recognition
Authors: Johanna Steen, Björn Forsström, Lena Israelsson, Akilan Krishnamurthy, Monika Hansson, Peter Sahlström, Ragnhild Stålesen, Victoria Odowd, Stephen Rapecki, Lars Klareskog, Anca Catrina, Peter Nilsson, Daniel Lightwood, Vivianne Malmström
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Anti-citrullinated protein antibodies (ACPA) can be detected many years before disease onset, implicating that not all ACPAs are pathogenic and that the autoantibodies undergo critical maturation steps closer to disease onset. We have studied the ACPA profile of synovial fluid and of monoclonal antibodies generated from plasma cells of the same synovial fluid to address these questions. <h3>Materials and methods</h3> IgG-secreting cells from RA synovial fluid were isolated, the variable Ig regions were amplified, and recombinant monoclonal antibodies were expressed. The antibody reactivity to citrullinated peptides were addressed both by a planar multi array of RA associated peptides, as well as on a 1 75 000 peptide micro-array of arginine/citrulline peptides from extracellular matrix proteins. The matching synovial fluid was also analysed on the peptide arrays. Chimeric monoclonal antibodies were produced based on IMGT predicted germline sequences of the ACPAs, to address the importance of hypermutations in the heavy versus the light chain. The induction of osteoclastogenesis by the ACPAs were tested in an <i>in vitro</i> assay. <h3>Results</h3> Sera from RA-patients display wide cross-reactivity between many citrullinated proteins and peptides. Synovial fluid replicates this pattern, and a glycine-rich consensus sequence could be deduced. The monoclonal ACPAs recognised different consensus sequences, of which some replicated the dominant polyclonal pattern. To dissect the contribution of the heavy and light chain to antigen recognition, chimeric variants were expressed where either the light or the heavy chain was exchanged with the respective germline sequence, or to an unrelated chain. Surprisingly, the ACPAs with the common consensus epitope were highly dependent on the light chain mutations for citrulline reactivity, while the heavy chain appeared primarily important for stability and conformation, independent on the acquired mutations. Even if these ACPA were highly cross-reactive, they did not cause osteoclastogenesis. The pathogenic ACPA was instead dependent on hypermutations in both heavy and light chains for citrulline reactivity, and had a more restricted citrulline peptide reactivity. <h3>Conclusions</h3> Our data lend support to the observed high cross-reactivity of ACPA between citrullinated peptides. We also find differences in citrulline-reactivity patterns and light chain contribution between pathogenic and non-pathogenic ACPA.
Range in Activity of Several Enzymes in Normal and Neoplastic Tissues of Mice
Authors: Jesse P. Greenstein, J. W. Thompson
Journal: JNCI Journal of the National Cancer Institute (1943)

Journal Article Range in Activity of Several Enzymes in Normal and Neoplastic Tissues of Mice Get access Jesse P. Greenstein, Jesse P. Greenstein senior biochemist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar J. W. Thompson J. W. Thompson pharmacologist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 4, Issue 3, December 1943, Pages 275–281, https://doi.org/10.1093/jnci/4.3.275 Published: 01 December 1943
Anaphylaxis associated with omalizumab administration: Risk factors and patient characteristics
Authors: Phillip L. Lieberman, Ilisten Jones, Richa Rajwanshi, Karin Rosén, Dale T. Umetsu
Journal: Journal of Allergy and Clinical Immunology (2017)

The omalizumab product label includes a black box warning for anaphylaxis. As of the end of 2016, there has been an estimated cumulative exposure of ∼31,000 patient-years in clinical trials and 819,000 patient-years in the postmarketing setting. Episodes of anaphylaxis have been observed in association with omalizumab use since the initial human studies and after its approval for allergic asthma in 2003. In 2016, Lieberman et al,1 reported data from a postmarketing case-control study (The Pharmacosurveillance Data Repository of Patients With and Without History of Anaphylactic Reactions Subsequent to Xolair Dosing [X-PAND], N = 30) that examined cases of anaphylaxis related to omalizumab use.
03.21 Alterations in t-cell surface glycosylation pattern and its relevance to galectin-1-mediated immunoregulatory deficiency in sle
Authors: Ákos Hornung, Enikő Szabó, Ágnes Czibula, Éva Monostori, László Kovács
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> We have previously shown that activated T-cells from systemic lupus erythematosus (SLE) patients are resistant to the apoptotic effects of galectin-1 (Gal-1), an endogenous immunoregulatory lectin. The expression of de <i>novo</i> synthesised, intracellular Gal-1 (icGal-1) was also deficient in SLE activated T-cells, and we have demonstrated that icGal-1 levels affect apoptosis induction by extracellular Gal-1 (ecGal-1). However, production of icGal-1 may not be the only regulatory factor in this process, since binding of ecGal-1 to T-cells and its apoptotic activity depends on the surface glycosylation of T-cells. We have hypothesised that the cell-surface glycosylation pattern, and consequently, lectin-binding ability in SLE T-cells is altered, and that the abnormal expression of glycosylation enzymes may account for these changes. <h3>Materials and methods</h3> Lectin-binding assays were performed using a set of plant lectins and human recombinant Gal-1 on resting and activated T-cells with multi-colour flow-cytometry in 9 patients with active SLE and 15 healthy controls. mRNA levels of thirteen glycosylation enzymes involved in the development of N-glycan structures on T-cells were measured with qPCR, and were correlated with lectin binding ability. <h3>Results</h3> As compared with the resting state, the increase in Gal-1 binding during activation was significantly lower in SLE T-cells than in controls, and the level of Gal-1 binding maximum was significantly reduced in SLE activated T-cells than in controls. Binding maximum of plant lectins that recognise high complexity N-glycans also increased less in SLE T-cells than in controls during activation. mRNA level of sialyltransferase ST3GAL6 was increased and neuraminidase Neu1 was decreased in active SLE patients as compared to controls. The ST6GAL1/NEU1 ratio in SLE patients positively correlated with the SLEDAI disease activity index. <h3>Conclusion</h3> SLE T-cells show decreased complexity of N-glycan structures. Increased ST3GAL6 and decreased Neu1 expression result in an increased density of terminal sialic acids, and this may explain the impaired Gal-1 binding. In addition to the previously described deficiency in icGal-1 expression upon activation, our present findings of an attenuated glycan complexity and a shift toward terminal sialylation provide a further mechanism of pathological T-cell activation and regulation of T-cell viability in SLE. <h3>Reference</h3> Deák M, Hornung Á, Novák J, Demydenko D, Szabó E, Czibula Á, Fajka-Boja R, Kriston-Pál É, Monostori É, Kovács L. Novel role for galectin-1 in T-cells under physiological and pathological conditions. <i>Immunobiology</i>. 2015 220(4):483–9.
Characterizing the clinical relevance of an embryonic stem cell phenotype in lung adenocarcinoma
Authors: M. M. Stevenson, W. Mostertz, C. Acharya, K. Walters, W. Barry, S. Tuchman, N. Ready, M. Onaitis, J. Crawford, A. Potti
Journal: Journal of Clinical Oncology (2009)

11001 Background: Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear whether these phenotypic similarities between normal/embryonic stem cells and mature tumor cells, specific to lung cancer, are a result of underlying biologic processes, such as specific molecular pathways and regulatory networks. Methods: Using a large cohort of lung cancer cell lines with associated gene expression data, genes associated with an embryonic stem cell identity were used to develop a ‘signature’ representative of embryonic stemness (ES) activity specific to lung adenocarcinoma. Differential biology was evaluated using Gene Set Enrichment Analysis (GSEA) and signatures of oncogenic pathway deregulation. The ES signature was applied to three independent early (stage I - IIIa) lung adenocarcinoma data sets (N = 634) with clinically annotated gene expression data. The relationship between the ES phenotype and cisplatin sensitivity was also evaluated. Results: Using Bayesian regression analysis, a 100 gene signature representative of ES activity in lung adenocarcinoma was developed and validated in a leave-one-out-analysis. GSEA identified gene sets significantly represented in the ES signature: signature of neoplastic transformation, signature of undifferentiated cancer, BRCA pathway, and fibroblast serum response pathway, all associated with cancer invasiveness. Adenocarcinomas with ES demonstrated increased activation of RAS (p = 0.0002), MYC (p = 0.0057), wound healing (angiogenesis) (p &lt; 0.0001), chromosomal instability (p &lt; 0.0001), and invasiveness (p &lt; 0.0001) gene signatures. Adenocarcinomas (N= 634) with ES had a decreased survival (p&lt;0.04). The ES signature was not prognostic in prostate, ovarian, or breast adenocarcinomas. Lung tumors (N=634) and adenocarcinoma cell lines (N=31) with ES were more resistant to cisplatin (p&lt;0.0001 and p=0.0063, respectively). Conclusions: Lung adenocarcinomas that share a common gene expression pattern with normal stem cells were associated with decreased survival and increased likelihood of resistance to cisplatin, indicating the aggressiveness of lung tumors with a stem cell phenotype. No significant financial relationships to disclose.
Hereditary angioedema with a mutation in the plasminogen gene
Authors: K. Bork, K. Wulff, L. Steinmüller‐Magin, I. Brænne, P. Staubach‐Renz, G. Witzke, J. Hardt
Journal: Allergy (2017)

Hereditary angioedema (HAE) with normal C1-INH (HAEnCI) may be linked to specific mutations in the coagulation factor 12 (FXII) gene (HAE-FXII) or functional mutations in other genes that are still unknown. We sought to identify and characterize a hitherto unknown type of HAE with normal C1-INH and without mutation in the F12 gene.The study comprised analysis of whole-exome sequencing, Sanger sequencing, and clinical data of patients.We detected a mutation in the plasminogen (PLG) gene in patients with HAEnCI. The mutation c.988A>G was located in exon 9 leading to the missense mutation p.Lys330Glu (K330E) in the kringle 3 domain of the PLG protein. The mutation was identified by next-generation sequencing in 14 patients with HAEnCI belonging to 4 of 7 families. Family studies revealed that this type of HAE was transmitted as an autosomal dominant trait. The PLG gene mutation was present in all studied symptomatic patients and was also found in 9 of 38 index patients from 38 further families with HAEnCI. Most patients had swelling of face/lips (78.3%) and tongue (78.3%). A total of 331 of all 3.795 tongue swellings (8.7%) were associated with dyspnea, voice changes, and imminent asphyxiation. Two women died by asphyxiation due to a tongue swelling.Hereditary angioedema with a mutation in the PLG gene is a novel type of HAE. It is associated with a high risk of tongue swellings.
Evolving beta-lactamase epidemiology in Enterobacteriaceae from Italian nationwide surveillance, October 2013: KPC-carbapenemase spreading among outpatients
Authors: Tommaso Giani, Alberto Antonelli, Mariasofia Caltagirone, Carola Mauri, Jessica Nicchi, Fabio Arena, Elisabetta Nucleo, Silvia Bracco, Annalisa Pantosti, Francesco Luzzaro, Laura Pagani, Gian Maria Rossolini
Journal: Eurosurveillance (2017)

Extended-spectrum beta-lactamases (ESBLs), AmpC-type beta-lactamases (ACBLs) and carbapenemases are among the most important resistance mechanisms in Enterobacteriaceae . This study investigated the presence of these resistance mechanisms in consecutive non-replicate isolates of Escherichia coli (n = 2,352), Klebsiella pneumoniae (n = 697), and Proteus mirabilis (n = 275) from an Italian nationwide cross-sectional survey carried out in October 2013. Overall, 15.3% of isolates were non-susceptible to extended-spectrum cephalosporins but susceptible to carbapenems (ESCR-carbaS), while 4.3% were also non-susceptible to carbapenems (ESCR-carbaR). ESCR-carbaS isolates were contributed by all three species, with higher proportions among isolates from inpatients (20.3%) but remarkable proportions also among those from outpatients (11.1%). Most ESCR-carbaS isolates were ESBL-positive (90.5%), and most of them were contributed by E. coli carrying bla CTX-M group 1 genes. Acquired ACBLs were less common and mostly detected in P. mirabilis . ESCR-carbaR isolates were mostly contributed by K. pneumoniae (25.1% and 7.7% among K. pneumoniae isolates from inpatients and outpatients, respectively), with bla KPC as the most common carbapenemase gene. Results showed an increasing trend for both ESBL and carbapenemase producers in comparison with previous Italian surveys, also among outpatients.
Clinical trials of tyrosine kinase inhibitors for lung cancer in China: a review
Authors: Shan Su, Yi-Long Wu
Journal: Journal of Hematology & Oncology (2017)

With the development of evidence-based medicine, clinical trials have become necessary for investigating and validating the efficacy of new treatments. Over the past 10 years, several clinical trials of new anticancer agents have been designed and launched in China; this has greatly promoted the development of novel agents as well as of innovative clinical study designs. However, despite the significant advances made in clinical trials for novel agents, improvements are still required. In this mini-review, we will summarize the ongoing clinical trials of small molecular inhibitors for the treatment of lung cancer in China, aiming specifically to highlight the active involvement of China in these clinical studies. Furthermore, we will discuss the urgent need for improvement of clinical trials and anticancer agent research in China.
Arteriolar Hyalinosis Predicts Increase in Albuminuria and GFR Decline in Normo- and Microalbuminuric Japanese Patients With Type 2 Diabetes
Authors: Tatsumi Moriya, Kazuki Omura, Madoka Matsubara, Yuki Yoshida, Kei Hayama, Motoshi Ouchi
Journal: Diabetes Care (2017)

OBJECTIVE This study investigated the association between renal histology, as assessed by morphometric analysis using light (LM) and electron (EM) microscopy, and changes in urinary albumin excretion (UAE) and glomerular filtration rate (GFR) in Japanese people with type 2 diabetes in the early stages of diabetic nephropathy. RESEARCH DESIGN AND METHODS We performed percutaneous renal biopsies in 29 patients with type 2 diabetes (22 men, mean ± SD age 49 ± 10 years and GFR 119 ± 27 mL/min/1.73 m2, with 15 normoalbuminuric [UAE &amp;lt;20 μg/min] and 14 microalbuminuric [UAE 20–200 μg/min]) to clarify which histological factors were associated with changes in UAE and GFR during 8.0 ± 3.5 years’ follow-up. Glomerular structural changes including mesangial volume fraction [Vv(Mes/glom)] were estimated using EM, whereas the index of arteriolar hyalinosis (IAH) score was assessed by LM. Patients underwent annual measurement of GFR using iohexol injection with simultaneous urine collections for UAE. RESULTS Vv(Mes/glom) was negatively correlated with baseline and follow-up GFR but not with UAE. The IAH score was positively correlated with UAE and negatively correlated with GFR at follow-up, but it was not correlated with either UAE or GFR at baseline. GFR at follow-up was significantly decreased from baseline in patients with IAH scores ≥2.0 and significantly lower than in patients with IAH scores &amp;lt;2.0. Patients with IAH scores &amp;lt;2.0 showed no significant change in GFR during follow-up. CONCLUSIONS Arteriolar hyalinosis is an additional histological predictor for albuminuria increase and GFR decline in normo- and microalbuminuric Japanese people with type 2 diabetes.
Abstract P219: Role of Angiotensin Type I Receptor and β <sub>1</sub> Integrin in Stretch-Induced Activation of Akt and JNK in Cardiac Myocytes
Authors: FNU Gerilechaogetu, Hao Feng, Honey B Golden, Ricardo J Cristales, Kumar Dasuri, Damir Nizamutdinov, Donald M Foster, Carl Tong, David E Dostal
Journal: Circulation Research (2011)

Cardiac hypertrophy is a common response to mechanical stimuli, such as increased hemodynamic load and exercise. However, the underlying mechanotransduction processes are poorly understood. Recent studies indicate that both β 1 integrin and angiotensin type I receptor (AT 1 R) can serve as mechanoreceptors in the intact myocardium and isolated cardiac myocytes. Mechanical stress induced activation of Akt and JNK has been associated with various aspects of hypertrophic growth. We used primary cultures of NRVM plated on deformable membranes to test whether static stretch-induced activation (phosphorylation) of Akt and JNK involves β 1 integrin and/or AT 1 R. In these studies, pretreatment with the AT 1 R antagonist Losartan (10 µM), significantly decreased mechanical stretch induced activation of Akt (Akt 473 , 47.1 ± 6.1%, p&lt;0.01 and Akt 308 , 33.1 ± 3.2%, p&lt;0.01, n=5), but not JNK after 15 min, compared to stretch alone. Although expression of dominant-negative β 1 D -integrin (Tac-β 1 D ) alone had no effect on stretch-induced Akt and JNK activation, the addition of Losartan to the culture medium decreased stretch-induced activation of both Akt (Akt 473 , 74.9 ± 10.4%, p&lt;0.01 and Akt 308 , 66.1 ± 8%, p&lt;0.01, n=5) and JNK (60.1 ± 2.5%, p&lt;0.01, n=5), compared to stretch in lacZ expressing cells. Because Rac1 is known to be activated by mechanical stretch in NRVM, we determined whether Rac1 is required for stretch-induced Akt and JNK activation. Adenovirus-mediated expression of dominant-negative Rac1 decreased mechanical stretch induced activation of Akt (Akt 473 , 36.3 ± 7.6%, p&lt;0.05 and Akt 308 , 29.8 ± 6.2%, p&lt;0.05, n=5), but not JNK. Whereas, in NRVM expressing dominant-negative Rac1, Losartan pretreatment further decreased stretch-induced activation of both Akt (Akt 473 , 64.9 ± 10.4%, p&lt;0.05 and Akt 308 , 50.8 ± 7.8%, p&lt;0.01, n=5) and JNK (66.7 ± 11%, p&lt;0.05, n=5). In summary, Akt activation in acutely stretched NRVM was mediated through the AT 1 R, whereas JNK activation could be mediated through either AT 1 R or β 1 integrin. The regulation Akt and JNK was also found to be significantly dependent on Rac1 activation. In conclusion, this study suggests that both AT 1 R and β 1 integrin are important mechanosensors that activate pathways that lead to cardiac myocyte hypertrophy.
EPIDEMIOLOGY OF INJURIES IN ENGLISH COMMUNITY LEVEL RUGBY UNION USING SMS PLAYER SELF-REPORTED DATA
Authors: Simon Roberts, Grant Trewartha, Mike England, Matt Attwood, Keith Stokes
Journal: British Journal of Sports Medicine (2017)

Background The reporting of non-time loss injuries in community sport can be challenging due to infrequent contact between players and team medical staff. Text messaging or short messaging service (SMS) is a possible option for players to self-report these injuries. Objective Assess the incidence, site and inciting event of self-reported match injuries using SMS in men's community rugby union players. Design Using a cohort study design, consenting English community rugby players were contacted by SMS every Monday morning over a 33-week season with a follow-up on Tuesday for non-responders. Questions ascertained whether they played on the previous Saturday, whether they sustained an injury which ‘inhibited or stopped them playing’, the injured body site and if the injury event was contact or non-contact related. Setting English community rugby union during season 2015/16. Participants A total of 2990 players from 81 clubs were invited to participate. Mobile telephone numbers were provided by 1178 players (39%) from 41 clubs. The weekly mean response rate of players reporting whether or not they played was 61±2%. Independent variables Player match exposure, playing position. Main Outcome Measurements Injury incidence. Results Players reported 860 injuries over 9025 matches (71.5 injuries per 1000 player-match hours; 95% CI: 66.7–76.2). Contact events accounted for 84% of injuries. The head was the most commonly injured site (11.1; 95% CI: 9.2–12.9). Injury incidence was similar in forwards (68.7 95% CI 61.8–75.6) and backs (71.7 95% CI 64.1–79.6) but forwards reported a higher incidence of shoulder injuries than backs (9.8 95% CI: 7.2–12.4 versus 5.4 95% CI: 3.3–7.5; P=0.014) and backs reported a higher incidence of thigh injuries (3.3 95% CI: 1.8–4.8 versus 10.6 95% CI: 7.6–13.6; P&lt;0.001). Conclusions SMS is a useful tool for recording self-reported injuries in large cohorts of community team sport players and may provide additional insight into injuries which may not result in missed matches.