tbuckley/cabot-search huggingface dataset:
NEXT-GENERATION RECOMBINANT IMMUNOTOXINS FOR GLIOBLASTOMAS AND MELANOMAS TREATMENT
Authors: C.-T. Kuan, I. H. Pastan, D. D. Bigner
Journal: Neuro-Oncology (2014)

BACKGROUND: Glioblastoma (GBM) remains uniformly lethal despite the progress of conventional therapies, which lack specificity and thus result in high toxicity to normal cells. Immunotargeting therapy such as recombinant immunotoxin (RIT) is an alternative and a Phase I clinical trial of MR1-1-PE38KDEL is undergoing at Duke University Medical Center. To avoid the production of neutralizing antibodies against toxin portion and to allow for repeat treatment cycles, a less immunogenic form of PE, LR-LO10, has been generated by silencing the human B cell epitopes on PE38 and removing the immunodominant T cell epitopes. We have previously developed an affinity-matured glycoprotein NMB (GPNMB)-specific RIT, F6V-PE38, which exhibits significant in vitro and anti-tumor activity against GBM and melanomas. Here we report a newly engineered F6V-LR-LO10 RIT for efficient, targeted therapy of GBM and other GPNMB-expressing cancer patients with normal immunity. METHODS: We have constructed an RIT, F6V-LR-LO10, by fusing a fully human F6V scFv, as VH-(G4S)3-VL, with a truncated form of Pseudomonas exotoxin A, LR-LO10. F6V-LR-LO10 was expressed in E. coli BL21 (DE3), and the inclusion bodies were reduced, refolded, and purified by ion exchange chromatography and gel filtration. The antigen binding of F6V-LR-LO10 was assessed by surface plasmon resonance and flow cytometric analysis. The cytotoxicity was measured by protein inhibition assay on GPNMB-expressing GBM and melanoma cells. The in vivo animal toxicity was tested in nude mice and anti-tumor activity will be assessed in human xenograft mouse models. RESULTS: The F6V-LR-LO10 protein was purified as a monomer of 51 kDa to 95% homogeneity. The F6V-LR-LO10 bound to GPNMB-coated chips with high affinity at KD = 1.1e-8 M. The F6V-LR-LO10 also bound to native GPNMB protein via flow cytometric analysis on GPNMB positive cell lines. We tested the in vitro activity of F6V-LR-LO10 on various glioma and melanoma xenograft cells and demonstrated cell-killing activity. The IC50 of F6V-LR-LO10 on GBM D392 cells was 1.5 ng/mL; the IC50 was 10 ng/mL and 15 ng/mL on melanoma DM443 and DM440 cells, respectively, and that was comparable to the IC50 of F6V-PE38, while negative control RIT did not kill those cells. The animal toxicity (MTD) was greatly reduced by >17 fold for F6V-LR-LO10 than F6V-PE38. CONCLUSIONS: Our experiments showed that a new fully human anti-GPNMB RIT, F6V-LR-LO10, is highly active with higher therapeutic index and is predicted to have low immunogenicity in humans. This next-generation RIT is suitable for further clinical development in therapy of GBM, melanoma, and other GPNMB-expressing malignancies. SECONDARY CATEGORY: Preclinical Experimental Therapeutics.
E Antigen and Anti-E in the Serum of Asymptomatic Carrier Mothers as Indicators of Positive and Negative Transmission of Hepatitis B Virus to Their Infants
Authors: Kiyshi Okada, Ichiro Kamiyama, Minako Inomata, Mitsunobu Imai, Yuzo Miyakawa, Makoto Mayumi
Journal: New England Journal of Medicine (1976)

Testing of serum samples of 23 pregnant women who were asymptomatic carriers of hepatitis B surface antigen for e antigen and antibody to e with an immunodiffusion technic identified 10 mothers with e antigen and seven with e antibody. Their babies were tested for hepatitis B surface antigen in serum at intervals for more than 12 months. In all 10 babies born to e-antigen-positive mothers hepatitis B surface antigen developed and persisted through the observation period, and all 10 elder siblings of these newborn babies were found to be asymptomatic carriers. In remarkable contrast, all seven babies born to mothers positive for antibody to e escaped antigenemia, and none of their three elder siblings carried surface antigen. On the basis of these results, e antigen may be used as an indicator of transmission, and antibody to e as that of absence of transmission of hepatitis B virus from carrier mothers to children.
A better way of sharing patient safety information is needed
Authors: K. Ferguson, I. A. Walker
Journal: BMJ (2012)

Aim: To determine whether up-regulation of basic fibroblast growth factor (bFGF) in VX2 cells reduces tumor necrosis. Materials and Methods: VX2 cells were transfected with expression vector containing cDNA of rabbit bFGF. Stable clones producing rabbit bFGF (bFGF-VX2) were selected. bFGF-VX2 (n=5) or non-transfected VX2 (control) (n=5) cells were implanted into leg muscle of 10 rabbits. The tumors were characterized 21 days after grafting. Results: Overexpression of bFGF by VX2 tumors significantly reduced necrosis (p&lt;0.0223) and increased cell viability (p&lt;0.0223), without effect on the mean vascular density. bFGF concentration was significantly higher in bFGF-VX2 tumors (p&lt;0.0062) and negatively correlated with tumor volume at day 21 (ρ=−0.927, p&lt;0.0034). Vascular endothelial growth factor concentration was significantly lower in bFGF-VX2 tumors (p&lt;0.0105) and negatively correlated with the bFGF concentration of tumors (ρ=−0.903, p&lt;0.0067). Conclusion: The overexpression of bFGF in VX2 cells increased tumor viability and reduced necrosis, making the evaluation of long-term anticancer therapies possible in this model.
AB0107 AKT activation by fibronectin fragment leads to NF-KB up-regulation in rheumatoid arthritic chondrocytes
Authors: T. Yasuda
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Increased fibronectin fragments are thought to contribute to joint destruction in rheumatoid arthritis (RA). However, the mechanism whereby fibronectin fragments cause catabolic activities is not totally understood. While COOH-terminal heparin-binding fibronectin fragment (HBFN-f)has been shown to activate nuclear factor (NF)-κB pathway, intracellular upstream events that cause NF-κB up-regulation in response to HBFN-f remain unclear. <h3>Objectives</h3> This study was aimed to elucidate the involvement of phosphoinositide-3-OH kinase (PI3K)/Akt pathwayin NF-κB activation by HBFN-f in RA chondrocytes. <h3>Methods</h3> Chondrocytes isolated from articular cartilage from RA knee joints were cultured in monolayer with HBFN-f. Secreted levels of nitric oxide (NO) in conditioned media were determined. Activation of NF-κB and Akt pathways was assessed with enzyme-linked immunosorbent assay (ELISA). Involvement of CD44 in HBFN-f action was evaluated using anti-CD44 antibody and high molecular weight hyaluronan (HA). <h3>Results</h3> In chondrocyte monolayer cultures, HBFN-f stimulated NO production in association with up-regulation of NF-κB and Akt. Inhibition studies using BAY11-7085 confirmed that NO production by HBFN-f was dependent on NF-κB pathway. Inhibition studies using LY294002 revealed the requirement of PI3K/Akt pathway for NF-κB activation by HBFN-f. Anti-CD44 treatment with anti-CD44 antibody and HA resulted in significant inhibition of HBFN-f actions on activation of Akt and NF-κB, and on NO production. <h3>Conclusions</h3> This is the first study demonstrating that HBFN-f activates PI3K/Akt pathway leading to up-regulation of NF-κB through interaction with CD44. Elucidation of intracellular pathways activated by fibronectin fragments may be helpful to understand the pathological process in RA cartilage destruction. <h3>Disclosure of Interest</h3> None Declared
AB0943 Monocyte/Neutrophil (M/N) CD64 Ratio is Useful for Differentiating Infection from Disease Activity in Systemic Lupus Erythematosus (SLE) Patients: Table 1.
Authors: A. Kikuchi-Taura, S. Tsuji, S. Ohshima, A. Yura, M. Katayama, A. Watanabe, S. Teshigawara, M. Yoshimura, E. Kudo-Tanaka, Y. Harada, Y. Katada, M. Matsushita, A. Kitatoube, J. Hashimoto, Y. Saeki
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Clinical decision-making in the management of fever is difficult when distinguishing infection and high disease activity in SLE. CD64 (FcγRI) is upregulated on monocytes as a response to interferon (IFN)-α in SLE<sup>1</sup>. In infection, upregulation of CD64 expression on neutrophils occurs with IFN-γ, granulocyte colony stimulating factor, or lipopolysaccharide. CD64 on neutrophils is known to be a sensitive and specific marker for detection of infection in rheumatoid arthritis patients (using a cutoff value of 2000 molecules per cell)<sup>2</sup>. <h3>Objectives</h3> We examined the utility of quantitative CD64 molecules expressed on monocytes and neutrophils, and calculated mCD64/nCD64 ratio as a marker for distinction between infection and disease activity in SLE. <h3>Methods</h3> In this study, 12 SLE patients with infections (iSLE), 10 SLE patients with high disease activity, (aSLE) (SLEDAI 12.1±7) and 20 healthy controls (HC) were enrolled. The expression level of CD64 per monocyte and neutrophil quantitatively were measured by flow cytometry, and the mCD64/nCD64 ratio were calculated. Comparisons of levels within each group were analyzed, and levels of respective measurements at both pre- and post-treatment were analyzed. <h3>Results</h3> Results of mCD64, nCD64 and m/nCD64 ratio are presented in Table1. The nCD64 value of iSLE and aSLE was 2000 molecules/cell or more together. There was no difference in mCD64 of iSLE and aSLE. m/nCD64 ratio was significantly lower among iSLE than in those without infection, aSLE, or healthy controls (p&lt;0.001). After each treatment, the value of mCD64 and nCD64 were significantly decreased in iSLE and aSLE. But there was no change in mCD64/nCD64 ratio in aSLE, on the other hand it was increased in iSLE (p&lt;0.01). <h3>Conclusions</h3> A cutoff value of 2000 molecules per cell on neutrophils did not clearly distinguish infection from exacerbation in SLE. However, our results suggest that calculating m/n CD64 ratio can be useful to distinguish infection or disease activity in SLE. Moreover, combined mCD64 and nCD64 could help to guide therapeutic decision in SLE. <h3>References</h3> Li, Y. et al. Arthritis Research &amp; Therapy 2010, 12:R90. Matsui, T. et al. The Journal of Rheumatology 2006; 33: 2416-24. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2779
Abstract 73: The transfection of high mobility group protein AT-hook 1 (HMGA1) is associated with the development of androgen independency in prostate cancer cells
Authors: Natsuki Takaha, Ichiro Takeuchi, Yasunori Kimura, Tsuyoshi Iwata, Terukazu Nakamura, Fumiya Hongo, Kazuya Mikami, Kazumi Kamoi, Koji Okihara, Akihiro Kawauchi, Tsuneharu Miki
Journal: Cancer Research (2012)

Abstract The level of HMGA1 is low in androgen-dependent prostate cancer cell line (LNCaP), but is high in androgen-independent prostate cancer cell lines (DU145, PC-3). We have reported that the level of HMGA1 expression in prostate cancer cells is correlated with the extent of chromosomal aberrations (Can Res, 2002) and that transfection of HMGA1 into prostate cancer cell lines induces unbalanced chromosomal rearrangement and expression of matrix metalloproteinase 2 (Prostate, 2004). This suggests that HMGA1 is a strong candidate gene playing a potential role in the progression of prostate cancer. These findings have prompted us to evaluate the effect of HMGA1 on androgen independency, which is associated with the progression of prostate cancer. The androgen-dependent LNCaP cell line was induced to an androgen-independent subline (LN95) by being maintained for long term in the absence of androgen. The absence of androgen induced a 2.5-fold increase in the level of HMGA1 in the LN95 cell line. Androgen deprivation in vitro for 4 days as well as that for 8 days in vivo induced significant increase in the level of HMGA1 in parental LNCaP. On the other hand, the level of HMGA1 in normal prostate of mice 4 days and 11 days after castration as well as sham operation was almost undetectable. The cell proliferation rates of LNCaP cell transfected with HMGA1a vector (LN-H1) and LNCaP cell transfected with control empty vector (LN-EV) were determined with various concentrations (0-1nM) of dihydrotestosterone (DHT) by WST-8 assay in order to examine the effect of HMGA1 on androgen sensitivity. The expression of HMGA1 protein in LNH1 was confirmed to be 3.2-fold as high as that in LNEV. In low concentration (0-0.01 nM) of DHT, LNEV cell could not keep proliferation over day 6, while LNH1 could maintain proliferation over day 6. The cell proliferation rate at day 8 of LN-H1 grown in low concentration (0-0.01 nM) of DHT was about 2-fold higher than that of LN-EV. In contrast, both LN-H1 and LN-EV cells grew equally well in higher concentrations (0.1-1 nM) of DHT and could also keep proliferation over day6. Suppression of HMGA1 in DU145 and PC-3 by siRNA decreased cell proliferation rate and colony formation ability by 40% and 10-fold, respectively, in androgen-deprived medium. These data suggest that HMGA1 is associated with the transition of prostate cancer cells from androgen-sensitive to androgen-independent growth and plays a role in the cell growth of androgen-independent prostate cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 73. doi:1538-7445.AM2012-73
FRI0507 Screening and diagnostic modalities in connective tissue disease-associated pulmonary arterial hypertension: a systematic review
Authors: H. Gladue, N. Altorok, W. Townsend, V. Mclaughlin, D. Khanna
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Pulmonary arterial hypertension (PAH) affects patients with connective tissue diseases (CTD), especially systemic sclerosis (SSc) and MCTD. Despite this, there continues to be delay in screening and diagnosis of these patients. <h3>Objectives</h3> We undertook a systematic review to summarize the best evidence for screening and diagnosis of PAH in CTD. <h3>Methods</h3> A systematic search was performed in Pubmed, EMBASE, Web of Science and Scopus databases up to June 2012 with an experienced librarian, related to PH and CTD. We only focused on WHO group I PAH and excluded manuscripts that did not rule out interstitial lung disease (WHO group III) or left heart disease (WHO group II), or if the diagnosis of pulmonary arterial hypertension (PAH) was not made by RHC. <h3>Results</h3> We started with 2805 titles, 838 abstracts, and included 21 manuscripts. Twelve studies assessed the tricuspid regurgitation velocity (VTR) or equivalent right ventricular systolic pressure (RVSP) using transthoracic echocardiogram (TTE) as a threshold for RHC in patients suspected as having PAH. 11 of these studies were in SSc, and one pertained to SLE. The screening threshold for RHC was VTR &gt;2.73 to &gt;3.16 m/s without symptoms or 2.5 to 3.0 m/s with symptoms and resulted in 20-67% of patients having RHC proven PAH (Table). In the SLE study, VTR &gt;3.0 m/s on TTE led to RHC in 3 patients and none had PAH. Three studies looked at pulmonary function tests and various DLCO% predicted cut-offs. These studies suggest that a low DLCO% 45-70% is associated with a 5.6-7.4% development of PAH, and the decline in DLCO% is associated with an increase in the specificity (For 60% cut off, spec= 45%, and for 50% cut off, spec=90%]) for PAH. Five studies looked at NT-ProBNP and a cut-off &gt;209pg/ml has a high sensitivity (90-100%) and a specificity ranging from 45-95%. Single studies looked at EKG findings, cardiac MRI, Chest X-ray, CT, autoantibodies, laboratory values and physical exam findings. <h3>Conclusions</h3> Our systematic review shows that most evidence exists for use of TTE, pulmonary function tests, and NT-ProBNP for screening and diagnosis of PAH in CTD. These data will be used to develop guidelines for screening and diagnosis of PAH in CTD. <h3>References</h3> Humbert, M., A. Yaici, et al. (2011). "Screening for pulmonary arterial hypertension in patients with systemic sclerosis: clinical characteristics at diagnosis and long-term survival." Arthritis Rheum<b>63</b>(11): 3522-3530. Vachiery, J. L. and G. Coghlan (2009). "Screening for pulmonary arterial hypertension in systemic sclerosis." Eur Respir Rev<b>18</b>(113): 162-169. <h3>Disclosure of Interest</h3> None Declared
GPs have continuing concern over primary care groups
Authors: L. Beecham
Journal: BMJ (1998)

The government has agreed to make £22m ($35.2m) available to help establish primary care groups, which it proposed in the NHS white paper for England, The New NHS .

The announcement came a few days after the leader of the BMA's family doctors' committee, Dr John Chisholm, asked the government to take action to allay GPs' worries. He said that the £22m “will go some way towards providing GPs and shadow primary …
An autopsy study suggests that diabetic nephropathy is underdiagnosed
Authors: Celine Q.F. Klessens, Tess D. Woutman, Kimberley A.M. Veraar, Malu Zandbergen, Elisabeth J.J. Valk, Joris I. Rotmans, Ron Wolterbeek, Jan A. Bruijn, Ingeborg M. Bajema
Journal: Kidney International (2016)
Abstract 4286: Hepatocyte growth factor-mediated gastrin-releasing peptide induces IL-8 expression through Ets-1 in gastric cancer cells.
Authors: Sung Ae Koh, Kyung Hee Lee, Eun Young Choi, Min Kyung Kim, Byung Ik Jang, Se Won Kim, Sang Woon Kim, Sun Kyo Song, Jae Ryong Kim
Journal: Cancer Research (2013)

Abstract Gastric cancer cells secrete a variety of pro-angiogenic molecules, including IL-8 and VEGF. However, factors regulating the expression of pro-angiogenic genes for gastric cancer remain largely undefined. We investigated the role of HGF-induced activation of GRP and Ets-1 transcription factor in expression of the pro-angioigenic factor, IL-8. The genes associated with angiogenesis induced by HGF were screened using cDNA microarray technology in two gastric cancer cell lines (NUGC-3 and MKN-28). First, GRP RNA and protein were confirmed to be up-regulated. Then, expression of GRP, Ets-1, and IL-8 were further estimated by Western blot analysis. A role for Ets-1 in HGF-induced up-regulation of IL-8 was determined by knockdown of Ets-1 with Ets-1 sh-RNA and a chromatin immune precipitation assay. The levels of GRP, Ets-1, and IL-8 were up-regulated in cells treated with HGF in a dose-dependent manner. HGF-induced expression of Ets-1 and IL-8 was increased more by GRP treatment, and inhibited by pre-treatment with an ERK 1/2 inhibitor (PD098059). HGF-induced up-regulation of IL-8 was repressed by Ets-1 knockdown. HGF enhanced the binding activity of Ets-1 to the IL-8 promoter in control cells, but not in the Ets-1 shRNA cells. We confirmed the functional role of HGF-induced Ets-1 in activation of the IL-8 promoter by the reporter gene assay. Down-regulation of IL-8 also decreased in vitro cell invasion. In conclusion, HGF mediated the GRP induction of IL-8 expression through Ets-1, which thus might serve as a promising target for gastric cancer therapy. Key words: HGF, GRP, Ets-1, IL-8 Citation Format: Sung Ae Koh, Kyung Hee Lee, Eun Young Choi, Min Kyung Kim, Byung Ik Jang, Se Won Kim, Sang Woon Kim, Sun Kyo Song, Jae Ryong Kim. Hepatocyte growth factor-mediated gastrin-releasing peptide induces IL-8 expression through Ets-1 in gastric cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4286. doi:10.1158/1538-7445.AM2013-4286
THU0342 Immunohistochemical Quantification by Stereological Technique of Immune-Competent Cells in Biopsies from Achilles Tendons in Healthy and Patients with Chronic Tendinopathy
Authors: M.S. Kragsnaes, U. Fredberg, K. Stribolt, S.G. Kjaer, K. Bendix, T. Ellingsen
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Limited data exist on the presence and function of immune-competent cells in chronic tendinopathic tendons, and their potential role in inflammation and tissue healing. <h3>Objectives</h3> To quantify subtypes of immune-competent cells in biopsies from non-ruptured chronic tendinopathic Achilles tendons and healthy control tendons. <h3>Methods</h3> Fifty patients with non-ruptured chronic Achilles tendinopathy and 15 healthy subjects were included. At time of inclusion, the Achilles tendons were examined clinically and evaluated with ultrasound with regard to tendon thickness and Doppler flow grade immediately before an ultrasound-guided tendon biopsy was obtained. Tissue samples were evaluated immunohistochemically by quantifying the presence of macrophages (CD68-KP1<sup>+</sup>), iron<sup>+</sup> hemosiderophages (Perls Blue), T-lymphocytes (CD3<sup>+</sup>), B-lymphocytes (CD20<sup>+</sup>), natural killer cells (CD56<sup>+</sup>), mast cells (NaSDCl<sup>+</sup>), Schwann cells (S100<sup>+</sup>) and endothelial cells (CD34<sup>+</sup>) using a stereological technique. Cell counts were expressed as number of positive cell profiles per biopsy area (c/a), except for CD68-KP1 and CD34, which were quantified using a point counting grid to estimate number of grid hits of stained cells which were then calibrated to the total biopsy area (expressed as cell fractional area (%)). Descriptive data are reported as median and range if nothing else specified. Comparisons between groups were made with Mann-Whitney <i>U</i> tests or Fisher9s Exact Tests. The level of significance was set at <i>P</i> &lt;0.05. <h3>Results</h3> Macrophages, T-lymphocytes, mast cells, and natural killer cells were observed in the majority (range: 52–96%) of biopsies from non-ruptured chronic tendinopathic Achilles tendons. <h3>Conclusions</h3> This study provides evidence for the presence of immune-competent cells in the majority of biopsies from non-ruptured chronic tendinopathic Achilles tendons. Macrophages and endothelial cells were significantly more numerous in chronic tendinopathic tendons than in healthy tendons. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1684
P238 METABOLICALLY INDUCED LIVER INFLAMMATION PROMOTES NASH DEVELOPMENT AND DIFFERS FROM ENDOTOXIN- AND CYTOKINE-INDUCED INFLAMMATION
Authors: W. Liang, J.H. Lindeman, A. Menke, D. Koonen, P.Y. Wielinga, M. Morrison, P. Mulder, L.A.M. Havekes, A.M. van den Hoek, R. Kleemann
Journal: Journal of Hepatology (2014)
Save Our Pubs &amp; Clubs
Authors: Jane Cassidy
Journal: BMJ (2011)

The Save Our Pubs & Clubs campaign wants to see an amendment to the public smoking ban, which it says has led to hundreds of pubs and clubs going out of business since 2007. It would like the United Kingdom to be brought into line with other European countries where smoking is still allowed in some licensed premises or in “comfortable” outdoor smoking rooms.

The television chef and pub owner Antony Worrall Thompson is the campaign’s patron. Supporters include the Working Men’s Club and Institute Union, 251 pubs and clubs, the artist David Hockney, and the musician Joe Jackson.

MPs who have pledged their support include Brian Binley (Conservative, Northampton South), Philip Davies (Conservative, Shipley), John Hemming (Liberal Democrat, Birmingham Yardley), Simon Kirby (Conservative, Brighton Kemptown), Greg Knight (Conservative, East Yorkshire), …