tbuckley/cabot-search huggingface dataset:
Anti-CD3 × Anti-Epidermal Growth Factor Receptor (EGFR) Bispecific Antibody Redirects T-Cell Cytolytic Activity to EGFR-Positive Cancers <i>In vitro</i> and in an Animal Model
Authors: Ursula Reusch, Magesh Sundaram, Pamela A. Davol, Sarah D. Olson, James B. Davis, Kurt Demel, Julie Nissim, Ritesh Rathore, Paul Y. Liu, Lawrence G. Lum
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Targeting epidermal growth factor receptor (EGFR) overexpressed by many epithelial-derived cancer cells with anti-EGFR monoclonal antibodies (mAb) inhibits their growth. A limited number of clinical responses in patients treated with the anti-EGFR mAb, (cetuximab), may reflect variability in EGFR type or signaling in neoplastic cells. This study combines EGFR-targeting with the non-MHC–restricted cytotoxicity of anti-CD3 activated T cells (ATC) to enhance receptor-directed cytotoxicity. Experimental Design: ATC from normal and patient donors were expanded ex vivo. Specific cytolytic activity of ATC armed with anti-CD3 × anti-EGFR (EGFRBi) against EGFR-expressing cancer cells derived from lung, pancreas, colon, prostate, brain, skin, or EGFR-negative breast cancer cells was evaluated in 51Cr release assays. In vivo studies comparing tumor growth delay induced by EGFRBi-armed ATCs or cetuximab were done in severe combined immunodeficient/Beige mice (SCID-Beige) bearing COLO 356/FG pancreatic and LS174T colorectal tumors. Results: At effector/target ratios from 3.125 to 50, both EGFRBi-armed normal and patient ATC were significantly more cytotoxic, by 23% to 79%, against EGFR-positive cells over ATC, cetuximab, anti-CD3 alone, or ATC armed with irrelevant BiAb directed at CD20. EGFRBi-armed ATC also secreted significantly higher levels of some TH1/TH2 cytokines compared with ATC alone. In mice, i.v. infusions of EGFRBi-armed ATC (0.001 mg equivalent/infusion) were equally effective as cetuximab (1 mg/infusion) alone for significantly delaying growth of established COLO 356/FG but not LS174T tumors compared with mice that received ATC alone or vehicle (P &amp;lt; 0.001). Conclusions: Combining EGFR antibody targeting with T cell–mediated cytotoxicity may overcome some limitations associated with EGFR-targeting when using cetuximab alone.
PWE-145 Prognostic factors influencing survival after liver resection for colorectal metastasis
Authors: S K P John, A Vallance, S Rehman, S Robinson, R Charnley, B Jaques, D Manas, S White
Journal: Gut (2012)

<h3>Introduction</h3> A variety of factors have been identified in the literature which influence survival following resection of colorectal liver metastases (CRLM). The aim of this study was to identify those factors which influence survival in patients undergoing resection of CRLM in a UK centre. <h3>Methods</h3> All patients having liver resection for CRLM during an 11-year period up to 2011 were identified from a prospectively maintained database and relevant clinical data retrieved from case records. Prognostic factors analysed included tumour size (&gt;5 cm or &lt;5 cm), lymph node status of primary tumour, margin positivity R1 (&lt;1 mm) or R0, neo-adjuvant chemotherapy (for liver), tumour differentiation, number of liver metastasis (4 or more), preoperative CEA (&gt;200 or &lt;200) and whether metastases were synchronous (ie, diagnosed &lt;12 months) or metachronous to the primary tumour. Overall survival (OS) was compared with Kaplan–Meier plots, log rank test. Multi-variate analysis was performed using Cox regression model (SPSS V.19). p&lt;0.05 considered significant. <h3>Results</h3> 432 patients underwent resection of CRLM during this period (67% male; mean age 64.5 years). The overall 5-year survival in this series was 43%. A pre-op CEA&gt;200 was present in 10% of patients and was associated with a poorer 5-year OS (24% vs 45%; p&lt;0.001). A resection margin &lt;1 mm was present in 16% of patients and this had a negative impact on 5 yr OS (15% vs 47%; p&lt;0.001). Tumour differentiation, number, size, presence of biliary or vascular invasion, relationship to primary disease, nodal status of primary, or the use of neoadjuvant chemotherapy had no impact on OS. Multi-variate analysis identified only the presence of a positive resection margin (OR 1.75; p&lt;0.05) and a pre-op CEA&gt;200 (OR 1.88; p&lt;0.01) as independent predictors of poorer OS. <h3>Conclusion</h3> Despite the wide variety of prognostic factors reported in the literature we were only able to identify a pre-op CEA&gt;200 and the presence of tumour within 1 mm of the resection margin as being of value in predicting survival. These variables are likely to identify patients who may benefit from intensive follow-up to enable early adjuvant chemotherapy postoperatively. <h3>Competing interests</h3> None declared.
Recurrent LRP1-SNRNP25 and KCNMB4-CCND3 fusion genes promote tumor cell motility in human osteosarcoma
Authors: Jilong Yang, Matti Annala, Ping Ji, Guowen Wang, Hong Zheng, David Codgell, Xiaoling Du, Zhiwei Fang, Baocun Sun, Matti Nykter, Kexin Chen, Wei Zhang
Journal: Journal of Hematology & Oncology (2014)

The identification of fusion genes such as SYT-SSX1/SSX2, PAX3-FOXO1, TPM3/TPM4-ALK and EWS-FLI1 in human sarcomas has provided important insight into the diagnosis and targeted therapy of sarcomas. No recurrent fusion has been reported in human osteosarcoma.Transcriptome sequencing was used to characterize the gene fusions and mutations in 11 human osteosarcomas.Nine of 11 samples were found to harbor genetic inactivating alterations in the TP53 pathway. Two recurrent fusion genes associated with the 12q locus, LRP1-SNRNP25 and KCNMB4-CCND3, were identified and validated by RT-PCR, Sanger sequencing and fluorescence in situ hybridization, and were found to be osteosarcoma specific in a validation cohort of 240 other sarcomas. Expression of LRP1-SNRNP25 fusion gene promoted SAOS-2 osteosarcoma cell migration and invasion. Expression of KCNMB4-CCND3 fusion gene promoted SAOS-2 cell migration.Our study represents the first whole transcriptome analysis of untreated human osteosarcoma. Our discovery of two osteosarcoma specific fusion genes associated with osteosarcoma cellular motility highlights the heterogeneity of osteosarcoma and provides opportunities for new treatment modalities.
Infliximab and newly diagnosed neoplasia in Crohn's disease: a multicentre matched pair study
Authors: L Biancone
Journal: Gut (2005)

<b>Background and aims:</b> The widespread use of anti-tumour necrosis factor α antibody (Infliximab) in Crohn's disease (CD) raises concerns about a possible cancer risk in the long term. In a matched pair study, we assessed whether Infliximab is associated with an increased risk of neoplasia. <b>Methods:</b> In a multicentre matched pair study, 404 CD patients treated with Infliximab (CD-IFX) were matched with 404 CD patients who had never received Infliximab (CD-C). Cases and controls were matched for sex, age (±5 years), site of CD, age at diagnosis (±5 years), immunosuppressant use, and follow up. New diagnoses of neoplasia from April 1999 to October 2004 were recorded. <b>Results:</b> Among the 404 CD-IFX, neoplasia was diagnosed in nine patients (2.22%) while among the 404 CD-C, seven patients developed neoplasia (1.73%) (odds ratio 1.33 (95% confidence interval 0.46–3.84); p = 0.40). The survival curve adjusted for patient year of follow up showed no differences between CD-IFX and CD-C (p = 0.90; log rank test). In the CD-IFX group, there was one cholangiocarcinoma, three breast cancers, one skin cancer, one leukaemia, one laryngeal cancer, and two anal carcinomas. Among the 7/404 (1.73%) CD-C, there were three intestinal adenocarcinomas (two caecum, one rectum), one basalioma, one spinalioma, one non-Hodgkin's lymphoma, and one breast cancer. Age at diagnosis of neoplasia did not differ between groups (CD-IFX <i>v</i> CD-C: median 50 (range 40–70 years) <i>v</i> 45 (27–72); p = 0.50). <b>Conclusion:</b> In our multicentre matched pair study, the frequency of a new diagnosis of neoplasia in CD patients treated with Infliximab was comparable with CD patients who had never received Infliximab.
Juvenile dermatomyositis in association with 22q11.2 deletion syndrome
Authors: N. Okiyama, T. Yamamoto, K. Watanabe, H. Yokozeki, K. Nishioka
Journal: British Journal of Dermatology (2005)

Journal Article Juvenile dermatomyositis in association with 22q11.2 deletion syndrome Get access N. Okiyama, N. Okiyama Department of Dermatology, Tokyo Medical and Dental University, 1‐5‐45 Yushima, Bunkyo‐ku, Tokyo, Japan E‐mail: naoko705@kd5.so‐net.ne.jp Search for other works by this author on: Oxford Academic Google Scholar T. Yamamoto, T. Yamamoto Department of Dermatology, Tokyo Medical and Dental University, 1‐5‐45 Yushima, Bunkyo‐ku, Tokyo, Japan E‐mail: naoko705@kd5.so‐net.ne.jp Search for other works by this author on: Oxford Academic Google Scholar K. Watanabe, K. Watanabe Department of Dermatology, Tokyo Medical and Dental University, 1‐5‐45 Yushima, Bunkyo‐ku, Tokyo, Japan E‐mail: naoko705@kd5.so‐net.ne.jp Search for other works by this author on: Oxford Academic Google Scholar H. Yokozeki, H. Yokozeki Department of Dermatology, Tokyo Medical and Dental University, 1‐5‐45 Yushima, Bunkyo‐ku, Tokyo, Japan E‐mail: naoko705@kd5.so‐net.ne.jp Search for other works by this author on: Oxford Academic Google Scholar K. Nishioka K. Nishioka Department of Dermatology, Tokyo Medical and Dental University, 1‐5‐45 Yushima, Bunkyo‐ku, Tokyo, Japan E‐mail: naoko705@kd5.so‐net.ne.jp Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 152, Issue 6, 1 June 2005, Pages 1370–1372, https://doi.org/10.1111/j.1365-2133.2005.06622.x Published: 01 June 2005
Physical activity education in the undergraduate curricula of all UK medical schools. Are tomorrow's doctors equipped to follow clinical guidelines?
Authors: Richard Weiler, Stephen Chew, Ngaire Coombs, Mark Hamer, Emmanuel Stamatakis
Journal: British Journal of Sports Medicine (2012)

Physical activity (PA) is a cornerstone of disease prevention and treatment. There is, however, a considerable disparity between public health policy, clinical guidelines and the delivery of physical activity promotion within the National Health Service in the UK. If this is to be addressed in the battle against non-communicable diseases, it is vital that tomorrow's doctors understand the basic science and health benefits of physical activity. The aim of this study was to assess the provision of physical activity teaching content in the curricula of all medical schools in the UK. Our results, with responses from all UK medical schools, uncovered some alarming findings, showing that there is widespread omission of basic teaching elements, such as the Chief Medical Officer recommendations and guidance on physical activity. There is an urgent need for physical activity teaching to have dedicated time at medical schools, to equip tomorrow's doctors with the basic knowledge, confidence and skills to promote physical activity and follow numerous clinical guidelines that support physical activity promotion.
Similarities and differences in lectin cytochemistry of laryngeal and tracheal epithelium and subepithelial seromucous glands in cases of sudden infant death and controls
Authors: F P Paulsen, T Tschernig, A S Debertin, W J Kleemann, R Pabst, B N Tillmann
Journal: Thorax (2001)

<h3>BACKGROUND</h3> It has been speculated that non-specific defence mechanisms of the epithelium and subepithelial seromucous glands play a role in the larynx and lungs in cases of sudden infant death. <h3>METHODS</h3> The larynx and trachea from five children who had died of sudden infant death (SID) syndrome and five control cases of comparable age were compared for the presence of lectin binding sites (12 different lectins tested). <h3>RESULTS</h3> The secretory product of mucin producing cells contained carbohydrates including galactose and sialic acids. Binding sites for fucose and N-acetyl-galactosamine were only present in some of the specimens and distribution revealed no correlation between cases of SID and controls. Epithelial cells and serous cells of seromucous glands contained binding sites for sialic acid in cases of SID and controls. Moreover, binding sites for mannose were detected in these cells but were only present in SID cases. The difference between the SID and control groups as to the presence/expression of concanavalin A was highly significant. <h3>CONCLUSIONS</h3> It is suggested that mucus hypersecretion in SID occurs in response to bacterial toxins or viral infection and is not specific. The different binding sites for mannose in cases of SID and controls could indicate differences in the production of antimicrobial peptides. A disturbed expression pattern of antimicrobial peptides in children who later succumb to SID could be responsible for an imbalance of the local microflora with a higher density of microorganisms on the mucosa. Further studies are required to elucidate the pattern of expression of antimicrobial peptides in subsequent SID victims.
Sulfatide-Reactive Natural Killer T Cells Abrogate Ischemia-Reperfusion Injury
Authors: Seung Hee Yang, Jung Pyo Lee, Hye Ryoun Jang, Ran-hui Cha, Seung Seok Han, Un Sil Jeon, Dong Ki Kim, Junghan Song, Dong-Sup Lee, Yon Su Kim
Journal: Journal of the American Society of Nephrology (2011)

There is a significant immune response to ischemia-reperfusion injury (IRI), but the role of immunomodulatory natural killer T (NKT) cell subtypes is not well understood. Here, we compared the severity of IRI in mice deficient in type I/II NKT cells (CD1d−/−) or type I NKT cells (Jα18−/−). The absence of NKT cells, especially type II NKT cells, accentuated the severity of renal injury, whereas repletion of NKT cells attenuated injury. Adoptively transferred NKT cells trafficked into the tubulointerstitium, which is the primary area of injury. Sulfatide-induced activation of type II NKT cells protected kidneys from IRI, but inhibition of NKT cell recruitment enhanced injury. In co-culture experiments, sulfatide-induced activation of NKT cells from either mice or humans attenuated apoptosis of renal tubular cells after transient hypoxia via hypoxia-inducible factor (HIF)-1α and IL-10 pathways. Renal tissue of patients with acute tubular necrosis (ATN) frequently contained NKT cells, and the number of these cells tended to negatively correlate with ATN severity. In summary, sulfatide-reactive type II NKT cells are renoprotective in IRI, suggesting that pharmacologic modulation of NKT cells may protect against ischemic injury.
Vaccination using oxidized low-density lipoprotein-pulsed dendritic cells reduces atherosclerosis in LDL receptor-deficient mice
Authors: Kim L.L. Habets, Gijs H.M. van Puijvelde, Leonie M. van Duivenvoorde, Eva J.A. van Wanrooij, Paula de Vos, Jan-Willem Cohen Tervaert, Theo J.C. van Berkel, Rene E.M. Toes, Johan Kuiper
Journal: Cardiovascular Research (2009)

Modification of lipoproteins plays an important role in the development of atherosclerosis. Oxidatively modified low-density lipoprotein (oxLDL) has a number of pro-inflammatory effects, whereas immunization with various forms of oxLDL is able to reduce atherosclerosis. The uptake of modified LDL by dendritic cells (DCs) and the presentation of epitopes thereof may form an important step in the immunomodulatory effects of LDL. In this study, we transferred oxLDL-pulsed mature DCs (mDCs) to LDL receptor-null (LDLr−/−) mice and examined the effects on atherosclerosis. Bone marrow-derived DCs were cultured for 10 days in the presence of granulocyte-macrophage colony-stimulating factor. Immature DCs were matured by lipopolysaccharide and pulsed with copper-oxidized LDL. These mDCs were transferred three times to LDLr−/− mice before the induction of atherosclerosis by Western-type diet feeding. The transfer of oxLDL-pulsed mDCs resulted in an 87% reduction in carotid artery lesion size (P < 0.001) with a concurrent increase in plaque stability, whereas treatment using mDCs pulsed with the atherosclerosis-irrelevant antigen, ovalbumin, did not influence lesion size or stability. Furthermore, the vaccination procedure resulted in the induction of oxLDL-specific T cells with a reduced Th1 profile and an increase in oxLDL-specific IgG levels, which contributed to a reduction in foam cell formation. These data indicate that vaccination with oxLDL-pulsed mDCs provides a novel and powerful strategy for the immunomodulation of atherosclerosis.
Major histocompatibility complex class II-associated peptides control the presentation of bacterial superantigens to T cells.
Authors: R Wen, G A Cole, S Surman, M A Blackman, D L Woodland
Journal: The Journal of Experimental Medicine (1996)

Recent studies have shown that only a subset of major histocompatibility complex (MHC) class II molecules are able to present bacterial superantigens to T cells, leading to the suggestion that class-II associated peptides may influence superantigen presentation. Here, we have assessed the potential role of peptides on superantigen presentation by (a) analyzing the ability of superantigens to block peptide-specific T cell responses and (b) analyzing the ability of individual peptides to promote superantigen presentation on I-Ab-expressing T2 cells that have a quantitative defect in antigen processing. A series of peptides is described that specifically promote either toxic shock syndrome toxin (TSST) 1 or staphylococcal enterotoxin A (SEA) presentation. Whereas some peptides promoted the presentation of TSST-1 (almost 5,000-fold in the case of one peptide), other peptides promoted the presentation of SEA. These data demonstrate that MHC class II-associated peptides differentially influence the presentation of bacterial superantigens to T cells.
Faecal calprotectin, lactoferrin, M2-pyruvate kinase and S100A12 in severe ulcerative colitis: a prospective multicentre comparison of predicting outcomes and monitoring response
Authors: D. Turner, S. T. Leach, D. Mack, K. Uusoue, R. McLernon, J. Hyams, N. Leleiko, T. D. Walters, W. Crandall, J. Markowitz, A. R. Otley, A. M. Griffiths, A. S. Day
Journal: Gut (2010)

<h3>Objective</h3> To compare four faecal markers for their ability to predict steroid refractoriness in severe paediatric ulcerative colitis (UC). Construct validity and responsiveness to change were also assessed. <h3>Methods</h3> This was a prospective multicentre cohort study. Stool samples from 101 children (13.3±3.6 years; Pediatric UC Activity Index (PUCAI) at admission 72±12 points) were obtained at the third day of intravenous steroid therapy. Repeated samples at discharge were obtained from 24 children. Predictive validity was assessed using diagnostic utility statistics to predict steroid failure (ie, the need for salvage treatment). Concurrent validity was assessed using correlational analysis with the following constructs: PUCAI, Lindgren and Seo scores, physician9s global assessment, albumin, erythrocyte sedimentation rate and C-reactive protein (CRP). Responsiveness was assessed using test utility and correlational strategies. <h3>Results</h3> Median values (IQR) were very high at baseline for all four markers (calprotectin 4215 μg/g (2297–8808); lactoferrin 212 μg/g (114–328); M2-pyruvate kinase (M2-PK) 363 U/g (119–3104); and S100A12 469 μg/g (193–1112)). M2-PK was numerically superior to the other three markers and CRP in predicting response to corticosteroid treatment (area under the receiver operating characteristic (ROC) curve 0.75 (95% CI 0.64 to 0.85; p&lt;0.001) vs &lt;0.65 for the others). However, it did not add to the predictive ability of the PUCAI (area under the ROC 0.81 (95% CI 0.73 to 0.89)). M2-PK also had the highest construct validity but with a modest mean correlation with all constructs (r=0.3; p&lt;0.05). None of the markers was responsive to change (Spearman9s rho correlation with change in the PUCAI &lt;0.1; p&gt;0.05, area under the ROC curve &lt;0.65; p&gt;0.05). <h3>Conclusions</h3> The four markers were greatly elevated in severe paediatric UC. Only M2-PK had good construct and predictive validity, and none was responsive to change. The PUCAI, a simple clinical index, performed better than the faecal markers in predicting outcome following a course of intravenous corticosteroids in severe UC.
Adaptive altruistic strategies
Authors: Dennis L. Krebs
Journal: Behavioral and Brain Sciences (2002)

Biological, cognitive, and learning explanations of altruism, selfishness, and self-control can be integrated in terms of adaptive strategies. The key to understanding why humans and other animals sometimes resist temptation and sacrifice their immediate interests for the sake of others lies in mapping the design of the evolved mental mechanisms that give rise to the decisions in question.
Effect of chlorphentermine on the lipids of rat lungs.
Authors: J Gloster, D Heath, P Hasleton, P Harris
Journal: Thorax (1976)

Chronic administration of chlorphentermine to rats resulted in a reduction of body weight compared to a normal control group. The weight of the heart, liver, kidney, and spleen was less in the treated group while the weight of the lungs was increased significantly. There was no change in the ratio of right ventricular to left ventricular weight in the rats treated with chlorphentermine, supporting the views that this drug does not cause pulmonary hypertension. Biochemical analysis showed that the increase in the weight of the lungs was due to the accumulation of phospholipid. All classes of phospholipid were affected, but particularly phosphatidyl choline, the tissue concentration of which increased nine times. Chlorphentermine also increased the proportion of palmitate present in pulmonary phosphatidyl choline. Histological examination of the lung after treatment with chlorphentermine showed evidence of this drug-induced lipidosis. No conclusion can as yet be reached as to the mechanism involved in the accumulation of phospholipid in the lung after chlorphentermine.
The expert patient: towards a novel definition
Authors: Jean-François Cordier
Journal: European Respiratory Journal (2014)

Experience of illness and knowledge of disease make the expert patient an empowered partner for health professionals http://ow.ly/x8vbjChronic diseases have become a major burden in many developed countries.Physicians and policy makers manage patients and set clinical as well as research goals.In recent years, however, it has become progressively apparent that, as the patients are the ones living with the disease, their views and wishes should be considered, and healthcare should be more patient-centred.Many guidelines stress the importance of patient education, especially now that patients have easy access to information through the internet, mass media, educational activities in hospitals, communities and patient groups.Those living with common conditions such as chronic obstructive pulmonary disease (COPD) and asthma, and even rare pulmonary disorders, progressively acquire both experience and knowledge of their condition.The importance of patient involvement not only in their own management but also in health policy planning and decision-making is now being emphasised in Europe.Task forces are beginning to include patients in their expert panels when setting guidelines.