tbuckley/cabot-search huggingface dataset:
A 28-Day Intrathecal Toxicity Study with Trastuzumab in Nonhuman Primates.
Authors: A. Braen, J. Perron, P. Tellier, A. Catala, G. Kolaitis, W. Geng
Journal: Cancer Research (2009)

Abstract Introduction: Trastuzumab is indicated for the treatment of patients with breast cancer whose tumors overexpress the HER2 protein. Brain metastases have been observed in breast cancer patients, being the highest in women with HER2-overexpressing tumors. The blood-brain barrier, however, may prevent trastuzumab from reaching appropriate concentrations in the cerebrospinal fluid (CSF). Case studies have been reported in which trastuzumab was intrathecally administered for the treatment of metastatic brain cancer in humans. However, no extensive preclinical safety evaluation has been performed for intrathecal application after repeat-dosing in a trastuzumab cross-reactive species using doses equivalent to or higher than those used in patients. To evaluate the potential of local effects, a 28-day toxicology study with weekly intrathecal administration of trastuzumab was performed in cynomolgus monkeys, a trastuzumab cross-reactive species. Preservative-free trastuzumab was used in this preclinical safety study, as caution has been raised for the intrathecal use of benzyl alcohol-containing solutions. Methods: Five male and five female monkeys were evaluated per dose group, of which two monkeys/sex/group were evaluated after a 4-week recovery period. Animals were assigned to 3 groups which received 4 weekly 30-minute intrathecal infusions at 0, 3, or 15 mg per dose at an infusion rate of 1.5 mL/hour. Endpoints evaluated included clinical signs, body weight, appetite, neurological examinations, clinical pathology, gross pathology, and histopathology of the brain (with inclusion of meninges), spinal cord, and infusion site. In addition, CSF and serum samples were collected for toxicokinetic evaluations. Results and Discussion: No test article-related effects on clinical signs, body weight, appetite, neurological examinations, clinical pathology, gross pathology or histopathology were noted. Of note is the absence of demyelination as was discussed as an uncertainty of intrathecally administered proteins. The doses used of 3 and 15 mg per dose resulted in 0.051 and 0.24 mg/g brain doses, respectively. Doses administered in clinical case reports ranged from 5 to 100 mg per dose. For a 1500 g human brain weight, these intrathecal doses would be equivalent to 0.0033 and 0.067 mg/g brain weight. At the high dose of 15 mg, maximum CSF concentrations (Cmax) were as high as 403 µg/mL. The applied doses and CSF concentrations achieved in the current study greatly exceeded those reported in patients (6.4 µg/mL at an intrathecal dose of 20 mg). Conclusion: The results of this 4-week toxicology study in monkeys with the results of the clinical case studies support future studies to evaluate intrathecal application of trastuzumab in patients with brain metastasis in HER2-positive breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5101.
Antidote for Factor Xa Anticoagulants
Authors: Jean M. Connors
Journal: New England Journal of Medicine (2015)

Oral anticoagulant options have exploded. Dabigatran, a direct thrombin inhibitor, was approved for use in the United States in 2010 for the prevention of stroke in patients with atrial fibrillation; this was rapidly followed by approval of the direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban within 5 years. The drive for the development of these drugs stemmed from the burdens associated with the use of the anticoagulants that had previously been available for outpatient treatment — subcutaneous heparins and oral vitamin K antagonists. Although these new drugs represent an important advance in anticoagulation therapy, concern over the lack of . . .
THU0082 Clinical Characteristics of Nonradiographic Axial Spondyloarthritis in Korea: in Comparison with Ankylosing Spondylitis
Authors: H. Jeong, I.Y. Kim, J. Hwang, H. Kim, C.H. Jeon, J. Lee, E.-M. Koh, H.-S. Cha
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> There has been considerable research into clinical characteristics of nr-axSpA in western European or American population, but no data about Asian population. <h3>Objectives</h3> To evaluate the clinical characteristics and outcomes of nonradiographic axial spondyloarthritis (nr-axSpA) in Korean patients. <h3>Methods</h3> A retrospective analysis was performed of 155 patients with nr-axSpA at a single tertiary hospital between January 2001 and January 2011. Baseline characteristics and clinical courses of nr-axSpA were reviewed and compared with the ankylosing spondylitis (AS). <h3>Results</h3> Fifty-two (33.5%) patients were female and mean disease duration was 61.4±46.1 months. In female, age at disease onset was older (33.4±11.4 vs 27.5±9.9 years, p=0.001) than male. When compared with AS, the mean age at symptom onset (29.5±10.8 vs 25.9±9.2, p&lt;0.001) was older and male to female ratio (2:1 vs 5:1, p=0.001) was lower in patients with nr-axSpA. Among nr-axSpA, 29 (18.7%) patients progressed to AS during the follow-up period. The proportion of female was lower (14.3 vs 38.1%, p=0.015) and disease duration was significantly longer (106.1±37.1 vs 51.2±41.8 months, p&lt;0.001) in patients with progressors than those of non-progressors. Minimal X-ray change at baseline was frequently found in progressors (69.0 vs 42.1%, p=0.009). Presence of syndesmophyte at baseline was a predictor for disease progression (HR 1.01, 95% CI 1.00-1.02, p=0.046). <h3>Conclusions</h3> The male predominance is more prominent in Korean patients with SpA compared with Caucasians. Female nr-axSpA patients had late symptom onset and less progression to AS. Bony change at baseline was associated with disease progression. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3463
CORONARY ATHEROSCLEROSIS AND INFLAMMATION IN SOUTH ASIANS (CAISA): A PROSPECTIVE EVALUATION OF MONOCYTE HETEROGENEITY IN SOUTH ASIAN CANADIANS
Authors: Christopher Franco, Carolyn Taylor, Kapilan Selvakumar, Brett Heilbron, Simone Cowan, Jaap Hamburger, Krishnan Ramanathan
Journal: Journal of the American College of Cardiology (2016)
Evaluation of Carotid Stenosis by Phonoangiography
Authors: Gary W. Duncan, James O. Gruber, C. Forbes Dewey, Gordon S. Myers, Robert S. Lees
Journal: New England Journal of Medicine (1975)

Quantitative spectral (frequency) analyses were performed on 60 carotid bruits in 48 patients with suspected carotid stenosis. The technic was totally noninvasive. Bruits were recorded at the skin surface, analyzed by a minicomputer, and the degree of arterial stenosis estimated using a recently derived theory of sound production by turbulent blood flow. This method has been named phonoangiography. Fifty of the 60 bruits (83 per cent) had spectrums characteristic of turbulent blood flow, and a residual lumen diameter could be calculated. Results from the noninvasvie technic compared well with data obtained from radiographic carotid arteriograms in the 50 bruits with internal carotid artery stenosis. The residual lumen diameter estimated from phonoangiography differed from the radiographic value by less than 1 mm in 83 per cent and less than 1.5 mm in 92 per cent of the studies. Phonoangiography appears to be a useful method for assessment of carotid artery stenosis.
A8.22 Thiol-activated hydrogen sulfide donors and their anti-inflammatory potential in the mouse macrophage cell line RAW264
Authors: S Loebsch, Y Zhao, M Xian, G Steiner, B Kloesch
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Hydrogen sulfide (H<sub>2</sub>S) is an important signalling molecule that regulates many physiological (blood pressure) and pathophysiological (inflammation) processes in organs and cellular systems. Inorganic H<sub>2</sub>S donors like sodium hydrogen sulfide (NaHS) rapidly but uncontrollably release H<sub>2</sub>S leading to negative side effects (activation of MAPkinases etc.). Therefore, inducible H<sub>2</sub>S donors have recently emerged as useful tools for studying the molecular mechanism of H<sub>2</sub>S. In this study we report about the chemical and biological evaluation of a new class of organic H<sub>2</sub>S donors which release H<sub>2</sub>S only upon activation by thiols. <h3>Materials and methods</h3> The H<sub>2</sub>S releasing compounds 5a, 8a and yz-5–093 were synthesised and kindly provided by M Xian´s group (Washington, USA). H<sub>2</sub>S release under physiological pH range (PBS, pH 7.4) was measured with a H<sub>2</sub>S-selective microelectrode. In intact cells, H<sub>2</sub>S production was monitored by the fluorescent probe WSP-1. To evaluate the anti-inflammatory potential of the H<sub>2</sub>S donors <i>in vitro</i>, mouse macrophages (RAW264 cell line) were incubated for 1 h with different concentrations (10–100 µM) of compounds 5a, 8a and yz-5–093 before the cells were stimulated for 24 h with LPS. IL-6 and TNF-α levels in cell culture supernatants were quantified by enzyme-linked immunosorbent assays (ELISAs). <h3>Results</h3> All three compounds released H<sub>2</sub>S at similar concentrations. Cotreatment of RAW264 cells with compounds 5a, 8a and yz-5–093 downregulated LPS-induced IL-6 expression in a dose-dependent manner. TNF-α production was only affected at the highest concentration (100 µM). <h3>Conclusion</h3> We demonstrate that thiol-inducible H<sub>2</sub>S donors represent a new scientific tool which allows to mimic the slow and continous H<sub>2</sub>S generation process <i>in vivo</i>. These donors might have therapeutic benefits in the treatment of chronic inflammatory disorders such as rheumatoid arthritis.
Abstract 1514: Proteomics of human dense breast stroma.
Authors: Jay W. Fox, Leann Mikesh, Lavakumar R. Aramadhaka, Christopher A. Moskulak
Journal: Cancer Research (2013)

Abstract Dense breast contains glandular and connective tissue. Less dense breasts are mainly comprised of fat tissue. Dense breast tissue itself is a risk factor for breast cancer with the risk being 4-6 fold higher in women with extremely dense breasts compared to fatty breasts. Typically, breast cancer is more likely to develop in the denser areas of the breast. Furthermore, on mammogram, a tumor is more difficult to detect in dense tissue than in fatty tissue because the tumor looks similar to the tissue that surrounds it. Recognition of the important role of the stroma during the progression of breast cancer leads to the possibility of new targets for the prevention or treatment of the primary breast cancer. In addition, clinically useful biomarkers for the early detection of risk for breast cancer in dense breasts could lead to a significant reduction of mortality. In this investigation we describe a detailed analysis of normal and dense breast stroma using laser microdissection in combination with mass spectrometry and immunohistochemistry of normal and dense breast stroma. Using this approach several potential markers for dense breast were identified and compared to stromal markers associated with breast cancer. Citation Format: Jay W. Fox, Leann Mikesh, Lavakumar R. Aramadhaka, Christopher A. Moskulak. Proteomics of human dense breast stroma. [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 1514. doi:10.1158/1538-7445.AM2013-1514
A9.05 Distinct subsets of interferon-stimulated genes are associated with incomplete and established systemic lupus erythematosus
Authors: A Psarras, MY Md Yusof, YM El-Sherbiny, EM Hensor, M Wittmann, P Emery, EM Vital
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background and objectives</h3> Type I interferons (IFN-I) are crucial to systemic lupus erythematosus (SLE) pathogenesis. However, IFN-I activity, as measured by interferon-stimulated gene (ISG) expression, has an unclear relationship with clinical features of disease. Incomplete lupus erythematosus (ILE) describes individuals who have new onset of features suggestive of SLE, but do not fulfil diagnostic criteria. Up to 20% of these patients eventually progress to SLE. The objective of this study is to compare ISG expression between patients with ILE and SLE to understand the role of IFN in onset of clinical features of SLE. <h3>Materials and methods</h3> Expression of 33 ISGs was measured using qPCR in PBMCs from individuals with SLE (n = 54), ILE (n = 27), and healthy controls (HC; n = 14). SLE was defined using 2012 ACR/SLICC criteria. ILE was defined as ANA +ve, 1–2 clinical ACR/SLICC criteria, and symptom duration &lt;12 months. Factor analysis (FA) was used to reduce expression data to a limited set of factors which were compared between patient groups using ANCOVA test. <h3>Results</h3> FA on SLE patients indicated two factors explaining 80% of the data variance. In total, 16 and 14 genes loaded onto Factors F1 and F2 respectively. The majority of variability was explained by F1; however, F2 appeared more relevant to the presence of fully established SLE. F1 and F2 were significantly different between patient groups (p = 0.005 and p = 0.044 respectively). F1 was similarly high in both SLE [SLE:HC=4.22 (1.80, 9.88), p = 0.001] and ILE [ILE:HC=2.96 (1.20, 7.32), p = 0.019]. In contrast, F2 was increased only in SLE [SLE:HC=1.38 (0.95, 2.00), p = 0.086] but not in ILE [ILE:HC=1.02 (0.69, 1.51), p = 0.917]; a significant difference was observed between SLE and ILE patients [SLE:ILE=1.35 (1.04, 1.77), p = 0.026]. <h3>Conclusions</h3> IFN-I activity is present in ILE. However, the majority of measured ISG expression (F1) cannot distinguish ILE and SLE. F1 represents genes that distinguish healthy individuals, but show little variation at different stages of the disease development. We define a subset of ISGs (F2) whose expression is only increased in patients with confirmed clinical SLE. ISG expression is not unidimensional: qualitative differences in expression of distinct ISGs contribute to clinical progression after disease initiation.
American Cancer Society Adopts New Prostate Cancer Screening Guidelines
Authors: John Bowersox
Journal: JNCI Journal of the National Cancer Institute (1992)

Journal Article American Cancer Society Adopts New Prostate Cancer Screening Guidelines Get access John Bowersox John Bowersox Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 84, Issue 24, 16 December 1992, Page 1857, https://doi.org/10.1093/jnci/84.24.1857 Published: 16 December 1992
Abstract 4390: Aurora kinases: potential therapeutic targets in K-Ras-induced lung cancer.
Authors: Edmilson O. dos Santos, Mateus N. Aoki, Daniela S. Bassères
Journal: Cancer Research (2013)

Abstract K-Ras-induced lung cancer is a very common disease, for which there are currently no effective therapies. Intense efforts are underway to identify K-Ras targets that play a crucial role in oncogenesis. We have previously shown that K-Ras-induced lung tumorigenesis is potentiated by the transcription factor NF-κB; and others have shown that Aurora kinases, not only play a significant role in tumorigenesis, but also can activate NF-κB. Therefore, we hypothesized that Aurora A and/or Aurora B are important K-Ras targets in lung cancer. In order to test this hypothesis, we first determined whether oncogenic K-Ras induces Aurora kinase expression. For that purpose, we used three different cell-based models: (1) an immortalized primary lung epithelial cell line and its isogenic K-Ras-transformed counterpart, (2) H1703 lung cancer cell line engineered to express oncogenic K-Ras inducibly, and (3) K-Ras positive lung cancer cell lines H358 and A549 stably expressing inducible shRNAs targeting K-Ras. In all cases, K-Ras expression positively correlated with Aurora A and Aurora B expression. In order to validate Aurora A an B as therapeutically relevant K-Ras targets in lung cancer, we used genetic and/or pharmacological approaches in the abovementioned cells to inactivate Aurora A or B. Inducible shRNA-mediated knockdown of Aurora A or B, as well as treatment with a dual Aurora A and B inhibitor (AI II), decreased growth, viability and migration of K-Ras positive H358 and A549 cell lines. Interestingly, in our primary isogenic model and in our H1703 K-Ras-inducible cell line, AI II reduced viability and induced apoptosis in an oncogenic K-Ras-dependent manner. This suggests that Aurora kinase inhibition therapy can specifically target K-Ras transformed cells. In conclusion, our results support our hypothesis that Aurora kinases are important K-Ras targets in lung cancer and suggest Aurora kinase inhibition as a novel approach for K-Ras-induced lung cancer therapy. Citation Format: Edmilson O. dos Santos, Mateus N. Aoki, Daniela S. Bassères. Aurora kinases: potential therapeutic targets in K-Ras-induced lung cancer. [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 4390. doi:10.1158/1538-7445.AM2013-4390
Chief of England's blood service dismissed
Authors: J. Warden
Journal: BMJ (1998)

A crisis in the management of the National Blood Authority for England has led to the removal of its chairman, Sir Colin Walker. The health secretary, Frank Dobson, told the Commons that Sir Colin refused to resign so he dismissed him from his £10000 ($16000) a year part time post.

This followed an independent report that Mr Dobson said was a damning indictment of the National Blood Authority. The report said that “widespread concern” existed among …
DISECCIÓN ENDSOCÓPICA SUBMUCOSA CON TÉCNICA DE HIDRODISECCIÓN: RESULTADOS Y CURVA DE APRENDIZAJE EN EL MODELO ANIMAL
Authors: D Martínez Ares, JM Esteban, Ó Nogales Rincón, J De La Peña García, S Rodriguez, A Calderon, A Orive Calzada, L López Rosés, E Sanchez Hernandez, JJ Vila Costa, G Fernandez Esparrach
Journal: Endoscopy (2013)

Introducción: la disección endoscópica submucosa (DES) es un tratamiento eficaz para la neoplasia digestiva precoz. Sin embargo, es un procedimiento largo y requiere un elevado nivel de experiencia por parte del endoscopista. Objetivo: valorar la eficacia y curva de aprendizaje de la DES gástrica utilizando un nuevo bisturí que combina la posibilidad de cauterización e inyección de fluido a alta presión. Métodos: 10 endoscopistas con limitada experiencia clínica realizaron DES gástricas en cerdos vivos. Se utilizaron dos técnicas: DES clásica y DES híbrida, utilizando para ésta última el water-jet hybrid knife (ERBE). Las variables analizadas fueron: número DES completadas en bloque, número de DES R0, tamaño, tiempo y velocidad de disección y complicaciones. Resultados: se realizaron un total de 50 DES (30híbridas y 20 clásicas) consiguiendo 46 (92%) DES en bloque y 25 (50%) R0, siendo la tasa de R0 inferior con la técnica híbrida (12, 40% vs. 13, 65%; p = 0,04). El tamaño fue similar (híbrida: 40,3 ± 13,2 mm; clásica: 35,5 ± 10,9 mm; p = 0.826) pero la técnica híbrida fue más rápida (velocidad: 20,8 ± 9,2 mm2/seg vs. 14,3 ± 9,3 mm2/seg; p = 0,033). La incidencia de perforaciones fue similar con ambas técnicas (híbrida: 4, 13% vs. clásica: 2,10%; p = 0,722). La curva de aprendizaje mostró una tendencia a mejorar la velocidad con ambas técnicas y una mejoría en la tasa R0 con la técnica híbrida (de 30% a 100%; p = 0,120). Conclusiones: la DES con técnica de hidrodisección es más rápida que la técnica clásica pero se asocia a una menor tasa de R0. Lla curva de aprendizaje de la técnica de hidrodisección es corta y muestra una rápida mejoría. La DES es una técnica muy eficaz y segura cuando se realiza de forma adecuada y la introducción de nuevas herramientas para facilitar su implementación debe realizarse con cuidado para evitar un impacto negativo en los Resultados:
Abstract 2342: Prognosis for patients with adenocarcinomas of lower esophagus, gastro-esophageal junction and cardia can be directly evaluated by immunohistochemistry of uPAR
Authors: Martin Illemann, Kjell Ovrebo, Arne Skarstein, Ib J. Christensen, Warner Alpízar-Alpízar, Lars Helgeland, Keld Danø, Boye S. Nielsen, Ole D. Laerum
Journal: Cancer Research (2010)

Abstract Adenocarcinomas of lower esophagus, gastro-esophageal junction and cardia in humans are highly invasive tumors with poor prognosis. In order to elucidate proteolytic mechanisms for the invasive behavior, we have studied the localization of urokinase-type plasminogen activator receptor (uPAR) in 65 cases. uPAR was expressed in nearly all cases of invasive adenocarcinomas by populations of cancer cells, macrophages and myofibroblasts. In areas with local carcinoma in situ lesions (15 cases), or with Barrett's metaplasia (21 cases) adjacent to the tumor tissue, and in six control cases with Barrett's metaplasia only, no uPAR-immunoreactivity was found. High local expression of uPAR therefore appears to be a characteristic marker for invasive behavior in this tumor. Using a simple scoring system for semi-quantitative estimation of uPAR-positivity on immmunohistochemically stained specimens, a significant association between high uPAR-score in cancer cells in the tumor core and short survival was found independent of tumor TNM-stage (HR=1.74, 95% CI: 1.05-2.88). High uPAR-score for each individual cell type (cancer cells, macrophages and myofibroblasts) was also associated with short survival. A diagnostic procedure for scoring of uPAR-positivity might be useful for this type of tumors. High local proteolytic activity mediated through the plasminogen activation system, with combined action of malignant and non-malignant accessory cells may be an important mechanism for the rapid progression and high mortality in this tumor type. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2342.
Diaphragmatic Paralysis with an Elevated Hemidiaphragm Masquerading as Lung Carcinoma Found During Myocardial Perfusion Imaging
Authors: MICHAEL E. SPIETH, DARCY L. KASNER, MICHAEL P. BULL
Journal: Clinical Nuclear Medicine (2002)

SPIETH, MICHAEL E. M.D.; KASNER, DARCY L.; BULL, MICHAEL P. B.S., C.N.M.T. Author Information